bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–10–02
197 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development



  1. Med Oncol. 2022 Sep 29. 39(12): 227
      Metabolic reprogramming wherein the cancer cells exhibit altered energetics is a hallmark of cancer. Although recent discoveries have enhanced our understanding of tumor metabolism, the therapeutic utility of targeting tumor metabolism is not yet realized. Glutamine, a non-essential amino acid, plays a critical role in regulating tumor metabolism and provides an alternative tumor energy source. In this study, we investigate the molecular mechanism regulated by glutamine and elucidate if targeting glutamine metabolism would enhance the efficacy of cancer chemotherapy. Using clonogenic and cell cycle analysis, we found that deprivation of glutamine suppress the growth of cancer cells. Mechanistically we demonstrate that glutamine stabilizes myc by preventing its ubiquitination through alpha-ketoglutarate. Inhibition of glutamine metabolism enhanced the sensitivity of tumor cells to chemotherapeutic agent paclitaxel. Our results delineate the mechanism behind glutamine-induced myc stabilization, and they provide a viable strategy to target cancer with a glutamine metabolism inhibitor in the clinic.
    Keywords:  Cancer; Glutamine; Metabolism; Myc
    DOI:  https://doi.org/10.1007/s12032-022-01834-5
  2. Theranostics. 2022 ;12(14): 6143-6154
      Rationale: Photodynamic therapy (PDT) is a clinically approved anticancer treatment with a promising therapeutic prospect, however, usually suffers from the unfavorable intracellular environment including cellular hypoxia and excessive glutathione (GSH). Comprehensive and long-term modulation of tumor intracellular environment is crucial for optimizing therapeutic outcomes. However, current strategies do not enable such requirements, mainly limited by flexible networks of intracellular metabolic avenues. Methods: A metabolic pre-intervention (MPI) strategy that targets critical pathways of cellular metabolism, ensuring long-term modulation of the intracellular environment. A versatile lipid-coating photosensitive metal-organic framework (MOF) nano-vehicle encapsulating aerobic respiration inhibitor metformin (Met) and GSH biosynthesis inhibitor buthionine sulfoximine (BSO) (termed PBMLR) was developed for comprehensive sustainable hypoxia alleviation and GSH downregulating. Results: Since MPI could effectively circumvent the compensatory accessory pathway, PBMLR, therefore functioned as an efficient singlet oxygen (1O2) radical generator during the subsequent laser irradiation process and enhanced PDT anti-tumor efficiency. We emphasized the concordance of long-term hypoxia alleviation, persistent GSH depletion, and tumor enrichment of photosensitizers, which is very meaningful for a broad therapeutic time window and the successful enhancement of PDT. Conclusion: Our findings indicate that maintaining the sensitivity of tumor cells via MPI could enhance anti-tumor PDT, and may be applied to other dynamic therapies such as radiodynamic therapy and sonodynamic therapy.
    Keywords:  glutathione; hypoxia; metabolic pre-intervention; metal-organic framework; photodynamic therapy
    DOI:  https://doi.org/10.7150/thno.75837
  3. Acta Pharm Sin B. 2022 Sep;12(9): 3567-3593
      As an emerging cancer therapeutic target, non-apoptotic cell death such as ferroptosis, necroptosis and pyroptosis, etc., has revealed significant potential in cancer treatment for bypassing apoptosis to enhance the undermined therapeutic efficacy triggered by apoptosis resistance. A variety of anticancer drugs, synthesized compounds and natural products have been proven recently to induce non-apoptotic cell death and exhibit excellent anti-tumor effects. Moreover, the convergence of nanotechnology with functional materials and biomedicine science has provided tremendous opportunities to construct non-apoptotic cell death-based nanomedicine for innovative cancer therapy. Nanocarriers are not only employed in targeted delivery of non-apoptotic inducers, but also used as therapeutic components to induce non-apoptotic cell death to achieve efficient tumor treatment. This review first introduces the main characteristics, the mechanism and various pharmacological modulators of different non-apoptotic cell death forms, including ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, lysosomal-dependent cell death, and oncosis. Second, we comprehensively review the latest progresses of nanomedicine that induces various forms of non-apoptotic cell death and focus on the nanomedicine targeting different pathways and components. Furthermore, the combination therapies of non-apoptotic cell death with photothermal therapy, photodynamic therapy, immunotherapy and other modalities are summarized. Finally, the challenges and future perspectives in this regard are also discussed.
    Keywords:  Anticancer; Autophagy; Combination therapies; Ferroptosis; Nanomedicine; Necroptosis; Non-apoptotic cell death; Pyroptosis
    DOI:  https://doi.org/10.1016/j.apsb.2022.03.020
  4. Front Pharmacol. 2022 ;13 950109
      Cancer is commonly thought to be the product of irregular cell division. According to the World Health Organization (WHO), cancer is the major cause of death globally. Nature offers an abundant supply of bioactive compounds with high therapeutic efficacy. Anticancer effects have been studied in a variety of phytochemicals found in nature. When Food and Drug Administration (FDA)-approved anticancer drugs are combined with natural compounds, the effectiveness improves. Several agents have already progressed to clinical trials based on these promising results of natural compounds against various cancer forms. Natural compounds prevent cancer cell proliferation, development, and metastasis by inducing cell cycle arrest, activating intrinsic and extrinsic apoptosis pathways, generating reactive oxygen species (ROS), and down-regulating activated signaling pathways. These natural chemicals are known to affect numerous important cellular signaling pathways, such as NF-B, MAPK, Wnt, Notch, Akt, p53, AR, ER, and many others, to cause cell death signals and induce apoptosis in pre-cancerous or cancer cells without harming normal cells. As a result, non-toxic "natural drugs" taken from nature's bounty could be effective for the prevention of tumor progression and/or therapy of human malignancies, either alone or in combination with conventional treatments. Natural compounds have also been shown in preclinical studies to improve the sensitivity of resistant cancers to currently available chemotherapy agents. To summarize, preclinical and clinical findings against cancer indicate that natural-sourced compounds have promising anticancer efficacy. The vital purpose of these studies is to target cellular signaling pathways in cancer by natural compounds.
    Keywords:  cancer; metastasis; natural compounds; reactive oxygen species; therapeutic efficacy
    DOI:  https://doi.org/10.3389/fphar.2022.950109
  5. J Adv Res. 2022 Sep 24. pii: S2090-1232(22)00209-0. [Epub ahead of print]
       INTRODUCTION: Inherent or acquired resistance to paclitaxel (PTX) is a pivotal challenge for chemotherapy treatment of multidrug-resistant (MDR) breast cancer. Although various targeted drug-delivery systems, including nanoparticles and liposomes, are effective for MDR cancer treatment, their efficacy is restricted by immunosuppressive tumor microenvironment (TME).
    METHODS: Ginsenosides Rg3 was used to formulate unique Rg3-based liposomes loaded with PTX to establish Rg3-PTX-LPs, which were prepared by the thin-film hydration method. The stability of the Rg3-PTX-LPs was evaluated by particle size analysis through dynamic light scattering. The active targeting effect of Rg3-based liposomes was examined in an MCF-7/T xenograft model by an in a vivo imaging system. To evaluate the antitumor activity and mechanism of Rg3-PTX-LP, MTT, apoptosis assays, TAM regulation, and TME remodeling were performed in MCF-7/T cells in vitro and in vivo.
    RESULTS: Rg3-PTX-LPs could specifically distribute to MCF7/T cancer cells and TME simultaneously, mainly through the recognition of GLUT-1. The drug resistance reversing capability and in vivo antitumor effect of Rg3-PTX-LPs were significantly improved compared with conventional cholesterol liposomes. The TME remodeling mechanisms of Rg3-PTX-LPs included inhibiting IL-6/STAT3/p-STAT3 pathway activation to repolarize protumor M2 macrophages to antitumor M1 phenotype, suppressing myeloid-derived suppressor cells (MDSCs), decreasing tumor-associated fibroblasts (TAFs) and collagen fibers in TME, and promoting apoptosis of tumor cells. Hence, through the dual effects of targeting tumor cells and TME remodeling, Rg3-PTX-LPs achieved a high tumor inhibition rate of 90.3%.
    CONCLUSION: Our multifunctional Rg3-based liposome developed in the present study offered a promising strategy for rescuing the drug resistance tumor treatment.
    Keywords:  MCF-7/T tumor; ginsenoside Rg3; liposomes; multidrug resistance; paclitaxel; tumor microenvironment remodeling
    DOI:  https://doi.org/10.1016/j.jare.2022.09.007
  6. Acta Biomater. 2022 Sep 27. pii: S1742-7061(22)00631-6. [Epub ahead of print]
      Many chemotherapeutic drugs and photosensitizers suffer from poor solubility, unspecific delivery and uncontrollable release, which severely impede their biomedical applications. Herein, we designed a type of ROS-cleavable hydrophilic diselenide nanoparticles through self-assembling of PEG-modified camptothecin (CPT, a hydrophobic drug) and meso-tetra (4-carboxyphenyl) porphine (TCPP, a hydrophobic photosensitizer). The TCPP@SeSe-CPT nanomedicine (particle size: 116.5 ± 1.9 nm) has stability for long-time blood circulation. Near-infrared (NIR) laser-triggered generation of ROS from TCPP can efficiently break the ROS-sensitive diselenide bond, which induces the decomposition of TCPP@SeSe-CPT nanomedicine for concurrent release of CPT and TCPP. Moreover, the released amounts of CPT and TCPP can be regulated by adjusting the NIR laser irradiation time. Such NIR-controlled release of CPT and TCPP can give rise to on-demand synergistic chemo-/photodynamic therapeutic effects for maximized tumor growth suppression with minimized side effects. STATEMENT OF SIGNIFICANCE: In this work, a ROS-cleavable diselenide nanoparticle was designed and successfully self-assembled with the hydrophobic drug camptothecin and photosensitizer TCPP into a hydrophilic TCPP@SeSe-CPT nanomedicine. Compared with traditional drug delivery systems, TCPP@SeSe-CPT nanomicelles could reduce premature drug release and co-deliver hydrophobic chemotherapeutic drugs/photosensitizers to tumors, which yielded a NIR-controlled synergistic chemo-/photodynamic therapeutic effect. Since diselenide bond is more sensitive than the traditional disulfide bond, under the 660 nm laser irradiation (300 mW/cm2), ROS generated from laser-excited TCPP in TCPP@SeSe-CPT nanomicelles could break the diselenium bonds to achieve the light-controlled release of CPT. In addition, the photosensitizer TCPP could also be imaged at the tumor site. Due to the photodynamic therapy from laser-excited TCPP and chemotherapy from photocontrolled release of CPT in TCPP@SeSe-CPT, our designed nanomicelles yielded potent antitumor effects both in vitro and in vivo.
    Keywords:  camptothecin; controlled release; nanomedicine; reactive oxygen species; synergistic therapy
    DOI:  https://doi.org/10.1016/j.actbio.2022.09.061
  7. Front Cell Dev Biol. 2022 ;10 984311
      Cancer is still one of the world's deadliest health concerns. As per latest statistics, lung, breast, liver, prostate, and cervical cancers are reported topmost worldwide. Although chemotherapy is most widely used methodology to treat cancer, poor pharmacokinetic parameters of anticancer drugs render them less effective. Novel nano-drug delivery systems have the caliber to improve the solubility and biocompatibility of various such chemical compounds. In this regard, cyclodextrins (CD), a group of natural nano-oligosaccharide possessing unique physicochemical characteristics has been highly exploited for drug delivery and other pharmaceutical purposes. Their cup-like structure and amphiphilic nature allows better accumulation of drugs, improved solubility, and stability, whereas CDs supramolecular chemical compatibility renders it to be highly receptive to various kinds of functionalization. Therefore combining physical, chemical, and bio-engineering approaches at nanoscale to specifically target the tumor cells can help in maximizing the tumor damage without harming non-malignant cells. Numerous combinations of CD nanocomposites were developed over the years, which employed photodynamic, photothermal therapy, chemotherapy, and hyperthermia methods, particularly targeting cancer cells. In this review, we discuss the vivid roles of cyclodextrin nanocomposites developed for the treatment and theranostics of most important cancers to highlight its clinical significance and potential as a medical tool.
    Keywords:  biomarker; breast carcinoma; chemotherapy; hydrophobic drug; photodynamic therapy; photothermal therapy; targeted delivery; theranostics
    DOI:  https://doi.org/10.3389/fcell.2022.984311
  8. Front Pharmacol. 2022 ;13 874510
      Cancer is an important cause of morbidity and mortality worldwide, irrespective of the level of human development. Globally, it was estimated that there were 19.3 million new cases of cancer and almost 10 million deaths from cancer in 2020. The importance of prevention, early detection as well as effective cancer therapies cannot be over-emphasized. One of the important strategies in cancer therapy is targeted drug delivery to the specific tumor sites. Nanogels are among the several drug delivery systems (DDS) being explored as potential candidates for targeted drug delivery in cancer therapy. Nanogels, which are new generation, versatile DDS with the possession of dual characteristics of hydrogels and nanoparticles have shown great potential as targeted DDS in cancer therapy. Nanogels are hydrogels with a three-dimensional (3D) tunable porous structure and a particle size in the nanometre range, from 20 to 200 nm. They have been visualized as ideal DDS with enormous drug loading capacity, and high stability. Nanogels can be modified to achieve active targeting and enhance drug accumulation in disease sites. They can be designed to be stimulus-responsive, and react to internal or external stimuli such as pH, temperature, light, redox, thus resulting in the controlled release of loaded drug. This prevents drug accumulation in non-target tissues and minimizes the side effects of the drug. Drugs with severe adverse effects, short circulation half-life, and easy degradability by enzymes, such as anti-cancer drugs, and proteins, are suitable for delivery by chemically cross-linked or physically assembled nanogel systems. This systematic review summarizes the evolution of nanogels for targeted drug delivery for cancer therapy over the last decade. On-going clinical trials and recent applications of nanogels as targeted DDS for cancer therapy will be discussed in detail. The review will be concluded with discussions on safety and regulatory considerations as well as future research prospects of nanogel-targeted drug delivery for cancer therapy.
    Keywords:  cancer therapy; future prospects; nanogels; nanoparticles; targeted drug delivery
    DOI:  https://doi.org/10.3389/fphar.2022.874510
  9. Int J Pharm. 2022 Sep 23. pii: S0378-5173(22)00775-X. [Epub ahead of print] 122221
      Centella asiatica, a medicinal herb used for wound healing, has a limited effect when delivered as an ointment. Centella asiatica's active component asiatic acid (AA) increases extracellular matrix development and reduces inflammation but cannot penetrate the stratum corneum to access deeper skin layers. To bypass the stratum corneum, we formulated two types of AA-loaded microneedle arrays. We fabricated, characterised and optimised a dissolving array made from chitosan and PVA and a hydrogel array made from chitosan and PVP. Both needles were strong and long enough to pierce the epidermis without breaking. Both were biocompatible with keratinocytes and fibroblasts (>75% viability at 100% concentration) and showed a sustained drug release over 48 hours. The hydrogel microneedle released more AA (52.2%) than the dissolving formulation (26.4%); thus, we evaluated them in an excisional rat model. The hydrogel microneedle arrays significantly increased the rate of wound closure compared to the control. This research has shown that the chitosan-PVA hydrogel microneedles could penetrate the epidermis, effectively release AA, and increase the wound closure rate. This AA-loaded delivery system shows promise as a natural treatment for wound healing and may be applied to other bioactive compounds with similar physiochemical properties in the future.
    Keywords:  Asiatic acid; chitosan; dissolving microneedles; hydrogel microneedles; topical dermal delivery; wound healing
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122221
  10. World J Gastroenterol. 2022 Jul 21. 28(27): 3422-3434
       BACKGROUND: The biochemical phenomenon defined as poly adenosine diphosphate (ADP)-ribosylation (PARylation) is essential for the progression of pancreatic cancer. However, the excessive accumulation of poly ADP-ribose (PAR) induces apoptosis-inducing factor (AIF) release from mitochondria and energy deprivation resulting in the caspase-independent death of cancer cells.
    AIM: To investigate whether sustained calcium supply could induce an anticancer effect on pancreatic cancer by PAR accumulation.
    METHODS: Two pancreatic cancer cell lines, AsPC-1 and CFPAC-1 were used for the study. Calcium influx and mitochondrial reactive oxygen species (ROS) were observed by fluorescence staining. Changes in enzyme levels, as well as PAR accumulation and energy metabolism, were measured using assay kits. AIF-dependent cell death was investigated followed by confirming in vivo anticancer effects by sustained calcium administration.
    RESULTS: Mitochondrial ROS levels were elevated with increasing calcium influx into pancreatic cancer cells. Then, excess PAR accumulation, decreased PAR glycohydrolase and ADP-ribosyl hydrolase 3 levels, and energy deprivation were observed. In vitro and in vivo antitumor effects were confirmed to accompany elevated AIF levels.
    CONCLUSION: This study visualized the potential anticancer effects of excessive PAR accumulation by sustained calcium supply on pancreatic cancer, however elucidating a clear mode of action remains a challenge, and it should be accompanied by further studies to assess its potential for clinical application.
    Keywords:  Anticancer effect; Apoptosis-inducing factor; Calcium; Nicotinamide adenine dinucleotide; Pancreatic cancer; Poly adenosine diphosphate-ribose; Poly adenosine diphosphate-ribose polymerase; Poly adenosine diphosphate-ribosylation; Reactive oxygen species
    DOI:  https://doi.org/10.3748/wjg.v28.i27.3422
  11. Front Pharmacol. 2022 ;13 963317
      Background: Prostate cancer is the second most common cancer in men and has the fourth highest mortality among men worldwide. Different combination therapies for cancer are being tested, and among them, the integration of natural products is increasing. This study reviews research on the combination of anticancer drugs and natural products for the treatment of prostate cancer and suggests future directions in this field. Methods: Articles were identified by searching the PubMed, Embase, and Cochrane Library databases. Search keywords included the following: "Antineoplastic agents," "Anticancer drug," "Phytotherapy," "Natural product," "Drug synergism," and "Synergistic effect". The selection process focused on whether the differences in efficacy of anticancer drugs were evaluated when combined with natural products. Results: Nineteen studies were included. All 19 studies evaluated efficacy in vitro, as well as 10 in vivo. There were 13 studies on a single compound extracted from natural products, three studies on mushroom and herb extracts, and three studies on herbal medicines consisting of three herbs, and a dietary supplement containing 10 herbs. Cancer cell lines used were PC-3 in nine studies, LNCaP in six studies, C4-2 in five studies, DU-145 in four studies, and 22Rv1 in two studies. Anti-cancer drugs co-administered were as follows: docetaxel in nine studies, doxorubicin and enzalutamide in three studies, paclitaxel and suberoylanilide hydroxamic acid in two studies, and cisplatin, vincristine, and bicalutamide in one study each. Conclusion: Although prostate cancer is prevalent worldwide, there are relatively few studies on the use of natural products with anticancer agents as treatment. Since it has reported that the efficacy of anticancer drugs is enhanced by coadministration of natural products, it is necessary to conduct further studies on this.
    Keywords:  combination therapy; complementary and alternative medicine; natural product; prostate cancer; scoping review; synergistic effect
    DOI:  https://doi.org/10.3389/fphar.2022.963317
  12. J Nanobiotechnology. 2022 Sep 24. 20(1): 423
      Cancer often develops multidrug resistance (MDR) when cancer cells become resistant to numerous structurally and functionally different chemotherapeutic agents. MDR is considered one of the principal reasons for the failure of many forms of clinical chemotherapy. Several factors are involved in the development of MDR including increased expression of efflux transporters, the tumor microenvironment, changes in molecular targets and the activity of cancer stem cells. Recently, researchers have designed and developed a number of small molecule inhibitors and derivatives of natural compounds to overcome various mechanisms of clinical MDR. Unfortunately, most of the chemosensitizing approaches have failed in clinical trials due to non-specific interactions and adverse side effects at pharmacologically effective concentrations. Nanomedicine approaches provide an efficient drug delivery platform to overcome the limitations of conventional chemotherapy and improve therapeutic effectiveness. Multifunctional nanomaterials have been found to facilitate drug delivery by improving bioavailability and pharmacokinetics, enhancing the therapeutic efficacy of chemotherapeutic drugs to overcome MDR. In this review article, we discuss the major factors contributing to MDR and the limitations of existing chemotherapy- and nanocarrier-based drug delivery systems to overcome clinical MDR mechanisms. We critically review recent nanotechnology-based approaches to combat tumor heterogeneity, drug efflux mechanisms, DNA repair and apoptotic machineries to overcome clinical MDR. Recent successful therapies of this nature include liposomal nanoformulations, cRGDY-PEG-Cy5.5-Carbon dots and Cds/ZnS core-shell quantum dots that have been employed for the effective treatment of various cancer sub-types including small cell lung, head and neck and breast cancers.
    Keywords:  ABC transporter; Cancer stem cells; Combinational therapy; Drug delivery; Multidrug resistance; Nanotechnology; P-glycoprotein; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12951-022-01626-z
  13. J Pharm Pharmacol. 2022 Sep 29. pii: rgac028. [Epub ahead of print]
       OBJECTIVES: Resveratrol (Res) was a naturally occurring polyphenol compound. It has various beneficial effects, including anti-inflammatory, anti-oxidant and anti-cancer effects. However, the anti-cancer activity was hindered by its low targeting and drug release performance. Thus, we synthesized transferrin-cathepsin B cleavable peptide modified mesoporous silica nanoparticle encapsulated Res (Tf-Res-MSN).
    METHODS: Res was encapsulated in mesoporous silica nanoparticles (MSN), which was a kind of drug carrier complex. Tf was modified to recognize the cancer cells. Cathepsin B cleavable peptide (Pep) was used to combine Res-MSN complex and Tf to construct the final product. Pep was used as linker and trigger for Res release.
    KEY FINDINGS: The smart nanocarriers were increased the drug release performance of Res in human breast cancer (MCF-7) cells. The physicochemical properties of Tf-Res-MSN were assessed by zeta potential, UV-Prove, diffraction scanning calorimetry (DSC), nitrogen physisorption analysis and transmission electron microscope (TEM). MTT assay, AO and Annexin V-FITC/PI staining were performed to explore the anti-tumour activity of Tf-Res-MSN. The results showed that Tf-Res-MSN significantly decreased cell viability and increased cell apoptosis. The inhibition rate and apoptotic rate of Tf-Res-MSN in MCF-7 cells were 95.75% and 80.8%, respectively.
    CONCLUSION: Our study demonstrated that Tf-Res-MSN was a valuable technique with potential value in breast cancer applications.
    Keywords:  breast cancer; mesoporous silica; resveratrol; transferrin
    DOI:  https://doi.org/10.1093/jpp/rgac028
  14. ACS Appl Mater Interfaces. 2022 Sep 26.
      Hypoxia at the tumor site limits the therapeutic effects of photodynamic therapy (PDT) in oral squamous cell carcinoma (OSCC), which is an oxygen-consumption process. Inhibiting cellular oxygen consumption and reducing cellular ATP production are expected to enhance PDT. In this study, we designed and constructed dandelion-like size-shrinkable nanoparticles for tumor-targeted delivery of hypoxia regulator resveratrol (RES) and photodynamic agent chlorine e6 (CE6). Both drugs were co-encapsulated in small-sized micelles modified with EGFR targeting ligand GE11, which was further conjugated on hyaluronic nanogel (NG) to afford RC-GMN. After targeted accumulation in tumors mediated by GE11 and enhanced penetration and retention (EPR) effects, RC-GMN was degraded by hyaluronidase (HAase) and resulted in small-sized micelles, allowing for deep penetration and dual-receptor-mediated cellular internalization. Resveratrol inhibited cellular oxygen consumption and provided sufficient oxygen for PDT, which consequently activated PDT to produce reactive oxygen species (ROS). Notably, we found that autophagy was overactivated in PDT, which was further strengthened by the hypoxia regulator resveratrol, elevating autophagic cell death. The synergistic effects of resveratrol and CE6 promoted autophagic cell death and apoptosis in the enhanced PDT, resulting in stronger antitumor effects in the orthotopic OSCC model. Therefore, the facilitated delivery of hypoxia regulator enhanced PDT efficacy by elevating oxygen content in tumor cells and inducing autophagic cell death and apoptosis, which offers an alternative strategy for enhancing the PDT effects against OSCC.
    Keywords:  autophagy; oral squamous cell carcinoma; photodynamic therapy; size-shrinkable nanoparticles; tumor hypoxia
    DOI:  https://doi.org/10.1021/acsami.2c10021
  15. ACS Biomater Sci Eng. 2022 Sep 27.
      Breast cancer treatment has been challenging all the time because cancer cells have multiple signaling pathways; so, breast cancer still remains a threat to the lives and health of many patients. While common single drug therapies inhibit only one pathway, the combination of multiple mechanisms offers the potential to simultaneously suppress multiple targets and pathways to kill cancer cells more effectively. It is reported that autophagy caused by autophagy inducers and apoptosis caused by some chemotherapeutic drugs can promote ferroptosis to some extent; herein, we combined these three pathways and constructed a multifunctional dual-responsive release nanosystem of Rap@mFe3O4-DOX-HA that achieved the ferroptosis-autophagy-apoptosis synergistic effect for cancer treatment. Mesoporous Fe3O4 (mFe3O4) was set as the carrier and can also release Fe ions for ferroptosis, the autophagy inducer rapamycin (Rap) was wrapped in the carrier to trigger autophagy, and the chemotherapeutic drug doxorubicin (DOX) was used as the apoptosis inducer. At the tumor site, the prepared Rap@mFe3O4-DOX-HA nanoparticles split and released DOX/Rap in response to H+/GSH. From in vivo and in vitro studies, it was found that Rap@mFe3O4-DOX-HA nanoparticles effectively inhibited the migration of 4T1 cells, furthermore, they struck cancer cells through multiple pathways and greatly improved the anti-tumor effect. Therefore, the strategy of multi-mechanism combination achieved a therapeutic effect of 1 + 1 > 2.
    Keywords:  H+-/GSH-responsive; apoptosis; autophagy; ferroptosis; multi-mechanism combination
    DOI:  https://doi.org/10.1021/acsbiomaterials.2c00778
  16. AAPS PharmSciTech. 2022 Sep 28. 23(7): 269
      Polymeric films are drug delivery systems that maintain contact with the delivery tissue and sustain a controlled release of therapeutic molecules. These systems allow a longer time of drug contact with the target site in the case of topical treatments and allow the controlled administration of drugs. They can be manufactured by various methods such as solvent casting, hot melt extrusion, electrospinning, and 3D bioprinting. Furthermore, they can employ various polymers, for example PVP, PVA, cellulose derivatives, chitosan, gelling gum, pectin, and alginate. Its versatility is also applicable to different routes of administration, as it can be administered to the skin, oral mucosa, vaginal canal, and eyeballs. All these factors allow numerous combinations to obtain a better treatment. This review focuses on exploring some possible ways to develop them and some particularities and advantages/disadvantages in each case. It also aims to show the versatility of these systems and the advantages and disadvantages in each case, as they bring the opportunity to develop different medicines to facilitate therapies for the most diverse purposes .
    Keywords:  Administration routes; Manufacturing processes; Material science; Pharmaceutical industry; Polymer science
    DOI:  https://doi.org/10.1208/s12249-022-02414-6
  17. PLoS One. 2022 ;17(9): e0274954
      Combination of photosensitizers (PS) with nanotechnology can improve the therapeutic efficiency of clinical Photodynamic Therapy (PDT) by converting visible light reactive PSs into Near-Infrared (NIR) light responsive molecules using Harmonic Nanoparticles (HNP). To test the PDT efficiency of HNP-PS conjugates, pathogenic S. aureus cell cultures were treated with perovskite (Barium Titanate) Second Harmonic Generation (SHG) nanoparticles conjugated to photosensitizers (PS) (we compared both FDA approved Protoporphyrin IX and Curcumin) and subjected to a femtosecond pulsed Near-Infrared (NIR) laser (800 nm, 232-228 mW, 12-15 fs pulse width at repetition rate of 76.9 MHz) for 10 minutes each. NIR PDT using Barium Titanate (BT) conjugated with Protoporphyrin IX as HNP-PS conjugate reduced the viability of S. aureus cells by 77.3 ± 9.7% while BT conjugated with Curcumin did not elicit any significant effect. Conventional PSs reactive only to visible spectrum light coupled with SHG nanoparticles enables the use of higher tissue penetrating NIR light to generate an efficient photodynamic effect, thereby overcoming low light penetration and tissue specificity of conventional visible light PDT treatments.
    DOI:  https://doi.org/10.1371/journal.pone.0274954
  18. Curr Res Food Sci. 2022 ;5 1625-1639
      The poor water solubility, bioavailability and stability of bioactive compounds have become the bottleneck restricting their wide application, thus developing a functional carrier to realize the efficient encapsulation and activity improvement of active hydrophobic substances has become a research hotspot. In this work, a functional glycosylated fish gelatin (called FG-COS conjugates) carrier based on fish gelatin (FG) and chitooligosaccharide (COS) via Maillard reaction was developed. The functional carrier exhibited good antioxidant activity and high encapsulation of curcumin (Cur). Enhanced antioxidant effect of Cur loaded in FG-COS conjugates (called FG-COS-Cur nanoparticles) was achieved, showing remarkable UV protection on Cur and enhanced intracellular antioxidant activity of FG-COS-Cur nanoparticles. Remarkably, FG-COS-Cur nanoparticles increased the cell viability of H2O2-induced oxidative damage Caco-2 cells, drastically reduced the levels of reactive oxygen species (ROS) and lactate dehydrogenase (LDH), and significantly increased intracellular antioxidant enzyme activities, which all exhibited a dose-response relationship. These findings suggested that the FG-COS conjugates with intrinsic antioxidant activity could effectively encapsulate Cur and improved bioavailability for hydrophobic active molecules in functional food field.
    Keywords:  Chitooligosaccharide; Curcumin; Enhanced antioxidant capacity; Fish gelatin; Maillard reaction
    DOI:  https://doi.org/10.1016/j.crfs.2022.09.019
  19. J Mater Chem B. 2022 Sep 29.
      Chemotherapy is a conventional cancer treatment in clinical settings. Although numerous nano drug delivery systems have been developed, the chemotherapeutic effect is greatly limited by abnormal tumor mechanics in solid tumors. Tumor stiffening and accumulated solid stress compress blood vessels and inhibit drug delivery to tumor cells, becoming critical challenges for chemotherapy. By loading doxorubicin (DOX), tissue plasminogen activator (tPA), and fibrin targeting peptide CREKA (Cys-Arg-Glu-Lys-Ala) within pH responsive amphiphilic block polymers, pyridyldithio-hydroxyethyl starch-Schiff base-polylactic acid (PA-HES-pH-PLA), we report a smart nanomedicine, DOX@CREKA/tPA-HES-pH-PLA (DOX@CREKA/tPA-HP), which exhibits a potent antitumor efficacy. In triple-negative breast cancer (TNBC) 4T1 tumors, DOX@CREKA/tPA-HP precisely targeted and effectively decomposed fibrin matrix. By measuring Young's Modulus of tumor slices and quantifying tumor openings, we demonstrated that DOX@CREKA/tPA-HP remarkably reduced tumor stiffness and solid stress. Consequently, the alleviated tumor mechanics decompressed tumor blood vessels, promoted drug delivery, and led to amplified antitumor effect. Our work reveals that decomposing fibrin is a significant means for modulating tumor mechanics, and DOX@CREKA/tPA-HP is a promising smart nanomedicine for treating TNBC.
    DOI:  https://doi.org/10.1039/d2tb01812h
  20. Front Pharmacol. 2022 ;13 945627
      With its high incidence and mortality rates, cancer is one of the largest health problems worldwide. Investigating various cancer treatment options has been the focus of many domestic and international researchers, and significant progress has been made in the study of the anticancer effects of traditional Chinese medicines. Osthole, a coumarin compound extracted from Cnidium monnieri (L.) Cuss., has become a new research hotspot. There have been many reports on its anticancer effects, and recent studies have elucidated that its underlying mechanism of action mainly involves inhibiting cancer cell proliferation, inducing cancer cell apoptosis, inhibiting invasion and migration of cancer cells, inhibiting cancer angiogenesis, increasing sensitivity to chemotherapy drugs, and reversing multidrug resistance of cancer cells. This mini-review summarizes the research progress on the anticancer effects of osthole in recent years.
    Keywords:  angiogenesis; anticancer; apoptosis; chemotherapy; metastasis; multidrug resistance; osthole; proliferation
    DOI:  https://doi.org/10.3389/fphar.2022.945627
  21. World J Gastroenterol. 2022 Jul 28. 28(28): 3637-3643
      Pancreatic cancer is highly aggressive and lethal. Due to the lack of effective methods for detecting the disease at an early stage, pancreatic cancer is frequently diagnosed late. Gemcitabine has been the standard chemotherapy drug for patients with pancreatic cancer for over 20 years, but its anti-tumor effect is limited. Therefore, FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) as well as combination therapies using gemcitabine and conventional agents, such as cisplatin and capecitabine, has also been administered; however, these have not resulted in complete remission. Therefore, there is a need to develop novel and effective therapies for pancreatic cancer. Recently, some studies have reported that combinations of gemcitabine and targeted drugs have had significant anti-tumor effects on pancreatic cancer cells. As gemcitabine induced DNA damage response, the proteins related to DNA damage response can be suitable additional targets for novel gemcitabine-based combination therapy. Furthermore, KRAS/ RAF/MEK/ERK signaling triggered by oncogenic mutated KRAS and autophagy are frequently activated in pancreatic cancer. Therefore, these characteristics of pancreatic cancer are potential targets for developing effective novel therapies. In this minireview, combinations of gemcitabine and targeted drugs to these characteristics, combinations of targeted drugs, combinations of natural products and anti-cancer agents, including gemcitabine, and combinations among natural products are discussed.
    Keywords:  Combination therapy; Gemcitabine; Pancreatic cancer; Targeted drug
    DOI:  https://doi.org/10.3748/wjg.v28.i28.3637
  22. Ther Adv Musculoskelet Dis. 2022 ;14 1759720X221124545
      For several thousand years (~4000) Boswellia serrata and Curcuma longa have been used in Aryuvedic medicine for treatment of various illnesses, including asthma, peptic ulcers, and rheumatoid arthritis, all of which are mediated through pathways associated with inflammation and pain. Although the in vivo pharmacology of both these natural ingredients is difficult to study because of poor bioavailability, in vitro data suggest that both influence gene expression mediated through nuclear factor kappa B (NF-κB). Therefore, the activity of pathways associated with inflammation (including NF-κB and lipoxygenase- and cyclooxygenase-mediated reduction in leukotrienes/prostaglandins) and those involved in matrix degradation and apoptosis are reduced, resulting in a reduction in pain. Additive activity of boswellic acids and curcumin was observed in preclinical models and synergism was suggested in clinical trials for the management of osteoarthritis (OA) pain. Overall, studies of these natural ingredients, alone or in combination, revealed that these extracts relieved pain from OA and other inflammatory conditions. This may present an opportunity to improve patient care by offering alternatives for patients and physicians, and potentially reducing nonsteroidal anti-inflammatory or other pharmacologic agent use. Additional research is needed on the effects of curcumin on the microbiome and the influence of intestinal metabolism on the activity of curcuminoids to further enhance formulations to ensure sufficient anti-inflammatory and antinociceptive activity. This narrative review includes evidence from in vitro and preclinical studies, and clinical trials that have evaluated the mechanism of action, pharmacokinetics, efficacy, and safety of curcumin and boswellic acids individually and in combination for the management of OA pain.
    Keywords:  Boswellia serrata; complementary and alternative medicine; curcuma longa; nonsteroidal anti-inflammatory drugs (NSAIDs); osteoarthritis (OA); pain management; phytotherapy
    DOI:  https://doi.org/10.1177/1759720X221124545
  23. Biochem Pharmacol. 2022 Sep 27. pii: S0006-2952(22)00351-3. [Epub ahead of print] 115257
      In recent years, experimental evidence suggested a possible role of the gut microbiota in the onset and development of several neurodegenerative disorders, such as AD and PD, MS and pain. Flavonoids, including anthocyanins, EGCG, the flavonol quercetin, and isoflavones, are plant polyphenolic secondary metabolites that have shown therapeutic potential for the treatment of various pathological conditions, including neurodegenerative diseases. This is due to their antioxidant and anti-inflammatory properties, despite their low bioavailability which often limits their use in clinical practice. In more recent years it has been demonstrated that flavonoids are metabolized by specific bacterial strains in the gut to produce their active metabolites. On the other way round, both naturally-occurring flavonoids and their metabolites promote or limit the proliferation of specific bacterial strains, thus profoundly affecting the composition of the gut microbiota which in turn modifies its ability to further metabolize flavonoids. Thus, understanding the best way of acting on this virtuous circle is of utmost importance to develop innovative approaches to many brain disorders. In this review, we summarize some of the most recent advances in preclinical and clinical research on the neuroinflammatory and neuroprotective effects of flavonoids on AD, PD, MS and pain, with a specific focus on their mechanisms of action including possible interactions with the gut microbiota, to emphasize the potential exploitation of dietary flavonoids as adjuvants in the treatment of these pathological conditions.
    Keywords:  EGCG; anthocyanins; isoflavones; microbiota; nutraceutical supplements; quercetin
    DOI:  https://doi.org/10.1016/j.bcp.2022.115257
  24. Front Bioeng Biotechnol. 2022 ;10 989602
      Purpose: Spinal cord injury (SCI) is a severely crippling injury. Scavenging reactive oxygen species (ROS) and suppressing inflammation to ameliorate secondary injury using biomaterials has turned into a promising strategy for SCI recuperation. Herein, epigallocatechin-3-gallate selenium nanoparticles (EGCG-Se NP) that scavenge ROS and attenuate inflammation were used for neuroprotection in SCI. Methods: EGCG-Se NP were arranged using a simple redox framework. The size, morphology, and chemical structure of the EGCG-Se NP were characterized. The protective effect of EGCG-Se NP for neuroprotection was examined in cell culture and in an SCI rat model. Results: EGCG-Se NP could promptly scavenge excess ROS and safeguard PC12 cells against H2O2-induced oxidative harm in vitro. After intravenous delivery in SCI rats, EGCG-Se NP significantly improved locomotor capacity and diminished the injury region by safeguarding neurons and myelin sheaths. Component studies showed that the main restorative impact of EGCG-Se NP was due to their ROS-scavenging and anti-inflammatory properties. Conclusion: This study showed the superior neuroprotective effect of EGCG-Se NP through ROS sequestration and anti-inflammatory capabilities. EGCG-Se NP could be a promising and effective treatment for SCI.
    Keywords:  epigallocatechin-3-gallate; inflammation; neuroprotection; reactive oxygen species; selenium nanoparticle; spinal cord injury
    DOI:  https://doi.org/10.3389/fbioe.2022.989602
  25. Front Nutr. 2022 ;9 1005181
      Traditional Chinese medicines (TCM), as the unique natural resource, are rich in polysaccharides, polyphenols, proteins, amino acid, fats, vitamins, and other components. Hence, TCM have high medical and nutritional values. Polysaccharides are one of the most important active components in TCM. Growing reports have indicated that TCM polysaccharides (TCMPs) have various biological activities, such as antioxidant, anti-aging, immunomodulatory, hypoglycemic, hypolipidemic, anti-tumor, anti-inflammatory, and other activities. Hence, the research progresses and future prospects of TCMPs must be systematically reviewed to promote their better understanding. The aim of this review is to provide comprehensive and systematic recombinant information on the extraction, purification, structure, chemical modification, biological activities, and potential mechanism of TCMPs to support their therapeutic effects and health functions. The findings provide new valuable insights and theoretical basis for future research and development of TCMPs.
    Keywords:  biological activities; extraction and purification; polysaccharides; structure; traditional Chinese medicines
    DOI:  https://doi.org/10.3389/fnut.2022.1005181
  26. Seizure. 2022 Sep 15. pii: S1059-1311(22)00201-1. [Epub ahead of print]102 14-21
      In recent years, there has been growing interest in the influences of food-drug interactions on the metabolism of antiseizure medications (ASM) and the management of epilepsy. Studies have proven the effectiveness of the ketogenic diet (KD) in controlling refractory epilepsy. However, dietary interventions such as the KD or its variants may induce significant changes in serum drug concentrations which counteracts the anticonvulsive effects of ASMs, leading to an increased risk of developing seizures. Interactions with enzymes within the cytochrome P450 system may also explain the dietary influences on serum concentrations of antiseizure drugs. The bioavailability of ASMs is also affected by several foods and nutritional supplements. Nevertheless, more studies are warranted to explore the mechanisms underlying food-drug interactions and the risks and benefits of combined drug-diet therapy.
    Keywords:  Antiseizure drug; Antiseizure drug metabolism; Ketogenic diet; Ketosis; Refractory seizures
    DOI:  https://doi.org/10.1016/j.seizure.2022.09.009
  27. Eur J Med Chem. 2022 Sep 13. pii: S0223-5234(22)00650-X. [Epub ahead of print]243 114748
      Currently, the number of new cancer cases and deaths worldwide is increasing year on year. In addition to the requirement for cancer prevention, the top priority is still to seek the effective cure of cancer. In over a half century of constant exploration, increasing attention has been paid to the excellent anticancer activity of natural products, with more and more natural products isolated, identified and detected. For this study, the focus lies the natural products of bisindole, where two indole molecules are indirectly linked or directly polymerized, developing the diversity of structure and mechanism, accompanied with the better anticancer activity than monomers. There has been a long history of applying indirubin and vincristine in cancer treatment, verifying the anticancer effect of bisindoles. Vincribine, midostaurin and other anticancer drugs have also been developed and commercialized. In this paper, a review regarding the potential therapeutic effect of bisindole alkaloids extracted from various natural products was carried out, in which the progress made in research of 242 bisindole alkaloids for cancer treatment was introduced. These compounds may be applicable as medicinal products for clinical research in the future.
    Keywords:  Anticancer drug; Bioactivity; Bisindole alkaloids; Cancer; Natural products
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114748
  28. Front Pharmacol. 2022 ;13 991644
      
    Keywords:  bio.natural meeting; bioactivity; natural products; natural products chemistry; pharmacology congress
    DOI:  https://doi.org/10.3389/fphar.2022.991644
  29. Acta Biomater. 2022 Sep 27. pii: S1742-7061(22)00632-8. [Epub ahead of print]
      Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis therapy and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. Herein, a hydrogel/nanosystem-mediated antiangiogenesis combined immunotherapy strategy was used to regulate the tumor microenvironment by the controlled release of apatinib, CD47 antibody (aCD47), and CpG. The combination of hydrogel with nanoparticles protected drug activity and maintained a long-term slow release of the drug for maximum synergistic efficacy. Apatinib promotes vascular normalization in tumors and enhances the efficacy of aCD47-based immunotherapy. The addition of Immunoadjuvant CpG further enhanced antigen presentation and stimulated the anti-tumor activity of macrophages to strengthen the efficacy of antiangiogenesis combined immunotherapy. The main effector immune cells, including CD4+ T, CD8+ T, NK, and activity DCs, were significantly increased after combination treatment, while the proportion of various immunosuppressive cells decreased significantly, especially MDSCs and M2-polarized macrophages. Based on an effective systemic immune response, the hydrogel/nanoparticle-mediated cooperative combination of antiangiogenesis and immunotherapy enhanced the synergistic effect for primary tumors and prevented metastasis for tumor treatment. The biomaterial-mediated antiangiogenesis combined immunotherapy strategy is a promising strategy for effective immunotherapy. STATEMENT OF SIGNIFICANCE: Relieving immunosuppression of the tumor microenvironment is the key to restoring and rebuilding the normal anti-tumor immune defense of the body. Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. For the combination of antiangiogenesis and immunotherapy, effective drug delivery to overcome local immune tolerance and regulate the tumor microenvironment to increase therapeutic effects is an important issue. The hydrogel/nanomaterial composite system constructs a dual sustained-release system to achieve step-by-step controlled release of antiangiogenic drugs and immune immunotherapy drugs to promote cooperative combination therapy.
    Keywords:  Antiangiogenesis; Hydrogel; Immunotherapy; Nanoparticles; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.actbio.2022.09.060
  30. Heliyon. 2022 Sep;8(9): e10654
      Due to their natural availability, biocompatibility, biodegradability, nontoxicity, flexibility, as well as improved structural and functional characteristics, pectin and pectin-based nanocomposites have become an interesting area of numerous researchers. Pectin is a polysaccharide that comes from plants and is used in a variety of products. The significance of pectin polysaccharide and its modified nanocomposites in a number of applications has been shown in numerous reviews. On their uses in pharmaceutical and medication delivery, there are, however, few review publications. The majority of papers on pectin polysaccharide do not structure their explanations of drug distribution and medicinal application. The biological application of pectin nanocomposite is also explained in this review, along with a recent publication. As a result, the goal of this review was in-depth analysis to summarize biological application of pectin and its modified nanocomposites. Due to their exceptional physicochemical and biological characteristics, pectin and its nanocomposites are remarkable materials for medicinal applications. In addition to enhancing the immune system, controlling blood cholesterol, and other things, they have been shown to have anticancer, antidiabetic, antioxidant, anti-inflammatory, immunomodulatory, and antibacterial properties. Because of their biocompatibility and properties that allow for regulated release, they have also received a lot of interest as drug carriers in targeted drug delivery systems. They have been used to administer medications to treat cancer, inflammation, pain, Alzheimer's, bacteria, and relax muscles. This review found that pectin and its derivatives have better drug delivery efficiency and are viable candidates for a wide range of medicinal applications. It has been advised to conduct further research on the subject of toxicity in order to produce commercial formulations that can serve as both therapeutic agents and drug carriers.
    Keywords:  Drug delivery; Nanocomposites; Pectin; Pharmaceuticals; Polysaccharide
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e10654
  31. Med Oncol. 2022 Sep 29. 39(12): 240
      Recently, nanotechnology is involved in various fields of science, of which medicine is one of the most obvious. The use of nanoparticles in the process of treating and diagnosing diseases has created a novel way of therapeutic strategies with effective mechanisms of action. Also, due to the remarkable progress of personalized medicine, the effort is to reduce the side effects of treatment paths as much as possible and to provide targeted treatments. Therefore, the targeted delivery of drugs is important in different diseases, especially in patients who receive combined drugs, because the delivery of different drug structures requires different systems so that there is no change in the drug and its effectiveness. Niosomes are polymeric nanoparticles that show favorable characteristics in drug delivery. In addition to biocompatibility and high absorption, these nanoparticles also provide the possibility of reducing the drug dosage and targeting the release of drugs, as well as the delivery of both hydrophilic and lipophilic drugs by Niosome vesicles. Since various factors such as components, preparation, and optimization methods are effective in the size and formation of niosomal structures, in this review, the characteristics related to niosome vesicles were first examined and then the in silico tools for designing, prediction, and optimization were explained. Finally, anticancer drugs delivered by niosomes were compared and discussed to be a suitable model for designing therapeutic strategies. In this research, it has been tried to examine all the aspects required for drug delivery engineering using niosomes and finally, by presenting clinical examples of the use of these nanocarriers in cancer, its clinical characteristics were also expressed.
    Keywords:  Characterization; In silico; Niosomes; Preparation; Structure; Targeted drug delivery
    DOI:  https://doi.org/10.1007/s12032-022-01836-3
  32. Front Pharmacol. 2022 ;13 979682
      Alzheimer's disease (AD) is one of the neurological ailments which continue to represent a major public health challenge, owing to increased life expectancy and aging population. Progressive memory loss and decrease in cognitive behavior, owing to irreversible destruction of neurons along with expensive therapeutic interventions, call for an effective, alternate, yet affordable treatment for Alzheimer's disease. Safe and effective delivery of neurotherapeutics in Alzheimer's like central nervous system (CNS) disorders still remains elusive despite the major advances in both neuroscience and drug delivery research. The blood-brain barrier (BBB) with its tight endothelial cell layer surrounded by astrocyte foot processes poses as a major barrier for the entry of drugs into the brain. Nasal drug delivery has emerged as a reliable method to bypass this blood-brain barrier and deliver a wide range of neurotherapeutic agents to the brain effectively. This nasal route comprises the olfactory or trigeminal nerves originating from the brain and terminating into the nasal cavity at the respiratory epithelium or olfactory neuroepithelium. They represent the most direct method of noninvasive entry into the brain, opening the most suitable therapeutic avenue for treatment of neurological diseases. Also, drugs loaded into nanocarriers can have better interaction with the mucosa that assists in the direct brain delivery of active molecules bypassing the BBB and achieving rapid cerebrospinal fluid levels. Lipid particulate systems, emulsion-based systems, vesicular drug delivery systems, and other nanocarriers have evolved as promising drug delivery approaches for the effective brain delivery of anti-Alzheimer's drugs with improved permeability and bioavailability via the nasal route. Charge, size, nature of neurotherapeutics, and formulation excipients influence the effective and targeted drug delivery using nanocarriers via the nasal route. This article elaborates on the recent advances in nanocarrier-based nasal drug delivery systems for the direct and effective brain delivery of the neurotherapeutic molecules. Additionally, we have attempted to highlight various experimental strategies, underlying mechanisms in the pathogenesis and therapy of central nervous system diseases, computational approaches, and clinical investigations pursued so far to attain and enhance the direct delivery of therapeutic agents to the brain via the nose-to-brain route, using nanocarriers.
    Keywords:  Alzheimer’s disease; brain-targeted drug delivery; intranasal formulations; nanocarrier; neurotherapeutics
    DOI:  https://doi.org/10.3389/fphar.2022.979682
  33. Nat Commun. 2022 Sep 28. 13(1): 5696
      Fatty liver is a highly heterogenous condition driven by various pathogenic factors in addition to the severity of steatosis. Protein insufficiency has been causally linked to fatty liver with incompletely defined mechanisms. Here we report that fatty liver is a sulfur amino acid insufficient state that promotes metabolic inflexibility via limiting coenzyme A availability. We demonstrate that the nutrient-sensing transcriptional factor EB synergistically stimulates lysosome proteolysis and methionine adenosyltransferase to increase cysteine pool that drives the production of coenzyme A and glutathione, which support metabolic adaptation and antioxidant defense during increased lipid influx. Intriguingly, mice consuming an isocaloric protein-deficient Western diet exhibit selective hepatic cysteine, coenzyme A and glutathione deficiency and acylcarnitine accumulation, which are reversed by cystine supplementation without normalizing dietary protein intake. These findings support a pathogenic link of dysregulated sulfur amino acid metabolism to metabolic inflexibility that underlies both overnutrition and protein malnutrition-associated fatty liver development.
    DOI:  https://doi.org/10.1038/s41467-022-33465-9
  34. ACS Appl Mater Interfaces. 2022 Sep 26.
      The construction of completely biocompatible and biodegradable tumor suppressors by a simple and reliable method is essential for the clinical application of cancer-targeted drugs. Herein, by inserting glucose oxidase (GOx), catalase (CAT), and chlorin e6 (Ce6) into human serum albumin (HSA) assembly molecules, we constructed a cancer-targeted cascade bioreactor for synergistic starvation and photodynamic therapy (PDT). The modification of HSA could block the GOx activity and reduce the cytotoxicity of normal cells and organs. Through active targeting and passive enhanced permeability and retention effect, the loading of AS1411 could promote the cascade bioreactors to effectively target nucleolin-overexpressed tumors. Once internalized by cancer cells, as a result of catalyzing hydrogen peroxide (H2O2) to produce oxygen (O2), the protein nano-cascade reactor promoted microenvironmental oxygenation, which would subsequently lead to an increase in cytotoxic singlet oxygen (1O2) production under light irradiation as well as the decomposition of intracellular glucose. In vitro and in vivo studies showed that the cascaded nanoreactors could significantly enhance therapeutic efficacy through synergistic starvation therapy and enhanced PDT as well as chemotherapy. This cascade strategy will be demonstrated in clinical applications with huge potential.
    Keywords:  cascade nanoreactor; drug-induced; self-assembly; synergistic; tumor therapy
    DOI:  https://doi.org/10.1021/acsami.2c09947
  35. Int J Biol Macromol. 2022 Sep 25. pii: S0141-8130(22)02137-7. [Epub ahead of print]
      Wound healing is a complicated cellular process with overlapping phases. Naringin (NAR); a flavanone glycoside, possesses numerous pharmacological effects such as anti-inflammatory, antioxidant and anti-apoptotic effects. In the current study, Arabic gum (AG)/pectin hydrogel was utilized to encapsulate NAR. Drug-loaded AG/pectin hydrogel exhibited excellent EE% of about 99.88 ± 0.096 and high DL% of about 16.64 ± 0.013. The formulated drug-loaded hydrogel was characterized using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Zetasizer analyzer, besides determination of equilibrium degree of swelling (EDS%). Afterwards, wound healing potential of NAR-loaded AG/pectin hydrogel was evaluated in an in vivo animal model. Results manifested that NAR-loaded AG/pectin hydrogel was able to accelerate wound healing in terms of enhanced angiogenesis, re-epithelialization and collagen deposition. Furthermore, it significantly (P < 0.001) down-regulated the mRNA expression of inflammatory mediators (TNF-α) and apoptosis (BAX). In addition, NAR-loaded AG/pectin hydrogel was found to possess potent antioxidant activity as it enhanced the levels of SOD and GSH, besides decreasing the levels of MPO, MDA and nitrite. These data suggest that NAR-loaded AG/pectin hydrogel could be utilized in wound healing applications.
    Keywords:  Anti-inflammatory effect; Antioxidant effect; Arabic gum; Hydrogel; Naringin; Pectin; Wound healing
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.200
  36. J Control Release. 2022 Sep 22. pii: S0168-3659(22)00630-7. [Epub ahead of print]351 164-173
      Nanoemulsion, or nanoscaled-size emulsions, is a thermodynamically stable system formed by blending two immiscible liquids, blended with an emulsifying agent to produce a single phase. Nanoemulsion science has advanced rapidly in recent years, and it has opened up new opportunities in a variety of fields, including pharmaceuticals, biotechnology, food, and cosmetics. Nanoemulsion has been recognized as a potential drug delivery technology for various drugs, such as photosensitizing agents (PS). In photodynamic therapy (PDT), PSs produce cytotoxic reactive oxygen species under specific light irradiation, which oxidize the surrounding tissues. Over the past decades, the idea of PS-loaded nanoemulsions has received researchers' attention due to their ability to overcome several limitations of common PSs, such as limited permeability, non-specific phototoxicity, hydrophobicity, low bioavailability, and self-aggregation tendency. This review aims to provide fundamental knowledge of nanoemulsion formulations and the principles of PDT. It also discusses nanoemulsion-based PDT strategies and examines nanoemulsion advantages for PDT, highlighting future possibilities for nanoemulsion use.
    Keywords:  Nanoemulsion; Nanomedicine; Nanoparticle; Photodynamic therapy; Photosensitizer
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.035
  37. J Ethnopharmacol. 2022 Sep 23. pii: S0378-8741(22)00787-5. [Epub ahead of print] 115748
       ETHNOPHARMACOLOGICAL RELEVANCE: With high mortality and morbidity rates, lung cancer (LC) has become one of the major threats to human health. The treatment strategies for LC currently face issues, such as drug resistance and body tolerance. Traditional Chinese medicine (TCM) is characterized by novel pharmacological mechanisms, low toxicity, and limited side effects. TCM includes a substantial number of biologically active ingredients, several of which are effective monomeric agents against LC. An increasing number of researchers are focusing their efforts on the discovery of active anti-cancer ingredients in TCM.
    AIM OF THE REVIEW: In this review, we summarized the anti-LC mechanisms of five types of TCM monomeric compounds. Our goal is to provide research ideas for the identification of new prospective medication candidates for the treatment of LC.
    MATERIALS AND METHODS: We collected reports on the anti-LC effects of TCM monomers from web databases, including PubMed, Science Direct, Web of Science, and Europe PubMed Central. Among the keywords used were "lung cancer," "traditional Chinese medicine," "pharmacology," and their combinations thereof. Then, we systematically summarized the anti-LC efficacy and related mechanisms of TCM monomers.
    RESULTS: Based on the available literature, this paper reviewed the therapeutic effects and mechanisms of five types of TCM monomers on LC. The characteristics of TCM monomers include the capabilities to suppress the tumor cell cycle, inhibit proliferation, induce apoptosis, promote autophagy, inhibit tumor cell invasion and metastasis, and enhance efficacy or reduce drug resistance when combined with cytotoxic agents and other methods to arrest the progression of LC and prolong the survival of patients.
    CONCLUSIONS: TCM contains numerous flavonoids, alkaloids, terpenoids, polyphenols, and other active compounds that are effective against LC. Given their chemical structure and pharmacological properties, these monomers are suitable as candidate drugs for the treatment of LC.
    Keywords:  Alkaloid; Flavonoid; Lung cancer; Monomer; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.jep.2022.115748
  38. Crit Rev Food Sci Nutr. 2022 Sep 26. 1-18
      Mental health is a global public concern that contributes raising disability and premature death. Anxiety undertakes around 3.6% of the global population, while psychological stress is a condition associated to anxiety with a prevalence of 36.5%. Treatment for both mental conditions consist mainly of psychological therapy and pharmacotherapy, but the long-term drugs use can trigger adverse effects. Growing evidence shows the effect of specific food compounds on stress and anxiety treatment. The aim of this systematic review is to describe the molecular mechanisms related to dietary polyphenols administration from food matrix (considering food, juices or herbal/food extracts) and their effects on stress and/or anxiety, as well as review the available clinical evidence. Search was based on PRISMA Guidelines using peer-reviewed journal articles sourced from PubMed and Web of Science. A total of 38 articles were considered as eligible. The major effects for anxiety management were: reduction of oxidative stress and inflammation; HPA axis modulation; and regulation of some serotonergic/adrenergic pathways. There is a very limited evidence to conclude about the real effect of dietary polyphenols on stress. Although pharmacological treatment for mood disorders is essential, alternative therapies are necessary using non-pharmacological compounds to improve the long-term treatment effectiveness.
    Keywords:  Polyphenols; anxiety; hypothalamic-pituitary-adrenal axis; inflammation; oxidative stress; stress
    DOI:  https://doi.org/10.1080/10408398.2022.2122925
  39. Int J Biol Macromol. 2022 Sep 26. pii: S0141-8130(22)02127-4. [Epub ahead of print]222(Pt A): 497-508
      The study aimed to develop folate decorated lipid chitosan hybrid nanoparticles for targeted delivery of 5-fluorouracil in colon cancer by utilizing the overexpressed folate receptors on the surface of HT-29 and HCT 116 cancer cell lines. The developed formulations were prepared by the ionic gelation method with slight modifications. The developed formulations exhibited spherical morphology, smaller particle size (158 to 225 nm), zeta potential (32.24 to 35.95 mV), PDI (0.19 to 0.35), and high encapsulation efficiency (85.3 % to 94.2 %) with optimal physicochemical characteristics. The in vitro release showed a biphasic release pattern with an initial burst release followed by a sustained release for 48 h. Moreover, the in vitro cell line study revealed that FA-CLPN-2 exhibited an enhanced cellular uptake and greater cytotoxic effect in HT-29 and HCT 116 cell lines compared to non-targeted CLPN-2 and free drug solution due to the folate receptor facilitated endocytosis process. The in vivo toxicity study revealed the safety and biocompatibility of the developed formulations in biological systems. The stability study demonstrates the stability of the developed formulations. Overall, these results suggest that the folate decorated lipid chitosan hybrid nanoparticles could be used as a potential delivery system for tumor-targeted therapy with reduced side effects.
    Keywords:  5-Fluorouracil; Chitosan; Colorectal cancer; Folic acid; Nanomedicine
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.196
  40. Curr Med Chem. 2022 09 22.
      Cancer remains a major worldwide health challenge. Current studies emphasize the tumor microenvironment that plays a vital role in tumor proliferation, invasion, metastasis, and drug resistance. The tumor microenvironment supports the cancer cell to evade conventional treatment such as surgery, radiotherapy, and chemotherapy. Moreover, the components of tumor microenvironments have a major contribution to developing therapy resistance in solid tumors. Therefore, targeting the tumor microenvironment can be a novel approach to achieving advancement in cancer nanomedicine. The recent progress in understanding TME and developing TME-responsive nanoparticles offers a great advantage in treating cancer drug resistance. These nanoparticles developed in response to TME stimuli such as low pH, redox, and hypoxia improve nanomedicine's pharmacokinetic and therapeutic efficacy. This review discusses the various components of the tumor microenvironment responsible for drug resistance and nanomedicine's role in overcoming it.
    Keywords:  cancer drug resistance; delivery systems; drug; nanomedicine; pharmacokinetics; tumor microenvironment
    DOI:  https://doi.org/10.2174/0929867329666220922111336
  41. Food Chem (Oxf). 2022 Dec 30. 5 100134
      Functional foods show non-toxic bioactive compounds that offer health benefits beyond their nutritional value and beneficially modulate one or more target functions in the body. In recent decades, there has been an increase in the trend toward consuming foods rich in bioactive compounds, less industrialized, and with functional properties. Spirulina, a cyanobacterium considered blue microalgae, widely found in South America, stands out for its rich composition of bioactive compounds, as well as unsaturated fatty acids and essential amino acids, which contribute to basic human nutrition and can be used as a protein source for diets free from animal products. In addition, they have colored compounds, such as chlorophylls, carotenoids, phycocyanins, and phenolic compounds which can be used as corants and natural antioxidants. In this context, this review article presents the main biological activities of spirulina as an anticancer, neuroprotective, probiotic, anti-inflammatory, and immune system stimulating effect. Furthermore, an overview of the composition of spirulina, its potential for different applications in functional foods, and its emerging technologies are covered in this review.
    Keywords:  Aminoacids; Carotenoids; Microalgae; Phenolic compounds; Phycocyanin; Unsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.fochms.2022.100134
  42. Curr Pharm Des. 2022 Sep 22.
      Colorectal cancer (CRC) is one of the most prevalent cancers globally. Despite recent progress in identifying etiologies and molecular genetics as well as new therapeutic approaches, the clinical outcome of current CRC therapies remains poor. This fact highlights the importance of further understanding of underlying mechanisms involved in colorectal tumor initiation and progression. Abnormal metabolic alterations offer an evolutional advantage for CRC tumor cells and enhance their aggressive phenotype. Therefore, dysregulation of cellular metabolism is intricately associated with colorectal tumorigenesis. This review summarizes recent findings regarding the CRC-related changes in cellular metabolic pathways such as glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and mitochondrial metabolism. We describe the oncogenic signaling pathways associated with metabolic dysregulation during malignant transformation and tumor progression. Given the crucial role of metabolic pathway alterations in pathogenesis of CRC, we provide an overview of novel pharmacological strategies for the treatment of CRC by targeting metabolic and signaling pathways.
    Keywords:  Colorectal cancer; Glucose metabolism; Metabolic pathways; Metabolic reprogramming; Signaling pathways; Targeted therapies; Warburg effect
    DOI:  https://doi.org/10.2174/1381612828666220922111342
  43. J Am Chem Soc. 2022 Sep 27.
      Surface modification with poly(ethylene glycol) (PEGylation) is an effective strategy to improve the colloidal stability of nanoparticles (NPs) and is often used to minimize cellular uptake and clearance of NPs by the immune system. However, PEGylation can also trigger the accelerated blood clearance (ABC) phenomenon, which is known to reduce the circulation time of PEGylated NPs. Herein, we report the engineering of stealth PEG NPs that can avoid the ABC phenomenon and, when modified with hyaluronic acid (HA), show specific cancer cell targeting and drug delivery. PEG NPs cross-linked with disulfide bonds are prepared by using zeolitic imidazolate framework-8 NPs as templates. The reported templating strategy enables the simultaneous removal of the template and formation of PEG NPs under mild conditions (pH 5.5 buffer). Compared to PEGylated liposomes, PEG NPs avoid the secretion of anti-PEG antibodies and the presence of anti-PEG IgM and IgG did not significantly accelerate the blood clearance of PEG NPs, indicating the inhibition of the ABC effect for the PEG NPs. Functionalization of the PEG NPs with HA affords PEG NPs that retain their stealth properties against macrophages, target CD44-expressed cancer cells and, when loaded with the anticancer drug doxorubicin, effectively inhibit tumor growth. The innovation of this study lies in the engineering of PEG NPs that can circumvent the ABC phenomenon and that can be functionalized for the improved and targeted delivery of drugs.
    DOI:  https://doi.org/10.1021/jacs.2c06877
  44. Front Pharmacol. 2022 ;13 1009868
      Cannabis sativa L. is a plant that contains numerous chemically active compounds including cannabinoids such as trans-Δ-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), and flavone derivatives, such as luteolin-7-O-glucuronide and apigenin glucuronide. In particular, the polar fraction of hemp including many phenolic compounds has been overlooked when compared with the more lipophilic fraction containing cannabinoids. Therefore, the aim of this study was to assess two extracts of industrial hemp (C. sativa) of different polarity (aqueous and hexane) by evaluating their antioxidant profile and their neuroprotective potential on pharmacological targets in the central nervous system (CNS). Several assays on in vitro antioxidant capacity (DPPH, superoxide radical, FRAP, ORAC), as well as inhibition of physiological enzymes such as acetylcholinesterase (AChE) and monoaminooxidase A (MAO-A) were carried out in order to find out how these extracts may be helpful to prevent neurodegenerative disorders. Neuro-2a cell line was selected to test the cytotoxic and neuroprotective potential of these extracts. Both extracts showed striking antioxidant capacity in the FRAP and ORAC assays, particularly the hexane extract, and interesting results for the DPPH and superoxide radical uptake assays, with the aqueous extract standing out especially in the latter. In enzyme inhibition assays, the aqueous extract showed AChE and MAO-A inhibitory activity, while the hexane extract only reached IC50 value for AChE inhibitory bioassay. Neuro-2a assays demonstrated that polyphenolic extract was not cytotoxic and exhibited cytoprotective properties against hydrogen peroxide and antioxidant response decreasing reactive oxygen species (ROS) production. These extracts could be a source of compounds with potential benefit on human health, especially related to neurodegenerative disorders.
    Keywords:  antioxidant; cannabidiol (CBD); cannabinoid; central nervous system (CNS); enzymatic inhibition; oxidative stress; polyphenol; trans-Δ-9-tetrahydrocannabinol (Δ9-THC)
    DOI:  https://doi.org/10.3389/fphar.2022.1009868
  45. J Drug Deliv Sci Technol. 2022 Oct;pii: 103751. [Epub ahead of print]76
      Photodynamic therapy (PDT), as the name suggests is a light-based, non-invasive therapeutic treatment method that has garnered immense interest in the recent past for its efficacy in treating several pathological conditions. PDT has prominent use in the treatment of several dermatological conditions, which consequently have cosmetic benefits associated with it as PDT improves the overall appearance of the affected area. PDT is commonly used for repairing sun-damaged skin, providing skin rejuvenation, curbing pre-cancerous cells, treating conditions like acne, keratosis, skin-microbial infections, and cutaneous warts, etc. PDT mediates its action by generating oxygen species that are involved in bringing about immunomodulation, suppression of microbial load, wound-healing, lightening of scarring, etc. Although there are several challenges associated with PDT, the prominent ones being pain, erythema, insufficient delivery of the photosensitizing agent, and poor clinical outcomes, still PDT stands to be a promising approach with continuous efforts towards maximizing clinical efficacy while being cautious of the side effects and working towards lessening them. This article discusses the major skin-related conditions which can be treated or managed by employing PDT as a better or comparable alternative to conventional treatment approaches such that it also brings about aesthetic improvements thereof.
    Keywords:  Acne; Actinic keratosis; Aminolevulinic acid; Cosmetic; Photodynamic therapy; Skin
    DOI:  https://doi.org/10.1016/j.jddst.2022.103751
  46. Eur J Pharm Sci. 2022 Sep 22. pii: S0928-0987(22)00182-8. [Epub ahead of print] 106297
      Based on phytosomes advantages over liposomes, hyaluronic acid (HA) with/out pegylated phospholipid was used to develop surface-modified genistein (Gen) phytosome as Gen pegylated hyaluophytosomes (G-PHA) and Gen hyaluophytosomes (G-HA) as novel delivery systems for breast cancer treatment. In this study, in-vitro characterization of G-HA and G-PHA shows PS 144.2 ±1.266 nm and 220.3 ±2.51 nm, ZP -30.9 ±0.75 and -32.06 ±0.305 respectively. Morphological elucidation shows HA covers the surface of G-HA and the presence of a transparent layer of PEG surrounding G-PHA. In-vitro release shows a significant slow Gen release from G-HA, and G-PHA compared to Gen solution and Gen phytosomes. In-vivo bioavailability data shows improvement in bioavailability for G-HA and G-PHA compared to Gen suspension (AUC0- T: :3.563 ±0.067, 2.092 ±0.058, 0.374 ±0.085 µg/ml*h respectively). Therapeutic evaluation of the prepared targeted formulations was carried out by subcutaneous injection in an EAC-induced breast cancer model in mice. G-HA and G-PHA show a promising chemotherapeutic effect in terms of lowering the tumor size and tumor biomarkers (CEA: -34.6, -44.7 & CA15.3: -77.8, -81.6 respectively). This reduction in their values compared to Gen phytosomes, Gen suspension, and the control group is attributed to high Gen accumulation at the target organ owing to targeting properties of HA that are used in phytosomal surface modification in G-HA. Additionally, the presence of MPEG2000-DSPE in G-PHA tends to improve interstitium lymphatic drainage following SC administration, resulting in maximizing the therapeutic benefits of breast cancer despite the difference in pharmacokinetics behavior compared to G-HA. These formulations can be further studied for metastatic breast cancer.
    Keywords:  Gen hyaluophytosome; Genistein; breast cancer; hyaluronic acid; pegylated hyaluophytosome lymphatic delivery
    DOI:  https://doi.org/10.1016/j.ejps.2022.106297
  47. J Food Biochem. 2022 Sep 27. e14386
      The intake of dietary fibers in the regular diet results in boosting the gut microbiome and health of the host in several ways. The misapprehension about such dietary fibers of being only an indigestible product has changed into indispensable ingredient that has to be included in every healthy diet. Inulin is considered to be an important naturally occurring fructan classified under such dietary fibers. The present review intends to provide a thorough knowledge on inulin in maintaining the gut microbiome of the human, supported by several studies conducted on the Drosophila melanogaster, mice, rat models as well as effect on human being. The extraction process of inulin has also been described in this review that would provide a brief knowledge about its stability and the conditions that have been optimized by the researchers in order to obtain a stable product. PRACTICAL APPLICATIONS: In order to meet the consumers demand, the food industries are trying to come up with new products that could eventually replace or lower the utilization of medically avail drugs and satisfy consumers by providing them with health benefits. The availability of functional food is the new trend that can improve health of the consumers with minimal use of the drugs. Therefore, inulin as a prebiotic can be utilized to produce several functional food products that could promote health benefits to the consumers. Apart from this, the review also justifies the efficacy of inulin as a fat replacer, stabilizer, and humectant in cosmetic industries. Research also suggests that inulin has also been used as nanoparticles in pharmaceutical industries. The overall review also depicts the different extraction process of inulin from different sources.
    Keywords:   Drosophila melanogaster ; Inulin; extraction; microbiota; prebiotic
    DOI:  https://doi.org/10.1111/jfbc.14386
  48. Sci Adv. 2022 Sep 30. 8(39): eabo1123
      Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. We demonstrate that exposure to chronic circadian disruption [chronic jetlag (CJL)] increases tumor burden in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological or genetic inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.
    DOI:  https://doi.org/10.1126/sciadv.abo1123
  49. Mater Today Bio. 2022 Dec;16 100436
      Chemodynamic therapy (CDT) is a promising tumor-specific treatment, but still suffering insufficient reactive oxygen species (ROS) levels due to its limited efficacy of Fenton/Fenton-like reaction. Polyphenol, as a natural reductant, has been applied to promote the efficacy of Fenton/Fenton-like reactions; however, its intrinsic pro-apoptosis effects was ignored. Herein, a novel CDT/polyphenol-combined strategy was designed, based on Avenanthramide C-loaded dendritic mesoporous silica (DMSN)-Au/Fe3O4 nanoplatforms with folic acid modification for tumor-site targeting. For the first time, we showed that the nanocomplex (DMSNAF-AVC-FA) induced ROS production in the cytoplasm via Au/Fe3O4-mediated Fenton reactions and externally damaged the mitochondrial membrane; simultaneously, the resultant increased mitochondrial membrane permeability can facilitate the migration of AVC into mitochondrial, targeting the DDX3 pathway and impairing the electron transport chain (ETC) complexes, which significantly boosted the endogenous ROS levels inside the mitochondrial. Under the elevated oxidative stress level via both intra- and extra-mitochondrial ROS production, the maximum mitochondrial membrane permeability was achieved by up-regulation of Bax/Bcl-2, and thereby led to massive release of Cytochrome C and maximum tumor cell apoptosis via Caspase-3 pathway. As a result, the as-designed strategy achieved synergistic cytotoxicity to 4T1 tumor cells with the cell apoptosis rate of 99.12% in vitro and the tumor growth inhibition rate of 63.3% in vivo, while very minor cytotoxicity to normal cells with cell viability of 95.4%. This work evidenced that natural bioactive compounds are powerful for synergistically boosting ROS level, providing new insight for accelerating the clinical conversion progress of CDT with minimal side effects.
    Keywords:  Avenanthramide C; Chemodynamic therapy; Mitochondrial; Polyphenol
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100436
  50. Oxid Med Cell Longev. 2022 ;2022 6293355
      Dendrobium officinale has a long history of being consumed as a functional food and medicinal herb for preventing and managing diseases. The phytochemical studies revealed that Dendrobium officinale contained abundant bioactive compounds, such as bibenzyls, polysaccharides, flavonoids, and alkaloids. The experimental studies showed that Dendrobium officinale and its bioactive compounds exerted multiple biological properties like antioxidant, anti-inflammatory, and immune-regulatory activities and showed various health benefits like anticancer, antidiabetes, cardiovascular protective, gastrointestinal modulatory, hepatoprotective, lung protective, and neuroprotective effects. In this review, we summarize the phytochemical studies, bioactivities, and the mechanism of actions of Dendrobium officinale, and the safety and current challenges are also discussed, which might provide new perspectives for its development of drug and functional food as well as clinical applications.
    DOI:  https://doi.org/10.1155/2022/6293355
  51. Nat Commun. 2022 Sep 26. 13(1): 5632
    TRACERx consortium
      Activating mutations in KRAS occur in 32% of lung adenocarcinomas (LUAD). Despite leading to aggressive disease and resistance to therapy in preclinical studies, the KRAS mutation does not predict patient outcome or response to treatment, presumably due to additional events modulating RAS pathways. To obtain a broader measure of RAS pathway activation, we developed RAS84, a transcriptional signature optimised to capture RAS oncogenic activity in LUAD. We report evidence of RAS pathway oncogenic activation in 84% of LUAD, including 65% KRAS wild-type tumours, falling into four groups characterised by coincident alteration of STK11/LKB1, TP53 or CDKN2A, suggesting that the classifications developed when considering only KRAS mutant tumours have significance in a broader cohort of patients. Critically, high RAS activity patient groups show adverse clinical outcome and reduced response to chemotherapy. Patient stratification using oncogenic RAS transcriptional activity instead of genetic alterations could ultimately assist in clinical decision-making.
    DOI:  https://doi.org/10.1038/s41467-022-33290-0
  52. J Control Release. 2022 Sep 24. pii: S0168-3659(22)00631-9. [Epub ahead of print]351 341-360
      Despite the tremendous theranostics potential of nano-scale drug delivery system (NDDS) in oncology field, their tumor-targeting efficiency and safety remain major challenges due to their proneness of off-target accumulation through widespread vascular endothelial gaps (up to 1 μm). To address this problem, in this research, micro-sized cellular platelet "ghosts" (PGs, 1.32 μm, platelet without inner granules and coagulation) were employed as carriers to ship hollow gold nanoparticles (HGNs, 58.7 nm), forming a hierarchical biosafe system (PG@HGNs) to reduce normal tissue interception and enhance tumor targeting delivery of HGNs for improved photothermal therapy. PGs were prepared by an optimized "swelling-extrusion-elution" method, HGNs were loaded in PGs (PG@HGNs) through a "hypotonic dialysis" method and the safety and biodistribution of the system was evaluated in vitro and in vivo. In in vitro condition that stimulated the tumoral vessel acidic microenvironment (pH = 6.5), PG@HGNs were demonstrated with enhanced membrane fluidity through down-regulation of the glycoprotein Ib expressed on the PGs. This change induced a burst release of nano-sized HGNs which were capable to traverse vascular endothelium layer on a tumor-endothelial cell transwell model, whilst the micro-sized PG carriers were intercepted. In comparison to nano-sized platelet membrane-coated carriers (PM@HGNs), PG@HGNs showed enhanced internalization and cytotoxicity to 4T1 cells. In animal models, PG@HGNs remarkably prolonged circulation most likely due to the presence of "self-recognition" receptor-CD47 of PGs, and effectively reduced normal tissue interception via the micro-scale size effect. These both contributed to the significantly improved tumor targeting efficiency of HGNs. PG@HGNs generated the greater antitumor photothermal efficacy alongside safety in the animals compared to PM@HGNs. Collectively, this study demonstrated the potential of the micro-scale PGs equipped with adjusted membrane GP Ib as biosafe vehicles for HGNs or possibly other nanodrugs. THE STATEMENT OF SIGNIFICANCE: Despite the tremendous theranostics potentials, the safety and tumor-targeting efficiency of nano-scale drug delivery systems (NDDS) are compromised by their undesirable accumulation in normal tissues with widespread vascular endothelial gaps, such as many tumor-targeted NDDSs still accumulated much in liver and/or spleen. Herein, we explored a micro-nano biomimetic cascade delivery system to address the above drawbacks. By forming a hierarchical biosafe system, micro-sized platelet "ghost" (PGs, 1.32 μm) was employed as tumor-targeted delivery carrier to transport hollow gold nanoparticles (HGNs, 58.7 nm). It was demonstrated that this micro-size system could maintain platelet membrane structure thus prolong in vivo circulation, while avoiding extravasation into normal tissues. PG@HGNs could sensitively respond to the acidic microenvironment near tumor vessel via down-regulation of glycoprotein Ib and rapidly release "nano-bullets"-HGNs to further penetrate into the tumor tissues through EPR effect, thus enhancing photothermal efficacy generated by HGNs under NIR irradiation. Collectively, the micro-scaled PGs could be biosafe vehicles for improved tumor-targeted delivery of HGNs or possibly other nanodrugs.
    Keywords:  Biosafe distribution; Platelet cellular ghost; Size switch; Tumor microenvironment; Tumor penetration; micro-size effect
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.036
  53. Genes Dis. 2022 Nov;9(6): 1727-1741
      Alterations in cellular metabolism may contribute to tumor proliferation and survival. Upregulation of the facilitative glucose transporter (GLUT) plays a key role in promoting cancer. GLUT5 mediates modulation of fructose utilization, and its overexpression has been associated with poor prognosis in several cancers. However, its metabolic regulation remains poorly understood. Here, we demonstrated elevated GLUT5 expression in human cholangiocarcinoma (CCA), using RNA sequencing data from samples of human tissues and cell lines, as compared to normal liver tissues or a cholangiocyte cell line. Cells exhibiting high-expression of GLUT5 showed increased rates of cell proliferation and ATP production, particularly in a fructose-supplemented medium. In contrast, GLUT5 silencing attenuated cell proliferation, ATP production, cell migration/invasion, and improved epithelial-mesenchymal transition (EMT) balance. Correspondingly, fructose consumption increased tumor growth in a nude mouse xenograft model, and GLUT5 silencing suppressed growth, supporting the tumor-inhibitory effect of GLUT5 downregulation. Furthermore, in the metabolic pathways of fructolysis-Warburg effect, the expression levels of relative downstream genes, including ketohexokinase (KHK), aldolase B (ALDOB), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4), as well as hypoxia-inducible factor 1 alpha (HIF1A), were altered in a GLUT5 expression-dependent manner. Taken together, these findings indicate that GLUT5 could be a potential target for CCA therapeutic approach via metabolic regulation.
    Keywords:  Cholangiocarcinoma; Fructose; Glucose transporter 5; Metabolic regulation; Warburg effect
    DOI:  https://doi.org/10.1016/j.gendis.2021.09.002
  54. Front Pharmacol. 2022 ;13 965390
      Rubia cordifolia (family: Rubiaceae) L (R. cordifolia) is a perennial botanical drug climbing vine. As the main part of the traditional Chinese medicine, the rhizome has a long history. A great number of literary studies have reported that it can be used for the improvement of blood circulation, hemostasis, activation of collaterals, etc. When it comes to the wide application of R. cordifolia in traditional medicine, we systematically review its traditional uses, phytochemistry and pharmacological effects. Literatures were systematically searched using several scientific databases, including China National Knowledge Infrastructure (CNKI), Baidu Scholar, PubMed, Web of Science, and other professional websites. Kew Botanical Garden and the iPlant were used for obtaining the scientific names and plant images of R. cordifolia. In addition, other information was also gathered from books including traditional Chinese herbal medicine, the Chinese Pharmacopoeia, and Chinese Materia Medica. So far, many prescriptions containing R. cordifolia have been widely used in the clinical treatment of abnormal uterine bleeding, primary dysmenorrhea and other gynecological diseases, allergic purpura, renal hemorrhage and other diseases. The phytochemistry studies have reported that more than 100 compounds are found in R. cordifolia, such as bicyclic peptides, terpenes, polysaccharides, trace elements, flavonoids, and quinones. Among them, quinones and peptides are the types of components with the highest contents in R. cordifolia. The modern pharmacological studies have revealed that R. cordifolia and its derived components have anti-tumor, anti-oxidative, anti-platelet aggregation, and anti-inflammatory effects. However, most studies are preclinical. The pharmacological mechanism of R. cordifolia has not been thoroughly studied. In addition, there are few pharmacokinetic and toxicity studies of R. cordifolia, therefore the clinical safety data for R. cordifolia is lacking. To sum up, this review for the first time summarizes a systemic and integrated traditional uses, chemical compositions, pharmacological actions and clinical applications of R. cordifolia, which provides the novel and full-scale insight for the drug development, medicinal value, and application of R. cordifolia in the future.
    Keywords:  Rubia cordifolia L.; clinical application; pharmacological activities; phytochemistry; traditional uses
    DOI:  https://doi.org/10.3389/fphar.2022.965390
  55. World J Gastroenterol. 2022 Aug 28. 28(32): 4600-4619
       BACKGROUND: Glycolysis caused by hypoxia-induced abnormal activation of hypoxia inducible factor-1α (HIF-1α) in the immune microenvironment promotes the progression of hepatocellular carcinoma (HCC), leading to enhanced drug resistance in cancer cells. Therefore, altering the immunosuppressive microenvironment by imp-roving the hypoxic state is a new goal in improving cancer treatment.
    AIM: To analyse the role of HIF-1α, which is closely related to tumour proliferation, invasion, metastasis, and angiogenesis, in the proliferation and invasion of liver cancer, and to explore the HIF-1α pathway-mediated anti-cancer mechanism of sirolimus (SRL) combined with Huai Er.
    METHODS: Previous studies on HCC tissues identified the importance of HIF-1α, glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA) expression. In this study, HepG2 and Huh7 cell lines were treated, under hypoxic and normoxic conditions, with a combination of SRL and Huai Er. The effects on proliferation, invasion, cell cycle, and apoptosis were analysed. Proteomics and genomics techniques were used to analyze the HIF-1α-related signalling pathway during SRL combined with Huai Er treatment and its inhibition of the proliferation of HCC cells.
    RESULTS: High levels of HIF-1α, LDHA, and GLUT-1 were found in poorly differentiated HCC, with lower patient survival rates. Hypoxia promoted the proliferation of HepG2 and Huh7 cells and weakened the apoptosis and cell cycle blocking effects of the SRL/Huai Er treatment. This was achieved by activation of HIF-1α and glycolysis in HCC, leading to the upregulation of LDHA, GLUT-1, Akt/mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), and Forkhead box P3 and downregulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p27. The hypoxia-induced activation of HIF-1α showed the greatest attenuation in the SRL/Huai Er (S50 + H8) group compared to the drug treatments alone (P < 0.001). The S50 + H8 treatment significantly downregulated the expression of mTOR and HIF-1α, and significantly reduced the expression of VEGF mRNA. Meanwhile, the combined blocking of mTOR and HIF-1α enhanced the downregulation of Akt/mTOR, HIF-1α, LDHA, and GLUT-1 mRNA and resulted in the downregulation of PTEN, p27, and VEGF mRNA (P < 0.001).
    CONCLUSION: SRL increases the anti-cancer effect of Huai Er, which reduces the promotion of hypoxia-induced HIF-1α on the Warburg effect by inhibition of the PI3K/Akt/mTOR-HIF-1α and HIF-1α-PTEN signalling pathways in HCC.
    Keywords:  Hepatocellular carcinoma; Huai Er; Hypoxia inducible factor-1α; Sirolimus; Warburg effect
    DOI:  https://doi.org/10.3748/wjg.v28.i32.4600
  56. Bioeng Transl Med. 2022 Sep;7(3): e10315
      Nanomaterials' unique structures at the nanometer level determine their incredible functions, and based on this, they can be widely used in the field of nanomedicine. However, nanomaterials do possess disadvantages that cannot be ignored, such as burst release, rapid elimination, and poor bioadhesion. Hydrogels are scaffolds with three-dimensional structures, and they exhibit good biocompatibility and drug release capacity. Hydrogels are also associated with disadvantages for biomedical applications such as poor anti-tumor capability, weak bioimaging capability, limited responsiveness, and so on. Incorporating nanomaterials into the 3D hydrogel network through physical or chemical covalent action may be an effective method to avoid their disadvantages. In nanocomposite hydrogel systems, multifunctional nanomaterials often work as the function core, giving the hydrogels a variety of properties (such as photo-thermal conversion, magnetothermal conversion, conductivity, targeting tumor, etc.). While, hydrogels can effectively improve the retention effect of nanomaterials and make the nanoparticles have good plasticity to adapt to various biomedical applications (such as various biosensors). Nanocomposite hydrogel systems have broad application prospects in biomedicine. In this review, we comprehensively summarize and discuss the most recent advances of nanomaterials composite hydrogels in biomedicine, including drug and cell delivery, cancer treatment, tissue regeneration, biosensing, and bioimaging, and we also briefly discussed the current situation of their commoditization in biomedicine.
    Keywords:  bioimaging; biosensing; cancer treatment; drug and cell delivery; nanocomposite hydrogels; tissue regeneration
    DOI:  https://doi.org/10.1002/btm2.10315
  57. ACS Nano. 2022 Sep 28.
      The further bioapplications of sonodynamic therapy (SDT) were hindered by the inadequate efficiency and poor degradability of sonosensitizers and the hypoxic tumor microenvironment (TME). Therefore, it is ideal to develop pH-sensitive sonosensitizers that generate abundant reactive oxygen species (ROS) and rapidly degrade in a neutral environment while slowly degrading in an acidic environment to reduce their long-term toxicity. Herein, the defective tungsten oxide nanobelts (WOx NBs) were developed as a type of pH-sensitive and biodegradable sonosensitizers with a high SDT efficiency and low toxicity for enhanced SDT. The defective oxygen sites of WOx NBs could inhibit the recombination of electrons and holes, making WOx NBs promising sonosensitizers that could generate abundant ROS under ultrasound (US) irradiation. Enhanced by the catalase (CAT) that reacted with H2O2 to generate O2, the WOx NBs exhibited better SDT performance against 4T1 cells in both normoxic and hypoxic environments. In addition, the WOx NBs could degrade by releasing protons (H+), resulting in intracellular acidification and inhibited cell motility that further enhanced the therapeutic effects of SDT. Assisted with CAT and ALG for hypoxia refinement and better retention, the WOx NBs enabled effective SDT and antimetastasis against 4T1 tumors in vivo. Most importantly, the WOx NBs could degrade rapidly in normal tissues but slowly in an acidic TME, which was favorable for their fast clearance, without any obvious long-term toxicity. Our work developed defective WOx NBs with a high SDT efficiency and pH-sensitive degradation for enhanced SDT, which extended the biomedical application of tungsten-based nanomaterials and the further development of SDT.
    Keywords:  WOx nanobelts; antimetastasis; biodegradable; oxygen defect; sonodynamic therapy; sonosensitizers
    DOI:  https://doi.org/10.1021/acsnano.2c07903
  58. Pharm Res. 2022 Sep 28.
       PURPOSE: Cancer is one of the most common and fatal disease, chemotherapy is the major treatment against many cancer types. The anti-apoptotic BCL-2 protein's expression was increased in many cancer types and Venetoclax (VLX; BCL-2 inhibitor) is a small molecule, which selectively inhibits this specified protein. In order to increase the clinical performance of this promising inhibitor as a repurposed drug, polymeric mixed micelles formulations approach was explored.
    METHODS: The Venetoclax loaded polymeric mixed micelles (VPMM) were prepared by using Pluronic® F-127 and alpha tocopherol polyethylene glycol 1000 succinate (TPGS) as excipients by thin film hydration method and characteristics. The percentage drug loading capacity, entrapment efficiency and in-vitro drug release studies were performed using HPLC method. The cytotoxicity assay, cell uptake and anticancer activities were evaluated in two different cancer cells i.e. MCF-7 (breast cancer) and A-549 (lung cancer).
    RESULTS: Particle size, polydispersity index and zeta potential of the VPMM was found to be 72.88 ± 0.09 nm, 0.078 ± 0.009 and -4.29 ± 0.24 mV, respectively. The entrapment efficiency and %drug loading were found to be 80.12 ± 0.23% and 2.13% ± 0.14%, respectively. The IC50 of VLX was found to be 4.78, 1.30, 0.94 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 1.24, 0.68, and 0.314 µg/ml at 24, 48, and 72 h, respectively in A549 cells. Whereas, IC50 of VPMM was found to be 0.42, 0.29, 0.09 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 0.85, 0.13, 0.008 µg/ml at 24, 48 and 72 h in A549 cells, respectively, indicating VPMM showing better anti-cancer activity compared to VLX. The VPMM showed better cytotoxicity which was further proven by other assays and explained the anti-cancer activity is shown through the generation of ROS, nuclear damage,apoptotic cell death and expression of caspase-3,7, and 9 activities in apoptotic cells.
    CONCLUSION: The current investigation revealed that the Venetoclax loaded polymeric mixed micelles (VPMM) revealed the enhanced therapeutic efficacy against breast and lung cancer in vitro models.
    Keywords:  TPGS; pluronic® F-127; polymeric mixed micelles; thin film hydration method; venetoclax
    DOI:  https://doi.org/10.1007/s11095-022-03395-8
  59. World J Stem Cells. 2022 Jul 26. 14(7): 490-502
      Stem cell fate determination is one of the central questions in stem cell biology, and although its regulation has been studied at genomic and proteomic levels, a variety of biological activities in cells occur at the metabolic level. Metabolomics studies have established the metabolome during stem cell differentiation and have revealed the role of metabolites in stem cell fate determination. While metabolism is considered to play a biological regulatory role as an energy source, recent studies have suggested the nexus between metabolism and epigenetics because several metabolites function as cofactors and substrates in epigenetic mechanisms, including histone modification, DNA methylation, and microRNAs. Additionally, the epigenetic modification is sensitive to the dynamic metabolites and consequently leads to changes in transcription. The nexus between metabolism and epigenetics proposes a novel stem cell-based therapeutic strategy through manipulating metabolites. In the present review, we summarize the possible nexus between metabolic and epigenetic regulation in stem cell fate determination, and discuss the potential preventive and therapeutic strategies via targeting metabolites.
    Keywords:  Epigenetic regulation; Metabolism; Nexus effect; Stem cell fate
    DOI:  https://doi.org/10.4252/wjsc.v14.i7.490
  60. Biomed Pharmacother. 2022 Sep 23. pii: S0753-3322(22)01112-X. [Epub ahead of print]155 113723
      Amorphous calcium phosphate nanoparticles (ACP NPs) exhibit excellent biocompatibility and biodegradability properties. ACP NPs were functionalized with two coumarin compounds (esculetin and euphorbetin) extracted from Euphorbia lathyris seeds (BC-ACP NPs) showing high loading capacity (0.03% and 0.34% (w/w) for esculetin and euphorbetin, respectively) and adsorption efficiency (2.6% and 33.5%, respectively). BC-ACP NPs, no toxic to human blood cells, showed a more selective cytotoxicity against colorectal cancer (CRC) cells (T-84 cells) (IC50, 71.42 µg/ml) compared to non-tumor (CCD18) cells (IC50, 420.77 µg/ml). Both, the inhibition of carbonic anhydrase and autophagic cell death appeared to be involved in their action mechanism. Interestingly, in vivo treatment with BC-ACPs NPs using two different models of CRC induction showed a significant reduction in tumor volume (62%) and a significant decrease in the number and size of polyps. A poor development of tumor vasculature and invasion of normal tissue were also observed. Moreover, treatment increased the bacterial population of Akkermansia by restoring antioxidant systems in the colonic mucosa of mice. These results show a promising pathway to design innovative and more efficient therapies against CRC based on biomimetic calcium phosphate NPs loaded with natural products.
    Keywords:  Calcium phosphate nanoparticles; Colon cancer; Esculetin; Euphorbetin; Euphorbia lathyris
    DOI:  https://doi.org/10.1016/j.biopha.2022.113723
  61. Nat Commun. 2022 Sep 27. 13(1): 5675
      Cells need to coordinate gene expression with their metabolic states to maintain cell homeostasis and growth. How cells transduce nutrient availability to appropriate gene expression remains poorly understood. Here we show that glycolysis regulates histone modifications and gene expression by activating protein kinase A (PKA) via the Ras-cyclic AMP pathway. The catalytic subunit of PKA, Tpk2 antagonizes Jhd2-catalyzed H3K4 demethylation by phosphorylating Jhd2 at Ser321 and Ser340 in response to glucose availability. Tpk2-catalyzed Jhd2 phosphorylation impairs its nuclear localization, reduces its binding to chromatin, and promotes its polyubiquitination and degradation by the proteasome. Tpk2-catalyzed Jhd2 phosphorylation also maintains H3K14 acetylation by preventing the binding of histone deacetylase Rpd3 to chromatin. By phosphorylating Jhd2, Tpk2 regulates gene expression, maintains normal chronological life span and promotes autophagy. These results provide a direct connection between metabolism and histone modifications and shed lights on how cells rewire their biological responses to nutrient signals.
    DOI:  https://doi.org/10.1038/s41467-022-33423-5
  62. J Control Release. 2022 Sep 24. pii: S0168-3659(22)00617-4. [Epub ahead of print]351 361-380
      Upon exhaustive research, the transdermal drug delivery system (TDDS) has appeared as a potential, well-accepted, and popular approach to a novel drug delivery system. Ease of administration, easy handling, minimum systemic exposure, least discomfort, broad flexibility and tunability, controlled release, prolonged therapeutic effect, and many more perks make it a promising approach for effective drug delivery. Although, the primary challenge associated is poor skin permeability. Skin is an intact barrier that serves as a primary defense mechanism to preclude any foreign particle's entry into the body. Owing to the unique anatomical framework, i.e., compact packing of stratum corneum with tight junction and fast anti-inflammatory responses, etc., emerged as a critical physiological barrier for TDDS. Fusion with other novel approaches like nanocarriers, specially designed transdermal delivery devices, permeation enhancers, etc., can overcome the limitations. Utilizing such strategies, some of the products are under clinical trials, and many are under investigation. This review explores all dimensions that overcome poor permeability and allows the drug to attain maximum potential. The article initially compiles fundamental features, components, and design of TDDS, followed by critical aspects and various methods, including in vitro, ex vivo, and in vivo methods of assessing skin permeability. The work primarily aimed to highlight the recent advancement in novel strategies for effective transdermal drug delivery utilizing active methods like iontophoresis, electroporation, sonophoresis, microneedle, needleless jet injection, etc., and passive methods such as the use of liposomes, SLN, NLC, micro/nanoemulsions, dendrimers, transferosomes, and many more nanocarriers. In all, this compilation will provide a recent insight on the novel updates along with basic concepts, the current status of clinical development, and challenges for the clinical translation of TDDS.
    Keywords:  Dendrimer; Lipid nanocarrier; Liposome; Microneedle; Permeation enhancement; Transdermal drug delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.025
  63. J Food Biochem. 2022 Oct 01. e14453
      Chemotherapy is the main method for controlling pancreatic cancer metastasis but the prevalent chemotherapy resistance limits its utilization. The response of oxidation and inflammation often promotes pancreatic cancer progression and chemo-resistance. It is critical to explore the potential natural products with few side effects to control inflammatory responses and understand the related mechanisms. Quercetin is a flavonoid widely found in numerous vegetables, fruits, and foods and is thought to have antioxidant and anti-inflammatory properties, which may be associated with improvement of chemotherapy sensitivity during pancreatic cancer treatment. Quercetin may sensitize pancreatic cancer cells to the chemotherapeutic agents, including bromodomain and extraterminal domain inhibitors (BETI), daunorubicin, gemcitabine, sulforaphane, doxorubicin, and tumor necrosis factor-related signaling apoptosis-inducing ligand (TRAIL). Meanwhile, during the chemo-resistance therapy, many signaling molecules are involved with toll-like receptor 4 (TLR4)-mediated oxidative and inflammatory pathway. The effects of quercetin on other oxidative and inflammatory pathways were also explored. Quercetin may exert antitumor activity during the prevention of pancreatic cancer progression by regulating oxidative and inflammatory networks, which can promote immune escape of cancer cells by inducing immunosuppressive cytokines. Studying these patterns will help us to better understand the functional role of quercetin in the improvement of pancreatic cancer chemo-sensitivity. PRACTICAL APPLICATIONS: Chemotherapy is the major way for treating pancreatic cancer metastasis but the prevalent chemotherapy resistance caused by oxidative and inflammatory responses limits its utilization. It is necessary to explore the potential natural products with few side effects to prevent the oxidative and inflammatory responses. Quercetin is a flavonoid widely found in numerous vegetables, fruits, and foods and is thought to have antioxidant and anti-inflammatory properties, which may be associated with improvement of chemotherapy sensitivity of pancreatic cancer treatment by sensitizing pancreatic cancer cells to various chemotherapeutic agents via the regulation of oxidative and inflammatory networks. Studying these patterns will help us to better understand the functional role of quercetin in the improvement of pancreatic cancer chemo-sensitivity.
    Keywords:  chemo-sensitivity; chemotherapeutic agents; oxidative-inflammatory networks; pancreatic cancer; quercetin
    DOI:  https://doi.org/10.1111/jfbc.14453
  64. Nutr Res. 2022 Sep 02. pii: S0271-5317(22)00081-1. [Epub ahead of print]107 48-64
      Anthocyanins have received the attention of the scientific community because of their antioxidant, antimetastatic, and cancer-inhibitory properties. The aim of this review is to comprehensively summarize the possible mechanisms by which anthocyanins exhibit anticarcinogenic properties in breast cancer (BC) cell lines and animal models. Anthocyanins inhibit proinflammatory, signal transducer and activator of transcription 3, and nuclear factor kappa-light-chain-enhancer of activated B cell pathways and increase the activities of detoxification enzymes. In addition, downregulation of metalloproteinases by anthocyanins inhibits tumor invasion and metastatic processes in experimental systems. Anthocyanins mediate anticancer and angiogenic effects by modifying multiple receptor families. Furthermore, inhibition of cell-cycle upstream polo-like kinase signaling, the chromosomal replication checkpoint, and ataxia telangiectasia mutated signaling may contribute to the anticarcinogenic effects of anthocyanins. Finally, anthocyanins induce mitochondrial-mediated apoptosis and downregulate the phosphatidylinositol-3-kinase/AKT/mTOR pathway. In conclusion, anthocyanins have been shown to exert potential antitumor effects against breast carcinogenesis in vitro and in vivo, providing insights into the use of anthocyanins as a natural chemopreventive intervention in BC.
    Keywords:  Anthocyanins; Breast cancer; Cancer prevention; Chemopreventive intervention; Signaling pathway
    DOI:  https://doi.org/10.1016/j.nutres.2022.08.005
  65. Phytother Res. 2022 Sep 30.
      Sorafenib (SF), a multi-kinase inhibitor, is the first FDA-approved systemic chemotherapy drug for advanced hepatocellular carcinoma (HCC). However, its clinical application is limited by severe toxicity and side effects associated with high applied doses. Sophora alopecuroides L. is traditionally used as Chinese herbal medicine for treating gastrointestinal diseases, bacillary dysentery, viral hepatitis, and other diseases, and exerts an important role in anti-tumor. Hence, we investigated the synergistic actions of seventeen flavonoids from this herb combined with SF against HCC cell lines and their primary mechanism. In the experiment, most compounds were found to prominently enhance the inhibitory effects of SF on HCC cells than their alone treatment. Among them, three compounds leachianone A (1), sophoraflavanone G (3), and trifolirhizin (17) exhibited significantly synergistic anticancer activities against MHCC97H cells at low concentration with IC50 of SF reduced by 5.8-fold, 3.6-fold, and 3.5-fold corresponding their CI values of 0.49, 0.66, and 0.46 respectively. Importantly, compounds 3 or 17 combined with SF could synergistically induce MHCC97H cells apoptosis via the endogenously mitochondrial-mediated apoptotic pathway, involving higher Bax/Bcl-2 expressions with the activation of caspase-9 and -3, and arrest the cell cycle in G1 phases. Strikingly, this synergistic effect was also closely related to the co-suppression of ERK and AKT signaling pathways. Furthermore, compound 3 significantly enhanced the suppression of SF on tumor growth in the HepG2 xenograft model, with a 79.3% inhibition ratio at high concentration, without systemic toxicity, compared to either agent alone. These results demonstrate that the combination treatment of flavonoid 3 and SF at low doses exert synergistic anticancer effects on HCC cells in vitro and in vivo.
    Keywords:  Sophora alopecuroides; Sorafenib; apoptosis; flavonoids; hepatocellular carcinoma; synergistic effect
    DOI:  https://doi.org/10.1002/ptr.7637
  66. Adv Sci (Weinh). 2022 Sep 25. e2202332
      Notwithstanding immune checkpoint blocking (ICB) therapy has made eminent clinical breakthroughs, overcoming immunologically "cold" tumors remains challenging. Here, a cascade potentiated nanomodulator AuPtAg-GOx is engineered for boosting immune responsiveness. Upon 1064 nm laser irradiation, AuPtAg-mediated mild photothermal therapy (PTT) activates cytotoxic T lymphocytes and reverses the immunogenic "cold" tumor microenvironment. Further, to amplify the thermal sensitivity of tumor cells, glucose oxidase (GOx) is introduced to suppress the production of heat shock proteins, thereby promoting mild photothermal therapy. Complementarily, AuPtAg nanozymes with catalase-like activity can ameliorate tumor hypoxia, significantly improving the GOx activity. As a result, the combination of AuPtAg-GOx with self-augmented photothermal ability and PD-L1 antibody can further escalate the antitumor efficacy. The AuPtAg-GOx-based synergistic starvation therapy, mild PTT, and immunotherapy cascade enhancement therapy strategy can be a favorable tool to effectively kill cancer cells.
    Keywords:  cascade reactor; immune system activation; mild photothermal therapy; nanozymes; starvation therapy; synergistic therapy
    DOI:  https://doi.org/10.1002/advs.202202332
  67. Heliyon. 2022 Sep;8(9): e10577
      The aim of this study was to develop nanoparticles (NPs) providing a targeted drug release directly on the epithelium of the intestinal mucosa. NPs were prepared via ionic gelation between cationic chitosan (Cs) and anionic polyphosphate (PP). The resulting NPs were characterized by their size, polydispersity index (PDI) and zeta potential. Isolated and cell-associated intestinal alkaline phosphatase (IAP) was employed to trigger polyphosphate cleavage in Cs-PP NPs which was quantified via malachite green assay. In parallel, the shift in zeta potential was determined. In-vitro drug release studies were performed in Franz diffusion cells with Cs-PP NPs containing rhodamine 123 as model active ingredient. Furthermore, cytotoxicity of Cs-PP NPs was assessed via resazurin assay on Caco-2 cells as well as via hemolysis assay on red blood cells. Cs-PP NPs exhibited an average size of 144.17 ± 10.95 nm and zeta potential of -12.6 ± 0.50 mV. The encapsulation efficiency of rhodamine 123 by Cs-PP NPs was 86.8%. After incubation with isolated IAP for 3 h the polyphosphate of Cs-PP NPs was cleaved to monophosphate and zeta potential raised up to -2.3 ± 0.30 mV. Cs-PP NPs showed a non-toxic profile. Within 3 h, 62.0 ± 10.8% and 14.1 ± 2.2% of total rhodamine 123 was released from Cs-PP NPs upon incubation with isolated as well as porcine intestine derived intestinal alkaline phosphatase (IAP), respectively. According to these results, Cs-PP NPs are promising drug delivery systems to enable a drug targeted release at the absorption membrane.
    Keywords:  Alkaline phosphatase; Chitosan; Drug delivery; Polymeric nanoparticles; Polyphosphate; Targeted release
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e10577
  68. Acta Pharm Sin B. 2022 Sep;12(9): 3475-3485
      Despite being a common therapy for hepatocellular carcinoma (HCC), insufficient thermal ablation can leave behind tumor residues that can cause recurrence. This is believed to augment M2 inflammatory macrophages that usually play a pro-tumorigenic role. To address this problem, we designed d-mannose-chelated iron oxide nanoparticles (man-IONPs) to polarize M2-like macrophages into the antitumor M1 phenotype. In vitro and in vivo experiments demonstrated that man-IONPs specifically targeted M2-like macrophages and accumulated in peri-ablation zones after macrophage infiltration was augmented under insufficient microwave ablation (MWA). The nanoparticles simultaneously induced polarization of pro-tumorigenic M2 macrophages into antitumor M1 phenotypes, enabling the transformation of the immunosuppressive microenvironment into an immunoactivating one. Post-MWA macrophage polarization exerted robust inhibitory effects on HCC progression in a well-established orthotopic liver cancer mouse model. Thus, combining thermal ablation with man-IONPs can salvage residual tumors after insufficient MWA. These results have strong potential for clinical translation.
    Keywords:  Hepatocellular carcinoma; Iron oxide nanoparticle; Macrophage polarization; Microwave ablation; Targeted therapy
    DOI:  https://doi.org/10.1016/j.apsb.2022.05.026
  69. Cancer Res. 2022 Sep 26. pii: CAN-22-1039. [Epub ahead of print]
      Autophagy is a conserved catabolic process that maintains cellular homeostasis. Autophagy supports lung tumorigenesis and is a potential therapeutic target in lung cancer. A better understanding of the importance of tumor cell-autonomous versus systemic autophagy in lung cancer could facilitate clinical translation of autophagy inhibition. Here, we exploited inducible expression of Atg5 shRNA to temporally control Atg5 levels and generate reversible tumor-specific and systemic autophagy loss mouse models of KrasG12D/+;p53-/- (KP) non-small cell lung cancer (NSCLC). Transient suppression of systemic but not tumor Atg5 expression significantly reduced established KP lung tumor growth without damaging normal tissues. In vivo 13C isotope tracing and metabolic flux analyses demonstrated that systemic Atg5 knockdown specifically led to reduced glucose and lactate uptake. As a result, carbon flux from glucose and lactate to major metabolic pathways, including the tricarboxylic acid cycle, glycolysis, and serine biosynthesis, was significantly reduced in KP NSCLC following systemic autophagy loss. Furthermore, systemic Atg5 knockdown increased tumor T cell infiltration, leading to T cell-mediated tumor killing. Importantly, intermittent transient systemic Atg5 knockdown, which resembles what would occur during autophagy inhibition for cancer therapy, significantly prolonged lifespan of KP lung tumor-bearing mice, resulting in recovery of normal tissues but not tumors. Thus, systemic autophagy supports the growth of established lung tumors by promoting immune evasion and sustaining cancer cell metabolism for energy production and biosynthesis, and the inability of tumors to recover from loss of autophagy provides further proof of concept that inhibition of autophagy is a valid approach to cancer therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1039
  70. Acta Pharm Sin B. 2022 Sep;12(9): 3529-3547
      Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic lipids and metabolic stress-induced liver injury. There are currently no approved effective pharmacological treatments for NAFLD. Traditional Chinese medicine (TCM) has been used for centuries to treat patients with chronic liver diseases without clear disease types and mechanisms. More recently, TCM has been shown to have unique advantages in the treatment of NAFLD. We performed a systematic review of the medical literature published over the last two decades and found that many TCM formulas have been reported to be beneficial for the treatment of metabolic dysfunctions, including Potentilla discolor Bunge (PDB). PDB has a variety of active compounds, including flavonoids, terpenoids, organic acids, steroids and tannins. Many compounds have been shown to exhibit a series of beneficial effects for the treatment of NAFLD, including anti-oxidative and anti-inflammatory functions, improvement of lipid metabolism and reversal of insulin resistance. In this review, we summarize potential therapeutic effects of TCM formulas for the treatment of NAFLD, focusing on the medicinal properties of natural active compounds from PDB and their underlying mechanisms. We point out that PDB can be classified as a novel candidate for the treatment and prevention of NAFLD.
    Keywords:  Acupuncture; Anti-inflammatory; Anti-oxidative; Endoplasmic reticulum stress; Insulin resistance; Intestinal microflora; Lipid metabolism; Natural active compounds; Nonalcoholic fatty liver disease (NAFLD); Potentilla discolor Bunge (PDB); Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.apsb.2022.05.001
  71. Front Bioeng Biotechnol. 2022 ;10 1005520
      The combination of photothermal therapy (PTT) and immune tumor therapy has emerged as a promising avenue for cancer treatment. However, the insufficient immune response caused by inefficient immunogenic cell death (ICD) inducers and thermal resistance, immunosuppression, and immune escape resulting from the hypoxic microenvironment of solid tumors severely limit its efficacy. Herein, we report an ultrasound and laser-promoted dual-gas nano-generator (calcium carbonate-polydopamine-manganese oxide nanoparticles, CPM NPs) for enhanced photothermal/immune tumor therapy through reprogramming tumor hypoxic microenvironment. In this system, CPM NPs undergo reactive decomposition in a moderately acidic tumor, resulting in the generation of calcium, manganese ions, carbon dioxide (CO2), and oxygen (O2). Calcium and manganese ions act as adjuvants that trigger an immune response. The cancer cell membrane rupture caused by sudden burst of bubbles (CO2 and O2) under ultrasound stimulation and the photothermal properties of PDA also contributed to the ICD effect. The generation of O2 alleviates tumor hypoxia and thus reduces hypoxia-induced heat resistance and immunosuppressive effects, thereby improving the therapeutic efficacy of combination PTT and immune therapy. The present study provides a novel approach for the fabrication of a safe and effective tumor treatment platform for future clinical applications.
    Keywords:  CaCO3-PDA-MnO2 nanoparticles; dual-gas nano-generator; immunotherapy; photothermal; ultrasound and laser
    DOI:  https://doi.org/10.3389/fbioe.2022.1005520
  72. Pharm Nanotechnol. 2022 Sep 28.
      Recent advances in electrospinning have transformed the process of fabricating ultrafine nano-fiber scaffolds with side benefits to drug delivery systems and delivery systems in general. The extremely thin quality of electrospun nanofiber scaffolds, along with an effective area of high specificity and a stereological porous structure, capacitates them for the delivery of biomolecules, genes, and drugs. Accordingly, the present study gives a close preface on certain approaches to incorporating drugs and biomolecules into an electrospun nanofiber scaffold, including blending, surface engineering and modification, coaxial electrospinning and emulsion-based systems. The study further elaborates certain biomedical applications of nanofibers as drug delivery systems, with case examples of Transdermal systems/ antibacterial agents/ wound dressing, cancer treatment, scaffolds for Growth Factor delivery and carriers for stem cells delivery systems.
    Keywords:  Drug Delivery System; Electrospinning; Electrospun Nanofibers; Growth Factor (GF); Stem Cell (SC); Wound Healing.
    DOI:  https://doi.org/10.2174/2211738510666220928161957
  73. J Food Biochem. 2022 Sep 28. e14426
      Alzheimer's disease (AD) is a neurological illness that causes memory loss over time. Currently, available pharmaceutical medicines and products are limited, and they have side effects at a higher price. Researchers and scientists have observed significant effects of nutraceuticals. Various preclinical and clinical studies were investigated for the Anti-Alzheimer's activity of nutraceuticals. The increasing ability of the pathogenesis of AD has led to the analysis of novel therapeutic targets, including the pathophysiological mechanisms and distinct cascades. So, current improvement will show the most adequate and prominent nutraceuticals and suggested concise mechanisms involving autophagy regulation, anti-inflammatory, antioxidant, mitochondrial homeostasis, and others. The effects of nutraceuticals cannot be ignored; it is important to investigate high-quality clinical trials. Given the potential of nutraceuticals to battle AD as multi-targeted therapies, it's vital to evaluate them as viable lead compounds for drug discovery and development. To the best of the authors 'knowledge, modification of blood-brain barrier permeability, bioavailability, and aspects of randomized clinical trials should be considered in prospective investigations. PRACTICAL APPLICATIONS: Advancements in molecular diagnostic and fundamentals have implemented particular usefulness for drug evaluation. An excess of experimental knowledge occurs regarding the effect of nutraceuticals on AD. There are various preclinical and clinical studies that have been done on nutraceuticals. In addition, various substitute inhibit and enhance some pathophysiological levels associated with AD. Nutraceuticals are easily available and have fewer side effects with cost-effective advantages. However, further investigations and clinical trials are required to encourage its effect on disease.
    Keywords:  Alzheimer's disease; flavonoid; nutraceuticals; oxidative stress; probiotics
    DOI:  https://doi.org/10.1111/jfbc.14426
  74. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Sep 25. e1854
      The second-generation taxane cabazitaxel has been clinically approved for the treatment of metastatic castration-resistant prostate cancer after docetaxel failure. Compared with the first-generation taxanes paclitaxel and docetaxel, cabazitaxel has potent anticancer activity and is less prone to drug resistance due to its lower affinity for the P-gp efflux pump. The relatively high hydrophobicity of cabazitaxel and the poor aqueous colloidal stability of the commercial formulation, following its preparation for injection, presents opportunities for new cabazitaxel formulations with improved features. This review provides an overview of cabazitaxel drug formulations and hydrophobic taxane drug delivery systems in general, and particularly focuses on emerging cabazitaxel delivery systems discovered in the past 5 years. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.
    Keywords:  cabazitaxel; drug delivery systems; liposomes; micelles; polymer
    DOI:  https://doi.org/10.1002/wnan.1854
  75. World J Stem Cells. 2022 Aug 26. 14(8): 587-598
      Medulloblastomas (MBs) are the most prevalent brain tumours in children. They are classified as grade IV, the highest in malignancy, with about 30% metastatic tumours at the time of diagnosis. Cancer stem cells (CSCs) are a small subset of tumour cells that can initiate and support tumour growth. In MB, CSCs contribute to tumour initiation, metastasis, and therapy resistance. Metabolic differences among the different MB groups have started to emerge. Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways, whereas Group 3 MBs upregulate glycolysis, gluconeogenesis, glutamine anabolism, and glut athione-mediated anti-oxidant pathways. Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically. In this review, we summarise the existing knowledge about metabolic rewiring in MB, with a particular focus on MB-CSCs. Finally, we highlight some of the emerging metabolism-based therapeutic strategies for MB.
    Keywords:  Cancer stem cells; Glycolysis; Lipids; Medulloblastoma; Metabolism; Stemness
    DOI:  https://doi.org/10.4252/wjsc.v14.i8.587
  76. Angew Chem Int Ed Engl. 2022 Sep 30.
      Photocatalytic micromotors that exhibit wireless and controllable motion by light have been extensively explored for cancer treatment by photodynamic therapy (PDT). However, overexpressed glutathione (GSH) in the tumor microenvironment can down-regulate the reactive oxygen species (ROS) level for cancer therapy. Herein, we present dendrite-shaped light-powered hematite microrobots as an effective GSH depletion agent for PDT of prostate cancer cells. These hematite microrobots can display negative phototactic motion under light irradiation and flexible actuation in a defined path controlled by an external magnetic field. Non-contact transportation of micro-sized cells can be achieved by manipulating the microrobot's motion. In addition, the biocompatible microrobots induce GSH depletion and greatly enhance PDT performance. The proposed dendrite-shaped hematite microrobots contribute to developing dual light/magnetic field-powered micromachines for the biomedical field.
    Keywords:  cells; micromachines; nanorobots
    DOI:  https://doi.org/10.1002/anie.202213505
  77. Sci Robot. 2022 Sep 28. 7(70): eade3311
      Ingestible devices have the potential to clear away barriers to oral delivery of biologics to improve drug bioavailability.
    DOI:  https://doi.org/10.1126/scirobotics.ade3311
  78. World J Gastroenterol. 2022 Jul 21. 28(27): 3314-3333
      The prevalence of nonalcoholic fatty liver disease (NAFLD) is rising worldwide, paralleling the epidemic of obesity. The liver is a key organ for the metabolism of proteins, fats and carbohydrates. Various types of fats and carbohydrates in isocaloric diets differently influence fat accumulation in the liver parenchyma. Therefore, nutrition can manage hepatic and cardiometabolic complications of NAFLD. Even moderately reduced caloric intake, which leads to a weight loss of 5%-10% of initial body weight, is effective in improving liver steatosis and surrogate markers of liver disease status. Among dietary patterns, the Mediterranean diet mostly prevents the onset of NAFLD. Furthermore, this diet is also the most recommended for the treatment of NAFLD patients. However, clinical trials based on the dietary interventions in NAFLD patients are sparse. Since there are only a few studies examining dietary interventions in clinically advanced stages of NAFLD, such as active and fibrotic steatohepatitis, the optimal diet for patients in these stages of the disease must still be determined. In this narrative review, we aimed to critically summarize the associations between different dietary patterns, obesity and prevention/risk for NAFLD, to describe specific dietary interventions' impacts on liver steatosis in adults with NAFLD and to provide an updated overview of dietary recommendations that clinicians potentially need to apply in their daily practice.
    Keywords:  Clinical guidance; Diet; Dietary patterns; Mediterranean diet; Nonalcoholic fatty liver disease; Nutrition; Obesity; Treatment
    DOI:  https://doi.org/10.3748/wjg.v28.i27.3314
  79. Hum Exp Toxicol. 2022 Jan-Dec;41:41 9603271221126487
      The present study was designed to investigate the antidiabetic effect of nerolidol on high-fat diet and streptozotocin-induced diabetic rats. Type 2 diabetes was induced in animals by feeding them a high-fat diet for 4 weeks and administering a single intraperitoneal dose of streptozotocin (35 mg/kg body weight). Diabetic rats were treated with nerolidol (25 mg/kg BW) for 28 days. Results showed that nerolidol treatment significantly reduced (p < 0.05) the level of elevated glucose, glycosylated hemoglobin and improved (p < 0.05) the body weight and insulin level. Nerolidol also considerably improved (p < 0.05) the carbohydrate metabolic enzyme activities and increased the glycogen storage in the liver of diabetic rats. Increased serum triglycerides, total cholesterol (C), low-density lipoproteins-C and very low-density lipoproteins-C levels were significantly lowered (p < 0.05), while reduction of serum high-density lipoprotein-C was alleviated after administration of nerolidol. In addition, nerolidol attenuated oxidative stress markers by significantly increasing (p < 0.05) the levels of superoxide dismutase, catalase, reduced glutathione, and lowering (p < 0.05) the level of thiobarbituric acid reactive substances, and lipid hydroperoxide. Similarly, nerolidol showed its pharmacological effects against hepatic markers via restoring (p < 0.05) the alleviated level of alanine transaminase, aspartate aminotransferase, and alkaline phosphatase. Finally, it improved insulin-dependent glucose transport in skeletal muscle by enhancing and activating glucose transporter protein-4. These findings confirmed the antidiabetic potential of nerolidol in type 2 diabetic rats. This may be related to a high antioxidant capacity, the restoration of plasma insulin and lipid levels, and the activation of insulin signaling in STZ/HFD-induced diabetic rats.
    Keywords:  Nerolidol; antidiabetic activity; glucose transporter protein-4; high fat diet; streptozotocin
    DOI:  https://doi.org/10.1177/09603271221126487
  80. Front Bioeng Biotechnol. 2022 ;10 991005
      Phase change materials (PCMs) are materials that are stimulated by the external enthalpy change (temperature) to realize solid-liquid and liquid-solid phase transformation. Due to temperature sensitivity, friendly modification, and low toxicity, PCMs have been widely used in smart drug delivery. More often than not, the drug was encapsulated in a solid PCMs matrix, a thermally responsive material. After the trigger implementation, PCMs change into a solid-liquid phase, and the loading drug is released accordingly. Therefore, PCMs can achieve precise release control with different temperature adjustments, which is especially important for small molecular drugs with severe side effects. The combination of drug therapy and hyperthermia through PCMs can achieve more accurate and effective treatment of tumor target areas. This study briefly summarizes the latest developments on PCMs as smart gate-keepers for anti-tumor applications in light of PCMs becoming a research hot spot in the nanomedicine sector in recent years.
    Keywords:  PCMs; controlled release; drug delivery; drug encapsulation; thermochemical therapy
    DOI:  https://doi.org/10.3389/fbioe.2022.991005
  81. Front Pharmacol. 2022 ;13 974054
      Bolbostemma paniculatum (Maxim.) Franquet is a unique species in China with a long history of medicinal use, which has the effects of detoxifying, dissolving lumps and dispersing swellings. And it is commonly used to treat many diseases, such as carbuncle and sore, acute mastitis, mammary cancer, scrofula and subcutaneous nodule traditionally. Modern clinical studies have found that B. paniculatum and its compounds can be used for the treatment of a variety of cancers, mastitis, hyperplasia of mammary glands, chronic lymphadenitis, cervical lymph tuberculosis and surgical wart skin diseases, and the curative effect is positive. At present, a variety of Chinese patent medicines containing B. paniculatum have been exploited and marketed in China for the treatment of cancers, breast diseases and flat warts. This review article comprehensively discussed the traditional application, botany, chemical components, pharmacological activities, and quality control of B. paniculatum, put forward some noteworthy issues and suggestions in current studies, and briefly discussed the possible development potential of this plant as well as future research perspectives. 96 compounds have been isolated from B. paniculatum, including triterpenoids, sterols, alkaloids and other components, of which triterpenoid saponins are the main bioactive components. The crude extracts and monomer compounds of B. paniculatum have a wide range of pharmacological activities, such as anti-tumor, antiviral, anti-inflammatory, immunoregulatory, and so on. Moreover, its anti-tumor mechanism involves many aspects, including inhibiting cell proliferation, promoting cell apoptosis, blocking the cell cycle, interfering with cell invasion and metastasis, suppressing angiogenesis, and regulating autophagy. While there is a lack of systematic and in-depth research on its anti-tumor active components and mechanism of action at the moment; and a tight connection between the chemical composition and pharmacological activity of B. paniculatum has also not been established. Besides, a systematic quality determination standard for B. paniculatum should also be built, in order to carry out further research.
    Keywords:  Bolbostemma paniculatum (Maxim.) Franquet; botany; chemical components; pharmacological activities; quality control; traditional application
    DOI:  https://doi.org/10.3389/fphar.2022.974054
  82. Int J Pharm. 2022 Sep 22. pii: S0378-5173(22)00781-5. [Epub ahead of print] 122227
      The objective of this study was to develop and evaluate an effective topical formulation to promote corneal epithelial wound healing. Ascorbyl glucoside (AA-2G), a stable prodrug of AA, was formulated in solid in oil (S/O) nanodispersions by emulsifying AA-2G solutions in cyclohexane using Span 85 as an emulsifying agent and freeze-drying emulsions to produce AA-2G - surfactant complex. The complexes were then dispersed in castor oil to produce S/O nanodispersions which were evaluated in terms of their particle size, polydispersity index, encapsulation efficiency, morphology, physical stability as well as the transcorneal permeation and accumulation of AA-2G. The same preparation procedure was used to prepare S/O nanodispersions of AA. S/O nanodispersions of AA and AA-2G were formulated into oily drops that were tested for efficacy in promoting wound healing after corneal epithelial depredation. AA-2G was loaded efficiently in S/O nanodispersions (EE >99%) in the form of spherical nanoparticles. S/O nanodispersions were physically stable and resulted in improved permeation (18x) and accumulation (7x) of AA-2G in transcorneal diffusion experiments in comparison to AA-2G solutions. Oily eye drops of AA-2G and AA showed no irritation and significant improvement in epithelial healing in vivo in comparison to AA-2G and AA solutions.
    Keywords:  Ascorbyl glucoside; Corneal epithelial debridement; Ophthalmic drug delivery; Solid in Oil Nanodispersions; Vitamin C; hydrophobic nanoparticles
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122227
  83. J Pharm Pharmacol. 2022 Sep 30. pii: rgac050. [Epub ahead of print]
       OBJECTIVES: Crataegus pinnatifida (C. pinnatifida), including C. pinnatifida Bge. and its variant C. pinnatifida Bge. var. major N, E. Br., has traditionally been used as a homologous plant for traditional medicine and food in ethnic medical systems in China. Crataegus pinnatifida, especially its fruit, has been used for more than 2000 years to treat indigestion, stagnation of meat, hyperlipidemia, blood stasis, heart tingling, sores, etc. This review aimed to provide a systematic summary on the botany, traditional uses, phytochemistry, pharmacology and clinical applications of C. pinnatifida.
    KEY FINDINGS: This plant contains flavonoids, phenylpropanoids, terpenoids, organic acids, saccharides and essential oils. Experimental studies showed that it has hypolipidemic, antimyocardial, anti-ischemia, antithrombotic, anti-atherosclerotic, anti-inflammatory, antineoplastic neuroprotective activity, etc. Importantly, it has good effects in treating diseases of the digestive system and cardiovascular and cerebrovascular systems.
    SUMMARY: There is convincing evidence from both in vitro and in vivo studies supporting the traditional uses of C. pinnatifida. However, multitarget network pharmacology and molecular docking technology should be used to study the interaction between the active ingredients and targets of C. pinnatifida. Furthermore, exploring the synergy of C. pinnatifida with other Chinese medicines to provide new understanding of complex diseases may be a promising strategy.
    Keywords:   Crataegus pinnatifida ; Chinese hawthorn; pharmacology; phytochemistry; traditional uses
    DOI:  https://doi.org/10.1093/jpp/rgac050
  84. Food Funct. 2022 Sep 26.
      Extensive phase II metabolic reactions (i.e., glucuronidation and sulfation) have resulted in low bioavailability and decreased biological effects of curcumin and quercetin. Compared to glucuronidation, information on the sulfation disposition of curcumin and quercetin is limited. In this study, we identified that BCRP and MRP4 played a critical role in the cellular excretion of curcumin-O-sulfate (C-O-S) and quercetin-O-sulfate (Q-O-S) by integrating chemical inhibition with transporter knock-down experiments. Inhibited excretion of sulfate (C-O-S and Q-O-S) caused significant reductions in cellular O-sulfation of curcumin (a maximal 74.4% reduction) and quercetin (a maximal 76.9% reduction), revealing a strong interplay of sulfation with efflux transport. It was further identified that arylsulfatase B (ARSB) played a crucial role in the regulation of cellular O-sulfation by transporters. ARSB overexpression significantly enhanced the reduction effect of MK-571 on the cellular O-sulfation (fmet) of the model compound (38.8% reduction for curcumin and 44.2% reduction for quercetin). On the contrary, ARSB knockdown could reverse the effect of MK-571 on the O-sulfation disposition of the model compound (29.7% increase for curcumin and 47.3% increase for quercetin). Taken together, ARSB has been proven to be involved in cellular O-sulfation, accounting for transporter-dependent O-sulfation of curcumin and quercetin. A better understanding of the interplay beneath metabolism and transport will contribute to the exact prediction of in vivo drug disposition and drug-drug interactions.
    DOI:  https://doi.org/10.1039/d2fo01436j
  85. Cell Oncol (Dordr). 2022 Sep 26.
       PURPOSE: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. As yet, chemotherapy with drugs such as doxorubicin is the main treatment strategy. However, drug resistance and dose-dependent toxicities restrict their clinical use. Natural products are major sources of anti-tumor drugs. OSW-1 is a natural compound with strong anti-cancer effects in several types of cancer, but its effects on the efficacy of chemotherapy in TNBC and its underlying mechanism remain unclear.
    METHODS: The inhibitory activities of OSW-1 and its combination with several chemotherapy drugs were tested using in vitro assays and in vivo subcutaneous and metastatic mouse TNBC models. The effects of the mono- and combination treatments on TNBC cell viability, apoptosis, autophagy and related signaling pathways were assessed using MTT, flow cytometry, RNA sequencing and immunology-based assays. In addition, the in vivo inhibitory effects of OSW-1 and (combined) chemotherapies were evaluated in subcutaneous and metastatic mouse tumor models.
    RESULTS: We found that OSW-1 induces Ca2+-dependent mitochondria-dependent intrinsic apoptosis and cyto-protective autophagy through the PI3K-Akt-mTOR pathway in TNBC cells in vitro. We also found that OSW-1 and doxorubicin exhibited strong synergistic anti-TNBC capabilities both in vivo and in vitro. Combination treatment strongly inhibited spontaneous and experimental lung metastases in 4T1 mouse models. In addition, the combination strategy of OSW-1 + Carboplatin + Docetaxel showed an excellent anti-metastatic effect in vivo.
    CONCLUSIONS: Our data revealed the mode of action and molecular mechanism underlying the effect of OSW-1 against TNBC, and provided a useful guidance for improving the sensitivity of TNBC cells to conventional chemotherapeutic drugs, which warrants further investigation.
    Keywords:  Chemotherapy; Combination therapy; OSW-1; PI3K-Akt-mTOR pathway; Triple negative breast cancer (TNBC)
    DOI:  https://doi.org/10.1007/s13402-022-00716-2
  86. Front Bioeng Biotechnol. 2022 ;10 1010724
      Immunotherapy has demonstrated great clinical success in the field of oncology in comparison with conventional cancer therapy. However, cancer immunotherapy still encounters major challenges that limit its efficacy against different types of cancers and the patients show minimal immune response to the immunotherapy. To overcome these limitations, combinatorial approaches with other therapeutics have been applied in the clinic. Simultaneously, nano-drug delivery system has played an important role in increasing the antitumor efficacy of various treatments and has been increasingly utilized for synergistic immunotherapy to further enhance the immunogenicity of the tumors. Specifically, they can promote the infiltration of immune cells within the tumors and create an environment that is more sensitive to immunotherapy, particularly in solid tumors, by accelerating tumor accumulation and permeability. Herein, this progress report provides a brief overview of the development of nano-drug delivery systems, classification of combinatory cancer immunotherapy and recent progress in tumor immune synergistic therapy in the application of nano-drug delivery systems.
    Keywords:  cancer therapy; immunotherapy; nano-drug delivery systems; nanomedicine; synergistic treatment
    DOI:  https://doi.org/10.3389/fbioe.2022.1010724
  87. Eur J Med Res. 2022 Sep 26. 27(1): 186
       BACKGROUND: Recently, the coronavirus (COVID-19) pandemic is a chief public health disaster caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are no established effective preventive or therapeutic anti-COVID-19 drugs available except for some recently approved vaccines. Still, countless recent studies recommend various alternative and complementary approaches against COVID-19, which are medicinal herbs employed as traditional remedies to enhance immunity to struggle with viral infections. In addition, physicians worldwide are highly interested in vitamin and mineral supplements to help them combat COVID-19 either through protection or treatment. Dietary supplements specifically vitamin D, vitamin C, and zinc provide good prophylactic and therapeutic support to the presently available treatment regimens. In the present work, we have focused on plant-based remedies with promising anti-COVID-19 activities.
    AIM: To enable investigators and researchers to identify potential herbal compounds with anti-COVID activity to be used as promising therapies to combat this pandemic.
    MAIN BODY: This review highlights the recently published studies concerning natural traditional herbs, herbal bioactive metabolites, dietary supplements, and functional foods that could help prevent and/or treat COVID-19. Herein, we explored medicinal herbs as potential inhibitors of SARS-CoV-2 and discussed how these studies help form larger discussions of diet and disease. Moreover, by investigating the herbal bioactive components, we have outlined several medicinal herbs that can fight against COVID-19 by hindering SARS-CoV-2 replication and entry to its host cells, deterring the cytokine storm, and several other means. Finally, we have summarized various herbal products, functional foods, and dietary supplements with potent bioactive compounds which can inhibit and/or prevent COVID-19 disease progression.
    CONCLUSIONS: Based on the studies reviewed in this work, it was concluded with no doubt that phytochemical components present in various herbs could have a starring role in the deterrence and cure of coronavirus contagion.
    Keywords:  Bioactive metabolites; COVID-19; Functional foods; Nutraceuticals; Phytochemicals; Traditional Chinese medicine
    DOI:  https://doi.org/10.1186/s40001-022-00818-5
  88. Pharm Dev Technol. 2022 Sep 28. 1-53
      The effectiveness of cisplatin in cancer treatment renders its use vital to clinicians. However, the accompanying side effects as cachexia, emesis and liver damage necessitate the use of a dietary supplement which is capable of hindering such undesirable complications. The branched chain amino acids as well as glutamine and arginine have been proven to be effective nutritional co-adjuvant therapeutic agents. Furthermore, new pharmaceutical approaches encompass designing organ-targeted nanoformulations to increase the medicinal efficacy. Therefore, the aim of the present study was to investigate the beneficial effects of liver-targeted amino acids-loaded nanoliposomes in counteracting the adverse hematopoietic and hepatic complications associated with cisplatin. Results revealed the use of the combination of two nanoliposomal formulations (one loading leucine + isolecuine + valine, and the other loading glutamine and arginine) given orally at a dose of 200 mg/kg for twelve days was effective against cisplatin-induced toxicities represented by improvement in the complete blood picture parameters, decrease in the serum hepatic enzymes levels, amelioration of the hepatic oxidative stress and cellular energy imbalance along with reduction in the histopathological abnormalities. It can be concluded that amino acids loaded nanoliposomes could be considered a new strategy in preventing cisplatin's adverse effects.
    Keywords:  Cisplatin; amino acids; liposomes; liver damage; nanoparticles
    DOI:  https://doi.org/10.1080/10837450.2022.2129687
  89. World J Clin Oncol. 2022 Jul 24. 13(7): 553-566
      Cancer is a leading cause of death worldwide. Nowadays, the therapies are inadequate and spur demand for improved technologies. Rapid growth in nanotechnology and novel nanomedicine products represents an opportunity to achieve sophisticated targeting strategies and multi-functionality. Nanomedicine is increasingly used to develop new cancer diagnosis and treatment methods since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity. Cancer nanotechnology and cancer immunotherapy are two parallel themes that have emerged over the last few decades while searching for a cure for cancer. Immunotherapy is revolutionizing cancer treatment, as it can achieve unprecedented responses in advanced-stage patients, including complete cures and long-term survival. A deeper understanding of the human immune system allows the establishment of combination regimens in which immunotherapy is combined with other treatment modalities (as in the case of the nanodrug Ferumoxytol). Furthermore, the combination of gene therapy approaches with nanotechnology that aims to silence or express cancer-relevant genes via one-time treatment is gradually progressing from bench to bedside. The most common example includes lipid-based nanoparticles that target VEGF-Α and KRAS pathways. This review focuses on nanoparticle-based platforms utilized in recent advances aiming to increase the efficacy of currently available cancer therapies. The insights provided and the evidence obtained in this paper indicate a bright future ahead for immuno-oncology applications of engineering nanomedicines.
    Keywords:  Cancer; Cell therapy; Gene; Immunotherapy; Nanomedicine
    DOI:  https://doi.org/10.5306/wjco.v13.i7.553
  90. J Immunother Cancer. 2022 Sep;pii: e002976. [Epub ahead of print]10(9):
      Despite accumulating evidence that supports the beneficial effects of physical exercise in inhibiting cancer progression, whether exercise modulates its effects through systemic and cellular changes in iron metabolism and immune-tumor crosstalk is unknown. Cancer cells have greater metabolic requirements than normal cells, with their survival and proliferation depending largely on iron bioavailability. Although iron is an essential mineral for mitogenesis, it also participates in a form of iron-dependent programmed cell death termed ferroptosis. In this short hypothesis paper, we speculate that modulating iron bioavailability, transport and metabolism with regular exercise can have significant implications for tumor and stromal cells in the tumor microenvironment, by affecting multiple tumor-autonomous and stromal cell responses.
    Keywords:  Cytokines; Macrophages; Metabolic Networks and Pathways; Tumor Biomarkers; Tumor Microenvironment
    DOI:  https://doi.org/10.1136/jitc-2021-002976
  91. J Ethnopharmacol. 2022 Sep 23. pii: S0378-8741(22)00784-X. [Epub ahead of print] 115745
       ETHNOPHARMACOLOGICAL RELEVANCE: Anadenanthera colubrina (Vell.) Brenan is an endemic tree to South America and different parts of it are used by the population for the treatment of various diseases, as well as in indigenous rituals. This species has high pharmacological potential but may present toxic potential due to the presence of psychotropic compounds.
    AIM OF THE STUDY: To review published studies with the species A. colubrina regarding ethnobotanical, phytochemical, pharmacological and toxicological aspects, as well as discuss perspectives for new research and protection of this species.
    MATERIALS AND METHODS: A literature review was performed by accessing published articles on databases such as: PubMed, ScienceDirect, Scielo, Scopus, Taylor and Francis online, Springer Link, National Center for Biotechnology Information (NCBI), ACS Publications, Chemspider and Google Scholar. The keywords used were: "Anadenanthera colubrina" or "Mimosa colubrina" or "Piptadenia colubrina" or "Piptadenia macrocarpa" or "Piptadenia grata" or "Anadenanthera macrocarpa" and "medicinal plants" or "pharmacological" or "phytochemicals" or "traditional use" or "toxicological" or "ethnobotanical" or "pre-clinical trial" or "clinical". Articles found by database searches and search engines were screened at four stages: (i) title screening, (ii) locality screening, (iii) abstract screening, and (iv) full text. Other articles found through supplementary searches were screened in the full text whenever available. Each article was assessed by three reviewers at the title and abstract screening stages, except for those found in Portuguese databases that were assessed by the native reviewer.
    RESULTS: This robust tree has been popularly useful for agroeconomic, medicinal and as a hallucinogen in religious rituals. According to the published studies, the main parts of the plant are the bark and seeds that are mostly used for respiratory conditions and as entheogens, respectively. It is a rich traditional herbal medicine with many pharmacological properties such as anti-inflammatory, antinociceptive, antidiarrheal, wound healing, antimicrobial, antitumoral, antioxidant, antiaddictive, insecticide and allelopathic that were described in in vitro and in vivo assays, and approximately 56 compounds were identified, suggesting a therapeutic potential for this species. Although most relate to medicinal uses, these are preliminaries and do not show the mechanism of action. The phytochemical assays showed the presence of phenolic compounds, flavonoids, triterpenes, steroids and alkaloids. Some of the compounds are anadanthoflavone, which is exclusive to this species, and no pharmacological or toxicological studies have yet demonstrated this compound. Another important compound is bufotenine which was isolated from seeds and is related to hallucinogenic and antiviral activity. The extracts made from leaves, bark, gum, and fruits appear to be safe, according to both in vivo and in vitro toxicology testing, which all shown low toxicity. Due to the presence of bufotenine in the seeds, it can be toxic, however, it was not found in toxicological assays with the seed extracts.
    CONCLUSIONS: Therefore, part of the studies confirms the popular use of A. colubrina, however, more assays with isolated compounds and with the different extracts are necessary to corroborate other uses and the mechanism of action of their pharmacological effects needs to discuss in more detail. Therefore, the present review would be identified the gaps and suggests further studies oriented to validate the popular use. Thus, it must be noted that the use of this species must be controlled in order to minimize the environmental impact, as most of the pharmacological potential was shown with the bark and seeds. Due to its wide use in folk medicine, it is part of the Brazilian medicinal species with priority for conservation.
    Keywords:  Fabaceae; Medicinal plants; Pharmacology; Phytochemistry
    DOI:  https://doi.org/10.1016/j.jep.2022.115745
  92. Curr Opin Gastroenterol. 2022 Sep 21.
       PURPOSE OF REVIEW: Several recent studies have corroborated a strong association between diet and gastric cancer risk; investigators have also identified dietary factors that protect against gastric cancer. This review summarizes the literature on this topic and guides future research directions.
    RECENT FINDINGS: High-salt intake disrupts the gastric mucosal defense barrier, promoting Helicobacter pylori colonization and penetration of other carcinogenic compounds. Processed foods, processed meats, red meat, alcohol, foods with high dietary fat, and dietary cholesterol increase the risk of gastric carcinogenesis. On the other hand, increased consumption of fruits, vegetables, whole grains, nuts, and a low-salt diet may offer a protective effect.
    SUMMARY: Despite decreases in gastric cancer incidence because of increased identification and treatment of H. pylori, gastric cancer remains one of the most common cancers worldwide with a high mortality rate. This disturbing statistic highlights the importance of reducing and eliminating other risk factors for gastric cancer. There is a strong body of evidence that alcohol, processed foods, high salt intake, high fat intake, and foods with animal products (meats, eggs, and dairy) increase the risk of gastric cancer. A diet that is high in whole grains, fruits, vegetables, nuts and is low in salt may reduce the risk of gastric cancer.
    DOI:  https://doi.org/10.1097/MOG.0000000000000875
  93. Nat Med. 2022 Sep 26.
      
    Keywords:  Breast cancer; Cancer therapy; Genomics; Targeted therapies
    DOI:  https://doi.org/10.1038/d41591-022-00097-x
  94. Bioeng Transl Med. 2022 Sep;7(3): e10311
      Photocleavable prodrugs enable controllable drug delivery to target sites modulated by light irradiation. However, the in vivo utility is usually hindered by their insolubility and inefficient delivery. In this study, we report a simple strategy of co-assembling boron-dipyrromethene-chlorambucil prodrug and near-infrared dye IR783 to fabricate photoresponsive nanoassemblies, which achieved both high prodrug loading capacity (~99%) and efficient light-triggered prodrug activation. The incorporated IR783 dye not only stabilized the nanoparticles and contributed tumor targeting as usual, but also exhibited degradation after light irradiation and in-situ monitoring of nanoparticle dissociation by fluorescent imaging. Systemic administration of the nanoparticles and localized light irradiation at tumor sites enabled monitorable and efficient drug release in vivo. Our results demonstrate that such prodrug-dye co-assembled nanomedicine is a promising formulation for photoresponsive drug delivery, which would advance the translation of photoresponsive nanomedicines.
    Keywords:  IR783 dye; drug delivery; in‐situ monitoring; nanomedicine; photocleavable prodrug; photopharmacology; self‐assembly
    DOI:  https://doi.org/10.1002/btm2.10311
  95. Cell Rep. 2022 Sep 27. pii: S2211-1247(22)01256-6. [Epub ahead of print]40(13): 111415
      Sphingolipids play important signaling and structural roles in cells. Here, we find that during de novo sphingolipid biosynthesis, a toxic metabolite is formed with critical implications for cancer cell survival. The enzyme catalyzing the first step in this pathway, serine palmitoyltransferase complex (SPT), is upregulated in breast and other cancers. SPT is dispensable for cancer cell proliferation, as sphingolipids can be salvaged from the environment. However, SPT activity introduces a liability as its product, 3-ketodihydrosphingosine (3KDS), is toxic and requires clearance via the downstream enzyme 3-ketodihydrosphingosine reductase (KDSR). In cancer cells, but not normal cells, targeting KDSR induces toxic 3KDS accumulation leading to endoplasmic reticulum (ER) dysfunction and loss of proteostasis. Furthermore, the antitumor effect of KDSR disruption can be enhanced by increasing metabolic input (via high-fat diet) to allow greater 3KDS production. Thus, de novo sphingolipid biosynthesis entails a detoxification requirement in cancer cells that can be therapeutically exploited.
    Keywords:  CP: Cancer; CP: Metabolism; cancer metabolism; cancer therapy; endoplasmic reticulum; ketodihydrosphingosine reductase; serine palmitoyltransferase
    DOI:  https://doi.org/10.1016/j.celrep.2022.111415
  96. Chin Med. 2022 Sep 29. 17(1): 114
       BACKGROUND: A biennial or perennial plant of the Apiaceae family, Eryngium caeruleum M. Bieb. is traditionally used in medicine as an antitoxic, diuretic, digestive, anti-inflammatory and analgesic drug. This plant is widely distributed in temperate regions around the world. Young leaves of the plant are used in cooking as aromatic cooked vegetables in various local products in Iran.
    PURPOSE: The current review aimed to highlight complete and updated information about the Eryngium caeruleum species, regarding botanical, ethnopharmacological, phytochemical data, pharmacological mechanisms as well as some nutritional properties. All this scientific evidence supports the use of this species in complementary medicine, thus opening new therapeutic perspectives for the treatment of some diseases.
    METHODS: The information provided in this updated review is collected from several scientific databases such as PubMed/Medline, ScienceDirect, Mendeley, Scopus, Web of Science and Google Scholar. Ethnopharmacology books and various professional websites were also researched.
    RESULTS: The phytochemical composition of the aerial parts and roots of E. caeruleum is represented by the components of essential oil (EO), phenolic compounds, saponins, protein, amino acids, fiber, carbohydrates, and mineral elements. The antioxidant, antimicrobial, antidiabetic, antihypoxic, and anti-inflammatory properties of E. caeruleum have been confirmed by pharmacological experiments with extracts using in vitro and in vivo methods. The syrup E. caeruleum relieved dysmenorrhea as effectively as Ibuprofen in the blinded, randomized, placebo-controlled clinical study.
    CONCLUSION: Current evidence from experimental pharmacological studies has shown that the different bioactive compounds present in the species E. caeruleum have multiple beneficial effects on human health, being potentially active in the treatment of many diseases. Thus, the traditional uses of this species are supported based on evidence. In future, translational and human clinical studies are necessary to establish effective therapeutic doses in humans.
    Keywords:  Bioactive molecules; Eryngium caeruleum; Ethnobotany; Pharmacological activities
    DOI:  https://doi.org/10.1186/s13020-022-00672-x
  97. Biomaterials. 2022 Sep 17. pii: S0142-9612(22)00453-7. [Epub ahead of print]289 121813
      Cancer cells and their stromal microenvironment are mutually supportive. Either destroying cancer cells or damaging stromal components cannot guarantee a satisfactory outcome in the long-term treatment. Herein, we showed that the tumor-stroma crosstalk was disturbed by nanoparticle-based photodynamic therapy (PDT) in pancreatic tumor models, leading to the persistent inhibition of extracellular matrix (ECM) secretion and the enhanced therapeutic effect. By employing a conditioned medium method, we found that the nanoparticulate PDT at a sub-lethal dosage down-regulated TGFβ signaling pathways, leading to the decrease in drug resistance, proliferation, and migration of the cancer cells. Meanwhile, pancreatic stellate cells (PSCs) were inactivated by PDT, hindering the secretion of ECM. Combining the results that PDT indiscriminately killed PSCs and cancer cells, we showed that the mutual support between the cancer cells and the stroma was interrupted. We further presented the inhibition of the crosstalk persistently enhanced tumor penetration in stroma-rich pancreatic tumor models. The loosened stroma not only facilitated tumor eradication by subsequent therapy but also improved the efficiency of gemcitabine treatment on monthly later recurrent tumors. Therefore, our work may boost the potential of PDT to be a valuable individual or adjuvant treatment for desmoplastic cancers.
    Keywords:  Anti-stroma therapy; Intratumor penetration; Photodynamic therapy; Tumor-stroma crosstalk
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121813
  98. Sci Rep. 2022 Sep 28. 12(1): 16165
      This study investigated for the first time a simple bio-synthesis approach for the synthesis of copper oxide nanoparticles (CuO NPs) using Annona muricata L (A. muricata) plant extract to test their anti-cancer effects. The presence of CuONPs was confirmed by UV-visible spectroscopy, Scanning electron microscope (SEM), and Transmission electron microscope (TEM). The antiproliferative properties of the synthesized nanoparticles were evaluated against (AMJ-13), (MCF-7) breast cancer cell lines, and the human breast epithelial cell line (HBL-100) as healthy cells. This study indicates that CuONPs reduced cell proliferation for AMJ-13 and MCF-7. HBL-100 cells were not significantly inhibited for several concentration levels or test periods. The outcomes suggest that the prepared copper oxide nanoparticles acted against the growth of specific cell lines observed in breast cancer. It was observed that cancer cells had minor colony creation after 24 h sustained CuONPs exposure using (IC50) concentration for AMJ-13 was (17.04 µg mL-1). While for MCF-7 cells was (18.92 µg mL-1). It indicates the uptake of CuONPs by cancer cells, triggering apoptosis. Moreover, treatment with CuONPs enhanced Lactate dehydrogenase (LDH) production, probably caused by cell membrane damage, creating leaks comprising cellular substances like lactate dehydrogenase. Hence, research results suggested that the synthesized CuONPs precipitated anti-proliferative effects by triggering cell death through apoptosis.
    DOI:  https://doi.org/10.1038/s41598-022-20360-y
  99. Food Chem. 2022 Aug 10. pii: S0308-8146(22)01884-2. [Epub ahead of print]402 133922
      In vitro experiments showed that i) phytates, tannins and saponins from pulses can alter vitamin D and K bioavailability and ii) meat decreased vitamin D bioaccessibility by impairing its stability during digestion. We aimed to confirm these results in vivo by force-feeding mice with emulsions containing either potatoes or semolina or chickpeas or meat. Vitamin D and K plasma responses decreased after a gavage with chickpeas or meat compared with potatoes (-62 % and -67 %, respectively for vitamin D, -40 % and -64 %, respectively for vitamin K; p < 0.05). Vitamin D and K intestinal contents were also reduced in mice force-fed with chickpeas or meat compared with potatoes (from -64 to -83 % and from -76 to -84 %, respectively for vitamin D and from -7 to -59 % and from -7 to -90 %, respectively for vitamin K; p < 0.05). The results confirm that chickpea and meat compounds can decrease vitamin D and K bioavailability.
    Keywords:  Beef; Bioavailability; Cereals; Chickpeas; Vitamin D; Vitamin K
    DOI:  https://doi.org/10.1016/j.foodchem.2022.133922
  100. World J Gastroenterol. 2022 Jul 21. 28(27): 3370-3382
      Colorectal cancer (CRC) is a leading cause of human mortality worldwide. As conventional anticancer therapy not always being effective, there is growing interest in innovative "drug-free" cancer treatments or interventions that improve the efficacy of established therapy. CRC is associated with microbiome alterations, a process known as dysbiosis that involves depletion and/or enrichment of particular gut bacterial species and their metabolic functions. Supplementing patient treatment with traditional probiotics (with or without prebiotics), next-generation probiotics (NGP), or postbiotics represents a potentially effective and accessible complementary anticancer strategy by restoring gut microbiota composition and/or by signaling to the host. In this capacity, restoration of the gut microbiota in cancer patients can stabilize and enhance intestinal barrier function, as well as promote anticarcinogenic, anti-inflammatory, antimutagenic or other biologically important biochemical pathways that show high specificity towards tumor cells. Potential benefits of traditional probiotics, NGP, and postbiotics include modulating gut microbiota composition and function, as well as the host inflammatory response. Their application in CRC prevention is highlighted in this review, where we consider supportive in vitro, animal, and clinical studies. Based on emerging research, NGP and postbiotics hold promise in establishing innovative treatments for CRC by conferring physiological functions via the production of dominant natural products and metabolites that provide new host-microbiota signals to combat CRC. Although favorable results have been reported, further investigations focusing on strain and dose specificity are required to ensure the efficacy and safety of traditional probiotics, NGP, and postbiotics in CRC prevention and treatment.
    Keywords:  Colorectal cancer; Gut microbiota; Next-generation probiotics; Postbiotics; Traditional probiotics
    DOI:  https://doi.org/10.3748/wjg.v28.i27.3370
  101. Biomaterials. 2022 Sep 15. pii: S0142-9612(22)00446-X. [Epub ahead of print]289 121806
      A carrier-free prodrug nanoparticle has emerged as a potential approach to cancer therapy. It plays a vital role in enhancing the tumor targeting and therapeutic efficacy of the anticancer agent at sites of intention wherein the prodrug nanoparticle is potentially activated. Herein, five derivatives of cathepsin B-cleavable prodrugs are synthesized via chemically conjugating different cathepsin B-cleavable peptides (Phe-Arg-Arg-Gly, Phe-Arg-Arg-Leu, Phe-Arg-Arg-Leu-Gly, Phe-Leu-Arg-Arg-Gly) to doxorubicin (DOX). The peptide-DOX prodrugs can spontaneously assemble into nanoparticles via their intermolecular hydrophobic and π-π stacking interactions. The resulting cathepsin B-cleavable prodrugs nanoparticles formed different nanoparticle structures according to the amphiphilicity and flexibility of different peptides and their particle stability and cellular uptake mechanism are carefully evaluated in vitro. Among five prodrug nanoparticles, the Phe-Arg-Arg-Leu-DOX (FRRL-DOX) nanoparticle was formed to a size of 167.5 ± 12.4 nm and stably maintains its nanoparticle structure in saline media for 3 days. The FRRL-DOX nanoparticle is well taken up by tumoral nuclei and effectively induces cancer cell death with minimal toxicity to normal cells. In addition, the FRRL-DOX nanoparticle shows 2.3-16.3-fold greater tumor-specific accumulation in vivo than other prodrug nanoparticles and free DOX. The therapeutic effect of FRRL-DOX is finally examined, demonstrating 2.1-fold better anticancer efficacy compared to that of free DOX. Notably, the FRRL-DOX nanoparticle does not exert serious toxicity in its repeated intravenous administration at a high dose of up to 10 mg/kg (equiv. to DOX). In conclusion, the peptide sequence for cathepsin B-cleavable prodrug nanoparticle is determined to be successfully optimized in a way of increasing its tumor selectivity and lowering toxicity to normal tissues.
    Keywords:  Cancer-targeting therapy; Carrier-free nanoparticle; Cathepsin B-sensitive linker; Nanomedicine; Prodrug
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121806
  102. J Cosmet Dermatol. 2022 Sep 26.
       BACKGROUND: In recent years the demands of depigmenting agents in cosmetics have been increase to treat skin conditions like hyperpigmentation and melasma. Tyrosinase is a major enzyme involve in hyperpigmentation. Kojic acid dipalimate (KAD) is an ester derivative of kojic acid and exhibit excellent tyrosinase inhibiting activity on human skin.
    OBJECTIVE: To develop and characterize a novel topical delivery system for KAD by using ethosomes and their in-vitro, in-vivo characterization for treatment of hyperpigmentation.
    METHODS: Different KAD loaded ethosomal suspensions were prepared using soy phosphatidylcholine, ethanol, propylene glycol and water with cold method. These formulations were evaluated for size, zeta potential, Polydispersity index, entrapment efficiency, FTIR spectroscopy and scanning electron microscopy (SEM). Afterwards the stability of optimized gel was checked and the in-vivo studies were carried out in order to evaluate the skin benefits.
    RESULTS: The optimized formulation has zeta potential, size and entrapment efficiency of -23.4mV, 148nm and 90.0008% respectively. SEM results showed vesicles were spherical in shape. Ethosomal gel had a good stability at lower temperature (8°C, 25°C). In addition, ethosomal gel gives significant decrease in skin melanin, erythema, and sebum level while it causes improvement in skin hydration level and elasticity during non-invasive in-vivo studies.
    CONCLUSION: The overall findings indicated that the prepared KAD loaded ethosomal formulation was stable and provides deep penetration of KAD into the skin. It offers a promising therapeutic approach for use in skin hyperpigmentation as it has skin whitening and moisturizing effects.
    Keywords:  Ehosomes; Kojic acid dipalmitate; Melanin; entrapment efficiency; hyperpigmentation
    DOI:  https://doi.org/10.1111/jocd.15408
  103. Phytomedicine. 2022 Sep 15. pii: S0944-7113(22)00545-1. [Epub ahead of print]107 154456
       BACKGROUND: Eugenol (1-allyl-4-hydroxy-3-methoxybenzene) is an important simple phenolic compound mainly derived from Syzygium aromaticum and many other plants. It is traditionally used in ayurveda and aromatherapy for the healing of many health problems. It also has significant applications in dentistry, agriculture, and flavour industry. This simple phenol has an eclectic range of pharmacological properties, such as antioxidant, anti-inflammatory, and anticancer activities. It is regarded as safe by the Food and Agricultural Organization of the United Nations due to its non-carcinogenic and non-mutagenic properties.
    PURPOSE: The aim of this comprehensive review is to present a critical and systematic assessment of the antitumor ability of eugenol and its associated molecular targets in various cancers.
    METHODS: It was carried out following the preferred reporting items for systematic reviews and meta-analysis guidelines. Risk of bias assessment was performed using the SYstematic review centre for laboratory animal experimentation guidelines. The literature search was performed in standard databases such as Science Direct, PubMed, Google Scholar, Scopus, and Web of Science using the keywords 'eugenol' or 'eugenol essential oil' and 'anti-cancer properties of eugenol'.
    RESULTS: The scientific information from fifty-three studies was encompassed in the present review work. Eugenol exhibits significant anticancer effects in a variety of biological pathways, namely apoptosis, autophagy, cell cycle progression, inflammation, invasion, and metastasis. Eugenol-induced apoptosis has been noticed in osteosarcoma, skin tumors, melanoma, leukemia, gastric and mast cells. It decreases the expression of cyclin D1, cyclin B, proliferating cell nuclear antigen, nuclear factor-ƙB, inhibitor of nuclear factor ƙB, and B-cell lymphoma-2. Eugenol increases the expression of B-cell lymphoma-2 (BCL-2) associated X, BH3-interacting domain death agonist, BCL-2 associated agonist of cell death, apoptotic protease activating factor 1, cytochrome c, p21, and p53.
    CONCLUSION: The anticancer potential exhibited by eugenol is mainly attributed to its anti-metastatic, anti-proliferative, anti-angiogenic, anti-inflammatory, cell cycle arrest, apoptotic, and autophagic effects. Hence, the use of eugenol alone or along with other chemotherapeutic anticancer agents is found to be very effective in cancer therapy.
    Keywords:  Anti-metastasis; Apoptosis; Cell cycle arrest; Eugenol; Pharmacokinetics
    DOI:  https://doi.org/10.1016/j.phymed.2022.154456
  104. Front Bioeng Biotechnol. 2022 ;10 969843
      The dual delivery platforms used in bone tissue engineering provide supplementary bioactive compounds that include distinct medicines and growth factors thereby aiding enhanced bone regeneration. The delivery of these compounds can be adjusted for a short or prolonged time based on the requirement by altering various parameters of the carrier platform. The platforms thus used are fabricated to mimic the niche of the bone microenvironment, either in the form of porous 3D structures, microspheres, or films. Thus, this review article focuses on the concept of dual drug delivery platform and its importance, classification of various platforms for dual drug delivery specific to bone tissue engineering, and finally highlights the foresight into the future direction of these techniques for better clinical applications.
    Keywords:  bone regeneration; bone tissue engineering; dual drug delivery platform; growth factors; osteogenesis ; scaffolds
    DOI:  https://doi.org/10.3389/fbioe.2022.969843
  105. Eur J Med Chem. 2022 Sep 09. pii: S0223-5234(22)00647-X. [Epub ahead of print]243 114745
      Caffeic acid-based compounds possess a high degree of structural diversity and show a variety of pharmacological properties, providing a useful framework for the discovery of new therapeutic agents. They are well-known analogues of antioxidants found in many natural products and synthetic compounds. The present review surveys the recent developments in structure-activity relationships (SAR) and mechanism of action (MOA) of various caffeic acid-containing compounds that play important roles in the design and synthesis of new bioactive molecules with antioxidant, antidiabetic, antiviral, antibacterial, anticancer, anti-inflammatory, and other properties. This review should provide inspiration to scientists in the research fields of organic synthesis and medicinal chemistry related to the development of new antioxidants with versatile therapeutic potential.
    Keywords:  Antioxidant; Biological applications; Caffeic acid; Drug discovery; SAR
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114745
  106. Nanomedicine (Lond). 2022 Sep 26.
      Nanourchins are multibranched nanoparticles with unique optical properties and surface spikes. Because of their unique properties, gold nanourchins have advantages over gold nanoparticles. The most used nanourchins are gold, tungsten, carbon, vanadium and sea urchins. The synthesis of various nanourchins and their clinical advancement are discussed in this review. ZFNs, TALENs and CRISPR/Cas9 are discussed to facilitate understanding of advancements in nanourchins. Nanourchins have been studied for Parkinson's disease, Alzheimer's disease and bioimaging. The synthesis of molybdenum diselenide nanourchins and their bioconjugations are also discussed. Nanourchins can be further explored to improve drug targeting and delivery. Researchers from several fields may contribute to the study of nanourchins as prospective nanocarriers with target specificity.
    Keywords:  Alzheimer's disease; cancer; gold nanoparticle; gold nanourchins; sea urchins; tungsten oxide nanourchins; vanadium oxide nanourchins
    DOI:  https://doi.org/10.2217/nnm-2022-0096
  107. Adv Chronic Kidney Dis. 2022 Jul;pii: S1548-5595(22)00068-4. [Epub ahead of print]29(4): 373-380
      Eating a net acid-producing diet can produce an "acid stress" of severity proportional to the diet net acid load, as indexed by the steady-state renal net acid excretion rate. Depending on how much acid or base is ingested or produced from endogenous metabolic processes and how well our homeostatic mechanisms can buffer or eliminate the additional acids or bases, we can alter our systemic acid-base balance. With increasing age, the kidney's ability to excrete daily net acid loads declines (a condition similar to that of mild CKD), invoking increased utilization of potential base stores (eg, bone, skeletal muscle) on a daily basis to mitigate the acid accumulation, thereby contributing to development of osteoporosis, loss of muscle mass, and age-related renal insufficiency. Patients suffering from more advanced CKD often present with more severe acid stress or metabolic acidosis, as the kidney can no longer excrete the entire acid load. Alkaline diets based on fruits and vegetables may have a positive effect on long-term preservation of renal function while maintaining nutritional status. This chapter discusses the biochemistry of dietary precursors that affect acid or base production.
    Keywords:  Alkali therapy; Children; Fruits and vegetables; Hypertension; Net acid excretion
    DOI:  https://doi.org/10.1053/j.ackd.2022.03.008
  108. Acta Biomater. 2022 Sep 21. pii: S1742-7061(22)00598-0. [Epub ahead of print]
      Injectable hydrogels based on various functional biocompatible materials have made rapid progress in the field of bone repair. In this study, a self-healing and injectable polysaccharide-based hydrogel was prepared for bone tissue engineering. The hydrogel was made of carboxymethyl chitosan (CMCS) and calcium pre-cross-linked oxidized gellan gum (OGG) cross-linked by the Schiff-base reaction. Meanwhile, magnetic hydroxyapatite/gelatin microspheres (MHGMs) were prepared by the emulsion cross-linking method. The antibacterial drugs, tetracycline hydrochloride (TH) and silver sulfadiazine (AgSD), were embedded into the MHGMs. To improve the mechanical and biological properties of the hydrogels, composite hydrogels were prepared by compounding hydroxyapatite (HAp) and drug-embedded MHGMs. The physical, chemical, mechanical and rheological properties of the composite hydrogels were characterized, as well as in vitro antibacterial tests and biocompatibility assays, respectively. Our results showed that the composite hydrogel with 6% (w/v) HAp and 10 mg/mL MHGMs exhibited good magnetic responsiveness, self-healing and injectability. Compared with the pure hydrogel, the composite hydrogel showed a 38.8% reduction in gelation time (196 to 120 s), a 65.6% decrease in swelling rate (39.4 to 13.6), a 51.9% increase in mass residual after degradation (79.5 to 120.8%), and a 143.7% increase in maximum compressive stress (53.6 to 130.6 KPa). In addition, this composite hydrogel showed good drug retardation properties and antibacterial effects against both S. aureus and E. coli. CCK-8 assay showed that composite hydrogel maintained high cell viability (> 87%) and rapid cell proliferation after 3 days, indicating that this smart hydrogel is expected to be an alternative scaffold for drug delivery and bone regeneration. STATEMENT OF SIGNIFICANCE: Biopolymer hydrogels have been considered as the promising materials for the treatment of tissue engineering and drug delivery. Injectable hydrogels with and self-healing properties and responsiveness to external stimuli have been extensively investigated as cell scaffolds and bone defects, due to their diversity and prolonged lifetime. Magnetism has also been involved in biomedical applications and played significant roles in targeted drug delivery and anti-cancer therapy. We speculate that development of dual cross-linked hydrogels basing biopolymers with multi-functionalities, such as injectable, self-healing, magnetic and anti-bacterial properties, would greatly broaden the application for bone tissue regeneration and drug delivery.
    Keywords:  bone repair; hydrogel; injectable; magnetic responsiveness; self-healing
    DOI:  https://doi.org/10.1016/j.actbio.2022.09.036
  109. Int J Biol Macromol. 2022 Sep 27. pii: S0141-8130(22)02153-5. [Epub ahead of print]
      Hydrogels designed with nanocellulose (i.e. cellulose nanocrystals (CNC), cellulose nanofibrils (CNF), and bacterial cellulose (BC)) have significant advantages as drug carriers due to their environmentally-benign features and excellent properties. Nanocellulose hydrogels have been demonstrated to sustainably deliver various kinds of drugs via different routes of administration, in which nanocellulose significantly improves the hydrogel properties and tunes the drug releasing profile. This article comprehensively summarizes the recent research progress on nanocellulose hydrogels in drug delivery. We carefully assessed the gelation methods for nanocellulose hydrogel design and highlighted the influence of nanocellulose on hydrogel properties and drug release behaviors. In particular, it is the first time to summarize the research on nanocellulose hydrogel-based drug carriers regarding specific routes of administration. This work provides a critical review of nanocellulose-based hydrogels as drug delivery vehicles, and also underlines the outlook in this field, with the objective to inspire/prompt future work, especially the practical applications of nanocellulose hydrogels in designing controlled drug delivery systems.
    Keywords:  Controlled releasing; Drug delivery; Hydrogel
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.214
  110. Front Cell Infect Microbiol. 2022 ;12 875513
      The trend toward herbal medicine as an alternative treatment for disease medication is increasing worldwide. However, insufficient pharmacologic information is available about the orally taken medicines. Not only herbal medicine, but also Western drugs, when passing through the gastrointestinal tract, interact with trillions of microbes (known as the gut microbiome [GM]) and their enzymes. Gut microbiome enzymes induce massive structural and functional changes to the herbal products and impact the bioavailability and efficacy of the herbal therapeutics. Therefore, traditional Chinese medicine (TCM) researchers extend the horizon of TCM research to the GM to better understand TCM pharmacology and enhance its efficacy and bioavailability. The study investigating the interaction between herbal medicine and gut microbes utilizes the holistic approach, making landmark achievements in the field of disease prognosis and treatment. The effectiveness of TCM is a multipathway modulation, and so is the GM. This review provides an insight into the understanding of a holistic view of TCM and GM interaction. Furthermore, this review briefly describes the mechanism of how the TCM-GM interaction deals with various illnesses.
    Keywords:  Chinese medicine; TCM; TCM-bacteria interaction; TCM-microbiota interaction; gut microbiota; medicine; prebiotics
    DOI:  https://doi.org/10.3389/fcimb.2022.875513
  111. Biomater Adv. 2022 Sep 17. pii: S2772-9508(22)00394-6. [Epub ahead of print]141 213117
      A versatile nanoformulation is designed by anchoring human transferrin protein (Tf) on fluoromagnetic upconverting nanoheaters, NaGdF4:Yb,Er (UCNP), loaded with Rose Bengal (RB), for multimodal imaging guided synergistic photothermal (PTT) and photodynamic therapy (PDT) at the targeted tumor site. The NIR excitation of the UCNP-RB Forster Resonance Energy Transfer (FRET) pair results in the reactive oxygen species (ROS) generation for PDT, whereas the non-radiative transitions in Er result in the heat required for PTT. The intravenously injected theranostic agent (UCNP@Tf-RB) enabled; (1) combinatorial PTT and PDT of 4T1 tumors with minimal systemic toxicity, (2) dual targeted (passive and active) tumor accumulation, (3) dual-modal imaging (MRI/photothermal), and, (4) excellent stability and biocompatibility. The in vitro therapy data corroborates the MRI findings that Tf conjugation resulted in actively targeted tumor accumulation via over-expressed transferrin receptors (TfR) on 4T1 cells. Real-time photothermal imaging enabled visualization of the tumor while receiving the therapy. The UCNP@Tf-RB, for synergistic PTT-PDT, and UCNP@Tf, for PTT only, caused rapid suppression of tumor with a tumor-growth inhibition index (TGII) of ~0.91, and 0.79, respectively. Histopathological examination demonstrated minimal damage to non-targeted tissues and caused significant damage to the tumor. This theranostic methodology enhances anti-cancer therapeutic efficiency, and announces the potential for pre-clinical cancer therapy.
    Keywords:  FRET; Photodynamic therapy; Photothermal therapy; Synergetic dual targeting; Upconversion nanoparticles
    DOI:  https://doi.org/10.1016/j.bioadv.2022.213117
  112. Biomed Pharmacother. 2022 Sep 24. pii: S0753-3322(22)01129-5. [Epub ahead of print]155 113740
      Despite conventional treatment options including chemoradiation, patients with the most aggressive primary brain tumor, glioblastoma multiforme (GBM), experience an average survival time of less than 15 months. Regarding the malignant nature of GBM, extensive research and discovery of novel treatments are urgently required to improve the patients' prognosis. Autophagy, a crucial physiological pathway for the degradation and recycling of cell components, is one of the exciting targets of GBM studies. Interventions aimed at autophagy activation or inhibition have been explored as potential GBM therapeutics. This review, which delves into therapeutic techniques to block or activate autophagy in preclinical and clinical research, aims to expand our understanding of available therapies battling GBM.
    Keywords:  Autophagy; Glioblastoma; Therapy; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.biopha.2022.113740
  113. ACS Appl Mater Interfaces. 2022 Sep 27.
      Hepatic stellate cells (HSCs), as an important part of the tumor microenvironment (TME), could be activated by tumor cells as cancer-associated fibroblasts (CAFs), thereby promoting the production of extracellular matrix (ECM) and favoring the development of tumors. Therefore, blocking the "CAFs-ECM" axis is a promising pathway to improve antitumor efficacy. Based on this, we developed a multifunctional nanosized delivery system composed of hyaluronic acid-modified pH-sensitive liposomes (CTHLs) and glycyrrheic acid-modified nanomicelles (DGNs), which combines the advantages of targeted delivery, pH-sensitivity, and deep drug penetration. To mimic actual TME, a novel HSCs+BEL-7402 cocultured cell model and a m-HSCs+H22 coimplanted mice model were established. As expected, CTHLs and DGNs could target CAFs and tumor cells, respectively, and promote the drug penetration and retention in tumor regions. Notably, CTHLs+DGNs not only exhibited a superior antitumor effect in three-level tumor-bearing mice but also presented excellent antimetastasis efficiency in lung-metastatic mice. The antitumor mechanism revealed that the lipid&micelle mixed formulations effectively inhibited the activation of CAFs, reduced the deposition of ECM, and reversed the epithelial-mesenchymal transition (EMT) of tumor cells. In brief, the nanosized delivery system composed of CTHLs and DGNs could effectively improve the therapeutic effect of liver cancer by blocking the "CAFs-ECM" axis, which has a good clinical application prospect.
    Keywords:  combination therapy; hepatocellular carcinoma; nanosized delivery system; tumor microenvironment; tumor-targeting
    DOI:  https://doi.org/10.1021/acsami.2c10446
  114. Am J Clin Nutr. 2022 Sep 30. pii: nqac284. [Epub ahead of print]
       BACKGROUND: Insulin resistance and hyperinsulinemia play important roles in the progression of multiple chronic disease and conditions. Diet modulates insulin response; however, evidence is limited regarding whether diets with higher insulinemic potential increase risk of invasive breast cancer.
    OBJECTIVES: We aimed to prospectively evaluate the association between a food-based empirical dietary index for hyperinsulinemia (EDIH) and the incidence of invasive breast cancer.
    METHODS: We prospectively followed 76,686 females from the Nurses' Health Study (NHS, 1984-2016) and 93,287 females from the Nurses' Health Study II (NHSII, 1991-2017). Diet was assessed by food frequency questionnaires every 4 years. The insulinemic potential of diet was evaluated using the previously established EDIH based on circulating C-peptide concentrations. Higher scores indicate higher insulinemic potential of the diet. Covariates included reproductive, hormonal, and anthropometric factors (height and BMI at age 18 years), race, socioeconomic status, total alcohol intake, total caloric intake, and physical activity.
    RESULTS: During 4,216,106 person-years of follow-up, we documented 10,602 breast cancer cases (6,689 NHS; 3,913 NHSII). In the pooled multivariable-adjusted analyses, females in the highest, compared with the lowest, EDIH quintile were at higher breast cancer risk (HRQ5vsQ1=1.15; 95% CI 1.07, 1.24; P-trend<0.01). Although heterogeneity by estrogen receptor (ER) status was non-significant, the strongest association between EDIH and breast cancer was observed for ER-negative tumors (HRQ5vsQ1=1.21; 95% CI 1.00, 1.46; P-trend=0.02). Among tumor molecular subtypes, the strongest associations were observed for human epidermal growth factor receptor 2 (HER2)-enriched tumors (HRQ5vsQ1=1.62; 95% CI 1.01, 2.61; P-trend=0.02).
    CONCLUSIONS: A dietary pattern contributing to hyperinsulinemia and insulin resistance was associated with greater breast cancer risk, especially ER-negative and HER2 enriched tumors. Our findings suggest that dietary modifications to reduce insulinemic potential may reduce risk of breast cancer.
    Keywords:  breast cancer, epidemiology, diet, dietary patterns; cohort study; hyperinsulinemia
    DOI:  https://doi.org/10.1093/ajcn/nqac284
  115. Mol Pharm. 2022 Sep 29.
      Central nervous system (CNS) diseases are among the most difficult to treat, mainly because the vast majority of the drugs fail to cross the blood-brain barrier (BBB) or to reach the brain at concentrations adequate to exert a pharmacological activity. The obstacle posed by the BBB has led to the in-depth study of strategies allowing the brain delivery of CNS-active drugs. Among the most promising strategies is the use of peptides addressed to the BBB. Peptides are versatile molecules that can be used to decorate nanoparticles or can be conjugated to drugs, with either a stable link or as pro-drugs. They have been used to deliver to the brain both small molecules and proteins, with applications in diverse therapeutic areas such as brain cancers, neurodegenerative diseases and imaging. Peptides can be generally classified as receptor-targeted, recognizing membrane proteins expressed by the BBB microvessels (e.g., Angiopep2, CDX, and iRGD), "cell-penetrating peptides" (CPPs; e.g. TAT47-57, SynB1/3, and Penetratin), undergoing transcytosis through unspecific mechanisms, or those exploiting a mixed approach. The advantages of peptides have been extensively pointed out, but so far few studies have focused on the potential negative aspects. Indeed, despite having a generally good safety profile, some peptide conjugates may display toxicological characteristics distinct from those of the peptide itself, causing for instance antigenicity, cardiovascular alterations or hemolysis. Other shortcomings are the often brief lifetime in vivo, caused by the presence of peptidases, the vulnerability to endosomal/lysosomal degradation, and the frequently still insufficient attainable increase of brain drug levels, which remain below the therapeutically useful concentrations. The aim of this review is to analyze not only the successful and promising aspects of the use of peptides in brain targeting but also the problems posed by this strategy for drug delivery.
    Keywords:  blood-brain-barrier; cell-penetrating peptides; drug delivery; peptides; receptor-mediated transcytosis
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00523
  116. Zhongguo Zhong Yao Za Zhi. 2022 Sep;47(18): 5040-5051
      Ultra-high-performance liquid chromatography-Q exactive orbitrap tandem mass spectrometry(UHPLC-QEOrbitrap-MS/MS) was used to explore the inhibitory effect and mechanism of ginkgo flavone aglycone(GA) combined with doxorubicin(DOX) on H22 cells. The effects of different concentrations of GA and DOX on the viability of H22 cells were investigated, and combination index(CI) was used to evaluate the effects. In the experiments, control(CON) group, DOX group, GA group, and combined GA and DOX(GDOX) group were constructed. Then the metabolomics strategy was employed to explore the metabolic markers that were significantly changed after combination therapy on the basis of single medication treatment, and by analyzing their biological significance, the effect and mechanism of the anti-tumor effect of GA combined with DOX were explained. The results revealed that when 30 μg·mL~(-1) GA and 0.5 μmol·L~(-1) DOX was determined as the co-administration concentration, the CI value was 0.808, indicating that the combination of GA and DOX had a synergistic anti-tumor effect. Metabolomics analysis identified 23 metabolic markers, including L-arginine, L-tyrosine and L-valine, mostly amino acids. Compared with the CON group, 22 and 17 metabolic markers were significantly down-regulated after DOX treatment and GA treatment, respectively. Compared with the DOX and GA groups, the treatment of GA combined with DOX further down-regulated the levels of these metabolic markers in liver cancer, which might contribute to the synergistic effect of the two. Five key metabolic pathways were found in pathway enrichment analysis, including glutathione metabolism, phenylalanine metabolism, arginine and proline metabolism, β-alanine metabolism, and valine, leucine and isoleucine degradation. These findings demonstrated that the combination of GA and DOX remarkably inhibited the viability of H22 cells and exerted a synergistic anti-tumor effect. The mechanism might be related to the influence of the energy supply of tumor cells by interfering with the metabolism of various amino acids.
    Keywords:  H22 cell; cell metabolomics; doxorubicin; ginkgo flavone aglycone; hepatocellular carcinoma; synergy
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20220506.401
  117. Front Immunol. 2022 ;13 972345
      Cancer immunotherapy has emerged as a novel anti-tumor treatment. Despite significant breakthroughs, cancer immunotherapy remains focused on several types of tumors that are sensitive to the immune system. Therefore, effective strategies to expand its indications and improve its efficacy become key factors for the further development of cancer immunotherapy. In recent decades, the anticancer activities of natural products are reported to have this effect on cancer immunotherapy. And the mechanism is largely attributed to the remodeling of the tumor immunosuppressive microenvironment. The compelling data highlight that natural products offer an alternative method option to improve immune function in the tumor microenvironment (TME). Currently, more attention is being paid to the discovery of new potential modulators of tumor immunotherapy from natural products. In this review, we describe current advances in employing natural products and natural small-molecule drugs targeting immune cells to avoid tumor immune escape, which may bring some insight for guiding tumor treatment.
    Keywords:  active chemicals; immune cells; natural products; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.972345
  118. Naunyn Schmiedebergs Arch Pharmacol. 2022 Sep 29.
      Aloe vera (L.) Burm.f. is nicknamed the 'Miracle plant' or sometimes as the 'Wonder plant'. It is a plant that has been used since ancient times for the innumerable health benefits associated with it. It is one of the important plants that has its use in conventional medicinal treatments. It is a perennial succulent, drought-tolerant member of the family Asphodelaceae. There are scores of properties associated with the plant that help in curing various forms of human ailments. Extracts and gels obtained from plants have been shown to be wonderful healers of different conditions, mainly various skin problems. Also, this plant is popular in the cosmetics industry. The underlying properties of the plant are now mainly associated with the natural phytochemicals present in the plant. Diverse groups of phytoingredients are found in the plant, including various phenolics, amino acids, sugars, vitamins, and different other organic compounds, too. One of the primary ingredients found in the plant is the aloin molecule. It is an anthraquinone derivative and exists as an isomer of Aloin A and Aloin B. Barbaloin belonging to the first group is a glucoside of the aloe-emodin anthrone molecule. Various types of pharmacological properties exhibited by the plant can be attributed to this chemical. Few significant ones are antioxidant, anti-inflammatory, anti-diabetic, anti-cancer, anti-microbial, and anti-viral, along with their different immunity-boosting actions. Recently, molecular coupling studies have also found the role of these molecules as a potential cure against the ongoing COVID-19 disease. This study comprehensively focuses on the numerous pharmacological actions of the primary compound barbaloin obtained from the Aloe vera plant along with the mechanism of action and the potent application of these natural molecules under various conditions.
    Keywords:  Aloe vera; Aloins; Anthraquinone; Barbaloin; Medicinal uses; Pharmacological actions
    DOI:  https://doi.org/10.1007/s00210-022-02294-4
  119. Onco Targets Ther. 2022 ;15 1021-1032
       Purpose: Non-small cell lung cancer (NSCLC) is a malignant tumor with high mortality. The Kirsten rat sarcoma vial oncogene (KRAS) gene can affect patient prognosis. In this study, we aim to explore the impact of KRAS mutation status on the clinical prognosis of NSCLC immunotherapy.
    Patients and Methods: Collected tumor samples from the Affiliated Cancer Hospital of Xinjiang Medical University and 220 patients with stage III-IV NSCLC were included the study. All patients are on first- or second-line therapy and not on targeted therapy. Based on the molecular profiles and clinical features, we analysis of the effect of KRAS mutation on the treatment outcome of NSCLC.
    Results: In this study, the main mutant subtypes of KRAS were G12C, G12D, and G12V. In the KRAS mutation group, the highest mutation frequency other than KRAS was TP53, followed by STK11 and KMT2C. We found that among patients received immunotherapy, KRAS-mutant patients were more sensitive to immunotherapy, with an objective response rate (ORR) of 65% and a disease control rate (DCR) of 80%. Survival analysis found that patients with KRAS mutation had better prognosis with immunotherapy than the non-KRAS mutation patients by comparing the overall survival (OS) (median OS: 18.1 months vs 12.2 months, p=0.0032) and progression-free survival (PFS) (media PFS: 7.9 months vs 3.6 months, p=0.01). We found that the patients with KRAS mutation had better prognosis with immunotherapy than with chemotherapy (median OS: 18.1 months vs 12.3 months, p=0.039, PFS 7.9 months vs 4.1 months, p=0.001). Patients with the KRAS G12C mutation had better results with immunotherapy than chemotherapy, but there was no significant difference in outcome between the two groups (OS: p=0.26 PFS: p=0.055). KRAS and TP53 co-mutation and KRAS and KMT2C co-mutation may improve response to immunotherapy.
    Conclusion: Our results suggested that the gene mutation profile of NSCLC in KRAS mutation group and non-KRAS mutation group were different. The patients with KRAS mutation will have better prognosis with immunotherapy.
    Keywords:  KRAS; NSCLC; immunotherapy; mutation; prognosis
    DOI:  https://doi.org/10.2147/OTT.S381825
  120. BMC Pharmacol Toxicol. 2022 Sep 26. 23(1): 71
       AIMS: The Blood-Brain Barrier (BBB) is a filter for most medications and blocks their passage into the brain. More effective drug delivery strategies are urgently needed to transport medications into the brain. This study investigated the biodistribution of thymoquinone (TQ) and the effect on enzymatic and non-enzymatic oxidative stress indicators in different brain regions, either in free form or incorporated into nanocarriers as mesoporous silica nanoparticles (MSNs). Lipid bilayer-coated MSNs.
    MATERIALS AND METHODS: MSNs and LB-MSNs were synthesized and characterized using a transmission electron microscope and dynamic light scattering to determine the particle size and zeta potential. TQ encapsulation efficiency and TQ's release profile from LB-MSNs were also examined. The impact of loading LB-MSNs with TQ-on-TQ delivery to different brain areas was examined using chromatographic measurement. Furthermore, nitric oxide, malondialdehyde (MDA), reduced glutathione, and catalase were evaluated as oxidant and antioxidant stress biomarkers.
    KEY FINDINGS: The LB-MSNs formulation successfully transported TQ to several areas of the brain, liver, and kidney, revealing a considerable increase in TQ delivery in the thalamus (81.74%) compared with that in the free TQ group and a considerable reduction in the cortex (-44%). The LB-MSNs formulation had no significant effect on TQ delivery in the cerebellum, striatum, liver, and kidney.
    SIGNIFICANCE: TQ was redistributed in different brain areas after being encapsulated in LB-MSNs, indicating that LB-MSNs have the potential to be developed as a drug delivery system for selective clinical application of specific brain regions.
    CONCLUSIONS: LB-MSNs are capable nanoplatforms that can be used to target medications precisely to specific brain regions.
    Keywords:  Biodistribution; Brain areas; Lipid bilayer; Mesoporous silica nanocarriers; Oxidative stress; Thymoquinone
    DOI:  https://doi.org/10.1186/s40360-022-00616-z
  121. Dose Response. 2022 Jul-Sep;20(3):20(3): 15593258221120485
      Phytochemicals (Pch) present in fruits, vegetables and other foods, are known to inhibit or induce drug metabolism and transport. An exhaustive search was performed in five databases covering from 2000 to 2021. Twenty-one compounds from plants were found to modulate CYP3A and/or P-gp activities and modified the pharmacokinetics and the therapeutic effect of 27 different drugs. Flavonols, flavanones, flavones, stilbenes, diferuloylmethanes, tannins, protoalkaloids, flavans, hyperforin and terpenes, reduce plasma concentration of cyclosporine, simvastatin, celiprolol, midazolam, saquinavir, buspirone, everolimus, nadolol, tamoxifen, alprazolam, verapamil, quazepam, digoxin, fexofenadine, theophylline, indinavir, clopidogrel. Anthocyanins, flavonols, flavones, flavanones, flavonoid glycosides, stilbenes, diferuloylmethanes, catechin, hyperforin, alkaloids, terpenes, tannins and protoalkaloids increase of plasma concentration of buspirone, losartan, diltiazem, felodipine, midazolam, cyclosporine, triazolam, verapamil, carbamazepine, diltiazem, aripiprazole, tamoxifen, doxorubicin, paclitaxel, nicardipine. Interactions between Pchs and drugs affect the gene expression and enzymatic activity of CYP3A and P-gp transporter, which has an impact on their bioavailability; such that co-administration of drugs with food, beverages and food supplements can cause a subtherapeutic effect or overdose. Therefore, it is important for the clinician to consider these interactions to obtain a better therapeutic effect.
    Keywords:  P-glycoprotein; activation/repression or inhibition of activity; area under the curve; cytochrome (CYP3A); expression; interaction drug; phytochemical
    DOI:  https://doi.org/10.1177/15593258221120485
  122. Int J Nanomedicine. 2022 ;17 4383-4400
       Purpose: In the search for new drug delivery platforms for cardiovascular diseases and coating of medical devices, we synthesized eptifibatide-functionalized silver nanoparticles (AgNPs-EPI) and examined the pharmacological activity of AgNPs-EPI on platelets and endothelial cells in vitro and ex vivo.
    Methods: Spherical AgNPs linked to eptifibatide were synthesized and characterized. Cytotoxicity was measured in microvascular endothelial cells (HMEC-1), platelets and red blood cells. Platelet mitochondrial respiration was measured using the Oxygraph-2k, a high-resolution modular respirometry system. The effect of AgNPs-EPI on the aggregation of washed platelets was measured by light aggregometry and the ex vivo occlusion time was determined using a reference laboratory method. The surface amount of platelet receptors such as P-selectin and GPIIb/IIIa was measured. The influence of AgNPS-EPI on blood coagulation science was assessed. Finally, the effect of AgNPs-EPI on endothelial cells was measured by the levels of 6-keto-PGF1alpha, tPa, cGMP and vWF.
    Results: We describe the synthesis of AgNPs using eptifibatide as the stabilizing ligand. The molecules of this drug are directly bonded to the surface of the nanoparticles. The synthesized AgNPs-EPI did not affect the viability of platelets, endothelial cells and erythrocytes. Preincubation of platelets with AgNPs-EPI protected by mitochondrial oxidative phosphorylation capacity. AgNPs-EPI inhibited aggregation-induced P-selectin expression and GPIIb/IIIa conformational changes in platelets. AgNPs-EPI caused prolongation of the occlusion time in the presence of collagen/ADP and collagen/adrenaline. AgNPs-EPI regulated levels of 6-keto-PGF1alpha, tPa, vWf and cGMP produced in thrombin stimulated HMEC-1 cells.
    Conclusion: AgNPs-EPI show anti-aggregatory activity at concentrations lower than those required by the free drug acting via regulation of platelet aggregation, blood coagulation, and endothelial cell activity. Our results provide proof-of-principle evidence that AgNPs may be used as an effective delivery platform for antiplatelet drugs.
    Keywords:  RGD; aggregation; antiplatelet; biocompatibility; coagulation system; drug delivery
    DOI:  https://doi.org/10.2147/IJN.S373691
  123. Colloids Surf B Biointerfaces. 2022 Sep 22. pii: S0927-7765(22)00541-0. [Epub ahead of print]220 112858
      The use of intelligent insulin delivery systems has become more important for treating diabetes. In this study, a dual-responsive oral insulin delivery nanocarrier that responds to glucose and pH has been developed. First, the oleic acid hydrophobic modified guar gum (GG) was synthesized by the esterification reaction, and the γ-polyglutamic acid (γ-PGA) was coupled with GG by the amidation reaction. The obtained pH-responsive copolymer (γ-PGA-GG) was cross-linked by concanavalin A to obtain pH/glucose dual-responsive nanocarriers, and insulin was effectively loaded into the dual-responsive nanocarriers. The insulin-loaded nanoparticles can achieve effective pH and glucose responses, releasing insulin on demand. In vitro and in vivo studies demonstrated the dual-responsive nanoparticles can protect insulin against the pH changes in the digestive tract and deliver insulin into the body to exert a hypoglycemic effect. Moreover, the dual-responsive nanoparticles have significant potential to be employed for oral insulin delivery.
    Keywords:  Glucose responsiveness; Nanoparticles; Oral insulin; Polyelectrolyte complex; pH responsiveness
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112858
  124. PLoS One. 2022 ;17(9): e0275273
       BACKGROUND: Comorbidity of Opisthorchis viverrini (OV) infection and nonalcoholic fatty-liver disease (NAFLD) enhances NAFLD progression to nonalcoholic steatohepatitis (NASH) by promoting severe liver inflammation and fibrosis. Here, we investigated the effect of supplementation with curcumin-loaded nanocomplexes (CNCs) on the severity of NASH in hamsters.
    METHODOLOGY: Hamsters were placed in experimental groups as follows: fed standard chow diet (normal control, NC); fed only high-fat and high-fructose (HFF) diet; O. viverrini-infected and fed HFF diet (HFFOV); group fed with blank nanocomplexes (HFFOV+BNCs); groups fed different doses of CNCs (25, 50 and 100 mg/kg body weight: HFFOV+CNCs25; HFFOV+CNCs50; HFFOV+CNCs100, respectively) and a group given native curcumin (HFFOV+CUR). All treatment were for three months.
    RESULTS: The HFF group revealed NAFLD as evidenced by hepatic fat accumulation, ballooning, mild inflammation and little or no fibrosis. These changes were more obvious in the HFFOV group, indicating development of NASH. In contrast, in the HFFOV+CNCs50 group, histopathological features indicated that hepatic fat accumulation, cell ballooning, cell inflammation and fibrosis were lower than in other treatment groups. Relevantly, the expression of lipid-uptake genes, including fatty-acid uptake (cluster of differentiation 36), was reduced, which was associated with the lowering of alanine aminotransferase, total cholesterol and triglyceride (TG) levels. Reduced expression of an inflammation marker (high-mobility group box protein 1) and a fibrosis marker (alpha smooth-muscle actin) were also observed in the HFFOV+CNCs50 group.
    CONCLUSION: CNCs treatment attenuates the severity of NASH by decreasing hepatic steatosis, inflammation, and fibrosis as well as TG synthesis. CNCs mitigate the severity of NASH in this preclinical study, which indicates promise for future use in patients.
    DOI:  https://doi.org/10.1371/journal.pone.0275273
  125. J Allergy Clin Immunol Pract. 2022 Sep 26. pii: S2213-2198(22)00961-8. [Epub ahead of print]
      Natural products are a category of complementary and alternative medicine that include medicinal plants, vitamins and dietary supplements. These products are often utilized by patients with allergies in conjunction with, or as an alternative to, their conventional medical therapies. Despite the wide use of these modalities, many clinicians often have limited knowledge and training in their use. It is important for health care providers to know the safety and risks of these products that their patients may use. This Clinical Commentary reviews the side effects and adverse reactions of several natural products commonly used by patients with allergies and gives an overview of the FDA requirements for manufacturing, advertising and distribution.
    Keywords:  adverse reactions; complementary and alternative medicine; herbs; integrative medicine; natural products; supplements
    DOI:  https://doi.org/10.1016/j.jaip.2022.09.025
  126. Biochem Pharmacol. 2022 Sep 19. pii: S0006-2952(22)00347-1. [Epub ahead of print]205 115253
      Lithocholic acid (LCA), one of the most common metabolic products of bile acids (BAs), is originally synthesized in the liver, stored in the gallbladder, and released to the intestine, where it assists absorption of lipid-soluble nutrients. LCA has recently emerged as a powerful reagent to inhibit tumorigenesis; however, the anti-tumor activity and molecular mechanisms of LCA in gallbladder cancer (GBC) remain poorly acknowledged. Here, we analyzed serum levels of LCA in human GBC and found that LCA was significantly downregulated in these patients, and reduced LCA levels were associated with poor clinical outcomes. Treatment of xenografts with LCA impeded tumor growth. Furthermore, LCA treatment in GBC cell lines decreased glutaminase (GLS) expression, glutamine (Gln) consumption, and GSH/GSSG and NADPH/NADP+ ratios, leading to cellular ferroptosis. In contrast, GLS overexpression in tumor cells fully restored GBC proliferation and decreased ROS imbalance, thus suppressing ferroptosis. Our findings reveal that LCA functions as a tumor-suppressive factor in GBC by downregulating GLS-mediated glutamine metabolism and subsequently inducing ferroptosis. This study may offer a new therapeutic strategy tailored to improve the treatment of GBC.
    Keywords:  Ferroptosis; Gallbladder cancer; Glutaminase; Glutamine; Lithocholic acid; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.bcp.2022.115253
  127. Front Immunol. 2022 ;13 968755
      Tripartite motif containing-21 (TRIM21), an E3 ubiquitin ligase, was initially found to be involved in antiviral responses and autoimmune diseases. Recently studies have reported that TRIM21 plays a dual role in cancer promoting and suppressing in the occurrence and development of various cancers. Despite the fact that TRIM21 has effects on multiple metabolic processes, inflammatory responses and the efficacy of tumor therapy, there has been no systematic review of these topics. Herein, we discuss the emerging role and function of TRIM21 in cancer metabolism, immunity, especially the immune response to inflammation associated with tumorigenesis, and also the cancer treatment, hoping to shine a light on the great potential of targeting TRIM21 as a therapeutic target.
    Keywords:  TRIM21; cancer treatment; immunity; metabolism; tumorigenesis
    DOI:  https://doi.org/10.3389/fimmu.2022.968755
  128. Crit Rev Food Sci Nutr. 2022 Sep 30. 1-16
      Nanotechnology is being used to create innovative food packaging systems that can inhibit the oxidation of foods, thereby improving their quality, safety, and shelf life. These nano-enabled antioxidant packaging materials may therefore increase the healthiness and sustainability of the food supply chain. Recent progress in the application of nanotechnology to create antioxidant packaging materials is reviewed in this paper. The utilization of nanoparticles, nanofibers, nanocrystals, and nanoemulsions to incorporate antioxidants into these packaging materials is highlighted. The application of nano-enabled antioxidant packaging materials to preserve meat, seafood, fruit, vegetable, and other foods is then discussed. Finally, future directions and challenges in the development of this kind of active packaging material are highlighted to stimulate new areas of future research. Nanotechnology has already been used to create antioxidant packaging materials that inhibit oxidative deterioration reactions in foods, thereby prolonging their shelf life and reducing food waste. However, the safety, cost, efficacy, and scale-up of this technology still needs to be established before it will be commercially viable for many applications.
    Keywords:  Antioxidants; active packaging; nanofibers; nanoparticles; nanotechnology
    DOI:  https://doi.org/10.1080/10408398.2022.2128035
  129. Biochimie. 2022 Sep 22. pii: S0300-9084(22)00230-9. [Epub ahead of print]
      Despite medical advances in treatment strategies over the past 30-years, epithelial ovarian cancer (EOC) continues to be defined by poor patient survival rates and aggressive, drug resistant relapse. Traditional approaches to cancer chemotherapy are typically limited by severe off-target effects on healthy tissue and aggressive drug-resistant recurrence. Recent shifts towards targeted therapies offer the possibility of circumventing the obstacles experienced by these treatments. While antibodies are the pioneering agents in such targeted therapies, several intrinsic characteristics of antibodies limits their clinical translation and efficacy. In contrast, oligonucleotide chemical antibodies, known as aptamers, are ideal for this application given their small size and lack of immunogenicity. This study explored the efficacy of a DNA aptamer, designed to target a well-established cancer biomarker, EpCAM, to deliver a chemotherapeutic drug. The results from this study support evidence that EpCAM aptamers can bind to epithelial ovarian cancer; and offers a valid alternative as a targeting ligand with tuneable specificity and sensitivity. It also supports the growing body of evidence that aptamers show great potential for application-specific, post-SELEX engineering through rational modifications. Through in vitro assays, these aptamers demonstrated cytotoxicity in both monolayer and tumoursphere assays, as well as in tumourigenic enriching assays. Further experimentation based on the results achieved in this project might aid in the development of novel cancer therapeutics and guide the novel designs of drugs for targeted drug delivery.
    Keywords:  Aptamer; Doxorubicin; EpCAM; Ovarian cancer; Targeted therapeutic; Transferrin receptor
    DOI:  https://doi.org/10.1016/j.biochi.2022.09.005
  130. Front Neurosci. 2022 ;16 977376
      Andrographolide is a natural antibiotic that has the ability to dispel heat, detoxify, reduce inflammation, and relieve pain. Recent research has shown that it can exert anti-inflammatory effects via multiple pathways and multiple targets (mediated by NF-κB, JAK/STAT, T cell receptor, and other signaling pathways). It can inhibit human lung cancer cells, colon cancer cells, osteosarcoma cells, and other tumor cells, as well as reduce bacterial virulence and inhibit virus-induced cell apoptosis. It can also regulate inflammatory mediator expression to protect the nervous system and effectively prevent mental illness. Additionally, andrographolide regulates the immune system, treats cardiovascular and cerebral vascular diseases, protects the liver, and the gallbladder. It is clear that andrographolide has a huge range of potential applications. The mechanism of andrographolide's anti-inflammatory, antibacterial, antiviral, and nervous system defense in recent years have been reviewed in this article.
    Keywords:  AKT; NF-κB; andrographolide; anti-inflammatory; anti-tumor; antiviral; nervous system
    DOI:  https://doi.org/10.3389/fnins.2022.977376
  131. Oncol Rep. 2022 Nov;pii: 202. [Epub ahead of print]48(5):
      Gomisin A (GA) is an effective component of Schisandra. The crude extracts of Schisandra chinensis and its active ingredients have been shown to inhibit multidrug resistance in tumour cells. Reactive oxygen species (ROS) have different roles in cancer and may contribute to therapy resistance. The human ovarian cancer (OC) cell lines SKOV3 and A2780, and a mouse model of OC, were used in the present study. MTT assay, colony formation assay, flow cytometry, western blot analysis, and haematoxylin and eosin (H&E) staining were performed to determine the antitumor effect of GA and paclitaxel (PTX) in vitro and in vivo. The ROS inhibitor N‑acetyl cysteine (NAC) was used to assess the mechanism underlying the chemosensitizing effects of GA. Notably, the proliferation of OC cells was inhibited by PTX, which could be enhanced by the ROS inhibitor NAC or GA. Treatment with NAC + PTX or GA + PTX enhanced the cell cycle arrest, but not apoptosis, induced by PTX. Moreover, the molecular mechanism underlying this effect may be that GA decreases the levels of ROS in ovarian cancer cells and inhibits cell cycle progression by downregulating the expression of the cell cycle proteins cyclin‑dependent kinase 4 and cyclin B1. In conclusion, the combination of PTX and the ROS inhibitor GA may be a novel strategy in OC chemotherapy.
    Keywords:  GA; OC; PTX; ROS; chemosensitization
    DOI:  https://doi.org/10.3892/or.2022.8417
  132. Pharm Dev Technol. 2022 Sep 28. 1-17
      Glioblastomas are tumors that present a high mortality rate. Artemether (ART) is a lactone with antitumor properties, demonstrating low bioavailability and water solubility. In the present study, we developed lipid-core nanocapsules (LNC) containing pequi oil (Caryocar brasiliense Cambess) as the oily core for ART-loaded LNCs (LNCART) and evaluated their effect on human glioblastoma cells (U-87 MG). LNCs were developed by interfacial deposition of a preformed polymer, followed by physicochemical characterization. LNCART revealed a diameter of 0.216 µm, polydispersity index of 0.161, zeta potential of -12.0 mV, and a pH of 5.53. Furthermore, mitochondrial viability, proliferation, total antioxidant status, and antioxidant enzyme activity were evaluated. ART reduced cell viability after 24 h and proliferation after 48 h of treatment at concentrations equal to or above 40 µg.mL-1. LNCART, at 1.25 µg.mL-1, reduced these parameters after 24 h of treatment. Furthermore, superoxide dismutase (SOD) activity was elevated, while glutathione reductase (GR) activity was reduced. These findings suggest that ART loaded into LNC may be a promising alternative to improve its pharmacological action and possible application as a therapeutic agent for glioblastoma.
    Keywords:  Caryocar brasiliense Cambess; antioxidant status; artemether; cell viability; human glioblastoma; polymeric lipid-core nanocapsules
    DOI:  https://doi.org/10.1080/10837450.2022.2128819
  133. Nanotechnology. 2022 Sep 30.
      Glioblastoma (GBM), the deadliest brain cancer, presents a multitude of challenges to the development of new therapies. The standard of care has only changed marginally in the past 17 years, and few new chemotherapies have emerged to supplant or effectively combine with temozolomide. Concurrently, new technologies and techniques are being investigated to overcome the pharmacokinetic challenges associated with brain delivery, such as the blood brain barrier (BBB), tissue penetration, diffusion, and clearance in order to allow for potent agents to successful engage in tumor killing. Alternative delivery modalities such as focused ultrasound and convection enhanced delivery (CED) allow for the local disruption of the blood brain barrier, and the latter in particular has shown promise in achieving broad distribution of agents in the brain. Furthermore, the development of polymeric nanocarriers to encapsulate a variety of cargo, including small molecules, proteins, and nucleic acids, have allowed for formulations that protect and control the release of said cargo to extend its half-life. The combination of local delivery and nanocarriers presents an exciting opportunity to address the limitations of current chemotherapies for GBM toward the goal of improving safety and efficacy of treatment. However, much work remains to establish standard criteria for selection and implementation of these modalities before they can be widely implemented in the clinic. Ultimately, engineering principles and nanotechnology have opened the door to a new wave of research that may soon advance the stagnant state of GBM treatment development.
    Keywords:  Brain Delivery; Convection Enhanced Delivery; Glioblastoma; Nanocarriers; Polymer
    DOI:  https://doi.org/10.1088/1361-6528/ac9683
  134. Int J Pharm. 2022 Sep 22. pii: S0378-5173(22)00786-4. [Epub ahead of print] 122232
      The objective of the present research was to develop, optimize, and evaluate rotigotine (RT)-loaded chitosan (CH) coated nanostructured lipid carriers (RT-CH-NLCs) for nose-to-brain delivery. The NLCs were prepared by homogenization and sonication technique as well as optimized by using three factors at three-level Box-Behnken design. The prepared NLCs were evaluated for particle size, zeta potential, entrapment efficiency, drug release, and ex vivo permeation. The pharmacokinetic study was conducted on albino Wistar rats to evaluate the bioavailability and neuropharmacokinetic parameters after intranasal administration of the optimized formulation (RT-CH-NLCs-OPT). The optimized formulation showed the particle size (170.48 ± 8.37 nm), PDI (0.19 ± 0.03), zeta potential (+ 26.73 mV), and entrapment efficiency (82.37 ± 2.48 %). In vitro drug release study displayed a sustained drug release pattern from RT-CH-NLCs-OPT (86.73±8.58 % in 24 h) in comparison to RT-Dis (98.61±7.24 % in 16 h). The permeability coefficient (PC) was found to be 11.39 ± 1.08×10-4 cm.h-1 and 2.34 folds higher than RT-Dis (4.85±1.53×10-4 cm.h-1). The relative bioavailability of RT from RT-CH-NLCs-OPT was 3.2-fold greater as compared to RT-Dis. The absolute bioavailability of RT after intranasal administration of RT-CH-NLCs-OPT was 2.1-fold higher than RT-CH-NLCs-OPT administered intravenously. The brain targeting and targeting potential was displayed by DTE (422.03 %) and DTP (76.03 %) after intranasal administration of RT-CH-NLCs-OPT as compared to RT-Dis (DTE 173.91 % and DTP 59.97 %). Furthermore, confocal laser scanning microscopy results confirmed better brain targeting for RT-CH-NLCs-OPT as compared to RT-Dis. From these findings, it could be concluded that RT-CH-NLCs could serve as a promising strategy for targeting RT through the intranasal route.
    Keywords:  Experimental design; Intranasal delivery; NLCs; Neuro-pharmacokinetic; Parkinsonism disease; Rotigotine, etc
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122232
  135. Curr Neuropharmacol. 2022 Sep 22.
      Pediatric malignant brain tumors represent the most frequent cause of cancer-related deaths in childhood. The triad of the therapeutic scheme of surgery, radiotherapy and chemotherapy has improved patient management, but with minimal improvement in patients' prognosis. Emerging molecular targets and mechanisms have pointed out novel approaches and schemes for pediatric brain tumor therapy, enabling personalized medical treatment. Advances in the field of epigenetics and their interplay with genetic changes have enriched our knowledge of the molecular heterogeneity of these neoplasms and have revealed important genes that affect crucial signaling pathways involved in tumor progression. The great potential of epigenetic therapy lies mainly in the widespread location and the reversibility of epigenetic alterations, proposing a wide range of targeting options, including the possible combination with chemo- and immunotherapy, significantly increasing their efficacy. Epigenetic drugs, including inhibitors of DNA methyltransferases, histone deacetylases and demethylases, are currently being tested in clinical trials on pediatric brain tumors. Additional novel epigenetic drugs include protein and enzyme inhibitors that modulate epigenetic modification pathways, such as Bromodomain and Extraterminal (BET) proteins, Cyclin-Dependent Kinase 9 (CDK9), AXL, Facilitates Chromatin Transcription (FACT), BMI1, and CREB Binding Protein (CBP) inhibitors, which can be used either as standalone or in combination with current treatment approaches. In this review, we discuss recent progress on epigenetic drugs that could be possibly used against the most common malignant tumors of childhood, such as medulloblastomas, high- grade gliomas and ependymomas.
    Keywords:  DNMTi; Drug repurposing; Ependymoma; Epigenetic drugs; Epigenetics; HDACi; Medulloblastoma; Pediatric brain tumors; Pediatric gliomas
    DOI:  https://doi.org/10.2174/1570159X20666220922150456
  136. Ann Oncol. 2022 Sep 23. pii: S0923-7534(22)04148-5. [Epub ahead of print]
       BACKGROUND: Seemingly normal tissues progressively become populated by mutant clones over time. Most of these clones bear mutations in well-known cancer genes but only rarely do they transform into cancer. This poses questions on what triggers cancer initiation and what implications somatic variation has for cancer early detection.
    DESIGN: We analysed recent mutational screens of healthy and cancer-free diseased tissues to compare somatic drivers and the causes of somatic variation across tissues. We then reviewed the mechanisms of clonal expansion and their relationships with age and diseases other than cancer. We finally discussed the relevance of somatic variation for cancer initiation and how it can help or hinder cancer detection and prevention.
    RESULTS: The extent of somatic variation is highly variable across tissues and depends on intrinsic features, such as tissue architecture and turnover, as well as the exposure to endogenous and exogenous insults. Most somatic mutations driving clonal expansion are tissue-specific and inactivate tumor suppressor genes involved in chromatin modification and cell growth signaling. Some of these genes are more frequently mutated in normal tissues than cancer, indicating a context-dependent cancer promoting or protective role. Mutant clones can persist over a long time or disappear rapidly, suggesting that their fitness depends on the dynamic equilibrium with the environment. The disruption of this equilibrium is likely responsible for their transformation into malignant clones and knowing what triggers this process is key for cancer prevention and early detection. Somatic variation should be considered in liquid biopsy, where it may contribute cancer-independent mutations, and in the identification of cancer drivers, since not all mutated genes favoring clonal expansion also drive tumorigenesis.
    CONCLUSIONS: Somatic variation and the factors governing homeostasis of normal tissues should be taken into account when devising strategies for cancer prevention and early detection.
    Keywords:  Somatic evolution; cancer early detection; cancer initiation; clone selection; driver gene; healthy tissues
    DOI:  https://doi.org/10.1016/j.annonc.2022.09.156
  137. Comb Chem High Throughput Screen. 2022 Sep 28.
       BACKGROUND: Hairy agrimony (Agrimonia pilosa Ledeb.) is a traditional medicinal plant widely used in Eastern Europe and Eastern Asia regions. The plant is harvested as it came into flower and could be dried for later usage. Hairy agrimony has been traditionally introduced to treat sore throat, abdominal pain, headache, mucoid dysentery, bloody and white discharge, parasites, and eczema.
    OBJECTIVE: Since the 1950s, various experimental reports relating to phytochemical and pharmacological aspects have been observed, but an overview is now not available. The current paper emphasizes on in-depth information about botanical description, traditional use, phytochemistry, and pharmacology.
    METHODS: The collection of previous research is basically depended on the reliable resources Sci-Finder, Google Scholar, ScienceDirect, reputation publishers, and thesis books.
    RESULTS: A. pilosa was found to contain a variety of chemical classes. To date, more than 160 secondary metabolites were separated, and the derivatives type flavonoids, phloroglucinols, tannins, isocoumarins, and triterpenoids are the main components. A. pilosa crude extracts and their isolates set a broad panel of pharmacological values, including anti-cancer, anti-microbial, anti-virus, anti-oxidant, anti-inflammation, anti-diabetes, anti-osteosarcoma, anti-aging, anti-nociception, anti-adipogenesis, anti-leishmaniasis, estrogenic-like activity, neuroprotective and hepatoprotective activities, and vascular relaxation.
    CONCLUSION: In vitro and in vivo results also successfully explained the pharmacological mechanisms of A. pilosa constituents. More bioassay-guided phytochemical and clinical studies are necessary.
    Keywords:  Agrimonia pilosa; pharmacology; phytochemistry; secondary metabolites.
    DOI:  https://doi.org/10.2174/1386207325666220928163930
  138. Nat Commun. 2022 Sep 27. 13(1): 5684
      High-glucose microenvironment in the diabetic foot ulcer (DFU) causes excessive glycation and induces chronic inflammation, leading to the difficulty of DFU healing. Hydrogen-rich water bath can promote the healing of DFU in clinic by virtue of the anti-inflammatory effect of hydrogen molecules, but the long-term daily soaking counts against the formation of a scab and cannot change the high-glucose microenvironment, limiting the outcome of DFU therapy. In this work, photocatalytic therapy of diabetic wound is proposed for sustainable hydrogen generation and local glucose depletion by utilizing glucose in the high-glucose microenvironment as a sacrificial agent. Hydrogen-incorporated titanium oxide nanorods are developed to realize efficient visible light (VIS)-responsive photocatalysis for glucose depletion and hydrogen generation, achieving a high efficacy of diabetic wound healing. Mechanistically, local glucose depletion and hydrogen generation jointly attenuate the apoptosis of skin cells and promote their proliferation and migration by inhibiting the synthesis of advanced glycation end products and the expression of their receptors, respectively. The proposed VIS-photocatalytic strategy provides a solution for facile, safe and efficient treatment of DFU.
    DOI:  https://doi.org/10.1038/s41467-022-33475-7
  139. J Appl Toxicol. 2022 Sep 30.
      Every day we are exposed to many environmental pollutants that can enter our body through different routes and cause adverse effects on our health. Epidemiological studies suggest that these pollutants are responsible for approximately 9 million deaths per year. Acute lymphoblastic leukemia (ALL) represents one of the major cancers affecting children and, although substantial progress has been made in its treatment, relapses are frequent after initial treatment and are now one of the leading causes of cancer-related death in pediatric patients. Currently, relatively little attention is paid to pollutant exposure during drug treatment and this is not taken into account for dose setting or regulatory purposes. In this work, we investigated how bisphenol A (BPA), its derivative bisphenol A diglycidyl ether (BADGE) and perfluorooctanoic acid (PFOA) alter vincristine treatment in acute lymphoblastic leukemia (ALL) when administered before or together with the drug. We found that these three pollutants at nanomolar concentrations, lower than those established by current regulations, can reduce the cytotoxic effects of vincristine on acute lymphoblastic leukemia (ALL) cells. Interestingly, we found that this is only achieved when exposure to pollutants occurs prior to administration of the chemotherapeutic drug. Moreover, we found that this effect could be mediated by activation of the PI3K/AKT pathway and stabilization of microtubules. This work strengthens the idea of starting to take into account exposure to pollutants to improve the efficacy of chemotherapy treatments.
    Keywords:  B-ALL; PI3K/AKT pathway; Pollutants; chemoresistance; circadian rhythms; microtubule stabilization
    DOI:  https://doi.org/10.1002/jat.4398
  140. J Comp Physiol B. 2022 Sep 27.
      Under the background of climate change, increasing attention has focused on the effects of ocean deoxygenation on marine organisms. However, few studies address the effects of different food deprivation states on hypoxia tolerance. We therefore investigated the metabolic responses of the Atlantic rock crab, Cancer irroratus (starved 28-35 days, fasted 3-5 days and recently fed). Starved-crab exhibited the lowest critical oxygen saturation (Scrit), while fed-crab had the highest Scrit. The fed-crab maintained an elevated postprandial oxygen consumption (MO2) even below the Scrit of fasted-crab indicating reserved aerobic scopes for critical activities in severe hypoxia. Following feeding, hypoxia (50% and 20% oxygen saturation, SO2) retarded the specific dynamic action resulting in lower peak MO2 and longer duration. The starved-crab exhibited a lower peak MO2, prolonged duration and higher energy expenditure than fasted-crab after feeding. The decline in arterial PO2 was most pronounced below the Scrit for both fasted- and starved-crab. The higher hemocyanin concentration ([Hc]) of fasted-crab (than starved-crab) suggested they had improved oxygen transport capacity, but hypoxia did not increase [Hc] during the 72-h experiment. Following feeding, the fasted-crab significantly increased L-lactate concentration ([L-lactate]) in 20% SO2, which was not observed in starved-crab. These results suggest starvation may trigger a cross-tolerance to hypoxia. Because crabs can undergo long periods of food deprivation in their natural environment, future studies should consider how this may affect their ability to deal with environmental perturbations.
    Keywords:  Aerobic metabolism; Critical oxygen partial pressure; Hemocyanin; L-Lactate; Specific dynamic action; Starvation
    DOI:  https://doi.org/10.1007/s00360-022-01462-5
  141. Int J Immunopathol Pharmacol. 2022 Jan-Dec;36:36 3946320221130727
       BACKGROUND: Lung cancer has the fastest increase in morbidity and mortality, and is one of the most threatening malignant tumors to human health and life. Both radiotherapy and targeted therapy are typical treatments after lung cancer surgery. Radiotherapy is a means of locally killing cancer lesions, and it plays an important role in the entire management of lung cancer. Gefitinib is one of the most commonly used targeted therapy drugs in the treatment of lung cancer. The purpose of this project is to explore the mechanism by which deacetylation of RBBP8 mediated by radiotherapy-promoting protein SIRT6 in lung adenocarcinoma enhances the sensitivity of targeted therapy.
    METHODS: In both the cell experiments and the animal experiments, the samples were divided into five groups: Model group, RT group, CT group, RT+CT group, and RT+CT+inhibitor group. The CCK8 method was used to detect the viability of each group of cells. The flow cytometry experiment was used to analyze the apoptotic characteristics of each group of cells. The scratch test was used to detect the migration ability of each group of cells. Transwell invasion test was used to determine the invasion ability of each group of cells. The lung tumor tissues of each group of mice were collected to analyze the tumor size, volume, and metastasis characteristics. The TUNEL experiment was used to detect the apoptosis characteristics of the cells in the lung cancer tissues of each group mice. Immunohistochemistry experiments were used to analyze the distribution and relative expression characteristics of protein SIRT6 in mouse lung cancer tissues. The colorimetric experiments were used to detect the activity of Caspase 3 and Caspase 8 in each group. Western blot method was used to detect the expression of SIRT6, RBBP8, and MYC in each group.
    RESULTS: In each experiment, the results of the experiment have mutually proven consistency, and there is no contradiction. In addition to the Model group, the other 4 groups used different treatment methods. The better the curative effect, the lower the cell viability of cancer cells and the higher the apoptotic ratio. This is reflected in the CCK8 test, flow cytometry analysis, cell scratch test, Transwell cell migration test, and TUNEL detection. At the same time, colorimetric detection and Western blot analysis also analyzed the levels of SIRT6, RBBP8 and other cancer-related proteins in each group at the molecular level, implying the importance of SIRT6 protein in the treatment process.
    CONCLUSION: Our project has proved that radiotherapy can promote the protein SIRT6 to deacetylate RBBP8 proteins, and ultimately enhance targeted therapy drug sensitivity.
    Keywords:  RBBP8; SIRT6; gefitinib; lung cancer; radiotherapy
    DOI:  https://doi.org/10.1177/03946320221130727
  142. J Biomed Sci. 2022 Sep 26. 29(1): 74
      The major concept of "oxidative stress" is an excess elevated level of reactive oxygen species (ROS) which are generated from vigorous metabolism and consumption of oxygen. The precise harmonization of oxidative stresses between mitochondria and other organelles in the cell is absolutely vital to cell survival. Under oxidative stress, ROS produced from mitochondria and are the major mediator for tumorigenesis in different aspects, such as proliferation, migration/invasion, angiogenesis, inflammation, and immunoescape to allow cancer cells to adapt to the rigorous environment. Accordingly, the dynamic balance of oxidative stresses not only orchestrate complex cell signaling events in cancer cells but also affect other components in the tumor microenvironment (TME). Immune cells, such as M2 macrophages, dendritic cells, and T cells are the major components of the immunosuppressive TME from the ROS-induced inflammation. Based on this notion, numerous strategies to mitigate oxidative stresses in tumors have been tested for cancer prevention or therapies; however, these manipulations are devised from different sources and mechanisms without established effectiveness. Herein, we integrate current progress regarding the impact of mitochondrial ROS in the TME, not only in cancer cells but also in immune cells, and discuss the combination of emerging ROS-modulating strategies with immunotherapies to achieve antitumor effects.
    Keywords:  Cisplatin resistance; Combination cancer immunotherapy; Hypoxia; Immunoescape; Inflammation; Lon protease (LonP1); Mitochondrial chaperone; Mitochondrial reactive oxygen species (mtROS); Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12929-022-00859-2
  143. Front Bioeng Biotechnol. 2022 ;10 994816
      Curcumin has been widely used for the treatment of age-associated diseases, and showed chondroprotective potential for post-traumatic osteoarthritis (OA). However, due to the irregular-shaped and large-sized defects on joint cartilage in degenerated OA, the in vivo delivery and therapeutic effect of curcumin for effective repair remain challenging. In this study, we first present a PEG-GelMA [Poly(Ethylene Glycol) Dimethacrylate-Gelatin Methacrylate, PGMs] hydrogel microgel-based curcumin delivery system for both improved anti-inflammatory and pro-regenerative effects in treatment for cartilage defects. The curcumin-loaded PGMs were produced by a microfluidic system based on light-induced gelation of gelatin methacrylate (GelMA). This PGMs embedding curcumin at a relative low dosage were demonstrated to promote the proliferation and chondrogenic differentiation of mesenchymal stem cells in vitro. More importantly, the PGMs were shown to attenuate the inflammatory response of chondrocytes under IL-1β stimulation. Lastly, the in vivo application of the injectable PGMs significantly promoted the repair of large-sized cartilage injury. These results confirmed that curcumin-loaded PGMs can not only enhance the chondroprotective efficacy under inflammatory conditions but also induce efficient cartilage regeneration. This study provides an advanced strategy with anti-inflammatory and pro-regenerative dual-role therapeutic for treatment of extensive cartilage injuries.
    Keywords:  Cartilage regeneration; Chondrogenic differentiation; Inflammatory response; Osteoarthritis; PEG-GelMA hydrogel microgel (PGMs)
    DOI:  https://doi.org/10.3389/fbioe.2022.994816
  144. AAPS PharmSciTech. 2022 Sep 26. 23(7): 266
      Cell-penetrating peptides have been widely used as a tool to gain access to cytosol for numerous applications. The review highlights the advances made in preclinical and clinical research using cell-penetrating peptides since their discovery in 1980s. Further, the emphasis is on summarizing the role of cell-penetrating peptides as permeation enhancers for transdermal and topical drug delivery applications. A summary table of preclinical studies utilizing various peptides in combination with different active ingredients and drug delivery systems is included. Lastly, we capture the challenges associated with the cell-penetrating peptides to translate the preclinical work to clinical applications.
    Keywords:  cell-penetrating peptide; drug delivery; permeation enhancement; skin; transdermal
    DOI:  https://doi.org/10.1208/s12249-022-02424-4
  145. Front Nutr. 2022 ;9 952553
      Obesity rates continue to rise, resulting in a global epidemic that shows no sign of slowing down. Our understanding of this complex disease is also constantly evolving, requiring healthcare providers to stay up to date with best practices. The application of plant-based diets (PBDs) may hold the key to a successful weight-control strategy. PBD refers to any dietary pattern that emphasizes the consumption of plant foods while excluding the consumption of most or all animal products. The purpose of this mini-review is to report on the application of PBDs as a potential treatment for obesity. PBDs have also been shown to be beneficial in the treatment of other non-communicable diseases, such as the prevention and treatment of type 2 diabetes. Many of the reported RCTs were of short duration. Longer-term studies, as well as studies focusing on strict adherence to the PBD regime, are needed. PBD is a beneficial approach to improving health, particularly in obese patients. Benefits include weight loss, improved cardiovascular health, lower blood pressure, and improved glucose metabolism.
    Keywords:  RCT; diabetes; glucose metabolism; obesity; overweight; plant-based diets; weight loss
    DOI:  https://doi.org/10.3389/fnut.2022.952553
  146. Brain Res Bull. 2022 Sep 23. pii: S0361-9230(22)00257-X. [Epub ahead of print]190 69-83
      Three different barriers are formed between the cerebrovascular and the brain parenchyma: the blood-brain barrier (BBB), the blood-cerebrospinal fluid barrier (BCSFB), and the cerebrospinal fluid-brain barrier (CBB). The BBB is the main regulator of blood and central nervous system (CNS) material exchange. The semipermeable nature of the BBB limits the passage of larger molecules and hydrophilic small molecules, Food and Drug Administration (FDA)-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Although the complexity of the BBB affects CNS drug delivery, understanding the composition and function of the BBB can provide a platform for the development of new methods for CNS drug delivery. This review summarizes the classification of the brain barrier, the composition and role of the basic structures of the BBB, and the transport, barrier, and destruction mechanisms of the BBB; discusses the advantages and disadvantages of different drug delivery methods and prospects for future drug delivery strategies.
    Keywords:  ABC transporter; Blood-brain barrier; Blood-cerebrospinal fluid barrier; Brain barrier; Brain drug delivery; Tight junctions
    DOI:  https://doi.org/10.1016/j.brainresbull.2022.09.017
  147. Biomaterials. 2022 Sep 16. pii: S0142-9612(22)00440-9. [Epub ahead of print]289 121800
      Nanoformulations of small molecule drugs are essential to effectively deliver them and treat a wide range of diseases. They are normally complex to develop, lack predictability, and exhibit low drug loading. Recently, nanoparticles made via co-assembly of hydrophobic drugs and organic dyes, exhibited drug-loading of up to 90% with high predictability from the drug structure. However, these particles have relatively short stability and can formulate only a small fraction of the drug space. Here, we developed an automated workflow to synthesize and select novel dye stabilizers, based on their ability to inhibit drug aggregation-induced emission (AIE). We first screened and identified 10 drugs with previously unknown strong AIE activity and exploited this trait to automatically synthesize and select a new ultra-stabilizer named R595. Interestingly, it shares several synthetic similarities and advantages with polydopamine. We found that R595 is superior to myriad types of excipients and solubilizers such as cyclodextrins, poloxamers, albumin, and previously published organic dyes, in both long-term stability and drug compatibility. We investigated the biodistribution, pharmacokinetics, safety and efficacy of the AIEgenic MEK inhibitor trametinib-R595 nanoparticles in vitro and in vivo and demonstrated that they are non-toxic and effective in KRAS driven colon and lung cancer models.
    Keywords:  Aggregation induced emission; Automated discovery; Drug delivery; KRAS; Nanomedicine
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121800
  148. Cancer Metastasis Rev. 2022 Sep 26.
      The dense cancer microenvironment is a significant barrier that limits the penetration of anticancer agents, thereby restraining the efficacy of molecular and nanoscale cancer therapeutics. Developing new strategies to enhance the permeability of cancer tissues is of major interest to overcome treatment resistance. Nonetheless, early strategies based on small molecule inhibitors or matrix-degrading enzymes have led to disappointing clinical outcomes by causing increased chemotherapy toxicity and promoting disease progression. In recent years, photodynamic therapy (PDT) has emerged as a novel approach to increase the permeability of cancer tissues. By producing excessive amounts of reactive oxygen species selectively in the cancer microenvironment, PDT increases the accumulation, penetration depth, and efficacy of chemotherapeutics. Importantly, the increased cancer permeability has not been associated to increased metastasis formation. In this review, we provide novel insights into the mechanisms by which this effect, called photodynamic priming, can increase cancer permeability without promoting cell migration and dissemination. This review demonstrates that PDT oxidizes and degrades extracellular matrix proteins, reduces the capacity of cancer cells to adhere to the altered matrix, and interferes with mechanotransduction pathways that promote cancer cell migration and differentiation. Significant knowledge gaps are identified regarding the involvement of critical signaling pathways, and to which extent these events are influenced by the complicated PDT dosimetry. Addressing these knowledge gaps will be vital to further develop PDT as an adjuvant approach to improve cancer permeability, demonstrate the safety and efficacy of this priming approach, and render more cancer patients eligible to receive life-extending treatments.
    Keywords:  Cancer microenvironment; Collagen; Enhanced permeability and retention; Epithelial-to-mesenchymal transition; Focal adhesion kinase; Integrin; Mechanosignaling; Photochemistry; Rho-associated kinase
    DOI:  https://doi.org/10.1007/s10555-022-10064-0
  149. J Nanobiotechnology. 2022 Sep 29. 20(1): 431
      Precision medicine has put forward the proposition of "precision targeting" for modern drug delivery systems. Inspired by techniques from biology, pharmaceutical sciences, and nanoengineering, numerous targeted drug delivery systems have been developed in recent decades. But the large-scale applications of these systems are limited due to unsatisfactory targeting efficiency, cytotoxicity, easy removability, and instability. As such, the natural endogenous cargo delivery vehicle-extracellular vesicles (EVs)-have sparked significant interest for its unique inherent targeting properties, biocompatibility, transmembrane ability, and circulatory stability. The membranes of EVs are enriched for receptors or ligands that interact with target cells, which endows them with inherent targeting mission. However, most of the natural therapeutic EVs face the fate of being cleared by macrophages, resulting in off-target. Therefore, the specificity of natural EVs delivery systems urgently needs to be further improved. In this review, we comprehensively summarize the inherent homing mechanisms of EVs and the effects of the donor cell source and administration route on targeting specificity. We then go over nanoengineering techniques that modify EVs for improving specific targeting, such as source cell alteration and modification of EVs surface. We also highlight the auxiliary strategies to enhance specificity by changing the external environment, such as magnetic and photothermal. Furthermore, contemporary issues such as the lack of a gold standard for assessing targeting efficiency are discussed. This review will provide new insights into the development of precision medicine delivery systems.
    Keywords:  Biodistribution; Drug delivery; Extracellular vesicles; Nanoengineering EVs; Targeting
    DOI:  https://doi.org/10.1186/s12951-022-01638-9
  150. Phytochemistry. 2022 Sep 21. pii: S0031-9422(22)00362-4. [Epub ahead of print] 113446
      The genus Datura has been used as an important traditional medicine in China, as well as in other countries worldwide. This review summarizes the latest progress and perspective of the genus Datura, from the aspects of botany, traditional uses, phytochemistry, pharmacology, and toxicology. Up to May 2022, literatures were collected from online scientific databases, including Google Scholar, PubMed, SciFinder, CNKI, ACS, and Web of Science, and information was also obtained from "Flora Republicae Populairs Sinicae", Chinese Pharmacopoeia, Chinese herbal classic books, and Ph.D. and M. Sc. dissertations. Studies on chemical constituents, pharmacological activities, and toxicity are mainly focused on D. metel, D. stramonium, and D. inoxia. Furthermore, 496 compounds have been discovered from the genus Datura, including withanolides, alkaloids, flavonoids, terpenoids, phenylpropanoids, steroids, amino acids, aromatics, and aliphatics. Among them, withanolides and alkaloids are two main active constituents. Pharmacological activities of extracts and compounds have been studied from the aspects of antitumor, antiinflammation, antioxidant, antimicrobial, antispasmodic, anticoagulant, analgesic, hypoglycemic and xanthine oxidase inhibitory activities, as well as the effects on central nervous system and immune system. Modern pharmacological studies have provided more clues to elucidate the traditional usages. The toxicity of the genus Datura is noteworthy, especially the potential toxicity on organs. This review would provide a comprehensive and constructive overview for new drug development and utilization of the genus Datura.
    Keywords:  Botany; Datura L.; Pharmacology; Phytochemistry; Solanaceae; Toxicology; Traditional use
    DOI:  https://doi.org/10.1016/j.phytochem.2022.113446
  151. Crit Rev Food Sci Nutr. 2022 Sep 30. 1-23
      Bioactive compounds (bioactives) such as phenolic acids, coumarins, flavonoids, lignans and carotenoids have a marked improvement effect on human health by acting on body tissues or cells. Nowadays, with increasing levels of knowledge, consumers prefer foods that can provide bioactives beside the necessary nutrients (e.g., vitamins, essential fatty acids and minerals). However, an important barrier for incorporating bioactives into foods is their low thermal stability. Nevertheless, thermal processing is widely used by the food industries to achieve food safety and desired texture. The aim of this work is to give an overview of encapsulation technology to improve thermal stability of bioactives incorporated into different food products. Almost all thermal analysis and non-thermal methods in the literature suggest that incorporation of bioactives into different walls can effectively improve the thermal stability of bioactives. The level of such thermal enhancement depends on the strength of the bioactive interaction and wall molecules. Furthermore, contradictory results have been reported in relation to the effect of encapsulation technique using the same wall on thermal stability of bioactives. To date, the potential to increase the thermal resistance of various bioactives by gums, carbohydrates, and proteins have been extensively studied. However, further studies on the comparison of walls and encapsulation methods to form thermally stable carriers seem to be needed. In this regard, the same nature of bioactives and the specific protocol in the report of study results should be considered to compare the data and select the optimum conditions of encapsulation to achieve maximum thermal stability.
    Keywords:  Bioactive compounds; encapsulation; food products; thermal stability
    DOI:  https://doi.org/10.1080/10408398.2022.2127145
  152. Front Pharmacol. 2022 ;13 974794
      Chronic inflammation is associated with various chronic diseases, including cardiovascular disease, neurodegenerative disease, and cancer, which severely affect the health and quality of life of people. Oxidative stress induced by unbalanced production and elimination of reactive oxygen species (ROS) is one of the essential risk factors for chronic inflammation. Recent studies, including the studies of mushrooms, which have received considerable attention, report that the antioxidant effects of natural compounds have more advantages than synthetic antioxidants. Mushrooms have been consumed by humans as precious nourishment for 3,000 years, and so far, more than 350 types have been identified in China. Mushrooms are rich in polysaccharides, peptides, polyphenols, alkaloids, and terpenoids and are associated with several healthy biological functions, especially antioxidant properties. As such, the extracts purified from mushrooms could activate the expression of antioxidant enzymes through the Keap1/Nrf2/ARE pathway to neutralize excessive ROS and inhibit ROS-induced chronic inflammation through the NF-κB pathway. Recently, the antioxidant properties of mushrooms have been successfully applied to treating cardiovascular disease (CAD), neurodegenerative diseases, diabetes mellitus, and cancer. The present review summarizes the antioxidant properties and the mechanism of compounds purified from mushrooms, emphasizing the oxidative stress regulation of mushrooms to fight against chronic inflammation.
    Keywords:  antioxidants; chronic diseases; edible fungi; molecular mechanisms; natural compounds
    DOI:  https://doi.org/10.3389/fphar.2022.974794
  153. Plant Physiol Biochem. 2022 Nov 01. pii: S0981-9428(22)00416-8. [Epub ahead of print]190 248-261
      The vital signaling molecule 5-Aminolevulinic acid (ALA) plays critical roles in signal transduction and biological modulation under abiotic stresses. In this study, we explored the effects of exogenous ALA on low-light (LL) stress-induced photosynthesis and antioxidant system damage in tall fescue (Festuca arundinacea Schreb.) seedlings. LL stress decreased morphological index values and chlorophyll contents, while also reduced net photosynthetic rate (Pn) and the maximum quantum yield of photosystem II photochemistry (Fv/Fm). Notably, these restrictions were substantially alleviated by exogenous ALA. Moreover, the contents of chlorophyll and its synthetic precursors were significantly increased after ALA treatment. Meanwhile, ALA observably enhanced expression level of FaCHLG, FaHEMA, FaPOR, and FaCAO, which encode the chlorophyll precursors biosynthesis enzymes. Exogenous ALA repaired the damage to the chloroplast ultrastructure caused by LL stress and promoted the formation of ordered thylakoids and grana lamella. ALA also improved Rubisco activity and expression level of the photosynthetic enzyme genes FaRuBP, FaPRK, and FaGADPH. Additionally, application of exogenous ALA decreased relative electrolytic leakage and the accumulation of malondialdehyde (MDA), hydrogen peroxide (H2O2), and superoxide radicals (O2∙-), and increased the gene expression levels and activity of antioxidant enzymes. The ratios of ascorbic acid (AsA) to dehydroascorbic acid (DHA) and reduced glutathione (GSH) to oxidized glutathione (GSSG) were also increased significantly by application of ALA. Furthermore, all responses could be reversed by treatment with levulinic acid (LA). Thus, these results indicated that ALA protects tall fescue from LL stress through scavenging ROS, improving photosynthetic enzyme activity levels, increasing photosynthetic pigments contents, repairing chloroplast damage, and enhancing the photosynthesis rate.
    Keywords:  Antioxidant capacity; Chloroplast ultrastructure; Low-light stress; Photosynthesis; Photosynthetic pigments; Tall fescue
    DOI:  https://doi.org/10.1016/j.plaphy.2022.09.010
  154. Front Med Technol. 2022 ;4 869155
      Exposure to Low-Energy Amplitude-Modulated Radiofrequency Electromagnetic Fields (LEAMRFEMF) represents a new treatment option for patients with advanced hepatocellular carcinoma (AHCC). We focus on two medical devices that modulate the amplitude of a 27.12 MHz carrier wave to generate envelope waves in the low Hz to kHz range. Each provides systemic exposure to LEAMRFEMF via an intrabuccal antenna. This technology differs from so-called Tumour Treating Fields because it uses different frequency ranges, uses electromagnetic rather than electric fields, and delivers energy systemically rather than locally. The AutemDev also deploys patient-specific frequencies. LEAMRFEMF devices use 100-fold less power than mobile phones and have no thermal effects on tissue. Tumour type-specific or patient-specific treatment frequencies can be derived by measuring haemodynamic changes induced by exposure to LEAMRFEMF. These specific frequencies inhibited growth of human cancer cell lines in vitro and in mouse xenograft models. In uncontrolled prospective clinical trials in patients with AHCC, minorities of patients experienced complete or partial tumour responses. Pooled comparisons showed enhanced overall survival in treated patients compared to historical controls. Mild transient somnolence was the only notable treatment-related adverse event. We hypothesize that intracellular oscillations of charged macromolecules and ion flows couple resonantly with LEAMRFEMF. This resonant coupling appears to disrupt cell division and subcellular trafficking of mitochondria. We provide an estimate of the contribution of the electromagnetic effects to the overall energy balance of an exposed cell by calculating the power delivered to the cell, and the energy dissipated through the cell due to EMF induction of ionic flows along microtubules. We then compare this with total cellular metabolic energy production and conclude that energy delivered by LEAMRFEMF may provide a beneficial shift in cancer cell metabolism away from aberrant glycolysis. Further clinical research may confirm that LEAMRFEMF has therapeutic value in AHCC.
    Keywords:  Warburg effect; cancer therapy; electromagnetic fields; hepatocellular carcinoma; metabolism; microtubules; mitochondria; radiofrequency
    DOI:  https://doi.org/10.3389/fmedt.2022.869155
  155. Food Sci Nutr. 2022 Sep;10(9): 2922-2934
      The present study was designed to evaluate the nutritional composition of melon pulp Maazoun variety, in order to explore its potential attitude as a natural source of nutrients and bioactive molecules. The chemical characterization showed that the pulp was rich in moisture, carbohydrate, dietary fibers, and minerals, as well as carotenoids and phenolic compounds. The chromatographic analysis indicated that amentoflavone (16.14 mg/100 g) and gallic acid (13.56 mg/100 g) were the most abundant phenolic compounds. Melon flesh has an interesting volatile profile in which, mostly esters and alcohols are considered as the key odorants of this appreciated fruit. Melon juice was filtered through crossflow microfiltration that provides more translucent juice and accentuation of yellow color. During clarification process, the permeate flux was reduced by 50% in approximately 40 min. Results proved that the richness of melons in nutrients and bioactive phytochemicals makes them useful as a potential source of antioxidants and suitable as nutraceutical supplements.
    Keywords:  bioactive compounds; clarification process; melon (Cucumis melo L.) pulp; membrane technology; volatile profile
    DOI:  https://doi.org/10.1002/fsn3.2888
  156. Biotechnol Adv. 2022 Sep 22. pii: S0734-9750(22)00133-1. [Epub ahead of print]61 108037
      Bioactive or nutraceutical ingredients have been widely used in pursuit of health and well-being. However, the environmental instability, poor solubility and bioavailability, and unspecific delivery highly limited their practical values. By virtue of the unique shell-like structure, definite disassembly/reassembly behavior, and excellent safety profile of ferritin protein, it stands out among of various nano-materials and is emerging as one of the most promising vehicles for the encapsulation and delivery of bioactive ingredients or drugs. In this review, we present a systematic overview of recent advances of ferritin-based delivery systems from single-encapsulation, co-encapsulation, to compartmentalized-encapsulation of bioactive ingredients or drugs. Different encapsulation strategies for cargo loading as well as their advantages and drawbacks have been critically reviewed. This study emphasized the importance of the construction of compartmentalized delivery systems through the usage of ferritin nanocages, which exhibit great potential for facilitating the synergistic functionality of different types of cargos. Lastly, the applications of ferritin nanocages for physicochemical improvements and functionality achievements of loaded cargos are summarized. In conclusion, ferritin protein nanocages not only are excellent nanocarriers, but also can act as"multi-seated" vehicles for co-encapsulation and compartmentalized encapsulation of different cargos simultaneously.
    Keywords:  Co-encapsulation; Compartmentalized-encapsulation; Ferritin nanocages; Single-encapsulation; Synergistic functionality
    DOI:  https://doi.org/10.1016/j.biotechadv.2022.108037
  157. Bioact Mater. 2023 Mar;21 299-312
      To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosuppressive cancers like triple-negative breast cancer (TNBC), induction of immunogenic cell death (ICD) at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors. Herein, a self-amplified biomimetic nanosystem, mEHGZ, was constructed by encapsulation of epirubicin (EPI), glucose oxidase (Gox) and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin (CRT) over-expressed tumor cell membrane. EPI acts as an ICD inducer, Gox and hemin medicate the cascade generation of reactive oxygen species (ROS) to strengthen the ICD effect, and CRT-rich membrane as "eat me" signal promote presentation of the released antigens by dendritic cells (DCs) to invoke the tumor-immunity cycle. The biomimetic delivery system displays an amplified ICD effect via Gox oxidation, hydroxyl radical generation and glutathione (GSH) depletion. The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes (CTLs) infiltration, reversing an immunosuppressive tumor microenvironment to an immunoresponsive one. Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis, supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody. This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.
    Keywords:  Biomimetic nanosystem; Cell membrane; Immunogenic cell death; Immunotherapy; anti-PD-L1 antibody
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.08.028
  158. Mol Biol (Mosk). 2022 Sep-Oct;56(5):56(5): 795-807
      Changes in metabolic pathways are often associated with the development of a wide range of pathologies. Increased glycolysis under conditions of sufficient tissue oxygen supply and its dissociation from the Krebs cycle, known as aerobic glycolysis or the Warburg effect, is a hallmark of many malignant neoplasms. Identification of specific metabolic shifts can characterize the metabolic programming of individual types of tumor cells, the stage of their transformation, and predict their metastatic potential. Viral infection can also alter the metabolism of cells to support the process of viral replication. Infection with human immunodeficiency virus type 1 (HIV-1) is associated with an increased incidence of various cancers, and for some viral proteins a direct oncogenic effect was demonstrated. In particular, we showed that the expression of HIV-1 reverse transcriptase (RT) in 4T1 breast adenocarcinoma cells increases the tumorigenic and metastatic potential of cells in vitro and in vivo by a mechanism associated with the ability of RT to induce reactive oxygen species in cells (ROS). The aim of this work was to study the molecular mechanism of this process, namely the effect of HIV-1 RT on the key metabolic pathways associated with tumor progression: glycolysis and mitochondrial respiration. Expression of HIV-1 RT had no effect on the glycolysis process. At the same time, it led to an increase in mitochondrial respiration and the level of ATP synthesis in the cell, while not affecting the availability of the substrates, carbon donors for the Krebs cycle, which excludes the effect of RT on the metabolic enzymes of cells. Increased mitochondrial respiration was associated with restoration of the mitochondrial network despite the RT-induced reduction in mitochondrial mass. Increased mitochondrial respiration may increase cell motility, which explains their increased tumorigenicity and metastatic potential. These data are important for understanding the pathogenesis of HIV-1 infection, including the stimulation of the formation and spread of HIV-1 associated malignancies.
    Keywords:  HIV-1; breast adenocarcinoma cells; glycolysis; metabolic enzymes; mitochondrial mass; mitochondrial respiration; reverse transcriptase
    DOI:  https://doi.org/10.31857/S0026898422050160
  159. Oxid Med Cell Longev. 2022 ;2022 9035547
      In the treatment of malignant tumors, the effectiveness of cisplatin (CP) is limited by its nephrotoxicity, leading to cisplatin-induced acute kidney injury (CP-AKI). Polydatin (PD) has been demonstrated to regulate autophagy in tumors, sepsis, and diabetes. We have recently confirmed that PD attenuated CP-AKI by inhibiting ferroptosis, but it is not clear whether PD can regulate autophagy to protect from CP-AKI. The purpose of this study was to investigate the effect of PD on autophagy in CP-treated HK-2 cells and CP-AKI mouse models, exploring the role of sirtuin 6 (SIRT6) upregulated by PD. In this study, the blocking of autophagy flux was observed in both CP-treated HK-2 cells in vitro and CP-AKI mouse models in vivo, whereas this blocking was reversed by PD, which was characterized by the increase of autophagy microtubule-associated protein light chain 3 II expression and autophagolysosome/autophagosome ratio and the decrease of p62 expression. Furthermore, PD also significantly increased the expression of SIRT6 in vivo and in vitro. The protective effect of PD manifested by the stimulating of autophagy flux, with the reducing of inflammatory response and oxidative stress, which included downregulation of tumor necrosis factor-α and interleukin-1β, decreased activity of myeloperoxidase and content of malondialdehyde, and increased activity of superoxide dismutase and level of glutathione, both in vivo and in vitro, was reversed by either inhibition of autophagy flux by chloroquine or downregulation of SIRT6 by OSS-128167. Taken together, the present findings provide the first evidence demonstrating that PD exhibited nephroprotective effects on CP-AKI by restoring SIRT6-mediated autophagy flux mechanisms.
    DOI:  https://doi.org/10.1155/2022/9035547
  160. Integr Cancer Ther. 2022 Jan-Dec;21:21 15347354221124861
      Owing to the crucial role of Src in cancer metastasis, interruption of Src and its signaling has been considered a promising strategy for cancer metastasis treatment. Cucurbitacin B, a dietary triterpenoid, has been shown to possess anti-proliferative and apoptosis-inducing activities in cholangiocarcinoma (CCA) cells via suppressing the activation of FAK which is a main downstream Src effector. We hypothesized that cucurbitacin B might act as a Src suppressant which conferring anti-metastasis effect against CCA cells. To investigate this, the role of Src in regulating metastasis behavior of CCA cells and the effect of cucurbitacin B on Src-mediated metastatic phenotype of these cells were determined. The results showed that activation of Src significantly enhanced the migratory and invasive abilities of CCA cells. Molecular analysis revealed that Src-facilitated metastasis behavior of CCA cells occurred by modifying expression of a wide range of metastasis-related genes in the cells. Consistent with gene expression results, activation of Src significantly induced the protein expression of 2 important metastasis-associated molecules, MMP-9 and VEGF. Cucurbitacin B markedly suppressed activation of Src and its key effector, FAK. As a consequence, the alteration of expression profiles of metastasis-associated genes induced by Src activator in CCA cells was diminished by cucurbitacin B treatment. The compound also down-regulated Src-induced expression of MMP-9 and VEGF proteins in the cells. Moreover, molecular docking analysis revealed that cucurbitacin B could interact with Src kinase domain and possibly restrain the kinase from being activated by hindering the ATP binding. In conclusion, cucurbitacin B exhibited anti-metastatic property in CCA cells via negatively influencing Src and Src-related oncogenic signaling. This compound may therefore be a potential therapeutic drug for further development as an anti-Src agent for treatment of metastatic CCA.
    Keywords:  FAK; Src; cholangiocarcinoma; cucurbitacin B; metastasis
    DOI:  https://doi.org/10.1177/15347354221124861
  161. Curr Med Chem. 2022 Sep 29.
       BACKGROUND: Tumor plasticity processes impact the treatment of different types of cancer, as an effect of this, the bioprospecting of therapies from natural and/or synthetic compounds that can regulate or modulate the immune system has increased considerably. Oxadiazole derivatives are structures that exhibit diverse biological activities. Therefore, this review aimed to evaluate the activity of oxadiazole compounds against tumor cell lines and their possible immune-mediated mechanisms.
    METHODS: A search in PubMed, Web of Science, and Science Direct databases was carried out on studies published from January 1, 2004, to January 31, 2022, using "oxadiazole*" in combination with the other descriptors "cancer" and "macrophage". Only experimental in vitro and in vivo articles were included. Similar search strategy was used in Derwent Innovation Index database for technology mapping. The search was performed on Drugbank using the descriptor oxadiazole for commercial mapping.
    RESULTS: 23 oxadiazole studies were included in this review and some biological activities linked to antitumoral and immunomodulation were listed. Oxadiazole derivatives inhibited tumor cell growth and proliferation, blocked cell cycle, modulated mitochondrial membrane potential, presented immunoregulatory activity by different mechanisms reducing proinflammatory cytokines levels and acted directly as selective inhibitors of the COX enzyme. There was an increase in oxadiazole patent publications in the last 11 years, with emphasis on chemistry, pharmacy and biotechnology applied to microbiology areas. Compounds with 1,2,4-oxadiazole isomer are predominant in patent publications and approved drugs as observed in the technological and commercial mapping.
    CONCLUSION: Therefore, oxadiazole derivatives are therapeutic molecules that can be considered promising for the development of cancer therapies.
    Keywords:  Cancer; Chemotherapy; Immunomodulation; Inflammatory mediators; Macrophages; Oxadiazoles
    DOI:  https://doi.org/10.2174/0929867329666220929145619
  162. Int J Nanomedicine. 2022 ;17 4401-4417
       Introduction: Currently, the main treatment for advanced breast cancer is still chemotherapy. Immunological and chemical combination therapy has a coordinated therapeutic effect and achieves some efficacy. However, the immunosuppressive tumor microenvironment is a major cause for the failure of immunotherapy in breast cancer. CpG oligodeoxynucleotides can activate the tumor immune microenvironment to reverse the failure of immunotherapy.
    Methods: In this study, we designed an amphiphilic peptide micelle system (Co-LMs), which can targeted delivery of the immune adjuvant CpG and the chemotherapeutic drug doxorubicin to breast cancer tumors simultaneously. The peptide micelle system achieved tumor microenvironment pH and redox-sensitive drug release.
    Results and Discussion: Co-LMs showed 2.3 times the antitumor efficacy of chemotherapy alone and 5.1 times the antitumor efficacy of immunotherapy alone in triple-negative breast cancer mice. Co-LMs activated cytotoxic CD8+ T lymphocytes and CD4+ T cells in mice to a greater extent than single treatments. We also found that Co-LMs inhibited the metastasis of circulating tumor cells in the bloodstream to some extent. These results indicate that the Co-LMs offer a promising therapeutic strategy against triple-negative breast cancer.
    Keywords:  CpG; chemo-immunotherapy; nanoparticles; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.2147/IJN.S377702
  163. Chembiochem. 2022 Sep 29.
      In recent years, peptide-based hydrogels have emerged as efficient biomaterials. The ability to mimic extracellular matrix environments broadens their biomedical applications, including 3D cell culturing, drug delivery, tissue engineering, and wound healing. While extensive research efforts are inclined to decipher the effect of amino acid switching or shuffling on the self-assembly of peptides, the action of the terminal protecting group requires prime attention and is still in its infancy. Keeping this in mind, herein, we report the comparative study of the effect of Fmoc (N-fluorenyl-9-methoxycarbonyl) and acetyl group as N-terminal protecting group in the ultra-short peptide (LIVAGD) undergoing self-assembly to form hydrogel. Additionally, C-terminal amino acid substitution in the self-assemblies of Fmoc LIVAGD and Fmoc LIVAGK was also explored. To examine the efficacy and potency of the hydrogels; MTT, antimicrobial, antihaemolytic, and anti-inflammatory assays were performed. Fmoc enhanced the biocompatibility and support towards cultured cells while lysine provided antibacterial effect to the hydrogel.  In vivo efficacy was examined and Fmoc protected peptides showed better wound healing. RT-PCR and docking studies validated the fact that Fmoc peptides-based hydrogels display anti-inflammatory action.
    Keywords:  Anti-inflammatory; Antibacterial; Hydrogel; self-assembly; wound healing
    DOI:  https://doi.org/10.1002/cbic.202200499
  164. Exp Hematol Oncol. 2022 Sep 28. 11(1): 66
      Similar to neurodegenerative diseases, the concept that tumors are prion like diseases has been proposed in recent years. p53, the most well-known tumor suppressor, has been extensively studied for its expression, mutation, and function in various tumors. Currently, an interesting phenomenon of p53 prion-like aggregation has been found in several tumors, and studies have found that its pathological aggregation may lead to functional alterations and ultimately affect tumor progression. It has been demonstrated that the mechanism of p53 aggregation involves its mutation, domains, isoform, etc. In addition to p53 itself, some other factors, including Zn2+ concentration, pH, temperature and chaperone abnormalities, can also contribute to p53 aggregation. Although there are some studies about the mechanism and role of p53 aggregation and amyloidosis in tumors, there still exist some controversies. In this paper, we review the mechanism of p53 amyloid fibril structure and discuss the characteristics and effects of p53 amyloid aggregation, as well as the pathogenic mechanism leading to the occurrence of aggregation in tumors. Finally, we summarize the various inhibitors targeting p53 aggregation and prion-like behavior. In conclusion, a comprehensive understanding of p53 aggregation can expand our understanding of the causes leading its loss of physiological function and that targeting p53 aggregation might be a promising therapeutic strategy for tumor therapy.
    Keywords:  Aggregation; Amyloid; Cancer; Mechanism; p53
    DOI:  https://doi.org/10.1186/s40164-022-00317-7
  165. Biofactors. 2022 Sep 26.
      The search for bioactive components for the development of functional foods and nutraceuticals has received tremendous attention. This is due to the increasing awareness of their therapeutic potentials, such as antioxidant, anti-inflammatory, antihypertensive, anti-cancer properties, etc. Food proteins, well known for their nutritional importance and their roles in growth and development, are also sources of peptide sequences with bioactive properties and physiological implications. Cereal and legume grains are important staples that are processed and consumed in various forms worldwide. However, they have received little attention compared to other foods. This review therefore is geared towards surveying the literature for an appraisal of research conducted on bioactive peptides in cereal and legume grains in order to identify what the knowledge gaps are. Studies on bioactive peptides from cereal and legume grains are still quite limited when compared to other food items and most of the research already carried out have been done without identifying the sequence of the bioactive peptides. However, the reports on the antioxidative, anticancer/inflammatory, antihypertensive, antidiabetic properties show there is much prospect of obtaining potent bioactive peptides from cereal and legume grains which could be utilized in the development of functional foods and nutraceuticals.
    Keywords:  anti-inflammatory; antioxidant; bioactive peptides; cereal grains; legume grains
    DOI:  https://doi.org/10.1002/biof.1889
  166. Pharm Dev Technol. 2022 Sep 26. 1-35
      Triptolide (TP), a diterpenoid triepoxide, exhibits strong anti-cancer activities, especially against pancreatic cancer, but its clinical application is limited by organ toxicity. TP was combined with diammonium glycyrrhizinate (DG), as a cytoprotective agent, in a novel oral complex lipid emulsion (TP/DG-CLE) to increase the therapeutic index of TP against pancreatic cancer. The emulsion was produced by subjecting phospholipid and active components to high shear conditions using high-pressure homogenization resulting in droplets of essentially neutral or small positive charge and consistent size below 200nm. Pharmacokinetic studies in Sprague Dawley rats revealed an AUC (0-8h) of TP following oral dosing of TP/DG-CLE that was 4-fold higher than that achieved for triptolide/diammonium glycyrrhizinate suspension, demonstrating significantly higher TP bioavailability and longer residence time in the bloodstream. Tissue distribution data obtained in mice demonstrated that TP/DG-CLE having a TP/DG weight ratio of 1:22.5 preferentially accumulated in the pancreas. Moreover, toxicology assays in rats provided indications of minor liver damage following daily administration of the emulsion for two weeks. Together these studies establish complex lipid emulsions containing triptolide and DG as a promising oral formulation for treatment of pancreatic cancer and establish a platform for developing new chemotherapeutic treatments.
    Keywords:  diammonium glycyrrhizinate; oral delivery; pancreas; pharmacokinetics; toxicology; triptolide
    DOI:  https://doi.org/10.1080/10837450.2022.2127767
  167. J Food Biochem. 2022 Sep 27. e14427
      Osteoarthritis (OA) is a disease due to the aging of the articular cartilage, a post-mitotic tissue that stays functioning until primary homeostatic processes fail. Because of pain and disability, OA significantly influences national healthcare expenses and patient quality of life. It is a whole-joint illness characterized by inflammatory and oxidative signaling pathways and significant epigenetic alterations that cause cartilage extracellular matrix degradation. The canonical Wnt pathway (Wnt/β-catenin pathway) and nuclear factor kappa B (NF-κB) signaling pathways may function in joint tissues by modulating the activity of synovial cells, osteoblasts, and chondrocytes. However, finding innovative ways to treat osteoarthritis and get the joint back to average balance is still a struggle. Nutraceuticals are dietary supplements that promote joint health by balancing anabolic and catabolic signals. New therapeutic methods for OA treatment have been developed based on many research findings that show nutraceuticals have strong anti-inflammation, antioxidant, anti-bone resorption, and anabolic properties. For the treatment of osteoarthritis, we explore the possible involvement of nutraceuticals that target the Wnt/β-catenin and NF-κB pathways. PRACTICAL APPLICATIONS: In keeping with the aging population, osteoarthritis is becoming more widespread. In this extensive research, we studied the role of the Wnt/β-catenin and NF-κB pathway in OA formation and progression. Nutraceuticals that target these OA-related signaling pathways are a viable therapy option. Wnt/β-catenin and NF-κB signaling pathway are inhibited by polyphenols, flavonoids, alkaloids, and vitamins from the nutraceutical category, making them possible therapeutic drugs for OA therapy.
    Keywords:  arthritis; bioactive compounds; inflammation; nutraceuticals; pathway; signaling
    DOI:  https://doi.org/10.1111/jfbc.14427
  168. World J Gastroenterol. 2022 Jul 28. 28(28): 3535-3554
      Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Viral hepatitis is a significant risk factor for HCC, although metabolic syndrome and diabetes are more frequently associated with the HCC. With increasing prevalence, there is expected to be > 1 million cases annually by 2025. Therefore, there is an urgent need to establish potential therapeutic targets to cure this disease. Peroxisome-proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that plays a crucial role in the patho-physiology of HCC. Many synthetic agonists of PPARγ suppress HCC in experimental studies and clinical trials. These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC. However, some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy. Thus natural PPARγ agonists can be an alternative to exploit this potential target for HCC treatment. In this review, the regulatory role of PPARγ in the pathogenesis of HCC is elucidated. Furthermore, the experimental and clinical scenario of both synthetic and natural PPARγ agonists against HCC is discussed. Most of the available literature advocates PPARγ as a potential therapeutic target for the treatment of HCC.
    Keywords:  Anticancer; Hepatocellular carcinoma; Natural agonists; Peroxisome proliferator-activated receptor-γ; Thiazolidinediones
    DOI:  https://doi.org/10.3748/wjg.v28.i28.3535
  169. Int J Pharm. 2022 Sep 24. pii: S0378-5173(22)00785-2. [Epub ahead of print] 122231
      Naringenin is a bioflavonoid mainly found in citrus fruits. It presents many pharmacological benefits, including a remarkable anti-inflammatory activity, but its oral bioavailability is poor. To overcome this drawback, this work proposes a transdermal administration of such bioflavonoid, considering its use in the chronic treatment of inflammatory conditions. For this, it aims to develop a chitosan-based film that guarantees a consistent transdermal delivery of the drug. First, naringenin's in vitro anti-inflammatory effect on T-cell proliferation was evaluated, followed by research on the modulation of gene expression for inflammatory factors in peripheral blood mononuclear cells. Chitosan films were then prepared and characterized. Afterward, naringenin release profile from a selected film was determined as well as the drug permeation across porcine skin provided by the film. Naringenin induced the expression of the anti-inflammatory factors IL-10 and TGF-β1 while inhibiting the expression of the pro-inflammatory cytokine IL-1β and limiting T-cell proliferation. The chitosan film was successfully developed, and the drug was progressively released to the physiological media following both first order and Korsmeyer-Peppas kinetics. When topically applied, the chitosan film guaranteed a constant and continuous diffusion of naringenin across the skin over 72 h. Indeed, the permeation flux of naringenin was 0.30 ± 0.01 µg/cm2/h, which means a concentration in the receptor solution 14-fold (p<0.05) higher than that provided by the drug solution. Thus, the chitosan film represents a promising transdermal alternative for the long-term treatment of inflammatory conditions using naringenin.
    Keywords:  Anti-inflammatory; Drug delivery; Flavonoid; Permeation; Skin
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122231
  170. Biomaterials. 2022 Sep 17. pii: S0142-9612(22)00450-1. [Epub ahead of print]289 121810
      Radiotherapy is adopted to obliterate multiple malignant tumors clinically, which might also induce antitumor immune response. However, traditional radiotherapy is not enough to ablate tumors and activate long-term immunological response. Here, we developed a hybrid nanoplatform (MGTe) composed of GTe (glutathione (GSH) decorated Te nanoparticles) and fusing tumor cell membranes (TM) and bacterial outer membranes (BM). In this nanoplatform, GTe was designed for radiotherapy sensitization, concurrently the fusion of TM and BM was expected for amplifying antitumor immune. With a high-Z element, MGTe could enhance radiosensitivity by reactive oxygen species (ROS) production and cancer cell immunogenic death (ICD) under X-ray irradiation, which would also trigger antitumor immune. At meanwhile, TM and BM would further enlarge the immunological effects through antigen presenting cells (APCs) maturation and cytotoxic T lymphocytes (CTLs) stimulation. In this synergistic strategy, the combination of MGTe and X-ray showed significant tumor inhibition by radiation-driven immunotherapy, which will find great potential as an attractive clinical alternative to fight against tumor with reduced side effects.
    Keywords:  Bacterial; Membrane fusion; Nanoparticle; Radiosentization; Tumor therapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121810
  171. Methods Mol Biol. 2023 ;2572 81-89
      Digital pathology has the potential to quantify tumor markers accurately and reproducibly with various cellular and subcellular localizations in tissues, thus filling a need in cancer research. As a case study, we quantified the percentage of necrosis, microvessels density, and monocarboxylate transporter 4 (MCT4) expression in two ovarian cancer patient-derived xenograft (PDX) models subcutaneously injected in NOD/SCID mice. PDX models were treated with bevacizumab, an antiangiogenic drug, that targets vascular endothelial growth factor A (VEGF-A). Specific signal analysis algorithms allowed us to study morphologic, vascular, and metabolic modifications induced by antiangiogenic therapy by a quantitative, reproducible, and reliable approach.
    Keywords:  Angiogenesis; Digital pathology; Glycolysis; Ovarian cancer; Tumor xenografts
    DOI:  https://doi.org/10.1007/978-1-0716-2703-7_6
  172. Int J Biol Macromol. 2022 Sep 22. pii: S0141-8130(22)02116-X. [Epub ahead of print]
      The hyperglycemia microenvironment of diabetic foot ulcer (DFU) led to impaired angiogenesis and delayed wound healing. An elevated matrix metalloproteinase (MMP) is one of the significant factors to delay healing. Herein, we designed a deferoxamine (DFO)-loaded MMP responsive hydrogel, thus promoting angiogenesis and accelerating wound healing by increasing the expression of hypoxia-inducible factor-1α (HIF-1α). Hyaluronic acid was modified with maleimide and grafted with MMP-cleavable peptides (HA-peptide). Then, HA-peptide was crosslinked with oxidized dextran (Dex-CHO) based on Schiff-base reaction. In vitro tests showed that the hydrogel had excellent swelling properties, degradation behavior, rheological characterization, and biocompatibility. Compared with an MMP-insensitive hydrogel, the MMP-cleavable hydrogel allowed for efficient release of DFO continuously within 24 h, which could address the problems of the extremely short half-life and neurotoxicity of DFO. In vivo experiments demonstrated that the hydrogel wound dressing facilitated faster wound epithelialization and accelerated angiogenesis in diabetic rats. Altogether, the DFO-loaded MMP-cleavable hydrogel may lead to a potential and novel treatment strategy of DFU.
    Keywords:  Deferoxamine; Diabetic wound healing; Hydrogel; MMP-cleavable; Self-healing
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.185
  173. Drug Metab Pers Ther. 2022 Sep 28.
       OBJECTIVES: To analyze the phytochemicals, antioxidant, and anticancer activities on MCF-7 human breast cancer cell line using aqueous, hydro-ethanol, and methanol extracts of different Unani drugs, e.g., Halela Siyah, Aftimoon, Bisfayej, Ustukhudoos, and Kutki.
    METHODS: The qualitative examination (alkaloids, terpenoids, tannins, and saponins), anticancer activity, and an antioxidant assay of the three different extracts were done by MTT assay and DPPH assay, respectively, using different Unani drugs.
    RESULTS: The qualitative examination confirmed the substantive presence of phytochemical constituents in all the extracts of these drugs. The Methanolic extract of Halela Siyah had the highest DPPH scavenging activity (91%), while Bisfayej had the lowest (58%). Similarly, the hydro-ethanolic extract showed approximately identical activity for Halela Siyah (89%), Aftimoon (88%), Bisfayej (84%), Kutki (82%), and Ustukhudoos (81%). The aqueous extracts of Halela Siyah (88%) had the highest DPPH scavenging activity, whereas Bisfayej (73%) had the lowest. The methanolic extract of Aftimoon demonstrated the greatest anticancer activity (IC50 - 108), while Aftimoon showed the least activity (IC50 - 316). Halela Siyah (IC50 - 175) and Aftimoon (IC50 - 178) showed substantially the same activity in aqueous extracts. Ustukhudoos hydro-ethanol extracts had the highest (IC50 - 130) activity, whereas Aftimoon had the lowest (IC50 - 204).
    CONCLUSIONS: In conclusion, our findings evaluated the presence of phytochemicals, good antioxidant activity, and anticancer activity in different extracts of drugs used in this study. The study shows these drugs have potential anticancer activity against breast cancer in MCF-7 cell lines.
    Keywords:  MCF-7 cell lines; Unani drugs; anticancer; antioxidant
    DOI:  https://doi.org/10.1515/dmpt-2022-0110
  174. J Biophotonics. 2022 Sep 28. e202200040
      Curcumin has great potential as a photosensitizer, but it has low solubility in aqueous solutions. This study reports the antimicrobial efficacy of photodynamic inactivation (PDI) mediated by a curcumin-loaded liquid crystal precursor (LCP) on in situ dental biofilms. Thirty volunteers used intraoral devices containing enamel samples for 48 h for biofilm formation. The samples were then removed from the device and treated either with LCP with 160 μM of curcumin plus illumination at 18 J/cm2 (C+L+ group) or with LCP without curcumin in the dark (C-L- group). Following this, the biofilm from the samples was plated for quantifying the viable colonies at 37°C for 48 h. Specific and nonspecific media were used for the presumptive isolation of Streptococcus mutans, Lactobacillus species/aciduric microorganisms, Candida species, and total microbiota. The C+L+ group showed a highly significant (p<0.001) reduction in the log10 (colony forming units/mL) values as compared to the C-L-group for all culture media. Hierarchical linear regression indicated that there may be predictors at individual volunteer level explaining the difference in the PDI efficacy among different individuals (p=0.001). The LCP system retained curcumin and released it slowly and continuously, thus protecting the drug from photodegradation. LCP with curcumin is considered effective for the photoinactivation of dental biofilms, but the PDI efficacy may differ based on the host's individual characteristics. This article is protected by copyright. All rights reserved.
    Keywords:  curcumin; dental plaque; liquid crystal; photochemotherapy
    DOI:  https://doi.org/10.1002/jbio.202200040
  175. Mol Biol (Mosk). 2022 Sep-Oct;56(5):56(5): 732-750
      Human cytomegalovirus (HCMV) DNA and proteins are often detected in malignant tumors, warranting studies of the role that HCMV plays in carcinogenesis and tumor progression. HCMV proteins were shown to regulate the key processes involved in tumorigenesis. While HCMV as an oncogenic factor just came into focus, its ability to promote tumor progression is generally recognized. The review discusses the viral factors and cell molecular pathways that affect the resistance of cancer cells to therapy. CMV inhibits apoptosis of tumor cells, that not only promotes tumor progression, but also reduces the sensitivity of cells to antitumor therapy. Autophagy was found to facilitate either cell survival or cell death in different tumor cells. In leukemia cells, HCMV induces a "protective" autophagy that suppresses apoptosis. Viral factors that mediate drug resistance and their interactions with key cell death pathways are necessary to further investigate in order to develop agents that can restore the tumor sensitivity to anticancer drugs.
    Keywords:  anticancer drug resistance; anticancer therapy; apoptosis; autophagy; cytomegalovirus; oncomodulation
    DOI:  https://doi.org/10.31857/S0026898422050135
  176. Med Oncol. 2022 Sep 29. 39(12): 221
      Sorafenib (SOR) is currently the first line molecular targeting agent for advanced liver cancer therapy. Unfortunately, the insensitivity of liver cancer patients to SOR relatively limits its effectiveness. Huaier (HUA), a natural medicinal parasitic fungus found on the Sophora japonica Linn., has been widely employed as an adjuvant medication for numerous malignancies due to its potent anti-tumoral properties. This study aims to elucidate the enhancing therapeutic efficacy of HUA on SOR treatment in hepatocellular carcinoma (HCC) cells and mouse models. The CCK-8, clone formation, flow cytometry, immunofluorescence, transmission electron microscopy, western blot, bioinformatic analysis, and xenograft tumor assays were performed to evaluate the synergistic anti-hepatoma efficacy and mechanisms of HUA-SOR combination treatment on HCC cells. The results revealed combination treatment further inhibited proliferation, promoted apoptosis, enhanced autophagy of HCC cells, and suppressed the growth of transplanted tumors in mice, compared with either HUA or SOR treatment alone. For Hep3B and Huh7 cells, the optimal synergistic doses of HUA in combination with SOR were 8 mg/mL + 4 μM and 4 mg/mL + 2 μM, with combination index values of 0.646 and 0.588, respectively. Additionally, the underlying mechanisms might be related to biological processes that are mediated by mammalian target of rapamycin (mTOR). The combination treatment downregulated the protein expression levels of p-mTOR, p-p70S6K, p62, and upregulated the protein expression levels of Beclin-1 and LC3B-II. The mTOR activator MHY1485 attenuated the effect of HUA-SOR combination by inhibiting autophagy, suggesting HUA may potentiate the sensitivity of HCC cells to SOR by partially inducing mTOR-mediated autophagic cell death. These findings might provide a rationale experimental foundation for clinical applications of HUA with SOR.
    Keywords:  Autophagic cell death; Hepatocellular carcinoma; Huaier; Sorafenib
    DOI:  https://doi.org/10.1007/s12032-022-01797-7
  177. Front Oncol. 2022 ;12 956793
      Colorectal cancer (CRC) is a common type of malignant digestive tract tumor with a high incidence rate worldwide. Currently, the clinical treatment of CRC predominantly include surgical resection, postoperative chemotherapy, and radiotherapy. However, these treatments contain severe limitations such as drug side effects, the risk of recurrence and drug resistance. Some natural compounds found in plants, fungi, marine animals, and bacteria have been shown to inhibit the occurrence and development of CRC. Although the explicit molecular mechanisms underlying the therapeutic effects of these compounds on CRC are not clear, classical signaling transduction pathways such as NF-kB and Wnt/β-catenin are extensively regulated. In this review, we have summarized the specific mechanisms regulating the inhibition and development of CRC by various types of natural compounds through nine signaling pathways, and explored the potential therapeutic values of these natural compounds in the clinical treatment of CRC.
    Keywords:  colorectal cancer; flavonoids; natural compounds; polyphenol; signaling pathway
    DOI:  https://doi.org/10.3389/fonc.2022.956793
  178. Front Pharmacol. 2022 ;13 983428
      Alismatis rhizoma is a traditional Chinese medicine. Studies have demonstrated that Alismatis rhizoma also has therapeutic effects on metabolic syndrome. However, the pharmacodynamic material basis and mechanism are still unclear. First, UHPLC/Q-Orbitrap MS was used to detect the chemical components of the Alismatis rhizoma extract, and 31 triterpenoids and 2 sesquiterpenes were preliminarily identified. Then, to investigate the mechanism of the Alismatis rhizoma extract on metabolic syndrome, a mouse model of metabolic syndrome induced by high-fructose drinks was established. The results of serum biochemical analysis showed that the levels of TG, TC, LDL-C, and UA after the Alismatis rhizoma extract treatment were markedly decreased. 1H-NMR was used to conduct non-targeted metabolomics studies. A total of 20 differential metabolites were associated with high-fructose-induced metabolic syndrome, which were mainly correlated with 11 metabolic pathways. Moreover, UHPLC/Q-Orbitrap MS lipidomics analysis found that a total of 53 differential lipids were screened out. The results showed that Alismatis rhizoma extract mainly reduces the synthesis of glycerophospholipid and ceramide and improves the secretion of bile acid. This study shows that the Alismatis rhizoma extract can treat metabolic syndrome mainly by inhibiting energy metabolism, amino acid metabolism, and regulating bile acid to reduce phospholipid content.
    Keywords:  Alismatis rhizoma extract; fructose; lipidomics; metabolic syndrome; metabolomics
    DOI:  https://doi.org/10.3389/fphar.2022.983428
  179. Bioact Mater. 2023 Mar;21 313-323
      Hydrogels are emerging as the most promising dressings due to their excellent biocompatibility, extracellular matrix mimicking structure, and drug loading ability. However, existing hydrogel dressings exhibit limited breathability, poor environmental adaptability, potential drug resistance, and limited drug options, which extremely restrict their therapeutic effect and working scenarios. Here, the current research introduces the first paradigm of hydrogel textile dressings based on novel gelatin glycerin hydrogel (glyhydrogel) fibers fabricated by the Hofmeister effect based wet spinning. Benefiting from the unique knitted structure, the textile dressing features excellent breathability (1800 times that of the commercially available 3 M dressing) and stretchability (535.51 ± 38.66%). Furthermore, the glyhydrogel textile dressing can also withstand the extreme temperature of -80 °C, showing the potential for application in subzero environments. Moreover, the introduction of glycerin endows the textile dressing with remarkable antibacterial property and expands the selection of loaded drugs (e.g., clindamycin). The prepared glyhydrogel textile dressing shows an excellent infected wound healing effect with a complete rat skin closure within 14 days. All these functions have not been achievable by traditional hydrogel dressings and provide a new approach for the development of hydrogel dressings.
    Keywords:  Breathable; Dual antibacterial; Hydrogel dressing; Hydrogel textile; Skin regeneration
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.08.014
  180. Chem Biol Interact. 2022 Sep 27. pii: S0009-2797(22)00403-3. [Epub ahead of print] 110198
      One of the leading global causes of death is cancer; even though several treatment methods have improved survival rates, the incidence and fatality rates remain high. Naphthoquinones are a type of quinone that is found in nature and has vital biological roles. These chemicals have anticancer (antineoplastic), analgesic, anti-inflammatory, antimalarial, antifungal, antiviral, antitrypanosomal, antischistosomal, leishmanicidal, and anti-ulcerative effects. Direct addition of a substituent group to the 1,4-naphthoquinone ring can alter the naphthoquinone's oxidation/reduction and acid/base characteristics, and the activity can be altered. Because of their pharmacological properties, such as anticancer activity and probable therapeutic application, naphthoquinones have greatly interested the scientific community. Some chemicals having a quinone ring in malignant cells have been found to have antiproliferative effects. Naphthoquinones' deadly impact is connected with the inhibition of electron transporters, the uncoupling of oxidative phosphorylation, the creation of ROS, and the formation of protein adducts, notably with -SH enzyme groups. This review article aims to discuss naphthoquinones and their derivatives, which act against cancer and their future perspectives. This review covers several studies highlighting the potent anticancer properties of naphthoquinones. Further, various proposed mechanisms of anticancer actions of naphthoquinones have been summarized in this review.
    Keywords:  Anticancer activity; Antiproliferative; Lapachol; Naphthoquinones
    DOI:  https://doi.org/10.1016/j.cbi.2022.110198
  181. Photodiagnosis Photodyn Ther. 2022 Sep 24. pii: S1572-1000(22)00416-1. [Epub ahead of print]40 103130
       OBJECTIVES: This study aimed to compare the antimicrobial effects of the shock wave enhanced emission photoacoustic streaming (SWEEPS) technique and Antimicrobial photodynamic therapy (aPDT) with curcumin and nano-curcumin photosensitizers on Enterococcus faecalis (E. faecalis) biofilm in root canals of extracted teeth.
    MATERIALS AND METHODS: This experimental study was conducted on extracted single-rooted human teeth. The teeth were decoronated at the cementoenamel junction, the root canals were instrumented with BioRace system, and their apices were sealed. Smear layer was removed, and the teeth were autoclave-sterilized. E. faecalis strains were cultured in sterile brain heart infusion (BHI) and a bacterial suspension with 0.5 McFarland standard concentration was prepared. The root canals were inoculated with the bacterial suspension and incubated at 37 °C for 4 weeks. The teeth were then divided into 12 groups (curcumin, nano-curcumin, curcumin + LED, nano-curcumin + LED, curcumin + SWEEPS, nano-curcumin + SWEEPS, curcumin + LED + SWEEPS, nano-curcumin + LED + SWEEPS, SWEEPS, positive control and negative control). The number of colony forming units (CFUs) was counted and analyzed by one-way ANOVA and Tukey's test.
    RESULTS: A significant difference was noted in colony count among the groups (P<0.001). LED alone had the lowest and nano-curcumin + LED + SWEEPS had the highest root canal cleaning efficacy. SWEEPS along with curcumin, nano-curcumin, and LED significantly decreased the bacterial count compared with other groups (P<0.05).
    CONCLUSION: Application of the SWEEPS technique with curcumin and nano-curcumin as photosensitizer activated by LED in aPDT improved the reduction of E. faecalis in root canals.
    Keywords:  Antimicrobial photodynamic therapy; Enterococcus faecalis; Er:YAG; Root Canals; SWEEPS
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103130
  182. Redox Biol. 2022 Sep 08. pii: S2213-2317(22)00236-1. [Epub ahead of print]57 102464
      Methionine is an essential amino acid, involved in the promotion of growth, immunity, and regulation of energy metabolism. Over the decades, research has long focused on the beneficial effects of methionine supplementation, while data on positive effects of methionine restriction (MR) were first published in 1993. MR is a low-methionine dietary intervention that has been reported to ameliorate aging and aging-related health concomitants and diseases, such as obesity, type 2 diabetes, and cognitive disorders. In addition, MR seems to be an approach to prolong lifespan which has been validated extensively in various animal models, such as Caenorhabditis elegans, Drosophila, yeast, and murine models. MR appears to be associated with a reduction in oxidative stress via so far mainly undiscovered mechanisms, and these changes in redox status appear to be one of the underlying mechanisms for lifespan extension and beneficial health effects. In the present review, the association of methionine metabolism pathways with redox homeostasis is described. In addition, the effects of MR on lifespan, age-related implications, comorbidities, and diseases are discussed.
    Keywords:  Aging; Cognitive disorders; Metabolic syndrome; Methionine restriction; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.redox.2022.102464
  183. Cancer Drug Resist. 2022 ;5(3): 612-624
      Aim: The development of chemotherapy resistance is the major obstacle in the treatment of advanced prostate cancer (PCa). Extracellular vesicles (EVs) secretion plays a significant role among different mechanisms contributing to chemoresistance. Hence, inhibition of EVs release may increase the efficacy of chemotherapeutic drugs against PCa. Methods: Paclitaxel (PTX) resistant PCa cells (PC3-R and DU145-R) were treated with GW4869, a known exosome biogenesis inhibitor. EVs were isolated from the conditioned media by ExoQuick-based precipitation method and characterized for concentration and size distribution by nanoparticle tracking analysis. The effect of GW4869 treatment on the survival and growth of PCa cells was assessed by MTT, and colony formation assays in vitro, and ectopic PC3-R xenografts in male athymic nude mice in vivo. The effect of other EV biogenesis inhibitors, imipramine and dimethyl amiloride (DMA), treatment was also analyzed on the survival of PC3-R cells. Results: GW4869 (10-20 µM) treatment of PTX resistant PCa cells significantly reduced the release of small EVs (50-100 nm size range) while increasing the release of larger EVs (> 150 nm in size), and inhibited their clonogenicity. Moreover, GW4869 (5-20 µM) treatment (24-72h) significantly inhibited the survival of PC3-R cells in a dose-dependent manner. We observed a similar growth inhibition with both imipramine (5-20 µg/mL) and DMA (5-20 µg/mL) treatment in PC3-R cells. Furthermore, GW4869 treatment (IP) in mice bearing PC3-R xenografts significantly reduced the tumor weight (65% reduction, P = 0.017) compared to the vehicle-treated control mice without causing any noticeable toxicity. Conclusion: Inhibiting the release of EVs could sensitize the resistant PCa cells to chemotherapy.
    Keywords:  GW4869; Prostate cancer; chemoresistance; extracellular vesicles; paclitaxel
    DOI:  https://doi.org/10.20517/cdr.2022.26
  184. Front Pharmacol. 2022 ;13 933732
      Ferritinophagy is a type of autophagy mediated by nuclear receptor activator 4 (NCOA4), which plays a role in inducing ferroptosis by regulating iron homeostasis and producing reactive oxygen species in cells. Under physiological conditions, ferritinophagy maintains the stability of intracellular iron by regulating the release of free iron. Studies have demonstrated that ferritinophagy is necessary to induce ferroptosis; however, under pathological conditions, excessive ferritinophagy results in the release of free iron in large quantities, which leads to lipid peroxidation and iron-dependent cell death, known as ferroptosis. Ferritinophagy has become an area of interest in recent years. We here in review the mechanism of ferritinophagy and its association with ferroptosis and various diseases to provide a reference for future clinical and scientific studies.
    Keywords:  NCOA4; ferritinophagy; ferroptosis; heme degradation; iron homeostasis
    DOI:  https://doi.org/10.3389/fphar.2022.933732
  185. Int Ophthalmol. 2022 Sep 26.
       PURPOSE: The aim of the present study was to investigate increase in delivery of drug upon formulation as mucoadhesive microemulsion system and further to investigate possibility of any cytotoxic effects using such formulation.
    MATERIAL AND METHODS: Considering hydrophilic and small molecular nature of the drug, it was attempted to be formulated as microemulsion, by using pseudo ternary phase diagram method. Thus, three types of microemulsions were prepared; oil in water, water in oil type and chitosan-coated microemulsion. These microemulsions were characterized for several physicochemical properties like size, zeta potential, Polydispersity index, and compared for in vitro cell viability and ex vivo corneal irritation study.
    RESULTS: All three microemulsions were quite stable, transparent and homogenous systems. They showed similar drug release pattern, but highest ex vivo goat corneal permeation was observed with Chitosan coated microemulsion when compared with ganciclovir solution.
    CONCLUSION: All microemulsions were found to be non-irritant in in vitro cell viability assay and ex vivo corneal irritation study, indicating the potential of using such systems for delivery of drug to eye.
    Keywords:  Cell viability assay; Chitosan; Ganciclovir; Microemulsions; Mucoadhesive
    DOI:  https://doi.org/10.1007/s10792-022-02514-z
  186. ChemMedChem. 2022 Sep 30.
      The efficacy of platinum drugs is limited by severe side effects, drug resistance, and poor pharmacokinetic properties. Utilizing long-lasting blood components as drug carriers is a promising strategy to improve the circulation half-lives and tumor accumulation of platinum drugs. Non-immunogenic blood cells such as erythrocytes and blood proteins such as albumins, which have long lifespans, are suitable for the delivery of platinum drugs. In this concept, we briefly summarize the strategies of applying blood components as promising carriers to deliver small-molecule platinum drugs for cancer treatment. Examples of platinum drugs that are encapsulated, non-covalently attached, and covalently bound to erythrocytes and plasma proteins such as albumin and apoferritin are introduced. The potential methods to increase the stability of platinum-based thiol-maleimide conjugates involved in these delivery systems are also discussed. This concept may enlighten researchers with more ideas on the future development of novel platinum drugs that have excellent pharmacokinetic properties and antitumor performance in vivo.
    Keywords:  Albumin; Anticancer Agents; Drug Delivery; Erythrocyte; Platinum Drugs
    DOI:  https://doi.org/10.1002/cmdc.202200482
  187. Front Oncol. 2022 ;12 980620
      It is widely thought that the tumor microenvironment (TME) provides the "soil" for malignant tumors to survive. Prior to metastasis, the interaction at the host site between factors secreted by primary tumors, bone-marrow-derived cells, with stromal components initiates and establishes a pre-metastatic niche (PMN) characterized by immunosuppression, inflammation, angiogenesis and vascular permeability, as well as lymphangiogenesis, reprogramming and organotropism. Ferroptosis is a non-apoptotic cell death characterized by iron-dependent lipid peroxidation and metabolic constraints. Ferroptotic cancer cells release various signal molecules into the TME to either suppress or promote tumor progression. This review highlights the important role played by ferroptosis in PMN, focusing on the relationship between ferroptosis and PMN characteristics, and discusses future research directions.
    Keywords:  ferroptosis; immune escape; pre-metastatic niche; therapeutic strategies; tumor
    DOI:  https://doi.org/10.3389/fonc.2022.980620
  188. J Nanobiotechnology. 2022 Sep 29. 20(1): 429
      Despite many nano-based strategies devoted to delivering cisplatin for tumor therapy, its clinical benefits are compromised by poor tissue penetration and limited DNA adducts formation of the drug. Herein, a cisplatin loading nanomotor based janus structured Ag-polymer is developed for cisplatin delivery of deeper tissue and increased DNA adducts formation. The nanomotor displayed a self-propelled tumor penetration fueled by hydrogen peroxide (H2O2) in tumor tissues, which is catalytically decomposed into a large amount of oxygen bubbles by Ag nanoparticles (NPs). Notably, cisplatin could elevate the intracellular H2O2 level through cascade reactions, further promote the degradation of Ag NPs accompanied with the Ag+ release, which could downregulate intracellular Cl- through the formation of AgCl precipitate, thereby enhancing cisplatin dechlorination and Pt-DNA formation. Moreover, polymer can also inhibit the activity of ALKBH2 (a Fe2+-dependent DNA repair enzyme) by chelating intracellular Fe2+ to increase the proportion of irreparable Pt-DNA cross-links. It is found that deep tissue penetration, as well as the increased formation and maintenance of Pt-DNA adducts induced by the nanomotor afford 80% of tumor growth inhibition with negligible toxicity. This work provides an important perspective of resolving chemotherapeutic barriers for boosting cisplatin therapy.
    Keywords:  Cisplatin chemotherapy; DNA adduct; Ion regulation; Nanomotor; Tumor penetration
    DOI:  https://doi.org/10.1186/s12951-022-01622-3
  189. Front Chem. 2022 ;10 1014208
      With high mortality, stroke has become a serious threat to human health. Nevertheless, the strategy for stroke therapy is quite limited in the clinic till now. In this research, we prepared a novel neuroprotective nanoformulation (OEA Liposomes) via encapsulating endogenous N-oleoylethanolamine (OEA) in liposomes for intravenous administration. The formulation largely increased the solubility and bioavailability of OEA. Then the following systematic experiments stated the excellent neuroprotective effect of OEA Liposomes in vivo. The survival rate of the nanodrug group was largely increased to 75%, while that of the Middle Cerebral Artery Occlusion (MCAO) group was only 41.7%. And the severe neurological functional deficit of the MCAO rats was also significantly improved. What's more, the OEA Liposomes could inhibit the apoptosis of neurons and the inflammation of reperfusion to a very slight level, indicating their outstanding neuroprotective effect. These results indicated that the OEA Liposomes have a great potential for clinic anti-stroke application.
    Keywords:  OEA; drug delivery; ischemia reperfusion; neurprotective effect; stroke
    DOI:  https://doi.org/10.3389/fchem.2022.1014208
  190. Neuro Endocrinol Lett. 2022 Sep 01. 43(3): 173-179
       BACKGROUNDS: The prognosis of patients with osteosarcoma in many cases remains poor, and life expectancy with lung metastases is around 12 months. Chemotherapy and radiotherapy can only temporarily control neoplastic progression, followed by developing chemo and radioresistant tumours.
    METHODS: This is a retrospective observational study on 15 patients diagnosed with osteosarcoma and treated by a multitherapy approach. The multitherapy consisted of somatostatin and analogous (octreotide) all-trans-retinoic acid (ATRA), β-Carotene, axerophthol dissolved in vitamin E, vitamin D, vitamin C, melatonin (MLT), proteoglycans, glycosaminoglycans, hydroxyurea, and sodium butyrate.
    RESULTS: This multitherapy increased the survival rate and life quality, without overt toxicity, compared to the standard treatment for osteosarcomas. The agents in this approach have several functions. They exert antiproliferative, antiangiogenic, cytostatic, antioxidant, antimetastatic, and immunomodulating features. Moreover, the inclusion of ATRA, MLT, and sodium butyrate has reinforced antitumor properties on cancer stem cells. Furthermore, the non-cytolytic and non-cytotoxic metronomic hydroxyurea dosage increased the biological therapy outcome by strengthening antitumor capability.
    FINDINGS: This multitherapy approach is effective against osteosarcoma.
    INTERPRETATION: The multistrategy of this multitherapy therapy are inhibiting the proliferative-invasiveness and neoplastic angiogenesis, silencing the survival system of cancer stem cells, enhancing the immunomodulatory and antioxidant activities, improving vitality and efficiency of normal cells, and depressing the efficiency and vitality of neoplastic ones.
  191. Med Clin North Am. 2022 Sep;pii: S0025-7125(22)00078-5. [Epub ahead of print]106(5): 767-784
      Two of the leading chronic diseases are cardiovascular disease (CVD) and cancer. A cornerstone of prevention for CVD and cancer is a healthy dietary pattern throughout the lifespan. Dietary patterns represent the totality of the diet and reflect habitual consumption of combinations and quantities of foods and nutrients that cumulatively affect health and disease. This article summarizes recent evidence on the relationship of diet quality as measured by adherence to healthy dietary patterns and CVD and cancer risk reduction. Optimal adherence to a healthy dietary pattern decreases CVD and cancer risk; even small changes in diet quality are beneficial.
    Keywords:  Cancer; Cardiovascular disease; Dietary recommendations; Healthy dietary patterns
    DOI:  https://doi.org/10.1016/j.mcna.2022.06.001
  192. Chem Biodivers. 2022 Sep 26. e202200202
      In this study, copper complexes with Curcumin (Cur) and 2,2'-bipyridine-5,5'-dicarboxylic acid (BPYD) were synthesized and their cytotoxicity on the MDA-MB-231 cell lines was evaluated. The resulting complex was characterized using FTIR, UV/VIS, CHNS, TGA, ICP-MS, and Mass spectroscopy techniques. The in-vitro cytotoxicity was studied on the MDA-MB-231 as a cancerous cell line and the HUVEC as a normal cell line. Reactive oxygen species (ROS) production was measured using the 2',7'-dichlorofluorescein diacetate (DCFDA) test in the MDA-MB-231 cancer cell lines. The in-vitro assays revealed that all synthesized copper complexes exhibited a higher cytotoxicity effect than carboplatin as a positive control on the MDA-MB-231 cells. While the synthesized complexes exhibited cytotoxic effects on cancerous cell lines, they are practically safe on normal cells. The Cu-Cur-BPYD complexes (a5 & b5) exhibited higher cytotoxicity on MDA-MB-231 cells with IC50 s around 4.9 and 2.3 mM, respectively. It can be concluded that the synthesized Cu-Cur-BPYD complexes (a5 & b5) could be considered effective anticancer candidates in complementary studies.
    Keywords:  anti-cancer activity; bipyridine dicarboxylate; copper (II) complexes; curcumin; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1002/cbdv.202200202
  193. Chemistry. 2022 Sep 28.
      Organelle-targeted type I photodynamic therapy (PDT) shows great potential to overcome the hypoxic microenvironment in solid tumors. Endoplasmic reticulum (ER) is an indispensable organelle in cells with important biological functions. When ER is damaged due to the production of reactive oxygen species (ROS), the accumulation of misfolded proteins will interfere with ER homeostasis, resulting in ER stress. Here, an ER-targeted benzophenothiazine-based photosensitizer NBS-ER was presented. ER targeting modification significantly reduced the dark toxicity and improved phototoxicity index (PI). NBS-ER could effectively produce O 2 -˙with near-infrared irradiation, making its phototoxicity under hypoxia close to that under normoxia. Meanwhile, the photoinduced ROS triggered ER stress and induced apoptosis. In addition, NBS-ER possessed excellent photodynamic therapeutic effect in 4T1-tumor-bearing mice.
    Keywords:  benzophenothiazine; endoplasmic reticulum; lysosome damage; superoxide anion radicals; type I photodynamic therapy
    DOI:  https://doi.org/10.1002/chem.202202680
  194. Int J Biol Macromol. 2022 Sep 24. pii: S0141-8130(22)02108-0. [Epub ahead of print]
      Suitable wound dressings for accelerating wound healing are actively being designed and synthesised. In this study, thiolated chitosan (tCh)/oxidized carboxymethyl cellulose (OCMC) hydrogel containing Cu doped borate bioglass (BG) was developed as a wound dressing to improve wound healing in a full-thickness skin defect of mouse animal model. Thiolation was also used to incorporate thiol groups into chitosan (Ch) to enhance its water solubility and mucoadhesion characteristics. Here, the in situ forming hydrogel was successfully developed using the Schiff-based reaction, and its physio-chemical and antibacterial characteristics were examined. Borate BG was also incorporated in the generated hydrogel to promote angiogenesis and tissue regeneration at the wound site. Investigations of in vitro cytotoxicity assays demonstrated that the synthesised hydrogels were non-toxic, antimicrobial, and promoted cell growth. These results inspired us to investigate the effectiveness of skin wound healing in a mouse model. On the backs of animals, two full-thickness wounds were created and treated utilising two different treatment conditions: (1) OCMC/tch hydrogel, (2) OCMC/tch/borate BG, and (3) control defect. The wound closure ratio, collagen deposition, and angiogenesis activity were measured after 14 days to determine the healing efficacy of the in situ hydrogels used as wound dressings. Overall, the hydrogel containing borate bioactive glass was maintained in the defect site, healing efficiency was replicable, and wound healing was apparent. In conclusion, we found consistent angiogenesis, remodelling, and accelerated wound healing, which we propose may have beneficial effects on the repair of skin defects.
    Keywords:  Angiogenesis; Antibacterial activity; Borate bioglass; Hydrogel; Oxidized carboxymethyl cellulose; Thiolated chitosan; Wound dressings
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.177
  195. Discov Oncol. 2022 Oct 01. 13(1): 97
       BACKGROUND: The activities of MYC, the androgen receptor, and its associated pioneer factors demonstrate substantial reprogramming between early and advanced prostate cancer. Although previous studies have shown a shift in cellular metabolic requirements associated with prostate cancer progression, the epigenetic regulation of these processes is incompletely described. Here, we have integrated chromatin immunoprecipitation sequencing (ChIP-seq) and whole-transcriptome sequencing to identify novel regulators of metabolism in advanced prostate tumors characterized by elevated MYC activity.
    RESULTS: Using ChIP-seq against MYC, HOXB13, and AR in LNCaP cells, we observed redistribution of co-bound sites suggestive of differential KMT2A activity as a function of MYC expression. In a cohort of 177 laser-capture microdissected foci of prostate tumors, KMT2A expression was positively correlated with MYC activity, AR activity, and HOXB13 expression, but decreased with tumor grade severity. However, KMT2A expression was negatively correlated with these factors in 25 LuCaP patient-derived xenograft models of advanced prostate cancer and 99 laser-capture microdissected foci of metastatic castration-resistant prostate cancer. Stratified by KMT2A expression, ChIP-seq against AR and HOXB13 in 15 LuCaP patient-derived xenografts showed an inverse association with sites involving genes implicated in lipid metabolism, including the arachidonic acid metabolic enzyme PLA2G4F. LuCaP patient-derived xenograft models grown as organoids recapitulated the inverse association between KMT2A expression and fluorine-18 labeled arachidonic acid uptake in vitro.
    CONCLUSIONS: Our study demonstrates that the epigenetic activity of transcription factor oncogenes exhibits a shift during prostate cancer progression with distinctive phenotypic effects on metabolism. These epigenetically driven changes in lipid metabolism may serve as novel targets for the development of novel imaging agents and therapeutics.
    Keywords:  Lipid metabolism; Prostate cancer; Transcriptional regulation
    DOI:  https://doi.org/10.1007/s12672-022-00565-3
  196. J Control Release. 2022 Sep 27. pii: S0168-3659(22)00638-1. [Epub ahead of print]
      The oral route is the most convenient and simplest mode of administration. Nevertheless, orally administration of some commonly used therapeutic drugs, such as polypeptides, therapeutic proteins, small-molecule drugs, and nucleic acids, remains a major challenge due to the harsh gastrointestinal environment and the limited oral bioavailability. Extracellular vesicles (EVs) are diverse, nanoscale phospholipid vesicles that are actively released by cells and play crucial roles in intercellular communications. Some EVs have been shown to survive with the gastrointestinal tract (GIT) and can cross biological barriers. The potential of EVs to cross the GIT barrier makes them promising natural delivery carriers for orally administered drugs. Here, we introduce the uniqueness of EVs and their feasibility as oral drug delivery vehicles (ODDVs). Then we provide a general description of the different cellular EVs based oral drug delivery systems (ODDSs) currently under study and emphasize the contribution of endogenous features and multifunctional properties of EVs to the delivery performance. The current obstacles of moving EVs based ODDSs from bench to bedside are also discussed.
    Keywords:  Bioavailability; Extracellular vesicles; Gastrointestinal barrier; Natural drug carriers; Oral administration
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.043
  197. Curr Drug Targets. 2022 Sep 22.
      Epidemiological evidence continues to accumulate on the effect of stress and depression with cancer initiation and progression. Depression has been introduced as an independent predictor of increased cancer mortality. Whereas early intervention for depression increases the survival rate. Even some evidence has given prognostic value for depression to predict cancer recurrence and mortality. This article presents current evidence on the correlations of molecular mechanisms of cancer and depression through; I. The evidence shows the role of pre-existing depression and anxiety in the development and progression of cancer. II. The Immune system performs a crucial role in stress, depression, and cancer. III. The role of stress and depression-induced inflammation. IV. The evidence has proposed that cancer may result in depression and the effect of depression on cancer outcome. In conclusion, the importance of preventive interventions to monitor patients' mental health during cancer treatment is very significant and should not be underestimated. In other words, the initial interventions can improve depressive symptoms and increase cancer survival. On the other hand, by identifying key biomarkers of depression, physicians can identify cancer patients who are at risk for depression or those who may not respond to routine treatments. Understanding how the cancer environment can cause pathophysiological phenomena helps develop new anti-depressant therapies and identify cancer patients that may be present during cancer. It can also help if the patients with cancer are prone to depression.
    Keywords:  Depression; anti-depressant; cancer; immune; stress; system
    DOI:  https://doi.org/10.2174/1389450123666220922094403