bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–12–11
forty-nine papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Targeting glycolysis for cancer therapy using drug delivery systems.
  2. Perspectives on Challenges in Cannabis Drug Delivery Systems: Where Are We?
  3. Multifunctional ROS-Responsive and TME-Modulated Lipid-Polymer Hybrid Nanoparticles for Enhanced Tumor Penetration.
  4. Cordycepin Inhibits the Growth of Hepatocellular Carcinoma by Regulating the Pathway of Aerobic Glycolysis.
  5. Orally administered docetaxel-loaded chitosan-decorated cationic PLGA nanoparticles for intestinal tumors: formulation, comprehensive in vitro characterization, and release kinetics.
  6. Targeting redox regulation and autophagy systems in cancer stem cells.
  7. Effects of the Mediterranean diet polyphenols on cancer development.
  8. Natural Products as the Modulators of Oxidative Stress: An Herbal Approach in the Management of Prostate Cancer.
  9. Mitochondrial respiration inhibitor enhances the anti-tumor effect of high-dose ascorbic acid in castration-resistant prostate cancer.
  10. Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research.
  11. 5-Fluorouracil nano-delivery systems as a cutting-edge for cancer therapy.
  12. Targeting of non-apoptotic cancer cell death mechanisms by quercetin: Implications in cancer therapy.
  13. A Comparative Study on Micelles, Liposomes and Solid Lipid Nanoparticles for Paclitaxel Delivery.
  14. Functions and modulation of PKM2 activity by human papillomavirus E7 oncoprotein (Review).
  15. Current advances on the therapeutic potential of pinocembrin: An updated review.
  16. [Research progress on liposome and nanomicelle targeted drug delivery system across blood-brain barrier].
  17. A two-pronged strategy to alleviate tumor hypoxia and potentiate photodynamic therapy by mild hyperthermia.
  18. Application of cinnamic acid in the structural modification of natural products: A review.
  19. Resveratrol derivatives: Synthesis and their biological activities.
  20. The magic bullet: Niclosamide.
  21. Recent advances in targeted gene silencing and cancer therapy by nanoparticle-based delivery systems.
  22. Natural flavonoids exhibit potent anticancer activity by targeting microRNAs in cancer: A signature step hinting towards clinical perfection.
  23. Marine-derived Natural Products as Anticancer Agents.
  24. Targeting ferroptosis, the achilles' heel of breast cancer: A review.
  25. Nanotechnology-based approaches overcome lung cancer drug resistance through diagnosis and treatment.
  26. Thiolated pectin-chitosan composites: Potential mucoadhesive drug delivery system with selective cytotoxicity towards colorectal cancer.
  27. Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias.
  28. Polyphenols and Lactobacillus reuteri in oral health.
  29. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.
  30. The impact of the microbiome in cancer: Targeting metabolism of cancer cells and host.
  31. Compartmentalized regulation of lipid signaling in oxidative stress and inflammation: Plasmalogens, oxidized lipids and ferroptosis as new paradigms of bioactive lipid research.
  32. Glutamine metabolism and radiosensitivity: Beyond the Warburg effect.
  33. [The p53 Tumor Suppressor and Copper Metabolism: An Unrevealed but Important Link].
  34. Natural compounds targeting nuclear receptors for effective cancer therapy.
  35. Tumor targeted delivery of mycobacterial adjuvant encapsulated chitosan nanoparticles showed potential anti-cancer activity and immune cell activation in tumor microenvironment.
  36. A review of recent strategies to improve the physical stability of phycocyanin.
  37. Luteolin: a flavonoid with a multifaceted anticancer potential.
  38. Autophagy: An important target for natural products in the treatment of bone metabolic diseases.
  39. Folate receptor-targeted near-infrared photodynamic therapy for folate receptor-overexpressing tumors.
  40. Licorice (Glycyrrhiza glabra L.)-Derived Phytochemicals Target Multiple Signaling Pathways to Confer Oncopreventive and Oncotherapeutic Effects.
  41. Metformin: new applications for an old drug.
  42. Vitamin D Supplementation: Does It Have a Preventative or Therapeutic Role in Cancer?
  43. Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels.
  44. Selenium, selenoproteins and cancer of the thyroid.
  45. Cancer Stem Cells: Biology and Therapeutic Implications.
  46. Implications of reactive oxygen species in lung cancer and exploiting it for therapeutic interventions.
  47. Nitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy.
  48. Editorial: Cancer systems biology.
  49. DNA damage independent inhibition of NF-kB transcription by anthracyclines.
  1. J Control Release. 2022 Dec 06. pii: S0168-3659(22)00817-3. [Epub ahead of print]
    Targeting glycolysis for cancer therapy using drug delivery systems.
    Yongzhuo Huang.
      There is close crosstalk between cancer metabolism and immunity. Cancer metabolism regulation is a promising therapeutic target for cancer immunotherapy. Warburg effect is characterized by abnormal glucose metabolism that includes common features of increased glucose uptake and lactate production. The aerobic glycolysis can reprogram the cancer cells and promote the formation of a suppressive immune microenvironment. As a case in point, lactate plays an essential role in tumorigenesis, which is the end product of glycolysis as well as serves as a fuel supporting cancer cell survival. Meanwhile, it is also an important immune regulator that drives immunosuppression in tumors. Immunometabolic therapy is to intervene tumor metabolism and regulate the related metabolites that participate in the innate and acquired immunity, thereby reinstalling the immune balance and eliciting anticancer immune responses. In this contribution to the Orations - New Horizons of the Journal of controlled Release I will provide an overview of glucose metabolism in tumors and its effects on drug resistance and tumor metastasis, and present the advance of glycolysis-targeting therapy strategies with drug delivery techniques, as well as discuss the challenges in glycolysis-targeting immunometabolic therapy.
    Keywords:  Glycolysis; Immunotherapy; Nanomedicine; Targeted drug delivery; Tumor microenvironment; cancer metabolism
    DOI:  https://doi.org/10.1016/j.jconrel.2022.12.003
  2. Med Cannabis Cannabinoids. 2022 Jan-Dec;5(1):5(1): 102-119
    Perspectives on Challenges in Cannabis Drug Delivery Systems: Where Are We?
    Manikandan Palrasu, Lillianne Wright, Manish Patel, Lindsey Leech, Scotty Branch, Shea Harrelson, Saeed Khan.
      Cannabis and its natural derivatives have emerged as promising therapeutics for multiple pathological and nonpathological medical conditions. For example, cannabinoids, the most popular and biologically active chemicals in cannabis, aid in many clinical ailments, including pain, inflammation, epilepsy, sleep disturbances or insomnia, multiple sclerosis, anorexia, schizophrenia, neurodegenerative diseases, anti-nausea, and most importantly, cancer. Despite the comprehensive benefits, certain aspects of cannabis present unique challenges in the medical cannabis landscape. Recent studies have highlighted the inherent challenges associated with cannabinoids' formulation like low solubility, rapid metabolism, poor bioavailability, and erratic pharmacokinetics - all of which contribute to the limited efficacy of cannabinoids. Several efforts are underway to address the bottlenecks and modify the formulations along with the delivery systems to achieve greater solubility/bioavailability, potency, and efficacy in treatment settings while minding the necessary standards for purity associated with the pharmaceutical industry. The current article presents a perspective on (1) a working knowledge of cannabinoids and their mechanisms of action, (2) the landscape of using medicinal cannabis for cancer-related medical conditions along with adversities, (3) current approaches, formulations, and challenges in medicinal cannabis delivery systems (oral, transdermal, pulmonary, and transmucosal), and lastly, (4) emerging approaches to improve delivery systems.
    Keywords:  Cancer; Cannabinoids; Cannabis; Drug delivery systems; Nanomedicine; Pain
    DOI:  https://doi.org/10.1159/000525629
  3. Int J Nanomedicine. 2022 ;17 5883-5897
    Multifunctional ROS-Responsive and TME-Modulated Lipid-Polymer Hybrid Nanoparticles for Enhanced Tumor Penetration.
    Rui Ni, Lele Huang, Zhen Li, Wenli Zhang, Yajie Wang, Yan Shen, Jianxin Wang, Weigen Lu.
       Purpose: To enhance tumor penetration by formulation design and tumor microenvironment (TME) modulation, herein a novel reactive oxygen species (ROS)-responsive size/shape transformable lipid-polymer hybrid nanoparticle (LPN) has been fabricated for the co-delivery of an anticancer and collagen-inhibition drug.
    Methods: A ROS-responsive poly(D, L-lactide)-thioketal-polyethylene glycol (PLA-TK-PEG) co-polymer was synthesized. LPNs were then fabricated by encapsulation of losartan (LST)-loaded micelles as the core to support paclitaxel (PTX)-loaded liposomes. The PEG content in the lipid shell of LPNs was then adjusted to obtain the size-/shape-transformable LPNs (M/LST-Lip/PTX-PEG5%). The ROS-responsiveness was observed in vitro by transmission electron microscopy and the tumor-penetration of the LPNs was evaluated in 3D tumor spheroids by confocal laser scanning microscopy. Tumor-targeting, tumor-penetrating, and antitumor efficacies of the NPs in 4T1 tumor-bearing mice were determined by in vivo imaging.
    Results: ROS-responsive micellar core degradation and the transformation of spherical LPNs (120nm) to smaller 40 mm discoid nanoparticles (NP) were observed. The transformable LPNs exhibited enhanced capacity of penetration in contrast to the un-transformable preparations in three-dimensional (3D) tumor spheroids. Furthermore, synergetic penetrating enhancement was achieved by LST-loaded transformable LPNs in 4T1 and fibroblast cell mixed 3D tumor spheroids. The improved tumor penetration of LST-loaded transformable LPNs was observed in vivo, which could be due to their collagen inhibiting and size/shape transformable effect. Due to their enhanced penetrability, LST and PTX-loaded transformable LPNs demonstrated significant in vivo antitumor efficacy in comparison to other preparations.
    Conclusion: The results confirmed the efficacy of M/LST-Lip/PTX-PEG5% in tumor targeting, collagen inhibition in TME, and enhanced tumor penetration. This novel drug delivery system can therefore play a substantial role in improving the therapeutic efficacy of antitumor drugs combined with TME-improving agents.
    Keywords:  ROS responsiveness; collagen inhibition; combination therapy; drug delivery; lipid-polymer hybrid nanoparticles; losartan; paclitaxel; tumor penetration
    DOI:  https://doi.org/10.2147/IJN.S383517
  4. Evid Based Complement Alternat Med. 2022 ;2022 6454482
    Cordycepin Inhibits the Growth of Hepatocellular Carcinoma by Regulating the Pathway of Aerobic Glycolysis.
    Ya Chen, Yuan Jiang, Xinyu Huang, Lin Chen, Hao Yang, Jian Zhao, Beibei Liang.
      Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China, with a high incidence and mortality rate. Glucose metabolism reprogramming is a major characteristic of tumor cells. Increasing evidence indicates that aerobic glycolysis is associated with tumor growth and insensitivity to chemotherapy. Cordycepin inhibits the growth of HCC cells, but the mechanism is yet to be elucidated. Herein, in vitro and in vivo methods were utilized to investigate the cordycepin-inhibited growth of HCC by regulating the metabolic pathway of aerobic glycolysis. In vitro analyses using colony formation and flow cytometry revealed that cordycepin inhibits HCC cells' proliferation and promotes apoptosis. In addition, cordycepin reduced the production of lactic acid and pyruvate, reduced the uptake of glucose, and decreased the extracellular acidification in HCC cells. Specifically, cordycepin inhibited the expression of HK2, LDHA, and PKM2 in aerobic glycolysis via the AMPK-Akt pathway. Taken together, these findings revealed that cordycepin reduces the tumor energy supply and decreases lactic acid production, thereby inhibiting the growth of HCC cells by regulating the metabolic pathway of aerobic glycolysis. These findings might provide novel insights into the mechanisms underlying cordycepin-mediated inhibition of tumor growth as well as a new treatment for HCC.
    DOI:  https://doi.org/10.1155/2022/6454482
  5. Beilstein J Nanotechnol. 2022 ;13 1393-1407
    Orally administered docetaxel-loaded chitosan-decorated cationic PLGA nanoparticles for intestinal tumors: formulation, comprehensive in vitro characterization, and release kinetics.
    Sedat Ünal, Osman Doğan, Yeşim Aktaş.
      Intestinal cancers are the third most lethal cancers globally, beginning as polyps in the intestine and spreading with a severe metastatic tendency. Chemotherapeutic drugs used in the treatment of intestinal tumors are usually formulated for parenteral administration due to poor solubility and bioavailability problems. Pharmaceutically, clinical failure due to a drug's wide biodistribution and non-selective toxicity is one of the major challenges of chemotherapy. In addition, parenteral drug administration in chronic diseases that require long-term drug use, such as intestinal tumors, is challenging in terms of patient compliance and poses a burden in terms of health economy. Especially in the field of chemotherapy research, oral chemotherapy is a subject that has been intensively researched in recent years, and developments in this field will provide serious breakthroughs both scientifically and socially. Development of orally applicable nanodrug formulations that can act against diseases seen in the distant region of the gastrointestinal tract (GIT), such as intestinal tumor, brings with it a series of difficulties depending on the drug and/or GIT physiology. The aim of this study is to develop an oral nanoparticle drug delivery system loaded with docetaxel (DCX) as an anticancer drug, using poly(lactic-co-glycolic acid) (PLGA) as nanoparticle material, and modified with chitosan (CS) to gain mucoadhesive properties. In this context, an innovative nanoparticle formulation that can protect orally administered DCX from GIT conditions and deliver the drug to the intestinal tumoral region by accumulating in mucus has been designed. For this purpose, DCX-PLGA nanoparticles (NPs) and CS/DCX-PLGA NPs were prepared, and their in vitro characteristics were elucidated. Nanoparticles around 250-300 nm were obtained. DCX-PLGA NPs had positive surface charge with CS coating. The formulations have the potential to deliver the encapsulated drug to the bowel according to the in vitro release studies in three different simulated GIT fluids for approximately 72 h. Mucin interaction and penetration into the artificial mucus layer were also investigated in detail, and the mucoadhesive and mucus-penetration characteristics of the formulations were examined. Furthermore, in vitro release kinetic studies of the NPs were elucidated. DCX-PLGA NPs were found to be compatible with the Weibull model, and CS/DCX-PLGA NPs were found to be compatible with the Peppas-Sahlin model. Within the scope of in vitro cytotoxicity studies, the drug-loaded NPs showed significantly higher cytotoxicity than a DCX solution on the HT-29 colon cell line, and CS/DCX-PLGA showed the highest cytotoxicity (p < 0.05). According to the permeability studies on the Caco-2 cell line, the CS/DCX-PLGA formulation increased permeability by 383% compared to free DCX (p < 0.05). In the light of all results, CS/DCX-PLGA NPs can offer a promising and innovative approach as an oral anticancer drug-loaded nanoformulation for intestinal tumors.
    Keywords:  PLGA; chitosan; docetaxel; intestinal tumors; oral drug delivery
    DOI:  https://doi.org/10.3762/bjnano.13.115
  6. Clin Exp Med. 2022 Dec 06.
    Targeting redox regulation and autophagy systems in cancer stem cells.
    Sameer Ullah Khan, Sheikh Rayees, Pankaj Sharma, Fayaz Malik.
      Cancer is a dysregulated cellular level pathological condition that results in tumor formation followed by metastasis. In the heterogeneous tumor architecture, cancer stem cells (CSCs) are essential to push forward the progression of tumors due to their strong pro-tumor properties such as stemness, self-renewal, plasticity, metastasis, and being poorly responsive to radiotherapy and chemotherapeutic agents. Cancer stem cells have the ability to withstand various stress pressures by modulating transcriptional and translational mechanisms, and adaptable metabolic changes. Owing to CSCs heterogeneity and plasticity, these cells display varied metabolic and redox profiles across different types of cancers. It has been established that there is a disparity in the levels of Reactive Oxygen Species (ROS) generated in CSCs vs Non-CSC and these differential levels are detected across different tumors. CSCs have unique metabolic demands and are known to change plasticity during metastasis by passing through the interchangeable epithelial and mesenchymal-like phenotypes. During the metastatic process, tumor cells undergo epithelial to mesenchymal transition (EMT) thus attaining invasive properties while leaving the primary tumor site, similarly during the course of circulation and extravasation at a distant organ, these cells regain their epithelial characteristics through Mesenchymal to Epithelial Transition (MET) to initiate micrometastasis. It has been evidenced that levels of Reactive Oxygen Species (ROS) and associated metabolic activities vary between the epithelial and mesenchymal states of CSCs. Similarly, the levels of oxidative and metabolic states were observed to get altered in CSCs post-drug treatments. As oxidative and metabolic changes guide the onset of autophagy in cells, its role in self-renewal, quiescence, proliferation and response to drug treatment is well established. This review will highlight the molecular mechanisms useful for expanding therapeutic strategies based on modulating redox regulation and autophagy activation to targets. Specifically, we will account for the mounting data that focus on the role of ROS generated by different metabolic pathways and autophagy regulation in eradicating stem-like cells hereafter referred to as cancer stem cells (CSCs).
    Keywords:  Autophagy; Cancer therapy; Mitophagy; Oxidative stress; Reactive oxygen species; Redox regulation; Redox-active compounds; Warburg effect
    DOI:  https://doi.org/10.1007/s10238-022-00955-5
  7. J Prev Med Hyg. 2022 Jun;63(2 Suppl 3): E74-E80
    Effects of the Mediterranean diet polyphenols on cancer development.
    Taygun Dayi, Adile Oniz.
      Globally, the second most common mortality reason is cancer. There are two types of risk factors for cancer: intrinsic (unmodifiable) and non-intrinsic (modifiable). Bad lifestyle behaviors are among the exogenous non-intrinsic risk factors that can be related to 30-50% of cancer development risk, among which can be counted the Western lifestyle. On the contrary, a potentially good lifestyle model to prevent cancer is the Mediterranean diet (MD), which is a plant-based nutrition model. The Mediterranean diet includes many beneficial nutrients and nutritional substances, such as dietary fibers, fatty acids, anti-oxidant and anti-inflammatory substances, etc. Among these beneficial substances, an important group is the one composed by polyphenols, the most common plant-synthesized secondary metabolites. Being a plant-based nutrition model, the Mediterranean diet provides many polyphenols, such as resveratrol, quercetin, phenolic acids, catechins, anthocyanins, oleocanthal, oleuropein, rosmarinic acid, gallic acid, hesperidin, naringenin, ellagic acid, etc. These substances show anti-proliferative, pro-apoptotic, anti-inflammatory, anti-oxidant, anti-migration, anti-angiogenic, anti-metastatic, and autophagy stimulator effects, which can potentially reduce cancer development risk, as was shown by some in vivo and in vitro studies on this topic. In this review of the literature we shed light on the effects and potential interactions between the Mediterranean diet polyphenols and cancer development.
    Keywords:  Cancer; Mediterranean diet; Polyphenols
    DOI:  https://doi.org/10.15167/2421-4248/jpmh2022.63.2S3.2749
  8. Adv Exp Med Biol. 2022 ;1391 161-179
    Natural Products as the Modulators of Oxidative Stress: An Herbal Approach in the Management of Prostate Cancer.
    Vinod K Nelson, Chitikela P Pullaiah, Mohammed Saleem Ts, Shubhadeep Roychoudhury, Sasikala Chinnappan, Beere Vishnusai, Ravishankar Ram Mani, Geetha Birudala, Kavya Sree Bottu.
      Prostate cancer is the most commonly diagnosed and frequently occurred cancer in the males globally. The current treatment strategies available to treat prostate cancer are not much effective and express various adverse effects. Hence, there is an urgent need to identify novel treatment that can improve patient outcome. From times immemorial, natural products are highly recognized for novel drug development for various diseases including cancer. Cancer cells generally maintain higher basal levels of reactive oxygen species (ROS) when compared to normal cells due to its high metabolic rate. However, initiation of excess intracellular ROS production can not be tolerated by the cancer cells and induce several cell death signals which are in contrast to normal cells. Therefore, small molecules of natural origin that induce ROS can potentially kill cancer cells in specific and provide a better opportunity to develop a novel drug therapy. In this review, we elaborated various classes of medicinal compounds and their mechanism of killing prostate cancer cells through direct or indirect ROS generation. This can generate a novel thought to develop promising drug candidate to treat prostate cancer patients.
    Keywords:  Oxidative stress; Prostate cancer; ROS
    DOI:  https://doi.org/10.1007/978-3-031-12966-7_10
  9. J Mol Med (Berl). 2022 Dec 07.
    Mitochondrial respiration inhibitor enhances the anti-tumor effect of high-dose ascorbic acid in castration-resistant prostate cancer.
    Jia Qiu, Tianhong Yang, Yali Long, Peng He, Wanqing Shen, Bing Zhang, Xinchong Shi, Lei Peng, Zhoulei Li, Xiangsong Zhang.
      Previous evidences have demonstrated that anti-tumor effect of high-dose ascorbic acid is associated with the generation of reactive oxygen species (ROS) via autoxidation. Hypoxia induces therapy resistance in castration-resistant prostate cancer. As a mitochondrial respiration inhibitor, metformin has the potential to improve tumor oxygenation. In this study, we evaluate the anti-tumor effect of ascorbic acid combined with metformin in prostate cancer. We demonstrated that ascorbic acid inhibits prostate cancer cells proliferation by generating ROS, and metformin enhances the anti-tumor effects of ascorbic acid. Mechanistically, metformin reduces oxygen consumption rate and NADP+/NADPH value in prostate cancer cells, thereby increases the ROS content induced by ascorbic acid. In addition, our data demonstrated that ascorbic acid inhibits p-AKT signaling in a ROS-dependent pathway, leading to inhibition of p-mTOR expression. And metformin inhibits the p-mTOR expression by activating the AMPK signaling pathway, exerting a synergistic effect on tumor suppression with ascorbic acid. Furthermore, metformin improves tumor oxygenation, and the combined treatment effect of ascorbic acid and metformin were demonstrated in a xenograft model of prostate cancer. Taken together, our data demonstrate that metformin enhances the anti-tumor proliferation effect of ascorbic acid by increasing ROS content in castration-resistant prostate cancer. This provides a new strategy for the clinical application of high-dose ascorbic acid as an anti-tumor drug. KEY MESSAGES: Ascorbic acid inhibits tumor growth by inducing ROS generation. As a mitochondrial respiration inhibitor, metformin inhibits cellular oxygen consumption rate to improve oxygenation of prostate cancer. Metformin enhances anti-tumor effect of ascorbic acid by increasing ROS content. Ascorbic acid inhibits the mTOR expression via PI3K-AKT pathway, and metformin inhibits the mTOR expression by inhibiting AMPK signaling in prostate cancer cells.
    Keywords:  Ascorbic acid; Castration-resistant prostate cancer; Mitochondrial respiration inhibitor
    DOI:  https://doi.org/10.1007/s00109-022-02273-5
  10. J Hematol Oncol. 2022 Dec 08. 15(1): 174
    Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research.
    Xuhui Tong, Rong Tang, Mingming Xiao, Jin Xu, Wei Wang, Bo Zhang, Jiang Liu, Xianjun Yu, Si Shi.
      Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.
    Keywords:  Cuproptosis; Ferroptosis; Nanoparticles; Necroptosis; Pyroptosis; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13045-022-01392-3
  11. Eur J Med Chem. 2022 Dec 01. pii: S0223-5234(22)00897-2. [Epub ahead of print]246 114995
    5-Fluorouracil nano-delivery systems as a cutting-edge for cancer therapy.
    Anai A Valencia-Lazcano, Dilawar Hassan, Mehrab Pourmadadi, Amin Shamsabadipour, Razieh Behzadmehr, Abbas Rahdar, Dora I Medina, Ana M Díez-Pascual.
      5-Fluorouracil (5-FU) is amongst the most commonly used antimetabolite chemotherapeutic agents in recent decades. However, its low bioavailability, short half-life, rapid metabolism and the development of drug resistance after chemotherapy limit its therapeutic efficiency. In this study, 5-FU applications as an anti-cancer drug for treating diverse types of cancers (e.g. colon, pancreatic and breast) have been reviewed. Different approaches lately designed to circumvent the drawbacks of 5-FU therapy are described herein, including 5-FU-loaded lipid-based nanoparticles (NPs), polymeric NPs (both stimuli and non-stimuli responsive), carbon-based nanostructures and inorganic NPs. Furthermore, co-delivery systems of 5-FU with other drugs (e.g. paclitaxel, gelatin-doxorubicin and naproxen) have been reviewed, which aid to attain better bioavailability, higher effectiveness at a lower concentration and lower toxicity. This review provides researchers with the latest progress on 5-FU-loaded nanocarriers, which show great potential as an advanced tool for cancer therapy.
    Keywords:  5-Fluorouracil; Cancer treatment; Drug delivery; Nanotechnology
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114995
  12. Front Pharmacol. 2022 ;13 1043056
    Targeting of non-apoptotic cancer cell death mechanisms by quercetin: Implications in cancer therapy.
    Hao Yang, Shan Xu, Lidan Tang, Jinhong Gong, Hufeng Fang, Jifu Wei, Dan Su.
      The ultimate goal of cancer treatment is to kill cancer cells, based on the use of various therapeutic agents, such as chemotherapy, radiotherapy, or targeted therapy drugs. Most drugs exert their therapeutic effects on cancer by targeting apoptosis. However, alterations in apoptosis-related molecules and thus assisting cells to evade death, eventually lead to tumor cell resistance to therapeutic drugs. The increased incidence of non-apoptotic cell death modes such as induced autophagy, mitotic catastrophe, senescence, and necrosis is beneficial to overcoming multidrug resistance mediated by apoptosis resistance in tumor cells. Therefore, investigating the function and mechanism of drug-induced non-apoptotic cell death modes has positive implications for the development of new anti-cancer drugs and therapeutic strategies. Phytochemicals show strong potential as an alternative or complementary medicine for alleviating various types of cancer. Quercetin is a flavonoid compound widely found in the daily diet that demonstrates a significant role in inhibiting numerous human cancers. In addition to direct pro-tumor cell apoptosis, both in vivo and in vitro experiments have shown that quercetin exerts anti-tumor properties by triggering diverse non-apoptotic cell death modes. This review summarized the current status of research on the molecular mechanisms and targets through which quercetin-mediated non-apoptotic mode of cancer cell death, including autophagic cell death, senescence, mitotic catastrophe, ferroptosis, necroptosis, etc.
    Keywords:  autophagy; mitotic catastrophe; non-apoptotic cancer cell death; quercetin; senescence
    DOI:  https://doi.org/10.3389/fphar.2022.1043056
  13. Int J Pharm. 2022 Dec 01. pii: S0378-5173(22)01019-5. [Epub ahead of print] 122464
    A Comparative Study on Micelles, Liposomes and Solid Lipid Nanoparticles for Paclitaxel Delivery.
    Shradha Dattani, Xiaoling Li, Charina Lampa, David Lechuga-Ballesteros, Amanda Barriscale, Behzad Damadzadeh, Bhaskara R Jasti.
      The purpose of this work was to compare the in vitro and in vivo characteristics of LDV-targeted lipid-based micelles liposomes and solid lipid nanoparticles (SLN) to provide further insights into their therapeutic potential for clinical development. Micelles liposomes and SLN were prepared using LDV peptide amphiphiles and palmitic acid-derived lipids using solvent evaporation thin-film hydration and microfluidic mixing respectively. Nanocarriers were characterized for their physicochemical properties paclitaxel loading efficiency in vitro release behavior stability in biological media as well as in vivo antitumor efficacy in melanoma xenograft model. TEM and DLS results confirmed the presence of paclitaxel-loaded nanosized micelles (6 to 12 nm) liposomes (123.31 ± 5.87 nm) and SLN (80.53 ± 5.37 nm). SLN demonstrated the slowest paclitaxel release rate and the highest stability in biological media compared to micelles and liposomes. Paclitaxel-loaded SLN demonstrated a statistically significant delay in tumor growth compared to mice treated with paclitaxel-loaded liposomes and paclitaxel-loaded micelles (p<0.05). The results obtained in this study indicate the potential of SLN as drug delivery vehicles for anticancer therapy.
    Keywords:  LDV; Liposomes; Micelles; Paclitaxel; Solid Lipid Nanoparticles; Targeting
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122464
  14. Oncol Lett. 2023 Jan;25(1): 7
    Functions and modulation of PKM2 activity by human papillomavirus E7 oncoprotein (Review).
    Chengzhi Gui, Mingyu Ji, Yiying Song, Jing Wang, Yunying Zhou.
      Most tumor cells still exhibit active glucose uptake and glycolysis under aerobic conditions, a phenomenon known as the Warburg effect or aerobic glycolysis. Pyruvate kinase, one of the key enzymes in the cell glycolysis pathway, can promote the conversion of glucose to pyruvate and produce energy. Pyruvate kinase M2 (PKM2), a competitive PK subtype, is an important regulator of the aerobic glycolysis pathway in tumor cells and plays a direct role in gene expression and cell cycle regulation. Human papillomavirus (HPV) persistence is the main risk factor for cervical cancer. In recent years, it has been discovered that HPV plays an important role in malignant anal tumors and oral cancer. HPV oncoprotein E7 can promote the Warburg effect and produce a large amount of ATP, which may meet the energy requirements of cancer cell division. There appears to be a regulatory relationship between HPV E7 and PKM2, but the specific mechanism is mostly unknown. The present review article discusses the role of HPV E7 in transcriptional regulation, enzyme activity regulation, protein kinase activity regulation, post-translational modification and the immune microenvironment of PKM2 in the occurrence and development of cervical cancer.
    Keywords:  HPV; PKM2; Warburg effect; metabolic regulation; non-metabolic regulation
    DOI:  https://doi.org/10.3892/ol.2022.13593
  15. Biomed Pharmacother. 2022 Dec 05. pii: S0753-3322(22)01421-4. [Epub ahead of print]157 114032
    Current advances on the therapeutic potential of pinocembrin: An updated review.
    Mahmoud H Elbatreek, Ismail Mahdi, Wafae Ouchari, Mona F Mahmoud, Mansour Sobeh.
      Pinocembrin (5,7-dihydroxyflavone) is a major flavonoid found in many plants, fungi and hive products, mainly honey and propolis. Several in vitro and preclinical studies revealed numerous pharmacological activities of pinocembrin including antioxidant, anti-inflammatory, antimicrobial, neuroprotective, cardioprotective and anticancer activities. Here, we comprehensively review and critically analyze the studies carried out on pinocembrin. We also discuss its potential mechanisms of action, bioavailability, toxicity, and clinical investigations. The wide therapeutic window of pinocembrin makes it a promising drug candidate for many clinical applications. We recommend some future perspectives to improve its pharmacokinetic and pharmacodynamic properties for better delivery that may also lead to new therapeutic advances.
    Keywords:  Biosynthesis; Clinical trials; Gut microbiota; Pharmacokinetics; Pharmacological activities; Pinocembrin
    DOI:  https://doi.org/10.1016/j.biopha.2022.114032
  16. Zhongguo Zhong Yao Za Zhi. 2022 Nov;47(22): 5965-5977
    [Research progress on liposome and nanomicelle targeted drug delivery system across blood-brain barrier].
    Xu Yang, Ling-Hui Zou, Wen-Ya Ding, Zhong-Bin Zhang, Jin-Qing Chen, Ji-Lang Li, Hong-Li Feng, Yu-Yang Li, Ling Tang, Jian-Fang Feng.
      The blood-brain barrier(BBB), a protective barrier between brain tissues and brain capillaries, can prevent drugs from entering the brain tissues to exert the effect, which greatly increases the difficulty in treating brain diseases. The drug delivery system across the BBB can allow efficient drug delivery across the BBB by virtue of carriers and formulations, thereby enhancing the therapeutic effect of drugs on brain tissue diseases. Liposomes and micelles have been extensively studied with advances in the targeted therapy across the BBB for the brain due to their unique structures and drug delivery advantages. This study summarized the research status of liposome and micelle drug delivery systems across the BBB based on the literature in recent years and analyzed their application advantages and mechanism in terms of trans-BBB capability, targeting, and safety. Moreover, the problems and possible countermeasures in the research on trans-BBB liposomes and micelles were discussed according to the current clinical translation, which may provide refe-rences and ideas for the development of trans-BBB targeted nano-drugs.
    Keywords:  blood-brain barrier; liposomes; micelles; targeted agents; targeted groups; targeted nano-drug delivery system
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20220726.602
  17. Biomater Sci. 2022 Dec 05.
    A two-pronged strategy to alleviate tumor hypoxia and potentiate photodynamic therapy by mild hyperthermia.
    Zhijie Zhang, Zibing Wang, Yuxuan Xiong, Chong Wang, Qingyuan Deng, Tian Yang, Qingqing Xu, Zhengtao Yong, Xiangliang Yang, Zifu Li.
      The application of photodynamic therapy (PDT) is limited by tumor hypoxia. To overcome hypoxia, catalase-like nanozymes are often used to catalyze endogenous H2O2 enriched in tumor tissues to O2. Nonetheless, the catalase activity may not be optimal at body temperature and the O2 supply may not meet the rapid O2 consumption of PDT. Herein, we provide a two-pronged strategy to alleviate tumor hypoxia based on hollow mesoporous Prussian blue nanoparticles (HMPB NPs). HMPB NPs can efficiently load the photosensitizer chlorin e6 (Ce6) and exhibit photothermal capability and temperature-dependent catalase activity. Under 808 nm laser irradiation, the photothermal effect of HMPB NPs elevated the catalase activity of HMPB NPs for O2 production. Furthermore, mild hyperthermia reduced cancer associated fibroblasts (CAFs) and induced extracellular matrix (ECM) degradation. The reduction of CAFs and the ECM decreased the solid stress of tumor tissues and normalized the tumor vasculature, which was beneficial for the external supplementation of O2 to tumors. Thereafter, under 606 nm laser irradiation, Ce6-mediated PDT generated excessive reactive oxygen species (ROS) that induced tumor cell apoptosis and achieved a high tumor inhibition rate of 92.2% in 4T1 breast tumors. Our work indicated that the alleviation of tumor hypoxia from both internal and external pathways significantly enhanced Ce6-mediated PDT against breast cancers.
    DOI:  https://doi.org/10.1039/d2bm01691e
  18. Phytochemistry. 2022 Dec 05. pii: S0031-9422(22)00448-4. [Epub ahead of print]206 113532
    Application of cinnamic acid in the structural modification of natural products: A review.
    Hao Deng, Qian Xu, Hong-Yan Guo, Xing Huang, Fener Chen, Lili Jin, Zhe-Shan Quan, Qing-Kun Shen.
      Natural products can generally exhibit a variety of biological activities, but most show mediocre performance in preliminary activity evaluation. Natural products often require structural modification to obtain promising lead compounds. Cinnamic acid (CA) is readily available and has diverse biological activities and low cytotoxicity. Introducing CA into natural products may improve their performance, enhance biological activity, and reduce toxic side effect. Herein, we aimed to discuss related applications of CA in the structural modification of natural products and provide a theoretical basis for future derivatization and drug development of natural products. Published articles, web databases (PubMed, Science Direct, SCI Finder, and CNKI), and clinical trial websites (https://clinicaltrials.gov/) related to natural products and CA derivatives were included in the discussion. Based on the inclusion criteria, 128 studies were selected and discussed herein. Screening natural products of CA derivatives allowed for classification by their biological activities. The full text is organized according to the biological activities of the derivatives, with the following categories: anti-tumor, neuroprotective, anti-diabetic, anti-microbial, anti-parasitic, anti-oxidative, anti-inflammatory, and other activities. The biological activity of each CA derivative is discussed in detail. Notably, most derivatives exhibited enhanced biological activity and reduced cytotoxicity compared with the lead compound. CA has various advantages and can be widely used in the synthesis of natural product derivatives to enhance the properties of drug candidates or lead compounds.
    Keywords:  Cinnamic acid; Natural products; Research progress; Structural modification
    DOI:  https://doi.org/10.1016/j.phytochem.2022.113532
  19. Eur J Med Chem. 2022 Nov 26. pii: S0223-5234(22)00864-9. [Epub ahead of print]246 114962
    Resveratrol derivatives: Synthesis and their biological activities.
    Laura Grau, Richard Soucek, M Dolors Pujol.
      Resveratrol, a natural compound known especially for its antioxidant properties and protective action, opens the door for both it and its structural derivatives to be considered not only as chemopreventive but also as cancer chemotherapeutic agents. Due to the pharmacokinetic problems of resveratrol that demonstrate its poor bioavailability, the study of new derivatives is of interest. Thus, in this work (E)-stilbenes derived directly from resveratrol and other cyclic analogues containing the benzofuran or indole nucleus have been synthesized. The synthesized compounds have been evaluated for their ability to affect tumor growth in vitro. Compounds 2, 3, 4 and 5 have shown cytotoxicity in human colon cancer (HT-29) and human pancreatic adenocarcinoma cells (MIA PaCa-2) higher than those of (E)-resveratrol. The indolic derivative 13, a cyclic analog of resveratrol, has shown in vitro cytotoxic activity 8 times higher than resveratrol against HT-29 cancer cells. The cyclic derivatives 8, 9 and 12 showed a high inhibition of cell growth in HCT-116 (KRas mutant) at 20 μM, while 13 shows moderate antiangiogenesis activity at 10 μM.
    Keywords:  Antitumor; Cyclic analogues; Cytotoxicity; KRas; Prodrug; Resveratrol; Stilbene
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114962
  20. Front Oncol. 2022 ;12 1004978
    The magic bullet: Niclosamide.
    Haowen Jiang, Albert M Li, Jiangbin Ye.
      The term 'magic bullet' is a scientific concept proposed by the German Nobel laureate Paul Ehrlich in 1907, describing a medicine that could specifically and efficiently target a disease without harming the body. Oncologists have been looking for a magic bullet for cancer therapy ever since. However, the current therapies for cancers-including chemotherapy, radiation therapy, hormone therapy, and targeted therapy-pose either pan-cytotoxicity or only single-target efficacy, precluding their ability to function as a magic bullet. Intriguingly, niclosamide, an FDA-approved drug for treating tapeworm infections with an excellent safety profile, displays broad anti-cancer activity in a variety of contexts. In particular, niclosamide inhibits multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB, and mTOR and activates tumor suppressor signaling pathways such as p53, PP2A, and AMPK. Moreover, niclosamide potentially improves immunotherapy by modulating pathways such as PD-1/PDL-1. We recently discovered that niclosamide ethanolamine (NEN) reprograms cellular metabolism through its uncoupler function, consequently remodeling the cellular epigenetic landscape to promote differentiation. Inspired by the promising results from the pre-clinical studies, several clinical trials are ongoing to assess the therapeutic effect of niclosamide in cancer patients. This current review summarizes the functions, mechanism of action, and potential applications of niclosamide in cancer therapy as a magic bullet.
    Keywords:  anti-tumor effect; epigenetics; magic bullet; metabolism; mitochondrial uncoupler; niclosamide; oncogenic pathways; tumor suppressors
    DOI:  https://doi.org/10.3389/fonc.2022.1004978
  21. Biomed Pharmacother. 2022 Dec 05. pii: S0753-3322(22)01454-8. [Epub ahead of print]157 114065
    Recent advances in targeted gene silencing and cancer therapy by nanoparticle-based delivery systems.
    Hongyan Liu, Xialin Zhu, Yuyan Wei, Chunhong Song, Yunshan Wang.
      Nanomedicine has emerged as a promising platform for disease treatment and much progress has been achieved in the clinical translation for cancer treatment. Several types of nanomedicines have been approved for therapeutic application. However, many nanoparticles still suffer from challenges in the translation from bench to bedside. Currently, nanoparticle-based delivery systems have been developed to explore their functions in targeted gene silencing and cancer therapy. This review describes the research progress of different nano-carriers in targeted gene editing, and the recent progress in co-delivery of anticancer drugs and small ribonucleic acid. We also summarize the strategies for improving the specificity of carrier systems. Finally, we discuss the functions of targeted nano-carriers in overcoming chemotherapeutic drug resistance in cancer therapy. As research continues to advance, a better understanding of the safety including long-term toxicity, immunogenicity, and body metabolism may impel nanoparticle translation.
    Keywords:  Cancer therapy; Drug resistance; Malignant tumor; Nanoparticle; Small interfering RNA; Targeted gene silencing
    DOI:  https://doi.org/10.1016/j.biopha.2022.114065
  22. Transl Oncol. 2022 Dec 05. pii: S1936-5233(22)00255-8. [Epub ahead of print]27 101596
    Natural flavonoids exhibit potent anticancer activity by targeting microRNAs in cancer: A signature step hinting towards clinical perfection.
    Hardeep Singh Tuli, Vivek Kumar Garg, Sakshi Bhushan, Vivek Uttam, Uttam Sharma, Aklank Jain, Katrin Sak, Vikas Yadav, Jose M Lorenzo, Kuldeep Dhama, Tapan Behl, Gautam Sethi.
      Cancer prevalence and its rate of incidence are constantly rising since the past few decades. Owing to the toxicity of present-day antineoplastic drugs, it is imperative to explore safer and more effective molecules to combat and/or prevent this dreaded disease. Flavonoids, a class of polyphenols, have exhibited multifaceted implications against several diseases including cancer, without showing significant toxicity towards the normal cells. Shredded pieces of evidence suggest that flavonoids can enhance drug sensitivity and suppress proliferation, metastasis, and angiogenesis of cancer cells by modulating several oncogenic or oncosuppressor microRNAs (miRNAs, miRs). They play pivotal roles in regulation of various biological and pathological processes, including various cancers. In the present review, the structure, chemistry and miR targeting efficacy of quercetin, luteolin, silibinin, genistein, epigallocatechin gallate, and cyanidin against several cancer types are comprehensively discussed. miRs are considered as next-generation medicine of recent times, and their targeting by naturally occurring flavonoids in cancer cells could be deemed as a signature step. We anticipate that our compilations related to miRNA-mediated regulation of cancer cells by flavonoids might catapult the clinical investigations and affirmation in the future.
    Keywords:  Anti-proliferation; Apoptosis; Cancer; Flavonoids; MicroRNAs; Synergism
    DOI:  https://doi.org/10.1016/j.tranon.2022.101596
  23. Med Chem. 2022 Dec 02.
    Marine-derived Natural Products as Anticancer Agents.
    Nancy Saini, Ritika Sirohi, Anuradha, Neetu Saini, Pankaj Wadhwa, Paranjeet Kaur, Vikas Sharma, Gurdeep Singh, Iqubal Singh, Sanjeev Kumar Sahu.
      Cancer is a deadly human disease on the rise due to changes in lifestyle, nutrition, and global warming. Cancer is characterized by uncontrolled, disordered, and undesired cell division. About 60% of cancer medicines approved by the FDA are made from natural ingredients. Intensive efforts over the last decade to better understand the vast chemical diversity provided by marine life have resulted in an intriguing "marine pipeline" of potential anticancer clinical and preclinical treatments. The molecular targets of marine products as anticancer drugs, as well as different reported compounds acting on distinct targets, are the topic of this review.
    Keywords:  Anticancer; anti-cancer; anti-prostate; marine compounds; marine drugs; natural
    DOI:  https://doi.org/10.2174/1573406419666221202144044
  24. Front Pharmacol. 2022 ;13 1036140
    Targeting ferroptosis, the achilles' heel of breast cancer: A review.
    Yang Liu, Yueting Hu, Yi Jiang, Jiawen Bu, Xi Gu.
      Ferroptosis is referred as a novel type of cell death discovered in recent years with the feature of the accumulation of iron-dependent lipid reactive oxygen species. Breast cancer is one of the most common malignant cancers in women. There is increasing evidence that ferroptosis can inhibit breast cancer cell growth, improve the sensitivity of chemotherapy and radiotherapy and inhibit distant metastases. Therefore, ferroptosis can be regarded a new target for tumor suppression and may expand the landscape of clinical treatment of breast cancer. This review highlights the ferroptosis mechanism and its potential role in breast cancer treatment to explore new therapeutic strategies of breast cancer.
    Keywords:  breast cancer; ferroptosis; iron; lipid; therapy
    DOI:  https://doi.org/10.3389/fphar.2022.1036140
  25. Drug Resist Updat. 2022 Nov 28. pii: S1368-7646(22)00103-0. [Epub ahead of print]66 100904
    Nanotechnology-based approaches overcome lung cancer drug resistance through diagnosis and treatment.
    Junnan Li, Lipeng Zhu, Hang Fai Kwok.
      Lung cancer continues to be a malignant tumor with high mortality. Two obstacles interfere with curative therapy of lung cancer: (i) poor diagnosis at the early stages, as symptoms are not specific or asymptomatic; and (ii) invariably emerging drug resistance after treatment. Some factors contributing to drug resistance include preexisting genetic/genomic drug-resistant alteration(s); activation of adaptive drug resistance pathways; remodeling of the tumor microenvironment; and pharmacological mechanisms or activation of drug efflux pumps. Despite the mechanisms explored to better understand drug resistance, a gap remains between molecular understanding and clinical application. Therefore, facilitating the translation of basic science into the clinical setting is a great challenge. Nanomedicine has emerged as a promising tool for cancer treatment. Because of their excellent physicochemical properties and enhanced permeability and retention effects, nanoparticles have great potential to revolutionize conventional lung cancer diagnosis and combat drug resistance. Nanoplatforms can be designed as carriers to improve treatment efficacy and deliver multiple drugs in one system, facilitating combination treatment to overcome drug resistance. In this review, we describe the difficulties in lung cancer treatment and review recent research progress on nanoplatforms aimed at early diagnosis and lung cancer treatment. Finally, future perspectives and challenges of nanomedicine are also discussed.
    Keywords:  Diagnosis; Drug resistance; Lung cancer; Nanoparticles; Treatment
    DOI:  https://doi.org/10.1016/j.drup.2022.100904
  26. Int J Biol Macromol. 2022 Dec 05. pii: S0141-8130(22)02906-3. [Epub ahead of print]
    Thiolated pectin-chitosan composites: Potential mucoadhesive drug delivery system with selective cytotoxicity towards colorectal cancer.
    Theodore Ebenezer Leonard, Alvaro Filbert Liko, Marsia Gustiananda, Agus Budiawan Naro Putra, Ario Betha Juanssilfero, Pietradewi Hartrianti.
      Mucoadhesive drug delivery systems (DDS) may promote safer chemotherapy for colorectal cancer (CRC) by maximizing local drug distribution and residence time. Carbohydrate polymers, e.g. pectin (P) and chitosan (CS), are potential biomaterials for CRC-targeted DDS due to their gelling ability, mucoadhesive property, colonic digestibility, and anticancer activity. Polymer mucoadhesion is augmentable by thiolation, e.g. pectin to thiolated pectin (TP). Meanwhile, P-CS polyelectrolyte complex has been shown to improve structural stability. Herein, we fabricated, characterized, and evaluated 5-fluorouracil-loaded primary DDS combining TP and CS as a composite (TPCF) through triple crosslinking actions (calcium pectinate, polyelectrolyte complex, disulfide). Combination of these crosslinking yields superior mucoadhesion property relative to single- or dual-crosslinked counterparts, with comparable drug release profile and drug compatibility. PCF and TPCF exhibited targeted cytotoxicity towards HT29 CRC cells with milder cytotoxicity towards HEK293 normal cells. In conclusion, TP-CS composites are promising next-generation mucoadhesive and selectively cytotoxic biomaterials for CRC-targeted DDS.
    Keywords:  Drug delivery system; Mucoadhesive; Pectin
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.12.012
  27. Alzheimers Dement. 2022 Dec 08.
    Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias.
    Nutrition, Metabolism and Dementia PIA, Alzheimer's Association ISTAART
      Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions.
    DOI:  https://doi.org/10.1002/alz.12845
  28. J Prev Med Hyg. 2022 Jun;63(2 Suppl 3): E246-E254
    Polyphenols and Lactobacillus reuteri in oral health.
    Zakira Naureen, Maria Chiara Medori, Kristjana Dhuli, Kevin Donato, Stephen Thaddeus Connelly, Francesco Bellinato, Paolo Gisondi, Matteo Bertelli.
      Oral health is one of the necessary preludes to the overall quality of life. Several medical procedures and therapies are available to treat oral diseases in general and periodontal diseases in particular, yet caries, periodontitis, oral cancer, and oral infections remain a global concern. Natural molecules, with their anti-oxidant, anti-inflammatory, and anti-microbic properties, are one of the main sources of oral health and dental health care, and should be supplemented to exploit their beneficial effects. A possible way to improve the intake of these molecules is adhering to a diet that is rich in fruits, vegetables, and probiotics, which has many beneficial properties and can improve overall health and wellbeing. The Mediterranean diet, in particular, provides several beneficial natural molecules, mainly because of the precious nutrients contained in its typical ingredients, mainly plant-based (olives, wine, citrus fruits, and many more). Its beneficial effects on several diseases and in increasing the overall wellbeing of the population are currently being studied by physicians. Among its nutrients, polyphenols (including, among other molecules, lignans, tannins, and flavonoids) seem to be of outmost importance: several studies showed their anticariogenic properties, as well as their effects in decreasing the incidence of non-communicable diseases. Therefore, plant-derived molecules - such as polyphenols - and probiotics - such as Lactobacillus reuteri - have shown a significant potential in treating and curing oral diseases, either alone or in combination, owing to their antioxidant and antimicrobial properties, respectively.
    Keywords:  Lactobacillus reuteri; Mediterranean diet; Oral health; Polyphenols
    DOI:  https://doi.org/10.15167/2421-4248/jpmh2022.63.2S3.2767
  29. NPJ Precis Oncol. 2022 Dec 09. 6(1): 91
    Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.
    Jessica K Lee, Smruthy Sivakumar, Alexa B Schrock, Russell Madison, David Fabrizio, Ole Gjoerup, Jeffrey S Ross, Garrett M Frampton, Pavel Napalkov, Meagan Montesion, Jennifer L Schutzman, Xin Ye, Priti S Hegde, Misako Nagasaka, Geoffrey R Oxnard, Ethan S Sokol, Sai-Hong Ignatius Ou, Zhen Shi.
      Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. We performed a pan-cancer analysis of KRAS-altered samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% of adult pan-cancer samples had KRAS alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, and prevalence was similar in liquid biopsies. Co-alteration landscapes were largely similar across KRAS mutations but distinct from KRAS wild-type, though differences were observed in some tumor types for tumor mutational burden, PD-L1 expression, microsatellite instability, and other mutational signatures. Prognosis of KRAS-mutant versus other genomic cohorts of lung, pancreatic, and colorectal cancer were assessed using a real-world clinicogenomic database. As specific KRAS inhibitors and combination therapeutic strategies are being developed, genomic profiling to understand co-alterations and other biomarkers that may modulate response to targeted or immunotherapies will be imperative.
    DOI:  https://doi.org/10.1038/s41698-022-00334-z
  30. Front Oncol. 2022 ;12 1029033
    The impact of the microbiome in cancer: Targeting metabolism of cancer cells and host.
    Jia-Ting Huang, Yu-Qin Mao.
      Abnormal metabolic alterations of cancer cells and the host play critical roles in the occurrence and development of tumors. Targeting cancer cells and host metabolism can provide novel diagnosis indicators and intervention targets for tumors. In recent years, it has been found that gut microbiota is involved in the metabolism of the host and cancer cells. Increasingly, gut microbiome and their metabolites have been demonstrated great influence on the tumor formation, prognosis and treatment. Specific gut microbial composition and metabolites are associated with the status of tumor in the host. Interventions on the gut microbiota can exert the protective effects on the tumor, through the manipulation of structure and its related metabolites. This may be the new approach to improve the efficacy of tumor prevention and treatment. Here, we discuss the effects and the underlying mechanisms of gut microbiota and microbial-derived metabolites in tumor progression and treatment.
    Keywords:  host; metabolism; microbiome; therapy; tumor
    DOI:  https://doi.org/10.3389/fonc.2022.1029033
  31. Prog Lipid Res. 2022 Dec 01. pii: S0163-7827(22)00062-5. [Epub ahead of print] 101207
    Compartmentalized regulation of lipid signaling in oxidative stress and inflammation: Plasmalogens, oxidized lipids and ferroptosis as new paradigms of bioactive lipid research.
    Alma M Astudillo, María A Balboa, Jesús Balsinde.
      Perturbations in lipid homeostasis combined with conditions favoring oxidative stress constitute a hallmark of the inflammatory response. In this review we focus on the most recent results concerning lipid signaling in various oxidative stress-mediated responses and inflammation. These include phagocytosis and ferroptosis. The best characterized event, common to these responses, is the synthesis of oxygenated metabolites of arachidonic acid and other polyunsaturated fatty acids. Major developments in this area have highlighted the importance of compartmentalization of the enzymes and lipid substrates in shaping the appropriate response. In parallel, other relevant lipid metabolic pathways are also activated and, until recently, there has been a general lack of knowledge on the enzyme regulation and molecular mechanisms operating in these pathways. Specifically, data accumulated in recent years on the regulation and biological significance of plasmalogens and oxidized phospholipids have expanded our knowledge on the involvement of lipid metabolism in the progression of disease and the return to homeostasis. These recent major developments have helped to establish the concept of membrane phospholipids as cellular repositories for the compartmentalized production of bioactive lipids involved in cellular regulation. Importantly, an enzyme classically described as being involved in regulating the homeostatic turnover of phospholipids, namely the group VIA Ca2+-independent phospholipase A2 (iPLA2β), has taken center stage in oxidative stress and inflammation research owing to its key involvement in regulating metabolic and ferroptotic signals arising from membrane phospholipids. Understanding the role of iPLA2β in ferroptosis and metabolism not only broadens our knowledge of disease but also opens possible new horizons for this enzyme as a target for therapeutic intervention.
    Keywords:  ferroptosis; inflammation; lipid mediators; phagocytosis; phospholipase A(2); phospholipid remodeling; plasmalogens
    DOI:  https://doi.org/10.1016/j.plipres.2022.101207
  32. Front Oncol. 2022 ;12 1070514
    Glutamine metabolism and radiosensitivity: Beyond the Warburg effect.
    Ryan S Alden, Mohammad Zahid Kamran, Bassel A Bashjawish, Brittany A Simone.
      Mounting data suggest that cancer cell metabolism can be utilized therapeutically to halt cell proliferation, metastasis and disease progression. Radiation therapy is a critical component of cancer treatment in curative and palliative settings. The use of metabolism-based therapeutics has become increasingly popular in combination with radiotherapy to overcome radioresistance. Over the past year, a focus on glutamine metabolism in the setting of cancer therapy has emerged. In this mini-review, we discuss several important ways (DNA damage repair, oxidative stress, epigenetic modification and immune modulation) glutamine metabolism drives cancer growth and progression, and present data that inhibition of glutamine utilization can lead to radiosensitization in preclinical models. Future research is needed in the clinical realm to determine whether glutamine antagonism is a feasible synergistic therapy that can be combined with radiotherapy.
    Keywords:  cancer; glutamine (Gln); immunotherapy; metabolism; radiation; radiosensitivity; sirpiglenastat; telaglenastat
    DOI:  https://doi.org/10.3389/fonc.2022.1070514
  33. Mol Biol (Mosk). 2022 Nov-Dec;56(6):56(6): 1057-1071
    [The p53 Tumor Suppressor and Copper Metabolism: An Unrevealed but Important Link].
    S A Tsymbal, A G Refeld, O A Kuchur.
      The balance of redox reactions and the fate of the tumor cell are closely related to the regulation of intracellular homeostasis of transition metals, among which copper and its compounds play a key role. Elevated levels of intracellular copper may be a cause and/or consequence of malignancy, since the metabolism of this metal affects the functioning of the electron transport chain, transcription regulation, cell growth, and migration. This wide range of actions is used in antitumor therapy: ROS generation and apoptosis mediated by copper addition, copper deprivation by chelators, and targeted inhibition of specific participants in the copper metabolism chain effectively reduce the survival of tumor cells. However, the exact mechanisms of influence on the cell cycle and cell death behind the activity of copper-associated drugs are still largely unexplored. Numerous attempts to identify them led to the identification of the induction of oxidative stress and the activation of apoptotic cascades via the p53 tumor suppressor, an integral attribute of the action of such compounds. At the same time, the influence of p53, apparently also extends onto the activity of copper metabolism proteins, mediating the processes of antioxidant protection and survival. More and more research data confirm that the interaction of copper and p53 is multifaceted and is not limited solely to ROS. The purpose of this review is to describe how p53 regulation is related to copper metabolic pathways and how this interaction can be used to improve the effectiveness of oncotherapy.
    Keywords:  Atox1; Ctr1; chemotherapy; copper metabolism; p53; reactive oxygen species; tumor therapy
    DOI:  https://doi.org/10.31857/S0026898422060222
  34. Cancer Metastasis Rev. 2022 Dec 08.
    Natural compounds targeting nuclear receptors for effective cancer therapy.
    Mangala Hegde, Sosmitha Girisa, Nikunj Naliyadhara, Aviral Kumar, Mohammed S Alqahtani, Mohamed Abbas, Chakrabhavi Dhananjaya Mohan, Sudha Warrier, Kam Man Hui, Kanchugarakoppal S Rangappa, Gautam Sethi, Ajaikumar B Kunnumakkara.
      Human nuclear receptors (NRs) are a family of forty-eight transcription factors that modulate gene expression both spatially and temporally. Numerous biochemical, physiological, and pathological processes including cell survival, proliferation, differentiation, metabolism, immune modulation, development, reproduction, and aging are extensively orchestrated by different NRs. The involvement of dysregulated NRs and NR-mediated signaling pathways in driving cancer cell hallmarks has been thoroughly investigated. Targeting NRs has been one of the major focuses of drug development strategies for cancer interventions. Interestingly, rapid progress in molecular biology and drug screening reveals that the naturally occurring compounds are promising modern oncology drugs which are free of potentially inevitable repercussions that are associated with synthetic compounds. Therefore, the purpose of this review is to draw our attention to the potential therapeutic effects of various classes of natural compounds that target NRs such as phytochemicals, dietary components, venom constituents, royal jelly-derived compounds, and microbial derivatives in the establishment of novel and safe medications for cancer treatment. This review also emphasizes molecular mechanisms and signaling pathways that are leveraged to promote the anti-cancer effects of these natural compounds. We have also critically reviewed and assessed the advantages and limitations of current preclinical and clinical studies on this subject for cancer prophylaxis. This might subsequently pave the way for new paradigms in the discovery of drugs that target specific cancer types.
    Keywords:  Cancer; Metastasis; Natural compounds; Nuclear receptors; Signaling molecules
    DOI:  https://doi.org/10.1007/s10555-022-10068-w
  35. Int Immunopharmacol. 2022 Nov 30. pii: S1567-5769(22)00948-1. [Epub ahead of print]114 109463
    Tumor targeted delivery of mycobacterial adjuvant encapsulated chitosan nanoparticles showed potential anti-cancer activity and immune cell activation in tumor microenvironment.
    Anush Chakraborty, Gargi Roy, Bharati Swami, Sangeeta Bhaskar.
      Targeting immunotherapeutics inside the tumor microenvironment (TME) with intact biological activity remains a pressing issue. Mycobacterium indicus pranii (MIP), an approved adjuvant therapy for leprosy has exhibited promising results in clinical trials of lung (NSCLC) and bladder cancer. Whole MIP as well as its cell wall fraction have shown tumor growth suppression and enhanced survival in mice model of melanoma, when administered peritumorally. Clinically, peritumoral delivery remains a procedural limitation. In this study, a tumor targeted delivery system was designed, where chitosan nanoparticles loaded with MIP adjuvants, when administered intravenously showed preferential accumulation within the TME, exploiting the principle of enhanced permeability and retention effect. Bio-distribution studies revealed their highest concentration inside the tumor after 6 h of administration. Interestingly, MIP adjuvant nano-formulations significantly reduced the tumor volume in the treated groups and increased the frequency of activated immune cells inside the TME. For chemoimmunotherapeutics studies, MIP nano-formulation was combined with standard dosage regimen of Paclitaxel. Combined therapy exhibited a further reduction in tumor volume relative to either of the MIP nano formulations. From this study a three-pronged strategy emerged as the underlying mechanism; chitosan and Paclitaxel have shown direct role in tumor cell death and the MIP nano-formulation activates the tumor residing immune cells which ultimately leads to the reduced tumor growth.
    Keywords:  Bacterial immunotherapy; Chitosan nanoparticles; MIP; Paclitaxel nanoparticles; Tumor targeted delivery
    DOI:  https://doi.org/10.1016/j.intimp.2022.109463
  36. Curr Res Food Sci. 2022 ;5 2329-2337
    A review of recent strategies to improve the physical stability of phycocyanin.
    Biao Yuan, Zhuxin Li, Honghong Shan, Badamkhand Dashnyam, Xiao Xu, David Julian McClements, Bingquan Zhang, Mingqian Tan, Zhixiang Wang, Chongjiang Cao.
      There is an increasing demand for more healthy and sustainable diets, which led to an interest in replacing synthetic colors with natural plant-based ones. Phycocyanin, which is commonly extracted from Spirulina platensis, has been explored as a natural blue pigment for application in the food industry. It is also used as a nutraceutical in food, cosmetic, and pharmaceutical products because of its potentially beneficial biological properties, such as radical scavenging, immune modulating, and lipid peroxidase activities. The biggest challenges to the widespread application of phycocyanin for this purpose are its high sensitivity to chemical degradation when exposed to heat, light, acids, high pressure, heavy metal cations, and denaturants. Consequently, it is of considerable importance to improve its chemical stability, which requires a thorough knowledge of the relationship between the structure, environment, and chemical reactivity of phycocyanin. To increase the application of this natural pigment and nutraceutical within foods and other products, the structure, biological activities, and factors affecting its stability are reviewed, as well as strategies that have been developed to improve its stability. The information contained in this article is intended to stimulate further studies on the development of effective strategies to improve phycocyanin stability and performance.
    Keywords:  Bioactivity; Encapsulation; Food matrix effects; Phycocyanin; Stability
    DOI:  https://doi.org/10.1016/j.crfs.2022.11.019
  37. Cancer Cell Int. 2022 Dec 08. 22(1): 386
    Luteolin: a flavonoid with a multifaceted anticancer potential.
    Parteek Prasher, Mousmee Sharma, Sachin Kumar Singh, Monica Gulati, Dinesh Kumar Chellappan, Flavia Zacconi, Gabriele De Rubis, Gaurav Gupta, Javad Sharifi-Rad, William C Cho, Kamal Dua.
      Therapeutic effect of phytochemicals has been emphasized in the traditional medicine owing to the presence of bioactive molecules, such as polyphenols. Luteolin is a flavone belonging to the flavonoid class of polyphenolic phytochemicals with healing effect on hypertension, inflammatory disorders, and cancer due to its action as pro-oxidants and antioxidants. The anticancer profile of luteolin is of interest due to the toxic effect of contemporary chemotherapy paradigm, leading to the pressing need for the development and identification of physiologically benevolent anticancer agents and molecules. Luteolin exerts anticancer activity by downregulation of key regulatory pathways associated with oncogenesis, in addition to the induction of oxidative stress, cell cycle arrest, upregulation of apoptotic genes, and inhibition of cell proliferation and angiogenesis in cancer cells. In this review, we discuss about the anticancer profile of luteolin.
    DOI:  https://doi.org/10.1186/s12935-022-02808-3
  38. Front Pharmacol. 2022 ;13 999017
    Autophagy: An important target for natural products in the treatment of bone metabolic diseases.
    Zhichao Li, Dandan Li, Hui Su, Haipeng Xue, Guoqing Tan, Zhanwang Xu.
      Bone homeostasis depends on a precise dynamic balance between bone resorption and bone formation, involving a series of complex and highly regulated steps. Any imbalance in this process can cause disturbances in bone metabolism and lead to the development of many associated bone diseases. Autophagy, one of the fundamental pathways for the degradation and recycling of proteins and organelles, is a fundamental process that regulates cellular and organismal homeostasis. Importantly, basic levels of autophagy are present in all types of bone-associated cells. Due to the cyclic nature of autophagy and the ongoing bone metabolism processes, autophagy is considered a new participant in bone maintenance. Novel therapeutic targets have emerged as a result of new mechanisms, and bone metabolism can be controlled by interfering with autophagy by focusing on certain regulatory molecules in autophagy. In parallel, several studies have reported that various natural products exhibit a good potential to mediate autophagy for the treatment of metabolic bone diseases. Therefore, we briefly described the process of autophagy, emphasizing its function in different cell types involved in bone development and metabolism (including bone marrow mesenchymal stem cells, osteoblasts, osteocytes, chondrocytes, and osteoclasts), and also summarized research advances in natural product-mediated autophagy for the treatment of metabolic bone disease caused by dysfunction of these cells (including osteoporosis, rheumatoid joints, osteoarthritis, fracture nonunion/delayed union). The objective of the study was to identify the function that autophagy serves in metabolic bone disease and the effects, potential, and challenges of natural products for the treatment of these diseases by targeting autophagy.
    Keywords:  autophagy; bone metabolism; fracture nonunion/delayed union; natural products; osteoarthritis; osteoporosis; rheumatoid arthritis
    DOI:  https://doi.org/10.3389/fphar.2022.999017
  39. World J Clin Oncol. 2022 Nov 24. 13(11): 880-895
    Folate receptor-targeted near-infrared photodynamic therapy for folate receptor-overexpressing tumors.
    Winn Aung, Atsushi B Tsuji, Kenjiro Hanaoka, Tatsuya Higashi.
       BACKGROUND: Photodynamic therapy (PDT) is a minimally invasive form of cancer therapy, and the development of a novel photosensitizer (PS) with optimal properties is important for enhancing PDT efficacy. Folate receptor (FR) membrane protein is frequently overexpressed in 40% of human cancer and a good candidate for tumor-specific targeting. Specific active targeting of PS to FR can be achieved by conjugation with the folate moiety. A folate-linked, near-infrared (NIR)-sensitive probe, folate-Si-rhodamine-1 (FolateSiR-1), was previously developed and is expected to be applicable to NIR-PDT.
    AIM: To investigate the therapeutic efficacy of NIR-PDT induced by FolateSiR-1, a FR-targeted PS, in preclinical cancer models.
    METHODS: FolateSiR-1 was developed by conjugating a folate moiety to the Si-rhodamine derivative through a negatively charged tripeptide linker. FR expression in the designated cell lines was examined by western blotting (WB). The selective binding of FolateSiR-1 to FR was confirmed in FR overexpressing KB cells (FR+) and tumors by fluorescence microscopy and in vivo fluorescence imaging. Low FR expressing OVCAR-3 and A4 cell lines were used as negative controls (FR-). The NIR light (635 ± 3 nm)-induced phototoxic effect of FolateSiR-1 was evaluated by cell viability imaging assays. The time-dependent distribution of FolateSiR-1 and its specific accumulation in KB tumors was determined using in vivo longitudinal fluorescence imaging. The PDT effect of FolateSiR-1 was evaluated in KB tumor-bearing mice divided into four experimental groups: (1) FolateSiR-1 (100 μmol/L) alone; (2) FolateSiR-1 (100 μmol/L) followed by NIR irradiation (50 J/cm2); (3) NIR irradiation (50 J/cm2) alone; and (4) no treatment. Tumor volume measurement and immunohistochemical (IHC) and histological examinations of the tumors were performed to analyze the effect of PDT.
    RESULTS: High FR expression was observed in the KB cells by WB, but not in the OVCAR-3 and A4 cells. Substantial FR-specific binding of FolateSiR-1 was observed by in vitro and in vivo fluorescence imaging. Cell viability imaging assays showed that NIR-PDT induced cell death in KB cells. In vivo longitudinal fluorescence imaging showed rapid peak accumulation of FolateSiR-1 in the KB tumors 2 h after injection. In vivo PDT conducted at this time point caused tumor growth delay. The relative tumor volumes in the PDT group were significantly reduced compared to those in the other groups [5.81 ± 1.74 (NIR-PDT) vs 12.24 ± 2.48 (Folate-SiR-1), vs 11.84 ± 3.67 (IR), vs 12.98 ± 2.78 (Untreated), at Day 16, P < 0.05]. IHC analysis revealed reduced proliferation marker Ki-67-positive cells in the PDT treated tumors, and hematoxylin-eosin staining revealed features of necrotic- and apoptotic cell death.
    CONCLUSION: FolateSiR-1 has potential for use in PDT, and FR-targeted NIR-PDT may open a new effective strategy for the treatment of FR-overexpressing tumors.
    Keywords:  Cancer; Fluorescence; Folate receptor; Near-infrared; Photodynamic therapy; Photosensitizer
    DOI:  https://doi.org/10.5306/wjco.v13.i11.880
  40. Onco Targets Ther. 2022 ;15 1419-1448
    Licorice (Glycyrrhiza glabra L.)-Derived Phytochemicals Target Multiple Signaling Pathways to Confer Oncopreventive and Oncotherapeutic Effects.
    Hardeep Singh Tuli, Vivek Kumar Garg, Jinit K Mehta, Ginpreet Kaur, Ranjan K Mohapatra, Kuldeep Dhama, Katrin Sak, Ajay Kumar, Mehmet Varol, Diwakar Aggarwal, Uttpal Anand, Jagjit Kaur, Ross Gillan, Gautam Sethi, Anupam Bishayee.
      Cancer is a highly lethal disease, and its incidence has rapidly increased worldwide over the past few decades. Although chemotherapeutics and surgery are widely used in clinical settings, they are often insufficient to provide the cure for cancer patients. Hence, more effective treatment options are highly needed. Although licorice has been used as a medicinal herb since ancient times, the knowledge about molecular mechanisms behind its diverse bioactivities is still rather new. In this review article, different anticancer properties (antiproliferative, antiangiogenic, antimetastatic, antioxidant, and anti-inflammatory effects) of various bioactive constituents of licorice (Glycyrrhiza glabra L.) are thoroughly described. Multiple licorice constituents have been shown to bind to and inhibit the activities of various cellular targets, including B-cell lymphoma 2, cyclin-dependent kinase 2, phosphatidylinositol 3-kinase, c-Jun N-terminal kinases, mammalian target of rapamycin, nuclear factor-κB, signal transducer and activator of transcription 3, vascular endothelial growth factor, and matrix metalloproteinase-3, resulting in reduced carcinogenesis in several in vitro and in vivo models with no evident toxicity. Emerging evidence is bringing forth licorice as an anticancer agent as well as bottlenecks in its potential clinical application. It is expected that overcoming toxicity-related obstacles by using novel nanotechnological methods might importantly facilitate the use of anticancer properties of licorice-derived phytochemicals in the future. Therefore, anticancer studies with licorice components must be continued. Overall, licorice could be a natural alternative to the present medication for eradicating new emergent illnesses while having just minor side effects.
    Keywords:  angiogenesis; apoptosis; cancer; cell cycle; licorice; nano-delivery; treatment
    DOI:  https://doi.org/10.2147/OTT.S366630
  41. J Basic Clin Physiol Pharmacol. 2022 Dec 07.
    Metformin: new applications for an old drug.
    Amirreza Naseri, Sarvin Sanaie, Sina Hamzehzadeh, Sepideh Seyedi-Sahebari, Mohammad-Salar Hosseini, Elnaz Gholipour-Khalili, Ehsan Rezazadeh-Gavgani, Reza Majidazar, Parya Seraji, Sara Daneshvar, Erfan Rezazadeh-Gavgani.
      Metformin is a biguanide, evolved as one of the most widely used medicines. The applications of this component include but are not limited to reducing blood glucose, weight loss, and polycystic ovary syndrome. Studies about other probable indications have emerged, indicating that this agent can also be utilized for other purposes. In this review, applications of metformin are noticed based on the current evidence. Metformin commonly is used as an off-label drug in non-alcoholic fatty liver disease (NAFLD), but it worsens inflammation and should not be used for this purpose, according to the latest research. Metformin decreased the risk of death in patients with liver cirrhosis. It is an effective agent in the prevention and improvement of survival in patients suffering hepatocellular carcinoma. There is evidence of the beneficial effects of metformin in colorectal cancer, early-stage prostate cancer, breast cancer, urothelial cancer, blood cancer, melanoma, and bone cancer, suggesting metformin as a potent anti-tumor agent. Metformin shows neuroprotective effects and provides a potential therapeutic benefit for mild cognitive impairment and Alzheimer's disease (AD). It also has been shown to improve mental function and reduce the incidence of dementia. Another condition that metformin has been shown to slow the progression of is Duchenne muscular dystrophy. Regarding infectious diseases, tuberculosis (TB) and coronavirus disease (COVID-19) are among the conditions suggested to be affected by metformin. The beneficial effects of metformin in cardiovascular diseases were also reported in the literature. Concerning renal function, studies showed that daily oral administration of metformin could ameliorate kidney fibrosis and normalize kidney structure and function. This study reviewed the clinical and preclinical evidence about the possible benefits of metformin based on recent studies. Numerous questions like whether these probable indications of metformin can be observed in non-diabetics, need to be described by future basic experiments and clinical studies.
    Keywords:  biguanides; central nervous system diseases; communicable diseases; liver diseases; metformin; neoplasms
    DOI:  https://doi.org/10.1515/jbcpp-2022-0252
  42. Nutr Cancer. 2022 Dec 10. 1-11
    Vitamin D Supplementation: Does It Have a Preventative or Therapeutic Role in Cancer?
    Michael J Duffy, Maeve Mullooly, Kathleen Bennett, John Crown.
      Although best known for its role in skeletal health, a deficiency of vitamin D has also been implicated in cancer formation and progression. The aim of this article was to review the relationship between circulating levels of vitamin D {25(OH)D} and both the risk of developing cancer and outcome from cancer. We also reviewed the effects of vitamin D supplementation on cancer risk and outcome. Our primary focus was on patients with colorectal and breast cancer, as these are two of the cancer types best investigated with respect to the effects of vitamin D on cancer risk and outcome. Based on our review of the literature, we conclude that although low circulating levels of 25(OH)D appears to be associated with an increased risk of developing breast and colorectal cancer, the available evidence suggests that supplementation of healthy subjects with vitamin D does not decrease cancer risk. Supplementation may however, improve outcomes in patients who develop cancer, but this finding remains to be confirmed in an appropriately powered randomized clinical trial.
    DOI:  https://doi.org/10.1080/01635581.2022.2145318
  43. Orphanet J Rare Dis. 2022 Dec 05. 17(1): 423
    Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels.
    Emily Shelkowitz, Russell P Saneto, Walla Al-Hertani, Charlotte M A Lubout, Nicholas V Stence, Mark S Brown, Patrick Long, Diana Walleigh, Julie A Nelson, Francisco E Perez, Dennis W W Shaw, Emma J Michl, Johan L K Van Hove.
       BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction.
    AIM: We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate.
    METHODS: Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS).
    RESULTS: Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable.
    CONCLUSION: KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.
    Keywords:  Benzoate; Epilepsy; Glycine; Ketogenic diet; Magnetic resonance spectroscopy; Nonketotic hyperglycinemia
    DOI:  https://doi.org/10.1186/s13023-022-02581-6
  44. J Trace Elem Med Biol. 2022 Dec 05. pii: S0946-672X(22)00195-X. [Epub ahead of print]76 127115
    Selenium, selenoproteins and cancer of the thyroid.
    Rui Manuel Rua, Fátima Nogales, Olimpia Carreras, María Luisa Ojeda.
      Selenium is an essential mineral element with important biological functions for the whole body through incorporation into selenoproteins. This element is highly concentrated in the thyroid gland. Selenoproteins provide antioxidant protection for this tissue against the oxidative stress caused by free radicals and contribute, via iodothyronine deiodinases, to the metabolism of thyroid hormones. It is known that oxidative stress plays a major role in carcinogenesis and that in recent decades there has been an increase in the incidence of thyroid cancer. The anti-carcinogenic action of selenium, although not fully understood, is mainly attributable to selenoproteins antioxidant properties, and to the ability to modulate cell proliferation (cell cycle and apoptosis), energy metabolism, and cellular immune response, significantly altered during tumorigenesis. Researchers have suggested that different forms of selenium supplementation may be beneficial in the prevention and treatment of thyroid cancer; however, the studies have several methodological limitations. This review is a summary of the current knowledge on how selenium and selenoproteins related to thyroid cancer.
    Keywords:  Oxidative stress; Selenium; Selenoproteins; Supplementation; Thyroid cancer
    DOI:  https://doi.org/10.1016/j.jtemb.2022.127115
  45. Arch Med Res. 2022 Nov 30. pii: S0188-4409(22)00154-0. [Epub ahead of print]
    Cancer Stem Cells: Biology and Therapeutic Implications.
    Hector Mayani, Antonieta Chávez-González, Karla Vázquez-Santillan, Jorge Contreras, Monica L Guzman.
      It is well recognized that most cancers derive and progress from transformation and clonal expansion of a single cell that possesses stem cell properties, i.e., self-renewal and multilineage differentiation capacities. Such cancer stem cells (CSCs) are usually present at very low frequencies and possess properties that make them key players in tumor development. Indeed, besides having the ability to initiate tumor growth, CSCs drive tumor progression and metastatic dissemination, are resistant to most cancer drugs, and are responsible for cancer relapse. All of these features make CSCs attractive targets for the development of more effective oncologic treatments. In the present review article, we have summarized recent advances in the biology of CSCs, including their identification through their immunophenotype, and their physiology, both in vivo and in vitro. We have also analyzed some molecular markers that might become targets for developing new therapies aiming at hampering CSCs regeneration and cancer relapse.
    Keywords:  Cancer; Leukemia; Microenvironment; Stem cells; Tumor
    DOI:  https://doi.org/10.1016/j.arcmed.2022.11.012
  46. Med Oncol. 2022 Dec 06. 40(1): 43
    Implications of reactive oxygen species in lung cancer and exploiting it for therapeutic interventions.
    K N ArulJothi, K Kumaran, Sowmya Senthil, A B Nidhu, Nashita Munaff, V B Janitri, Rangasamy Kirubakaran, Sachin Kumar Singh, Gaurav Gupt, Kamal Dua, Anand Krishnan.
      Lung cancer is the second (11.4%) most commonly diagnosed cancer and the first (18%) to cause cancer-related deaths worldwide. The incidence of lung cancer varies significantly among men, women, and high and low-middle-income countries. Air pollution, inhalable agents, and tobacco smoking are a few of the critical factors that determine lung cancer incidence and mortality worldwide. Reactive oxygen species are known factors of lung carcinogenesis resulting from the xenobiotics and their mechanistic paths are under critical investigation. Reactive oxygen species exhibit dual roles in cells, as a tumorigenic and anti-proliferative factor, depending on spatiotemporal context. During the precancerous state, ROS promotes cancer origination through oxidative stress and base-pair substitution mutations in pro-oncogenes and tumor suppressor genes. At later stages of tumor progression, they help the cancer cells in invasion, and metastases by activating the NF-kB and MAPK pathways. However, at advanced stages, when ROS exceeds the threshold, it promotes cell cycle arrest and induces apoptosis in cancer cells. ROS activates extrinsic apoptosis through death receptors and intrinsic apoptosis through mitochondrial pathways. Moreover, ROS upregulates the expression of beclin-1 which is a critical component to initiate autophagy, another form of programmed cell death. ROS is additionally involved in an intermediatory step in necroptosis, which catalyzes and accelerates this form of cell death. Various therapeutic interventions have been attempted to exploit this cytotoxic potential of ROS to treat different cancers. Growing body of evidence suggests that ROS is also associated with chemoresistance and cancer cell immunity. Considering the multiple roles of ROS, this review highlights the exploitation of ROS for various therapeutic interventions. However, there are still gaps in the literature on the dual roles of ROS and the involvement of ROS in cancer cell immunity and therapy resistance.
    Keywords:  Cancer therapy; Lung cancer; Oxidative stress; Programmed cell death; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s12032-022-01900-y
  47. Nitric Oxide. 2022 Dec 02. pii: S1089-8603(22)00125-2. [Epub ahead of print]
    Nitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy.
    Gregory Pappas, Melissa L Wilkinson, Andrew J Gow.
      Nitric oxide can interact with a wide range of proteins including many that are involved in metabolism. In this review we have summarized the effects of NO on glycolysis, fatty acid metabolism, the TCA cycle, and oxidative phosphorylation with reference to skeletal muscle. Low to moderate NO concentrations upregulate glucose and fatty acid oxidation, while higher NO concentrations shift cellular reliance toward a fully glycolytic phenotype. Moderate NO production directly inhibits pyruvate dehydrogenase activity, reducing glucose-derived carbon entry into the TCA cycle and subsequently increasing anaploretic reactions. NO directly inhibits aconitase activity, increasing reliance on glutamine for continued energy production. At higher or prolonged NO exposure, citrate accumulation can inhibit multiple ATP-producing pathways. Reduced TCA flux slows NADH/FADH entry into the ETC. NO can also inhibit the ETC directly, further limiting oxidative phosphorylation. Moderate NO production improves mitochondrial efficiency while improving O2 utilization increasing whole-body energy production. Long-term bioenergetic capacity may be increased because of NO-derived ROS, which participate in adaptive cellular redox signaling through AMPK, PCG1-α, HIF-1, and NF-κB. However, prolonged exposure or high concentrations of NO can result in membrane depolarization and opening of the MPT. In this way NO may serve as a biochemical rheostat matching energy supply with demand for optimal respiratory function.
    Keywords:  Cellular respiration; Exercise; Glycolysis; Metabolism; Mitochondria; Nitric oxide
    DOI:  https://doi.org/10.1016/j.niox.2022.11.006
  48. Front Genet. 2022 ;13 1083902
    Editorial: Cancer systems biology.
    Jesús Espinal-Enríquez, Claudia Rangel-Escareño, Frank Emmert-Streib.
      
    Keywords:  biomarkers in cancer; cancer Metabolism; cancer immunobiology; cancer systems biology; non-coding regulation in cancer
    DOI:  https://doi.org/10.3389/fgene.2022.1083902
  49. Elife. 2022 Dec 07. pii: e77443. [Epub ahead of print]11
    DNA damage independent inhibition of NF-kB transcription by anthracyclines.
    Angelo Ferreira Chora, Dora Pedroso, Eleni Kyriakou, Nadja Pejanovic, Henrique Colaço, Raffaella Gozzelino, André Barros, Katharina Willmann, Tiago R Velho, Catarina Moita, Isa Santos, Pedro Pereira, Silvia Carvalho, Filipa Batalha Martins, João A Ferreira, Sérgio Fernandes de Almeida, Vladimir Benes, Josef Anrather, Sebastian Weis, Miguel P Soares, Arie Geerlof, Jacques Neefjes, Michael Sattler, Ana C Messias, Ana Neves Costa, Luis F Moita.
      Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here we show that the extensively used anthracyclines Doxorubicin, Daunorubicin and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon responsive genes in primary mouse (Mus musculus) macrophages. Using an NMR-based structural approach, we demonstrate that anthracyclines disturb the complexes formed between the NF-kB subunit RelA and its DNA binding sites. The anthracycline variants Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. These findings have implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis.
    Keywords:  immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.77443
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