bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2020‒12‒13
101 papers selected by
Ayesh Seneviratne
University of Toronto


  1. Inflamm Regen. 2020 Nov 05. 40(1): 29
    Kurosawa S, Iwama A.
      Hematopoietic stem cells (HSCs) have self-renewal capacity and differentiation potential into all lineages of blood cells throughout the lifetime of an organism. The function of HSCs gradually changes during aging. To date, various stress factors influencing HSC aging have been identified. The increased production of reactive oxygen species and DNA damage responses are causatively attributed to HSC aging. The increased apolarity is a prominent feature of aged HSCs, whereas it is less obvious in young HSCs. The bone marrow (BM) microenvironment niche is a crucial factor for HSC aging. Mesenchymal stem cells show skewed differentiation during aging, which leads to decreased bone formation and increased adipogenesis. The accumulation of adipocytes confers negative effects on hematopoiesis. Loss of sympathetic nerve fibers or adrenoreceptor β3 signaling induces premature HSC and niche aging. Epigenetic regulators such as polycomb group proteins and the sirtuin family of proteins act to prevent premature aging. Targeting these factors, several rejuvenation strategies for aged HSCs have been employed in mice. However, we still do not know whether these strategies can be extrapolated to human HSCs. Aging is frequently accompanied by the development of clonal hematopoiesis, which is called age-related clonal hematopoiesis (ARCH) or clonal hematopoiesis of indeterminate potential (CHIP). Most ARCH/CHIP mutations occur in genes encoding epigenetic regulators including DNMT3A, TET2, and ASXL1, which suggests the relevance of epigenetic drift during the aging process. ARCH/CHIP is a strong risk factor for subsequent hematologic cancer. Notably, it also has an impact on the development of non-malignant disorders such as coronary heart disease. Further studies are warranted to decipher the complete picture of molecular crosstalk that regulates HSC aging.
    Keywords:  Age-related clonal hematopoiesis; Aging; Clonal hematopoiesis of indeterminate potential; DNA damage; Epigenetics; Hematopoietic stem cell; Polarity; Reactive oxygen species; Senescence; Stem cell niche
    DOI:  https://doi.org/10.1186/s41232-020-00138-3
  2. Cureus. 2020 Nov 30. 12(11): e11791
    Khouja JH, Al Jasir B, Bargawi AA, Kutbi M.
      Background Cardiovascular disease (CVD) remains the major cause of global mortality. Applying a comprehensive interventional program may reduce the incidence of cardiovascular disease and its complications. Objective This study compared the effects of a three-month intervention involving lifestyle modification and physical activity with standard care in women ≥30 years having a moderate to high risk of CVD, with respect to improving physical activity and cardiovascular disease risk factors at the National Guard Residential City in Jeddah, Saudi Arabia, in 2015. Methods The effects of this community-based lifestyle program were assessed through a randomized controlled trial from January 1st to September 6th, 2015. Women in the intervention group (n = 31) received health education, exercise training, and diet counselling as individuals and in groups according to the participant's risk. Women in the control group (n = 28) received one health education session at the screening site. The primary outcome was the proportion of women with moderate Framingham risk scores (FRS) reducing their risk by 10% and the proportion of women with high FRS reducing their risk by 25%. The secondary outcome was the proportion of women reducing their risk by ≥1 risk category. Results The mean participant age was 42 ± 8 years. At three-month's follow-up, reductions were greater in the intervention group and the difference between groups was statistically significant (p < 0.05). Lifestyle intervention program significantly reduced systolic blood pressure (-9.2 mmHg), blood glucose (-45 mg/dL) and Framingham risk score (-13.6). Linear regression analysis revealed a significant improvement in the Framingham risk score (p < 0.01). Conclusion In a population of women with moderate-to-high risk of CVD, a personalized lifestyle modification program showed positive association in improving the 10-year cardiovascular Framingham risk score after three months.
    Keywords:  cardiovascular diseases; framingham risk score; life style modification; randomized controlled trial
    DOI:  https://doi.org/10.7759/cureus.11791
  3. Mol Ther Methods Clin Dev. 2020 Dec 11. 19 438-446
    Rust BJ, Becker PS, Chandrasekaran D, Kubek SP, Peterson CW, Adair JE, Kiem HP.
      Current approaches for hematopoietic stem cell gene therapy typically involve lentiviral gene transfer in tandem with a conditioning regimen to aid stem cell engraftment. Although many pseudotyped envelopes have the capacity to be immunogenic due to their viral origins, thus far immune responses against the most common envelope, vesicular stomatitis virus glycoprotein G (VSV-G), have not been reported in hematopoietic stem cell gene therapy trials. Herein, we report on two Fanconi anemia patients who underwent autologous transplantation of a lineage-depleted, gene-modified hematopoietic stem cell product without conditioning. We observed the induction of robust VSV-G-specific immunity, consistent with low/undetectable gene marking in both patients. Upon further interrogation, adaptive immune mechanisms directed against VSV-G were detected following transplantation in both patients, including increased VSV-G-specific T cell responses, anti-VSV-G immunoglobulin G (IgG), and cytotoxic responses that can specifically kill VSV-G-expressing target cell lines. A proportion of healthy controls also displayed preexisting VSV-G-specific CD4+ and CD8+ T cell responses, as well as VSV-G-specific IgG. Taken together, these data show that VSV-G-pseudotyped lentiviral vectors have the ability to elicit interfering adaptive immune responses in the context of certain hematopoietic stem cell transplantation settings.
    Keywords:  VSV-G envelope; adaptive immunity; cell therapy; fanconi anemia; gene therapy; lentivirus; lineage depletion; transplant; vector pseudotype
    DOI:  https://doi.org/10.1016/j.omtm.2020.10.002
  4. Int J Mol Sci. 2020 Dec 08. pii: E9344. [Epub ahead of print]21(24):
    Rivera JC, Abrigo J, Tacchi F, Simon F, Brandan E, Santos RA, Bader M, Chiong M, Cabello-Verrugio C.
      Skeletal muscle atrophy, which occurs in lipopolysaccharide (LPS)-induced sepsis, causes a severe muscle function reduction. The increased autophagy contributes to sepsis-induced skeletal muscle atrophy in a model of LPS injection, increasing LC3II/LC3I ratio, autophagy flux, and autophagosomes. Angiotensin-(1-7) (Ang-(1-7)) has anti-atrophic effects via the Mas receptor in skeletal muscle. However, the impact of Ang-(1-7) on LPS-induced autophagy is unknown. In this study, we determined the effect of Ang-(1-7) on sepsis-induced muscle autophagy. C57BL6 wild-type (WT) mice and mice lacking the Mas receptor (KO Mas) were injected with LPS together with the systemic administration of Ang-(1-7) to determine autophagy in skeletal muscle. We also evaluated autophagy and p38 and c-Jun N-terminal kinase (JNK)activation. Our results show that Ang-(1-7) prevents LPS-induced autophagy in the diaphragm, tibialis anterior, and gastrocnemius of WT mice, which is demonstrated by a decrease in the LC3II/LC3I ratio and mRNA levels of lc3b and ctsl. This effect was lost in KO Mas mice, suggesting the role of the Mas receptor. The results in C2C12 cells show that Ang-(1-7) reduces several LPS-dependent effects, such as autophagy (LC3II/LC3I ratio, autophagic flux, and autophagosomes), activation of p38 and JNK, B-cell lymphoma-2 (BCL2) phosphorylation, and disassembly of the Beclin1/BCL2 complex. In conclusion, Ang-(1-7)/Mas receptor reduces LPS-induced autophagy in skeletal muscle. In vitro assays indicate that Ang-(1-7) prevents LPS-induced autophagy and modifies the MAPK signaling and the disassembly of a complex involved at the beginning of autophagy.
    Keywords:  LPS; autophagy; muscle wasting; renin-angiotensin system
    DOI:  https://doi.org/10.3390/ijms21249344
  5. Atherosclerosis. 2020 Nov 28. pii: S0021-9150(20)31527-6. [Epub ahead of print]
    So J, Wu D, Lichtenstein AH, Tai AK, Matthan NR, Maddipati KR, Lamon-Fava S.
      BACKGROUND AND AIMS: The independent effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on chronic inflammation through their downstream lipid mediators, including the specialized pro-resolving lipid mediators (SPM), remain unstudied. Therefore, we compared the effects of EPA and DHA supplementation on monocyte inflammatory response and plasma polyunsaturated fatty acids (PUFA) SPM lipidome.METHODS: After a 4-week lead-in phase (baseline), 9 men and 12 postmenopausal women (50-75 years) with chronic inflammation received two phases of 10-week supplementation with 3 g/day EPA and DHA in a random order, separated by a 10-week washout.
    RESULTS: Compared with baseline, EPA and DHA supplementation differently modulated LPS-stimulated monocyte cytokine expression. EPA lowered TNFA (p < 0.001) whereas DHA reduced TNFA (p < 0.001), IL6 (p < 0.02), MCP1 (p < 0.03), and IL10 (p < 0.01). DHA lowered IL10 expression relative to EPA (p = 0.03). Relative to baseline, EPA, but not DHA, decreased the ratios of TNFA/IL10 and MCP1/IL10 (both p < 0.01). EPA and DHA also significantly changed plasma PUFA SPM lipidome by replacing n-6 AA derivatives with their respective derivatives including 18-hydroxy-EPA (+5 fold by EPA) and 17- and 14-hydroxy-DHA (+3 folds by DHA). However, DHA showed a wider effect than EPA by also significantly increasing EPA derivatives and DPA-derived SPM at a greater expense of AA derivatives. Different groups of PUFA derivatives mediated the differential effects of EPA and DHA on monocyte cytokine expression.
    CONCLUSIONS: EPA and DHA had distinct effects on monocyte inflammatory response with a broader effect of DHA in attenuating pro-inflammatory cytokines. These differential effects were potentially mediated by different groups of PUFA derivatives, suggesting immunomodulatory activities of SPM and their intermediates.
    Keywords:  DHA; EPA; Inflammation; Monocytes; Randomized crossover trial; Specialized pro-resolving lipid mediators
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2020.11.018
  6. Int J Mol Sci. 2020 Dec 03. pii: E9247. [Epub ahead of print]21(23):
    Meurer SK, Weiskirchen R.
      Transforming growth factor-β1 (TGF-β1) is a pleiotropic factor sensed by most cells. It regulates a broad spectrum of cellular responses including hematopoiesis. In order to process TGF-β1-responses in time and space in an appropriate manner, there is a tight regulation of its signaling at diverse steps. The downstream signaling is mediated by type I and type II receptors and modulated by the 'accessory' receptor Endoglin also termed cluster of differentiation 105 (CD105). Endoglin was initially identified on pre-B leukemia cells but has received most attention due to its high expression on activated endothelial cells. In turn, Endoglin has been figured out as the causative factor for diseases associated with vascular dysfunction like hereditary hemorrhagic telangiectasia-1 (HHT-1), pre-eclampsia, and intrauterine growth restriction (IUPR). Because HHT patients often show signs of inflammation at vascular lesions, and loss of Endoglin in the myeloid lineage leads to spontaneous inflammation, it is speculated that Endoglin impacts inflammatory processes. In line, Endoglin is expressed on progenitor/precursor cells during hematopoiesis as well as on mature, differentiated cells of the innate and adaptive immune system. However, so far only pro-monocytes and macrophages have been in the focus of research, although Endoglin has been identified in many other immune system cell subsets. These findings imply a functional role of Endoglin in the maturation and function of immune cells. Aside the functional relevance of Endoglin in endothelial cells, CD105 is differentially expressed during hematopoiesis, arguing for a role of this receptor in the development of individual cell lineages. In addition, Endoglin expression is present on mature immune cells of the innate (i.e., macrophages and mast cells) and the adaptive (i.e., T-cells) immune system, further suggesting Endoglin as a factor that shapes immune responses. In this review, we summarize current knowledge on Endoglin expression and function in hematopoietic precursors and mature hematopoietic cells of different lineages.
    Keywords:  CD105; Endoglin; TGF-β-signaling; adaptive immunity; hematopoiesis; hematopoietic stem cells; innate immunity
    DOI:  https://doi.org/10.3390/ijms21239247
  7. Curr Opin Lipidol. 2020 Dec 03.
    Dollet L, Pendergrast LA, Zierath JR.
      PURPOSE OF REVIEW: The aim of this review is to present the latest findings on the role of the circadian clock in the control of metabolism, and the therapeutic potential of chronotherapy to regulate energy homeostasis in humans.RECENT FINDINGS: We summarized the recent advances related to circadian clock regulation of food intake and energy expenditure. In peripheral organs, mitochondrial oxidative capacity and lipolysis show circadian pattern in humans, and rhythms disruption may be involved in the pathogenesis of metabolic diseases. Indeed, circadian desynchrony affects food intake, insulin sensitivity, and increases the risk of developing metabolic disease. Time-targeted strategies, which aim to synchronize external cues with the molecular clock to improve metabolic outcomes, have positive effects on metabolism in humans, with several studies showing that time-targeted feeding improves body weight loss and glucose tolerance.
    SUMMARY: The interest in time-targeted strategies to prevent or manage metabolic disturbances has grown this past year with encouraging health benefits. To maximize the therapeutic effect of these strategies, further research is warranted to delineate the molecular regulation of metabolic processes controlled by the clock and especially its modulation in contexts such as aging, sex differences, or metabolic diseases.
    DOI:  https://doi.org/10.1097/MOL.0000000000000722
  8. Haematologica. 2020 Dec 10. Online ahead of print 0
    Wang T, Xia C, Weng Q, Wang K, Dong Y, Hao S, Dong F, Liu X, Liu L, Geng Y, Guan Y, Du J, Cheng T, Cheng H, Wang J.
      Hematopoietic stem cells (HSCs) are dominantly quiescent under homeostasis, which is a key mechanism of maintaining the HSC pool for life-long hematopoiesis. Dormant HSCs poise to be immediately activated on urgent conditions and can return to quiescence after regaining homeostasis. To date, the molecular networks of regulating the threshold of HSC dormancy, if exist, remain largely unknown. Here, we unveiled that deletion of Nupr1, a gene preferentially expressed in HSCs, activated the quiescence HSCs under homeostatic status, which conferred engraftment competitive advantage on HSCs without compromising their stemness and multi-lineage differentiation abilities in serial transplantation settings. Following an expansion protocol, the Nupr1-/- HSCs proliferate more robustly than their wild type counterparts in vitro. Nupr1 inhibits the expression of p53 and the rescue of which offsets the engraftment advantage. Our data unveil the de novo role of Nupr1 as an HSC quiescence-regulator, which provides insights into accelerating the engraftment efficacy of HSC transplantation by targeting the HSC quiescence-controlling network.
    DOI:  https://doi.org/10.3324/haematol.2019.239186
  9. Curr Diabetes Rev. 2020 Dec 07.
    Al-Duhaidahawi D, Hasan SA, Al-Zubaidy HFS.
      BACKGROUND: For thousands of years, natural food products have been a medicine for diseases that affect the human body, including diabetes mellitus. Lately, several investigations have studied the flavonoids derivatives of plant origins and their biological activity. Given our need to know more mechanisms for treating this disease, Methods: we will do a thorough research review on treating diabetes mellitus based on flavonoids, its therapeutic potential, and biological action.RESULTS: Flavonoids reduces complications in addition to its vital role as effective supplements for preventing diabetes mellitus by regulating glucose metabolism, lipid profile, liver enzyme activity, a protein kinase inhibitor, PPAR, AMPK with NF-κB Conclusion: Articles that we reviewed showed the positive role of flavonoids, which at a certain way reduce diabetes, but its side effects are still missing, this review focus on the different type of dietary flavonoids along with their mechanism in reducing blood glucose and enhance insulin sensitivity as well as some side effects.
    Keywords:  diabetes mellitus; flavonoids; hesperidin; insulin resistance; kaempferol; lipogenesis
    DOI:  https://doi.org/10.2174/1573399817666201207200346
  10. Cancers (Basel). 2020 Dec 03. pii: E3617. [Epub ahead of print]12(12):
    Acharya UH, Walter RB.
      Despite the availability of an increasing number of targeted therapeutics and wider use of allogeneic hematopoietic stem cell transplantation, many patients with acute myeloid leukemia (AML) ultimately succumb to this disease. Given their remarkable efficacy in B-acute lymphoblastic leukemia and other CD19-expressing B cell malignancies, there is hope adoptive cellular transfer, particularly chimeric antigen receptor (CAR)-modified immune effector cell (IEC) therapies, may afford a novel, potent immune-based approach for the treatment of AML that complements or replaces existing ones and improves cure rates. However, it is unclear how best to translate the success of these therapies from B cell malignancies, where use of highly potent immunotherapies is facilitated by identified target antigens with near ubiquitous expression on malignant cells and non-fatal consequences from "on-target, off-tumor cell" toxicities. Herein, we review the current status of CAR-modified IEC therapies for AML, with considerations regarding suitable, relatively leukemia-restricted target antigens, expected toxicities, and interactions of the engineered cells with a profoundly immunosuppressive tumor microenvironment that restricts their therapeutic efficacy. With these challenges in mind, we will discuss possible strategies to improve the cells' potency as well as their therapeutic window for optimal clinical use in AML.
    Keywords:  T cell; acute myeloid leukemia; adoptive cell transfer; antigen; antitumor efficacy; chimeric antigen receptor (CAR); microenvironment; natural killer cell; resistance; safety
    DOI:  https://doi.org/10.3390/cancers12123617
  11. Int J Mol Sci. 2020 Dec 04. pii: E9262. [Epub ahead of print]21(23):
    Rochette L, Mazini L, Malka G, Zeller M, Cottin Y, Vergely C.
      The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs is a major goal in repair medicine. Stem cells are classified by their potential to differentiate into functional cells. Compared with other sources, adipose-derived stem cells (ADSCs) have the advantage of being abundant and easy to obtain. ADSCs are considered to be tools for replacing, repairing, and regenerating dead or damaged cells. The capacity of ADSCs to maintain their properties depends on the balance of complex signals in their microenvironment. Their properties and the associated outcomes are in part regulated by reactive oxygen species, which mediate the oxidation-reduction state of cells as a secondary messenger. ADSC therapy has demonstrated beneficial effects, suggesting that secreted factors may provide protection. There is evidence that ADSCs secrete a number of cytokines, growth factors, and antioxidant factors into their microenvironment, thus regulating intracellular signaling pathways in neighboring cells. In this review, we introduce the roles of ADSCs in the protection of cells by modulating inflammation and immunity, and we develop their potential therapeutic properties.
    Keywords:  adipose derived stem cells; oxidative stress; stem cells; tissue protection
    DOI:  https://doi.org/10.3390/ijms21239262
  12. Syst Rev. 2020 Dec 09. 9(1): 288
    Sarker A, Das R, Ether S, Saif-Ur-Rahman KM.
      INTRODUCTION: The disease burden caused by type 2 diabetes mellitus is a prime public health concern. The prevalence and rate of deaths from diabetes mellitus in low- and middle-income countries (LMICs) are higher than the high-income countries. Increased physical activity and a balanced diet are essential and successful measures to prevent the onset of diabetes mellitus. This systematic review aims to explore the available non-pharmacological approaches for the prevention of type 2 diabetes mellitus in LMICs.METHODS AND ANALYSIS: Six online databases will be explored to get related randomized controlled trials (RCTs) published in English from inception to September 2020, and two coders will independently screen, identify studies, extract data, and assess the risk of bias in each article. The searched articles will be included by applying specific inclusion and exclusion criteria. Joanna Briggs Institute's tool for RCTs will be used for appraising the trials critically. Narrative synthesis and pooled effect of the interventions will be demonstrated. A meta-analysis will be conducted using the random-effects model if assumptions are fulfilled.
    DISCUSSION: This review is an attempt to explore the available non-pharmacological approaches for the prevention of type 2 diabetes mellitus in LMICs. Findings from the review will highlight effective non-pharmacological measures for the prevention of type 2 diabetes mellitus to guide policy for future strategies.
    SYSTEMATIC REVIEW REGISTRATION: The review protocol has been registered ( CRD42020191507 ).
    Keywords:  Intervention; LMICs; Meta-analysis; Non-pharmacological; Systematic review; Type 2 diabetes
    DOI:  https://doi.org/10.1186/s13643-020-01550-z
  13. Mol Cancer Ther. 2020 Dec 10.
    Toth RK, Warfel NA.
      Cancer progression and the onset of therapeutic resistance are often the results of uncontrolled activation of survival kinases. The proviral integration for the Moloney murine leukemia virus (PIM) kinases are oncogenic serine/threonine kinases that regulate tumorigenesis by phosphorylating a wide range of substrates that control cellular metabolism, proliferation, and survival. Because of their broad impact on cellular processes that facilitate progression and metastasis in many cancer types, it has become clear that the activation of PIM kinases is a significant driver of resistance to various types of anticancer therapies. As a result, efforts to target PIM kinases for anticancer therapy have intensified in recent years. Clinical and preclinical studies indicate that pharmacologic inhibition of PIM has the potential to significantly improve the efficacy of standard and targeted therapies. This review focuses on the signaling pathways through which PIM kinases promote cancer progression and resistance to therapy, as well as highlights biological contexts and promising strategies to exploit PIM as a therapeutic target in cancer.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0535
  14. EMBO Mol Med. 2020 Dec 07. e12798
    Lu W, Yu W, He J, Liu W, Yang J, Lin X, Zhang Y, Wang X, Jiang W, Luo J, Zhang Q, Yang H, Peng S, Yi Z, Ren S, Chen J, Siwko S, Nussinov R, Cheng F, Zhang H, Liu M.
      Immune checkpoint blockade (ICB) has a limited effect on colorectal cancer, underlining the requirement of co-targeting the complementary mechanisms. Here, we identified prostaglandin E2 (PGE2 ) receptor 4 (EP4) as the master regulator of immunosuppressive myeloid cells (IMCs), which are the major driver of resistance to ICB therapy. PGE2 -bound EP4 promotes the differentiation of immunosuppressive M2 macrophages and myeloid-derived suppressor cells (MDSCs) and reduces the expansion of immunostimulated M1 macrophages. To explore the immunotherapeutic role of EP4 signaling, we developed a novel and selective EP4 antagonist TP-16. TP-16 effectively blocked the function of IMCs and enhanced cytotoxic T-cell-mediated tumor elimination in vivo. Cell co-culture experiments revealed that TP-16 promoted T-cell proliferation, which was impaired by tumor-derived CD11b+ myeloid cells. Notably, TP-16 and anti-PD-1 combination therapy significantly impeded tumor progression and prolonged mice survival. We further demonstrated that TP-16 increased responsiveness to anti-PD-1 therapy in an IMC-related spontaneous colorectal cancer mouse model. In summary, this study demonstrates that inhibition of EP4-expressing IMCs may offer a potential strategy for enhancing the efficacy of immunotherapy for colorectal cancer.
    Keywords:  colorectal cancer; immunosuppressive myeloid cells; immunotherapy; prostaglandin E2 receptor 4
    DOI:  https://doi.org/10.15252/emmm.202012798
  15. Int J Mol Sci. 2020 Dec 04. pii: E9263. [Epub ahead of print]21(23):
    Yashima H, Terasaki M, Sotokawauchi A, Matsui T, Mori Y, Saito T, Osaka N, Kushima H, Hiromura M, Ohara M, Fukui T, Yamagishi SI.
      Advanced glycation end products (AGEs) are localized in macrophage-derived foam cells within atherosclerotic lesions, which could be associated with the increased risk of atherosclerotic cardiovascular disease under diabetic conditions. Although foam cell formation of macrophages has been shown to be enhanced by AGEs, the underlying molecular mechanism remains unclear. Since cyclin-dependent kinase 5 (Cdk5) is reported to modulate inflammatory responses in macrophages, we investigated whether Cdk5 could be involved in AGE-induced CD36 gene expression and foam cell formation of macrophages. AGEs significantly increased Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and Cdk5 and CD36 gene expression in U937 human macrophages, all of which were inhibited by DNA aptamer raised against RAGE (RAGE-aptamer). Cdk5 and CD36 gene expression levels were correlated with each other. An antioxidant, N-acetyl-l-cysteine, mimicked the effects of RAGE-aptamer on AGE-exposed U937 cells. A selective inhibitor of Cdk5, (R)-DRF053, attenuated the AGE-induced Dil-ox-LDL uptake and CD36 gene expression, whereas anti-CD36 antibody inhibited the Dil-ox-LDL uptake but not Cdk5 gene expression. The present study suggests that AGEs may stimulate ox-LDL uptake into macrophages through the Cdk5-CD36 pathway via RAGE-mediated oxidative stress.
    Keywords:  AGEs; CD36; Cdk5; RAGE-aptamer; macrophages
    DOI:  https://doi.org/10.3390/ijms21239263
  16. J Endocrinol. 2020 Dec 01. pii: JOE-20-0473.R1. [Epub ahead of print]
    Régnier M, Van Hul M, Knauf C, Cani PD.
      Overweight and obesity are associated with several cardiometabolic risk factors, including insulin resistance, type 2 diabetes, low-grade inflammation and liver diseases. The gut microbiota is a potential contributing factor regulating energy balance. However, although the scientific community acknowledges that the gut microbiota composition and its activity (e.g., production of metabolites and immune-related compounds) are different between healthy subjects and subjects with overweight/obesity, the causality remains insufficiently demonstrated. The development of low-grade inflammation and related metabolic disorders has been connected with metabolic endotoxaemia and increased gut permeability. However, the mechanisms acting on the regulation of the gut barrier and eventually cardiometabolic disorders are not fully elucidated. In this review, we debate several characteristics of the gut microbiota, gut barrier function and metabolic outcomes. We examine the role of specific dietary compounds or nutrients (e.g., prebiotics, probiotics, polyphenols, sweeteners, and a fructose-rich diet) as well as different metabolites produced by the microbiota in host metabolism, and we discuss how they control several endocrine functions and eventually have either beneficial or deleterious effects on host health.
    DOI:  https://doi.org/10.1530/JOE-20-0473
  17. Cell Death Dis. 2020 Dec 10. 11(12): 1045
    Coni S, Serrao SM, Yurtsever ZN, Di Magno L, Bordone R, Bertani C, Licursi V, Ianniello Z, Infante P, Moretti M, Petroni M, Guerrieri F, Fatica A, Macone A, De Smaele E, Di Marcotullio L, Giannini G, Maroder M, Agostinelli E, Canettieri G.
      Eukaryotic Translation Initiation Factor 5A (EIF5A) is a translation factor regulated by hypusination, a unique posttranslational modification catalyzed by deoxyhypusine synthetase (DHPS) and deoxyhypusine hydroxylase (DOHH) starting from the polyamine spermidine. Emerging data are showing that hypusinated EIF5A regulates key cellular processes such as autophagy, senescence, polyamine homeostasis, energy metabolism, and plays a role in cancer. However, the effects of EIF5A inhibition in preclinical cancer models, the mechanism of action, and specific translational targets are still poorly understood. We show here that hypusinated EIF5A promotes growth of colorectal cancer (CRC) cells by directly regulating MYC biosynthesis at specific pausing motifs. Inhibition of EIF5A hypusination with the DHPS inhibitor GC7 or through lentiviral-mediated knockdown of DHPS or EIF5A reduces the growth of various CRC cells. Multiplex gene expression analysis reveals that inhibition of hypusination impairs the expression of transcripts regulated by MYC, suggesting the involvement of this oncogene in the observed effect. Indeed, we demonstrate that EIF5A regulates MYC elongation without affecting its mRNA content or protein stability, by alleviating ribosome stalling at five distinct pausing motifs in MYC CDS. Of note, we show that blockade of the hypusination axis elicits a remarkable growth inhibitory effect in preclinical models of CRC and significantly reduces the size of polyps in APCMin/+ mice, a model of human familial adenomatous polyposis (FAP). Together, these data illustrate an unprecedented mechanism, whereby the tumor-promoting properties of hypusinated EIF5A are linked to its ability to regulate MYC elongation and provide a rationale for the use of DHPS/EIF5A inhibitors in CRC therapy.
    DOI:  https://doi.org/10.1038/s41419-020-03174-6
  18. Mol Med Rep. 2021 Feb;pii: 96. [Epub ahead of print]23(2):
    Li H, Wang B, Li D, Li J, Luo Y, Dan J.
      Age‑related renal diseases, which account for various progressive renal disorders associated with cellular and organismal senescence, are becoming a substantial public health burden. However, their aetiologies are complicated and their pathogeneses remain poorly understood. Telomeres and telomerase are known to be essential for maintaining the integrity and stability of eukaryotic genomes and serve crucial roles in numerous related signalling pathways that activate renal functions, such as repair and regeneration. Previous studies have reported that telomere dysfunction served a role in various types of age‑related kidney disease through various different molecular pathways. The present review aimed to summarise the current knowledge of the association between telomeres and ageing‑related kidney diseases and explored the contribution of dysfunctional telomeres to these diseases. The findings may help to provide novel strategies for treating patients with renal disease.
    DOI:  https://doi.org/10.3892/mmr.2020.11735
  19. Cell Death Differ. 2020 Dec 07.
    Li C, Sheng M, Lin Y, Xu D, Tian Y, Zhan Y, Jiang L, Coito AJ, Busuttil RW, Farmer DG, Kupiec-Weglinski JW, Ke B.
      Foxo1 transcription factor is an evolutionarily conserved regulator of cell metabolism, oxidative stress, inflammation, and apoptosis. Activation of Hedgehog/Gli signaling is known to regulate cell growth, differentiation, and immune function. However, the molecular mechanisms by which interactive cell signaling networks restrain oxidative stress response and necroptosis are still poorly understood. Here, we report that myeloid-specific Foxo1 knockout (Foxo1M-KO) mice were resistant to oxidative stress-induced hepatocellular damage with reduced macrophage/neutrophil infiltration, and proinflammatory mediators in liver ischemia/reperfusion injury (IRI). Foxo1M-KO enhanced β-catenin-mediated Gli1/Snail activity, and reduced receptor-interacting protein kinase 3 (RIPK3) and NIMA-related kinase 7 (NEK7)/NLRP3 expression in IR-stressed livers. Disruption of Gli1 in Foxo1M-KO livers deteriorated liver function, diminished Snail, and augmented RIPK3 and NEK7/NLRP3. Mechanistically, macrophage Foxo1 and β-catenin colocalized in the nucleus, whereby the Foxo1 competed with T-cell factor (TCF) for interaction with β-catenin under inflammatory conditions. Disruption of the Foxo1-β-catenin axis by Foxo1 deletion enhanced β-catenin/TCF binding, activated Gli1/Snail signaling, leading to inhibited RIPK3 and NEK7/NLRP3. Furthermore, macrophage Gli1 or Snail knockout activated RIPK3 and increased hepatocyte necroptosis, while macrophage RIPK3 ablation diminished NEK7/NLRP3-driven inflammatory response. Our findings underscore a novel molecular mechanism of the myeloid Foxo1-β-catenin axis in regulating Hedgehog/Gli1 function that is key in oxidative stress-induced liver inflammation and necroptosis.
    DOI:  https://doi.org/10.1038/s41418-020-00695-7
  20. J Cell Mol Med. 2020 Dec 09.
    Cuijpers I, Papageorgiou AP, Carai P, Herwig M, Mügge A, Klein T, Hamdani N, Jones EAV, Heymans S.
      The metabolic syndrome (MetS) is an escalating problem worldwide, causing left ventricular stiffening, an early characteristic of diastolic dysfunction for which no treatment exists. As diastolic dysfunction and stiffening in MetS patients are associated with increased circulating dipeptidyl peptidase-4 (DPP-4) levels, we investigated whether the clinically approved DPP-4 inhibitor linagliptin reduces left ventricular stiffness in MetS-induced cardiac disease. Sixteen-week-old obese ZSF1 rats, displaying the MetS and left ventricular stiffness, received linagliptin-supplemented or placebo diet for four weeks. Linagliptin significantly reduced obesity, hyperlipidaemia, and hyperglycaemia and improved left ventricular relaxation. This improved relaxation was related to decreased cardiac fibrosis and cardiomyocyte passive stiffness (Fpassive ). The reduced Fpassive was the result of titin isoform switching from the stiff N2B to the more flexible N2BA and increased phosphorylation of total titin and specifically its N2Bus region (S4080 and S3391). Importantly, DPP-4 directly cleaved titin in vitro, resulting in an increased Fpassive , which was prevented by simultaneous administration of linagliptin. In conclusion, linagliptin improves left ventricular stiffness in obese ZSF1 rats by preventing direct DPP4-mediated titin cleavage, as well as by modulating both titin isoform levels and phosphorylation. Reducing left ventricular stiffness by administering linagliptin might prevent MetS-induced early diastolic dysfunction in human.
    Keywords:  cardiomyocyte passive stiffness; left ventricular stiffening; linagliptin; metabolic syndrome; titin
    DOI:  https://doi.org/10.1111/jcmm.16122
  21. Int J Mol Sci. 2020 Dec 03. pii: E9216. [Epub ahead of print]21(23):
    Taberner-Cortés A, Vinué Á, Herrero-Cervera A, Aguilar-Ballester M, Real JT, Burks DJ, Martínez-Hervás S, González-Navarro H.
      Type 2 diabetes mellitus (T2DM) increases morbimortality in humans via enhanced susceptibility to cardiovascular disease (CVD). Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are drugs designed for T2DM treatment to diminish hyperglycaemia by reducing up to 90% of renal tube glucose reabsorption. Clinical studies also suggest a beneficial action of SGLT2i in heart failure and CVD independent of its hypoglycaemiant effect. In the present study, we explored the effect of SGLT2i dapagliflozin (DAPA) in the metabolism and atherosclerosis in Apoe-/-Irs2+/- mice, which display accelerated atherosclerosis induced by insulin resistance. DAPA treatment of Apoe-/-Irs2+/- mice, which were fed a high-fat, high-cholesterol diet, failed to modify body weight, plasma glucose or lipid. Carbohydrate metabolism characterisation showed no effect of DAPA in the glucose tolerance test (GTT) despite augmented insulin levels during the test. In fact, decreased C-peptide levels in DAPA-treated mice during the GTT suggested impaired insulin release. Consistent with this, DAPA treatment of Apoe-/-Irs2+/- isolated islets displayed lower glucose-stimulated insulin secretion compared with vehicle-treated islets. Moreover, insulin-signalling experiments showed decreased pAKT activation in DAPA-treated adipose tissue indicating impaired insulin signalling in this tissue. No changes were seen in lesion size, vulnerability or content of macrophages, vascular smooth muscle cells, T cells or collagen. DAPA did not affect circulating inflammatory cells or cytokine levels. Hence, this study indicates that DAPA does not protect against atherosclerosis in insulin-resistant mice in hypercholesterolemic conditions.
    Keywords:  SGLT2i; atherosclerosis; glucose metabolism; insulin resistance; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms21239216
  22. Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30651-3. [Epub ahead of print]
    Sadiku P, Willson JA, Ryan EM, Sammut D, Coelho P, Watts ER, Grecian R, Young JM, Bewley M, Arienti S, Mirchandani AS, Sanchez Garcia MA, Morrison T, Zhang A, Reyes L, Griessler T, Jheeta P, Paterson GG, Graham CJ, Thomson JP, Baillie K, Thompson AAR, Morgan JM, Acosta-Sanchez A, Dardé VM, Duran J, Guinovart JJ, Rodriguez-Blanco G, Von Kriegsheim A, Meehan RR, Mazzone M, Dockrell DH, Ghesquiere B, Carmeliet P, Whyte MKB, Walmsley SR.
      Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.
    Keywords:  COPD; GYS1; gluconeogenesis; glycogen; glycogenesis; glycogenolysis; glycolysis; inflammation; neutrophil
    DOI:  https://doi.org/10.1016/j.cmet.2020.11.016
  23. J Neurosci. 2020 Dec 10. pii: JN-RM-2360-19. [Epub ahead of print]
    Woods C, Marques-Lopes J, Contoreggi NH, Milner TA, Pickel VM, Wang G, Glass MJ.
      There are significant neurogenic and inflammatory influences on blood pressure, yet the role played by each of these processes in the development of hypertension is unclear. Tumor necrosis factor alpha (TNFα) has emerged as a critical modulator of blood pressure and neural plasticity, however the mechanism by which TNFα signaling contributes to the development of hypertension is uncertain. We present evidence that the TNFα type 1 receptor (TNFR1) plays a key role in heightened glutamate signaling following slow-pressor angiotensin II (AngII) in the hypothalamic paraventricular nucleus (PVN), a key central coordinator of blood pressure control. Fourteen-day administration of a slow-pressor dose of angiotensin II (AngII) in male mice was associated with transcriptional and post-transcriptional (increased plasma membrane affiliation) regulation of TNFR1 in the PVN. Further, TNFR1 was shown to be critical for elevated NMDA-mediated excitatory currents in sympathoexcitatory PVN neurons following AngII infusion. Finally, silencing PVN TNFR1 prevented the increase in systolic blood pressure induced by AngII. These findings indicate that TNFR1 modulates a cellular pathway involving an increase in NMDA-mediated currents in the PVN, suggesting a mechanism whereby TNFR1 activation contributes to hypertension mediated by AngII via heightened glutamate-dependent signaling.SIGNIFICANCE STATEMENT:Inflammation is critical for the emergence of hypertension, yet the mechanisms by which inflammatory mediators contribute to this dysfunction are not clearly defined. We show that tumor necrosis factor alpha (TNFα) receptor 1 (TNFR1) in the paraventricular hypothalamic nucleus (PVN), a critical neuroregulator of cardiovascular function, plays an important role in the development of hypertension in mice. In the PVN, TNFR1 expression and plasma membrane localization are upregulated during hypertension induced by angiotensin II (AngII). Further, TNFR1 activation was essential for NMDA signaling and the potentiation of NMDA currents during hypertension. Finally, TNFR1 silencing in the PVN inhibits elevated blood pressure induced by AngII. These results point to a critical role for hypothalamic TNFR1 signaling in hypertension.
    DOI:  https://doi.org/10.1523/JNEUROSCI.2360-19.2020
  24. Elife. 2020 Dec 08. pii: e59616. [Epub ahead of print]9
    Mann SN, Hadad N, Nelson Holte M, Rothman AR, Sathiaseelan R, Ali Mondal S, Agbaga MP, Unnikrishnan A, Subramaniam M, Hawse J, Huffman DM, Freeman WM, Stout MB.
      Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.
    Keywords:  medicine; mouse; rat
    DOI:  https://doi.org/10.7554/eLife.59616
  25. Trends Mol Med. 2020 Dec 05. pii: S1471-4914(20)30294-X. [Epub ahead of print]
    MacRae CA, Deo RC, Shaw SY.
      Despite increasing ability to understand and correct molecular derangements in disease, genomics and novel phenotypic assays are unevenly deployed in clinical practice. This has hampered translational research and our ability to identify clinically actionable subtypes of disease. Historic examples illustrate how the perspectives of stakeholders across the healthcare ecosystem can influence adoption of innovations in healthcare. Consideration of these factors, from discovery to implementation, can accelerate adoption of new molecular and digital phenotypes in a 'learning' healthcare ecosystem.
    Keywords:  digital health; genomics; healthcare innovation; phenotypes; systemic barriers
    DOI:  https://doi.org/10.1016/j.molmed.2020.11.007
  26. Evid Based Complement Alternat Med. 2020 ;2020 6295402
    Zhang Y, Peng L, Li W, Dai T, Nie L, Xie J, Ai Y, Li L, Tian Y, Sheng J.
      Moringa oleifera Lam. is an essential herb used for the treatment of inflammation, diabetes, high blood pressure, and other diseases. In this study, phenolic extracts of M. oleifera leaves were obtained and analyzed. The results showed that the main identifiable phenols were astragalin, chlorogenic acid, isoquercitrin, kaempferitrin, luteolin, quercetin, and rutin. The effects of M. oleifera polyphenol extract (MOPE) on experimental colitis induced by 3% dextran sulfate sodium (DSS) were investigated. The results showed that oral administration of MOPE significantly alleviated the symptoms of DSS-induced colitis. MOPE significantly reduced weight loss, the disease activity index, colon shortening, and mucosal damage. In addition, MOPE attenuated the infiltration of CD3+ T cells, CD177+ neutrophils, and F4/80+ macrophages and significantly inhibited the secretion of IL-6 and TNF-α. After the MOPE administration, the expression of proteins associated with the NF-κB signaling pathway changed. Specifically, compared with that of the DSS group, the protein expression of NF-κB p65 and p-IκBα was downregulated, and the expression of IκBα was upregulated. This study revealed the anti-inflammatory effects and mechanisms of MOPE in the colon, indicating its potential use in preventing inflammation-driven diseases.
    DOI:  https://doi.org/10.1155/2020/6295402
  27. Behav Brain Res. 2020 Dec 08. pii: S0166-4328(20)30742-7. [Epub ahead of print] 113043
    Chen M, Huang N, Liu J, Huang J, Shi J, Jin F.
      The pathogenesis and etiology of diabetes mellitus (DM) and Alzheimer's disease (AD) share many common cellular and molecular themes. Recently, a growing body of research has shown that AMP-activated protein kinase (AMPK), a biomolecule that regulates energy balance and glucose and lipid metabolism, plays key roles in DM and AD. In this review, we summarize the relevant research on the roles of AMPK in DM and AD, including its functions in gluconeogenesis and insulin resistance (IR) and its relationships with amyloid β-protein (Aβ), Tau and AMPK activators. In DM, AMPK is involved in the regulation of glucose metabolism and IR. AMPK is closely related to gluconeogenesis, which can not only be activated by the upstream kinases liver kinase B1 (LKB1), transforming growth factor β-activated kinase 1 (TAK1), and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) but also regulate the downstream kinases glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxy kinase (PEPCK), thereby affecting gluconeogenesis and ameliorating DM. Moreover, AMPK can regulate glucose transporter 4 (GLUT4) and free fatty acids to improve IR. In AD, AMPK can ameliorate abnormal brain energy metabolism, not only by reduces Aβ deposition through β-secretase but also reduces tau hyperphosphorylation through sirtuin 1 (SIRT1) and protein phosphatase 2A (PP2A). Therefore, AMPK is a bridge between DM and AD.
    DOI:  https://doi.org/10.1016/j.bbr.2020.113043
  28. Medicine (Baltimore). 2020 Dec 04. 99(49): e22877
    Yu P, Li W, Li H, Ouyang S, Cai H, Wu J, Tang C, Huang Q.
      BACKGROUND: Aging is a phenomenon that human's physiology and psychology is progressive decline for natural environment. Health Qigong, as a convenient and effective exercise therapy,is widely used for anti-aging. However, there are no systematic reviews or meta-analysises to evaluate the efficacy and safety of Health Qigong on anti-aging.METHODS: We will systematically search for 7 English databases(PubMed, Excerpta Medica Database, MEDLINE, Web of Science, Cochrane Library, SpringerLink, and WHO International Clinical Trials Registry Platform) and 4 Chinese databases(namely the China National Knowledge Infrastructure Database, the Wanfang Database, the Chinese Scientific Journal Database, and the Chinese BioMedical Literature Database) from their inceptions to August 2020. Randomized controlled trials (RCTs) using Health Qigong to anti-aging will be included. After the selection and extraction of eligible studies, a meta-analysis will be undertaken to assess the efficacy and safety of Health Qigong on anti-aging. Moreover, study selection, data extraction, and the evaluation of the methodological quality of trials will each be independently completed by at least 2 researchers. The Review Manager Software V.5.3 will be employed for meta-analysis to assess the risk of bias, data synthesis, and subgroup analysis.
    RESULTS: This review will provide the latest knowledge and evidence on the efficacy and safety of Health Qigong for anti-aging through the analysis of various evaluation scales.
    CONCLUSION: The conclusion of this review will help clinicians provide effective exercise therapy for anti-aging.
    REGISTRATION NUMBER: INPLASY202090017.
    DOI:  https://doi.org/10.1097/MD.0000000000022877
  29. Bone Marrow Transplant. 2020 Dec 07.
    Maziarz RT, Levis M, Patnaik MM, Scott BL, Mohan SR, Deol A, Rowley SD, Kim DDH, Hernandez D, Rajkhowa T, Haines K, Bonifacio G, Rine P, Purkayastha D, Fernandez HF.
      We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362).
    DOI:  https://doi.org/10.1038/s41409-020-01153-1
  30. Am J Transplant. 2020 Dec 09.
    Schaenman JM, Diamond JM, Greenland JR, Gries C, Kennedy CC, Parulekar AD, Rozenberg D, Singer JP, Singer LG, Snyder LD, Bhorade S.
      Many lung transplant candidates and recipients are older and frailer compared to previous eras. Older patients are at increased risk for pre- and post-transplant mortality, but this risk is not explained by numerical age alone. This manuscript represents the product of the American Society of Transplantation (AST) conference on frailty. Experts in the field reviewed the latest published research on assessment of elderly and frail lung transplant candidates. Physical frailty, often defined as slowness, weakness, low physical activity, shrinking, and exhaustion, and frailty evaluation is an important tool for evaluation of age-associated dysfunction. Another approach is assessment by cumulative deficits, and both types of frailty are common in lung transplant candidates. Frailty is associated with death or delisting before transplant, and may be associated with post-transplant mortality. Sarcopenia, cognitive dysfunction, depression, and nutrition are other important components for patient evaluation. Aging-associated inflammation, telomere dysfunction, and adaptive immune system senescence may also contribute to frailty. Developing tools for frailty assessment and interventions holds promise for improving patient outcomes before and after lung transplantation.
    DOI:  https://doi.org/10.1111/ajt.16439
  31. Semin Cancer Biol. 2020 Dec 05. pii: S1044-579X(20)30261-3. [Epub ahead of print]
    Peitzsch C, Gorodetska I, Klusa D, Shi Q, Alves TC, Pantel K, Dubrovska A.
      Metabolic reprogramming is one of the main hallmarks of cancer cells. It refers to the metabolic adaptations of tumor cells in response to nutrient deficiency, microenvironmental insults, and anti-cancer therapies. Metabolic transformation during tumor development plays a critical role in the continued tumor growth and progression and is driven by a complex interplay between the tumor mutational landscape, epigenetic modifications, and microenvironmental influences. Understanding the tumor metabolic vulnerabilities might open novel diagnostic and therapeutic approaches with the potential to improve the efficacy of current tumor treatments. Prostate cancer is a highly heterogeneous disease harboring different mutations and tumor cell phenotypes. While the increase of intra-tumor genetic and epigenetic heterogeneity is associated with tumor progression, less is known about metabolic regulation of prostate cancer cell heterogeneity and plasticity. This review summarizes the central metabolic adaptations in prostate tumors, state-of-the-art technologies for metabolic analysis, and the perspectives for metabolic targeting and diagnostic implications.
    Keywords:  Prostate cancer; cancer stem cells; circulating tumor cells; disseminated tumor cells; metabolic biomarkers; metabolic heterogeneity; metabolic reprogramming; metabolic therapies; metabolomics
    DOI:  https://doi.org/10.1016/j.semcancer.2020.12.002
  32. Cell Syst. 2020 Dec 02. pii: S2405-4712(20)30455-5. [Epub ahead of print]
    Arai F, Stumpf PS, Ikushima YM, Hosokawa K, Roch A, Lutolf MP, Suda T, MacArthur BD.
      Changes in stem cell activity may underpin aging. However, these changes are not completely understood. Here, we combined single-cell profiling with machine learning and in vivo functional studies to explore how hematopoietic stem cell (HSC) divisions patterns evolve with age. We first trained an artificial neural network (ANN) to accurately identify cell types in the hematopoietic hierarchy and predict their age from single-cell gene-expression patterns. We then used this ANN to compare identities of daughter cells immediately after HSC divisions and found that the self-renewal ability of individual HSCs declines with age. Furthermore, while HSC cell divisions are deterministic and intrinsically regulated in young and old age, they are variable and niche sensitive in mid-life. These results indicate that the balance between intrinsic and extrinsic regulation of stem cell activity alters substantially with age and help explain why stem cell numbers increase through life, yet regenerative potency declines.
    Keywords:  aging; artificial neural network; hematopoietic stem cell; machine learning; self-renewal
    DOI:  https://doi.org/10.1016/j.cels.2020.11.004
  33. Vaccines (Basel). 2020 Dec 04. pii: E735. [Epub ahead of print]8(4):
    Venkatraman S, Meller J, Hongeng S, Tohtong R, Chutipongtanate S.
      The study of immune evasion has gained a well-deserved eminence in cancer research by successfully developing a new class of therapeutics, immune checkpoint inhibitors, such as pembrolizumab and nivolumab, anti-PD-1 antibodies. By aiming at the immune checkpoint blockade (ICB), these new therapeutics have advanced cancer treatment with notable increases in overall survival and tumor remission. However, recent reports reveal that 40-60% of patients fail to benefit from ICB therapy due to acquired resistance or tumor relapse. This resistance may stem from increased expression of co-inhibitory immune checkpoints or alterations in the tumor microenvironment that promotes immune suppression. Because these mechanisms are poorly elucidated, the transcription factors that regulate immune checkpoints, known as "master regulators", have garnered interest. These include AP-1, IRF-1, MYC, and STAT3, which are known to regulate PD/PD-L1 and CTLA-4. Identifying these and other potential master regulators as putative therapeutic targets or biomarkers can be facilitated by mining cancer literature, public datasets, and cancer genomics resources. In this review, we describe recent advances in master regulator identification and characterization of the mechanisms underlying immune checkpoints regulation, and discuss how these master regulators of immune checkpoint molecular expression can be targeted as a form of auxiliary therapeutic strategy to complement traditional immunotherapy.
    Keywords:  cancer immune response; immune checkpoint inhibitor; transcription factors; tumor microenvironment
    DOI:  https://doi.org/10.3390/vaccines8040735
  34. Cells. 2020 Dec 04. pii: E2600. [Epub ahead of print]9(12):
    De Oliveira MP, Liesa M.
      Tumors remodel their metabolism to support anabolic processes needed for replication, as well as to survive nutrient scarcity and oxidative stress imposed by their changing environment. In most healthy tissues, the shift from anabolism to catabolism results in decreased glycolysis and elevated fatty acid oxidation (FAO). This change in the nutrient selected for oxidation is regulated by the glucose-fatty acid cycle, also known as the Randle cycle. Briefly, this cycle consists of a decrease in glycolysis caused by increased mitochondrial FAO in muscle as a result of elevated extracellular fatty acid availability. Closing the cycle, increased glycolysis in response to elevated extracellular glucose availability causes a decrease in mitochondrial FAO. This competition between glycolysis and FAO and its relationship with anabolism and catabolism is conserved in some cancers. Accordingly, decreasing glycolysis to lactate, even by diverting pyruvate to mitochondria, can stop proliferation. Moreover, colorectal cancer cells can effectively shift to FAO to survive both glucose restriction and increases in oxidative stress at the expense of decreasing anabolism. However, a subset of B-cell lymphomas and other cancers require a concurrent increase in mitochondrial FAO and glycolysis to support anabolism and proliferation, thus escaping the competing nature of the Randle cycle. How mitochondria are remodeled in these FAO-dependent lymphomas to preferably oxidize fat, while concurrently sustaining high glycolysis and increasing de novo fatty acid synthesis is unclear. Here, we review studies focusing on the role of mitochondrial FAO and mitochondrial-driven lipid synthesis in cancer proliferation and survival, specifically in colorectal cancer and lymphomas. We conclude that a specific metabolic liability of these FAO-dependent cancers could be a unique remodeling of mitochondrial function that licenses elevated FAO concurrent to high glycolysis and fatty acid synthesis. In addition, blocking this mitochondrial remodeling could selectively stop growth of tumors that shifted to mitochondrial FAO to survive oxidative stress and nutrient scarcity.
    Keywords:  ATF4; ISR; cancer; fatty acid oxidation; glycolysis; lipogenesis; mitochondria
    DOI:  https://doi.org/10.3390/cells9122600
  35. Antioxidants (Basel). 2020 Dec 03. pii: E1227. [Epub ahead of print]9(12):
    Morelli MB, Gambardella J, Castellanos V, Trimarco V, Santulli G.
      The potential beneficial effects of the antioxidant properties of vitamin C have been investigated in a number of pathological conditions. In this review, we assess both clinical and preclinical studies evaluating the role of vitamin C in cardiac and vascular disorders, including coronary heart disease, heart failure, hypertension, and cerebrovascular diseases. Pitfalls and controversies in investigations on vitamin C and cardiovascular disorders are also discussed.
    Keywords:  COVID–19; GULO; SVCT; Vitamin C; ascorbic acid; blood pressure; coronavirus; dietary supplements; drug formulations; endothelial dysfunction; heart failure; hypertension; infections; liposomes; oxidative stress; stroke; vascular permeability
    DOI:  https://doi.org/10.3390/antiox9121227
  36. Int J Mol Sci. 2020 Dec 04. pii: E9254. [Epub ahead of print]21(23):
    Pietrzak B, Tomela K, Olejnik-Schmidt A, Mackiewicz A, Schmidt M.
      Secretory IgA (SIgA) is the dominant antibody class in mucosal secretions. The majority of plasma cells producing IgA are located within mucosal membranes lining the intestines. SIgA protects against the adhesion of pathogens and their penetration into the intestinal barrier. Moreover, SIgA regulates gut microbiota composition and provides intestinal homeostasis. In this review, we present mechanisms of SIgA generation: T cell-dependent and -independent; in different non-organized and organized lymphoid structures in intestinal lamina propria (i.e., Peyer's patches and isolated lymphoid follicles). We also summarize recent advances in understanding of SIgA functions in intestinal mucosal secretions with focus on its role in regulating gut microbiota composition and generation of tolerogenic responses toward its members.
    Keywords:  gut; immune homeostasis; microbiota; mucosal secretions; secretory immunoglobulin A; tolerance
    DOI:  https://doi.org/10.3390/ijms21239254
  37. Front Endocrinol (Lausanne). 2020 ;11 586909
    Cai Z, Li H.
      Androgens are some of the most important sex hormones in men, and they maintain important physiological activities in the human body. Cognitive impairment is one of the most common manifestations of aging in the elderly population and an important factor affecting the quality of life of elderly individuals. The levels of sex hormones in elderly people decrease with age, and low levels of androgens in older male individuals have been closely linked to the development of cognitive impairment. Basic studies have shown that androgens have neuroprotective effects and that androgen deficiency impairs cognitive function by increasing oxidative stress and decreasing synaptic plasticity, among other effects. Additionally, clinical studies have also shown that androgen deficiency is closely related to cognitive impairment. This article reviews the relationship between low androgen levels and cognitive impairment, their potential mechanisms, and the effects of testosterone supplementation in improving cognition.
    Keywords:  aging; androgen; cognitive impairment; molecular mechanism; older men
    DOI:  https://doi.org/10.3389/fendo.2020.586909
  38. Adv Healthc Mater. 2020 Dec 11. e2001728
    Sun P, Jia L, Hai J, Lu S, Chen F, Liang K, Sun S, Liu H, Fu X, Zhu Y, Wang B.
      Carbon monoxide (CO) as an emerging treatment holds great promise for inducing the apoptosis of cancer cells. Here coordination assembled strategy is first reported for synthesis of Cu(II)-flavone coordination polymer (NCu-FleCP) CO nanoprodrug that is stable in normal physiological conditions, and yet readily reduces to small size prodrug complex and releases CO on demand under glutathione (GSH) and near infrared (NIR) light. Specifically, after uptaking by cancer cells, local GSH attacked coordination bond within NCu-FleCP, resulting in the release of Cu(I) and free Fle. The CC bond of Fle is cleavage under NIR light to release CO for gas therapy, and Cu(I) reacts with local H2 O2 through Fenton like reaction to generate hydroxyl radicals (• OH) for chemodynamic therapy. Detailed in vitro and in vivo experiments demonstrate that the CO prodrug system in generating a sufficient quantity of CO and • OH offers remarkable destructive effects against cancer cells without causing toxicity to surrounding normal tissues. The study provides a solid foundation to develop smart coordination polymer CO prodrugs with on-demand CO release, enhanced permeability and retention effect, and biodegradability for multimodal synergistic therapy.
    Keywords:  CO gas therapy; Fenton reaction; chemodynamic therapy; coordination polymers; nanoreactors
    DOI:  https://doi.org/10.1002/adhm.202001728
  39. Hematol Oncol Stem Cell Ther. 2020 Dec 05. pii: S1658-3876(20)30178-3. [Epub ahead of print]
    Hong S, Rybicki L, Corrigan D, Hamilton BK, Sobecks R, Kalaycio M, Gerds AT, Dean R, Hill B, Pohlman B, Jagadeesh D, Anwer F, Majhail NS.
      OBJECTIVE/BACKGROUND: Relapse is the most common cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). No standard of care exists, and a wide range of treatments are used for post-alloHCT relapse. In the recent era, several novel therapies including targeted agents are available for acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).METHODS: We reviewed outcomes after alloHCT relapse, with or without use of these newer agents for ALL, AML, and MDS. In total, 115 adults with relapsed or refractory ALL (n = 17), AML (n = 67), and MDS (n = 31) at median 5 (range, 1-64) months after their first alloHCT in 2010-2018 were included.
    RESULTS: Median follow-up was 19 (range, 6-80) months after relapse from alloHCT. Targeted agents were given to 29 (25%) patients. In multivariable analysis, use of targeted agent at any time point after relapse was not associated with survival. Matched unrelated (vs. matched sibling; hazard ratio [HR] 1.70; p = .027) or haploidentical donor grafts (vs. matched sibling; HR 2.69; p = .003), presence of Grade II-IV acute graft-versus-host disease before relapse (HR 2.46; p < .001), and less than 12 months from HCT to relapse (<6 vs. > 12 months; HR 6.34; p < .001; 6-12 vs. > 12 months; HR 3.16; p = .005) were adverse prognostic factors for post-relapse survival.
    CONCLUSION: Outcomes after alloHCT relapse remain poor regardless of the novel agent use. Innovative treatment strategies are needed to improve outcomes after relapse post-alloHCT.
    Keywords:  Allogeneic stem cell transplantation; Post-transplant relapse; Relapse; Survival
    DOI:  https://doi.org/10.1016/j.hemonc.2020.11.006
  40. Cell Signal. 2020 Dec 05. pii: S0898-6568(20)30352-1. [Epub ahead of print] 109875
    Velazquez FN, Hernandez-Corbacho M, Trayssac M, Stith JL, Bonica J, Jean B, Pulkoski-Gross MJ, Carroll BL, Salama MF, Hannun YA, Snider AJ.
      Sphingolipids and their synthetic enzymes have emerged as critical mediators in numerous diseases including inflammation, aging, and cancer. One enzyme in particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P), has been extensively implicated in these processes. SK catalyzes the phosphorylation of sphingosine to S1P and exists as two isoforms, SK1 and SK2. In this review, we will discuss the contributions from the laboratory of Dr. Lina Obeid that have defined the roles for several bioactive sphingolipids in signaling and disease with an emphasis on her work defining SK1 in cellular fates and pathobiologies including proliferation, senescence, apoptosis, and inflammation.
    DOI:  https://doi.org/10.1016/j.cellsig.2020.109875
  41. Int J Environ Res Public Health. 2020 Dec 04. pii: E9049. [Epub ahead of print]17(23):
    Kim Y, Keogh JB, Clifton PM.
      There is an association between the consumption of artificial sweeteners and Type 2 diabetes in cohort studies, but intervention studies do not show a clear elevation of blood glucose after the use of artificial sweeteners. The objective of this study was to examine whether two commonly used artificial sweeteners had an adverse effect on glucose control in normal-weight subjects, and in overweight and obese subjects when consumed for 2 weeks. In the study, 39 healthy subjects (body-mass index, kg/m2) (18-45) without Type 2 diabetes with an age of 18-75 years were randomly assigned to 0.6 L/day of an artificially sweetened soft drink containing acesulfame K (950) and aspartame (951) or 0.6 L/day of mineral water for 2 weeks each in a crossover study. There was a 4 week washout period with no drinks consumed. Glucose levels were read by a continuous glucose monitor (CGM) during each 2 week period. A 75 g oral glucose-tolerance test (OGTT) was performed at the beginning and end of each intervention period. Blood samples were collected at baseline, and 1 and 2 h for glucose and insulin. A 2 week intake of artificially sweetened beverage (ASB) did not alter concentrations of fasting glucose and fasting insulin, the area under the curve (AUC) for OGTT glucose and insulin, the incremental area under the curve (iAUC) for OGTT glucose and insulin, the homeostatic model assessment for insulin resistance (HOMA-IR), and the Matsuda index compared with the baseline and with the changes after a 2 week intake of mineral water. Continuous 2 week glucose concentrations were not significantly different after a 2 week intake of ASB compared with a 2 week intake of mineral water. This study found no harmful effect of the artificially sweetened soft drink containing acesulfame K (950) and aspartame (951) on glucose control when consumed for 2 weeks by people without Type 2 diabetes.
    Keywords:  artificial sweetener; continuous glucose monitoring; glucose; insulin
    DOI:  https://doi.org/10.3390/ijerph17239049
  42. Ther Innov Regul Sci. 2020 May;54(3): 640-644
    Kieffer CM, Robertson AS.
      BACKGROUND: Since 2008, the US Food and Drug Administration (FDA) has required that drug manufacturers conduct postmarket cardiovascular outcomes trials (CVOTs) for approved type 2 diabetes mellitus (T2DM) drugs. The utility and impact of these studies in determining atherosclerotic cardiovascular risk was reviewed during an FDA Advisory Committee Meeting held on October 24, 2018. Drug manufacturers and patient advocates at this meeting contended that the FDA-required CVOT studies discouraged private sector investment into developing novel T2DM drugs. Here, we explore these contentions by reviewing private sector investment in T2DM drug development from 2000 through 2008, followed by a deductive analysis of how associated events-including the implementation of the CVOT requirement-may have precipitated any observed changes.METHODS: We collected and analyzed industry-sponsored interventional trials for T2DM initiated between January 1, 2000, and December 31, 2017, and compared observed trends with those seen across all trials, specific diseases, and against patent filings of novel antidiabetic agents.
    RESULTS: The analysis shows a marked decline in initiated T2DM clinical trials from 2008 through 2017. Possible influencing factors, including the 2008 financial crisis and a slow in the discovery of novel antidiabetic agents may have contributed, but could not fully account for this decline in T2DM studies.
    CONCLUSIONS: These observations are consistent with the statements made by industry representatives and patient advocates at the 2018 Advisory Committee meeting. As the FDA reconsiders postmarket requirements for T2DM products, these observations underscore the importance of considering more efficient postmarket study structures to assess cardiovascular safety beyond mandatory CVOTs.
    Keywords:  cardiovascular outcomes trials; data-driven; drug development; postmarketing; regulatory science
    DOI:  https://doi.org/10.1007/s43441-019-00098-y
  43. Clin Mol Allergy. 2020 Dec 02. 18(1): 24
    Muraki M, Kita H, Gleich GJ.
      BACKGROUND: Eosinophils play an important role in allergic inflammation. Glucocorticosteroids have been used as an anti-inflammatory medication for inflammatory diseases involving eosinophil infiltration. Some effect of nebulized lidocaine has been reported when treating certain patients with asthma, which is also an inflammatory disease. The goal of this study was to examine the effects of dexamethasone and lidocaine on eosinophil proliferation and differentiation using a model of human umbilical cord blood mononuclear cells (UCMC) cultured with IL-5.METHODS: UCMC were cultured with IL-5 (5 ng/mL) for 4 weeks. The effects of dexamethasone and lidocaine on the number and morphology of eosinophilic cells were visualized with Wright-Giemsa and cyanide-resistant peroxidase stains. Moreover, the effect on eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPX) contents in cultured cells were evaluated using radioimmunoassay.
    RESULTS: The number of eosinophilic cells and EDN and EPX content in cultured cells increased in a time-dependent manner in the presence of IL-5. Dexamethasone treatment slightly decreased the number of eosinophilic cells in one week, but this effect was lost in 2-4 weeks. Macrophages in cultured UCMC treated with dexamethasone contained more eosinophil granule proteins. Both EDN and EPX content in cultured cells were reduced by dexamethasone. Lidocaine decreased the number of eosinophilic cells and reduced both EDN and EPX contents in cultured cells.
    CONCLUSIONS: Dexamethasone suppressed the production of eosinophil granule proteins and may also induce apoptosis of eosinophils, while lidocaine suppresses eosinophilopoiesis.
    Keywords:  Dexamethasone; Eosinophil peroxidase; Eosinophil-derived neurotoxin; Eosinophilopoiesis; Lidocaine; Umbilical cord blood
    DOI:  https://doi.org/10.1186/s12948-020-00138-1
  44. Aging (Albany NY). 2020 Dec 03. 12
    Hsiao YJ, Chang WH, Chen HY, Hsu YC, Chiu SC, Chiang CC, Chang GC, Chen YJ, Wang CY, Chen YM, Lin CY, Chen YJ, Yang PC, Chen JJW, Yu SL.
      Microphthalamia-associated transcription factor (MITF) is a critical mediator in melanocyte differentiation and exerts oncogenic functions in melanoma progression. However, the role of MITF in non-small cell lung cancer (NSCLC) is still unknown. We found that MITF is dominantly expressed in the low-invasive CL1-0 lung adenocarcinoma cells and paired adjacent normal lung tissues. MITF expression is significantly associated with better overall survival and disease-free survival in NSCLC and serves as an independent prognostic marker. Silencing MITF promotes tumor cell migration, invasion and colony formation in lung adenocarcinoma cells. In xenograft mouse model, MITF knockdown enhances metastasis and tumorigenesis, but decreases angiogenesis in the Matrigel plug assay. Whole transcriptome profiling of the landscape of MITF regulation in lung adenocarcinoma indicates that MITF is involved in cell development, cell cycle, inflammation and WNT signaling pathways. Chromatin immunoprecipitation assays revealed that MITF targets the promoters of FZD7, PTGR1 and ANXA1. Moreover, silencing FZD7 reduces the invasiveness that is promoted by silencing MITF. Strikingly, MITF has significantly inverse correlations with the expression of its downstream genes in lung adenocarcinoma. In summary, we demonstrate the suppressive role of MITF in lung cancer progression, which is opposite to the canonical oncogenic function of MITF in melanoma.
    Keywords:  FZD7; WNT pathway; metastasis; transcriptome profiling
    DOI:  https://doi.org/10.18632/aging.202171
  45. Nutrients. 2020 Dec 08. pii: E3771. [Epub ahead of print]12(12):
    L'homme L, Sermikli BP, Staels B, Piette J, Legrand-Poels S, Dombrowicz D.
      Growth differentiation factor-15 (GDF-15) and its receptor GFRAL are both involved in the development of obesity and insulin resistance. Plasmatic GDF-15 level increases with obesity and is positively associated with disease progression. Despite macrophages have been recently suggested as a key source of GDF-15 in obesity, little is known about the regulation of GDF-15 in these cells. In the present work, we sought for potential pathophysiological activators of GDF15 expression in human macrophages and identified saturated fatty acids (SFAs) as strong inducers of GDF15 expression and secretion. SFAs increase GDF15 expression through the induction of an ER stress and the activation of the PERK/eIF2/CHOP signaling pathway in both PMA-differentiated THP-1 cells and in primary monocyte-derived macrophages. The transcription factor CHOP directly binds to the GDF15 promoter region and regulates GDF15 expression. Unlike SFAs, unsaturated fatty acids do not promote GDF15 expression and rather inhibit both SFA-induced GDF15 expression and ER stress. These results suggest that free fatty acids may be involved in the control of GDF-15 and provide new molecular insights about how diet and lipid metabolism may regulate the development of obesity and T2D.
    Keywords:  CHOP; ER stress; GDF15; macrophage; obesity; saturated fatty acids; stearate
    DOI:  https://doi.org/10.3390/nu12123771
  46. Int J Mol Sci. 2020 Dec 03. pii: E9238. [Epub ahead of print]21(23):
    Yeh CH, Chou YJ, Kao CH, Tsai TF.
      The ageing of human populations has become a problem throughout the world. In this context, increasing the healthy lifespan of individuals has become an important target for medical research and governments. Cardiac disease remains the leading cause of morbidity and mortality in ageing populations and results in significant increases in healthcare costs. Although clinical and basic research have revealed many novel insights into the pathways that drive heart failure, the molecular mechanisms underlying cardiac ageing and age-related cardiac dysfunction are still not fully understood. In this review we summarize the most updated publications and discuss the central components that drive cardiac ageing. The following characters of mitochondria-related dysfunction have been identified during cardiac ageing: (a) disruption of the integrity of mitochondria-associated membrane (MAM) contact sites; (b) dysregulation of energy metabolism and dynamic flexibility; (c) dyshomeostasis of Ca2+ control; (d) disturbance to mitochondria-lysosomal crosstalk. Furthermore, Cisd2, a pro-longevity gene, is known to be mainly located in the endoplasmic reticulum (ER), mitochondria, and MAM. The expression level of Cisd2 decreases during cardiac ageing. Remarkably, a high level of Cisd2 delays cardiac ageing and ameliorates age-related cardiac dysfunction; this occurs by maintaining correct regulation of energy metabolism and allowing dynamic control of metabolic flexibility. Together, our previous studies and new evidence provided here highlight Cisd2 as a novel target for developing therapies to promote healthy ageing.
    Keywords:  Cisd2; calcium homeostasis; cardiac ageing; energy flexibility; mitochondria; mitochondria-associated membranes (MAMs)
    DOI:  https://doi.org/10.3390/ijms21239238
  47. Best Pract Res Clin Haematol. 2020 Dec;pii: S1521-6926(20)30092-X. [Epub ahead of print]33(4): 101224
    Clark MC, Stein A.
      Despite the approval of a number of new targeted therapies for acute myeloid leukemia (AML), median overall survival still remains poor, ranging from 12 to 18 months in most patients. Based on the success of blinatumomab, the CD19-targeted bispecific antibody for the treatment of acute lymphoblastic leukemia, the development of several CD33-targeted bispecific antibodies for AML are being investigated in clinical trials. In this review article of CD33-targeted bispecific antibodies, we describe the rationale for targeting CD3 x CD33, summarize the data from four ongoing phase 1 studies, review the major toxicity associated with CD33-targeted bispecific antibody therapy of cytokine release syndrome (CRS) and steps to mitigate CRS, and describe possible mechanisms of resistance to CD33-targeted bispecific antibody therapy. Future development to try to improve outcomes include combination therapies to reduce the tumor burden prior to starting treatment, combining with immune checkpoint inhibition therapy such as anti-PD-1/PDL1 antibodies, and the use of second generation bispecific antibodies that target two different antigens and recruit other effector cells such as nature killer cells and macrophages.
    Keywords:  Acute myeloid leukemia; Bispecific antibodies; CD33; Cytokine release syndrome; Immunotherapy
    DOI:  https://doi.org/10.1016/j.beha.2020.101224
  48. Int J Clin Pharmacol Ther. 2020 Dec 10.
    Seidling HM, Wien K, Fabricius J, John C, Hauser J, Renner K, Schäfer P, Krisam J, Haefeli WE.
      OBJECTIVE: To assess the effect of a routine medication review service in German community pharmacies (ATHINA) on drug-related problems (DRPs) and patient-related outcomes.MATERIALS AND METHODS: From 2015 to 2017, ATHINA patients were invited by their pharmacists to participate in a prospective, observational trial, meaning that they needed to attend to a follow-up visit (T2) 3 - 6 months after the routine ATHINA baseline (T0) and concluding visit (T1) to assess implementation rates of the pharmacists' interventions. Moreover, they were asked to fill in 2 surveys on drug treatment-related quality of life and satisfaction with the amount of information received about medicines at T0, T1, and T2.
    RESULTS: Of 132 recruited patients, 115 completed T2. At T0, pharmacists documented a DRP or information need for 114 of 115 patients. About half of these issues were resolved leading to 43/115 patients without any DRP or information need at T1 and 50/115 patients without any DRP or information need at T2 (i.e., absolute reduction by 42.6%, p < 0.001). Also, the number of patients who felt that their daily life was not impaired at all or only very slightly by their drug treatment increased from 54.7% (58/106) at T0 to 67.6% (73/108, p = 0.011) at T2. While the overall satisfaction score with the amount of information on medicines increased from 10.2 ± 5.5 at T0 over 14.6 ± 3.8 (T1) to 15.4 ± 3.1 (T2, p < 0.001), this increase did not correlate with reduced information needs.
    CONCLUSION: The results suggest that the intervention improves medication- and patient-related outcomes. However, causal relationships are still questionable.
    DOI:  https://doi.org/10.5414/CP203841
  49. J Clin Invest. 2020 Dec 08. pii: 139333. [Epub ahead of print]
    Hu M, Zhou M, Bao X, Pan D, Jiao M, Liu X, Li F, Li CY.
      Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia Telangiectasia Mutated (ATM) protein plays a central role in sensing DNA double strand breaks and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance immune checkpoint blockade (ICB) therapy. However, the molecular mechanism involved is not clearly elucidated. Here we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA and activation of the cGAS/STING pathway. Genetic depletion of ATM in murine cancer cells significantly delayed tumor growth in syngeneic mouse hosts in a T-cell dependent manner. Furthermore, chemical inhibition of ATM significantly potentiated anti-PD1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating TFAM, which led to mitochondrial DNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits for ICB therapy. Our study therefore provides strong evidence that ATM may serve both as a therapeutic target and a biomarker to enable ICB therapy.
    Keywords:  Cancer immunotherapy; Cytokines; DNA repair; Oncology
    DOI:  https://doi.org/10.1172/JCI139333
  50. Am J Cancer Res. 2020 ;10(11): 3784-3800
    Wang L, Stadlbauer B, Lyu C, Buchner A, Pohla H.
      Cancer stem cells (CSCs) are a small population among cancer cells, defined as capable of self-renewal, and driving tumor growth, metastasis, and therapeutic relapse. The development of therapeutic strategies to target CSCs is of great importance to prevent tumor metastasis and relapse. Increasing evidence shows that shikonin has inhibiting effects on CSCs. This study was to determine the effect of shikonin on prostate CSCs, and on drug resistant cells. Sphere formation assay was used to enrich prostate CSCs. The effect of shikonin on viability, proliferation, migration, and invasion was studied. Typical CSCs markers were analyzed by flow cytometry and RT-qPCR. The cytotoxic mechanism of shikonin was analyzed by staining for annexin V, reactive oxygen species (ROS) and mitochondrial membrane potential. To study the effect of shikonin on drug-resistant cells a cabazitaxel resistant cell line was established. Shikonin inhibited the viability, proliferation, migration, and invasion of prostate CSCs. Shikonin enhanced the antitumor effect of cabazitaxel, which is a second-line chemotherapeutic drug in advanced prostate cancer. Shikonin induced apoptosis through generating ROS and disrupting the mitochondrial membrane potential. Furthermore, shikonin suppressed the expression of ALDH3A1 and ABCG2 in prostate CSCs, which are two markers related to drug-resistance. When inhibiting the expression of ABCG2 and ALDH3A1, the cabazitaxel resistant cells acquired more sensibility to cabazitaxel. Shikonin enhances the cytotoxic activity of cabazitaxel in prostate CSCs and reverses the cabazitaxel-resistant state.
    Keywords:  ABCG2; ALDH3A1; Prostate cancer; cabazitaxel; cancer stem cells; drug-resistance; shikonin
  51. Adv Gerontol. 2020 ;33(3): 450-458
    Kim LB, Russkikh GS, Putyatina AN, Tsypysheva OB.
      The content of vascular endothelial growth factor-A (VEGF-A) in blood plasma and its relationship with lipid and extracellular matrix metabolism in working-aged men (19-69 years), living and working in the European part of the Arctic zone of the Russian Federation (Russian Arctic), were studied. No age dependence of the plasma VEGF-A content was found. The correlation analysis, performed in different age groups, revealed significant associations of VEGF-A level with lipid parameters (CS, LDL-C, Apo B, atherogenicity coefficient, Apo B /Apo A1 ratio) and extracellular matrix metabolism (blood TIMP-4, MMP-2, MMP-3, MMP-9, hyaluronan, total and peptide-bound hydroxyproline, glycosaminoglycans). The established correlations indicate the formation of relationships between angiogenesis, atherogenesis and fibrosis at a specific period of life of northerners in the Russian Arctic.
    Keywords:  European part of the Arctic zone of the Russian Federation; aging; angiogenesis; hypoxia; vascular endothelial growth factor (VEGF)
  52. Int J Mol Sci. 2020 Dec 04. pii: E9268. [Epub ahead of print]21(23):
    Armstrong VS, Fitzgerald LW, Bathe OF.
      Excessive muscle loss is commonly observed in cancer patients and its association with poor prognosis has been well-established. Cancer-associated sarcopenia differs from age-related wasting in that it is not responsive to nutritional intervention and exercise. This is related to its unique pathogenesis, a result of diverse and interconnected mechanisms including inflammation, disordered metabolism, proteolysis and autophagy. There is a growing body of evidence that suggests that the tumor is the driver of muscle wasting by its elaboration of mediators that influence each of these pro-sarcopenic pathways. In this review, evidence for these tumor-derived factors and putative mechanisms for inducing muscle wasting will be reviewed. Potential targets for future research and therapeutic interventions will also be reviewed.
    Keywords:  cancer; mediators; muscle wasting; pathophysiology; sarcopenia; tumor; tumor-derived
    DOI:  https://doi.org/10.3390/ijms21239268
  53. Int J Mol Sci. 2020 Dec 08. pii: E9346. [Epub ahead of print]21(24):
    Yamane T.
      Primitive erythrocytes are the first hematopoietic cells observed during ontogeny and are produced specifically in the yolk sac. Primitive erythrocytes express distinct hemoglobins compared with adult erythrocytes and circulate in the blood in the nucleated form. Hematopoietic stem cells produce adult-type (so-called definitive) erythrocytes. However, hematopoietic stem cells do not appear until the late embryonic/early fetal stage. Recent studies have shown that diverse types of hematopoietic progenitors are present in the yolk sac as well as primitive erythroblasts. Multipotent hematopoietic progenitors that arose in the yolk sac before hematopoietic stem cells emerged likely fill the gap between primitive erythropoiesis and hematopoietic stem-cell-originated definitive erythropoiesis and hematopoiesis. In this review, we discuss the cellular origin of primitive erythropoiesis in the yolk sac and definitive hematopoiesis in the fetal liver. We also describe mechanisms for developmental switches that occur during embryonic and fetal erythropoiesis and hematopoiesis, particularly focusing on recent studies performed in mice.
    Keywords:  developmental switch; embryonic hematopoiesis; erythropoiesis; fetal hematopoiesis; fetal liver; hematopoietic stem cell; primitive erythrocyte; transcription factor; yolk sac
    DOI:  https://doi.org/10.3390/ijms21249346
  54. J Pediatr Hematol Oncol. 2020 Dec 09.
    Sharma A, Rastogi N, Chatterjee G, Kapoor R, Nivargi S, Yadav SP.
      BACKGROUND: Haploidentical family donor is universally available and is fast emerging as an alternative donor choice for children with leukemia needing hematopoietic stem cell transplant (HSCT). Here we describe our experience of treating children with acute leukemia by haploidentical HSCT with posttransplant cyclophosphamide (PTCy).METHODS: We retrospectively analyzed the outcome data of 17 children with acute leukemia who underwent related haploidentical HSCT. Fifteen were in complete remission (CR) before HSCT: CR1-6, CR2-7, and CR3-2 and 2 were not in remission. Donors were mobilized with granulocyte colony stimulating factor. The conditioning was nonmyeloablative in 4 and myeloablative in 13. All received PTCy 50 mg/kg on days 3 and 4 as graft-versus-host disease (GVHD) prophylaxis along with tacrolimus or cyclosporine and mycophenolate mofetil. A median of 8.94 million of CD34 cells/kg was infused.
    RESULTS: All patients were engrafted for neutrophil and platelets, except 1 child with refractory acute myeloid leukemia disease who relapsed before engraftment. Five children relapsed (4 died and 1 child with CD20-positive leukemia is disease free after Rituximab therapy). There was 1 transplant-related mortality due to grade IV GVHD. Remaining 11 patients are in CR. Acute GVHD was seen in 4 patients. Out of 4, 3 children later developed chronic GVHD and all are alive and disease free. Three of 4 children who received nonmyeloablative conditioning have relapsed. Overall survival is 70.5% and event-free survival is 64.7%. Median follow-up of all patients was 393 days.
    CONCLUSION: Haploidentical HSCT with PTCy is a safe and effective therapy for children with acute leukemia. Myeloablative conditioning and chronic GVHD lead to improved disease-free survival.
    DOI:  https://doi.org/10.1097/MPH.0000000000002030
  55. Cell Death Dis. 2020 Dec 09. 11(12): 1044
    Kim Y, Gautam S, Aseer KR, Kim J, Chandrasekaran P, Mazucanti CH, Ghosh P, O'Connell JF, Doyle ME, Appleton A, Lehrmann E, Liu QR, Egan JM.
      Cannabinoid 1 receptor (CB1R) expression is upregulated in the liver with viral hepatitis, cirrhosis, and both alcoholic and non-alcoholic fatty liver disease (FLD), whereas its expression is muted under usual physiological conditions. Inhibiting CB1R has been shown to be beneficial in preserving hepatic function in FLD but it is unclear if inhibiting CB1R during an inflammatory response to an acute hepatic injury, such as toxin-induced injury, would also be beneficial. We found that intrinsic CB1R in hepatocytes regulated liver inflammation-related gene transcription. We tested if nullification of hepatocyte-specific CB1R (hCNR1-/-) in mice protects against concanavalin A (Con A)-induced liver injury. We looked for evidence of liver damage and markers of inflammation in response to Con A by measuring liver enzyme levels and proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-17) in serum collected from hCNR1-/- and control mice. We observed a shift to the right in the dose-response curve for liver injury and inflammation in hCNR1-/- mice. We also found less inflammatory cell infiltration and focal necrosis in livers of hCNR1-/- mice compared to controls, resulting from downregulated apoptotic markers. This anti-apoptotic mechanism results from increased activation of nuclear factor kappa B (NF-κB), especially cAMP-dependent cannabinoid signaling and membrane-bound TNF-α, via downregulated TNF-α receptor 2 (TNFR2) transcription levels. Collectively, these findings provide insight into involvement of CB1R in the pathogenesis of acute liver injury.
    DOI:  https://doi.org/10.1038/s41419-020-03261-8
  56. J Aging Phys Act. 2020 Dec 08. pii: japa.2020-0201. [Epub ahead of print] 1-8
    Fernandes JFT, Lamb KL, Norris JP, Moran J, Drury B, Borges NR, Twist C.
      Aging is anecdotally associated with a prolonged recovery from resistance training, though current literature remains equivocal. This brief review considers the effects of resistance training on indirect markers of muscle damage and recovery (i.e., muscle soreness, blood markers, and muscle strength) in older males. With no date restrictions, four databases were searched for articles relating to aging, muscle damage, and recovery. Data from 11 studies were extracted for review. Of these, four reported worse symptoms in older compared with younger populations, while two have observed the opposite, and the remaining studies (n = 6) proposed no differences between age groups. It appears that resistance training can be practiced in older populations without concern for impaired recovery. To improve current knowledge, researchers are urged to utilize more ecologically valid muscle-damaging bouts and investigate the mechanisms which underpin the recovery of muscle soreness and strength after exercise in older populations.
    Keywords:  dynapenia; fatigue; muscle soreness; muscle strength; sarcopenia
    DOI:  https://doi.org/10.1123/japa.2020-0201
  57. J Gerontol A Biol Sci Med Sci. 2020 Dec 07. pii: glaa309. [Epub ahead of print]
    Dalle S, Van Roie E, Hiroux C, Vanmunster M, Coudyzer W, Suhr F, Bogaerts S, Van Thienen R, Koppo K.
      Old skeletal muscle exhibits decreased anabolic sensitivity, eventually contributing to muscle wasting. Besides anabolism, also muscle inflammation and catabolism are critical players in regulating the old skeletal muscle's sensitivity. Omega-3 fatty acids (ω-3) are an interesting candidate to reverse anabolic insensitivity via anabolic actions. Yet, it remains unknown whether ω-3 also attenuates muscle inflammation and catabolism. The present study investigates the effect of ω-3 supplementation on muscle inflammation and metabolism (anabolism/catabolism) upon resistance exercise (RE). Twenty-three older adults (OA) (65-84yr;8♀) were randomized to receive ω-3 (~3g·d -1) or corn oil (PLAC) and engaged in a 12-wk RE program (3x·wk -1). Before and after intervention, muscle volume, strength and systemic inflammation were assessed, and muscle biopsies were analysed for markers of anabolism, catabolism and inflammation. Isometric knee-extensor strength increased in ω-3 (+12.2%), but not in PLAC (-1.4%; pinteraction=0.015), whereas leg press strength improved in both conditions (+27.1%; ptime<0.001). RE, but not ω-3, decreased inflammatory (p65NF-κB) and catabolic (FOXO1, LC3b) markers, and improved muscle quality. Yet, muscle volume remained unaffected by RE and ω-3. Accordingly, muscle anabolism (mTORC1) and plasma CRP remained unchanged by RE and ω-3, whereas serum IL-6 tended to decrease in ω-3 (pinteraction=0.07). These results show that, despite no changes in muscle volume, RE-induced gains in isometric strength can be further enhanced by ω-3. However, ω-3 did not improve RE-induced beneficial catabolic or inflammatory adaptations. Irrespective of muscle volume, gains in strength (primary criterion for sarcopenia) might be explained by changes in muscle quality due to muscle inflammatory or catabolic signaling.
    Keywords:  Muscle wasting; aging; anabolic resistance; inflammation; resistance training; sarcopenia
    DOI:  https://doi.org/10.1093/gerona/glaa309
  58. Food Res Int. 2020 Dec;pii: S0963-9969(20)30802-4. [Epub ahead of print]138(Pt B): 109777
    Feng W, Liu J, Tan Y, Ao H, Wang J, Peng C.
      Turbulence of gut microbiota metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids is an important factor in the development of diseases. Many polysaccharides are effective on diseases including ulcerative colitis (UC), yet most studies investigating the mechanisms of polysaccharides mainly focused on their effects on gut microbiota composition and SCFAs, and other metabolites of gut microbiota are often neglected. Here, we examined the effects of polysaccharides from Atractylodes macrocephala Koidz. (AMP) on experimental UC induced by dextran sulfate sodium (DSS) and explored underlying mechanisms of AMP by 16S rDNA-based gut microbiota analysis and untargeted fecal and plasma metabolomics. In addition, a multiscale, multifactorial network was constructed to visualize the mechanisms of AMP. The results showed that AMP significantly increased body weight and ameliorated colonic injury in DSS treated mice. AMP also partly restored the perturbed gut microbiota composition induced by DSS. Untargeted fecal and plasma metabolomics showed that AMP can not only modulate the production of SCFAs by gut microbiota, but also the ability to digest food nutrients, metabolism of amino acids and bile acids, production of cadaverine and other metabolites by hosts and gut microbiota. The study demonstrated that, in addition to SCFAs, AMP can extensively modulate the metabolism of gut microbiota and hosts to achieve the therapeutic effects. This study adds new mechanisms of polysaccharides in treating diseases.
    Keywords:  Atractylodes macrocephala Koidz.; Gut microbiota; Metabolomics; Polysaccharides; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.foodres.2020.109777
  59. Mol Carcinog. 2020 Dec 07.
    Ahmad I, Nasti TH, Rihan HM, Jimenez H, Elmets CA, Yusuf N.
      Ultraviolet (UV) B irradiation of the skin induces acute inflammation, as characterized by erythema, edema, and immunosuppression, and is subsequently linked to the progression of skin cancer. Toll-like receptor 4 (TLR4), a component of innate immunity, has been shown to play an important role in cancer. To elucidate the role of TLR4 in UVB-induced tumor development, TLR4-proficient (C3H/HeN) and TLR4-deficient (C3H/HeJ) mice were exposed to multiple doses of UVB radiation (200 mJ/cm2 ) for 40 weeks. Photocarcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared with TLR4-proficient mice, whereas significantly greater numbers of tumors occurred in TLR4-proficient mice. There was significant upregulation of inflammatory markers like COX-2, PGE2 , S100A8, and S100A9 in the skin of TLR4-proficient mice than the skin of TLR4-deficient mice. Furthermore, we found that TLR4-proficient mice had a significantly higher number of Gr1+CD11b+ myeloid cells CD4+CD25+ regulatory T-cells than TLR4-deficient mice. Furthermore, the levels of interferon (IFN)-γ cytokine was increased and the levels of interleukin (IL)-4, IL-10, and IL-17 cytokines were decreased in serum, skin, and tumor lysates of TLR4-deficient mice in comparison with samples from TLR4-proficient mice. Together, our data indicate that TLR4-mediated inflammation may cause suppression of antitumor responses and trigger the development of UVB-induced skin cancers. Thus, strategies to inhibit TLR4-mediated immune suppression may allow us to develop preventive and therapeutic approaches for the management of UVB-induced cutaneous tumors.
    Keywords:  Toll-like receptor-4; immune system; skin cancer; ultraviolet radiation
    DOI:  https://doi.org/10.1002/mc.23271
  60. Food Sci Biotechnol. 2020 Dec;29(12): 1619-1640
    Kim C, Hwang JK.
      Skeletal muscle plays a vital role in the conversion of chemical energy into physical force. Muscle atrophy, characterized by a reduction in muscle mass, is a symptom of chronic disease (cachexia), aging (sarcopenia), and muscle disuse (inactivity). To date, several trials have been conducted to prevent and inhibit muscle atrophy development; however, few interventions are currently available for muscle atrophy. Recently, food ingredients, plant extracts, and phytochemicals have received attention as treatment sources to prevent muscle wasting. Flavonoids are bioactive polyphenol compounds found in foods and plants. They possess diverse biological activities, including anti-obesity, anti-diabetes, anti-cancer, anti-oxidation, and anti-inflammation. The effects of flavonoids on muscle atrophy have been investigated by monitoring molecular mechanisms involved in protein turnover, mitochondrial activity, and myogenesis. This review summarizes the reported effects of flavonoids on sarcopenia, cachexia, and disuse muscle atrophy, thus, providing an insight into the understanding of the associated molecular mechanisms.
    Keywords:  Flavonoids; Mitochondrial activity; Muscle atrophy; Myogenesis; Protein turnover
    DOI:  https://doi.org/10.1007/s10068-020-00816-5
  61. Toxicol Appl Pharmacol. 2020 Dec 07. pii: S0041-008X(20)30475-0. [Epub ahead of print] 115353
    Mishra A, Behura A, Kumar A, Ghosh A, Naik L, Mawatwal S, Mohanty SS, Mishra A, Saha S, Bhutia SK, Singh R, Dhiman R.
      Background Host-directed therapy is considered a novel anti-tuberculosis strategy in tackling the tuberculosis burden through autophagy induction by various inducers to curtail the growth of intracellular Mycobacterium tuberculosis. Methods In this study, we investigated the anti-tubercular role of soybean lectin, a lectin isolated from Glycine max (Soybean). Effect of SBL on intracellular mycobacterial viability through autophagy and the mechanism involved in differentiated THP-1 cells was studied using different experimental approaches. Results We initially performed a time kinetic experiment with the non-cytotoxic dose of SBL (20 μg/ml) and observed autophagy induction after 24 h of treatment. Abrogation of autophagy in the presence of 3-MA and an increase in LC3 puncta formation upon Baf-A1 addition elucidated the specific effect on autophagy and autophagic flux. SBL treatment also led to autophagy induction in mycobacteria infected macrophages that restricted the intracellular mycobacterial growth, thus emphasizing the host defensive role of SBL induced autophagy. Mechanistic studies revealed an increase in P2RX7 expression, NF-κB activation and reactive oxygen species generation upon SBL treatment. Inhibition of P2RX7 expression suppressed NF-κB dependent ROS level in SBL treated cells. Moreover, SBL induced autophagy was abrogated in the presence of either different inhibitors or P2RX7 siRNA, leading to the reduced killing of intracellular mycobacteria. Conclusion Taken together, these results conclude that SBL induced autophagy exerts an anti-mycobacterial effect in P2RX7-NF-κB dependent manner through the generation of ROS. General significance This study has provided a novel anti-mycobacterial role of SBL, which may play an important role in devising new therapeutic interventions.
    Keywords:  Autophagy; Human Macrophages; NF-κB; P2RX7; ROS; Soybean Lectin; Tuberculosis
    DOI:  https://doi.org/10.1016/j.taap.2020.115353
  62. J Intern Med. 2020 Nov 29.
    Rathsman B, Haas J, Persson M, Ludvigsson J, Svensson AM, Lind M, Andersson Franko M, Nyström T.
      BACKGROUND: Microvascular complications are common in people with diabetes, where poor glycemic control is the major contributor. The aim of this study was to explore the association between elevated LDL-cholesterol levels and the risk of retinopathy, or nephropathy in young individuals with type 1 diabetes.METHODS: This was a nationwide observational population-based cohort study, including all children and adults with a duration of type 1 diabetes of ≤10 years, identified in the Swedish National Diabetes Register between 1998-2017. We calculated the crude incidence rates with 95% confidence intervals (CIs) and used multivariable Cox regression to estimate crude and adjusted hazard ratios (HRs) of retinopathy, or nephropathy in four LDL-cholesterol categories: <2.6 (Reference), 2.6-3.4, 3.4-4.1, and > 4.1 mmol/L.
    RESULTS: In total 11024/12350 (retinopathy/nephropathy, both cohorts, respectively) children and adults (median age 21 years, female 42%) were followed up to 28 years from diagnosis until end of study. Median duration of diabetes when entering the study were 6 and 7 years in the retinopathy and nephropathy cohort, respectively. Median LDL-cholesterol was 2.4 mmol/L and median HbA1c level was 61 mmol/mol (7.7 %). After multivariable adjustment the HRs (95% CI) for retinopathy in individuals with LDL-cholesterol levels of 2.6-3.4, 3.4-4.1, or >4.1 mmol/L were: 1.13 (1.03-1.23), 1.16 (1.02-1.32) and 1.18 (0.99-1.41), compared with the reference. The corresponding numbers for nephropathy were: 1.15 (0.96-1.32), 1.30 (1.03-1.65), and 1.41 (1.06-1.89).
    CONCLUSIONS: Young individuals with type 1 diabetes exposed to high LDL-cholesterol levels have an increased risk of retinopathy and nephropathy independent of glycemia and other identified risk factors for vascular complications.
    DOI:  https://doi.org/10.1111/joim.13212
  63. Br J Pharmacol. 2020 Dec 07.
    Bercea CI, Cottrell GS, Tamagnini F, McNeish AJ.
      Hypertension is often characterised by impaired vasodilation involving dysfunction of multiple vasodilatory mechanisms. ω-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can reduce blood pressure, and vasodilation. In the endothelium, DHA and EPA improve function including increased nitric oxide bioavailability. However, animal studies show that DHA- and EPA-mediated vasodilation persists after endothelial removal, indicating a role for vascular smooth muscle cells (VSMCs). The vasodilatory effects of ω-3 PUFAs on VSMCs are mediated via opening of large conductance calcium-activated potassium channels (BKCa ), ATP-sensitive potassium channels (KATP ) and possibly members of the Kv7 family of voltage-activated potassium channels, resulting in hyperpolarisation and relaxation. ω-3 PUFA actions on BKCa and voltage-gated ion channels involve electrostatic interactions that are dependent on the polyunsaturated acyl tail, cis-geometry of these double bonds and negative charge of the carboxyl headgroup; suggesting structural manipulation of ω-3 PUFA could generate novel, targeted, therapeutic leads.
    DOI:  https://doi.org/10.1111/bph.15336
  64. Mol Med Rep. 2021 Feb;pii: 127. [Epub ahead of print]23(2):
    Chen S, Hu Y, Zhang J, Zhang P.
      Inflammation of alveolar macrophages is the primary pathological factor leading to acute lung injury (ALI), and NF‑κB activation and HO‑1 inhibition are widely involved in inflammation. Salusin‑β has been reported to contribute to the progression of the inflammatory response, but whether salusin‑β could regulate inflammation in lipopolysaccharide (LPS)‑induced ALI remains unknown. The present study aimed to investigate the role of salusin‑β in LPS‑induced ALI and to uncover the potential underlying mechanisms. Sprague‑Dawley rats were subjected to LPS administration, and then pathological manifestations of lung tissues, inflammatory cytokines levels in bronchoalveolar lavage fluid (BALF) and expression of salusin‑β in macrophages of lung tissues were assessed. NR8383 cells with or without salusin‑β knockdown were treated with LPS, and then the concentration of inflammatory cytokines, and the expression of high mobility group box‑1 (HMGB1), NF‑κB signaling molecules and heme oxygenase‑1 (HO‑1) levels were detected. The results showed that LPS caused injury of lung tissues, increased the levels of proinflammatory cytokines in BALF, and led to higher expression of salusin‑β or macrophages in lung tissues of rats. In vitro experiments, LPS also upregulated salusin‑β expression in NR8383 cells. Knockdown of salusin‑β using short hairpin (sh)RNA inhibited the LPS‑induced generation of inflammatory cytokines. LPS also enhanced HMGB1, phosphorylated (p)‑IκB and p‑p65 expression, but reduced HO‑1 expression in both lung tissues and NR8383 cells, which were instead inhibited by the transfection of sh‑salusin‑β. In addition, knockdown of HO‑1 using shRNA reversed the inhibitory effect of sh‑salusin‑β on the LPS‑induced generation of inflammatory cytokines, activation of NF‑κB signaling and inactivation of HO‑1. In conclusion, this study suggested that knockdown of salusin‑β may inhibit LPS‑induced inflammation in alveolar macrophages by blocking NF‑κB signaling and upregulating HO‑1 expression.
    DOI:  https://doi.org/10.3892/mmr.2020.11766
  65. Am J Lifestyle Med. 2020 Jul-Aug;14(4):14(4): 397-405
    Joshi S, Ettinger L, Liebman SE.
      Hypertension is a global epidemic and a risk factor for many adverse outcomes, including cardiovascular disease, kidney disease, and death. Lifestyle plays a significant role in the development and maintenance of hypertension, and guidelines from several organizations recommend lifestyle modifications as first-line intervention for hypertensive patients. Data supporting the use of plant-based diets in the treatment of hypertension goes back almost a century. More recently, clinical trial data, including randomized controlled trials, have established plant-based diets as an effective lifestyle intervention for high blood pressure (BP). Plant-based diets differ from the standard American diet in a myriad of ways, with some substances being present in either substantially higher or lower amounts. Although the precise mechanism of a plant-based diet's beneficial effects on BP is unknown, many of these differences may be responsible. Attributes of a plant-based diet that may lower BP include a lower energy content leading to weight loss, a lower sodium content, an increased potassium content, reduced oxidative stress, higher bioavailability of the vasodilator nitric oxide, and beneficial effects on the microbiome. The evidenced-based benefits of plant-based diets in treating hypertension should lead providers to advocate for this dietary pattern for their patients.
    Keywords:  blood pressure; hypertension; plant-based diets; sodium
    DOI:  https://doi.org/10.1177/1559827619875411
  66. Br J Pharmacol. 2020 Oct;177(19): 4386-4399
    McKenna M, McDougall JJ.
      A significant number of cannabinoids are known to have analgesic and anti-inflammatory properties in various diseases. Due to their presynaptic/terminal location, cannabinoid receptors can inhibit synaptic transmission and have the potential to regulate neurogenic inflammation. Neurogenic inflammation occurs when a noxious signal is detected in the periphery initiating an antidromic axon reflex in the same sensory neurone leading to depolarization of the afferent terminal. Neuropeptides are subsequently released and contribute to vasodilation, plasma extravasation and modulation of immune cells. Endocannabinoids, synthetic cannabinoids and phytocannabinoids can reduce neuroinflammation by inhibiting afferent firing and inflammatory neuropeptide release. Thus, in addition to a direct effect on vascular smooth muscle and inflammatory cells, cannabinoids can reduce inflammation by silencing small diameter neurones. This review examines the neuropharmacological processes involved in regulating antidromic depolarization of afferent nerve terminals by cannabinoids and the control of neurogenic inflammation in different diseases.
    Keywords:  Cannabis; arthritis; asthma; inflammation; migraine; pain
    DOI:  https://doi.org/10.1111/bph.15208
  67. Immun Ageing. 2020 Nov 09. 17(1): 33
    Nunn AVW, Guy GW, Brysch W, Botchway SW, Frasch W, Calabrese EJ, Bell JD.
      Infection with SARs-COV-2 displays increasing fatality with age and underlying co-morbidity, in particular, with markers of the metabolic syndrome and diabetes, which seems to be associated with a "cytokine storm" and an altered immune response. This suggests that a key contributory factor could be immunosenescence that is both age-related and lifestyle-induced. As the immune system itself is heavily reliant on mitochondrial function, then maintaining a healthy mitochondrial system may play a key role in resisting the virus, both directly, and indirectly by ensuring a good vaccine response. Furthermore, as viruses in general, and quite possibly this new virus, have also evolved to modulate immunometabolism and thus mitochondrial function to ensure their replication, this could further stress cellular bioenergetics. Unlike most sedentary modern humans, one of the natural hosts for the virus, the bat, has to "exercise" regularly to find food, which continually provides a powerful adaptive stimulus to maintain functional muscle and mitochondria. In effect the bat is exposed to regular hormetic stimuli, which could provide clues on how to resist this virus. In this paper we review the data that might support the idea that mitochondrial health, induced by a healthy lifestyle, could be a key factor in resisting the virus, and for those people who are perhaps not in optimal health, treatments that could support mitochondrial function might be pivotal to their long-term recovery.
    DOI:  https://doi.org/10.1186/s12979-020-00204-x
  68. Mol Med Rep. 2021 Feb;pii: 95. [Epub ahead of print]23(2):
    Xu L, Song Q, Ouyang Z, Zhang X, Zhang C.
      Pneumonia accounts for ~1.3 million mortalities in children per year worldwide. MicroRNAs are implicated in several diseases, including cancer and pneumonia; however, the role of let7f‑5p in pneumonia is not completely understood. In the present study, lipopolysaccharide (LPS) was used to establish an in vitro pneumonia model in A549 and WI‑38 cells. The reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting results demonstrated that let7f‑5p expression levels were significantly decreased, whereas MAPK6 expression levels were significantly increased in the peripheral venous blood of patients with pneumonia and in LPS‑induced A549 and WI‑38 cells compared with healthy volunteers and control cells, respectively. Furthermore, the dual‑luciferase reporter assay demonstrated that let7f‑5p targeted the 3'‑untranslated region of MAPK6. The ELISA and RT‑qPCR results demonstrated that let7f‑5p mimic ameliorated LPS‑induced inflammatory injury in A549 and WI‑38 cells, as demonstrated by decreased expression levels of proinflammatory cytokines, including TNF‑α and IL‑6. In addition, the Cell Counting Kit‑8 assay results indicated that let7f‑5p mimic ameliorated LPS‑induced reductions in cell viability, and the western blotting results demonstrated that let7f‑5p mimic reversed LPS‑induced activation of the STAT3 signaling pathway. Notably, the aforementioned let7f‑5p‑mediated effects were reversed by MAPK6 overexpression. Collectively, the results of the present study suggested that let7f‑5p inhibited inflammation by targeting MAPK6 in the in vitro pneumonia model, thus let7f‑5p may serve as a potential novel therapeutic target for pneumonia.
    DOI:  https://doi.org/10.3892/mmr.2020.11734
  69. FEBS J. 2020 Dec 07.
    Shiino H, Furuta S, Kojima R, Kimura K, Endo T, Tamura Y.
      Most phospholipids are synthesized in the endoplasmic reticulum and distributed to other cellular membranes. Although the vesicle transport contributes to the phospholipid distribution among the endomembrane system, exactly how phospholipids are transported to, from and between mitochondrial membranes remains unclear. To gain insights into phospholipid transport routes into mitochondria, we expressed the Escherichia coli phosphatidylserine synthase PssA in various membrane compartments with distinct membrane topologies in yeast cells lacking a sole phosphatidylserine synthase (Cho1). Interestingly, PssA could complement loss of Cho1 when targeted to the ER, peroxisome, or lipid droplet membranes. Synthesized phosphatidylserine could be converted to phosphatidylethanolamine by Psd1, the mitochondrial PS decarboxylase, suggesting that phospholipids synthesized in the peroxisomes and LDs can efficiently reach mitochondria. Furthermore, we found that PssA integrated into the mitochondrial inner membrane from the matrix side could partially complement the loss of Cho1. The phosphatidylserine synthesized in the mitochondrial inner membrane was also converted to phosphatidylethanolamine, indicating that phosphatidylserine flops across the mitochondrial inner membrane to become phosphatidylethanolamine. These findings expand our understanding of the intracellular phospholipid transport routes via mitochondria.
    Keywords:  PssA; mitochondria; phosphatidylserine synthase; phospholipid
    DOI:  https://doi.org/10.1111/febs.15657
  70. Diabetol Metab Syndr. 2020 Nov 18. 12(1): 100
    Ajlouni K, Khader Y, Alyousfi M, Al Nsour M, Batieha A, Jaddou H.
      BACKGROUND: Multiple epidemiological studies were conducted amongst a variety of ethnic groups and showed discrepancies in the prevalence of metabolic syndrome (MeS) and its individual components. This study aimed to determine the prevalence of MeS in Jordan using both the Adult Treatment Panel Guidelines (ATP III) and the International Diabetes Federation (IDF) criteria. The study also aimed to assess the changes in the prevalence of MeS over time and determine its association with sociodemographic variables.METHODS: Data from the 2017 Cardiovascular Disease Risk Factors Survey were used for this study. Socio-demographic and clinical data were collected using a structured questionnaire. Blood samples were taken for biochemical measurements. Furthermore, anthropometric characteristics were measured by the same team of trained field researchers. A sample of 4,056 individuals aged between 18 and 90 years was included in this study. The findings from the 2017 survey were compared with the findings of a 2009 survey that adopted the same methods and procedures.
    RESULTS: According to the IDF criteria, the crude prevalence of Metabolic syndrome was 48.2% (52.9% among men and 46.2% among women; p < 0.001). Using the ATP III criteria, the prevalence was 44.1% (51.4% among men and 41% among women, p < 0.001). The age-standardized prevalence rate of metabolic syndrome was 44% (95% CI 42.7, 45.4) and 39.9% (95% CI 39.6, 41.2), according to both the IDF definition and ATP III criteria, respectively. The Kappa measure of agreement showed excellent agreement between the two definitions (k = 81.9%, p < 0.001). Of all participants, 41.7% met both the IDF and ATP III diagnostic criteria, 6.6% met the IDF criteria only, and 2.5% met the ATP III criteria only. The age-standardized prevalence rate of metabolic syndrome was significantly higher in 2017 (45.7% in men and 44.5% in women) than that in 2009 survey (34.6% in men and 39.8% in women). Gender, age, occupation, region, and marital status were significantly associated with metabolic syndrome.
    CONCLUSIONS: The prevalence of metabolic syndrome in Jordan is considerably high and it is increasing. Healthy lifestyle programs encouraging appropriate dietary habits and physical activity are strongly recommended in Jordan.
    Keywords:  Diabetes; Hypertension; Metabolic syndrome; Obesity
    DOI:  https://doi.org/10.1186/s13098-020-00610-7
  71. Int J Mol Sci. 2020 Dec 04. pii: E9273. [Epub ahead of print]21(23):
    Méresse S, Fodil M, Fleury F, Chénais B.
      Fucoxanthin is a well-known carotenoid of the xanthophyll family, mainly produced by marine organisms such as the macroalgae of the fucus genus or microalgae such as Phaeodactylum tricornutum. Fucoxanthin has antioxidant and anti-inflammatory properties but also several anticancer effects. Fucoxanthin induces cell growth arrest, apoptosis, and/or autophagy in several cancer cell lines as well as in animal models of cancer. Fucoxanthin treatment leads to the inhibition of metastasis-related migration, invasion, epithelial-mesenchymal transition, and angiogenesis. Fucoxanthin also affects the DNA repair pathways, which could be involved in the resistance phenotype of tumor cells. Moreover, combined treatments of fucoxanthin, or its metabolite fucoxanthinol, with usual anticancer treatments can support conventional therapeutic strategies by reducing drug resistance. This review focuses on the current knowledge of fucoxanthin with its potential anticancer properties, showing that fucoxanthin could be a promising compound for cancer therapy by acting on most of the classical hallmarks of tumor cells.
    Keywords:  DNA repair; EMT; angiogenesis; apoptosis; cancer; cell growth arrest; fucoxanthin; inflammation; invasion; migration
    DOI:  https://doi.org/10.3390/ijms21239273
  72. Med Sci (Paris). 2020 Dec;36(12): 1113-1117
    Cherfils-Vicini J, Gilson É.
      Aging is an alteration of our physiological capacities that is accompanied by an increased susceptibility to develop a wide range of diseases and which determines in large part our longevity. Despite intensive research on the origin of aging, its etiology is still poorly understood. We discuss here the hypothesis that the telomere shortening, programmed to start at the end of embryogenesis in numerous tissues, couples development with aging by a time-dependent regulation of a set of interconnected processes essential for the somatic maintenance of genome, epigenome, metabolism, circadian clock and immunity.
    DOI:  https://doi.org/10.1051/medsci/2020242
  73. Clin Chim Acta. 2020 Dec 03. pii: S0009-8981(20)30553-2. [Epub ahead of print]
    Hou K, Li S, Zhang M, Qin X.
      Caveolin-1 is considered an important pathophysiological factor in atherosclerosis development. Previous studies indicate that caveolin-1 exhibits a pathogenic capacity in atherosclerosis via the regulation of membrane trafficking, cholesterol metabolism and cellular signal transduction. Accumulating evidence shows that autophagy activation influences the progression and development of atherosclerosis in multiple ways, including cholesterol metabolism, inflammatory responses and lipid transcytosis. However, how caveolin-1 is involved in autophagy activation in atherosclerosis remains unclear, and the precise mechanisms of caveolin-1 on autophagic flux in atherosclerosis need to be further investigated. Clarifying the roles and mechanisms of caveolin-1 in the regulation of autophagy activation is of great importance, contributing to the ability to manipulate caveolin-1 as a novel therapeutic approach for atherosclerosis. In this review, we summarize the understanding of the molecular structure, biological roles and biochemical functions of caveolin-1 to date and discuss the roles and mechanisms of caveolin-1 in autophagy activation. The emphasis on the potential of caveolin-1 to be a novel therapeutic target in atherosclerosis and understanding its precise functions and exact mechanisms in autophagic flux will provide evidence for future experimental research and aid in the development of novel therapeutic strategies for atherosclerosis.
    Keywords:  Atherosclerosis; Autophagy; Caveolin-1; Inflammatory response; Lipid metabolism
    DOI:  https://doi.org/10.1016/j.cca.2020.11.020
  74. Proc Natl Acad Sci U S A. 2020 Dec 07. pii: 202006828. [Epub ahead of print]
    Lee JY, Nam M, Son HY, Hyun K, Jang SY, Kim JW, Kim MW, Jung Y, Jang E, Yoon SJ, Kim J, Kim J, Seo J, Min JK, Oh KJ, Han BS, Kim WK, Bae KH, Song J, Kim J, Huh YM, Hwang GS, Lee EW, Lee SC.
      Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.
    Keywords:  ELOVL5; FADS1; arachidonic acid; ferroptosis; lipid peroxidation
    DOI:  https://doi.org/10.1073/pnas.2006828117
  75. PLoS One. 2020 ;15(12): e0243179
    Palladini G, Ferrigno A, Di Pasqua LG, Berardo C, Rizzo V, Perlini S, Vairetti M.
      BACKGROUND: The comparison of hepatic steatosis animal models has allowed the understanding of mechanisms involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the progression to nonalcoholic steatohepatitis (NASH). We investigated the changes in serum levels of trace elements and inflammation markers in fatty livers using two rat models of NAFLD, the methionine and choline deficient (MCD) diet model and Obese-Zucker rats.MATERIAL AND METHODS: NAFLD was induced in male Wistar rats by 3-week MCD diet administration, after which, blood samples were collected. 12-week old Obese (fa/fa) and Lean (fa/-) male Zucker rats were also used. Serum levels of hepatic enzymes, Urea, Uric acid, Ca2+, Cl, Fe, K, Na, Mg and Zn were quantified, as well as the inflammation markers TNF-alpha, IL-1beta and IL-6.
    RESULTS: In MCD rats, a serum increase in Cl, Mg and Na and a decrease in Ca2+, Zn were detected in comparison with control rats. An increase in only serum Ca2+ was found in Obese-Zucker rats. In MCD rat serum, Zn was inversely correlated with IL-1beta, IL-6, TNF-alpha, Urea and Uric Acid; Ca2+ was inversely correlated with IL-1beta, IL-6 and Urea; Cl and Mg were directly correlated with Uric Acid and Urea, respectively. In Obese-Zucker rats, Cl and IL-1beta were inversely correlated, whereas Ca2+ and Urea where directly correlated, as well Fe and TNF-alpha.
    CONCLUSIONS: The serum concentrations of trace elements change significantly only in MCD rats, which spontaneously progress to NASH. The causes of these changes may be a result of defense strategies of the organism, which is regulated by immunoregulatory cytokines. These results might suggest that the impairment of trace element status should be taken into account when the effectiveness of a pharmacological treatment is under evaluation.
    DOI:  https://doi.org/10.1371/journal.pone.0243179
  76. Fish Shellfish Immunol. 2020 Dec 04. pii: S1050-4648(20)30750-6. [Epub ahead of print]
    Zhang Y, Wei Z, Yang M, Liu D, Pan M, Wu C, Zhang W, Mai K.
      This study was conducted to explore the beneficial role of taurine against chronic high carbohydrate diet-induced oxidative stress, endoplasmic reticulum (ER) stress and inflammation, and to understand the underlying molecular mechanisms in turbot. Two 10-week feeding trials were simultaneously conducted. For the one, six experimental diets with graded levels of taurine supplementation (0, 0.4%, 0.8%, 1.2%, 1.6% and, 2.0%, respectively) and 15% of carbohydrate were used. For the other one, three graded levels of dietary taurine (0.4%, 1.2% and 2.0%, respectively) with 21% of carbohydrate were used. The results showed that higher expression level of inflammation cytokines and ER stress related genes were detected in higher dietary carbohydrate group. In both feeding trials, 1.2% of dietary taurine supplementation improved anti-oxidative status by decreasing the content of malondialdehyde, increasing the catalase activity and total anti-oxidative capacities. In feeding trial 1, appropriate taurine supplementation lowerd contents of tumour necrosis factor-a, interleukin-6, aspartate aminotransferase and alkaline phosphatase in plasma, and decreased the expressions of pro-inflammatory cytokines, such as interleukin-8 (il-8) and interferon-γ (ifn-γ). Furthermore, dietary taurine reduced ER stress by decreasing the mRNA levels of activating transcription factor 6, protein kinase R-like endoplasmic reticulum kinase and G protein-coupled receptor 78. The optimal dietary taurine content was estimated as 1.40% based on the analysis of specific growth rate. In feeding trial 2, dietary taurine supplementation attenuated liver inflammation partly referring to significantly down-regulated mRNA levels of nuclear transcription factor-κB p65, ifn-γ, interleukin1β and up-regulate the transcript of ribosomal protein S6 kinase 1. Dietary taurine supplementation in feeding trial 2 significantly increased the Nrf2-related factor 2 protein level and decreased the NFκB p65 protein level only at 21% of dietary carbohydrate level. Taurine can alleviate the oxidative damage and inflammation caused by 21% of dietary carbohydrate to a certain degree. Overall, the present study confirmed that dietary taurine supplementation improved growth performance and anti-oxidative response, and reduced liver inflammatory and ER stress processes induced by high dietary carbohydrate in turbot.
    Keywords:  ER stress; carbohydrate; inflammation; taurine; turbot
    DOI:  https://doi.org/10.1016/j.fsi.2020.11.029
  77. Stem Cells Int. 2020 ;2020 8845635
    Farahani RA, Zhu XY, Tang H, Jordan KL, Lerman A, Lerman LO, Eirin A.
      Background: Coexisting metabolic syndrome (MetS) and renal artery stenosis (RAS) are linked to poor renal outcomes. Mesenchymal stem/stromal cell- (MSC-) derived extracellular vesicles (EVs) from lean animals show superior ability to repair the experimental MetS+RAS kidney compared to EVs from MetS pig MSCs. We hypothesized that MetS leads to selective packaging in porcine EVs of microRNAs capable of targeting mitochondrial genes, interfering with their capacity to repair the MetS+RAS kidney.Methods: Five groups of pigs (n = 7 each) were studied after 16 weeks of diet-induced MetS and RAS (MetS+RAS) and MetS+RAS 4 weeks after a single intrarenal delivery of EVs harvested from allogeneic adipose tissue-derived MSCs isolated from Lean or MetS pigs, and Lean or MetS sham controls. Single-kidney blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multidetector CT, whereas EV microRNA cargo, renal tubular mitochondrial structure and bioenergetics, and renal injury pathways were assessed ex vivo.
    Results: microRNA sequencing revealed 19 dysregulated microRNAs capable of targeting several mitochondrial genes in MetS-EVs versus Lean-EVs. Lean- and MetS-EVs were detected in the stenotic kidney 4 weeks after administration. However, only MetS-EVs failed to improve renal mitochondrial density, structure, and function or attenuate oxidative stress, tubular injury, and fibrosis. Furthermore, Lean-EVs but not MetS-EVs restored RBF and GFR in MetS+RAS.
    Conclusion: MetS alters the cargo of mitochondria-related microRNAs in swine MSC-derived EVs, which might impair their capacity to repair the poststenotic kidney in MetS+RAS. These observations may contribute to develop approaches to improve the efficacy of MSC-EVs for patients with MetS.
    DOI:  https://doi.org/10.1155/2020/8845635
  78. Nutrients. 2020 Dec 07. pii: E3759. [Epub ahead of print]12(12):
    Badal VD, Vaccariello ED, Murray ER, Yu KE, Knight R, Jeste DV, Nguyen TT.
      Aging is determined by complex interactions among genetic and environmental factors. Increasing evidence suggests that the gut microbiome lies at the core of many age-associated changes, including immune system dysregulation and susceptibility to diseases. The gut microbiota undergoes extensive changes across the lifespan, and age-related processes may influence the gut microbiota and its related metabolic alterations. The aim of this systematic review was to summarize the current literature on aging-associated alterations in diversity, composition, and functional features of the gut microbiota. We identified 27 empirical human studies of normal and successful aging suitable for inclusion. Alpha diversity of microbial taxa, functional pathways, and metabolites was higher in older adults, particularly among the oldest-old adults, compared to younger individuals. Beta diversity distances significantly differed across various developmental stages and were different even between oldest-old and younger-old adults. Differences in taxonomic composition and functional potential varied across studies, but Akkermansia was most consistently reported to be relatively more abundant with aging, whereas Faecalibacterium, Bacteroidaceae, and Lachnospiraceae were relatively reduced. Older adults have reduced pathways related to carbohydrate metabolism and amino acid synthesis; however, oldest-old adults exhibited functional differences that distinguished their microbiota from that of young-old adults, such as greater potential for short-chain fatty acid production and increased butyrate derivatives. Although a definitive interpretation is limited by the cross-sectional design of published reports, we integrated findings of microbial composition and downstream functional pathways and metabolites, offering possible explanations regarding age-related processes.
    Keywords:  centenarians; cognition; functional potential; healthy aging; immunosenescence; inflammation; metabolites; microbes
    DOI:  https://doi.org/10.3390/nu12123759
  79. N Engl J Med. 2020 Dec 05.
    Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK, Foell J, de la Fuente J, Grupp S, Handgretinger R, Ho TW, Kattamis A, Kernytsky A, Lekstrom-Himes J, Li AM, Locatelli F, Mapara MY, de Montalembert M, Rondelli D, Sharma A, Sheth S, Soni S, Steinberg MH, Wall D, Yen A, Corbacioglu S.
      Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).
    DOI:  https://doi.org/10.1056/NEJMoa2031054
  80. Am J Clin Nutr. 2020 Dec 09. pii: nqaa302. [Epub ahead of print]
    Reed DR, Alhadeff AL, Beauchamp GK, Chaudhari N, Duffy VB, Dus M, Fontanini A, Glendinning JI, Green BG, Joseph PV, Kyriazis GA, Lyte M, Maruvada P, McGann JP, McLaughlin JT, Moran TH, Murphy C, Noble EE, Pepino MY, Pluznick JL, Rother KI, Saez E, Spector AC, Sternini C, Mattes RD.
      In November 2019, the NIH held the "Sensory Nutrition and Disease" workshop to challenge multidisciplinary researchers working at the interface of sensory science, food science, psychology, neuroscience, nutrition, and health sciences to explore how chemosensation influences dietary choice and health. This report summarizes deliberations of the workshop, as well as follow-up discussion in the wake of the current pandemic. Three topics were addressed: A) the need to optimize human chemosensory testing and assessment, B) the plasticity of chemosensory systems, and C) the interplay of chemosensory signals, cognitive signals, dietary intake, and metabolism. Several ways to advance sensory nutrition research emerged from the workshop: 1) refining methods to measure chemosensation in large cohort studies and validating measures that reflect perception of complex chemosensations relevant to dietary choice; 2) characterizing interindividual differences in chemosensory function and how they affect ingestive behaviors, health, and disease risk; 3) defining circuit-level organization and function that link and interact with gustatory, olfactory, homeostatic, visceral, and cognitive systems; and 4) discovering new ligands for chemosensory receptors (e.g., those produced by the microbiome) and cataloging cell types expressing these receptors. Several of these priorities were made more urgent by the current pandemic because infection with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing coronavirus disease of 2019 has direct short- and perhaps long-term effects on flavor perception. There is increasing evidence of functional interactions between the chemosensory and nutritional sciences. Better characterization of this interface is expected to yield insights to promote health, mitigate disease risk, and guide nutrition policy.
    Keywords:  food intake; food preferences; liking; olfaction; sweet
    DOI:  https://doi.org/10.1093/ajcn/nqaa302
  81. Diabetes Obes Metab. 2020 Dec 02.
    Dash S, Paterson AD.
      Weight loss attenuates many obesity related comorbidities, but is difficult to sustain with dietary change. Dietary adherence, not macronutrient composition, is a better predictor of weight loss. Weight loss induced endocrine changes promote food intake and increase energy efficiency contributing to the difficulty with dietary adherence and weight regain. Macronutrient preference is partly genetically determined, suggesting personalized dietary interventions might be more successful. In this issue, Li et al report that a genetic risk score (GRS) comprising the cumulative weighted effects of variants previously associated with increased lean mass associate with increased satiety and weight loss 6 months after initiating a low but not high fat diet. The effects were attenuated by 2-years. These findings suggest that genetic variants may influence response to specific diet. Further studies are now needed to assess whether genetically determined lean mass is causally associated with dietary response. Significant strides have recently been made in identifying additional genetic determinants of lean mass, which will enable such investigation and potentially inform future nutritional studies. This article is protected by copyright. All rights reserved.
    Keywords:  genetic risk score; lean mass; weight loss
    DOI:  https://doi.org/10.1111/dom.14275
  82. Cancer Biol Med. 2020 Nov 15. 17(4): 879-895
    Sun D, Li H, Cao M, He S, Lei L, Peng J, Chen W.
      As the most populous country in the world, China has made strides in health promotion in the past few decades. With the aging population, the burden of cancer in China continues to grow. Changes in risk factors for cancer, especially diet, obesity, diabetes, and air pollution, continue to fuel the shift of cancer transition in China. The burden of upper gastrointestinal cancer in China is decreasing, but still heavy. The rising burden of colorectal, prostate, and breast cancers is also significant. Lung cancer became the top cause of cancer-related deaths, together with smoking as the most important contributor to cancer deaths. The Chinese government has taken several approaches to control cancer and cancer-related risk factors. Many achievements have been made, but some challenges remain. Health China 2030 is ambitious and depicts a bright vision of the future for cancer control in China. The decrease in the cancer burden in China will require cross-sector collaboration and coordinated efforts on primary and secondary preventions by governments, public health organizations, and individuals. In this review, we describe the trends of cancer burden and discuss cancer-related risk factors in China, identifying strategies to reduce the burden of cancer in China.
    Keywords:  Cancer burden; China; prevention; risk factor; time trends
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2020.0387
  83. Curr Drug Targets. 2020 Dec 09.
    Dhote V, Samundre P, Ganeshpurkar A, Upaganlawar A.
      Advancing age presents a major challenge for the elderly population in terms of quality of life. The risk of cognitive impairment, motor in-coordination, and behavioral inconsistency due to neuronal damage is relatively higher in aging individuals of society. The brain, through its structural and functional integrity, regulates vital physiological events; however, the susceptibility of the brain to aging-related disturbances signal the onset of neurodegenerative diseases. Mitochondrial dysfunctions impair bioenergetic mechanism, synaptic plasticity, and calcium homeostasis in the brain, thus sufficiently implying mitochondria as a prime causal factor in accelerating aging-related neurodegeneration. We reviewed the fundamental functions of mitochondria in a healthy brain and aimed to address the key issues in aging-related diseases by asking: 1) What goes wrong with mitochondria in the aging brain? 2) What are the implications of mitochondrial damage on motor functions and psychiatric symptoms? 3) How environmental chemicals and metabolic morbidities affect mitochondrial functions? Further, we share insight on opportunities and pitfalls in drug discovery approaches targeting mitochondria to slow down the progression of aging and related neurodegenerative diseases.
    Keywords:  Aging; Mitochondria; Synaptic plasticity; biomarkers; membrane permeability; metabolic morbidity; neuropsychiatric symptoms
    DOI:  https://doi.org/10.2174/1389450121999201209202247
  84. Adv Gerontol. 2020 ;33(3): 429-435
    Ivko OM, Linkova NS, Ilina AR, Sharova AA, Ryzhak GA.
      Night work provides biorhythms desynchronization, disorder of melatonin-producing function and accelerated pineal gland aging. One of the promising geroprotectors restoring the pineal melatonin synthesis is the AEDG (Ala-Glu-Asp-Gly) peptide. AEDG peptide increases in 1,7 times the 6-sulfatoxymelatonin (6-SOMT) excretion in the urine of middle-aged people. Moreover, AEDG peptide normalized circadian Clock and Csnk1e genes hyper expression in leukocytes in 1,9-2,1 times and increases the Cry2 gene hypo expression in peripheral blood lymphocytes in 2 times in people with reduced melatonin-producing epiphysis function. The geroprotective effect of the AEDG peptide is based on its ability to restore the epiphysis melatonin-producing function by means regulation of human circadian genes expression.
    Keywords:  AEDG peptide; accelerated aging; circadian genes; melatonin; pineal gland
  85. Diabetes Obes Metab. 2020 Dec 02.
    Beysen C, Schroeder P, Wu E, Brevard J, Ribadeneira M, Lu W, Dole K, O'Reilly TE, Morrow L, Hompesch M, Hellerstein MK, Li K, Johansson L, Kelly PF.
      AIMS: Hepatic de novo lipogenesis (DNL) is an attractive therapeutic target for treating non-alcoholic fatty liver disease (NAFLD) but clinical data on the safety and efficacy of fatty acid synthase (FASN) inhibitors is limited. To Here we assess the therapeutic potential of fatty acid synthase (FASN) inhibition with FT-4101, a potent, selective, orally bioavailable, small-molecule for the treatment of NASH by 1) evaluating the dose-response of single FT-4101 doses (3, 6 and 9 mg) on hepatic DNL in healthy subjects (study 1) and 2) demonstrating the safety, tolerability and efficacy on hepatic steatosis after 12 weeks FT-4101 dosing in NALFD patients (study 2).MATERIALS AND METHODS: In study 1, three sequential cohorts of healthy males (n=10/cohort) were randomized to receive a single dose of FT-4101 (n=5/cohort) or placebo (n=5/cohort) followed by crossover dosing after 7 days. Hepatic DNL was assessed during fructose stimulation from 13C-acetate incorporation. In study 2, male and female NAFLD subjects (n=14) randomly received 12 weeks of intermittent once-daily dosing (4 cycles of 2 weeks on, followed by 1 week off treatment) of 3 mg FT-4101 (n=9) or placebo (n=5). Steady-state DNL based on deuterated water labelling, hepatic steatosis using magnetic resonance imaging-proton density fat fraction and sebum lipids and circulating biomarkers were assessed.
    RESULTS: Single and repeat dosing of FT-4101 was safe and well tolerated. Single FT-4101 doses inhibited hepatic DNL dose-dependently. Twelve weeks of 3 mg FT-4101 treatment improved hepatic steatosis and inhibited hepatic DNL. Decreases in sebum sapienate content with FT-4101 at week 11 were not significant compared to placebo and rebounded at week 12. Biomarkers of liver function, glucose, and lipid metabolism were unchanged.
    CONCLUSIONS: FASN inhibition with 3 mg FT-4101 safely reduces hepatic DNL and steatosis in NAFLD patients. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1111/dom.14272
  86. Clin Hypertens. 2020 Nov 15. 26(1): 23
    Onuh JO, Aliani M.
      Hypertension is a chronic health condition in which blood pressure is usually elevated beyond normal levels. It can progress with serious complications if left undetected and untreated. Incidence of hypertension is on the increase worldwide with debilitating consequences on the health systems of many countries. It is a multifactorial disorder that requires a multi-pronged approach to address it. One such approach is the use of metabolomics or metabolite profiling to understand its underlying cause and possibly control it. Changes in metabolites profiles have been used to accurately predict so many disease conditions in addition to identifying possible biomarkers and pathways associated in their pathogenicity. This will enable their early detection, diagnosis and treatment as well as likely complications that may arise and also assist in development of biomarkers for clinical uses. The objective of this review therefore is to present some of the current knowledge on the application of metabolomics profiling in hypertension and blood pressure control.
    Keywords:  Biomarkers; Hypertension; Metabolites; Metabolomics; Pathways
    DOI:  https://doi.org/10.1186/s40885-020-00157-9
  87. Nutrients. 2020 Dec 04. pii: E3737. [Epub ahead of print]12(12):
    Bardova K, Funda J, Pohl R, Cajka T, Hensler M, Kuda O, Janovska P, Adamcova K, Irodenko I, Lenkova L, Zouhar P, Horakova O, Flachs P, Rossmeisl M, Colca J, Kopecky J.
      Long-chain n-3 polyunsaturated fatty acids (Omega-3) and anti-diabetic drugs thiazolidinediones (TZDs) exhibit additive effects in counteraction of dietary obesity and associated metabolic dysfunctions in mice. The underlying mechanisms need to be clarified. Here, we aimed to learn whether the futile cycle based on the hydrolysis of triacylglycerol and re-esterification of fatty acids (TAG/FA cycling) in white adipose tissue (WAT) could be involved. We compared Omega-3 (30 mg/g diet) and two different TZDs-pioglitazone (50 mg/g diet) and a second-generation TZD, MSDC-0602K (330 mg/g diet)-regarding their effects in C57BL/6N mice fed an obesogenic high-fat (HF) diet for 8 weeks. The diet was supplemented or not by the tested compound alone or with the two TZDs combined individually with Omega-3. Activity of TAG/FA cycle in WAT was suppressed by the obesogenic HF diet. Additive effects in partial rescue of TAG/FA cycling in WAT were observed with both combined interventions, with a stronger effect of Omega-3 and MSDC-0602K. Our results (i) supported the role of TAG/FA cycling in WAT in the beneficial additive effects of Omega-3 and TZDs on metabolism of diet-induced obese mice, and (ii) showed differential modulation of WAT gene expression and metabolism by the two TZDs, depending also on Omega-3.
    Keywords:  adipocytes; glucose homeostasis; insulin; lipogenesis; obesity
    DOI:  https://doi.org/10.3390/nu12123737
  88. Cells. 2020 Dec 08. pii: E2635. [Epub ahead of print]9(12):
    Krause N, Wegner A.
      The interest in fructose metabolism is based on the observation that an increased dietary fructose consumption leads to an increased risk of obesity and metabolic syndrome. In particular, obesity is a known risk factor to develop many types of cancer and there is clinical and experimental evidence that an increased fructose intake promotes cancer growth. The precise mechanism, however, in which fructose induces tumor growth is still not fully understood. In this article, we present an overview of the metabolic pathways that utilize fructose and how fructose metabolism can sustain cancer cell proliferation. Although the degradation of fructose shares many of the enzymes and metabolic intermediates with glucose metabolism through glycolysis, glucose and fructose are metabolized differently. We describe the different metabolic fates of fructose carbons and how they are connected to lipogenesis and nucleotide synthesis. In addition, we discuss how the endogenous production of fructose from glucose via the polyol pathway can be beneficial for cancer cells.
    Keywords:  AKR1B1; HFCS; KHK; SORD; cancer metabolism; fructose metabolism; lipogenesis; pentose phosphate pathway; polyol pathway
    DOI:  https://doi.org/10.3390/cells9122635
  89. Neurochem Int. 2020 Dec 04. pii: S0197-0186(20)30319-3. [Epub ahead of print] 104928
    Singh P, Sivanandam TM, Konar A, Thakur MK.
      Cognitive abilities are compromised with advancing age posing a great risk for the development of dementia and other related brain disorders. Genetic susceptibility as well as environmental exposures determine the fate of cognitive aging and its transition to pathological states. Emerging epidemiological and observational studies have revealed the importance of lifestyle factors including dietary patterns and nutritional intake in the maintenance of cognitive health and reducing the risk of neurodegenerative disorders. In this context, nutraceutical interventions have gained considerable attention in preventing age-related cognitive deficits and counteracting pathological processes. Nutraceuticals include dietary plants and derivatives, food supplements and processed foods with nutritional and pharmaceutical values. The present review highlights the importance of nutraceuticals in attenuating cognitive aging and its progression to dementia, with specific emphasis on chemical constituents, neurocognitive properties and mechanism of action.
    Keywords:  Aging; Cognition; Dementia; Dietary supplements; Nutrition; Phytochemicals
    DOI:  https://doi.org/10.1016/j.neuint.2020.104928
  90. Viruses. 2020 Dec 05. pii: E1394. [Epub ahead of print]12(12):
    Hahn F, Wangen C, Häge S, Peter AS, Dobler G, Hurst B, Julander J, Fuchs J, Ruzsics Z, Überla K, Jäck HM, Ptak R, Muehler A, Gröppel M, Vitt D, Peelen E, Kohlhof H, Marschall M.
      The ongoing pandemic spread of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) demands skillful strategies for novel drug development, drug repurposing and cotreatments, in particular focusing on existing candidates of host-directed antivirals (HDAs). The developmental drug IMU-838, currently being investigated in a phase 2b trial in patients suffering from autoimmune diseases, represents an inhibitor of human dihydroorotate dehydrogenase (DHODH) with a recently proven antiviral activity in vitro and in vivo. Here, we established an analysis system for assessing the antiviral potency of IMU-838 and DHODH-directed back-up drugs in cultured cell-based infection models. By the use of SARS-CoV-2-specific immunofluorescence, Western blot, in-cell ELISA, viral yield reduction and RT-qPCR methods, we demonstrated the following: (i) IMU-838 and back-ups show anti-SARS-CoV-2 activity at several levels of viral replication, i.e., protein production, double-strand RNA synthesis, and release of infectious virus; (ii) antiviral efficacy in Vero cells was demonstrated in a micromolar range (IMU-838 half-maximal effective concentration, EC50, of 7.6 ± 5.8 µM); (iii) anti-SARS-CoV-2 activity was distinct from cytotoxic effects (half-cytotoxic concentration, CC50, >100 µM); (iv) the drug in vitro potency was confirmed using several Vero lineages and human cells; (v) combination with remdesivir showed enhanced anti-SARS-CoV-2 activity; (vi) vidofludimus, the active determinant of IMU-838, exerted a broad-spectrum activity against a selection of major human pathogenic viruses. These findings strongly suggest that developmental DHODH inhibitors represent promising candidates for use as anti-SARS-CoV-2 therapeutics.
    Keywords:  IMU-838; SARS-CoV-2; antiviral therapy; dihydroorotate dehydrogenase (DHODH) inhibitors; host-directed antivirals (HDAs); vidofludimus
    DOI:  https://doi.org/10.3390/v12121394
  91. Sci Total Environ. 2020 Nov 25. pii: S0048-9697(20)37290-9. [Epub ahead of print] 143759
    Bao M, Li J, Chen H, Chen Z, Xu D, Wen Y.
      The secondary metabolism of plants is key for mediating responses to environmental stress, but few studies have examined how the relationship between secondary metabolism and the stress response of plants is affected by exposure to chiral herbicides. Here, we studied the enantioselective disturbance of the chiral herbicide imazethapyr (IM) on the secondary metabolism and nutrient levels of wheat seedlings. The bioactive enantiomer R-IM significantly increased the contents of major secondary metabolites, including phenolic acids, flavonoids, and carotenoids but greatly inhibited the production of benzoxazine. The antioxidant system also responded strongly to R-IM; specifically, the activities of SOD, CAT, and GPX enzymes were all significantly induced, and the GSH content initially increased but then decreased. Furthermore, the nutrient levels of wheat seedlings were also affected; dietary fiber content decreased, while the contents of the microelements Fe, Mn, and Zn increased. In sum, this study provides new insight into the phytotoxic effects of IM and raises new questions on the role of secondary metabolites and nutrients in mediating enantioselective effects.
    Keywords:  Bioactive substance; Chiral pesticides; Nutritional quality; Secondary metabolism; Wheat
    DOI:  https://doi.org/10.1016/j.scitotenv.2020.143759
  92. J Mol Cell Cardiol. 2020 Dec 07. pii: S0022-2828(20)30336-9. [Epub ahead of print]
    Cortassa S, Juhaszova M, Aon MA, Zorov DB, Sollott SJ.
      Heart failure (HF) is a progressive, debilitating condition characterized, in part, by altered ionic equilibria, increased ROS production and impaired cellular energy metabolism, contributing to variable profiles of systolic and diastolic dysfunction with significant functional limitations and risk of premature death. We summarize current knowledge concerning changes of intracellular Na+ and Ca2+ control mechanisms during the disease progression and their consequences on mitochondrial Ca2+ homeostasis and the shift in redox balance. Absent existing biological data, our computational modeling studies advance a new 'in silico' analysis to reconcile existing opposing views, based on different experimental HF models, regarding variations in mitochondrial Ca2+ concentration that participate in triggering and perpetuating oxidative stress in the failing heart and their impact on cardiac energetics. In agreement with our hypothesis and the literature, model simulations demonstrate the possibility that the heart's redox status together with cytoplasmic Na+ concentrations act as regulators of mitochondrial Ca2+ levels in HF and of the bioenergetics response that will ultimately drive ATP supply and oxidative stress.. The resulting model predictions propose future directions to study the evolution of HF as well as other types of heart disease, and to develop novel testable mechanistic hypotheses that may lead to improved therapeutics.
    Keywords:  Ca(2+) signaling; Computational modeling; Energetic adaptation; Intracellular sodium; Oxidative stress; Redox signaling
    DOI:  https://doi.org/10.1016/j.yjmcc.2020.11.013
  93. Avicenna J Phytomed. 2020 Nov-Dec;10(6):10(6): 584-593
    Emmanuel U, Onyekachi J, Uchenna O.
      Objective: Lonchocarpus sericeus stembark decoction has been extensively employed in folkloric medicine in many parts of Nigeria as a remedy for pain as well as inflammation. The plant was studied for its anti-inflammatory as well as analgesic potency using standard biological models.Materials and Methods: The stembark of L. sericeus was evaluated for anti-inflammatory properties using egg albumin and xylene-induced oedema models. The pain-relieving property was evaluated using acetic acid-induced writhing and thermally-induced pain models. Median lethal dose determination (intraperitoneal LD50), quantification of some phytochemicals as well as phytochemical screening were also performed.
    Results: The LD50 of stembark extract of L. sericeus was found to be 3,100 mg/kg (i. p). The crude extract and fractions (310-930 mg/kg) effectively reduced oedema caused by egg albumin and xylene and exhibited high analgesic properties in inhibiting pain induced by acetic acid and heat. These reductions were dose-dependent and statistically significant (p<0.05-0.001) when compared to distilled water and similar to prototype drugs employed. Quantitative determinations of some bio-active constituents of the plant showed a higher flavonoid content (0.52±0.02 mg/100 g) compared to alkaloids (0.36±0.02 mg/100 g) and flavonoids (0.49±0.03 mg/100 g). Phytochemical screening of the stembark showed the presence of alkaloids, cardiac glycosides, flavonoids terpenes, tannins and saponins.
    Conclusion: These results imply that the stembark extract of L. sericeus possesses anti-inflammatory and analgesic potency and these data validate its wide use in folkloric medicine for inflammation and pain management.
    Keywords:  Analgesia; Inflammation; Lonchocarpus sericeus; Phytochemicals
  94. Adv Gerontol. 2020 ;33(3): 444-449
    Gunin AG, Golubtzova NN.
      The aim of this work was to examine the content of aryl hydrocarbon receptor interacting protein (AIP) in fibroblasts of human dermis from 20 weeks of pregnancy until 85 years old, and defining of a role of AIP in age-dependent changes in the number of fibroblasts in the dermis. AIP, proliferating cells nuclear antigen (PCNA) were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for AIP in the dermis is gradually increased from 20 weeks of pregnancy until 85 years old. A total number and percent of PCNA positive fibroblasts in dermis decreased with progression of age. Most sufficient age-dependent reduction in a total and PCNA positive number of dermal fibroblast was observed from antenatal until 40 years of life. Correlation analysis showed that both age-dependent decrease in the number of fibroblasts and retardation of their proliferation are significantly associated with age-related increase in the number of AIP positive fibroblasts in dermis. Results allow to suggest that AIP is involved in age-dependent decrease in the number and proliferation of fibroblasts in human dermis.
    Keywords:  AIP; PCNA; aging; fibroblasts; skin
  95. Curr Opin Pharmacol. 2020 Dec 02. pii: S1471-4892(20)30132-6. [Epub ahead of print]54 209-220
    Chatham JC, Young ME, Zhang J.
      The post-translational modification of serine and threonine residues of proteins by O-linked N-acetylglucosamine (O-GlcNAc) regulates diverse cellular processes in the cardiovascular system. UDP-GlcNAc is a substrate for O-GlcNAc transferase, which catalyzes the attachment of O-GlcNAc to proteins. O-GlcNAcase catalyzes the removal of O-GlcNAc from proteins. UDP-GlcNAc is the end product of the hexosamine biosynthesis pathway, which is regulated primarily by glucose-6-phosphate-Glutamine:fructose-6-phosphate amidotransferase (GFAT). GFAT catalyzes the formation of glucosamine-6-phosphate from fructose-6-phosphate and glutamine. Whereas O-GlcNAc is essential for cell viability, sustained increases in O-GlcNAc levels have been implicated in the etiology of many chronic diseases and is associated with glucose toxicity and diabetic complications in various organs including the cardiovascular system. This review provides an overview of the regulation of protein O-GlcNAcylation followed by a discussion of potential mechanisms by which dysregulation in O-GlcNAc cycling contributes to the adverse effects of diabetes on the cardiovascular system.
    DOI:  https://doi.org/10.1016/j.coph.2020.11.005
  96. Chin Med J (Engl). 2020 Dec 03.
    Xu WL, Shi BJ, Li SL, Yu FX, Guo LN, Li M, Hu ZG, Li GX, Zhou H.
      BACKGROUND: High agglomeration of myeloid-derived suppressor cells (MDSCs) in neuroblastoma (NB) impeded therapeutic effects. This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dose doxorubicin (DOX) to enhance immune efficacy in NB.METHODS: Bagg albino (BALB/c) mice were used as tumor-bearing mouse models by injecting Neuro-2a cells, and MDSCs were eliminated by DOX or dopamine (DA) administration. Tumor-bearing mice were randomly divided into 2.5 mg/kg DOX, 5.0 mg/kg DOX, 50.0 mg/kg DA, and control groups (n = 20). The optimal drug and its concentration for MDSC inhibition were selected according to tumor inhibition. NB antigen-specific cytotoxic T cells (CTLs) were prepared. Tumor-bearing mice were randomly divided into DOX, CTL, anti-ganglioside (GD2), DOX+CTL, DOX+anti-GD2, and control groups. Following low-dose DOX administration, immunotherapy was applied. The levels of human leukocyte antigen (HLA)-I, CD8, interleukin (IL)-2 and interferon (IFN)-γ in peripheral blood, CTLs, T-helper 1 (Thl)/Th2 cytokines, perforin, granzyme and tumor growth were compared among the groups. The Wilcoxon two-sample test and repeated-measures analysis of variance were used to analyze results.
    RESULTS: The slowest tumor growth (F = 6.095, P = 0.018) and strongest MDSC inhibition (F = 14.632, P = 0.001) were observed in 2.5 mg/kg DOX group. Proliferation of T cells was increased (F = 448.721, P = 0.000) and then decreased (F = 2.047, P = 0.186). After low-dose DOX administration, HLA-I (F = 222.489), CD8 (F = 271.686), Thl/Th2 cytokines, CD4 and CD8 lymphocytes, granzyme (F = 2376.475) and perforin (F = 488.531) in tumor, IL-2 (F = 62.951) and IFN-γ (F = 240.709) in peripheral blood of each immunotherapy group were all higher compared with the control group (all of P values < 0.05). The most significant increases in the aforementioned indexes and the most notable tumor growth inhibition were observed in DOX+anti-GD2 and DOX+CTL groups.
    CONCLUSIONS: Low-dose DOX can be used as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering immune efficacy in NB.
    DOI:  https://doi.org/10.1097/CM9.0000000000001234
  97. Expert Rev Clin Pharmacol. 2020 Dec 11.
    Watanabe Y, Tatsuno I.
      INTRODUCTION: : An epidemiological study of Greenlandic Inuit suggested the importance of omega-3 polyunsaturated fatty acids (PUFAs) in preventing ischemic heart disease. After this landmark study, large-scale epidemiological studies have examined the benefits of omega-3 PUFAs in the prevention of cardiovascular diseases.AREAS COVERED: : This article reviews studies on omega-3 PUFAs in the past 50 years, and identifies issues relevant to cardiovascular risk.
    EXPERT OPINION: : Recent studies have focused on the anti-inflammatory effects of omega-3 PUFAs and specialized pro-resolving mediators. High-purity eicosapentaenoic acid (EPA) ethyl ester and EPA/docosahexaenoic acid (DHA) preparations have been developed primarily for the treatment of hypertriglyceridemia. Various trials on the cardiovascular protective effects of omega-3 PUFAs have been reported, but the results have not been consistent. Some issues of the trials have been suggested, such as using low-dose omega-3 PUFAs and not including hypertriglyceridemia in subject selection criteria. REDUCE-IT study that used a high dose of high-purity EPA preparation showed a relative reduction in cardiovascular events, but, the STRENGTH study that used a high dose of EPA/DHA preparation did not support this benefit. This article reviews the research on the roles of omega-3 PUFAs in cardiovascular diseases, including progress in understanding the molecular mechanisms and recent large-scale clinical trials.
    Keywords:  Cardiovascular disease; REDUCE-IT; STRENGTH; fatty acid metabolism; omega-3 polyunsaturated fatty acids
    DOI:  https://doi.org/10.1080/17512433.2021.1863784
  98. Diabetol Metab Syndr. 2020 Nov 11. 12(1): 98
    Salles BIM, Cioffi D, Ferreira SRG.
      BACKGROUND: Research on intestinal microbiota has grown considerably, as well as the interest on probiotics' supplementation effects on metabolism. Considering high prevalence rates of metabolic diseases linked by insulin resistance, we performed a systematic review of existing literature which addressed the role of probiotics in modulating insulin sensitivity in animals and humans.METHODS: This systematic review was based on PRISMA guidelines. Searches for original articles published in English from 1990 to January 2020 were made in the electronic database of PubMed from the National Library of Medicine, using Medical Subject Headings to identify longitudinal studies conducted in animals and humans which reported effects of probiotics in a variety of insulin resistance parameters.
    RESULTS: Overall, results from 27 probiotic interventions (Lactobacillus, Bifidobacterium, Clostridium and Akkermansia) indicated significant beneficial changes in insulin resistance measures in animal studies. Additionally, they improved lipid profile, inflammatory and oxidative markers, short-chain fatty acids production and microbiota composition. In seven clinical trials, samples and designs were heterogeneous. Five showed benefits in insulin resistance parameters and in two others no effect was detected.
    CONCLUSION: Available data regarding the effects of certain probiotics do not guarantee sustained amelioration of insulin resistance in humans. Consistent beneficial results for intestinal barrier function, immune system and metabolism were reported in animals may encourage long-term randomized clinical trials in people with obesity and cardiometabolic risk. Whether supplementation with probiotics in combination with medications and/or prebiotics, associated with a healthy lifestyle, will prove useful to attenuate insulin resistance requires further investigation.
    Keywords:  Endotoxemia; Gut microbiota; Inflammation; Insulin resistance; Prediabetes; Probiotics; Short-chain fatty acids; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1186/s13098-020-00603-6
  99. Rev Saude Publica. 2020 ;pii: S0034-89102020000100297. [Epub ahead of print]54 129
    Bárrios MJ, Marques R, Fernandes AA.
      OBJECTIVE: To identify the strategies developed by people in the aging process to keep living in their own home, despite the weaknesses and difficulties they face.METHODS: The research was carried out based on a survey of population aged 65 years or older in the Portuguese municipality of Portimão. Data were collected by questionnaire, in 2017, and submitted to statistical and content analysis.
    RESULTS: Most respondents own their household, where they feel safe and satisfied, and they show awareness and concern about the changes they have to make in their home to stay there. In addition to housing and livability conditions, health, economic resources, social network, and available services play a major role in the community.
    CONCLUSIONS: We identified several strategies used by older adults to stay in their households as they age and the ways they mobilize their available resources, as well as constraints of aging in place.
    DOI:  https://doi.org/10.11606/s1518-8787.2020054001942
  100. Adv Gerontol. 2020 ;33(3): 590-594
    Krysiuk OB, Deineko VV, Kantemirova RK, Sukhonos YA, Arutiunov VA.
      The article analyzes the results of the impact of an integrated approach to lifestyle modification, including Nordic walking, rational nutrition and pharmacotherapy, on the quality of life of elderly people (average age 72,5±3,6 years). A significant improvement in the pain scale indicator of the MOS SF-36 was revealed after six months (p=0,001), which was also determined by the end of the year (p=0,0001). A tendency to improve the quality of life was revealed in the Minnesota Questionnaire after six months (p=0,0617). A significant improvement in the Minnesota Quality of Life Questionnaire was found after a year of applying this approach (p=0,0001). The relationship of improving quality of life indicators and a significant decrease in systolic blood pressure (p=0,0016) and diastolic blood pressure (p=0,0032) in elderly people after a one-year practice of an original approach to lifestyle modification is discussed.
    Keywords:  Nordic Walking; blood pressure; elderly people; quality of life