bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2020‒12‒20
ninety-six papers selected by
Ayesh Seneviratne
University of Toronto


  1. Signal Transduct Target Ther. 2020 Dec 18. 5(1): 288
    Carter JL, Hege K, Yang J, Kalpage HA, Su Y, Edwards H, Hüttemann M, Taub JW, Ge Y.
      Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.
    DOI:  https://doi.org/10.1038/s41392-020-00361-x
  2. Hematology Am Soc Hematol Educ Program. 2020 Dec 04. 2020(1): 590-597
    Chong EA, Porter DL.
      Both older and newer cell therapies have demonstrated impressive responses in otherwise poor-prognosis lymphomas. Consequently, cellular therapy now plays a major role in the management of many non-Hodgkin lymphomas. In this article, we examine the role of chimeric antigen receptor (CAR) T cells, allogeneic stem cell transplantation, and virus-directed T cells for treatment of lymphomas. We review the current indications for CAR T cells and discuss our clinical approach to selecting and treating patients with aggressive B-cell lymphomas to receive CD19-directed CAR T cells. In addition, we highlight newer cell therapies and provide an overview of promising future approaches that have the potential to transform immunotherapy with cells to treat lymphomas.
    DOI:  https://doi.org/10.1182/hematology.2020000174
  3. Trends Mol Med. 2020 Dec 04. pii: S1471-4914(20)30284-7. [Epub ahead of print]
    Willmes CG.
      
    DOI:  https://doi.org/10.1016/j.molmed.2020.11.001
  4. Front Immunol. 2020 ;11 585367
    Sezaki M, Hayashi Y, Wang Y, Johansson A, Umemoto T, Takizawa H.
      Lifelong blood production is maintained by bone marrow (BM)-residing hematopoietic stem cells (HSCs) that are defined by two special properties: multipotency and self-renewal. Since dysregulation of either may lead to a differentiation block or extensive proliferation causing dysplasia or neoplasia, the genomic integrity and cellular function of HSCs must be tightly controlled and preserved by cell-intrinsic programs and cell-extrinsic environmental factors of the BM. The BM had been long regarded an immune-privileged organ shielded from immune insults and inflammation, and was thereby assumed to provide HSCs and immune cells with a protective environment to ensure blood and immune homeostasis. Recently, accumulating evidence suggests that hemato-immune challenges such as autoimmunity, inflammation or infection elicit a broad spectrum of immunological reactions in the BM, and in turn, influence the function of HSCs and BM environmental cells. Moreover, in analogy with the emerging concept of "trained immunity", certain infection-associated stimuli are able to train HSCs and progenitors to produce mature immune cells with enhanced responsiveness to subsequent challenges, and in some cases, form an inflammatory or infectious memory in HSCs themselves. In this review, we will introduce recent findings on HSC and hematopoietic regulation upon exposure to various hemato-immune stimuli and discuss how these challenges can elicit either beneficial or detrimental outcomes on HSCs and the hemato-immune system, as well as their relevance to aging and hematologic malignancies.
    Keywords:  BM environment; hematopoietic stem cells; immune-memory; infection; inflammation
    DOI:  https://doi.org/10.3389/fimmu.2020.585367
  5. Front Immunol. 2020 ;11 604142
    Sharma V, Wright KL, Epling-Burnette PK, Reuther GW.
      The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are associated with clonal myelopoiesis, elevated risk of death due to thrombotic complications, and transformation to acute myeloid leukemia (AML). JAK2 inhibitors improve the quality of life for MPN patients, but these approved therapeutics do not readily reduce the natural course of disease or antagonize the neoplastic clone. An understanding of the molecular and cellular changes requisite for MPN development and progression are needed to develop improved therapies. Recently, murine MPN models were demonstrated to exhibit metabolic vulnerabilities due to a high dependence on glucose. Neoplastic hematopoietic progenitor cells in these mice express elevated levels of glycolytic enzymes and exhibit enhanced levels of glycolysis and oxidative phosphorylation, and the disease phenotype of these MPN model mice is antagonized by glycolytic inhibition. While all MPN-driving mutations lead to aberrant JAK2 activation, these mutations often co-exist with mutations in genes that encode epigenetic regulators, including loss of function mutations known to enhance MPN progression. In this perspective we discuss how altered activity of epigenetic regulators (e.g., methylation and acetylation) in MPN-driving stem and progenitor cells may alter cellular metabolism and contribute to the MPN phenotype and progression of disease. Specific metabolic changes associated with epigenetic deregulation may identify patient populations that exhibit specific metabolic vulnerabilities that are absent in normal hematopoietic cells, and thus provide a potential basis for the development of more effective personalized therapeutic approaches.
    Keywords:  EZHZ2; HDAC11; JAK2; epigenetic; metabolism; myeloproliferative neoplasm; stem cell; therapy
    DOI:  https://doi.org/10.3389/fimmu.2020.604142
  6. Int J Prev Med. 2020 ;11 170
    Sobhani V, Mehrtash M, Shirvani H, Fasihi-Ramandi M.
      Background: Nowadays, the use of green tea supplements has increased. Studies have shown that green tea can have positive effects on anti-inflammatory and antioxidative factors, as well as improve aerobic performance capacity. Therefore, in this study, we investigate the effects of this supplement on inflammatory factors, total antioxidant capacity responses, and maximum oxygen uptake (VO2 Max) of healthy young men in summer.Methods: This study is a double-blind randomized controlled trial (RCT) in which 15 young men (age 25.06 ± 2.1) were randomly assigned into the green tea (GT) and placebo groups. Subjects performed maximum aerobic exercises (shuttle run 20 m) in separate workouts (14 days) in summer. They consumed 640 mg green tea extracts or maltodextrin 90 min before exercise in a double-blind design. Blood samples were collected before and after the exercise and then evaluated in the biochemistry laboratory. In this study, one way analysis of variance (ANOVA) tests were used for the statistical analysis.
    Results: The results of this study show that green tea supplement significantly slowed down the increasing tumor necrosis factor alpha (TNF-α) (GT: 15.03 ± 4.31 [pg/ml], placebo: 31.38 ± 7.18 [pg/ml], [P = 0.000]); increased the total antioxidant capacity (GT: 1.04 ± 0.06 [mm], placebo group: 0.72 ± 0.04 [mm], [P = 0.001 VO2]); and Max (GT: 44.43 ± 3.06 [ml/kg/min], placebo group: 34.88 ± 1.30 [ml/kg/min], [P = 0.001]) in the supplement group than placebo. In addition, no significant differences in interleukin 1 beta (IL-1β) was observed between thee groups (GT: 26.86 ± 5.05 [pg/ml], placebo group: 23.47 ± 3.16 [pg/ml], [P = 0.251]).
    Conclusions: The consumption of green tea supplements 90 min before aerobic exercise may decrease inflammation and oxidative stress factors and improve VO2 Max in summer.
    Keywords:  Exercise; hot temperature; inflammation; oxidative stress; tea
    DOI:  https://doi.org/10.4103/ijpvm.IJPVM_64_19
  7. Mol Ther Nucleic Acids. 2021 Mar 05. 23 142-153
    Russomanno G, Jo KB, Abdul-Salam VB, Morgan C, Endruschat J, Schaeper U, Osman AH, Alzaydi MM, Wilkins MR, Wojciak-Stothard B.
      Circulating levels of endothelial miR-150 are reduced in pulmonary arterial hypertension (PAH) and act as an independent predictor of patient survival, but links between endothelial miR-150 and vascular dysfunction are not well understood. We studied the effects of endothelial miR-150 supplementation and inhibition in PAH mice and cells from patients with idiopathic PAH. The role of selected mediators of miR-150 identified by RNA sequencing was evaluated in vitro and in vivo. Endothelium-targeted miR-150 delivery prevented the disease in Sugen/hypoxia mice, while endothelial knockdown of miR-150 had adverse effects. miR-150 target genes revealed significant associations with PAH pathways, including proliferation, inflammation, and phospholipid signaling, with PTEN-like mitochondrial phosphatase (PTPMT1) most markedly altered. PTPMT1 reduced inflammation and apoptosis and improved mitochondrial function in human pulmonary endothelial cells and blood-derived endothelial colony-forming cells from idiopathic PAH. Beneficial effects of miR-150 in vitro and in vivo were linked with PTPMT1-dependent biosynthesis of mitochondrial phospholipid cardiolipin and reduced expression of pro-apoptotic, pro-inflammatory, and pro-fibrotic genes, including c-MYB, NOTCH3, transforming growth factor β (TGF-β), and Col1a1. In conclusion, we are the first to show that miR-150 supplementation attenuates pulmonary endothelial damage induced by vascular stresses and may be considered as a potential therapeutic strategy in PAH.
    Keywords:  PTPMT1; cardiolipin; endothelial; fibrosis; microRNA; mitochondria; proliferation; pulmonary hypertension; remodelling; vascular
    DOI:  https://doi.org/10.1016/j.omtn.2020.10.042
  8. JMIR Diabetes. 2020 Dec 16. 5(4): e21551
    Yost O, DeJonckheere M, Stonebraker S, Ling G, Buis L, Pop-Busui R, Kim N, Mizokami-Stout K, Richardson C.
      BACKGROUND: Type 2 diabetes mellitus (T2DM) is preventable; however, few patients with prediabetes participate in prevention programs. The use of user-friendly continuous glucose monitors (CGMs) with low-carbohydrate diet coaching is a novel strategy to prevent T2DM.OBJECTIVE: This study aims to determine the patient satisfaction and feasibility of an intervention combining CGM use and low-carbohydrate diet coaching in patients with prediabetes to drive dietary behavior change.
    METHODS: We conducted a mixed methods, single-arm pilot and feasibility study at a suburban family medicine clinic. A total of 15 adults with prediabetes with hemoglobin A1c (HbA1c) levels between 5.7% and 6.4% and a BMI >30 kg/m2 were recruited to participate. The intervention and assessments took place during 3 in-person study visits and 2 qualitative phone interviews (3 weeks and 6 months after the intervention). During visit 1, participants were asked to wear a CGM and complete a food intake and craving log for 10 days. During visit 2, the food intake and craving log along with the CGM results of the participants were reviewed and the participants received low-carbohydrate diet coaching, including learning about carbohydrates and personalized feedback. A second CGM sensor, with the ability to scan and record glucose trends, was placed, and the participants logged their food intake and cravings as they attempted to reduce their total carbohydrate intake (<100 g/day). During visit 3, the participants reviewed their CGM and log data. The primary outcome was satisfaction with the use of CGM and low-carbohydrate diet. The secondary outcomes included feasibility, weight, and HbA1c change, and percentage of time spent in hyperglycemia. Changes in attitudes and risk perception of developing diabetes were also assessed.
    RESULTS: The overall satisfaction rate of our intervention was 93%. The intervention induced a weight reduction of 1.4 lb (P=.02) and a reduction of HbA1c levels by 0.71% (P<.001) since enrollment. Although not significantly, the percentage of time above glucose goal and average daily glucose levels decreased slightly during the study period. Qualitative interview themes indicated no major barriers to CGM use; the acceptance of a low-carbohydrate diet; and that CGMs helped to visualize the impact of carbohydrates on the body, driving dietary changes.
    CONCLUSIONS: The use of CGMs and low-carbohydrate diet coaching to drive dietary changes in patients with prediabetes is feasible and acceptable to patients. This novel method merits further exploration, as the preliminary data indicate that combining CGM use with low-carbohydrate diet coaching drives dietary changes, which may ultimately prevent T2DM.
    Keywords:  blood glucose self-monitoring; diet modification; low carbohydrate diet; prediabetes; prevention & control; type 2 diabetes mellitus
    DOI:  https://doi.org/10.2196/21551
  9. Nutrients. 2020 Dec 09. pii: E3782. [Epub ahead of print]12(12):
    Visioli F, Poli A.
      One of the most controversial areas of nutrition research relates to fats, particularly essential fatty acids, in the context of cardiovascular disease risk. A critical feature of dietary fatty acids is that they incorporate into the plasma membrane, modifying fluidity and key physiological functions. Importantly, they can reshape the bioavailability of eicosanoids and other lipid mediators, which direct cellular responses to external stimuli, such as inflammation and chronic stress conditions. This paper provides an overview of the most recent evidence, as well as historical controversies, linking fat consumption with human health and disease. We underscore current pitfalls in the area of fatty acid research and critically frame fatty acid intake in the larger context of diet and behavior. We conclude that fundamental research on fatty acids and lipids is appropriate in certain areas, but the rigor and reproducibility are lacking in others. The pros and cons are highlighted throughout the review, seeking to guide future research on the important area of nutrition, fat intake, and cardiovascular disease risk.
    Keywords:  cardiovascular disease; fatty acids; omega 3 fatty acids; omega 6 fatty acids
    DOI:  https://doi.org/10.3390/nu12123782
  10. Stem Cell Res Ther. 2020 Dec 11. 11(1): 538
    Ohta H, Liu X, Maeda M.
      OBJECTIVE: Arteriosclerosis is an age-related disease and a leading cause of cardiovascular disease. In animal experiments, mesenchymal stem cells and its culture-conditioned medium have been shown to be promising tools for prevention or treatment of arteriosclerosis. On the basis of these evidences, we aimed to assess whether administration of autologous adipose-derived mesenchymal stem cells (Ad-MSC) is safe and effective for treatment of arteriosclerosis.METHODS: We retrospectively reviewed clinical records of patients with arteriosclerosis who had received autologous Ad-MSC administration at our clinic. Patients' characteristics were recorded and data on lipid profile, intimal-media thickness (IMT), cardio-ankle vascular index (CAVI), and ankle-brachial index (ABI) before and after Ad-MSC administration were collected and compared.
    RESULTS: Treatment with Ad-MSC significantly improved HDL, LDL, and remnant-like particle (RLP) cholesterol levels. No adverse effect or toxicity was observed in relation to the treatment. Of the patients with abnormal HDL values before treatment, the vast majority showed improvement in the values. Overall, the measurements after treatment were significantly increased compared with those before treatment (p < 0.01). In addition, decreases in LDL cholesterol and RLP levels were observed after treatment in patients who had abnormal LDL cholesterol or RLP levels before treatment. The majority of patients with pre-treatment abnormal CAVI values had improved values after treatment. In patients with available IMT values, a significant decrease in the IMT values was found after therapy (p < 0.01). All patients with borderline arteriosclerosis disease had improved laboratory findings after treatment. In general, post-treatment values were significantly decreased as compared with pre-treatment values. Of the patients with normal ABI values before treatment at the same time as CAVI, the vast majority remained normal after treatment.
    CONCLUSIONS: These findings suggest that Ad-MSC administration is safe and effective in patients developing arteriosclerosis, thereby providing an attractive tool for anti-aging application.
    Keywords:  Adipose-derived mesenchymal stem cell; Anti-aging; Arteriosclerosis; Efficacy; Safety
    DOI:  https://doi.org/10.1186/s13287-020-02067-x
  11. Diabetes Metab Syndr Obes. 2020 ;13 4763-4777
    Yehualashet AS.
      Diabetes mellitus (DM) is a chronic endocrine disease distinguished by hyperglycemia due to disturbance in carbohydrate or lipid metabolism or insulin function. To date, diabetes, and its complications, is established as a global cause of morbidity and mortality. The intended aim during the management of diabetes is to maintain blood glucose close to normal because the majority of patients have poor control of their elevated blood glucose and are highly prone to severe macrovascular and microvascular complications. To decrease the burden of the disease and its complications, scientists from various disciplines are working intensively to identify novel and promising drug targets for diabetes and its complications. Increased and ongoing investigations on mechanisms relating to diabetes and associated complications could potentially consider inflammatory cascades as a promising component of the strategy in the prevention and control of diabetes and its complications. The potential of targeting mediators of inflammation like toll-like receptors (TLRs) are part of current investigation by the scientific community. Hence, the aim of the present review is to discuss the role of TLRs as a potential drug target for diabetes and diabetes associated complications.
    Keywords:  TLR; complication; diabetes mellitus; immunity; inflammation
    DOI:  https://doi.org/10.2147/DMSO.S274844
  12. Compr Rev Food Sci Food Saf. 2020 Jul;19(4): 1908-1933
    Peng M, Tabashsum Z, Anderson M, Truong A, Houser AK, Padilla J, Akmel A, Bhatti J, Rahaman SO, Biswas D.
      The bioactive ingredients in commonly consumed foods include, but are not limited to, prebiotics, prebiotic-like components, probiotics, and postbiotics. The bioactive ingredients in functional foods have also been associated with beneficial effects on human health. For example, they aid in shaping of gut microflora and promotion of immunity. These functional components also contribute in preventing serious diseases such as cardiovascular malfunction and tumorigenesis. However, the specific mechanisms of these positive influences on human health are still under investigation. In this review, we aim to emphasize the major contents of probiotics, prebiotics, and prebiotic-like components commonly found in consumable functional foods, and we present an overview of direct and indirect benefits they provide on human health. The major contributors are certain families of metabolites, specifically short-chain fatty acids and polyunsaturated fatty acids produced by probiotics, and prebiotics, or prebiotic-like components such as flavonoids, polyphenols, and vitamins that are found in functional foods. These functional ingredients in foods influence the gut microbiota by stimulating the growth of beneficial microbes and the production of beneficial metabolites that, in turn, have direct benefits to the host, while also providing protection from pathogens and maintaining a balanced gut ecosystem. The complex interactions that arise among functional food ingredients, human physiology, the gut microbiota, and their respective metabolic pathways have been found to minimize several factors that contribute to the incidence of chronic disease, such as inflammation oxidative stress.
    Keywords:  bioactive ingredient; disease; functional food; gut microbiota; prebiotic; probiotic
    DOI:  https://doi.org/10.1111/1541-4337.12565
  13. FASEB Bioadv. 2020 Dec;2(12): 720-733
    Teruya T, Goga H, Yanagida M.
      Metabolites in human biofluids document the physiological status of individuals. We conducted comprehensive, non-targeted, non-invasive metabolomic analysis of urine from 27 healthy human subjects, comprising 13 young adults (30 ± 3 years) and 14 seniors (76 ± 4 years). Quantitative analysis of 99 metabolites revealed 55 that displayed significant differences in abundance between the two groups. Forty-four did not show a statistically significant relationship with age. These include 13 standard amino acids, 5 methylated, 4 acetylated, and 9 other amino acids, 6 nucleosides, nucleobases, and derivatives, 4 sugar derivatives, 5 sugar phosphates, 4 carnitines, 2 hydroxybutyrates, 1 choline, and 1 ethanolamine derivative, and glutathione disulfide. Abundances of 53 compounds decreased, while 2 (glutathione disulfide, myo-inositol) increased in elderly people. The great majority of age-linked markers were highly correlated with creatinine. In contrast, 44 other urinary metabolites, including urate, carnitine, hippurate, and betaine, were not age-linked, neither declining nor increasing in elderly subjects. As metabolite profiles of urine and blood are quite different, age-related information in urine offers additional valuable insights into aging mechanisms of endocrine system. Correlation analysis of urinary metabolites revealed distinctly inter-related groups of compounds.
    Keywords:  LC‐MS; creatinine; glutathione; human endocrine aging; non‐targeted metabolomics; pseudouridine; urinary age markers
    DOI:  https://doi.org/10.1096/fba.2020-00047
  14. Elife. 2020 12 15. pii: e60827. [Epub ahead of print]9
    Zhang H, Alder NN, Wang W, Szeto H, Marcinek DJ, Rabinovitch PS.
      Aging-associated diseases, including cardiac dysfunction, are increasingly common in the population. However, the mechanisms of physiologic aging in general, and cardiac aging in particular, remain poorly understood. Age-related heart impairment is lacking a clinically effective treatment. Using the model of naturally aging mice and rats, we show direct evidence of increased proton leak in the aged heart mitochondria. Moreover, our data suggested ANT1 as the most likely site of mediating increased mitochondrial proton permeability in old cardiomyocytes. Most importantly, the tetra-peptide SS-31 prevents age-related excess proton entry, decreases the mitochondrial flash activity and mitochondrial permeability transition pore opening, rejuvenates mitochondrial function by direct association with ANT1 and the mitochondrial ATP synthasome, and leads to substantial reversal of diastolic dysfunction. Our results uncover the excessive proton leak as a novel mechanism of age-related cardiac dysfunction and elucidate how SS-31 can reverse this clinically important complication of cardiac aging.
    Keywords:  SS-31; aging; cardiomyocyte; cell biology; mitochondria; mouse; proton leak; rat
    DOI:  https://doi.org/10.7554/eLife.60827
  15. Front Cell Dev Biol. 2020 ;8 599376
    Ma C, Sun Y, Pi C, Wang H, Sun H, Yu X, Shi Y, He X.
      Oxidative stress is one of the main causes of aging. The process of physiological aging is always accompanied by increased levels of endogenous oxidative stress. Exogenous oxidants have contributed to premature cellular senescence. As a deacetylase located in mitochondrial matrix, Sirt3 plays critical roles in mitochondrial energy metabolism, oxidative stress regulation, and cellular senescence. However, it remains unknown whether Sirt3 exerts the analogous role in cellular senescence caused by two different oxidation pathways. In this study, the function of Sirt3 was investigated in age-related natural senescence and H2O2-induced premature senescence of rat bone marrow mesenchymal stem cells (MSCs). Our results showed that Sirt3 expression was significantly decreased in both senescent MSCs, which was concerned with reduced cellular reactive oxygen species (ROS) and aggravated DNA injury. Sirt3 repletion could partly reverse the senescence-associated phenotypic features in natural and premature senescent MSCs. Moreover, Sirt3 replenishment led to the reduction in the levels of cellular ROS by enhancing the expression and activity of superoxide dismutase 2 (SOD2), thus maintaining the balance of intracellular oxidation and antioxidation and ameliorating oxidative stress damage. Altogether, Sirt3 inhibits MSC natural senescence and H2O2-induced premature senescence through alleviating ROS-induced injury and upregulating SOD2 expression and activity. Our research indicates that Sirt3 might contribute to uncovering the novel mechanisms underlying MSC senescence and provide new insights to aging and oxidative stress-related diseases.
    Keywords:  Sirt3; cellular senescence; mesenchymal stem cells; oxidative stress; superoxide dismutase 2
    DOI:  https://doi.org/10.3389/fcell.2020.599376
  16. Circ Res. 2020 Dec 18.
    Chen K, Wang S, Sun QW, Zhang B, Ullah MF, Sun Z.
      Rationale: Cardiac aging is an important contributing factor for heart failure which affects a large population but remains poorly understood. Objective: The purpose of this study is to investigate whether Klotho plays a role in cardiac aging. Methods and Results: Heart function declined in old mice (24 months), as evidenced by decreases in fractional shortening, ejection fraction, and cardiac output. Heart size and weight, cardiomyocyte size and cardiac fibrosis were increased in old mice, indicating that aging causes cardiac hypertrophy and remodeling. Circulating Klotho levels were dramatically decreased in old mice, which prompted us to investigate whether the Klotho decline may cause heart aging. We found that Klotho gene mutation (KL-/-) largely decreased serum klotho levels and impaired heart function. Interestingly, supplement of exogenous secreted Klotho prevented heart failure, hypertrophy, and remodeling in both old mice and KL (-/-) mice. Secreted Klotho treatment inhibited excessive cardiac oxidative stress, senescence and apoptosis in old mice and KL (-/-) mice. Serum phosphate levels in KL (-/-) mice were kept in the normal range, suggesting that Klotho deficiency-induced heart aging is independent of phosphate metabolism. Mechanistically, Klotho deficiency suppressed glutathione reductase (GR) expression and activity in the heart via inhibition of transcription factor Nrf2. Furthermore, cardiac-specific overexpression of GR prevented excessive oxidative stress, apoptosis, and heart failure in both old and KL (-/-) mice. Conclusions: Klotho deficiency causes cardiac aging via impairing the Nrf2-GR pathway. Supplement of exogenous secreted Klotho represents a promising therapeutic strategy for aging-associated cardiomyopathy and heart failure.
    Keywords:  cardiac aging; glutathione reductase; klotho
    DOI:  https://doi.org/10.1161/CIRCRESAHA.120.317348
  17. Cancers (Basel). 2020 Dec 16. pii: E3788. [Epub ahead of print]12(12):
    Saggese P, Sellitto A, Martinez CA, Giurato G, Nassa G, Rizzo F, Tarallo R, Scafoglio C.
      Metabolic reprogramming is a hallmark of cancer, with consistent rewiring of glucose, glutamine, and mitochondrial metabolism. While these metabolic alterations are adequate to meet the metabolic needs of cell growth and proliferation, the changes in critical metabolites have also consequences for the regulation of the cell differentiation state. Cancer evolution is characterized by progression towards a poorly differentiated, stem-like phenotype, and epigenetic modulation of the chromatin structure is an important prerequisite for the maintenance of an undifferentiated state by repression of lineage-specific genes. Epigenetic modifiers depend on intermediates of cellular metabolism both as substrates and as co-factors. Therefore, the metabolic reprogramming that occurs in cancer likely plays an important role in the process of the de-differentiation characteristic of the neoplastic process. Here, we review the epigenetic consequences of metabolic reprogramming in cancer, with particular focus on the role of mitochondrial intermediates and hypoxia in the regulation of cellular de-differentiation. We also discuss therapeutic implications.
    Keywords:  cancer epigenetics; cancer metabolism; cell differentiation in cancer; mitochondrial metabolism
    DOI:  https://doi.org/10.3390/cancers12123788
  18. Cells Tissues Organs. 2020 Dec 16. 1-6
    Mohammed RN.
      Hematopoietic stem cells (HSCs) are a rare population of cells that reside mainly in the bone marrow and are capable of generating and fulfilling the entire hematopoietic system upon differentiation. Thirty-six healthy donors, attending the HSCT center to donate their bone marrow, were categorized according to their age into child (0-12 years), adolescence (13-18 years), and adult (19-59 years) groups, and gender into male and female groups. Then, the absolute number of HSCs and mature immune cells in their harvested bone marrow was investigated. Here, we report that the absolute cell number can vary considerably based on the age of the healthy donor, and the number of both HSCs and immune cells declines with advancing age. The gender of the donor (male or female) did not have any impact on the number of the HSCs and immune cells in the bone marrow. In conclusion, since the number of HSCs plays a pivotal role in the clinical outcome of allogeneic HSC transplantations, identifying a younger donor regardless the gender is critical.
    Keywords:  Age; Bone marrow microenvironment; Gender; Hematopoietic stem cells; Immune cells
    DOI:  https://doi.org/10.1159/000510774
  19. Front Immunol. 2020 ;11 573915
    Liao W, Du C, Wang J.
      Cytosolic DNA sensing is a fundamental mechanism by which organisms handle various stresses, including infection and genotoxicity. The hematopoietic system is sensitive to stresses, and hematopoietic changes are often rapid and the first response to stresses. Based on the transcriptome database, cytosolic DNA sensing pathways are widely expressed in the hematopoietic system, and components of these pathways may be expressed at even higher levels in hematopoietic stem and progenitor cells (HSPCs) than in their certain progeny immune cells. Recent studies have described a previously unrecognized role for cytosolic DNA sensing pathways in the regulation of hematopoiesis under both homeostatic and stress conditions. In particular, the recently discovered cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a critical modulator of hematopoiesis. Perturbation of the cGAS-STING pathway in HSPCs may be involved in the pathogenesis of hematopoietic disorders, autoimmune diseases, and inflammation-related diseases and may be candidate therapeutic targets. In this review, we focus on the recent findings of the cGAS-STING pathway in the regulation of hematopoiesis, and its physiopathological significance including its implications in diseases and therapeutic potential.
    Keywords:  Cytosolic DNA sensing; Hematopoiesis; Hematopoietic stem and progenitor cells; Innate Immunity and inflammation; cGAS-STING pathway
    DOI:  https://doi.org/10.3389/fimmu.2020.573915
  20. Mol Metab. 2020 Dec 09. pii: S2212-8778(20)30216-7. [Epub ahead of print] 101142
    Lee J, Walter MF, Korach KS, Noguchi CT.
      OBJECTIVE: Erythropoietin (EPO), the cytokine required for erythropoiesis, contributes to metabolic regulation of fat mass and glycemic control. EPO treatment in mice on high fat diet (HFD) improved glucose tolerance and decreased body weight gain via reduced fat mass in males and ovariectomized females. The decreased fat accumulation with EPO treatment during HFD in ovariectomized females was abrogated with estradiol supplementation, providing evidence for estrogen related gender specific EPO action in metabolic regulation. In this study we examine the cross talk between estrogen mediated through estrogen receptor α (ERα) and EPO in regulation of glucose metabolism and fat mass accumulation.METHODS: Wild type (WT) mice and mice with mouse models with ERα knockout (ERα-/-) and with targeted deletion of ERα in adipose tissue (ERαadipoKO) were used to examine erythropoietin treatment during high fat diet feeding and after diet-induced obesity.
    RESULTS: ERα-/- mice on HFD exhibit increased fat mass and glucose intolerance. EPO treatment on HFD reduced fat accumulation in male WT and ERα-/- mice and female ERα-/- mice but not female WT mice. EPO reduced HFD increase in adipocyte size in WT mice but not in mice with deletion of ERα independent of EPO stimulated reduction in fat mass. EPO treatment also improved glucose tolerance and insulin tolerance significantly greater in female ERα-/- mice and female ERαadipoKO compared with WT control. Increased metabolic activity by EPO is associated with browning of white adipocytes, as shown by reduction of white fat-associated genes, and induction of brown fat specific uncoupling protein1 (UCP1).
    CONCLUSIONS: This study clearly identifies the role of estrogen signaling in modifying EPO regulation of glucose metabolism and in the sex-differential EPO effect on fat mass regulation. Cross talk between EPO and estrogen is implicated for metabolic homeostasis and regulation of body mass in female mice.
    Keywords:  Erythropoietin; estrogen receptor α; fat mass; gender-specific; obesity
    DOI:  https://doi.org/10.1016/j.molmet.2020.101142
  21. Front Endocrinol (Lausanne). 2020 ;11 579981
    Hannibal L, Theimer J, Wingert V, Klotz K, Bierschenk I, Nitschke R, Spiekerkoetter U, Grünert SC.
      Glycogen storage disease subtypes I and III (GSD I and GSD III) are monogenic inherited disorders of metabolism that disrupt glycogen metabolism. Unavailability of glucose in GSD I and induction of gluconeogenesis in GSD III modify energy sources and possibly, mitochondrial function. Abnormal mitochondrial structure and function were described in mice with GSD Ia, yet significantly less research is available in human cells and ketotic forms of the disease. We hypothesized that impaired glycogen storage results in distinct metabolic phenotypes in the extra- and intracellular compartments that may contribute to pathogenesis. Herein, we examined mitochondrial organization in live cells by spinning-disk confocal microscopy and profiled extra- and intracellular metabolites by targeted LC-MS/MS in cultured fibroblasts from healthy controls and from patients with GSD Ia, GSD Ib, and GSD III. Results from live imaging revealed that mitochondrial content and network morphology of GSD cells are comparable to that of healthy controls. Likewise, healthy controls and GSD cells exhibited comparable basal oxygen consumption rates. Targeted metabolomics followed by principal component analysis (PCA) and hierarchical clustering (HC) uncovered metabolically distinct poises of healthy controls and GSD subtypes. Assessment of individual metabolites recapitulated dysfunctional energy production (glycolysis, Krebs cycle, succinate), reduced creatinine export in GSD Ia and GSD III, and reduced antioxidant defense of the cysteine and glutathione systems. Our study serves as proof-of-concept that extra- and intracellular metabolite profiles distinguish glycogen storage disease subtypes from healthy controls. We posit that metabolite profiles provide hints to disease mechanisms as well as to nutritional and pharmacological elements that may optimize current treatment strategies.
    Keywords:  energy deficiency; glycogen storage disease; inborn error of metabolism; metabolism; metabolomics; mitochondria; redox homeostasis
    DOI:  https://doi.org/10.3389/fendo.2020.579981
  22. Mech Ageing Dev. 2020 Dec 14. pii: S0047-6374(20)30212-8. [Epub ahead of print] 111416
    Chehaitly A, Vessieres E, Guihot AL, Henrion D.
      The present review focuses on the effect of aging on flow-mediated outward remodeling (FMR) via alterations in estrogen metabolism, oxidative stress and inflammation. In ischemic disorders, the ability of the vasculature to adapt or remodel determines the quality of the recovery. FMR, which has a key role in revascularization, is a complex phenomenon that recruits endothelial and smooth muscle cells as well as the immune system. FMR becomes progressively less with age as a result of an increase in inflammation and oxidative stress, in part of mitochondrial origin. The alteration in FMR is greater in older individuals with risk factors and thus the therapy cannot merely amount to exercise with or without a mild vasodilating drug. Interestingly, the reduction in FMR occurs later in females. Estrogen and its alpha receptor (ERα) play a key role in FMR through the control of dilatory pathways including the angiotensin II type 2 receptor, thus providing possible tools to activate FMR in older subjects although only experimental data is available. Indeed, the main issue is the reversibility of the vascular damage induced over time, and to date promoting prevention and limiting exposure to the risk factors remain the best options in this regard.
    Keywords:  Arterial outward remodeling; aging; blood flow; collateral growth; estrogens; gender; mitochondria
    DOI:  https://doi.org/10.1016/j.mad.2020.111416
  23. Aging (Albany NY). 2020 Dec 14.
    Shats I, Li X.
      
    Keywords:  NAMPT inhibitors; bacterial nicotinamidase; deamidated NAD synthesis; host-microbe interaction; nicotinamide riboside
    DOI:  https://doi.org/10.18632/aging.104219
  24. Ned Tijdschr Geneeskd. 2020 Nov 05. pii: D5205. [Epub ahead of print]164
    van Zeventer IA, Buisman SC, de Graaf AO, de Haan G, Jansen JH, Huls G.
      Upon ageing, hematopoietic stem or progenitor cells harboring acquired leukemia-associated mutations may expand clonally and become detectable in peripheral blood. So-called clonal hematopoiesis may be detected in 5-55% of (otherwise healthy) individuals aged ≥ 70 years. Clonal hematopoiesis is associated with a higher risk of developing hematological neoplasms, although most individuals never develop malignant disease. Surprisingly, clonal hematopoiesis is also recognized as a new cardiovascular risk factor. Specific patient categories may be at higher risk for the consequences of clonal hematopoiesis. For future risk stratification, there is a need to distinguish high-risk clonal hematopoiesis from 'physiological' ageing processes. In this article we summarize current knowledge on clonal hematopoiesis and its clinical implications. Given the widespread application of next-generation sequencing in routine diagnostics, multidisciplinary recommendations for clinical management of individuals with detected clonal hematopoiesis should be developed.
  25. Neurology. 2020 Dec 14. pii: 10.1212/WNL.0000000000011338. [Epub ahead of print]
    Burt RK, Balabanov R, Han X, Quigley K, Arnautovic I, Helenowski I, Rose J, Siddique T.
      OBJECTIVE: To test the hypothesis that autologous non-myeloablative hematopoietic stem cell transplantation (HSCT) is safe and shows efficacy in the treatment of stiff person spectrum disorder (SPSD).METHODS: Twenty-three participants were treated in a prospective open-label cohort study of safety and efficacy. Following stem cell mobilization with cyclophosphamide (2 g/m2) and filgrastim (5--10 ug/kg/day), participants were treated with cyclophosphamide (200 mg/kg) divided as 50 mg/kg IV on day --5 to day --2, rATG (thymoglobulin) given IV at 0.5 mg/kg on day --5, 1 mg/kg on day --4 and --3, and 1.5 mg/kg on days --2, and --1 (total dose 5.5 mg/kg), and rituximab 500 mg IV on days --6 and +1. Unselected peripheral blood stem cells were infused on day 0. Safety was assessed by survival and NCI common toxicity criteria for adverse events during HSCT. Outcome was assessed by ≥ 50% decrease or discontinuation of anti-spasmodic drugs and by quality of life instruments.
    RESULTS: There was no treatment-related mortality. One participant died 1 year after transplant from disease progression. 74% of participants responded, 47% have stayed in remission for a mean of 3.5 years, and 26% did not respond. When compared to non-responders, responders were more likely to have pre-transplant intermittent muscle spasms (16/17 vsversus 0/6), normal reflexes (12/17 vsversus 0/6) and positive cerebrospinal fluid anti-GAD serology (12/14 vsversus 2/6). Compared to responders, non-responders were more likely to have lead pipe rigidity (4/6 vsversus 0/17), and EMG documented simultaneous contraction of agonist / antagonist limb muscles (4/6 vsversus 1/17). Pre-HSCT use of prescription SSRI and or SNRI was more common in those who relapsed or never responded (9/12) compared to those responders who never relapsed (0/11).
    CONCLUSION: In this cohort, HSCT was safe, but beneficial effect of HSCT was variable and predominately confined to participants with episodic spasms, normal tendon reflexes, without simultaneous co-contraction of limb agonist antagonist muscles, and who were not taking SSRI or SNRI antidepressants.
    CLASSIFICATION OF EEVIDENCE: This study provides Class IV evidence that for a subset of people with SPSD, autologous non-myeloablative HSCT improves outcomes.
    CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT02282514.
    DOI:  https://doi.org/10.1212/WNL.0000000000011338
  26. Food Sci Nutr. 2020 Dec;8(12): 6513-6527
    Zhang J, Yi C, Han J, Ming T, Zhou J, Lu C, Li Y, Su X.
      Studies have documented the benefits of fish oil in different diseases because of its high n-3 polyunsaturated fatty acid content. However, these studies mostly used commercially available fish oil supplements with a ratio of 18/12 for eicosapentaenoic acid and docosahexaenoic acid (DHA). However, increasing DHA content for this commonly used ratio might bring out a varied metabolic effect, which have remained unclear. Thus, in this study, a novel tuna oil (TO) was applied to investigate the effect of high-DHA content on the alteration of the gut microbiota and obesity in high-fat diet mice. The results suggest that high-DHA TO (HDTO) supplementation notably ameliorates obesity and related lipid parameters and restores the expression of lipid metabolism-related genes. The benefits of TOs were derived from their modification of the gut microbiota composition and structure in mice. A high-fat diet triggered an increased Firmicutes/Bacteroidetes ratio that was remarkably restored by TOs. The number of obesity-promoting bacteria-Desulfovibrio, Paraeggerthella, Terrisporobacter, Millionella, Lachnoclostridium, Anaerobacterium, and Ruminiclostridium-was dramatically reduced. Desulfovibrio desulfuricans, Alistipes putredinis, and Millionella massiliensis, three dysbiosis-related species, were especially regulated by HDTO. Regarding the prevention of obesity, HDTO outperforms the normal TO. Intriguingly, HDTO feeding to HFD-fed mice might alter the arginine and proline metabolism of intestinal microbiota.
    Keywords:  dietary obesity; gut microbiota; novel high‐DHA tuna oil
    DOI:  https://doi.org/10.1002/fsn3.1941
  27. Cancer Sci. 2020 Dec 19.
    Morita M, Kudo K, Shima H, Tanuma N.
      Cancer metabolism is influenced by availability of nutrients in the microenvironment and can to some extent be manipulated by dietary modifications that target oncogenic metabolism. As yet, few dietary interventions have been scientifically proven to mitigate disease progression or enhance any other kind of therapy in human cancer. But recent advances in understanding of cancer metabolism enable us to predict or devise effective dietary interventions that might antagonize tumor growth. In fact, evidence emerging from preclinical models suggests that appropriate combinations of specific cancer therapies with dietary interventions could critically impact therapeutic efficacy. Here, we review the potential benefits of precision nutrition approaches in augmenting efficacy of cancer treatment.
    DOI:  https://doi.org/10.1111/cas.14777
  28. Cells. 2020 Dec 16. pii: E2701. [Epub ahead of print]9(12):
    Fajstova A, Galanova N, Coufal S, Malkova J, Kostovcik M, Cermakova M, Pelantova H, Kuzma M, Sediva B, Hudcovic T, Hrncir T, Tlaskalova-Hogenova H, Kverka M, Kostovcikova K.
      Diet is a strong modifier of microbiome and mucosal microenvironment in the gut. Recently, components of western-type diets have been associated with metabolic and immune diseases. Here, we studied how high-sugar diet (HSD) consumption influences gut mucosal barrier and immune response under steady state conditions and in a mouse model of acute colitis. We found that HSD significantly increased gut permeability, spleen weight, and neutrophil levels in spleens of healthy mice. Subsequent dextran sodium sulfate administration led to severe colitis. In colon, HSD significantly promoted neutrophil infiltration and increased the levels of IL-6, IL-1β, and TNF-α. Moreover, HSD-fed mice had significantly higher abundance of pathobionts, such as Escherichia coli and Candida, in fecal samples. Although germ-free mice colonized with microbiota of conventionally reared mice that consumed different diets had equally severe colitis, mice colonized with HSD microbiota showed markedly increased infiltration of neutrophils to the gut. The induction of colitis in Toll-like receptor 4 (TLR4)-deficient HSD-fed mice led to significantly milder colitis than in wild-type mice. In conclusion, our results suggested a significant role of HSD in disruption of barrier integrity and balanced mucosal and systemic immune response. In addition, these processes seemed to be highly influenced by resident potentially pathogenic microbiota or metabolites via the TLR4 signaling pathway.
    Keywords:  high-sugar diet; inflammatory bowel diseases; metabolites; microbiome; mucosal barrier; neutrophils
    DOI:  https://doi.org/10.3390/cells9122701
  29. Dev Cell. 2020 Dec 07. pii: S1534-5807(20)30925-4. [Epub ahead of print]
    Davis OB, Shin HR, Lim CY, Wu EY, Kukurugya M, Maher CF, Perera RM, Ordonez MP, Zoncu R.
      Lysosomes promote cellular homeostasis through macromolecular hydrolysis within their lumen and metabolic signaling by the mTORC1 kinase on their limiting membranes. Both hydrolytic and signaling functions require precise regulation of lysosomal cholesterol content. In Niemann-Pick type C (NPC), loss of the cholesterol exporter, NPC1, causes cholesterol accumulation within lysosomes, leading to mTORC1 hyperactivation, disrupted mitochondrial function, and neurodegeneration. The compositional and functional alterations in NPC lysosomes and nature of aberrant cholesterol-mTORC1 signaling contribution to organelle pathogenesis are not understood. Through proteomic profiling of NPC lysosomes, we find pronounced proteolytic impairment compounded with hydrolase depletion, enhanced membrane damage, and defective mitophagy. Genetic and pharmacologic mTORC1 inhibition restores lysosomal proteolysis without correcting cholesterol storage, implicating aberrant mTORC1 as a pathogenic driver downstream of cholesterol accumulation. Consistently, mTORC1 inhibition ameliorates mitochondrial dysfunction in a neuronal model of NPC. Thus, cholesterol-mTORC1 signaling controls organelle homeostasis and is a targetable pathway in NPC.
    Keywords:  ESCRT; NPC1; autophagy; cholesterol; lysosome; mTORC1; mitochondria; proteolysis; proteomics
    DOI:  https://doi.org/10.1016/j.devcel.2020.11.016
  30. Prostaglandins Leukot Essent Fatty Acids. 2020 Dec 05. pii: S0952-3278(20)30177-0. [Epub ahead of print]164 102219
    Lamon-Fava S, So J, Mischoulon D, Ziegler TR, Dunlop BW, Kinkead B, Schettler PJ, Nierenberg AA, Felger JC, Maddipati KR, Fava M, Rapaport MH.
      BACKGROUND: Eicosapentaenoic acid (EPA) supplementation is an effective treatment option in major depressive disorder (MDD) associated with chronic low-grade inflammation. EPA is the precursor of specialized pro-resolving lipid mediators (SPMs) termed resolvins (Rv), that serve important roles in the resolution of inflammation. The objective of this study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites and SPMs in MDD patients.METHODS: In a 2-site study, 61 MDD patients with body mass index >25 kg/m2 and serum high-sensitivity C-reactive protein ≥3 μg/mL were enrolled in a 12-week randomized trial comparing EPA 1, 2, and 4 g/d to placebo. Plasma EPA (mol%) and SPMs (pg/mL) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry.
    RESULTS: Plasma EPA and SPM concentrations did not change in the placebo group during 12 weeks of treatment. Plasma EPA and EPA-derived metabolites increased significantly and dose-dependently in all EPA supplementation arms. The increase in 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of RvE1-3, was significantly greater with the 4 g/d EPA dose than the other doses from week 4 to 12. RvE1 was undetected in all treatment groups, while RvE2 was detected in half of the subjects both at baseline and after treatment, with dose-dependent increases. RvE3 was detected only after supplementation, dose-dependently. A significant reduction in plasma arachidonic acid (AA), relative to baseline, was observed in all EPA arms. This was in contrast with an increase in AA-derived SPM lipoxin B4 (LXB4) in the 4 g/d arm.
    CONCLUSIONS: Our results show a robust effect of EPA 4 g/d supplementation in increasing plasma EPA and 18-HEPE levels, associated with improved conversion to RvE2-3, and LXB4 levels.
    Keywords:  Eicosapentaenoic acid (EPA); Omega-3 fatty acids; Pro-resolving lipid mediators (SPM); major depressive disorder (MDD)
    DOI:  https://doi.org/10.1016/j.plefa.2020.102219
  31. Int J Mol Sci. 2020 Dec 16. pii: E9580. [Epub ahead of print]21(24):
    Alsharairi NA.
      Gut microbiota is well known as playing a critical role in inflammation and asthma development. The very low-calorie ketogenic diet (VLCKD) is suggested to affect gut microbiota; however, the effects of VLCKD during pregnancy and lactation on the infant gut microbiota are unclear. The VLCKD appears to be more effective than caloric/energy restriction diets for the treatment of several diseases, such as obesity and diabetes. However, whether adherence to VLCKD affects the infant gut microbiota and the protective effects thereof on asthma remains uncertain. The exact mechanisms underlying this process, and in particular the potential role of short chain fatty acids (SCFAs), are still to be unravelled. Thus, the aim of this review is to identify the potential role of SCFAs that underlie the effects of VLCKD during pregnancy and lactation on the infant gut microbiota, and explore whether it incurs significant implications for reducing asthma.
    Keywords:  SCFAs; asthma; infant gut microbiota; ketogenic diet; lactation; pregnancy
    DOI:  https://doi.org/10.3390/ijms21249580
  32. Biomedicines. 2020 Dec 15. pii: E615. [Epub ahead of print]8(12):
    Rybtsova N, Berezina T, Kagansky A, Rybtsov S.
      According to the World Health Organization, the population of over 60 will double in the next 30 years in the developed countries, which will enforce a further raise of the retirement age and increase the burden on the healthcare system. Therefore, there is an acute issue of maintaining health and prolonging active working longevity, as well as implementation of early monitoring and prevention of premature aging and age-related disorders to avoid early disability. Traditional indicators of biological age are not always informative and often require extensive and expensive analysis. The study of blood factors is a simple and easily accessible way to assess individual health and supplement the traditional indicators of a person's biological age with new objective criteria. With age, the processes of growth and development, tissue regeneration and repair decline; they are gradually replaced by enhanced catabolism, inflammatory cell activity, and insulin resistance. The number of senescent cells supporting the inflammatory loop rises; cellular clearance by autophagy and mitophagy slows down, resulting in mitochondrial and cellular damage and dysfunction. Monitoring of circulated blood factors not only reflects these processes, but also allows suggesting medical intervention to prevent or decelerate the development of age-related diseases. We review the age-related blood factors discussed in recent publications, as well as approaches to slowing aging for healthy and active longevity.
    Keywords:  aging; aging biomarkers; biological age; blood factors; inflammation; metabolic disorders; senescence
    DOI:  https://doi.org/10.3390/biomedicines8120615
  33. J Endocr Soc. 2021 Jan 01. 5(1): bvaa168
    Mollah ML, Yang HS, Jeon S, Kim K, Cheon YP.
      Ovarian reserve and fertility are reduced by aging and a poor energy balance. To date, the relationships of high energy accumulation and aging with the ovarian reserve have not been elucidated. Here, the effects of obesity on the aging ovarian reserve were evaluated in a leptin-deficient (ob/ob) mouse model. Abnormal estrous cyclicity appeared as early as 6 weeks and worsened with aging. The blood level patterns of 17β-estradiol (E2), testosterone (T), and progesterone (P4) with aging were similar between lean and ob/ob mice. The blood level of E2 but not P4 or T was similar at 24 weeks. Many more atretic follicles but fewer corpora lutea were observed in ob/ob mice than in lean mice within all age groups. Anti-Müllerian hormone (Amh) mRNA levels were similar between genotypes. Dazl, Stra8, and ZP3 mRNAs were highly expressed in ob/ob mice after 12 weeks. Sohlh1 and Ybx2 mRNAs were highly expressed at 24 weeks in ob/ob compared with lean mice. In addition, SOHLH1-positive primordial follicle counts were significantly increased in ob/ob mice at 24 weeks. The proportions of AMH-positive secondary and small antral follicles were similar between genotypes. Together, these results show that the ovarian reserve lasts longer in ob/ob mice than in lean mice, suggesting that the loss of normal physiological or physical status causes decreased fertility at a young age in ob/ob mice and that an increase in adipocytes without leptin, as in ob/ob mice, can improve the ovarian reserve. Such knowledge can be applied to understanding reproductive dysfunction.
    Keywords:  fertility; meiosis-stage marker; ob/ob; ovarian reserve; sex steroid hormone
    DOI:  https://doi.org/10.1210/jendso/bvaa168
  34. Food Funct. 2020 Dec 17.
    Rutledge GA, Sandhu AK, Miller MG, Edirisinghe I, Burton-Freeman BB, Shukitt-Hale B.
      Blueberries (BB) contain an array of bioactive phenolic compounds that may play a protective role against various age-related diseases. Here we explored the metabolic fate of BB phenolics and their relationship to cognitive function after chronic (90 days) supplementation of freeze-dried BB (24 g d-1, equivalent to 1 cup of fresh BB) or control in a randomized, double-blind, parallel study with 38 healthy older adults (60-75 years). Blood samples were collected at fasting (t = 0 h) and 2 h after a breakfast meal on days 0 (no treatment), 45, and 90, and a battery of cognitive tests was also conducted on these days. Hippuric acid, phloroglucinaldehyde, syringic acid, ferulic acid-glucuronide, cyanidin-3-O-galactoside, cyanidin-3-O-glucoside, malvidin-3-O-galactoside, malvidin-3-O-glucoside, peonidin-3-O-xyloside, peonidin glucuronide, and petunidin-3-O-glucoside concentrations were significantly altered after 90 days of BB consumption compared to control. Stepwise regression was used to assess the relationship between significantly altered concentrations of plasma phenolics and observed improvements in cognition. Among participants in the BB group, changes in switch errors on the task-switching test (TST) from day 0 to 90 were associated with changes in postprandial levels of plasma ferulic acid-glucuronide, syringic acid, and malvidin-3-galactoside (R2 = 0.521, p < 0.05). Changes in repetition errors on the California Verbal Learning Test (CVLT-II) from day 0 to 90 were associated with changes in postprandial levels of ferulic acid-glucuronide, syringic acid, and hippuric acid (R2 = 0.807, p < 0.001). These findings demonstrate that the addition of easily achievable quantities of BB to the diets of older adults significantly alters levels of circulating phenolic compounds which are related to improvements in cognition.
    DOI:  https://doi.org/10.1039/d0fo02125c
  35. Arterioscler Thromb Vasc Biol. 2020 Dec 17. ATVBAHA120305565
    Engelbrecht E, MacRae CA, Hla T.
      Membrane phospholipid metabolism forms lysophospholipids, which possess unique biochemical and biophysical properties that influence membrane structure and dynamics. However, lysophospholipids also function as ligands for G protein-coupled receptors that influence embryonic development, postnatal physiology, and disease. The 2 most well-studied species-lysophosphatidic acid and S1P (sphingosine 1-phosphate)-are particularly relevant to vascular development, physiology, and cardiovascular diseases. This review summarizes the role of lysophosphatidic acid and S1P in vascular developmental processes, endothelial cell biology, and their roles in cardiovascular disease processes. In addition, we also point out the apparent connections between lysophospholipid biology and the Wnt pathway, an evolutionarily conserved fundamental developmental signaling system. The discovery that components of the lysophospholipid signaling system are key genetic determinants of cardiovascular disease has warranted current and future research in this field. As pharmacological approaches to modulate lysophospholipid signaling have entered the clinical sphere, new findings in this field promise to influence novel therapeutic strategies in cardiovascular diseases.
    Keywords:  cardiovascular diseases; embryonic development; endothelial cells; lysophospholipids; sphingosine
    DOI:  https://doi.org/10.1161/ATVBAHA.120.305565
  36. Int J Mol Sci. 2020 Dec 09. pii: E9364. [Epub ahead of print]21(24):
    Gupta A, Cady C, Fauser AM, Rodriguez HC, Mistovich RJ, Potty AGR, Maffulli N.
      Stem cells for regenerative medicine purposes offer therapeutic benefits, but disadvantages are still ill defined. The benefit of stem cells may be attributed to their secretion of growth factors (GFs), cytokines (CKs), and extracellular vesicles (EVs), including exosomes. We present a novel cell-free stem cell-derived extract (CCM), formulated from human progenitor endothelial stem cells (hPESCs), characterized for biologically active factors using ELISA, nanoparticle tracking analysis and single particle interferometric reflectance imaging sensing. The effect on fibroblast proliferation and ability to induce stem cell migration was analyzed using Alamar Blue proliferation and Transwell migration assays, respectively. GFs including IGFBP 1, 2, 3, and 6, insulin, growth hormone, PDGF-AA, TGF-α, TGF-β1, VEGF, and the anti-inflammatory cytokine, IL-1RA were detected. Membrane enclosed particles within exosome size range and expressing exosome tetraspanins CD81 and CD9 were identified. CCM significantly increased cell proliferation and induced stem cell migration. Analysis of CCM revealed presence of GFs, CKs, and EVs, including exosomes. The presence of multiple factors including exosomes within one formulation, the ability to promote cell proliferation and induce stem cell migration may reduce inflammation and pain, and augment tissue repair.
    Keywords:  cytokines; exosomes; extracellular vesicles; growth factors; musculoskeletal injuries; osteoarthritis; progenitor cells; regenerative medicine; stem cells
    DOI:  https://doi.org/10.3390/ijms21249364
  37. Food Sci Nutr. 2020 Dec;8(12): 6727-6737
    Sugimoto K, Hosomi R, Yoshida M, Fukunaga K.
      Our research team has successfully prepared high-quality scallop oil (SCO), containing high eicosapentaenoic acid (EPA) and phospholipids (PL) from the internal organs of Japanese giant scallop (Patinopecten yessoensis) which is the largest unutilized marine resource in Japan. In this study, we prepared SCOs from scallop internal organs obtained from Mutsu (Aomori) and Uchiura (Hokkaido) bays in Japan, and named them SCO-M and SCO-U, respectively. This study aimed to investigate the effects of dietary SCO-M and SCO-U on cholesterol metabolism in obese type-II diabetic KK-Ay mice. Four-week-old male KK-Ay mice were divided into four groups. The Control group was fed with AIN93G-modified high-fat (3 wt% soybean oil + 17 wt% lard) diet, and the other groups were fed with high-fat diet, in which 7 wt% of the lard contained in the Control diet was replaced with SCO-M, SCO-U, or tuna oil (TO). After the mice had been fed with the experimental diet for 49 days, their serum, liver, and fecal lipid contents, as well as their liver messenger ribonucleic acid expression levels, were evaluated. The SCO-M and SCO-U groups were significantly decreased liver cholesterol contents compared to those of the Control and TO groups, partially through the enhancement of the fecal neutral sterol excretions and the tendency to increase the cholesterol 7α-hydroxylase expression level of the liver. These results indicated that dietary SCO-M and SCO-U exhibited cholesterol-lowering functions in the liver that can help prevent the development of lifestyle-related diseases.
    Keywords:  Japanese giant scallop (Patinopecten yessoensis); cholesterol metabolism; docosahexaenoic acid; eicosapentaenoic acid; n-3 polyunsaturated fatty acid
    DOI:  https://doi.org/10.1002/fsn3.1967
  38. Glob Health Med. 2019 Oct 31. 1(1): 3-10
    Nakatani H.
      Japan is aging rapidly, and its society is changing. Population aging and social change are mutually linked and appear to form a vicious cycle. Post-war Japan started to invest intensively in infectious disease control by expanding health services and achieving universal medical insurance coverage in 1961. The high economic growth in the 1960s contributed to generate a thick middle class layer, but the lingering economic slump after the economic bubble crisis after 1991 and globalization weakened this segment of society. Health disparity has been acknowledged and social determinates of health have been focused. In this article, the author reviewed the response course to health challenges posed by population aging in Japan, and aims to offer lessons to learn for Asian nations that are also rapidly aging. The core viewpoints include: i) review health policy transformations until the super-aged society, ii) discuss how domestic issues in aging can be a global issue, iii) analyze its relationship with Japanese global health engagement, iv) debate the context of social determinates of health, and v) synthesize these issues and translate to future directions.
    Keywords:  Japan; Population aging; SDGs; UHC; policy transformation; social determinates of health
    DOI:  https://doi.org/10.35772/ghm.2019.01011
  39. Nutrients. 2020 Dec 14. pii: E3821. [Epub ahead of print]12(12):
    Um HJ, Ko JW, Won SB, Kwon YH.
      Although vitamin B6 is contained in various foods, its deficiency is one of the most common micronutrient deficiencies worldwide. Furthermore, patients with obesity and cardiovascular disease are more likely to have suboptimal vitamin B6 status than healthy people. Therefore, we investigated the effects of dietary vitamin B6 restriction on hepatic gene expression and function in obese mice. C57BL/6J male mice were fed a low-fat (LF) or high-fat (HF) diet in combination with sufficient (7 mg pyridoxine/kg diet) or insufficient (1 mg) amounts of vitamin B6 for 16 weeks. Analysis of microarray data revealed that expressions of 4000 genes were significantly altered by the experimental diets (LF7, LF1, HF7, and HF1). The effects of dietary fat content on gene expressions were markedly greater than vitamin B6 content. Only three differentially expressed genes (DEGs) were overlapped between the LF1/LF7 and HF1/HF7 comparison. In the LF1/LF7 comparison, 54 upregulated DEGs were enriched in gene ontology (GO) terms associated with the sterol metabolic process and 54 downregulated DEGs were enriched in GO terms associated with immune response. In HF1/HF7 comparison, 26 upregulated DEGs were enriched in GO terms associated with amino acid catabolic process. High-fat consumption downregulated gene expressions associated with vitamin B6-dependent pathways. In conclusion, our data suggest that obesity may differentially regulate vitamin B6-associated metabolic pathways in the body.
    Keywords:  amino acid metabolism; dietary vitamin B6 restriction; high-fat diet; immunity; mice; sterol metabolism; transcriptome
    DOI:  https://doi.org/10.3390/nu12123821
  40. Nutrients. 2020 Dec 16. pii: E3849. [Epub ahead of print]12(12):
    Schaefer E, Demmelmair H, Horak J, Holdt L, Grote V, Maar K, Neuhofer C, Teupser D, Thiel N, Goeckeler-Leopold E, Maggini S, Koletzko B.
      Breastfed infants require an adequate supply of critical nutrients for growth, tissue functions, and health. Recommended intakes for several nutrients are considerably higher in lactating than non-lactating women but are not always met with habitual diets. We report a randomized, double-blind clinical trial in 70 healthy lactating women in Germany evaluating the effects of supplementation with multiple micronutrients, lutein, and docosahexaenoic acid (DHA) compared to placebo on maternal nutrient status and milk composition. The primary endpoint was the effect on the change of human milk DHA content (as a proportion of total milk fatty acids) during 12 weeks of supplementation. Maternal blood and milk biomarkers were measured as secondary endpoints. Supplementation increased maternal milk DHA by 30% compared to a decline in the placebo group. Supplementation also increased maternal blood DHA (17%), eicosapentaenoic acid (4%), 25-OH-vitamin D (24%), vitamin B12 (12%), lutein (4%), and beta carotene (49%), while homocysteine decreased. No significant difference in the number of adverse events was observed between supplementation and placebo groups. In conclusion, multi-micronutrient supplementation was safe and increased maternal blood and milk concentrations of selected nutrients in healthy women.
    Keywords:  docosahexaenoic acid; lactation; lutein; maternal biomarkers; micronutrients
    DOI:  https://doi.org/10.3390/nu12123849
  41. Front Immunol. 2020 ;11 593348
    Pang H, Luo S, Xiao Y, Xia Y, Li X, Huang G, Xie Z, Zhou Z.
      Type 1 diabetes mellitus (T1DM) is a complex autoimmune disorder that mainly affects children and adolescents. The elevated blood glucose level of patients with T1DM results from absolute insulin deficiency and leads to hyperglycemia and the development of life-threatening diabetic complications. Although great efforts have been made to elucidate the pathogenesis of this disease, the precise underlying mechanisms are still obscure. Emerging evidence indicates that small extracellular vesicles, namely, exosomes, take part in intercellular communication and regulate interorgan crosstalk. More importantly, many findings suggest that exosomes and their cargo are associated with the development of T1DM. Therefore, a deeper understanding of exosomes is beneficial for further elucidating the pathogenic process of T1DM. Exosomes are promising biomarkers for evaluating the risk of developingty T1DM, monitoring the disease state and predicting related complications because their number and composition can reflect the status of their parent cells. Additionally, since exosomes are natural carriers of functional proteins, RNA and DNA, they can be used as therapeutic tools to deliver these molecules and drugs. In this review, we briefly introduce the current understanding of exosomes. Next, we focus on the relationship between exosomes and T1DM from three perspectives, i.e., the pathogenic role of exosomes in T1DM, exosomes as novel biomarkers of T1DM and exosomes as therapeutic tools for T1DM.
    Keywords:  biomarkers; exosomes; microRNAs; therapy; type 1 diabetes mellitus
    DOI:  https://doi.org/10.3389/fimmu.2020.593348
  42. Curr Opin Clin Nutr Metab Care. 2020 Dec 15. Publish Ahead of Print
    Ferguson EJ, Seigel JW, McGlory C.
      PURPOSE OF REVIEW: To examine recent findings related to the influence of omega-3 (ω-3) fatty acid supplementation on skeletal muscle anabolism with a particular focus on situations of skeletal muscle disuse.RECENT FINDINGS: Skeletal muscle disuse results in a reduction in fed and fasted rates of skeletal muscle protein synthesis leading to the loss of skeletal muscle mass. Recent evidence has suggested that supplementation with ω-3 fatty acids during a period of skeletal muscle disuse increases the ω-3 fatty acid composition of skeletal muscle membranes, heightens rates of skeletal muscle protein synthesis, and protects against skeletal muscle loss. The protective effects of ω-3 fatty acids towards skeletal muscle during disuse appear to be related to changes in mitochondrial bioenergetics suggesting crosstalk between mitochondria and the regulation of skeletal muscle protein synthesis.
    SUMMARY: ω-3 fatty acid ingestion is a potential preventive therapy to combat skeletal muscle-disuse atrophy but additional, appropriately powered randomized controlled trials are now needed in a range of populations before firm conclusions can be made.
    DOI:  https://doi.org/10.1097/MCO.0000000000000723
  43. Front Mol Neurosci. 2020 ;13 568426
    Badawi Y, Nishimune H.
      The neuromuscular junction (NMJ) is a chemical synapse formed between a presynaptic motor neuron and a postsynaptic muscle cell. NMJs in most vertebrate species share many essential features; however, some differences distinguish human NMJs from others. This review will describe the pre- and postsynaptic structures of human NMJs and compare them to NMJs of laboratory animals. We will focus on age-dependent declines in function and changes in the structure of human NMJs. Furthermore, we will describe insights into the aging process revealed from mouse models of accelerated aging. In addition, we will compare aging phenotypes to other human pathologies that cause impairments of pre- and postsynaptic structures at NMJs. Finally, we will discuss potential intervention approaches for attenuating age-related NMJ dysfunction and sarcopenia in humans.
    Keywords:  active zone (AZ); aging; caloric restriction; exercise; laminin; neuromuscular disease; progeria; synapse
    DOI:  https://doi.org/10.3389/fnmol.2020.568426
  44. Am J Transplant. 2020 Dec 17.
    Chandran S, Leung J, Hu C, Laszik ZG, Tang Q, Vincenti FG.
      Interleukin-6 (IL-6) is a proinflammatory cytokine and key regulator of Treg: T effector cell (Teff) balance. We hypothesized that IL-6 blockade with tocilizumab, a monoclonal antibody to IL-6R, would increase Tregs, dampen Teff function, and control graft inflammation. We conducted a randomized controlled clinical trial (2014-2018) of clinically stable kidney transplant recipients on calcineurin inhibitor, mycophenolate mofetil and prednisone, with subclinical graft inflammation noted on surveillance biopsies during the first year post-transplant. Subjects received tocilizumab (8 mg/kg IV every 4 weeks; 6 doses; n=16) or no treatment (controls; n=14) on top of usual maintenance immunosuppression. Kidney biopsies pre- and post-treatment were analyzed using Banff criteria. Blood was analyzed for serum cytokines, Treg frequencies, and T cell effector molecule expression (IFN-γ, IL-17, granzyme B) post-stimulation ex vivo. Tocilizumab-treated subjects were more likely to show improved Banff ti-score (62.5% vs. 21.4%, p=0.03), increased Treg frequency (3.6±1.7% vs. 7.1±5.5%, p=0.0168), and a blunted Teff cytokine response compared to controls. Changes in Banff i- and t-scores were not significantly different. The treatment was relatively well-tolerated with no patient deaths or graft loss. Blockade of IL-6 is a novel and promising treatment option to regulate the T cell alloimmune response in kidney transplant recipients. NCT02108600.
    DOI:  https://doi.org/10.1111/ajt.16459
  45. Sci Rep. 2020 Dec 14. 10(1): 21853
    Dorronsoro A, Lang V, Ferrin I, Fernández-Rueda J, Zabaleta L, Pérez-Ruiz E, Sepúlveda P, Trigueros C.
      Interleukin (IL)-6 is a pleiotropic cytokine involved in the regulation of hematological and immune responses. IL-6 is secreted chiefly by stromal cells, but little is known about its precise role in the homeostasis of human mesenchymal stromal cells (hMSCs) and the role it may play in hMSC-mediated immunoregulation. We studied the role of IL-6 in the biology of bone marrow derived hMSC in vitro by silencing its expression using short hairpin RNA targeting. Our results show that IL-6 is involved in immunosuppression triggered by hMSCs. Cells silenced for IL-6 showed a reduced capacity to suppress activated T-cell proliferation. Moreover, silencing of IL-6 significantly blocked the capacity of hMSCs to proliferate. Notably, increasing the intracellular level of IL-6 but not recovering the extracellular level could restore the proliferative impairment observed in IL-6-silenced hMSC. Our data indicate that IL-6 signals in hMSCs by a previously undescribed intracellular mechanism.
    DOI:  https://doi.org/10.1038/s41598-020-78864-4
  46. Int J Prev Med. 2020 ;11 160
    Abshirini M, Mahaki B, Bagheri F, Siassi F, Koohdani F, Qorbani M, Yavari P, Sotoudeh G.
      Background: The relationship between dietary fat quality (DFQ) indices and pre-diabetes has not been well studied. This study aimed to determine the association of DFQ indices and fatty acid intake with pre-diabetes.Methods: This case-control study included 150 subjects with normal fasting blood glucose (FBG) and 147 pre-diabetic subjects. Dietary intake was assessed by a validated food-frequency questionnaire. DFQ indices including atherogenicity (AI) and thrombogenicity (TI), the ratios of hypo- and hypercholesterolemic (h:H), polyunsaturated:saturated (P:S) and n-3:n-6 polyunsaturated fatty acids were calculated. FBG test and 2-hour oral glucose tolerance test (OGTT) were measured.
    Results: After adjustment for some confounding variables, a positive association was found between intake of total saturated fatty acids (SFA), myristic acid, palmitic acid, and pre-diabetes, and a negative association was observed among n-3 polyunsaturated fatty acids, eicosapentaenoic, docosahexaenoic and arachidonic acids intake and pre-diabetes. AI was found to be positively associated with pre-diabetes (OR 6.68, 95% CI 2.57-17.34). An inverse relationship was observed between n-3:n-6 (OR 0.37, 95% CI 0.14-0.93) and h:H (OR 0.20, 95% CI 0.07-0.52) ratios with pre-diabetes.
    Conclusions: Higher intake of dietary n-3 fatty acids was adversely, whereas SFA intake was positively related to pre-diabetes morbidity. DFQ indices may be a useful measure to investigate fat intakes and blood glucose disturbances.
    Keywords:  Dietary fat quality; fatty acids; polyunsaturated fatty acids; pre-diabetes
    DOI:  https://doi.org/10.4103/ijpvm.IJPVM_243_18
  47. Biology (Basel). 2020 Dec 16. pii: E474. [Epub ahead of print]9(12):
    Germain N, Dhayer M, Boileau M, Fovez Q, Kluza J, Marchetti P.
      Metabolic reprogramming is crucial to respond to cancer cell requirements during tumor development. In the last decade, metabolic alterations have been shown to modulate cancer cells' sensitivity to chemotherapeutic agents including conventional and targeted therapies. Recently, it became apparent that changes in lipid metabolism represent important mediators of resistance to anticancer agents. In this review, we highlight changes in lipid metabolism associated with therapy resistance, their significance and how dysregulated lipid metabolism could be exploited to overcome anticancer drug resistance.
    Keywords:  antimetabolic cooperativity; cancer drug resistance; lipid metabolism; synthetic lethality
    DOI:  https://doi.org/10.3390/biology9120474
  48. J Cell Mol Med. 2020 Dec 18.
    Mokhtari Y, Pourbagheri-Sigaroodi A, Zafari P, Bagheri N, Ghaffari SH, Bashash D.
      In the dark path of tumorigenesis, the more carefully the cancer biology is studied, the more brilliant answers could be given to the countless questions about its orchestrating derivers. The identification of the correlation between Toll-like receptors (TLRs) and different processes involved in carcinogenesis was one of the single points of blinding light highlighting the interconnection between the immune system and cancer. TLRs are a wide family of single-pass membrane-spanning receptors that have developed through the evolution to recognize the structurally conserved molecules derived from microorganisms or damaged cells. But this is not everything about these receptors as they could orchestrate several downstream signalling pathways leading to the formation or suppression of cancer cells. The present review is tempted to provide a concise schematic about the biology and the characters of TLRs and also summarize the major findings of the regulatory role of TLRs and their associated signalling in the pathogenesis of human cancers.
    Keywords:  Toll-like receptor (TLR); cancer; immune system; inflammation; pattern-recognition receptor
    DOI:  https://doi.org/10.1111/jcmm.16214
  49. Clin Transplant. 2020 Dec 12. e14186
    Entwistle TR, Miura K, Keevil BG, Morris J, Yonan N, Pohl M, Green AC, Fildes JE.
      Cardiovascular disease (CVD) is common after cardiothoracic transplantation. In a pilot intervention we assessed feasibility and potential effectiveness of dietary interventions to reduce CVD risk. We recruited patients from a tertiary hospital and randomly allocated them to a Mediterranean or low-fat diet for twelve months. Feasibility was measured by patient participation, retention and adherence. Changes in weight, body mass index (BMI), heart rate, blood pressure, glucose markers and blood lipids were assessed using longitudinal Generalized Estimating Equation regression models with 95% confidence intervals. Of 56 heart and 60 lung transplant recipients, 52 (45%) consented, 41 were randomised and 39 (95%) completed the study with good adherence to randomized diets. After 12 months, changes in many risk factors were seen in the Mediterranean and low-fat diet groups respectively including mean BMI (-0.5 vs. 0.0kg/m2 ), systolic/diastolic blood pressure +0.5/+0.1 vs -4.4/-3.5 mmHg; fasting glucose -0.26 vs -0.27 mmol/L; total cholesterol -0.56 vs -0.40 mmol/L. Changes in BMI and systolic/diastolic blood pressure in 49 eligible patients who did not take part were +0.7 kg/m2 and +2.5/+1.8 mmHg. Thus such dietary interventions in cardiothoracic transplant patients are feasible, and potentially beneficial. A definitive nutritional intervention study in these high-risk patients is warranted.
    Keywords:  Mediterranean diet; cardiothoracic transplantation; cardiovascular risk; feasibility; low-fat diet
    DOI:  https://doi.org/10.1111/ctr.14186
  50. Mediators Inflamm. 2020 ;2020 6672636
    Wang Y, Qi W, Song G, Pang S, Peng Z, Li Y, Wang P.
      High-fructose diet induced changes in gut microbiota structure and function, which have been linked to inflammatory response. However, the effect of small or appropriate doses of fructose on gut microbiota and inflammatory cytokines is not fully understood. Hence, the abundance changes of gut microbiota in fructose-treated Sprague-Dawley rats were analyzed by 16S rRNA sequencing. The effects of fructose diet on metabolic disorders were evaluated by blood biochemical parameter test, histological analysis, short-chain fatty acid (SCFA) analysis, ELISA analysis, and Western blot. Rats were intragastrically administered with pure fructose at the dose of 0 (Con), 2.6 (Fru-L), 5.3 (Fru-M), and 10.5 g/kg/day (Fru-H) for 20 weeks. The results showed that there were 36.5% increase of uric acid level in the Fru-H group when compared with the Con group. The serum proinflammatory cytokines (IL-6, TNF-α, and MIP-2) were significantly increased (P < 0.05), and the anti-inflammatory cytokine IL-10 was significantly decreased (P < 0.05) with fructose treatment. A higher fructose intake induced lipid accumulation in the liver and inflammatory cell infiltration in the pancreas and colon and increased the abundances of Lachnospira, Parasutterella, Marvinbryantia, and Blantia in colonic contents. Fructose intake increased the expressions of lipid accumulation proteins including perilipin-1, ADRP, and Tip-47 in the colon. Moreover, the higher level intake of fructose impaired intestinal barrier function due to the decrease of the expression of tight junction proteins (ZO-1 and occludin). In summary, there were no negative effects on body weight, fasting blood glucose, gut microbiota, and SCFAs in colonic contents of rats when fructose intake is in small or appropriate doses. High intake of fructose can increase uric acid, proinflammatory cytokines, intestinal permeability, and lipid accumulation in the liver and induce inflammatory response in the pancreas and colon.
    DOI:  https://doi.org/10.1155/2020/6672636
  51. Epigenetics. 2020 Dec 14.
    Saito T, Whatmore P, Taylor JF, Fernandes JMO, Adam AC, Tocher DR, Espe M, Skjærven KH.
      Micronutrients (vitamins and minerals) have been less well studied compared to macronutrients (fats, proteins, and carbohydrates) although they play important roles in growth, metabolism, and maintenance of tissues. Hence, there is growing interest to understand the influence of micronutrients across various aspects in nutritional research. In the last two decades, aquaculture feeds have been shifted to containing more plant-based materials to meet the increasing demand and maintain the sustainability in the industry. In cultured fish, changing raw materials in feeds alters the requirement levels of micronutrients. A recent whole life cycle feeding trial of Atlantic salmon (Salmo salar) with graded levels of micronutrient packages has concluded that the levels of several B-vitamins and microminerals need to be increased from the current recommendation levels for optimal growth and fish welfare when plant-based diets are used. Here, we show the effect of micronutrient supplementation on transcriptional and epigenetic regulation by using liver samples from the same feeding trial. Specifically, our aim is to reveal the mechanisms of altered cell metabolism, which results in improved growth performance by micronutrient surpluses, at gene expression and DNA methylation levels. Our results strongly indicate that micronutrient supplementation suppresses gene expression in lipid metabolism in a dose-dependent manner and broadly affects DNA methylation in cell adhesion and cell signalling. In particular, it increases DNA methylation levels on the acetyl-CoA carboxylase alpha promoter in a concentration-dependent manner, which further suggests that acetyl-CoA carboxylase alpha is an upstream epigenetic regulator controlling its downstream lipid biosynthesis activities. This study demonstrates a comprehensive analysis to reveal an important role of micronutrients in lipid metabolism through epigenetic control of gene expression.
    Keywords:  Acetyl-CoA; Acetyl-CoA carboxylase alpha; Aquaculture; Atlantic salmon; DNA methylation; Epigenetics; Lipid metabolism; Micronutrient; RRBS; Steroid biosynthesis
    DOI:  https://doi.org/10.1080/15592294.2020.1859867
  52. Cognition. 2020 Dec 09. pii: S0010-0277(20)30343-7. [Epub ahead of print]207 104524
    Hilton C, Johnson A, Slattery TJ, Miellet S, Wiener JM.
      Aging is accompanied by changes in general cognitive functioning which may impact the learning rate of older adults; however, this is often not controlled for in cognitive aging studies. We investigated the contribution of differences in learning rates to age-related differences in landmark knowledge acquired from route learning. In Experiment 1 we used a standard learning procedure in which participants received a fixed amount of exposure to a route. Consistent with previous research, we found age-related deficits in associative cue and landmark sequence knowledge. Experiment 2 controlled for differences in learning rates by using a flexible exposure learning procedure. Specifically, participants were trained to a performance criterion during route learning before being tested on the content of their route knowledge. While older adults took longer to learn the route than younger adults, the age-related differences in associative cue knowledge were abolished. The deficit in landmark sequence knowledge, however, remained. Experiment 3 replicated these results and introduced a test situation in which a deficit in landmark sequence knowledge yielded an increased likelihood of disorientation in older adults. The findings of this study suggest that age-related deficits in landmark associative cue knowledge are attenuated by controlling for learning rates. In contrast, landmark sequence knowledge deficits persist and are best explained by changes in the learning strategy of older adults to acquire task essential associative cue knowledge at the expense of supplementary sequence knowledge.
    Keywords:  Aging; Learning; Route navigation; Spatial cognition
    DOI:  https://doi.org/10.1016/j.cognition.2020.104524
  53. High Blood Press Cardiovasc Prev. 2020 Dec 14.
    Elena B, María Izarbe MC, Susana OG, Sebastián MG, José Luis SM, José María DM, Miguel Ángel TC.
      INTRODUCTION: Cellular senescence and fibrosis are important phenomena in the development of heart failure (HF). These processes are closely related to telomeric length (TL).AIM: To assess cellular senescence in HF through the study of TL in peripheral blood mononuclear cells (PBMCs).
    METHODS: Using real-time PCR, TL was measured in PBMCs from 20 patients diagnosed with HF, aged between 51 and 77 years (50% males). Ten patients had HF with reduced ejection fraction (HFrEF) and ten had preserved EF (HFpEF). TL was measured in 20 healthy controls matched by age and gender. Obtained values were compared with an internal control, the 36B4 gene, which never modifies its expression, and correlated with the clinical parameters.
    RESULTS: TL mean was 1327 in patients with HF (95% CI 1309-1344) compared to 1286 (95% CI 1264-1308) in controls (p = 0.005). No differences were found when studying the correlation of telomere size with subgroups by gender, left ventricle ejection fraction (LVEF), presence of ischemic heart disease, smoking, Chronic Obstructive Pulmonary Disease (COPD), NYHA stage, degree of renal function or number of hospital admissions in the previous year. A significant and negative correlation was found between age and renal function (r = - 0.544, p < 0.05), as well as LVEF and NT-proBNP values (ρ = - 0.475, p < 0.05).
    CONCLUSIONS: TL is shorter in patients with HF when compared with age and gender balanced controls. The shortening of TL is independent of age, gender and degree of kidney function, and does not correlate with LVEF decrease or functional status.
    Keywords:  Biomarkers; Cellular aging; Heart failure; Telomeres
    DOI:  https://doi.org/10.1007/s40292-020-00421-x
  54. Chronic Dis Transl Med. 2020 Dec;6(4): 215-218
    Wang H, Jing ZC.
      
    Keywords:  Cardiomyopathies; Cardiovascular disease; Inflammation
    DOI:  https://doi.org/10.1016/j.cdtm.2020.09.003
  55. Int J Environ Res Public Health. 2020 Dec 16. pii: E9424. [Epub ahead of print]17(24):
    Brancaccio M, Mennitti C, Cesaro A, Fimiani F, Moscarella E, Caiazza M, Gragnano F, Ranieri A, D'Alicandro G, Tinto N, Mazzaccara C, Lombardo B, Pero R, Limongelli G, Frisso G, Calabrò P, Scudiero O.
      Moderate exercise combined with proper nutrition are considered protective factors against cardiovascular disease and musculoskeletal disorders. However, physical activity is known not only to have positive effects. In fact, the achievement of a good performance requires a very high oxygen consumption, which leads to the formation of oxygen free radicals, responsible for premature cell aging and diseases such as heart failure and muscle injury. In this scenario, a primary role is played by antioxidants, in particular by natural antioxidants that can be taken through the diet. Natural antioxidants are molecules capable of counteracting oxygen free radicals without causing cellular cytotoxicity. In recent years, therefore, research has conducted numerous studies on the identification of natural micronutrients, in order to prevent or mitigate oxidative stress induced by physical activity by helping to support conventional drug therapies against heart failure and muscle damage. The aim of this review is to have an overview of how controlled physical activity and a diet rich in antioxidants can represent a "natural cure" to prevent imbalances caused by free oxygen radicals in diseases such as heart failure and muscle damage. In particular, we will focus on sulfur-containing compounds that have the ability to protect the body from oxidative stress. We will mainly focus on six natural antioxidants: glutathione, taurine, lipoic acid, sulforaphane, garlic and methylsulfonylmethane.
    Keywords:  athletes; heart failure; muscle damage and diet supplementation; oxidative stress; sport activity; sulfur-containing compounds
    DOI:  https://doi.org/10.3390/ijerph17249424
  56. J Clin Transl Res. 2020 Jul 16. 6(1): 27-35
    Sourg HAA, Ahmed ABM, Elhakeem RF, Lutfi MF.
      Background: Pathophysiology of hypertension and bronchial asthma (BA) shares many similarities, especially those related to the metabolic syndrome (MS).Aim: In this study, the indicators of the MS were evaluated in normoglycemic normotensive asthmatic patients to clarify if the components of the MS can still interact to increase the risk of BA, provided that blood pressure and glucose level are kept within the normal physiological ranges.
    Methods: Body mass index (BMI), waist circumference (WC), mean arterial blood pressure (MABP), fasting blood glucose (FBG) and fasting blood insulin (FBI) levels, the quantitative insulin sensitivity check index (QUICKI), serum lipid profile, and spirometric measurements were all compared between 120 asthmatic patients and 59 non-asthmatic subjects. Cigarette smoking, pregnancy, age below 20 years or above 40 years, diabetes mellitus and hypertension, and other chronic diseases were excluded from all studied groups.
    Results: Asthmatic patients demonstrated higher WC (median [25th-75th interquartile]=88.50 [78.00-101.75], FBI [19.98 (11.12-40.14)], and triglyceride (TG) level [109.5 (76.50-134.0)]) compared with non-asthmatic subjects (81.00 [72.00-92.00], 13.78 [8.84-30.24], and 89.00 [64.25-104], P<0.05). QUICKI and MABP were lower in asthmatic patients (0.310 [0.283-0.338] and 86.66 [83.33-93.33]) compared with non-asthmatic subjects (0.320 [0.297-0.353] and 93.33 [83.33-93.33]), (P<0.05). BMI, FBG, low-density lipoprotein, high-density lipoprotein, and total cholesterol levels were comparable in the studied groups.
    Conclusions: The present finding gives further evidence for higher WC, FBI, TG level, and insulin resistance in normotensive, normoglycemic asthmatic patients compared to healthy controls.
    Relevance for Patients: The findings of this study suggested that abdominal obesity, hypertriglyceridemia, hyperinsulinemia, and insulin resistance may still be interacting and hence increase the risk of BA in normotensive, normoglycemic subjects.
    Keywords:  bronchial asthma; diabetes mellitus; hypertension; insulin resistance; metabolic syndrome
  57. Int J Environ Res Public Health. 2020 Dec 14. pii: E9339. [Epub ahead of print]17(24):
    Jakubiak GK, Pawlas N, Cieślar G, Stanek A.
      Diabetes mellitus is an important risk factor for the development of cardiovascular diseases. Peripheral arterial disease affecting lower limb arteries is one of the clinical manifestations of atherosclerosis. The frailty syndrome (Frailty) is a problem associated with diminution of physiological reserves. The ankle-brachial index is a commonly used tool for diagnosing peripheral arterial disease (PAD). The usefulness of the ankle-brachial index (ABI) is limited in people with diabetes because of calcification of the middle layer of arteries. In this population, toe-brachial index should be measured. Frailty may be associated with worse prognosis for patients undergoing revascularization. Amputation may be an important factor leading to the development of Frailty. The risk of amputation and the prognosis after revascularization may be modified by some medications and blood glucose levels. The purpose of this paper is to review the literature about the association between PAD, especially in patients living with diabetes and Frailty.
    Keywords:  Frailty; diabetes; lower limb ischemia; peripheral arterial disease
    DOI:  https://doi.org/10.3390/ijerph17249339
  58. J Biochem Mol Toxicol. 2020 Dec 14. e22681
    Nkpaa KW, Owoeye O, Amadi BA, Adedara IA, Abolaji AO, Wegwu MO, Farombi EO.
      Manganese (Mn) exposure is causing public health concerns as well as heavy alcohol consumption. This study investigates the mechanisms of neurotoxicity associated with Mn and ethanol (EtOH) exposure in the rat cerebellar cortex. Experimental animals received 30 mg/kg of Mn alone, 5 g/kg of EtOH alone, co-exposed with 30 mg/kg of Mn and 1.25 or 5 g/kg EtOH, while control animals received water by oral gavage for 35 days. Subsequently, alterations in the neuronal morphology of the cerebellar cortex, oxidative/nitrosative stress, acetylcholinesterase (AChE) activity, neuro-inflammation and protein expression of p53, BAX, caspase-3, and BCL-2 were investigated. The results indicate that Mn alone and EtOH alone induce neuronal alterations in the cerebellar cortex, decrease glutathione level and antioxidant enzyme activities, along with an increase in AChE activity, lipid peroxidation, and hydrogen peroxide generation. Mn alone and EtOH alone also increased neuro-inflammatory markers, namely nitric oxide, myeloperoxidase activity, interleukin-1β, tumor necrosis factor-α, and nuclear factor-κB (NF-κB) levels in the cerebellar cortex. Immunohistochemistry analysis further revealed that exposure of Mn alone and EtOH alone increases the protein expression of cyclooxygenase-2, BAX, p53, and caspase-3 and decrease BCL-2 in the rat cerebellar cortex. Furthermore, the results indicated that Mn co-exposure with EtOH at 1.25 and 5 g/kg EtOH significantly (p ≤ .05) increases the toxicity in the cerebellum when compared with the toxicity of Mn or EtOH alone. Taken together, co-exposure of Mn and EtOH exacerbates neuronal alterations, oxidative/nitrosative stress, AChE activity, pro-inflammatory cytokines, NF-κB signal transcription, and apoptosis induction in the rat cerebellar cortex.
    Keywords:  apoptosis; co-exposure; ethanol; inflammation; manganese; oxidative stress
    DOI:  https://doi.org/10.1002/jbt.22681
  59. Compr Rev Food Sci Food Saf. 2019 Mar;18(2): 548-564
    Khan BM, Liu Y.
      The extremely vast biodiversity represented by marine mollusks alongside their widespread utility as a source of food and their high nutritional value has aroused great interest from the scientific community. Furthermore, they can be caught with ease, and their commercial breeding and farming is rampant. This article comprehends the global availability of these organisms, their pretreatment and handling procedures, and their health-promoting potential with a focus on their antiviral, anti-inflammatory, and antimicrobial properties. The emphasis herein is on their potential use in the food and nutraceutical industry. In addition, mollusks consumption as part of everyday diet can also be helpful in avoiding many ailments as they are rich in vital nutrients and active secondary metabolites, as well as have the ability to enhance immune response. Moreover, the available literature suggests that normal cooking practices have no notable adverse effects on their nutritional value and they retain certain bioactivities even after the action of digestive enzymes. Though mollusks have been widely studied in relation to the health-promoting effects reviewed here, there is still more scope for further research in this direction in order to fully utilize this enormous source of food and nutraceuticals.
    Keywords:  anti-inflammatory; antimicrobial; antiviral; food industry; functional foods; mollusks; nutraceuticals
    DOI:  https://doi.org/10.1111/1541-4337.12429
  60. Clin Chem. 2020 Dec 14. pii: hvaa277. [Epub ahead of print]
    Ibrahim NE, Januzzi JL.
      BACKGROUND: Several large trials have demonstrated cardiac benefits in patients with and without established cardiovascular disease treated with sodium-glucose co-transporter 2 inhibitors (SGLT2i). Most recently, in patients with heart failure with reduced ejection fraction (HFrEF), the risk of worsening HF or cardiovascular death was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. Biomarkers may provide insight into understanding the mechanism of cardiovascular benefit observed in patients receiving SLGT2i. Several mechanisms have been proposed, including improvement in ventricular unloading due to the natriuretic effects, afterload reduction via reduction in blood pressure and improvement in vascular function, improvement in cardiac metabolism and bioenergetics, and reduction in cardiac fibrosis and necrosis, among others.CONTENT: We discuss several animal and human studies on the effect of SGLT2i on various biomarkers. Modest reduction or blunting of rise over time in concentrations of atrial natriuretic peptide, B-type natriuretic peptide, and N-terminal pro B-type natriuretic peptide and reduction in high-sensitivity troponin has been observed in patients receiving SLGT2i. Concentrations of biomarkers such as sST2 and galectin-3 have been unchanged whereas inflammatory markers such as fibronectin 1, interleukin-6, matrix metalloproteinase 7, and tumor necrosis factor-1 are decreased with SGLT2i therapy.
    SUMMARY: The effect of SLGT2i on various circulating biomarkers allows insight into the understanding of mechanisms of cardiovascular benefits with SGLT2i use. Further studies are needed to understand such mechanisms and to understand how biomarkers can be used for risk prediction and personalization of care in patients receiving SLGT2i.
    Keywords:  SGLT2 inhibitors; biomarkers; heart failure
    DOI:  https://doi.org/10.1093/clinchem/hvaa277
  61. Diabetes Care. 2020 Dec 14. pii: dc201983. [Epub ahead of print]
    Wolf P, Fellinger P, Pfleger L, Beiglböck H, Krumpolec P, Barbieri C, Gastaldelli A, Harreiter J, Metz M, Scherer T, Zeyda M, Baumgartner-Parzer S, Marculescu R, Trattnig S, Kautzky-Willer A, Krššák M, Krebs M.
      OBJECTIVE: Recent studies indicate that sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP), potentially counteracting the glucose-lowering potency, and stimulates lipid oxidation and lipolysis. However, the acute effects of SGLT-2 inhibition on hepatic glycogen, lipid, and energy metabolism have not yet been analyzed. We therefore investigated the impact of a single dose of dapagliflozin (D) or placebo (P) on hepatic glycogenolysis, hepatocellular lipid (HCL) content and mitochondrial activity (kATP).RESEARCH DESIGN AND METHODS: Ten healthy volunteers (control [CON]: age 30 ± 3 years, BMI 24 ± 1 kg/m2, HbA1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m2, HbA1c 6.1 ± 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). 1H/13C/31P MRS was performed before, 90-180 min (MR1), and 300-390 min (MR2) after administration of 10 mg dapagliflozin or placebo. EGP was assessed by tracer dilution techniques.
    RESULTS: Compared with CON-P, EGP was higher in CON-D (10.0 ± 0.3 vs. 12.4 ± 0.5 μmol kg-1 min-1; P < 0.05) and comparable in T2DM-D and T2DM-P (10.1 ± 0.7 vs. 10.4 ± 0.5 μmol kg-1 min-1; P = not significant [n.s.]). A strong correlation of EGP with glucosuria was observed (r = 0.732; P < 0.01). The insulin-to-glucagon ratio was lower after dapagliflozin in CON-D and T2DM-D compared with baseline (P < 0.05). Glycogenolysis did not differ between CON-P and CON-D (-3.28 ± 0.49 vs. -2.53 ± 0.56 μmol kg-1 min-1; P = n.s.) or T2DM-P and T2DM-D (-0.74 ± 0.23 vs. -1.21 ± 0.33 μmol kg-1 min-1; P = n.s.), whereas gluconeogenesis was higher after dapagliflozin in CON-P compared with CON-D (6.7 ± 0.6 vs. 9.9 ± 0.6 μmol kg-1 min-1; P < 0.01) but not in T2DM. No significant changes in HCL and kATP were observed.
    CONCLUSIONS: The rise in EGP after SGLT-2 inhibition is due to increased gluconeogenesis, but not glycogenolysis. Changes in glucagon and the insulin-to-glucagon ratio are not associated with an increased hepatic glycogen breakdown. HCL and kATP are not significantly affected by a single dose of dapagliflozin.
    DOI:  https://doi.org/10.2337/dc20-1983
  62. Arch Endocrinol Metab. 2020 Dec 15. pii: 2359-3997000000313. [Epub ahead of print]
    Chueire VB, Muscelli E.
      Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.
    Keywords:  FFAs; T2D; incretin effect; insulin secretion; insulin sensitivity
    DOI:  https://doi.org/10.20945/2359-3997000000313
  63. J Exp Med. 2021 Mar 01. pii: e20201416. [Epub ahead of print]218(3):
    He F, Huang Y, Song Z, Zhou HJ, Zhang H, Perry RJ, Shulman GI, Min W.
      White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Mice with adipose-specific deletion of mitochondrial redox Trx2 develop hyperglycemia, hepatic insulin resistance, and hepatic steatosis. Trx2-deficient WAT exhibited excessive mitophagy, increased inflammation, and lipolysis. Mechanistically, mitophagy was induced through increasing ROS generation and NF-κB-dependent accumulation of autophagy receptor p62/SQSTM1, which recruits damaged mitochondria with polyubiquitin chains. Importantly, administration of ROS scavenger or NF-κB inhibitor ameliorates glucose and lipid metabolic disorders and T2DM progression in mice. Taken together, this study reveals a previously unrecognized mechanism linking mitophagy-mediated adipose inflammation to T2DM with hepatic insulin resistance.
    DOI:  https://doi.org/10.1084/jem.20201416
  64. BMC Pediatr. 2020 Dec 14. 20(1): 557
    Hollowood-Jones K, Adams JB, Coleman DM, Ramamoorthy S, Melnyk S, James SJ, Woodruff BK, Pollard EL, Snozek CL, Kruger U, Chuah J, Hahn J.
      BACKGROUND: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.METHODS: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.
    RESULTS: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules. Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.
    CONCLUSIONS: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.
    Keywords:  Autism; Fisher discriminant analysis; Logistic regression; Metabolic profile; Metabolomics; Mothers
    DOI:  https://doi.org/10.1186/s12887-020-02437-7
  65. Chemosphere. 2020 Dec 11. pii: S0045-6535(20)33464-0. [Epub ahead of print]267 129267
    Chiang SS, Chen LS, Chu CY.
      Hypertension is one of the most common illnesses worldwide. Accurate control of blood pressure can help reduce the incidence of complications. Nω-nitro-l-arginine methyl ester (l-NAME) is a nitric oxide synthase inhibitor that increases oxidative stress and inflammatory responses, activating the expression of transforming growth factor-beta (TGF-β), which thickens the vessel wall and ultimately contributes to hypertension. Studies have shown that seeds of Camellia oleifera Abel and Camellia sinensis (L). O. Kuntze (Oolong tea) possesses antibacterial, antioxidant, and anti-inflammatory functions. Therefore, this study aimed was to investigate the functional components in the seed pomace ethanol extracts of C. oleifera Abel (CPE) and Oolong tea (OPE) and to evaluate the ameliorative effects of CPE and OPE on oxidative stress, inflammation, and vascular remodeling in l-NAME induced hypertensive C57BL/6J mice. After 8 weeks of treatment, all CPE and OPE dose groups significantly reduced systolic and diastolic blood pressure, by over 30 mmHg and 15 mmHg, respectively. Additionally, CPE and OPE decreased transforming growth factor-beta (TGF-β) expression in the thoracic aortic and thoracic aortic intima-media thickness. Moreover, CPE and OPE decreased the malondialdehyde concentration in the liver by over 33%, as well as levels of tumor necrosis factor-α, interleukin 6, and interleukin-1β in the kidney and heart. Collectively, CPE and OPE can reduce oxidative stress and vascular remodeling, lowering blood pressure, and reducing the risk of cardiovascular disease.
    Keywords:  Camellia oleifera Abel; Camellia sinensis (L). O. kuntze (oolong tea); Hypertension; Nω-nitro-l-arginine methyl Ester; Tea seed pomace
    DOI:  https://doi.org/10.1016/j.chemosphere.2020.129267
  66. Front Physiol. 2020 ;11 518876
    Ding YJ, Li GY, Xu CD, Wu Y, Zhou ZS, Wang SG, Li C.
      Glucose metabolism is a biologically important metabolic process. Glycogen synthase kinase (GSK-3) is a key enzyme located in the middle of the sugar metabolism pathway that can regulate the energy metabolism process in the body through insulin signaling. This paper mainly explores the regulatory effect of glycogen synthase kinase on the metabolism of glycogen and trehalose in the brown planthopper (Nilaparvata lugens) by RNA interference. In this paper, microinjection of the target double-stranded GSK-3 (dsGSK-3) effectively inhibited the expression of target genes in N. lugens. GSK-3 gene silencing can effectively inhibit the expression of target genes (glycogen phosphorylase gene, glycogen synthase gene, trehalose-6-phosphate synthase 1 gene, and trehalose-6-phosphate synthase 2 gene) in N. lugens and trehalase activity, thereby reducing glycogen and glucose content, increasing trehalose content, and regulating insect trehalose balance. GSK-3 can regulate the genes chitin synthase gene and glucose-6-phosphate isomerase gene involved in the chitin biosynthetic pathway of N. lugens. GSK-3 gene silencing can inhibit the synthesis of chitin N. lugens, resulting in abnormal phenotypes and increased mortality. These results indicated that a low expression of GSK-3 in N. lugens can regulate the metabolism of glycogen and trehalose through the insulin signal pathway and energy metabolism pathway, and can regulate the biosynthesis of chitin, which affects molting and wing formation. The relevant research results will help us to more comprehensively explore the molecular mechanism of the regulation of energy and chitin metabolism of insect glycogen synthase kinases in species such as N. lugens.
    Keywords:  Nilaparvata lugens; RNA interference; chitin metabolism; glycogen and trehalose metabolism; glycogen synthase kinase 3
    DOI:  https://doi.org/10.3389/fphys.2020.518876
  67. Med Res Rev. 2020 Dec 13.
    Vaiserman A, Koliada A, Lushchak O, Castillo MJ.
      The steady rise in life expectancy occurred across all developed countries during the last century. This demographic trend is, however, not accompanied by the same healthspan extension. This is since aging is the main risk factor for all age-associated pathological conditions. Therefore, slowing the rate of aging is suggested to be more efficient in preventing or delaying age-related diseases than treat them one by one, which is the common approach in a current pharmacological disease-oriented paradigm. To date, a variety of medications designed to treat particular pathological conditions have been shown to exhibit pro-longevity effects in different experimental models. Among them, there are many commonly used prescription and over-the-counter pharmaceuticals such as metformin, rapamycin, aspirin, statins, melatonin, vitamin antioxidants, etc. All of them are being increasingly investigated in preclinical and clinical trials with the aim of determine whether they have potential for extension of human healthspan. The results from these trials are frequently inconclusive and fall short of initial expectations, suggesting that innovative research ideas and additional translational steps are required to overcome obstacles for implementation of such approaches in clinical practice. In this review, recent advances and challenges in the field of repurposing widely used conventional pharmaceuticals to target the aging process are summarized and discussed.
    Keywords:  Antiaging pharmacology; Drug repurposing; Geroscience; Healthspan; Life extension
    DOI:  https://doi.org/10.1002/med.21773
  68. Glob Health Med. 2020 Feb 29. 2(1): 39-43
    Mizushima D, Dung NTH, Dung NT, Matsumoto S, Tanuma J, Gatanaga H, Trung NV, Kinh NV, Oka S.
      With expanding antiretroviral therapy (ART) in Vietnam, the use of second-line ART with ritonavir-boosted lopinavir (LPV/r) is increasing. However, little is known regarding the effect of LPV/r on dyslipidemia (DL) and cardiovascular disease (CVD) in people with HIV in Vietnam. A cross-sectional study was performed in a cohort of HIV-infected Vietnamese patients on ART at the National Hospital for Tropical Diseases in Hanoi, Vietnam. In addition to DL, we included hypertension (HT) and hyperglycemia (HG) as non-communicable diseases. Blood pressure, casual blood sugar levels, and the lipid profile were evaluated cross-sectionally in October and November 2016. The incidence of CVD was calculated in the cohort. We determined factors associated with diseases by univariate and multivariate analyses. A total of 1,346 subjects were evaluated for their non-communicable diseases. The subjects' mean age was 39.2 years and 41.8% were women. A total of 10.5% of the subjects had exposure to LPV/r. DL, HT, and HG was diagnosed in 53.5%, 24.4%, and 0.8% of the subjects, respectively. In multivariate analysis, age (OR = 1.040; 95% CI, 1.025-1.055), female sex (OR = 0.335; 95% CI, 0.264-0.424), and LPV/r exposure (OR = 3.251; 95% CI, 2.030-5.207) were significantly associated with DL. The incidence rate of CVD was 1.87/1,000 person-years (15 incidental cases in 8,013 person-years). LPV/r exposure was not a risk factor for the incidence of CVD. Although a causative relation with LPV/r and CVD was not identified in this study, attention should be paid to CVD for patients on LPV/r in the future.
    Keywords:  Vietnamese; cardiovascular disease; dyslipidemia; human immunodeficiency virus; lopinavir-boosted ritonavir
    DOI:  https://doi.org/10.35772/ghm.2019.01035
  69. Food Sci Nutr. 2020 Dec;8(12): 6633-6642
    Cho I, Song HO, Cho JH.
      Dietary supplementation of flavonoids has been shown to reduce the severity of neurodegenerative disorders such as dementia, Parkinson's disease, and Alzheimer's disease by their antioxidant effects. However, their low bioavailabilityin vivo raises the question of how much their antioxidant capacity actually contributes to the mitigating effects. The physicochemical properties of flavonoids suggest they could function as mitochondrial uncouplers. Moreover, mitochondrial uncoupling alleviated neurodegeneration in Caenorhabditis elegans during aging in previous research. Therefore, we investigated whether various flavonoids (fisetin, quercetin, apigenin, chrysin, catechin, and naringenin) could reduce neuronal defects by mitochondrial uncoupling in C. elegans. Both neuronal defects and mitochondrial membrane potential were reduced in aged worms in nearly all of the flavonoid treatments suggesting that flavonoids may reduce neurodegeneration in C. elegans. However, there was no significant reduction of neuronal defects in mitophagy-deficient pink-1/pdr-1 double mutants under flavonoid treatments. These results suggest that flavonoids could function as mitochondrial uncouplers to mitigate neurodegeneration in aged C. elegans, possibly via a PINK1/Parkin mitophagy process.
    Keywords:  C. elegans; flavonoids; mitochondrial uncoupling; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1002/fsn3.1956
  70. PLoS Biol. 2020 Dec 14. 18(12): e3001003
    Ladyzhets S, Antel M, Simao T, Gasek N, Cowan AE, Inaba M.
      Stem-cell niche signaling is short-range in nature, such that only stem cells but not their differentiating progeny receive self-renewing signals. At the apical tip of the Drosophila testis, 8 to 10 germline stem cells (GSCs) surround the hub, a cluster of somatic cells that organize the stem-cell niche. We have previously shown that GSCs form microtubule-based nanotubes (MT-nanotubes) that project into the hub cells, serving as the platform for niche signal reception; this spatial arrangement ensures the reception of the niche signal specifically by stem cells but not by differentiating cells. The receptor Thickveins (Tkv) is expressed by GSCs and localizes to the surface of MT-nanotubes, where it receives the hub-derived ligand Decapentaplegic (Dpp). The fate of Tkv receptor after engaging in signaling on the MT-nanotubes has been unclear. Here we demonstrate that the Tkv receptor is internalized into hub cells from the MT-nanotube surface and subsequently degraded in the hub cell lysosomes. Perturbation of MT-nanotube formation and Tkv internalization from MT-nanotubes into hub cells both resulted in an overabundance of Tkv protein in GSCs and hyperactivation of a downstream signal, suggesting that the MT-nanotubes also serve a second purpose to dampen the niche signaling. Together, our results demonstrate that MT-nanotubes play dual roles to ensure the short-range nature of niche signaling by (1) providing an exclusive interface for the niche ligand-receptor interaction; and (2) limiting the amount of stem cell receptors available for niche signal reception.
    DOI:  https://doi.org/10.1371/journal.pbio.3001003
  71. Gerontologist. 2020 Dec 16. pii: gnaa207. [Epub ahead of print]
    Lee KH, Lee JY, Kim B.
      BACKGROUND AND OBJECTIVES: The concept of person-centered care has been utilized/adapted to various interventions to enhance health-related outcomes and ensure the quality of care delivered to persons living with dementia. A few systematic reviews have been conducted on the use of person-centered interventions in the context of dementia care, but to date, none have analyzed intervention effect by intervention type and target outcome. This study aimed to review person-centered interventions used in the context of dementia care and examine their effectiveness.RESEARCH DESIGN AND METHODS: A systematic review and meta-analysis were conducted. We searched through five databases for randomized controlled trials that utilized person-centered interventions in persons living with dementia from 1998 to 2019. Study quality was assessed using the National Institute for Health and Clinical Excellence. The outcomes of interest for the meta-analysis were behavioral and psychological symptoms in dementia (BPSD) and cognitive function assessed immediately after the baseline measurement.
    RESULTS: In total, 36 studies were systematically reviewed. Intervention types were: reminiscence, music, and cognitive therapies, and multisensory stimulation. Thirty studies were included in the meta-analysis. Results showed a moderate effect size for overall intervention, a small one for music therapy, and a moderate one for reminiscence therapy on BPSD and cognitive function.
    DISCUSSION AND IMPLICATIONS: Generally speaking, person-centered interventions showed immediate intervention effects on reducing BPSD and improving cognitive function, although the effect size and significance of each outcome differed by intervention type. Thus, healthcare providers should consider person-centered interventions as a vital element in dementia care.
    Keywords:  Behavioral and psychological symptoms in dementia; Cognitive function; Reminiscence therapy
    DOI:  https://doi.org/10.1093/geront/gnaa207
  72. Trends Cardiovasc Med. 2020 Dec 15. pii: S1050-1738(20)30157-2. [Epub ahead of print]
    Ali MAM, Spinler SA.
      Coronavirus disease of 2019 (COVID-19) is the respiratory viral infection caused by the coronavirus SARS-CoV2 (Severe Acute Respiratory Syndrome Coronavirus 2). Despite being a respiratory illness, COVID-19 is found to increase the risk of venous and arterial thromboembolic events. Indeed, the link between COVID-19 and thrombosis is attracting attention from the broad scientific community. In this review we will analyze the current available knowledge of the association between COVID-19 and thrombosis. We will highlight mechanisms at both molecular and cellular levels that may explain this association. In addition, the article will review the antithrombotic properties of agents currently utilized or being studied in COVID-19 management. Finally, we will discuss current professional association guidance on prevention and treatment of thromboembolism associated with COVID-19.
    DOI:  https://doi.org/10.1016/j.tcm.2020.12.004
  73. J Prev Alzheimers Dis. 2021 ;8(1): 110-116
    Buckinx F, Aubertin-Leheudre M.
      Aging is associated with cognitive declines leading to mild cognitive impairments or Alzheimer disease. Nutrition appear to protect from aging. Some dietary factors could either increase or protect against cognitive declines. This article aimed to provide GRADE recommendations related to nutrition aspects able to prevent or to treat cognitive impairments. A comprehensive literature review was performed using Medline database. The GRADE approach was used to classify quality of the existing evidence (systematic review or meta-analysis).The GRADE process led us to formulate seven key nutritional recommendations to manage cognitive declines, but did not allow us to do it for protein, vitamin B or antioxidants. Thus, 1) adherence to a Mediterranean diet (GRADE 1B); 2) high-level of consumption of mono- or poly- unsaturated fatty acids combined to a low consumption of saturated fatty acids (GRADE 1B); 3) high consumption of fruits and vegetables (GRADE 1B); 4) higher vitamin D intake (GRADE 1C) than the recommended daily allowance. In addition, a ketogenic diet, a low consumption of whole-fat dairy products or a caloric restriction are promising nutritional habits although the evidence does not yet support widespread uptake (GRADE 2C). In conclusion, nutrition is an important modifiable factor to prevent or protect against cognitive decline. Nevertheless, more studies are required to determine specific guidelines such as duration and amounts of nutrients to help older adult to maintain a healthy cognitive life.
    Keywords:  GRADE process; aging; cognitive impairment; diet guidelines
    DOI:  https://doi.org/10.14283/jpad.2020.40
  74. Medicine (Baltimore). 2020 Dec 11. 99(50): e23730
    Huang L, Wang J, Xu R, Liu Y, Liu Z.
      BACKGROUND: Atherosclerosis is the pathological basis of many cardiovascular and cerebrovascular diseases, and its pathogenesis is complex. Recent studies revealed a significant role of gut microbiota in the onset and development of atherosclerosis. Traditional Chinese medicine has rich clinical experience and unique advantages in the treatment of atherosclerosis. A large number of studies have proved that traditional Chinese medicine has the functions of reducing blood lipid, regulating gut microbiota, and resisting inflammation. The aim of this systematic review is to observe the randomized controlled trial of traditional Chinese medicine in treating gut microbiota, so as to evaluate the effectiveness and safety of traditional Chinese medicine in treating atherosclerosis patients.METHODS: The English database (PubMed, Web of Science, Embase, the Cochrane Library) and Chinese database (China National Knowledge Infrastructure, the Chongqing VIP Chinese Science, and Technology Periodic Database, Wanfang Database, and China Biomedical Literature Database) will be searched up to October 2020. We will also manually search the Chinese clinical trial register, conference papers, and unpublished studies or references. Randomized control trials of traditional Chinese medicine treatment of atherosclerosis were collected comprehensively, and 2 researchers will independently screen literature, data extraction, and evaluation the quality of literature methodology. The primary outcomes are lipid metabolism and gut microbiota and their metabolites. The secondary outcomes are the change of inflammatory markers. Meta-analysis was performed by RevMan 5.3.5 software. The Grades of Recommendation, Assessment, Development, and Evaluation will be used to evaluate the outcome quality of evidence.
    RESULTS: This study will comprehensively review the existing evidence of traditional Chinese medicine in treating atherosclerosis from the perspective of gut microbiota.
    CONCLUSION: This study will provide information on the effectiveness and safety of traditional Chinese medicine in treating atherosclerosis from the perspective of gut microbiota.
    UNIQUE INPLASY NUMBER: INPLASY2020110056.
    DOI:  https://doi.org/10.1097/MD.0000000000023730
  75. Life Sci. 2020 Dec 14. pii: S0024-3205(20)31672-6. [Epub ahead of print] 118913
    Famurewa AC, Edeogu CO, Offor FI, Besong EE, Akunna GG, Maduagwuna EK.
      AIM: Cyclophosphamide (CYP) chemotherapy induces bladder toxicity and hemorrhagic cystitis in cancer patients constituting a current clinical concern. Oxidative inflammatory cascades have been implicated as the mechanism contributing to CYP bladder urotoxicity. We thus assayed to explore whether zinc (Zn) supplementation could mitigate CYP-induced urotoxicity and evaluate the possible underlying mechanism in rats.MAIN METHOD: Rats were orally administered Zn (100 mg/kg b.w./day) for 10 days against urotoxicity induced by single injection of CYP (150 mg/kg b.w., ip) on day 7.
    KEY FINDINGS: CYP significantly depressed bladder activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH) levels, whereas malondialdehyde level was increased prominently. In addition, CYP induced marked increases in the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by histological alterations. CYP prominently increased bladder inducible nitric oxide synthase (iNOS) activity, nuclear factor-kappa B (NF-ĸB) and expression of caspase-3 protein. Zinc supplementation considerably abrogated the bladder urotoxicity by restoring redox balance, proinflammatory and apoptotic cascades and alleviated histopathological changes.
    SIGNIFICANCE: This is the first to reveal zinc potential to prevent CYP-induced urotoxic hemorrhagic cystitis via restoring redox balance and enhancing anti-inflammatory and antiapoptotic mechanisms in rat bladder.
    Keywords:  Apoptosis; Cyclophosphamide; Inflammation; Oxidative stress; Urotoxicity
    DOI:  https://doi.org/10.1016/j.lfs.2020.118913
  76. Am J Med. 2020 Dec 09. pii: S0002-9343(20)31092-5. [Epub ahead of print]
    Krittanawong C, Isath A, Hahn J, Wang Z, Fogg SE, Bandyopadhyay D, Jneid H, Virani SS, Wilson Tang WH.
      INTRODUCTION: Edible mushrooms have a great nutritional value including high protein, essential amino acids, fiber, vitamins (B1, B2, B12, C and D), minerals (Ca, K, Mg, Na, P, Cu, Fe, Mn and Se), low fatty foods and sodium. The objective of this systematic review was to determine the relationship between edible mushroom consumption and overall cardiovascular risk.METHODS: We systematically searched Ovid MEDLINE, Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from database inception from 1966 through August 2020 for observational studies that reported the association between edible mushroom consumption and cardiovascular risk. Two investigators independently reviewed data. Conflicts were resolved through consensus.
    RESULTS: Of 1479 studies, we identified 7 prospective studies. Edible mushroom consumption may have favorable effects on lipid profiles by changing some metabolic markers such as LDL cholesterol, HDL cholesterol, total cholesterol and triglycerides. Moreover, edible mushroom consumption is probably associated with reduced mean blood pressure. The beneficial overall cardiovascular risk, stroke risk, coronary artery disease of edible mushroom consumption is not consistent.
    CONCLUSIONS: Edible mushroom consumption has not been shown to conclusively affect cardiovascular risk factors to date. However, potential health benefits may exist including a favorable alteration of lipid profiles and blood pressure reduction.
    Keywords:  Acute myocardial infarction; Cardiovascular disease; Mushroom consumption; Stroke; Systematic review
    DOI:  https://doi.org/10.1016/j.amjmed.2020.10.035
  77. Compr Rev Food Sci Food Saf. 2019 May;18(3): 817-831
    Tanna B, Mishra A.
      In recent years, marine organisms including seaweeds have been highlighted as potential sources of useful metabolites and bioactive compounds, with vast biological and physiological activities. Seaweeds have long been used as a food source, for medicinal purposes, and as dietary supplements in various Asian countries, and their potential benefits have recently attracted the attention of many Western and European countries. Their commercial value depends on their applications in the food, nutraceutical, and pharmaceutical industries. Seaweeds are considered a potential source of nutraceuticals or functional foods, and analysis of taste-oriented motives has revealed that seaweeds are preferentially selected over other types of marine foods by seafood consumers and people with high levels of health, education, and living status. It is a general perception that health conscious people prefer environmentally friendly food sources, and present an opportunity to focus on seaweed-based foods, which have significant nutritional benefits to humans. Among the various bioactive constituents, seaweed polysaccharides have been proven to possess various beneficial properties including anticoagulant, anti-inflammatory, antioxidant, anticarcinogenic, and antiviral activities. The diversity and composition of seaweed polysaccharides play vital roles in these biological activities. Seaweeds are a rich source of sulfated polysaccharides, which are responsible for much of the bioactivity, as they can interact with various textures and cellular proteins. A number of toxicological assays and clinical trials suggest that the ingestion of seaweeds as functional foods should be considered worldwide to improve immune responses. In this review, different polysaccharides from seaweeds and their compositions and potential nutraceutical applications are discussed.
    Keywords:  bioactivity; functional food; marine algae; nutraceuticals; sulfated polysaccharides
    DOI:  https://doi.org/10.1111/1541-4337.12441
  78. Disaster Med Public Health Prep. 2020 Aug;14(4): 427-428
    Morse SS.
      
    DOI:  https://doi.org/10.1017/dmp.2020.407
  79. J Clin Oncol. 2020 Dec 16. JCO2001576
    Crabb SJ, Griffiths G, Marwood E, Dunkley D, Downs N, Martin K, Light M, Northey J, Wilding S, Whitehead A, Shaw E, Birtle AJ, Bahl A, Elliott T, Westbury C, Sundar S, Robinson A, Jagdev S, Kumar S, Rooney C, Salinas-Souza C, Stephens C, Khoo V, Jones RJ.
      PURPOSE: Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel.PATIENTS AND METHODS: ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status.
    RESULTS: One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash.
    CONCLUSION: The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.
    DOI:  https://doi.org/10.1200/JCO.20.01576
  80. Compr Rev Food Sci Food Saf. 2019 Jul;18(4): 1070-1096
    Saleh ASM, Wang P, Wang N, Yang L, Xiao Z.
      Obesity and chronic diet-related diseases such as type 2 diabetes, hypertension, cardiovascular disease, cancers, and celiac are increasing worldwide. The increasing prevalence of these diseases has led nutritionists and food scientists to pay more attention to the relationship between diet and different disease risks. Among different foods, rice has received increasing attention because it is a major component of billions of peoples' diets throughout the world. Rice is commonly consumed after polishing or whitening and the polished grain is known a high glycemic food because of its high starch content. In addition, the removal of the outer bran layer during rice milling results in a loss of nutrients, dietary fiber, and bioactive components. Therefore, many studies were performed to investigate the potential health benefits for the consumption of whole brown rice (BR) grain in comparison to the milled or white rice (WR). The objective of this work was to review the recent advances in research performed for purposes of evaluation of nutritional value and potential health benefits of the whole BR grain. Studies carried out for purposes of developing BR-based food products are reviewed. BR safety and preservation treatments are also explored. In addition, economic and environmental benefits for the consumption of whole BR instead of the polished or WR are presented. Furthermore, challenges facing the commercialization of BR and future perspectives to promote its utilization as food are discussed.
    Keywords:  brown rice; chronic diseases; dietary fiber; health benefits; nutritional quality; white rice
    DOI:  https://doi.org/10.1111/1541-4337.12449
  81. Cancer Lett. 2020 Dec 09. pii: S0304-3835(20)30664-9. [Epub ahead of print]
    Mavingire N, Campbell P, Wooten J, Aja J, Davis MB, Loaiza-Perez A, Brantley E.
      Breast cancer stem cells (BCSCs) promote endocrine therapy (ET) resistance, also known as endocrine resistance in hormone receptor (HR) positive breast cancer. Endocrine resistance occurs via mechanisms that are not yet fully understood. In vitro, in vivo and clinical data suggest that signaling cascades such as Notch, hypoxia inducible factor (HIF), and integrin/Akt promote BCSC-mediated endocrine resistance. Once HR positive breast cancer patients relapse on ET, targeted therapy agents such as cyclin dependent kinase inhibitors are frequently implemented, though secondary resistance remains a threat. Here, we discuss Notch, HIF, and integrin/Akt pathway regulation of BCSC activity and potential strategies to target these pathways to counteract endocrine resistance. We also discuss a plausible link between elevated BCSC-regulatory gene levels and reduced survival observed among African American women with basal-like breast cancer which lacks HR expression. Should future studies reveal a similar link for patients with luminal breast cancer, then the use of agents that impede BCSC activity could prove highly effective in improving clinical outcomes among African American breast cancer patients.
    Keywords:  Breast cancer; Disparities; Endocrine resistance; Endocrine therapy; Stem cells
    DOI:  https://doi.org/10.1016/j.canlet.2020.12.014
  82. Exp Mol Med. 2020 Dec 14.
    Perillo B, Tramontano A, Pezone A, Migliaccio A.
      Lysine-specific histone demethylase 1 (LSD1) represents the first example of an identified nuclear protein with histone demethylase activity. In particular, it plays a special role in the epigenetic regulation of gene expression, as it removes methyl groups from mono- and dimethylated lysine 4 and/or lysine 9 on histone H3 (H3K4me1/2 and H3K9me1/2), behaving as a repressor or activator of gene expression, respectively. Moreover, it has been recently found to demethylate monomethylated and dimethylated lysine 20 in histone H4 and to contribute to the balance of several other methylated lysine residues in histone H3 (i.e., H3K27, H3K36, and H3K79). Furthermore, in recent years, a plethora of nonhistone proteins have been detected as targets of LSD1 activity, suggesting that this demethylase is a fundamental player in the regulation of multiple pathways triggered in several cellular processes, including cancer progression. In this review, we analyze the molecular mechanism by which LSD1 displays its dual effect on gene expression (related to the specific lysine target), placing final emphasis on the use of pharmacological inhibitors of its activity in future clinical studies to fight cancer.
    DOI:  https://doi.org/10.1038/s12276-020-00542-2
  83. J Frailty Aging. 2021 ;10(1): 70-71
    Tosato M, Varone F, Ciccullo A, Calvani R, Moschese D, Potenza A, Siciliano M, Fantoni M.
      COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, showed higher severity and lethality in male older adults . There are currently no specific treatments. Studies are evaluating the efficacy of monoclonal antibodies against interleukin-6 receptor. Here we present the case of a 98-years old man admitted to our COVID-Hospital with acute respiratory failure. Comprehensive geriatric assessment showed no signs of frailty. First-line therapy with hydroxychloroquine and anticoagulants was not effective. Patient was administered intravenous monoclonal antibodies, and he showed remarkable clinical improvement. This case suggests that age alone should not preclude access to new therapeutic approaches. Comprehensive, multisciplinary, multidomain approaches are needed to develop patient-tailored treatments against COVID-19.
    Keywords:  Frailty; aging; comprehensive geriatric assesment; covid-19
    DOI:  https://doi.org/10.14283/jfa.2020.41
  84. World J Hepatol. 2020 Nov 27. 12(11): 883-896
    Chapman B, Sinclair M, Gow PJ, Testro AG.
      Malnutrition is highly prevalent in liver cirrhosis and its presence carries important prognostic implications. The clinical conditions and pathophysiological mechanisms that cause malnutrition in cirrhosis are multiple and interrelated. Anorexia and liver decompensation symptoms lead to poor dietary intake; metabolic changes characterised by elevated energy expenditure, reduced glycogen storage, an accelerated starvation response and protein catabolism result in muscle and fat wasting; and, malabsorption renders the cirrhotic patient unable to fully absorb or utilise food that has been consumed. Malnutrition is therefore a considerable challenge to manage effectively, particularly as liver disease progresses. A high energy, high protein diet is recognised as standard of care, yet patients struggle to follow this recommendation and there is limited evidence to guide malnutrition interventions in cirrhosis and liver transplantation. In this review, we seek to detail the factors which contribute to poor nutritional status in liver disease, and highlight complexities far greater than "poor appetite" or "reduced oral intake" leading to malnutrition. We also discuss management strategies to optimise nutritional status in this patient group, which target the inter-related mechanisms unique to advanced liver disease. Finally, future research requirements are suggested, to develop effective treatments for one of the most common and debilitating complications afflicting cirrhotic patients.
    Keywords:  Chronic liver disease; Cirrhosis; Liver transplantation; Malnutrition; Nutrition; Sarcopenia
    DOI:  https://doi.org/10.4254/wjh.v12.i11.883
  85. Int J Mol Sci. 2020 Dec 14. pii: E9505. [Epub ahead of print]21(24):
    Behl T, Kaur I, Sehgal A, Zengin G, Brisc C, Brisc MC, Munteanu MA, Nistor-Cseppento DC, Bungau S.
      While the most common manifestations associated with rheumatoid arthritis (RA) are synovial damage and inflammation, the systemic effects of this autoimmune disorder are life-threatening, and are prevalent in 0.5-1% of the population, mainly associated with cardiovascular disorders (CVDs). Such effects have been instigated by an altered lipid profile in RA patients, which has been reported to correlate with CV risks. Altered lipid paradox is related to inflammatory burden in RA patients. The review highlights general lipid pathways (exogenous and endogenous), along with the changes in different forms of lipids and lipoproteins in RA conditions, which further contribute to elevated risks of CVDs like ischemic heart disease, atherosclerosis, myocardial infarction etc. The authors provide a deep insight on altered levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) in RA patients and their consequence on the cardiovascular health of the patient. This is followed by a detailed description of the impact of anti-rheumatoid therapy on the lipid profile in RA patients, comprising DMARDs, corticosteroids, anti-TNF agents, anti-IL-6 agents, JAK inhibitors and statins. Furthermore, this review elaborates on the prospects to be considered to optimize future investigation on management of RA and treatment therapies targeting altered lipid paradigms in patients.
    Keywords:  DMARDs; HDL-C; LDL-C; atherosclerosis; cardiovascular disorders; inflammatory burden; lipid paradox; lipoproteins; rheumatoid arthritis
    DOI:  https://doi.org/10.3390/ijms21249505
  86. Front Pharmacol. 2020 ;11 504624
    Tan JN, Mohd Saffian S, Buang F, Jubri Z, Jantan I, Husain K, Mohd Fauzi N.
      Background: Gynura species have been used traditionally to treat various ailments, such as fever, pain, and to control blood glucose level. This systematic review critically discusses studies regarding Gynura species that exhibited antioxidant and anti-inflammatory effects, thus providing perspectives and instructions for future research of the plants as a potential source of new dietary supplements or medicinal agents. Methods: A literature search from internet databases of PubMed, Scopus, Science Direct, e-theses Online Service, and ProQuest was carried out using a combination of keywords such as "Gynura," "antioxidant," "anti-inflammatory," or other related words. Research articles were included in this study if they were experimental (in vitro and in vivo) or clinical studies on the antioxidant or anti-inflammatory effects of Gynura species and if they were articles published in English. Results: Altogether, 27 studies on antioxidant and anti-inflammatory effects of Gynura species were selected. The antioxidant effects of Gynura species were manifested by inhibition of reactive oxygen species production and lipid peroxidation, modulation of glutathione-related parameters, and enzymatic antioxidant production or activities. The anti-inflammatory effects of Gynura species were through the modulation of inflammatory cytokine production, inhibition of prostaglandin E2 and nitric oxide production, cellular inflammatory-related parameters, and inflammation in animal models. The potential anti-inflammatory signaling pathways modulated by Gynura species are glycogen synthase kinase-3, nuclear factor erythroid 2-related factor 2, PPARγ, MAPK, NF-κB, and PI3K/Akt. However, most reports on antioxidant and anti-inflammatory effects of the plants were on crude extracts, and the chemical constituents contributing to bioactivities were not clearly understood. There is a variation in quality of studies in terms of design, conduct, and interpretation, and in-depth studies on the underlying mechanisms involved in antioxidant and anti-inflammatory effects of the plants are in demand. Moreover, there is limited clinical study on antioxidant and anti-inflammatory effects of Gynura species. Conclusion: This review highlighted antioxidant and anti-inflammatory effects of genus Gynura and supported their traditional uses to treat oxidative stress and inflammatory-related diseases. This review is expected to catalyze further studies on genus Gynura. However, extensive preclinical data need to be generated from toxicity and pharmacokinetic studies before clinical studies can be pursued for their development into clinical medicines to treat oxidative stress and inflammatory conditions.
    Keywords:  Gynura; anti-inflammatory; antioxidant; medicinal; plant; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphar.2020.504624
  87. Compr Rev Food Sci Food Saf. 2019 Jul;18(4): 910-922
    Lenssen KGM, Bast A, de Boer A.
      The efficacy of botanicals in medicines can be substantiated with evidence on traditional use, whereas in foodstuffs, this is often not possible. In Europe, for example, the evaluation and subsequent authorization of health claims on herbal dietary supplements (HDS) have been put on hold by the European Commission. This study aims to analyze the role of evidence on traditional use in international legal frameworks of foods and pharmaceuticals. Both legal sources as well as scientific studies offering insights into these regulatory frameworks were included into the analysis. The international approach toward evidence on traditional use for substantiating efficacy of botanicals varies highly. For herbal medicines, substantiating efficacy with evidence on traditional use is possible in all studied jurisdictions, except for Japan and the United States. HDS efficacy can only be substantiated with evidence on traditional use in India and New Zealand, although the enforcing authorities do not describe which data are required. Australia and Canada regulate botanicals in a separate "borderline" category from foods and pharmaceuticals. Both jurisdictions allow for substantiating efficacy with evidence on traditional use. This study's second objective was to assess the applicability of the international approaches in the European legal framework, in light of the ongoing political debate regarding the use of traditional evidence. Implementation of the analyzed international approaches would require major revisions of the current European legal framework. This review of international approaches might, however, aid in deciding upon future approaches for substantiating health claims with evidence on traditional use.
    Keywords:  EFSA; botanicals; food; nutrition and health claims regulation; pharmaceuticals; risk assessment; traditional use
    DOI:  https://doi.org/10.1111/1541-4337.12446
  88. Rev Med Interne. 2020 Dec 08. pii: S0248-8663(20)30787-6. [Epub ahead of print]
    Yelnik CM, Bruckert É.
      Hypercholesterolemia refers to dyslipidemia with an increased circulating cholesterol levels. This is the most common dyslipidemia and is associated with an increased risk of developing atheromatous cardiovascular diseases. One of the major challenges in primary prevention is to define the threshold for therapeutic intervention that allow to obtain a significant clinical benefit without unnecessarily expose the patient to potential side effects of lipid-lowering treatments. It is also important to recall to screen patient for heterozygous familial hypercholesterolemia, a common genetic disease of lipid metabolism responsible for particularly severe and early coronary disease. In this article, the issues of hypercholesterolemia screening, the definition of therapeutic targets and expected benefits as well as the modalities of therapeutic management (by also addressing the problem of statin intolerance) will be addressed.
    Keywords:  Cardiovascular disease; Dyslipidemia; Dyslipidémie; Hypercholesterolemia; Hypercholestérolémie; Maladie cardiovasculaire; Prevention; Prévention; Statines; Statins
    DOI:  https://doi.org/10.1016/j.revmed.2020.11.007
  89. Acta Biochim Pol. 2020 Dec 17.
    Gramatyka M, Widłak P, Gabryś D, Kulik R, Sokół M.
      We aimed to evaluate whether resveratrol affects radiation-induced changes in metabolite profiles of the mouse heart. Hearts were irradiated in vivo with a single 2 Gy dose during the resveratrol administration and metabolite profiles of heart tissue were analyzed by the untargeted HR-MAS NMR approach twenty weeks after irradiation. The administration of resveratrol mitigated the radiation-induced decline in the content of choline-containing compounds and unsaturated lipids, which might reflect the stabilization of cell membrane structure against radiation-related damage. Results obtained with this mouse model suggest that the resveratrol supplementation may prevent metabolic changes related to radiation-induced damage in the heart.
    DOI:  https://doi.org/10.18388/abp.2020_5403
  90. J Biomol Struct Dyn. 2020 Dec 15. 1-13
    Salekeen R, Ahmed A, Islam ME, Billah MM, Rahman H, Islam KMD.
      A metabolic network of energy-sensing molecular pathways drives the biological ageing process. Regulating certain network elements can help decelerate the ageing process and ameliorate ageing associated disorders. Bioactive phytopeptides are a prospective avenue for anti-ageing therapeutics and rejuvenation biotechnology. The present study investigates the potential of therapeutic plant peptides against cellular senescence by targeting three key proteins in the ageing network - target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). This investigation screened a library of reported bioactive peptides using standard cheminformatic methods including in-silico ADMET, molecular docking, molecular dynamics simulation and molecular mechanics calculation. The retrieved simulation data predict 25 diverse phytopeptides as potential safe and drug-like anti-ageing biologics with half-lives >20 h and bioavailability scores >0.40. The best docked peptide, Cycloleonuripeptide B, exhibited strong binding affinity and stable complex formation with mTOR (-17.5 kCal/mol), SIRT1 (-28.54 kCal/mol) and two active sites in AMPK (-41.8 kCal/mol; -36.0 kCal/mol) during molecular dynamics simulations. The computational study acts as a foundation for future laboratory and clinical research into the potential of repurposing therapeutic phytopeptides against cellular senescence and associated pathophysiology. Communicated by Ramaswamy H. Sarma.
    Keywords:  Anti-Ageing; molecular docking; molecular dynamics; peptide therapeutics; plant peptides; rejuvenation biotechnology
    DOI:  https://doi.org/10.1080/07391102.2020.1859411
  91. Am J Chin Med. 2020 Dec 10. 1-19
    Song C, Jeong D, Hong YH, Li WY, Lee SW, Hossain MA, Taamalli A, Kim JH, Kim JH, Cho JY.
      Olea europaea is a beneficial edible plant with a number of biological activities like anti-inflammatory, anti-oxidant, antithrombic, antihyperglycemic, and anti-ischemic activities. The mechanisms behind the antiphotoaging and anti-inflammatory effects of Olea europaea are not fully understood. To investigate how an ethanol extract of Olea europaea (Oe-EE) exerts these effects, we explored its activities in human keratinocytes and dermal fibroblasts. We assessed the anti-oxidant effects of Oe-EE via 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2[Formula: see text]-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assays and measured the expression levels of matrix metalloproteinases (MMPs), cyclooxygenase-2, interleukin (IL)-6, tumor necrosis factor (TNF)-[Formula: see text], and moisturizing factors. Antiphotoaging and anti-inflammatory mechanisms of Oe-EE were explored by assessing signaling molecule activation via immunoblotting. Oe-EE treatment decreased the mRNA expression level of MMPs, cyclooxygenase-2, IL-6, and TNF-[Formula: see text] and restored type I collagen, filaggrin, and sirtuin 1 expression in UVB-irradiated cells. Furthermore, Oe-EE inhibited the activities of several activator protein 1 regulatory enzymes, including extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), and inhibited nuclear factor (NF)-[Formula: see text]B pathway signaling proteins. Therefore, our results indicate that Oe-EE has photoaging-protective and anti-inflammatory effects.
    Keywords:  AP-1; Anti-Inflammatory Effect; Antiphotoaging Effect; NF-[Formula: see text]B; Olea europaea
    DOI:  https://doi.org/10.1142/S0192415X20500950
  92. Curr Drug Metab. 2020 Dec 16.
    Hua F, Peng L, Qiang K, Zhi-Long Z, Ji W, Jia-Yi C.
      BACKGROUND: Erigeron breviscapus (Vant.) Hand-Mazz. is a plant species in the Compositae family. More than 10 types of compounds-such as flavonoids, caffeinate esters, and volatile oils-have been identified in Erigeron breviscapus; however, it remains unknown as to which compounds are associated with its clinical efficacy. In recent years, flavonoids and phenolic acids have been considered as the main effective components of Erigeron breviscapus. The metabolism and mechanisms of these compounds in vivo have been extensively studied to improve our understanding of the drug.METHODS: In the present review, we summarize the relationships among these compounds, their metabolites, and their pharmacodynamics. Many methods have been implemented to improve the separation and bioavailability of these compounds from Erigeron breviscapus.
    RESULTS: In China, Erigeron breviscapus has been used for many years. In recent years, through the study of its metabolism and the mechanisms of its effective components, the effects of Erigeron breviscapus in the treatment of various diseases have been extensively studied. Findings have indicated that Erigeron breviscapus improves cardiovascular and cerebrovascular function, and that one of its ingredients, scutellarin, has potential value in the treatment of Alzheimer's disease, cancer, diabetic vascular complications, and other conditions. In addition, phenolic acid compounds and their metabolites also play an important role in anti-oxidation, anti-inflammation, and improving blood lipids.
    CONCLUSION: Erigeron breviscapus plays an important role in the prevention and treatment of cardiovascular/cerebrovascular diseases, neuroprotection, and cancer through many different mechanisms of action. Further investigation of its efficacious components and metabolites may provide more possibilities for the clinical application of traditional Chinese medicine and the development of novel drugs.
    Keywords:  Erigeron breviscapus; flavonoids; metabolism; pharmacological mechanism; phenolic acids; scutellarin
    DOI:  https://doi.org/10.2174/1389200221666201217093255