bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–01–03
sixty-one papers selected by
Ayesh Seneviratne, University of Toronto
  1. Aging of the immune system and impaired muscle regeneration: A failure of immunomodulation of adult myogenesis.
  2. The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia.
  3. Regulation of Cholesterol Metabolism by Bioactive Components of Soy Proteins: Novel Translational Evidence.
  4. Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers.
  5. Increased demand for NAD+ relative to ATP drives aerobic glycolysis.
  6. Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types-Tumour Microenvironment and Metabolism.
  7. Сord blood hematopoietic stem cells ex vivo enhance the bipotential commitment of adipose mesenchymal stromal progenitors.
  8. Sugar-induced dysregulation of purine metabolism impacts lifespan.
  9. Mitochondrial DNA in extracellular vesicles declines with age.
  10. Mediterranean Diet Decreases the Initiation of Use of Vitamin K Epoxide Reductase Inhibitors and Their Associated Cardiovascular Risk: A Randomized Controlled Trial.
  11. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission.
  12. Inflammaging and the Skin.
  13. NAD+ metabolism and its roles in cellular processes during ageing.
  14. Dietary Ferulic Acid Supplementation Improves Antioxidant Capacity and Lipid Metabolism in Weaned Piglets.
  15. ARDD 2020: from aging mechanisms to interventions.
  16. Arterial elementary calcium signaling in aging.
  17. Age-dependent accumulation of dicarbonyls and advanced glycation endproducts (AGEs) associates with mitochondrial stress.
  18. NAD+ metabolism, stemness, the immune response, and cancer.
  19. Venetoclax/decitabine for a pediatric patient with chronic myelomonocytic leukemia.
  20. Obesity induced by high-fat diet is associated with critical changes in biological and molecular functions of mesenchymal stromal cells present in visceral adipose tissue.
  21. Blood stem cells SELect quiescence.
  22. Key Metabolic Pathways in MSC-Mediated Immunomodulation: Implications for the Prophylaxis and Treatment of Graft Versus Host Disease.
  23. Metformin-induced weight loss in patients with or without type 2 diabetes/prediabetes: A retrospective cohort study.
  24. Regulation of Autophagy by Glycolysis in Cancer.
  25. High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells.
  26. Targeted metabolomics as a tool in discriminating endocrine from primary hypertension.
  27. Diacetyl odor shortens longevity conferred by food deprivation in C. elegans via downregulation of DAF-16/FOXO.
  28. A multi-level assessment of the bidirectional relationship between aging and the circadian clock.
  29. Whole Blood Metabolomics in Aging Research.
  30. Lipid metabolism dysregulation in diabetic retinopathy.
  31. NLRP3 deficiency-induced hippocampal dysfunction and anxiety-like behavior in mice.
  32. Interferon Gamma Mediates Hematopoietic Stem Cell Activation and Niche Relocalization through BST2.
  33. Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras-Raf-MAPK signalling.
  34. Role of lactic acid bacteria in flavor development in traditional Chinese fermented foods: A review.
  35. Hepatic synthesis of triacylglycerols containing medium-chain fatty acids is dominated by diacylglycerol acyltransferase 1 and efficiently inhibited by etomoxir.
  36. Triglycerides as target of cardiovascular risk reduction.
  37. When aging meets tregs: It's all about ROS stress.
  38. The mitochondria-targeted derivative of the classical uncoupler of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone is an effective mitochondrial recoupler.
  39. Paternal metabolic and cardiovascular programming of their offspring: A systematic scoping review.
  40. Role of Dyslipidemia in Early Vascular Aging Syndrome.
  41. Gut microbiota and aging.
  42. Toll-Like Receptor 2 at the Crossroad between Cancer Cells, the Immune System, and the Microbiota.
  43. Diet and fat metabolism - uncovering key determinants of diabetes risk prediction in populations of African descent.
  44. Short Term Acyl-CoA:Cholesterol Acyltransferase Inhibition, Combined with Apoprotein A1 Over-expression, Promotes Atherosclerosis Inflammation Resolution Mice.
  45. Proinflammatory Cytokines Perturb Mouse and Human Pancreatic Islet Circadian Rhythmicity and Induce Uncoordinated β-Cell Clock Gene Expression via Nitric Oxide, Lysine Deacetylases, and Immunoproteasomal Activity.
  46. Novel drug for WHIM.
  47. Caloric Intake in Renal Patients: Repercussions on Mineral Metabolism.
  48. The effect of inflammatory factors and their inhibitors on the hematopoietic stem cells fate.
  49. Metabolism meets apoptosis in AML.
  50. Transduction of Primary AML Cells with Lentiviral Vector for In Vitro Study or In Vivo Engraftment.
  51. Implementation Science to Increase Adoption of Genomic Medicine: An Urgent Need.
  52. Metabolic regulation of the bone marrow microenvironment in leukemia.
  53. Olive leaf extract impairs mitochondria by pro-oxidant activity in MDA-MB-231 and OVCAR-3 cancer cells.
  54. A systematic review of randomized controlled trials of dietary interventions for weight loss in adults in the Middle East and north Africa region.
  55. Hats off to the CIM Reviewers of 2020.
  56. Love thy Aged? A State-Level Analysis of Religiosity and Mobility in Aging Populations During the Novel Coronavirus (COVID-19) Pandemic.
  57. Cannabinoids in the Management of Acute Pain: A Systematic Review and Meta-analysis.
  58. Targeting the Mevalonate Pathway in Cancer.
  59. Distract NK cell killing: give them a fatty meal.
  60. Insulin-Stimulated Muscle Glucose Uptake and Insulin Signaling in Lean and Obese Humans.
  61. Food Implications in Central Sensitization Syndromes.
  1. Exp Gerontol. 2020 Dec 23. pii: S0531-5565(20)30548-9. [Epub ahead of print] 111200
    Aging of the immune system and impaired muscle regeneration: A failure of immunomodulation of adult myogenesis.
    James G Tidball, Ivan Flores, Steven S Welc, Michelle Wehling-Henricks, Eisuke Ochi.
      Skeletal muscle regeneration that follows acute injury is strongly influenced by interactions with immune cells that invade and proliferate in the damaged tissue. Discoveries over the past 20 years have identified many of the key mechanisms through which myeloid cells, especially macrophages, regulate muscle regeneration. In addition, lymphoid cells that include CD8+ T-cells and regulatory T-cells also significantly affect the course of muscle regeneration. During aging, the regenerative capacity of skeletal muscle declines, which can contribute to progressive loss of muscle mass and function. Those age-related reductions in muscle regeneration are accompanied by systemic, age-related changes in the immune system, that affect many of the myeloid and lymphoid cell populations that can influence muscle regeneration. In this review, we present recent discoveries that indicate that aging of the immune system contributes to the diminished regenerative capacity of aging muscle. Intrinsic, age-related changes in immune cells modify their expression of factors that affect the function of a population of muscle stem cells, called satellite cells, that are necessary for normal muscle regeneration. For example, age-related reductions in the expression of growth differentiation factor-3 (GDF3) or CXCL10 by macrophages negatively affect adult myogenesis, by disrupting regulatory interactions between macrophages and satellite cells. Those changes contribute to a reduction in the numbers and myogenic capacity of satellite cells in old muscle, which reduces their ability to restore damaged muscle. In addition, aging produces changes in the expression of molecules that regulate the inflammatory response to injured muscle, which also contributes to age-related defects in muscle regeneration. For example, age-related increases in the production of osteopontin by macrophages disrupts the normal inflammatory response to muscle injury, resulting in regenerative defects. These nascent findings represent the beginning of a newly-developing field of investigation into mechanisms through which aging of the immune system affects muscle regeneration.
    Keywords:  Aging; Muscle inflammation; Muscle injury; Muscle regeneration; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.exger.2020.111200
  2. Int J Mol Sci. 2020 Dec 23. pii: E91. [Epub ahead of print]22(1):
    The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia.
    Vanina Romanello.
      Sarcopenia is a chronic disease characterized by the progressive loss of skeletal muscle mass, force, and function during aging. It is an emerging public problem associated with poor quality of life, disability, frailty, and high mortality. A decline in mitochondria quality control pathways constitutes a major mechanism driving aging sarcopenia, causing abnormal organelle accumulation over a lifetime. The resulting mitochondrial dysfunction in sarcopenic muscles feedbacks systemically by releasing the myomitokines fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), influencing the whole-body homeostasis and dictating healthy or unhealthy aging. This review describes the principal pathways controlling mitochondrial quality, many of which are potential therapeutic targets against muscle aging, and the connection between mitochondrial dysfunction and the myomitokines FGF21 and GDF15 in the pathogenesis of aging sarcopenia.
    Keywords:  FGF21; GDF15; fission; fusion; mitochondrial dynamics; mitokines; mitophagy; myokines; sarcopenia
    DOI:  https://doi.org/10.3390/ijms22010091
  3. Int J Mol Sci. 2020 Dec 28. pii: E227. [Epub ahead of print]22(1):
    Regulation of Cholesterol Metabolism by Bioactive Components of Soy Proteins: Novel Translational Evidence.
    Giusy Rita Caponio, David Q-H Wang, Agostino Di Ciaula, Maria De Angelis, Piero Portincasa.
      Hypercholesterolemia represents one key pathophysiological factor predisposing to increasing risk of developing cardiovascular disease worldwide. Controlling plasma cholesterol levels and other metabolic risk factors is of paramount importance to prevent the overall burden of disease emerging from cardiovascular-disease-related morbidity and mortality. Dietary cholesterol undergoes micellization and absorption in the small intestine, transport via blood, and uptake in the liver. An important amount of cholesterol originates from hepatic synthesis, and is secreted by the liver into bile together with bile acids (BA) and phospholipids, with all forming micelles and vesicles. In clinical medicine, dietary recommendations play a key role together with pharmacological interventions to counteract the adverse effects of chronic hypercholesterolemia. Bioactive compounds may also be part of initial dietary plans. Specifically, soybean contains proteins and peptides with biological activity on plasma cholesterol levels and this property makes soy proteins a functional food. Here, we discuss how soy proteins modulate lipid metabolism and reduce plasma cholesterol concentrations in humans, with potential outcomes in improving metabolic- and dyslipidemia-related conditions.
    Keywords:  cardiovascular diseases; cholesterol; health; proteins; soybean
    DOI:  https://doi.org/10.3390/ijms22010227
  4. Cancers (Basel). 2020 Dec 29. pii: E68. [Epub ahead of print]13(1):
    Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers.
    Fulvio Massaro, Florent Corrillon, Basile Stamatopoulos, Nathalie Meuleman, Laurence Lagneaux, Dominique Bron.
      Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.
    Keywords:  aging; bone marrow niche; hematologic malignancies; hematopoiesis; inflammaging; inflammation; mesenchymal stromal cells
    DOI:  https://doi.org/10.3390/cancers13010068
  5. Mol Cell. 2020 Dec 22. pii: S1097-2765(20)30904-7. [Epub ahead of print]
    Increased demand for NAD+ relative to ATP drives aerobic glycolysis.
    Alba Luengo, Zhaoqi Li, Dan Y Gui, Lucas B Sullivan, Maria Zagorulya, Brian T Do, Raphael Ferreira, Adi Naamati, Ahmed Ali, Caroline A Lewis, Craig J Thomas, Stefani Spranger, Nicholas J Matheson, Matthew G Vander Heiden.
      Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD+/NADH ratio. This change in NAD+/NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD+ to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD+ is in excess of the demand for ATP.
    Keywords:  Aerobic Glycolysis; Cell Metabolism; Fermentation; NAD+; PDK; Warburg Effect
    DOI:  https://doi.org/10.1016/j.molcel.2020.12.012
  6. Int J Mol Sci. 2020 Dec 25. pii: E141. [Epub ahead of print]22(1):
    Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types-Tumour Microenvironment and Metabolism.
    George Anderson.
      This article reviews the dynamic interactions of the tumour microenvironment, highlighting the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3β, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven 'backward' conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3β by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. The emphasis on metabolic interactions across cell types in the tumour microenvironment provides novel future research and treatment directions.
    Keywords:  acetyl-CoA; aryl hydrocarbon receptor; cancer; immune; melatonin; mitochondria; racism; treatment; tumour microenvironment
    DOI:  https://doi.org/10.3390/ijms22010141
  7. Life Sci. 2020 Dec 28. pii: S0024-3205(20)31730-6. [Epub ahead of print] 118970
    Сord blood hematopoietic stem cells ex vivo enhance the bipotential commitment of adipose mesenchymal stromal progenitors.
    L B Buravkova, M I Ezdakova, I V Andrianova, A N Gornostaeva, P I Bobyleva, E R Andreeva.
       AIMS: Stroma-dependent ex vivo expansion of hematopoietic stem progenitor cells (HSPCs) is a valid approach for cell therapy needs. Our goal was to verify whether HSPCs can affect stromal cells to optimize their functions during ex vivo expansion.
    MAIN METHODS: HSPCs from cord blood (cb) were cocultured with growth-arrested adipose mesenchymal stromal cells (MSCs). Commitment-related transcriptional and secretory profiles as well as hematopoiesis-supportive activity of intact and osteo-induced MSCs were examined.
    KEY FINDINGS: During expansion, cbHSPCs affected the functional state of MSCs, contributing to the formation of early stromal progenitors with a bipotential osteo-adipogenic profile. This was evidenced by the upregulation of certain MSC genes of osteo- and adipodifferentiation (ALPL, RUNX2, BGLAP, CEBPA, ADIPOQ), as well as by elevated alkaline phosphatase activity and altered osteoprotein patterns. Joint paracrine profiles upon coculture were characterized by a balance of "positive" (GM-SCF) and "negative" (IP-10, MIP-1α, MCP-3) myeloid regulators, effectively supporting expansion of both committed and primitive cbHSPCs. Short-term (72 h) osteoinduction prior to coculture resulted in more pronounced shift of the bipotential transcriptomic and osteoprotein profiles. The increased proportions of late primitive CD133-/CD34+cbHSPCs and unipotent CFUs suggested that cbHSPCs after expansion on osteo-MSCs were more committed versus cbHSPCs from coculture with non-differentiated MSCs.
    SIGNIFICANCE: During ex vivo expansion, cbHSPCs can drive the bipotential osteo-adipogenic commitment of MSCs, providing a specific hematopoiesis-supportive milieu. Short-term preliminary osteo-induction enhanced the development of the bipotential profile, leading to more pronounced functional polarization of cbHSPCs, which may be of interest in an applied context.
    Keywords:  Adipose tissue-derived mesenchymal stromal cells (MSCs); Bipotential commitment; Coculture; Cord blood hematopoietic stem and progenitor cells (cbHSPCs); Osteoproteins
    DOI:  https://doi.org/10.1016/j.lfs.2020.118970
  8. Aging (Albany NY). 2020 12 27.
    Sugar-induced dysregulation of purine metabolism impacts lifespan.
    Claudia Lennicke, Eliano Dos Santos, Helena M Cochemé.
      
    Keywords:  Drosophila; aging; diabetes; metabolic disease; obesity; purine catabolism; sugar diet; uric acid
    DOI:  https://doi.org/10.18632/aging.104223
  9. Aging Cell. 2020 Dec 23. e13283
    Mitochondrial DNA in extracellular vesicles declines with age.
    Stephanie Lazo, Nicole Noren Hooten, Jamal Green, Erez Eitan, Nicolle A Mode, Qing-Rong Liu, Alan B Zonderman, Ngozi Ezike, Mark P Mattson, Paritosh Ghosh, Michele K Evans.
      The mitochondrial free radical theory of aging suggests that accumulating oxidative damage to mitochondria and mitochondrial DNA (mtDNA) plays a central role in aging. Circulating cell-free mtDNA (ccf-mtDNA) isolated from blood may be a biomarker of disease. Extracellular vesicles (EVs) are small (30-400 nm), lipid-bound vesicles capable of shuttling proteins, nucleic acids, and lipids as part of intercellular communication systems. Here, we report that a portion of ccf-mtDNA in plasma is encapsulated in EVs. To address whether EV mtDNA levels change with human age, we analyzed mtDNA in EVs from individuals aged 30-64 years cross-sectionally and longitudinally. EV mtDNA levels decreased with age. Furthermore, the maximal mitochondrial respiration of cultured cells was differentially affected by EVs from old and young donors. Our results suggest that plasma mtDNA is present in EVs, that the level of EV-derived mtDNA is associated with age, and that EVs affect mitochondrial energetics in an EV age-dependent manner.
    Keywords:  aging; biomarker; circulating cell-free mitochondrial DNA; exosomes; extracellular vesicles; intercellular communication; microvesicles; mitochondrial DNA
    DOI:  https://doi.org/10.1111/acel.13283
  10. Nutrients. 2020 Dec 19. pii: E3895. [Epub ahead of print]12(12):
    Mediterranean Diet Decreases the Initiation of Use of Vitamin K Epoxide Reductase Inhibitors and Their Associated Cardiovascular Risk: A Randomized Controlled Trial.
    Sara Castro-Barquero, Margarita Ribó-Coll, Camille Lassale, Anna Tresserra-Rimbau, Olga Castañer, Xavier Pintó, Miguel Ángel Martínez-González, José V Sorlí, Jordi Salas-Salvadó, José Lapetra, Enrique Gómez-Gracia, Ángel M Alonso-Gómez, Miquel Fiol, Lluis Serra-Majem, Emilio Sacanella, Francisco Javier Basterra-Gortari, Olga Portolés, Nancy Babio, Montserrat Cofán, Emilio Ros, Ramón Estruch, Álvaro Hernáez.
      Our aim is to assess whether following a Mediterranean Diet (MedDiet) decreases the risk of initiating antithrombotic therapies and the cardiovascular risk associated with its use in older individuals at high cardiovascular risk. We evaluate whether participants of the PREvención con DIeta MEDiterránea (PREDIMED) study allocated to a MedDiet enriched in extra-virgin olive oil or nuts (versus a low-fat control intervention) disclose differences in the risk of initiation of: (1) vitamin K epoxide reductase inhibitors (acenocumarol/warfarin; n = 6772); (2) acetylsalicylic acid as antiplatelet agent (n = 5662); and (3) other antiplatelet drugs (cilostazol/clopidogrel/dipyridamole/ditazol/ticlopidine/triflusal; n = 6768). We also assess whether MedDiet modifies the association between the antithrombotic drug baseline use and incident cardiovascular events. The MedDiet intervention enriched with extra-virgin olive oil decreased the risk of initiating the use of vitamin K epoxide reductase inhibitors relative to control diet (HR: 0.68 [0.46-0.998]). Their use was also more strongly associated with an increased risk of cardiovascular disease in participants not allocated to MedDiet interventions (HRcontrol diet: 4.22 [1.92-9.30], HRMedDiets: 1.71 [0.83-3.52], p-interaction = 0.052). In conclusion, in an older population at high cardiovascular risk, following a MedDiet decreases the initiation of antithrombotic therapies and the risk of suffering major cardiovascular events among users of vitamin K epoxide reductase inhibitors.
    Keywords:  4-hydroxycoumarins; Mediterranean Diet; platelet aggregation inhibitors; prevention; randomized controlled trials
    DOI:  https://doi.org/10.3390/nu12123895
  11. N Engl J Med. 2020 12 24. 383(26): 2526-2537
    Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission.
    QUAZAR AML-001 Trial Investigators
       BACKGROUND: Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.
    METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.
    RESULTS: A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment.
    CONCLUSIONS: CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.).
    DOI:  https://doi.org/10.1056/NEJMoa2004444
  12. J Invest Dermatol. 2020 Dec 21. pii: S0022-202X(20)32294-6. [Epub ahead of print]
    Inflammaging and the Skin.
    Suzanne M Pilkington, Silvia Bulfone-Paus, Christopher E M Griffiths, Rachel E B Watson.
      As global life expectancy continues to rise, we are challenged with maintaining health into old age. One strategy is to target the chronic low-level inflammation associated with aging, termed inflammaging. This is characterized by increased levels of circulating proinflammatory cytokines and a shift toward cellular senescence, changes that are believed to drive many age-associated conditions, including dementia, arthritis, and type 2 diabetes. As with other organs, the skin undergoes functional decline during aging, becoming more fragile and susceptible to infection; however, the contribution of inflammaging is not well-understood. This review article describes the evidence for inflammaging in the skin, its relationship with senescence, and how this relates to declining skin structure and function.
    DOI:  https://doi.org/10.1016/j.jid.2020.11.006
  13. Nat Rev Mol Cell Biol. 2020 Dec 22.
    NAD+ metabolism and its roles in cellular processes during ageing.
    Anthony J Covarrubias, Rosalba Perrone, Alessia Grozio, Eric Verdin.
      Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.
    DOI:  https://doi.org/10.1038/s41580-020-00313-x
  14. Nutrients. 2020 Dec 12. pii: E3811. [Epub ahead of print]12(12):
    Dietary Ferulic Acid Supplementation Improves Antioxidant Capacity and Lipid Metabolism in Weaned Piglets.
    Youxia Wang, Xiaoling Chen, Zhiqing Huang, Daiwen Chen, Bing Yu, Jie Yu, Hong Chen, Jun He, Yuheng Luo, Ping Zheng.
      Ferulic acid (FA) is a phenolic compound that has antioxidant, hepatoprotective, anticarcinogenic, anti-inflammatory, antiallergic, antimicrobial, antiviral, and vasodilatory effects. This study was conducted to explore the effects of dietary FA supplementation on antioxidant capacity and lipid metabolism in weaned piglets. Eighteen 21-day-old castrated male DLY (Duroc × Landrace × Yorkshire) weaned piglets were randomly divided into control, 0.05%, and 0.45% FA groups. The results showed that, in serum, CAT and T-SOD activities and content of HDL-C were increased, but the content of MDA and the activities of T-CHO and LDL-C were decreased, by FA supplementation. In liver, dietary FA supplementation increased CAT, T-SOD, and GSH-PX activities and upregulated the mRNA levels of SOD1, SOD2, CAT, GST, GPX1, GR, Nrf2, HSL, CPT1b, and PPARα but decreased the contents of MDA and TG. Furthermore, dietary FA supplementation increased the protein level of Nrf2, HO-1, and NQO-1. In longissimus dorsi muscle, dietary FA supplementation increased the activity of T-SOD and the mRNA abundance of SOD1, SOD2, CAT, GST, GPX1, GR, and Nrf2 but decreased the contents of MDA and T-CHO. Additionally, dietary FA supplementation increased the protein expressions of Nrf2, HO-1, and NQO1. Together, our data suggest that FA could improve antioxidant capacity and lipid metabolism in weaned piglets.
    Keywords:  antioxidant capacity; ferulic acid; lipid metabolism; weaned piglets
    DOI:  https://doi.org/10.3390/nu12123811
  15. Aging (Albany NY). 2020 Dec 30. 12
    ARDD 2020: from aging mechanisms to interventions.
    Garik V Mkrtchyan, Kotb Abdelmohsen, Pénélope Andreux, Ieva Bagdonaite, Nir Barzilai, Søren Brunak, Filipe Cabreiro, Rafael de Cabo, Judith Campisi, Ana Maria Cuervo, Marco Demaria, Collin Y Ewald, Evandro Fei Fang, Richard Faragher, Luigi Ferrucci, Adam Freund, Carlos G Silva-García, Anastasia Georgievskaya, Vadim N Gladyshev, David J Glass, Vera Gorbunova, Aubrey de Grey, Wei-Wu He, Jan Hoeijmakers, Eva Hoffmann, Steve Horvath, Riekelt H Houtkooper, Majken K Jensen, Martin Borch Jensen, Alice Kane, Moustapha Kassem, Peter de Keizer, Brian Kennedy, Gerard Karsenty, Dudley W Lamming, Kai-Fu Lee, Nanna MacAulay, Polina Mamoshina, Jim Mellon, Marte Molenaars, Alexey Moskalev, Andreas Mund, Laura Niedernhofer, Brenna Osborne, Heidi H Pak, Andrey Parkhitko, Nuno Raimundo, Thomas A Rando, Lene Juel Rasmussen, Carolina Reis, Christian G Riedel, Anais Franco-Romero, Björn Schumacher, David A Sinclair, Yousin Suh, Pam R Taub, Debra Toiber, Jonas T Treebak, Dario Riccardo Valenzano, Eric Verdin, Jan Vijg, Sergey Young, Lei Zhang, Daniela Bakula, Alex Zhavoronkov, Morten Scheibye-Knudsen.
      Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA.
    Keywords:  aging; artificial intelligence; drug discovery; interventions
    DOI:  https://doi.org/10.18632/aging.202454
  16. Aging (Albany NY). 2020 Dec 27.
    Arterial elementary calcium signaling in aging.
    Mario Kassmann, Gang Fan, Maik Gollasch.
      
    Keywords:  T-type calcium channels; aging; calcium sparks; caveolae; ryanodine receptors; vascular smooth muscle
    DOI:  https://doi.org/10.18632/aging.104220
  17. Free Radic Biol Med. 2020 Dec 22. pii: S0891-5849(20)31684-1. [Epub ahead of print]
    Age-dependent accumulation of dicarbonyls and advanced glycation endproducts (AGEs) associates with mitochondrial stress.
    Firoz Akhter, Doris Chen, Asma Akhter, Shi Fang Yan, Shirley ShiDu Yan.
      Aging is a strong risk factor for brain dementia and cognitive decline. Age-related accumulation of metabolites such as advanced glycation end products (AGEs) could serve as danger signals to initiate and accelerate disease process and neurodegeneration. The underlying causes and consequences of cerebral AGEs accumulation remain largely unknown. Here, we comprehensively investigate age-related accumulation of AGEs and dicarbonyls, including methylglyoxal (MG), glyoxal (GO), and 3-deoxyglucosone (3-DG), and the effects of mitochondrial reactive oxygen species (ROS) on cerebral AGEs accumulation, mitochondrial function, and oxidative stress in the aging human and mouse brain. We demonstrate that AGEs, including arginine and lysine derived N(6)-carboxymethyl lysine (CML), Nε-(1-Carboxyethyl)-L-lysine (CEL), and methylglyoxal-derived hydroimidazolone-1 (MG-H1), were significantly elevated in the cerebral cortex and hippocampus with advanced age in mice. Accordingly, aging mouse and human brains revealed decrease in activities of mitochondrial respiratory chain complexes I & IV and ATP levels, and increased ROS. Notably, administration of mitoTEMPO (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mTEMPO), a scavenger of mitochondrial ROS, not only suppressed ROS production but also reduced aged-induced accumulation of AGEs and dicarbonyls. mTEMPO treatment improved mitochondrial respiratory function and restored ATP levels. Our findings provide evidence linking age-related accumulation of toxic metabolites (AGEs) to mitochondrial oxidative stress. This highlights a novel mechanism by which AGEs-dependent signaling promotes carbonyl stress and sustained mitochondrial dysfunction. Eliminating formation and accumulation of AGEs may represent a new therapeutic avenue for combating cognitive decline and mitochondrial degeneration relevant to aging and neurodegenerative diseases including Alzheimer's disease.
    Keywords:  Advanced glycation end products (AGEs); Aging; Reactive oxygen species (ROS); dicarbonyls; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.12.021
  18. Signal Transduct Target Ther. 2021 Jan 01. 6(1): 2
    NAD+ metabolism, stemness, the immune response, and cancer.
    Lola E Navas, Amancio Carnero.
      NAD+ was discovered during yeast fermentation, and since its discovery, its important roles in redox metabolism, aging, and longevity, the immune system and DNA repair have been highlighted. A deregulation of the NAD+ levels has been associated with metabolic diseases and aging-related diseases, including neurodegeneration, defective immune responses, and cancer. NAD+ acts as a cofactor through its interplay with NADH, playing an essential role in many enzymatic reactions of energy metabolism, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, and the TCA cycle. NAD+ also plays a role in deacetylation by sirtuins and ADP ribosylation during DNA damage/repair by PARP proteins. Finally, different NAD hydrolase proteins also consume NAD+ while converting it into ADP-ribose or its cyclic counterpart. Some of these proteins, such as CD38, seem to be extensively involved in the immune response. Since NAD cannot be taken directly from food, NAD metabolism is essential, and NAMPT is the key enzyme recovering NAD from nicotinamide and generating most of the NAD cellular pools. Because of the complex network of pathways in which NAD+ is essential, the important role of NAD+ and its key generating enzyme, NAMPT, in cancer is understandable. In the present work, we review the role of NAD+ and NAMPT in the ways that they may influence cancer metabolism, the immune system, stemness, aging, and cancer. Finally, we review some ongoing research on therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41392-020-00354-w
  19. Pediatr Blood Cancer. 2020 Dec 27. e28865
    Venetoclax/decitabine for a pediatric patient with chronic myelomonocytic leukemia.
    John C Molina, Julie M Asare, Laura Tuschong, Robert R West, Katherine R Calvo, Rebecca Persky, Alison M Boyce, Dima A Hammoud, Steven M Holland, Dennis Hickstein, Nirali N Shah.
      Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS)/myeloproliferative disorder most commonly seen in the elderly. We describe an adolescent with monosomy 7 CMML presenting as central diabetes insipidus (DI), who was treated with venetoclax and decitabine as a bridge to hematopoietic stem cell transplantation (HSCT). Central DI is a rare manifestation of monosomy 7-associated MDS including CMML, itself a rare manifestation of GATA2 deficiency, particularly in children. Venetoclax/decitabine was effective for treatment of CMML as a bridge to HSCT.
    DOI:  https://doi.org/10.1002/pbc.28865
  20. Aging (Albany NY). 2020 Dec 27. 12
    Obesity induced by high-fat diet is associated with critical changes in biological and molecular functions of mesenchymal stromal cells present in visceral adipose tissue.
    Mustafa Burak Acar, Şerife Ayaz-Güner, Giovanni Di Bernardo, Hüseyin Güner, Ayşegül Murat, Gianfranco Peluso, Servet Özcan, Umberto Galderisi.
      The mesenchymal stromal cells (MSCs) residing within the stromal component of visceral adipose tissue appear to be greatly affected by obesity, with impairment of their functions and presence of senescence. To gain further insight into these phenomena, we analyzed the changes in total proteome content and secretome of mouse MSCs after a high-fat diet (HFD) treatment compared to a normal diet (ND). In healthy conditions, MSCs are endowed with functions mainly devoted to vesicle trafficking. These cells have an immunoregulatory role, affecting leukocyte activation and migration, acute inflammation phase response, chemokine signaling, and platelet activities. They also present a robust response to stress. We identified four signaling pathways (TGF-β, VEGFR2, HMGB1, and Leptin) that appear to govern the cells' functions. In the obese mice, MSCs showed a change in their functions. The immunoregulation shifted toward pro-inflammatory tasks with the activation of interleukin-1 pathway and of Granzyme A signaling. Moreover, the methionine degradation pathway and the processing of capped intronless pre-mRNAs may be related to the inflammation process. The signaling pathways we identified in ND MSCs were replaced by MET, WNT, and FGFR2 signal transduction, which may play a role in promoting inflammation, cancer, and aging.
    Keywords:  mesenchymal stromal cells; senescence; visceral adipose tissue
    DOI:  https://doi.org/10.18632/aging.202423
  21. Blood. 2020 Dec 24. 136(26): 2967-2968
    Blood stem cells SELect quiescence.
    Elisa Laurenti.
      
    DOI:  https://doi.org/10.1182/blood.2020009554
  22. Front Immunol. 2020 ;11 609277
    Key Metabolic Pathways in MSC-Mediated Immunomodulation: Implications for the Prophylaxis and Treatment of Graft Versus Host Disease.
    Andre J Burnham, Elisabetta Manuela Foppiani, Edwin M Horwitz.
      Mesenchymal stromal cells (MSCs) are spindle-shaped, plastic-adherent cells in vitro with potent immunosuppressive activity both in vitro and in vivo. MSCs have been employed as a cellular immunotherapy in diverse preclinical models and clinical trials, but most commonly as agents for the prophylaxis or therapy of graft versus host disease after hematopoietic cell transplantation. In addition to the oft studied secreted cytokines, several metabolic pathways intrinsic to MSCs, notably indoleamine 2,3-dioxygenase, prostaglandin E2, hypoxia-inducible factor 1 α, heme oxygenase-1, as well as energy-generating metabolism, have been shown to play roles in the immunomodulatory activity of MSCs. In this review, we discuss these key metabolic pathways in MSCs which have been reported to contribute to MSC therapeutic effects in the setting of hematopoietic cell transplantation and graft versus host disease. Understanding the contribution of MSC metabolism to immunomodulatory activity may substantially inform the development of future clinical applications of MSCs.
    Keywords:  PGE2; aerobic glycolysis; graft versus host disease; heme oxygenase-1; hypoxia-inducible factor 1 α; indoleamine 2,3-dioxygenase; kynurenine; mesenchymal stromal cell
    DOI:  https://doi.org/10.3389/fimmu.2020.609277
  23. Obes Res Clin Pract. 2020 Dec 29. pii: S1871-403X(20)30624-4. [Epub ahead of print]
    Metformin-induced weight loss in patients with or without type 2 diabetes/prediabetes: A retrospective cohort study.
    Tariq Chukir, Lindsay Mandel, Beverly G Tchang, Nada A Al-Mulla, Leon I Igel, Rekha B Kumar, Jonathan Waitman, Louis J Aronne, Alpana P Shukla.
      It is unknown whether weight loss outcomes differ with metformin monotherapy in patients with obesity with or without type 2 diabetes (T2DM)/prediabetes (PreDM). In this retrospective study, 6- or 12-month weight loss outcomes were compared in 222 patients with or without T2DM/preDM who completed metformin monotherapy. Average weight loss was similar between groups, euglycemic vs. T2DM/preDM (6 months: 6.5 [6.0%] vs. 6.5 [6.1%] p = 0.97; 12 months: 7.4 [6.2%] vs. 7.3 [7.7%], p = 0.92). Categorical weight losses (≥5% and ≥10% of baseline weight) were also similar. Comparable clinically significant weight loss was achieved with metformin monotherapy in patients with obesity with or without T2DM/PreDM.
    Keywords:  Metformin; Obesity; Type 2 diabetes; Weight loss; Weight management
    DOI:  https://doi.org/10.1016/j.orcp.2020.12.005
  24. Cancer Manag Res. 2020 ;12 13259-13271
    Regulation of Autophagy by Glycolysis in Cancer.
    Ying Chu, Yi Chang, Wei Lu, Xiumei Sheng, Shengjun Wang, Huaxi Xu, Jie Ma.
      Autophagy is a critical cellular process that generally protects cells and organisms from harsh environment, including limitations in adenosine triphosphate (ATP) availability or a lack of essential nutrients. Metabolic reprogramming, a hallmark of cancer, has recently gained interest in the area of cancer therapy. It is well known that cancer cells prefer to utilize glycolysis rather than oxidative phosphorylation (OXPHOS) as their major energy source to rapidly generate ATP even in aerobic environment called the Warburg effect. Both autophagy and glycolysis play essential roles in pathological processes of cancer. A mechanism of metabolic changes to drive tumor progression is its ability to regulate autophagy. This review will elucidate the role and the mechanism of glycolysis in regulating autophagy during tumor growth. Indeed, understanding how glycolysis can modulate cellular autophagy will enable more effective combinatorial therapeutic strategies.
    Keywords:  autophagy; glycolysis; lactate; lung cancer; metabolism
    DOI:  https://doi.org/10.2147/CMAR.S279672
  25. Cell Metab. 2020 Dec 17. pii: S1550-4131(20)30660-4. [Epub ahead of print]
    High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells.
    Sangmoo Jeong, Angela Maria Savino, Rachel Chirayil, Ersilia Barin, Yuanming Cheng, Sun-Mi Park, Alexandra Schurer, Edouard Mullarky, Lewis C Cantley, Michael G Kharas, Kayvan R Keshari.
      A significant increase in dietary fructose consumption has been implicated as a potential driver of cancer. Metabolic adaptation of cancer cells to utilize fructose confers advantages for their malignant growth, but compelling therapeutic targets have not been identified. Here, we show that fructose metabolism of leukemic cells can be inhibited by targeting the de novo serine synthesis pathway (SSP). Leukemic cells, unlike their normal counterparts, become significantly dependent on the SSP in fructose-rich conditions as compared to glucose-rich conditions. This metabolic program is mediated by the ratio of redox cofactors, NAD+/NADH, and the increased SSP flux is beneficial for generating alpha-ketoglutarate from glutamine, which allows leukemic cells to proliferate even in the absence of glucose. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, dramatically reduces leukemia engraftment in mice in the presence of high fructose, confirming the essential role of the SSP in the metabolic plasticity of leukemic cells.
    Keywords:  in vivo isotope tracing; metabolic flux; redox; serine synthesis pathway
    DOI:  https://doi.org/10.1016/j.cmet.2020.12.005
  26. J Clin Endocrinol Metab. 2020 Dec 31. pii: dgaa954. [Epub ahead of print]
    Targeted metabolomics as a tool in discriminating endocrine from primary hypertension.
    Zoran Erlic, Parminder Reel, Smarti Reel, Laurence Amar, Alessio Pecori, Casper K Larsen, Martina Tetti, Christina Pamporaki, Cornelia Prehn, Jerzy Adamski, Aleksander Prejbisz, Filippo Ceccato, Carla Scaroni, Matthias Kroiss, Michael C Dennedy, Jaap Deinum, Katharina Langton, Paolo Mulatero, Martin Reincke, Livia Lenzini, Anne-Paule Gimenez-Roqueplo, Guillaume Assié, Anne Blanchard, Maria Christina Zennaro, Emily Jefferson, Felix Beuschlein.
       CONTEXT: Identification of patients with endocrine forms of hypertension (EHT) (primary hyperaldosteronism [PA], pheochromocytoma/paraganglioma [PPGL] and Cushing syndrome [CS]) provides the basis to implement individualized therapeutic strategies. Targeted metabolomics (TM) have revealed promising results in profiling cardiovascular diseases and endocrine conditions associated with hypertension.
    OBJECTIVE: Use TM to identify distinct metabolic patterns between primary hypertension (PHT) and EHT and test its discriminating ability.
    DESIGN: Retrospective analyses of PHT and EHT patients from a European multicentre study (ENSAT-HT). TM was performed on stored blood samples using liquid chromatography mass spectrometry. To identify discriminating metabolites a "classical approach" (CA) (performing a series of univariate and multivariate analyses) and a "machine learning approach" (MLA) (using Random Forest) were used.
    PATIENTS: The study included 282 adult patients (52% female; mean age 49 years) with proven PHT (n=59) and EHT (n=223 with 40 CS, 107 PA and 76 PPGL), respectively.
    RESULTS: From 155 metabolites eligible for statistical analyses, 31 were identified discriminating between PHT and EHT using the CA and 27 using the MLA, of which 15 metabolites (C9, C16, C16:1, C18:1, C18:2, arginine, aspartate, glutamate, ornithine, spermidine, lysoPCaC16:0, lysoPCaC20:4, lysoPCaC24:0, PCaeC42:0, SM C18:1, SM C20:2) were found by both approaches. The ROC curve built on the top 15 metabolites from the CA provided an area under the curve (AUC) of 0.86, which was similar to the performance of the 15 metabolites from MLA (AUC 0.83).
    CONCLUSIONS: TM identifies distinct metabolic pattern between PHT and EHT providing promising discriminating performance.
    Keywords:  Cushing syndrome; arterial hypertension; pheochromocytoma; primary aldosteronism; screening; targeted metabolomics
    DOI:  https://doi.org/10.1210/clinem/dgaa954
  27. Aging Cell. 2020 Dec 31. e13300
    Diacetyl odor shortens longevity conferred by food deprivation in C. elegans via downregulation of DAF-16/FOXO.
    Sangsoon Park, Murat Artan, Dae-Eun Jeong, Hae-Eun H Park, Heehwa G Son, Sieun S Kim, Yoonji Jung, Yunji Choi, Jin I Lee, Kyuhyung Kim, Seung-Jae V Lee.
      Dietary restriction extends lifespan in various organisms by reducing the levels of both nutrients and non-nutritional food-derived cues. However, the identity of specific food-derived chemical cues that alter lifespan remains unclear. Here, we identified several volatile attractants that decreased the longevity on food deprivation, a dietary restriction regimen in Caenorhabditis elegans. In particular, we found that the odor of diacetyl decreased the activity of DAF-16/FOXO, a life-extending transcription factor acting downstream of insulin/IGF-1 signaling. We then demonstrated that the odor of lactic acid bacteria, which produce diacetyl, reduced the nuclear accumulation of DAF-16/FOXO. Unexpectedly, we showed that the odor of diacetyl decreased longevity independently of two established diacetyl receptors, ODR-10 and SRI-14, in sensory neurons. Thus, diacetyl, a food-derived odorant, may shorten food deprivation-induced longevity via decreasing the activity of DAF-16/FOXO through binding to unidentified receptors.
    Keywords:   C.  elegans ; aging; diacetyl; dietary restriction; longevity
    DOI:  https://doi.org/10.1111/acel.13300
  28. J Neurochem. 2020 Dec 28.
    A multi-level assessment of the bidirectional relationship between aging and the circadian clock.
    M Renate Buijink, Stephan Michel.
      The daily temporal order of physiological processes and behavior contribute to the wellbeing of many organisms including humans. The central circadian clock, which coordinates the timing within our body, is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Like other parts of the brain, aging impairs the SCN function, which in turn promotes the development and progress of aging related diseases. We here review the impact of aging on the different levels of the circadian clock machinery - from molecules to organs - with a focus on the role of the SCN. We find that the molecular clock is less effected by aging compared to other cellular components of the clock. Proper rhythmic regulation of intracellular signaling, ion channels and neuronal excitability of SCN neurons are greatly disturbed in aging. This suggests a disconnect between the molecular clock and the electrophysiology of these cells. The neuronal network of the SCN is able to compensate for some of these cellular deficits. However, it still results in a clear reduction in the amplitude of the SCN electrical rhythm, suggesting a weakening of the output timing signal. Consequently, other brain areas and organs not only show aging-related deficits in their own local clocks, but also receive a weaker systemic timing signal. The negative spiral completes with the weakening of positive feed-back from the periphery to the SCN. Consequently, chronotherapeutic interventions should aim at strengthening overall synchrony in the circadian system using life-style and/or pharmacological approaches.
    Keywords:  Chronotherapy; Neurodegeneration; Neuronal network; Senescence; Suprachiasmatic nucleus; peripheral clocks
    DOI:  https://doi.org/10.1111/jnc.15286
  29. Int J Mol Sci. 2020 Dec 26. pii: E175. [Epub ahead of print]22(1):
    Whole Blood Metabolomics in Aging Research.
    Hiroshi Kondoh, Masahiro Kameda, Mitsuhiro Yanagida.
      Diversity is observed in the wave of global aging because it is a complex biological process exhibiting individual variability. To assess aging physiologically, markers for biological aging are required in addition to the calendar age. From a metabolic perspective, the aging hypothesis includes the mitochondrial hypothesis and the calorie restriction (CR) hypothesis. In experimental models, several compounds or metabolites exert similar lifespan-extending effects, like CR. However, little is known about whether these metabolic modulations are applicable to human longevity, as human aging is greatly affected by a variety of factors, including lifestyle, genetic or epigenetic factors, exposure to stress, diet, and social environment. A comprehensive analysis of the human blood metabolome captures complex changes with individual differences. Moreover, a non-targeted analysis of the whole blood metabolome discloses unexpected aspects of human biology. By using such approaches, markers for aging or aging-relevant conditions were identified. This information should prove valuable for future diagnosis or clinical interventions in diseases relevant to aging.
    Keywords:  aging; antioxidant; fasting; frailty; metabolites; metabolomics; whole blood
    DOI:  https://doi.org/10.3390/ijms22010175
  30. J Lipid Res. 2020 Dec 23. pii: jlr.TR120000981. [Epub ahead of print]
    Lipid metabolism dysregulation in diabetic retinopathy.
    Julia V Busik.
      Lipid metabolic abnormalities have emerged as potential risk factors for the development and progression of diabetic complications, including diabetic retinopathy (DR).  This review article provides an overview of the results of clinical trials evaluating the potential benefits of lipid lowering drugs, such as fibrates, omega 3 fatty acids, and statins, for the prevention and treatment of DR. Although several clinical trials demonstrated that treatment with fibrates leads to improvement of DR, there is a dissociation between the protective effects of fibrates in the retina, and the intended blood lipid classes, including plasma triglycerides, total cholesterol or HDL/LDL cholesterol ratio. Guided by these findings, plasma lipid and lipoprotein-independent mechanisms are addressed based on clinical, cell culture and animal model studies. Potential retinal-specific effects of fatty acids oxidation products, cholesterol, and ceramide, as well as lipid independent effects of PPAR alpha activation are summarized based on current literature. Overall, this review highlights promising potential of lipid-based treatment strategies further enhanced by the new knowledge of intra-retinal lipids and lipoproteins in DR.
    Keywords:  Ceramides; Cholesterol; Diabetes; Eye/retina; Omega-3 fatty acids; Oxidized fatty acids; diabetic retinopathy
    DOI:  https://doi.org/10.1194/jlr.TR120000981
  31. Brain Res. 2020 Dec 23. pii: S0006-8993(20)30578-3. [Epub ahead of print] 147220
    NLRP3 deficiency-induced hippocampal dysfunction and anxiety-like behavior in mice.
    Yulia K Komleva, Olga L Lopatina, Iana V Gorina, Anton N Shuvaev, Anatoly Chernykh, Ilia V Potapenko, Alla B Salmina.
      Neuroinflammation has been classified as a trigger of behavioral alterations and cognitive impairments in many neurological conditions, including Alzheimer's disease, major depression, anxiety and others. Regardless of the cause of neuroinflammation, key molecules, which sense neuropathological conditions, are intracellular multiprotein signaling inflammasomes. Increasing evidence shows that the inflammatory response, mediated by activated nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasomes, is associated with the onset and progression of a wide range of diseases of the CNS. However, whether the NLRP3 inflammasome in the CNS is involved in the learning, development of anxiety and adult neurogenesis remains elusive. Therefore, the present study was designed to assess NLRP3 inflammasome contribution in anxiety and reveal its potential involvement in the experimental acquisition of fear responses and hippocampal neurogenesis. Behavioral, immunohistochemical and electrophysiological alterations were measured to evaluate role of neuroinflammation in the limbic system of mice. In this study, we describe interrelated neurophysiological mechanisms, which culminate in absence of NLRP3 inflammasome in young 4 months mice. These include the following: anxious behavior and deterioration in learning and memory of fear conditioning; impairment of adult neurogenesis; reduction and altered morphology of astrocytes in the brain; hyperexcitability in basolateral amygdala (BLA); impaired activation in axons of pyramidal cells of CA1 hippocampal zone in NLRP3 KO mice particularly via the Schaffer collateral pathway; and impaired synaptic transduction in pyramidal cells mediated by an embarrassment of neurotransmitter release from presynaptic site in CA3 hippocampal zone. The present study has demonstrated the novel findings that basal level of NLRP3 inflammasome in the brain of young mice is required for conditioning-induced plasticity in the ventral hippocampus and the basolateral amygdala. The deletion of NLRP3 impair synaptic transduction and caused anxiety-like behavior and labored fear learning, suggesting that low grade inflammation, mediated by NLRP3 expression, play a key role in memory consolidation.
    Keywords:  Anxiety; Astrocyte; Fear conditioning; NLRP3 inflammasome; Neurogenesis; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.brainres.2020.147220
  32. Cell Rep. 2020 Dec 22. pii: S2211-1247(20)31519-9. [Epub ahead of print]33(12): 108530
    Interferon Gamma Mediates Hematopoietic Stem Cell Activation and Niche Relocalization through BST2.
    Marcus A Florez, Katie A Matatall, Youngjae Jeong, Laura Ortinau, Paul W Shafer, Anne M Lynch, Roman Jaksik, Marek Kimmel, Dongsu Park, Katherine Y King.
      During chronic infection, the inflammatory cytokine interferon gamma (IFNγ) damages hematopoietic stem cells (HSCs) by disrupting quiescence and promoting excessive terminal differentiation. However, the mechanism by which IFNγ hinders HSC quiescence remains undefined. Using intravital 3-dimensional microscopy, we find that IFNγ disrupts the normally close interaction between HSCs and CXCL12-abundant reticular (CAR) cells in the HSC niche. IFNγ stimulation increases expression of the cell surface protein BST2, which we find is required for IFNγ-dependent HSC relocalization and activation. IFNγ stimulation of HSCs increases their E-selectin binding by BST2 and homing to the bone marrow, which depends on E-selectin binding. Upon chronic infection, HSCs from mice lacking BST2 are more quiescent and more resistant to depletion than HSCs from wild-type mice. Overall, this study defines a critical mechanism by which IFNγ promotes niche relocalization and activation in response to inflammatory stimulation and identifies BST2 as a key regulator of HSC quiescence. VIDEO ABSTRACT.
    Keywords:  BST2; E-selectin; hematopoietic stem cell; homing; infection; inflammation; interferon gamma; niche
    DOI:  https://doi.org/10.1016/j.celrep.2020.108530
  33. J Cell Mol Med. 2020 Dec 25.
    Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras-Raf-MAPK signalling.
    Yongye Huang, Kexun Yuan, Meifang Tang, Jiaming Yue, Lijun Bao, Shuang Wu, Yanxin Zhang, Yin Li, Yihang Wang, Xu Ou, Jiaxin Gou, Qi Zhao, Lin Yuan.
      Melatonin exhibits antitumour activities in the treatment of many human cancers. In the present study, we aimed to improve the therapeutic potential of melatonin in gastric cancer. Our results confirmed that melatonin dose-dependently suppressed the proliferation and necrosis, and increased G0/G1 phase arrest, apoptosis, autophagy and endoplasmic reticulum (ER) stress. The Ras-Raf-MAPK signalling pathway was activated in cells after melatonin treatment. RNA-seq was performed and GSEA analysis further confirmed that many down-regulated genes in melatonin-treated cells were associated with proliferation. However, GSEA analysis also indicated that many pathways related to metastasis were increased after melatonin treatment. Subsequently, combinatorial treatment was conducted to further investigate the therapeutic outcomes of melatonin. A combination of melatonin and thapsigargin increased the apoptotic rate and G0/G1 cell cycle arrest when compared to treatment with melatonin alone. Melatonin in combination with thapsigargin triggered the increased expression of Bip, LC3-II, phospho-Erk1/2 and phospho-p38 MAPK. In addition, STF-083010, an IRE1a inhibitor, further exacerbated the decrease in survival rate induced by combinatorial treatment with melatonin and thapsigargin. Collectively, melatonin was effective in gastric cancer treatment by modifying ER stress.
    Keywords:  ER stress; RNA-seq; autophagy; combinatorial treatment; melatonin
    DOI:  https://doi.org/10.1111/jcmm.16237
  34. Crit Rev Food Sci Nutr. 2020 Dec 30. 1-15
    Role of lactic acid bacteria in flavor development in traditional Chinese fermented foods: A review.
    Yingying Hu, Lang Zhang, Rongxin Wen, Qian Chen, Baohua Kong.
      Traditional Chinese fermented foods are favored by consumers due to their unique flavor, texture and nutritional values. A large number of microorganisms participate in the process of fermentation, especially lactic acid bacteria (LAB), which are present in almost all fermented foods and contribute to flavor development. The formation process of flavor is complex and involves the biochemical conversion of various food components. It is very important to fully understand the conversion process to direct the flavor formation in foods. A comprehensive link between the LAB community and the flavor formation in traditional Chinese fermented foods is reviewed. The main mechanisms involved in the flavor formation dominated by LAB are carbohydrate metabolism, proteolysis and amino acid catabolism, and lipolysis and fatty acid metabolism. This review highlights some useful novel approaches for flavor enhancement, including the application of functional starter cultures and metabolic engineering, which may provide significant advances toward improving the flavor of fermented foods for a promising market.
    Keywords:  Traditional Chinese fermented foods; bacterial diversity; flavor development; lactic acid bacteria; metabolic pathway
    DOI:  https://doi.org/10.1080/10408398.2020.1858269
  35. Mol Metab. 2020 Dec 22. pii: S2212-8778(20)30224-6. [Epub ahead of print] 101150
    Hepatic synthesis of triacylglycerols containing medium-chain fatty acids is dominated by diacylglycerol acyltransferase 1 and efficiently inhibited by etomoxir.
    Klaus Wunderling, Christina Leopold, Isabell Jamitzky, Mohamed Yaghmour, Fabian Zink, Dagmar Kratky, Christoph Thiele.
       OBJECTIVE: Medium-chain fatty acids (MCFAs) play an increasing role in human nutrition. In the liver, one fraction is used for synthesis of MCFA-containing triacylglycerol (MCFA-TG), the rest is used for oxidative energy production or ketogenesis. We investigated which enzymes catalyze the synthesis of MCFA-TG and how inhibition of MCFA-TG synthesis or fatty acid (FA) oxidation influences the metabolic fate of the MCFAs.
    METHODS: Fatty acid metabolism was followed by time-resolved tracing of alkyne-labeled FAs in freshly isolated mouse hepatocytes. Quantitative data were obtained by mass spectrometry of several hundred labeled lipid species. Wildtype hepatocytes as well as cells from diacylglycerol acyltransferase (DGAT)1-/- mice were treated with inhibitors against DGAT1, DGAT2, or FA β-oxidation.
    RESULTS: Inhibition or deletion of DGAT1 resulted in a reduction of MCFA-TG synthesis by 70%, while long-chain (LC)FA-TG synthesis was reduced by 20%. In contrast, DGAT2 inhibition increased MCFA-TG formation by 50%, while LCFA-TG synthesis was reduced by 5-25%. Inhibition of β-oxidation by the specific inhibitor teglicar strongly increased MCFA-TG synthesis. In contrast, the widely used β-oxidation inhibitor etomoxir blocked MCFA-TG synthesis, phenocopying DGAT1 inhibition.
    CONCLUSIONS: DGAT1 is the major enzyme for hepatic MCFA-TG synthesis. Its loss can only partially be compensated by DGAT2. Specific inhibition of β-oxidation gives rise to a compensatory increase in MCFA-TG synthesis, whereas etomoxir blocks both β-oxidation and MCFA-TG synthesis, indicating a strong off-target effect on DGAT1.
    DOI:  https://doi.org/10.1016/j.molmet.2020.101150
  36. Curr Opin Lipidol. 2021 Feb 01. 32(1): 76-77
    Triglycerides as target of cardiovascular risk reduction.
    Uwe J F Tietge.
      
    DOI:  https://doi.org/10.1097/MOL.0000000000000724
  37. Am J Transplant. 2021 Jan;21(1): 3
    When aging meets tregs: It's all about ROS stress.
    Xian C Li.
      
    DOI:  https://doi.org/10.1111/ajt.16436
  38. PLoS One. 2020 ;15(12): e0244499
    The mitochondria-targeted derivative of the classical uncoupler of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone is an effective mitochondrial recoupler.
    Iliuza R Iaubasarova, Ljudmila S Khailova, Alexander M Firsov, Vera G Grivennikova, Roman S Kirsanov, Galina A Korshunova, Elena A Kotova, Yuri N Antonenko.
      The synthesis of a mitochondria-targeted derivative of the classical mitochondrial uncoupler carbonyl cyanide-m-chlorophenylhydrazone (CCCP) by alkoxy substitution of CCCP with n-decyl(triphenyl)phosphonium cation yielded mitoCCCP, which was able to inhibit the uncoupling action of CCCP, tyrphostin A9 and niclosamide on rat liver mitochondria, but not that of 2,4-dinitrophenol, at a concentration of 1-2 μM. MitoCCCP did not uncouple mitochondria by itself at these concentrations, although it exhibited uncoupling action at tens of micromolar concentrations. Thus, mitoCCCP appeared to be a more effective mitochondrial recoupler than 6-ketocholestanol. Both mitoCCCP and 6-ketocholestanol did not inhibit the protonophoric activity of CCCP in artificial bilayer lipid membranes, which might compromise the simple proton-shuttling mechanism of the uncoupling activity on mitochondria.
    DOI:  https://doi.org/10.1371/journal.pone.0244499
  39. PLoS One. 2020 ;15(12): e0244826
    Paternal metabolic and cardiovascular programming of their offspring: A systematic scoping review.
    Claudia Eberle, Michaela F Kirchner, Raphaela Herden, Stefanie Stichling.
       BACKGROUND: There is lots of evidence that maternal peri-gestational metabolic, genomic and environmental conditions are closely linked to metabolic and cardiovascular outcomes in their offspring later in life. Moreover, there is also lotsof evidence that underlining mechanisms, such as molecular as well as epigenetic changes may alter the intrauterine environment leading to cardio-metabolic diseases in their offspring postnatal. But, there is also increasing evidence that cardio-metabolic diseases may be closely linked to their paternal metabolic risk factors, such as obesity, Type 2 Diabetes and other risk factors.
    OBJECTIVE: To analyse the evidence as well as specific risk factors of paternal trans-generational programming of cardio-metabolic diseases in their offspring.
    METHODS: Within a systematic scoping review, we performed a literature search in MEDLINE (PubMed) and EMBASE databases in August 2020 considering original research articles (2000-2020) that examined the impact of paternal programming on metabolic and cardiovascular offspring health. Epidemiological, clinical and experimental studies as well as human and animal model studies were included.
    RESULTS: From n = 3.199 citations, n = 66 eligible studies were included. We selected n = 45 epidemiological as well as clinical studies and n = 21 experimental studies. In brief, pre-conceptional paternal risk factors, such as obesity, own birth weight, high-fat and low-protein diet, undernutrition, diabetes mellitus, hyperglycaemia, advanced age, smoking as well as environmental chemical exposure affect clearly metabolic and cardiovascular health of their offspring later in life.
    CONCLUSIONS: There is emerging evidence that paternal risk factors, such as paternal obesity, diabetes mellitus, nutritional habits, advanced age and exposure to environmental chemicals or cigarette smoke, are clearly associated with adverse effects in metabolic and cardiovascular health in their offspring. Compared to maternal programming, pre-conceptional paternal factors might also have also a substantial effect in the sense of trans-generational programming of their offspring and need further research.
    DOI:  https://doi.org/10.1371/journal.pone.0244826
  40. Turk J Med Sci. 2020 Dec 28.
    Role of Dyslipidemia in Early Vascular Aging Syndrome.
    Alparslan KiliÇ, Onur Baydar, Denİz ElÇİk, Zİya Apaydin, Mehmet Mustafa Can.
       OBJECTIVE: Arterial stiffness, known as a predictor of early vascular aging, was defined as the main determinant of cardiovascular mortality and morbidity. However, the relationship between lipid profile and increased arterial stiffness is not clear. The aim of this study, to investigate the relationship between lipid profiles and increased arterial stiffness in patients with early vascular aging syndrome.
    METHODS: A total of 1582 participants, 504 (31.8%) of were male and the mean age was 52.8 ±14.2 years were enrolled in the study. Patients who applied to the hospital for various reasons and who had undergone 24-hour blood pressure Holter monitoring were included in this study. Patients were divided into four groups according to pulse wave velocity (PWV) quartiles (Q1 (<6,3), Q2 (6,3-7,4), Q3 (7,5-8,8), Q4 (>8,8)).
    RESULTS: We found that in the highest PWV group, patients had higher systolic blood pressure( SBP), diastolic blood pressure (DBP), glucose, BUN, creatinine, urinary albumin excretion (UAE), uric acid(UA), total cholesterol (TC), low-density lipoprotein ( LDL-C), Triglycerid (TG) and Non- high-density lipoprotein (HDL-C )levels. Additionally; Diabetes Mellitus (DM), age, Non-HDL-C and TG/ HDL-C levels were detected as independent risk factors of increased PWV in ordinal logistic regression analysis.
    CONCLUSIONS: Our study demonstrates that lipid parameters are strongly correlated with increased PWVvalue and early vascular aging. In daily clinical practice, TG\ HDL-C ratio, known as atherogenic index might be used routinely for predicted of early vascular aging and subclinical atherosclerosis.
    Keywords:  Arterial Stiffness; Lipid profile; Vascular Aging
    DOI:  https://doi.org/10.3906/sag-2008-165
  41. Crit Rev Food Sci Nutr. 2020 Dec 30. 1-56
    Gut microbiota and aging.
    Zongxin Ling, Xia Liu, Yiwen Cheng, Xiumei Yan, Shaochang Wu.
      Aging is characterized by the functional decline of tissues and organs and increased risk of aging-associated disorders, which pose major societal challenges and are a public health priority. Despite extensive human genetics studies, limited progress has been made linking genetics with aging. There is a growing realization that the altered assembly, structure and dynamics of the gut microbiota actively participate in the aging process. Age-related microbial dysbiosis is involved in reshaping immune responses during aging, which manifest as immunosenescence (insufficiency) and inflammaging (over-reaction) that accompany many age-associated enteric and extraenteric diseases. The gut microbiota can be regulated, suggesting a potential target for aging interventions. This review summarizes recent findings on the physiological succession of gut microbiota across the life-cycle, the roles and mechanisms of gut microbiota in healthy aging, alterations of gut microbiota and aging-associated diseases, and the gut microbiota-targeted anti-aging strategies.
    Keywords:  Aging; bacterial diversity; fecal microbiota transplantation; gut microbiota; lifespan; succession
    DOI:  https://doi.org/10.1080/10408398.2020.1867054
  42. Int J Mol Sci. 2020 Dec 10. pii: E9418. [Epub ahead of print]21(24):
    Toll-Like Receptor 2 at the Crossroad between Cancer Cells, the Immune System, and the Microbiota.
    Antonino Di Lorenzo, Elisabetta Bolli, Lidia Tarone, Federica Cavallo, Laura Conti.
      Toll-like receptor 2 (TLR2) expressed on myeloid cells mediates the recognition of harmful molecules belonging to invading pathogens or host damaged tissues, leading to inflammation. For this ability to activate immune responses, TLR2 has been considered a player in anti-cancer immunity. Therefore, TLR2 agonists have been used as adjuvants for anti-cancer immunotherapies. However, TLR2 is also expressed on neoplastic cells from different malignancies and promotes their proliferation through activation of the myeloid differentiation primary response protein 88 (MyD88)/nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway. Furthermore, its activation on regulatory immune cells may contribute to the generation of an immunosuppressive microenvironment and of the pre-metastatic niche, promoting cancer progression. Thus, TLR2 represents a double-edge sword, whose role in cancer needs to be carefully understood for the setup of effective therapies. In this review, we discuss the divergent effects induced by TLR2 activation in different immune cell populations, cancer cells, and cancer stem cells. Moreover, we analyze the stimuli that lead to its activation in the tumor microenvironment, addressing the role of danger, pathogen, and microbiota-associated molecular patterns and their modulation during cancer treatments. This information will contribute to the scientific debate on the use of TLR2 agonists or antagonists in cancer treatment and pave the way for new therapeutic avenues.
    Keywords:  DAMPs; Toll-like receptor 2; cancer; combined therapies; tumor microbiota; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms21249418
  43. J Clin Endocrinol Metab. 2020 Dec 31. pii: dgaa914. [Epub ahead of print]
    Diet and fat metabolism - uncovering key determinants of diabetes risk prediction in populations of African descent.
    Amber B Courville, Stephanie T Chung.
      
    Keywords:  African descent; de novo lipogenesis; fatty acids; type 2 diabetes risk
    DOI:  https://doi.org/10.1210/clinem/dgaa914
  44. Mol Pharmacol. 2020 Dec 31. pii: MOLPHARM-AR-2020-000108. [Epub ahead of print]
    Short Term Acyl-CoA:Cholesterol Acyltransferase Inhibition, Combined with Apoprotein A1 Over-expression, Promotes Atherosclerosis Inflammation Resolution Mice.
    Jaume Amengual, Yoscar Ogando, Cyrus Nikain, Alexandra Quezada, Kun Qian, Tomas Vaisar, Edward A Fisher.
      Acyl-CoA:cholesterol acyltransferase (ACAT) mediates cellular cholesterol esterification. In atherosclerotic plaque macrophages, ACAT promotes cholesteryl ester accumulation, resulting in foam cell formation and atherosclerosis progression. Its complete inactivation in mice, however, showed toxic effects because of an excess of free cholesterol (FC) in macrophages, which can cause ER stress, cholesterol crystal formation, and inflammasome activation. Our previous studies showed that long-term partial ACAT inhibition, achieved by dietary supplementation with Fujirebio F1394, delays atherosclerosis progression in apoprotein E-deficient (Apoe-/- ) mice by reducing plaque foam cell formation without inflammatory or toxic effects. Here, we determined whether short-term partial inhibition of ACAT, in combination with an enhanced systemic FC acceptor capacity, has synergistic benefits. Thus, we crossbred Apoe-/- with human apoprotein A1-transgenic (APOA1tg/tg ) mice, which have elevated cholesterol-effluxing high-density lipoprotein particles, and subjected Apoe-/- and APOA1tg/tg/Apoe-/- mice to an atherogenic diet to develop advanced plaques. Then mice were either euthanized (baseline) or fed purified standard diet with or without F1394 for four more weeks. Plaques of APOA1tg/tg/Apoe-/- mice fed F1394 showed a 60% reduction of macrophages accompanied by multiple other benefits, such as reduced inflammation and favorable changes in extracellular composition, in comparison to Apoe-/- baseline mice. In addition, there was no accumulation of cholesterol crystals or signs of toxicity. Overall, these results show that short-term partial ACAT inhibition, coupled to increased cholesterol efflux capacity, favorably remodels atherosclerosis lesions, supporting the potential of these combined therapies in the treatment of advanced atherosclerosis. Significance Statement Short-term pharmacological inhibition of ACAT-mediated cholesterol esterification, in combination with increased free cholesterol efflux acceptors, has positive effects in mice by (1) reducing the inflammatory state of the plaque macrophages, and (2) favoring compositional changes associated with plaque stabilization. These effects occur without toxicity, showing the potential of these combined therapies in the treatment of advanced atherosclerosis.
    Keywords:  apolipid proteins; atherosclerosis; cholesterol; cholesterol metabolism/lipoproteins; macrophages
    DOI:  https://doi.org/10.1124/molpharm.120.000108
  45. Int J Mol Sci. 2020 Dec 23. pii: E83. [Epub ahead of print]22(1):
    Proinflammatory Cytokines Perturb Mouse and Human Pancreatic Islet Circadian Rhythmicity and Induce Uncoordinated β-Cell Clock Gene Expression via Nitric Oxide, Lysine Deacetylases, and Immunoproteasomal Activity.
    Phillip Alexander Keller Andersen, Volodymyr Petrenko, Peter Horskjær Rose, Melissa Koomen, Nico Fischer, Seyed Mojtaba Ghiasi, Tina Dahlby, Charna Dibner, Thomas Mandrup-Poulsen.
      Pancreatic β-cell-specific clock knockout mice develop β-cell oxidative-stress and failure, as well as glucose-intolerance. How inflammatory stress affects the cellular clock is under-investigated. Real-time recording of Per2:luciferase reporter activity in murine and human pancreatic islets demonstrated that the proinflammatory cytokine interleukin-1β (IL-1β) lengthened the circadian period. qPCR-profiling of core clock gene expression in insulin-producing cells suggested that the combination of the proinflammatory cytokines IL-1β and interferon-γ (IFN-γ) caused pronounced but uncoordinated increases in mRNA levels of multiple core clock genes, in particular of reverse-erythroblastosis virus α (Rev-erbα), in a dose- and time-dependent manner. The REV-ERBα/β agonist SR9009, used to mimic cytokine-mediated Rev-erbα induction, reduced constitutive and cytokine-induced brain and muscle arnt-like 1 (Bmal1) mRNA levels in INS-1 cells as expected. SR9009 induced reactive oxygen species (ROS), reduced insulin-1/2 (Ins-1/2) mRNA and accumulated- and glucose-stimulated insulin secretion, reduced cell viability, and increased apoptosis levels, reminiscent of cytokine toxicity. In contrast, low (<5,0 μM) concentrations of SR9009 increased Ins-1 mRNA and accumulated insulin-secretion without affecting INS-1 cell viability, mirroring low-concentration IL-1β mediated β-cell stimulation. Inhibiting nitric oxide (NO) synthesis, the lysine deacetylase HDAC3 and the immunoproteasome reduced cytokine-mediated increases in clock gene expression. In conclusion, the cytokine-combination perturbed the intrinsic clocks operative in mouse and human pancreatic islets and induced uncoordinated clock gene expression in INS-1 cells, the latter effect associated with NO, HDAC3, and immunoproteasome activity.
    Keywords:  chronobiology; diabetes; epigenetics; immuno-metabolism; nitric oxide synthase
    DOI:  https://doi.org/10.3390/ijms22010083
  46. Blood. 2020 Dec 24. 136(26): 2968-2969
    Novel drug for WHIM.
    Jan Palmblad.
      
    DOI:  https://doi.org/10.1182/blood.2020008848
  47. Nutrients. 2020 Dec 23. pii: E18. [Epub ahead of print]13(1):
    Caloric Intake in Renal Patients: Repercussions on Mineral Metabolism.
    Angela Vidal, Rafael Ríos, Carmen Pineda, Ignacio López, Ana I Raya, Escolástico Aguilera-Tejero, Mariano Rodríguez.
      The aim of this paper is to review current knowledge about how calorie intake influences mineral metabolism focussing on four aspects of major interest for the renal patient: (a) phosphate (P) handling, (b) fibroblast growth factor 23 (FGF23) and calcitriol synthesis and secretion, (c) metabolic bone disease, and (d) vascular calcification (VC). Caloric intake has been shown to modulate P balance in experimental models: high caloric intake promotes P retention, while caloric restriction decreases plasma P concentrations. Synthesis and secretion of the phosphaturic hormone FGF23 is directly influenced by energy intake; a direct correlation between caloric intake and FGF23 plasma concentrations has been shown in animals and humans. Moreover, in vitro, energy availability has been demonstrated to regulate FGF23 synthesis through mechanisms in which the molecular target of rapamycin (mTOR) signalling pathway is involved. Plasma calcitriol concentrations are inversely proportional to caloric intake due to modulation by FGF23 of the enzymes implicated in vitamin D metabolism. The effect of caloric intake on bone is controversial. High caloric intake has been reported to increase bone mass, but the associated changes in adipokines and cytokines may as well be deleterious for bone. Low caloric intake tends to reduce bone mass but also may provide indirect (through modulation of inflammation and insulin regulation) beneficial effects on bone. Finally, while VC has been shown to be exacerbated by diets with high caloric content, the opposite has not been demonstrated with low calorie intake. In conclusion, although prospective studies in humans are needed, when planning caloric intake for a renal patient, it is important to take into consideration the associated changes in mineral metabolism.
    Keywords:  calories; diet; kidney disease; mineral metabolism
    DOI:  https://doi.org/10.3390/nu13010018
  48. Cell Biol Int. 2021 Jan 02.
    The effect of inflammatory factors and their inhibitors on the hematopoietic stem cells fate.
    Sahar Najafi, Majid Ghanavat, Saied Shahrabi, Zahra Gatavizadeh, Najmaldin Saki.
      Inflammatory cytokines exert different effects on hematopoietic stem cells (HSCs), lead to the development of various cell lineages in bone marrow (BM) and are thus a differentiation axis for HSCs. The content used in this article has been obtained by searching PubMed database and Google Scholar search engine of English-language articles (1995-2020) using "Hematopoietic stem cell ","Inflammatory cytokine", "Homeostasis" and "Myelopoiesis ". Inflammatory cytokines are involved in the differentiation and proliferation of hematopoietic progenitors to compensate for cellular death due to inflammation. Since each of these cytokines differentiates HSCs into a specific cell line, the difference in the effect of these cytokines on the fate of HSC progenitors can be predicted. Inhibitors of these cytokines can also control the inflammatory process as well as the cells involved in leukemic conditions. In general, inflammatory signaling can specify the dominant cell line in BM to counteract inflammation and leukemic condition via stimulating or inhibiting hematopoietic progenitors. Therefore, detection of the effects of inflammatory cytokines on the differentiation of HSCs can be an appropriate approach to check inflammatory and leukemic conditions and the suppression of these cytokines by their inhibitors allows for control of homeostasis in stressful conditions. This article is protected by copyright. All rights reserved.
    Keywords:  Cytokine; Inflammation; Interleukins; Stem Cells
    DOI:  https://doi.org/10.1002/cbin.11545
  49. Leuk Lymphoma. 2020 Dec 25. 1-3
    Metabolism meets apoptosis in AML.
    Natalia Timofeeva, Varsha Gandhi.
      
    DOI:  https://doi.org/10.1080/10428194.2020.1858294
  50. STAR Protoc. 2020 Dec 18. 1(3): 100163
    Transduction of Primary AML Cells with Lentiviral Vector for In Vitro Study or In Vivo Engraftment.
    Aaron D Schimmer, Rashim Pal Singh, Ayesh K Seneviratne, Geethu E Thomas, Neil MacLean, Rose Hurren.
      We describe a method to silence genes in primary acute myeloid leukemia cells by transducing them with shRNA in lentiviral vectors. The transduction of primary non-adherent cells is particularly challenging. The protocol will aid in performing such experiments and is particularly helpful to prepare cells for in vivo engraftment studies. Use of a special medium supplemented with cytokines preserves the viability of the leukemic stem cells and their ability to engraft the marrow of immune-deficient mice. For complete details on the use and execution of this protocol, please refer to Singh et al. (2020).
    Keywords:  Cancer; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2020.100163
  51. J Pers Med. 2020 Dec 29. pii: E19. [Epub ahead of print]11(1):
    Implementation Science to Increase Adoption of Genomic Medicine: An Urgent Need.
    Hana Bangash, Iftikhar J Kullo.
      Advances in genomics have the potential to improve human health [...].
    DOI:  https://doi.org/10.3390/jpm11010019
  52. Blood Rev. 2020 Dec 09. pii: S0268-960X(20)30136-3. [Epub ahead of print] 100786
    Metabolic regulation of the bone marrow microenvironment in leukemia.
    Binyan Xu, Rong Hu, Zhao Liang, Tong Chen, Jianyu Chen, Yuxing Hu, Yirong Jiang, Yuhua Li.
      Most leukemia patients experience little benefit from immunotherapy, in part due to the immunosuppressive bone marrow microenvironment. Various metabolic mechanisms orchestrate the behaviors of immune cells and leukemia cells in the bone marrow microenvironment. Furthermore, leukemia cells regulate the bone marrow microenvironment through metabolism to generate an adequate supply of energy and to escape antitumor immune surveillance. Thus, the targeting of the interaction between leukemia cells and the bone marrow microenvironment provides a new therapeutic avenue. In this review, we describe the concept of the bone marrow microenvironment and several important metabolic processes of leukemia cells within the bone marrow microenvironment, including carbohydrate, lipid, and amino acid metabolism. In addition, we discuss how these metabolic pathways regulate antitumor immunity and reveal potential therapeutic targets.
    Keywords:  Bone marrow microenvironment; Immunotherapy; Leukemia; Metabolic regulation
    DOI:  https://doi.org/10.1016/j.blre.2020.100786
  53. Biomed Pharmacother. 2020 Dec 24. pii: S0753-3322(20)31332-9. [Epub ahead of print]134 111139
    Olive leaf extract impairs mitochondria by pro-oxidant activity in MDA-MB-231 and OVCAR-3 cancer cells.
    Reyes Benot-Dominguez, Maria Grazia Tupone, Vanessa Castelli, Michele d'Angelo, Elisabetta Benedetti, Massimiliano Quintiliani, Benedetta Cinque, Iris Maria Forte, Maria Grazia Cifone, Rodolfo Ippoliti, Barbara Barboni, Antonio Giordano, Annamaria Cimini.
      Breast and ovarian cancers are the leading and fifth reason for tumor death among females, respectively. Recently, many studies demonstrated antiproliferative activities of natural aliments in cancer. In this study, we investigated the antitumor potential of Olive Leaf Extract (OLE) in triple-negative breast and ovarian cancer cells. A HPLC/DAD analysis on OLE has been performed to assess the total polyphenolics and other secondary metabolites content. HCEpiC, MDA-MB-231, and OVCAR-3 cell lines were used. MTS, Cytofluorimetric, Western Blot analysis were performed to analyze cell viability, cell proliferation, apoptosis, and oxidative stress. Fluorimetric and IncuCyte® analyses were carried out to evaluate apoptosis and mitochondrial function. We confirmed that OLE, containing a quantity of oleuropein of 87 % of the total extract, shows anti-proliferative and pro-apoptotic activity on MDA-MB-231 cells. For the first time, our results indicate that OLE inhibits OVCAR-3 cell viability inducing cell cycle arrest, and it also increases apoptotic cell death up-regulating the protein level of cleaved-PARP and caspase 9. Moreover, our data show that OLE treatment causes a significant decrease in mitochondrial functionality, paralleled by a reduction of mitochondrial membrane potential. Interestingly, OLE increased the level of intracellular and mitochondrial reactive oxygen species (ROS) together with a decreased activity of ROS scavenging enzymes, confirming oxidative stress in both models. Our data demonstrate that mitochondrial ROS generation represented the primary mechanism of OLE antitumor activity, as pretreatment with antioxidant N-acetylcysteine prevented OLE-induced cell cycle arrest and apoptosis.
    Keywords:  Mediterranean diet; Mitochondria; OLE; Ovarian cancer; ROS; TNBC
    DOI:  https://doi.org/10.1016/j.biopha.2020.111139
  54. Clin Obes. 2020 Dec 26. e12434
    A systematic review of randomized controlled trials of dietary interventions for weight loss in adults in the Middle East and north Africa region.
    Hadeel Zaghloul, Hadya Elshakh, Abdullah Elzafarany, Odette Chagoury, Barbara McGowan, Shahrad Taheri.
      The prevalence and incidence of obesity, and associated complications, such as type 2 diabetes, in the Middle East and north Africa (MENA) region rank among the highest in the world. Little is known about the effectiveness of dietary weight loss interventions conducted in the MENA region. We conducted a systematic review of randomized clinical trials aiming to assess the effectiveness of dietary interventions for weight loss in the adult population originating from and residing in the MENA region. In accordance with PRISMA guidelines, PubMed, CINAHL, Cochrane, and EMBASE were systematically searched for randomized controlled trials (RCT) using dietary interventions for weight loss conducted in the MENA region. RCTs examining weight loss as an outcome in adults (≥ 18 years old) were included. The Cochrane Collaboration tool for assessing risk of bias was used to ascertain the quality of the eligible RCTs and the Template for Intervention Description and Replication for population health and policy interventions (TIDieR-PHP) checklist was used to evaluate the reporting of the interventions. Twenty-nine RCTs including 2792 adults from five countries in the MENA region met the search criteria. Study participants were predominantly middle-aged females. Duration of follow up was mostly 3 months or less. Weight loss ranged from -0.7 to 16 kg across all intervention groups and the average weight loss was 4.8 kg. There was paucity of description of the weight loss interventions and variations amongst studies did not allow a meta-analysis of findings. It was not possible to draw firm conclusions on the effectiveness of dietary weight loss interventions in the region. High quality studies using more structured interventions of longer duration with standardized outcome measures are needed in the MENA region to support clinical practice with evidence-based interventions for obesity.
    Keywords:  Middle East; diet; north Africa; systematic review; weight loss
    DOI:  https://doi.org/10.1111/cob.12434
  55. Clin Invest Med. 2020 Dec 27. 43(4): E1
    Hats off to the CIM Reviewers of 2020.
    Robert Bortolussi, Alex Levit, Dilini Vethanayagam.
      For over 40 years the Journal of Clinical and Investigative Medicine (CIM) has published articles of value to clinician investigators in Canada and elsewhere. We try our best to strive for the highest standards and to remain relevant to our readers, but we cannot achieve these goals without the help of our reviewers, all of whom play a vital role in maintaining the integrity of the scientific process. Without their efforts, academic excellence would falter. So, a massive "thank you" to the more than 80 reviewers who have contributed their talent and time to CIM over the past year (September 1, 2019 to August 31, 2020).
  56. J Aging Health. 2020 Dec 31. 898264320984016
    Love thy Aged? A State-Level Analysis of Religiosity and Mobility in Aging Populations During the Novel Coronavirus (COVID-19) Pandemic.
    Terrence D Hill, Kelsey E Gonzalez, Laura Upenieks.
      Objectives: We test whether the association between state religiosity and distance traveled is moderated by population age during the novel coronavirus (COVID-19) pandemic. Methods: Mobility is operationalized as the state-level average median distance traveled from February 24 to May 4 across the contiguous United States. Shelter-in-place rates are operationalized as the state-level percentage of users staying home. State religiosity is measured with an index of aggregated religious identities, beliefs, and practices. Population age is indicated by the state percentage of adults aged 65 years and older. We model population mobility using regression with state clustered robust SEs. Results: We observe that religious states tend to travel more during the early stages of the pandemic. However, the behavioral risks associated with state religiosity are less pronounced in states with larger older populations. Discussion: We contribute to our understanding of the social patterning of pandemic mobility in aging populations.
    Keywords:  COVID-19; aging populations; coronavirus; mobility; religion/spirituality
    DOI:  https://doi.org/10.1177/0898264320984016
  57. Cannabis Cannabinoid Res. 2020 ;5(4): 290-297
    Cannabinoids in the Management of Acute Pain: A Systematic Review and Meta-analysis.
    Aaron Gazendam, Nicholas Nucci, Kyle Gouveia, Hassaan Abdel Khalik, Luc Rubinger, Herman Johal.
      Objective: To synthesize the best evidence surrounding the efficacy of cannabinoids for acute pain in the clinical setting based on subjective pain scores and observed adverse effects. Design: Systematic review with meta-analysis. Data Sources: PubMed, Embase, Cochrane Databases, and Google Scholar. Eligibility Criteria: English-language randomized-controlled clinical trials comparing cannabinoids with placebo in patients with acute pain. Data Extraction and Synthesis: Study quality was assessed using the Cochrane risk of bias tool. All stages were conducted independently by a team of three reviewers. Data were pooled through meta-analysis and stratified by route of administration. Primary Outcomes and Measures: Patient-reported pain and adverse events (AEs). Results: Six trials (678 participants) were included examining oral (5 trials) and intramuscular (1 trial) cannabinoids. Overall, there was a small but statistically significant treatment effect favoring the use of cannabinoids over placebo (-0.90, 95% confidence interval [CI] -1.69 to -0.1, i 2=65%, p=0.03). When stratified by route of administration, intramuscular cannabinoids were found to have a significant reduction in pain relative to placebo (-2.98, 95% CI -4.09 to -1.87, i 2=0%, p<0.0001). No difference in effect was observed between oral cannabinoids and placebo (-0.21, 95% CI -0.64 to 0.22, i 2=3%, p=0.34). Serious AEs were rare, and similar across the cannabinoid (14/374, 3.7%) and placebo groups (8/304, 2.6%). Conclusions: There is low-quality evidence indicating that cannabinoids may be a safe alternative for a small but significant reduction in subjective pain score when treating acute pain, with intramuscular administration resulting in a greater reduction relative to oral. Higher quality, long-term randomized-controlled trials examining whether there may be a role for cannabinoids in treating acute pain are required.
    Keywords:  acute pain; cannabinoids; meta-analysis; surgical pain; systematic review
    DOI:  https://doi.org/10.1089/can.2019.0079
  58. Trends Cancer. 2020 Dec 21. pii: S2405-8033(20)30309-5. [Epub ahead of print]
    Targeting the Mevalonate Pathway in Cancer.
    Dennis Juarez, David A Fruman.
      The mevalonate synthesis inhibitors, statins, are mainstay therapeutics for cholesterol management and cardiovascular health. Thirty years of research have uncovered supportive roles for the mevalonate pathway in numerous cellular processes that support oncogenesis, most recently macropinocytosis. Central to the diverse mechanisms of statin sensitivity is an acquired dependence on one mevalonate pathway output, protein geranylgeranylation. New chemical prenylation probes and the discovery of a novel geranylgeranyl transferase hold promise to deepen our understanding of statin mechanisms of action. Further, insights into statin selection and the counterproductive role of dietary geranylgeraniol highlight how we should assess statins in the clinic. Lastly, rational combination strategies preview how statins will enter the oncology toolbox.
    Keywords:  cholesterol; combinations; mevalonate; prenylation; statins
    DOI:  https://doi.org/10.1016/j.trecan.2020.11.008
  59. Blood. 2020 Dec 24. 136(26): 2969-2970
    Distract NK cell killing: give them a fatty meal.
    Lisa R Forbes.
      
    DOI:  https://doi.org/10.1182/blood.2020008216
  60. J Clin Endocrinol Metab. 2020 Dec 31. pii: dgaa919. [Epub ahead of print]
    Insulin-Stimulated Muscle Glucose Uptake and Insulin Signaling in Lean and Obese Humans.
    Paola A Ramos, Kelli A Lytle, Danae Delivanis, Søren Nielsen, Nathan K LeBrasseur, Michael D Jensen.
       PURPOSE: Skeletal muscle is the primary site for insulin-stimulated glucose disposal and muscle insulin resistance is central to abnormal glucose metabolism in obesity. Whether muscle insulin signaling to the level of Akt/AS160 is intact in insulin resitant obese humans is controversial.
    METHODS: We defined a linear range of insulin-stimulated systemic and leg glucose uptake in 14 obese and 14 non-obese volunteers using a 2-step insulin clamp (Protocol 1) and then examined the obesity-related defects in muscle insulin action in 16 non-obese and 25 obese male and femal volunteers matched for fitness using a one-step, hyperinsulinemic, euglycemic clamp coupled with muscle biopsies (Protocol 2).
    RESULTS: Insulin-stimulated glucose disposal (Si) was reduced by > 60% (P < 0.0001) in the obese group in Protocol 2; however, the phosphorylation of Akt and its downstream effector AS160 were not different between non-obese and obese groups. The increase in phosphorylation of Akt2 in response to insulin was positively correlated with Si for both the non-obese (r=0.53, P=0.03) and the obese (r=0.55, P= 0.01) groups. Total muscle GLUT4 protein was 17% less (P < 0.05) in obese subjects.
    MAIN CONCLUSIONS: We suggest that reduced muscle glucose uptake in obesity is not due to defects in the insulin signaling pathway at the level of Akt/AS160, which suggests there remain significnt gaps in our knowledge of muscle insulin resistance in obesity. Our data imply that models of acute lipotoxicity don't replicate the pathophysiology of obesity.
    Keywords:  Akt signaling; glucose uptake; insulin clamp; insulin resistance; obesity; skeletal muscle
    DOI:  https://doi.org/10.1210/clinem/dgaa919
  61. J Clin Med. 2020 Dec 19. pii: E4106. [Epub ahead of print]9(12):
    Food Implications in Central Sensitization Syndromes.
    Elena Aguilar-Aguilar, Helena Marcos-Pasero, Maria P Ikonomopoulou, Viviana Loria-Kohen.
      Fibromyalgia (FM), chronic fatigue syndrome (CFS) and multiple chemical sensitivity (MCS) are some of the central sensitization syndromes (CSSs). The complexity of their diagnosis, the high interindividual heterogeneity and the existence of multi-syndromic patients requires a multifaceted treatment. The scientific literature is contradictory regarding the role of food in CSS, and evidence on the role of nutrition in MCS is particularly scarce. This review consists in gathering information about the current status of dietary recommendations (i.e., special dietary interventions, the role of additives, presence of micronutrient deficiencies, nutritional supplements and elimination of other nutrients and substances) and discussing the scientific evidence in depth to shed light on appropriate nutritional treatment managements for CSS patients. Current indications show that dietary modifications may vastly improve the patients' quality of life at a low cost. We suggest personalized treatment, taking into consideration the severity of the disease symptoms, quality of life, coexistence with other diseases, pharmacological treatment, changing clinical characteristics, nutritional status, energy requirements and food tolerances, among others, as the best ways to tailor specific dietary interventions. These approaches will partially overcome the lack of scientific and clinical research on MSC. Patients should also be advised on the serious consequences of following dietary guidelines without a dietitian's and clinician's supervision.
    Keywords:  additives; central sensitization syndromes; chronic fatigue syndrome; dietary interventions; fibromyalgia; functional somatic syndromes; micronutrient deficiencies; multiple chemical sensitivity; nutritional supplements
    DOI:  https://doi.org/10.3390/jcm9124106
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