bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–04–25
nineteen papers selected by
Ayesh Seneviratne, University of Toronto
  1. Importance of Clonal Hematopoiesis in Heart Failure.
  2. Lipid metabolism and lipid signals in aging and longevity.
  3. Beyond weight loss in nonalcoholic fatty liver disease: the role of carbohydrate restriction.
  4. A comprehensive transcriptome signature of murine hematopoietic stem cell aging.
  5. Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism.
  6. Vitamin D insufficiency is associated with metabolic syndrome independent of insulin resistance and obesity in young, but not in old adults - Results from The Berlin Aging Study II.
  7. Mitochondrial Sirt3 contributes to the bone loss caused by aging or estrogen deficiency.
  8. Ketogenic diet alleviates colitis by reduction of colonic group 3 innate lymphoid cells through altering gut microbiome.
  9. Autologous fecal microbiota transplantation can retain the metabolic achievements of dietary interventions.
  10. Strategies for Dodging the Obstacles in CAR T Cell Therapy.
  11. Mitochondrial metabolism as a target for acute myeloid leukemia treatment.
  12. Enemy or ally? Fasting as an essential regulator of immune responses.
  13. Aged Garlic Extract Reduces IL-6: A Double-Blind Placebo-Controlled Trial in Females with a Low Risk of Cardiovascular Disease.
  14. Base Editors Flex Sights on Sickle-Cell Disease.
  15. Caloric restriction creates a metabolic pattern of chronological aging delay that in budding yeast differs from the metabolic design established by two other geroprotectors.
  16. One Stone, Two Birds: The Roles of Tim-3 in Acute Myeloid Leukemia.
  17. Ketogenic diets and appetite regulation.
  18. Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections.
  19. Lipid effects of sodium-glucose cotransporter 2 inhibitors.
  1. Trends Cardiovasc Med. 2021 Apr 20. pii: S1050-1738(21)00049-9. [Epub ahead of print]
    Importance of Clonal Hematopoiesis in Heart Failure.
    Nicholas W Chavkin, Kyung-Duk Min, Kenneth Walsh.
      Heart failure is prevalent in the elderly population. Inflammatory processes can contribute to the progression of heart failure by altering the balance of tissue healing and pathological remodeling during the injury response. New findings show that aging can alter immune cell phenotypes through the process of clonal hematopoiesis. This condition results from acquired somatic DNA mutations in specific driver genes that give rise to clonal expansions of mutant hematopoietic cells with overactive inflammatory properties. Recent clinical and experimental studies have shown that clonal hematopoiesis is prevalent in heart failure patients and associated with poor prognosis. In this review, we summarize current evidence that associates clonal hematopoiesis with the progression of heart failure. We further describe the mechanistic links between clonal hematopoiesis and the pro-inflammatory responses that can contribute to pathological outcomes in the heart. Finally, we provide perspectives on future research directions in the area of clonal hematopoiesis and heart failure.
    Keywords:  Clonal Hematopoiesis; Heart Failure; Inflammation
    DOI:  https://doi.org/10.1016/j.tcm.2021.04.005
  2. Dev Cell. 2021 Apr 16. pii: S1534-5807(21)00309-9. [Epub ahead of print]
    Lipid metabolism and lipid signals in aging and longevity.
    Ayse Sena Mutlu, Jonathon Duffy, Meng C Wang.
      Lipids play crucial roles in regulating aging and longevity. In the past few decades, a series of genetic pathways have been discovered to regulate lifespan in model organisms. Interestingly, many of these regulatory pathways are linked to lipid metabolism and lipid signaling. Lipid metabolic enzymes undergo significant changes during aging and are regulated by different longevity pathways. Lipids also actively modulate lifespan and health span as signaling molecules. In this review, we summarize recent insights into the roles of lipid metabolism and lipid signaling in aging and discuss lipid-related interventions in promoting longevity.
    Keywords:  aging; lipid metabolism; lipid signals; longevity
    DOI:  https://doi.org/10.1016/j.devcel.2021.03.034
  3. Curr Opin Clin Nutr Metab Care. 2021 Apr 16.
    Beyond weight loss in nonalcoholic fatty liver disease: the role of carbohydrate restriction.
    Renata Risi, Rossella Tozzi, Mikiko Watanabe.
       PURPOSE OF REVIEW: The low fat diet (LFD) is currently the first choice to treat nonalcoholic fatty liver disease (NAFLD) alongside with physical activity. However, low carbohydrate diets (LCDs) and ketogenic diets have gained attention lately, thanks to their favourable impact in reducing intrahepatic triglyceride content. We therefore aimed at providing an update on recent evidence evaluating the hepatoprotective effects of such dietary interventions.
    RECENT FINDINGS: Novel findings confirmed previous evidence by showing beneficial effects on liver fat content reduction for both LFDs and LCDs. The further restriction of carbohydrates to less than 50 g/day, usually leading to ketosis, confirmed to produce an improvement in NAFLD, with very low-calorie ketogenic diets possibly proving particularly beneficial thanks to the significant weight loss that can be obtained.
    SUMMARY: Most of the latest evidence shows that carbohydrate restriction plays a fundamental role in the modulation of lipid metabolism leading to similar efficacy in improving NAFLD compared with LFDs. The hepatoprotective role of carbohydrate restriction appears to be boosted when ketogenesis is induced, when the total calorie intake is extremely reduced, or, possibly, when dietary interventions have reduced content in free sugars, making such interventions valuable tools to deal with NAFLD.
    DOI:  https://doi.org/10.1097/MCO.0000000000000762
  4. Blood. 2021 Apr 19. pii: blood.2020009729. [Epub ahead of print]
    A comprehensive transcriptome signature of murine hematopoietic stem cell aging.
    Arthur Flohr Svendsen, Daozheng Yang, Kyung Mok Kim, Seka S Lazare, Natalia Skinder, Erik Zwart, Anna Mura-Meszaros, Albertina Ausema, Björn von Eyss, Gerald de Haan, Leonid V Bystrykh.
      We surveyed 16 published and unpublished data sets to determine whether a consistent pattern of transcriptional deregulation in aging murine hematopoietic stem cells (HSC) exists. Despite substantial heterogeneity between individual studies, we uncovered a core and robust HSC aging signature. We detected increased transcriptional activation in aged HSCs, further confirmed by chromatin accessibility analysis. Unexpectedly, using two independent computational approaches, we established that deregulated aging genes consist largely of membrane-associated transcripts, including many cell surface molecules previously not associated with HSC biology. We show that Selp, the most consistent deregulated gene, is not merely a marker for aged HSCs but is associated with HSC functional decline. Additionally, single-cell transcriptomics analysis revealed increased heterogeneity of the aged HSC pool. We identify the presence of transcriptionally "young-like" HSCs in aged bone marrow. We share our results as an online resource and demonstrate its utility by confirming that exposure to sympathomimetics, and deletion of Dnmt3a/b, molecularly resembles HSC rejuvenation or aging, respectively.
    DOI:  https://doi.org/10.1182/blood.2020009729
  5. Circ Res. 2021 Apr 23.
    Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism.
    Wusheng Xiao, William M Oldham, Carnen Priolo, Arvind K Pandey, Joseph Loscalzo.
      Rationale: Specific mechanisms linking inflammation and metabolic re-programming, two hallmarks of many pathobiological processes, remain incompletely defined. Objective: To delineate the integrative regulatory actions governing inflammation and metabolism in endothelial cells (ECs). Methods and Results: Metabolomic profiling, glucose labeling and tracing, and Seahorse extracellular flux analyses revealed that the inflammatory mediators, tumor necrosis factor α (TNFα) and lipopolysaccharide (LPS), extensively reprogram cellular metabolism, and particularly enhance glycolysis, mitochondrial oxidative phosphorylation (OXPHOS), and the pentose phosphate pathway (PPP) in primary human arterial ECs. Mechanistically, the enhancement in glycolysis and PPP is mediated by activation of the nuclear factor-κB (NF-κB)-6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase 3 (PFKFB3) axis and upregulation of glucose 6-phosphate dehydrogenase (G6PD), respectively; while enhanced OXPHOS was attributed to suppression of the forkhead box O1 (FOXO1)-pyruvate dehydrogenase kinase 4 (PDK4) axis. Restoration of the FOXO1-PDK4 axis attenuated the TNFα- or LPS-induced increase in OXPHOS but worsened inflammation in vitro, whereas enhancement of OXPHOS by pharmacological blockade of PDKs attenuated inflammation in mesenteric vessels of LPS-treated mice. Notably, suppression of G6PD expression or its activity potentiated the metabolic shift to glycolysis and/or endothelial inflammation, while inhibition of the NF-κB-PFKFB3 signaling, conversely, blunted the increased glycolysis and/or inflammation in in vitro and in vivo sepsis models. Conclusions: These results indicate that inflammatory mediators modulate the metabolic fates of glucose, and that stimulation of glycolysis promotes inflammation, whereas enhancement of OXPHOS and the PPP suppresses inflammation in the endothelium. Characterization of these immunometabolic phenotypes may have implications for the pathogenesis and treatment of many cardiovascular diseases.
    Keywords:  Glucose-6-phosphate dehydrogenase; metabolic reprogramming; phosphofructo-2-kinase/fructose-2,6,bisphosphatase 3; pyruvate dehydrogenase kinase 4
    DOI:  https://doi.org/10.1161/CIRCRESAHA.120.318805
  6. Diabetes Metab Res Rev. 2021 Apr 22.
    Vitamin D insufficiency is associated with metabolic syndrome independent of insulin resistance and obesity in young, but not in old adults - Results from The Berlin Aging Study II.
    Nikolaus Buchmann, Nils Eckstein, Dominik Spira, Ilja Demuth, Elisabeth Steinhagen-Thiessen, Kristina Norman.
       PURPOSE: Age-related changes affect vitamin D absorption and metabolism. Low 25-hydroxyvitamin D concentrations have been reported as risk factor for the development of metabolic syndrome (MetS). However, recent evaluations suggest this association might be explained by obesity or insulin resistance in subjects with MetS. Our aim was to analyze associations between vitamin D insufficiency and MetS in a young cohort without diabetes and two senior cohorts with and without diabetes.
    METHODS: 416 young and 1357 older BASE-II participants were analyzed. Type 2 diabetes (T2D) was defined according to European Society of Cardiology (ESC) guidelines, MetS as suggested by International Diabetes Federation/American Heart Association/National Heart, Lung and Blood Institute (IDF/AHA/NHLBI 2009). Vitamin D insufficiency was defined as 25-hydroxyvitamin D concentrations < 50 nmol/l. Among other confounders, BMI and insulin resistance were taken into account.
    RESULTS: MetS was prevalent in 7.7% of the young and in 35.6% of the older BASE-II participants and T2D occurred in 12.7% of the older participants. In young subjects without diabetes, vitamin D insufficiency was associated with an independent 3.2-fold increased odds of having MetS (OR: 3.2 CI: 1.0-8.7; p=0.042). However, in the older participants, this association was lost once BMI was taken into account among those with diabetes, and once insulin resistance was taken into account among those without diabetes.
    CONCLUSION: Independent associations between vitamin D insufficiency and MetS were only found among young subjects without diabetes. In the older adults, BMI annihilated these associations among subjects without diabetes as did HOMA-IR among subjects with diabetes. This article is protected by copyright. All rights reserved.
    Keywords:  diabetes; dietary vitamin D intake; metabolic syndrome; vitamin D
    DOI:  https://doi.org/10.1002/dmrr.3457
  7. JCI Insight. 2021 Apr 20. pii: 146728. [Epub ahead of print]
    Mitochondrial Sirt3 contributes to the bone loss caused by aging or estrogen deficiency.
    Wen Ling, Kimberly Krager, Kimberly K Richardson, Aaron D Warren, Filipa Ponte, Nukhet Aykin-Burns, Stavros C Manolagas, Maria Almeida, Ha-Neui Kim.
      Altered mitochondria activity in osteoblasts and osteoclast has been implicated in the loss of bone mass associated with aging and estrogen deficiency - the two most common causes of osteoporosis. However, the mechanisms that control mitochondrial metabolism in bone cells during health or disease remain unknown. The mitochondrial deacetylase Sirtuin-3 (Sirt3) has been earlier implicated in age-related diseases. Here, we show that deletion of Sirt3 had no effect on the skeleton of young mice but attenuated the age-related loss of bone mass in both sexes. This effect was associated with impaired bone resorption. Osteoclast progenitors from aged Sirt3 null mice were able to differentiate into osteoclasts. Albeit, the differentiated cells exhibited impaired polykaryon formation and resorptive activity as well as decreased oxidative phosphorylation and mitophagy. The Sirt3 inhibitor LC-0296 recapitulated the effects of Sirt3 deletion in osteoclast formation and mitochondrial function, and its administration to aging mice increased bone mass. Deletion of Sirt3 also attenuated the increase in bone resorption and loss of bone mass caused by estrogen deficiency. These findings suggest that Sirt3 inhibition and the resulting impairment of osteoclast mitochondrial function could be a novel therapeutic intervention for the two most important causes of osteoporosis.
    Keywords:  Bone Biology; Mitochondria; Osteoclast/osteoblast biology; Osteoporosis
    DOI:  https://doi.org/10.1172/jci.insight.146728
  8. Signal Transduct Target Ther. 2021 Apr 23. 6(1): 154
    Ketogenic diet alleviates colitis by reduction of colonic group 3 innate lymphoid cells through altering gut microbiome.
    Cheng Kong, Xuebing Yan, Yongqiang Liu, Linsheng Huang, Yefei Zhu, Jide He, Renyuan Gao, Matthew F Kalady, Ajay Goel, Huanlong Qin, Yanlei Ma.
      Accumulating evidence suggests that ketogenic diets (KDs) mediate the rise of circulating ketone bodies and exert a potential anti-inflammatory effect; however, the consequences of this unique diet on colitis remain unknown. We performed a series of systematic studies using a dextran sulfate sodium (DSS) animal model of inflammatory colitis. Animals were fed with a KD, low-carbohydrate diet (LCD), or normal diet (ND). Germ-free mice were utilized in validation experiments. Colon tissues were analyzed by transcriptome sequencing, RT2 profiler PCR array, histopathology, and immunofluorescence. Serum samples were analyzed by metabolic assay kit. Fecal samples were analyzed by 16S rRNA gene sequencing, liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. We observed that KD alleviated colitis by altering the gut microbiota and metabolites in a manner distinct from LCD. Quantitative diet experiments confirmed the unique impact of KD relative to LCD with a reproducible increase in Akkermansia, whereas the opposite was observed for Escherichia/Shigella. After colitis induction, the KD protected intestinal barrier function, and reduced the production of RORγt+CD3- group 3 innate lymphoid cells (ILC3s) and related inflammatory cytokines (IL-17α, IL-18, IL-22, Ccl4). Finally, fecal microbiota transplantation into germ-free mice revealed that the KD- mediated colitis inhibition and ILC3 regulation were dependent on the modification of gut microbiota. Taken together, our study presents a global view of microbiome-metabolomics changes that occur during KD colitis treatment, and identifies the regulation of gut microbiome and ILC3s as novel targets involving in IBD dietary therapy.
    DOI:  https://doi.org/10.1038/s41392-021-00549-9
  9. Eur J Intern Med. 2021 Apr 18. pii: S0953-6205(21)00110-2. [Epub ahead of print]
    Autologous fecal microbiota transplantation can retain the metabolic achievements of dietary interventions.
    Ehud Rinott, Ilan Youngster, Anat Yaskolka Meir, Gal Tsaban, Alon Kaplan, Hila Zelicha, Elad Rubin, Omry Koren, Iris Shai.
       BACKGROUND: We recently reported that autologous fecal microbiota transplantation (aFMT), derived from the time of maximal weight-loss and administrated in the regain-phase, might preserve weight loss and glycemic control in moderately obese subjects, and is associated with specific microbiome signatures. Here, we sought to explore the global effect of aFMT on adipokines, inflammatory markers and blood cholesterol and on the overall gut microbiome preservation.
    METHODS: In the DIRECT-PLUS weight-loss trial, abdominally obese participants were randomized to three distinct weight-loss diets. Following the expected weight loss phase (0-6 m), 90 participants were randomized to receive their personal frozen fecal microbiota or placebo oral capsules (ten 1 g-capsules over ten sessions-total=100 g) during the expected weight regain phase (8-14 m).
    RESULTS: Of the 90 participants (age=52 yr; 0-6 m weight loss=-8.3 kg), 95.6% ingested at least 80/100 oral aFMT/placebo capsules over 6 months. Overall, the gut microbiome community structure was associated with plasma levels of leptin, cholesterol and interleukin-6 at baseline and after 6 m, whereas 6 m (weight loss phase) changes in specific microbiome species associated with the dynamic of leptin and inflammatory biomarkers. Following the 8-14 m aFMT administration phase, aFMT maintained decreased levels of leptin (ΔaFMT=-3.54 ng/mL vs. Δplacebo=-0.82 ng/mL;P = 0.04), C-reactive-protein (ΔaFMT=-1.45 mg/L vs. Δplacebo=-0.66 mg/L;P = 0.009), Interleukin-6 (ΔaFMT=-0.03pg/mL vs. Δplacebo=1.11pg/mL;P = 0.03) and total cholesterol (ΔaFMT=2.2 mg/dl vs. Δplacebo=13.1 mg/dl;P = 0.04) achieved in the weight loss phase. Overall, aFMT induced a significant preservatory effect on personal gut microbiome global composition (P = 0.03;Jensen-Shannon distance), as compared to placebo.
    CONCLUSIONS: aFMT treatment in the regain phase might retain weight-loss induced metabolic benefits. These findings may suggest a novel aFMT treatment approach for personal metabolic attainment preservation.
    Keywords:  Inflammatory markers; Personalized medicine; Weight loss; Weight regain; aFMT
    DOI:  https://doi.org/10.1016/j.ejim.2021.03.038
  10. Front Oncol. 2021 ;11 627549
    Strategies for Dodging the Obstacles in CAR T Cell Therapy.
    Pooria Safarzadeh Kozani, Pouya Safarzadeh Kozani, Fatemeh Rahbarizadeh, Shahryar Khoshtinat Nikkhoi.
      Chimeric antigen receptor (CAR) T cell therapy has offered cancer patients a new alternative therapeutic choice in recent years. This novel type of therapy holds tremendous promise for the treatment of various hematologic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) and lymphoma. However, CAR T cell therapy has experienced its ups and downs in terms of toxicities and efficacy shortcomings. Adverse events such as cytokine release syndrome (CRS), neurotoxicity, graft rejection, on-target off-tumor toxicities, and tumor relapse have tied the rescuing hands of CAR T cell therapies. Moreover, in the case of solid tumor treatment, CAR T cell therapies have not yielded encouraging results mainly due to challenges such as the formidable network of the tumor microenvironments (TME) that operates in a suppressive fashion resulting in CAR T cell dysfunction. In this review, we tend to shine a light on emerging strategies and solutions for addressing the mentioned barriers. These solutions might dramatically help shorten the gap between a successful clinical outcome and the hope for it.
    Keywords:  adoptive cell therapy; chimeric antigen receptor; immunotherapy; solid tumors; toxicities; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.627549
  11. Cancer Metab. 2021 Apr 21. 9(1): 17
    Mitochondrial metabolism as a target for acute myeloid leukemia treatment.
    Svetlana B Panina, Jingqi Pei, Natalia V Kirienko.
      Acute myeloid leukemias (AML) are a group of aggressive hematologic malignancies resulting from acquired genetic mutations in hematopoietic stem cells that affect patients of all ages. Despite decades of research, standard chemotherapy still remains ineffective for some AML subtypes and is often inappropriate for older patients or those with comorbidities. Recently, a number of studies have identified unique mitochondrial alterations that lead to metabolic vulnerabilities in AML cells that may present viable treatment targets. These include mtDNA, dependency on oxidative phosphorylation, mitochondrial metabolism, and pro-survival signaling, as well as reactive oxygen species generation and mitochondrial dynamics. Moreover, some mitochondria-targeting chemotherapeutics and their combinations with other compounds have been FDA-approved for AML treatment. Here, we review recent studies that illuminate the effects of drugs and synergistic drug combinations that target diverse biomolecules and metabolic pathways related to mitochondria and their promise in experimental studies, clinical trials, and existing chemotherapeutic regimens.
    Keywords:  Acute myeloid leukemia (AML); Drug combinations; Leukemia stem cells; Mitocans; Mitochondria; Mitochondrial abnormalities/alterations; Mitochondrial metabolism; Synergy
    DOI:  https://doi.org/10.1186/s40170-021-00253-w
  12. Trends Immunol. 2021 Apr 14. pii: S1471-4906(21)00056-9. [Epub ahead of print]
    Enemy or ally? Fasting as an essential regulator of immune responses.
    Christoph Wilhelm, Jayagopi Surendar, Fotios Karagiannis.
      Nutrition is essential for supplying an organism with sufficient energy to maintain its bodily functions. Apart from serving as an energy supply, the immunomodulatory effects of diet are emerging as a central aspect of human health. The latest evidence suggests that dietary restriction may play an important regulatory role by influencing the activation and effector functions of immune cells. However, depending on the context, nutrient restriction may have both pathogenic and beneficial effects. Here, we discuss the diverse roles of fasting programs, including ketogenesis in infection and chronic inflammation, aiming to clarify their detrimental and/or beneficial effects. Understanding these differences may help identify conditions under which dietary interventions might serve as putative effective approaches to treat various diseases.
    Keywords:  caloric restriction; immune response; infection-induced anorexia; ketogenic diet; ketone bodies
    DOI:  https://doi.org/10.1016/j.it.2021.03.007
  13. Evid Based Complement Alternat Med. 2021 ;2021 6636875
    Aged Garlic Extract Reduces IL-6: A Double-Blind Placebo-Controlled Trial in Females with a Low Risk of Cardiovascular Disease.
    Martiné Wlosinska, Ann-Christin Nilsson, Joanna Hlebowicz, Mohammed Fakhro, Malin Malmsjö, Sandra Lindstedt.
       Background: Chronic inflammation is a risk factor for cardiovascular disease. The aim of the study was to evaluate whether a daily supplementation of aged garlic extract (AGE) could reduce inflammation in females with low risk for cardiovascular disease. The study was conducted at a single center, as a parallel randomized placebo-controlled trial.
    Method: 63 females with a Framingham risk score over 10 underwent cardiac computed tomography (CT) scan. Of those, patients with a coronary artery calcium (CAC) scores less than 5 (n = 31) met the inclusion criteria and were randomized, in a double-blind manner to an intake of placebo or AGE (2400 mg daily) for 1 year.
    Results: Main outcome measure was changes in inflammatory biomarkers, blood pressure, fastening blood glucose, and blood lipids. A total of 29 patients (14 in the AGE group and 15 in the placebo group) completed the study and were analyzed. Females treated with AGE showed lower levels of inflammatory marker IL-6 after 12 months of treatment compared to females receiving placebo (p < 0.05). The blood lipids had a trend towards a lowering effect in females treated with AGE; however, this trend was not significant.
    Conclusion: The present study concludes that AGE lowers IL-6 in females with a risk profile of cardiovascular disease. We could also conclude that risk prediction with cardiac CT  scan turned out to be superior in estimating the risk of cardiac disease compared to Framingham risk score. This trial is registered with NCT03860350.
    DOI:  https://doi.org/10.1155/2021/6636875
  14. CRISPR J. 2021 Apr;4(2): 166-168
    Base Editors Flex Sights on Sickle-Cell Disease.
    Anna Cereseto, Thomas J Cradick, Kevin Davies.
      
    DOI:  https://doi.org/10.1089/crispr.2021.29125.kda
  15. Oncotarget. 2021 Mar 30. 12(7): 608-625
    Caloric restriction creates a metabolic pattern of chronological aging delay that in budding yeast differs from the metabolic design established by two other geroprotectors.
    Karamat Mohammad, Vladimir I Titorenko.
      Caloric restriction and the tor1Δ mutation are robust geroprotectors in yeast and other eukaryotes. Lithocholic acid is a potent geroprotector in Saccharomyces cerevisiae. Here, we used liquid chromatography coupled with tandem mass spectrometry method of non-targeted metabolomics to compare the effects of these three geroprotectors on the intracellular metabolome of chronologically aging budding yeast. Yeast cells were cultured in a nutrient-rich medium. Our metabolomic analysis identified and quantitated 193 structurally and functionally diverse water-soluble metabolites implicated in the major pathways of cellular metabolism. We show that the three different geroprotectors create distinct metabolic profiles throughout the entire chronological lifespan of S. cerevisiae. We demonstrate that caloric restriction generates a unique metabolic pattern. Unlike the tor1Δ mutation or lithocholic acid, it slows down the metabolic pathway for sulfur amino acid biosynthesis from aspartate, sulfate and 5-methyltetrahydrofolate. Consequently, caloric restriction significantly lowers the intracellular concentrations of methionine, S-adenosylmethionine and cysteine. We also noticed that the low-calorie diet, but not the tor1Δ mutation or lithocholic acid, decreases intracellular ATP, increases the ADP:ATP and AMP:ATP ratios, and rises intracellular ADP during chronological aging. We propose a model of how the specific remodeling of cellular metabolism by caloric restriction contributes to yeast chronological aging delay.
    Keywords:  caloric restriction; cellular aging; geroprotectors; metabolism; methionine
    DOI:  https://doi.org/10.18632/oncotarget.27926
  16. Front Immunol. 2021 ;12 618710
    One Stone, Two Birds: The Roles of Tim-3 in Acute Myeloid Leukemia.
    Zhiding Wang, Jinghong Chen, Mengzhen Wang, Linlin Zhang, Li Yu.
      T cell immunoglobulin and mucin protein 3 (Tim-3) is an immune checkpoint and plays a vital role in immune responses during acute myeloid leukemia (AML). Targeting Tim-3 kills two birds with one stone by balancing the immune system and eliminating leukemia stem cells (LSCs) in AML. These functions make Tim-3 a potential target for curing AML. This review mainly discusses the roles of Tim-3 in the immune system in AML and as an AML LSC marker, which sheds new light on the role of Tim-3 in AML immunotherapy.
    Keywords:  AML; LSC; Tim-3; antibody; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2021.618710
  17. Curr Opin Clin Nutr Metab Care. 2021 Apr 19.
    Ketogenic diets and appetite regulation.
    Jessica Roekenes, Catia Martins.
       PURPOSE OF REVIEW: The popularity of ketogenic diets in the treatment of obesity has increased dramatically over the last years, namely due to their potential appetite suppressant effect. The purpose of this review was to examine the latest evidence regarding the impact of ketogenic diets on appetite.
    RECENT FINDINGS: The majority of the studies published over the last 2 years adds to previous evidence and shows that ketogenic diets suppress the increase in the secretion of the hunger hormone ghrelin and in feelings of hunger, otherwise see when weight loss is induced by non-ketogenic diets. Research done using exogenous ketones point out in the same direction. Even though the exact mechanisms by which ketogenic diets suppress appetite remain to be fully determined, studies show that the more ketotic participants are (measured as β-hydroxybutyrate plasma concentration), the smaller is the increase in ghrelin and hunger and the larger is the increase in the release of satiety peptides. Further evidence for a direct effect of ketones on appetite comes from studies using exogenous ketones.
    SUMMARY: The appetite suppressant effect of ketogenic diets may be an important asset for improving adherence to energy restricted diets and weight loss outcomes.
    DOI:  https://doi.org/10.1097/MCO.0000000000000760
  18. Front Physiol. 2021 ;12 663869
    Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections.
    Cindy B McReynolds, Irene Cortes-Puch, Resmi Ravindran, Imran H Khan, Bruce G Hammock, Pei-An Betty Shih, Bruce D Hammock, Jun Yang.
      Polyunsaturated fatty acids are metabolized into regulatory lipids important for initiating inflammatory responses in the event of disease or injury and for signaling the resolution of inflammation and return to homeostasis. The epoxides of linoleic acid (leukotoxins) regulate skin barrier function, perivascular and alveolar permeability and have been associated with poor outcomes in burn patients and in sepsis. It was later reported that blocking metabolism of leukotoxins into the vicinal diols ameliorated the deleterious effects of leukotoxins, suggesting that the leukotoxin diols are contributing to the toxicity. During quantitative profiling of fatty acid chemical mediators (eicosanoids) in COVID-19 patients, we found increases in the regioisomeric leukotoxin diols in plasma samples of hospitalized patients suffering from severe pulmonary involvement. In rodents these leukotoxin diols cause dramatic vascular permeability and are associated with acute adult respiratory like symptoms. Thus, pathways involved in the biosynthesis and degradation of these regulatory lipids should be investigated in larger biomarker studies to determine their significance in COVID-19 disease. In addition, incorporating diols in plasma multi-omics of patients could illuminate the COVID-19 pathological signature along with other lipid mediators and blood chemistry.
    Keywords:  ARDS; COVID-19; DiHOME; EpOME; inflammation; leukotoxin; linoleate diol; lipid mediators
    DOI:  https://doi.org/10.3389/fphys.2021.663869
  19. Curr Opin Lipidol. 2021 Apr 16.
    Lipid effects of sodium-glucose cotransporter 2 inhibitors.
    Julieta Lazarte, Tharsan Kanagalingam, Robert A Hegele.
       PURPOSE OF REVIEW: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used antihyperglycemic drugs that show remarkable cardiorenal protective effects in patients with or without type 2 diabetes. Furthermore, they are effective among patients across a wide range of baseline renal and cardiac function. Numerous mechanisms have been evaluated to understand these remarkable clinical benefits. From an early stage, these agents were noted to affect the plasma lipid profile. Here we review lipid profile alterations attributable to SGLT2 inhibitors and also some mechanisms explored in model systems and human studies.
    RECENT FINDINGS: SGLT2 inhibitors given to patients with diabetes as monotherapy shift substrate utilization from carbohydrates to lipids, and have mild effects on the lipid profile. Increased LDL cholesterol appears to be associated with increased hepatic production and decreased catabolism. Increased HDL cholesterol and decreased triglycerides appear to be associated with improved insulin sensitivity and increased lipolysis. Lipid effects of SGLT2 inhibitors are further modulated by background therapy with other diabetes medications and statins.
    SUMMARY: The minor lipid profile alterations observed in patients treated with SGLT2 inhibitors are offset by the staggering range of beneficial pleiotropic mechanisms that likely explain the marked cardiorenal benefits of these agents.
    DOI:  https://doi.org/10.1097/MOL.0000000000000751
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