bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒02‒28
thirty-two papers selected by
Ayesh Seneviratne
University of Toronto


  1. Front Oncol. 2020 ;10 621458
      Metabolism in acute myeloid leukemia (AML) cells is dependent primarily on oxidative phosphorylation. However, in order to sustain their high proliferation rate and metabolic demand, leukemic blasts use a number of metabolic strategies, including glycolytic metabolism. Understanding whether monocarboxylate transporters MCT1 and MCT4, which remove the excess of lactate produced by cancer cells, represent new hematological targets, and whether their respective inhibitors, AR-C155858 and syrosingopine, can be useful in leukemia therapy, may reveal a novel treatment strategy for patients with AML. We analyzed MCT1 and MCT4 expression and function in hematopoietic progenitor cells from healthy cord blood, in several leukemic cell lines and in primary leukemic blasts from patients with AML, and investigated the effects of AR-C155858 and syrosingopine, used alone or in combination with arabinosylcytosine, on leukemic cell proliferation. We found an inverse correlation between MCT1 and MCT4 expression levels in leukemic cells, and showed that MCT4 overexpression is associated with poor prognosis in AML patients. We also found that AR-C155858 and syrosingopine inhibit leukemic cell proliferation by activating two different cell-death related pathways, i.e., necrosis for AR-C155858 treatment and autophagy for syrosingopine, and showed that AR-C155858 and syrosingopine exert an anti-proliferative effect, additive to chemotherapy, by enhancing leukemic cells sensitivity to chemotherapeutic agents. Altogether, our study shows that inhibition of MCT1 or MCT4 impairs leukemic cell proliferation, suggesting that targeting lactate metabolism may be a new therapeutic strategy for AML, and points to MCT4 as a potential therapeutic target in AML patients and to syrosingopine as a new anti-proliferative drug and inducer of autophagy to be used in combination with conventional chemotherapeutic agents in AML treatment.
    Keywords:  AR-C155858; MCT1; MCT4; acute myeloid leukemia; autophagy; lactate metabolism; syrosingopine
    DOI:  https://doi.org/10.3389/fonc.2020.621458
  2. Aging (Albany NY). 2021 Feb 17. 13
      The interplay between microbiota and host metabolism plays an important role in health. Here, we examined the relationship between age, gut microbiome and host serum metabolites in male C57BL/6J mice. Fecal microbiome analysis of 3, 6, 18, and 28 months (M) old mice showed that the Firmicutes/Bacteroidetes ratio was highest in the 6M group; the decrease of Firmicutes in the older age groups suggests a reduced capacity of gut microflora to harvest energy from food. We found age-dependent increase in Proteobacteria, which may lead to altered mucus structure more susceptible to bacteria penetration and ultimately increased intestinal inflammation. Metabolomic profiling of polar serum metabolites at fed state in 3, 12, 18 and 28M mice revealed age-associated changes in metabolic cascades involved in tryptophan, purine, amino acids, and nicotinamide metabolism. Correlation analyses showed that nicotinamide decreased with age, while allantoin and guanosine, metabolites in purine metabolism, increased with age. Notably, tryptophan and its microbially derived compounds indole and indole-3-lactic acid significantly decreased with age, while kynurenine increased with age. Together, these results suggest a significant interplay between bacterial and host metabolism, and gut dysbiosis and altered microbial metabolism contribute to aging.
    Keywords:  aging; gut microbiome; metabolism; serum metabolome
    DOI:  https://doi.org/10.18632/aging.202525
  3. Cell Signal. 2021 Feb 22. pii: S0898-6568(21)00047-4. [Epub ahead of print] 109959
      Insulin is the main anabolic hormone secreted by β-cells of the pancreas stimulating the assimilation and storage of glucose in muscle and fat cells. It modulates the postprandial balance of carbohydrates, lipids and proteins via enhancing lipogenesis, glycogen and protein synthesis and suppressing glucose generation and its release from the liver. Resistance to insulin is a severe metabolic disorder related to a diminished response of peripheral tissues to the insulin action and signaling. This leads to a disturbed glucose homeostasis that precedes the onset of type 2 diabetes (T2D), a disease reaching epidemic proportions. A large number of studies reported an association between elevated circulating fatty acids and the development of insulin resistance. The increased fatty acid lipid flux results in the accumulation of lipid droplets in a variety of tissues. However, lipid intermediates such as diacylglycerols and ceramides are also formed in response to elevated fatty acid levels. These bioactive lipids have been associated with the pathogenesis of insulin resistance. More recently, sphingosine 1-phosphate (S1P), another bioactive sphingolipid derivative, has also been shown to increase in T2D and obesity. Although many studies propose a protective role of S1P metabolism on insulin signaling in peripheral tissues, other studies suggest a causal role of S1P on insulin resistance. In this review, we critically summarize the current state of knowledge of S1P metabolism and its modulating role on insulin resistance. A particular emphasis is placed on S1P and insulin signaling in hepatocytes, skeletal muscle cells, adipocytes and pancreatic β-cells. In particular, modulation of receptors and enzymes that regulate S1P metabolism can be considered as a new therapeutic option for the treatment of insulin resistance and T2D.
    Keywords:  Adipocytes; Hepatocytes; Insulin resistance; Skeletal muscle cells; Sphingolipids; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cellsig.2021.109959
  4. Front Oncol. 2021 ;11 625707
      Pediatric, adolescent and young adult (AYA) patients receiving novel cancer immunotherapies may develop associated toxicities with overlapping signs and symptoms that are not always easily distinguished from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection/clinical sequelae. We describe 2 diagnostically challenging cases of SARS-CoV-2 and Multi-Inflammatory Syndrome-Adult (MIS-A), in patients with a history of acute lymphoblastic leukemia following cellular therapy administration and review evolving characterization of both the natural course of SARS-CoV-2 infection and toxicities experienced in younger cancer immunotherapy patients. Vigilant monitoring for unique presentations and epidemiologic surveillance to promptly detect changes in incidence of either condition may be warranted.
    Keywords:  COVID-19; MIS-A; MIS-C; SARS-CoV-2; cancer immunotherapy
    DOI:  https://doi.org/10.3389/fonc.2021.625707
  5. Geroscience. 2021 Feb 24.
      Frailty is a geriatric syndrome characterized by age-related declines in function and reserve resulting in increased vulnerability to stressors. The most consistent laboratory finding in frail subjects is elevation of serum IL-6, but it is unclear whether IL-6 is a causal driver of frailty. Here, we characterize a new mouse model of inducible IL-6 expression (IL-6TET-ON/+ mice) following administration of doxycycline (Dox) in food. In this model, IL-6 induction was Dox dose-dependent. The Dox dose that increased IL-6 levels to those observed in frail old mice directly led to an increase in frailty index, decrease in grip strength, and disrupted muscle mitochondrial homeostasis. Littermate mice lacking the knock-in construct failed to exhibit frailty after Dox feeding. Both naturally old mice and young Dox-induced IL-6TET-ON/+ mice exhibited increased IL-6 levels in sera and spleen homogenates but not in other tissues. Moreover, Dox-induced IL-6TET-ON/+ mice exhibited selective elevation in IL-6 but not in other cytokines. Finally, bone marrow chimera and splenectomy experiments demonstrated that non-hematopoietic cells are the key source of IL-6 in our model. We conclude that elevated IL-6 serum levels directly drive age-related frailty, possibly via mitochondrial mechanisms.
    Keywords:  Frailty; IL-6; Mouse; Transgenic models
    DOI:  https://doi.org/10.1007/s11357-021-00343-z
  6. Food Nutr Res. 2021 ;65
      Background: Tartary buckwheat has beneficial effects on glucose and lipid metabolism of patients with type 2 diabetes mellitus. However, the physiological effects of a soluble dietary fiber (SDF) from tartary buckwheat have rarely been studied, especially in vivo.Objective: This study aimed to examine the hypoglycemic and hypolipidemic effects of SDF from tartary buckwheat bran on high-fat diet/streptozotocin-induced diabetic mice.
    Design: The SDF of tartary buckwheat bran was collected according to the Association of Official Analytical Chemists method 991.43. Diabetic mice were treated with high-fat diets supplemented with 0.5, 1, and 2% SDF for 8 weeks. Parameters related to glucose and lipid metabolism and relevant mechanisms, including the excretion of short-chain fatty acids and the glycemic signaling pathway in the liver, were investigated. In addition, the structural characterization of a purified polysaccharide from SDF of tartary buckwheat bran was illustrated.
    Result: Supplementation with SDF in the diet resulted in reduced levels of fasting blood glucose, improved oral glucose tolerance, increased levels of liver glycogen and insulin, as well as improved lipid profiles in both the serum and liver, in diabetic mice. The amelioration of glucose and lipid metabolism by SDF was accompanied by an increase in the short-chain fatty acid levels in the cecum and co-regulated by hepatic adenosine-5'-monophosphate-activated protein kinase (AMPK) phosphorylation. A neutral tartary buckwheat polysaccharide with an average molecular weight of 19.6 kDa was purified from the SDF, which consisted mainly of glucose with α-glycosidic bonds.
    Conclusions: The SDF of tartary buckwheat bran exhibits hypoglycemic and hypolipidemic effects in diabetic mice, contributing to the anti-diabetic mechanisms of tartary buckwheat.
    Keywords:  AMP-activated protein kinase; glucose metabolism; lipid metabolism; short-chain fatty acids; soluble dietary fiber; tartary buckwheat
    DOI:  https://doi.org/10.29219/fnr.v65.4998
  7. J Hepatol. 2021 Feb 22. pii: S0168-8278(21)00112-4. [Epub ahead of print]
      In recent years, major advances have been made regarding our understanding on the mechanisms underlying fibrosis progression and regression, and on how coordinated dialog between parenchymal and non-parenchymal cells impacts on the fibrogenic process. Recent studies have highlighted that metabolic reprogramming of parenchymal cells, immune cells (immunometabolism) and hepatic stellate cells is required to support their energy and anabolic demands for acquisition and/or changes in their phenotype and effector functions. In this review, we summarize the current knowledge on how targeting cell-intrinsic metabolic modifications of the main fibrogenic cell actors may impact on fibrosis progression and discuss the anti-fibrogenic potential of metabolically-targeted interventions.
    Keywords:  Fibrosis; autophagy; glucose metabolism; hepatic stellate cells; hepatocytes; immunometabolism; innate-like lymphoid cells; lipid metabolism; macrophages; nuclear receptors
    DOI:  https://doi.org/10.1016/j.jhep.2021.02.012
  8. Clin Cancer Res. 2021 Feb 25. pii: clincanres.4271.2020. [Epub ahead of print]
      On November 28, 2018, the Food and Drug Administration approved gilteritinib (Xospata; Astellas, Northbrook, IL), a small molecule FMS-like tyrosine kinase 3 (FLT3) inhibitor, for treatment of relapsed or refractory (R/R) acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test. In the ADMIRAL Study, patients were randomized 2:1 to receive gilteritinib or standard chemotherapy and stratified by response to first-line treatment and intensity of prespecified chemotherapy. Efficacy was established on interim analysis based on complete remission (CR)+CR with partial hematologic recovery (CRh) rate, duration of CR+CRh, and conversion from transfusion dependence (TD) to transfusion independence (TI) in 138 patients in the gilteritinib arm. With median follow-up of 4.6 months (95% CI 2.8-15.8 months) at interim analysis, the CR+CRh rate was 21% (95% confidence interval [CI], 15%-29%), median duration of CR+CRh was 4.6 (range, 0.1-15.8+) months, and conversion from TD to TI was 31%. Revised labeling approved May 29, 2019 included the results of the final analysis, showing an improvement in overall survival (OS) with gilteritinib compared to chemotherapy (hazard ratio [HR] 0.64 [95% CI 0.49-0.83], 1-sided p=0.0004); median OS 9.3 months vs 5.6 months). The OS benefit was observed in both high and low chemotherapy intensity subgroups. Labeling includes a boxed warning for differentiation syndrome (DS) and warnings for posterior reversible encephalopathy syndrome, QT prolongation, pancreatitis, and embryo-fetal toxicity. Safe use requires frequent monitoring of electrocardiograms and blood chemistries. Assessments of long-term safety are pending.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-4271
  9. J Food Biochem. 2021 Feb 24. e13673
      Rheumatoid arthritis (RHA) is one of the most prevalent complex, chronic, inflammatory diseases, manifested by elevated oxidative stress and inflammatory biomarkers. Prolonged administration of NSAIDs, steroids, and DMARDs, used in the treatment of RHA, is associated with deleterious side effects. This necessitates the urge of new and safe approaches for RHA management, based on the complementary and alternative system of medicine. Documented evidences have suggested that supplementation with nutritional, dietary, and herbal components; can play a crucial role as an adjuvant, in the alleviation of the RHA symptoms, through their influence on the pathological inflammatory processes. Dietary phenolic compounds, flavonoids, carotenoids, and alkaloids with their ability to modulate prooxidant and pro-inflammatory pathways, have been effective in delaying the arthritic disease progression. Moreover, in scientific explorations, herbs containing phenolic compounds, alkaloids, carotenoids flavonoids, spices such as ginger, turmeric, Ayurvedic formulations, different diets such as Mediterranean diet, vegan diet, beverages, and oils such as sesame oil, rice bran oil, vitamins, and probiotics are proven to modulate the action of inflammatory molecules, involved in RHA pathology. Subsequently, the purpose of this review article is to summarize various in vitro, in vivo, and clinical studies in RHA, which have documented remarkable insights into the anti-inflammatory, antioxidant, analgesic, and immunomodulatory, bone erosion preventing properties of dietary, nutritional, and herbal components with the focus on their molecular level mechanisms involved in RHA. Even though major findings were derived from in vitro studies, several in vivo and clinical studies have established the use of diet, herbal, and nutritional management in RHA treatment. PRACTICAL APPLICATIONS: Thickening of the synovial membrane, bone erosion, and cartilage destruction is known to trigger rheumatoid arthritis causing inflammation and pain in bone joints. Continuous intake of NSAIDs, steroids, and DMARD therapy are associated with detrimental side effects. These side effects can be overcome by the use of dietary, nutritional, and herbal interventions based on the complementary and alternative therapy. This concept portrays the food components and other natural components having the potential to promote health, improve general well-being, and reduce the risk of RHA.
    Keywords:  alternative medicine; complementary; diet management; inflammation; nutraceutical; rheumatoid arthritis
    DOI:  https://doi.org/10.1111/jfbc.13673
  10. Cell Stem Cell. 2021 Feb 22. pii: S1934-5909(21)00018-7. [Epub ahead of print]
      The implications of stem cell heterogeneity for disease pathogenesis and therapy are poorly defined. JAK2V617F+ myeloproliferative neoplasms (MPNs), harboring the same mutation in hematopoietic stem cells (HSCs), display diverse phenotypes, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These chronic malignant disorders are ideal models to analyze the pathological consequences of stem cell heterogeneity. Single-cell gene expression profiling with parallel mutation detection demonstrated that the megakaryocyte (Mk)-primed HSC subpopulation expanded significantly with enhanced potential in untreated individuals with JAK2V617F+ ET, driven primarily by the JAK2 mutation and elevated interferon signaling. During treatment, mutant HSCs were targeted preferentially in the Mk-primed HSC subpopulation. Interestingly, homozygous mutant HSCs were forced to re-enter quiescence, whereas their heterozygous counterparts underwent apoptosis. This study provides important evidence for the association of stem cell heterogeneity with the pathogenesis and therapeutic response of a malignant disease.
    Keywords:  JAK2V617F; MPN; hematopoietic stem cells; heterogeneity; inflammation; interferon; megakaryocyte lineage priming; pathogenesis; single cell RNA-Seq; therapeutic response
    DOI:  https://doi.org/10.1016/j.stem.2021.01.018
  11. Signal Transduct Target Ther. 2021 Feb 26. 6(1): 94
      The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs). Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases (CVD), cancers, and inflammatory diseases. This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2. Thus, we herein present a synopsis of AA metabolism in human health, cardiovascular and cancer biology, and the signaling pathways involved in these processes. To explore the role of the AA metabolism and potential therapies, we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.
    DOI:  https://doi.org/10.1038/s41392-020-00443-w
  12. Blood Cancer J. 2021 Feb 22. 11(2): 41
      Progress in the understanding of the biology and therapy of acute myeloid leukemia (AML) is occurring rapidly. Since 2017, nine agents have been approved for various indications in AML. These included several targeted therapies like venetoclax, FLT3 inhibitors, IDH inhibitors, and others. The management of AML is complicated, highlighting the need for expertise in order to deliver optimal therapy and achieve optimal outcomes. The multiple subentities in AML require very different therapies. In this review, we summarize the important pathophysiologies driving AML, review current therapies in standard practice, and address present and future research directions.
    DOI:  https://doi.org/10.1038/s41408-021-00425-3
  13. Cell Stem Cell. 2021 Feb 18. pii: S1934-5909(21)00015-1. [Epub ahead of print]
      Neural stem cells (NSCs) generate neurons throughout life in the hippocampal dentate gyrus. With advancing age, levels of neurogenesis sharply drop, which has been associated with a decline in hippocampal memory function. However, cell-intrinsic mechanisms mediating age-related changes in NSC activity remain largely unknown. Here, we show that the nuclear lamina protein lamin B1 (LB1) is downregulated with age in mouse hippocampal NSCs, whereas protein levels of SUN-domain containing protein 1 (SUN1), previously implicated in Hutchinson-Gilford progeria syndrome (HGPS), increase. Balancing the levels of LB1 and SUN1 in aged NSCs restores the strength of the endoplasmic reticulum diffusion barrier that is associated with segregation of aging factors in proliferating NSCs. Virus-based restoration of LB1 expression in aged NSCs enhances stem cell activity in vitro and increases progenitor cell proliferation and neurogenesis in vivo. Thus, we here identify a mechanism that mediates age-related decline of neurogenesis in the mammalian hippocampus.
    Keywords:  Lamin; aging; asymmetric segregation; diffusion barrier; hippocampus; neural stem cell; neurogenesis; nuclear lamina; proliferation
    DOI:  https://doi.org/10.1016/j.stem.2021.01.015
  14. CMAJ. 2021 Feb 22. 193(8): E270-E277
      BACKGROUND: New case-mix tools from the Canadian Institute for Health Information offer a novel way of exploring the prevalence of chronic disease and multimorbidity using diagnostic data. We took a comprehensive approach to determine whether the prevalence of chronic disease and multimorbidity has been rising in Ontario, Canada.METHODS: In this observational study, we applied case-mix methodology to a population-based cohort. We used 10 years of patient-level data (fiscal years 2008/09 to 2017/18) from multiple care settings to compute the rolling 5-year prevalence of 85 chronic diseases and multimorbidity (i.e., the co-occurrence of 2 or more diagnoses). Diseases were further classified based on type and severity. We report both crude and age- and sex-standardized trends.
    RESULTS: The number of patients with chronic disease increased by 11.0% over the 10-year study period to 9.8 million in 2017/18, and the number with multimorbidity increased 12.2% to 6.5 million. Overall increases from 2008/09 to 2017/18 in the crude prevalence of chronic conditions and multimorbidity were driven by population aging. After adjustments for age and sex, the prevalence of patients with ≥ 1 chronic conditions decreased from 70.2% to 69.1%, and the prevalence of multimorbidity decreased from 47.1% to 45.6%. This downward trend was concentrated in minor and moderate diseases, whereas the prevalence of many major chronic diseases rose, along with instances of extreme multimorbidity (≥ 8 conditions). Age- and sex-standardized resource intensity weights, which reflect relative expected costs associated with patient diagnostic profiles, increased 4.6%.
    INTERPRETATION: Evidence of an upward trend in the prevalence of chronic disease was mixed. However, the change in case mix toward more serious conditions, along with increasing patient resource intensity weights overall, may portend a future need for population health management and increased health system spending above that predicted by population aging.
    DOI:  https://doi.org/10.1503/cmaj.201473
  15. mBio. 2021 Feb 23. pii: e03444-20. [Epub ahead of print]12(1):
      Lipids are biologically active molecules involved in a variety of cellular processes and immunological functions, including inflammation. It was recently shown that phospholipids and their derivatives, lysophospholipids, can reactivate latent (dormant) tumor cells, causing cancer recurrence. However, the potential link between lipids and HIV latency, persistence, and viral rebound after cessation of antiretroviral therapy (ART) has never been investigated. We explored the links between plasma lipids and the burden of HIV during ART. We profiled the circulating lipidome from plasma samples from 24 chronically HIV-infected individuals on suppressive ART who subsequently underwent an analytic treatment interruption (ATI) without concurrent immunotherapies. The pre-ATI viral burden was estimated as time-to-viral-rebound and viral load set points post-ATI. We found that higher pre-ATI levels of lysophospholipids, including the proinflammatory lysophosphatidylcholine, were associated with faster time-to-viral-rebound and higher viral set points upon ART cessation. Furthermore, higher pre-ATI levels of the proinflammatory by-product of intestinal lysophosphatidylcholine metabolism, trimethylamine-N-oxide (TMAO), were also linked to faster viral rebound post-ART. Finally, pre-ATI levels of several phosphatidylcholine species (lysophosphatidylcholine precursors) correlated strongly with higher pre-ATI levels of HIV DNA in peripheral CD4+ T cells. Our proof-of-concept data point to phospholipids and lysophospholipids as plausible proinflammatory contributors to HIV persistence and rapid post-ART HIV rebound. The potential interplay between phospholipid metabolism and both the establishment and maintenance of HIV latent reservoirs during and after ART warrants further investigation.IMPORTANCE The likelihood of HIV rebound after stopping antiretroviral therapy (ART) is a combination of the size of HIV reservoirs that persist despite ART and the host immunological and inflammatory factors that control these reservoirs. Therefore, there is a need to comprehensively understand these host factors to develop a strategy to cure HIV infection and prevent viral rebound post-ART. Lipids are important biologically active molecules that are known to mediate several cellular functions, including reactivating latent tumor cells; however, their role in HIV latency, persistence, and post-ART rebound has never been investigated. We observed significant links between higher levels of the proinflammatory lysophosphatidylcholine and its intestinal metabolic by-product, trimethylamine-N-oxide, and both faster time-to-viral-rebound and higher viral load set point post-ART. These data highlight the need for further studies to understand the potential contribution of phosphatidylcholine and lysophosphatidylcholine metabolism in shaping host immunological and inflammatory milieu during and after ART.
    Keywords:  HIV; HIV persistence; TMAO; choline; lipids; lysophosphatidylcholine; lysophospholipid; phospholipid; viral rebound
    DOI:  https://doi.org/10.1128/mBio.03444-20
  16. Cancer Biol Med. 2021 Feb 15. 18(1): 63-73
      Intermittent fasting (IF) is becoming a prevailing topic worldwide, as it can cause changes in the body's energy metabolism processes, improve health, and affect the progression of many diseases, particularly in the circumstance of oncology. Recent research has shown that IF can alter the energy metabolism of tumor cells, thereby inhibiting tumor growth and improving antitumor immune responses. Furthermore, IF can increase cancer sensitivity to chemotherapy and radiotherapy and reduce the side effects of these traditional anticancer treatments. IF is therefore emerging as a promising approach to clinical cancer treatment. However, the balance between long-term benefits of IF compared with the harm from insufficient caloric intake is not well understood. In this article, we review the role of IF in tumorigenesis and tumor therapy, and discuss some scientific problems that remain to be clarified, which might provide some assistance in the application of IF in clinical tumor therapy.
    Keywords:  Intermittent fasting; energy metabolism; immune escape; immunotherapy; tumor
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2020.0250
  17. Cell Mol Life Sci. 2021 Feb 27.
      Lipids and fatty acids play crucial roles in plant immunity, which have been highlighted over the past few decades. An increasing number of studies have shown that these molecules are pivotal in the interactions between plants and their diverse pathogens. The roles played by plant lipids fit in a wide spectrum ranging from the first physical barrier encountered by the pathogens, the cuticle, to the signalling pathways that trigger different immune responses and expression of defence-related genes, mediated by several lipid molecules. Moreover, lipids have been arising as candidate biomarkers of resistance or susceptibility to different pathogens. Studies on the apoplast and extracellular vesicles have been highlighting the possible role of lipids in the intercellular communication and the establishment of systemic acquired resistance during plant-pathogen interactions. From the pathogen perspective, lipid metabolism and specific lipid molecules play pivotal roles in the pathogen's life cycle completion, being crucial during recognition by the plant and evasion from the host immune system, therefore potentiating infection. Studies conducted in the last years have contributed to a better understanding of the language of lipids during the cross-talk between plants and pathogens. However, it is essential to continue exploring the knowledge brought up to light by transcriptomics and proteomics studies towards the elucidation of lipid signalling processes during defence and disease. In this review, we present an updated overview on lipids associated to plant-pathogen interactions, exploiting their roles from the two sides of this battle.
    Keywords:  Apoplast; Biomarkers; Extracellular vesicles; Fatty acids; Plant–pathogen interaction; Signalling
    DOI:  https://doi.org/10.1007/s00018-021-03791-0
  18. Aging (Albany NY). 2021 Feb 17. 13
      Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) induces profound oxidative injury and neuronal cell death. It mimics ischemia-reperfusion neuronal injury. CPI-1189 is a novel tumor necrosis factor alpha-inhibiting compound with potential neuroprotective function. Here in SH-SY5Y neuronal cells and primary murine cortical neurons, CPI-1189 pretreatment potently inhibited OGDR-induced viability reduction and cell death. In OGDR-stimulated neuronal cells, p38 phosphorylation was blocked by CPI-1189. In addition, CPI-1189 alleviated OGDR-induced reactive oxygen species production, lipid peroxidation, and glutathione consumption. OGDR-induced neuronal cell apoptosis was also inhibited by CPI-1189 pretreatment. Furthermore, in SH-SY5Y cells and cortical neurons, CPI-1189 alleviated OGDR-induced programmed necrosis by inhibiting mitochondrial p53-cyclophilin D-adenine nucleotide translocase 1 association, mitochondrial depolarization, and lactate dehydrogenase release to the medium. In summary, CPI-1189 potently inhibited OGDR-induced oxidative injury and neuronal cell death.
    Keywords:  CPI-1189; neurons; oxidative injury; oxygen glucose deprivation/re-oxygenation; signaling
    DOI:  https://doi.org/10.18632/aging.202528
  19. Metabolism. 2021 Feb 22. pii: S0026-0495(21)00033-0. [Epub ahead of print] 154733
      It is well-established that mitochondria are the powerhouses of the cell, producing adenosine triphosphate (ATP), the universal energy currency. However, the most significant strengths of the electron transport chain (ETC), its intricacy and efficiency, are also its greatest downfalls. A reliance on metal complexes (FeS clusters, hemes), lipid moities such as cardiolipin, and cofactors including alpha-lipoic acid and quinones render oxidative phosphorylation vulnerable to environmental toxins, intracellular reactive oxygen species (ROS) and fluctuations in diet. To that effect, it is of interest to note that temporal disruptions in ETC activity in most organisms are rarely fatal, and often a redundant number of failsafes are in place to permit continued ATP production when needed. Here, we highlight the metabolic reconfigurations discovered in organisms ranging from parasitic Entamoeba to bacteria such as pseudomonads and then complex eukaryotic systems that allow these species to adapt to and occasionally thrive in harsh environments. The overarching aim of this review is to demonstrate the plasticity of metabolic networks and recognize that in times of duress, life finds a way.
    Keywords:  ATP; Energy; Metabolic reconfiguration; Metabolism; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.metabol.2021.154733
  20. Front Immunol. 2020 ;11 620348
      Alzheimer's disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients' lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, neurofibrillary tangles and chronic neuroinflammation. To date, there is no cure that prevents progression of AD. In this review, we elaborate on how bioactive lipids, including sphingolipids (SL) and specialized pro-resolving lipid mediators (SPM), affect ongoing neuroinflammatory processes during AD and how we may exploit them for the development of new biomarker panels and/or therapies. In particular, we here describe how SPM and SL metabolism, ranging from ω-3/6 polyunsaturated fatty acids and their metabolites to ceramides and sphingosine-1-phosphate, initiates pro- and anti-inflammatory signaling cascades in the central nervous system (CNS) and what changes occur therein during AD pathology. Finally, we discuss novel therapeutic approaches to resolve chronic neuroinflammation in AD by modulating the SPM and SL pathways.
    Keywords:  Alzheimer’s disease; bioactive lipids; ceramide; neuroinflammation; specialized pro-resolving mediator; sphingolipids; sphingosine-1-phosphate
    DOI:  https://doi.org/10.3389/fimmu.2020.620348
  21. Regen Med. 2021 Feb 24.
      Regenerative medicine, poised to transform 21st century healthcare, has aspired to enrich care options by bringing cures to patients in need. Science-driven responsible and regulated translation of innovative technology has enabled the launch of previously unimaginable care pathways adopted prudently for select serious diseases and disabilities. The collective resolve to advance the design, manufacture and validity of affordable regenerative solutions aims to democratize such health benefits for all. The objective of this Review is to outline the framework and prerequisites that underpin clinical readiness of regenerative care. Integrated research and development, specialized workforce education and accessible evidence-based practice implementation are at the core of realizing an equitable regenerative medicine vision.
    Keywords:  chronic disease; healthcare delivery; innovation; manufacturing; model of care; patient; population; practice; regeneration; regulation; supply chain; workforce
    DOI:  https://doi.org/10.2217/rme-2020-0178
  22. Nat Commun. 2021 02 22. 12(1): 1209
      Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1β after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.
    DOI:  https://doi.org/10.1038/s41467-021-21461-4
  23. Stem Cell Reports. 2021 Feb 16. pii: S2213-6711(21)00051-5. [Epub ahead of print]
      Human mesenchymal stem/stromal cell (hMSC)-based cell therapies are promising for treating a variety of diseases. The unique immunomodulatory properties of hMSCs have extended their therapeutic potential beyond tissue regeneration. However, extensive pre-clinical culture expansion inevitably drives cells toward replicative "aging" and a consequent decline in quality. These "in vitro-aged" hMSCs resemble biologically aged cells, which have been reported to show senescence signatures, diminished immunosuppressive capacity, and weakened regenerative potential as well as pro-inflammatory features. In this review, we have surveyed the literature to explore the intimate relationship between the inflammatory status of hMSCs and their in vitro aging process. We posit that a shift from an anti-inflammatory to a pro-inflammatory phenotype of culture-expanded hMSCs contributes to a deterioration in their therapeutic efficacy. Potential molecular and cellular mechanisms underpinning this phenomenon have been discussed. We have also highlighted studies that leverage these mechanisms to make culture-expanded hMSCs more amenable for clinical use.
    Keywords:  SASP; aging; allogeneic stem cell therapy; extracellular matrix; glycosaminoglycan; heparan sulfate; immunomodulation; inflammation; rejuvenating mesenchymal stem cells; secretome
    DOI:  https://doi.org/10.1016/j.stemcr.2021.01.021
  24. Hist Philos Life Sci. 2021 Feb 23. 43(1): 28
      Prevention of age-related disorders is increasingly in focus of health policies, and it is hoped that early intervention on processes of deterioration can promote healthier and longer lives. New opportunities to slow down the aging process are emerging with new fields such as personalized nutrition. Data-intensive research has the potential to improve the precision of existing risk factors, e.g., to replace coarse-grained markers such as blood cholesterol with more detailed multivariate biomarkers. In this paper, we follow an attempt to develop a new aging biomarker. The vision among the project consortium, comprising both research and industrial partners, is that the new biomarker will be predictive of a range of age-related conditions, which may be preventable through personalized nutrition. We combine philosophical analysis and ethnographic fieldwork to explore the possibilities and challenges of managing aging through bodily signs that are not straightforwardly linked to symptomatic disease. We document how the improvement of measurement brings about new conceptual challenges of demarcating healthy and unhealthy states. Moreover, we highlight that the reframing of aging as risk has social and ethical implications, as it is generative of normative notions of what constitutes successful aging and good citizenship.
    Keywords:  Aging biomarker; Healthy aging; Medicalization; Personalized nutrition; Philosophy of aging
    DOI:  https://doi.org/10.1007/s40656-021-00367-w
  25. Mol Metab. 2021 Feb 17. pii: S2212-8778(21)00035-1. [Epub ahead of print] 101195
      BACKGROUND: Nicotinamide adenine dinucleotide (NAD+), a critical coenzyme present in every living cell, is involved in a myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD+ is often studied in the context of aging, cancer, neurodegenerative and metabolic disorders.SCOPE OF REVIEW: Cellular NAD+ depletion is associated with compromised adaptive cellular stress responses, impaired neuronal plasticity, impaired DNA repair and cellular senescence. Growing evidence has shown the efficacy of boosting NAD+ levels by using NAD+ precursors in various diseases. This review aims to provide a comprehensive understanding into the role of NAD+ in aging and other pathologies and discusses potential therapeutic targets.
    MAJOR CONCLUSIONS: An alteration in the NAD+/NADH ratio or the NAD+ pool size can lead to derailment of the biological system and contribute to various neurodegenerative disorders, aging, and tumorigenesis. Due to the varied distribution of NAD+/NADH in different locations within the cell, the direct role of impaired NAD+-dependent processes in humans remains unestablished. In this regard, longitudinal studies are needed to quantify NAD+ and its related metabolites. Future research should focus on measuring the fluxes through pathways associated with NAD+ synthesis and degradation.
    Keywords:  Aging; Cancer; Metabolism; NAD(+); Neurodegeneration; Sirtuins
    DOI:  https://doi.org/10.1016/j.molmet.2021.101195
  26. Cell Metab. 2021 Feb 17. pii: S1550-4131(21)00057-7. [Epub ahead of print]
      Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP, respiration generates biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Here, we show that in addition to depleting intracellular aspartate, electron transport chain (ETC) inhibition depletes aspartate-derived asparagine, increases ATF4 levels, and impairs mTOR complex I (mTORC1) activity. Exogenous asparagine restores proliferation, ATF4 and mTORC1 activities, and mTORC1-dependent nucleotide synthesis in the context of ETC inhibition, suggesting that asparagine communicates active respiration to ATF4 and mTORC1. Finally, we show that combination of the ETC inhibitor metformin, which limits tumor asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumor asparagine consumption, effectively impairs tumor growth in multiple mouse models of cancer. Because environmental asparagine is sufficient to restore tumor growth in the context of respiration impairment, our findings suggest that asparagine synthesis is a fundamental purpose of tumor mitochondrial respiration, which can be harnessed for therapeutic benefit to cancer patients.
    Keywords:  asparaginase; asparagine; cancer metabolism; cancer treatment; dietary restriction; metformin; respiration
    DOI:  https://doi.org/10.1016/j.cmet.2021.02.001
  27. Oncotarget. 2021 Feb 02. 12(3): 131-144
      Although numerous drugs seemingly extend healthspan in mice, only a few extend lifespan in mice and only one does it consistently. Some of them, alone or in combination, can be used in humans, without further clinical trials.
    Keywords:  aging; longevity; mTOR; metformin; rapamycin
    DOI:  https://doi.org/10.18632/oncotarget.27882
  28. Ageing Res Rev. 2021 Feb 20. pii: S1568-1637(21)00055-6. [Epub ahead of print] 101308
      Corona virus disease 2019 (COVID-19) is a global emergency able to overwhelm the healthcare capacities worldwide and to affect the older generation especially. When addressing the pathophysiological mechanisms and clinical manifestations of COVID-19, it becomes evident that the disease targets pathways and domains affected by the main aging- and frailty-related pathophysiological changes. A closer analysis of the existing data supports a possible role of biological age rather than chronological age in the prognosis of COVID-19. There is a need for systematic, consequent action of identifying frail (not only older, not only multimorbid, not only symptomatic) persons at risk of poor outcomes in order to protect our oldest generation from COVID-19.
    Keywords:  Biological age; COVID-19; Corona virus disease 2019; Frailty; SARS-CoV-2; Severe acute respiratory syndrome-corona virus 2
    DOI:  https://doi.org/10.1016/j.arr.2021.101308
  29. Blood. 2021 Feb 25. 137(8): 1010-1011
      
    DOI:  https://doi.org/10.1182/blood.2020009205