bims-minfam 2021-02-14 papers

bims-minfam

Biomed News

on Inflammation and metabolism in ageing and cancer

Issue of 2021–02–14
29 papers selected by
Ayesh Seneviratne, University of Toronto

"Cell Membrane Theory of Senescence" and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications.
Sensing and Signaling of Methionine Metabolism.
Age-specific microbiota in altering host inflammatory and metabolic signaling as well as metabolome based on the sex.
Dietary Fish, Fish Nutrients, and Immune Function: A Review.
Yin and Yang: The dual effects of interferons on hematopoiesis.
Magnesium in Aging, Health and Diseases.
IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis.
Aging of the Suprachiasmatic Nucleus, CIRCLONSA syndrome, implications for regenerative medicine and restoration of the master body clock.
Towards a Large-Scale Assessment of the Relationship between Biological and Chronological Aging: The INSPIRE Mouse Cohort.
Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging.
Outcomes following hematopoietic stem cell transplantation in patients treated with standard chemotherapy with or without gemtuzumab ozogamicin for acute myeloid leukemia.
JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells.
Regenerative medicine lexicon.
Obesity-induced inflammation: The impact of the hematopoietic stem cell niche.
Suppression of p16 alleviates the senescence-associated secretory phenotype.
COVID-19 and hematopoietic stem cell transplantation and immune effector cell therapy: a US cancer center experience.
Regulation of the Wound Healing Response during Aging.
Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2.
Mitochondrial dynamics in cancer stem cells.
Dietary Fruit and Vegetable Supplementation Suppresses Diet-Induced Atherosclerosis in LDL Receptor Knockout Mice.
Nutraceuticals against Oxidative Stress in Autoimmune Disorders.
Vitamin D and Its Role in the Lipid Metabolism and the Development of Atherosclerosis.
From bench to bedside: updates in basic science, translational and clinical research on muscle fatigue in cancer cachexia.
Splicing alterations in healthy aging and disease.
Glutamine Synthetase as a Therapeutic Target for Cancer Treatment.
The metabolic reprogramming in acute myeloid leukemia patients depends on their genotype and is a prognostic marker.
XPO1 inhibitors represent a novel therapeutic option in Adult T-cell Leukemia, triggering p53-mediated caspase-dependent apoptosis.
Circadian Mechanisms in Medicine.
MtDNA mutations and aging-not a closed case after all?

Biomolecules. 2021 Feb 08. pii: 241. [Epub ahead of print]11(2):

"Cell Membrane Theory of Senescence" and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications.

Undurti N Das.

  Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.

Keywords:  aging; bioactive lipids; cell membrane; inflammation; sirtuins; unsaturated fatty acids

DOI:  https://doi.org/10.3390/biom11020241
Metabolites. 2021 Jan 31. pii: 83. [Epub ahead of print]11(2):

Sensing and Signaling of Methionine Metabolism.

Linda Lauinger, Peter Kaiser.

  Availability of the amino acid methionine shows remarkable effects on the physiology of individual cells and whole organisms. For example, most cancer cells, but not normal cells, are hyper dependent on high flux through metabolic pathways connected to methionine, and diets restricted for methionine increase healthy lifespan in model organisms. Methionine's impact on physiology goes beyond its role in initiation of translation and incorporation in proteins. Many of its metabolites have a major influence on cellular functions including epigenetic regulation, maintenance of redox balance, polyamine synthesis, and phospholipid homeostasis. As a central component of such essential pathways, cells require mechanisms to sense methionine availability. When methionine levels are low, cellular response programs induce transcriptional and signaling states to remodel metabolic programs and maintain methionine metabolism. In addition, an evolutionary conserved cell cycle arrest is induced to ensure cellular and genomic integrity during methionine starvation conditions. Methionine and its metabolites are critical for cell growth, proliferation, and development in all organisms. However, mechanisms of methionine perception are diverse. Here we review current knowledge about mechanisms of methionine sensing in yeast and mammalian cells, and will discuss the impact of methionine imbalance on cancer and aging.

Keywords:  S-adenosylmethionine; aging; cancer; cell cycle; methionine; methionine/SAM sensing

DOI:  https://doi.org/10.3390/metabo11020083
Hepatobiliary Surg Nutr. 2021 Jan;10(1): 31-48

Age-specific microbiota in altering host inflammatory and metabolic signaling as well as metabolome based on the sex.

Lili Sheng, Prasant Kumar Jena, Ying Hu, Yu-Jui Yvonne Wan.

   Background: Metabolism is sex-different, and the direct link between gut microbiota and aging-associated metabolic changes needs to be established in both sexes.
Methods: Gene expression, metabolic and inflammatory signaling, gut microbiota profile, and metabolome were studied during aging and after fecal microbiota transplantation (FMT) in mice of both sexes.
Results: Our data revealed young female mice and aged male mice were the most insulin sensitive and resistant group, respectively. In addition, aging reduced sex difference in insulin sensitivity. Such age- and sex-dependent metabolic phenotypes were accompanied by shifted gut microbiota profile and altered abundance of bacterial genes that produce butyrate, propionate, and bile acids. After receiving feces from the aged males (AFMT), the most insulin-resistant group, recipients of both sexes had increased hepatic inflammation and serum endotoxin. However, AFMT only increased insulin resistance in female mice and abolished sex difference in insulin sensitivity. Additionally, such changes were accompanied by narrowed sex difference in metabolome. Metabolomics data revealed that age-associated insulin resistance in males was accompanied by increased sugar alcohols and dicarboxylic acids as well as reduced aromatic and branched-chain amino acids. Further, receiving feces from the young females (YFMT), the most insulin-sensitive group, reduced body weight and fasting blood glucose in male recipients and improved insulin sensitivity in females, leading to enhanced sex differences in insulin sensitivity and metabolome.
Conclusions: Aging systemically affected inflammatory and metabolic signaling based on the sex. Gut microbiome is age and sex-specific, which affects inflammation and metabolism in a sex-dependent manner.

Keywords:  Aging; fecal transplantation; insulin sensitivity; metabolome; microbiome

DOI:  https://doi.org/10.21037/hbsn-20-671
Front Nutr. 2020 ;7 617652

Dietary Fish, Fish Nutrients, and Immune Function: A Review.

Carlos O Mendivil.

  Dietary habits have a major impact on the development and function of the immune system. This impact is mediated both by the intrinsic nutritional and biochemical qualities of the diet, and by its influence on the intestinal microbiota. Fish as a food is rich in compounds with immunoregulatory properties, among them omega-3 fatty acids, melatonin, tryptophan, taurine and polyamines. In addition, regular fish consumption favors the proliferation of beneficial members of the intestinal microbiota, like short-chain fatty acid-producing bacteria. By substituting arachidonic acid in the eicosanoid biosynthesis pathway, long-chain omega-3 fatty acids from fish change the type of prostaglandins, leukotrienes and thromboxanes being produced, resulting in anti-inflammatory properties. Further, they also are substrates for the production of specialized pro-resolving mediators (SPMs) (resolvins, protectins, and maresins), lipid compounds that constitute the physiological feedback signal to stop inflammation and give way to tissue reparation. Evidence from human observational and interventional studies shows that regular fish consumption is associated with reduced incidence of chronic inflammatory conditions like rheumatoid arthritis, and that continuous infusion of fish oil to tube-fed, critically ill patients may improve important outcomes in the ICU. There is also evidence from animal models showing that larger systemic concentrations of omega-3 fatty acids may counter the pathophysiological cascade that leads to psoriasis. The knowledge gained over the last few decades merits future exploration of the potential role of fish and its components in other conditions characterized by deregulated activation of immune cells and a cytokine storm like viral sepsis or COVID-19.

Keywords:  fish; immune function; immunity; microbiota; omega-3; seafood

DOI:  https://doi.org/10.3389/fnut.2020.617652
Exp Hematol. 2021 Feb 08. pii: S0301-472X(21)00034-5. [Epub ahead of print]

Yin and Yang: The dual effects of interferons on hematopoiesis.

Yasmin Demerdash, Bailee Kain, Marieke A G Essers, Katherine Y King.

Interferons are an ancient and well-conserved group of inflammatory cytokines most famous for their role in viral immunity. A decade ago, we discovered that interferons also play an important role in the biology of hematopoietic stem cells (HSCs), which are responsible for lifelong blood production. Though we have learned a great deal about the role of interferons on HSC quiescence, differentiation, and self-renewal, there remains some controversy regarding how interferons impact these stem cells, with differing conclusions depending on experimental models and clinical context. Here, we review the contradictory roles of Type 1 and 2 interferons in hematopoiesis. Specifically, we highlight the roles of interferons in embryonic and adult hematopoiesis, along with short-term and long-term adaptive and maladaptive responses to inflammation. We discuss experimental challenges in the study of these powerful yet short-lived cytokines and strategies to address those challenges. We further review the contribution by interferons to disease states including bone marrow failure and aplastic anemia as well as their therapeutic use to treat myeloproliferative neoplasms and viral infections, including SARS-CoV2. Understanding the opposing effects of interferons on hematopoiesis will elucidate immune responses and bone marrow failure syndromes, and future therapeutic approaches for patients undergoing HSC transplantation or fighting infectious diseases and cancer.

DOI: https://doi.org/10.1016/j.exphem.2021.02.002
Nutrients. 2021 Jan 30. pii: 463. [Epub ahead of print]13(2):

Magnesium in Aging, Health and Diseases.

Mario Barbagallo, Nicola Veronese, Ligia J Dominguez.

  Several changes of magnesium (Mg) metabolism have been reported with aging, including diminished Mg intake, impaired intestinal Mg absorption and renal Mg wasting. Mild Mg deficits are generally asymptomatic and clinical signs are usually non-specific or absent. Asthenia, sleep disorders, hyperemotionality, and cognitive disorders are common in the elderly with mild Mg deficit, and may be often confused with age-related symptoms. Chronic Mg deficits increase the production of free radicals which have been implicated in the development of several chronic age-related disorders. Numerous human diseases have been associated with Mg deficits, including cardiovascular diseases, hypertension and stroke, cardio-metabolic syndrome and type 2 diabetes mellitus, airways constrictive syndromes and asthma, depression, stress-related conditions and psychiatric disorders, Alzheimer's disease (AD) and other dementia syndromes, muscular diseases (muscle pain, chronic fatigue, and fibromyalgia), bone fragility, and cancer. Dietary Mg and/or Mg consumed in drinking water (generally more bioavailable than Mg contained in food) or in alternative Mg supplements should be taken into consideration in the correction of Mg deficits. Maintaining an optimal Mg balance all through life may help in the prevention of oxidative stress and chronic conditions associated with aging. This needs to be demonstrated by future studies.

Keywords:  aging; dementia; diabetes; diseases; health; hypertension; longevity; magnesium; osteoporosis; oxidative stress

DOI:  https://doi.org/10.3390/nu13020463
Metabolites. 2021 Jan 29. pii: 79. [Epub ahead of print]11(2):

IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis.

Stephan Wueest, Eleonora Seelig, Katharina Timper, Mark P Lyngbaek, Kristian Karstoft, Marc Y Donath, Helga Ellingsgaard, Daniel Konrad.

  Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical trial were analyzed. In the latter study, obese human subjects with or without type 2 diabetes were randomly assigned to recurrent placebo or intravenous tocilizumab (an IL-6 receptor antibody) administration during a 12-week exercise training intervention. Twelve weeks of tocilizumab administration (in combination with exercise training) trend wise enhanced the decrease in circulating leptin levels (-2.7 ± 8.2% in the placebo vs. -20.6 ± 5.6% in tocilizumab, p = 0.08) and significantly enhanced the increase in circulating adiponectin (3.4 ± 3.7% in the placebo vs. 27.0 ± 6.6% in tocilizumab, p = 0.01). In addition, circulating adiponectin levels were negatively correlated with the homeostatic model assessment of insulin resistance (HOMA-IR), indicating that increased adiponectin levels positively affect insulin sensitivity in people with obesity. In conclusion, IL-6 receptor blockade increases circulating adiponectin levels in people with obesity.

Keywords:  adipokine; tocilizumab; white adipose tissue

DOI:  https://doi.org/10.3390/metabo11020079
Rejuvenation Res. 2021 Feb 11.

Aging of the Suprachiasmatic Nucleus, CIRCLONSA syndrome, implications for regenerative medicine and restoration of the master body clock.

Victor Björk.

The suprachiasmatic nucleus (SCN) in the brain is the master regulator of the circadian clocks throughout the human body. With increasing age the circadian clock in humans and other mammals becomes increasingly disorganized leading to a large number of more or less well categorized problems. While a lot of aging research has focused on the peripheral clocks in tissues across organisms, it remains a paramount task to quantify aging of the most important master clock, the human SCN. Furthermore, a pipeline needs to be developed with therapies to mitigate the systemic cellular circadian dysfunction in the elderly and ultimately repair and reverse aging of the SCN itself. A disease classification for the aging SCN, Circadian Clock Neuronal Senile Atrophy, (CIRCLONSA syndrome), would improve research funding and goal-oriented biotechnological entrepreneurship.

DOI: https://doi.org/10.1089/rej.2020.2388
J Frailty Aging. 2021 ;10(2): 121-131

Towards a Large-Scale Assessment of the Relationship between Biological and Chronological Aging: The INSPIRE Mouse Cohort.

Y Santin, S Lopez, I Ader, S Andrieu, N Blanchard, A Carrière, L Casteilla, B Cousin, N Davezac, P De Souto Barreto, C Dray, N Fazilleau, D Gonzalez-Dunia, P Gourdy, S Guyonnet, N Jabrane-Ferrat, O Kunduzova, F Lezoualc'h, R Liblau, L O Martinez, C Moro, P Payoux, L Pénicaud, V Planat-Bénard, C Rampon, Y Rolland, J-P Schanstra, F Sierra, P Valet, A Varin, N Vergnolle, B Vellas, J Viña, B P Guiard, A Parini.

  Aging is the major risk factor for the development of chronic diseases. After decades of research focused on extending lifespan, current efforts seek primarily to promote healthy aging. Recent advances suggest that biological processes linked to aging are more reliable than chronological age to account for an individual's functional status, i.e. frail or robust. It is becoming increasingly apparent that biological aging may be detectable as a progressive loss of resilience much earlier than the appearance of clinical signs of frailty. In this context, the INSPIRE program was built to identify the mechanisms of accelerated aging and the early biological signs predicting frailty and pathological aging. To address this issue, we designed a cohort of outbred Swiss mice (1576 male and female mice) in which we will continuously monitor spontaneous and voluntary physical activity from 6 to 24 months of age under either normal or high fat/high sucrose diet. At different age points (6, 12, 18, 24 months), multiorgan functional phenotyping will be carried out to identify early signs of organ dysfunction and generate a large biological fluids/feces/organs biobank (100,000 samples). A comprehensive correlation between functional and biological phenotypes will be assessed to determine: 1) the early signs of biological aging and their relationship with chronological age; 2) the role of dietary and exercise interventions on accelerating or decelerating the rate of biological aging; and 3) novel targets for the promotion of healthy aging. All the functional and omics data, as well as the biobank generated in the framework of the INSPIRE cohort will be available to the aging scientific community. The present article describes the scientific background and the strategies employed for the design of the INSPIRE Mouse cohort.

Keywords:  INSPIRE program; biological aging; biomarkers; frailty; mouse cohort

DOI:  https://doi.org/10.14283/jfa.2020.43
Cell Stem Cell. 2021 Feb 04. pii: S1934-5909(21)00010-2. [Epub ahead of print]

Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging.

Peng Deng, Quan Yuan, Yingduan Cheng, Jiong Li, Zhenqing Liu, Yan Liu, Ye Li, Trent Su, Jing Wang, Mari Ekimyan Salvo, Weiguang Wang, Guoping Fan, Karen Lyons, Bo Yu, Cun-Yu Wang.

  Skeletal aging is a complex process, characterized by a decrease in bone formation, an increase in marrow fat, and stem cell exhaustion. Loss of H3K9me3, a heterochromatin mark, has been proposed to be associated with aging. Here, we report that loss of KDM4B in mesenchymal stromal cells (MSCs) exacerbated skeletal aging and osteoporosis by reducing bone formation and increasing marrow adiposity via increasing H3K9me3. KDM4B epigenetically coordinated β-catenin/Smad1-mediated transcription by removing repressive H3K9me3. Importantly, KDM4B ablation impaired MSC self-renewal and promoted MSC exhaustion by inducing senescence-associated heterochromatin foci formation, providing a mechanistic explanation for stem cell exhaustion with aging. Moreover, while KDM4B was required for parathyroid hormone-mediated bone anabolism, KDM4B depletion accelerated bone loss and marrow adiposity induced by a high-fat diet. Our results suggest that the epigenetic rejuvenation and reversing bone-fat imbalance might be new strategies for preventing and treating skeletal aging and osteoporosis by activating KDM4B in MSCs.

Keywords:  bone marrow adiposity; bone metabolism; mesenchymal stem cells; mesenchymal stromal cells; osteoporosis; parathyroid hormone; senescence-associated heterochromatin foci; skeletal aging; stem cell self-renewal

DOI:  https://doi.org/10.1016/j.stem.2021.01.010
Bone Marrow Transplant. 2021 Feb 09.

Outcomes following hematopoietic stem cell transplantation in patients treated with standard chemotherapy with or without gemtuzumab ozogamicin for acute myeloid leukemia.

Cécile Pautas, Emmanuel Raffoux, Juliette Lambert, Ollivier Legrand, Sylvain Chantepie, Lauris Gastaud, Jean-Pierre Marolleau, Xavier Thomas, Pascal Turlure, Rebecca J Benner, Erik Vandendries, Karïn Gogat, Hervé Dombret, Sylvie Castaigne.

The phase 3 ALFA-0701 trial demonstrated improved outcomes with fractionated-dose gemtuzumab ozogamicin (GO) combined with standard chemotherapy vs. standard chemotherapy alone in adults with de novo acute myeloid leukemia (AML). We examined post-transplant outcomes and occurrence of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients who received hematopoietic stem cell transplantation (HSCT) as follow-up therapy in ALFA-0701. Patients aged 50-70 years were randomized to standard chemotherapy with or without GO (3 mg/m2 on days 1, 4, and 7 of induction and day 1 on each of two consolidation courses). Allogeneic HSCT was recommended for patients in first complete remission with matched (related or unrelated) donor, except those with core-binding factor AML or normal karyotype and either NPM1+/FLT3-ITDwt or CEBPA+ AML. Eighty-five patients (GO: n = 32; control: n = 53) received HSCT in first complete remission or after relapse/primary induction failure. Three patients (GO: n = 2; control: n = 1 [received GO as follow-up therapy]) developed VOD/SOS after HSCT or conditioning. Post-transplant survival, non-relapse mortality, and relapse were not different between arms. Results indicate fractionated-dose GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant VOD/SOS or mortality and thus does not preclude the use of HSCT as consolidation treatment.

DOI: https://doi.org/10.1038/s41409-020-01207-4
Blood Adv. 2021 Feb 09. 5(3): 889-899

JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells.

Hannah Lawson, Catarina Sepulveda, Louie N van de Lagemaat, Jozef Durko, Melania Barile, Andrea Tavosanis, Elise Georges, Alena Shmakova, Penny Timms, Roderick N Carter, Lewis Allen, Joana Campos, Milica Vukovic, Amelie V Guitart, Peter Giles, Marie O'Shea, Douglas Vernimmen, Nicholas M Morton, Neil P Rodrigues, Berthold Göttgens, Christopher J Schofield, Andreas Lengeling, Dónal O'Carroll, Kamil R Kranc.

Lifelong multilineage hematopoiesis critically depends on rare hematopoietic stem cells (HSCs) that reside in the hypoxic bone marrow microenvironment. Although the role of the canonical oxygen sensor hypoxia-inducible factor prolyl hydroxylase has been investigated extensively in hematopoiesis, the functional significance of other members of the 2-oxoglutarate (2-OG)-dependent protein hydroxylase family of enzymes remains poorly defined in HSC biology and multilineage hematopoiesis. Here, by using hematopoietic-specific conditional gene deletion, we reveal that the 2-OG-dependent protein hydroxylase JMJD6 is essential for short- and long-term maintenance of the HSC pool and multilineage hematopoiesis. Additionally, upon hematopoietic injury, Jmjd6-deficient HSCs display a striking failure to expand and regenerate the hematopoietic system. Moreover, HSCs lacking Jmjd6 lose multilineage reconstitution potential and self-renewal capacity upon serial transplantation. At the molecular level, we found that JMJD6 functions to repress multiple processes whose downregulation is essential for HSC integrity, including mitochondrial oxidative phosphorylation (OXPHOS), protein synthesis, p53 stabilization, cell cycle checkpoint progression, and mTORC1 signaling. Indeed, Jmjd6-deficient primitive hematopoietic cells display elevated basal and maximal mitochondrial respiration rates and increased reactive oxygen species (ROS), prerequisites for HSC failure. Notably, an antioxidant, N-acetyl-l-cysteine, rescued HSC and lymphoid progenitor cell depletion, indicating a causal impact of OXPHOS-mediated ROS generation upon Jmjd6 deletion. Thus, JMJD6 promotes HSC maintenance and multilineage differentiation potential by suppressing fundamental pathways whose activation is detrimental for HSC function.

DOI: https://doi.org/10.1182/bloodadvances.2020002702
Regen Med. 2020 Dec;15(12): 2325-2328

Regenerative medicine lexicon.

Andre Terzic.



Keywords:  advanced therapies; dictionary; global; glossary; healthcare; innovation; linguistics; patient; regeneration; science

DOI:  https://doi.org/10.2217/rme-2020-0194
JCI Insight. 2021 Feb 08. pii: 145295. [Epub ahead of print]6(3):

Obesity-induced inflammation: The impact of the hematopoietic stem cell niche.

Emily Bowers, Kanakadurga Singer.

Obesity and obesity-related diseases like type 2 diabetes (T2D) are prominent global health issues; therefore, there is a need to better understand the mechanisms underlying these conditions. The onset of obesity is characterized by accumulation of proinflammatory cells, including Ly6chi monocytes (which differentiate into proinflammatory macrophages) and neutrophils, in metabolic tissues. This shift toward chronic, low-grade inflammation is an obese-state hallmark and highly linked to metabolic disorders and other obesity comorbidities. The mechanisms that induce and maintain increased inflammatory myelopoiesis are of great interest, with a recent focus on how obesity affects more primitive hematopoietic cells. The hematopoietic system is constantly replenished by proper regulation of hematopoietic stem and progenitor (HSPC) pools in the BM. While early research suggests that chronic obesity promotes expansion of myeloid-skewed HSPCs, the involvement of the hematopoietic stem cell (HSC) niche in regulating obesity-induced myelopoiesis remains undefined. In this review, we explore the role of the multicellular HSC niche in hematopoiesis and inflammation, and the potential contribution of this niche to the hematopoietic response to obesity. This review further aims to summarize the potential HSC niche involvement as a target of obesity-induced inflammation and a driver of obesity-induced myelopoiesis.

DOI: https://doi.org/10.1172/jci.insight.145295
Aging (Albany NY). 2021 Feb 06. 13

Suppression of p16 alleviates the senescence-associated secretory phenotype.

Raquel Buj, Kelly E Leon, Marlyn A Anguelov, Katherine M Aird.

  Oncogene-induced senescence (OIS) is characterized by increased expression of the cell cycle inhibitor p16, leading to a hallmark cell cycle arrest. Suppression of p16 in this context drives proliferation, senescence bypass, and contributes to tumorigenesis. OIS cells are also characterized by the expression and secretion of a widely variable group of factors collectively termed the senescence-associated secretory phenotype (SASP). The SASP can be both beneficial and detrimental and affects the microenvironment in a highly context-dependent manner. The relationship between p16 suppression and the SASP remains unclear. Here, we show that knockdown of p16 decreases expression of the SASP factors and pro-inflammatory cytokines IL6 and CXCL8 in multiple models, including OIS and DNA damage-induced senescence. Notably, this is uncoupled from the senescence-associated cell cycle arrest. Moreover, low p16 expression in both cancer cell lines and patient samples correspond to decreased SASP gene expression, suggesting this is a universal effect of loss of p16 expression. Together, our data suggest that p16 regulates SASP gene expression, which has implications for understanding how p16 modulates both the senescent and tumor microenvironment.

Keywords:  LMNB1; inflammation; interleukin-6; interleukin-8; melanoma

DOI:  https://doi.org/10.18632/aging.202640
Blood Adv. 2021 02 09. 5(3): 861-871

COVID-19 and hematopoietic stem cell transplantation and immune effector cell therapy: a US cancer center experience.

Katie Maurer, Anna Saucier, Haesook T Kim, Utkarsh Acharya, Clifton C Mo, Julie Porter, Cindy Albert, Corey Cutler, Joseph H Antin, John Koreth, Mahasweta Gooptu, Rizwan Romee, Catherine J Wu, Robert J Soiffer, Sarah Nikiforow, Caron Jacobson, Vincent T Ho.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), identified in late 2019 as the causative agent of COVID-19, was declared a pandemic by the World Health Organization on 11 March 2020. Widespread community transmission in the United States triggered a nationwide shutdown, raising major challenges for administration of hematopoietic stem cell transplant (HSCT) and chimeric antigen receptor (CAR)-T cell therapies, leading many centers to delay or cancel operations. We sought to assess the impact of the COVID-19 pandemic on operations and clinical outcomes for HSCT and CAR-T cellular therapies at the Dana-Farber Cancer Institute by reviewing administration and outcomes in 127 cell therapy patients treated during the initial COVID-19 surge: 62 adult allogeneic HSCT (allo-HSCT), 38 autologous HSCT (auto-HSCT), and 27 CAR-T patients. Outcomes were compared with 66 allo-HSCT, 43 auto-HSCT, and 33 CAR-T patients treated prior to the pandemic. A second control cohort was evaluated for HSCT groups to reflect seasonal variation in infections. Although there were changes in donor selection and screening as well as cryopreservation patterns of donor products, no differences were observed across groups in 100-day overall survival, progression-free survival, rates of non-COVID-19 infections, including hospital length of stay, neutrophil engraftment, graft failure, acute graft-versus-host disease in allo-HSCT patients, or cytokine release syndrome and neurotoxicity in CAR-T patients. No HSCT patients contracted COVID-19 between days 0 and 100. One CAR-T patient contracted COVID-19 at day +51 and died of the disease. Altogether, our data indicate that cellular therapies can be safely administered throughout the ongoing COVID-19 pandemic with appropriate safeguards.

DOI: https://doi.org/10.1182/bloodadvances.2020003883
J Invest Dermatol. 2021 Feb 05. pii: S0022-202X(20)32360-5. [Epub ahead of print]

Regulation of the Wound Healing Response during Aging.

Xiaolei Ding, Parisa Kakanj, Maria Leptin, Sabine A Eming.

An effective healing response is critical to promote and ensure healthy aging. Major discoveries in both fields-repair and aging-have led to a better understanding of the mechanisms regulating the healing response and of the complexity of the aging process. It will now be important to translate and connect those findings to improve our insights into the decline of regeneration in the elderly. Furthermore, we need to understand how this process can be stalled to maintain and promote tissue resilience. Furthermore, it remains to be explored how the findings in model organisms are conserved in human wounds and how these findings might be translated into the clinic.

DOI: https://doi.org/10.1016/j.jid.2020.11.014
Int J Mol Sci. 2021 Jan 25. pii: 1156. [Epub ahead of print]22(3):

Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2.

Megan T Zangara, Isabel Johnston, Erin E Johnson, Christine McDonald.

  In addition to their classical roles as bacterial sensors, NOD1 and NOD2 have been implicated as mediators of metabolic disease. Increased expression of NOD1 and/or NOD2 has been reported in a range of human metabolic diseases, including obesity, diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Although NOD1 and NOD2 share intracellular signaling pathway components, they are differentially upregulated on a cellular level and have opposing impacts on metabolic disease development in mouse models. These NOD-like receptors may directly mediate signaling downstream of cell stressors, such as endoplasmic reticulum stress and calcium influx, or in response to metabolic signals, such as fatty acids and glucose. Other studies suggest that stimulation of NOD1 or NOD2 by their bacterial ligands can result in inflammation, altered insulin responses, increased reactive oxygen signaling, and mitochondrial dysfunction. The activating stimuli for NOD1 and NOD2 in the context of metabolic disease are controversial and may be a combination of both metabolic and circulating bacterial ligands. In this review, we will summarize the current knowledge of how NOD1 and NOD2 may mediate metabolism in health and disease, as well as highlight areas of future investigation.

Keywords:  ER stress; NLR; diabetes; high fat diet; hypoxia; insulin resistance; metabolic syndrome; metabolism; mitochondria; obesity

DOI:  https://doi.org/10.3390/ijms22031156
Cell Mol Life Sci. 2021 Feb 13.

Mitochondrial dynamics in cancer stem cells.

Dane T Sessions, David F Kashatus.

  Many tumors are now understood to be heterogenous cell populations arising from a minority of epithelial-like cancer stem cells (CSCs). CSCs demonstrate distinctive metabolic signatures from the more differentiated surrounding tumor bulk that confer resistance to traditional chemotherapeutic regimens and potential for tumor relapse. Many CSC phenotypes including metabolism, epithelial-to-mesenchymal transition, cellular signaling pathway activity, and others, arise from altered mitochondrial function and turnover, which are regulated by constant cycles of mitochondrial fusion and fission. Further, recycling of mitochondria through mitophagy in CSCs is associated with maintenance of reactive oxygen species levels that dictate gene expression. The protein machinery that drives mitochondrial dynamics is surprisingly simple and may represent attractive new therapeutic avenues to target CSC metabolism and selectively eradicate tumor-generating cells to reduce the risks of metastasis and relapse for a variety of tumor types.

Keywords:  Cancer stem cells; EMT; Metabolism; Mitochondrial dynamics; Mitochondrial morphology; Signaling; Therapeutic resistance

DOI:  https://doi.org/10.1007/s00018-021-03773-2
J Nutr. 2021 Feb 09. pii: nxaa410. [Epub ahead of print]

Dietary Fruit and Vegetable Supplementation Suppresses Diet-Induced Atherosclerosis in LDL Receptor Knockout Mice.

Weimin Guo, Sharon H Kim, Dayong Wu, Lijun Li, Edwin Frank Ortega, Michael Thomas, Simin Nikbin Meydani, Mohsen Meydani.

   BACKGROUND: Epidemiologic studies suggest that fruit and vegetable (F&V) consumption is inversely associated with incidence of cardiovascular disease (CVD). However, evidence for causality is lacking, and the underlying mechanisms are not well understood.
OBJECTIVES: We aimed to determine whether there is a causal relation between consuming high levels of F&V and prevention of atherosclerosis, the hallmark of CVD pathogenesis. Furthermore, the underlying mechanisms were determined.
METHODS: Six-week-old male LDL receptor-knockout mice were randomly assigned to 3 diet groups (12 mice/group) for 20 wk: control (CON, 10% kcal fat, 0.20 g/kg cholesterol), atherogenic (Ath, 27% kcal fat, 0.55 g/kg cholesterol), and Ath supplemented with 15% F&V (Ath + FV) (equivalent to 8-9 servings/d in humans). F&V was added as a freeze-dried powder that was prepared from the 24 most commonly consumed F&Vs in the United States. Body weight, aortic atherosclerotic lesion area, hepatic steatosis area, serum lipid profile and proinflammatory cytokine TNF-α concentrations, gut microbiota, and liver TNF-α and fatty acid synthase (Fasn) mRNA concentrations were assessed.
RESULTS: F&V supplementation did not affect weight gain. Mice fed the Ath + FV diet had a smaller aortic atherosclerotic lesion area (71.7% less) and hepatic steatosis area (80.7% less) than those fed the Ath diet (both P < 0.001) independent of impact on weight, whereas no difference was found between Ath + FV and CON groups in these 2 pathologic markers. Furthermore, F&V supplementation prevented Ath diet-induced dyslipidemia (high concentrations of serum TG and VLDL cholesterol and lower concentrations of HDL cholesterol), reduced serum TNF-α concentration (by 21.5%), suppressed mRNA expression of liver TNF-α and Fasn, and ameliorated Ath-induced gut microbiota dysbiosis.
CONCLUSIONS: Our results indicate that consuming a large quantity and variety of F&Vs causally attenuates diet-induced atherosclerosis and hepatic steatosis in mice. These effects of F&Vs are associated with, and may be mediated through, improved atherogenic dyslipidemia, alleviated gut dysbiosis, and suppressed inflammation.

Keywords:  LDL receptor knockout mice; atherosclerosis; dyslipidemia; fruits and vegetables; gut microbiota; hepatic steatosis; inflammation

DOI:  https://doi.org/10.1093/jn/nxaa410
Antioxidants (Basel). 2021 Feb 08. pii: 261. [Epub ahead of print]10(2):

Nutraceuticals against Oxidative Stress in Autoimmune Disorders.

Carmen Mannucci, Marco Casciaro, Emanuela Elisa Sorbara, Fabrizio Calapai, Eleonora Di Salvo, Giovanni Pioggia, Michele Navarra, Gioacchino Calapai, Sebastiano Gangemi.

  Antioxidant mechanisms are constituted of enzymes, endogenous, and non-enzymatic, exogenous, which have the role of counterbalancing oxidative stress. Intake of these compounds occurs in the diet. Vegetables, plants, and fruits contain a wide range of alkaloids, polyphenols, and terpenoids which are called "phytochemicals". Most of these substances are responsible for the positive properties of fruits and vegetables, which are an essential part of a healthy life with roles in ameliorating chronic illnesses and favoring longevity. Nutraceuticals are substances contained in a food or fragment of it influencing health with positive effects on health helping in precenting or treating disorders. We conducted a review illustrating the principal applications of nutraceuticals in autoimmune disorders. Literature reported several studies about exogenous dietary antioxidant supplementation in diverse autoimmune diseases such as rheumatoid arthritis, lupus, diabetes, and multiple sclerosis. In these pathologies, promising results were obtained in some cases. Positive outcomes were generally associated with a reduction of oxidative stress parameters and a boost to antioxidant systems, and sometimes with anti-inflammatory effects. The administration of exogenous substances through food derivates or dietary supplements following scientific standardization was demonstrated to be effective. Further bias-free and extended studies should be conducted that include ever-increasing oxidative stress biomarkers.

Keywords:  ROS; autoimmune; diabetes; exogenous antioxidants; immunity; inflammation; integrators; nutraceuticals; oxidative stress; supplement

DOI:  https://doi.org/10.3390/antiox10020261
Biomedicines. 2021 Feb 09. pii: 172. [Epub ahead of print]9(2):

Vitamin D and Its Role in the Lipid Metabolism and the Development of Atherosclerosis.

Andrei Mihai Surdu, Oana Pînzariu, Dana-Mihaela Ciobanu, Alina-Gabriela Negru, Simona-Sorana Căinap, Cecilia Lazea, Daniela Iacob, George Săraci, Dacian Tirinescu, Ileana Monica Borda, Gabriel Cismaru.

  Vitamin D, a crucial hormone in the homeostasis and metabolism of calcium bone, has lately been found to produce effects on other physiological and pathological processes genomically and non-genomically, including the cardiovascular system. While lower baseline vitamin D levels have been correlated with atherogenic blood lipid profiles, 25(OH)D supplementation influences the levels of serum lipids in that it lowers the levels of total cholesterol, triglycerides, and LDL-cholesterol and increases the levels of HDL-cholesterol, all of which are known risk factors for cardiovascular disease. Vitamin D is also involved in the development of atherosclerosis at the site of the blood vessels. Deficiency of this vitamin has been found to increase adhesion molecules or endothelial activation and, at the same time, supplementation is linked to the lowering presence of adhesion surrogates. Vitamin D can also influence the vascular tone by increasing endothelial nitric oxide production, as seen in supplementation studies. Deficiency can lead, at the same time, to oxidative stress and an increase in inflammation as well as the expression of particular immune cells that play a pivotal role in the development of atherosclerosis in the intima of the blood vessels, i.e., monocytes and macrophages. Vitamin D is also involved in atherogenesis through inhibition of vascular smooth muscle cell proliferation. Furthermore, vitamin D deficiency is consistently associated with cardiovascular events, such as myocardial infarction, STEMI, NSTEMI, unstable angina, ischemic stroke, cardiovascular death, and increased mortality after acute stroke. Conversely, vitamin D supplementation does not seem to produce beneficial effects in cohorts with intermediate baseline vitamin D levels.

Keywords:  25-OH vitamin D; atherosclerosis; bone metabolism; cardiovascular; ischemic heart disease; ischemic stroke; myocardial infarction; osteomalacia; rickets; vitamin D

DOI:  https://doi.org/10.3390/biomedicines9020172
Curr Opin Clin Nutr Metab Care. 2021 Feb 05.

From bench to bedside: updates in basic science, translational and clinical research on muscle fatigue in cancer cachexia.

Katherine M Jackson, Calvin L Cole, Richard F Dunne.

PURPOSE OF REVIEW: Cancer cachexia is a syndrome of loss of weight and muscle mass that leads to reduced strength, poor physical performance and functional impairment. Muscular fatigue is a distressing syndrome that patients with cachexia suffer from and can impair quality of life. Here, we review recent updates in muscular fatigue in cancer cachexia research with a focus on mechanisms, biomarkers and potential therapies.
RECENT FINDINGS: Both in mice and humans, research has shown that muscle fatigue can be independent of muscular atrophy and can happen early in cancer development or in precachexia. Inflammatory pathways, mitochondrial dysfunction and gut microbiota have recently been studied to play an important role in muscle fatigue in preclinical models. Exercise can target these pathways and has been studied as a therapeutic intervention to improve muscle fatigue.
SUMMARY: Heightened inflammation within muscle, altered muscle function and muscle fatigue can begin prior to clinical evidence of cachexia, making early recognition and intervention challenging. The emergence of cachexia mouse models and translational and clinical research studying muscle fatigue will hopefully lead to new therapies targeting the underlying mechanisms of cancer cachexia. Exercise will need to be tested in larger randomized studies before entering into daily practice.

DOI: https://doi.org/10.1097/MCO.0000000000000738
Wiley Interdiscip Rev RNA. 2021 Feb 09. e1643

Splicing alterations in healthy aging and disease.

Brittany Lynn Angarola, Olga Anczuków.

  Alternative RNA splicing is a key step in gene expression that allows generation of numerous messenger RNA transcripts encoding proteins of varied functions from the same gene. It is thus a rich source of proteomic and functional diversity. Alterations in alternative RNA splicing are observed both during healthy aging and in a number of human diseases, several of which display premature aging phenotypes or increased incidence with age. Age-associated splicing alterations include differential splicing of genes associated with hallmarks of aging, as well as changes in the levels of core spliceosomal genes and regulatory splicing factors. Here, we review the current known links between alternative RNA splicing, its regulators, healthy biological aging, and diseases associated with aging or aging-like phenotypes. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing.

Keywords:  RNA; aging; alternative splicing; disease; splicing factors

DOI:  https://doi.org/10.1002/wrna.1643
Int J Mol Sci. 2021 Feb 08. pii: 1701. [Epub ahead of print]22(4):

Glutamine Synthetase as a Therapeutic Target for Cancer Treatment.

Go Woon Kim, Dong Hoon Lee, Yu Hyun Jeon, Jung Yoo, So Yeon Kim, Sang Wu Lee, Ha Young Cho, So Hee Kwon.

  The significance of glutamine in cancer metabolism has been extensively studied. Cancer cells consume an excessive amount of glutamine to facilitate rapid proliferation. Thus, glutamine depletion occurs in various cancer types, especially in poorly vascularized cancers. This makes glutamine synthetase (GS), the only enzyme responsible for de novo synthesizing glutamine, essential in cancer metabolism. In cancer, GS exhibits pro-tumoral features by synthesizing glutamine, supporting nucleotide synthesis. Furthermore, GS is highly expressed in the tumor microenvironment (TME) and provides glutamine to cancer cells, allowing cancer cells to maintain sufficient glutamine level for glutamine catabolism. Glutamine catabolism, the opposite reaction of glutamine synthesis by GS, is well known for supporting cancer cell proliferation via contributing biosynthesis of various essential molecules and energy production. Either glutamine anabolism or catabolism has a critical function in cancer metabolism depending on the complex nature and microenvironment of cancers. In this review, we focus on the role of GS in a variety of cancer types and microenvironments and highlight the mechanism of GS at the transcriptional and post-translational levels. Lastly, we discuss the therapeutic implications of targeting GS in cancer.

Keywords:  anticancer effect; cancer metabolism; glutamine metabolism; glutamine synthetase

DOI:  https://doi.org/10.3390/ijms22041701
Blood Adv. 2021 Jan 12. 5(1): 156-166

The metabolic reprogramming in acute myeloid leukemia patients depends on their genotype and is a prognostic marker.

Caroline Lo Presti, Florence Fauvelle, Marie-Christine Jacob, Julie Mondet, Pascal Mossuz.

Leukemic cells display some alterations in metabolic pathways, which play a role in leukemogenesis and in patients' prognosis. To evaluate the characteristics and the impact of this metabolic reprogramming, we explore the bone marrow samples from 54 de novo acute myeloid leukemia (AML) patients, using an untargeted metabolomics approach based on proton high-resolution magic angle spinning-nuclear magnetic resonance. The spectra obtained were subjected to multivariate statistical analysis to find specific metabolome alterations and biomarkers correlated to clinical features. We found that patients display a large diversity of metabolic profiles, according to the different AML cytologic subtypes and molecular statuses. The link between metabolism and molecular status was particularly strong for the oncometabolite 2-hydroxyglutarate (2-HG), whose intracellular production is directly linked to the presence of isocitrate dehydrogenase mutations. Moreover, patients' prognosis was strongly impacted by several metabolites, such as 2-HG that appeared as a good prognostic biomarker in our cohort. Conversely, deregulations in phospholipid metabolism had a negative impact on prognosis through 2 main metabolites (phosphocholine and phosphoethanolamine), which could be potential aggressiveness biomarkers. Finally, we highlighted an overexpression of glutathione and alanine in chemoresistant patients. Overall, our results demonstrate that different metabolic pathways could be activated in leukemic cells according to their phenotype and maturation levels. This confirms that metabolic reprogramming strongly influences prognosis of patients and underscores a particular role of certain metabolites and associated pathways in AML prognosis, suggesting common mechanisms developed by leukemic cells to maintain their aggressiveness even after well-conducted induction chemotherapy.

DOI: https://doi.org/10.1182/bloodadvances.2020002981
Blood Cancer J. 2021 Feb 01. 11(2): 27

XPO1 inhibitors represent a novel therapeutic option in Adult T-cell Leukemia, triggering p53-mediated caspase-dependent apoptosis.

Eline Boons, Tatiane C Nogueira, Tim Dierckx, Soraya Maria Menezes, Maarten Jacquemyn, Sharon Tamir, Yosef Landesman, Lourdes Farré, Achiléa Bittencourt, Keisuke Kataoka, Seishi Ogawa, Robert Snoeck, Graciela Andrei, Johan Van Weyenbergh, Dirk Daelemans.

DOI: https://doi.org/10.1038/s41408-021-00409-3
N Engl J Med. 2021 02 11. 384(6): 550-561

Circadian Mechanisms in Medicine.

Ravi Allada, Joseph Bass.

DOI: https://doi.org/10.1056/NEJMra1802337
Signal Transduct Target Ther. 2021 Feb 10. 6(1): 56

MtDNA mutations and aging-not a closed case after all?

Alexander M Wolf.

DOI: https://doi.org/10.1038/s41392-021-00479-6