bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒03‒21
twenty papers selected by
Ayesh Seneviratne
University of Toronto
  1. CD70-specific CAR T-cells have potent activity against Acute Myeloid Leukemia (AML) without HSC toxicity.
  2. Metabolic Reprogramming in Anticancer Drug Resistance: A Focus on Amino Acids.
  3. Metabolic parameters in smokers undergoing smoking reduction.
  4. Venetoclax enhances T cell-mediated anti-leukemic activity by increasing ROS production.
  5. Metabolomics, heart disease and aging.
  6. Mitochondrial Inhibition: a Treatment Strategy in Cancer?
  7. Cap-independent translation: A shared mechanism for lifespan extension by rapamycin, acarbose, and 17α-estradiol.
  8. Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation.
  9. Novel Targeted Therapeutics in Acute Myeloid Leukemia: an Embarrassment of Riches.
  10. Role of CaMKII in the regulation of fatty acids and lipid metabolism.
  11. Lipid Metabolism in Tumor-Associated B Cells.
  12. NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy.
  13. Lipid Metabolism and Lipidomics Applications in Cancer Research.
  14. Flux control in the aging cascade.
  15. Venetoclax combination therapy induces deep AML remission with eradication of leukemic stem cells and remodeling of clonal haematopoiesis.
  16. Cardiac retinoic acid levels decline in heart failure.
  17. AI identifies distinct subgroups of HFpEF.
  18. Triglyceride lowering by omega-3 fatty acids: a mechanism mediated by N-acyl taurines.
  19. Covid-19: AstraZeneca vaccine is not linked to increased risk of blood clots, finds European Medicine Agency.
  20. Aging: All roads lead to mitochondria.
  1. Blood. 2021 Mar 15. pii: blood.2020008221. [Epub ahead of print]
    CD70-specific CAR T-cells have potent activity against Acute Myeloid Leukemia (AML) without HSC toxicity.
    Tim Sauer, Kathan Parikh, Sandhya Sharma, Bilal Omer, David Nikolov Sedloev, Qian Chen, Linus Angenendt, Christoph Schliemann, Michael Schmitt, Carsten Müller-Tidow, Stephen Gottschalk, Cliona M Rooney.
      The prognosis of patients with acute myeloid leukemia (AML) remains dismal highlighting the need for novel innovative treatment strategies. The application of chimeric antigen receptor (CAR) T-cell therapy to AML patients has been limited in particular by the lack of a tumor-specific target antigen. CD70 is a promising antigen to target AML as it is expressed on the majority of leukemic blasts, whereas little or no expression is detectable in normal bone marrow samples. To target CD70 on AML cells, we generated a panel of CD70-CARs that contained a common single chain variable fragment (scFv) for antigen detection but differed in size and flexibility of the extracellular spacer, and in the transmembrane and the co-stimulatory domains. These CD70scFv CARs were compared with a CAR construct that contained the human CD27, the ligand of CD70 fused to the CD3z chain (CD27z). The structural composition of the CAR strongly influenced expression levels, viability, expansion and cytotoxic capacities of CD70scFv CAR T-cells, but the CD27z-CAR T-cells demonstrated superior proliferation and anti-tumor activity in vitro and in vivo, compared to all CD70scFv-CARs. While CD70-CAR T-cells recognized activated virus-specific T-cells (VSTs) that expressed CD70, they did not prevent colony formation by normal hematopoietic stem cells (HSCs). Thus, CD70-targeted immunotherapy is a promising new treatment strategy for patients with CD70-positive AML that does not affect normal hematopoiesis but will require monitoring of virus-specific T-cell responses.
    DOI:  https://doi.org/10.1182/blood.2020008221
  2. Trends Cancer. 2021 Mar 15. pii: S2405-8033(21)00046-7. [Epub ahead of print]
    Metabolic Reprogramming in Anticancer Drug Resistance: A Focus on Amino Acids.
    Erica Pranzini, Elisa Pardella, Paolo Paoli, Sarah-Maria Fendt, Maria Letizia Taddei.
      Overcoming anticancer drug resistance is a major challenge in cancer therapy, requiring innovative strategies that consider the extensive tumor heterogeneity and adaptability. We provide recent evidence highlighting the key role of amino acid (AA) metabolic reprogramming in cancer cells and the supportive microenvironment in driving resistance to anticancer therapies. AAs sustain the acquisition of anticancer resistance by providing essential building blocks for biosynthetic pathways and for maintaining a balanced redox status, and modulating the epigenetic profile of both malignant and non-malignant cells. In addition, AAs support the reduced intrinsic susceptibility of cancer stem cells to antineoplastic therapies. These findings shed new light on the possibility of targeting nonresponding tumors by modulating AA availability through pharmacological or dietary interventions.
    Keywords:  amino acids; anticancer drug resistance; cancer metabolism
    DOI:  https://doi.org/10.1016/j.trecan.2021.02.004
  3. J Clin Transl Endocrinol. 2021 Mar;23 100249
    Metabolic parameters in smokers undergoing smoking reduction.
    Stanley H Hsia, Monica L Nisis, Martin L Lee, Candice Goldstein, Theodore C Friedman.
      Introduction: Few human studies have explored the mechanisms of smoking-induced insulin resistance. Aims: To prospectively examine the metabolic changes of smoking reduction.Methods: Cigarette smokers (n = 22; ½-2 packs per day) were enrolled in a smoking reduction program (counseling plus bupropion × 8 weeks; Phase I) followed by monitoring only (no counseling or bupropion × 16 weeks; Phase II). We serially measured exhaled carbon monoxide (CO) and urine nicotine metabolites; fat distribution, and metabolic parameters by hyperinsulinemic clamps including hepatic glucose output (HGO) and indirect calorimetry, adjusted for total caloric intake and expenditure.
    Results: CO and nicotine metabolite levels fell with smoking reduction during Phase I (all p < 0.05), without any further changes through Phase II. Central-to-peripheral fat ratio increased during Phase I, but then fell during Phase II (all p < 0.05). Over 24 weeks, basal HGO fell (p = 0.02); and falling CO and nicotine metabolite levels correlated inversely with changes in glucose oxidation, and directly with changes in weight (all p < 0.05).
    Conclusions: Smoking reduction produced a transient worsening of central fat redistribution followed by a more significant improvement; along with other net beneficial metabolic effects.
    Keywords:  Abdominal adiposity; Glucose oxidation; Glucose uptake; Hepatic glucose output; Insulin resistance; Smoking reduction
    DOI:  https://doi.org/10.1016/j.jcte.2021.100249
  4. Blood. 2021 Mar 16. pii: blood.2020009081. [Epub ahead of print]
    Venetoclax enhances T cell-mediated anti-leukemic activity by increasing ROS production.
    JongBok Lee, Dilshad H Khan, Rose Hurren, Mingjing Xu, Yoosu Na, Hyeonjeong Kang, Sara Mirali, Xiaoming Wang, Marcela Victoria Gronda, Yulia Jitkova, Neil MacLean, Andrea Arruda, Zoe Alaniz, Marina Y Konopleva, Michael Andreeff, Mark D Minden, Li Zhang, Aaron D Schimmer.
      Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent, Azacytidine, achieves complete response with or without count recovery in approximately 70% of treatment-naïve elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that Venetoclax directly activated T cells to increase their cytotoxicity against AML in vitro and in vivo. Venetoclax enhanced T cell effector function by increasing ROS generation through inhibition of respiratory chain supercomplexes formation. In addition, Azacytidine induced a viral-mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T-cell mediated cytotoxicity. Similar findings were seen in patients treated with Venetoclax as this treatment increased ROS generation and activated T cells. Collectively, this study demonstrates a new immune mediated mechanism of action for Venetoclax and Azacytidine in the treatment of AML and highlights a potential combination of Venetoclax and adoptive cell therapy for patients with AML.
    DOI:  https://doi.org/10.1182/blood.2020009081
  5. Aging (Albany NY). 2021 Mar 10.
    Metabolomics, heart disease and aging.
    Michela Piedepalumbo, Walter J Koch, Claudio de Lucia.
      
    Keywords:  aging; elderly; heart disease; metabolism; metabolomics
    DOI:  https://doi.org/10.18632/aging.202804
  6. Curr Oncol Rep. 2021 Mar 17. 23(4): 49
    Mitochondrial Inhibition: a Treatment Strategy in Cancer?
    Maria J Bueno, Jose L Ruiz-Sepulveda, Miguel Quintela-Fandino.
      PURPOSE OF REVIEW: Mitochondria have a major impact on virtually all processes linked to oncogenesis. Thus, mitochondrial metabolism inhibition has emerged as a promising anticancer strategy. In this review, we discuss the anticancer potential of mitochondrial inhibitors, with particular focus on metformin, in the context of more effective, targeted therapeutic modalities, and diagnostic strategies for cancer patients.RECENT FINDINGS: Metformin has gained interest as an antitumor agent. However, promising results have not been translated into remarkable advances in the clinical practice. Recent findings emphasize the need of providing a metabolic context in which mitochondrial inhibitors may elicit its anticancerous effects. In addition, mitochondria are critical regulators in orchestrating immune responses. Thus, the immunomodulatory effect of mitochondrial inhibitors should also be taken into account to optimize its clinical use. Targeting mitochondrial metabolic network represents a promising therapeutic strategy in cancer. However, there is a need to define the metabolic context in which mitochondrial inhibitors are more effective, as well as how the cross-talk between many immunological functions and mitochondrial functionality may be exploited for a therapeutic benefit in cancer patients.
    Keywords:  Cancer therapy; Metabolic context; Mitochondrial inhibitors; Mitochondrial metabolism; immunotherapy
    DOI:  https://doi.org/10.1007/s11912-021-01033-x
  7. Aging Cell. 2021 Mar 20. e13345
    Cap-independent translation: A shared mechanism for lifespan extension by rapamycin, acarbose, and 17α-estradiol.
    Ziqian Shen, Abby Hinson, Richard A Miller, Gonzalo G Garcia.
      We hypothesized that rapamycin (Rapa), acarbose (ACA), which both increase mouse lifespan, and 17α-estradiol, which increases lifespan in males (17aE2) all share common intracellular signaling pathways with long-lived Snell dwarf, PAPPA-KO, and Ghr-/- mice. The long-lived mutant mice exhibit reduction in mTORC1 activity, declines in cap-dependent mRNA translation, and increases in cap-independent translation (CIT). Here, we report that Rapa and ACA prevent age-related declines in CIT target proteins in both sexes, while 17aE2 has the same effect only in males, suggesting increases in CIT. mTORC1 activity showed the reciprocal pattern, with age-related increases blocked by Rapa, ACA, and 17aE2 (in males only). METTL3, required for addition of 6-methyl-adenosine to mRNA and thus a trigger for CIT, also showed an age-dependent increase blunted by Rapa, ACA, and 17aE2 (in males). Diminution of mTORC1 activity and increases in CIT-dependent proteins may represent a shared pathway for both long-lived-mutant mice and drug-induced lifespan extension in mice.
    Keywords:  17α-estradiol; acarbose; aging; protein translation; rapamycin; signal transduction
    DOI:  https://doi.org/10.1111/acel.13345
  8. Blood. 2021 Mar 15. pii: blood.2021010867. [Epub ahead of print]
    Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation.
    Livius Penter, Yi Zhang, Alexandra Savell, Teddy Huang, Nicoletta Cieri, Emily M Thrash, Seunghee Kim-Schulze, Aashna Jhaveri, Jingxin Fu, Srinika Ranasinghe, Shuqiang Li, Wandi Zhang, Emma S Hathaway, Matthew Nazzaro, Haesook T Kim, Helen Chen, Magdalena Thurin, Scott J Rodig, Mariano Severgnini, Carrie Cibulskis, Stacey Gabriel, Kenneth J Livak, Corey Cutler, Joseph H Antin, Sarah Nikiforow, John Koreth, Vincent T Ho, Philippe Armand, Jerome Ritz, Howard Streicher, Donna Neuberg, F Stephen Hodi, Sacha Gnjatic, Robert J Soiffer, Xiaole Shirley Liu, Matthew S Davids, Pavan Bachireddy, Catherine J Wu.
      Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade (ICB) in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GvL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the ETCTN 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T cell populations and increased expression of markers of T cell activation and co-stimulation such as PD-1, HLA-DR and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GvL outcomes.
    DOI:  https://doi.org/10.1182/blood.2021010867
  9. Curr Hematol Malig Rep. 2021 Mar 18.
    Novel Targeted Therapeutics in Acute Myeloid Leukemia: an Embarrassment of Riches.
    Nicole R Grieselhuber, Alice S Mims.
      PURPOSE OF REVIEW: Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow that has a poor prognosis with traditional cytotoxic chemotherapy, especially in elderly patients. In recent years, small molecule inhibitors targeting AML-associated IDH1, IDH2, and FLT3 mutations have been FDA approved. However, the majority of AML cases do not have a targetable mutation. A variety of novel agents targeting both previously untargetable mutations and general pathways in AML are currently being investigated. Herein, we review selected new targeted therapies currently in early-phase clinical investigation in AML.RECENT FINDINGS: The DOT1L inhibitor pinometostat in KMT2A-rearranged AML, the menin inhibitors KO-539 and SYNDX-5613 in KMT2Ar and NPM1-mutated AML, and the mutant TP53 inhibitor APR-246 are examples of novel agents targeting specific mutations in AML. In addition, BET inhibitors, polo-like kinase inhibitors, and MDM2 inhibitors are promising new drug classes for AML which do not depend on the presence of a particular mutation. AML remains in incurable disease for many patients but advances in genomics, epigenetics, and drug discovery have led to the development of many potential novel therapeutic agents, many of which are being investigated in ongoing clinical trials. Additional studies will be necessary to determine how best to incorporate these novel agents into routine clinical treatment of AML.
    Keywords:  Acute myeloid leukemia; Bromodomain inhibitors; DOT1L; MDM2 inhibitors; Menin inhibitors; Polo-like kinase inhibitors; Targeted therapy
    DOI:  https://doi.org/10.1007/s11899-021-00621-9
  10. Diabetes Metab Syndr. 2021 Mar 03. pii: S1871-4021(21)00067-9. [Epub ahead of print]15(2): 589-594
    Role of CaMKII in the regulation of fatty acids and lipid metabolism.
    Jitcy S Joseph, Krishnan Anand, Sibusiso T Malindisa, Oladapo F Fagbohun.
      BACKGROUND & AIMS: Previous studies have reported the beneficial roles of the activation of calmodulin-dependent protein kinase (CaMK)II to many cellular functions associated with human health. This review aims at discussing its activation by exercise as well as its roles in the regulation of unsaturated, saturated, omega 3 fatty acids, and lipid metabolism.METHODS: A wide literature search was conducted using online database such as 'PubMed', 'Google Scholar', 'Researcher', 'Scopus' and the website of World Health Organization (WHO) as well as Control Disease and Prevention (CDC). The criteria for the search were mainly lipid and fatty acid metabolism, diabetes, and metabolic syndrome (MetS). A total of ninety-seven articles were included in the review.
    RESULTS: Calmodulin-dependent protein kinase activation by exercise is helpful in controlling membrane lipids related with type 2 diabetes and obesity. CaMKII regulates many health beneficial cellular functions in individuals who exercise compared with those who do not exercise. Regulation of lipid metabolism and fatty acids are crucial in the improvement of metabolic syndrome.
    CONCLUSIONS: Approaches that involve CaMKII could be a new avenue for designing novel and effective therapeutic modalities in the treatment or better management of metabolic diseases such as type 2 diabetes and obesity.
    Keywords:  CaMKII; Lipid oxidation; Metabolic syndrome; Obesity; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.dsx.2021.02.037
  11. Adv Exp Med Biol. 2021 ;1316 133-147
    Lipid Metabolism in Tumor-Associated B Cells.
    Fan Yang, Fang Wan.
      Breakthroughs have been made in the cancer immunotherapy field focusing on utilizing T cells' antitumor immunity, and the lipid metabolism of tumor-associated B cells is not well studied compared to T cells. Accumulating evidence suggested that B cells also play important roles in tumor biology and antitumor immunity, especially the germinal center B cells that present in the tumor-related tertiary lymphoid structures. Due to scarce studies on lipid metabolisms of tumor-associated B cells, this chapter mainly summarized findings on B cell lipid metabolism and discussed B cell development and major transcription factors, tumor-associated B cell populations and their potential functions in antitumor immunity, fatty acid oxidation in germinal center B cells, and tumor microenvironment factors that potentially affect B cell lipid metabolism, focusing on hypoxia and nutrients competition, as well as lipid metabolites that affect B cell function, including cholesterol, geranylgeranyl pyrophosphate, oxysterols, and short-chain fatty acids.
    Keywords:  B cells; Cancer; Cholesterol; Germinal center; Lipid metabolism
    DOI:  https://doi.org/10.1007/978-981-33-6785-2_9
  12. Aging Cell. 2021 Mar 18. e13329
    NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy.
    Beimeng Yang, Xiuli Dan, Yujun Hou, Jong-Hyuk Lee, Noah Wechter, Sudarshan Krishnamurthy, Risako Kimura, Mansi Babbar, Tyler Demarest, Ross McDevitt, Shiliang Zhang, Yongqing Zhang, Mark P Mattson, Deborah L Croteau, Vilhelm A Bohr.
      Senescence phenotypes and mitochondrial dysfunction are implicated in aging and in premature aging diseases, including ataxia telangiectasia (A-T). Loss of mitochondrial function can drive age-related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in A-T patient fibroblasts, and in ATM-deficient cells and mice. Senescence is mediated by stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide riboside (NR) prevents senescence and SASP by promoting mitophagy in a PINK1-dependent manner. NR treatment also prevents neurodegeneration, suppresses senescence and neuroinflammation, and improves motor function in Atm-/- mice. Our findings suggest a central role for mitochondrial dysfunction-induced senescence in A-T pathogenesis, and that enhancing mitophagy as a potential therapeutic intervention.
    Keywords:  Ataxia Telangiectasia; Nicotinamide riboside; SASP; mitophagy; senescence
    DOI:  https://doi.org/10.1111/acel.13329
  13. Adv Exp Med Biol. 2021 ;1316 1-24
    Lipid Metabolism and Lipidomics Applications in Cancer Research.
    Meixia Pan, Chao Qin, Xianlin Han.
      Lipids are the critical components of cellular and plasma membrane, which constitute an impermeable barrier of cellular compartments, and play important roles on numerous cellular processes including cell growth, proliferation, differentiation, and signaling. Alterations in lipid metabolism have been implicated in the development and progression of cancers. However, unlike other biomolecules, the diversity in the structures and characteristics of lipid species results in the limited understanding of their metabolic alterations in cancers. Lipidomics is an emerging discipline that studies lipids in a large scale based on analytical chemistry principles and technological tools. Multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) uses direct infusion to avoid difficulties from alterations in concentration, chromatographic anomalies, and ion-pairing alterations to improve resolution and achieve rapid and accurate qualitative and quantitative analysis. In this chapter, lipids and lipid metabolism relevant to cancer research are introduced, followed by a brief description of MDMS-SL and other shotgun lipidomics techniques and some applications for cancer research.
    Keywords:  Cancer; Immunity; Lipid metabolism; Lipidomics; Lipids; Mass spectrometry
    DOI:  https://doi.org/10.1007/978-981-33-6785-2_1
  14. Aging (Albany NY). 2021 Mar 13.
    Flux control in the aging cascade.
    Bernd Moosmann.
      
    Keywords:  free radicals; lipid peroxidation; longevity; radical chain reaction; rate-limiting step
    DOI:  https://doi.org/10.18632/aging.202821
  15. Blood Cancer J. 2021 Mar 19. 11(3): 62
    Venetoclax combination therapy induces deep AML remission with eradication of leukemic stem cells and remodeling of clonal haematopoiesis.
    Romain Vazquez, Claire Breal, Loria Zalmai, Chloe Friedrich, Carole Almire, Adrien Contejean, Sylvain Barreau, Eric Grignano, Lise Willems, Benedicte Deau-Fischer, Patricia Franchi, Marguerite Vignon, Justine Decroocq, Rudy Birsen, Lauriane Goldwirt, Sophie Kaltenbach, Lucile Couronne, Michaela Fontenay, Olivier Kosmider, Didier Bouscary, Nicolas Chapuis.
      
    DOI:  https://doi.org/10.1038/s41408-021-00448-w
  16. JCI Insight. 2021 Mar 16. pii: 137593. [Epub ahead of print]
    Cardiac retinoic acid levels decline in heart failure.
    Ni Yang, Lauren Parker, Jianshi Yu, Jace W Jones, Ting Liu, Kyriakos N Papanicolaou, C Conover Talbot, Kenneth B Margulies, Brian O'Rourke, Maureen Kane, D Brian Foster.
      Though low circulating levels of the vitamin A metabolite, all-trans retinoic acid (ATRA), are associated with increased risk of cardiovascular events and all-cause mortality, few studies have addressed whether cardiac retinoid levels are altered in the failing heart. Here, we show that proteomic analyses of human and guinea pig heart failure (HF) are consistent a decline in resident cardiac ATRA. Quantitation of the retinoids in ventricular myocardium by mass spectrometry reveals 32 and 39% ATRA decreases in guinea pig HF and in patients with idiopathic dilated cardiomyopathy (IDCM), respectively, despite ample reserves of cardiac vitamin A. ATRA (2mg/kg/day) is sufficient to mitigate cardiac remodeling and prevent functional decline in guinea pig HF. Though cardiac ATRA declines in both guinea pig HF human IDCM, levels certain retinoid metabolic enzymes diverge. Specifically, high expression of the ATRA-catabolizing enzyme, CYP26A1, in human IDCM could dampen prospects for an ATRA-based therapy. Pertinently, a pan-CYP26 inhibitor, talarozole, abrogates the impact of phenylephrine on ATRA decline and hypertrophy in neonatal rat ventricular myocytes. Taken together, we submit that low cardiac ATRA attenuates the expression of critical ATRA-dependent gene programs in HF and that strategies to normalize ATRA metabolism, like CYP26 inhibition, may have therapeutic potential.
    Keywords:  Cardiology; Heart failure
    DOI:  https://doi.org/10.1172/jci.insight.137593
  17. Nat Rev Cardiol. 2021 Mar 19.
    AI identifies distinct subgroups of HFpEF.
    Gregory B Lim.
      
    DOI:  https://doi.org/10.1038/s41569-021-00545-0
  18. J Clin Invest. 2021 Mar 15. pii: 147558. [Epub ahead of print]131(6):
    Triglyceride lowering by omega-3 fatty acids: a mechanism mediated by N-acyl taurines.
    Karin E Bornfeldt.
      Interest in omega-3 fatty acids (colloquially known as fish oils) to lower residual cardiovascular risk in statin-treated patients has increased markedly in the wake of recent cardiovascular outcome trials. The triglyceride-lowering effects of omega-3 fatty acids are generally thought to occur by reduced hepatic VLDL production. In this issue of the JCI, Grevengoed et al. used mouse models and human plasma samples to reveal an additional mechanism whereby these polyunsaturated fatty acids can lower plasma triglycerides. Their findings indicate that omega-3 fatty acid-derived N-acyl taurines (NATs) greatly accumulate in bile and also in plasma following omega-3 supplementation. The authors further show that one of these NATs (C22:6 NAT) inhibited intestinal triglyceride hydrolysis and lipid absorption, which resulted in lower plasma triglycerides and protection against hepatic triacylglycerol accumulation in mice fed a high-fat diet. The findings open a potential avenue for triglyceride lowering by omega-3 fatty acids conjugated to taurine.
    DOI:  https://doi.org/10.1172/JCI147558
  19. BMJ. 2021 Mar 19. 372 n774
    Covid-19: AstraZeneca vaccine is not linked to increased risk of blood clots, finds European Medicine Agency.
    Elisabeth Mahase.
      
    DOI:  https://doi.org/10.1136/bmj.n774
  20. Semin Cell Dev Biol. 2021 Mar 16. pii: S1084-9521(21)00030-6. [Epub ahead of print]
    Aging: All roads lead to mitochondria.
    Jyung Mean Son, Changhan Lee.
      Mitochondria were described as early as 1890 as ubiquitous intracellular structures by Ernster and Schatz (1981) [1]. Since then, the accretion of knowledge in the past century has revealed much of the molecular details of mitochondria, ranging from mitochondrial origin, structure, metabolism, genetics, and signaling, and their implications in health and disease. We now know that mitochondria are remarkably multifunctional and deeply intertwined with many vital cellular processes. They are quasi-self organelles that still possess remnants of its bacterial ancestry, including an independent genome. The mitochondrial free radical theory of aging (MFRTA), which postulated that aging is a product of oxidative damage to mitochondrial DNA, provided a conceptual framework that put mitochondria on the map of aging research. However, several studies have more recently challenged the general validity of the theory, favoring novel ideas based on emerging evidence to understand how mitochondria contribute to aging and age-related diseases. One prominent topic of investigation lies on the fact that mitochondria are not only production sites for bioenergetics and macromolecules, but also regulatory hubs that communicate and coordinate many vital physiological processes at the cellular and organismal level. The bi-directional communication and coordination between the co-evolved mitochondrial and nuclear genomes is especially interesting in terms of cellular regulation. Mitochondria are dynamic and adaptive, rendering their function sensitive to cellular context. Tissues with high energy demands, such as the brain, seem to be uniquely affected by age-dependent mitochondrial dysfunction, providing a foundation for the development of novel mitochondrial-based therapeutics and diagnostics.
    Keywords:  Aging; Communication; Genomic instability; Immunity; Inflammation; Longevity; Mitochondria; Mitochondrial-derived peptides; Mitonuclear; Oxidative stress
    DOI:  https://doi.org/10.1016/j.semcdb.2021.02.006
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:22:00.