bims-minfam 2021-10-17 papers

bims-minfam

Biomed News

on Inflammation and metabolism in ageing and cancer

Issue of 2021–10–17
twenty-one papers selected by
Ayesh Seneviratne, University of Toronto

Friends and foes: Extracellular vesicles in aging and rejuvenation.
Clonal hematopoiesis is associated with risk of severe Covid-19.
Clonal hematopoiesis driven by DNMT3A and TET2 mutations: role in monocyte and macrophage biology and atherosclerotic cardiovascular disease.
Mesenchymal Stem Cell Transplantation for the Treatment of Age-Related Musculoskeletal Frailty.
Targeting neurotransmitter-mediated inflammatory mechanisms of psychiatric drugs to mitigate the double burden of multimorbidity and polypharmacy.
Cellular senescence in the tumor microenvironment and context-specific cancer treatment strategies.
The tumor suppression theory of aging.
Clonal Architecture and Evolutionary Dynamics in Acute Myeloid Leukemias.
mTOR-dependent translation amplifies microglia priming in aging mice.
Hematopoietic stem cell mobilization strategies to support high-dose chemotherapy: A focus on relapsed/refractory germ cell tumors.
Lipid droplets as metabolic determinants for stemness and chemoresistance in cancer.
Biological Aspects of Inflamm-Aging in Childhood Cancer Survivors.
Selecting implementation strategies to drive Age-Friendly Health System Adoption.
Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission after 5-azacitidine and venetoclax: a multicenter retrospective study.
A Vegan Diet Is Associated with a Significant Reduction in Dietary Acid Load: Post Hoc Analysis of a Randomized Controlled Trial in Healthy Individuals.
Sarcopenia, frailty and type 2 diabetes mellitus (Review).
Co-Treatments of Edible Curcumin from Turmeric Rhizomes and Chemotherapeutic Drugs on Cytotoxicity and FLT3 Protein Expression in Leukemic Stem Cells.
Tea and its phytochemicals: Hidden health benefits & modulation of signaling cascade by phytochemicals.
Geriatric medicine in the era of climate change.
Community-driven online initiatives have reshaped scientific engagement.
Interplay Between Cardiolipin and Plasmalogens in Barth Syndrome.

FASEB Bioadv. 2021 Oct;3(10): 787-801

Friends and foes: Extracellular vesicles in aging and rejuvenation.

Brian V Lananna, Shin-Ichiro Imai.

  Extracellular vesicles (EVs) are released by many different cell types throughout the body and play a role in a diverse range of biological processes. EVs circulating in blood as well as in other body fluids undergo dramatic alterations over an organism's lifespan that are only beginning to be elucidated. The exact nature of these changes is an area of active and intense investigation, but lacks clear consensus due to the substantial heterogeneity in EV subpopulations and insufficiencies in current technologies. Nonetheless, emerging evidence suggests that EVs regulate systemic aging as well as the pathophysiology of age-related diseases. Here, we review the current literature investigating EVs and aging with an emphasis on consequences for the maintenance of human healthspan. Intriguingly, the biological utility of EVs both in vitro and in vivo and across contexts depends on the states of the source cells or tissues. As such, EVs secreted by cells in an aged or pathological state may impose detrimental consequences on recipient cells, while EVs secreted by youthful or healthy cells may promote functional improvement. Thus, it is critical to understand both functions of EVs and tip the balance toward their beneficial effects as an antiaging intervention.

Keywords:  NAD+ metabolism; ageing; aging; exosome; extracellular vesicle; longevity

DOI:  https://doi.org/10.1096/fba.2021-00077
Nat Commun. 2021 10 13. 12(1): 5975

Clonal hematopoiesis is associated with risk of severe Covid-19.

Kelly L Bolton, Youngil Koh, Michael B Foote, Hogune Im, Justin Jee, Choong Hyun Sun, Anton Safonov, Ryan Ptashkin, Joon Ho Moon, Ji Yeon Lee, Jongtak Jung, Chang Kyung Kang, Kyoung-Ho Song, Pyoeng Gyun Choe, Wan Beom Park, Hong Bin Kim, Myoung-Don Oh, Han Song, Sugyeong Kim, Minal Patel, Andriy Derkach, Erika Gedvilaite, Kaitlyn A Tkachuk, Brian J Wiley, Ireaneus C Chan, Lior Z Braunstein, Teng Gao, Elli Papaemmanuil, N Esther Babady, Melissa S Pessin, Mini Kamboj, Luis A Diaz, Marc Ladanyi, Michael J Rauh, Pradeep Natarajan, Mitchell J Machiela, Philip Awadalla, Vijai Joseph, Kenneth Offit, Larry Norton, Michael F Berger, Ross L Levine, Eu Suk Kim, Nam Joong Kim, Ahmet Zehir.

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15-2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15-3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22-3.30, p = 6×10-3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15-2.13, p = 5×10-3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

DOI: https://doi.org/10.1038/s41467-021-26138-6
Curr Opin Hematol. 2021 Oct 13.

Clonal hematopoiesis driven by DNMT3A and TET2 mutations: role in monocyte and macrophage biology and atherosclerotic cardiovascular disease.

Isidoro Cobo, Tiffany Tanaka, Christopher K Glass, Calvin Yeang.

PURPOSE OF REVIEW: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the presence of somatic mutations in hematopoietic cells, is associated with advanced age and increased mortality due to cardiovascular disease. Gene mutations in DNMT3A and TET2 are the most frequently identified variants among patients with CHIP and provide selective advantage that spurs clonal expansion and myeloid skewing. Although DNMT3A and TET2 appear to have opposing enzymatic influence on DNA methylation, mounting data has characterized convergent inflammatory pathways, providing insights to how CHIP may mediate atherosclerotic cardiovascular disease (ASCVD).
RECENT FINDINGS: We review a multitude of studies that characterize aberrant inflammatory signaling as result of DNMT3A and TET2 deficiency in monocytes and macrophages, immune cells with prominent roles in atherosclerosis. Although specific DNA methylation signatures associated with these known epigenetic regulators have been identified, many studies have also characterized diverse modulatory functions of DNTM3A and TET2 that urge cell and context-specific experimental studies to further define how DNMT3A and TET2 may nonenzymatically activate inflammatory pathways with clinically meaningful consequences.
SUMMARY: CHIP, common in elderly individuals, provides an opportunity understand and potentially modify age-related chronic inflammatory ASCVD risk.

DOI: https://doi.org/10.1097/MOH.0000000000000688
Int J Mol Sci. 2021 Sep 29. pii: 10542. [Epub ahead of print]22(19):

Mesenchymal Stem Cell Transplantation for the Treatment of Age-Related Musculoskeletal Frailty.

Elancheleyen Mahindran, Jia Xian Law, Min Hwei Ng, Fazlina Nordin.

  Projected life expectancy continues to grow worldwide owing to the advancement of new treatments and technologies leading to rapid growth of geriatric population. Thus, age-associated diseases especially in the musculoskeletal system are becoming more common. Loss of bone (osteoporosis) and muscle (sarcopenia) mass are conditions whose prevalence is increasing because of the change in population distribution in the world towards an older mean age. The deterioration in the bone and muscle functions can cause severe disability and seriously affects the patients' quality of life. Currently, there is no treatment to prevent and reverse age-related musculoskeletal frailty. Existing interventions are mainly to slow down and control the signs and symptoms. Mesenchymal stem cell (MSC) transplantation is a promising approach to attenuate age-related musculoskeletal frailty. This review compiles the present knowledge of the causes and changes of the musculoskeletal frailty and the potential of MSC transplantation as a regenerative therapy for age-related musculoskeletal frailty.

Keywords:  aging; bone; frailty; mesenchymal stem cells; muscle; musculoskeletal system

DOI:  https://doi.org/10.3390/ijms221910542
Brain Behav Immun Health. 2021 Dec;18 100353

Targeting neurotransmitter-mediated inflammatory mechanisms of psychiatric drugs to mitigate the double burden of multimorbidity and polypharmacy.

Stephanie M Matt.

  The increased incidence of multimorbidities and polypharmacy is a major concern, particularly in the growing aging population. While polypharmacy can be beneficial, in many cases it can be more harmful than no treatment, especially in individuals suffering from psychiatric disorders, who have elevated risks of multimorbidity and polypharmacy. Age-related chronic inflammation and immunopathologies might contribute to these increased risks in this population, but the optimal clinical management of drug-drug interactions and the neuro-immune mechanisms that are involved warrants further investigation. Given that neurotransmitter systems, which psychiatric medications predominantly act on, can influence the development of inflammation and the regulation of immune function, it is important to better understand these interactions to develop more successful strategies to manage these comorbidities and complicated polypharmacy. I propose that expanding upon research in translationally relevant human in vitro models, in tandem with other preclinical models, is critical to defining the neurotransmitter-mediated mechanisms by which psychiatric drugs alter immune function. This will define more precisely the interactions of psychiatric drugs and other immunomodulatory drugs, used in combination, enabling identification of novel targets to be translated into more efficacious diagnostic, preventive, and therapeutic interventions. This interdisciplinary approach will aid in better precision polypharmacy for combating adverse events associated with multimorbidity and polypharmacy in the future.

Keywords:  Aging; Inflammation; Neurotransmitter; Polypharmacy; Psychiatric disease

DOI:  https://doi.org/10.1016/j.bbih.2021.100353
FEBS J. 2021 Oct 15.

Cellular senescence in the tumor microenvironment and context-specific cancer treatment strategies.

Tadahito Yasuda, Hideo Baba, Takatsugu Ishimoto.

  Cellular senescence in cancer development is known to have tumor-suppressive and tumor-promoting roles. Recent studies have revealed numerous molecular mechanisms of senescence followed by SASP induction and showed the significance of senescence on both sides. Cellular senescence in stromal cells is one of the reasons for therapeutic resistance in advanced cancer; thus, it is an inevitable phenomenon to address while seeking an effective cancer treatment strategy. This review summarizes the molecular mechanisms regarding cellular senescence, focusing on the dual roles played by senescence, and offers some direction toward successful treatments targeting harmful senescent cells.

Keywords:  CAFs; SASP; epigenome; senescence; senolytic drug

DOI:  https://doi.org/10.1111/febs.16231
Mech Ageing Dev. 2021 Oct 09. pii: S0047-6374(21)00155-X. [Epub ahead of print] 111583

The tumor suppression theory of aging.

Alexander M Wolf.

  Despite continued increases in human life expectancy, the factors determining the rate of human biological aging remain unknown. Without understanding the molecular mechanisms underlying aging, efforts to prevent aging are unlikely to succeed. The tumor suppression theory of aging introduced here proposes somatic mutation as the proximal cause of aging, but postulates that oncogenic transformation and clonal expansion, not functional impairment, are the relevant consequences of somatic mutation. Obesity and caloric restriction accelerate and decelerate aging due to their effect on cell proliferation, during which most mutations arise. Most phenotypes of aging are merely tumor-suppressive mechanisms that evolved to limit malignant growth, the dominant age-related cause of death in early and middle life. Cancer limits life span for most long-lived mammals, a phenomenon known as Peto's paradox. Its conservation across species demonstrates that mutation is a fundamental but hard limit on mammalian longevity. Cell senescence and apoptosis and differentiation induced by oncogenes, telomere shortening or DNA damage evolved as a second line of defense to limit the tumorigenic potential of clonally expanding cells, but accumulating senescent cells, senescence-associated secretory phenotypes and stem cell exhaustion eventually cause tissue dysfunction and the majority, if not most, phenotypes of aging.

Keywords:  aging; cancer; cell senescence; somatic mutation; tumor suppression

DOI:  https://doi.org/10.1016/j.mad.2021.111583
Cancers (Basel). 2021 Sep 29. pii: 4887. [Epub ahead of print]13(19):

Clonal Architecture and Evolutionary Dynamics in Acute Myeloid Leukemias.

Matthieu Duchmann, Lucie Laplane, Raphael Itzykson.

  Acute myeloid leukemias (AML) results from the accumulation of genetic and epigenetic alterations, often in the context of an aging hematopoietic environment. The development of high-throughput sequencing-and more recently, of single-cell technologies-has shed light on the intratumoral diversity of leukemic cells. Taking AML as a model disease, we review the multiple sources of genetic, epigenetic, and functional heterogeneity of leukemic cells and discuss the definition of a leukemic clone extending its definition beyond genetics. After introducing the two dimensions contributing to clonal diversity, namely, richness (number of leukemic clones) and evenness (distribution of clone sizes), we discuss the mechanisms at the origin of clonal emergence (mutation rate, number of generations, and effective size of the leukemic population) and the causes of clonal dynamics. We discuss the possible role of neutral drift, but also of cell-intrinsic and -extrinsic influences on clonal fitness. After reviewing available data on the prognostic role of genetic and epigenetic diversity of leukemic cells on patients' outcome, we discuss how a better understanding of AML as an evolutionary process could lead to the design of novel therapeutic strategies in this disease.

Keywords:  acute myeloid leukemia; clonal heterogeneity; drug resistance; evolutionary dynamics; prognosis

DOI:  https://doi.org/10.3390/cancers13194887
J Clin Invest. 2021 Oct 15. pii: e155208. [Epub ahead of print]131(20):

mTOR-dependent translation amplifies microglia priming in aging mice.

Lily Keane, Ignazio Antignano, Sean-Patrick Riechers, Raphael Zollinger, Anaelle A Dumas, Nina Offermann, Maria E Bernis, Jenny Russ, Frederike Graelmann, Patrick Neil McCormick, Julia Esser, Dario Tejera, Ai Nagano, Jun Wang, Claude Chelala, Yvonne Biederbick, Annett Halle, Paolo Salomoni, Michael T Heneka, Melania Capasso.

DOI: https://doi.org/10.1172/JCI155208
World J Clin Oncol. 2021 Sep 24. 12(9): 746-766

Hematopoietic stem cell mobilization strategies to support high-dose chemotherapy: A focus on relapsed/refractory germ cell tumors.

Eleni Porfyriou, Sylvia Letsa, Christos Kosmas.

  High-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation has been explored and has played an important role in the management of patients with high-risk germ cell tumors (GCTs) who failed to be cured by conventional chemotherapy. Hematopoietic stem cells (HSCs) collected from the peripheral blood, after appropriate pharmacologic mobilization, have largely replaced bone marrow as the principal source of HSCs in transplants. As it is currently common practice to perform tandem or multiple sequential cycles of HDCT, it is anticipated that collection of large numbers of HSCs from the peripheral blood is a prerequisite for the success of the procedure. Moreover, the CD34+ cell dose/kg of body weight infused after HDCT has proven to be a major determinant of hematopoietic engraftment, with patients who receive > 2 × 106 CD34+ cells/kg having consistent, rapid, and sustained hematopoietic recovery. However, many patients with relapsed/refractory GCTs have been exposed to multiple cycles of myelosuppressive chemotherapy, which compromises the efficacy of HSC mobilization with granulocyte colony-stimulating factor with or without chemotherapy. Therefore, alternative strategies that use novel agents in combination with traditional mobilizing regimens are required. Herein, after an overview of the mechanisms of HSCs mobilization, we review the existing literature regarding studies reporting various HSC mobilization approaches in patients with relapsed/refractory GCTs, and finally report newer experimental mobilization strategies employing novel agents that have been applied in other hematologic or solid malignancies.

Keywords:  Germ cell tumors; Granulocyte colony-stimulating factor; Hematopoietic stem cell transplantation; Hematopoietic stem cells; Plerixafor

DOI:  https://doi.org/10.5306/wjco.v12.i9.746
World J Stem Cells. 2021 Sep 26. 13(9): 1307-1317

Lipid droplets as metabolic determinants for stemness and chemoresistance in cancer.

Alba Royo-García, Sarah Courtois, Beatriz Parejo-Alonso, Pilar Espiau-Romera, Patricia Sancho.

  Previously regarded as simple fat storage particles, new evidence suggests that lipid droplets (LDs) are dynamic and functional organelles involved in key cellular processes such as membrane biosynthesis, lipid metabolism, cell signalling and inflammation. Indeed, an increased LD content is one of the most apparent features resulting from lipid metabolism reprogramming necessary to support the basic functions of cancer cells. LDs have been associated to different cellular processes involved in cancer progression and aggressiveness, such as tumorigenicity, invasion and metastasis, as well as chemoresistance. Interestingly, all of these processes are controlled by a subpopulation of highly aggressive tumoral cells named cancer stem cells (CSCs), suggesting that LDs may be fundamental elements for stemness in cancer. Considering the key role of CSCs on chemoresistance and disease relapse, main factors of therapy failure, the design of novel therapeutic approaches targeting these cells may be the only chance for long-term survival in cancer patients. In this sense, their biology and functional properties render LDs excellent candidates for target discovery and design of combined therapeutic strategies. In this review, we summarise the current knowledge identifying LDs and CSCs as main contributors to cancer aggressiveness, metastasis and chemoresistance.

Keywords:  Cancer stem cells; Chemoresistance; Lipid droplets; Lipid metabolism; Lipids; Stemness

DOI:  https://doi.org/10.4252/wjsc.v13.i9.1307
Cancers (Basel). 2021 Sep 30. pii: 4933. [Epub ahead of print]13(19):

Biological Aspects of Inflamm-Aging in Childhood Cancer Survivors.

Francesca Rossi, Alessandra Di Paola, Elvira Pota, Maura Argenziano, Daniela Di Pinto, Maria Maddalena Marrapodi, Caterina Di Leva, Martina Di Martino, Chiara Tortora.

  Anti-cancer treatments improve survival in children with cancer. A total of 80% of children treated for childhood cancer achieve 5-year survival, becoming long-term survivors. However, they undergo several chronic late effects related to treatments. In childhood cancer survivors a chronic low-grade inflammation, known as inflamm-aging, is responsible for frailty, a condition characterized by vital organ failure and by premature aging processes. Inflamm-aging is closely related to chemotherapy and radiotherapy, which induce inflammation, accumulation of senescent cells, DNA mutations, and the production of reactive oxygen species. All these conditions are responsible for the onset of secondary diseases, such as osteoporosis, cardiovascular diseases, obesity, and infertility. Considering that the pathobiology of frailty among childhood cancer survivors is still unknown, investigations are needed to better understand frailty's biological and molecular processes and to identify inflamm-aging key biomarkers in order to facilitate the screening of comorbidities and to clarify whether treatments, normally used to modulate inflamm-aging, may be beneficial. This review offers an overview of the possible biological mechanisms involved in the development of inflamm-aging, focusing our attention on immune system alteration, oxidative stress, cellular senescence, and therapeutic strategies.

Keywords:  childhood cancer survivors; frailty; immune system; inflamm-aging; oxidative stress; senescence; therapeutic strategies

DOI:  https://doi.org/10.3390/cancers13194933
J Am Geriatr Soc. 2021 Oct 15.

Selecting implementation strategies to drive Age-Friendly Health System Adoption.

Robert E Burke, Rebecca T Brown, Bruce Kinosian.

DOI: https://doi.org/10.1111/jgs.17489
Ann Hematol. 2021 Oct 09.

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission after 5-azacitidine and venetoclax: a multicenter retrospective study.

Oren Pasvolsky, Shai Shimony, Ron Ram, Avichai Shimoni, Liat Shargian, Batia Avni, Ofir Wolach, Tzippy Shochat, Ronit Yerushalmi, Odelia Amit, Pia Raanani, Moshe Yeshurun.

  The combination of hypomethylating agents and venetoclax has revolutionized the therapeutic landscape of acute myeloid leukemia (AML), especially for patients previously deemed unfit for curative-intent treatment. Some of these patients undergo allogeneic hematopoietic cell transplant (alloHCT); yet, there are scarce data regarding transplantation outcomes. We conducted a multicenter nationwide retrospective cohort study, including patients with AML who underwent alloHCT in CR1 after frontline treatment with azacitidine plus venetoclax only (aza-ven group). We collected a historical control group of patients who achieved CR1 after first-line intensive chemotherapy only, followed by alloHCT (intensive group). Patients in the aza-ven group (n = 24) were transplanted between 2019 and 2021. Compared to the intensive group, patients in the aza-ven group were older (median age 71.7 vs. 58.4 years), had higher incidence of therapy-related AML and AML with antecedent hematologic disorder and had more often adverse cytogenetics. They had a higher percentage of allografts from matched-unrelated donors, and reduced intensity conditioning was more commonly used. The estimated 12 months non relapse mortality was 19.1% in the aza-ven group and 11.8% in the intensive group. The estimated 12 months relapse-free survival and overall survival were 58% and 63% in the aza-ven group and 54% and 70% in the intensive group, respectively. The cumulative incidence of acute GVHD at 6 months and of chronic GVHD at 12 months were 58% and 40% in the aza-ven group and 62% and 42% in the intensive group, respectively. Analysis of the aza-ven group revealed that HCT-CI score and ELN risk category were predictive of RFS in both univariate analysis as well as multivariate analysis. Our data suggests that alloHCT for AML patients achieving first CR with aza-ven appears feasible, with short-term post-transplant outcomes similar to those expected after traditional intensive chemotherapy.

Keywords:  Acute myeloid leukemia; Allogeneic hematopoietic cell transplant; Azacitidine; Venetoclax

DOI:  https://doi.org/10.1007/s00277-021-04693-8
Int J Environ Res Public Health. 2021 Sep 23. pii: 9998. [Epub ahead of print]18(19):

A Vegan Diet Is Associated with a Significant Reduction in Dietary Acid Load: Post Hoc Analysis of a Randomized Controlled Trial in Healthy Individuals.

Alexander Müller, Amy Marisa Zimmermann-Klemd, Ann-Kathrin Lederer, Luciana Hannibal, Stefanie Kowarschik, Roman Huber, Maximilian Andreas Storz.

  The composition of diet strongly affects acid-base homeostasis. Western diets abundant in acidogenic foods (meat and cheese) and deficient in alkalizing foods (fruits and vegetables) increase dietary acid load (DAL). A high DAL has been associated with numerous health repercussions, including cardiovascular disease and type-2-diabetes. Plant-based diets have been associated with a lower DAL; however, the number of trials exploring this association is limited. This randomized-controlled trial sought to examine whether an isocaloric vegan diet lowers DAL as compared to a meat-rich diet. Forty-five omnivorous individuals were randomly assigned to a vegan diet (n = 23) or a meat-rich diet (n = 22) for 4 weeks. DAL was determined using potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores at baseline and after 3 and 4 weeks, respectively. After 3 weeks, median PRAL (-23.57 (23.87)) and mean NEAPR (12.85 ± 19.71) scores were significantly lower in the vegan group than in the meat-rich group (PRAL: 18.78 (21.04) and NEAPR: 60.93 ± 15.51, respectively). Effects were mediated by a lower phosphorus and protein intake in the vegan group. Our study suggests that a vegan diet is a potential means to reduce DAL, whereas a meat-rich diet substantially increases the DAL burden.

Keywords:  diet; dietary acid load; health; meat; net endogenous acid production; nutrition; plant-based; potential renal acid load; vegan; vegetarian

DOI:  https://doi.org/10.3390/ijerph18199998
Mol Med Rep. 2021 Dec;pii: 854. [Epub ahead of print]24(6):

Sarcopenia, frailty and type 2 diabetes mellitus (Review).

Hiroki Nishikawa, Shinya Fukunishi, Akira Asai, Keisuke Yokohama, Hideko Ohama, Shuhei Nishiguchi, Kazuhide Higuchi.

  Skeletal muscle is the largest and most energy‑consuming organ in the human body, which plays an important role in energy metabolism and glucose uptake. There is a notable decrease in glucose uptake in the skeletal muscle of patients with type 2 diabetes mellitus (DM). Endurance exercise can reduce hyperglycemia and improve insulin resistance in patients with type 2 DM. Insulin exerts a variety of effects, many of which are mediated by Akt, including increasing glucose uptake, promoting glycogen synthesis and inhibiting glycogen degradation, increasing free fatty acid uptake, increasing protein synthesis, promoting muscle hypertrophy and inhibiting protein degradation. Skeletal muscle mass progressively declines with aging, resulting in loss of muscle strength and physical function. Sarcopenia is a syndrome characterized by loss of skeletal muscle mass and muscle weakness or loss of physical function, and frailty is another syndrome that has received great interest in recent years. Decreased organ function results in vulnerability to external stress. Frailty is associated with falls, fractures and hospitalization; however, there is the reversibility of returning to a healthy state with appropriate interventions. Frailty is classified into three subgroups: Physical frailty, social frailty and cognitive frailty, whereby sarcopenia is the main component of physical frailty. The present review discusses the associations between sarcopenia, frailty and type 2 DM based on current evidence.

Keywords:  frailty; insulin; sarcopenia; skeletal muscle; type 2 diabetes mellitus

DOI:  https://doi.org/10.3892/mmr.2021.12494
Molecules. 2021 Sep 24. pii: 5785. [Epub ahead of print]26(19):

Co-Treatments of Edible Curcumin from Turmeric Rhizomes and Chemotherapeutic Drugs on Cytotoxicity and FLT3 Protein Expression in Leukemic Stem Cells.

Fah Chueahongthong, Singkome Tima, Sawitree Chiampanichayakul, Cory Berkland, Songyot Anuchapreeda.

  This study aims to enhance efficacy and reduce toxicity of the combination treatment of a drug and curcumin (Cur) on leukemic stem cell and leukemic cell lines, including KG-1a and KG-1 (FLT3+ LSCs), EoL-1 (FLT3+ LCs), and U937 (FLT3- LCs). The cytotoxicity of co-treatments of doxorubicin (Dox) or idarubicin (Ida) at concentrations of the IC10-IC80 values and each concentration of Cur at the IC20, IC30, IC40, and IC50 values (conditions 1, 2, 3, and 4) was determined by MTT assays. Dox-Cur increased cytotoxicity in leukemic cells. Dox-Cur co-treatment showed additive and synergistic effects in several conditions. The effect of this co-treatment on FLT3 expression in KG-1a, KG-1, and EoL-1 cells was examined by Western blotting. Dox-Cur decreased FLT3 protein levels and total cell numbers in all the cell lines in a dose-dependent manner. In summary, this study exhibits a novel report of Dox-Cur co-treatment in both enhancing cytotoxicity of Dox and inhibiting cell proliferation via FLT3 protein expression in leukemia stem cells and leukemic cells. This is the option of leukemia treatment with reducing side effects of chemotherapeutic drugs to leukemia patients.

Keywords:  FLT-3; chemotherapeutic drug; co-treatment; curcumin; leukemia; leukemic stem cell

DOI:  https://doi.org/10.3390/molecules26195785
Food Chem. 2021 Sep 09. pii: S0308-8146(21)02104-X. [Epub ahead of print]371 131098

Tea and its phytochemicals: Hidden health benefits & modulation of signaling cascade by phytochemicals.

Sagar Bag, Anupam Mondal, Anusha Majumder, Avishek Banik.

  Tea, one of the most widely consumed beverages, is prepared from the leaves of the Camellia sinensis. The promising health recompenses of tea have been linked to its different phenolic components, which have diverse biological characteristics. Tea also contains several flavonoids, alkaloids, phenolic, theanine, etc., which are associated with anti-oxidant characteristics and a variety of health benefits. It can also lower the pervasiveness of neurological disorders as well as prevent different types of cancer, metabolic syndromes, cardiovascular diseases, urinary stone, obesity, type 2 diabetes. Keeping in mind that tea helps to improve health and prevents many diseases, its consumption has been regarded as a "health-promoting habit" and current medical investigators have established the scientific basis for this concept over time. The current review provides new updated information and perspectives on the tea phytochemicals and their overall health benefits based on molecular processes, experimental studies, and clinical trials.

Keywords:  Antioxidant activities; Bioactive compounds; Health benefits; Phytochemicals; Signal transduction; Tea

DOI:  https://doi.org/10.1016/j.foodchem.2021.131098
Age Ageing. 2021 Oct 13. pii: afab199. [Epub ahead of print]

Geriatric medicine in the era of climate change.

Bethan Davies, Mahmood F Bhutta.

  Climate change has been termed the greatest threat to human health of the 21st century. Older people and those living with frailty are more vulnerable to the effects of climate change including heatwaves and extreme weather events, and therefore, we have a responsibility to advocate for action on the climate emergency and take steps to reduce the environmental impact of our care provision. The NHS contributes 5.7% to the carbon footprint of the UK, and by reviewing the financial costs associated with frailty, we estimate the carbon footprint of frailty to be 1.7 MtCO2e, or 7% of the total NHS carbon footprint. Resource use also increases with age with particular interventions and medical equipment such as hearing and mobility aids being predominantly associated with the care of older people. The NHS has committed to net zero carbon emissions by 2045 and in order to achieve this we all need to act-balancing the triple bottom line of environmental, social and financial impacts alongside outcomes for patients and populations when making decisions about care. The principles of sustainable healthcare are already embedded in the geriatrician's holisitic approach to the care of older people and those living with frailty, and the imperative to reduce the carbon footprint of healthcare should add weight to the argument for extending the role of the geriatrician into other specialties. It is time to begin our journey to net-zero geriatric medicine.

Keywords:  climate change; frailty; older people; sustainability

DOI:  https://doi.org/10.1093/ageing/afab199
Nat Rev Mater. 2021 Oct 08. 1-3

Community-driven online initiatives have reshaped scientific engagement.

James P K Armstrong, Irene de Lázaro, Natalie J Kirkland, Wilson Poon, Shrey Sindhwani.

  Scientists have reacted to COVID-19 restrictions by organizing virtual seminars and journal clubs to maintain engagement. We reflect on our experiences and lessons learned from organizing such initiatives and highlight how, far from being temporary substitutes of in-person counterparts, they can help foster more diverse, inclusive and environmentally friendly scientific exchange.

Keywords:  Careers; Conferences and meetings; Scientific community

DOI:  https://doi.org/10.1038/s41578-021-00384-y
J Inherit Metab Dis. 2021 Oct 16.

Interplay Between Cardiolipin and Plasmalogens in Barth Syndrome.

José Carlos Bozelli, Richard M Epand.

  Barth Syndrome (BTHS) is a rare inherited metabolic disease resulting from mutations in the gene of the enzyme tafazzin, which catalyzes the acyl chain remodeling of the mitochondrial-specific lipid cardiolipin (CL). Tissue samples of individuals with BTHS present abnormalities in the level and the molecular species of CL. In addition, in tissues of a tafazzin knockdown mouse as well as in cells derived from BTHS patients it has been shown that plasmalogens, a subclass of glycerophospholipids, also have abnormal levels. Likewise, administration of a plasmalogen precursor to cells derived from BTHS patients led to an increase in plasmalogen and to some extent CL levels. These results indicate an interplay between CL and plasmalogens in BTHS. This interdependence is supported by the concomitant loss in these lipids in different pathological conditions. However, currently the molecular mechanism linking CL and plasmalogens is not fully understood. Here, a review of the evidence showing the linkage between the levels of CL and plasmalogens is presented. In addition, putative mechanisms that might play a role in this interplay are proposed. Finally, the opportunity of therapeutic approaches based on the regulation of plasmalogens as new therapies for the treatment of BTHS is discussed. This article is protected by copyright. All rights reserved.

Keywords:  Barth Syndrome; cardiolipin; lipid disorders; lipid metabolism; plasmalogen replacement therapy; plasmalogens

DOI:  https://doi.org/10.1002/jimd.12449