bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2020‒12‒27
forty papers selected by
Ayesh Seneviratne
University of Toronto


  1. Front Pharmacol. 2020 ;11 588449
    Kumari R, Palaniyandi S, Hildebrandt GC.
      Allogeneic hematopoietic stem cell transplantation (HSCT) is the solitary therapeutic therapy for many types of hematological cancers. The benefits of this procedure are challenged by graft vs. host disease (GVHD), causing significant morbidity and mortality. Recent advances in the metabolomics field have revolutionized our understanding of complex human diseases, clinical diagnostics and allow to trace the de novo biosynthesis of metabolites. There is growing evidence for metabolomics playing a role in different aspects of GVHD, and therefore metabolomic reprogramming presents a novel tool for this disease. Pre-transplant cytokine profiles and metabolic status of allogeneic transplant recipients is shown to be linked with a threat of acute GVHD. Immune reactions underlying the pathophysiology of GVHD involve higher proliferation and migration of immune cells to the target site, requiring shifts in energy supply and demand. Metabolic changes and reduced availability of oxygen result in tissue and cellular hypoxia which is extensive enough to trigger transcriptional and translational changes. T cells, major players in acute GVHD pathophysiology, show increased glucose uptake and glycolytic activity. Effector T (Teff) cells activated during nutrient limiting conditions in vitro or multiplying during GVHD in vivo, depend more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Dyslipidemia, such as the increase of medium and long chain fatty and polyunsaturated acids in plasma of GVHD patients, has been observed. Sphingolipids associate with inflammatory conditions and cancer. Chronic GVHD (cGVHD) patients show reduced branched-chain amino acids (BCAAs) and increased sulfur-containing metabolites post HSCT. Microbiota-derived metabolites such as aryl hydrocarbon receptor (AhR) ligands, bile acids, plasmalogens and short chain fatty acids vary significantly and affect allogeneic immune responses during acute GVHD. Considering the multitude of possibilities, how altered metabolomics are involved in GVHD biology, multi-timepoints related and multivariable biomarker panels for prognosticating and understanding GVHD are needed. In this review, we will discuss the recent work addressing metabolomics reprogramming to control GVHD in detail.
    Keywords:  allogeneic hematopoietic cell transplantation; glycolysis; graft versus host disease; krebs cycle; t cells
    DOI:  https://doi.org/10.3389/fphar.2020.588449
  2. Scand J Med Sci Sports. 2020 Dec 20.
    Hodun K, Chabowski A, Baranowski M.
      Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid found in all eukaryotic cells. Although it may function as an intracellular second messenger, most of its effects are induced extracellularly via activation of a family of five specific membrane receptors. S1P is enriched in plasma, where it is transported by high-density lipoprotein and albumin, as well as in erythrocytes and platelets which store and release large amounts of this sphingolipid. S1P regulates a host of cellular processes such as growth, proliferation, differentiation, migration, and apoptosis suppression. It was also shown to play an important role in skeletal muscle physiology and pathophysiology. In recent years, S1P metabolism in both muscle and blood was found to be modulated by exercise. In this review, we summarize the current knowledge on the effect of acute exercise and training on S1P metabolism, highlighting the role of this sphingolipid in skeletal muscle adaptation to physical effort.
    Keywords:  dhS1P; dihydrosphingosine-1-phosphate; exercise; red blood cells; skeletal muscle; sphinganine-1-phosphate; sphingoid base-1-phosphate; training
    DOI:  https://doi.org/10.1111/sms.13907
  3. Blood Adv. 2020 Dec 22. 4(24): 6342-6352
    Jahn N, Terzer T, Sträng E, Dolnik A, Cocciardi S, Panina E, Corbacioglu A, Herzig J, Weber D, Schrade A, Götze K, Schröder T, Lübbert M, Wellnitz D, Koller E, Schlenk RF, Gaidzik VI, Paschka P, Rücker FG, Heuser M, Thol F, Ganser A, Benner A, Döhner H, Bullinger L, Döhner K.
      Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.
    DOI:  https://doi.org/10.1182/bloodadvances.2020002673
  4. Biofactors. 2020 Dec 21.
    Daily JW, Kang S, Park S.
      Luteolin is a widely distributed flavone herbs and vegetables. It has anti-oxidant and anti-inflammatory activities and improves glucose metabolism by potentiating insulin sensitivity and improving β-cell function and mass. Alzheimer's disease (AD) is induced by the deposition of amyloid-beta (Aβ) in the hippocampus and the formation of neurotoxic Aβ plaques. The Aβ deposition is associated with increased formation of Aβ from amyloid precursor protein by up-regulation of β-secretase and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1). Furthermore, Aβ accumulation is increased by brain insulin resistance. The impairment of insulin/IGF-1 signaling mainly in the hippocampus and brain insulin resistance is connected to signals originating in the liver and gut microbiota, known as the gut microbiota-liver-brain axis. This indicates that the changes in the production of short-chain fatty acids by the gut microbiota and pro-inflammatory cytokines can alter insulin resistance in the liver and brain. Luteolin is detected in the brain tissues after passing through the blood-brain barrier, where it can directly influence neuroinflammation and brain insulin resistance and modulate Aβ deposition. Luteolin (10-70 mg/kg bw for rodents) can modulate the systemic and brain insulin resistance, and it suppresses AD development directly, and it influences Aβ deposition by activation of the gut microbiota-liver-brain axis. In this review, we evaluate the potential of luteolin to mitigate two potential causes of AD, neuroinflammatory processes, and disruption of glucose metabolism in the brain. This review suggests that luteolin intake can enhance brain insulin resistance and neuroinflammation, directly and indirectly, to protect against the development of Alzheimer's-like disease, and the gut microbiota-liver-brain axis is mainly involved in the indirect pathway. However, most studies have been conducted in animal studies, and human clinical trials are needed.
    Keywords:  Alzheimer's disease; amyloid-β; brain insulin resistance; gut microbiota-liver-brain axis; luteolin
    DOI:  https://doi.org/10.1002/biof.1703
  5. Hypertension. 2020 Dec 21. HYPERTENSIONAHA12014584
    Tseng E, Appel LJ, Yeh HC, Pilla SJ, Miller ER, Juraschek SP, Maruthur NM.
      Elevated blood pressure and blood pressure-related morbidity are extraordinarily common in persons with diabetes. The Dietary Approaches to Stop Hypertension dietary pattern and dietary sodium reduction are recommended as lifestyle interventions in individuals with diabetes. However, these recommendations have largely been based on studies conducted in persons without diabetes. In this review, we summarize available evidence from trials that tested the effects of these 2 dietary interventions on blood pressure in people with diabetes. Overall, of the 3 trials (total n=151) that tested the effects of the Dietary Approaches to Stop Hypertension dietary pattern in persons with diabetes, 2 trials documented that the Dietary Approaches to Stop Hypertension dietary pattern lowered blood pressure. While 16 trials (total n=445) tested the effects of sodium reduction in persons with diabetes, results were inconsistent, likely because of design limitations, for example, brief duration, small sample size, and low baseline blood pressure levels, as well as differences in the mode of intervention delivery (behavioral interventions, feeding studies, and sodium supplements). In conclusion, there is a substantial need for additional research on the blood pressure lowering effects of the Dietary Approaches to Stop Hypertension diet and sodium reduction in people with diabetes and hypertension, given the high prevalence of hypertension and the dearth of high-quality trials in this population.
    Keywords:  Dietary Approaches to Stop Hypertension; blood pressure; diabetes mellitus; sodium-restricted diet
    DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.120.14584
  6. Crit Rev Food Sci Nutr. 2020 Dec 22. 1-14
    Alhabeeb H, Sohouli MH, Lari A, Fatahi S, Shidfar F, Alomar O, Salem H, Al-Badawi IA, Abu-Zaid A.
      Cardiovascular disease (CVD) is the greatest cause of premature death and disability globally. Numerous therapeutic strategies have been developed to improve and prevent the adverse cardiovascular events, including nutritional approaches. This systematic review and meta-analysis summarized the evidence on orange juice consumption on CVD risk factors. Four databases were searched up to September 2020. Ten randomized controlled trials were included in the final analysis. Pooled results demonstrated a significant effect of orange juice on glucose (WMD: -2.92 mg/dl, 95% CI: -5.327, -0.530, p = 0.017), insulin (WMD: -1.229 μU/ml, 95% CI: -2.083, -0.374, p = 0.005), HOMA-IR (WMD: -0.464, 95% CI: -0.747, -0.181, p = 0.001), total cholesterol (WMD: -9.84 mg/dl, 95% CI: -15.43, -4.24, p = 0.001), LDL-C (WMD: -9.14 mg/dl, 95% CI: -15.79, -2.49, p = 0.007), and CRP (WMD: -0.467 mg/l, 95% CI: -0.815, -0.120, p = 0.008) compared to control group. However, the effect of orange juice on body composition factors and other CVD risk factors was not significant compared to control group. These lowering effects of glucose, HOMA-IR, total cholesterol, and LDL-C were robust in subgroups with orange juice consumption ≥500 ml/day. This meta-analysis suggests that orange juice may be beneficial in improving several CVD risk factors.
    Keywords:  Orange juice; blood pressure; body composition; glucose metabolism; lipid profile; meta-analysis
    DOI:  https://doi.org/10.1080/10408398.2020.1865263
  7. Front Mol Biosci. 2020 ;7 577284
    Kim JH, Lee JE, Kim T, Yeom MH, Park JS, di Luccio E, Chen H, Dong Z, Lee KW, Kang NJ.
      7,3',4'-Trihydroxyisoflavone (7,3',4'-THIF) is a metabolite of daidzein which is a representative isoflavone found in soybean. Recent studies suggested that 7,3',4'-THIF exerts a hypopigmentary effect in B16F10 cells, however, its underlying molecular mechanisms and specific target protein remain unknown. Here, we found that 7,3',4'-THIF, but not daidzein, inhibited α-melanocyte-stimulating hormone (MSH)-induced intracellular and extracellular melanin production in B16F10 cells by directly targeting melanocortin 1 receptor (MC1R). Western blot data showed that 7,3',4'-THIF inhibited α-MSH-induced tyrosinase, tyrosinase-related protein-1 (TYRP-1), and tyrosinase-related protein-2 (TYRP-2) expressions through the inhibition of Microphthalmia-associated transcription factor (MITF) expression and cAMP response element-binding (CREB) phosphorylation. 7,3',4'-THIF also inhibited α-MSH-induced dephosphorylation of AKT and phosphorylation of p38 and cAMP-dependent protein kinase (PKA). cAMP and Pull-down assays indicated that 7,3',4'-THIF strongly inhibited forskolin-induced intracellular cAMP production and bound MC1R directly by competing with α-MSH. Moreover, 7,3',4'-THIF inhibited α-MSH-induced intracellular melanin production in human epidermal melanocytes (HEMs). Collectively, these results demonstrate that 7,3',4'-THIF targets MC1R, resulting in the suppression of melanin production, suggesting a protective role for 7,3',4'-THIF against melanogenesis.
    Keywords:  3′; 4′-Trihydroxyisoflavone; 7; depigmentation; melanocortin 1 receptor; melanogenesis; α-MSH
    DOI:  https://doi.org/10.3389/fmolb.2020.577284
  8. J Periodontol. 2020 Dec 20.
    Aquino-Martinez R, Eckhardt BA, Rowsey JL, Fraser DG, Khosla S, Farr JN, Monroe DG.
      BACKGROUND: Coinciding with other chronic co-morbidities, the prevalence of periodontal disease increases with aging. Mounting evidence has established that senescent cells accumulate at sites of age-related pathologies, where they promote "non-microbial" inflammation. We hypothesized that alveolar bone osteocytes develop senescence characteristics in old age.METHODS: Alveolar bone samples were obtained from young (6 months) and old (20-22 months) mice to evaluate the expression of senescence biomarkers by immunofluorescent staining. Osteocyte-enriched fractions were used to characterize the age-related senescence-associated secretory phenotype (SASP) gene expression profile. Primary alveolar bone cells were exposed to the SASP via in vitro senescent conditioned media (SCM) administration. A multiplex assay confirmed protein levels of specific cytokines. Interactions with bacterial components were evaluated by stimulating cells with lipopolysaccharide (LPS).
    RESULTS: Increased senescence-associated distension of satellites (SADS) and p16Ink4a mRNA expression were identified in alveolar bone osteocytes with aging. These findings were associated with increased levels of DNA damage, and activated p38 MAPK, both inducers of senescence. Furthermore, interleukin-6 (Il6), Il17, Igfbp4 and Mmp13 were significantly upregulated with aging in osteocyte-enriched samples. Interestingly, SCM potentiated the LPS-induced expression of Il1α, Il1β, and Il6. Cell migration and differentiation were also impeded by SCM. These in vitro effects were ameliorated by the p38 MAPK inhibitor SB202190.
    CONCLUSIONS: Accumulation of senescent osteocytes contributes to deterioration of the periodontal environment by exacerbating chronic inflammation and reducing regeneration in old age. Cellular senescence is a cell-intrinsic response to DNA damage, and a host-related mechanism associated with aging that could potentiate inflammation induced by bacterial components. This article is protected by copyright. All rights reserved.
    Keywords:  Aging; Alveolar Bone Loss; Cellular Senescence; DNA damage; Inflammation; Periodontal Diseases
    DOI:  https://doi.org/10.1002/JPER.20-0529
  9. Aging (Albany NY). 2020 Dec 20. 12
    Hernandez-Valladares M, Aasebø E, Berven F, Selheim F, Bruserud Ø.
      Patients with acute myeloid leukemia (AML) have a median age of 65-70 years at diagnosis. Elderly patients have more chemoresistant disease, and this is partly due to decreased frequencies of favorable and increased frequencies of adverse genetic abnormalities. However, aging-dependent differences may also contribute. We therefore compared AML cell proteomic and phosphoproteomic profiles for (i) elderly low-risk and younger low-risk patients with favorable genetic abnormalities; and (ii) high-risk patients with adverse genetic abnormalities and a higher median age against all low-risk patients with lower median age. Elderly low-risk and younger low-risk patients showed mainly phosphoproteomic differences especially involving transcriptional regulators and cytoskeleton. When comparing high-risk and low-risk patients both proteomic and phosphoproteomic studies showed differences involving cytoskeleton and immunoregulation but also transcriptional regulation and cell division. The age-associated prognostic impact of cyclin-dependent kinases was dependent on the cellular context. The protein level of the adverse prognostic biomarker mitochondrial aldehyde dehydrogenase (ALDH2) showed a similar significant upregulation both in elderly low-risk and elderly high-risk patients. Our results suggest that molecular mechanisms associated with cellular aging influence chemoresistance of AML cells, and especially the cytoskeleton function may then influence cellular hallmarks of aging, e.g. mitosis, polarity, intracellular transport and adhesion.
    Keywords:  ALDH2; acute myeloid leukenia; age; cytogenetics; risk
    DOI:  https://doi.org/10.18632/aging.202361
  10. Blood Adv. 2020 Dec 22. 4(24): 6086-6097
    Hou L, Voit RA, Sankaran VG, Springer TA, Yuki K.
      β2 integrins are well-known leukocyte adhesion molecules consisting of 4 members: CD11a-d. Their known biological functions range widely from leukocyte recruitment, phagocytosis, to immunological synapse formation, but the studies have been primarily focused on CD11a and CD11b. CD11c is 1 of the 4 members and is extremely homologous to CD11b. It has been well known as a dendritic cell marker, but the characterization of its function has been limited. We found that CD11c was expressed on the short-term hematopoietic stem cells and multipotent progenitor cells. The lack of CD11c did not affect the number of hematopoietic stem and progenitor cells (HSPCs) in healthy CD11c knockout mice. Different from other β2 integrin members, however, CD11c deficiency was associated with increased apoptosis and significant loss of HSPCs in sepsis and bone marrow transplantation. Although integrins are generally known for their overlapping and redundant roles, we showed that CD11c had a distinct role of regulating the expansion of HSPCs under stress. This study shows that CD11c, a well-known dendritic cell marker, is expressed on HSPCs and serves as their functional regulator. CD11c deficiency leads to the loss of HSPCs via apoptosis in sepsis and bone marrow transplantation.
    DOI:  https://doi.org/10.1182/bloodadvances.2020002504
  11. Cancers (Basel). 2020 Dec 17. pii: E3801. [Epub ahead of print]12(12):
    Cao Z, Weygant N, Chandrakesan P, Houchen CW, Peng J, Qu D.
      Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies.
    Keywords:  DCLK1; cancer stem cells; immunotherapies; microenvironment; tuft cells
    DOI:  https://doi.org/10.3390/cancers12123801
  12. Front Physiol. 2020 ;11 584782
    Yao J, Hu P, Zhu Y, Xu Y, Tan Q, Liang X.
      Compared with wild grass carp (Ctenopharyngodon idellus), intensively cultured fish displayed disordered lipid metabolism, showing excess lipid deposition in the hepatopancreas and muscle. Lotus leaf prevents fat accumulation in humans and may have similar effects on fish. This study explored the regulatory mechanisms by which the dietary addition of an alcoholic extract of lotus leaf (AELL) reduced lipid deposition in the hepatopancreas and muscle of juvenile grass carp. The fish (average initial weight: 34.00 ± 0.40 g) were fed four experimental diets containing different AELL levels (0, 0.07, 0.14, and 0.21%) for 8 weeks. Serum components, lipid droplet size, triacylglycerol (TAG) content, enzymatic activities, and mRNA levels of genes related to lipid metabolism in the hepatopancreas and muscle were analyzed. The results show that dietary AELL supplementation significantly reduced the TAG content and lipid droplet area in the histological sections as well as the fatty acid synthase (FAS) activity in both the hepatopancreas and muscle but enhanced the activities of lipoprotein lipase (LPL) and carnitine palmitoyltransferase I (CPT1) in both tissues. In addition, dietary AELL supplementation decreased the mRNA expression of genes involved in fatty acid uptake (cd36, fatp1/fatp4/fatp6, fabp10/fabp11, acsl1/acsl4) and de novo lipid synthesis (pgd, g6pd, and fasn) as well as the transcription factors pparg and srebf1 in the hepatopancreas and muscle but increased the mRNA levels of genes relating to lipid catabolism (cpt1a, lipe, pnpla2, lpl), lipid transportation (apob), and the transcription factor ppara in both tissues. In conclusion, dietary AELL supplementation reduced lipid accumulation in the hepatopancreas and muscle by affecting the gene expression of proteins with known effects on lipid metabolism in juvenile grass carp.
    Keywords:  Ctenopharyngodon idellus; lipid catabolism; lipid transportation; lipogenesis; molecular pathway; plant extract
    DOI:  https://doi.org/10.3389/fphys.2020.584782
  13. Int Immunopharmacol. 2020 Dec 16. pii: S1567-5769(20)33731-0. [Epub ahead of print]91 107264
    Kumar A, Sawhney G, Kumar Nagar R, Chauhan N, Gupta N, Kaul A, Ahmed Z, Sangwan PL, Satheesh Kumar P, Yadav G.
      Bakuchiol (BAK) has been reported to have a diverse pharmacological property as an antibiotic, anti-cancer, anti-hypolipidemic, anti-inflammatory and anti-convulsant agent. This study aimed to elucidate the immunomodulation and anti-inflammatory mechanism of bakuchiol using lipopolysaccharide stimulated RAW 264.7 macrophages and various animal models. The present study has shown that BAK significantly suppressed the pro-inflammatory cytokine expression in a dose-dependent manner and its oral administration significantly decreased delayed hypersensitivity responses as compared to control group. The assessment of immunomodulatory activity was carried out by the testing Hemagglutinating antibody (HA) titer, delayed type hypersensitivity (DTH) responses and phagocytic index by carbon clearance test. On the other hand, it showed significant decrease in circulating antibody titer and carbon clearance assay in a concentration-dependent manner. BAK has significantly potentiated the cellular immunity as well as humoral immunity by facilitating the footpad thickness responses in sheep RBCs in sensitized mice by significantly decreasing circulating antibody titer. Molecular studies revealed that BAK inhibited the activation of upstream mediator nuclear factor-κB by suppressing the phosphorylation of IκBα and p65. The responses were statistically significant as compared with the control (*p < 0.05, **p < 0.01).
    Keywords:  BAK; Bakuchiol; Cell-mediated immunity; Humoral immunity; Immunomodulatory activities and Cytokines assay; In-vitro; In-vivo; Macrophages; Phagocytic response; RAW 264.7
    DOI:  https://doi.org/10.1016/j.intimp.2020.107264
  14. Plast Reconstr Surg. 2021 Jan 01. 147(1S-2): 33S-37S
    Singh KK.
      SUMMARY: The genetic basis of youthfulness is poorly understood. The aging of skin depends on both intrinsic factors and extrinsic factors. Intrinsic factors include personal genetics, and extrinsic factors include environmental exposure to solar radiation and pollution. We recently reported the critical role of the mitochondria in skin aging phenotypes: wrinkle formation, hair graying, hair loss, and uneven skin pigmentation. This article focuses on molecular mechanisms, specifically mitochondrial mechanisms underlying skin aging. This contribution describes the development of an mitochondrial DNA depleter-repleter mouse model and its usefulness in developing strategies and identifying potential agents that can either prevent, slow, or mitigate skin aging, lentigines, and hair loss. The ongoing research efforts include the transplantation of young mitochondria to rejuvenate aging skin and hair to provide youthfulness in humans.
    DOI:  https://doi.org/10.1097/PRS.0000000000007619
  15. Ann Hematol. 2020 Dec 19.
    Angenendt L, Hilgefort I, Mikesch JH, Schlüter B, Berdel WE, Lenz G, Stelljes M, Schliemann C.
      Low intake of magnesium has been associated with the occurrence of lymphomas and decreased magnesium levels suppress the cytotoxic function of T cells and natural killer cells in patients with "X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia" (XMEN) syndrome. These cell types are also important mediators of immune-mediated effects after allogeneic hematopoietic stem cell transplantation. Here, we show that high posttransplant magnesium levels independently associate with a lower incidence of relapse, a higher risk of acute graft-versus-host disease, and a higher non-relapse mortality in 368 patients with acute myeloid leukemia from our center. Magnesium serum levels might impact on donor-cell-mediated immune responses in acute myeloid leukemia.
    Keywords:  Acute myeloid leukemia; Allogeneic hematopoietic stem cell transplantation; GVHD; GVL; Magnesium
    DOI:  https://doi.org/10.1007/s00277-020-04382-y
  16. Aging (Albany NY). 2020 Dec 13. 12
    Brinkmann V, Schiavi A, Shaik A, Puchta DR, Ventura N.
      Genetic, dietary, and environmental factors concurrently shape the aging process. The aryl hydrocarbon receptor (AhR) was discovered as a dioxin-binding transcription factor involved in the metabolism of different environmental toxicants in vertebrates. Since then, the variety of pathophysiological processes regulated by the AhR has grown, ranging from immune response, metabolic pathways, and aging. Many modulators of AhR activity may impact on aging and age-associated pathologies, but, whether their effects are AhR-dependent has never been explored. Here, using Caenorhabditis elegans, as an elective model organism for aging studies, we show for the first time that lack of CeAHR-1 can have opposite effects on health and lifespan in a context-dependent manner. Using known mammalian AhR modulators we found that, ahr-1 protects against environmental insults (benzo(a)pyrene and UVB light) and identified a new role for AhR-bacterial diet interaction in animal lifespan, stress resistance, and age-associated pathologies. We narrowed down the dietary factor to a bacterially extruded metabolite likely involved in tryptophan metabolism. This is the first study clearly establishing C. elegans as a good model organism to investigate evolutionarily conserved functions of AhR-modulators and -regulated processes, indicating it can be exploited to contribute to the discovery of novel information about AhR in mammals.
    Keywords:  C. elegans; aging; aryl hydrocarbon receptor; environment; microbiota
    DOI:  https://doi.org/10.18632/aging.202316
  17. J Clin Invest. 2020 Dec 15. pii: 144930. [Epub ahead of print]
    Boonyaratanakornkit J, Morishima C, Selke S, Zamora D, McGuffin SA, Shapiro AE, Campbell VL, McClurkan CL, Jing L, Gross R, Liang J, Postnikova E, Mazur S, Lukin VV, Chaudhary A, Das MK, Fink SL, Bryan A, Greninger AL, Jerome KR, Holbrook MR, Gernsheimer TB, Wener MH, Wald A, Koelle DM.
      BACKGROUND: SARS-CoV-2-specific antibodies may protect from reinfection and disease, providing rationale for administration of plasma containing SARS-CoV-2 neutralizing antibodies (nAb) as a treatment for COVID-19. Clinical factors and laboratory assays to streamline plasma donor selection, and the durability of nAb responses, are incompletely understood.METHODS: Potential convalescent plasma donors with virologically-documented SARS-CoV-2 infection were tested for serum IgG to SARS-CoV-2 spike protein S1 domain, nucleoprotein (NP), and for nAb.
    RESULTS: Amongst 250 consecutive persons, including 27 (11%) requiring hospitalization, studied a median of 67 days since symptom onset, 97% were seropositive on one or more assays. Sixty percent of donors had nAb titers ≥1:80. Correlates of higher nAb titer included older age (adjusted odds ratio [AOR] 1.03/year of age, 95% CI 1.00-1.06), male sex (AOR 2.08, 95% CI 1.13-3.82), fever during acute illness (AOR 2.73, 95% CI 1.25-5.97), and disease severity represented by hospitalization (AOR 6.59, 95% CI 1.32-32.96). Receiver operating characteristic (ROC) analyses of anti-S1 and anti-NP antibody results yielded cutoffs that corresponded well with nAb titers, with the anti-S1 assay being slightly more predictive. NAb titers declined in 37 of 41 paired specimens collected a median of 98 days (range, 77-120) apart (P<0.001). Seven individuals (2.8%) were persistently seronegative and lacked T cell responses.
    CONCLUSIONS: Nab titers correlated with COVID-19 severity, age, and sex. Standard commercially available SARS-CoV-2 IgG results can serve as useful surrogates for nAb testing. Functional nAb levels were found to decline and a small proportion of persons recovered from COVID-19 lack adaptive immune responses.
    Keywords:  Adaptive immunity; Immunoglobulins; Infectious disease; Virology
    DOI:  https://doi.org/10.1172/JCI144930
  18. Comp Biochem Physiol B Biochem Mol Biol. 2020 Dec 16. pii: S1096-4959(20)30141-X. [Epub ahead of print] 110547
    Kong XT, Wang Z, Mou JJ, Li CS, Xue HL, Wu M, Chen L, Xu JH, Xu LX.
      Harderian gland (HG) plays an important role in the physiological adaptation to terrestrial life, however, the mechanisms underlying the changes in the structure and function of the HG during aging remain unclear. This study investigated autophagy and apoptosis in the HG of striped dwarf hamsters (Cricetulus barabensis) of different ages (sub-adult, adult and aged groups) in both males and females. The results showed that LC3II/LC3I and puncta of LC3 were significantly higher in adult and aged individuals than sub-adults, whereas P62 decreased with age. Bax/bcl2was the highest in sub-adults of male and female individuals. Caspase3 activity was the highest in sub-adults of male and female individuals, and the citrate synthase activity was highest in sub-adults of females. ATP synthase, citrate synthase, dynamin-related protein 1 and mitochondrial fission factor (Mff) were the highest in sub-adults of females. Peptidylglycine α-amidating monooxygenase were the highest in the aged group, and those of gonadotropin-releasing hormone was the highest in the adult group. LC3II/LC3I, P62, Drp1, Fis, and bax/bcl2 were higher in males than that in females. These results suggest that apoptosis mainly affects growth and development in the HG, whereas autophagy affects aging. The difference of the HG weight and mitochondrial function between sexes is mainly related to the apoptosis.
    Keywords:  Aging; Apoptosis; Autophagy; Cricetulus barabensis; Harderian gland; Mitochondrion fission; Striped dwarf hamsters
    DOI:  https://doi.org/10.1016/j.cbpb.2020.110547
  19. J Invest Dermatol. 2020 Dec 18. pii: S0022-202X(20)32284-3. [Epub ahead of print]
    Fitsiou E, Pulido T, Campisi J, Alimirah F, Demaria M.
      Chronic exposure to UVR is known to disrupt tissue homeostasis, accelerate the onset of age-related phenotypes, and increase the risk for skin cancer-a phenomenon defined as photoaging. In this paper, we review the current knowledge on how UV exposure causes cells to prematurely enter cellular senescence. We describe the mechanisms contributing to the accumulation of senescent cells in the skin and how the persistence of cellular senescence can promote impaired regenerative capacity, chronic inflammation, and tumorigenesis associated with photoaging. We conclude by highlighting the potential of senolytic drugs in delaying the onset and progression of age-associated phenotypes in the skin.
    DOI:  https://doi.org/10.1016/j.jid.2020.09.031
  20. Front Plant Sci. 2020 ;11 601478
    Yang J, Li C, Kong D, Guo F, Wei H.
      Stomata are valves on the leaf surface controlling carbon dioxide (CO2) influx for photosynthesis and water loss by transpiration. Thus, plants have to evolve elaborate mechanisms controlling stomatal aperture to allow efficient photosynthesis while avoid excessive water loss. Light is not only the energy source for photosynthesis but also an important signal regulating stomatal movement during dark-to-light transition. Our knowledge concerning blue and red light signaling and light-induced metabolite changes that contribute to stomatal opening are accumulating. This review summarizes recent advances on the signaling components that lie between the perception of blue/red light and activation of the PM H+-ATPases, and on the negative regulation of stomatal opening by red light-activated phyB signaling and ultraviolet (UV-B and UV-A) irradiation. Besides, light-regulated guard cell (GC)-specific metabolic levels, mesophyll-derived sucrose, and CO2 concentration within GCs also play dual roles in stomatal opening. Thus, light-induced stomatal opening is tightly accompanied by brake mechanisms, allowing plants to coordinate carbon gain and water loss. Knowledge on the mechanisms regulating the trade-off between stomatal opening and closure may have potential applications toward generating superior crops with improved water use efficiency (CO2 gain vs. water loss).
    Keywords:  Arabidopsis thaliana; guard cell metabolism; light signaling; negative mechanism; stomatal movement; trade-off
    DOI:  https://doi.org/10.3389/fpls.2020.601478
  21. Plast Reconstr Surg. 2021 Jan 01. 147(1S-2): 25S-32S
    Bramwell LR, Harries LW.
      SUMMARY: Cellular senescence is a state of stable cell cycle arrest that has increasingly been linked with cellular, tissue, and organismal aging; targeted removal of senescent cells brings healthspan and lifespan benefits in animal models. Newly emerging approaches to specifically ablate or rejuvenate senescent cells are now the subject of intense study to explore their utility to provide novel treatments for the aesthetic signs and diseases of aging in humans. Here, we discuss different strategies that are being trialed in vitro, and more recently in vivo, for the targeted removal or reversal of senescent cells. Finally, we describe the evidence for a newly emerging molecular mechanism that may underpin senescence; dysregulation of alternative splicing. We will explore the potential of restoring splicing regulation as a novel "senotherapeutic" approach and discuss strategies by which this could be integrated into the established portfolio of skin aging therapeutics.
    DOI:  https://doi.org/10.1097/PRS.0000000000007618
  22. Plast Reconstr Surg. 2021 Jan 01. 147(1S-2): 1S-2S
    Rohrich RJ.
      
    DOI:  https://doi.org/10.1097/PRS.0000000000007631
  23. J Proteome Res. 2020 Dec 21.
    Wang L, Zhang Y, Liu X, Zhao X, Ouyang Y, Qiu G, Lv W, Zheng F, Wang Q, Lu X, Peng X, Wu T, Lehmann R, Wang C, Jia W, Xu G.
      Large-scale population screenings are not feasible by applying laborious oral glucose tolerance tests, but using fasting blood glucose (FPG) and glycated hemoglobin (HbA1c), a considerable number of diagnoses are missed. A novel marker is urgently needed to improve the diagnostic accuracy of broad-scale diabetes screening in easy-to-collect blood samples. In this study, by applying a novel knowledge-based, multistage discovery and validation strategy, we scaled down from 108 diabetes-associated metabolites to a diagnostic metabolite triplet (Met-T), namely hexose, 2-hydroxybutyric/2-hydroxyisobutyric acid, and phenylalanine. Met-T showed in two independent cohorts, each comprising healthy controls, prediabetic, and diabetic individuals, distinctly higher diagnostic sensitivities for diabetes screening than FPG alone (>79.6 vs <68%). Missed diagnoses decreased from >32% using fasting plasma glucose down to <20.4%. Combining Met-T and fasting plasma glucose further improved the diagnostic accuracy. Additionally, a positive association of Met-T with future diabetes risk was found (odds ratio: 1.41; p = 1.03 × 10-6). The results reveal that missed prediabetes and diabetes diagnoses can be markedly reduced by applying Met-T alone or in combination with FPG and it opens perspectives for higher diagnostic accuracy in broad-scale diabetes-screening approaches using easy to collect sample materials.
    Keywords:  diabetes screening; liquid chromatography-mass spectrometry; metabolite markers; metabolomics; prediction of diabetes risk
    DOI:  https://doi.org/10.1021/acs.jproteome.0c00786
  24. Nutrients. 2020 Dec 17. pii: E3858. [Epub ahead of print]12(12):
    Franck M, de Toro-Martín J, Garneau V, Guay V, Kearney M, Pilon G, Roy D, Couture P, Couillard C, Marette A, Vohl MC.
      Consumption of red raspberries has been reported to exert acute beneficial effects on postprandial glycemia, insulinemia, triglyceridemia, and cytokine levels in metabolically disturbed subjects. In a two-arm parallel-group, randomized, controlled trial, 59 subjects with overweight or abdominal obesity and with slight hyperinsulinemia or hypertriglyceridemia were randomized to consume 280 g/day of frozen raspberries or to maintain their usual diet for 8 weeks. Primary analyses measured metabolic differences between the groups. Secondary analyses performed with omics tools in the intervention group assessed blood gene expression and plasma metabolomic changes following the raspberry supplementation. The intervention did not significantly affect plasma insulin, glucose, inflammatory marker concentrations, nor blood pressure. Following the supplementation, 43 genes were differentially expressed, and several functional pathways were enriched, a major portion of which were involved in the regulation of cytotoxicity, immune cell trafficking, protein signal transduction, and interleukin production. In addition, 10 serum metabolites were found significantly altered, among which β-alanine, trimethylamine N-oxide, and bioactive lipids. Although the supplementation had no meaningful metabolic effects, these results highlight the impact of a diet rich in raspberry on the immune function and phospholipid metabolism, thus providing novel insights into potential immune-metabolic pathways influenced by regular raspberry consumption.
    Keywords:  berry fruits; gene expression; immunity; metabolic syndrome; multi-omics; phenolic compounds; sphingolipids
    DOI:  https://doi.org/10.3390/nu12123858
  25. Circ Res. 2020 Dec 21.
    Pérez-Hernández Duran M, Leo-Macias A, Keegan S, Jouni M, Kim JC, Agullo-Pascual E, Vermij SH, Zhang M, Liang FX, Burridge P, Fenyo D, Rothenberg E, Delmar M.
      Rationale: The cardiac sodium channel NaV1.5 has a fundamental role in excitability and conduction. Previous studies have shown that sodium channels cluster together in specific cellular subdomains. Their association with intracellular organelles in defined regions of the myocytes, and the functional consequences of that association, remain to be defined. Objective: To characterize a subcellular domain formed by sodium channel clusters in the crest region of the myocytes, and the subjacent subsarcolemmal mitochondria (SSM).Methods and Results: Through a combination of imaging approaches including super-resolution microscopy and electron microscopy we identified, in adult cardiac myocytes, a NaV1.5 subpopulation in close proximity to SSM; we further found that SSM preferentially host the mitochondrial Na+/Ca2+ exchanger (NCLX). This anatomical proximity led us to investigate functional changes in mitochondria resulting from sodium channel activity. Upon TTX exposure, mitochondria near NaV1.5 channels accumulated more Ca2+ and showed increased ROS production when compared to interfibrillar mitochondria. Finally, crosstalk between NaV1.5 channels and mitochondria was analyzed at a transcriptional level. We found that SCN5A and SLC8B1 (which encode NaV1.5 and NCLX, respectively) are negatively correlated both in a human transcriptome dataset (GTEx) and in human-induced pluripotent stem cell-derived cardiac myocytes deficient in SCN5A. Conclusions: We describe an anatomical hub (a couplon) formed by sodium channel clusters and SSM. Preferential localization of NCLX to this domain allows for functional coupling where the extrusion of Ca2+ from the mitochondria is powered, at least in part, by the entry of sodium through NaV1.5 channels. These results provide a novel entry-point into a mechanistic understanding of the intersection between electrical and structural functions of the heart.
    Keywords:  Nav1.5; mitochondrial NCLX; mitochondrial homeostasis; subsarcolemmal mitochondria
    DOI:  https://doi.org/10.1161/CIRCRESAHA.120.318239
  26. Metabolites. 2020 Dec 17. pii: E512. [Epub ahead of print]10(12):
    Wood PL.
      Fatty Acyl esters of Hydroxy Fatty Acids (FAHFA) encompass three different lipid families which have incorrectly been classified as wax esters. These families include (i) Branched-chain FAHFAs, involved in the regulation of glucose metabolism and inflammation, with acylation of an internal branched-chain hydroxy-palmitic or -stearic acid; (ii) ω-FAHFAs, which function as biosurfactants in a number of biofluids, are formed via acylation of the ω-hydroxyl group of very-long-chain fatty acids (these lipids have also been designated as o-acyl hydroxy fatty acids; OAHFA); and (iii) Ornithine-FAHFAs are bacterial lipids formed by the acylation of short-chain 3-hydroxy fatty acids and the addition of ornithine to the free carboxy group of the hydroxy fatty acid. The differences in biosynthetic pathways and cellular functions of these lipid families will be reviewed and compared to wax esters, which are formed by the acylation of a fatty alcohol, not a hydroxy fatty acid. In summary, FAHFA lipid families are both unique and complex in their biosynthesis and their biological actions. We have only evaluated the tip of the iceberg and much more exciting research is required to understand these lipids in health and disease.
    Keywords:  FAHFA; OAHFA; ornithine; wax esters; ω-hydroxylation
    DOI:  https://doi.org/10.3390/metabo10120512
  27. Immun Ageing. 2020 Dec 21. 17(1): 40
    Sbierski-Kind J, Goldeck D, Buchmann N, Spranger J, Volk HD, Steinhagen-Thiessen E, Pawelec G, Demuth I, Spira D.
      BACKGROUND: Obesity is associated with chronic low-grade inflammation leading to metabolic and cardiovascular diseases, but a subset of obese individuals is considered insulin sensitive (IS). The underlying pathophysiologic mechanisms remain elusive and clinical studies on the relationship between inflammatory markers and metabolically healthy obesity (MHO) are scarce.METHODS: In this cross-sectional analysis, we included a sample of 437 older participants (60-84 years) from the Berlin Aging Study II (BASE-II). Peripheral blood mononuclear cells were isolated, immune cell subsets were analyzed with multiparameter flow cytometry and systemic cytokine levels were measured. Immune cell parameters were correlated with metabolic measures and multiple linear regression analysis was conducted and adjusted for various demographic and clinical factors.
    RESULTS: We found that frequencies of naïve and memory CD4+ and CD8+ T cells inversely correlated with measures for insulin sensitivity in the older population. Moreover, the percentages of naïve CD4+ and CD8+ T cells were significantly higher, whereas activated T cells and IL-6 levels were lower in IS compared to insulin resistant (IR) obese individuals. The percentages of naïve CD4+ and CD8+ T cells were predictive for impaired insulin sensitivity (ß = 0.16, p = 0.01 and ß = 0.11, p = 0.04), and the association of naïve CD4+ T cells with insulin sensitivity persisted after multivariate adjustment (ß = 0.14, p = 0.02).
    CONCLUSIONS: These findings support the hypothesis that parameters of systemic inflammation can differentiate IS from IR obese individuals that are at higher risk for cardiometabolic diseases and may have clinical implications with regard to obesity treatment stratification.
    TRIAL REGISTRATION: DRKS00009277 . Registered 31 August 2015 - Retrospectively registered.
    Keywords:  Aging; Insulin resistance; Obesity; Systemic inflammation; T cell senescence
    DOI:  https://doi.org/10.1186/s12979-020-00211-y
  28. Front Pharmacol. 2020 ;11 523962
    Xie J, Luo FX, Shi CY, Jiang WW, Qian YY, Yang MR, Song S, Dai TY, Peng L, Gao XY, Tao L, Tian Y, Sheng J.
      Moringa oleifera Lam. (M. oleifera) is valuable plant distributed in many tropical and subtropical countries. It has a number of medicinal uses and is highly nutritious. M. oleifera has been shown to inhibit tumor cell growth, but this effect has not been demonstrated on prostate cancer cells. In this study, we evaluated the inhibitory effect of M. oleifera alkaloids (MOA) on proliferation and migration of PC3 human prostate cancer cells in vitro and in vivo. Furthermore, we elucidated the mechanism of these effects. The results showed that MOA inhibited proliferation of PC3 cells and induced apoptosis and cell cycle arrest. Furthermore, MOA suppressed PC3 cell migration and inhibited the expression of matrix metalloproteinases (MMP)-9. In addition, MOA significantly downregulated the expression of cyclooxygenase 2 (COX-2), β-catenin, phosphorylated glycogen synthase 3β, and vascular endothelial growth factor, and suppressed production of prostaglandin E2 (PGE2). Furthermore, FH535 (β-catenin inhibitor) and MOA reversed PGE2-induced PC3 cell proliferation and migration, and the effects of MOA and FH535 were not additive. In vivo experiments showed that MOA (150 mg/kg) significantly inhibited growth of xenograft tumors in mice, and significantly reduced the protein expression levels of COX-2 and β-catenin in tumor tissues. These results indicate that MOA inhibits the proliferation and migration, and induces apoptosis and cell cycle arrest of PC3 cells. Additionally, MOA inhibits the proliferation and migration of PC3 cells through suppression of the COX-2 mediated Wnt/β-catenin signaling pathway.
    Keywords:  COX-2-wnt/β-catenin signaling pathway; Moringa oleifera alkaloids; cell growth and migration; prostate cancer PC3 cells
    DOI:  https://doi.org/10.3389/fphar.2020.523962
  29. Eur J Immunol. 2020 Dec 21.
    Vansarla G, Håkansson AP, Bergenfelz C.
      HAMLET is a protein-lipid complex with a specific and broad bactericidal and tumoricidal activity, that lacks cytotoxic activity against healthy cells. In this study, we show that HAMLET also has general immune-stimulatory effects on primary human monocyte-derived dendritic cells and macrophages (Mo-DC and Mo-M) and murine RAW264.7 macrophages. HAMLET, but not its components alpha-lactalbumin or oleic acid, induces mature CD14low/- CD83+ Mo-DC and M1-like CD14+ CD86++ Mo-M surface phenotypes. Concomitantly, inflammatory mediators, including IL-2, IL-6, IL-10, IL-12 and MIP-1α, were released in the supernatant of HAMLET-stimulated cells, indicating a mainly pro-inflammatory phenotype. The HAMLET-induced phenotype was mediated by calcium, NFκB and p38 MAPK signaling in Mo-DCs and calcium, NFκB and ERK signaling in Mo-M as inhibitors of these pathways almost completely blocked the induction of mature Mo-DCs and M1-like Mo-M. Compared to unstimulated Mo-DCs, HAMLET-stimulated Mo-DC were more potent in inducing T cell proliferation and HAMLET-stimulated macrophages were more efficient in phagocytosis of Streptococcus pneumoniae in vitro. This indicates a functionally activated phenotype of HAMLET-stimulated DCs and macrophages. Combined, we propose that HAMLET has a two-fold anti-bacterial activity; one inducing direct cytotoxic activity, the other indirectly mediating elimination of bacteria by activation of immune cells of the myeloid lineage. This article is protected by copyright. All rights reserved.
    Keywords:  HAMLET; alpha-lactalbumin; dendritic cells; macrophages; myeloid cells
    DOI:  https://doi.org/10.1002/eji.202048813
  30. J Pak Med Assoc. 2020 Nov;70(11): 2065-2069
    Sharma S, Mandal A, Kant R, Jachak S, Jagzape M.
      Diabetes is on the rise, and has become a major public health issue. In view of limitations of available glucose lowering therapy, there is a need to explore and develop natural remedies with anti-diabetic properties. Spices such as cinnamon, cloves, bay leaves, and turmeric display insulin-enhancing activity in vitro. Cinnamon or Dalchini is popularly use as a spice for its fragrance and flavour in wide variety of traditional foods. Among various types of cinnamon, C. zeylanicum is well known as effective substitute for diabetes. Cinnamaldehyde is one of the major constituents (65-80%) of bark oil extracted from C. Zeylonicum which seems to reduce plasma blood glucose concentration more effectively when it is compared with metformin. It enhances the expression of proteins involved in glucose transport, insulin signalling, and regulates dyslipidaemia. This review describes the basic and clinical pharmacology of cinnamon.
    Keywords:   Cinnamon, Glycaemic control, Type 2 Diabetes Mellitus
  31. J Infect Dis. 2020 Dec 22. pii: jiaa775. [Epub ahead of print]
    Hearps AC, Angelovich TA, Trevillyan JM, Wong ME, Calmy A, Hoy JF, Jaworowski A.
      BACKGROUND: Statins may help prevent cardiovascular disease (CVD) in people with HIV (PWH) with chronic inflammation due to their pleotropic lipid lowering and anti-inflammatory properties.METHODS: The impact of 48 weeks of rosuvastatin therapy on inflammation and immune activation in a double-blind, placebo-controlled trial in PWH at moderate CVD risk was assessed.
    RESULTS: Rosuvastatin not alter plasma levels of IL-6, soluble (s)TNF-RII, CXCL10, sCD14 or sVCAM-1 (p≥0.1 for all). Proportions of CD16 + monocyte subsets were increased in PWH receiving rosuvastatin.
    CONCLUSIONS: The potential benefits of statin use in PWH with normal lipid levels requires further clinical outcome research.
    Keywords:  HIV; cardiovascular disease; chronic inflammation; immune activation; monocytes; rosuvastatin
    DOI:  https://doi.org/10.1093/infdis/jiaa775
  32. Cancers (Basel). 2020 Dec 17. pii: E3802. [Epub ahead of print]12(12):
    Augustin RC, Delgoffe GM, Najjar YG.
      Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT.
    Keywords:  cellular energetics; immunometabolism; immunotherapy
    DOI:  https://doi.org/10.3390/cancers12123802
  33. J Cachexia Sarcopenia Muscle. 2020 Dec 22.
    Thibaut MM, Sboarina M, Roumain M, Pötgens SA, Neyrinck AM, Destrée F, Gillard J, Leclercq IA, Dachy G, Demoulin JB, Tailleux A, Lestavel S, Rastelli M, Everard A, Cani PD, Porporato PE, Loumaye A, Thissen JP, Muccioli GG, Delzenne NM, Bindels LB.
      BACKGROUND: Cancer cachexia is a debilitating metabolic syndrome contributing to cancer death. Organs other than the muscle may contribute to the pathogenesis of cancer cachexia. This work explores new mechanisms underlying hepatic alterations in cancer cachexia.METHODS: We used transcriptomics to reveal the hepatic gene expression profile in the colon carcinoma 26 cachectic mouse model. We performed bile acid, tissue mRNA, histological, biochemical, and western blot analyses. Two interventional studies were performed using a neutralizing interleukin 6 antibody and a bile acid sequestrant, cholestyramine. Our findings were evaluated in a cohort of 94 colorectal cancer patients with or without cachexia (43/51).
    RESULTS: In colon carcinoma 26 cachectic mice, we discovered alterations in five inflammatory pathways as well as in other pathways, including bile acid metabolism, fatty acid metabolism, and xenobiotic metabolism (normalized enrichment scores of -1.97, -2.16, and -1.34, respectively; all Padj < 0.05). The hepatobiliary transport system was deeply impaired in cachectic mice, leading to increased systemic and hepatic bile acid levels (+1512 ± 511.6 pmol/mg, P = 0.01) and increased hepatic inflammatory cytokines and neutrophil recruitment to the liver of cachectic mice (+43.36 ± 16.01 neutrophils per square millimetre, P = 0.001). Adaptive mechanisms were set up to counteract this bile acid accumulation by repressing bile acid synthesis and by enhancing alternative routes of basolateral bile acid efflux. Targeting bile acids using cholestyramine reduced hepatic inflammation, without affecting the hepatobiliary transporters (e.g. tumour necrosis factor α signalling via NFκB and inflammatory response pathways, normalized enrichment scores of -1.44 and -1.36, all Padj < 0.05). Reducing interleukin 6 levels counteracted the change in expression of genes involved in the hepatobiliary transport, bile acid synthesis, and inflammation. Serum bile acid levels were increased in cachectic vs. non-cachectic cancer patients (e.g. total bile acids, +5.409 ± 1.834 μM, P = 0.026) and were strongly correlated to systemic inflammation (taurochenodeoxycholic acid and C-reactive protein: ρ = 0.36, Padj = 0.017).
    CONCLUSIONS: We show alterations in bile acid metabolism and hepatobiliary secretion in cancer cachexia. In this context, we demonstrate the contribution of systemic inflammation to the impairment of the hepatobiliary transport system and the role played by bile acids in the hepatic inflammation. This work paves the way to a better understanding of the role of the liver in cancer cachexia.
    Keywords:  Bile acids; Cholestyramine; Hepatobiliary transport system; IL-6; Liver
    DOI:  https://doi.org/10.1002/jcsm.12652
  34. Medicine (Baltimore). 2020 Dec 24. 99(52): e23550
    Wang S, Wang X, Zhang Y, Zhou T, Hu S, Tian P, Li Z, Li Y, Gui Y, Dong J, Hou W.
      BACKGROUND: Fluoropyrimidine combined with oxaliplatin-based chemotherapy have become the first-line treatment for advanced colorectal cancer (CRC). Chinese herbal injections (CHIs), as an important part of TCM, have been widely applied as adjunctive treatments to chemotherapy in patients with advanced CRC. However, the efficacy of this combination therapy has not been evaluated comprehensively.METHODS: We will conduct this systematic review and meta-analysis in accordance with the Preferred Reported Items for Systematic Review and Meta-analysis (PRISMA) guidelines. 7 databases will be searched for related randomized controlled trials (RCTs) from their inception to August 31, 2020: PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals (VIP), SinoMED and Wanfang Database. Two researchers will perform study selection, data extraction, and assessment of risk of bias independently. The primary outcomes are the disease control rate (DCR) and the objective response rate (ORR), the secondary outcomes are progression-free survival (PFS), survival rate, quality of life (QoL) and adverse effects. Cochrane Review Manager (RevMan 5.3) software will be used to analyze the outcomes.
    RESULTS AND CONCLUSION: This systematic review will evaluate the efficacy of CHIs and fluoropyrimidine and oxaliplatin-based chemotherapy for advanced CRC so as to provide valuable evidence to the application of CHIs in advanced CRC.
    SYSTEMATIC REVIEW REGISTRATION: INPLASY registration number: INPLASY2020100050.
    DOI:  https://doi.org/10.1097/MD.0000000000023550
  35. Int J Food Sci Nutr. 2020 Dec 19. 1-6
    Canas JA.
      Dysmetabolic obesity during childhood and adolescence currently represents one of the greatest therapeutic challenge for healthcare systems worldwide. The global rates of obesity have more than doubled in the last 30 years. Recent meta-analysis from national surveys and food composition studies suggest an inverse association between lower carotenoid levels and the prevalence of Metabolic Syndrome in the general population, independent of serum retinol (vitamin A) levels. In children, two double-blind randomised placebo-controlled studies describing the effects of diet vs. mixed carotenoid supplementation on insulin resistance, adipokines and the rate of accrual of subcutaneous abdominal fat, implicate supplementation of these compounds to achieve targetable levels may be useful in the management of obesity accrual in this population. We will discuss the role of carotenoids and their conversion products (retinoids) in adipogenesis, lipolysis, insulin resistance and the pathophysiology of the metabolic syndrome and review the animal studies, which help support these findings.
    Keywords:  Obesity; carotenoids; metabolic syndrome; visceral fat
    DOI:  https://doi.org/10.1080/09637486.2020.1852193
  36. Zhongguo Zhong Yao Za Zhi. 2020 Oct;45(20): 4836-4845
    Xue-Xue W, Ai-Wu Y, Zhu-Ping T, Ying LI, Can-Wei LI, Meng-Ran F, Wei-Hong L, Peng-Fei G.
      Alcohol is considered to be one of the main causes for gastric injury, and alcoholic gastric injury has been becoming one of the global health problems, which seriously affects the quality of human life. Many studies suggest that the active components extracted from Chinese herbal medicine can effectively reduce the degree of alcohol-induced gastric injury. The active components and its mechanism of anti-alcoholic gastric injury of Chinese herbal medicine reported in recent five years were preliminarily summarized according to the classification of terpenoids, flavonoids, polyphenols, polysaccharides, volatile oils, phenylpropanoids and alkaloids in this paper. The terpenoids could improve oxidative stress and inflammatory response by regulating relevant signaling pathways. The flavonoids are mainly related to antioxidant and anti-inflammatory properties. The polyphenols mainly regulate the level of relevant factors involved in inflammatory pathway, oxidative stress and apoptosis pathway. The polysaccharides could enhance the ability of gastric mucosal defense factor by inhibiting oxidative stress injury and inflammatory response. Phenylpropanoids could enhance the gastric mucosal defense factor. The volatile oils mainly inhibit H~+/K~+-ATPase activity or inflammatory reaction. Alkaloids are closely related to the inhibition of inflammatory response and the improvement of antioxidant system. This paper aims to provide reference for further research and development of Chinese herbal medicine against alcoholic gastric injury.
    Keywords:  Chinese herbal medicine; active component; alcoholic gastric injury; mechanism
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20200917.609
  37. Int J Mol Sci. 2020 Dec 17. pii: E9613. [Epub ahead of print]21(24):
    Neamah WH, Busbee PB, Alghetaa H, Abdulla OA, Nagarkatti M, Nagarkatti P.
      Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR and a known carcinogen. While AhR activation by TCDD leads to significant immunosuppression, how this translates into carcinogenic signal is unclear. Recently, we demonstrated that activation of AhR by TCDD in naïve C57BL6 mice leads to massive induction of myeloid derived-suppressor cells (MDSCs). In the current study, we investigated the role of the gut microbiota in TCDD-mediated MDSC induction. TCDD caused significant alterations in the gut microbiome, such as increases in Prevotella and Lactobacillus, while decreasing Sutterella and Bacteroides. Fecal transplants from TCDD-treated donor mice into antibiotic-treated mice induced MDSCs and increased regulatory T-cells (Tregs). Injecting TCDD directly into antibiotic-treated mice also induced MDSCs, although to a lesser extent. These data suggested that TCDD-induced dysbiosis plays a critical role in MDSC induction. Interestingly, treatment with TCDD led to induction of MDSCs in the colon and undetectable levels of cysteine. MDSCs suppressed T cell proliferation while reconstitution with cysteine restored this response. Lastly, blocking CXC chemokine receptor 2 (CXCR2) impeded TCDD-mediated MDSC induction. Our data demonstrate that AhR activation by TCDD triggers dysbiosis which, in turn, regulates, at least in part, induction of MDSCs.
    Keywords:  2,3,7,8-tetrachlorodibenzo-p-dioxin; CXCR2; aryl hydrocarbon receptor; microbiome; myeloid-derived suppressor cell
    DOI:  https://doi.org/10.3390/ijms21249613
  38. Front Physiol. 2020 ;11 584248
    Golubev AG.
      The death toll of the current COVID-19 pandemic is strongly biased toward the elderly. COVID-19 case fatality rate (CFR) increases with age exponentially, its doubling time being about 7 years, irrespective of countries and epidemic stages. The same age-dependent mortality pattern known as the Gompertz law is featured by the total mortality and its main constituents attributed to cardiovascular, metabolic, neurological, and oncological diseases. Among patients dying of COVID-19, most have at least one of these conditions, whereas none is found in most of those who pass it successfully. Thus, gerontology is indispensable in dealing with the pandemic, which becomes a benchmark for validating the gerontological concepts and advances. The two basic alternative gerontological concepts imply that either aging results from the accumulation of stochastic damage, or is programmed. Based on these different grounds, several putative anti-aging drugs have been proposed as adjuvant means for COVID-19 prevention and/or treatment. These proposals are reviewed in the context of attributing the molecular targets of these drugs to the signaling pathways between the sensors of resource availability and the molecular mechanisms that allocate resources to storage, growth and reproduction or to self-maintenance and repair. Each of the drugs appears to reproduce only a part of the physiological responses to reduced resource availability caused by either dietary calories restriction or physical activity promotion, which are the most robust means of mitigating the adverse manifestations of aging. In the pathophysiological terms, the conditions of the endothelium, which worsen as age increases and may be significantly improved by the physical activity, is a common limiting factor for the abilities to withstand both physical stresses and challenges imposed by COVID-19. However, the current anti-epidemic measures promote sedentary indoor lifestyles, at odds with the most efficient behavioral interventions known to decrease the vulnerability to both the severe forms of COVID-19 and the prevalent aging-associated diseases. To achieve a proper balance in public health approaches to COVID-19, gerontologists should be involved in crosstalk between virologists, therapists, epidemiologists, and policy makers. The present publication suggests a conceptual background for that.
    Keywords:  COVID-19; aging; anti-aging drugs; physiological balances; public health; signaling pathways; theories
    DOI:  https://doi.org/10.3389/fphys.2020.584248
  39. Hydrobiologia. 2021 ;848(2): 371-383
    Ebm N, Guo F, Brett MT, Bunn SE, Kainz MJ.
      The River Continuum Concept implies that consumers in headwater streams have greater dietary access to terrestrial basal resources, but recent studies have highlighted the dietary importance of high-quality algae. Algae provide consumers with physiologically important omega-3 (n-3) polyunsaturated fatty acids (PUFA), particularly eicosapentaenoic acid (EPA). However, terrestrial plants and most benthic stream algae lack the long-chain (LC) n-3 PUFA docosahexaenoic acid (DHA, 22:6n-3), which is essential for neural development in fish and other vertebrates. We sampled subalpine streams to investigate how the PUFA composition of neural (brain and eyes), muscle, and liver tissues of freshwater fish is related to their potential diets (macroinvertebrates, epilithon, fresh and conditioned terrestrial leaves). The PUFA composition of consumers was more similar to epilithon than to terrestrial leaves. Storage lipids of eyes most closely resembled dietary PUFA (aquatic invertebrates and algae). However, DHA and arachidonic acid (ARA, 20:4n-6) were not directly available in the diet but abundant in organs. This implies that algal PUFA were selectively retained or were produced internally via enzymatic PUFA conversion by aquatic consumers. This field study demonstrates the nutritional importance of algal PUFA for neural organs in aquatic consumers of headwater regions.
    Keywords:  Docosahexaenoic acid; Fish brain; Fish eyes; Food quality; Headwaters; Stream food webs
    DOI:  https://doi.org/10.1007/s10750-020-04445-1