bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒01‒17
fifty-nine papers selected by
Ayesh Seneviratne
University of Toronto

  1. Cell. 2021 Jan 07. pii: S0092-8674(20)31750-5. [Epub ahead of print]
    Chakravarti D, LaBella KA, DePinho RA.
      The escalating social and economic burden of an aging world population has placed aging research at center stage. The hallmarks of aging comprise diverse molecular mechanisms and cellular systems that are interrelated and act in concert to drive the aging process. Here, through the lens of telomere biology, we examine how telomere dysfunction may amplify or drive molecular biological processes underlying each hallmark of aging and contribute to development of age-related diseases such as neurodegeneration and cancer. The intimate link of telomeres to aging hallmarks informs preventive and therapeutic interventions designed to attenuate aging itself and reduce the incidence of age-associated diseases.
  2. Trends Cancer. 2021 Jan 11. pii: S2405-8033(20)30337-X. [Epub ahead of print]
    Panigrahi G, Ambs S.
      Comorbid chronic diseases affect cancer patients with an increasing frequency as populations get older. They negatively and disproportionately impact underserved populations and influence cancer diagnosis, tumor biology and metastasis, and choice of treatment. Many comorbidities are associated with a delayed cancer diagnosis. Although the relationship between comorbidities and cancer risk and survivorship has been studied extensively, we still lack knowledge on how they affect tumor biology and the metastatic process. Here, we will discuss our current understanding of mechanisms linking comorbidities to an adverse tumor biology and lethality and introduce thoughts of how we can close existing gaps in this knowledge. We argue that research into comorbidity-induced alterations in cancer metastasis, immunity, and metabolism should be prioritized.
    Keywords:  cancer; comorbidity; diabetes; health disparity; immunity; metabolism; metastasis; obesity; survival
  3. Cancer Lett. 2021 Jan 11. pii: S0304-3835(20)30680-7. [Epub ahead of print]
    Paredes F, Williams HC, San Martin A.
      The ability of tumor cells to adapt to changes in oxygen tension is essential for tumor development. Low oxygen concentration influences cellular metabolism and, thus, affects proliferation, migration, and invasion. A focal point of the cell's adaptation to hypoxia is the transcription factor HIF1α (hypoxia-inducible factor 1 alpha), which affects the expression of specific gene networks involved in cellular energetics and metabolism. This review illustrates the mechanisms by which HIF1α-induced metabolic adaptation promotes angiogenesis, participates in the escape from immune recognition, and increases cancer cell antioxidant capacity. In addition to hypoxia, metabolic inhibition of 2-oxoglutarate-dependent dioxygenases regulates HIF1α stability and transcriptional activity. This phenomenon, known as pseudohypoxia, is frequently used by cancer cells to promote glycolytic metabolism to support biomass synthesis for cell growth and proliferation. In this review, we highlight the role of the most important metabolic intermediaries that are at the center of cancer's biology, and in particular, the participation of these metabolites in HIF1α retrograde signaling during the establishment of pseudohypoxia. Finally, we will discuss how these changes affect both the development of cancers and their resistance to treatment.
    Keywords:  Hypoxia; Metabolites; Pseudo-hypoxia; TCA
  4. Antioxidants (Basel). 2021 Jan 09. pii: E81. [Epub ahead of print]10(1):
    Lee J, Noh S, Lim S, Kim B.
      Type 2 diabetes mellitus (T2DM) is one of the largest public health problems worldwide. Insulin resistance-related metabolic dysfunction and chronic hyperglycemia result in devastating complications and poor prognosis. Even though there are many conventional drugs such as metformin (MET), Thiazolidinediones (TZDs), sulfonylureas (SUF), dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon like peptide 1 (GLP-1) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, side effects still exist. As numerous plant extracts with antidiabetic effects have been widely reported, they have the potential to be a great therapeutic agent for type 2 diabetes with less side effects. In this study, sixty-five recent studies regarding plant extracts that alleviate type 2 diabetes were reviewed. Plant extracts regulated blood glucose through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. The anti-inflammatory and antioxidant properties of plant extracts suppressed c-Jun amino terminal kinase (JNK) and nuclear factor kappa B (NF-κB) pathways, which induce insulin resistance. Lipogenesis and fatty acid oxidation, which are also associated with insulin resistance, are regulated by AMP-activated protein kinase (AMPK) activation. This review focuses on discovering plant extracts that alleviate type 2 diabetes and exploring its therapeutic mechanisms.
    Keywords:  antioxidant; diabetes mellitus; glucose transport; inflammation; lipid metabolism; plant extracts
  5. Mol Oncol. 2021 Jan 14.
    Labib M, Kelley SO.
      Analysis of circulating tumor cells (CTCs) collected from patient's blood offers a broad range of opportunities in the field of precision oncology. With new advances in profiling technology, it is now possible to demonstrate an association between the molecular profiles of CTCs and tumor response to therapy. In this Review, we discuss mechanisms of tumor resistance to therapy and their link to phenotypic and genotypic properties of CTCs. We summarize key technologies used to isolate and analyze CTCs and discuss recent clinical studies that examined CTCs for genomic and proteomic predictors of responsiveness to therapy. We also point out current limitations that still hamper the implementation of CTCs into clinical practice. We finally reflect on how these shortcomings can be addressed with the likely contribution of multiparametric approaches and advanced data analytics.
    Keywords:  CTC enrichment; drug selection; microfluidics; molecular profiling; precision oncology; tumor resistance
  6. Metabolites. 2021 Jan 08. pii: E41. [Epub ahead of print]11(1):
    Rangholia N, Leisner TM, Holly SP.
      The primacy of lipids as essential components of cellular membranes is conserved across taxonomic domains. In addition to this crucial role as a semi-permeable barrier, lipids are also increasingly recognized as important signaling molecules with diverse functional mechanisms ranging from cell surface receptor binding to the intracellular regulation of enzymatic cascades. In this review, we focus on ether lipids, an ancient family of lipids having ether-linked structures that chemically differ from their more prevalent acyl relatives. In particular, we examine ether lipid biosynthesis in the peroxisome of mammalian cells, the roles of selected glycerolipids and glycerophospholipids in signal transduction in both prokaryotes and eukaryotes, and finally, the potential therapeutic contributions of synthetic ether lipids to the treatment of cancer.
    Keywords:  alkylglycerol; apoptosis; cancer; ether lipid; glycerolipid; glycerophospholipid; platelet; signal transduction; signaling
  7. Science. 2021 01 15. 371(6526): 255-260
    Li J, Halitschke R, Li D, Paetz C, Su H, Heiling S, Xu S, Baldwin IT.
      Many plant specialized metabolites function in herbivore defense, and abrogating particular steps in their biosynthetic pathways frequently causes autotoxicity. However, the molecular mechanisms underlying their defense and autotoxicity remain unclear. Here, we show that silencing two cytochrome P450s involved in diterpene biosynthesis in the wild tobacco Nicotiana attenuata causes severe autotoxicity symptoms that result from the inhibition of sphingolipid biosynthesis by noncontrolled hydroxylated diterpene derivatives. Moreover, the diterpenes' defensive function is achieved by inhibiting herbivore sphingolipid biosynthesis through postingestive backbone hydroxylation products. Thus, by regulating metabolic modifications, tobacco plants avoid autotoxicity and gain herbivore defense. The postdigestive duet that occurs between plants and their insect herbivores can reflect the plant's solutions to the "toxic waste dump" problem of using potent chemical defenses.
  8. Int J Mol Sci. 2021 Jan 09. pii: E604. [Epub ahead of print]22(2):
    Roosterman D, Cottrell GS.
      In 1937, Sir H. A Krebs first published the Citric Acid Cycle, a unidirectional cycle with carboxylic acids. The original concept of the Citric Acid Cycle from Krebs' 1953 Nobel Prize lecture illustrates the unidirectional degradation of lactic acid to water, carbon dioxide and hydrogen. Here, we add the heart lactate dehydrogenase•proton-linked monocarboxylate transporter 1 complex, connecting the original Citric Acid Cycle to the flow of energy and material. The heart lactate dehydrogenase•proton-linked monocarboxylate transporter 1 complex catalyses the first reaction of the Citric Acid Cycle, the oxidation of lactate to pyruvate, and thus secures the provision of pyruvic acid. In addition, we modify Krebs' original concept by feeding the cycle with oxaloacetic acid. Our concept enables the integration of anabolic processes and allows adaption of the organism to recover ATP faster.
    Keywords:  Citric Acid Cycle; exercise; malic acid; memory formation; oxidative phosphorylation; succinic acid
  9. Obes Rev. 2021 Jan 11.
    Hariharan R, Mousa A, de Courten B.
      The rising incidence of obesity and type 2 diabetes is contributing to the escalating burden of disease globally. These metabolic disorders are closely linked with diet and in particular with carbohydrate consumption; hence, it is important to understand the underlying mechanisms that influence carbohydrate metabolism. Amylase, the enzyme responsible for the digestion of starch, is coded by the genes AMY1A, AMY1B, and AMY1C (salivary amylase) and AMY2A and AMY2B (pancreatic amylase). Previous studies demonstrate wide variations in AMY1A copy numbers, which can be attributed to several genetic, nutritional, and geographical diversities seen in populations globally. Current literature suggests that AMY1A copy number variations are important in obesity and other cardiometabolic disorders through their effects on glucose and lipid homeostasis, inflammatory markers, and the gut microbiome. This review synthesizes the available evidence to improve understanding of the role of AMY1A in obesity and related cardiometabolic risk factors and disorders including insulin resistance and type 2 diabetes, cardiovascular risk and inflammation, and the gut microbiome.
    Keywords:  AMY1A; amylase; blood pressure; cardiovascular disease; cardiovascular risk factors; gut microbiome; inflammation; lipids; obesity; type 2 diabetes
  10. Obes Med. 2021 Jan 06. 100312
    Pang J, Liu M, Ling W, Jin T.
      COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a pandemic since WHO made the statement on March 11, 2020. The infection is causing a high mortality in old people, especially those with obesity, type 2 diabetes (T2D) or cardiovascular diseases (CVD). Extra cautions are needed in the treatment of those patients. The CVD drugs ACEIs and ARBs, as well as the T2D drugs GLP-1R agonists, were shown to activate angiotensin-converting enzyme 2 (ACE2) expression in experimental animals. Elevated ACE2 expression may accelerate virus entrance into the host cells during the infection for its replication. However, expression of the soluble ACE2, may neutralize the virus to limit the infection and replication. Given that obese, diabetes and CVD patients often take those medicines in the treatment and prevention of blood pressure and glucose elevation, it remains to be determined whether those medicines represent friend or foe in the treatment of COVID-19. We suggest that retrospective studies should be conducted to determine the exact impact of those medicines in obese, diabetic, or CVD patients who had COVID-19. Results obtained will provide guidance whether those drugs can be utilized in COVID-19 patients with obesity, diabetic, or CVD.
    Keywords:  ACE2; ACEIs; ARBs; COVID-19; GLP-1; GLP-1R; Retrospective studies; sACE2
  11. Cancer. 2021 Jan 15.
    Abou Dalle I, Kantarjian HM, Ravandi F, Daver N, Wang X, Jabbour E, Estrov Z, DiNardo CD, Pemmaraju N, Ferrajoli A, Jain N, Wang SA, Jammal N, Borthakur G, Naqvi K, Pelletier S, Pierce S, Andreeff M, Garcia-Manero G, Cortes JE, Kadia TM.
      BACKGROUND: New drug combinations have led to significant improvements in remission rates for patients with acute myeloid leukemia (AML). However, many patients with high-risk AML who respond to their initial treatment and are not candidates for allogeneic stem cell transplantation (ASCT) will eventually relapse with poor outcomes.METHODS: In this phase 2 trial, the efficacy of lenalidomide maintenance was evaluated in patients with high-risk AML who had achieved their first or second remission after induction chemotherapy and at least 1 consolidation cycle and who were not candidates for immediate ASCT. Lenalidomide was given orally at 10 to 20 mg daily on days 1 to 28 of a 28-day cycle for up to 24 cycles.
    RESULTS: A total of 28 patients were enrolled in this study with a median age of 61 years (range, 24-87 years). The median number of cycles was 8 (range, 1-24 cycles). Ten patients (36%) completed 24 months of maintenance treatment. With a median follow-up of 22.5 months (range, 2.6-55 months), 12 patients (43%) relapsed after a median of 3 months (range, 0.7-23 months). The median duration of remission for all patients was 18.7 months (range, 0.7-55.1 months). The 2-year overall survival and relapse-free survival rates from the time of enrollment were 63% and 50%, respectively. Overall, lenalidomide was well tolerated; serious adverse events of grade 3 or 4, including rash (n = 5), thrombocytopenia (n = 4), neutropenia (n = 4), and fatigue (n = 2), were observed in 13 patients (46%).
    CONCLUSIONS: Lenalidomide is a safe and feasible maintenance strategy in patients with high-risk AML who are not candidates for ASCT, and it has beneficial effects for patients with negative measurable residual disease.
    Keywords:  acute myeloid leukemia (AML); immunomodulation; lenalidomide; maintenance
  12. Anat Rec (Hoboken). 2021 Jan 11.
    Smith OAM, Duncan C, Pears N, Profico A, O'Higgins P.
      BACKGROUND: Aging of the head and especially the face have been studied intensively, yet questions remain about the timing and rates of aging throughout adulthood and about the extent to which aging differs between men and women. Here we address these issues by developing statistical models of craniofacial aging to describe and compare aging through the life course in both sexes.METHODS: We selected cranial surface meshes from 254 females and 252 males, aged from 20 to 90 years from the Headspace project, Liverpool, UK. 16 anatomical landmarks and 59 semilandmarks on curves and surfaces were used to parameterise these. Modes and degrees of aging throughout adulthood were assessed and compared among sexes using Procrustes based geometric morphometric methods.
    RESULTS: Regression analyses of form through the whole age range indicate that age accounts for a small proportion of total variance in both sexes, but form is significantly related to age and males and females age in significantly different ways. Further analyses indicate that aging differs in character, timing and rates in both sexes between early and later phases of adulthood. Sexual differences in aging are evident in early and later phases of adulthood.
    CONCLUSIONS: The study adds to knowledge of the aging of adult craniofacial form and sexual dimorphism. It is based on a local population and so the findings are directly applicable to that population. Further studies are needed to assess generalisability and to provide better data on population differences to facilitate clinical assessment and treatment planning. This article is protected by copyright. All rights reserved.
    Keywords:  Facial aging; morphometrics; sexual differences; surface scanning
  13. JAMA Oncol. 2021 Jan 14.
    Wang L, Paller CJ, Hong H, De Felice A, Alexander GC, Brawley O.
      Importance: Multiple systemic treatments are available for metastatic castration-sensitive prostate cancer (mCSPC), with unclear comparative effectiveness and safety and widely varied costs.Objective: To compare the effectiveness and safety determined in randomized clinical trials of systemic treatments for mCSPC.
    Data Sources: Bibliographic databases (MEDLINE, Embase, and Cochrane Central), regulatory documents (US Food and Drug Administration and European Medicines Agency), and trial registries ( and European Union clinical trials register) were searched from inception through November 5, 2019.
    Study Selection, Data Extraction, and Synthesis: Eligible studies were randomized clinical trials evaluating the addition of docetaxel, abiraterone acetate, apalutamide, or enzalutamide to androgen-deprivation therapy (ADT) for treatment of mCSPC. Two investigators independently performed screening. Discrepancies were resolved through consensus. A Cochrane risk-of-bias tool was used to assess trial quality. Relative effects of competing treatments were assessed by bayesian network meta-analysis and survival models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used.
    Main Outcomes and Measures: Overall survival, radiographic progression-free survival, and serious adverse events (SAEs).
    Results: Seven trials with 7287 patients comparing 6 treatments (abiraterone acetate, apalutamide, docetaxel, enzalutamide, standard nonsteroidal antiandrogen, and placebo/no treatment) were identified. Ordered from the most to the least effective determined by results of clinical trials, treatments associated with improved overall survival when added to ADT included abiraterone acetate (hazard ratio [HR], 0.61; 95% credible interval [CI], 0.54-0.70), apalutamide (HR, 0.67; 95% CI, 0.51-0.89), and docetaxel (HR, 0.79; 95% CI, 0.71-0.89); treatments associated with improved radiographic progression-free survival when added to ADT included enzalutamide (HR, 0.39; 95% CI, 0.30-0.50), apalutamide (HR, 0.48; 95% CI, 0.39-0.60), abiraterone acetate (HR, 0.51; 95% CI, 0.45-0.58), and docetaxel (HR, 0.67; 95% CI 0.60-0.74). Docetaxel was associated with substantially increased SAEs (odds ratio, 23.72; 95% CI, 13.37-45.15), abiraterone acetate with slightly increased SAEs (odds ratio, 1.42; 95% CI, 1.10-1.83), and other treatments with no significant increase in SAEs. Risk of bias was noted for 4 trials with open-label design, 3 trials with missing data, and 2 trials with potential unprespecified analyses.
    Conclusions and Relevance: In this network meta-analysis, as add-on treatments to ADT, abiraterone acetate and apalutamide may provide the largest overall survival benefits with relatively low SAE risks. Although enzalutamide may improve radiographic progression-free survival to the greatest extent, longer follow-up is needed to examine the overall survival benefits associated with enzalutamide.
  14. Stem Cell Rev Rep. 2021 Jan 09.
    Kim A, Lee KG, Kwon Y, Lee KI, Yang HM, Habib O, Kim J, Kim ST, Kim SJ, Kim JS, Hwang DY.
      Human embryonic stem cells (hESCs) hold promise in regenerative medicine but allogeneic immune rejections caused by highly polymorphic human leukocyte antigens (HLAs) remain a barrier to their clinical applications. Here, we used a CRISPR/Cas9-mediated HLA-editing strategy to generate a variety of HLA homozygous-like hESC lines from pre-established hESC lines. We edited four pre-established HLA-heterozygous hESC lines and created a mini library of 14 HLA-edited hESC lines in which single HLA-A and HLA-B alleles and both HLA-DR alleles are disrupted. The HLA-edited hESC derivatives elicited both low T cell- and low NK cell-mediated immune responses. Our library would cover about 40% of the Asian-Pacific population. We estimate that HLA-editing of only 19 pre-established hESC lines would give rise to 46 different hESC lines to cover 90% of the Asian-Pacific population. This study offers an opportunity to generate an off-the-shelf HLA-compatible hESC bank, available for immune-compatible cell transplantation, without embryo destruction. Graphical Abstract.
    Keywords:  CRISPR/Cas9; HLA homozygous-like hESCs; HLA-editing; Human embryonic stem cells; Immune-compatible hESC banking
  15. Front Aging Neurosci. 2020 ;12 617071
    Thelen M, Brown-Borg HM.
      The aging process causes many changes to the brain and is a major risk factor for the development of neurodegenerative diseases such as Alzheimer's Disease (AD). Despite an already vast amount of research on AD, a greater understanding of the disease's pathology and therapeutic options are desperately needed. One important distinction that is also in need of further study is the ability to distinguish changes to the brain observed in early stages of AD vs. changes that occur with normal aging. Current FDA-approved therapeutic options for AD patients have proven to be ineffective and indicate the need for alternative therapies. Aging interventions including alterations in diet (such as caloric restriction, fasting, or methionine restriction) have been shown to be effective in mediating increased health and lifespan in mice and other model organisms. Because aging is the greatest risk factor for the development of neurodegenerative diseases, certain dietary interventions should be explored as they have the potential to act as a future treatment option for AD patients.
    Keywords:  Alzheimer's disease; aging; diet; interventions; lifespan
  16. Curr Dev Nutr. 2020 Nov;4(11): nzaa160
    Petersen KS, Bowen KJ, Tindall AM, Sullivan VK, Johnston EA, Fleming JA, Kris-Etherton PM.
      Lipids and lipoproteins are major targets for cardiovascular disease (CVD) prevention. Findings from a limited number of clinical trials suggest diet-induced atherogenic lipoprotein lowering can be altered in the presence of chronic low-grade inflammation or insulin resistance. This review summarizes results from randomized controlled trials that have examined diet-induced changes in lipids/lipoproteins by inflammatory or insulin sensitivity status. In addition, mechanisms to explain these clinical observations are explored. Post hoc analyses of data from a limited number of randomized controlled trials suggest attenuation of diet-induced lipid/lipoprotein lowering in individuals with inflammation and/or insulin resistance. These findings are supported by experimental studies showing that inflammatory stimuli and hyperinsulinemia alter genes involved in endogenous cholesterol synthesis and cholesterol uptake, reduce cholesterol efflux, and increase fatty acid biosynthesis. Further a priori defined research is required to better characterize how chronic low-grade inflammation and insulin resistance modulate lipid and lipoprotein responsiveness to guide CVD risk reduction in individuals presenting with these phenotypes.
    Keywords:  C-reactive protein (CRP); cholesterol; diet; inflammation; insulin resistance; proprotein convertase subtilisin/kexin type 9 (PCSK9)
  17. Semin Cancer Biol. 2021 Jan 09. pii: S1044-579X(21)00005-5. [Epub ahead of print]
    Varela-López A, Vera-Ramírez L, Giampieri F, Navarro-Hortal MD, Forbes-Hernández TY, Battino M, Quiles JL.
      Evidence demonstrates the importance of lipid metabolism and signaling in cancer cell biology. De novo lipogenesis is an important source of lipids for cancer cells, but exogenous lipid uptake remains essential for many cancer cells. Dietary lipids can modify lipids present in tumor microenvironment affecting cancer cell metabolism. Clinical trials have shown that diets rich in polyunsaturated fatty acids (PUFA) can negatively affect tumor growth. However, certain n-6 PUFAs can also contribute to cancer progression. Identifying the molecular mechanisms through which lipids affect cancer progression will provide an opportunity for focused dietary interventions that could translate into the development of personalized diets for cancer control. However, the effective mechanisms of action of PUFAs have not been fully clarified yet. Mitochondria controls ATP generation, redox homeostasis, metabolic signaling, apoptotic pathways and many aspects of autophagy, and it has been recognized to play a key role in cancer. The purpose of this review is to summarize the current evidence linking dietary lipids effects on mitochondrial aspects with consequences for cancer progression and the molecular mechanisms that underlie this association.
    Keywords:  Apoptosis; autophagy; bioenergetics; lipogenesis; redox biology
  18. Trends Cell Biol. 2021 Jan 06. pii: S0962-8924(20)30255-5. [Epub ahead of print]
    Sercel AJ, Carlson NM, Patananan AN, Teitell MA.
      Mammalian cells, with the exception of erythrocytes, harbor mitochondria, which are organelles that provide energy, intermediate metabolites, and additional activities to sustain cell viability, replication, and function. Mitochondria contain multiple copies of a circular genome called mitochondrial DNA (mtDNA), whose individual sequences are rarely identical (homoplasmy) because of inherited or sporadic mutations that result in multiple mtDNA genotypes (heteroplasmy). Here, we examine potential mechanisms for maintenance or shifts in heteroplasmy that occur in induced pluripotent stem cells (iPSCs) generated by cellular reprogramming, and further discuss manipulations that can alter heteroplasmy to impact stem and differentiated cell performance. This additional insight will assist in developing more robust iPSC-based models of disease and differentiated cell therapies.
    Keywords:  heteroplasmy; induced pluripotent stem cell; mitochondrial DNA; pluripotency; reprogramming
  19. Cell Death Discov. 2021 Jan 13. 7(1): 10
    Chaurasiya A, Garg S, Khanna A, Narayana C, Dwivedi VP, Joshi N, E Anam Z, Singh N, Singhal J, Kaushik S, Kaur Kahlon A, Srivastava P, Marothia M, Kumar M, Kumar S, Kumari G, Munjal A, Gupta S, Singh P, Pati S, Das G, Sagar R, Ranganathan A, Singh S.
      Hijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.
  20. Cells. 2021 Jan 08. pii: E100. [Epub ahead of print]10(1):
    Lan T, Chen L, Wei X.
      The relationship between chronic inflammation and neoplastic diseases is not fully understood. The inflammatory microenvironment of a tumor is an intricate network that consists of numerous types of cells, cytokines, enzymes and signaling pathways. Recent evidence shows that the crucial components of cancer-related inflammation are involved in a coordinated system to influence the development of cancer, which may shed light on the development of potential anticancer therapies. Since the last century, considerable effort has been devoted to developing gene therapies for life-threatening diseases. When it comes to modulating the inflammatory microenvironment for cancer therapy, inflammatory cytokines are the most efficient targets. In this manuscript, we provide a comprehensive review of the relationship between inflammation and cancer development, especially focusing on inflammatory cytokines. We also summarize the clinical trials for gene therapy targeting inflammatory cytokines for cancer treatment. Future perspectives concerned with new gene-editing technology and novel gene delivery systems are finally provided.
    Keywords:  cancer therapy; cytokine; gene therapy; inflammation; tumor microenvironment
  21. J Aging Soc Policy. 2021 Jan 11. 1-15
    Rozario PA, Pizzo M.
      Singapore now faces one of the fastest aging populations in the world, leading the country's political leaders to fear the implications of population aging for the country's economic viability. We analyzed National Day Rally speeches from 2011 to 2015 by Prime Minister Lee Hsien Loong to examine how policymakers conceptualized the challenges related to its aging population. Findings point to the government's manifest and latent emphasis on its economic viability when developing social policies to address the well-being of its aging population. Its approaches to welfare provision are informed by a neoliberalist agenda that requires its citizens to exercise personal responsibility and self-reliance, and to rely on their family and community for mutual assistance. Despite its highly interventionist approach, the government is clear about its residual role in the provision of safety nets. A neoliberalist reconceptualization of citizenship serves to restrict older citizen's claims to basic social assistance.
    Keywords:  Neoliberalism; Singapore; policymaking; successful aging
  22. Contemp Clin Trials. 2021 Jan 09. pii: S1551-7144(21)00006-9. [Epub ahead of print] 106270
    Liu X, Morris MC, Dhana K, Ventrelle J, Johnson K, Bishop L, Hollings CS, Boulin A, Laranjo N, Stubbs BJ, Reilly X, Carey VJ, Wang Y, Furtado JD, Marcovina SM, Tangney C, Aggarwal NT, Arfanakis K, Sacks FM, Barnes LL.
      Alzheimer's dementia (AD) is the sixth leading cause of death in the U.S., with an estimated $305 billion cost of care in 2020. Currently there are no cures or therapies to ameliorate the disease progression and symptoms. Growing evidence links a diet characterized by high antioxidant components with benefits to cognitive function, which is indicative of the preventative potential of dietary interventions. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study is a 3-year, multicenter, randomized controlled trial to test the effects of the MIND diet on cognitive function in 604 individuals at risk for AD. Men and women ages 65 to 84 years were recruited. Eligible participants were randomized to either the MIND diet with mild caloric restriction or their usual diet with mild caloric restriction. Cognitive assessments, medical history, blood pressure, anthropometric measurements, and blood and urine sample collections will be taken at baseline and follow-up visits. MRI scans will be completed on approximately half of the enrolled participants at the start and end of the study. Unique features of the MIND study include: 1) a dietary pattern, rather than single nutrient or food, tested in an at-risk population; 2) foods featured as key components of the MIND diet (i.e. extra-virgin olive oil, blueberries, and nuts) provided for participants; and 3) MRI scans of brain structure and volume that may provide potential mechanistic evidence on the effects of the diet. Results from the study will be crucial to the development of dietary guidelines for the prevention of AD.
    Keywords:  Aging; Cognition; MIND diet; Nutrition; Randomized controlled trial; Study design; Study protocols
  23. Int J Vitam Nutr Res. 2021 Jan 13. 1-18
    Islam MT, Quispe C, Martorell M, Docea AO, Salehi B, Calina D, Reiner Ž, Sharifi-Rad J.
       The novel coronavirus (SARS-CoV-2) causing COVID-19 disease pandemic has infected millions of people and caused more than thousands of deaths in many countries across the world. The number of infected cases is increasing day by day. Unfortunately, we do not have a vaccine and specific treatment for it. Along with the protective measures, respiratory and/or circulatory supports and some antiviral and retroviral drugs have been used against SARS-CoV-2, but there are no more extensive studies proving their efficacy. In this study, the latest publications in the field have been reviewed, focusing on the modulatory effects on the immunity of some natural antiviral dietary supplements, vitamins and minerals. Findings suggest that several dietary supplements, including black seeds, garlic, ginger, cranberry, orange, omega-3 and -6 polyunsaturated fatty acids, vitamins (e.g., A, B vitamins, C, D, E), and minerals (e.g., Cu, Fe, Mg, Mn, Na, Se, Zn) have anti-viral effects. Many of them act against various species of respiratory viruses, including severe acute respiratory syndrome-related coronaviruses. Therefore, dietary supplements, including vitamins and minerals, probiotics as well as individual nutritional behaviour can be used as adjuvant therapy together with antiviral medicines in the management of COVID-19 disease.
    Keywords:  coronavirus; dietary supplements; immune system; micronutrients; minerals; pandemic COVID-19; respiratory viruses; vitamins
  24. Nat Commun. 2021 Jan 15. 12(1): 377
    Ch R, Rey G, Ray S, Jha PK, Driscoll PC, Dos Santos MS, Malik DM, Lach R, Weljie AM, MacRae JI, Valekunja UK, Reddy AB.
      Circadian clocks coordinate mammalian behavior and physiology enabling organisms to anticipate 24-hour cycles. Transcription-translation feedback loops are thought to drive these clocks in most of mammalian cells. However, red blood cells (RBCs), which do not contain a nucleus, and cannot perform transcription or translation, nonetheless exhibit circadian redox rhythms. Here we show human RBCs display circadian regulation of glucose metabolism, which is required to sustain daily redox oscillations. We found daily rhythms of metabolite levels and flux through glycolysis and the pentose phosphate pathway (PPP). We show that inhibition of critical enzymes in either pathway abolished 24-hour rhythms in metabolic flux and redox oscillations, and determined that metabolic oscillations are necessary for redox rhythmicity. Furthermore, metabolic flux rhythms also occur in nucleated cells, and persist when the core transcriptional circadian clockwork is absent in Bmal1 knockouts. Thus, we propose that rhythmic glucose metabolism is an integral process in circadian rhythms.
  25. Nutr Neurosci. 2021 Jan 15. 1-10
    Zupo R, Griseta C, Battista P, Donghia R, Guerra V, Castellana F, Lampignano L, Bortone I, Lozupone M, Giannelli G, De Pergola G, Boeing H, Sardone R, Panza F.
      OBJECTIVES: Consistency among population-based studies investigating the relationship between diet and cognition in older inhabitants in the Mediterranean area is poor. The present study investigated whether diet changes over 12 years were associated with cognitive function in older people in Southern-Italy.METHODS: From the 'Salus in Apulia Study', that includes the MICOL and GreatAGE Studies, 584 participants were selected, firstly enrolled in MICOL3 (M3) and later in the GreatAGE Study (MICOL4, M4). Foods and micronutrients intake were recorded in both studies, and global cognitive function in M4, assessed with the Mini Mental State Examination.
    RESULTS: Plant-based foods, particularly coffee and vegetables, as well as vitamin A sources, were inversely associated to age-related cognitive impairment. Alcohol consumption showed a detrimental role on cognition, while red meat appeared to be beneficial in the present study, although its role is traditionally considered harmful for cognitive function.
    DISCUSSION: Our study confirmed that a traditional Mediterranean dietary pattern based on agricultural products and low alcohol consumption may help to prevent/delay age-related cognitive impairment.
    Keywords:  Dementia; Italy; Mediterranean diet; Salus in Apulia Study‌; cognitive impairment; food intake; micronutrients; population study
  26. Haematologica. 2021 Jan 14.
    Amoah A, Keller A, Emini R, Hoenicka M, Liebold A, Vollmer A, Eiwen K, Soller K, Sakk V, Zheng Y, Florian MC, Geiger H.
      In this study, we characterize age-related phenotypes of human hematopoietic stem cells (HSCs). We report increased frequencies of HSC, HPC and lineage negative cells in the elderly but a decreased frequency of multi-lymphoid progenitors. Aged human HSCs further exhibited a delay in initiating division ex vivo though without changes in their division kinetics. The activity of the small RhoGTPase Cdc42 was elevated in aged human hematopoietic cells and we identified a positive correlation between Cdc42 activity and the frequency of HSCs upon aging. The frequency of human HSCs polar for polarity proteins was, similar to the mouse, decreased upon aging, while inhibition of Cdc42 activity via the specific pharmacological inhibitor of Cdc42 activity, CASIN, resulted in re-polarisation of aged human HSCs with respect to Cdc42. Elevated activity of Cdc42 in aged HSCs thus contributed to age-related changes in HSCs. Xeno-transplants, using NBSGW mice as recipients, showed elevated chimerism in recipients of aged compared to young HSCs. Aged HSCs treated with CASIN ex vivo displayed an engraftment profile similar to recipients of young HSCs. Taken together, our work reveals strong evidence for a role of elevated Cdc42 activity in driving aging of human HSCs, and similar to mice, this presents a likely possibility for attenuation of aging in human HSCs.
  27. Crit Rev Food Sci Nutr. 2021 Jan 11. 1-19
    Jiang Y, Sun-Waterhouse D, Chen Y, Li F, Li D.
      Cardiovascular diseases (CVDs) rank as the first leading cause of death globally. High dietary polyphenol (especially flavonoids) intake has strongly been associated with low incidence of the primary outcome, overall mortality, blood pressure, inflammatory biomarkers, onset of new-onset type 2 diabetes mellitus (T2DM), and obesity. Phytogenic flavonoids affect the physiological and pathological processes of CVDs by modulating various biochemical signaling pathways. Non-coding RNAs (ncRNAs) have attracted increasing attention as fundamental regulator of gene expression involved in CVDs. Among the different ncRNA subgroups, long ncRNAs (lncRNAs) have recently emerged as regulatory eukaryotic transcripts and therapeutic targets with important and diverse functions in health and diseases. lncRNAs may be associated with the initiation, development and progression of CVDs by modulating acute and chronic inflammation, adipogenesis and lipid metabolism, and cellular physiology. This review summarizes this research on the modulatory effects of lncRNAs and their roles in mediating cellular processes. The mechanisms of action of flavonoids underlying their therapeutic effects on CVDs are also discussed. Based on our review, flavonoids might facilitate a significant epigenetic modification as part (if not full) of their tissue-/cell-related biological effects. This finding may be attributed to their interaction with cellular signaling pathways involved in chronic diseases. Certain lncRNAs might be the target of specific flavonoids, and some critical signaling processes involved in the intervention of CVDs might mediate the therapeutic roles of flavonoids.
    Keywords:  Atherosclerosis; cardiovascular diseases; flavonoids; lncRNAs; noncoding RNAs
  28. Nat Med. 2021 Jan 11.
    Asnicar F, Berry SE, Valdes AM, Nguyen LH, Piccinno G, Drew DA, Leeming E, Gibson R, Le Roy C, Khatib HA, Francis L, Mazidi M, Mompeo O, Valles-Colomer M, Tett A, Beghini F, Dubois L, Bazzani D, Thomas AM, Mirzayi C, Khleborodova A, Oh S, Hine R, Bonnett C, Capdevila J, Danzanvilliers S, Giordano F, Geistlinger L, Waldron L, Davies R, Hadjigeorgiou G, Wolf J, Ordovás JM, Gardner C, Franks PW, Chan AT, Huttenhower C, Spector TD, Segata N.
      The gut microbiome is shaped by diet and influences host metabolism; however, these links are complex and can be unique to each individual. We performed deep metagenomic sequencing of 1,203 gut microbiomes from 1,098 individuals enrolled in the Personalised Responses to Dietary Composition Trial (PREDICT 1) study, whose detailed long-term diet information, as well as hundreds of fasting and same-meal postprandial cardiometabolic blood marker measurements were available. We found many significant associations between microbes and specific nutrients, foods, food groups and general dietary indices, which were driven especially by the presence and diversity of healthy and plant-based foods. Microbial biomarkers of obesity were reproducible across external publicly available cohorts and in agreement with circulating blood metabolites that are indicators of cardiovascular disease risk. While some microbes, such as Prevotella copri and Blastocystis spp., were indicators of favorable postprandial glucose metabolism, overall microbiome composition was predictive for a large panel of cardiometabolic blood markers including fasting and postprandial glycemic, lipemic and inflammatory indices. The panel of intestinal species associated with healthy dietary habits overlapped with those associated with favorable cardiometabolic and postprandial markers, indicating that our large-scale resource can potentially stratify the gut microbiome into generalizable health levels in individuals without clinically manifest disease.
  29. Aging Cell. 2021 Jan 14. e13304
    Heng D, Sheng X, Tian C, Li J, Liu L, Gou M, Liu L.
      Stem cell transplantation has been generally considered as promising therapeutics in preserving or recovering functions of lost, damaged, or aging tissues. Transplantation of primordial germ cells (PGCs) or oogonia stem cells (OSCs) can reconstitute ovarian functions that yet sustain for only short period of time, limiting potential application of stem cells in preservation of fertility and endocrine function. Here, we show that mTOR inhibition by INK128 extends the follicular and endocrine functions of the reconstituted ovaries in aging and premature aging mice following transplantation of PGCs/OSCs. Follicular development and endocrine functions of the reconstituted ovaries by transplanting PGCs into kidney capsule of the recipient mice were maintained by INK128 treatment for more than 12 weeks, in contrast to the controls for only about 4 weeks without receiving the mTOR inhibitors. Comparatively, rapamycin also can prolong the ovarian functions but for limited time. Furthermore, our data reveal that INK128 promotes mitochondrial function in addition to its known function in suppression of immune response and inflammation. Taken together, germline stem cell transplantation in combination with mTOR inhibition by INK128 improves and extends the reconstituted ovarian and endocrine functions in reproductive aging and premature aging mice.
    Keywords:  Hormone; INK128; aging; primordial germ cells; rapamycin; reconstituted ovary; stem cell transplantation
  30. Foods. 2021 Jan 12. pii: E146. [Epub ahead of print]10(1):
    Lee D, Lee HJ, Yoon JW, Kim M, Jo C.
      This study investigated the effects of different aging methods on the changes in the concentrations of aroma volatiles of beef. One half (n = 15) of the beef strip loins were dry-aged, and the other half were wet-aged, and both aging processes continued for 28 days. The aroma volatiles from dry- and wet-aged samples were analyzed at seven-day intervals (n = 3 for each aging period). As the aging period increased, dry-aged beef showed higher concentrations of volatile compounds than those in wet-aged beef (p < 0.05). Most changes in the concentrations of aroma volatiles of dry-aged beef were associated with propanal, 2-methylbutanal, 2-methylpropanal, 1-butanamine, trimethylamine, 2-methyl-2-propanethiol, and ethyl propanoate, which were mainly produced by lipid oxidation and/or microbial activity (e.g., proteolysis and lipolysis) during the dry aging period. Therefore, we suggest that the differences in aroma between dry- and wet-aged beef could result from increased lipid oxidation and microbial activity in dry-aged beef possibly owing to its ambient exposure to oxygen.
    Keywords:  aging periods; aroma volatiles; dry aging; wet aging
  31. J Clin Invest. 2021 Jan 14. pii: 131698. [Epub ahead of print]
    Fortin J, Bassi C, Ramachandran P, Li WY, Tian R, Zarrabi I, Hill G, Snow BE, Haight J, Tobin C, Hodgson K, Wakeham A, Stambolic V, Mak TW.
      In order to sustain proficient life-long hematopoiesis, hematopoietic stem cells (HSCs) must possess robust mechanisms to preserve their quiescence and genome integrity. DNA-damaging stress can perturb HSC homeostasis by affecting their survival, self-renewal and differentiation. Ablation of the kinase ATM, a master regulator of the DNA damage response, impairs HSC fitness. Paradoxically, we show here that loss of a single allele of Atm enhances HSC functionality in mice. To explain this observation, we explored a possible link between ATM and the tumor suppressor PTEN, which also regulates HSC function. We generated and analyzed a knock-in mouse line (PtenS398A/S398A), in which PTEN cannot be phosphorylated by ATM. Similar to Atm+/-, PtenS398A/S398A HSCs have enhanced hematopoietic reconstitution ability, accompanied by resistance to apoptosis induced by genotoxic stress. Single-cell transcriptomic analyses and functional assays revealed that dormant PtenS398A/S398A HSCs aberrantly tolerate elevated mitochondrial activity and the accumulation of reactive oxygen species, which are normally associated with HSC priming for self-renewal or differentiation. Our results unveil a molecular connection between ATM and PTEN, which couples the response to genotoxic stress and dormancy in HSC.
    Keywords:  DNA repair; Hematology; Hematopoietic stem cells; Stem cells
  32. Aging (Albany NY). 2021 Jan 10. 12
    Wu JW, Hu H, Li D, Ma LK.
      Myocardial ischemia-reperfusion injury (MIRI) results in increased myocardial infarct size and leads to poor clinical outcomes. Hypoxia-inducible factor 2-alpha (HIF2α) exerts myocardial protective effects during MIRI through as yet unclear mechanisms. Here, we show that knockdown of HIF2α with cardiotropic recombinant adeno-associated virus serotype 9 (rAAV9) in mouse hearts significantly increased the infarct sizes during myocardial ischemia/reperfusion (MI/R). In addition, HIF2α transcriptionally regulated the expression of interleukin 6 (IL-6) in cardiomyocytes to elicit cardioprotection. Likewise, IL-6 deficiency aggravated MIRI, while treatment with recombinant IL-6 had cardioprotective effects and rescued the mice with HIF2α knockdown. Furthermore, IL-6 treatment significantly activated the PI3K/Akt and STAT3 signaling pathways in the myocardium during MI/R, and the specific inhibitors wortmannin (specific phosphoinositide 3-kinase inhibitor) and Stattic (specific STAT3 inhibitor) substantially abolished HIF2α/IL-6-induced cardioprotection. These studies suggest that HIF2α transcription regulates the expression of IL-6 in cardiomyocytes and plays a protective role during MI/R.
    Keywords:  HIF2α; IL-6; myocardial ischemia-reperfusion injury
  33. Haematologica. 2021 Jan 14.
    Liu Y, Dahl M, Debnath S, Rothe M, Smith EM, Grahn THM, Warsi S, Chen J, Flygare J, Schambach A, Karlsson S.
      Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure disorder with pure red blood cell aplasia associated with physical malformations and a predisposition to cancer. Twenty-five percent of patients with DBA have mutations in a gene encoding ribosomal protein S19 (RPS19). Our previous proof-of-concept studies demonstrated that DBA phenotype could be successfully treated using lentiviral vectors in Rps19-deficient DBA mice. In our present study, we developed a clinically applicable single gene self-inactivating lentiviral vector, containing the human RPS19 cDNA driven by the human elongation factor 1α short promoter, that can be used for clinical gene therapy development for RPS19-deficient DBA. We examined the efficacy and safety of the vector in a Rps19-deficient DBA mouse model and in human primary RPS19-deficient CD34+ cord blood cells. We observed that transduced Rps19-deficient bone marrow cells could reconstitute mice longterm and rescue the bone marrow failure and severe anemia observed in Rps19-deficient mice, with a low risk of mutagenesis and a highly polyclonal insertion site pattern. More importantly, the vector can also rescue impaired erythroid differentiation in human primary RPS19-deficient CD34+ cord blood hematopoietic stem cells. Collectively, our results demonstrate the efficacy and safety of using a clinically applicable lentiviral vector for the successful treatment of Rps19-deficient DBA in a mouse model and in human primary CD34+ cord blood cells. These findings show that this vector can be used to develop clinical gene therapy for RPS19-deficient DBA patients.
  34. BMJ Open Diabetes Res Care. 2021 Jan;pii: e001840. [Epub ahead of print]9(1):
    MacDonald CS, Nielsen SM, Bjørner J, Johansen MY, Christensen R, Vaag A, Lieberman DE, Pedersen BK, Langberg H, Ried-Larsen M, Midtgaard J.
      INTRODUCTION: The effects of lifestyle interventions in persons with type 2 diabetes (T2D) on health-related quality of life (HRQoL) and subjective well-being are ambiguous, and no studies have explored the effect of exercise interventions that meet or exceed current recommended exercise levels. We investigated whether a 1-year intensive lifestyle intervention is superior in improving HRQoL compared with standard care in T2D persons.RESEARCH DESIGN AND METHODS: We performed secondary analyses of a previously conducted randomized controlled trial (April 2015 to August 2016). Persons with non-insulin-dependent T2D (duration ≤10 years) were randomized to 1-year supervised exercise and individualized dietary counseling (ie, 'U-TURN'), or standard care. The primary HRQoL outcome was change in the 36-item Short Form Health Survey (SF-36) physical component score (PCS) from baseline to 12 months of follow-up, and a key secondary outcome was changes in the SF-36 mental component score (MCS).
    RESULTS: We included 98 participants (U-TURN group=64, standard care group=34) with a mean age of 54.6 years (SD 8.9). Between-group analyses at 12-month follow-up showed SF-36 PCS change of 0.8 (95% CI -0.7 to 2.3) in the U-TURN group and deterioration of 2.4 (95% CI -4.6 to -0.1) in the standard care group (difference of 3.2, 95% CI 0.5 to 5.9, p=0.02) while no changes were detected in SF-36 MCS. At 12 months, 19 participants (30%) in the U-TURN group and 6 participants (18%) in the standard care group achieved clinically significant improvement in SF-36 PCS score (adjusted risk ratio 2.6, 95% CI 1.0 to 4.5 corresponding to number needed to treat of 4, 95% CI 1.6 to infinite).
    CONCLUSION: In persons with T2D diagnosed for less than 10 years, intensive lifestyle intervention improved the physical component of HRQoL, but not the mental component of HRQoL after 1 year, compared with standard care.
    Keywords:  diabetes mellitus; exercise; life style; quality of life; type 2
  35. Cancers (Basel). 2021 Jan 07. pii: E188. [Epub ahead of print]13(2):
    Brockmueller A, Sameri S, Liskova A, Zhai K, Varghese E, Samuel SM, Büsselberg D, Kubatka P, Shakibaei M.
      Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor cells are known as the Warburg effect. Adaptive metabolic alterations in cancer cells can be attributed to mutations in key metabolic enzymes and transcription factors. The features of the Warburg phenotype may serve as promising markers for the early detection and treatment of tumors. Besides, the glycolytic process of tumors is reversible and could represent a therapeutic target. So-called mono-target therapies are often unsafe and ineffective, and have a high prevalence of recurrence. Their success is hindered by the ability of tumor cells to simultaneously develop multiple chemoresistance pathways. Therefore, agents that modify several cellular targets, such as energy restriction to target tumor cells specifically, have therapeutic potential. Resveratrol, a natural active polyphenol found in grapes and red wine and used in many traditional medicines, is known for its ability to target multiple components of signaling pathways in tumors, leading to the suppression of cell proliferation, activation of apoptosis, and regression in tumor growth. Here, we describe current knowledge on the various mechanisms by which resveratrol modulates glucose metabolism, its potential as an imitator of caloric restriction, and its therapeutic capacity in tumors.
    Keywords:  anti-tumor action; combinatorial therapy; resveratrol; tumor glucose metabolism; warburg phenomenon
  36. Ageing Res Rev. 2021 Jan 09. pii: S1568-1637(21)00003-9. [Epub ahead of print] 101256
    Santin Y, Resta J, Parini A, Mialet-Perez J.
      Population aging is one of the most significant social changes of the twenty-first century. This increase in longevity is associated with a higher prevalence of chronic diseases, further rising healthcare costs. At the molecular level, cellular senescence has been identified as a major process in age-associated diseases, as accumulation of senescent cells with aging leads to progressive organ dysfunction. Of particular importance, mitochondrial oxidative stress and consequent organelle alterations have been pointed out as key players in the aging process, by both inducing and maintaining cellular senescence. Monoamine oxidases (MAOs), a class of enzymes that catalyze the degradation of catecholamines and biogenic amines, have been increasingly recognized as major producers of mitochondrial ROS. Although well-known in the brain, evidence showing that MAOs are also expressed in a variety of peripheral organs stimulated a growing interest in the extra-cerebral roles of these enzymes. Besides, the fact that MAO-A and/or MAO-B are frequently upregulated in aged or dysfunctional organs has uncovered new perspectives on their roles in pathological aging. In this review, we will give an overview of the major results on the regulation and function of MAOs in aging and age-related diseases, paying a special attention to the mechanisms linked to the increased degradation of MAO substrates or related to MAO-dependent ROS formation.
    Keywords:  ROS; age-associated chronic diseases; autophagy; mitochondria; monoamine oxidases; senescence
  37. Blood Cancer Discov. 2021 Jan;2(1): 70-91
    Flümann R, Rehkämper T, Nieper P, Pfeiffer P, Holzem A, Klein S, Bhatia S, Kochanek M, Kisis I, Pelzer BW, Ahlert H, Hauer J, da Palma Guerreiro A, Ryan JA, Reimann M, Riabinska A, Wiederstein J, Krüger M, Deckert M, Altmüller J, Klatt AR, Frenzel LP, Pasqualucci L, Béguelin W, Melnick AM, Sander S, Montesinos-Rongen M, Brunn A, Lohneis P, Büttner R, Kashkar H, Borkhardt A, Letai A, Persigehl T, Peifer M, Schmitt CA, Reinhardt HC, Knittel G.
      Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in MYD88, as well as BCL2 copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a Myd88 and Bcl2-driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased PD-L1 expression, compared to GCB-DLBCL. In vivo experiments in our ABC-DLBCL model showed that combined venetoclax and RMP1-14 significantly increased the overall survival of lymphoma bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring MYD88 and BCL2 aberrations.
  38. Nat Med. 2021 01;27(1): 34-44
    Ganesh K, Massagué J.
      Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.
  39. J Am Coll Cardiol. 2021 Jan 19. pii: S0735-1097(20)37868-2. [Epub ahead of print]77(2): 189-204
    Pietri P, Stefanadis C.
      Cardiovascular aging and longevity are interrelated through many pathophysiological mechanisms. Many factors that promote atherosclerotic cardiovascular disease are also implicated in the aging process and vice versa. Indeed, cardiometabolic disorders such as hyperglycemia, insulin resistance, dyslipidemia, and arterial hypertension share common pathophysiological mechanisms with aging and longevity. Moreover, genetic modulators of longevity have a significant impact on cardiovascular aging. The current knowledge of genetic, molecular, and biochemical pathways of aging may serve as a substrate to introduce interventions that might delay cardiovascular aging, thus approaching the goal of longevity. In the present review, the authors describe pathophysiological links between cardiovascular aging and longevity and translate these mechanisms into clinical data by reporting genetic, dietary, and environmental characteristics from long-living populations.
    Keywords:  aging; cardiovascular disease; longevity
  40. Cell Mol Life Sci. 2021 Jan 15.
    Tabassum R, Ripatti S.
      Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide leading to 31% of all global deaths. Early prediction and prevention could greatly reduce the enormous socio-economic burden posed by CVDs. Plasma lipids have been at the center stage of the prediction and prevention strategies for CVDs that have mostly relied on traditional lipids (total cholesterol, total triglycerides, HDL-C and LDL-C). The tremendous advancement in the field of lipidomics in last two decades has facilitated the research efforts to unravel the metabolic dysregulation in CVDs and their genetic determinants, enabling the understanding of pathophysiological mechanisms and identification of predictive biomarkers, beyond traditional lipids. This review presents an overview of the application of lipidomics in epidemiological and genetic studies and their contributions to the current understanding of the field. We review findings of these studies and discuss examples that demonstrates the potential of lipidomics in revealing new biology not captured by traditional lipids and lipoprotein measurements. The promising findings from these studies have raised new opportunities in the fields of personalized and predictive medicine for CVDs. The review further discusses prospects of integrating emerging genomics tools with the high-dimensional lipidome to move forward from the statistical associations towards biological understanding, therapeutic target development and risk prediction. We believe that integrating genomics with lipidome holds a great potential but further advancements in statistical and computational tools are needed to handle the high-dimensional and correlated lipidome.
    Keywords:  Biomarkers; Disease risk; Genome-wide association studies; Lipid species; Pathophysiology
  41. Stem Cells Dev. 2021 Jan 15.
    Döring M, Cabanillas Stanchi KM, Lenglinger K, Treuner C, Gieseke F, Erbacher A, Mezger M, Vaegler M, Schlegel PG, Greil J, Bettoni da Cunha Riehm C, Faul C, Schumm M, Lang P, Handgretinger R, Müller I.
      Steroid-refractory graft-versus-host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). Alternative treatment options are often insufficient. Several studies have proven the efficacy of mesenchymal stromal cells (MSC) in the treatment of therapy-refractory acute GvHD in adult and pediatric patients. Long-term data in pediatric patients is scarce. In this retrospective analysis, a total of 25 patients with a median age of 10.6 years (range 0.6-22.1 years) who received bone marrow-derived MSC after alloHSCT for the treatment of steroid-refractory °III and °IV GvHD, were analyzed. The median observation period of the surviving patients was 9.3 years (1.3-12.7 years) after HSCT. Among the 25 patients, 10 (40.0%) died (relapse (n=3), multi-organ failure (n=6), cardiorespiratory failure (n=1)) at median 0.5 years (0.2-2.3 years) after HSCT. Partial response and complete remission (PR, CR) of the GvHD was achieved in 76.0% and 24.0% of the patients, respectively. Transplant-related mortality was 0% in the patients who achieved CR after MSC treatment, and 26.3% for those with PR. A median improvement by one intestinal or liver GvHD stage (range 1-4) could be achieved after MSC application. No potentially MSC-related long-term adverse effects, e. g. secondary malignancy, were identified. In conclusion, the intravenous application of allogeneic MSC was safe and proved effective for the treatment of steroid-refractory GvHD. However, larger, prospective and randomized trials are needed to evaluate these findings.
  42. Cells. 2021 Jan 10. pii: E117. [Epub ahead of print]10(1):
    Minciacchi VR, Kumar R, Krause DS.
      Chronic myeloid leukemia (CML) has been a "model disease" with a long history. Beginning with the first discovery of leukemia and the description of the Philadelphia Chromosome and ending with the current goal of achieving treatment-free remission after targeted therapies, we describe here the journey of CML, focusing on molecular pathways relating to signaling, metabolism and the bone marrow microenvironment. We highlight current strategies for combination therapies aimed at eradicating the CML stem cell; hopefully the final destination of this long voyage.
    Keywords:  bone marrow microenvironment; chronic myeloid leukemia; combination therapies; history; metabolism; targeted therapy
  43. Am J Med. 2021 Jan 11. pii: S0002-9343(21)00009-7. [Epub ahead of print]
    Krittanawong C, Isath A, Hahn J, Wang Z, Narasimhan B, Kaplin SL, Jneid H, Virani SS, Tang WHW.
      Fish consumption and cardiovascular disease events have shown inconsistent results. We performed a systematic review of peer-reviewed publications from an extensive query of Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from database inception to September 2020 for observational studies that reported the association between fish consumption and cardiovascular disease events. We identified and reviewed 24 studies related to fish consumption and the effect on cardiovascular outcomes. The study population included a total of 714,526 individuals and multiple cohorts from several countries. We found that fried fish consumption is probably associated with a reduced risk of overall cardiovascular disease events and myocardial infarction risk. In contrast, fried fish consumption is probably associated with an increased risk of overall cardiovascular disease events and myocardial infarction risk. No studies to date have shown any significant association between fish consumption and stroke. Our analysis suggests that fish consumption may reduce cardiovascular disease events, but fried fish consumption was associated with an increased risk of cardiovascular events.
    Keywords:  Acute myocardial infarction; Cardiovascular disease; Fish consumption; Stroke; Systematic review
  44. Syst Rev. 2021 Jan 09. 10(1): 18
    Pillay J, Riva JJ, Tessier LA, Colquhoun H, Lang E, Moore AE, Thombs BD, Wilson BJ, Tzenov A, Donnelly C, Émond M, Holroyd-Leduc J, Milligan J, Keto-Lambert D, Rahman S, Vandermeer B, Tricco AC, Straus SE, Thomas SM, Mitchelmore BR, Rolland-Harris E, Hartling L.
      BACKGROUND: An estimated 20-30% of community-dwelling Canadian adults aged 65 years or older experience one or more falls each year. Fall-related injuries are a leading cause of hospitalization and can lead to functional independence. Many fall prevention interventions, often based on modifiable risk factors, have been studied. Apart from the magnitude of the benefits and harms from different interventions, the preferences of older adults for different interventions as well as the relative importance they place on the different potential outcomes may influence recommendations by guideline panels. These reviews on benefits and harms of interventions, and on patient values and preferences, will inform the Canadian Task Force on Preventive Health Care to develop recommendations on fall prevention for primary care providers.METHODS: To review the benefits and harms of fall prevention interventions, we will update a previous systematic review of randomized controlled trials with adaptations to modify the classification of interventions and narrow the scope to community-dwelling older adults and primary-care relevant interventions. Four databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Ageline), reference lists, trial registries, and relevant websites will be searched, using limits for randomized trials and date (2016 onwards). We will classify interventions according to the Prevention of Falls Network Europe (ProFANE) Group's taxonomy. Outcomes include fallers, falls, injurious falls, fractures, hip fractures, institutionalization, health-related quality of life, functional status, and intervention-related adverse effects. For studies not included in the previous review, screening, study selection, data extraction on outcomes, and risk of bias assessments will be independently undertaken by two reviewers with consensus used for final decisions. Where quantitative analysis is suitable, network or pairwise meta-analysis will be conducted using a frequentist approach in Stata. Assessment of the transitivity and coherence of the network meta-analyses will be undertaken. For the reviews on patient preferences and outcome valuation (relative importance of outcomes), we will perform de novo reviews with searches in three databases (MEDLINE, PsycInfo, and CINAHL) and reference lists for cross-sectional, longitudinal quantitative, or qualitative studies published from 2000. Selection, data extraction, and risk of bias assessments suitable for each study design will be performed in duplicate. The analysis will be guided by a narrative synthesis approach, which may include meta-analysis for health-state utilities. We will use the CINeMa approach to a rate the certainty of the evidence for outcomes on intervention effects analyzed using network meta-analysis and the GRADE approach for all other outcomes.
    DISCUSSION: We will describe the flow of literature and characteristics of all studies and present results of all analyses and summary of finding tables. We will compare our findings to others and discuss the limitations of the reviews and the available literature.
    SYSTEMATIC REVIEW REGISTRATION: This protocol has not been registered.
    Keywords:  CINeMA; Fall prevention; GRADE; Guideline; Patient values and preferences; Systematic review
  45. Cell Rep. 2021 Jan 12. pii: S2211-1247(20)31613-2. [Epub ahead of print]34(2): 108624
    Schlein C, Fischer AW, Sass F, Worthmann A, Tödter K, Jaeckstein MY, Behrens J, Lynes MD, Kiebish MA, Narain NR, Bussberg V, Darkwah A, Jespersen NZ, Nielsen S, Scheele C, Schweizer M, Braren I, Bartelt A, Tseng YH, Heeren J, Scheja L.
      Thermoneutral conditions typical for standard human living environments result in brown adipose tissue (BAT) involution, characterized by decreased mitochondrial mass and increased lipid deposition. Low BAT activity is associated with poor metabolic health, and BAT reactivation may confer therapeutic potential. However, the molecular drivers of this BAT adaptive process in response to thermoneutrality remain enigmatic. Using metabolic and lipidomic approaches, we show that endogenous fatty acid synthesis, regulated by carbohydrate-response element-binding protein (ChREBP), is the central regulator of BAT involution. By transcriptional control of lipogenesis-related enzymes, ChREBP determines the abundance and composition of both storage and membrane lipids known to regulate organelle turnover and function. Notably, ChREBP deficiency and pharmacological inhibition of lipogenesis during thermoneutral adaptation preserved mitochondrial mass and thermogenic capacity of BAT independently of mitochondrial biogenesis. In conclusion, we establish lipogenesis as a potential therapeutic target to prevent loss of BAT thermogenic capacity as seen in adult humans.
    Keywords:  ChREBP; brown adipose tissue; cardiolipins; de novo lipogenesis; energy expenditure; fatty acid synthesis; fatty acids; lipidome; mitochondria; mitophagy; non-shivering thermogenesis; phospholipids; thermoneutrality; triacylglycerols; whitening
  46. STAR Protoc. 2021 Mar 19. 2(1): 100248
    Stevens BM, O'Brien C, Jordan CT, Jones CL.
      Isolation of leukemia stem cells presents a challenge due to the heterogeneity of the immunophenotypic markers commonly used to identify blood stem cells. Several studies have reported that relative levels of reactive oxygen species (ROS) can be used to enrich for stem cell populations, suggesting a potential alternative to surface antigen-based methods. Here, we describe a protocol to enrich for stem cells from human acute myeloid leukemia specimens using relative levels of ROS. This protocol provides consistent enrichment of leukemia stem cells. For complete details on the use and execution of this protocol, please refer to Lagadinou et al. (2013) and Pei et al. (2018).
    Keywords:  Cancer; Flow cytometry/mass cytometry; Metabolism; Stem cells
  47. Viruses. 2021 01 11. pii: E90. [Epub ahead of print]13(1):
    Tanner JE, Alfieri C.
      Enteric symptomology seen in early-stage severe acute respiratory syndrome (SARS)-2003 and COVID-19 is evidence of virus replication occurring in the intestine, liver and pancreas. Aberrant lipid metabolism in morbidly obese individuals adversely affects the COVID-19 immune response and increases disease severity. Such observations are in line with the importance of lipid metabolism in COVID-19, and point to the gut as a site for intervention as well as a therapeutic target in treating the disease. Formation of complex lipid membranes and palmitoylation of coronavirus proteins are essential during viral replication and assembly. Inhibition of fatty acid synthase (FASN) and restoration of lipid catabolism by activation of AMP-activated protein kinase (AMPK) impede replication of coronaviruses closely related to SARS-coronavirus-2 (CoV-2). In vitro findings and clinical data reveal that the FASN inhibitor, orlistat, and the AMPK activator, metformin, may inhibit coronavirus replication and reduce systemic inflammation to restore immune homeostasis. Such observations, along with the known mechanisms of action for these types of drugs, suggest that targeting fatty acid lipid metabolism could directly inhibit virus replication while positively impacting the patient's response to COVID-19.
    Keywords:  SREBP-1; antiviral; endoplasmic reticulum stress response; envelope protein; mTORC1; membrane protein; nonstructural protein; replicative organelle; spike protein; unfolded protein response
  48. Cells. 2021 Jan 07. pii: E89. [Epub ahead of print]10(1):
    Kim H, Oh B, Park-Min KH.
      Bone is a dynamic tissue and is constantly being remodeled by bone cells. Metabolic reprogramming plays a critical role in the activation of these bone cells and skeletal metabolism, which fulfills the energy demand for bone remodeling. Among various metabolic pathways, the importance of lipid metabolism in bone cells has long been appreciated. More recent studies also establish the link between bone loss and lipid-altering conditions-such as atherosclerotic vascular disease, hyperlipidemia, and obesity-and uncover the detrimental effect of fat accumulation on skeletal homeostasis and increased risk of fracture. Targeting lipid metabolism with statin, a lipid-lowering drug, has been shown to improve bone density and quality in metabolic bone diseases. However, the molecular mechanisms of lipid-mediated regulation in osteoclasts are not completely understood. Thus, a better understanding of lipid metabolism in osteoclasts can be used to harness bone cell activity to treat pathological bone disorders. This review summarizes the recent developments of the contribution of lipid metabolism to the function and phenotype of osteoclasts.
    Keywords:  cholesterol; fatty acids; lipids; metabolism; osteoclasts; statin
  49. J Am Board Fam Med. 2021 Jan-Feb;34(1):34(1): 132-143
    Bazargan M, Wisseh C, Adinkrah E, Boyce S, King EO, Assari S.
      OBJECTIVES: Existing epidemiologic information shows disparities in low-dose aspirin use by race. This study investigates the frequency, pattern, and correlates of both self- and clinician-prescribed low-dose aspirin use among underserved African Americans aged 55 years and older.METHODS: This cross-sectional study conducted a comprehensive evaluation of all over-the-counter and prescribed medications used among 683 African American older adults in South Central Los Angeles, California. Correlation between use of low-dose aspirin and sociodemographic variables, health care continuity, health behaviors, and several major chronic medical conditions were examined. In addition, the use of low-dose aspirin as self prescribed versus clinician prescribed was examined. Multivariate logistic regression was performed to examine correlates of low-dose aspirin use.
    RESULTS: Overall, 37% of participants were taking low-dose aspirin. Sixty percent of low-dose aspirin users were taking low-dose aspirin as self prescribed and 40% were taking it as prescribed by a clinician. Major aspirin-drug interactions were detected in 75% of participants who used low-dose aspirin, but no significant differences in aspirin-drug interactions were found between those who used aspirin as self prescribed and those who used it as clinician prescribed. No negative association between being diagnosed with gastrointestinal conditions and aspirin used was detected. Being diagnosed with diabetes mellitus or a heart condition was associated with higher use of aspirin. However, only 50% with high risk of cardiovascular took prescribed (38%) or self-prescribed (62%) low-dose aspirin. One third of participants aged 70 years and older with low risk of cardiovascular were using aspirin.
    CONCLUSIONS: Among underserved African-American middle-aged and older adults, many who could potentially benefit from aspirin are not taking it; and many taking aspirin have no indication to do so and risk unnecessary side effects. Compared with non-Hispanic Whites, African Americans are more likely to be diagnosed with diabetes, hypertension, and heart conditions at earlier stages of life; as a result, the role of preventive intervention, including safe and appropriate use of low-dose aspirin among this segment of our population, is more salient. Interventional studies are needed to promote safe and effective use of low-dose aspirin among underserved African-American adults.
    Keywords:  African Americans; Aging; Aspirin; Cardiovascular Diseases; Cross-Sectional Studies; Logistic Models; Los Angeles; Minority Health; Preventive Health Services; Primary Prevention; Secondary Prevention
  50. Cancer Discov. 2021 Jan 12. pii: candisc.0738.2020. [Epub ahead of print]
    Bjelosevic S, Gruber E, Newbold A, Shembrey C, Devlin JR, Hogg SJ, Kats L, Todorovski I, Fan Z, Abrehart TC, Pomilio G, Wei A, Gregory GP, Vervoort SJ, Brown KK, Johnstone RW.
      Internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITD) occurs in 30% of poor prognosis acute myeloid leukaemias (AMLs). Limited clinical efficacy of FLT3 inhibitors highlights the need for alternative therapeutic modalities in this subset of disease. Using human and murine models of FLT3-ITD-driven AML, we demonstrate that FLT3-ITD promotes serine synthesis and uptake via ATF4-dependent transcriptional regulation of genes in the de novo serine biosynthesis pathway and neutral amino acid transport. Genetic or pharmacological inhibition of PHGDH, the rate-limiting enzyme of de novo serine biosynthesis, selectively inhibited proliferation of FLT3-ITD AMLs in vitro and in vivo. Moreover, pharmacological inhibition of PHGDH sensitised FLT3-ITD AMLs to the standard of care chemotherapeutic cytarabine. Collectively, these data reveal novel insights into FLT3-ITD-induced metabolic reprogramming and reveal a targetable vulnerability in FLT3-ITD AML.
  51. J Clin Oncol. 2021 Jan 12. JCO2001801
    O'Neill AT, Chakraverty R.
      Relapse of hematologic malignancy is the major reason for treatment failure after allogeneic stem cell transplantation. Graft-versus-leukemia (GVL) responses are critical to prevent relapse but may fail as a result of tumor immune evasion, for example through antigen loss or T cell dysfunction. In silico pipelines for the discovery of tumor-expressed antigens and novel therapies that target immune evasion mechanisms (small molecule, biological, immune cell transfer) are potential strategies to sustain or reimpose GVL. A key challenge will be how experimental therapies to enhance GVL can progress from first-in-human trials to prospective, controlled trials that evaluate efficacy and lead to regulatory approval.