Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 1 min 52 sec ago

Human milk and infant formula differentially alters the microbiota composition and functional gene relative abundance in the small and large intestines in weanling rats.

Sun, 21/07/2019 - 18:44
Related Articles Human milk and infant formula differentially alters the microbiota composition and functional gene relative abundance in the small and large intestines in weanling rats. Eur J Nutr. 2019 Jul 19;: Authors: Liu Z, Subbaraj A, Fraser K, Jia H, Chen W, Day L, Roy NC, Young W Abstract PURPOSE: Human breast milk is the optimal source of nutrients for growing infants. However, many circumstances can arise which preclude breast milk feeding, leading to the use of infant formula, including during the weaning period. Many diet-related effects are modulated by the gut microbiome. Therefore, we investigated the effect of human milk (HM) or infant formula (IF) on the gut microbiota in weanling rats. METHODS: The gut microbiota of weanling male Sprague-Dawley rats fed HM or IF for 28 days was analysed by shotgun metagenome sequencing. Caecal contents were analysed by liquid chromatography-mass spectrometry metabolomics. RESULTS: Numerous genera within the Proteobacteria phylum were relatively more abundant in the ileum, caecum, and colon of rats fed HM, including ileal Escherichia (HM = 9.6% ± 4.3 SEM; IF = 0.9% ± 0.3 SEM; P = 0.03). Other taxa that differed between HM- and IF-fed rats included Prevotella and Ruminococcus. Overall, more differences were observed in the ileum than the caecum and colon between rats fed HM and IF. For the rats fed IF, in the ileum, the relative abundance of Bifidobacterium was higher (HM = 1.7% ± 0.7 SEM; IF = 5.0% ± 1.5 SEM; P = 0.04) with gene functions related to carbohydrate and amino acid metabolism also decreased. In the caecum, metabolic features such as bile acids were elevated while amino sugars were also decreased. CONCLUSION: Our results show that HM and IF composition differences are reflected in the gut microbiome composition and function in both the small and large intestines. PMID: 31325042 [PubMed - as supplied by publisher]

Acute and short-term administrations of delta-9-tetrahydrocannabinol modulate major gut metabolomic regulatory pathways in C57BL/6 mice.

Sun, 21/07/2019 - 18:44
Related Articles Acute and short-term administrations of delta-9-tetrahydrocannabinol modulate major gut metabolomic regulatory pathways in C57BL/6 mice. Sci Rep. 2019 Jul 19;9(1):10520 Authors: Oza M, Becker W, Gummadidala PM, Dias T, Omebeyinje MH, Chen L, Mitra C, Jesmin R, Chakraborty P, Sajish M, Hofseth LJ, Banerjee K, Wang Q, Moeller PDR, Nagarkatti M, Nagarkatti P, Chanda A Abstract Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound in Cannabis, which is studied extensively for its medicinal value. A central gap in the science is the underlying mechanisms surrounding THC's therapeutic effects and the role of gut metabolite profiles. Using a mass-spectrometry based metabolomics, we show here that intraperitoneal injection of THC in C57BL/6 mice modulates metabolic profiles that have previously been identified as integral to health. Specifically, we investigated the effects of acute (single THC injection denoted here as '1X') and short -term (five THC injections on alternate days denoted as '5X') THC administration on fecal and intestinal tissue metabolite profiles. Results are consistent with the hypothesis that THC administration alters host metabolism by targeting two prominent lipid metabolism pathways: glycerophospholipid metabolism and fatty acid biosynthesis. PMID: 31324830 [PubMed - in process]

Boosting NAD+ with a small molecule that activates NAMPT.

Sun, 21/07/2019 - 18:44
Related Articles Boosting NAD+ with a small molecule that activates NAMPT. Nat Commun. 2019 Jul 19;10(1):3241 Authors: Gardell SJ, Hopf M, Khan A, Dispagna M, Hampton Sessions E, Falter R, Kapoor N, Brooks J, Culver J, Petucci C, Ma CT, Cohen SE, Tanaka J, Burgos ES, Hirschi JS, Smith SR, Sergienko E, Pinkerton AB Abstract Pharmacological strategies that boost intracellular NAD+ are highly coveted for their therapeutic potential. One approach is activation of nicotinamide phosphoribosyltransferase (NAMPT) to increase production of nicotinamide mononucleotide (NMN), the predominant NAD+ precursor in mammalian cells. A high-throughput screen for NAMPT activators and hit-to-lead campaign yielded SBI-797812, a compound that is structurally similar to active-site directed NAMPT inhibitors and blocks binding of these inhibitors to NAMPT. SBI-797812 shifts the NAMPT reaction equilibrium towards NMN formation, increases NAMPT affinity for ATP, stabilizes phosphorylated NAMPT at His247, promotes consumption of the pyrophosphate by-product, and blunts feedback inhibition by NAD+. These effects of SBI-797812 turn NAMPT into a "super catalyst" that more efficiently generates NMN. Treatment of cultured cells with SBI-797812 increases intracellular NMN and NAD+. Dosing of mice with SBI-797812 elevates liver NAD+. Small molecule NAMPT activators such as SBI-797812 are a pioneering approach to raise intracellular NAD+ and realize its associated salutary effects. PMID: 31324777 [PubMed - in process]

l-Proline protects mice challenged by Klebsiella pneumoniae bacteremia.

Sun, 21/07/2019 - 18:44
Related Articles l-Proline protects mice challenged by Klebsiella pneumoniae bacteremia. J Microbiol Immunol Infect. 2019 Jul 05;: Authors: Chen X, Qin S, Zhao X, Zhou S Abstract OBJECTIVE: K. pneumoniae, a common pathogen that frequently causes bacteremia in clinic, is unresponsive to most of known antibiotics, thus cumulatively exacerbating empirical therapy failures. Effective strategies to control Klebsiella pneumoniae bacteremia are in high demand. One possibility is to mobilize host defense mechanisms against bacterial pathogens. METHODS: We employed GC/MS-based metabolomics to identify the changes of metabolism in mice challenged by K. pneumoniae (ATCC 43816) bacteremia. RESULTS: Compared with the mice that compromised from K. pneumoniae bacteremia, mice that survived from infection displayed the varied metabolomic profile. The differential analysis of metabolome showed that Ethanedioic acid, d-Glucose, l-Glutamine, Myo-inositol, and l-Proline were more likely associated with the host surviving a K. pneumoniae bacteremia. Further pathway enrichment analysis proposed that arginine and proline metabolism involved in outcome of K. pneumoniae bacteremia. The follow-up data showed that exogenous l-Proline but not d-Proline could decline the loads of Klebsiella pneumonia in infected blood and tissues (lung, liver and spleen) and increase the mouse survival. CONCLUSION: Our study provides an exercisable strategy of identifying metabolic biomarkers from surviving host and highlights the possibility of utilizing the metabolic biomarker as a therapy for K. pneumoniae bacteremia. PMID: 31324551 [PubMed - as supplied by publisher]

Biomarkers in neonatal hypoxic-ischemic encephalopathy-Review of the literature to date and future directions for research.

Sun, 21/07/2019 - 18:44
Related Articles Biomarkers in neonatal hypoxic-ischemic encephalopathy-Review of the literature to date and future directions for research. Handb Clin Neurol. 2019;162:281-293 Authors: Murray DM Abstract The widespread introduction of therapeutic hypothermia as a standard of care in hypoxic-ischemic encephalopathy (HIE) has brought increasing pressure on clinicians to make an early and accurate assessment of the degree of hypoxic injury (HI) that has occurred and the severity of the encephalopathy that will ensue. No single blood-based marker is currently robust enough to detect significant HI or predict outcome. However, research in the field has been active in the last 10 years and we know that HIE is associated with predictable alterations in the expression of a number of inflammatory proteins, neuron-specific proteins, metabolite pathways, and microRNA. These alterations evolve quickly over the first hours and days of life. Predictive power varies depending on the timing of measurement of the biomarker, the sample type, and the case mix of the cohort examined. Combining clinical data with biochemical measurements is currently the most likely path toward improved detection and prediction of outcome in neonatal HIE. PMID: 31324315 [PubMed - in process]

A highly sensitive ultra-high performance liquid chromatography/tandem mass spectrometry method with in-source fragmentation for rapid quantification of raspberry ketone.

Sun, 21/07/2019 - 18:44
Related Articles A highly sensitive ultra-high performance liquid chromatography/tandem mass spectrometry method with in-source fragmentation for rapid quantification of raspberry ketone. J Food Drug Anal. 2019 Jul;27(3):778-785 Authors: Yuan B, Zhao D, Du R, Kshatriya D, Bello NT, Simon JE, Wu Q Abstract Raspberry ketone (RK) is the characteristic aromatic compound in raspberry (Rubus idaeus L.) with wide applications as food additive and anti-obesity agent. However, quantification of RK has presented difficulties in MS detection and reliable LC-MS method for RK analysis in literature is in limit to date. In order to facilitate quality control of raspberry derived products and RK metabolomics study, this study aimed to develop a validated and sensitive UHPLC-MS/MS method. Strong in-source fragmentation was noted and the fragmental ion of 107 m/z produced was selected as the precursor ion for MRM detection, and as such the electrospray ionization performance was optimized by fractional factorial design to accommodate such ion-source dissociation behavior as well as its moderate volatility. A pathway involving the formation of quinone-like structure with strong conjugation was proposed to explain the intense in-source fragmentation. The MRM transition was optimized with product ion of 77 m/z selected as the quantifier ion. The method featured low limit of quantification of ∼2 ng/mL and allowed for rapid detection of RK in fresh raspberries following direct sample preparation. RK contents were found to be higher from locally grown and harvested farm sources compared to commercial products shipped into the state, and higher in those at late-stage compared with early-stage maturity. No correlations in RK content between organic and non-organic labels were noted. PMID: 31324293 [PubMed - in process]

Human Breast Milk Promotes the Secretion of Potentially Beneficial Metabolites by Probiotic Lactobacillus reuteri DSM 17938.

Sun, 21/07/2019 - 18:44
Related Articles Human Breast Milk Promotes the Secretion of Potentially Beneficial Metabolites by Probiotic Lactobacillus reuteri DSM 17938. Nutrients. 2019 Jul 09;11(7): Authors: Mai TT, Tran DQ, Roos S, Rhoads JM, Liu Y Abstract Human breast milk (HBM) may have beneficial effects on Lactobacillus reuteri DSM 17938 (LR 17938) -mediated immunomodulation. We aimed to determine the effects of HBM on proliferation of LR 17938 in vitro and its associated proteins and metabolites in culture, in order to provide mechanistic insights into the health benefits of LR 17938. LR 17938 was cultured anaerobically in MRS bacterial culture media, HBM (from 6 mothers), and 2 types of cow-milk formula. The colony-forming unit (CFU) was calculated to evaluate LR 17938 growth. Sixteen-hour-fermented supernatants were used for metabolomics, and bacterial lysates were used for proteomics analysis. We found that growth of LR 17938 was 10 times better in HBM than in formula. We detected 261/452 metabolites upregulated when LR 17938 cultured in HBM compared to in formula, mainly participating in the glyoxylate cycle (succinate), urea cycle (citrulline), methionine methylation (N-acetylcysteine), and polyamine synthesis (spermidine). The significantly up-regulated enzymes were also involved in the formation of acetyl-CoA in the glyoxylate cycle and the antioxidant N-acetylcysteine. In conclusion, HBM enhances the growth of LR 17938 compared to formula and promotes LR 17938-associated metabolites that relate to energy and antioxidant status, which may be linked to the physiological effects of L. reuteri. PMID: 31323989 [PubMed - in process]

Metabolomic Studies of Tissue Injury in Nonhuman Primates Exposed to Gamma-Radiation.

Sun, 21/07/2019 - 18:44
Related Articles Metabolomic Studies of Tissue Injury in Nonhuman Primates Exposed to Gamma-Radiation. Int J Mol Sci. 2019 Jul 09;20(13): Authors: Cheema AK, Mehta KY, Rajagopal MU, Wise SY, Fatanmi OO, Singh VK Abstract Exposure to ionizing radiation induces a complex cascade of systemic and tissue-specific responses that lead to functional impairment over time in the surviving population. However, due to the lack of predictive biomarkers of tissue injury, current methods for the management of survivors of radiation exposure episodes involve monitoring of individuals over time for the development of adverse clinical symptoms and death. Herein, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that were exposed to a single dose of 7.2 Gy whole-body 60Co γ-radiation that either survived or succumbed to radiation toxicities over a 60-day period. This study involved the delineation of the radiation effects in the liver, kidney, jejunum, heart, lung, and spleen. We found robust metabolic changes in the kidney and liver and modest changes in other tissue types at the 60-day time point in a cohort of NHPs. Remarkably, we found significant elevation of long-chain acylcarnitines in animals that were exposed to radiation across multiple tissue types underscoring the role of this class of metabolites as a generic indicator of radiation-induced normal tissue injury. These studies underscore the utility of a metabolomics approach for delineating anticipatory biomarkers of exposure to ionizing radiation. PMID: 31323921 [PubMed - in process]

1H HR-MAS NMR-Based Metabolomics of Cancer Cells in Response to Treatment with the Diruthenium Trithiolato Complex [(p-MeC6H4iPr)2Ru2(SC6H4-p-But)3]+ (DiRu-1).

Sun, 21/07/2019 - 18:44
Related Articles 1H HR-MAS NMR-Based Metabolomics of Cancer Cells in Response to Treatment with the Diruthenium Trithiolato Complex [(p-MeC6H4iPr)2Ru2(SC6H4-p-But)3]+ (DiRu-1). Metabolites. 2019 Jul 18;9(7): Authors: Primasová H, Paul LEH, Diserens G, Primasová E, Vermathen P, Vermathen M, Furrer J Abstract The trithiolato bridged diruthenium complex DiRu-1 [(p-MeC6H4iPr)2Ru2(SC6H4-p-But)3]+ is highly cytotoxic against various cancer cell lines, but its exact mode of action remains unknown. The present 1H HR-MAS NMR-based metabolomic study was performed on ovarian cancer cell line A2780, on its cis-Pt resistant variant A2780cisR, and on the cell line HEK-293 treated with 0.03 µM and 0.015 µM of DiRu-1 corresponding to full and half IC50 doses, respectively, to investigate the mode of action of this ruthenium complex. The resulting changes in the metabolic profile of the cell lines were studied using HR-MAS NMR of cell lysates and a subsequent statistical analysis. We show that DiRu-1 in a 0.03 µM dose has significant impact on the levels of a number of metabolites, such as glutamine, glutamate, glutathione, cysteine, lipid, creatine, lactate, and acetate, especially pronounced in the A2780cisR cell line. The IC50/2 dose shows some significant changes, but full IC50 appears to be necessary to observe the full effect. Overall, the metabolic changes observed suggest that redox homeostasis, the Warburg effect, and the lipid metabolism are affected by DiRu-1. PMID: 31323867 [PubMed]

metabolomics; +28 new citations

Sat, 20/07/2019 - 15:31
28 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/07/20PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +28 new citations

Sat, 20/07/2019 - 12:29
28 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/07/20PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +20 new citations

Fri, 19/07/2019 - 15:10
20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/07/19PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +20 new citations

Fri, 19/07/2019 - 12:10
20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/07/19PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Shift in the paradigm towards next-generation microbiology.

Thu, 18/07/2019 - 12:02
Shift in the paradigm towards next-generation microbiology. FEMS Microbiol Lett. 2019 Jul 17;: Authors: Stres B, Kronegger L Abstract In this work, the position of contemporary microbiology is considered from the perspective of scientific success, and a list of historical points and lessons learned from the fields of medical microbiology, microbial ecology and systems biology are presented. In addition, patterns in the development of top-down research topics that emerged over time as well as overlapping ideas and personnel, which are the first signs of trans-domain research activities in the fields of metagenomics, metaproteomics, metatranscriptomics and metabolomics, are explored through analysis of the publication networks of 28.654 papers using the computer programme Pajek. The current state of affairs is defined, and the need for meta-analyses to leverage publication biases in the field of microbiology is put forward as a very important emerging field of microbiology, especially since microbiology is progressively dealing with multiscale systems. Consequently, the need for cross-fertilisation with other fields/disciplines instead of 'more microbiology' is needed to advance the field of microbiology as such. The reader is directed to consider how novel technologies, the introduction of big data approaches and artificial intelligence have transformed microbiology into a multi-scale field and initiated a shift away from its history of mostly manual work and towards a largely technology-, data- and statistics-driven discipline that is often coupled with automation and modelling. PMID: 31314103 [PubMed - as supplied by publisher]

Systemic and local metabolic alterations in sleep deprivation-induced stress: A multi-platform mass- spectrometry-based lipidomics and metabolomics approach.

Thu, 18/07/2019 - 12:02
Systemic and local metabolic alterations in sleep deprivation-induced stress: A multi-platform mass- spectrometry-based lipidomics and metabolomics approach. J Proteome Res. 2019 Jul 17;: Authors: Yoon SJ, Long NP, Jung KH, Kim HM, Hong YJ, Fang Z, Kim SJ, Kim TJ, Anh NH, Hong SS, Kwon SW Abstract Sleep deprivation (SD) is known to be associated with metabolic disorders and chronic diseases. Complex metabolic alterations induced by SD at the omics scale and the associated biomarker candidates have been proposed. However, in vivo systemic and local metabolic shift patterns of the metabolome and lipidome in acute and chronic partial SD models remain to be elucidated. In the present study, the serum, hypothalamus, and hippocampus CA1 of sleep-deprived rats (SD rats) from acute and chronic sleep restriction models were analyzed using three different omics platforms for the discovery and mechanistic assessment of systemic and local SD-induced dysregulated metabolites. We found a similar pattern of systemic metabolome alterations between two models, for which the area under the curve (AUC) of receiver operating characteristic (ROC) curves was AUC = 0.813 and 0.836 with the pseudotargeted and untargeted metabolomics approach, respectively. However, SD-induced systemic lipidome alterations were significantly different and appeared to be model-dependent (AUC = 0.374). Comprehensive pathway analysis of the altered lipidome and metabolome in the hypothalamus indicated the abnormal behavior of eight metabolic and lipid metabolic pathways. The metabolism of the hippocampus CA1 was subtle in two SD models. Collectively, these results extend our understanding of the quality of sleep and suggest metabolic targets in developing diagnostic biomarkers for better SD control. PMID: 31313932 [PubMed - as supplied by publisher]

Nutrition and Metabolic Profiles in the Natural History of Dementia: Recent Insights from Systems Biology and Life Course Epidemiology.

Thu, 18/07/2019 - 12:02
Nutrition and Metabolic Profiles in the Natural History of Dementia: Recent Insights from Systems Biology and Life Course Epidemiology. Curr Nutr Rep. 2019 Jul 16;: Authors: Lefèvre-Arbogast S, Wagner M, Proust-Lima C, Samieri C Abstract PURPOSE OF REVIEW: Worldwide, approximately 50 million people have dementia (mostly Alzheimer's disease). Dementia results from a multicomponent pathophysiology that follows complex dynamics over many years before symptoms become apparent. Nutrition may represent a target of choice for the primary prevention of dementia; however, there is still no firm answer on how to prevent dementia efficiently. We provide a broad overview of recent studies leveraging system biology and life-long epidemiology to address the multidimensionality and dynamical patterns underlying dementia and improve knowledge on the link between nutrition, cardiometabolic health and dementia risk. RECENT FINDINGS: The aging of reference population-based cohort studies, the increasing availability of cutting-edge biomarkers (e.g., brain imaging, metabolomics) and the refinement of statistical tools to model complex exposures and dynamical health outcomes have yielded substantial progress in the understanding of dementia. Systems biology coupled with life-course epidemiology will pave the way toward novel precision nutrition approaches for prevention and management of dementia. PMID: 31313074 [PubMed - as supplied by publisher]

Modified HEPES one-pot synthetic strategy for gold nanostars.

Thu, 18/07/2019 - 12:02
Modified HEPES one-pot synthetic strategy for gold nanostars. R Soc Open Sci. 2019 Jun;6(6):190160 Authors: Mulder DW, Phiri MM, Jordaan A, Vorster BC Abstract Gold nanostars are being used more regularly in the biosensing field. Despite their useful attributes, there is still a need to optimize aspects of the synthesis and stability. The seedless, synthetic method comprising 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) is a facile, rapid method; however, it produces heteromorphic nanostars. The modification of a HEPES method resulted in a silver-assisted, seedless gold nanostar synthesis method. The nanostars resulting from this method were monodispersed, multi-branched and approximately 37 ± 2 nm in diameter. It proved to be a repeatable method that produced homogeneous and robust nanostars. Once functionalized with polyvinylpyrrolidone 10 000, the new nanostars were observed to be stable in various environments such as salt, ionic strength and cell culture medium. In conclusion, the addition of the silver nitrate improved the morphology of the reported HEPES nanostars for the purpose of nanobiosensor development. PMID: 31312487 [PubMed]

Magnetic Resonance Spectroscopy-based Metabolomic Biomarkers for Typing, Staging, and Survival Estimation of Early-Stage Human Lung Cancer.

Thu, 18/07/2019 - 12:02
Magnetic Resonance Spectroscopy-based Metabolomic Biomarkers for Typing, Staging, and Survival Estimation of Early-Stage Human Lung Cancer. Sci Rep. 2019 Jul 16;9(1):10319 Authors: Berker Y, Vandergrift LA, Wagner I, Su L, Kurth J, Schuler A, Dinges SS, Habbel P, Nowak J, Mark E, Aryee MJ, Christiani DC, Cheng LL Abstract Low-dose CT has shown promise in detecting early stage lung cancer. However, concerns about the adverse health effects of radiation and high cost prevent its use as a population-wide screening tool. Effective and feasible screening methods to triage suspicious patients to CT are needed. We investigated human lung cancer metabolomics from 93 paired tissue-serum samples with magnetic resonance spectroscopy and identified tissue and serum metabolomic markers that can differentiate cancer types and stages. Most interestingly, we identified serum metabolomic profiles that can predict patient overall survival for all cases (p = 0.0076), and more importantly for Stage I cases alone (n = 58, p = 0.0100), a prediction which is significant for treatment strategies but currently cannot be achieved by any clinical method. Prolonged survival is associated with relative overexpression of glutamine, valine, and glycine, and relative suppression of glutamate and lipids in serum. PMID: 31311965 [PubMed - in process]

Reply to Nikaido: The pyruvate cycle provides respiratory energy and potentiates aminoglycosides to kill multidrug-resistant bacteria.

Thu, 18/07/2019 - 12:02
Reply to Nikaido: The pyruvate cycle provides respiratory energy and potentiates aminoglycosides to kill multidrug-resistant bacteria. Proc Natl Acad Sci U S A. 2019 Jul 16;: Authors: Li H, Zhang TT, Chen ZG, Ye JZ, Zhang S, Yang J, Peng XX, Peng B PMID: 31311875 [PubMed - as supplied by publisher]

TNF-alpha driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.

Thu, 18/07/2019 - 12:02
TNF-alpha driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging. Blood. 2019 Jul 16;: Authors: Davizon-Castillo P, McMahon B, Aguila S, Bark D, Ashworth K, Allawzi A, Campbell RA, Montenont E, Nemkov T, D'Alessandro A, Clendenen N, Shih L, Sanders NA, Higa K, Cox A, Padilla-Romo Z, Hernandez G, Wartchow E, Trahan GD, Nozik-Grayck E, Jones K, Pietras E, DeGregori J, Rondina MT, Di Paola J Abstract Aging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified TNF- as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF- receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status and thrombocytosis. Single-cell RNA-sequencing (scRNA-seq) analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF- was endogenously increased), and from young mice exposed to exogenous TNF- exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF- blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF- levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously-unrecognized evidence that TNF- critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis. PMID: 31311815 [PubMed - as supplied by publisher]

Pages