scholarly journals Metabolomics of aging in primary fibroblasts from small and large breed dogs

2021 ◽  
Author(s):  
Paul S. Brookes ◽  
Ana G. Jimenez
Keyword(s):  
Aging Process ◽  
Tca Cycle ◽  
Therapeutic Strategies ◽  
Targeted Metabolomics ◽  
The Tca Cycle ◽  
Age Dependent ◽  
Primary Fibroblasts ◽  
Aging Rates ◽  
Underlying Mechanisms ◽  
Metabolomics Analysis

AbstractAmong several animal groups (eutherian mammals, birds, reptiles) lifespan positively correlates with body mass over several orders of magnitude. Contradicting this pattern are domesticated dogs, with small dog breeds exhibiting significantly longer lifespans than large dog breeds. The underlying mechanisms of differing aging rates across body masses are unclear, but it is generally agreed that metabolism is a significant regulator of the aging process. Herein, we performed a targeted metabolomics analysis on primary fibroblasts isolated from small and large breed young and old dogs. Regardless of size, older dogs exhibited lower glutathione and ATP, consistent with a role for oxidative stress and bioenergetic decline in aging. Furthermore, several size-specific metabolic patterns were observed with aging, including: (i) An apparent defect in the lower half of glycolysis in large old dogs at the level of pyruvate kinase. (ii) Increased glutamine anaplerosis into the TCA cycle in large old dogs. (iii) A potential defect in co-enzyme A biosynthesis in large old dogs. (iv) Low nucleotide levels in small young dogs that corrected with age. (v) An age dependent increase in carnitine in small dogs that was absent in large dogs. Overall, these data support the hypothesis that alterations in metabolism may underlie the different lifespans of small versus large breed dogs, and further work in this area may afford potential therapeutic strategies to improve the lifespan of large dogs.

scholarly journals Metabolomics of aging in primary fibroblasts from small and large breed dogs

GeroScience ◽  
2021 ◽  
Author(s):  
Paul S. Brookes ◽  
Ana Gabriela Jimenez
Keyword(s):  
Aging Process ◽  
Tca Cycle ◽  
Therapeutic Strategies ◽  
Targeted Metabolomics ◽  
The Tca Cycle ◽  
Age Dependent ◽  
Primary Fibroblasts ◽  
Aging Rates ◽  
Underlying Mechanisms ◽  
Coenzyme A Biosynthesis

AbstractAmong several animal groups (eutherian mammals, birds, reptiles), lifespan positively correlates with body mass over several orders of magnitude. Contradicting this pattern are domesticated dogs, with small dog breeds exhibiting significantly longer lifespans than large dog breeds. The underlying mechanisms of differing aging rates across body masses are unclear, but it is generally agreed that metabolism is a significant regulator of the aging process. Herein, we performed a targeted metabolomics analysis on primary fibroblasts isolated from small and large breed young and old dogs. Regardless of size, older dogs exhibited lower glutathione and ATP, consistent with a role for oxidative stress and bioenergetic decline in aging. Furthermore, several size-specific metabolic patterns were observed with aging, including the following: (i) An apparent defect in the lower half of glycolysis in large old dogs at the level of pyruvate kinase. (ii) Increased glutamine anaplerosis into the TCA cycle in large old dogs. (iii) A potential defect in coenzyme A biosynthesis in large old dogs. (iv) Low nucleotide levels in small young dogs that corrected with age. (v) An age-dependent increase in carnitine in small dogs that was absent in large dogs. Overall, these data support the hypothesis that alterations in metabolism may underlie the different lifespans of small vs. large breed dogs, and further work in this area may afford potential therapeutic strategies to improve the lifespan of large dogs.

scholarly journals Rapid metabolic and bioenergetic adaptations of astrocytes under hyperammonemia – a novel perspective on hepatic encephalopathy

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Marcel Zimmermann ◽  
Andreas S. Reichert
Keyword(s):  
Hepatic Encephalopathy ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Therapeutic Strategies ◽  
Cellular Processes ◽  
Cellular Models ◽  
The Tca Cycle ◽  
Underlying Mechanisms

Abstract Hepatic encephalopathy (HE) is a well-studied, neurological syndrome caused by liver dysfunctions. Ammonia, the major toxin during HE pathogenesis, impairs many cellular processes within astrocytes. Yet, the molecular mechanisms causing HE are not fully understood. Here we will recapitulate possible underlying mechanisms with a clear focus on studies revealing a link between altered energy metabolism and HE in cellular models and in vivo. The role of the mitochondrial glutamate dehydrogenase and its role in metabolic rewiring of the TCA cycle will be discussed. We propose an updated model of ammonia-induced toxicity that may also be exploited for therapeutic strategies in the future.

scholarly journals Activation of the TCA Cycle to Provide Immune Protection in Zebrafish Immunized by High Magnesium-Prepared Vibrio alginolyticus Vaccine

2021 ◽  
Vol 12 ◽  
Author(s):  
Jun Yang ◽  
Xiao-li Yang ◽  
Yu-bin Su ◽  
Xuan-xian Peng ◽  
Hui Li
Keyword(s):  
Tca Cycle ◽  
Dependent Manner ◽  
High Concentration ◽  
Immune Genes ◽  
Bacterial Diseases ◽  
The Tca Cycle ◽  
Aquaculture Industry ◽  
Innate Immune Genes ◽  
Underlying Mechanisms ◽  
Dose Dependent

Vaccines are safe and efficient in controlling bacterial diseases in the aquaculture industry and are in line with green farming. The present study develops a previously unreported approach to prepare a live-attenuated V. alginolyticus vaccine by culturing bacteria in a high concentration of magnesium to attenuate bacterial virulence. Furthermore, metabolomes of zebrafish immunized with the live-attenuated vaccines were compared with those of survival and dying zebrafish infected by V. alginolyticus. The enhanced TCA cycle and increased fumarate were identified as the most key metabolic pathways and the crucial biomarker of vaccine-mediated and survival fish, respectively. Exogenous fumarate promoted expression of il1β, il8, il21, nf-κb, and lysozyme in a dose-dependent manner. Among the five innate immune genes, the elevated il1β, il8, and lysozyme are overlapped in the vaccine-immunized zebrafish and the survival from the infection. These findings highlight a way in development of vaccines and exploration of the underlying mechanisms.

Liquid-liquid extraction of succinate using a dicopper cryptate

2020 ◽  
Author(s):  
Riccardo Mobili ◽  
Sonia La Cognata ◽  
Francesca Merlo ◽  
Andrea Speltini ◽  
Massimo Boiocchi ◽  
...  
Keyword(s):  
Aqueous Phase ◽  
Visible Spectrum ◽  
Tca Cycle ◽  
Residual Concentration ◽  
Waste Products ◽  
Liquid Liquid Extraction ◽  
The Tca Cycle ◽  
Quantitative Extraction ◽  
Uv Visible

<div> <p>The extraction of the succinate dianion from a neutral aqueous solution into dichloromethane is obtained using a lipophilic cage-like dicopper(II) complex as the extractant. The quantitative extraction exploits the high affinity of the succinate anion for the cavity of the azacryptate. The anion is effectively transferred from the aqueous phase, buffered at pH 7 with HEPES, into dichloromethane. A 1:1 extractant:anion adduct is obtained. Extraction can be easily monitored by following changes in the UV-visible spectrum of the dicopper complex in dichloromethane, and by measuring the residual concentration of succinate in the aqueous phase by HPLC−UV. Considering i) the relevance of polycarboxylates in biochemistry, as e.g. normal intermediates of the TCA cycle, ii) the relevance of dicarboxylates in the environmental field, as e.g. waste products of industrial processes, and iii) the recently discovered role of succinate and other dicarboxylates in pathophysiological processes including cancer, our results open new perspectives for research in all contexts where selective recognition, trapping and extraction of polycarboxylates is required. </p> </div>

scholarly journals Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression

2021 ◽  
Vol 22 (5) ◽  
pp. 2746
Author(s):  
Dimitri Shcherbakov ◽  
Reda Juskeviciene ◽  
Adrián Cortés Sanchón ◽  
Margarita Brilkova ◽  
Hubert Rehrauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Response ◽  
Mitochondrial Gene ◽  
Tca Cycle ◽  
Brain Mitochondria ◽  
Mitochondrial Gene Expression ◽  
Rna Seq ◽  
The Tca Cycle ◽  
Neurological Phenotype

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).

scholarly journals The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 762
Author(s):  
Edward V. Prochownik ◽  
Huabo Wang
Keyword(s):  
Metabolic Pathways ◽  
Redox State ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Vascular Supply ◽  
Extrinsic Factors ◽  
The Tca Cycle ◽  
Initial Substrate ◽  
Numerous Cell ◽  
Bio Synthesis

Pyruvate occupies a central metabolic node by virtue of its position at the crossroads of glycolysis and the tricarboxylic acid (TCA) cycle and its production and fate being governed by numerous cell-intrinsic and extrinsic factors. The former includes the cell’s type, redox state, ATP content, metabolic requirements and the activities of other metabolic pathways. The latter include the extracellular oxygen concentration, pH and nutrient levels, which are in turn governed by the vascular supply. Within this context, we discuss the six pathways that influence pyruvate content and utilization: 1. The lactate dehydrogenase pathway that either converts excess pyruvate to lactate or that regenerates pyruvate from lactate for use as a fuel or biosynthetic substrate; 2. The alanine pathway that generates alanine and other amino acids; 3. The pyruvate dehydrogenase complex pathway that provides acetyl-CoA, the TCA cycle’s initial substrate; 4. The pyruvate carboxylase reaction that anaplerotically supplies oxaloacetate; 5. The malic enzyme pathway that also links glycolysis and the TCA cycle and generates NADPH to support lipid bio-synthesis; and 6. The acetate bio-synthetic pathway that converts pyruvate directly to acetate. The review discusses the mechanisms controlling these pathways, how they cross-talk and how they cooperate and are regulated to maximize growth and achieve metabolic and energetic harmony.

scholarly journals Infectious disease-associated encephalopathies

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Maria C. Barbosa-Silva ◽  
Maiara N. Lima ◽  
Denise Battaglini ◽  
Chiara Robba ◽  
Paolo Pelosi ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Cognitive Deficits ◽  
Brain Function ◽  
Cell Activation ◽  
Therapeutic Strategies ◽  
Barrier Dysfunction ◽  
Glial Cell Activation ◽  
The Central Nervous System ◽  
Underlying Mechanisms

AbstractInfectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood–brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation. Graphic abstract

scholarly journals Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2634
Author(s):  
Beatriz Soldevilla ◽  
Angeles López-López ◽  
Alberto Lens-Pardo ◽  
Carlos Carretero-Puche ◽  
Angeles Lopez-Gonzalvez ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Metabolic Networks ◽  
Tca Cycle ◽  
Metabolomic Profile ◽  
Diagnostic Potential ◽  
The Tca Cycle ◽  
Novel Biomarkers ◽  
Potential Methods ◽  
Clinical Potential ◽  
First Time

Purpose: High-throughput “-omic” technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research.

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