Small molecule metabolites: discovery of biomarkers and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 20, 2023

Metabolic abnormalities lead to the dysfunction of metabolic pathways and metabolite accumulation or deficiency which is well-recognized hallmarks diseases. Metabolite signatures that have close proximity subject's phenotypic informative dimension, are useful for predicting diagnosis prognosis diseases as well monitoring treatments. The lack early biomarkers could poor serious outcomes. Therefore, noninvasive methods with high specificity selectivity desperately needed. Small molecule metabolites-based metabolomics has become a specialized tool biomarker pathway analysis, revealing possible mechanisms human various deciphering therapeutic potentials. It help identify functional related variation delineate biochemical changes indicators pathological damage prior disease development. Recently, scientists established large number profiles reveal underlying networks target exploration in biomedicine. This review summarized analysis on potential value small-molecule candidate metabolites clinical events, may better diagnosis, prognosis, drug screening treatment. We also discuss challenges need be addressed fuel next wave breakthroughs.

Language: Английский

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Ketone body β-hydroxybutyrate ameliorates colitis by promoting M2 macrophage polarization through the STAT6-dependent signaling pathway

BMC Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: April 15, 2022

Abstract Background Ketone body β-hydroxybutyrate (BHB) has received more and attentions, because it possesses a lot of beneficial, life-preserving effects in the fields clinical science medicine. However, role BHB intestinal inflammation not yet been investigated. Methods Colonic mucosa inflammatory bowel disease (IBD) patients healthy controls were collected for evaluation level. Besides, therapeutic effect exogenous murine model acute dextran sulfate sodium (DSS)-induced colitis assessed by weight change, colon length, activity index, histopathological sections. The regulatory effectors analyzed RT-qPCR, immunofluorescence, microbe analysis vivo. Moreover, molecular mechanism was further verified bone marrow-derived macrophages (BMDMs). Results In this study, significantly reduced levels found colonic from IBD correlated with index. addition, we demonstrated that administration alleviated severity experimental colitis, which characterized less loss, shortening, histology scores, as well decreased crypt loss epithelium damage. Furthermore, resulted increased expression M2 macrophage-associated genes, including IL-4Ra, IL-10, arginase 1 (Arg-1), chitinase-like protein 3, following DSS exposure, suggesting an macrophage skewing vitro experiment revealed addition directly promoted STAT6 phosphorylation macrophage-specific gene IL-4-stimulated macrophages. obviously macrophage-induced mucosal repair through promoting epithelial proliferation. enhancement on anti-inflammation completely inhibited inhibitor AS1517499. Conclusions summary, show promotes polarization STAT6-dependent signaling pathway, contributes to resolution damaged tissues. Our finding suggests supplement may be useful approach treatment.

Language: Английский

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Ketones and the Heart: Metabolic Principles and Therapeutic Implications

Circulation Research, Journal Year: 2023, Volume and Issue: 132(7), P. 882 - 898

Published: March 30, 2023

The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone a critical cardiac fuel have diverse roles the regulation of cellular processes such as metabolism, inflammation, crosstalk multiple organs that mediate disease. This review focuses on role metabolism health disease with an emphasis therapeutic potential ketosis treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative contributes to dysfunction pathologic remodeling during development HF. Growing evidence supports adaptive HF promote normal function attenuate progression. Enhanced utilization is mediated increased availability due systemic autonomous upregulation ketolytic enzymes. Therapeutic strategies designed restore high-capacity show promise address deficits underpin progression However, mechanisms involved beneficial effects yet be defined represent important future lines inquiry. In addition use energy substrate oxidation, modulate myocardial glucose fatty acids, two vital substrates regulate hypertrophy. salutary may also include extra-cardiac modulating immune responses, reducing fibrosis, promoting angiogenesis vasodilation. Additional pleotropic signaling properties AcAc discussed including epigenetic protection against stress. Evidence benefit feasibility examined preclinical clinical studies. Finally, ongoing trials reviewed perspective translation therapeutics

Language: Английский

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A review of healthy role of dietary fiber in modulating chronic diseases

Food Research International, Journal Year: 2024, Volume and Issue: 191, P. 114682 - 114682

Published: June 27, 2024

Language: Английский

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Ketone Body 3‐Hydroxybutyrate Ameliorates Atherosclerosis via Receptor Gpr109a‐Mediated Calcium Influx

Advanced Science, Journal Year: 2021, Volume and Issue: 8(9)

Published: March 1, 2021

Atherosclerosis is a chronic inflammatory disease that can cause acute cardiovascular events. Activation of the NOD-like receptor family, pyrin domain containing protein 3 (NLRP3) inflammasome enhances atherogenesis, which links lipid metabolism to sterile inflammation. This study examines impact an endogenous metabolite, namely ketone body 3-hydroxybutyrate (3-HB), on mouse model atherosclerosis. It found daily oral administration 3-HB significantly ameliorate Mechanistically, reduce M1 macrophage proportion and promote cholesterol efflux by acting macrophages through its G-protein-coupled 109a (Gpr109a). 3-HB-Gpr109a signaling promotes extracellular calcium (Ca2+) influx. The elevation intracellular Ca2+ level reduces release from endothelium reticulum (ER) mitochondria, thus inhibits ER stress triggered store depletion. As NLRP3 be activated stress, inhibit activation inflammasome, triggers increase inhibition efflux. concluded nutritional supplementation attenuates atherosclerosis in mice.

Language: Английский

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Prebiotics and Postbiotics Synergistic Delivery Microcapsules from Microfluidics for Treating Colitis

Advanced Science, Journal Year: 2022, Volume and Issue: 9(16)

Published: April 11, 2022

Abstract Manipulation of gut microbiota by bacterial metabolites has shown protective effects against colitis; while the efficacy is strictly limited poor oral delivery efficiency and single drug usage. Here, a novel prebiotics postbiotics synergistic microcapsule composed indole‐3‐propionic acid (IPA) postbiotic three including alginate sodium, resistant starch (RS), chitosan via microfluidic electrospray for preventing treating colitis are proposed. It found that administration IPA microcapsules (IPA@MC) to mice can exert significant colitis, suggesting therapeutic synergy between postbiotics. Furthermore, mechanism IPA@MC revealed in modulating microbiota, significantly increasing overall richness abundance short‐chain fatty acids (SCFA) producing bacteria such as Faecalibacterium Roseburia . These results indicate ideal candidates colitis.

Language: Английский

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Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease

Frontiers in Physiology, Journal Year: 2022, Volume and Issue: 13

Published: July 4, 2022

Non-alcoholic fatty liver disease (NAFLD), the most common chronic diseases, arise from non-alcoholic (NAFL) characterized by excessive fat accumulation as triglycerides. Although NAFL is benign, it could progress to steatohepatitis (NASH) manifested with inflammation, hepatocyte damage and fibrosis. A subset of NASH patients develops end-stage diseases such cirrhosis hepatocellular carcinoma. The pathogenesis NAFLD highly complex strongly associated perturbations in lipid glucose metabolism. Lipid disposal pathways, particular, impairment condensation acetyl-CoA derived β-oxidation into ketogenic pathway influence hepatic loads Current evidence suggests that ketogenesis dispose up two-thirds lipids entering liver, its dysregulation significantly contribute pathogenesis. Moreover, ketone body administration mice humans shows a significant improvement NAFLD. This review focuses on role We possible mechanisms through which impaired may promote progression. Finally, sheds light therapeutic implications diet

Language: Английский

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The Promise of Niacin in Neurology

Neurotherapeutics, Journal Year: 2023, Volume and Issue: 20(4), P. 1037 - 1054

Published: April 21, 2023

Language: Английский

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Ketones and the cardiovascular system

Nature Cardiovascular Research, Journal Year: 2023, Volume and Issue: 2(5), P. 425 - 437

Published: April 10, 2023

Language: Английский

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Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3534 - 3534

Published: Feb. 10, 2023

The increased metabolic activity of the heart as a pump involves high demand mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical activities accomplished mainly via oxidative phosphorylation, supplying up to 95% necessary ATP production, with rest attained by substrate-level phosphorylation in glycolysis. In normal human heart, fatty acids provide principal fuel (40-70%) generation, followed glucose (20-30%), lesser degree (<5%) other substrates (lactate, ketones, pyruvate amino acids). Although ketones contribute 4-15% under situations, rate use is drastically diminished hypertrophied failing which switches ketone bodies an alternate are oxidized lieu glucose, if adequately abundant, they reduce myocardial fat delivery usage. Increasing cardiac body oxidation appears beneficial context failure (HF) pathological cardiovascular (CV) conditions. Also, enhanced expression genes crucial break down facilitates or usage averts slows HF, potentially avoiding glucose-derived carbon needed anabolic processes. These issues utilization HF CV diseases herein reviewed pictorially illustrated.

Language: Английский

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