BackgroundPathological cardiac hypertrophy is commonly resulted from sustained pressure overload and/or metabolic disorder and eventually leads to heart failure, lacking specific drugs in clinic. Here, we aimed to identify promising anti-hypertrophic drug(s) for heart failure and related metabolic disorders by using a luciferase reporter-based high-throughput screening.MethodsA screen of the FDA-approved compounds based on luciferase reporter was performed, with identified luteolin as a promising anti-hypertrophic drug. We systematically examined the therapeutic efficacy of luteolin on cardiac hypertrophy and heart failure in vitro and in vivo models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin.ResultsAmong 2,570 compounds in the library, luteolin emerged as the most robust candidate against cardiomyocyte hypertrophy. Luteolin dose-dependently blocked phenylephrine-induced cardiomyocyte hypertrophy and showed extensive cardioprotective roles in cardiomyocytes as evidenced by transcriptomics. More importantly, gastric administration of luteolin effectively ameliorated pathological cardiac hypertrophy, fibrosis, metabolic disorder, and heart failure in mice. Cross analysis of large-scale transcriptomics and drug-target interacting investigations indicated that peroxisome proliferator activated receptor γ (PPARγ) was the direct target of luteolin in the setting of pathological cardiac hypertrophy and metabolic disorders. Luteolin can directly interact with PPARγ to inhibit its ubiquitination and subsequent proteasomal degradation. Furthermore, PPARγ inhibitor and PPARγ knockdown both prevented the protective effect of luteolin against phenylephrine-induced cardiomyocyte hypertrophy in vitro.ConclusionOur data clearly supported that luteolin is a promising therapeutic compound for pathological cardiac hypertrophy and heart failure by directly targeting ubiquitin-proteasomal degradation of PPARγ and the related metabolic homeostasis.
Background and aimsThe metabolomic profile of a biofluid can be affected by age, and thus provides detailed information about the metabolic alterations in biological processes and reflects the in trinsic rule regulating the growth and developmental processes.MethodsTo systemically investigate the characteristics of multiple metabolic profiles associated with canine growth, we analyzed the metabolomics in the plasma and urine samples from 15 young and 15 adult beagle dogs via UHPLC-Q-TOFMS-based metabolomics. Blood routine and serum biochemical analyses were also performed on fasting blood samples.ResultsThe metabolomics results showed remarkable differences in metabolite fingerprints both in plasma and urine between the young and adult groups. The most obvious age-related metabolite alterations include decreased serumlevels of oxoglutaric acid and essential amino acids and derivatives but increased levels of urine levels of O-acetylserine. These changes primarily involved in amino acid metabolism and bile secretion pathways. We also found that the levels of glutamine were consistently higher in both serum and urine of adults, while N-acetylhistamine and uracil concentrations were much lower in the adult group compared to younger ones.ConclusionOur study provides a whole metabolic profile of serum and urine characteristics of young and adult canines, identifying several metabolites that were significantly associated with age change, which provides theoretical support for the nutrition-related research and age-related homeostasis maintenance in dogs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.