A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure.

Background: Pathological 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. Methods: A 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. Results: Among 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. Conclusion: Our 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.

Multiomic Analysis Reveals Core Regulatory Mechanisms underlying Steroidal Glycoalkaloid Metabolism in Potato Tubers.

Steroidal glycoalkaloids (SGAs) present in germinated potato tubers are toxic; however, the mechanisms underlying SGA metabolism are poorly understood. Therefore, integrated transcriptome, metabolome, and hormone analyses were performed in this study to identify and characterize the key regulatory genes, metabolites, and phytohormones related to glycoalkaloid regulation. Based on transcriptome sequencing of bud eyes of germinated and dormant potato tubers, a total of 6260 differentially expressed genes were identified, which were mainly responsible for phytohormone signal transduction, carbohydrate metabolism, and secondary metabolite biosynthesis. Two TCP14 genes were identified as the core transcription factors that potentially regulate SGA synthesis. Metabolite analysis indicated that 149 significantly different metabolites were detected, and they were enriched in metabolic and biosynthetic pathways of secondary metabolites. In these pathways, the α-solanine content was increased and the expression of genes related to glycoalkaloid biosynthesis was upregulated. Levels of gibberellin and jasmonic acid were increased, whereas that of abscisic acid was decreased. This study lays a foundation for investigating the biosynthesis and regulation of SGAs and provides the reference for the production and consumption of potato tubers.

Comparative plasma and urine metabolomics analysis of juvenile and adult canines.

Background and aims: The 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. Methods: To 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. Results: The 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. Conclusion: Our 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.

Formation and instability of silver nanofilament in Ag-based programmable metallization cells.

In this paper, we report on the formation and rupture of Ag nanofilament on planar Ag/TiO2/Pt cells using visual observation. During the forming process, the filament tends to stay very thin. Specifically, it is so thin that it breaks up into a chain of nanospheres (according to Rayleigh instability) right after the formation has been completed. Similar mechanical breakup may also impact vertically stacked cells, causing reliability concerns.