Purpose Doxorubicin (Dox) is a classic anthracycline chemotherapy drug with cause cumulative and dose-dependent cardiotoxicity. This study aimed to investigate the potential role and molecular mechanism of phenylacetylglutamine (PAGln), a novel gut microbiota metabolite, in Dox-induced cardiotoxicity (DIC). Methods DIC models were established in vivo and in vitro, and a series of experiments were performed to verify the cardioprotective effect of PAGln. RNA sequencing (RNA-seq) was employed to explore the mechanism of PAGln in DIC. Subsequently, the differentially expressed genes (DEGs) were subjected to comprehensive analysis using diverse public databases, and RT-PCR was used to confirm the expression levels of the candidate genes. Finally, molecular docking techniques were used for validation. Results PAGln effectively prevented both in vivo and in vitro Dox-induced myocardial injury and cell apoptosis. RNA-seq results showed that 40 genes were up-regulated and 54 down-regulated in the Dox group compared to the Con group, displaying opposite changes in the Dox + PAGln group. Enrichment analysis highlighted several mechanisms by which PAGln alleviated Dox-induced cardiotoxicity, including the lipid metabolic process, calcium-mediated signaling, positive regulation of store-operated calcium channel activity, and hypertrophic cardiomyopathy. In vitro and in vivo experiments confirmed that PAGln treatment could reverse the changes in the expression levels of Klb, Ece2, Nmnat2, Casq1, Pak1, and Apob in Dox. Molecular docking results showed that these genes had good binding activity with PAGln. Conclusions PAGln shows potential in alleviating Dox-induced cardiotoxicity, with Ece2 identified as key regulatory molecules related to endothelial dysfunction.
Mengxue He,Aiyang Liu,Jiachen Shi,Yong-Jiang Xu,Yuanfa Liu
Introduction: Cannabidiol (CBD) has important pharmacological activity, which includes antispasmodic, antioxidant, antithrombotic, and antianxiety properties. CBD has been applied as a health supplement to atherosclerosis. However, CBDs effect on gut microbiota and metabolic phenotype is unclear.Materials and Methods: We constructed a high production of cardiovascular risk factors, such as trimethylamine-N-oxide (TMAO) and phenylacetylglutamine (PAGln), in a mouse model using Clostridium sporogenes colonization. We used 16S ribosomal RNA (rRNA) gene sequencing and ultra-high performance liquid chromatography-quadrupole time-of flight mass spectrometry-based metabolomics to evaluate the effect of CBD on gut microbiota and plasma metabolites.Results: CBD decreased the levels of creatine kinase (CK), alanine transaminase (ALT), and low-density lipoprotein cholesterol and markedly increased high-density lipoprotein cholesterol. Furthermore, CBD treatment increased the abundance of beneficial bacteria, which include Lachnospiraceae_NK4A136 and Blautia in the gut, but it decreased the levels of TMAO and PAGln in the plasma.Conclusion: CBD might have beneficial effects for cardiovascular protection.
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