Oenothein B ameliorates hepatic injury in alcoholic liver disease mice by improving oxidative stress and inflammation and modulating the gut microbiota.

Introduction: Alcoholic liver disease (ALD) is a global health problem for which there is no current food and drug administration (FDA)-approved therapy. Oenothein B (OEB) is a macrocyclic dimer ellagic tannin that possesses abundant biological activities including antioxidant, anti-inflammation, antitumor, immunomodulatory, and antimicrobial properties. Materials and methods: In this study, the hepatoprotective effect of OEB against ALD was investigated in vivo and in vitro. Results: We found that OEB treatment dramatically reduced alcohol-induced hepatic injury, as evidenced by decreased levels of aminotransferases and inflammatory biomarkers and increased antioxidant capacity in OEB-treated groups. Discussion: OEB treatment alleviated oxidative stress by upregulating the Keap1/Nrf2 signaling pathway and inhibited inflammation by downregulating the TLR4/NF-κB signaling pathway. Additionally, OEB treatment positively improved alcohol-induced intestinal microbial dysbiosis by modulating the structure and composition of gut microbiota. Interestingly, we observed the increasement of short-chain fatty acid (SCFA) producers (Muribaculaceae) and the decreasement of Gram-negative bacteria (Akkermansia) in the OEB treatment groups, which may contribute to the inhibition of hepatic oxidative stress and inflammation via the gut-liver axis. In summary, our findings indicate that OEB is a promising therapeutic strategy for preventing and treating ALD.

Enhanced Identification of Potential Pleiotropic Genetic Variants for Bone Mineral Density and Breast Cancer.

Epidemiological and clinical evidences have shown that bone mineral density (BMD) has a close relationship with breast cancer (BC). They might potentially have a shared genetic basis. By incorporating information about these pleiotropic effects, we may be able to explore more of the traits' total heritability. We applied a recently developed conditional false discovery rate (cFDR) method to the summary statistics from two independent GWASs to identify the potential pleiotropic genetic variants for BMD and BC. By jointly analyzing two large independent GWASs of BMD and BC, we found strong pleiotropic enrichment between them and identified 102 single-nucleotide polymorphisms (SNPs) in BMD and 192 SNPs in BC with cFDR < 0.05, including 230 SNPs that might have been overlooked by the standard GWAS analysis. cFDR-significant genes were enriched in GO terms and KEGG pathways which were crucial to bone metabolism and/or BC pathology (adjP < 0.05). Some cFDR-significant genes were partially validated in the gene expressional validation assay. Strong interactions were found between proteins produced by cFDR-significant genes in the context of biological mechanism of bone metabolism and/or BC etiology. Totally, we identified 7 pleiotropic SNPs that were associated with both BMD and BC (conjunction cFDR < 0.05); CCDC170, ESR1, RANKL, CPED1, and MEOX1 might play important roles in the pleiotropy of BMD and BC. Our study highlighted the significant pleiotropy between BMD and BC and shed novel insight into trait-specific as well as the potentially shared genetic architecture for both BMD and BC.

Genetic sharing with coronary artery disease identifies potential novel loci for bone mineral density.

Bone mineral density (BMD) is a complex trait with high missing heritability. Numerous evidences have shown that BMD variation has a relationship with coronary artery disease (CAD). This relationship may come from a common genetic basis called pleiotropy. By leveraging the pleiotropy with CAD, we may be able to improve the detection power of genetic variants associated with BMD. Using a recently developed conditional false discovery rate (cFDR) method, we jointly analyzed summary statistics from two large independent genome wide association studies (GWAS) of lumbar spine (LS) BMD and CAD. Strong pleiotropic enrichment and 7 pleiotropic SNPs were found for the two traits. We identified 41 SNPs for LS BMD (cFDR<0.05), of which 20 were replications of previous GWASs and 21 were potential novel SNPs that were not reported before. Four genes encompassed by 9 cFDR-significant SNPs were partially validated in the gene expression assay. Further functional enrichment analysis showed that genes corresponding to the cFDR-significant LS BMD SNPs were enriched in GO terms and KEGG pathways that played crucial roles in bone metabolism (adjP<0.05). In protein-protein interaction analysis, strong interactions were found between the proteins produced by the corresponding genes. Our study demonstrated the reliability and high-efficiency of the cFDR method on the detection of trait-associated genetic variants, the present findings shed novel insights into the genetic variability of BMD as well as the shared genetic basis underlying osteoporosis and CAD.