Depression and hepatobiliary diseases: a bidirectional Mendelian randomization study.

Background: More and more evidence suggests a close association between depression and hepatobiliary diseases, but its causal relationship is not yet clear. Method: Using genome-wide association studies (GWAS) to summarize data, independent genetic variations associated with depression were selected as instrumental variables. Firstly, we designed a univariate Mendelian randomization (UVMR) analysis with two samples and simultaneously conducted reverse validation to evaluate the potential bidirectional causal relationship between depression and various hepatobiliary diseases. Secondly, we conducted a multivariate Mendelian randomization (MVMR) analysis on diseases closely related to depression, exploring the mediating effects of waist to hip ratio, hypertension, and daytime nap. The mediating effects were obtained through MVMR. For UVMR and MVMR, inverse variance weighted method (IVW) is considered the most important analytical method. Sensitivity analysis was conducted using Cochran'Q, MR Egger, and Leave-one-out methods. Results: UVMR analysis showed that depression may increase the risk of non-alcoholic fatty liver disease (OR, 1.22; 95% CI, 1.03-1.46; p=0.0248) in liver diseases, while depression does not increase the risk of other liver diseases; In biliary and pancreatic related diseases, depression may increase the risk of cholelithiasis (OR, 1.26; 95% CI, 1.05-1.50; p=0.0120), chronic pancreatitis (OR, 1.61; 95% CI, 1.10-2.35; p=0.0140), and cholecystitis (OR, 1.23; 95% CI, 1.03-1.48; p=0.0250). In addition, through reverse validation, we found that non-alcoholic fatty liver disease, cholelithiasis, chronic pancreatitis, cholecystitis, or the inability to increase the risk of depression (p>0.05). The waist to hip ratio, hypertension, and daytime nap play a certain role in the process of depression leading to non-alcoholic fatty liver disease, with a mediating effect of 35.8%. Conclusion: Depression is a susceptibility factor for non-alcoholic fatty liver disease, and the causal effect of genetic susceptibility to depression on non-alcoholic fatty liver disease is mediated by waist-hip ratio, hypertension, and daytime nap.

Knockdown of Obg-like ATPase 1 enhances sorafenib sensitivity by inhibition of GSK-3ß/ß-catenin signaling in hepatocellular carcinoma cells.

Background: To clarify the molecular mechanism of hepatocellular carcinoma (HCC), conducive to developing an effective HCC therapy. Owing to the severe drug resistance, the clinical use of sorafenib, which is approved for HCC treatment, is limited. The precise molecular mechanisms of sorafenib drug resistance remain unclear. In the current work, we evaluated the role of Obg-like ATPase 1 (OLA1) in sorafenib resistance in HCC. Methods: The survival of HCC patients between OLA1 expression and sorafenib treatment was analyzed by Kaplan-Meier plotter. Cell viability was measured by cell counting kit-8 (CCK-8) and colony formation assays. Cell death was detected by propidium iodide (PI) and trypan blue staining. The mRNA and protein levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB), respectively. Results: We found that OLA1 was highly correlated with sorafenib resistance of HCC through a public database. Further study showed that knockdown of OLA1 enhanced cell proliferation inhibition and cell death induced by sorafenib, along with a reduction of proliferation-associated proteins (c-Myc and cyclin D1) and increase of apoptosis-related proteins (cleaved caspase-3 and cleaved PARP) in HCC cells. In addition, knockdown of OLA1 reduced the activation of glycogen synthase kinase 3ß (GSK-3ß)/ß-catenin. Conclusions: Our results proved that OLA1 can be a potential target to enhance sorafenib sensitivity in HCC.

Schisandrin B attenuates lipopolysaccharide-induced activation of hepatic stellate cells through Nrf-2-activating anti-oxidative activity.

Activated hepatic stellate cells (HSCs) are known to have a potential role in increasing the deposition of ECM and elevating proliferation in liver fibrosis, which can be driven by lipopolysaccharide (LPS). Schisandrin B (SB) is a dibenzocyclooctadiene derivative of Schisandra chinensis with anti-oxidative stress activity, but its effective target is unknown. Here, we have evaluated whether SB is protective against the LPS-induced activation of HSCs and have explored the underlying anti-oxidative stress mechanisms of SB. HSCs were treated with SB 1 h prior to LPS, and then incubated for indicated time. Nrf-2 in HSCs was inhibited genetically. The simultaneous effects on Nrf-2 activity, oxidative stress, cell proliferation, and ECM deposition were examined. SB decreased LPS-induced cell proliferation, fibrosis, and oxidative stress in HSCs. We further demonstrated that the protective effects of SB in LPS-induced HSCs activation involve the modulation of Nrf-2. SB, specifically targeting Nrf-2, attenuates the oxidative stress in HSCs. SB also reduces LPS-induced fibrosis and cell viability in HSCs. In addition, Nrf-2 may serve as a therapeutic target for infections or periods of chronic oxidative stress and may help with future drug discovery.