Nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), is a liver disease worldwide without approved therapeutic drugs. Anti-inflammatory and hepatoprotective drug bicyclol and multi-pharmacological active drug berberine, respectively, have shown beneficial effects on NAFLD in murine nutritional models and patients, though the therapeutic mechanisms remain to be illustrated. Here, we investigated the combined effects of bicyclol and berberine on mouse steatosis induced by Western diet (WD), and NASH induced by WD/CCl4. The combined use of these was rather safe and better reduced the levels of transaminase in serum and triglycerides and cholesterol in the liver than their respective monotherapy, accompanied with more significantly attenuating hepatic inflammation, steatosis, and ballooning in mice with steatosis and NASH. The combined therapy also significantly inhibited fibrogenesis, characterized by the decreased hepatic collagen deposition and fibrotic surface. As per mechanism, bicyclol enhanced lipolysis and β-oxidation through restoring the p62-Nrf2-CES2 signaling axis and p62-Nrf2-PPARα signaling axis, respectively, while berberine suppressed de novo lipogenesis through downregulating the expression of acetyl-CoA carboxylase and fatty acid synthetase, along with enrichment of lipid metabolism-related Bacteroidaceae (family) and Bacteroides (genus). Of note, the combined use of bicyclol and berberine did not influence each other but enhanced the overall therapeutic role in the amelioration of NAFLD. Conclusion: Combined use of bicyclol and berberine might be a new available strategy to treat NAFLD.

Inflammation is an important biological process which contributes to risk for depression, in part as a result of the production of proinflammatory cytokines and of alterations in glutamatergic neurotransmission. Ketamine has anti-inflammatory properties which might contribute to its antidepressant effects. This study was designed to clarify mechanisms of action for ketamine and its active metabolites, (2R,6R;2S,6S)-hydroxynorketamine (HNK), which also appear to play a major role in ketamine's rapid antidepressant effects. An HMC3 human microglial cell line was used as a model system to test a possible role for ketamine in immune response regulation that might contribute to its antidepressant effects. Our results highlight the fact that ketamine and its two active metabolites can regulate the type I interferon pathway mediated, at least partially, through signal transducer and activation of transcription 3 (STAT3) which plays a major role in the immune response. Specifically, STAT3 downstream genes that were modulated by either ketamine or its active metabolites were enriched in the "response to type I interferon" pathway. Our data also suggest that STAT3 might play a role in ketamine's antidepressant effects, mediated, at least in part, through eukaryotic elongation factor 2 (EEF2), resulting in the augmentation of brain-derived neurotropic factor (BDNF) expression and promoting the synthesis of synaptic proteins postsynaptic density protein 95 (PSD95) and synapsin I (SYN1).

Treatment with direct-acting antivirals (DAAs) cures most patients infected with hepatitis C virus (HCV) in the real world. However, some patients, especially those with the underlying advanced liver disease, have a limited reduction of liver injury after achieving a sustained viral response (SVR). Bicyclol was widely used in clinics for the treatment of a variety of liver injuries but with an unknown mechanism for the treatment of hepatitis C. We investigated the anti-inflammatory effects and mechanisms of bicyclol in HCV-infected hepatocytes and further confirmed the putative results in a mouse hepatitis model induced by the coinjection of polyinosinic-polycytidylic acid [poly (I:C)] and D-galactosamine (D-GalN). The results showed that the activation of nuclear factor kappa B (NF-κB) and the subsequent increase of inflammatory factors were directly induced by HCV infection and were persistent after clearance of the virus in Huh7.5 cells. Bicyclol decreased the activation of NF-κB and the levels of inflammatory factors in HCV-infected hepatocytes by inhibiting the activation of the ROS-MAPK-NF-κB pathway, and the effect was synergistic with DAAs in HCV-infected hepatocytes. Bicyclol attenuated the ROS-MAPK-NF-κB axis via recovering mitochondrial function without a dependence on dihydronicotinamide adenine dinucleotide phosphate oxidase and superoxide dismutases. The anti-inflammatory effects and mechanism of bicyclol were verified in mouse hepatitis induced by the coinjection of poly(I:C)/D-GalN. Bicyclol directly ameliorates the chronic inflammation caused by HCV infection and might be used with DAAs or after DAA therapy for ultimately curing chronic hepatitis C.

The cell adhesion between leukocytes and endothelial cells plays an important balanced role in the pathophysiological function, while excessive adhesion caused by etiological agents is associated with the occurrence and development of many acute and chronic diseases. Cell adhesion inhibitors have been shown to have a potential therapeutic effect on these diseases, therefore, efficient and specific inhibitors against cell adhesion are highly desirable. Here, using lipopolysaccharide-induced human umbilical vein endothelial cells (HUVECs) and calcein-AM-labeled human monocytic cell THP-1, we established a high-throughput screening model for cell adhesion inhibitors with excellent model evaluation parameters. Using the drug repurposing strategy, we screened out lifitegrast, a potent cell adhesion inhibitor, which inhibited cell adhesion between HUVEC and THP-1 cells by directly interrupting the adhesion interaction between HUVEC and THP-1 cells and showed a strong therapeutic effect on the mouse acute liver injury induced by poly (I:C)/D-GalN. Therefore, the screening model is suitable for screening and validating cell adhesion inhibitors, which will promote the research and development of inhibitors for the treatment of diseases caused by excessive cell adhesion.