Wulingsan Alleviates MAFLD by Activating Autophagy via Regulating the AMPK/mTOR/ULK1 Signaling Pathway.

Here, we presented the study of the molecular mechanisms underlying the action of Wulingsan (WLS) in rats with metabolic-associated fatty liver disease (MAFLD) induced by a high-fat diet (HFD). High-performance liquid chromatography was employed to identify the chemical components of WLS. After 2 weeks of HFD induction, MAFLD rats were treated with WLS in three different doses for 6 weeks, a positive control treatment or with a vehicle. Lipid metabolism, liver function, oxidative stress, and inflammatory factors as well as pathomorphological changes in liver parenchyma were assessed in all groups. Finally, the expressions of autophagy-related markers, adenosine monophosphate-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)/unc-51-like kinase-1 (ULK1) signaling pathway-related genes, and proteins in liver were detected. The results revealed that WLS significantly ameliorated liver injury, the dysfunction of the lipid metabolism, the oxidative stress, and overall inflammatory status. Furthermore, WLS increased the expressions of LC3B-II, Beclin1, p-AMPK, and ULK1, along with decreased p62, p-mTOR, and sterol regulatory element-binding protein-1c levels. In conclusion, we showed that WLS is capable of alleviating HFD-induced MAFLD by improving lipid accumulation, suppressing oxidative stress and inflammation, and promoting autophagy.

Network meta-analysis on efficacy and safety of different biologics for ulcerative colitis.

BACKGROUND: Therapeutic options for ulcerative colitis (UC) have increased since the introduction of biologics a few decades ago. Due to the wide range of biologics available, physicians have difficulty in selecting biologics and do not know how to balance the best drug between clinical efficacy and safety. This study aimed to compare the efficacy and safety of biologics in treating ulcerative colitis. METHODS: In this study, eight electronic databases (PubMed, Web of Science, Cochrane, Embase, Sinomed, China National Knowledge Infrastructure, Chongqing VIP Information, and WanFang Data) were searched to collect eligible studies without language restrictions. Retrieved 1 June 2023, from inception. All articles included in the mesh analysis are randomised controlled trials (RCTs). The inclusion of drugs for each outcome was ranked using a curved surface under cumulative ranking (SUCRA). Higher SUCRA scores were associated with better outcomes, whereas lower SUCRA scores were associated with better safety. This study has registered with PROSPERO, CRD42023389483. RESULTS: Induction Therapy: Among the biologic therapies evaluated for induction therapy, vedolizumab demonstrated the highest efficacy in achieving clinical remission (OR vs daclizumab, 9.09; 95% CI, 1.01-81.61; SUCRA 94.1) and clinical response. Guselkumab showed the lowest risk of recurrence of UC (SUCRA 94.9%), adverse events resulting in treatment discontinuation (SUCRA 94.8%), and serious infections (SUCRA 78.0%). Maintenance Therapy: For maintenance therapy, vedolizumab ranked highest in maintaining clinical remission (OR vs mesalazine 4.36; 95% CI, 1.65-11.49; SUCRA 89.7) and endoscopic improvement (SUCRA 92.6). Infliximab demonstrated the highest efficacy in endoscopic improvement (SUCRA 92.6%). Ustekinumab had the lowest risk of infections (SUCRA 92.9%), serious adverse events (SUCRA 91.3%), and serious infections (SUCRA 67.6%). CONCLUSION: Our network meta-analysis suggests that vedolizumab is the most effective biologic therapy for inducing and maintaining clinical remission in UC patients. Guselkumab shows promise in reducing the risk of recurrence and adverse events during induction therapy. Infliximab is effective in improving endoscopic outcomes during maintenance therapy. Ustekinumab appears to have a favorable safety profile. These findings provide valuable insights for clinicians in selecting the most appropriate biologic therapy for UC patients.

Protective Effect of Danshen Zexie Decoction Against Non-Alcoholic Fatty Liver Disease Through Inhibition of ROS/NLRP3/IL-1ß Pathway by Nrf2 Signaling Activation.

Lipid metabolism disorders are a prominent characteristic in the pathological development of non-alcoholic fatty liver disease (NAFLD). Danshen zexie decoction (DZD) is a Chinese herbal medicine that is based on zexie decoction and has an effect of regulating lipid mechanism. However, the anti-NAFLD effect and mechanism of DZD remain unclear. In this study, we observed the therapeutic effect of DZD on NAFLD rats and investigated its possible mechanisms. Sixty Sprague Dawley rats were randomly assigned to six groups: control group, model group, Yishanfu (polyene phosphatidylcholine) group, and low, medium and high-dose DZD groups. High-fat diet (HFD) was fed to the rats to establish an NAFLD model, and each treatment group was given corresponding drugs at the same time for eight consecutive weeks. The results revealed that the obvious lipid metabolism disorder and liver injury induced by HFD were alleviated by treatment with DZD, which was verified by decreased serum TC, TG, ALT, AST, liver TC, TG, and FFA, as well as the alleviation of hepatic steatosis. The production of ROS in rats was reduced after treatment with DZD. The SOD activity and GSH content were increased with DZD treatment, while the MDA level was decreased. The administration of DZD could decrease serum IL-1ß and IL-18 contents. Moreover, DZD upregulated the expressions of Nrf2, HO-1, GCLC, and GCLM, while it suppressed the expressions of NLRP3, caspase-1, GSDMD, and GSDMD-N. In conclusion, the data showed that DZD can reduce lipid accumulation, alleviate oxidative stress and inflammation, and inhibit pyroptosis in NAFLD rats, which might be ascribed to suppression of the ROS/NLRP3/IL-1ß signaling pathway by activation of Nrf2. Overall, these results indicated that DZD is expected to be a therapeutic drug for NAFLD.

Protective effect of Chushizi (Fructus Broussonetiae) on acetaminophen-induced rat hepatitis by inhibiting the Toll-like receptor 3/c-Jun N-terminal kinase/c-jun/c-fos/janus protein tyrosine kinase/activators of transcription 3 pathway.

OBJECTIVE: To observe the intervention of Chushizi (Fructus Broussonetiae) (CSZ) on drug-induced liver injury (DILI) in rats, as well as indicators of liver function, serum levels of inflammatory cytokines, and expression of proteins and mRNA associated with toll-like receptor 3 (TLR3) and the signal transducer and activator of transcription 3 (STAT3) pathway in the liver [TLR3, janus protein tyrosine kinase 2 (JAK2), c-jun, c-fos, c-Jun N-terminal kinase 2 (JNK2), and STAT3]. METHODS: Forty specified pathogen free grade Sprague-Dawley rats were randomly divided into the control group, the model group, the silybin group and the CSZ group. Rats were given acetaminophen (APAP) to trigger DILI. Histopathology of the liver was observed by hematoxylin-eosin staining. The levels of alanine aminotransferase (ALT), aspartate transaminase (AST), direct bilirubin (DBIL), and total bilirubin (TBIL) in serum were detected by a semi-automatic biochemical instrument. Content of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-13, and IL-22 in serum were detected by the enzyme-linked immunosorbent assay, the expression of TLR3, phosphorylation of JAK2 (p-JAK2), while c-jun and c-fos proteins in the liver were determined by immunohistochemistry; expression of JNK2, and STAT3 in the liver were assayed by Western blot and real-time quantitative polymerase chain reaction. P-JNK2 and p-STAT3 in the liver were assayed by Western blot. RESULTS: After treatment, the activity of ALT, AST, and concentrations of TBIL, DBIL, TNF-α, IL-6, as well as IL-13 in serum, were lower than those in the model group, and expression of p-JAK2, TLR3, c-jun, c-fos, p-STAT3, and p-JNK2 could be downregulated. CONCLUSION: Our findings suggest that CSZ is a valid medicine to alleviate APAP-induced DILI, while its partial mechanism may regulate the TLR3/JNK/ c-jun/c-fos/JAK/STAT3 pathway.