The Upregulation of Leucine-Rich Repeat Containing 1 Expression Activates Hepatic Stellate Cells and Promotes Liver Fibrosis by Stabilizing Phosphorylated Smad2/3.

Liver fibrosis poses a significant global health risk due to its association with hepatocellular carcinoma (HCC) and the lack of effective treatments. Thus, the need to discover additional novel therapeutic targets to attenuate liver diseases is urgent. Leucine-rich repeat containing 1 (LRRC1) reportedly promotes HCC development. Previously, we found that LRRC1 was significantly upregulated in rat fibrotic liver according to the transcriptome sequencing data. Herein, in the current work, we aimed to explore the role of LRRC1 in liver fibrosis and the underlying mechanisms involved. LRRC1 expression was positively correlated with liver fibrosis severity and significantly elevated in both human and murine fibrotic liver tissues. LRRC1 knockdown or overexpression inhibited or enhanced the proliferation, migration, and expression of fibrogenic genes in the human hepatic stellate cell line LX-2. More importantly, LRRC1 inhibition in vivo significantly alleviated CCl4-induced liver fibrosis by reducing collagen accumulation and hepatic stellate cells' (HSCs) activation in mice. Mechanistically, LRRC1 promoted HSC activation and liver fibrogenesis by preventing the ubiquitin-mediated degradation of phosphorylated mothers against decapentaplegic homolog (Smad) 2/3 (p-Smad2/3), thereby activating the TGF-ß1/Smad pathway. Collectively, these results clarify a novel role for LRRC1 as a regulator of liver fibrosis and indicate that LRRC1 is a promising target for antifibrotic therapies.

Protective Effect of Anthocyanins on Radiation-induced Hippocampal Injury through Activation of SIRT3.

BACKGROUND: Neuronal cell apoptosis is associated with radiation exposure. It is urgent to study the radiation protection of hippocampal neurons. OBJECTIVE: The purpose of this study was to investigate the protective effect of anthocyanins on radiation and its potential mechanism. MATERIALS AND METHODS: The irradiation was carried out at room temperature with 4-Gy dose. Anthocyanins were intraperitoneally administered to rats prior to radiation exposure. The immunohistology and survival of neurons within the hippocampi, neuroprotective effects of anthocyanin, mean ROS accumulation and SIRT3 expression by Western Blot and qRTPCR were performed. RESULTS: Anthocyanins inhibit radiation-induced apoptosis by activating SIRT3. SIRT3 mRNA increased 24 hours after anthocyanin performed, accompanied by an increase in SIRT3 protein and activity. CONCLUSION: Anthocyanin can effectively resist radiation-induced oxidation and support its role in scavenging cellular reactive oxygen species. The results showed that anthocyanin protected hippocampal neurons from apoptosis through the activity of SIRT3 after irradiation.

N-acetyl-L-tryptophan attenuates hepatic ischemia-reperfusion injury via regulating TLR4/NLRP3 signaling pathway in rats.

The aim of this study was to investigate the changes of TLR4/NLRP3 signal during hepatic ischemia-reperfusion injury (HIRI) and to verify whether N-acetyl-L-tryptophan (L-NAT) protected hepatocytes by regulating the activation of TLR4/NLRP3 signal. We have established the rat HIRI model and H2O2-induced cell damage model to simulate ischemia-reperfusion injury and detect the corresponding indicators. Compared with the sham group, Suzuki score and the level of serum ALT increased after HIRI, accompanied by an increased expression of NLRP3, ASC, Caspase-1, IL-1ß, TLR4, and NF-κB. While L-NAT pretreatment reversed the above-mentioned changes. Compared with the control group, cells in the H2O2 treated group became smaller in cell volume and round in shape with unclear boundaries. Similar to the phenotypes in vivo, H2O2 treatment also induced significant increase in expression of pyroptosis-related proteins (NLRP3, ASC, Caspase-1 and IL-1ß) and inflammatory factors (TLR4 and NF-κB). While L-NAT pretreatment attenuated injuries caused by H2O2. In conclusion, the present findings demonstrate that L-NAT alleviates HIRI by regulating activation of NLRP3 inflammasome, which may be related to the TLR4/NF-κB signaling pathway.