Chaihu Shugan San (CHSGS), a classic traditional Chinese medicinal formula, has been widely used in clinics for emotional disease. Here the protective effect and possible mechanisms of Chaihu Shugan San in stress-induced liver injury were investigated. The animal experimental protocol has been reviewed and approved by Laboratory Animal Ethics Committee of Jinan University, in compliance with the Institutional Animal Care Guidelines. Mice were administered CHSGS for 7 days and subjected to 18-h acute stress before being killed. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malondialdehyde (MDA) levels in serum were measured with commercial kits. Histomorphology of the liver was analyzed by hematoxylin-eosin staining and immunohistochemistry. Glutathione (GSH) content, 4-hydroxynonenal (4-HNE), brain and muscle Arnt-like protein-1 (BMAL1) and arachidonate 15-lipoxygenase (ALOX15) protein were detected by LC-MS and Western blot, respectively. The results showed that CHSGS ameliorated acute stress-induced liver damage by reducing ALT and AST levels in serum and inflammatory infiltration in liver tissue. Network pharmacology analysis showed that CHSGS was associated with lipid peroxidation. Further analysis confirmed that MDA and 4-HNE levels declined and GSH level increased in livers of stressed mice after CHSGS administration. CHSGS also lowered BMAL1 expression, a pivotal factor in circadian rhythm, in livers of stressed mice. In conclusion, CHSGS ameliorated stress-induced liver injury by repressing lipid peroxidation and regulating circadian rhythm. Our studies implicate that CHSGS is promising as a therapy for stress-induced liver injury, and lay foundation for designing novel prophylactic and therapeutic strategies for stress-induced liver injury.

To provide new ideas for further research and treatment of nonalcoholic fatty liver fibrosis, we used bioinformatics technology to search the gene microarray data related to this disease and identified differentially expressed genes and potential therapeutic drugs. Gene Expression Omnibus (GEO) was used to search the entry of "nonalcoholic fatty liver fibrosis"; the GSE109345 microarray data was downloaded, the differentially expressed genes in the control group and the fibrosis model group were screened with the BioJupie analysis platform, and GO function, KEGG pathway, protein-protein interaction (PPI) network analysis and visualization were conducted for the differentially expressed genes. Finally, through the Connectivity Map (CMap) data platform, compounds with potential efficacy on nonalcoholic fatty liver fibrosis were predicted. A total of 109 differentially expressed genes were screened, including 70 up-regulated genes and 39 down-regulated genes. Functional analysis showed that differentially expressed genes were mainly involved in protein kinase B signal transduction, extracellular domain function, small molecule binding and other functions; pathway analysis showed that these genes participated in retinol metabolism, steroid hormone synthesis, and arachidonic acid metabolism; PPI network analysis showed that metallopeptidase inhibitor 1 (TIMP1), chemokine (C-C motif) ligand 2 (CCL2), recombinant signal regulatory protein beta 1 (SIRPB1), and cytochrome P450 (CYP) were the main genes related to nonalcoholic fatty liver fibrosis. CMap analysis showed that pioglitazone, midodrine, arecoline and other compounds had potential efficacy in nonalcoholic fatty liver fibrosis. Thus, by screening for differentially expressed genes, related genes and potential therapeutic compounds effective in the treatment of non-alcoholic fatty liver fibrosis can be identified, as well as new ideas and approaches for the clinical treatment of non-alcoholic fatty liver fibrosis.

Hepatic fibrosis is a common pathological link of multiple chronic liver diseases, and further causes cirrhosis and even liver cancer. Tibetan medicine possessed significant and unique clinical effects in the prevention and treatment of hepatic fibrosis through unique medication methods such as single prescription, time synergy, and dialectical combination prescription. Pharmacological experimental studies have shown that a variety of Tibetan medicine formulas and herbs have anti-fibrotic effects, and their main pharmacological action mechanism involves inhibiting lipid peroxidation, reducing liver stellate cell activation and proliferation, regulating collagen metabolism, etc. This review summarizes the research progress of the clinical application and pharmacodynamic mechanism of Tibetan medicine in the prevention and treatment of liver fibrosis, aiming to provide a reference for the development of clinical use and innovative drugs discovery of Tibetan medicine against hepatic fibrosis.

In this study, we investigated the effect and mechanism of glaucocalyxin A on transforming growth factor-β1 (TGF-β1)-induced differentiation of lung fibroblasts by Western blotting, cellular immunofluorescence and collagen gel contraction assays. We monitored the phosphorylation of Smad3, measured extracellular regulated protein kinases (ERK) 1/2 and glycogen synthase kinse3β (Ser9) activity and the level of β-catenin to elucidate the role of glaucocalyxin A. The results show that glaucocalyxin A significantly decreased the expression of α-smooth muscle actin in lung fibroblasts; glaucocalyxin A remarkably reduced the formation of filaments and collagen gel contraction of lung fibroblasts; glaucocalyxin A notably down-regulated the production of fibronectin; glaucocalyxin A did not affect the phosphorylation level of Smad3 and ERK1/2; glaucocalyxin A markedly inhibited the phosphorylation of GSK3β (Ser9) and the levels of β-catenin; a GSK3β (S9A) mutant significantly inhibited lung fibroblast differentiation; and SKL2001, a β-catenin activator, partly reversed the inhibition of lung fibroblast differentiation by glaucocalyxin A. These results suggest that glaucocalyxin A significantly inhibits the differentiation of lung fibroblasts, which is related to the down-regulation of GSK3β/β-catenin signaling.

Epithelial mesenchymal transition (EMT) is a reprogramming process of epithelial to mesenchymal transition, in which epithelial cells lose polarity and intercellular adhesion and acquire stronger migration and invasion ability similar to mesenchymal cells. EMT is a critical step during the pathogenesis of pulmonary fibrosis. Lung epithelial cells can differentiate into myofibroblasts through EMT, which accelerates the fibrosis process. In recent years, a large number of studies have shown that non-coding RNAs (ncRNAs) are involved in the EMT process of lung epithelial cells, at the same time, some natural medicines were found to prevent and treat pulmonary fibrosis by intervening in ncRNAs related to pulmonary fibrosis. In this review, we summarize the expression change and biological function of vital ncRNAs in EMT progression during pulmonary fibrosis, as well as the research progress of EMT related ncRNA mediated by natural medicines on pulmonary fibrosis, aiming to provide new insights into the research of ncRNAs and the exploration of new pharmacological targets of natural medicine.

We analyzed the main chemical constituents of Huangqi decoction by HPLC coupled with diode array and evaporative light scattering detectors (HPLC-DAD-ELSD). The study on the mechanism of Huangqi decoction was based on network pharmacology and included multi-components, multi-targets, and multi-pathways in the treatment of non-alcoholic fatty liver disease (NAFLD). The chemical "fingerprints" of 15 batches of Huangqi decoction were established. Network pharmacology was used to screen and analyze the targets and pathways of the components of Huangqi decoction, and a "component-target-pathway" network was constructed to predict the mechanism of Huangqi decoction for the treatment of NAFLD. HPLC analysis of Huangqi decoction revealed 27 common peaks and the main chemical constituents were identified. Gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that glycyrrhetinic acid, isoliquiritigenin, glycyrrhizic acid, astragaloside Ⅳ, liquiritigenin, and astragaloside Ⅰ, the main active components of Huangqi decoction, may act on RAC-alpha serine/threonine-protein kinase (AKT1), interleukin-6 (IL-6), vascular endothelial cell growth factor A (VEGFA), mitogen-activated protein kinase 8 (MAPK8), and signal transducer and activator of transcription 3 (STAT3), and may regulate pathways involving phosphatidylinositol-3-kinases (PI3K)/protein kinase B (AKT), insulin resistance, hypoxia inducible factor-1 (HIF-1), tumor necrosis factor (TNF), among others. A decrease in insulin resistance, a reduction of inflammation, and anti-oxidative stress-related effects may be the mechanism of Huangqi decoction for the treatment of NAFLD.

S-phase kinase-associated protein 2 (Skp2) is one of the components of E3 ubiquitin ligase, which can induce proteasome-mediated proteolysis or regulate labeled substrates to promote cell proliferation and migration and inhibit cell apoptosis and senescence by connecting the ubiquitin chains of K48 and K63 to different substrates. Skp2 is also a potential drug target in a variety of fibrotic diseases, is highly expressed in a variety of fibrotic diseases, and regulates the occurrence and progression of these diseases. This paper reviews Skp2's structure, downstream targets, and cellular regulation and then focuses on research progress on Skp2 in various fibrotic diseases, such as liver fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, corneal fibrosis, and cardiac fibrosis, which may help provide a new research approaches for clinical development of Skp2-targeted antifibrotic drugs.

Fibrosis is a common manifestation of organ damage and failure. According to relevant statistics in the United States, deaths caused by fibrotic diseases account for 45% of all deaths in the country. Therefore, fibrotic diseases have received widespread attention worldwide. As a key kinase that regulates energy balance, AMP-activated protein kinase (AMPK), which mainly controls the transformation of cells from anabolic to catabolism, and restores the energy balance by phosphorylating its substrates. Therefore, it has become the core of treatment for diabetes and other metabolic-related diseases. Numerous recent pathological studies have shown that the expression of AMPK in fibrotic tissues is significantly down-regulated compared with normal tissues, and activation of AMPK could improve various fibrotic pathological processes (including autophagy dysfunction, oxidative stress, fibroblast proliferation, epithelial-mesenchymal transition, fibroblast-to-myofibroblast differentiation). Therefore, this review will discuss the structure and function of AMPK and its role in important phenotypes of fibrotic diseases, and provide evidence for AMPK as an important target for prevention and treatment of fibrosis.

Liver fibrosis is a common pathological process that many chronic liver diseases must undergo to develop into cirrhosis and hepatocellular carcinoma. Liver fibrosis is regulated by a variety of cytokines and signal pathways during its occurrence and development. In recent years, a large number of studies showed that ferroptosis is closely related to liver fibrosis. Compared with normal liver, the levels of irons and lipid peroxidation in the liver with fibrosis are significantly increased. Therefore, ferroptosis may be a potential target for the diagnosis, prevention, and treatment of liver fibrosis. This review summarizes the role of ferroptosis in liver fibrosis, thus to provide new ideas for the treatment of liver fibrosis.

Cardiac fibrosis is a vital pathological feature of various cardiovascular diseases, including myocardial infarction and heart failure. However, there have been few clinical interventions to treat cardiac fibrosis. Noncoding RNAs (ncRNAs) are a class of RNAs that do not encode proteins. ncRNAs participate in various cellular biological processes and regulate gene expression at transcription, post-transcription and epigenetic levels. Recent studies demonstrate that ncRNAs participate in the regulation of cardiac fibrosis by affecting the proliferation and transition of cardiac fibroblasts. ncRNAs can be used as potential intervention targets and biomarkers for cardiac fibrosis, provide new strategies and approach for treating and preventing fibrosis associated cardiovascular diseases. This review summarizes the function and mechanisms of ncRNAs in cardiac fibrosis.