Tirzepatide: A new glucagon-like peptide-1 receptor/glucose-dependent insulinotropic peptide receptor dual agonist / 中国临床药理学与治疗学

Tirzepatide is the first-in-class dual agonist of glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic peptide (GIP) receptor, which plays a variety of physiological effects by imitating natural GLP-1 and GIP. In the completed large phase III series of clinical studies of SURPASS and SURMOUNT, Tirzepatide has demonstrated excellent effects in decreasing glycosylated hemoglobin, reducing weight, improving blood lipid and other metabolic indicators, and is superior to the currently approved GLP-1 receptor agonist. Gastrointestinal reaction is the most common adverse event of the drug, which is generally mild to moderate, and decreases with continuous administration. On May 13, 2022, Tirzepatide was approved for listing by FDA, the current indication is to improve glycemic control of adult patients with type 2 diabetes (T2D) as an adjunct of diet and exercise. In addition to T2D and obesity, there are also extensive and in-depth studies on other metabolic fields. This paper makes a systematic overview of this.

LncRNA MALAT1/MiR-145 Adjusts IL-1β-Induced Chondrocytes Viability and Cartilage Matrix Degradation by Regulating ADAMTS5 in Human Osteoarthritis

PURPOSE: Accumulating evidence suggests that microRNA-145 (miR-145) plays an important role in osteoarthritis (OA), which is a chronic progressive joint disease. Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes metastasis in cancers and functions as a sponge for miR-145. However, the role of MALAT1/miR-145 in OA pathogenesis has not yet been elucidated. MATERIALS AND METHODS: The expression of MALAT1 and miR-145 was examined by quantitative real-time PCR; the interaction between miR-145, MALAT1 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 5 was verified by luciferase reporter assay. Correlations among MALAT1, miR-145, and ADAMTS5 were analyzed by Spearman rank analysis. Chondrocytes viability and cartilage extracellular matrix (ECM) degradation were investigated with cell viability assay and Western blotting analyzing expression of ADAMTS5, collagen type 2 alpha 1 (COL2A1), aggrecan (ACAN), and cartilage oligomeric matrix protein (COMP). RESULTS: MALAT1 was upregulated, and miR-145 was downregulated in OA samples and IL-1β-induced chondrocytes. Mechanically, miR-145 could directly bind to MALAT1 and ADAMTS5. Moreover, miR-145 expression was negatively correlated with MALAT1 and ADAMTS5 expression in OA patients, whereas MALAT1 and ADAMTS5 expression was positively correlated. Functionally, overexpression of MALAT1 inhibited chondrocyte viability and promoted cartilage ECM degradation in IL-1β-induced chondrocytes. In support thereof, MALAT1 silencing and miR-145 upregulation exerted the opposite effect in IL-1β-induced chondrocytes. Moreover, the effect of MALAT1 was counteracted by miR-145 upregulation, and ADAMTS5 restoration could abate miR-145 effects. CONCLUSION: An MALAT1/miR-145 axis contributes to ECM degradation in IL-1β-induced chondrocytes through targeting ADAMTS5, suggesting that MALAT1/miR-145/ADAMTS5 signaling may underlie human OA pathogenesis.

Roles of liver sinusoidal endothelial cells in liver diseases / 中国药理学通报

Liver sinusoidal endothelial cells (LSECs) are the highest proportion of liver non-parenchymal cells with fenestrae structure and high endocytic ability maintaining liver homeostasis and playing an indispensable role in the physiology and patholo-gy of the liver.LSECs are involved in the regulation of patholog-ical process in nonalcoholic fatty liver disease(NAFLD),alco-holic fatty liver(AFL),hepatocellular carcinoma(HCC),liverregeneration and liver fibrosis mainly via antiinflammation,endocytosis,secretion of angiocrine signals and maintaining thequiescence phenotype of HSCs.This review highlights the physiological function of LSECs and the different roles in different pathological conditions,which aims to provide a new perspectivefor the treatment of liver diseases through targeting LSECs.

Progress on roles and mechanisms of farnesoid X receptor (FXR) in chronic liver diseases / 中国药理学通报

Farnesoid X receptor ( FXR) plays a key role in me-tabolism of substance, such as bile acid, lipid, glucose,( etc) . Newly published credible discoveries have claimed that as a reg-ulatory hub in metabolism, FXR is closely linked with diverse chronic liver diseases, including viral hepatitis, alcoholic fatty liver disease, nonalcoholic fatty liver disease, hepatic fibrosis and hepatocellular carcinoma. This review summarizes the roles and mechanisms of FXR during the courses of chronic liver dis-eases, aiming at providing novel insights and therapeutic target for antifibrotic research and drug development.

Study on mechanism of NOXs in liver fibrosis / 中国药理学通报

Nicotinamide adenine dinucleotide phosphate oxidase ( NOXs) contributes to the production of reactive oxygen species ( ROS) in liver fibrosis, resulting in the activation of endoplas-mic reticulum stress ( ERS ) and IRE1α-XBP1 signaling path-way. ROS is a series of oxygen metabolites and its derivatives, produced by the single electron reduction of molecular oxygen ( O2 ) , including superoxide anion ( O2- ) , hydroxyl radical (-OH) , hydrogen peroxide ( H2 O2 ) , hypochlorite ion ( OCl-) and so on. They can interact with a large number of molecules, including small inorganic molecules, proteins, lipids, carbohy-drates and nucleic acids, resulting in lipid peroxidation of cell damaging molecules. And as a second messenger, ROS can also affect the proliferation and activation of HSC in liver fibrosis, and induce the hepatocyte apoptosis through a variety of cellular signal transduction. Here we review the current status of the study on the mechanism of NOXs in liver fibrosis.

Research progress of role of SOCS-3 in treating liver fibrosis / 中国药理学通报

Liver fibrosis occurs as compensatory responses to tis-sue repairing process in a wide range of chronic liver injures.It is characterized by excessive deposition of extracellular matrix (ECM)in liver tissues.The new discovery shows that suppres-sor of cytokine signaling (SOCS-3)is strictly associated with fi-brogenic progression of chronic liver diseases.Recent basic and clinical investigations also demonstrate that liver fibrogenesis is accompanied by SOCS-3,which critically determines the patho- genesis and prognosis of liver fibrosis.This review summarizes current knowledge on SOCS-3 and the relationships between SOCS-3 and liver fibrosis.On the other hand,it also presents the different strategies that have been used in experimental mod-els to counteract excessive SOCS-3 and the role of SOCS-3 in the prevention and treatment of liver fibrosis.

Experimental study on the treatment of BioLiver Ⅰ bioartificial liver support system to two types of acute liver failure canine models / 解放军医学杂志

Objective To assess the efficacy and safety of BioLiver Ⅰ bioartificial liver support system (BALSS) on the treatment of two types of acute liver failure (ALF) canine models. Methods The drug induced ALF canine model was established by multiple subcutaneous injections of acetaminophen. Another model was operated to resect 80 percent of the liver tissue. The primary hepatocytes were separated from the swine and cultured within the BALSS. The ALF models were treated by BioLiver ⅠBALSS for 6 hours. The changes of physiological, biochemical and histological parameters were observed before and after the treatment. Results The canines developed ALF 48 hours after injections of acetaminophen, the established rate of the model was 63 3%. While the other ALF canine model developed 24 hours after 80 percent liver resection and the established rate was 84 2%. Using our modified enzymatic digestion method, the yield of hepatocytes was (1 0～3 0)?10 10 per swine with high viability. BioLiver ⅠBALSS treatment resulted in beneficial effects on blood biochemical parameters. The pathological lesions of the liver were repaired. BALSS treatment was harmless to other organs. The ALF canines in drug group survived longer than in operation group. Conclusion This type of BALSS can provide safe and efficacious liver function support in the two types of ALF canine models, and it may be as an hepaful and important therapy to ALF