PROTAC-DB 2.0: an updated database of PROTACs.

Proteolysis targeting chimeras (PROTACs), which harness the ubiquitin-proteasome system to selectively induce targeted protein degradation, represent an emerging therapeutic technology with the potential to modulate traditional undruggable targets. Over the past few years, this technology has moved from academia to industry and more than 10 PROTACs have been advanced into clinical trials. However, designing potent PROTACs with desirable drug-like properties still remains a great challenge. Here, we report an updated online database, PROTAC-DB 2.0, which is a repository of structural and experimental data about PROTACs. In this 2nd release, we expanded the number of PROTACs to 3270, which corresponds to a 96% expansion over the first version. Meanwhile, the numbers of warheads (small molecules targeting the proteins of interest), linkers, and E3 ligands (small molecules recruiting E3 ligases) have increased to over 360, 1500 and 80, respectively. In addition, given the importance and the limited number of the crystal target-PROTAC-E3 ternary complex structures, we provide the predicted ternary complex structures for PROTACs with good degradation capability using our PROTAC-Model method. To further facilitate the analysis of PROTAC data, a new filtering strategy based on the E3 ligases is also added. PROTAC-DB 2.0 is available online at http://cadd.zju.edu.cn/protacdb/.

Intercellular crosstalk of hepatic stellate cells in liver fibrosis: New insights into therapy.

Liver fibrosis is a dynamic wound-healing process characterized by the net accumulation of extracellular matrix. There is no efficient antifibrotic therapy other than liver transplantation to date. Activated hepatic stellate cells (HSCs) are the major cellular source of matrix-producing myofibroblasts, playing a central role in the initiation and progression of liver fibrosis. Paracrine signals from resident and inflammatory cells such as hepatocytes, liver sinusoidal endothelial cells, hepatic macrophages, natural killer/natural killer T cells, biliary epithelial cells, hepatic progenitor cells, and platelets can directly or indirectly regulate HSC differentiation and activation. Intercellular crosstalk between HSCs and those "responded" cells has been a critical event involved in HSC activation and fibrogenesis. This review summarizes recent advancement regarding intercellular communication between HSCs and other "responded cells" during liver fibrosis and experimental models of intercellular crosstalk systems, and provides novel ideas for potential antifibrotic therapeutic strategy.

Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure. Recently, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3K/AKT in fibrotic processes is increasingly prominent, with PI3K/AKT inhibitors currently under clinical evaluation in IPF. Therefore, PI3K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.

Genetic dominance of transforming growth factor-ß1 polymorphisms in chronic liver disease.

Chronic liver disease (CLD) is an extremely common clinical condition accompanied by sustained inflammatory response leading to tissue damage. Transforming growth factor-ß1 (TGF-ß1) is known as a master immune regulator in CLDs, but the association between TGF-ß1 polymorphisms and CLD risk is controversial and inconclusive, and the genetic dominance of CLDs remains unknown. In this study, the relationship between TGF-ß1 polymorphisms and CLD susceptibility is systematically analyzed based on 35 eligible studies. Individuals with the TGF-ß1-509 allele (TT or CT) or codon 10 allele (Pro/Pro) show an increased risk of CLDs. Subgroup analyses indicate TGF-ß1-509C/T has a significant correlation with cirrhosis and chronic hepatitis C, codon 10 is associated with chronic hepatitis B occurrence, and codon 25 exhibits a relationship with autoimmune hepatitis risk. Missense mutations in G29E, A105S, D191N, and F321L of TGF-ß1 are the genetic factors of HCC susceptibility. Furthermore, the TGF-ß1 gene expression is significantly elevated in CLD patients, and the TGF-ß1 codon 263 is located close to the region where the TGF-ß1 dimerization interacts, indicating the TGF-ß1 codon 263 variant may affect the secretion of TGF-ß1 by altering its dimerization. Together, our findings provide new insights into the immune regulator gene TGF-ß1 polymorphisms as susceptibility factors for CLD occurrence and regulators for TGF-ß1 expression, which have implications for the regulation of immune factors during CLD development.