Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology:Implications for Alzheimer's disease therapy

Alzheimer's disease(AD),characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates,is the most common neurodegenerative disorder with limited therapeutic agents.Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates,and transcription factor EB(TFEB)is a master regulator of autophagy and lysosomal biogenesis.Thus,small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy.Here,we found that celastrol,an active ingredient isolated from the root extracts of Tripterygium wilfordii(Lei Gong Teng in Chinese)enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains.Importantly,celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice,two commonly used AD animal models.Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol.Overall,our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models.Therefore,Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.

Arabidopsis EXTRA-LARGE G PROTEIN 1(XLG1) functions together with XLG2 and XLG3 in PAMP-triggered MAPK activation and immunity

Pattern-triggered immunity(PTI) is an essential strategy used by plants to deploy broad-spectrum resistance against pathogen attacks. Heterotrimeric G proteins have been reported to contribute to PTI.Of the three non-canonical EXTRA-LARGE G PROTEINs(XLGs) in Arabidopsis thaliana, XLG2 and XLG3 were shown to positively regulate immunity,but XLG1 was not considered to function in defense,based on the analysis of a weak xlg1 allele.In this study, we characterized the xlg1 xlg2 xlg3 triple knockout mutants generated from an xlg1 knockout allele. The strong xlg1 xlg2 xlg3 triple mutants compromised pathogen-associated molecular pattern(PAMP)-triggered activation of mitogen-activated protein kinases(MAPKs) and resistance to pathogen infection. The three XLGs interacted with MAPK cascade proteins involved in defense signaling, including the MAPK kinase kinases MAPKKK3 and MAPKKK5, the MAPK kinases MKK4 and MKK5, and the MAPKs MPK3 and MPK6. Expressing a constitutively active form of MKK4 restored MAPK activation and partially recovered the compromised disease resistance seen in the strong xlg1 xlg2 xlg3 triple mutant. Furthermore, mutations of all three XLGs largely restored the phenotype of the autoimmunity mutant bak1-interacting receptor-like kinase 1. Our study reveals that all three XLGs function redundantly in PAMP-triggered MAPK activation and plant immunity.

Drug discovery of sclerostin inhibitors

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA,the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis;however, it conferred high cardiovascular risk in clinical trials. Furthermore,romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.