Celastrol induces ferroptosis in activated HSCs to ameliorate hepatic fibrosis via targeting peroxiredoxins and HO-1

Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron- and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfordii, shows effective anti-fibrotic and anti-inflammatory activities in multiple hepatic diseases. However, the exact molecular mechanisms of action and the direct protein targets of celastrol in the treatment of liver fibrosis remain largely elusive. Here, we discover that celastrol exerts anti-fibrotic effects via promoting the production of reactive oxygen species (ROS) and inducing ferroptosis in activated hepatic stellate cells (HSCs). By using activity-based protein profiling (ABPP) in combination with bio-orthogonal click chemistry reaction and cellular thermal shift assay (CETSA), we show that celastrol directly binds to peroxiredoxins (PRDXs), including PRDX1, PRDX2, PRDX4 and PRDX6, through the active cysteine sites, and inhibits their anti-oxidant activities. Celastrol also targets to heme oxygenase 1 (HO-1) and upregulates its expression in activated-HSCs. Knockdown of PRDX1, PRDX2, PRDX4, PRDX6 or HO-1 in HSCs, to varying extent, elevated cellular ROS levels and induced ferroptosis. Taken together, our findings reveal the direct protein targets and molecular mechanisms via which celastrol ameliorates hepatic fibrosis, thus supporting the further development of celastrol as a promising therapeutic agent for liver fibrosis.

Impairment of the autophagy-lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (Aβ) peptides and microtubule associated protein tau (MAPT/tau) in neuronal cells are hallmarks of AD. So far, the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited. Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes. Recently, there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis. Interestingly, the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD. Here, we first summarize the recent genetic, pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD. We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins, Aβ and MAPT/tau, in AD. Finally, we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials. Overall, this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.

Relationship between CT enhancement degree and multiple vascular parameters of microvessels and mature vessels of renal clear cell carcinoma / 实用放射学杂志

Objective To elucidate the correlation between the enhancement degree of renal clearcell carcinoma (RCC) on dynamic contrast-enhanced CT and multiple vascular morphometric characteristics including microvessels and mature vessels.Methods A retrospective review was carried out on the records of 37 patients pathologically diagnosed with RCC who underwent plain and triphasic contrast-enhanced CT.The absolute (enhancement attenuation-pre-enhancement attenuation) and relative(absolute enhancement value÷cortex enhancement attenuation) enhancement values of RCC were measured in arterial,venous and delayed phases.And all lesions were divided into hypervascular and hypovascular groups.The number,mean area,perimeter and diameter,shape factor (4π*area/perimeter2) and the total area of microvessels and mature vessels were obtained by CD34 or a-SMA immunohistochemical staining.Then the correlation of radiographic parameters and various vascular morphometric parameters were analyzed.Results In arterial,venous and delayed phases,the absolute enhancement values were positively correlated with the number and the total area of microvessels and mature vessels (P0.05).In addition, the significant differences in the number of microvessels and mature vessels between hypervascular and hypovascular groups were found (P<0.05).Conclusion CT enhancement degrees of RCC are related to multiple vascular morphometric indicators,which gives us more insights in the mechanism of RCC enhancement on CT.