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.

Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy

Mitochondria as a signaling platform play crucial roles in deciding cell fate. Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage. Mitophagy, one selective autophagy, is the key mitochondrial quality control that effectively removes damaged mitochondria. However, the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear. Here, we examined the functional implication of mitophagy in the anticancer properties of magnolol, a natural product isolated from herbal

Complementary and alternative medicine among Singapore cancer patients

<p><b>INTRODUCTION</b>This study evaluates determinants, expectations, association with quality of life (QOL) and doctor's awareness of Complementary and Alternative Medicine (CAM) use in Singapore cancer patients.</p><p><b>MATERIAL AND METHODS</b>We interviewed 316 patients visiting the Cancer Centre of the National University Hospital on behaviour, attitudes and expectations towards CAM and assessed QOL via Euroqol Questionnaire (EQ-5D). Medical information was obtained from oncologists.</p><p><b>RESULTS</b>One hundred and seventy-three patients (55%) reported CAM use after cancer diagnosis. Chinese ethnicity, tertiary education, age <65 years and previous CAM use were independent predictors of CAM use. Fifty-one per cent of CAM users informed their doctors about their use and 15% of doctors reported to be aware of CAM use in these patients. Thirty-seven per cent believed CAM to be equally or more effective than conventional cancer therapies and 78% expected at least basic knowledge about CAM from their oncologists. Twenty-fi ve per cent of patients reported concurrent use of oral CAM and chemotherapy, of which oncologists were unaware in 86% of cases. CAM users had higher EuroQol utility scores than non-CAM users (0.79 versus 0.73, respectively, P = 0.03), in particularly those aged >or=65 years and those with stage IV disease.</p><p><b>CONCLUSION</b>Singapore cancer patients show high prevalence of CAM use, high expectations regarding its effectiveness and doctors' knowledge on CAM and many use it concurrently with chemotherapy or radiotherapy. Since oncologists are generally unaware of CAM use in their patients, doctor-patient communication on CAM use needs to be improved. The association of CAM use and higher QOL scores in some subgroups deserves further exploration.</p>