Background: Oxidative stress from elevated reactive oxygen species (ROS) has been reported to induce cell apoptosis and may provide a means to target cancer cells. Celastrol is a natural bioactive compound that was recently shown to increase ROS levels and cause apoptosis in cancer cells. However, the underlying mechanism for this cytotoxic action remains unclear and direct molecular targets of Celastrol have not been identified. Methods: Proteome microarray, surface plasmon resonance, isothermal titration calorimetry and molecular simulation were used to identify the molecular target of Celastrol. Binding and activity assays were used to validate the interaction of Celastrol with target protein in cell-free and gastric cancer cell lysates. We then assessed target transcript levels in in biopsy specimens obtained from patients with gastric cancer. Gastric cancer growth-limiting and cytotoxic activity of Celastrol was evaluated in BALB/c nu/nu mice. Results: Our data show that Celastrol directly binds to an antioxidant enzyme, peroxiredoxin-2 (Prdx2), which then inhibits its enzyme activity at both molecular and cellular level. Inhibition of Prdx2 by Celastrol increased cellular ROS levels and led to ROS-dependent endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis in gastric cancer cells. Functional tests demonstrated that Celastrol limits gastric cancer cells, at least in part, through targeting Prdx2. Celastrol treatment of mice implanted with gastric cancer cells also inhibited tumor growth, associated with Prdx2 inhibition and increased ROS. Analysis of human gastric cancer also showed increased Prdx2 levels and correlation with survival. Conclusion: Our studies have uncovered a potential Celastrol-interacting protein Prdx2 and a ROS-dependent mechanism of its action. The findings also highlight Prdx2 as a potential target for the treatment of gastric cancer.
As a thiol-dependent enzyme, thioredoxin reductase (TrxR) is a promising antibacterial drug target. Ebselen, an organo-selenium with well-characterized toxicology and pharmacology, was recently reported to have potent antibacterial activity against Staphylococcus aureus. In this paper, we demonstrated that ebselen has strong bactericidal activity against multidrug-resistant (MDR) S. aureus based on taking TrxR as a major target and disruption of the redox microenvironment. Further, the topical therapeutic efficacy of ebselen for staphylococcal skin infections was assessed in a rat model. Treatment with ebselen significantly reduced the bacterial load and the expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) in S. aureus skin lesions; further, wound healing and pathological changes were obvious improved in ebselen-treated rats compare to controls. Finally, ebselen was found to sensitize S. aureus to curcumin, which may be due to their synergistic effects in inhibiting bacterial TrxR. Altogether, ebselen is an effective topical antibacterial agent in animal model of MDR S. aureus LT-1 skin infection. This may lay the foundation for further analysis and development of ebselen as an antibacterial agent for topical treatment of MDR staphylococcal infections.
The COVID-19 pandemic has posed a significant health threat globally. Timely and appropriate vaccination is a key step to reduce the morbidity and mortality from COVID-19. The clinical course of COVID-19 infection and the effects of COVID-19 vaccination are influenced by patients’ health situations and involve a systemic physiological reaction. Just like an “endocrine phenotype” of COVID-19 infection, endocrine dysfunction after COVID-19 vaccination also acquired clinical concerns. In the present review, we briefly introduce the commonly available vaccines against SARS-CoV-2, summarize the influence of COVID-19 vaccines on the endocrine system, and explore the underlying pathogenic mechanisms.
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