Cell Stress & Chaperones最新文献

Osteoarthritis (OA) is characterized primarily by the degeneration of articular cartilage, with a high prevalence and disability rate. The functional phenotype of chondrocytes, as the sole cell type within cartilage, is vital for OA progression. Due to the avascular nature of cartilage and its limited regenerative capacity, repair following injury poses significant challenges. Various cellular stressors, including hypoxia, nutrient deprivation, oxidative stress, and collagen mutations, can lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), resulting in ER stress (ERS). In response to restore ER homeostasis as well as cellular vitality and function, a series of adaptive mechanisms are triggered, including the unfolded protein response (UPR), ER-associated degradation (ERAD), and ER-phagy. Prolonged or severe ERS may exceed the adaptive capacity of cells, leading to dysregulation in apoptosis and autophagy-key pathogenic factors contributing to chondrocyte damage and OA progression. This review examines the relationship between ERS in OA chondrocytes and both apoptosis and autophagy in order to identify potential therapeutic targets and strategies for prevention and treatment of OA.

HER2-positive breast cancer (HER2+ BC) is distinguished by its poor prognosis, propensity for early onset, and high risk of recurrence and metastasis. Consequently, anti-HER2-targeted therapy has emerged as a principal strategy in the treatment of this form of breast cancer. Pyrotinib, a novel irreversible pan-HER2 tyrosine kinase inhibitor, has brought fresh hope to patients with advanced HER2+ breast cancer. In this study, we conducted a comprehensive exploration of pyrotinib's anti-tumor mechanism. The in vitro results showed that pyrotinib significantly inhibited SKBR3 cells viability and induced apoptosis by promoting HER2 endocytosis and ubiquitylation, leading to HER2 degradation through the displacement of HSP90 from HER2. Beyond targeting the HER2 signaling pathway, pyrotinib also induced DNA damage, which was mediated by the activation of the ROS/HSF-1 signaling pathway and the downregulation of PCNA expression. Furthermore, the in vivo results demonstrated a pronounced anticancer effect of pyrotinib in the SKBR3 xenograft mouse model, concomitant with a reduction in HER2 expression. In summary, our findings provide novel insights into the mechanism of pyrotinib in the treatment of HER2+ BC.

A recent elegant cryo-electron tomography study of the populations of different GroEL-GroES chaperonins complexes in whole bacterial cells (Wagner, Carvajal et al. 2024) contributes to the resolution of a long-standing debate about their mechanism, and reconciles three-decade-old results from in vitro biochemical studies, with new, refined in situ observations. Biochemists working with purified proteins often wonder if their findings faithfully reflect the situation in the crowded environment of cells, when their proteins mingle with concentrated metabolites and bump into membranes and thousands of different unrelated proteins. Here, cryo-electron tomography confirmed that careful in vitro protein biochemistry research still has a bright future.

Inflammatory bowel diseases (IBD) are driven by an exaggerated inflammatory response, which leads to a marked increase in oxidative stress. This, in turn, exacerbates the inflammatory process and causes significant cellular and tissue damage. Intestinal dysbiosis, a common observation in IBD patients, alters the production of bacterial metabolites, including short-chain fatty acids (SCFAs), which are key by-products of dietary fiber fermentation. While the role of SCFAs in intestinal physiology is still being elucidated, this study aimed to investigate their effects on intestinal oxidative stress, particularly under inflammatory conditions induced by the proinflammatory mediator tumour necrosis factor alpha (TNF-α). The Caco-2/TC7 cell line was employed as an in vitro model of the intestinal epithelium, and the cells were treated with a range of SCFAs, including acetate, propionate, and butyrate. The levels of protein and lipid oxidation were quantified, as well as the activity of antioxidant enzymes. Our findings demonstrate that microbiota-derived SCFAs can effectively mitigate TNF-α-induced oxidative stress by modulating antioxidant enzyme activity. The proinflammatory mediator TNF-α induces lipid peroxidation by inhibiting catalase and glutathione peroxidase activities. SCFAs are able to upregulate antioxidant enzyme activity to restore lipid oxidative levels. These results underscore the critical role of the gut microbiota in maintaining intestinal homeostasis and highlight the therapeutic potential of SCFAs in managing oxidative stress-related pathologies.

Osteoarthritis(OA), a common degenerative joint disease, is characterized by the apoptosis of chondrocytes as a primary pathophysiological change, with endoplasmic reticulum stress(ERS) playing a crucial role. It has been demonstrated that an imbalance in endoplasmic reticulum(ER) homeostasis can lead to ERS, activating three cellular adaptive response pathways through the unfolded protein response(UPR) to restore ER homeostasis. Mild ERS exerts a protective effect on cells, while prolonged ERS that disrupts the self-regulatory balance of the endoplasmic reticulum activates apoptotic signaling pathways, leading to chondrocyte apoptosis and hastening OA progression. Hence, controlling the ERS signaling pathway and its apoptotic factors has become a critical focus for preventing and treating OA. This review aims to elucidate the key mechanisms of ERS pathway-induced apoptosis, associated targets, and regulatory pathways, offering valuable insights to enhance the mechanistic understanding of OA. And it also reviews the mechanisms studied for ERS-related drugs or compounds for the treatment of OA.