SB-505124

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition characterised by bladder pain, urinary frequency, and urgency, which impacts quality of life. The pathogenesis remains unclear, though bladder fibrosis resulting from epithelial-mesenchymal transition (EMT) plays a key role. Transforming growth factor-β1 (TGF-β1) is a critical inducer of EMT and has been implicated in IC/BPS, although the molecular mechanisms are not fully understood. Rho-associated kinase (ROCK), a downstream effector of TGF-β1, may be involved in this process. This study aimed to explore the role of TGF-β1 in regulating EMT through ROCK in IC/BPS. An interstitial cystitis model in rats was established by intraperitoneal injection of cyclophosphamide (CYP). EMT in SV-HUC-1 cells was induced with recombinant TGF-β1 and modulated by treatment with the TGF-β receptor inhibitor SB505124 and the ROCK inhibitor Y-27632. Mechanical pain sensitivity was assessed using the Von Frey test, and serum TGF-β1 levels were measured by ELISA. Fibrosis markers in bladder tissue and cell were analyzed by H&E staining, Masson's trichrome, Western blotting, immunohistochemistry, and immunofluorescence. Results showed CYP-induced rats exhibited mechanical pain, elevated serum TGF-β1, and aggravated bladder fibrosis. In addition, TGF-β1, ROCK, and fibrosis-related proteins (vimentin, N-cadherin, fibroblast-specific protein 1, α-smooth muscle actin) were upregulated, while E-cadherin was reduced. Inhibition of TGF-β1 and ROCK reversed these changes, though the ROCK inhibitor did not affect TGF-β1 levels. This study demonstrates that TGF-β1 mediates EMT in bladder epithelial cells via ROCK, contributing to IC/BPS pathogenesis, and suggests that TGF-β1 and ROCK inhibitors may offer potential therapeutic strategies for IC/BPS.

Low-grade gliomas (LGG) are known for their slow growth yet retain the potential to progress to more aggressive malignancies. Glioma cells are frequently exposed to stressors such as hypoxia, nutrient deprivation, and oxidative stress, which disrupt protein folding within the endoplasmic reticulum (ER), leading to ER stress and activation of the unfolded protein response (UPR). ER stress plays a complex role in glioma initiation, progression, and resistance to chemotherapy. Dysregulated signaling between mitochondria and the ER can further exacerbate ER stress, impacting glioma cell survival and proliferation. Elucidating the molecular mechanisms by which mitochondrial interactions influence ER stress may reveal novel therapeutic targets for LGG treatment.

ER-stress related mitochondrial protein-coding genes (ERSMGs) linked to LGG prognosis were identified using Mitocarta3.0, Genecards, CGGA, and TCGA data. A prognostic model was developed via univariate and LASSO-Cox regression and validated by ROC curves. OMA1's role was assessed through knockdown experiments in LGG cell lines.

Eleven ERSMGs were significantly associated with LGG prognosis. The model achieved reliable predictive accuracy (AUC > 0.6) and stratified patients into high- and low-risk groups with distinct survival rates. High-risk patients exhibited increased sensitivity to SB505124. OMA1 knockdown in LGG cells induced ER stress by promoting mitochondrial fusion, increasing mtROS, ultimately inhibiting cell proliferation and invasion.

This study provides a novel prognostic model based on ERSMGs, offering novel insights into LGG progression and invasion. OMA1-mediated mitochondrial dysfunction and ER stress play critical roles in glioma cell growth and survival, representing potential therapeutic targets.