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Heat shock protein 90 (HSP90) is a pivotal molecular chaperone with multifaceted roles in cellular health and disease. Herein, we explore how HSP90 orchestrates cellular stress responses, particularly through its partnership with heat shock factor 1 (HSF-1). PU-H71, a selective inhibitor of HSP90, demonstrates significant potential in cancer therapy by targeting a wide array of oncogenic pathways. By inducing the degradation of multiple client proteins, PU-H71 disrupts critical signaling pathways such as MAPK, PI3K/Akt, JAK/STAT, EGFR, and mTOR, which are essential for cancer cell survival, proliferation, and metastasis. We examined its impact on combating triple-negative breast cancer and enhancing the effectiveness of carbon-ion beam therapy, offering new avenues for cancer treatment. Furthermore, the dual inhibition of HSP90A and HSP90B1 by PU-H71 proves highly effective in the context of myeloma, providing fresh hope for patients with this challenging malignancy. We delve into its potential to induce apoptosis in B-cell lymphomas that rely on Bcl6 for survival, highlighting its relevance in the realm of hematologic cancers. Shifting our focus to hepatocellular carcinoma, we explore innovative approaches to chemotherapy. Moreover, the current review elucidates the potential capacity of PU-H71 to suppress glial cell activation paving the way for developing novel therapeutic strategies for neuroinflammatory disorders. Additionally, the present report also suggests the promising role of PU-H71 in JAK2-dependent myeloproliferative neoplasms. Eventually, our report sheds more light on the multiple functions of HSP90 protein as well as the potential therapeutic benefit of its selective inhibitor PU-H71 in the context of an array of diseases, laying the foundations for the development of novel therapeutic approaches that could achieve better treatment outcomes. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve long-term remission, underscoring a significant unmet therapeutic need. BMS-477118, a reversible inhibitor of dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical and clinical studies with minimal adverse effects compared to other antidiabetic agents. However, the potential benefits of BMS-477118 in chronic UC have not yet been explored. In this study, we aimed to investigate the effects of BMS-477118 in rats subjected to chronic dextran sodium sulfate (DSS) administration. Our findings indicate that BMS-477118 activates the interconnected positive feedback loop involving AMPK, SIRT1, and FOXO3a, improving histological appearance in injured rat colons. BMS-477118 also reduced fibrotic changes associated with the chronic nature of the animal model, alleviated macroscopic damage and disease severity, and improved the colon weight-to-length ratio. Additionally, BMS-477118 prevented DSS-induced weight loss and enhanced tight junction proteins. These effects, in conjunction with reduced oxidative stress and its potential anti-inflammatory, antiapoptotic, and autophagy-inducing properties, fostered prolonged survival in rats with chronic UC. To conclude, BMS-477118 has the potential to activate the AMPK/SIRT1/FOXO3a signaling pathway in inflamed colons. These results suggest that the AMPK/SIRT1/FOXO3a pathway could be a new therapeutic target for UC. Further research is mandatory to explore the therapeutic possibilities of this pathway. Additionally, continued studies on the therapeutic potential of BMS-477118 and other DPP4 inhibitors are promising for creating new treatments for various conditions, including UC in diabetic patients. [ABSTRACT FROM AUTHOR]

Introduction: Liver fibrosis is a significant global health burden that lacks effective therapies. It can progress to cirrhosis and hepatocellular carcinoma (HCC). Aberrant hedgehog pathway activation is a key driver of fibrogenesis and cancer, making hedgehog inhibitors potential antifibrotic and anticancer agents. Methods: We evaluated simvastatin and STA-9090, alone and combined, in rats fed a high-fat diet (HFD) and exposed to diethylnitrosamine and thioacetamide (DENA/TAA). Simvastatin inhibits HMG-CoA reductase, depleting cellular cholesterol required for Sonic hedgehog (Shh) modification and signaling. STA-9090 directly inhibits HSP90 chaperone interactions essential for Shh function. We hypothesized combining these drugs may provide liver protective effects through complementary targeting of the hedgehog pathway. Endpoints assessed included liver function tests, oxidative stress markers, histopathology, extracellular matrix proteins, inflammatory cytokines, and hedgehog signaling components. Results: HFD and DENA/TAA caused aberrant hedgehog activation, contributing to fibrotic alterations with elevated liver enzymes, oxidative stress, dyslipidemia, inflammation, and collagen deposition. Monotherapies with simvastatin or STA-9090 improved these parameters, while the combination treatment provided further enhancements, including improved survival, near-normal liver histology, and compelling hedgehog pathway suppression. Discussion: Our findings demonstrate the enhanced protective potential of combined HMG CoA reductase and HSP90 inhibition in rats fed a HFD and exposed to DENA and TAA. This preclinical study could help translate hedgehog-targeted therapies to clinical evaluation for treating this major unmet need. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colorectal area that demonstrates a dramatically increasing incidence worldwide. This study provides novel insights into the capacity of the exogenous β-hydroxybutyrate and ketogenic diet (KD) consumption to alleviate dextran sodium sulfate (DSS)-induced UC in rats. Remarkably, both interventions attenuated disease activity and colon weight-to-length ratio, and improved macro and microstructures of the damaged colon. Importantly, both β-hydroxybutyrate and KD curbed the DSS-induced aberrant NLRP3 inflammasome activation as observed in mRNA and protein expression analysis. Additionally, inhibition of the NLRP3/NGSDMD-mediated pyroptosis was detected in response to both regimens. In parallel, these modalities attenuated caspase-1 and its associated consequences of IL-1β and IL-18 overproduction. They also mitigated apoptosis as indicated by the inactivation of caspase-3. The anti-inflammatory effects of BHB and KD were confirmed by the reported decline in the levels of inflammatory markers including MPO, NFκB, IL-6, and TNF-α. Moreover, these interventions exhibited antioxidative properties by reducing ROS production and improving antioxidative enzymes. Their effectiveness in mitigating UC was also evident in the renovation of normal intestinal epithelial barrier function, as shown by correcting the discrepancies in the levels of tight junction proteins ZO-1, OCLN, and CLDN5. Furthermore, their effects on the intestinal microbiota homeostasis were investigated. In terms of autophagy, exogenous β-hydroxybutyrate upregulated BECN-1 and downregulated p62, which may account for its superiority over KD in attenuating colonic damage. In conclusion, this study provides experimental evidence supporting the potential therapeutic use of β-hydroxybutyrate or β-hydroxybutyrate-boosting regimens in UC. [ABSTRACT FROM AUTHOR]

Background: prevention of smoking is a key strategy to improve general health. However, survey data from Jeddah, Saudi Arabia have indicated that a large number of female medical students are addicted to smoking despite the knowledge of its harmful effects. This article comparatively explores the impact of smoking on health among female medical students in Jeddah, Saudi Arabia. Data were collected as part of a program of qualitative and quantitative research investigating the prevalence of smoking among female medical students. Objectives:to study the prevalence of smoking among females in the college of ibn Sina and it is impact on their health in relation to personal and family character, CAP knowledge attitude and practice, and association of medical condition as chronic bronchitis and bronchial asthma. Methods:the study was conducted among female's students attending college of ibn Sina-Jeddah-Saudi Arabia. An open-ended questionnaire was developed to cover the objectives. Conclusion: this study indicated that across the targeted sites, the descriptions made by female smokers about the harmful impact of smoking on their health were often vague. After assessment of the risk factor and variables that may increase prevalence of smoking among medical students, the prevalence of smoking was only 7.95% and used to practice smoking habit despite the knowledge of its side effects. [ABSTRACT FROM AUTHOR]