Cisplatin, a widely used chemotherapeutic agent, has proven efficacy against various malignancies. However, its clinical utility is hampered by its dose-limiting toxicities, including nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression. This review aims to provide a comprehensive overview of cisplatin toxicity, encompassing its underlying mechanisms, risk factors, and emerging therapeutic strategies. The mechanisms of cisplatin toxicity are multifactorial and involve oxidative stress, inflammation, DNA damage, and cellular apoptosis. Various risk factors contribute to the interindividual variability in susceptibility to cisplatin toxicity. The risk of developing cisplatin-induced toxicity could be related to pre-existing conditions, including kidney disease, hearing impairment, neuropathy, impaired liver function, and other comorbidities. Additionally, this review highlights the emerging therapeutic strategies that could be applied to minimize cisplatin-induced toxicities and aid in optimizing cisplatin treatment regimens, improving patient outcomes, and enhancing the overall quality of cancer care.

The cell cycle is tightly regulated to ensure controlled cell proliferation. Dysregulation of the cell cycle machinery is a hallmark of cancer that leads to unchecked growth. This review comprehensively analyzes key molecular regulators of the cell cycle and how they contribute to carcinogenesis when mutated or overexpressed. It focuses on cyclins, cyclin‐dependent kinases (CDKs), CDK inhibitors, checkpoint kinases, and mitotic regulators as therapeutic targets. Promising strategies include CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib for breast cancer treatment. Other possible targets include the anaphase‐promoting complex/cyclosome (APC/C), Skp2, p21, and aurora kinase inhibitors. However, challenges with resistance have limited clinical successes so far. Future efforts should focus on combinatorial therapies, next‐generation inhibitors, and biomarkers for patient selection. Targeting the cell cycle holds promise but further optimization is necessary to fully exploit it as an anti‐cancer strategy across diverse malignancies.

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.

Idiopathic pulmonary fibrosis (IPF) is an irreversible and life-threatening lung disease of unknown etiology presenting only a few treatment options. TGF-β signaling orchestrates a cascade of events driving pulmonary fibrosis (PF). Notably, recent research has affirmed the augmentation of TGF-β receptor (TβR) signaling via HSP90 activation. HSP90, a molecular chaperone, adeptly stabilizes and folds TβRs, thus intricately regulating TGF-β1 signaling. Our investigation illuminated the impact of alvespimycin, an HSP90 inhibitor, on TGF-β-mediated transcriptional responses by inducing destabilization of TβRs. This outcome stems from the explicit interaction of TβR subtypes I and II with HSP90, where they are clients of this cellular chaperone. It is worth noting that regulation of proteasome-dependent degradation of TβRs is a critical standpoint in the termination of TGF-β signal transduction. Oleuropein, the principal bioactive compound found in Olea europaea, is acknowledged for its role as a proteasome activator. In this study, our aim was to explore the efficacy of a combined therapy involving oleuropein and alvespimycin for the treatment of PF. We employed a PF rat model that was induced by intratracheal bleomycin infusion. The application of this dual therapy yielded a noteworthy impediment to the undesired activation of TGF-β/mothers against decapentaplegic homologs 2 and 3 (SMAD2/3) signaling. Consequently, this novel combination showcased improvements in both lung tissue structure and function while also effectively restraining key fibrosis markers such as PDGF-BB, TIMP-1, ACTA2, col1a1, and hydroxyproline. On a mechanistic level, our findings unveiled that the antifibrotic impact of this combination therapy likely stemmed from the enhanced degradation of both TβRI and TβRII. In conclusion, the utilization of proteasomal activators in conjunction with HSP90 inhibitors ushers in a promising frontier for the management of PF.

Beta‐blockers are commonly used medications that antagonize β‐adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta‐blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta‐adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta‐blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta‐blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.

Insulin resistance and diabetes are associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) conditions, which are distinguished by metabolic dysfunction, oxidative stress and inflammation. Sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, is fundamental in regulating metabolic pathways, reducing inflammation, and improving antioxidant defenses. This is the first study to investigate the effects of SRT1720, a SIRT1 activator, in diabetic rats on a high-fat diet. SRT1720 significantly lowered fasting blood glucose and insulin levels and enhanced glucose tolerance and HOMA-IR and QUICKI scores, indicating increased insulin sensitivity. The treatment also reduced total cholesterol, triglycerides, and LDL levels, showing amelioration of dyslipidemia. Moreover, SRT1720 lowered markers of liver fibrosis, including TGF-β, TIMP-1, Col1a1, and hydroxyproline, and decreased inflammation by reducing NFκB activity and pro-inflammatory cytokines (TNF-α and IL-6). Furthermore, SRT1720 augmented Nrf2 activity and HO-1 levels. Consequently, the SRT1720's protective role improved liver function and histology and prolonged rats' survival. These functions were suppressed by the co-administration of the SIRT1 inhibitor EX527, confirming that the beneficial effects of SRT1720 are SIRT1-dependent. Correlation analyses uncovered that increased SIRT1 activity was strongly associated with decreased oxidative stress, inflammation, insulin resistance, and fibrosis markers. To conclude, our results find that SRT1720 represents a promising therapeutic strategy for managing Type 2 diabetes in NAFLD or NASH patients possibly through the modulation of the SIRT1/Nrf2/NFκB signaling pathwa. SRT1720 could potentially halt or reverse the progression of these conditions and associated complications and merits further investigations.