The pharmacological treatment of endometriosis using SPRMs requires improvement. The pure PR-agonist dienogest (DNG), a clinically established progestin, can serve as a reference compound for comparison. Its efficacy and safety have been well characterised in preclinical in vitro and in vivo studies, as well as in qualified pivotal clinical studies for the treatment of endometriosis. The pharmacodynamic profile of Dienogest (DNG) is compared with the experience of using the pure PR antagonist Vilaprisan and the mixed PR agonist/antagonist Asoprisnil to treat endometriosis. Unfortunately, the clinical development of Vilaprisan was suspended due to long-term toxicology findings in animals that require further clarification. The clinical development of Asoprisnil, however, was discontinued due to concerns regarding SPRM-associated endometrial changes, although the interpretation of PAEC has been debated. Additionally, another SPRM, Ulipristal acetate, has been associated with rare but serious cases of liver injury. However, Vilaprisan is primarily supported by fibroid-related clinical development, whereas Asoprisnil has limited Phase II endometriosis evidence. Nevertheless, this new mesoprogestin, Asoprisnil, has shown signs of tissue-selective activity in limited clinical and preclinical studies. Continuing the strategy of using mixed PR agonists/antagonists could inspire further drug development. The preclinical profile of the new mesoprogestin EC313 has been presented, showing a higher PR agonistic/antagonistic quotient than Asoprisnil, with comparatively elevated anti-endometriotic activity. Furthermore, EC313 increases the progesterone receptor isoform B/A ratio, but its clinical efficacy remains unproven as it is still in the early stages of development. Based on the preclinical data currently available, the next generation of mesoprogestins warrants further investigation for the treatment of endometriosis and related gynaecological disorders. This prompts consideration of whether there is potential to enhance the effectiveness of drug discovery strategies within this particular pharmacological class.

Cardiovascular complications increasingly challenge survivors of urological cancers, given the cardiotoxicity of therapies such as androgen deprivation, vascular endothelial growth factor receptor inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and chemotherapy. This narrative review addresses the complex crosstalk between urological cancer treatment and cardiovascular disease. It summarizes cardiovascular toxicities linked to major antineoplastic agents, explores underlying mechanisms including metabolic and immune-mediated effects, and proposes strategies for surveillance, diagnosis, and management. Highlighting the need for multidisciplinary collaboration, it outlines future directions for research to optimize cardiovascular outcomes in this high-risk population. The increasing complexity of cardiovascular care in patients with urological malignancies highlights the need for closer collaboration between cardiologists, urologists, and oncologists, with uro-cardio-oncology emerging as an important multidisciplinary field.

Steroid hormones play a pivotal role in fish sex differentiation, yet the dynamic expression patterns of key steroidogenic enzymes during this process remain incompletely characterized. Here, we combined genome-wide identification, time series transcriptomes spanning gonadal development (5-360 days post-hatch), and multiple hormone treatment experiments (17α-methyltestosterone, estrone, and etonogestrel) to investigate the Cyp11, Cyp17, Cyp19, and Cyp21 subfamilies in mandarin fish (Siniperca chuatsi). Seven steroidogenic Cyp genes were identified, showing teleost-specific expansion, with one duplicated pair (cyp17a2 and cyp2u1) exhibiting strong purifying selection. Expression profiling revealed pronounced sexually dimorphic and stage-specific patterns: During female differentiation (20-30 days), cyp19a1a and associated genes were highly expressed, coinciding with ovarian differentiation; during male differentiation (30-60 days), cyp17a2 and related genes were upregulated, aligning with testicular development. Exogenous hormone treatments further demonstrated that these genes are dynamically responsive: cyp19a1a and cyp17a2 were highly responsive to androgenic and progestogenic treatments, and their expression changes correlated closely with gonadal sex reversal phenotypes observed histologically. Collectively, this study provides a comprehensive expression atlas of steroidogenic Cyp genes during gonadal differentiation and identifies key hormonally responsive candidates for sex control in aquaculture.

Monensin, a polyether ionophore widely used in veterinary medicine, has recently emerged as a multimodal anticancer candidate. This review provides a comprehensive overview of preclinical studies showing that monensin exerts selective cytotoxic and anti-progression effects across a wide range of malignancies. Its activity spans breast cancer to leukemia, reflecting both versatility and significant therapeutic potential. In breast cancer, monensin reduces proliferation, induces apoptosis, and enhances chemosensitivity, suggesting a role in combination therapies. In prostate cancer, it disrupts androgen receptor signaling, induces oxidative stress, and triggers mitochondria-dependent apoptosis. In pancreatic cancer, it suppresses EGFR signaling and promotes programmed cell death, while in ovarian and cervical cancers, it inhibits proliferation, migration, and invasion by modulating EGFR and MEK/ERK pathways and enhancing SUMOylation. In renal carcinoma, monensin induces cell-cycle arrest, autophagy, and apoptosis, whereas in bladder and squamous cell carcinoma, it interferes with EGFR-related signaling and lectin-mediated interactions. It selectively kills liver cancer cells through intracellular Na[+] overload and mitochondrial damage, and in thyroid cancer, it disrupts cellular respiration and AMPK/mTOR signaling. In glioblastoma, it exhibits both anti-tumor and anti-angiogenic effects, while in hematologic malignancies such as leukemia and lymphoma, it induces apoptosis, cell-cycle arrest, and glycosylation alterations. Collectively, these findings highlight monensin as a highly promising, broad-spectrum anticancer candidate. Its multifaceted mechanisms of action and consistent efficacy across diverse tumor types provide a compelling rationale for continued preclinical evaluation and potential clinical translation. These insights position monensin as an innovative therapeutic avenue, offering new hope for the development of versatile and effective cancer treatments.

Background/Objectives: Cisplatin-induced testicular toxicity is commonly associated with oxidative stress; however, the early biological events preceding overt tissue injury remain incompletely characterized. Identifying interventions capable of preserving redox homeostasis during this subacute phase may improve our understanding of the initial mechanisms underlying testicular dysfunction. This study investigated whether methylsulfonylmethane (MSM), a naturally occurring organosulfur compound with antioxidant properties, modulates early oxidative responses in a subacute rat model of cisplatin-induced testicular toxicity. Methods: Thirty-two adult male Sprague-Dawley rats were randomly assigned to Control, Cisplatin (CIS), MSM, and CIS + MSM groups (n = 8/group). MSM (500 mg/kg/day, intraperitoneally) was administered for 10 consecutive days, while a single dose of cisplatin (7 mg/kg, intraperitoneally) was given on day 7. Oxidative stress biomarkers, antioxidant enzyme activities, intratesticular testosterone concentrations, inflammatory cytokines, GPX4 and HO-1 protein expression, histopathological alterations, and correlation analyses were evaluated. Results: Cisplatin exposure induced a marked oxidative imbalance, evidenced by increased malondialdehyde levels and reduced superoxide dismutase, catalase, glutathione peroxidase, and intratesticular testosterone concentrations (p < 0.05). MSM administration attenuated lipid peroxidation, restored antioxidant enzyme activities, and preserved intratesticular testosterone levels. Western blot analysis demonstrated a significant increase in GPX4 protein expression following cisplatin exposure, whereas MSM normalized GPX4 expression toward control values. In contrast, HO-1 expression and intratesticular IL-6 and TNF-α levels did not differ among the experimental groups. Histopathological evaluation revealed only mild structural alterations without corresponding differences in Johnsen score, indicating that biochemical and molecular disturbances preceded overt tissue degeneration. Correlation analysis further demonstrated close associations between antioxidant defense and preservation of endocrine function. Conclusions: Subacute cisplatin exposure primarily disrupted testicular redox homeostasis before prominent histopathological injury became evident. MSM was associated with attenuation of these early oxidative alterations accompanied by improved endogenous antioxidant enzyme activity, higher intratesticular testosterone concentrations, and normalization of GPX4 expression. These findings suggest that MSM may contribute to the maintenance of testicular redox homeostasis during the early phase of cisplatin-induced toxicity under the present experimental conditions.

Breast cancer is a highly heterogeneous malignancy with multiple molecular subtypes and variable treatment responses. Despite advances in endocrine therapy, HER2-targeted therapy, chemotherapy, and immunotherapy, treatment resistance and disease recurrence remain major clinical challenges. There is growing evidence that transcriptional plasticity and enhancer relinking contribute to tumor progression and treatment adaptation, highlighting the powerful role of epigenetic regulators. CREB-binding protein (CBP) and E1A-associated protein p300 (EP300) are transcriptional coactivators that regulate breast cancer enhancer activity and lineage-specific gene expression. Emerging research suggests that CBP/p300 is more of a context-dependent vulnerability point than a universal carcinogenic driver. ER-positive tumors exhibit a strong dependence on CBP/p300-mediated transcriptional programs, while the triple-negative breast cancer subgroup, including androgen receptor-positive and immunosuppressive tumors, may rely on CBP/p300-dependent signaling to maintain survival and treatment resistance. This is in contrast to their role in HER2-positive breast cancer. This review summarizes the biological functions of CBP/p300 in breast cancer and discusses subtype-specific vulnerability, biomarker-directed patient stratification, drug resistance mechanisms, rational combination strategies, and current translational challenges, emphasizing the need for precise treatment of breast cancer.