Intracerebral hemorrhage (ICH) represents the most severe subtype of stroke, and the lack of effective clinical pharmacotherapies poses a substantial threat to human health. Hematoma plays a crucial role in determining the prognosis of ICH patients by causing primary mechanical extrusion, followed by secondary brain injuries, such as cerebral edema, iron-mediated oxidative stress, and inflammation resulting from its degradation products. 5α-androst-3β,5α,6β-triol (TRIOL) is a neuroprotective steroid currently undergoing phase II clinical trial for acute ischemic stroke with anti-oxidative and anti-inflammatory properties. However, whether TRIOL can protect brain against ICH injury remains unclear. In this study, we found that TRIOL significantly improved neurological function while reducing hematoma volume, cerebral edema, and tissue damage after ICH. Moreover, TRIOL enhanced microglial hematoma clearance through promoting CD36-mediated erythrophagocytosis and CD163-associated hemoglobin scavenging, while simultaneously reducing the release of microglial inflammatory factors and activating the antioxidative transcription factor Nrf2. Additionally, TRIOL inhibited neuron mediated hematoma absorption by suppressing heme oxygenase 2 (HO-2) and protected neurons against ICH-induced damage in vitro and in vivo. TRIOL also mitigated neuronal iron-dependent oxidative damage by increasing ferritin levels but decreasing divalent metal transporter 1 (DMT1) expression. Overall, these findings highlight the promising potential of TRIOL as a drug candidate for treating ICH.

Aging has been deemed the primary factor in erectile dysfunction (ED). Herein, age‐related changes in the erectile response and histomorphology were detected, and the relationship between aging and ED was investigated based on gene expression levels. Thirty male Sprague–Dawley (SD) rats were randomly divided into 6 groups, and intracavernous pressure (ICP) and mean arterial pressure (MAP) were measured. Subsequently, the corpus cavernosum (CC) was harvested and prepared for histological examinations of apoptosis, oxidative stress (OS), and fibrosis. Then, the microarray dataset (GSE10804) was analyzed to identify differentially expressed genes (DEGs) in ED progression, and hub genes were selected. In addition, aged CC smooth muscle cells (CCSMCs) were isolated to evaluate the function of the hub gene by siRNA interference, qRT–PCR, immunofluorescence staining, enzyme‐linked immunosorbent assay, western blot analysis, CCK‐8 assay, EdU staining, and flow cytometry approaches. The ICP/MAP and smooth muscle cell (SMC)/collagen ratios declined with aging, while apoptosis and OS levels increased with aging. The enriched functions and pathways of the DEGs were investigated, and 15 hub genes were identified, among which IGFBP3 was significantly upregulated. The IGFBP3 upregulation was verified in the CC of aging rats. Furthermore, aged CCSMCs were transfected with siRNA to knock down IGFBP3 expression. The viability and proliferation of the CCSMCs increased, while apoptosis, OS, and fibrosis decreased. Our findings demonstrate that the erectile response of SD rats declines in parallel with enhanced CC apoptosis, OS, and fibrosis with aging. Upregulation of IGFBP3 plays an important role; furthermore, downregulation of IGFBP3 improves the viability and proliferation of CCSMCs and alleviates apoptosis, OS, and fibrosis. Thus, IGFBP3 is a potential therapeutic target for age‐related ED.

Oncolytic virus is an effective therapeutic strategy for cancer treatment, which exploits natural or manipulated viruses to selectively target and kill cancer cells. However, the innate antiviral system of cancer cells may resistant to the treatment of oncolytic virus. M1 virus is a newly identified oncolytic virus belonging to alphavirus species, but the molecular mechanisms underlying its anticancer activity are largely unknown. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays. RNA seq analysis was used to analyze the gene alternation after M1 virus infection. Small interfering RNAs transfection for gene knockdown was used for gene functional tests. Caspase-3/7 activity was detected by Caspase-Glo Assay Systems. A mice model of orthotopic bladder tumor was established to determine the oncolytic effectiveness of the M1 virus. The expression of cleaved-Caspase 3 as well as Ki-67 in tumor cells were detected by immunohistochemical analysis. To further define the molecular factors involved in M1 virus-mediated biological function, we knocked down genes related to alphavirus’ activity and found that CCDC6 plays an important role in the oncolytic activity of M1 virus. Moreover, knocked down of CCDC6 augments the reproduction of M1 virus and resulted in endoplasmic reticulum (ER) stress-induced cell apoptosis in vitro as well as in vivo orthotopic bladder cancer model. Our research provides a rational new target for developing new compounds to promote the efficacy of oncolytic virus therapy.

Key Points: Peritoneal mucosal-associated invariant T (MAIT) cells were characterized by single-cell RNA sequencing, histological imaging, and flow cytometry. Activation of MAIT cells modulated glucose metabolism in mesothelial cells by TCRV α 7.2-MHC class 1–related protein 1 signaling and triggered peritoneal fibrogenesis. Pharmacological inhibition of MAIT cell function by acetyl-6-formylpterin mitigated peritoneal fibrosis. Background: Peritoneal fibrosis is a serious complication of long-term peritoneal dialysis (PD) and abdominal surgeries, yet effective treatments remain elusive. Given the known roles of mucosal-associated invariant T (MAIT) cells in immune responses and fibrotic diseases, we investigated their involvement in PD-induced peritoneal fibrosis to identify potential therapeutic targets. Methods: We used single-cell RNA sequencing and flow cytometry to characterize the activation and function of peritoneal MAIT cells in patients undergoing long-term PD. Our investigation focused on the molecular pathways activated by these cells, particularly the MHC class 1–related protein 1 (MR1)-mediated interaction with mesothelial cells and subsequent activation of the mTOR complex 1 signaling pathway. We further assessed the effect of inhibiting MAIT cells on fibrogenesis using both in vitro models and Mr1 knockout mice. Results: Our study revealed that long-term PD significantly enhanced the activation of MAIT cells, particularly the proinflammatory MAIT17 subtype. These activated cells contributed to peritoneal fibrogenesis by binding to the MR1 receptor on mesothelial cells, which triggered hyperglycolysis through the mTOR complex 1 pathway, ultimately leading to fibrogenesis. Notably, we demonstrated that blocking the MR1–MAIT interaction, either through genetic knockout or pharmacological inhibition with acetyl-6-formylpterin, effectively mitigated fibrosis. Conclusions: This study identified MAIT cells as crucial drivers of PD-induced peritoneal fibrosis.

Pyroptosis, driven by the N-terminal domain of gasdermin proteins (GSDM), promotes antitumor immunity by attracting lymphocytes to the tumor microenvironment (TME). However, current pyroptosis-inducing therapies like drug injections and phototherapy are limited to localized treatments, making them unsuitable for widespread or microscopic metastatic lesions. This study engineered oncolytic M1 viruses (rM1-mGSDME_FL and rM1-mGSDME_NT) to selectively deliver GSDME to tumor cells. These modified viruses enhanced tumor cell death in breast cancer models, suppressed tumor growth, extended survival in mice, and boosted immune cell infiltration, demonstrating significant anticancer potential through pyroptosis induction.

As the most common cancer of the genitourinary system, prostate cancer (PCa) is a global men′s health problem whose treatments are an urgent research issue. Treatment options for PCa include active surveillance (AS), surgery, endocrine therapy, chemotherapy, radiation therapy, immunotherapy, etc. However, as the cancer progresses, the effectiveness of treatment options gradually decreases, especially in metastatic castration-resistant prostate cancer (mCRPC), for which there are fewer therapeutic options and which have a shorter survival period and worse prognosis. For this reason, oncolytic viral therapy (PV), with its exceptional properties of selective tumor killing, relatively good safety in humans, and potential for transgenic delivery, has attracted increasing attention as a new form of anti-tumor strategy for PCa. There is growing evidence that OV not only kills tumor cells directly by lysis but can also activate anticancer immunity by acting on the tumor microenvironment (TME), thereby preventing tumor growth. In fact, evidence of the efficacy of this strategy has been observed since the late 19th century. However, subsequently, interest waned. The renewed interest in this therapy was due to advances in biotechnological methods and innovations at the end of the 20th century, which was also the beginning of PCa therapy with OV. Moreover, in combination with chemotherapy, radiotherapy, gene therapy or immunotherapy, OV viruses can have a wide range of applications and can provide an effective therapeutic result in the treatment of PCa.