[Establishment of a model of reproductive system injury in male Wistar rats in high-altitude hypoxia environment].

OBJECTIVE: To establish a model of reproductive system injury in male rats at high altitude using the low-pressure hypoxic animal laboratory and study the changes in the testicular tissue, semen parameters, blood gas and oxidative stress in male rats at different altitudes. METHODS: Sixty male Wistar rats were randomly assigned to be raised on the plains (the plains group, n = 20), at an altitude of 4 000 m (the plateau model group Ⅰ, n = 20), or at an altitude of 6 000 m (the plateau model group Ⅱ, n = 20) for a spermatogenic cycle of 14 days. After establishment of the model of high-altitude reproductive system injury, the testis tissues of the rats were harvested for HE staining and observed for histopathological changes under the light microscope, and their epididymedes collected for preparation of sperm suspension and detection of sperm motility, sperm count and the percentage of morphologically abnormal sperm (MAS). The blood gas level and oxidative stress-related indexes in different groups were also measured using the serological test. RESULTS: With the elevation of altitude, the levels of pH and PO2 were decreased, those of PCO2, Hct, K+, Cl－ and Hb increased markedly, while that of Na+ exhibited no significant change. The model rats also showed folded spermatogenic tubule walls, thinned spermatogenic epithelia, disorderly arranged and reduced number of spermatogenic cells, and increased vascuolization in the spermatogenic epithelia, with decreased sperm motility and count, increased percentage of MAS, elevated concentration of malondialdehyde (MDA) and reduced activity of superoxide dismutase (SOD). CONCLUSIONS: A model of reproductive system injury was successfully established in male rats at a simulated altitude of 4 000 m. With increasing of the altitude to 6000 m, oxidative damage to the testicular tissue was aggravated, sperm motility decreased, and the percentage of MAS increased, indicating that an altitude of 6 000 m may cause serious damage to the rat reproductive system.

Case report and literature review of rezvilutamide in the treatment of hormone-sensitive prostate cancer.

Background: Prostate cancer represents a major health concern worldwide, with the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and locally advanced prostate cancer posing a particular challenge. Rezvilutamide, a new androgen receptor antagonist from China, has shown early promise; however, its real-world effectiveness and safety profile require further evidence. This case series evaluates the preliminary clinical outcomes of rezvilutamide in combination with androgen deprivation therapy (ADT), focusing on PSA response and radiological findings across various stages of prostate cancer in four patients. Case description: Case 1 details a 68-year-old male with low-volume mHSPC who exhibited a positive therapeutic response, demonstrated by decreasing PSA levels and improved radiographic results, despite experiencing mild side effects related to the drug. Case 2 describes a 71-year-old male with high-volume mHSPC who had a favorable outcome, with no significant changes in tumor size or metastatic spread and no negative reactions to the drug. Case 3 involves a 55-year-old male with locally advanced prostate cancer, who saw a reduction in PSA levels and a small decrease in tumor volume, yet with ongoing bladder involvement. Genetic testing showed no significant mutations. Case 4 presents a 74-year-old male with extensive metastatic disease who initially responded to the treatment but later exhibited disease advancement and an ATM gene mutation, signaling a shift to metastatic castration-resistant prostate cancer (mCRPC). This finding underscores the crucial role of genetic testing in directing future treatment, with therapies such as olaparib or chemotherapy being advised. Conclusions: Rezvilutamide has shown a potential benefit in the management of mHSPC and locally advanced prostate cancer, generally with a mild safety profile. Initial positive responses, particularly in PSA decline and radiographic progression, are promising. Nevertheless, the varying responses, notably concerning genetic mutations, highlight the necessity for tailored treatment approaches. Due to the small cohort and brief follow-up period, more extensive research with larger populations and prolonged monitoring is essential to conclusively determine the benefits and safety of rezvilutamide. The utilization of genetic insights is key to refining treatment decisions and enhancing outcomes for patients with advanced prostate cancer.

A novel genes-based signature with prognostic value and predictive ability to select patients responsive to Atezolizumab treatment in bladder cancer: an analysis on data from real-world studies.

Background: There is a lack of molecular markers that effectively predict response to treatment with immune checkpoint inhibitors in patients with uroepithelial bladder carcinoma. The purpose of this study was to explore molecular markers that effectively predict the efficacy of Atezolizumab in the treatment of uroepithelial bladder carcinoma based on real-world clinical trial data. Methods: Gene expression and clinical information of two groups of patients in two datasets, IMvigor210 and GSE176307, who were treated effectively and ineffectively with the programmed cell death 1 ligand 1 (PD-L1) inhibitor Atezolizumab, were obtained. Bioinformatic methods were used to screen out differentially expressed genes and detect the correlation between their expression and immune-related indicators. Subsequently, we assessed the ability of differentially expressed genes to predict the therapeutic response and prognosis of bladder cancer patients following Atezolizumab treatment. Results: A total of 2 differentially expressed genes, CXC motif chemokine ligand 9 (CXCL9) and CXC motif chemokine ligand 10 (CXCL10) [all P<0.05, log|fold change (FC)| >1], which were co-upregulated, were screened as study targets. In The Cancer Genome Atlas (TCGA) database, CXCL9/10 mRNA expression was positively correlated with both PD-L1 and tumor mutation burden (TMB) (all P<0.05). In the IMvigor210 dataset, the area under the receiver operating characteristic (ROC) curve for CXCL9, CXCL10 and PD-L1 mRNA expression to predict response to treatment with Atezolizumab were 0.645, 0.636 and 0.566, respectively; And CXCL9/10 mRNA was effective in predicting overall survival in patients receiving treatment (all P<0.05). In the GSE176307 dataset, the area under the ROC curve for CXCL9, CXCL10 and PD-L1 mRNA expression to predict response to treatment with Atezolizumab were 0.829, 0.829 and 0.765, respectively; And CXCL9/10 mRNA was not effective in predicting overall survival in patients receiving treatment (all P>0.05). Conclusions: The mRNA expression levels of CXCL9/10 have the potential to serve as a molecular marker for predicting the therapeutic response and overall survival outcomes of bladder cancer patients treated with Atezolizumab.

Development and validation of a predictive model for penile cancer based on the surveillance, epidemiology, and end results database and multi-center cases.

PURPOSE: Penile cancer (PC) is a great impact on the quality of life and psychological status of patients. This study aimed to construct nomograms using data from the Surveillance, Epidemiology, and End Results (SEER) database to predict overall survival (OS) and cancer-specific survival (CSS) in patients with penile cancer (PC). METHODS: Patients were divided into a training cohort (n = 634) and a validation cohort (n = 272) in a 7:3 ratio. Independent risk factors influencing the prognosis of PC were screened using univariate and multivariate Cox analyses, and models for predicting PC were developed. Data from 203 patients with PC in four tertiary hospitals in Gansu Province from 2012 to 2021 were externally validated. RESULTS: Univariate analysis and multivariate analysis showed revealed that the OS-related factors were age, grade, T stage, N stage, M stage and tumor size (p < 0.05); the CSS-related factors were age, mode of surgery, T stage, N stage, M stage and tumor size (p < 0.05). The C-indices of the OS and CSS nomograms in the training cohort were 0.743 [95% confidence interval (CI) (0.714-0.772)] and 0.797 (0.762-0.832), respectively. The C-indices of the OS and CSS nomograms in the internal validation cohort were 0.735 (0.686-0.784) and 0.755 (0.688-0.822), respectively, and those in the external validation cohort were 0.801 (0.746-0.856) and 0.863 (0.812-0.914), respectively. Receiver operating characteristic (ROC) curves, calibration curves, and survival curves all demonstrated good predictive performance of the nomograms. CONCLUSION: The nomograms for PC were developed using the SEER database. The accuracy and clinical usefulness of the model were validated through a combination of internal and external validations.

Effects of L-carnitine Administration on Sperm and Sex Hormone Levels in a Male Wistar Rat Reproductive System Injury Model in a High-Altitude Hypobaric Hypoxic Environment.

The plateau environment impacts male reproductive function, causing decreased sperm quality and testosterone levels. L-carnitine can improve the semen microenvironment. However, the role of L-carnitine in a high-altitude environment remains unclear. In our study, we investigated the effects of L-carnitine administration in a male Wistar rat reproductive system injury model in the context of a simulated high-altitude environment. Rats were randomly divided into a normal control group (group A1, A2-low dose and A3-high dose) and high-altitude model groups (group B, C-low dose and D-high dose) with 20 rats in each group. With the exception of the normal control group exposed to normoxic conditions, the other groups were maintained in a hypobaric oxygen chamber that simulated an altitude of 6000 m for 28 days. In the experimental period, the low-dose groups (A2 and C) were administered 50 mg/kg L-carnitine via intraperitoneal injection once a day, and the high-dose groups (A3 and D) were given 100 mg/kg. After the feeding period, blood samples were collected to assess blood gas, serum hormone levels and oxidative stress. Sperm from the epididymis were collected to analyse various sperm parameters. After obtaining the testicular tissue, the morphological and pathological changes were observed under a light microscope and transmission electron microscopy (TEM). The impact of the simulated high-altitude environment on the rat testis tissue is obvious. Specifically, a decreased testicular organ index and altered indices of arterial blood gas and serum sex hormone levels caused testicular tissue morphological damage, reduced sperm quality, increased sperm deformity rate and altered malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) concentrations. The results demonstrate that L-carnitine can be administered as a preventive intervention to reduce the reproductive damage caused by high-altitude hypobaric and hypoxic environments and improve semen quality in a rat model.

Hotspots and development frontiers of circRNA based on bibliometric analysis.

Background and purpose: Circular RNAs (circRNAs) are a big group of members of the noncoding RNA family following long non-coding RNA and microRNA. They play a regulatory role in many biological processes. Analyzing their current research status and future development trends is conducive to a more comprehensive understanding of circRNAs and contributes to the dedication to the biological field. Methods: The literature on circRNA from 2000 to 2021 in the Web of Science Core Collection of the Web of Science database with "circular RNA" as the subject was searched. R Studio's Bibliometrix package and biblioshiny software were used for publication trend analysis, citation analysis, keyword analysis, author analysis, research institution analysis, source analysis, country analysis, and collaboration analysis for all documents and highly cited documents. Results: From 2000 to 2021, 3,186 circRNA-related articles were published worldwide, of which 193 were highly cited. The number of published articles had shown an explosive increase after 2013. These articles were mainly from Chinese research institutions and authors, but the country with the highest average number of citations per year in highly cited documents was Germany. Scientific research institutions came from countries represented by Germany, USA, China, Australia and Canada all had different degrees of cooperation. The theme and key points of the research had evolved over time from expression to the role and mechanism of circRNA in diseases, especially in cancer. CDR1as, circFOXO3, circHIPK3, circITCH, circMTO1, circSMARCA5 and circZNF609 are circRNAs that are mainly studied currently, their studies mainly involve cell biology, biological functions and cancer. The future research direction and trend would still be the application of circRNA in diseases. Conclusion: The basic situation and development trend of circRNA related research we described provide a direction for future research.

Roles of circRNAs in prostate cancer: Expression, mechanism, application and potential.

Circular RNA (circRNA) is a member of the non-coding RNA family that is formed by trans-splicing. Because of its unique structure and characteristics, it has extraordinary value for the diagnosis, treatment, and prognosis of diseases, particularly for tumors. Study of the role of circRNAs in the occurrence and development of prostate cancer has made considerable progress, but many areas remain that require further exploration and improvement. This article describes research into sequencing expression profiles, expression regulation, potential value as biomarkers, mechanism in the occurrence and development, therapy resistance, relationship with clinicopathological features, and prognostic value of circRNAs in prostate cancer from the past few years.

PEBP4 silencing inhibits hypoxia-induced epithelial-to-mesenchymal transition in prostate cancer cells.

Hypoxia induced epithelial-to-mesenchymal transition (EMT) to facilitate the tumor biology. Phosphatidylethanolamine-binding protein 4 (PEBP4) is a member of the PEBP family and has been reported to be upregulated in various cancer types. The definite function of PEBP4 in regulating the EMT of prostate cancer, however, is still unclear. Here, we examined the functional role of PEBP4 and the underlying molecular mechanisms in hypoxia-induced EMT in prostate cancer cells. Our results showed that PEBP4 mRNA and protein expression was markedly increased in the human prostate cancer tissues and cell lines. Knockdown of PEBP4 significantly inhibited hypoxia-induced migration/invasion and EMT program. Furthermore, knockdown of PEBP4 prevented hypoxia-induced the expression of p-Akt and p-mTOR in prostate cancer cells. Taken together, this study reported here provided evidence that knockdown of PEBP4 inhibited hypoxia-induced EMT in prostate cancer cells. Our study uncovered a novel role for PEBP4 in prostate cancer progression, which might support the potential for PEBP4 targeting in prostate cancer therapy.

SAHA, an HDAC inhibitor, attenuates antibody-mediated allograft rejection.

BACKGROUND: Antibody-mediated rejection (AMR) is gaining increasing recognition as a critical causative factor contributing to graft loss in organ transplantation. However, current therapeutic options for prevention and treatment of AMR are very limited and ineffective. The impact of epigenetic modification in B-cell function and its involvement in AMR is still yet to be explored. METHODS: The impacts of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on isolated murine B-cell viability, proliferation, apoptosis, expression of surface marker, and secretion of immunoglobulin and interleukin-10 were investigated. In vivo, a murine cardiac transplant model was used to evaluate the effect of SAHA on splenic B-cell subsets and on AMR in Rag1(-/-) recipient mice after reconstitution of allostimulated B cells. RESULTS: SAHA possesses capability to repress B-cell function. Specifically, SAHA is potent to decrease the viability of isolated B cells by inducing apoptosis. SAHA was also found capable of suppressing the expression of B-cell costimulatory molecules and, as a result, addition of SAHA into the cultures attenuated B-cell proliferation and immunoglobulin secretion. In line with these results, administration of SAHA significantly suppressed AMR in Rag1(-/-) recipient mice after reconstitution of allostimulated B cells along with enhanced cardiac allograft survival time. Mechanistic studies revealed that SAHA promotes B-cell secretion of interleukin-10. CONCLUSIONS: Our data support that SAHA could be a promising immunosuppressive agent with potential beneficial effect on prevention and treatment of AMR.

SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection.

Suberoylanilide hydroxamic acid (SAHA), as a histone deacetylase (HDAC) inhibitor (HDACi), was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibitors (CNIs) to inhibit allograft rejection and its underlying mechanism remain elusive. In this study, we demonstrated the synergistic effects of SAHA and non-therapeutic dose of tacrolimus (FK506) in prolonging the allograft survival in a murine cardiac transplant model. Concomitant intragraft examination revealed that allografts from SAHA-treated recipients showed significantly lower levels of IL-17 expression, and no discernable difference for IL-17 expressions was detected between SAHA- and SAHA/FK506-treated allograft as compared with allografts from FK506-treated animals. In contrast, administration of FK506 significantly suppressed interferon (IFN)-γ but increased IL-10 expression as compared with that of SAHA-treated animals, and this effect was independent of SAHA. Interestingly, SAHA synergizes with FK506 to promote Foxp3 and CTLA4 expression. In vitro, SAHA reduced the proportion of Th17 cells in isolated CD4⁺ T-cell population and decreased expressions of IL-17A, IL-17F, STAT3 and RORγt in these cells. Moreover, SAHA enhances suppressive function of regulatory T (Treg) cells by upregulating the expression of CTLA-4 without affecting T effector cell proliferation, and increased the proportion of Treg by selectively promoting apoptosis of T effector cells. Therefore, SAHA, a HDACi, may be a promising immunosuppressive agent with potential benefit in conjunction with CNI drugs.

Preconditioning with physiological levels of ethanol protect kidney against ischemia/reperfusion injury by modulating oxidative stress.

BACKGROUND: Oxidative stress due to excessive production of reactive oxygen species (ROS) and subsequent lipid peroxidation plays a critical role in renal ischemia/reperfusion (IR) injury. The purpose of current study is to demonstrate the effect of antecedent ethanol exposure on IR-induced renal injury by modulation of oxidative stress. MATERIALS AND METHODS: Bilateral renal warm IR was induced in male C57BL/6 mice after ethanol or saline administration. Blood ethanol concentration, kidney function, histological damage, inflammatory infiltration, cytokine production, oxidative stress, antioxidant capacity and Aldehyde dehydrogenase (ALDH) enzymatic activity were assessed to evaluate the impact of antecedent ethanol exposure on IR-induced renal injury. RESULTS: After bilateral kidney ischemia, mice preconditioned with physiological levels of ethanol displayed significantly preserved renal function along with less histological tubular damage as manifested by the reduced inflammatory infiltration and cytokine production. Mechanistic studies revealed that precondition of mice with physiological levels of ethanol 3 h before IR induction enhanced antioxidant capacity characterized by significantly higher superoxidase dismutase (SOD) activities. Our studies further demonstrated that ethanol pretreatment specifically increased ALDH2 activity, which then suppressed lipid peroxidation by promoting the detoxification of Malondialdehyde (MDA) and 4-hydroxynonenal (HNE). CONCLUSIONS: Our results provide first line of evidence indicating that antecedent ethanol exposure can provide protection for kidneys against IR-induced injury by enhancing antioxidant capacity and preventing lipid peroxidation. Therefore, ethanol precondition and ectopic ALDH2 activation could be potential therapeutic approaches to prevent renal IR injury relevant to various clinical conditions.

Experimental study on inhibitory effects of histone deacetylase inhibitor MS-275 and TSA on bladder cancer cells.

OBJECTIVE: To investigate the inhibitory effect of histone deacetylase (HDAC) inhibitors (MS-275 and TSA) on T24 human bladder cancer cells in vitro, and explore the possible mechanism. METHODS: The MTT assay was employed to evaluate the inhibitory effect of MS-275 and TSA on T24 cell growth. FCM was used to analyze the variation of T24 cell cycle distribution and the apoptotic ratio after T24 cells were treated with MS-275 and TSA. Histone acetylation level was detected by Western blot. mRNA expression of p21 WAF1/CIP1, cyclin A, and cyclin E was measured by FQ-PCR. Dynamic changes of Bcl-2 and bax expression were detected by FCM. RESULTS: MS-275 and TSA inhibited T24 cell growth in a concentration and time-dependent manner. Treatment with 4 µmol/l MS-275 or 0.4 µmol/l TSA blocked cell cycling in the G0/G1 phase and induced a significant increase in cell apoptosis. MS-275 and TSA significantly increased the level of histone acetylation, induced p21CIP1WAF1 mRNA expression, and inhibited cyclin A mRNA expression, though no significant effect was observed on cyclin E. Bcl-2 expression was down-regulated, while bax expression was up-regulated. CONCLUSION: HDAC inhibitors can block bladder cancer cell cycle in vitro and induce apoptosis. The molecular mechanism may be associated with increased level of histone acetylation, down-regulation of p21WAF1/CIP1 expression, up-regulation of cyclin A expression, and dynamic change of bcl-2 and bax expression.