Network pharmacology analysis of Icariside II against bladder cancer.

As a global health threat, bladder cancer (BC) is a common urological disease characterized by a high risk of progression and recurrence. Icariside II (ICA-II), a flavonol glycoside, exhibits antitumor ability in various tumors. However, there is no systematic study exploring the pharmacological mechanism of ICA-II in BC. We used public databases to obtain potential targets of ICA-II and related genes in BC. Bioinformatics analysis and molecular docking were used to identify potential targets and signaling pathways. Then, MTT, cell cycle assays and western blot (WB) were used to validate the predicted pathways in bladder cell lines, and in situ bladder cancer models were also established to verify the effect of ICA-II. Our research demonstrated that these ICA-II hub genes were related to the cell cycle. Then, our molecular docking analysis confirmed the interaction between ICA-II and CCNB1. In addition, our in vitro experiment demonstrated that ICA-II restrained the proliferation of BC cells mainly by blocking the cell cycle. WB also verified that ICA-II decreased the expression levels of CCNB1. In situ BC models showed that ICA-II had no hepatotoxicity or nephrotoxicity and could suppress the growth of in situ BC. In summary, during this study, we found that ICA-II had low toxicity in the kidney and liver. Network pharmacology was used, and both cell and animal experiments verified that ICA-II has a good therapeutic effect on bladder cancer, which may inhibit the proliferation and progression of bladder cancer by blocking the cell cycle of BC cells.

Preoperative systemic inflammation response index is an independent prognostic marker for BCG immunotherapy in patients with non-muscle-invasive bladder cancer.

BACKGROUND: The Systemic Inflammatory Response Index (SIRI) is a novel prognostic biomarker based on peripheral blood counts of neutrophils, monocytes, and lymphocytes. Recent evidence suggests that it is associated with poor prognosis in various cancers. However, the predictive value of the SIRI in non-muscle-invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette-Guerin (BCG) immunotherapy remains elusive. Therefore, this study aimed to evaluate the potential of SIRI as a prognostic factor in these patients. METHODS: A total of 540 patients with NMIBC who underwent BCG immunotherapy following transurethral resection of bladder tumor (TURBT) were enrolled in this study. Using receiver operating characteristic (ROC) curves and the Youden index, patients were divided into high and low SIRI groups based on the cutoff values. Univariable and multivariable logistic regression analyses were performed to identify independent predictors of BCG non-response. Thereafter, propensity score matching (PSM) was used to eliminate bias due to confounding factors between the low and high SIRI groups. Finally, the Kaplan-Meier method was used to compare recurrence-free survival (RFS) and progression-free survival (PFS) between the two groups. RESULTS: Multivariable logistic regression analysis revealed that high SIRI (p = 0.001), high MLR (p = 0.015), and high tumor pathological T stage (p = 0.015) were significantly correlated with non-response to BCG therapy. In addition, both RFS and PFS were shorter in the high SIRI group than in the other group before and after PSM (both p < 0.05). Collectively, our results indicate that the combination of tumor pathological T staging and the SIRI can enhance the predictive power of BCG response. CONCLUSION: Pretreatment peripheral blood SIRI can be employed to predict the response to BCG immunotherapy and the prognosis of NMIBC patients. Taken together, the combination of T stage and SIRI demonstrated robust performance in predicting the response to BCG immunotherapy in NMIBC patients.

The effect of SSRIs on Semen quality: A systematic review and meta-analysis.

Selective serotonin reuptake inhibitors (SSRIs) are widely used for a variety of diseases, and their impact on semen quality is unclear. We performed a systematic search in PubMed and Embase, and after a strict screening, we included 4 studies with a total of 222 male participants. In result, SSRIs reduced normal sperm morphology (95% CI [-16.29, -3.77], p = 0.002), sperm concentration (95%CI [-43.88, -4.18], p = 0.02), sperm motility (95%CI [-23.46, -0.47], p = 0.04) and sperm DNA fragmentation index (DFI) (95% CI [6.66,21.93], p = 0.0002), without a statistically significant effect on semen volume (95%CI [-0.75,0.65], p = 0.89). Moreover, the impact on both sperm morphology and sperm concentration were observed within the 3-month period of SSRIs use. In general, our meta-analysis showed that SSRIs have a negative effect on semen quality. More larger, randomized, well-controlled clinical studies should be conducted to support our conclusion.

Increased Circulating Cytokines Have a Role in COVID-19 Severity and Death With a More Pronounced Effect in Males: A Systematic Review and Meta-Analysis.

Background: Coronavirus disease 2019 (COVID-2019), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide epidemic and claimed millions of lives. Accumulating evidence suggests that cytokines storms are closely associated to COVID-19 severity and death. Here, we aimed to explore the key factors related to COVID-19 severity and death, especially in terms of the male patients and those in western countries. Methods: To clarify whether inflammatory cytokines have role in COVID-19 severity and death, we systematically searched PubMed, Embase, Cochrane library and Web of Science to identify related studies with the keywords "COVID-19″ and "cytokines". The data were measured as the mean with 95% confidence interval (CI) by Review Manager 5.3 software. The risk of bias was assessed for each study using appropriate checklists. Results: We preliminarily screened 13,468 studies from the databases. A total of 77 articles with 13,468 patients were ultimately included in our study. The serum levels of cytokines such as interleukin-6 (IL-6), IL-10, interleukin-2 receptor (IL-2R), tumor necrosis factor (TNF)-α, IL-1ß, IL-4, IL-8 and IL-17 were higher in the severity or death group. Notably, we also found that the circulating levels of IL-6, IL-10, IL-2R and TNF-α were significantly different between males and females. The serum levels of IL-6, IL-10, IL-2R and TNF-α were much higher in males than in females, which implies that the increased mortality and severity in males was partly due to the higher level of these cytokines. Moreover, we found that in the severe and non-survivor groups, European patients had elevated levels of IL-6 compared with Asian patients. Conclusion: These large-scale data demonstrated that the circulating levels of IL-6, IL-10, IL-2R, IL-1ß, IL-4, IL-8 and IL-17 are potential risk factors for severity and high mortality in COVID-19. Simultaneously, the upregulation of these cytokines may be driving factors for the sex and region predisposition.

Novel sequential therapy with metformin enhances the effects of cisplatin in testicular germ cell tumours via YAP1 signalling.

BACKGROUND: Testicular germ cell tumours (TGCTs) are the most commonly diagnosed malignancy in young men. Although cisplatin has been shown to be effective to treat TGCT patients, long-term follow-up has shown that TGCT survivors who accepted cisplatin treatment suffered from a greater number of adverse reactions than patients who underwent orchiectomy alone. As metformin has shown an anticancer effect in various cancers, we investigated whether metformin could enhance the effects of cisplatin to treat TGCTs. METHODS: The anticancer effects of different treatment strategies consisting of metformin and cisplatin in TCam-2 and NTERA-2 cells were assessed in vitro and in vivo. First, we used a colony formation assay, CCK-8 and MTT assays to explore the viability of TGCT cells. Flow cytometry was used to assess the cell cycle and apoptosis of TGCTs. Then, Western blotting was used to detect the protein expression of TGCTs cells after different treatments. In addition, a xenograft model was used to investigate the effects of the different treatments on the proliferation of TGCT cells. Immunohistochemistry assays were performed to analyse the expression of related proteins in the tissues from the xenograft model. RESULTS: Metformin inhibited the proliferation of TCam-2 and NTERA-2 cells by arresting them in G1 phase, while metformin did not induce apoptosis in TGCT cells. Compared with cisplatin monotherapy, the CCK-8, MTT assay and colony formation assay showed that sequential treatment with metformin and cisplatin produced enhanced anticancer effects. Further study showed that metformin blocked the cells in G1 phase by inducing phosphorylated YAP1 and reducing the expression of cyclin D1, CDK6, CDK4 and RB, which enhanced the chemosensitivity of cisplatin and activated the expression of cleaved caspase 3 in TGCTs. CONCLUSIONS: Our study discovers the important role of YAP1 in TGCTs and reports a new treatment strategy that employs the sequential administration of metformin and cisplatin, which can reduce the required cisplatin dose and enhance the sensitivity of TGCT cells to cisplatin. Therefore, this sequential treatment strategy may facilitate the development of basic and clinical research for anticancer therapies to treat TGCTs.

Intracavernous Pressure Recording in a Cavernous Nerve Injury Rat Model.

The bilateral cavernous nerve (CN) injury rat model has been extensively used to simulate clinical cavernous nerve injury associated with erectile dysfunction (ED) for evaluating the effect of clinical therapeutic methods. However, the methods of CN injury model construction are flawed and varied in the ED research field. It is CN crush injury that is the most commonly used method in recent years. This study aims to provide a detailed description of the procedure of bilateral CN injury rat model construction and measurement of intracavernous pressure (ICP) recording, providing a reliable and reproducible CN injury rat model. This work successfully developed the CN injury method of hemostat crush injury using a syringe needle as hard support and a hemostat with a rubber sleeve. Also, this method concludes that a voltage of 1.0 V, frequency of 20 Hz, and pulse-width of 5 ms are the optimized stimulation parameters for ICP recording in a bilateral CN injury rat model.

Clinical Characterization of Mismatch Repair Gene-Deficient Metastatic Castration-Resistant Prostate Cancer.

Mismatch repair-deficient (dMMR) prostate cancer is rare and has not been well studied. We aimed to evaluate the clinical characterization of dMMR metastatic castration-resistant prostate cancer (mCRPC) patients. The MMR genes include MLH1, MLH3, MSH2, MSH6, PMS1, PMS2, and EPCAM, and were analyzed by targeted sequencing of plasma cell-free DNA samples. A total of 109 mCRPC patients were identified, including 50 patients with MMR alterations (pathogenic alterations, n = 7; alterations of unknown significance, n = 43) and 59 patients with wild-type MMR. For the seven patients with pathogenic MMR alterations, the median age at diagnosis was 63.5 years, and 42.9% had a Gleason score ≥8. The median time from androgen deprivation therapy (ADT) initiation to CRPC was 24 months. Compared with the wild-type MMR subgroup, patients with MMR alterations, pathogenic MMR alterations, or MMR alterations of unknown significance showed higher rates of hotspot missense mutations or copy number amplifications in the AR gene (24/50 vs. 10/59, P = 7.8 × 10-4; 7/7 vs. 10/59, P = 2.5 × 10-5; 17/43 vs. 10/59, P = 0.013). The presence of any MMR alterations was associated with an inferior response to abiraterone [median progression-free survival (PFS): 5.0 vs. 10.9 months, P = 0.022]. Shorter PFS times were observed in both the pathogenic MMR alteration subgroup (median PFS: 5 months) and the MMR alterations of unknown significance subgroup (median PFS: 5.3 months), compared with the PFS of those with wild-type MMR genes (median PFS: 10.9 months, P = 0.052). There was no statistically significant difference in response to docetaxel chemotherapy between the MMR alterations of unknown significance and the wild-type MMR subgroups (median PFS: 8.2 vs. 8.1 months, P = 0.23). Our results demonstrate that dMMR mCRPC patients have an equivalent response to standard ADT and taxane-based chemotherapy treatments compared with wild-type MMR patients. Patients with both pathogenic and unknown significance alterations of MMR genes had poorer responses to abiraterone therapy.

Gene set based systematic analysis of prostate cancer and its subtypes.

Aim: A gene set based systematic analysis strategy is used to investigate prostate tumors and its subclusters with focuses on similarities and differences of biological functions. Results: Dysregulation of methylation status, as well as RAS/RAF/ERK and PI3K-ATK signaling pathways, were found to be the most dramatic changes during prostate cancer tumorigenesis. Besides, neural and inflammation microenvironment is also significantly divergent between tumor and adjacent tissues. Insights of subclasses within prostate tumor cohorts revealed four different clusters with distinct gene expression patterns. We found that samples are mainly clustered by immune environments and proliferation traits. Conclusion: The findings of this article may help to advance the progress of identifying better diagnosis biomarkers and therapeutic targets.

The effect of metformin therapy on incidence and prognosis in prostate cancer: A systematic review and meta-analysis.

The relationship between metformin and prostate cancer (PCa) remains controversial. To clarify this association, the PubMed, Embase and Cochrane library databases were systematically searched from their inception dates to May 23, 2018, using the keywords "metformin" and "prostate cancer" to identify the related studies. The results included incidence, overall survival (OS), PCa-specific survival (CSS) and recurrence-free survival (RFS), which were measured as hazard ratios (HR) with a 95% confidence interval (95% CI) using Review Manager 5.3 software. A total of 30 cohort studies, including 1,660,795 patients were included in this study. Our study revealed that metformin treatment improves OS, CSS and RFS in PCa (HR = 0.72, 95% CI: 0.59-0.88, P = 0.001; HR = 0.78, 95% CI: 0.64-0.94, P = 0.009; and HR = 0.60, 95% CI: 0.42-0.87 P = 0.006, respectively) compared with non-metformin treatment. However, metformin usage did not reduce the incidence of PCa (HR = 0.86, 95% CI: 0.55-1.34, P = 0.51). In conclusion, compared with non-metformin treatment, metformin therapy can significantly improve OS, CSS and RFS in PCa patients. No association was noted between metformin therapy and PCa incidence. This study indicates a useful direction for the clinical treatment of PCa.

Spider peptide toxin lycosin-I induces apoptosis and inhibits migration of prostate cancer cells.

Spider toxins are molecularly diverse and some display not only a strong antibacterial effect but also exhibit significant inhibition of tumor growth and promote tumor cell apoptosis. The aim of the present investigation was to explore different antitumor effects of the spider peptide toxin lycosin-I through different pathways at different concentrations. It was found that by inactivating STAT3 pathway, high concentrations of lycosin-I induce apoptosis in prostate cancer cells and low concentrations of lycosin-I inhibit the migration of prostate cancer cells. This finding provides favorable evidence for further study of the molecular diversity of spider toxins. Impact statement The spider peptide toxin has become an important research topic. These toxins are molecularly diverse and some display not only a strong antibacterial effect but also exhibit significant inhibition of tumor growth and promote tumor cell apoptosis. Inspired by previous studies, the present study aims to investigate the effects of different concentrations of lycosin-I on the invasiveness and apoptosis of human prostate cancer cells. The findings provide favorable evidence for further study of the molecular diversity of spider toxins.