Network pharmacological analysis and experimental study of melatonin in chronic prostatitis/chronic pelvic pain syndrome.

This study is aimed at exploring the potential mechanisms of melatonin (MT) in treating chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using network pharmacology and experimental study. The target genes of MT were acquired from the Swiss Target Prediction, SuperPred, SEA, and PharmMapper databases, and the CP/CPPS targets were collected based on OMIM, DisGeNET, and GeneCards databases. The intersection of MT and CP/CPPS target genes was analyzed. A PPI network was constructed using Cytoscape to identify core targets. The shared targets underwent GO and KEGG enrichment analyses by Using R software. Molecular docking of MT with core targets was performed using AutoDock and PyMOL. GROMACS software was used for molecular dynamics simulation. And using cell experiments to verify the potential effect of MT in CP/CPPS. Network pharmacology analysis reveals 284 shared targets between MT and CP/CPPS, with AKT1, SRC, HSP90AA1, PTGS2, BCL2L1, ALB, CASP3, NFKB1, HIF1A, and ESR1 identified as key targets. Enrichment analysis indicates that MT affects CP/CPPS through various biological processes, and pathway analysis emphasizes the significance of PI3K-Akt, MAPK, Ras, FoxO, HIF-1, EGFR, and apoptosis pathways. Molecular docking confirms strong binding between MT and core targets. It is worth noting that the molecular dynamics simulation showed that the average binding free energy of AKT1, PTGS2, ALB, HSP90AA1 proteins, and MT was - 26.15, - 29.48, - 18.59, and - 20.09 kcal/mol, respectively. These results indicated that AKT1, PTGS2, ALB, and HSP90AA1 proteins were strongly bound to MT. Cell experiments demonstrate that MT can inhibit the secretion of IL-1ß, IL-6, and TNF-α in LPS-induced RWPE-1 cells, alleviate inflammation, and suppress cell apoptosis and oxidative stress. Network pharmacology, molecular docking, molecular dynamics simulation, and cell experiments showed that MT could play a role in CP/CPPS by regulating multiple targets and pathways. These findings provide an important scientific basis for further exploration of the molecular mechanism and clinical application of MT in CP/CPPS treatment and are expected to provide new ideas and directions for the development of novel therapeutic strategies.

The methodological quality assessment of systematic reviews/meta-analyses of chronic prostatitis/chronic pelvic pain syndrome using AMSTAR2.

BACKGROUND: This study aimed to assess the methodological quality of the systematic reviews/meta-analyses (SRs/MAs) of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using A Measurement Tool to Assess systematic Reviews (AMSTAR2) and to explore the potential influencing factors. METHODS: PubMed, EMBASE and Cochrane Library databases were searched for relevant studies. AMSTAR2 was used for evaluating the methodological quality of eligible SRs/MAs. Differences between methodological characteristics of SRs/MAs were compared using chi-square tests. The intra-class correlation coefficient (ICC) was used to assess reviewer agreement in the pre-experiment. Multivariate regression analysis was used to identify potential factors affecting methodological quality. RESULTS: A total of 45 SRs/MAs were included. After AMSTAR2 evaluation, only two (4.4%) of 45 SRs/MAs were moderate, three (6.7%) were rated as low quality, and the remainder 40 (88.9%) were rated as critically low quality. Among the 16 items of AMSTAR2, item 3 and item 10 had the poorest adherence. Item 4 received the most significant number of "Partial Yes" responses. Univariable analysis indicated that there were significant differences in methodological quality in SRs between different continents (P = 0.027) as well as between preregistered SRs and those that were not (P = 0.004). However, in multivariate analysis, there was no significant association between methodological quality and the following research characteristics: publication year, continent, whether reporting followed Preferred Reporting Items for Systematic Reviews (PRISMA), preregistration, funding support, randomized controlled trials (RCT) enrollment, whether SR was published in the Cochrane Database of Systematic Reviews (CDSR), and whether with meta-analysis. Additionally, subgroup analysis based on interventional SRs/MAs showed that continent was independently associated with the methodological quality of SRs/MAs of CP/CPPS via univariable and multivariate analysis. CONCLUSIONS: Our study demonstrates that the methodological quality of SRs/MAs of CP/CPPS was generally poor. SRs/MAs of CP/CPPS should adopt the AMSTAR2 to enhance their methodological quality.

Glial Cells of the Central Nervous System: A Potential Target in Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is one of the most common diseases of the male urological system while the etiology and treatment of CP/CPPS remain a thorny issue. Cumulative research suggested a potentially important role of glial cells in CP/CPPS. This narrative review retrospected literature and grasped the research process about glial cells and CP/CPPS. Three types of glial cells showed a crucial connection with general pain and psychosocial symptoms. Microglia might also be involved in lower urinary tract symptoms. Only microglia and astrocytes have been studied in the animal model of CP/CPPS. Activated microglia and reactive astrocytes were found to be involved in both pain and psychosocial symptoms of CP/CPPS. The possible mechanism might be to mediate the production of some inflammatory mediators and their interaction with neurons. Glial cells provide a new insight to understand the cause of complex symptoms of CP/CPPS and might become a novel target to develop new treatment options. However, the activation and action mechanism of glial cells in CP/CPPS needs to be further explored.

Berberine Affects the Proliferation, Migration, Invasion, Cell Cycle, and Apoptosis of Bladder Cancer Cells T24 and 5637 by Down-Regulating the HER2/PI3K/AKT Signaling Pathway.

OBJECTIVE: To assess the anticancer effect, target, and mechanism of berberine on bladder cancer. METHODS: Bladder cancer T24 and 5637 cells were treated with different concentrations of berberine. Then, cell proliferation was assessed by cell counting kit-8 (CCK8) measure, cell migration and invasion were assessed by transwell method, cell cycle and apoptosis were assessed by flow cytometry, and the expression of human epidermal growth factor receptor-2/PhosphoInositide-3 Kinase/AKT Serine/Threonine Kinase (HER2/PI3K/AKT) proteins were assessed by Western blot. Berberine molecular docking and HER2 target were performed using the AutoDock Tools 1.5.6. Finally, HER2 inhibitors CP-724714 and berberine were used independently or in combination to detect AKT and P-AKT protein downstream changes by Western blot. RESULTS: Berberine inhibited the proliferation of T24 and 5637 bladder cancer cells in a concentration-dependent and time-dependent manner. Berberine can significantly inhibit the migration, invasion, and cell cycle progression of T24 and 5637 bladder cancer cells, promote their apoptosis, and down-regulate the expression of HER2/PI3K/AKT proteins. Berberine showed good docking with HER2 molecular target and had a similar and synergistic effect with HER2 inhibitor in T24 and 5637 bladder cancer cells. CONCLUSIONS: Berberine inhibited the proliferation, migration, invasion, and cell cycle progression of T24 and 5637 bladder cancer cells and promoted their apoptosis by down-regulating HER2/PI3K/AKT signaling pathway.

Myeloperoxidase: a new target for the treatment of stroke?

Myeloperoxidase is an important inflammatory factor in the myeloid system, primarily expressed in neutrophils and microglia. Myeloperoxidase and its active products participate in the occurrence and development of hemorrhagic and ischemic stroke, including damage to the blood-brain barrier and brain. As a specific inflammatory marker, myeloperoxidase can be used in the evaluation of vascular disease occurrence and development in stroke, and a large amount of experimental and clinical data has indicated that the inhibition or lack of myeloperoxidase has positive impacts on stroke prognosis. Many studies have also shown that there is a correlation between the overexpression of myeloperoxidase and the risk of stroke. The occurrence of stroke not only refers to the first occurrence but also includes recurrence. Therefore, myeloperoxidase is significant for the clinical evaluation and prognosis of stroke. This paper reviews the potential role played by myeloperoxidase in the development of vascular injury and secondary brain injury after stroke and explores the effects of inhibiting myeloperoxidase on stroke prognosis. This paper also analyzes the significance of myeloperoxidase etiology in the occurrence and development of stroke and discusses whether myeloperoxidase can be used as a target for the treatment and prediction of stroke.

Bibliometric Analysis and Systematic Review of Global Coronavirus Research Trends Before COVID-19: Prospects and Implications for COVID-19 Research.

Coronaviruses (CoV) cause respiratory and intestinal infections. We conducted this bibliometric analysis and systematical review to explore the CoV-related research trends from before COVID-19. We systematically searched the Ovid MEDLINE, Ovid Embase, and Web of Science (WOS) databases for published bibliometric analyses of CoV from database inception to January 24, 2021. The WOS Collection was searched from inception to January 31, 2020, to acquire the CoV-related publications before COVID-19. One-Way ANOVA and Bonferroni multiple-comparison tests were used to compare differences. Visualization mapping and keyword cluster graphs were made to illustrate the research topics and hotpots. We included 14,141 CoV-related publications for the bibliometric analysis and 16 (12 articles) CoV-related bibliometric analyses for the systematic review. Both the systematic review and bibliometric analysis showed (1) the number of publications showed two steep upward trajectories in 2003-2004 and in 2012-2014; (2) the research hotpots mainly focused on the mechanism, pathology, epidemiology, clinical diagnosis, and treatment of the coronavirus in MERS-CoV and SARS-Cov; (3) the USA, and China; the University of Hong Kong; and Yuen KY, came from the University of Hong Kong contributed most; (4) the Journal of Virology had the largest number of CoV related studies. More studies should focus on prevention, diagnosis, and treatment in the future.

Siponimod for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, with an unpredictable course. Current MS therapies such as disease-modifying therapies focus on treating exacerbations, preventing new exacerbations and avoiding the progression of disability. Siponimod (BAF312) is an oral treatment, a selective sphingosine-1-phosphate (S1P) receptor modulator, for the treatment of adults with relapsing forms of MS including active, secondary progressive MS with relapses. OBJECTIVES: To assess the benefits and adverse effects of siponimod as monotherapy or combination therapy versus placebo or any active comparator for people diagnosed with MS. SEARCH METHODS: On 18 June 2020, we searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Trials Register, which contains studies from CENTRAL, MEDLINE and Embase, and the trials registry databases ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP). We also handsearched relevant journals and screened the reference lists of published reviews and retrieved articles and searched reports (2004 to June 2020) from the MS societies in Europe and America. SELECTION CRITERIA: We included randomised parallel controlled clinical trials (RCTs) that evaluated siponimod, as monotherapy or combination therapy, versus placebo or any active comparator in people with MS. There were no restrictions on dose or administration frequency. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We discussed disagreements and resolved them by consensus among the review authors. Our primary outcomes wereworsening  disability , relapse and adverse events, and secondary outcomes were annualised relapse rate, gadolinium-enhancing lesions, new lesions or enlarged pre-existing lesions and mean change of brain volume. We independently evaluated the certainty of evidence using the GRADE approach. We contacted principal investigators of included studies for additional data or confirmation of data. MAIN RESULTS: Two studies (1948 participants) met our selection criteria, 608 controls and 1334 treated with siponimod. The included studies compared siponimod with placebo. Overall, all studies had a high risk of bias due to selective reporting and attrition bias.  Comparing siponimod administered at a dose of 2 mg to placebo, we found that siponimod may reduce the number of participants with disability progression at six months (56 fewer people per 1000; risk ratio (RR) 0.78, 95% confidence interval (CI) 0.65 to 0.94; 1 study, 1641 participants; low-certainty evidence) and annualised relapse rate (RR 0.43, 95% CI 0.34 to 0.56; 2 studies, 1739 participants; low-certainty evidence). But it might lead to little reduction in the number of participants with new relapse (166 fewer people per 1000; RR 0.38, 95% CI 0.15 to 1.00; 1 study, 94 participants; very low-certainty evidence). We observed no evidence of a difference   due to adverse events for siponimod at 2 mg compared to placebo (14 more people per 1000; RR 1.52, 95% CI 0.85 to 2.71; 2 studies, 1739 participants, low-certainty evidence). In addition, due to the high risk of inaccurate magnetic resonance imaging (MRI) data in the two included studies, we could not combine data for active lesions on MRI scans. Both studies had high attrition bias resulting from the unbalanced reasons for dropouts among groups and high risk of bias due to conflicts of interest. Siponimod may reduce the number of gadolinium-enhancing T1-weighted lesions at two years of follow-up (RR 0.14, 95% CI 0.10 to 0.19; P < 0.0001; 1 study, 1641 participants; very low-certainty evidence). There may be no evidence of a difference between groups in the number of participants with at least one serious adverse event excluding relapses (113 more people per 1000; RR 1.80, 95% CI 0.37 to 8.77; 2 studies, 1739 participants; low-certainty evidence) at six months. No data were available regarding cardiac adverse events. In terms of safety profile, the most common adverse events associated with siponimod were headache, back pain, bradycardia, dizziness, fatigue, influenza, urinary tract infection, lymphopenia, nausea, alanine amino transferase increase and upper respiratory tract infection. These adverse events have dose-related effects and rarely led to discontinuation of treatment. AUTHORS' CONCLUSIONS: Based on the findings of the RCTs included in this review, we are uncertain whether siponimod interventions are beneficial for people with MS. There was low-certainty evidence to support that siponimod at a dose of 2 mg orally once daily as monotherapy compared with placebo may reduce the annualised relapse rate and the number of participants who experienced disability worsening, at 6 months. However, the certainty of the evidence to support the benefit in reducing the number of people with a relapse is very low.  The risk of withdrawals due to adverse events requires careful monitoring of participants over time. The duration of all studies was less than 24 months, so the efficacy and safety of siponimod over 24 months are still uncertain, and further exploration is needed in the future. There is no high-certainty data available to evaluate the benefit on MRI outcomes. We assessed the certainty of the body of evidence for all outcomes was low to very low, downgraded due to serious study limitations, imprecision and indirectness. We are uncertain whether siponimod is beneficial for people with MS. More new studies with robust methodology and longer follow-up are needed to evaluate the benefit of siponimod for the management of MS and to observe long-term adverse effects. Also, in addition to comparing with placebo, more new studies are needed to evaluate siponimod versus other therapeutic options.

Association Between Alcohol Consumption and Risk of Bladder Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

BACKGROUND: Controversial results of the association between alcohol consumption and risk of bladder cancer were reported by the previous meta-analyses. OBJECTIVE: To quantitatively investigate the association between alcohol consumption and risk of bladder cancer based on prospective cohort studies, and explore whether there is potential dose-response relation. METHOD: PubMed, EMBASE, the Cochrane Library databases, China Biology Medicine disc (CBM), and Chinese National Knowledge Infrastructure (CNKI) were searched for relevant studies. Categorical meta-analysis was performed for risk estimates of any alcohol consumers versus non-drinkers as well as different drinking degrees (light, moderate, and heavy) versus none. And two-stage generalized least-squares regression and restricted cubic spline, as well as fixed-effects dose-response models, were used for linear and nonlinear dose-response relation exploration. RESULTS: 9 prospective cohort studies including 1,971,396 individuals were finally included. We did not observe a significant association between alcohol intake and the risk of bladder cancer in the entire population. Linear association was detected in those who consumed alcohol from liquor or spirits (P linear=0.02). One drink increment each day of alcohol could elevate the risk of bladder cancer by 9% (RR=1.09; 95%CI: 1.01-1.17). Alcohol was a risk factor of bladder cancer for male drinkers (RR=1.23; 95%CI: 1.13-1.35; I2=3.7%), while none linear or nonlinear relation was found. CONCLUSION: No significant association between alcohol consumption and bladder cancer risk was found in the entire population, but there was a linear dose-response relation in those who consume alcohol from liquor or spirits. Alcohol may elevate the risk of bladder cancer in males in a dose-independent way. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, PROSPERO (CRD42020216195).

Role of RNA N6-Methyladenosine Modification in Male Infertility and Genital System Tumors.

Epigenetic alterations, particularly RNA methylation, play a crucial role in many types of disease development and progression. Among them, N6-methyladenosine (m6A) is the most common epigenetic RNA modification, and its important roles are not only related to the occurrence, progression, and aggressiveness of tumors but also affect the progression of many non-tumor diseases. The biological effects of RNA m6A modification are dynamically and reversibly regulated by methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). This review summarized the current finding of the RNA m6A modification regulators in male infertility and genital system tumors and discussed the role and potential clinical application of the RNA m6A modification in spermatogenesis and male genital system tumors.

Association between alcohol intake, mild cognitive impairment and progression to dementia: a dose-response meta-analysis.

BACKGROUND: Mild cognitive impairment (MCI) is a cognitive state falling between normal aging and dementia. The relation between alcohol intake and risk of MCI as well as progression to dementia in people with MCI (PDM) remained unclear. OBJECTIVE: To synthesize available evidence and clarify the relation between alcohol intake and risk of MCI as well as PDM. METHOD: We searched electronic databases consisting of PubMed, EMBASE, Cochrane Library, and China Biology Medicine disc (CBM) from inception to October 1, 2019. Prospective studies reporting at least three levels of alcohol exposure were included. Categorical meta-analysis was used for quantitative synthesis of the relation between light, moderate and heavy alcohol intake with risk of MCI and PDM. Restricted cubic spline and fixed-effects dose-response models were used for dose-response analysis. RESULT: Six cohort studies including 4244 individuals were finally included. We observed an unstable linear relation between alcohol intake (drinks/week) and risk of MCI (P linear = 0.0396). It suggested that a one-drink increment per week of alcohol intake was associated with an increased risk of 3.8% for MCI (RR, 1.038; 95% CI 1.002-1.075). Heavy alcohol intake (> 14 drinks/week) was associated with higher risk of PDM (RR = 1.76; 95% CI 1.10-2.82). And we found a nonlinear relation between alcohol intake and risk of PDM. Drinking more than 16 drinks/week (P nonlinear = 0.0038, HR = 1.42; 95% CI 1.00-2.02), or 27.5 g/day (P nonlinear = 0.0047, HR = 1.46; 95% CI 1.00-2.11) would elevate the risk of PDM. CONCLUSION: There was a nonlinear dose-response relation between alcohol intake and risk of PDM. Excessive alcohol intake would elevate the risk of PDM.