The relationship between the Composite Dietary Antioxidant Index (CDAI) and urinary phthalate concentrations has yet to be explored. This study utilized data from the 2011-2018 NHANES database. Weighted multivariable linear regression models were employed to examine the relationship between CDAI and urinary phthalate concentrations. Subgroup analyses were conducted to explore differences in associations across various subgroups. Additionally, restricted cubic spline (RCS) analyses were performed to investigate potential nonlinear relationships between CDAI and urinary phthalate concentrations. In the multivariable linear regression model, fully adjusted for confounding variables, CDAI was significantly associated with lower concentrations of high-molecular-weight (HMW) phthalates, including MCOP (β = -0.724, 95% CI: -1.454, -0.006) and MECP (β = -0.297, 95% CI: -0.618, -0.091). MBzP also showed a significant negative association with CDAI (β = -0.212, 95% CI: -0.353, -0.071). For low-molecular-weight (LMW) phthalates, there was a significant association between CDAI and lower MiBP concentrations (β = -0.136, 95% CI: -0.318, -0.046). Subgroup analyses indicated a negative correlation between CDAI and urinary phthalate concentrations in participants aged 60 years and older, as well as in male participants. Weighted RCS analysis demonstrated a linear relationship between CDAI and urinary phthalate concentrations. CDAI negatively correlated with urinary phthalate concentrations; further research is needed for validation.

Background:Renal fibrosis (RF), the end-stage progression of chronic kidney disease (CKD), remains a challenge due to limited effective therapies. Icariside II (ICA-II), a metabolite of icariin from the Chinese herb Epimedium, has shown therapeutic promise in treating diabetic CKD. However, the underlying molecular mechanisms remain elusive. This study sought to elucidate these mechanisms using an integrated approach: network pharmacology, molecular dynamics (MD) simulations, and in vitro experiments. Methods:Network pharmacology was integrated with public databases to identify ICA-II targets and RF-associated genes. Key targets were prioritized using protein-protein interaction (PPI) networks. Molecular docking and MD simulations assessed ICA-II-target interactions. In vitro, transforming growth factor β1 (TGF-β1)-induced normal rat kidney-49 fibroblast (NRK-49F) and human kidney 2 (HK2) cells were treated with ICA-II, with Cell Counting Kit-8 (CCK-8) assays, western blotting, and immunofluorescence evaluating cell viability, fibrotic markers and signaling proteins. Results:Network pharmacology revealed ten key targets: AKT1, mTOR, EGFR, ESR1, BCL2, CASP3, TP53, CTNNB1, HSP90AA1, and HSP90AB1. Critical pathways included PI3K/Akt/mTOR, lipid and atherosclerosis, and EGFR tyrosine kinase inhibitor resistance. Molecular docking showed stable ICA-II binding to mTOR (docking energy: -12 kcal/mol), confirmed by MD simulations over 100 ns. In vitro studies in NRK-49F and HK2 cells demonstrated that ICA-II directly binds to mTOR, as evidenced by cellular thermal shift assay (CETSA). This interaction potentially inhibits mTOR activity, leading to a significant downregulation of TGF-β1-induced expression of type I collagen and α-smooth muscle actin (α-SMA). Conclusions:ICA-II demonstrates anti-fibrotic effects through a multi-target, multi-pathway regulatory network. Its beneficial role in RF may involve direct inhibition of mTOR activity, thereby attenuating excessive extracellular matrix (ECM) accumulation. These findings provide a theoretical and experimental basis for ICA-II as a promising candidate for the treatment of RF.

OBJECTIVE:Androgen deprivation therapy (ADT) was the frontline treatment for patients with prostate cancer ineligible for radical prostatectomy. However, the development of resistance to ADT significantly limits its clinical efficacy. METHODS:Using a genome-wide CRISPR/Cas9 knockout (GeCKO) library screen combined with single-cell RNA sequencing (scRNA-seq) analysis, we identified key genes involved in ADT resistance. RESULTS:Macrophage migration inhibitory factor (MIF) was identified as a critical mediator of ADT resistance. Inhibition of MIF significantly overcomes ADT resistance. Moreover, we found that the androgen receptor (AR), but not its splice variant AR-V7, negatively regulates MIF expression. Consequently, inhibition of the AR signaling pathway via ADT results in the upregulation of MIF expression. Elevated expression of MIF promotes prostate cancer cell proliferation by upregulating AMPD2 expression. CONCLUSIONS:Our findings demonstrate that ADT induces MIF upregulation, which in turn drives prostate cancer cell proliferation via upregulating AMPD2 expression, eventually contributing to the development of resistance to ADT.

To investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, homocysteine, and male infertility with varicocele in North China. One Hundred infertile males with varicocele (VC; grade II-III, VC group) and 100 healthy males with normal semen parameters and no varicocele (NC group) were recruited for PCR microarray, blood and semen testing. Compared with the CC genotype in the NC group, the TT genotype in the NC group and the CC genotype in the VC group showed no significant changes in sperm motility (P=0.191; P=0.130), sperm density (P=0.591, P=0.643), plasma homocysteine level (P=0.511; P=0.677), and seminal plasma MDA (P=0.752; P=0.451). In contrast, VC patients with the TT genotype had higher plasma homocysteine level and seminal plasma MDA levels (P <0.001), lower partial pressure of oxygen in seminal pulse (PO2; P <0.001) and poorer sperm quality (P <0.001), as compared with the CC genotype. This suggests that MTHFR C677C>T may not be a risk factor for male Varicocele in North China. However, this may affect the oxidative stress associated with homocysteine expression, which in turn affects semen parameters in VC patients. Larger studies are needed to validate our findings.

PURPOSE:Cavernous nerve injury induced erectile dysfunction (ED) is a refractory complication with high incidence in person under radical prostatectomy. Studies have shown that relaxin-2 (RLX-2) plays a vital role of endothelial protection, vasodilation, anti-fibrosis and neuroprotection in a variety of diseases. However, whether penile cavernous erection can benefit from RLX-2 remains unknown. The purpose of the experiment was to explore the effects of RLX-2 on ED in the rat suffering with bilateral cavernous nerve injury (BCNI).MATERIALS AND METHODS:The rats were divided into three groups: Sham group was underwent sham operation, BCNI+RLX group or BCNI group was underwent bilateral cavernous nerve crush and then randomly treated with RLX-2 (0.4 mg/kg/d) or saline by continuous administration using a subcutaneously implanted micro pump for 4 weeks respectively. Then, erectile function was evaluated by electrical stimulation of cavernous nerves. Cavernous nerves and penile tissues and were collected for histological evaluation.RESULTS:Erectile function of rats with BCNI was partially improved after RLX-2 treatment. The BCNI group had lower expression of relaxin family peptide receptor (RXFP) 1, p-AKT/AKT, p-eNOS/eNOS ratios than sham operation rats, but RLX-2 could partially reversed these changes. Histologically, the BCNI+RLX group had a significant effect on preservation of neurofilament, neuronal glial antigen 2 of penile tissue and nNOS of cavernous nerves when compared with BCNI group. RLX-2 could inhibited the lever of BCNI induced corporal fibrosis and apoptosis via regulating TGFβ1-Smad2/3-CTGF pathway and the expression of Bax/Bcl-2 ratio, caspase3.CONCLUSIONS:RLX-2 could improve erectile function of BCNI rats by protecting cavernous nerve and endothelial function and suppressing corporal fibrosis and apoptosis via RXFP1 and AKT/eNOS pathway. Our findings may provide a promising treatment for refractory BCNI induced ED.

Purpose To assess the diverse cell populations of human corpus cavernosum in patients with severe erectile dysfunction (ED) at the single-cell level. Methods Penile tissues collected from three patients were subjected to single-cell RNA sequencing using the BD Rhapsody™ platform. Common bioinformatics tools were used to analyze cellular heterogeneity and gene expression profiles from generated raw data, including the packages Seurat, Monocle, and CellPhoneDB. Results Disease-related heterogeneity of cell types was determined in the cavernous tissue such as endothelial cells (ECs), smooth muscle cells, fibroblasts, and immune cells. Reclustering analysis of ECs identified an arteriole ECs subcluster and another one with gene signatures of fibroblasts. The proportion of fibroblasts was higher than the other cell populations and had the most significant cellular heterogeneity, in which a distinct subcluster co-expressed endothelial markers. The transition trajectory of differentiation from smooth muscle cells into fibroblasts was depicted using the pseudotime analysis, suggesting that the expansion of corpus cavernosum is possibly compromised as a result of fibrosis. Cell-cell communications among ECs, smooth muscle cells, fibroblasts, and macrophages were robust, which indicated that inflammation may also have a crucial role in the development of ED. Conclusions Our study has demonstrated a comprehensive single-cell atlas of cellular components in human corpus cavernosum of ED, providing in-depth insights into the pathogenesis. Future research is warranted to explore disease-specific alterations for individualized treatment of ED.

BACKGROUND:Neurogenic erectile dysfunction (NED) caused by cavernous nerve (CN) injury is a typical complication after pelvic surgery, which lacks efficient treatments. Acetyl-L-carnitine (ALCAR) has been proven to promote nerve repair.OBJECTIVES:To investigate the effect and potential mechanism of ALCAR in the treatment of NED.MATERIALS AND METHODS:Thirty-two rats were randomly divided into bilateral CN injury (BCNI) group, BCNI + lower-dose ALCAR (50 mg/kg/day) group, BCNI + higher-dose (100 mg/kg/day) group, and sham-operated group. Erectile function was assessed 14 days after daily intraperitoneal injection of ALCAR or placebo. The penile tissues were gathered for subsequent histological and molecular biological analysis. Rat Schwann cell (SC) line S16 was used to verify the mechanism of ALCAR in vitro.RESULTS:We found that the erectile function of the rats in the BCNI group was severely impaired, which was improved considerably in both BCNI+ALCAR-LD and BCNI+ALCAR-HD groups. Also, we observed decreased smooth muscle and increased collagen content in the corpus cavernosum in the BCNI group. The expressions of fibrosis markers transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and Smad 2/3 were significantly up-regulated in the BCNI group. The above changes were alleviated after the administration of lower and higher-dose ALCAR. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate pathway (cGMP) was promoted and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was inhibited in the corpus cavernosum of BCNI rats after ALCAR treatment, accompanied by increased neuronal nitric oxide synthase (nNOS) and down-regulated tyrosine hydroxylase (TH). In vitro, ALCAR promoted the migration and proliferation of SC and increased the expression of 22-kD peripheral myelin protein and nerve growth factor (NGF). Further, rats treated with ALCAR had high expression of ATF3 and S100 in the distal nerve tissues of the CN extrusion site.DISCUSSION AND CONCLUSION:ALCAR could promote nerve repair and regeneration, inhibit penile fibrosis, and improve penile erection by promoting the proliferation and migration of SC and the secretion of NGF. Our study confirms that ALCAR may be a potential treatment strategy for NED.

PURPOSE:As the mechanism of interaction between circular RNAs (circRNAs) and microRNAs (miRNAs) in regulating the development of prostate cancer (PCa) is not clear, this study focuses on investigating these effects.MATERIALS AND METHODS:Sample tissues were collected from the PCa of patients, and microarray analysis of human circRNAs was conducted. The expression of circ_0001686, hsa_miR-411-5p (miR-411-5p) were also detected by qRT-PCR. Circ_0001686 and miR-411-5p mimics were transfected into the PCa cell lines (CWR22RV1and LNCaP) and MTT, colony formation, Transwell, and scratch wound assays were used to analyze the biological behaviors of PCa cells. Si-circ_0001686 and ASO-miR-411-5p were used as negative controls, and dual-luciferase reporter assays were performed to verify the interactions among circ_0001686, miR-411-5p, and SMAD3/TGFBR2. The levels of SMAD3 and TGFBR2 in different treated PCa cells were measured by western blot, and in vivo experiments in a nude mouse model were carried out to strengthen the in vitro findings of miR-411-5p.RESULTS:The expression of circ_0001686 was up-regulated, while the expression of miR-411-5p was down-regulated in PCa cells. Moreover, circ_0001686 promoted cell proliferation, migration, and invasion. Molecular mechanism exploration revealed that circ_0001686 could reduce miR-411-5p, affecting the downstream target genes of SMAD3 and TGFBR2. In vitro and in vivo studies verified that miR-411-5p inhibits PCa progression.CONCLUSIONS:Circ_0001686 can reduce miR-411-5p to increase the expression of SMAD3/TGFBR2, which consequently promotes the proliferation, invasion, and migration of PCa cells.

Background and Objective Although epimedium herb (EH) has been widely used in ancient Chinese medicine to enhance sexual activity, its pharmacological mechanism is not clear. Modern studies have shown that epimedium herb is rich in icariin (ICA, a flavonoid compound), and 91.2% of icariin is converted to icariside II (ICA II) by hydrolytic enzymes in intestinal bacteria after oral administration. YS-10 is a synthetic derivative of icariside II. The aim of this review was to summarize the contemporary evidence regarding the pharmacokinetics, therapeutic properties, and molecular biological mechanisms of ICA and some ICA derivatives for erectile dysfunction therapy. Methods A detailed search was conducted in the PubMed database using keywords and phrases, such as “icariin” AND “erectile dysfunction”, “icariside II” AND “erectile dysfunction”. The publication time is limited to last 20 years. Articles had to be published in peer reviewed journals. Key Content and Findings ICA and its some derivatives showed the specific inhibition on phosphodiesterase type 5 (PDE5) and the promotion of testosterone synthesis. In addition, by regulating various reliable evidence of signaling pathways such as PI3K/AKT, TGFβ1/Smad2, p38/MAPK, Wnt and secretion of various cytokines, ICA and ICA derivatives can activate endogenous stem cells (ESCs) leading to endothelial cell and smooth muscle cell proliferation, nerve regeneration and fibrosis inhibition, repair pathological changes in penile tissue and improve erectile function. Conclusions ICA and some of its derivatives could be a potential treatment for restoring spontaneous erections. In addition ICA and his derivatives may also be valuable as a regenerative medicine approach for other diseases, but more clinical and basic researches with high quality and large samples are recommended.

BACKGROUND:The long non-coding (lncRNA) RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is known to promote tumorigenesis, whereas microRNA-145 (miR-145) plays an antitumor role in several cancers. In this study, we aimed to elucidate the role of MALAT1 and miR-145 in prostate cancer cells and investigate the effect of MALAT1 downregulation on prostate cancer (PCa) cells in vitro in vivo.METHODS:The Cancer Genome Atlas (TCGA) datasets were used to carry out the initial bioinformatics analysis; the findings were then tested in LNCaP and CWR22Rv1 cell lines. Western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the levels of MALAT1 and miR-145 along with related biomarkers. Furthermore, wound-healing and Transwell assays were performed to test the migratory and invasive abilities of PCa cells. Luciferase reporter assays were used to validate the relationship between MALAT1 and miR-145; their down-stream target genes were also studied. To further substantiate these findings in an animal model, tumor studies including immunofluorescence staining of tissues were carried in nude mice.RESULTS:The expression of MALAT1 was upregulated in both LNCaP cell lines and CWR22Rv1 cell lines (F=2.882, t=13.370, P<0.001; F=2.268, t=15.859, P<0.001). Knockdown of MALAT1 reduced the migratory and invasive capabilities of PCa cells (F=0.017, t=12.212, P<0.001; F=10.723, t=6.016, P=0.002). Using direct binding, MALAT1 suppressed the antitumor function of miR-145, which in turn upregulated transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) via SMAD3 and TGFBR2 (F=2.097, t=5.389, P=0.006; F=1.306, t=4.155, P=0.014).CONCLUSIONS:We confirmed that MALAT1 acts as a competing endogenous RNA (ceRNA) of miR-145. The MALAT1 based regulation of MiR-145-5p-SMAD3/TGFBR2 interactions could be an intriguing molecular pathway for the progression of PCa.

With the increasing prevalence of obesity worldwide, obesity-related female stress urinary incontinence (FSUI) has become a key health problem. Recent studies indicated that FSUI is primarily caused by obesity-related pathological changes, such as fat droplet deposition, and results in pelvic floor nerve, vascular, and urethral striated muscle injury. Meanwhile, treatments for obesity-associated FSUI (OA-FSUI) have garnered much attention. Although existing OA-FSUI management strategies, including weight loss, pelvic floor muscle exercise, and urethral sling operation, could play a role in symptomatic relief; they cannot reverse the pathological changes in OA-FSUI. The continued exploration of safe and reliable treatments has led to regenerative therapy becoming a particularly promising area of researches. Specifically, micro-energy, such as low-intensity pulsed ultrasound (LIPUS), low-intensity extracorporeal shock wave therapy (Li-ESWT), and pulsed electromagnetic field (PEMF), have been shown to restore the underlying pathological changes of OA-FSUI, which might be related by regulation endogenous stem cells (ESCs) to restore urine control function ultimately in animal experiments. Therefore, ESCs may be a target for repairing pathological changes of OA-FSUI. The aim of this review was to summarize the OA-FSUI-related pathogenesis, current treatments, and to discuss potential therapeutic options. In particular, this review is focused on the effects and related mechanisms of micro-energy therapy for OA-FSUI to provide a reference for future basically and clinical researches.

With the continuous integration and intersection of life sciences, engineering and physics, the application for micro-energy in the basic and clinical research of regenerative medicine (RM) has made great progress. As a key target in the field of RM, stem cells have been widely used in the studies of regeneration. Recent studies have shown that micro-energy can regulate the biological behavior of stem cells to repair and regenerate injured organs and tissues by mechanical stimulation with appropriate intensity. Integrins-mediated related signaling pathways may play important roles in transducing mechanical force about micro-energy. However, the complete mechanism of mechanical force transduction needs further research. The purpose of this article is to review the biological effect and mechanism of micro-energy treatment on stem cells, to provide reference for further research.

组织工程是涉及材料学、生命科学和生物工程学的交叉学科,旨在恢复组织或器官部分或全部功能.近年来,脱细胞异体真皮(Human acellular dermal mantrix,HADM)更多地运用在泌尿外科、男科生殖系统疾病中,脱细胞异体真皮的兴起及其技术在实验及临床领域的成功应用,已经为许多泌尿外科、男科疾病的治疗提供新的方法与途径.本文就HADM在泌尿男科生殖系疾病中的应用及研究进展予以综述.

Background: This study aims to present the trends of incidence and mortality of kidney cancer from 1990 to 2016 by age, gender, geographical region, regional, and sociodemographic index (SDI), and then forecast the future trends to 2030. Methods: Data of this study were gathered from the Global Burden of Disease Study (GBD), including 195 countries and territories, accounting for 21 regions. Over-time trends from 1990 to 2016 were analyzed by gender, geographical region, age range and SDI. Based on the big data, we forecasted the future trends to 2030 by ARIMA model. All the data were analyzed by R software (x64 version 3.5.1), SAS (version 9.3) and SPSS (version 22.0). Results: Globally, in 2016, there were 342,100 [95% uncertainty interval (UI), 330,759-349,934] incident cases of kidney cancer and the number of deaths were 131,800 (127,335-136,185). The age-standardized incidence rate (ASIR) and death rate (ASDR) were 4.97 (4.81-5.09) per 100,000 and 2.00 (1.93-2.06) per 100,000, respectively. Globally, the estimated risk of kidney cancer for male within the age of 30 and 70 is around 0.79% compared to 0.41% for female. In other words, the probability of developing kidney cancer was generally higher in male than in female. By 2030, incidence of kidney cancer in both sexes are projected to increase substantially in high SDI, followed by middle SDI, low-middle SDI, and low SDI countries. High SDI and low SDI countries will also have increased mortality rates of kidney cancers. Globally, the trends in deaths due to kidney cancer will remain stable. Conclusions: The incidence and death rate of kidney cancer are highly variable among SDI countries and regions but have increased uniformly from 1990 to 2016. By 2030, the future incidence of kidney cancer will grow continuously especially in high SDI countries, middle SDI, low-middle SDI, and low SDI countries.

With the continuous integration and intersection of life sciences, engineering and physics, the application for micro-energy in the basic and clinical research of regenerative medicine (RM) has made great progress. As a key target in the field of RM, stem cells have been widely used in the studies of regeneration. Recent studies have shown that micro-energy can regulate the biological behavior of stem cells to repair and regenerate injured organs and tissues by mechanical stimulation with appropriate intensity. Integrins-mediated related signaling pathways may play important roles in transducing mechanical force about microenergy. However, the complete mechanism of mechanical force transduction needs further research. The purpose of this article is to review the biological effect and mechanism of micro-energy treatment on stem cells, to provide reference for further research.

Background: This research aims to identify the current and future trends in the incidence and death rate of prostate cancer and to provide the necessary data support for making relevant health decisions. Methods: This study used the collected data and methodologies to describe the incidence and mortality trends of prostate cancer from 1990 to 2016. Based on the data, this paper projected the future trends in prostate cancer incidence and death rate. Results: In 2016, prostate cancer cases [1,435,742; 95% uncertainty interval (UI), 1,293,395-1,618,655] were nearly 2.5-fold the number in 1990 (579,457; 95% UI, 521,564-616,107). Deaths increased by 2.0fold from 191,687 (95% UI, 168,885-209,254) in 1990 to 380,916 (95% UI, 320,808-412,868) in 2016. The global age-standardized incidence rate (ASIR) increased from 17.75 (95% UI, 18.91-15.95) in 1990 to 22.12 (95% UI, 19.92-24.91) in 2016, changing 24.62%. The global change of age-standardized death rate (ASDR) has declined slightly, but in some regions it shows a trend of growth. By sociodemographic index (SDI) subtypes, prostate cancer will frequently occur in high SDI countries from 1990 to 2030. Simultaneously, the highest mortality will present in low SDI countries. Conclusions: Through projecting and analyzing incidence and mortality rate of prostate cancer, from 1990 to 2030, by different ages, regions and SDI sub-types, this result may reveal the relationship between prostate cancer and financial development. At the same time, the result also showed a sufficiently heavy burden of prostate cancer, but the burden varies greatly in each region. The burden is a challenge and will require attention for all levels of society. The current study is beneficial to formulate more specific and efficient policies.

Background: Previous study has reported that loss of epithelial androgen receptor (AR) may promote tumor progression and cause TRAMP mouse model die earlier. The detail mechanisms, however, remain unclear. Methods: Immunohistochemistry assay, Western blot and real-time PCR were used to detect the expression of epithelial and mesenchymal markers. RNA extraction, RT-PCR, quantitative RT-PCR, BrdU incorporation assays, flow cytometry and other experimental technics were also used in present work. Results: Decreased expression of epithelial markers (Cytokeratin 8, NKX3 .1 and E-cadherin) and increased expression of mesenchymal markers (alpha-SMA, Vimentin, and N-cadherin) in were found in AR knockout TRAMP tumors. Further investigation indicated that AR signal deprivation is associated with cell morphology transition, high cell mobility, high cell invasion rate and resistance to anoikis in TRAMP prostate tumor cells. Together, these findings implied knockout AR in TRAMP prostate tumor may lead to EMT, which may result in earlier metastasis, and then cause TRAMP mice die earlier. TGF-131 is responsible for EMT in AR knockout TRAMP tumor cells. Conclusions: In conclusion, ADT therapy induced hormone refractory prostate cancer may gain the ability of metastasis through cell?s EMT which is a phase of poor differentiation. Anti -EMT drugs should be developed to battle the tumor metastasis induced by ADT therapy.