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A high concentration of oxalate is associated with an increased risk of kidney calcium oxalate (CaOx) stones, and the degradation of exogenous oxalate mainly depends on oxalate-degrading enzymes from the intestinal microbiome. We found that Zinc Gluconate supplement to patients with CaOx kidney stones could significantly improve the abundance of oxalate metabolizing bacteria in human body through clinical experiments on the premise of simultaneous antibiotic treatment and the imbalance ofLactobacillusand OxDC was involved in CaOx kidney stones through clinical sample analysis. Then, we identified that Zn2+could be used as an external factor to improve the activity of OxDC and protectLactobacillus, achieved the preventive effect on rats with stones aggravated by antibiotics. Finally, by analyzing the three-dimensional structure of OxDC and somein vitroexperiments, we propose a hypothesis Zn2+increases the metabolism of oxalate in humans through its positive effects onLactobacillusand OxDC to reduce CaOx kidney stone symptoms in rats.IMPORTANCEUrinary stone disease is one of the most common urological disorders, and 70%-80% of urinary stones are calcium oxalate (CaOx) stones. We found the structural basis and metabolic mechanism by which oxalate decarboxylase metabolizes oxalate were elucidated, and Zn2+was illustrated to have therapeutic effects on CaOx stones by improving the tolerance of Lactobacillus to antibiotics. According to that, proper Zn2+levels in the diet, the consumption of more probiotic food and avoidance of the antibiotic overuse might be desirable measures for the prevention and treatment of kidney stones.Graphical Abstract

Malaymycin (1), a new cyclopentenone-containing tetrahydroquinoline alkaloid, and mccrearamycin E (2), a geldanamycin analogue bearing a rare ring-contracted cyclopentenone moiety, and a C2-symmetric macrodiolide (7) were isolated from Streptomyces malaysiensis SCSIO41397. Their structures including absolute configurations were determined by detailed analyses of NMR and HRMS data and ECD calculations. The occurrence of mccrearamycin E (2) bearing a ring-contracted cyclopentenone is rare in the geldanamycin class. All isolated compounds were evaluated for their cytotoxicities against five cancer cell lines. As a result, compounds 1, 4, 5, and 7 showed cytotoxicity against some or all of the five cancer cell lines with IC50 values ranging from 0.067 to 7.2 μM. In particular, compound 1 inhibited the growth of C42B and H446 cell lines with IC50 values of 67 and 70 nM, respectively. Malaymycin (1) significantly induced cell cycle arrest at the G0/G1 phase in C42B cell lines and caused cell shrinkage and inhibited the expression of the androgen receptor (AR) at both the mRNA and protein levels in a dose-dependent manner. Further examination by qRT-PCR analysis showed that 1 strongly suppressed the expression of AR target genes KLK2 and KLK3 in the C42B and 22RV1 cell lines, which suggested that 1 might be a promising potential lead compound for the development of a treatment for the castration-resistant prostate cancer (CRPC).

Castration-resistant prostate cancer (CRPC) almost invariably occurs after androgen-deprivation therapy (ADT) for the advanced metastatic disease. It is generally believed that among multiple mechanisms and signaling pathways, CRPC is significantly driven by the reactivation of androgen receptor (AR) signaling in ADT-treated patients with castrate levels of androgen, partially at least mediated by the androgen biosynthesis within the tumor, also known as intratumoral or intraprostatic androgen biosynthesis. Steroidogenic enzymes, such as CYP11A1, CYP17A1, HSD3B1, AKR1C3 and SRD5A, are essential to catalyze the conversion of the initial substrate cholesterol into potent androgens that confers the CRPC progression. Accumulating evidences indicate that many steroidogenic enzymes are upregulated in the progression setting; however, little is known about the dysregulation of these enzymes in CRPC. Orphan nuclear receptors (ONRs) are members of the nuclear receptor superfamily, of which endogenous physiological ligands are unknown and which are constitutively active independent of any physiological ligands. Studies have validated that besides AR, ONRs could be the potential therapeutic targets for prostate cancer, particularly the lethal CRPC progression. Early studies reveal that ONRs play crucial roles in the transcriptional regulation of steroidogenic enzyme genes. Notably, we and others show that three distinct ONRs, including liver receptor homolog-1 (LRH-1, NR5A2), steroidogenic factor 1 (SF-1, AD4BP, NR5A1) and estrogen-related receptor α (ERRα, NR3B1), can contribute to the CRPC progression by promotion of the intratumoral androgen synthesis via their direct transcriptional regulation on multiple steroidogenic enzymes. This review presents an overview of the current understanding on the intratumoral androgen biosynthesis in CRPC, with a special focus on the emerging roles of ONRs in this process.

Prostate cancer (PCa) is considered as the most common cancer of urologic neoplasms, and its development and prognosis are associated with many factors. Chemokine receptor signaling combine with advances in advanced clinicopathological characteristics have provided new insights into the molecular landscape of prostate cancer. Chemokine (C-C motif) ligand 5 (CCL5) is an important member of the CC subfamily of chemokines. The expression of chemokine CCL5 is positively correlated with poor prognostic features in patients with PCa. Current study suggested that CCL5/CCR5 axis plays a significant role in the proliferation, metastasis, angiogenesis, drug resistance of prostate cancer cells and promotes self-renewal of prostate cancer stem cells (PCSCs). Due to the major domination in CCL5 by prostate cancer and the high cancer-specific mortality with prostate cancer, research on the CCL5/CCR5 axis effective antagonists is widespread application. However, challenges for precision oncology of CCL5/CCR5 axis and effective antagonists in CRPC remain. Herein, we summarized the crucial role of CCL5 in promoting the development of PCa and discussed the antitumor application of the antagonists of CCL5/CCR5 axis.

Prostate cancer (PCa) is a malignant tumor with an extremely high prevalence. Doxorubicin is the first-line clinical treatment for castration-resistant PCa. Clinically, relapse is almost inevitable due to the cancer cells' increasing resistance to doxorubicin. Our previous studies have revealed that retinoic acid-related orphan nuclear receptor γ (RORγ) is a key protein for cancer progression and a promising target for PCa therapy. Though, RORγ's role and mechanism in doxorubicin-resistant PCa remain unclear. To study the mechanism of doxorubicin resistance, we generated a doxorubicin-resistant PCa cell line C4-2B (C4-2B DoxR) in this study, by culturing cells in an increasing doxorubicin concentration. Here, we show that RORγ expression was upregulated in C4-2B DoxR cells compared with that in normal C4-2B cells. The RORγ-stably-overexpressing PCa cell line constructed by lentiviral transfection showed an obvious improvement in doxorubicin resistance and a trend toward castration resistance. Furthermore, RORγ-specific small molecule inhibitors XY018, GSK805, and SR2211 can significantly inhibit the proliferation of C4-2B DoxR cells and promote their apoptosis. Collectively, these results have demonstrated the correlation between the upregulation of RORγ and the development of PCa's doxorubicin resistance, thus providing new ideas for solving the problem of chemotherapy drug resistance in PCa.

Investigating antibacterial process at a molecular level is helpful to fully understand the mechanism of bacteriostasis and develop new antimicrobial agents. Herein, a simple but effective sensor strategy of antibacterial nanocomposite combined with surface-enhanced Raman scattering (SERS) substrate was applied for the robust detection of bacteriostatic process. The synergistic SERS effect of nanocomposite and Ag nanoparticles (NPs) substrate was confirmed by finite difference time domain (FDTD) solutions. A curcumin liposome@Au NPs nanocomposite was designed and prepared as a kind of bacteriostatic agent and SERS material as well. By means of electrostatic attraction between the nanocomposite and bacteria (methicillin resistant staphylococcus aureus, MRSA), specific detection of MRSA and monitoring of the molecular structure changes after bacteriostaticeffect were realized by SERS. Important intermediates produced in the bacteriostatic process were also measured at the same time. The relationship between the relative peak intensities and the structure of MRSA were thus established. The results were verified by high performance liquid chromatography-mass spectrometry (HPLC-MS), reactive oxygen species (ROS) kit, and flow cytometry. The detection strategy we proposed could not only be used for real-time detection of bacteriostatic processes with a high efficiency, but also a powerful tool for analyzing the mechanism in biochemical processes.

To investigated the association between serum total testosterone and Gleason score upgrading of low-risk prostate cancer after radical prostatectomy (RP).Medline, Web of Science, Embase, and Cochrane Library databases were searched to identify eligible studies published before October 2021. Multivariate adjusted odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated using random or fixed effects models.Five studies comprising 1,203 low-risk prostate cancer patients were included. The results showed that low serum total testosterone (300 ng/dL) is associated with a high rate of Gleason score upgrading after RP (OR, 2.3; 95% CI, 1.38-3.83; p0.001; I², 92.2%). Notably, sensitivity and meta-regression analyses further strengthen the reliability of our results.Our results support the idea that low serum total testosterone is associated with a high rate of Gleason score upgrading in prostate cancer patients after RP. It is beneficial for urologist to ensure close monitoring of prostate-specific antigen levels and imaging examination when choosing non-RP treatment for low-risk prostate cancer patients.

Background Zoledronic acid (ZA) does not improve the overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC); however, little is known about the efficacy of ZA in to hormone-sensitive prostate cancer (HSPC), metastatic hormone-sensitive prostate cancer (mHSPC), and non- metastatic castration-resistant prostate cancer (nmCRPC). Therefore, we assessed the efficacy of ZA in patients with prostate cancer (PCa) and different disease statuses. Methods Fifteen eligible randomized-control trials (RCTs) with ZA intervention, including 8280 participants with HSPC, mHSPC, nmCRPC, and mCRPC, were analyzed. The primary and secondary outcome were overall survival(OS), and skeletal-related events (SREs), and bone mineral density (BMD). Results The participants included 8280 men (7856 non-Asian and 424 Asian). Seven trials yielded a pooled hazard ratio (HR) of 0.95 (0.88, 1.03; P = 0.19) for OS. Subgroup analysis revealed no significant improvement in OS in the HSPC, castration-resistant prostate cancer (CRPC), M0 and M1(bone metastasis) groups, with pooled HR (95%CI) of 0.96 (0.88,1.05), 0.78 (0.46,1.33), 0.95 (0.81,1.13), 0.85 (0.69,1.04) respectively. The Asian group exhibited improved in OS with an HR of 0.67 (0.48, 0.95; P = 0.02), whereas the non-Asian group showed no improvement in OS with an HR of 0.97 (0.90, 1.06; P = 0.52). Five trials yielded pooled odds ratio (OR) of 0.65 (0.45, 0.95; P = 0.02) for SREs. In the subgroup, SREs were significantly decreased in the M1 and Asian groups with ORs of 0.65 (0.45, 0.95; P = 0.02) and 0.42 (0.24, 0.71; P = 0.001), respectively. Six trials yielded a pooled mean difference (MD) of 8.08 (5.79, 10.37; P < 0.001) for BMD. In the HSPC we observed a stable improvement in increased BMD percentage with an MD (95%CI) of 6.65 (5.67, 7.62) (P = 0.001). Conclusions ZA intervention does not significantly improve OS in patients with prostate cancer (HSPC, CRPC, M0, M1) but probably improves OS in the Asian populations. M1 and Asian groups had exhibit a significant reduction in SREs regardless of the HSPC or CRPC status after ZA administration. Moreover, ZA treatment increases BMD percentage.

The Polycomb protein enhancer of zeste homolog 2 (EZH2) has critical roles in prostate cancer (PCa) progression and drug-resistance, which remains an obstacle for PCa treatment. Enzalutamide (ENZ) is a second-generation androgen receptor antagonist employed for treatment of metastatic castration-resistant prostate cancer A considerable proportion of tumors eventually develop resistance during treatment. Thus, agents that can overcome resistance to PCa are needed urgently. Ilicicolin A (Ili-A), an ascochlorin derivative isolated from the coral-derived fungus Acremonium sclerotigenum GXIMD 02501, shows antiproliferative activity in human PCa cells, but its mechanism of action against Castration-resistant prostate cancer is not known. Herein, RNA-sequencing showed the EZH2 pathway to be involved in PCa proliferation. Ili-A at low doses reduced the protein level of EZH2, leading to transcriptional change. Interestingly, Ili-A suppressed the binding of EZH2 to promoter regions in AR/serine/threonine polo-like kinase-1/aurora kinase A. Moreover, Ili-A could enhance the anticancer activity of enzalutamide in CRPC cancer models. These data suggest that Ili-A could be used in combination with enzalutamide to treat CRPC.

We aimed to determine the cancer detection rate and complications of transrectal prostate biopsy (TRBx) and transperineal prostate biopsy (TPBx) in the hospital. However, given the use of antibiotic prophylaxis in TPBx remains controversial according to the current guidelines, we also investigated the safety and side effects of TPBx with and without antibiotic prophylaxis.A total of 777 patients who underwent prostate biopsy were enrolled in this study in accordance with the criteria. The primary outcome was pooled infectious complications (sepsis, fever, symptomatic urinary tract infection and urinary retention), and the secondary outcome was prostate cancer detection rate.Findings showed that TPBx and TRBx were equivalent in terms of prostate cancer detection rate (TPBx: 50.4% vs. TRBx: 47.3%; P = 0.424) and urinary retention (TPBx: 5% vs. TRBx: 6.3%; P = 0.451). However, TRBx had significantly higher incidences of sepsis (risk ratios, RR: 3.65, 95% confidence interval [CI]: 1.21-11.03; P = 0.014) and symptomatic urinary tract infection (RR: 3.04, 95% CI: 1.07-8.66; P = 0.029) than TPBx. Notably, for TPBx, patients who received a single dose of cephazolin prophylaxis were not associated with the risk of sepsis (RR: 0.78, 95% CI: 0.13-4.63; P = 0.783) and symptomatic urinary tract infection (RR: 1.17, 95% CI: 0.24-5.74; P = 0.848) in contrast to patients who did not receive any antibiotic prophylaxis. Meanwhile, no effects on prostate cancer detection rate and urinary retention were observed in the TPBx group.Our findings indicated that TPBx significantly reduced infectious complications compared with TRBx and should therefore be preferred. Importantly, we need to re-examine whether the antibiotic prophylaxis should be routinely applied before TPBx in consideration of increasing antibiotic resistance. This result complements the current national guidelines. Nevertheless, future studies on this topic with improved quality and increased sample size are still needed to minimise bacterial resistance.

To evaluate predictive factors affecting the stone-free rates (SFR) and complications of minimally invasive percutaneous nephrolithotomy (MPCNL) under local infiltration anesthesia (LIA) METHODS: A retrospective analysis was conducted on 976 consecutive patients who underwent MPCNL under LIA from January 2015 to June 2018. Postoperative complications were classified according to modified Clavien classification system. Univariate and multivariate logistic regression analyses were used to determine factors affecting SFR and complications.The pain was acceptable with postoperative visual analog scale (VAS) scores being 3.58, 2.99, 2.25, and 2.07 after 0, 6, 24, and 48 h, respectively. The SFR after primary MPCNL reached 85.7%. Postoperative complications were recorded in 77 patients (7.9%). In the univariate logistic analysis, larger stone size, staghorn stone, and multiple calyxes were significantly associated with lower SFR. The higher American Society of Anesthesiologists (ASA) score, staghorn stone, positive urine culture, multiple tracts, and longer operation time were associated with occurrence of complications. However, hydronephrosis was associated with lower complication rate. Multivariate analysis indicated that larger stone size (P 0.001) and staghorn stone (P 0.001) were associated with lower SFR, while development of complications was independently influenced by higher ASA score (P = 0.002), multiple tract (P = 0.004), and staghorn stone (P = 0.028).MPCNL can be safely and effectively performed under LIA. Stone size and staghorn stone are factors associated with SFR while ASA score, multiple tracts, and staghorn stone are associated with the development of complications. For the first time, we developed a model to predict the SFR and complications in MPCNL under LIA.

Background: The prognostic value of chromogranin-A (CHGA) as a biomarker of prostate cancer (PCa) has been evaluated extensively. However, to date the results still remain controversial. This study aims to perform a meta-analysis on previous studies in order to determine whether CHGA would be a biomarker for survival in PCa patients. Methods: MEDLINE, Embase, Web of Science, and Cochrane Library databases were searched to identify eligible studies published before September 2018, regarding the association of CHGA gene expression with survival outcomes in patients with PCa. Multivariate adjusted HRs and associated 95% CIs were calculated using random effects models. Results: Ten cohort studies involving 3,172 patients were finally included. According to the included studies, circulating CHGA levels were tested in serum, plasma, and tissues. The results showed an association between high CHGA expression and worse overall survival (OS) (HR=1.24, 95% CI: 1.07–1.44; P=0.004; I2=77.6%) in PCa patients. However, no significant association was observed between increasing CHGA expression and shorter progression-free survival (HR=1.73, 95% CI: 0.92–3.28; P=0.090; I2=73.9%). The results of sensitivity analysis validated the rationality and reliability of our analysis. Conclusion: Current evidence indicates that high CHGA expression is a potential marker for poor OS in PCa. Future studies are needed to explore tailored treatments that directly target CHGA for the improvement of survival in men with PCa.

Malaymycin (

In order to realize the accurate and early diagnosis of liver fibrosis, a long slow pathological process which may lead to cirrhosis or even liver cancer, liver targeting tags made up of gold nanostars and glycyrrhetinic acid are reported in this paper. Gold nanostars (GNSs) and GNS liver targeting tags (GLTTs) were injected into model mice with stage S1 liver fibrosis and normal mice via the tail vein respectively, then the SERS spectra were collected. GLTTs had a better detection effect on liver tissue than unmodified GNSs (12.85 times), and better detection reproducibility as well. Moreover, according to the MTT and survival analysis experiments, GLTTs also had better biocompatibility. Hence, the changes of 10 SERS signals and other substances in the early stage of liver fibrosis were analyzed at the molecular level, and the SERS characteristic peaks that could be used for the diagnosis of early liver fibrosis were screened out. Revealed by the experimental results, the GLTTs designed and prepared were applicable to the efficient SERS detection of early liver fibrosis in mice, and the strategy we have proposed might be a potential approach for the early diagnosis of this disease in clinics.

Introduction: To analyze the risk factors for the progression to severe sepsis,or septic shock,in pre-hospital patients with urolith Induced obstructive urosepsis, so as to facilitate the early identification of high-risk patients.Materials and Methods: Datas were retrospectively reviewed from 160 patients of urolith induced obstructive urosepsis between December 2013 and December 2019. There were 49 patients complicated by severe sepsis (severe sepsis group), 12 patients with septic shock (septic shock group), and 99 patients without progression to severe sepsis or septic shock (sepsis group). The data covered age, gender, BMI , time interval from ED to admission, WBC count, NLR, HGB, etc. Datas were analyzed by univariate analyses and multivariate logistic regression analysis.Results: Univariate analysis showed that the differences of age, the time interval from ED to admission, history of diabetes mellitus, history of CKI, NLR, HGB, platelet count, TBil, SCr, ALB, PT, APTT, INR, PCT, and positive rate of pathogens in blood culture were statistically significant (P < 0.05). Multivariate logistic regression analysis showed that age, SCr, and history of CKI were independent risk factors for progression to severe sepsis, or septic shock (P < 0.05).Conclusions: Aged ≥ 65 years, SCr ≥ 248 mol/L, and history of CKI were independent risk factors for progression to severe sepsis, or septic shock, in patients with urolith induced obstructive urosepsis. The key to prevent urosepsis from progression is to improve our understanding of disease dynamics, control the risk factors, and intervene the pre-hospital patients with multidisciplinary modalities as early as possible.

The impact of marital status on the prognosis amongst patients diagnosed with prostate cancer remains controversial. Thus, a meta-analysis was performed to determine whether marital status can influence the prognosis in patients with prostate cancer.Literature search of the MEDLINE, PsycINFO, Embase and Cochrane Library databases was conducted to identify eligible studies published before April 2020. Multivariate adjusted risk estimates and corresponding 95% confidence intervals (CIs) were extracted and calculated using the random effects model.A total of 11 observational studies comprising 1,457,799 patients diagnosed with prostate cancer were identified. Results indicated that unmarried status (separated, divorced, widowed or never married) was associated with an increased risk of all-cause mortality (hazard ratio, HR = 1.39, 95% CI: 1.30-1.50; P.001; I2 = 92.2%) compared with married status, especially for divorced and never-married patients. Similarly, being unmarried had an elevated risk of cancer-specific mortality (HR = 1.29, 95% CI: 1.17-1.41; P.001; I2 = 82.5%) in patients with prostate cancer. A significant difference was also observed between unmarried status and shorter overall survival (HR = 1.37, 95% CI: 1.20-1.56; P.001; I2 = 94.5%).Results demonstrated that unmarried status is associated with a worse prognosis regarding mortality and survival in patients diagnosed with prostate cancer, particularly in divorced and never-married patients. Hence, further research should explore the potential mechanisms which can benefit the development of novel, more personalised management methods for unmarried patients with prostate cancer.

In order to achieve real-time and in situ detection of endotoxin, which is an important and significant clinical test index, surface-enhanced Raman spectroscopy (SERS) chip integrated array microchambers within bioscaffold nanostructures and a SERS monitoring strategy were proposed in this paper. After sputtering of nanogold on the cicada wing, which was selected as a natural template, and polydimethylsiloxane bonding, array-type chambers within bioscaffold nanostructures were prepared for in situ bacterial culture and monitoring of endotoxin in the bacteriostasis process by SERS. Meanwhile, the SERS tag modified with the DNA aptamer was prepared and added into this complex biochemical reaction to further improve the sensitivity and selectivity. A new method for in situ detection of endotoxin was thus established. The detection time was shortened to 100 s, and the detection limit was as low as 6.25 ng/mL. Pseudomonas aeruginosa was cultured in situ in the chamber of the SERS chip with antimicrobial agents in 0-72 h. The endotoxin released in the antibacterial process was monitored by the designed SERS detection strategy. The results obtained by SERS analysis were consistent with those of the ELISA kit.

Background: Periodontal disease is reportedly associated with the risk of various systemic diseases, including pancreatic and lung cancers. However, its association with prostate cancer remains inconclusive. Herein, we explored the association of periodontal disease with the risk of prostate cancer through a meta-analysis. Materials and Methods: MEDLINE, Embase, Web of Sciences and Cochrane Library databases were searched for eligible publications up to April 2020. Multivariate adjusted risk estimates with corresponding 95% confidence intervals (CIs) were extracted and calculated using random- or fixed-effect models. Results: Nine cohort studies involving 3.353 prostate cancer cases with 440.911 participants were identified and included in the meta-analysis. We found that periodontal disease significantly increased the risk of prostate cancer by 1.40-fold (hazard ratio [HR]=1.40, 95% CI: 1.16-1.70; P=0.001; I2=76.1%) compared with normal condition. Interestingly, the risk of developing prostate cancer was not significant in patients treated with periodontal therapy (HR=1.22, 95% CI: 0.86-1.73; P=0.272; I2=65.2%). The results of subgroup analyses were also consistent and significant when stratified by study design and follow-up period, whereas conflicting results were observed in periodontal disease ascertainment stratification. These findings were robust as indicated by sensitivity analyses. Conclusions: Periodontal disease was associated with the increased risk of prostate cancer, whereas no significant association was observed in patients treated with periodontal therapy. Hence, the awareness and importance for maintaining oral health should be improved, and the underlying mechanisms linking periodontal disease and prostate cancer should be fully explored in future research.

Patients with bladder cancer have a high risk of suicide. This study aimed to assess how bladder cancer increases suicide risk and to identify the demographic and clinical factors associated with suicidal death among patients with bladder cancer.Literature search of MEDLINE, PsycINFO, Embase, Web of Sciences and Cochrane Library databases was conducted up to April 2020 to identify eligible studies related to the incidence and risk factors of suicide after bladder cancer diagnosis. Summary multivariate-adjusted risk estimates and their associated 95% confidence intervals (CIs) were calculated using inverse variance method with random or fixed-effect modeling.Five retrospective cohorts comprising 563,680 patients with bladder cancer were included. Higher risk of suicide by 1.90-fold was observed among patients with bladder cancer (hazard ratio, HR = 1.90, 95% CI: 1.29-2.81; P = 0.001; ISuicide risk is increased among patients with bladder cancer, particularly those aged 70 years or older, unmarried and those with regional bladder cancer. Hence, early psychological support must be provided during the follow-up period of these special populations with a high suicide risk.

Prostate cancer stem cells (PCSCs) play a critical role in prostate cancer progression and metastasis, which remains an obstacle for successful prostate cancer treatment. Tumor-associated macrophages (TAMs) are the most abundant immune cell population within the tumor microenvironment (TME). Systematic investigation of the interaction and network signaling between PCSCs and TAMs may help in searching for the critical target to suppress PCSCs and metastasis. Herein, we demonstrated that TAMs-secreted CCL5 could significantly promote the migration, invasion, epithelial–mesenchymal transition (EMT) of prostate cancer cells as well as the self-renewal of PCSCs in vitro. QPCR screening validated STAT3 as the most significant response gene in prostate cancer cells following CCL5 treatment. RNA-sequencing and mechanistic explorations further revealed that CCL5 could promote PCSCs self-renewal and prostate cancer metastasis via activating the β-catenin/STAT3 signaling. Notably, CCL5 knockdown in TAMs not only significantly suppressed prostate cancer xenografts growth and bone metastasis but also inhibited the self-renewal and tumorigenicity of PCSCs in vivo. Finally, clinical investigations and bioinformatic analysis suggested that high CCL5 expression was significantly correlated with high Gleason grade, poor prognosis, metastasis as well as increased PCSCs activity in prostate cancer patients. Taken together, TAMs/CCL5 could promote PCSCs self-renewal and prostate cancer metastasis via activating β-catenin/STAT3 signaling. This study provides a novel rationale for developing TAMs/CCL5 as a potential molecular target for PCSCs elimination and metastatic prostate cancer prevention.

Background/Aims: Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibits antitumor effects. However, the detailed mechanism underlying PPI, particularly in enhancing the effect of the androgen receptor inhibitor enzalutamide in controlling castration-resistant prostate cancer (CRPC) has not been explored. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) expression was measured by quantitative real time-PCR (qRT-PCR). Western blot analysis was performed to determine the protein expression levels of MUC1, p65, and p50. Silencing of HOTAIR was evaluated using the siRNA procedure. The promoter activity of the MUC1 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expression of HOTAIR, p65, and MUC1 was conducted by transient transfection assay. A xenograft tumor model in nude mice was used to further evaluate the effect of the combination of PPI and enzalutamide in vivo. Results: We showed that PPI significantly inhibited growth and induced cell cycle arrest in CRPC cells. PPI also decreased p65 and MUC1 protein expression and reduced HOTAIR expression. Exogenously expressed p65 resisted the PPI-inhibited expression of HOTAIR, whereas silenced HOTAIR reduced MUC1 protein but exerted no effect on the expression of p65 and p50 proteins. Conversely, exogenously expressed HOTAIR resisted the PPI-inhibited MUC1 protein expression, and excessive expression of MUC1 antagonized the PPI-inhibited cell growth. Notably, PPI combined with enzalutamide exerted a synergistic effect. Consistent with this finding, PPI inhibited tumor growth, HOTAIR expression, as well as p65 and MUC1 protein expressions in vivo. Conclusions: Our results indicate that PPI inhibits the growth of CRPC cells by inhibiting p65 protein and concomitantly reducing HOTAIR expression, thereby suppressing MUC1 gene expression. The novel regulatory interaction of p65 and HOTAIR converge in the inhibition of MUC1 expression and overall PPI response. The combination of PPI and enzalutamide exhibits synergy. This study reveals a novel mechanism underlying the synergistic inhibitory effect of PPI and enzalutamide on the growth of CRPC cells.

Desmosium styracifolium (D. styracifolium), which is considered as a Chinese herbal medicine, has been reported to treat the kidney stone diseases. However, the potential phytochemically active components and the underlying mechanisms associated with its efficacy in targeting urolithiasis remain to be elucidated. This study aims to investigate the anti-urolithiatic effect of total flavonoids of D. styracifolium (TFDS) on calcium oxalate (CaOx) renal stones in Sprague-Dawley rats. Animal models of CaOx urolithiasis were established in male Sprague-Dawley rats by adding 5% w/w hydroxy-L-proline (HLP) in regular rat chow. The TFDS orally at 100, 400 mg/kg, respectively, were administered along with HLP for 28 days. At the end of 28 days of treatment, urine and serum samples were collected for crystalluria determination and various biochemical analysis. Kidney tissues were isolated and processed for antioxidant parameters measurement and histopathological examinations. HLP-induced hyperoxaluria alone reliably caused CaOx nephrolithiasis in rats. We showed that TFDS significantly reduced crystalluria and CaOx crystal deposits in the kidney sections as compared to untreated HLP group. Also, TFDS was observed to decrease urinary oxalate excretion, alleviate the pro-acidosis condition, improve the impaired renal functions and renal epithelial cell injury. Moreover, TFDS protected against the oxidative stress changes via reducing MDA content, increasing CAT and GSH-Px activities in renal homogenate, as well as attenuating the expression of MCP-1, OPN and TGF-β proteins. These results indicated that TFDS had beneficial effect on inhibition of CaOx formation in the rat kidney probably through a combination of antioxidant, anti-inflammatory, urine alkalinizing activities, and lowering the concentration of urinary stone-forming constituents. Thus, TFDS might have clinical implications in preventing oxidative renal cell injury and, ultimately, kidney stone formation. The data provide a rationale for the medicinal use of TFDS in nephrolithiasis and identify this agent as a potential source of new antiurolithic drugs.

Coral-derived microorganisms have been historically proven to be prolific sources of bioactive secondary metabolites. Twelve benzopyranone and/or xanthone derivatives, including a new benzopyranone with an uncommon carboxyl group at C-8, coniochaetone K (1), were obtained from the Beibu Gulf-derived coral symbiotic fungus Cladosporium halotolerans GXIMD 02502. Their structures were determined by extensive spectroscopic data interpretation and comparison with literature values. The absolute configuration of 1 was accomplished by comparison of specific optical rotation as well as quantum chemical ECD calculations. The in vitro cytotoxicity of compounds 1–12 against two human prostatic cancer cell lines, C4-2B and 22RV1, were evaluated. And compounds 1, 3, 6–8, and 10–11 demonstrated significant cytotoxicity with inhibitions ranging from 55.8% to 82.1% at the concentration of 10 μM.

Endocrine therapies (e.g. tamoxifen and aromatase inhibitors) targeting estrogen action are effective in decreasing mortality of breast cancer. However, their efficacy is limited by intrinsic and acquired resistance. Our previous study demonstrated that overexpression of a histone methyltransferase NSD2 drives tamoxifen resistance in breast cancer cells and that NSD2 is a potential biomarker of tamoxifen resistant breast cancer. Here, we found that DZNep, an indirect inhibitor of histone methyltransferases, potently induces the degradation of NSD2 protein and inhibits the expression of NSD2 target genes (HK2, G6PD, GLUT1 and TIGAR) involved in the pentose phosphate pathway (PPP). DZNep treatment of tamoxifen-resistant breast cancer cells and xenograft tumors also strongly inhibits tumor growth and the cancer cell survival through decreasing cell production of NADPH and glutathione (GSH) and invoking elevated ROS to cause apoptosis. These findings suggest that DZNep-like agents can be developed to target NSD2 histone methyltransferase for effective treatment of tamoxifen-resistant breast cancer.

Aim Sarcopenia as a reliable prognostic predictor in urologic oncology surgery remains controversial, and no consensus amongst researchers exists regarding the management of patients with sarcopenia. This meta-analysis was conducted to investigate the association between sarcopenia and postoperative outcomes after urologic oncology surgery. Methods A systematic search in MEDLINE (via PubMed), Embase, Web of Science and Cochrane Library databases was conducted to identify the potential studies published before August 2019. Odds ratios and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated through inverse variance with random or fixed effects models. Results Seventeen retrospective cohorts comprising 3,948 patients were included with sarcopenia prevalence between 25% and 68.9%. Patients with sarcopenia had significantly shorter overall survival (OS; HR = 2.06, 95% CI: 1.44–2.95; P Conclusions Sarcopenia is an independent poor prognostic factor for patients undergoing urologic oncology surgery, particularly postoperative risks of short survival and increased mortality. Thus, preoperative sarcopenia evaluation can provide clinicians with important information to guide and individualise patient management and improve surgical outcomes.

This study aims to design a novel semirigid ureterorenoscope with irrigation and vacuum suction system and a modified ureteral access sheath (UAS) named Sotn ureterorenoscope® (Sotn=ShuoTong Medical Company) to overcome the deficiencies of the current procedure and to improve the efficiency and safety of using Sotn ureterorenoscope® for treatment of upper urinary calculi.Fifty-eight patients, comprising 31 males and 27 females, were evaluated. The medical records of 58 patients with upper urinary calculi treated with Sotn ureterorenoscope® from March 2015 to June 2017 were retrospectively reviewed at the Second Affiliate Hospital of Guangzhou University of Chinese Medicine in China. The primary outcome was stone-free rate (SFR) assessed by computed tomography on the 1st day and one month after treatment. The secondary outcome was postoperative complication rate.The mean and SD of operative duration was 78.5 (30.4) min, and the mean and SD of stone size was 15.6 (5.6) mm. The primary overall SFR was 89.7% (52/58) and 100% at 1 month follow-up. Complication, which was Clavien I (minor fever managed by antipyretic therapy), was detected in 1.7% (1/58) of the patients.Sotn ureterorenoscope® is technically feasible, efficacious and safe for treatment of upper urinary calculi because of its advantages of high SFR and low complication rates.

A novel microfluidic chip with integrated Teflon AF1600 surface liquid core optical waveguide (LCW) modified with nano gold was proposed and fabricated in this article. Physical deposite method was used to integrate Teflon AF1600 LCW into microchannel. After that, the inner surface of Teflon AF1600 LCW was chemically modified at temperature of 40 °C, subsequent nano gold were in situ immobilied on the silanized inner surface of Teflon AF LCW precoated with a thin layer of poly(diallyldimethylammonium chloride) within microchannel by a chemical self-assembly method. Under the optimized conditions, the prepared microfluidic SERS chip exhibited high sensitivity for R6G with detection limit of 10−11 mol/L and SERS enhancement factor (EF) of 2.7 × 108. Compared to single nano gold SERS enhancement substrate within a microfluidic chip, the SERS detection sensitivity for R6G was improved 4 orders of magnitude. Apart from high SERS enhancement effect, the as-prepared integrated microstructure had extremely good SERS detection reproducibility and duration stability. Furthermore, it was successfully used to detect the bovine serum albumin (BSA), and exhibited excellent SERS response. The research showed great prospects and technical support for design and fabrication of integrated SERS microfluidic chip and sensitive detection of trace biochemical samples.

Phosphatidylcholine oxidation is closely related to many neurodegenerative diseases. In this paper, Raman spectroscopy was proposed to continuously monitor the oxidation of phosphatidylcholine and provide deep understanding of this biochemical process. To increase the detection sensitivity, surface-enhanced Raman spectroscopy (SERS) with a micro–nanosilver-complex substrate was prepared by electrodeposition. The prepared SERS substrate had an enhancement factor as high as 7.8 × 107, ensuring detection sensitivity in the phosphatidylcholine-oxidation process. It was illustrated that the oxidation of phosphatidylcholine in an ethanol–water solution under the experimental conditions could be monitored and well described by second-order kinetics by continuously measuring and analyzing the SERS spectra of phosphatidylcholine-oxidation intermediates in 20 days. Meanwhile, the oxidation products were confirmed by mass spectrometry, and the oxidation process was in good concordance with mass-spectrometry detectio...

Whether the diagnosis of prostate cancer is a contributory psychological stress that causes excess risk of suicide among affected men remains controversial. We performed a meta-analysis of previous studies to investigate suicide incidence and associated risk factors among men diagnosed with prostate cancer. The MEDLINE, Embase, Cochrane Library, and PsycINFO databases were searched to identify eligible studies published before April 2018. The inverse variance method with random-effects modeling was used to calculate summary relative risks (RRs) and their associated 95% confidence intervals (CIs). Eight observational studies involving 1,281,393 men diagnosed with prostate cancer and 842,294 matched prostate cancer-free men were included. An overall increased RR of suicide of 2.01 (95% CI: 1.52–2.64; P

Whether androgen deprivation therapy (ADT) causes excess thromboembolic events (TEs) in men with prostate cancer (PCa) remains controversial and is the subject of the US Food and Drug Administration safety warning. This study aims to perform a systematic review and meta-analysis on previous studies to determine whether ADT is associated with TEs in men with PCa. Medline, Embase, and Cochrane Library databases were searched for relevant studies. These studies comprised those that compared ADT versus control to treat PCa, reported TEs as outcome, and were published before January 2018. Multivariate adjusted hazard ratios (HRs) and associated 95% confidence intervals (CIs) were calculated using random- or fixed-effects models. Five retrospective population-based cohort studies involving 170,851 ADT users and 256,704 non-ADT users were identified. Deep venous thrombosis (DVT) was found significantly associated with gonadotropin-releasing hormone (GnRH) agonists alone (HR = 1.47, 95% CI: 1.07–2.03; P = 0.017; I2 = 96.3%), GnRH agonists plus oral antiandrogen (AA) (HR = 2.55, 95% CI: 2.21–2.94; P

A “sandwich” microfluidic surface enhanced Raman scattering (SERS) chip with Ag film@nanoAu prepared in a microchannel was proposed and fabricated in situ. The integrated composite Ag film@nanoAu was prepared in situ by way of chemical plating and self-assembly. Firstly, the preparation conditions were optimized. On the basis of that, the influence of the laser focus position along the vertical direction and the materials of the cover plates on the SERS effect were investigated and optimized in detail. The optimized SERS effect was observed when the laser was focused on the interface of the sample and the SERS substrate. The SERS intensity of Rhodamine 6G (R6G) decreased 2.5 times and 2.1 times when PDMS or glass was used as the cover plate separately. Compared to single gold and silver SERS substrates, the composite of Ag film@nanoAu integrated in the microfluidic channel resulted in the peak intensity increasing 3–5 times during the SERS detection of R6G at 1507 cm−1. The enhancing effect could be attributed to the change in the local electromagnetic field which was caused by the synergistic sensitizing effect between the Au nanoparticles and the underlying silver mirror film. It was illustrated that the detection limit for R6G was 10−8 M and the enhancement factor (EF) was 3.8 × 105 with a relative standard deviation (RSD) of approximately 10% in the as-prepared microfluidic SERS chip.

Desmodium styracifolium (D. styracifolium) has been widely used in traditional Chinese medicine for the treatment of urolithiasis. This work was undertaken to investigate extracts from different polarity fractions of D. styracifolium for possible antilithic effects as well as antioxidant potential to explore the underlying phytochemically active constituents of this plant. The extracts of D. styracifolium were divided into four different polarity fractions by petroleum ether (Fr. PE), chloroform (Fr. CH), ethyl acetate (Fr. EA), and n-butyl alcohol (Fr. NB). The antilithic and antioxidant effects were evaluated and compared in vivo on an animal model of calcium oxalate (CaOx) urolithiasis, which was established by administration of 1 % ethylene glycol along with 2 % ammonium chloride in drinking water for 28 days. A total of 60 male Sprague-Dawley rats were randomly divided into six groups: normal control group, lithogenic group, and four different polarity fractions of D. styracifolium-treated groups. At the end of the study, urine, blood, and kidney tissue samples were all collected for evaluation. Among the four polarity fractions of D. styracifolium extracts, the Fr. PE and Fr. NB treatment significantly reduced the CaOx crystal deposition in kidneys, prevented the renal toxic changes like pH, Cr, and BUN. In addition, Fr. PE and Fr. NB treatment significantly decreased urinary excretion of oxalate along with a increase of citrate excretion. The increased amounts of malondialdehyde and decreased activities of superoxide dismutase, catalase, and glutathione peroxidase were detected in lithogenic group, D. styracifolium extracts treatment prevented the oxidative stress changes especially for the Fr. PE and Fr. NB extracts. In conclusion, our data suggest that the extracts from D. styracifolium possess the antiurolithic activity, possibly mediated through the inhibition of CaOx crystal aggregation as well as the alleviation of oxidative injury in the kidney, and the Fr. PE and Fr. NB extracts are the active fractions of D. styracifolium extract.

Background Polyphyllin I (PPI), one of the steroidal saponins in paris polyphylla, has been reported to exhibit antitumor effects. However, the detailed molecular mechanism underlying this has not been elucidated. Methods Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and Flow cytometry assays, respectively. Cell invasion and migration were examined by Transwell invasion and wound healing assays. Western blot analysis was performed to examine the protein expressions of zeste homolog 2 (EZH2), DNA methyltransferase 1 (DNMT1). QRT-PCR was used to examine the levels of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR). Small interfering RNAs (siRNAs) method was used to knockdown HOTAIR. Exogenously expressions of HOTAIR, DNMT1 and EZH2 were carried out by Transient transfection assays. EZH2 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. A nude mice xenograft model was used to confirm the findings in vitro. Results We showed that PPI significantly inhibited growth, induced cell cycle arrest of castration-resistant prostate cancer (CRPC) cells. In addition, PPI also reduced the migration and invasion in CRPC cells. In mechanism, we found that PPI decreased the protein expressions of EZH2, DNMT1 and levels of HOTAIR. Interestingly, silenced HOTAIR reduced EZH2 and DNMT1 protein expressions. On the contrary, exogenously expressed HOTAIR resisted PPI-inhibited EZH2 and DNMT1 protein expressions, EZH2 promoter activity and cell growth. Moreover, excessive EZH2 antagonized PPI-suppressed DNMT1 protein expression or vice versa. Consistent with this, PPI inhibited tumor growth, HOTAIR, the protein expressions of DNMT1 and EZH2 in vivo. Conclusion Our results show that PPI inhibits growth of CRPC cells through inhibition of HOTAIR expression, subsequently; this results in the repression of DNMT1 and EZH2 expressions. The interactions among HOTAIR, DNMT1 and EZH2, and reciprocal regulation of DNMT1 and EZH2 contribute to the overall responses of PPI. This study reveals a novel mechanism for HOTAIR-mediated regulating DNMT1 and EZH2 in response to PPI in inhibition of the growth of CRPC cells.

Prostate cancer is the second most common cause of cancer-related deaths worldwide. The mucin 1 (MUC1) oncoprotein is highly expressed in human prostate cancers with aggressive features. However, the role for MUC1 in occurrence and progression of castration-resistant prostate cancer (CRPC) remained elusive. In this study, we showed that solamargine, a major steroidal alkaloid glycoside, inhibited the growth of CRPC cells, which was enhanced in the presence of metformin. Furthermore, we found that solamargine increased phosphorylation of AMPKα, whereas reducing the protein expression and promoter activity of MUC1. A greater effect was observed in the presence of metformin. In addition, solamargine reduced NF-κB subunit p65 protein expression. Exogenously expressed p65 resisted solamargine-reduced MUC1 protein and promoter activity. Interestingly, exogenously expressed MUC1 attenuated solamargine-stimulated phosphorylation of AMPKα and, more importantly reversed solamargine-inhibited cell growth. Finally, solamargine increased phosphorylation of AMPKα, while inhibiting MUC1, p65 and tumor growth were observed in vivo. Overall, our results show that solamargine inhibits the growth of CRPC cells through AMPKα-mediated inhibition of p65, followed by reduction of MUC1 expression in vitro and in vivo. More importantly, metformin facilitates the antitumor effect of solamargine on CRPC cells.

Supplemental Digital Content is available in the text, Background: The association between serum C-peptide concentration and prostate cancer remains unexplored. Therefore, we conducted a meta-analysis to assess whether C-peptide serum concentrations are associated with increased prostate cancer risk. Methods: Several databases were searched to identify relevant original research articles published before November 2017. Random-effects models were used to summarize the overall estimate of the multivariable-adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Results: Nine observational studies involving 11,796 participants were identified. The findings of the meta-analysis indicated that the association between serum C-peptide concentration and prostate cancer was not significant (OR: 1.15, 95% CI: 0.85–1.54; for highest versus lowest category C-peptide concentrations, P = .376). The associations were inconsistent, as indicated by subgroup analyses. Conclusion: Although our findings provided no support for the hypothesis that serum C-peptide concentration is associated with excess risk of prostate cancer, people must pay attention to this aspect and increase physical activity or modify dietary habits to constrain insulin secretion, which possibly lead to decreased incidence of prostate cancer. Hence, well-designed observational studies involving different ethnic populations are still needed.