Cyclopentenone-Containing Tetrahydroquinoline and Geldanamycin Alkaloids from Streptomyces malaysiensis as Potential Anti-Androgens against Prostate Cancer Cells.

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).

Periodontal disease and the risk of prostate cancer: a meta-analysis of cohort studies.

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.

Predictive factors of stone-free rate and complications in patients undergoing minimally invasive percutaneous nephrolithotomy under local infiltration anesthesia.

PURPOSE: 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. RESULTS: 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). CONCLUSIONS: 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.

Orphan nuclear receptor RORγ confers doxorubicin resistance in prostate cancer.

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.

Diagnosis accuracy of PCA3 level in patients with prostate cancer: a systematic review with meta-analysis.

OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Small-cell carcinoma of the prostate: A report of 2 cases and review of the literature].

OBJECTIVE: To investigate the clinicopathological characteristics and improve the clinical treatment of prostatic small-cell carcinoma (PSCC). METHODS: We reported 2 cases of PSCC derived from prostate cancer after treated by androgen blockade and prostate electrotomy and reviewed the relevant literature. RESULTS: Two patients with PSA elevation were diagnosed with prostate cancer by prostatic puncture biopsy and treated by maximum androgen blockade, which reduced their total PSA to the normal level. Later, due to difficult urination, they both underwent prostate electrotomy, followed by chemotherapy or radiotherapy for PSCC confirmed by postoperative pathology. Nevertheless, they died at 8 to 9 months after the discovery of PSCC. CONCLUSIONS: PSCC can derive from prostate cancer after treatment, which may be attributed to the pathological mutation induced by long-term endocrine therapy. PSCC is more malignant than prostate cancer, and its prognosis is poor.

Dynamic Monitoring of the Oxidation Process of Phosphatidylcholine Using SERS Analysis.

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 detection. The use of SERS in following a biochemical process has advantages, including simple instrumentation, a low cost, a short detection time, and no sample pretreatment. Therefore, as a kind of vibration spectrum, SERS is preferable to traditional detection approaches such as MS, HPLC, and MRI for the dynamic monitoring and analysis of complex biochemical processes.

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1-Enzalutamide Combination Treatment.

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.

HOTAIR-mediated reciprocal regulation of EZH2 and DNMT1 contribute to polyphyllin I-inhibited growth of castration-resistant prostate cancer cells in vitro and in vivo.

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.

[Inhibitory effect of polyphyllin â on the proliferation of prostate cancer PC3 cells via ERK1/2/P65/DNMT1 and its molecular mechanism].

OBJECTIVE: To explore the inhibitory effect of polyphyllin Ⅰ (PPⅠ) on the proliferation of castration-resistant prostate cancer PC3 cells and its molecular mechanism. METHODS: We cultured human prostate cancer PC3 cells in vitro and treated them with PPⅠ at the concentrations of 0 (blank group), 0.4, 0.8, 1.2, 1.6, 2.0, and 2.4 µmol/L for 24, 48, and 72 hours, respectively. Then we detected the proliferation of the cells by MTT assay, measured their apoptosis by flow cytometry, and determined the expressions of p-ERK1/2, ERK1/2, NF-κB/p65 and DNMT1 proteins as well as the level of NF-κB/p65 in the cells additionally treated with the ERK1/2 inhibitor SP600125 by Western blot. RESULTS: Compared with the blank control group, the PPⅠ-treated PC3 cells showed a concentration- and time-dependent reduction of the survival rate (1.00 ± 0.00 vs 0.85 ± 0.05, P < 0.01) at 0.4 µmol/L after 48 hours of intervention, concentration-dependent early apoptosis at 0.8 µmol/L (4.83 ± 0.95 vs 13.83 ± 2.97, P < 0.01), time-dependent increase of the expressions of p-ERK1/2 (1.00 ± 0.00 vs 1.73 ± 0.17, P < 0.01) and ERK1/2 (1.00 ± 0.00 vs 1.36 ± 0.12, P < 0.01) at 2 hours, and concentration-dependent decrease of the expressions of NF-κB/p65 and DNMT1 at 1.2 µmol/L (1.00 ± 0.00 vs 0.78 ± 0.10 and 0.63 ± 0.06, P < 0.01) and 1.6 µmol/L (1.00 ± 0.00 vs 0.67 ± 0.11 and 0.52 ± 0.09, P<0.01). Inhibition of ERK1/2 phosphorylation with PD98059 markedly reversed PPⅠ-induced decrease of the NF-κB/p65 expression as compared with that in the PPⅠ group (0.86 ± 0.18 vs 0.43 ± 0.09, P < 0.05). CONCLUSIONS: PPⅠ induces the early apoptosis and suppresses the proliferation of PC3 cells, probably by activating the ERK1/2 pathway and inhibiting the expressions of the NF-κB/p65 and DNMT1 proteins.

[Staging Based Strategies and Practice for Prostate Cancer].

Authors raised that staging based strategies and practice of integrative medicine (IM) by combining syndrome typing and disease identification, and choosing suitable measures in accordance with different persons and seasonal conditions after more than ten years' clinical practice and researches. Radical operation as prior (as evil eliminating) and strengthening vital qi in perioerative period are best strategy for promoting rapid rehabilitation of early stage prostate cancer patients. Strengthening body resistance to eliminate evil was used in treating advanced prostate cancer patients. For example, a comprehensive treatment program for hormone-dependent patients was combined with endocrinotherapy and Chinese herbs for synergisic efficacy-enhancing actions. In this way, these patients' quality of life (QOL) were improved and time to castration resistant prostate cancer (CRPC) was delayed, even some patients were clinically cured. There are lack of effective medicines and methods for CRPC patients. Greatly tonifying original qi is mainly used for improving their clinical symptoms and prolonging survivals. Practice has proved staging based strategies and practice of IM has favorable advantages in treating prostate cancer, especially showing prospect in prolonging survival and postponing progression of advanced prostate cancer patients. Besides, it also could provide beneficial considerations and inspiration for combination of syndrome typing and disease identification.

[Kidney-tonifying Chinese medicine for male infertility: A systematic review of randomized controlled trials].

OBJECTIVE: To systematically evaluate the efficacy and safety of kidney-tonifying traditional Chinese medicine in the treatment of male infertility. METHODS: Based on the principles and methods of Cochrane systematic reviews, we searched CNKI, VIP, and Wanfang databases from inception to December 2012 for randomized controlled clinical trials addressing the treatment of male infertility with kidney-tonifying traditional Chinese medicine. According to the inclusion and exclusion criteria and retrieval strategies, we extracted the data, evaluated the quality of the included literature, and conducted meta-analysis using the RevMan 5. 2 software. RESULTS: Twenty trials involving 2,272 patients were included, and the sample size of each study was from 60 to 270 cases. All the studies were graded as of poor quality, with Jadad scores of no more than 3 points. The results of meta-analysis showed that the total effectiveness rate of traditional Chinese medicine versus Western medicine on male infertility was RR = 1.71, 95% CI 1.19-2.47, and that of Chinese-Western combined therapy versus Western medicine was RR = 1.15, 95% CI 1.01-1.30. Both traditional Chinese medicine and Chinese-Western combined therapy showed a significantly better total effectiveness than Western medicine alone in improving the pregnancy rate without serious adverse reactions. CONCLUSION: Due to the poor methodological quality and high heterogeneity of the included studies, the evidence for the efficacy and safety of kidney-tonifying traditional Chinese drugs in the treatment of male infertility is of but limited value, and further validation is needed by more high-quality studies.

Prostate Volume is A Predictor of Gleason Score Upgrading after Radical Prostatectomy in Low-Risk Prostate Cancer: A Systematic Review and Meta-analysis.

PURPOSE: The prediction of Gleason score (GS) upgrading in patients diagnosed with low-risk prostate cancer is particularly important when opting for active surveillance (AS). Thus, we aimed to explore the association between prostate volume and GS upgrading after radical prostatectomy in low-risk prostate cancer through a meta-analysis. METHODS: Multiple databases (Web of Science, MEDLINE, Embase, Scopus, and the Cochrane Library) were searched for eligible studies regarding this issue and reporting sufficient data up to May 2023. Specific search terms such as prostate cancer, radical prostatectomy, and prostate volume were used in our search strategy. Multivariable-adjusted odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated using random effects models according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. RESULTS: Twenty studies comprising 14,823 patients who underwent radical prostatectomy matched our eligibility criteria. Moreover, GS upgrading between biopsy and surgical pathological specimens occurs in 32.2% (4,771) of cases. The results showed that smaller prostate volume is significantly associated with GS upgrading in patients with low-risk prostate cancer (OR = 1.08, 95% CI = 1.05-1.11; P < 0.001; I-square [I2] = 89.8%) from biopsy to radical prostatectomy after adjusting for confounding factors. Moreover, the results of our subgroup analyses revealed that smaller prostate volume remained a substantial risk factor of GS upgrading in the studies designed as retrospective cohorts and case-control studies performed in America, Italy, Turkey, and China. The findings are robust as indicated by sensitivity and meta-regression analyses. CONCLUSION: Smaller prostate volume predicts clinically substantial GS upgrading in patients diagnosed with lowrisk prostate cancer after radical prostatectomy. The intriguing findings might be helpful when management options other than surgery are selected based on the inability to recognise the true pathological GS of patients for AS. Further studies focus on risk-stratification and treatment planning for patients with low-grade prostate cancer are still needed to verify our results.

The safety and efficacy of Sotn ureteroscopy for renal and upper ureteral calculi: a prospective multicenter randomized controlled trial.

BACKGROUND: Sotn ureteroscopy is a new lithotripsy procedure developed on the basis of ureteroscopy and includes a rigid ureteral access sheath, standard mirror, lithotripsy mirror, and Sotn perfusion aspirator. Thus, we performed a prospective multicenter randomized controlled trial comparing the safety and efficacy of Sotn ureteroscopy in the treatment of renal and upper ureteral calculi. METHODS: In this study, 224 patients with renal and upper ureteral calculi were randomly divided equally into study and control groups from March 2018 to March 2022. All the patients were approved by the hospital ethics committee (proof number: ZF-2018-164-01 and ZF-2018-165-01) of 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 month after treatment and operation duration. The secondary outcome was postoperative complication rate. RESULTS: In total, for upper ureteral calculi, the SFR of 1 day after operation of the Sotn ureteroscopy group was significantly higher than the rigid ureteroscopy group (83.6% vs. 60%, P=0.006). Moreover, operative time (33.7±1.80 vs. 52.9±2.73 min, P<0.005) of the Sotn ureteroscopy group was significantly lower than the rigid ureteroscopy group. Additionally, the SFR of 1 day after operation and operative time for the study group (Sotn ureteroscopy combined with flexible ureteroscopy) and the control group (flexible ureteroscopy alone) were 63.2% and 36.8% (P=0.005), 65.6±4.06 and 80.3±4.91 (P=0.023), respectively. However, there were no significant differences in the SFR of 1 month after operation, success rate of ureteral access sheath placement, and postoperative complications between the two groups (P>0.05). In subgroups with stone diameters ≥1.5 cm and stone CT values ≥1000 Hounsfield units, Sotn ureteroscopy showed more advantages in terms of the SFR of 1 day after operation. Importantly, complications such as ureteral injury, sepsis, fever, and severe hematuria were not statistically different between the two groups (P>0.05). CONCLUSIONS: For renal and upper ureteral calculi, Sotn ureteroscopy has the advantage of a higher SFR of 1 day after the operation and a shorter operative time, suggesting that the Sotn ureteroscopy may have further potential applications in clinics.

Fu-Zheng-Yi-Liu Formula inhibits the stem cells and metastasis of prostate cancer via tumor-associated macrophages/C-C motif chemokine ligand 5 pathway in tumor microenvironment.

Prostate cancer (PCa) is the second most common malignancy among men globally. The Fu-Zheng-Yi-Liu (FZYL) Formula has been widely utilized in the treatment of PCa. This study investigates whether the FZYL Formula can inhibit PCa by targeting the TAMs/CCL5 pathway. We conducted in vitro co-cultures and in vivo co-injections of PCa cells and TAMs to mimic their interaction. Results showed that the FZYL Formula significantly reduced the proliferation, colony formation, subpopulations of PCSCs, and sphere-formation efficacy of PCa cells, even in the presence of TAM co-culture. Additionally, the Formula markedly decreased the migration, invasion, and epithelial-mesenchymal transition (EMT) of PCa cells induced by TAMs. The FZYL Formula also reversed M2 phenotype polarization in TAMs and dose-dependently reduced their CCL5 expression and secretion, with minimal cytotoxicity observed. Mechanistic studies confirmed that the TAMs/CCL5 axis is a critical target of the FZYL Formula, as the addition of exogenous CCL5 partially reversed the formula's inhibitory effects on PCSCs self-renewal in the co-culture system. Importantly, the Formula also significantly inhibited the growth of PCa xenografts, bone metastasis, and PCSCs activity in vivo by targeting the TAMs/CCL5 pathway. Overall, this study not only elucidates the immunomodulatory mechanism of the FZYL Formula in PCa therapy but also highlights the TAMs/CCL5 axis as a promising therapeutic target.

[Short-course kidney-invigorating therapy improves near-term semen quality in asthenozoospermic men with kidney deficiency].

OBJECTIVE: To evaluate the effect of short-course kidney-invigorating therapy on near-term semen quality in asthenozoospermic men with kidney deficiency. METHODS: Based on the differential types in traditional Chinese medicine, 121 asthenozoospermia patients received at our clinic of andrology were divided into groups A (kidney-yin deficiency), B (kidney-yang deficiency) and C (spleen and kidney deficiency), and treated with Yougui Decoction plus Wuziyanzong Pills, Jinkuishenqi Pills plus Wuziyanzong Pills, and Shizi Decoction plus Liujunzi Decoction, respectively, all given once daily for 4 weeks. Sperm parameters of the patients were analyzed with the computer-assisted sperm analysis system before and after treatment and compared among the three groups. RESULTS: The baseline sperm concentrations in groups A, B and C ([70.4 +/- 38.6], [73.5 +/- 40.2] and [56.0 +/-34.4] x 10(6)/ml) showed no significant differences from those after medication ([74.4 +/- 32.6], [67.0 +/- 30.8] and [58.6 +/- 24.6] x 10(6)/ml) (P > 0.05). The percentages of grade a sperm in the three groups were (12.9 +/- 5.3)%, (13.7 +/- 7.7)% and (12.9 +/- 6.4)% respectively after treatment, significantly higher than (9.9 +/- 6.7)%, (9.3 +/- 5.4)% and (9.0 +/- 6.8)% before treatment (P < 0.05), and so were the percentages of grade a + b sperm ([37.4 +/- 10.2 ]%, [35.7 +/- 13.7]% and [35.9 +/- 12.3]% after treatment versus [29.6 +/- 13.2]%, [27.5 +/- 10.4]% and [28.3 +/- 12.1]% before treatment, P < 0.05). All the three groups showed significantly increased sperm motility after treatment ([53.8 +/- 10.5]%, [52.6 +/- 15.2]% and [51.1 +/- 13.1]%) as compared with the baseline levels ([44.3 +/- 14.0]%, [43.5 +/- 15.0]% and [42.4 +/- 14.9]%) (P < 0.05). The cure rate and total effectiveness rate were significantly higher in group B than in A (P < 0.05), but had no significant differences between either A and C or B and C (P > 0.05). CONCLUSION: Short-course kidney-invigorating therapy can significantly improve near-term semen quality in asthenozoospermic men with kidney asthenia, especially in those with kidney-yang deficiency, and it has no obvious adverse effects.

Zn2+ regulates human oxalate metabolism by manipulating oxalate decarboxylase to treat calcium oxalate stones.

A high concentration of oxalate is associated with an increased risk of kidney calcium oxalate (CaOx) stones, and the degradation of exogenous oxalate mostly 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 humans through clinical experiments on patients also subjected to antibiotic treatment. The analysis of clinical samples revealed that an imbalance of Lactobacillus and oxalate decarboxylase (OxDC) was involved in the formation of CaOx kidney stones. Then, we identified that Zn2+ could be used as an external factor to improve the activity of OxDC and promote Lactobacillus in the intestinal flora, and this treatment achieved a therapeutic effect on rats with stones aggravated by antibiotics. Finally, by analyzing the three-dimensional structure of OxDC and completing in vitro experiments, we propose a model of the Zn2+-induced reduction of CaOx kidney stone symptoms in rats by increasing the metabolism of oxalate through the positive effects of Zn2+ on Lactobacillus and OxDC.

System analysis identifies UBE2C as a novel oncogene target for adrenocortical carcinoma.

Ubiquitin Conjugating Enzyme 2C (UBE2C) is an emerging target gene for tumor progression. However, the tumorigenic effect and mechanism of UBE2C in adrenocortical carcinoma (ACC) remains unclear. Systematic investigation of the tumorigenic effect of UBE2C may help in understanding its prognostic value in adrenocortical carcinoma. First, we exploited the intersection on DFS-related genes, OS-related genes, highly expressed genes in adrenocortical carcinoma as well as differentially expressed genes (DEGs) between tumor and normal, and then obtained 20 candidate genes. UBE2C was identified to be the most significant DEG between tumor and normal. It is confirmed that high expression of UBE2C was strongly associated with poor prognosis in patients with ACC by analyzing RNA-seq data of ACC obtained from the Cancer Genome Atlas (TCGA) database implemented by ACLBI Web-based Tools. UBE2C expression could also promote m6A modification and stemness in ACC. We found that UBE2C expression is positively associated with the expression of CDC20, CDK1, and CCNA2 using ACLBI Web-based Tools, indicated the hyperactive cell cycle progression present in ACC with high UBE2C expression. In addition, UBE2C knockdown could significantly inhibit the proliferation, migration, invasion, EMT of adrenocortical carcinoma cells as well as the cell cycle progression in vitro. Notably, pan-cancer analysis also identified UBE2C as an oncogene in various tumors. Taken together, UBE2C was strongly associated with poor prognosis of patients with ACC by promoting cell cycle progression and EMT. This study provides a new theoretical basis for the development of UBE2C as a molecular target for the treatment of ACC.

A novel alternative strategy for monitoring and insight into liver fibrosis progression: The combination of surface-enhanced Raman spectroscopy (SERS) and gut microbiota.

Nowadays, the studies on the interaction and relationship between the intestinal microorganisms and liver diseases are increasing. However, it is still a huge challenge for the in-depth investigation and dynamic monitoring of such a complex network. Herein, a significant discovery was made. A strong association between gut microbial structural and functional genomics and SERS spectra of hepatocytes were revealed. Based on the study of gut microbes and SERS spectra, complementary information could be provided for the mechanism analysis of related diseases. Liver fibrosis, a chronic liver disease that lack specific cure was thus comprehensive studied. Liver targeting gold nanoparticle dimers were prepared as the SERS tags, and abundant SERS peak signals were acquired. Meanwhile, the gut microbiomes were also comparative studied. The changes of carbohydrates and lipids in liver cells were observed at the early stages of liver fibrosis, and TLR4 (toll-like receptors 4) was activated to elicit immune responses. Then again, oxidative stress, endotoxin and serum inflammatory factors were the major observations at the late stages. The SERS signals and the microbiome analysis were well confirmed and complemented each other, which suggested that the detection strategy could be another valuable method for the "gut-liver axis" study.

Icariin inhibits prostate cancer bone metastasis and destruction via suppressing TAM/CCL5-mediated osteoclastogenesis.

BACKGROUND: Bone metastasis occurs in nearly 70% of patients with metastatic prostate cancer (PCa), and represents the leading cause of death in patients with PCa. Emerging evidence has demonstrated the potential activities of icariin in modulating bone metabolism and remodelling the tumor microenvironment (TME). However, whether icariin could inhibit PCa bone metastasis and destruction by modulating the TME as well as the underlying mechanisms remains unclear. PURPOSE: This study investigated whether icariin could inhibit PCa bone metastasis and destruction by modulating the bone TME as well as the underlying mechanisms. METHODS: Osteoclasts were induced from mouse bone marrow-derived macrophages (BMMs) or Raw264.7 cells. PCa cells were cultured in the conditional medium (CM) of macrophages in vitro or co-injected with macrophages in vivo to simulate their coexistence in the TME. Multiple molecular biology experiments and the mouse RM1-Luc PCa bone metastasis model were used to explore the inhibitory activity and mechanism of icariin on PCa metastasis and bone destruction. RESULTS: Icariin treatment significantly suppressed PCa growth, bone metastasis and destruction as well as osteoclastogenesis in vivo. Furthermore, icariin remarkably inhibited osteoclast differentiation, even in the presence of the CM of tumor-associated macrophages (TAMs), while exhibiting no obvious effect on osteoblasts. Moreover, icariin suppressed the M2 phenotype polarization of Raw264.7-derived TAMs and transcriptionally attenuated their CC motif chemokine ligand 5 (CCL5) expression and secretion via inhibiting SPI1. Additionally, CCL5 induced the differentiation and chemotaxis of osteoclast precursor cells by binding with its receptor CCR5. The clinicopathological analysis further verified the positive correlation between the TAM/CCL5/CCR5 axis and osteoclastogenesis within the TME of PCa patients. More importantly, icariin remarkably suppressed PCa metastasis-induced bone destruction in vivo by inhibiting osteoclastogenesis via downregulating the TAM/CCL5 pathway. CONCLUSION: Altogether, these results not only implicate icariin as a promising candidate immunomodulator for PCa bone metastasis and destruction but also shed novel insight into targeting TAM/CCL5-mediated osteoclastogenesis as a potential treatment strategy for osteolytic bone metastasis. This study helps to advance the understanding of the crosstalk between bone TME and bone homeostasis.