[Corrigendum] High expression of the secreted protein dickkopf homolog 4: Roles in invasion and metastasis of renal cell carcinoma and its association with Von Hippel-Lindau gene.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that the ß-actin bands data shown to portray the control experiments in the western blots in Fig. 3C and 4F were apparently identical. The authors have re­examined their data, and realize that the control bands in Fig. 3C had inadvertently been selected incorrectly. The revised version of Fig. 3, containing the correct ß-actin bands in Fig. 3C, is shown below. Note that this error did not affect the major conclusions reported in the paper. All the authors agree with the publication of this corrigendum, and thank the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this. The authors regret this mistake went unnoticed during the compilation of the figure in question, and apologize to the readership for any confusion that this may have caused. [International Journal of Molecular Medicine 33: 1319­1326, 2014; DOI: 10.3892/ijmm.2014.1673].

Inflammation induced by lipopolysaccharide advanced androgen receptor expression and epithelial-mesenchymal transition progress in prostatitis and prostate cancer.

BACKGROUND: To explore the mechanism of prostatic inflammation on prostate cancer (PCa) by comparing the changes of prostate epithelial cells and PCa cells in an inflammatory environment. METHODS: First, immunohistochemistry (IHC) was used to compare the level of expression of TNF-α, IL-1ß, IL-6, and TGF-ß between benign prostatic hyperplasia (BPH), prostatitis, and PCa. Then primary prostate epithelial cells were sampled from patients who were suspected of PCa and had histological prostatitis (HP) confirmed by pathological biopsy. Lipopolysaccharide (LPS) or BAY11-7082 were used to investigate the change of androgen receptor (AR) and AR-mediated transcription, epithelial-mesenchymal transition (EMT) in primary prostate epithelial cells, and lymph node carcinoma of the prostate (LNCap) cells. RESULTS: TNF-α, IL-1ß, IL-6, and TGF-ß were significantly increased in HP and PCa compared with those in BPH patients. The proliferation of primary prostate epithelial cells and LNCap cells got the inflection point at LPS 10 µg/mL. In an inflammatory environment with 10 µg/mL LPS, both primary prostate epithelial cell and LNCap cell viability increased, and AR, AR-mediated transcription, and EMT processes were significantly increased. Inhibitors of NF-κB with 10 nM BAY11-7082 decreased AR, AR-mediated transcription, and EMT processes. CONCLUSIONS: NF-κB regulates AR expression and EMT in prostatitis and PCa, and NF-κB inhibitors may have potential therapeutic value.

circPRRC2A promotes angiogenesis and metastasis through epithelial-mesenchymal transition and upregulates TRPM3 in renal cell carcinoma.

Background: Circular RNAs (circRNAs) have been identified as essential regulators in a plethora of cancers. Nonetheless, the mechanistic functions of circRNAs in Renal Cell Carcinoma (RCC) remain largely unknown. Methods: In this study, we aimed to identify novel circRNAs that regulate RCC epithelial-mesenchymal transition (EMT), and to subsequently determine their regulatory mechanisms and clinical significance. Results: circPRRC2A was identified by circRNA microarray and validated by qRT-PCR. The role of circPRRC2A in RCC metastasis was evaluated both in vitro and in vivo. We found that increased expression of circPRRC2A is positively associated with advanced clinical stage and worse survivorship in RCC patients. Mechanistically, our results indicate that circPRRC2A prevents the degradation of TRPM3, a tissue-specific oncogene, mRNA by sponging miR-514a-5p and miR-6776-5p. Moreover, circPRRC2A promotes tumor EMT and aggressiveness in patients with RCC. Conclusions: These findings infer the exciting possibility that circPRRC2A may be exploited as a therapeutic and prognostic target for RCC patients.

Corpus cavernosum smooth muscle cell dysfunction and phenotype transformation are related to erectile dysfunction in prostatitis rats with chronic prostatitis/chronic pelvic pain syndrome.

BACKGROUND: The relationship between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED) has been shown in many studies. However, the specific mechanism remains unclear. This study was to investigate the corpus cavernosum smooth muscle cell function and phenotype transformation in Experimental autoimmune prostatitis (EAP) rats. METHODS: EAP was induced in rats by using prostate protein supplemented with immuneadjuvant extraction, and the max-ICP and MAP were measured. IHC and Masson staining were done to assess inflammatory infiltration and collagen deposition in the corpus cavernosum, respectively. Subsequently, normal rat and EAP rat CCSMCs were purified by tissue block implantation and differential adherence method. The oxidative stress, smooth muscle phenotype transformation, cell cycle and intracellular calcium ion transport were also evaluated. RESULTS: The ratio of max ICP/MAP in EAP rats significantly reduced, and the TNF-α content and collagen deposition in the corpus cavernosum markedly increased as compared to healthy rats. High-purity rat CCSMCs were obtained. Oxidative stress was evident and the cGMP content decreased in the EAP rat CCSMCs. The expression of Cav1.2, IP3R1 and RyR2 increased, but the SERCA2 expression decreased in EAP rat CCSMCs, which was accompanied by increased intracellular calcium. Increased expression of OPN, collagen and KCa3.1, decreased Calponin expression and increased proportion of cells in the S phase were also observed in the EAP rat CCSMCs. CONCLUSION: CP causes oxidative stress and imbalance of intracellular calcium in CCSMCs and promotes CCSMCs transformation from contractile to synthetic state, which may be involved in the pathogenesis of ED.

Urethral ultrasonography: A novel diagnostic tool for dysuria following bipolar transurethral plasma kinetic prostatectomy.

Urethral ultrasonography is non-invasive and able to indicate the urethral lumen clearly, as well as the surrounding tissues of the posterior urethra, without contrast agent or X-ray irradiation. In this paper, we evaluate the reliability of urethral ultrasonography in the diagnosis of dysuria following bipolar transurethral plasma kinetic prostatectomy (TUPKP). A total of 120 benign prostate hyperplasia (BPH) patients with dysuria undergoing TUPKP were enrolled in this study, with a mean age of 72.8 years. All the patients received urethral ultrasonography, urethroscopy and bladder neck urethra stenosis oulectomy. Among the 120 cases, there were 22 cases of bladder neck closure, 20 bladder orifice stricture, 60 urethral stricture, 10 prostate remnants, 2 calculi in prostatic urethra, 4 dysfunction of bladder detrusor muscle and 2 flap of internal urethral orifice. χ2-test was used for the comparison of ultrasonography and urethral cystoscopy in the diagnosis of dysuria following TRPKP, and no significant difference was found between two diagnostic tools (χ 2 = 0.94, P > 0.05). Urethral ultrasonography is a reliable and minimally invasive diagnostic tool for dysuria following TUPKP and is conducive to early treatment of dysuria following prostatectomy.

Epigallocatechin-3-gallate inhibits migration and invasion of human renal carcinoma cells by downregulating matrix metalloproteinase-2 and matrix metalloproteinase-9.

The anticancer properties of epigallocatechin-3-gallate (EGCG) are documented in the treatment of several types of cancer; however, there is no relevant evidence for its efficacy in the treatment of renal cell carcinoma (RCC). In the present study, the therapeutic effects of EGCG in vitro were investigated, with particular attention to the metastatic behavior of human RCC cells. MTT assays and flow cytometry were performed to detect the effects of EGCG on the proliferation and apoptosis of RCC cells. The migration and invasion abilities of RCC cells following treatment with EGCG were assessed by wound-healing and Transwell assays, respectively. Gelatin zymography and western blot analysis were performed to analyze the effect of EGCG on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression levels. The results suggested that EGCG was able to inhibit the proliferation of RCC cells, induce apoptosis and effectively suppressed the migration and invasion of RCC cells. In addition, EGCG treatment resulted in the downregulation of MMP-2 and MMP-9 in RCC cells. We hypothesize that the anticancer effect associated with EGCG may involve the downregulation of MMP-2 and MMP-9. The present results suggest the potential of EGCG as a novel therapeutic agent against RCC.

Comparison of two kinds of cutaneous ureterostomy using in radical cystectomy.

OBJECTIVE: To investigate the merits and 10 year follow-up results of two kinds of cutaneous ureterostomy operation in patients with the radical cystectomy. METHODS: We retrospective analyzed the information of patients underwent radical cystectomy in the past 10 years, comparing and analyzing the consequence of application value, early and long-term follow-up results using two kinds of cutaneous ureterostomy in patients with radical cystectomy. RESULTS: Unilateral ureteral cutaneous ureterostomy didn't increase patients' early and long-term complications, and improved the patient's life satisfaction. CONCLUSION: The unilateral cutaneous ureterostomy didn't increase postoperative complications in patients, while improving the patient's life satisfaction. Unilateral ureteral cutaneous ureterostomy is an important complement to urinary diversion after radical cystectomy and the best choice for cutaneous ureterostomy.

Combination of quercetin and hyperoside inhibits prostate cancer cell growth and metastasis via regulation of microRNA­21.

Previous studies have reported that hyperoside and quercetin in combination (QH; 1:1) inhibited the growth of human leukemia cells. The aim of the present study was to investigate the anti­cancer effect of QH on prostate cancer cells. The results demonstrated that QH decreased the production of reactive oxygen species (ROS) and increased antioxidant capacity in PC3 cells at various concentrations (2.5­60 µg/ml) with peak inhibition and augmentation changes of 3.22­ and 3.00­fold, respectively. Following treatment with QH for 48 and 72 h, the IC50-values on PC3 cells were 19.7 and 12.4 µg/ml, respectively. Western blot analysis revealed that QH induced apoptosis in human prostate cancer cells via activation of caspase­3 and cleavage of poly(adenosine diphosphate ribose) polymerase. In addition, QH significantly inhibited the invasion and migration of PC3 cells as well as reduced the expression of numerous prostate tumor­associated microRNAs (miRs), including miR­21, compared to that of untreated human prostate cancer cells. QH was also found to enhance the expression of tumor suppressor programmed cell death protein 4, which was negatively regulated by miR­21. Furthermore, induced overexpression of miR­21 using pre­miR­21 oligonucleotides attenuated the beneficial effect of QH on prostate cancer cells. In conclusion, the results of the present study indicated that QH exerted an anti­cancer effect on human prostate cancer cells, the mechanism of which proceeded, at least in part, via the inhibition of the miR­21 signaling pathway.

Metformin inhibits cell growth by upregulating microRNA-26a in renal cancer cells.

Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties and may reduce cancer risk and improve prognosis. However, the mechanism by which metformin affects various cancers, including renal cancer still unknown. MiR-26a induces cell growth, cell cycle and cell apoptosis progression via direct targeting of Bcl-2, clyclin D1 and PTEN in cancer cells. In the present study, we used 786-O human renal cancer cell lines to study the effects and mechanisms of metformin. Metformin treatment inhibited RCC cells proliferation by increasing expression of miR-26a in 786-O cells (P < 0.05). As a result, protein abundance of Bcl-2 and cyclin D1 was decreased and PTEN was increased in cells exposed to metformin. Also over-expression of miR-26a can inhibited cell proliferation by down-regulating Bcl-2, cyclin D1 and up-regulating PTEN expression. Therefore, these data for the first time provide novel evidence for a mechanism that the anticancer activities of metformin are due to upregulation of miR-26a and affect its downstream target gene.

Metastatic prostate adenocarcinoma posing as urothelial carcinoma of the right ureter: a case report and literature review.

This is a case report of a 67-year-old patient with distant metastasis of prostate cancer to the right ureter which caused hydronephrosis. At the beginning, both of the cytology of the morning urine and imaging findings were consistent with urothelial carcinoma. Nephroureterectomy was subsequently performed. Interestingly, the pathological examination of the excised ureter revealed that the malignancy was derived from the prostate. No skeletal metastasis was detected. However, after four months of follow-up, several abnormal signal shadows were reported in skeletal scintigraphy and the prostate specific antigen (PSA) was gradually increasing. We present such a case for its unique presentation. A review of the literature is also provided.

Protective effects of quercetin and hyperoside on renal fibrosis in rats with unilateral ureteral obstruction.

Prevention of renal fibrosis is an important therapeutic strategy in the treatment of obstructive nephropathy. The purpose of the present study was to identify whether the combination of two natural plant-derived flavanoids, quercetin and hyperoside (QH), could inhibit renal fibrosis in the model of unilateral ureteral obstruction (UUO) in rats. QH mixtures (1:1) were fed to Wistar rats, and UUO ligation was performed on all the rats with the exception of the sham group. Masson's trichrome staining was used for interstitial fibrosis, while immunohistochemistry and western blot analysis were used to detect the expression of α-smooth muscle actin (SMA) and fibronectin (FN). In the QH group, the expression of SMA and FN was significantly lower than that in the untreated UUO group. In addition, QH administration significantly inhibited the SMA and FN expression of mesangial cells induced by interleukin-1ß. Consequently, it was evident that combinational QH therapy prevented UUO-induced renal fibrosis. Based on these findings, the combinatorial intervention of phytomedicine may present an improved treatment strategy for renal fibrotic disease.

Bromodomain 4 protein is a predictor of survival for urothelial carcinoma of bladder.

BACKGROUND: Bromodomain 4 (BRD4) protein is a double bromodomain-containing protein that binds preferentially to acetylated chromatins. BRD4 is essential for cellular growth and has been implicated in cell cycle control, DNA replication and carcinogenesis. However, its expression profile and prognostic value in urothelial carcinoma of the bladder (UCB) have not been investigated. METHODS: Real-time quantitative PCR (qRT-PCR) and Western blot were used to explore BRD4 expression in UCBs and normal bladder tissues. Moreover immunohistochemistry (ICH) was used to detect the expression of BRD4 in UCBs. Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. RESULTS: Up-regulated expression of BRD4 mRNA and protein was observed in the majority of UCBs by qRT-PCR and Western blot when compared with their paired normal bladder tissues. Clinicopathological analysis was showed a significant correlation existed between the higher expression of BRD4 protein with the histological grade, lymph node metastasis and distant metastasis (P < 0.05); Survival analysis by Kaplan-Meier survival curve and log-rank test demonstrated that elevated BRD4 expression in bladder cancer tissue predicted poorer overall survival (OS) compared with group in lower expression. Notably, multivariate analyses by Cox's proportional hazard model revealed that expression of BRD4 was an independent prognostic factor in UCB. CONCLUSIONS: These results suggest that the aberrant expression of BRD4 in human UCB is possibly involved in the tumorigenesis and development, and the BRD4 protein could act as a potential biomarker for prognosis assessment of bladder cancer. Further studies on the cellular functions of BRD4 need to address these issues.

Fibrinogen alpha chain precursor and apolipoprotein A-I in urine as biomarkers for noninvasive diagnosis of calcium oxalate nephrolithiasis: a proteomics study.

UNLABELLED: Calcium oxalate nephrolithiasis is the most common urological disease, but noninvasive and convenient methods of diagnosis are rarely available. OBJECTIVE: The present study aimed to identify potential urine biomarkers for noninvasive diagnosis of CaOx nephrolithiasis. METHODOLOGY: Urine samples from 72 patients with CaOx nephrolithiasis and 30 healthy controls were collected and proteomics analysis was performed using matrix-assisted laser desorption/ionization-time of flight-mass spectrometer (MALDI-TOF-MS). RESULTS: Thirteen proteins/peptides displayed statistically significant differences. The peptides of m/z 1207.23 and 2773.86 were selected by the genetic algorithm (GA) to build a possible diagnostic model. The area under the curve of m/z 1207.23 and 2773.86 was 0.936 and 0.987, respectively. The diagnostic model in distinguishing patients and healthy subjects showed 100% sensitivity and specificity. The peak at m/z 2773.86 was identified as fibrinogen alpha chain (FGA) with the sequence G.EGDFLAEGGGVR.G, and the peak at m/z 2773.86 was identified as apolipoprotein A-I (apoA-I) with the sequence L.PVLESFKVSFLSALEEYTKKLNTQ. CONCLUSION: The study results strongly suggested that urinary FGA and apoA-I are highly sensitive and specific biomarkers for noninvasive diagnosis of CaOx nephrolithiasis.

High expression of the secreted protein dickkopf homolog 4: roles in invasion and metastasis of renal cell carcinoma and its association with Von Hippel-Lindau gene.

The aim of this study was to investigate the effects of the dickkopf homolog 4 (DKK4)/Wnt/ß-catenin signaling pathway on tumorigenesis and metastasis in clear cell renal cell carcinoma (ccRCC), as well as to elucidate the underlying mechanisms. We examined the expression of DKK4 in 30 cases of ccRCC and matched adjacent normal tissues, and investigated its correlation with clinicopathological characteristics. Stable DKK4-transfected cells were established, and DKK4 functional analyses were performed, including a T-cell factor/lymphoid enhancer factor (TCF/LEF) reporter assay, and experiments on cell viability, apoptosis, invasive capability and tumor growth in vivo. Finally, western blot analysis was performed to detect Von Hippel-Lindau (VHL) expression in 50 clinical specimens. The expression levels of the DKK4, ß-catenin and ß-catenin downstream target genes, cyclin D1 and c-myc, were determined in the these specimens, as well as in RCC4(-), T3-14(+) cell lines by qRT-PCR and western blot analysis. The same tests were also performed in human embryonic kidney (HEK)293 cells which were transfected with the pCDH-DKK4 plasmid. After 6 weeks the tumor weight significantly increased in the mice transfected with the tumor cells. DKK4 mRNA and protein expression levels were significantly upregulated (p<0.001). DKK4 was distinctly overexpressed (68.0%) in all patient tissues. VHL(-) samples accounted for 60.0% of all samples, while DKK4 expression was significantly upregulated in 50% of these samples, indicating a correlation with VHL(-) expression (r=0.403, p<0.05). We also observed reduced expression levels of cyclin D1, c-myc and ß-catenin (to a greater extent) in the VHL(-), RCC4(-) and T3-14(+) cells, as well as in the stably transfected HEK293 cells. DKK4 may be an oncogene, and its upregulated expression may be involved in the pathogenesis of ccRCC as a downstream gene of VHL. By activating other pathways apart from the Wnt/ß-catenin pathway, DKK4 may play an important role in ccRCC tumorigenesis and metastasis.

Foxl1 inhibits tumor invasion and predicts outcome in human renal cancer.

UNLABELLED: The Forkhead Box L1 (Foxl1) transcription factor regulates epithelial proliferation and development of gastrointestinal tract, and has been implicated in gastrointestinal and pancreatic tumorigenesis. However, the role of Foxl1 in renal cancer development and progression remains to be elucidated. The study was conducted to investigate the expression of Foxl1 and its prognostic significance in clear cell renal cell carcinoma (ccRCC). Meanwhile, the function of Foxl1 in human ccRCC was further investigated in cell culture models. METHODS: Real-time quantitative PCR, western-blot, immunohistochemistry were used to explore Foxl1 expression in primary ccRCC clinical specimens and ccRCC cell lines. Foxl1 expression was up-regulated by over-expression vector in 786-O and ACHN cells, proliferation, cell cycle, migration and invasion were assayed. RESULTS: Foxl1 expression was down-regulated in the majority of the ccRCC clinical tissue specimens at both mRNA and protein levels. Clinic pathological analysis showed that Foxl1 expression was significantly correlated with tumor stage, lymph node metastasis, distant metastasis, clinical TNM stage (cTNM) and histological grade of renal cancer. The Kaplan-Meier survival curves revealed that low Foxl1 expression was associated with poor prognosis in ccRCC patients. Foxl1 expression was an independent prognostic marker of overall ccRCC patient survival in a multivariate analysis. Mechanistic analyses demonstrated that over-expression of Foxl1 inhibits tumor cell growth, migration and invasion in renal cancer cells. CONCLUSIONS: These results suggest that Foxl1 expression is a candidate predictor of clinical outcome in patients with resected ccRCC and it plays an inhibitory role in renal tumor progression.

Argonaute 2 is up-regulated in tissues of urothelial carcinoma of bladder.

UNLABELLED: Argonaute 2 proteins (Ago2) have been demonstrated to be widely expressed and involved in post-transcriptional gene silencing and play key roles in carcinogenesis. However, its expression profile and prognostic value in urothelial carcinoma of the bladder (UCB) have not been investigated. METHODS: Real-time quantitative PCR (qRT-PCR) and Western blot were used to explore Ago2 expression in UCBs and normal bladder tissues. Moreover immunohistochemistry (ICH) was used to detect the expression of Ago2 in UCBs. Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. RESULTS: Up-regulated expression of Ago2 mRNA and protein was observed in the majority of UCBs by qRT-PCR and Western blot when compared with their paired normal bladder tissues. Clinic pathological analysis was showed a significant correlation existed between the higher expression of Ago2 protein with the Histological grade, lymph node metastasis and Distant metastasis (P<0.05); Survival analysis by Kaplan-Meier survival curve and log-rank test demonstrated that elevated Ago2 expression in cancer tissue predicted poorer overall survival (OS) compared with group in lower expression (62.2% VS 86.3%, P<0.05). Notably, multivariate analyses by Cox's proportional hazard model revealed that expression of Ago2 was an independent prognostic factor in UCB. CONCLUSIONS: These results suggest that the aberrant expression of Ago2 in human UCB is possibly involved with tumorigenesis and development, and the Ago2 protein could act as a potential biomarker for prognosis assessment of bladder cancer. Further studies on the cellular functions of Ago2 need to address these issues.

VPA inhibits renal cancer cell migration by targeting HDAC2 and down-regulating HIF-1α.

Cell migration plays major roles in human renal cancer-related death, but the molecular mechanisms remain unclear. Valproic acid (VPA) is a broad-spectrum inhibitor of class I and II histone deacetylases and shows great anticancer activity in a variety of human cancers. In this study, we found that VPA significantly inhibited cell migration but not proliferation of human renal cancer ACHN cells. Mechanistic studies found that VPA significantly inhibited the expression of HIF-1α. Knockdown of HIF-1α could obviously inhibited cell migration, while over-expression of HIF-1α markedly rescued the inhibition of VPA on cell migration. Further studies found that knockdown of HDAC2 completely mimicked the effects of VPA on HIF-1α and cell migration, and over-expression of HIF-1α could also rescue the effects of HDAC2 knockdown on cell migration. Collectively, these results indicated that the potential of specific inhibition of HDAC2 by small molecular chemicals may lead to future therapeutic agents in human renal cancer treatment.

Urinary neutrophil gelatinase-associated lipocalin, a biomarker for systemic inflammatory response syndrome in patients with nephrolithiasis.

BACKGROUND: The objective of this study was to determine the diagnostic value of neutrophil gelatinase-associated lipocalin (NGAL), C-reactive protein (CRP), and procalcitonin (PCT) in the prognosis of patients presenting with the systemic inflammatory response syndrome (SIRS) with nephrolithiasis. METHODS: Urine NGAL protein levels were measured by enzyme-linked immunosorbent assay in 87 patients presenting with nephrolithiasis who were diagnosed as SIRS. Additionally, 52 patients presenting with nephrolithiasis but without urinary tract infection and 30 healthy controls were also included in the study. Levels of serum CRP and PCT were also taken into consideration. RESULTS: Median urinary NGAL levels were significantly increased in the SIRS cohorts compared with nephrolithiasis without urinary tract infection patients (4.28 ng/mL versus 2.69 ng/mL, P < 0.001), and NGAL was markedly elevated even in the early stage of SIRS (3.23 ng/mL versus 2.69 ng/mL, P < 0.001). According to the receiver-operating characteristic analysis, NGAL demonstrated a high diagnostic value compared with either PCT or CRP. In the later stage of SIRS, NGAL remained a highly sensitive (76.8%) and specific (86.5%) diagnostic marker compared with either PCT or CRP. Moreover, the area under the curves of NGAL (0.822) were also superior to those seen in either PCT (0.657) or CRP (0.761). CONCLUSION: Urinary NGAL is a highly sensitive and specific predictor of SIRS for patients presenting with nephrolithiasis. Further study of NGAL as a reliable biomarker of SIRS is required.

Combination of quercetin and hyperoside has anticancer effects on renal cancer cells through inhibition of oncogenic microRNA-27a.

Quercetin and hyperoside (QH) in combination (1:1 ratio) have previously been shown to inhibit the growth of human leukemia cells. Here, we investigated the anticancer activity of the same mixture in 786-O renal cancer cells. QH decreased the generation of reactive oxygen species (ROS) by up to 2.25-fold and increased the antioxidant capacity by up to 3-fold in 786-O cells (3.8-60 µg/ml), whereas IC50 values for viability were 18.2, 18.7 and 11.8 µg/ml, respectively. QH also induced caspase-3 cleavage (2-fold) and increased PARP cleavage. Specificity protein (Sp) transcription factors are overexpressed in cancer cells and regulate genes required for cell proliferation, survival and angiogenesis. QH treatment decreased the expression of Sp1, Sp3 and Sp4 mRNA and this was accompanied by decreased protein expression. Moreover, expression of the Sp-dependent anti-apoptotic survival gene survivin was also significantly reduced, both at the mRNA and protein levels. QH decreased microRNA-27a (miR-27a) and induced the zinc finger protein ZBTB10, an Sp-repressor, suggesting that interactions between QH and the miR-27a-ZBTB10 axis play a role in Sp downregulation. This was confirmed by transfection of cells with a specific mimic for miR-27a, which partially reversed the effects of QH. These findings are consistent with previous studies on botanical anticancer agents in colon cancer cells.

Preventive effect of phosphodiesterase 5 inhibitor tadalafil on experimental post-pyelonephritic renal injury in rats.

BACKGROUND: To evaluate the effects of Tadalafil, a phosphodiesterase 5 enzyme inhibitor, on Escherichia coli-induced renal damage in an acute pyelonephritis (PN) rat model. METHODS: Experimental PN was induced in 32 Wistar rats, and four groups were formed: group 1 (no treatment), group 2 (antibiotic), group 3 (Tadalafil), and group 4 (antibiotic + Tadalafil). Antibiotic was given on days 3 to 8, and Tadalafil was administered between days 0 and 28 of bacterial inoculation. Half of the rats were killed on the ninth day (early period) and histopathological parameters, immunohistochemical renal fibrosis markers, and oxidant/antioxidant system activities were evaluated. The rest of the rats were killed at the sixth week of the study and evaluated for histopathological parameters and renal fibrosis markers. RESULTS: Inflammatory activity was significantly milder in rats treated with antibiotic + Tadalafil versus no treatment group both in the early and late periods. In the late period, interstitial fibrosis or tubular atrophy was lower in the antibiotic + Tadalafil group versus the no treatment and antibiotic groups, and in Tadalafil versus antibiotic group. Tadalafil administration significantly reduced renal malondialdehyde and nitric oxide levels and enhanced superoxide dismutase and catalase activities. In addition, circulating tumor necrosis factor α, interleukin 1ß was greatly reduced in Tadalafil group versus the no treatment group. CONCLUSIONS: We have provided the first evidence that phosphodiesterase 5 enzyme inhibitor Tadalafil ameliorates circulating inflammatory cytokines, reverses oxidant/antioxidant dysfunction and eventually possesses an overall protective effect on renal tissue from Escherichia coli-induced PN-related kidney injury. Phophodieterase 5 inhibitor might be a novel therapeutic target for PN.