Heparanase inhibitor OGT 2115 induces prostate cancer cell apoptosis via the downregulation of MCL­1.

Heparanase (HPSE), an endo-ß-D-glucuronidase, cleaves heparan sulfate and serves an important role in the tumor microenvironment and thus in tumorigenesis. HPSE is known to promote tumor cell evasion of apoptosis. However, the underlying mechanism of this requires further study. In the present study, the results demonstrated that myeloid cell leukemia-1 (MCL-1), an antiapoptotic protein, and HPSE were upregulated in prostate cancer tissues compared with adjacent normal tissues. In addition, the HPSE inhibitor, OGT 2115, inhibited PC-3 and DU-145 prostate cancer cell viability in a dose-dependent manner, with IC50 values of 20.2 and 97.2 µM, respectively. Furthermore, annexin V/PI double-staining assays demonstrated that OGT 2115 induced apoptosis in prostate cancer cells. OGT 2115 treatment markedly decreased MCL-1 protein expression levels, whereas RNA interference-mediated downregulation of MCL-1 and OGT 2115 drug treatment synergistically induced apoptosis in PC-3 and DU-145 cells. In vivo, OGT 2115 40 mg/kg (ig) significantly inhibited PC-3 cell xenograft growth in nude mice and increased the positive TUNEL staining rate of xenograft tissues. It was therefore hypothesized that MCL-1 was an important signaling molecule in OGT 2115-induced apoptosis. The results of the present study also demonstrated that the proteasome inhibitor, MG-132, markedly inhibited the downregulation of MCL-1 protein expression levels induced by OGT 2115. However, the protein synthesis inhibitor, cycloheximide, did not affect the role of OGT 2115 in regulating MCL-1. In summary, the results of the present study demonstrated that the proapoptotic activity of OGT 2115 was achieved by downregulating MCL-1.

Cigarette Smoke Mediates Nasal Epithelial Barrier Dysfunction via TNF-α.

BACKGROUND: Extensive data suggest that exposure to cigarette smoke can induce pulmonary epithelial barrier dysfunction. However, the effects of cigarette smoke on the nasal epithelial barrier are still unclear. Here, we investigated the consequence and mechanism of cigarette smoke on the nasal epithelial barrier. METHODS: Sprague Dawley rats were exposed to cigarette smoke for 3 or 6 months, and changes in inflammatory markers and nasal barrier function were evaluated. Moreover, underlying mechanisms were explored. Finally, normal human bronchial epithelial cells were cultured with or without tumor necrosis factor-alpha (TNF-α) in vitro, and the levels of continuity and tight junction-associated proteins were measured. RESULTS: In vivo experiments showed that the nasal mucosal barrier function of rats exposed to cigarette smoke was disturbed. Indeed, proteins associated with tight junctions were decreased, and the levels of inflammatory factors, such as IL-8, IL-6, and TNF-α, were dramatically increased in comparison to those of control animals. In vitro, TNF-α was shown to disrupt the continuity of proteins associated with tight junctions and to downregulate the expression of these proteins in bronchial epithelial cells. CONCLUSIONS: We found that cigarette smoke disrupted the nasal mucosal barrier, and the extent of the damage was correlated with the duration of cigarette smoke exposure. We showed that TNF-α can disrupt the continuity and attenuate the expression of tight junction proteins in human bronchial epithelial cells. Therefore, cigarette smoke may induce nasal epithelial barrier dysfunction through TNF-α.

[Research Advances on the Relationship between Overt Hyperthyroidism and Risk of Erectile Dysfunction].

Studies have demonstrated the detrimental effects of overt hyperthyroidism on sexual functioning.Here,we comprehensively reviewed the studies that focused on the association between overt hyperthyroidism and erectile dysfunction (ED).After the systematic searching for relevant studies,we find that overt hyperthyroidism is significantly associated with the high risk of ED.The prevalence of ED in patients with hyperthyroidism ranges from 3.05% to 85%,while that in general population is 2.16% to 33.8%.A study reported that the erectile functioning of the hyperthyroidism patients was improved (International Index of Erectile Function:22.1±6.9 vs. 25.2±5.1) after the achievement of euthyroidism.The underlying mechanism of the increase in the risk of ED by overt hyperthyroidism might be correlated to the dysfunction of hypothalamus-pituitary-thyroid axis,dysregulation of sex hormones,abnormal expression of thyroid hormone receptors,and psychiatric or psychological disturbances (e.g.,depression,anxiety,and irritability).Since limited clinical trials have been conducted,additional well-designed cohorts with sizable samples are warranted to elucidate the evidence and mechanism of hyperthyroidism predisposing to ED.The present review indicates that overt hyperthyroidism and the risk of ED are associated,which reminds the clinicians should assess the thyroid stimulating hormone in hyperthyroidism patients presenting with ED,especially in those without positive conventional laboratory findings for causing ED.

Low prognostic nutritional index is associated with poor outcome in middle-aged and elderly patients with non-metastatic nasopharyngeal carcinoma: a retrospective cohort study.

BACKGROUND: Prognostic nutritional index (PNI) and age are effective prognostic factors for patients with non-metastatic nasopharyngeal carcinoma (NPC), and an interaction between them may exist. However, the age cutoff value is generally set at 45 years in current studies. The clinical implications of PNI in middle-aged and elderly patients are unclear. Therefore, we aimed to uncover this issue. PATIENTS AND METHODS: We retrospectively collected data from 132 middle-aged and elderly (≥ 45 years old) patients with non-metastatic NPC. The association between covariates and the PNI was analyzed using 2 or t-test. The effect of PNI on the prognosis was evaluated using univariate and multivariate Cox regression analyses. Unadjusted and multivariate-adjusted models were applied. Stratified and interactive analyses were performed to investigate the potential source of heterogeneity. RESULTS: Median age (61.0 years versus 59.5 years) and the proportion of patients aged ≥ 60 years (57.6% versus 50.0%) in the low-PNI group were higher than those in the high-PNI group (P > 0.05). The patients with a low PNI had shorter overall survival (OS) (hazard ratio (HR) = 0.86, 95% confidence interval (CI) = 0.80-0.93; P < 0.001) and progression-free survival (PFS) (HR = 0.93, 95% CI = 0.87-0.99; P = 0.034). The results remained stable after three adjusted models of covariates, including age (P < 0.05). No significant interactions were observed in middle-aged (45-59 years) and elderly (≥ 60 years) subgroups for OS and PFS (P for interaction > 0.05). CONCLUSION: Although there is an interaction between PNI and age, PNI is an independent prognostic factor in middle-aged and elderly patients with non-metastatic NPC.

Association between 5α-reductase inhibitors therapy and incidence, cancer-specific mortality, and progression of prostate cancer: evidence from a meta-analysis.

5α-reductase inhibitors (5-ARI) are widely employed for the treatment of benign prostatic hyperplasia. It has been noted that 5-ARI exhibit the potential to attenuate the risk of prostate cancer, but consistent agreement has not been achieved. Moreover, the effect of 5-ARI on cancer-specific mortality and progression of prostate cancer remains unclear. Therefore, the goal of the current meta-analysis was to elucidate the impact of 5-ARI on the incidence and progression of prostate cancer. We searched for all studies assessing the effect of 5-ARI on risk of prostate cancer in PubMed, Embase, Medline, and Cochrane Library databases. Pooled relative risk (RR) and corresponding 95% confidence intervals (CIs) were accepted to evaluate the association between 5-ARI and the risk of prostate cancer. Synthetic results implied that subjects who accepted 5-ARI compared with the placebo group experienced a distinctly weakened overall incidence of prostate cancer (RR = 0.74; 95% CI: 0.66-0.82; P < 0.001). Subgroup analyses further revealed that 5-ARI reduction of the incidence of prostate cancer was limited to low-grade (Gleason score 2-6; RR = 0.68; 95% CI: 0.57-0.81; P < 0.001) and intermediate-grade tumors (Gleason score 7; RR = 0.81; 95% CI: 0.67-0.97; P = 0.023), but not high-grade tumors (Gleason score >7; RR = 1.19; 95% CI: 0.98-1.43; P = 0.069). The results also showed that 5-ARI treatment did not significantly alter prostate cancer-specific mortality (RR = 1.0; 95% CI: 0.95-1.05; P = 0.916). In addition, it was worth noting that 5-ARI treatment acted in a protective role that presented a dramatic benefit to delay the progression of low-risk tumors (RR = 0.58; 95% CI: 0.43-0.78; P < 0.001).

Diabetes mellitus and the risk of urolithiasis: a meta-analysis of observational studies.

Diabetes mellitus (DM) might increase the risk of urolithiasis, but the results were inconsistent. Hence, we conducted a meta-analysis to assess the association between DM and the risk of urolithiasis. We searched PubMed, Embase, and Cochrane Library to identify the relevant observational studies up to November 2014. Reference lists of retrieved articles were also reviewed. Summary relative risks (RRs) and corresponding 95% confidence intervals (CIs) were used to estimate the association between DM and the risk of urolithiasis. We identified 3 case-control studies and 4 cohort studies regarding DM and the risk of urolithiasis, involving 247,531 participants. Analyses of all studies showed that DM was associated with an increased risk of urolithiasis (RR=1.24, 95% CI: 1.14-1.35). There was heterogeneity among studies (p=0.027, I2=57.9%). The association between DM and the risk of urolithiasis was not significantly differed by gender, but this association was inconsistent in the North American and Asian populations. When restricting the analysis to studies that had adjusted for body mass index (n=2) or hypertension (n=3), the RRs were 1.46 (95% CI: 1.03-2.06) and 1.22 (95% CI: 1.01-1.48), respectively. There was no significant publication bias (p=0.96 for Egger's regression asymmetry test). Our study provided evidence that there was a significant direct association of DM and the risk of urolithiasis. However, this finding was based on the observational studies, and more well-designed randomized controlled trials were needed.