Association between Parkinson's Disease and Diabetes Mellitus: From Epidemiology, Pathophysiology and Prevention to Treatment.

Diabetes mellitus (DM) and Parkinson's disease (PD) are both age-related diseases of global concern being among the most common chronic metabolic and neurodegenerative diseases, respectively. While both diseases can be genetically inherited, environmental factors play a vital role in their pathogenesis. Moreover, DM and PD have common underlying molecular mechanisms, such as misfolded protein aggregation, mitochondrial dysfunction, oxidative stress, chronic inflammation, and microbial dysbiosis. Recently, epidemiological and experimental studies have reported that DM affects the incidence and progression of PD. Moreover, certain antidiabetic drugs have been proven to decrease the risk of PD and delay its progression. In this review, we elucidate the epidemiological and pathophysiological association between DM and PD and summarize the antidiabetic drugs used in animal models and clinical trials of PD, which may provide reference for the clinical translation of antidiabetic drugs in PD treatment.

KLK6 Functions as an Oncogene and Unfavorable Prognostic Factor in Bladder Urothelial Carcinoma.

Background: Kallikrein-related peptidase 6 (KLK6) has been substantiated as a diagnostic, prognostic, and therapeutic molecular in several cancer types. In our study, we attempt to explore the biological functions of KLK6 in bladder urothelial carcinoma (BLCA). Methods: KLK6 gene expression prognostic, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and immune infiltration were analyzed using The Cancer Genome Atlas (TCGA) database. In vitro and in vivo experimental measurements, including CCK8, transwell migration, TUNEL, and nude mouse transplanted tumor model, were used to evaluate the antineoplastic activities of KLK6 loss-of-function. Results: The combination of bioinformatics analyses and experimental measurements demonstrate that KLK6 expression is aberrantly upregulated in human specimens and cell lines of BLCA. GO and GSEA enrichment analyses exhibited that KLK6 is implicated in the inflammatory response and immune infiltration, suggesting that upregulation of KLK6 may be associated with the progression of BLCA. Knockdown of KLK6 is able to inhibit the growth and migration and trigger apoptosis of RT4 and T24 cells. Moreover, the TCGA database indicates that KLK6 high expression in BLCA patients showed a poorer prognosis than those patients with KLK6 low expression. Univariate and multivariate regression analyses suggest KLK6 as an independent prognostic factor to predict unfavorable OS in patients with BLCA. Conclusion: KLK6 is an independent prognostic factor and an antitumor target of BLCA. KLK6 expression positively correlates with several immune cells infiltration, indicating that inhibition of KLK6 may contribute to immunotherapy of BLCA.

Evaluating the biological functions of the prognostic genes identified by the Pathology Atlas in bladder cancer.

The prognosis­associated genes of urinary bladder cancer have been systematically investigated in the Pathology Atlas project based on The Cancer Genome Atlas data. However, the biological functions of most genes in bladder cancer remain unknown. The present study investigated the biological function of 12 of the most significant survival­associated genes (ABRACL, MITD1, ZNF524, EMP1, HSPB6, CXorf38, TRIM38, ZNF182, ZNF195, SPRN, PTPN6 and LIPT1) in urothelial cancer reported by the Pathology Atlas project, with respect to cell proliferation and migration. In vitro, proliferation and migration analyses of T24 cells were performed following the transfection of the 12 prognostic genes. The results were validated with a small interfering (si)RNA library. Immunohistochemistry (IHC) analysis of clinical samples was performed to determine the association between gene expression and tumor metastasis. Furthermore, RNA sequencing was used to investigate the downstream signals. Among the 12 prognostic genes, MIT­domain containing protein 1 (MITD1) transfection was demonstrated to inhibit T24 cell migration to a certain degree. Experiments performed with a 7­gene siRNA library demonstrated that MITD1 knockdown markedly upregulated cell migratory abilities. Mechanistically, the influence of MITD1 on cell signal transduction was assessed via RNA sequencing. Cell migration­associated genes, including KISS1, SPANXB1, SPINT1, PIWIL2, SNAI1, APLN and CTHRC1 were dysregulated. IHC analysis demonstrated that MITD1 protein expression was notably lower in metastatic lymph nodes compared with the primary tumors. Taken together, the results of the present study suggest that the prognostic gene, MITD1 may serve as a migration inhibitor, and be developed as a potential therapeutic target for improving the prognosis of bladder cancer.

Laparoscopic cytoreductive nephrectomy is associated with significantly improved survival compared with open cytoreductive nephrectomy or targeted therapy alone.

The aim of the present study was to compare the survival outcomes for patients with metastatic renal cell carcinoma (mRCC) who underwent laparoscopic cytoreductive nephrectomy (CN) vs. open CN vs. targeted therapy (TT) alone at our institution. A retrospective chart review was performed at our institution for patients who underwent CN prior to TT (laparoscopic, n=48; open, n=48) or who were deemed unfit for surgery and received TT alone (n=36), between January 2007 and December 2012. Kaplan-Meier estimated survival and Cox proportional hazards analyses were performed. Laparoscopic CN was associated with significantly longer survival compared with open CN or TT alone (median survival 24 vs. <12 months, respectively; P<0.01). On multivariate analysis, laparoscopic CN was an independent predictor of survival [hazard ratio (HR)=0.48, P<0.01), controlling for preoperative risk factors, while survival was similar between open CN and TT alone (HR=0.85, P=0.54). In our experience, laparoscopic CN appears to be a significant predictor of survival in mRCC. Selection bias of the surgeon for patients with improved survival may account for clinical variables that were otherwise difficult to quantify. For patients who were not candidates for laparoscopic CN, open CN did not confer a survival benefit over TT alone, while it was associated with increased morbidity.

Targeted p21 activation by a new double stranded RNA suppresses human prostate cancer cells growth and metastasis.

We have previously demonstrated that miR-1236-3p and its sequence homology dsRNA, dsRNA-245 (which is completely complementary to the p21 promoter) had potential ability to upregulate p21 expression by targeting specific promoter sequence and inhibited bladder cancer (BCa). However, we still know little about the effect of miR-1236-3p on prostate cancer and which dsRNA has an inhibitory effect on prostate cancer (PCa)? Here, we confirmed that miR-1236-3p was decreased in PCa cells and tissues. MiR-1236-3p inhibited PCa cells growth and metastasis by activating p21. Furthermore, we demonstrated that dsP21-245 could inhibit PCa cells growth and metastasis by activating p21 expression. Microarray experiments displayed that miR-1236-3p could affect AKT signaling pathway. We demonstrated that miR-1236-3p significantly suppressed the AKT pathway by inhibiting TLR2 expression while activating p21 expression in PCa cells; this influence was independent of p21 activation. In summary, our results provided evidence that both endogenous and exogenous small RNAs might function to induce p21 expression by interacting with the same promoter region, therefore impeding PCa development. Additionally, our results indicated that miRNA activation could activate the expression of some unknown genes as well as cell signaling pathways. This indicated the need for the further study of clinical applications of RNA activation.

Targeted hydroxyethyl starch prodrug for inhibiting the growth and metastasis of prostate cancer.

Prostate cancer is one of the most prevalent malignancies among men. Although chemotherapy has been an effective therapeutic approach for treating metastatic prostate cancer, serious undesired side effects have hampered its wide application clinically. In this work, a pH-responsive LHRH-conjugated hydroxyethyl starch-doxorubicin (HES-DOX/LHRH) prodrug was facilely synthesized by conjugating oxidized HES (HES-CHO) with DOX and LHRH through an acid-sensitive Schiff base bond. The resulting prodrug spontaneously self-assembled into nanoscopic micelle with a radius of about 55 nm in an aqueous environment. HES-DOX/LHRH significantly improved the in vivo tissue distribution of the drug. Compared to its non-targeted counterpart, targeted HES-DOX/LHRH demonstrated a greater in vitro anti-proliferative capability toward mouse RM-1 prostate cells. More importantly, targeted HES-DOX/LHRH exhibited higher levels of anti-tumor and anti-metastasis activities against an RM-1-xenografted mouse model, with lower systemic toxicity compared to free DOX·HCl and non-targeted HES-DOX. Hence, these results revealed that targeted HES-DOX/LHRH possesses great potential application in clinical chemotherapy of metastatic prostate cancer.