Ovarian cancer (OC) is the leading cause of death from gynecological malignancy. However, the mechanism by which OC develops remains largely unknown. Increases in cytosolic free Cacan result in different physiological changes including cell growth, differentiation and death. The transient receptor potential (TRP) C channels are nonselective cation channels with permeability to Ca 2 þ . Here we report that TRPC3 channels promote human OC growth. The TRPC3 protein levels in human OC specimens were greatly increased than those in normal ovarian specimens. Downregulating TRPC3 expression in SKOV3 cells, a human OC cell line, led to reduction of proliferation, suppression in epidermal growth factor-induced Ca 2 þ influx, dephosphorylation of Cdc2 and CaMKIIa and prolonged progression through M phase of these cells. Further, decreased the expression of TRPC3 suppressed the tumor formation generated by injecting SKOV3 cells in nude mice. Together, our results suggest that increased activity of TRPC3 channels is necessary for the development of OCs.

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Endosomal escape is a bottleneck in the efficient delivery of therapeutics using nanoparticles; therefore understanding how this property can be optimized is important for achieving better therapeutic outcomes. It has been demonstrated that pH-responsive nanoparticles (pHlexi nanoparticles) have potential to achieve effective escape from the endosomal compartments of the cell. In this paper a library of five pHlexi particles with tunable disassembly pH were synthesized by combining poly(ethylene glycol)-b-poly(2-(diethylamino)ethyl methacrylate) (PEG-b-PDEAEMA) with random copolymers of 2-(diethylamino)ethyl methacrylate and 2-(diisopropylamino)ethyl methacrylate. A series of cellular studies were conducted to investigate the effect of particle composition on in vitro behavior. Endosomal escape was probed using a calcein escape assay in NIH/3T3 fibroblast cells, demonstrating endosomal escape increased with increasing particle concentration. Interestingly, it was shown that endosomal escape was most efficient with particles that disassemble at high (pH 7.2) or low (pH 4.9) pH, with particles that disassemble between pH 5.8 and 6.6 inducing decreased levels of endosomal escape. This change in endosomal escape behavior suggests particles can induce escape by different pathways. The results show that tuning the core component of pHlexi particles can improve the effectiveness of endosomal escape capabilities and thus their ability to act as effective delivery systems.

Background:The generation of human-induced pluripotent stem cells (iPS) has raised expectations for disease modeling, drug discovery, and cell therapy. Results: VP16-polycistronic vectors display enhanced reprogramming capacity. Conclusion: Primary tubular renal cells are amenable for iPSC reprogramming in the absence of oncogenes. Significance: Kidney-derived iPSCs provide a reliable cellular platform for the study of kidney pathology and drug discovery studies.

Hyper-homocysteinemia (HHcy) is associated with microalbuminuria and glomerular injury in general and diabetic populations. However, HHcy’s role in hypertensive patients was not studied. We investigated whether HHcy is an independent risk factor for renal function decline and development of chronic kidney disease (CKD) in hypertensive men and women. This was a community-based prospective cohort study of 2,387 hypertensive adults without CKD at baseline, with a mean follow-up of 4.4 years. Baseline and follow-up levels of plasma Hcy, folate, vitamin B12, blood pressure and other pertinent covariables were obtained. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/per 1.73 m2 and an eGFR decline rate >1 ml/min/per 1.73 m2/year. There was a graded association between Hcy tertiles and eGFR decline. Subjects in the 3rd tertile of Hcy levels had an accelerated rate of eGFR decline and an increased risk of incident CKD, as compared with those in the 1st tertile, after adjusting for age, gender, baseline diabetes, SBP, BMI, smoking, dyslipidemia, eGFR, folate and vitamin B12 levels. In conclusion, in this prospective cohort of Chinese hypertensive adults, elevated baseline plasma Hcy can serve as an independent biomarker to predict renal function decline and incident CKD.