11 research outputs found
Role of Protease-Activated Receptor 2 in Regulating Focal Segmental Glomerulosclerosis
Background /Aims: The underlying mechanisms leading to focal segmental glomerulosclerosis (FSGS) are lacking. In this report, we examined the role of protease-activated receptors (PARs) subtype PAR2 and its downstream signals in regulating the pathophysiological process of FSGS. Methods: Nephropathy was induced by intravenous injections of adriamycin (ADR) in rats to study FSGS. Western Blot analysis and ELISA were employed to determine the protein expression levels of PAR2 and its downstream signal pathways as well as the levels of PICs. Results: In ADR rats, expression of PAR2, PKCξ and PKA was amplified and this was accompanied with increases of pro-inflammatory cytokines (PICs) including IL-1β, IL-6 and TNF-ι. Inhibition of PAR2 signal by systemic administration of FSLLRY-NH2 (FSL) attenuated amplification of PICs. Notably, FSL further influenced key molecular mediators during development of FSGS. i.e., it specifically restored the impaired nephrin and attenuated the exaggerated transforming growth factor beta 1 (TGF-β1), caspase-9 and desmin thereby improving worsened renal functions and glomerular injury. Consistent with this, in cultured podocytes FSL also largely restored downregulation of nephrin and attenuated amplifications of caspase-9 and desmin induced by TGF-β1. Conclusions: Results of this study suggest that PAR2 plays an important role in mediating renal injury induced by glomerulosclerosis. Inhibition of PAR2 signal pathway has a protective effect on FSGS mainly via PIC and TGF-β1 mechanisms. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of FSGS observed in patients
Anti-Atherosclerotic Effects Mediated by the Combination of Probucol and Amygdalin in Apolipoprotein E-Knockout Mice Fed with a High Fat Diet
The fusion landscape of hepatocellular carcinoma
Most cases of hepatocellular carcinoma (HCC) are already advanced at the time of diagnosis, which limits treatment options. Challenges in earlyâstage diagnosis may be due to the genetic complexity of HCC. Gene fusion plays a critical function in tumorigenesis and cancer progression in multiple cancers, yet the identities of fusion genes as potential diagnostic markers in HCC have not been investigated. Here, we employed STARâFusion and identified 43 recurrent fusion events in our own and four public RNAâseq datasets. We identified 2354 different gene fusions in two hepatitis B virus (HBV)âHCC patients. Validation analysis against the four RNAâseq datasets revealed that only 1.8% (43/2354) were recurrent fusions. Comparison with the four fusion databases demonstrated that 19 recurrent fusions were not previously annotated to diseases and three were annotated as diseaseârelated fusion events. Finally, we validated six of the novel fusion events, including RP11â476K15.1âCTDâ2015H3.2, by RTâPCR and Sanger sequencing of 14 pairs of HBVârelated HCC samples. In summary, our study provides new insights into gene fusions in HCC and may contribute to the development of antiâHCC therapy