IRS-1 ELISA Kit

The exact role of VD deficiency in the development of non-alcoholic fatty liver disease (NAFLD) remains unknown. In this study, we induced VD deficiency by feeding Female Sprague-Dawley rats a VD deficient (VDD) Diet and studied the hepatic changes associated with VD deficiency. Simultaneously, we provided the VDD rats with VD or 8-methoxy psoralen (8-MOP), a suggested vitamin D receptor agonist, to test the reversibility of the hepatic changes. VDD Rats developed borderline non-alcoholic steatohepatitis (NASH) with considerable elevation in hepatic triglycerides, total cholesterol, and malondialdehyde. Furthermore, VD deficiency induced the expression of crucial enzymes and transcription factors involved in denovo lipogenesis, which justified the hepatic lipid accumulation. Insulin receptor signaling was affected by VD deficiency, demonstrated by the elevation in insulin substrate-1 (IRS1) and reduction in insulin substrate-2 (IRS2) signaling. Treatment with VD or 8-MOP attenuated IRS1 signaling and its downstream targets, leading to a decline in de novo lipogenesis, while the elevation in IRS2 expression resulted in the nuclear exclusion of forkhead box O1 (FoxO1) and diminished gluconeogenesis, a vital source of acetyl-CoA for de novo lipogenesis. Moreover, 8-MOP and Calcipotriol modulated insulin signaling in human hepatocyte cell line L02, which highlighted the crucial role of VD in the regulation of hepatic lipid contents in rats and humans. Silencing of the vitamin D receptor expression in L02 diminished the inhibitory effect of Calcipotriol and 8-MOP on fatty acid synthase and acetyl-CoA carboxylase 1 and provided the evidence that 8-MOP actions mediated via vitamin D receptor.

Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive soft-tissue sarcoma amenable only to surgical resection. Oncolytic herpes simplex viruses (oHSVs) are a promising experimental therapy. We previously showed that basal interferon (IFN) and nuclear factor kappa B (NF kappa B) signaling upregulate IFN-stimulated gene (ISG) expression and restrict efficient viral infection and cell-to-cell spread in similar to 50% of tested MPNSTs. Stimulator of Interferon Genes (STING) integrates DNA sensor activity and mediates downstream IFN signaling in infected cells. We sought to identify STING's role in oHSV resistance and contribution to basal ISG upregulation in MPNSTs. We show that the level of STING activity in human MPNST cell lines is predictive of oHSV sensitivity and that resistant cell lines have intact mechanisms for detection of cytosolic double-stranded DNA (dsDNA). Furthermore, we show that STING downregulation renders MPNSTs more permissive to oHSV infection and cell-to-cell spread. While next-generation viruses can exploit this loss of STING activity, first-generation viruses remain restricted. Finally, STING is not integral to the previously-observed basal ISG upregulation, indicating that other pathways contribute to basal IFN signaling in resistant MPNSTs. These data broaden our understanding of the intrinsic pathways in MPNSTs and their role in oHSV resistance and offer potential targets to potentiate oncolytic virus activity.