Rabbit Anti-Human IRS1 (a.a. 4-267) Polyclonal antibody

Aims: Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone that is a precursor of sexual hormones. It is reduced during aging and is strongly associated with insulin resistance and obesity. There is evidence for beneficial effects of this steroid, in both human and animal models, during perimenopause. However, the impact of DHEA treatment during late postmenopause on glucose metabolism is not clearly documented. We tested the hypothesis that DHEA supplementation could improve insulin sensitivity in an ovariectomized obese rat model (OVX) that was fed a high-fat diet for 11 weeks. Main methods: Female Wistar rats at 8 weeks of age were OVX or SHAM-operated. Eight weeks after the surgery, the animals were randomly treated with vehicle or DHEA for 3 weeks. Food intake, metabolic parameters and insulin sensitivity were evaluated. Key findings: Following the ovariectomy, increased body weight gain, adiposity index, and feeding efficiency were observed, despite there being no change in food and energy intake. The OVX rats also displayed glucose intolerance, insulin resistance, decreased insulin-induced IRS1/2 tyrosine phosphorylation in the skeletal muscle, and reduced serum VLDL-c and TAG levels. OVX rats treated with 10 mg/kg DHEA (OVX + DHEA) exhibited estradiol (E-2) serum levels similar to SHAM animals, with no change in uterus mass. DHEA treatment also resulted in an increase in energy intake. Significance: Despite the positive effects of DHEA supplementation observed in menopausal women and ovariectomized rats, a potential negative effect on glucose metabolism and insulin action in the late postmenopausal condition in diet-induced obese OVX rats are reported.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas resistant to most cancer treatments. Surgical resection remains the primary treatment, but this is often incomplete, ultimately resulting in high mortality and morbidity rates. There has been a resurgence of interest in oncolytic virotherapy because of encouraging preclinical and clinical trial results. Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells, lysing the cell and inducing antitumor immunity. We previously showed that basal interferon (IFN) signaling increases interferon-stimulated gene (ISG) expression, restricting viral replication in almost 50% of MPNSTs. The FDA-approved drug ruxolitinib (RUX) temporarily resets this constitutively active STAT signaling and renders the tumor cells susceptible to oHSV infection in cell culture. In the studies described here, we translated our in vitro results into a syngeneic MPNST tumor model. Consistent with our previous results, murine MPNSTs exhibit a similar IFN- and ISG-mediated oHSV-resistance mechanism, and virotherapy alone provides no antitumor benefit in vivo. However, pretreatment of mice with ruxolitinib reduced ISG expression, making the tumors susceptible to oHSV infection. Ruxolitinib pretreatment improved viral replication and altered the oHSV-induced immune-mediated response. Our results showed that this combination therapy increased CD8 thorn T-cell activation in the tumor microenvironment and that this population was indispensable for the antitumor benefit that follows from the combination of RUX and oHSV. These data suggest that JAK inhibition prior to oncolytic virus treatment augments both oHSV replication and the immunotherapeutic efficacy of oncolytic herpes virotherapy. (C) 2018 AACR.