BackgroundOxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox.HypothesisWe hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction.Methods and ResultsWe examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP.ConclusionTaken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.

Increased uric acid levels have been implicated in the pathogenesis of metabolic syndrome. To examine the mechanisms by which this occurs, we hypothesized that an increase in heme oxygenase 1, a potent antioxidant gene, will decrease uric acid levels and adipocyte dysfunction via suppression of ROS and xanthine oxidase (XO) levels. We examined the effect of uric acid on adipogenesis in human mesenchymal stem cells (MSCs) in the presence and absence of cobalt protoporphyrin (CoPP), an HO-1 inducer, and tin mesoporphyrin (SnMP), an HO activity inhibitor. Uric acid increased adipogenesis by increasing NADPH oxidase expression and elevation in the adipogenesis markers C/EBPα, PPARγ, and Mest, while decreasing small lipid droplets and Wnt10b levels. We treated MSCs with fructose, a fuel source that increases uric acid levels. Our results showed that fructose increased XO expression as compared to the control and concomitant treatment with CoPP significantly decreased XO expression and uric acid levels. These beneficial effects of CoPP were reversed by SnMP, supporting a role for HO activity in mediating these effects. These findings demonstrate that increased levels of HO-1 appear crucial in modulating the phenotype of adipocytes exposed to uric acid and in downregulating XO and NADPH oxidase levels.

Objectives: To utilize the RSSearch Patient Registry (RSSPR) to examine local control (LC), overall survival (OS), and toxicities following stereotactic body radiation therapy (SBRT) for stage I (T1-T2/N0) medically inoperable small cell lung carcinoma (SCLC). Materials and Methods: We searched the RSSPR for medically inoperable stage I SCLC patients treated with definitive SBRT. Potential predictive factors of OS were estimated using the Kaplan-Meier method as well as a Cox proportional hazards model. Results: Twenty-one patients were identified with medically inoperable stage I SCLC that met inclusion criteria. Fourteen patients had stage IA SCLC (T1N0) and 7 patients had stage IB SCLC (T2N0) with a median gross tumor volume of 10.1 cm3 (range: 0.72 to 41.4 cm3). The median number of fractions was 4 (range: 3 to 5), and the median BED10 was 105.6 Gy10 (range: 72 to 239.7 Gy10). Four patients received adjuvant chemotherapy. One- and 2-year actuarial OS rates were 73.1% (95% confidence interval [CI]: 36.8%-90.1%) and 36.6% (95% CI: 9.0%-65.7%), respectively. Factors found to be associated with 1-year OS on univariate analysis included T2 disease (85.5% vs. 33.3%; P=0.03), adjuvant chemotherapy (100% vs. 66.3%; P=0.11), and gross tumor volume ≥10 cm3 (100% vs. 52.5%; P=0.10). On multivariate analysis, adjuvant chemotherapy was associated with improved OS (hazard ratio=0.07 [95% CI: 0.13-0.37; P=0.002]). The 1-, 2-, and 3-year LC rates were 100%, and 1- and 2-year progression-free survival (PFS) rates were 85.7% (95% CI: 33.4-97.9%) and 42.9% (95% CI: 1.1-85.3%), respectively. Similar to OS, patients with T1N0 disease had superior PFS as compared to T2N0 disease (P=0.01). Toxicities were reported by 3/21 (14.3%) of patients with none ≥ grade 3 and no esophageal toxicities. Conclusions: SBRT was well-tolerated in the treatment of stage I SCLC with excellent LC achieved. Patients with T1N0 stage IA SCLC were noted to have improved PFS and OS following SBRT as compared with T2N0 Stage IB SCLC. Adjuvant chemotherapy was found to result in improved OS for stage I SCLC patients over SBRT alone.

These data indicate that patients recovering from TBI have blunted IL-6, IL-10, and cortisol responses following a peak exercise test compared to non-TBI controls. This lack of an exercise response may represent impaired hypothalamic-pituitary-adrenal axis function.

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