Uric Acid-Induced Adipocyte Dysfunction Is Attenuated by HO-1 Upregulation: Potential Role of Antioxidant Therapy to Target Obesity

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

Factors Associated with Functional Decline in Elderly Female Breast Cancer Patients in Appalachia

Background Functional status has been previously shown in the elderly cancer population to predict both mortality as well as treatment tolerance. The goal of this study was to determine if there are certain subsets of the elderly breast cancer population that are at higher risk of experiencing functional decline following treatment. Methods Patient charts from the Edwards Comprehensive Cancer Center in Huntington, West Virginia, from January 2006 - January 2016 were reviewed. Relevant inclusion criteria included patients of 65 years of age and older with a new diagnosis of Stage 0-III breast cancer. Functional decline was defined as an increase of at least one point in Eastern Cooperative Oncology Group (ECOG) scores within one year of diagnosis. ECOG performance status was subjectively determined by the physician. Fisher's exact test and Pearson's Chi-squared test were initially utilized to assess potential factors associated with functional decline such as pretreatment ECOG score, age at diagnosis, stage, hormone receptor status, type of surgery received, whether radiation therapy, chemotherapy, or hormonal therapy was received, medical comorbidities, body mass index (BMI), complaints of weakness at diagnosis, and ambulatory status. Factors that were found to be significant were further assessed via multivariate logistic regressions. Results Three-hundred and fourteen patients were identified as meeting inclusion criteria. At one-year follow-up, 45 patients (14.3% of the cohort) had documented functional decline. On initial analysis, factors associated with functional decline included Stage III disease (p=0.002) and complaints of weakness at diagnosis (p=0.004). Following multivariate analysis, Stage III disease (p = 0.02), complaints of weakness at diagnosis (p = 0.04), and bilateral mastectomy (p = 0.03) were significantly associated with functional decline. Conclusion Patients who were diagnosed with Stage III breast cancer, had complaints of weakness at time of diagnosis, or had bilateral mastectomies were more likely to have a decline in functional status at one-year follow-up. Awareness of factors associated with functional decline in the elderly Appalachian population with Stage 0-III breast cancer will be useful during discussions regarding patient expectations, treatment, and goals of care. Elderly breast cancer patients for whom bilateral prophylactic mastectomies are not indicated may be better served by lumpectomy alone (based on patient age, hormone receptor status, and tumor size), lumpectomy followed by radiation therapy, or unilateral mastectomy to maximize the likelihood of functional preservation following treatment.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Salvage Stereotactic Body Radiation Therapy for Locally Recurrent Previously Irradiated Head and Neck Squamous Cell Carcinoma: An Analysis from the RSSearch® Registry

Objectives To report on overall survival (OS), local control (LC), dose-outcome relationships, and related toxicities following stereotactic body radiation therapy (SBRT) for locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN). Methods We queried the prospectively-maintained RSSearch (R) Registry for patients with rSCCHN treated with five-fraction SBRT from January 2008 to November 2016. Patients with non-squamous cell histology, missing registry data regarding prior irradiation, those treated with less than five fractions of SBRT, and those treated with SBRT in primary or boost settings were excluded. LC and OS were estimated using the Kaplan-Meier method with comparisons between groups completed using log-rank t-tests and multivariable Cox regression. Logistic regression analyses were used to examine factors predictive of toxicity. Results Forty-five rSCCHN patients treated with SBRT delivered in five fractions at 12 radiotherapy centers were identified. Prescription doses >= 40 Gy were associated with higher one-year rates of OS, LC, and a higher likelihood of experiencing toxicities. Acute and late toxicity rates were low (22.2% and 15.6%, respectively) and were all Grade 1-2 with only one late Grade 3 esophagitis. Conclusion Salvage SBRT for rSCCHN resulted in outcomes comparable to prior single-institutional reports in a multi-institutional cohort across clinical settings with low toxicity, thus supporting more widespread adoption of SBRT with recommended doses >= 40 Gy.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Uric Acid-Induced Adipocyte Dysfunction Is Attenuated by HO-1 Upregulation: Potential Role of Antioxidant Therapy to Target Obesity

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

Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet

<div><p>Background</p><p>Oxidative 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.</p><p>Hypothesis</p><p>We 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.</p><p>Methods and Results</p><p>We 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.</p><p>Conclusion</p><p>Taken 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.</p></div

Effect of high-fructose (HFr) supplementation (500 μM) on markers of oxidative stress and HO-1 and SIRT1 gene expressions in hepatocytes treated with and without CoPP (5 μM) and SnMP (5 μM).

<p>(A) Isoprostanes level in condition media of hepatocytes (B) heme content measurement in hepatocytes (C) superoxide measurement in hepatocytes. (D) HO-1 mRNA levels (E) SIRT-1 protein levels. (F) Effect of Biliverdin and Tempol on SIRT1 expression in fructose (Fr)-treated hepatocytes. Hepatocytes were treated with biliverdin (10 μM) and with Tempol (100 μM) in presence of fructose (500 μM) for 24 hours. Results are mean±SE, n = 6/group. * <i>p</i><0.05 vs CTR; # <i>p</i><0.05 vs HFr, + <i>p</i><0.05 vs HFr+CoPP.</p

Effect of induction of HO-1 (CoPP) and inhibition of HO (SnMP) on metabolic profile and hepatic lipid content in mice fed a high fructose diet for 8 weeks.

<p>(A) Blood pressure. (B) Fasting blood glucose levels. (C) HOMA-IR (D) Plasma ALT levels. (E) Triglycerides levels in hepatic tissue. (F) Cholesterol levels in hepatic tissue. Results are mean±SE, n = 6/group. * <i>p</i><0.05 vs CTR; # <i>p</i><0.05 vs HFr, + <i>p</i><0.05 vs HFr+CoPP.</p

Effect of induction of HO-1 (CoPP) and inhibition of HO (SnMP) in mice fed a high fructose diet for 8 weeks on hepatic lipogenesis and FFA levels.

<p>(A) Oil Red O staining of lipids in liver and quantitative analysis of different groups, magnifications: 40X (n = 4). A representative section for each group is shown; (B) Hepatic FFA levels. (C) Elvol6 and Srebp-1c mRNA levels measured by RT-PCR and (D) ACC and SCD-1 mRNA expressions measured by RT-PCR. Results are mean±SE, n = 6/group. * <i>p</i><0.05 vs CTR; # <i>p</i><0.05 vs HFr, + <i>p</i><0.05 vs HFr+CoPP.</p