Abstract available in The FASEB Journal.

Infertility is one of the major complications of obesity. Studies have shown that administration of leptin modulated the expression of Β-catenin in the ovary and reversed obesity-induced infertility in rats. Coenzyme Q10 (CoQ10), an antioxidant, supplies the energy used for ovulation, oocyte and embryo development and prevents DNA damage that causes infertility. We hypothesized that leptin when combined with CoQ10 could greatly improve fertility. Twenty-one female Sprague-Dawley rats were used in this study and divided into five treatments groups. Group I rats was fed rat chow diet (RCD) while groups II to V were fed High-fat diet (HFD) for 14 weeks to induce infertility. Group 1 RCD and group II HFD control rats received 1 ml of saline intraperitoneally (i.p.) twice daily for 2 days, group III HFD rats received 1 ml of 100 µg of leptin i.p. twice daily for 2 days, group IV HFD rats received 10 mg/kg of CoQ10 i.p. for 2 weeks plus saline twice daily for 2 days. Group V HFD rats received 1 ml of 100 µg of leptin i.p. twice daily for 2 days plus 10 mg/kg of CoQ1o i.p. for 2 weeks. Estrous cycle was checked daily and food intake and body weight measured twice weekly before and after treatments. Fourteen days post treatment, all the animals were sacrificed. The blood and tissues were collected for analysis. The results show a significant decrease in food intake and body weight and regular estrous cycle restored in groups III and V rats. There was significant (p < 0.05) increase in spleen weight in groups IV and V. FSH level increased significantly (p < 0.05) in the leptin plus CoQ10 treated group while CoQ10 level was increased significantly (p < 0.05) in the leptin-treated group. Β-catenin expression was decreased in group IV and V, suggesting that Β-catenin expression may be downregulated by COQ10 administration. These results indicate that synergistic action of leptin and CoQ10 could delay the onset of obesity-induced infertility exhibited by the reduction of food intake and body weight. In conclusion, combinations of CoQ10 with leptin can improve fertility in obese infertile female rats and could provide a novel therapeutic strategy for the treatment of female infertility.

Metabolic syndrome (MetS) is a major risk factor for cardiovascular disease yet it has been little studied in Hispanic children of rural areas. This pilot study aimed to estimate the prevalence of MetS and its components (high waist circumference (WC), elevated blood pressure (BP), high triglycerides (TRI), low high-density lipoprotein (HDL), and hyperglycemia) in a sample of Hispanic children aged 2 to 10 years from northeast Tennessee (TN). Between June and October 2015, 46 Hispanic children were recruited during their well-child visit at a community health center in Johnson City, TN. Anthropometric data, blood pressure readings, and a blood sample were collected. Descriptive statistics were used to estimate the prevalence of MetS and its components. Chi-squared test or Fisher’s exact test was used to test differences of proportions. Results showed that 41.3% of Hispanic children (mean age:6.8 years; SD:2.5) were overweight or obese (Body Mass index (BMI) for age and sex ≥85th percentile), 15.2% had a high WC (≥90th percentile for age and sex), 30.4% had elevated BP (systolic or diastolic BP for age, sex and height ≥90th percentile), 13.0% had low HDL (≤5th percentile for age and sex), and 45.6% had high TRI (≥95th percentile for age and sex). Overall, 17 (37%) children were negative for every component of MetS, 17 (37%) were positive for one component, 6 (13%) for two components, 5 (11%) for three components, and 1 (2%) for four components. The prevalence of MetS (≥3 components) was 13%. While the prevalence of MetS did not vary by sex, it tended to be higher (33.3%) in children aged 4 or younger than in 5 to 10 (12.1%) year olds (P=0.05). The prevalence of having 2 or more positivities for MetS was significantly higher among overweight/obese children than in children with lean weight (47.4% vs. 11.1%, P=0.03). Findings provide evidence that Hispanic children are at high risk for MetS. Prevention efforts should begin early and target children with elevated BMI.

CHARACTERIZATION OF STAPHYLOCOCCAL NUCLEASE AND TUDOR DOMAIN CONTAINING PROTEIN 1 (SND1) AS A MOLECULAR TARGET IN HEPATOCELLULAR CARCINOMA AND NON-ALCOHOLIC STEATOHEPATITIS Nidhi Jariwala, PhD A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Integrative Life Sciences Virginia Commonwealth University, 2017 Devanand Sarkar, M.B.B.S., PhD. Associate Professor, Department of Human and Molecular Genetics Virginia Commonwealth University Richmond, Virginia SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). Oncoprotein SND1 regulates gene expression at a post-transcriptional level in multiple cancers including hepatocellular carcinoma (HCC). In the present study, we characterize oncogenic functions of SND1 in HCC employing a novel transgenic mouse model (Alb/SND1) and present SND1 as a potential molecular target in HCC management. We show that Alb/SND1 mice develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibit a relative increase in inflammatory markers and spheroid-generating tumor initiating cells (TiC). Mechanistic investigations defined roles for Akt and NF-κB signaling pathways in promoting TiC formation in Alb/SND1 mice. Intravenous administration of the selective SND1 inhibitor 3', 5'-deoxythymidine bisphosphate (pdTp) inhibited tumor formation without effects on body weight or liver function. We conclude that SND1 drives pro-oncogenic transcriptomic and proteomic changes in hepatocyte resulting in aggressive HCC. SND1 specific RNA interactome is identified with RNA immunoprecipitation sequencing (RIPSeq) approach. With an adjusted p value of2-fold enrichment over control, 282 mRNAs were identified to significantly associate with SND1 protein. We focused on the tumor suppressor Protein Tyrosine Phosphatase non-receptor type 23 (PTPN23) because its regulation by SND1 and its role in HCC are not known. In current study, we confirm that SND1 post-transcriptionally downregulates PTPN23. Pursuing functional studies with tetracycline inducible overexpression system, we validate that PTPN23 inhibits tyrosine kinase signaling, proliferation, epithelial to mesenchymal transition, migration, invasion and in vivo tumorigenesis. Alb/SND1 mice also manifest steatosis and fibrosis at one year of age. Coupled with a pro-inflammatory hepatic phenotype, we conclude that Alb/SND1 livers present NASH. High fat diet causes severe NASH and aggressive NASH induced HCC in Alb/SND1 mice. Serum and hepatic lipid profiling shows that hepatocyte specific SND1 overexpression associate with elevated triglyceride and cholesterol LDL levels. Contrarily, hepatocyte specific deletion of SND1 (SND1ΔHEP) in vivo, significantly protects against age dependent steatosis. Association of SND1 in NASH pathology is novel discovery and we present preliminary evidence confirming role of SND1 in promoting NASH.

Throughout the years, women have been the focus of eating disorders and body image research. With women being the focus of research in these areas, disorders such as Anorexia Nervosa, Bulimia Nervosa, and Body Dysmorphic Disorder (BDD) have caught the eyes of researchers. With this new discovery, there has been a recent surge of research on body image issues and men. Originally termed reverse anorexia or bigorexia, Muscle Dysmorphia (MD) has gained the attention of researchers for about a decade (Grieve, 2007; Pope, Katz & Hudson, 1993; Pope, Gruber, Choi, Olivardia & Phillips, 1997). The Muscle Dysmorphia Inventory (MDI) was created to measure the symptoms of MD and provide clinicians with an inventory that would aid them in the diagnosis and treatment of MD (Short, 2005). The MDI is a 34-item scale that uses the etiological model proposed by Grieve (2007) and assesses or evaluates the four proposed diagnostic criteria of MD (Short, 2005). Short (2005) developed questions using the four criteria of MD outlined by Olivardia (2001). While the MDI has shown good internal consistency (Cronbach’s alpha = .87; Short, 2005), no other psychometric properties have been assessed. The goal of this study was to assess the validity and reliability of the MDI so that the accuracy of the measure will be known and it may be used as a diagnostic tool in clinical settings. The hypothesis of the study was that the MDI is a reliable and valid measure. This study assessed the reliability and validity of the MDI through a correlational design. Test-retest reliability and Cronbach’s alpha were used to identify the reliability of the MDI. The MDI was compared to tests that measure traits of MD and to self-reported behaviors, which assessed concurrent and predictive validity of the MDI. The MDI appears to be a good diagnostic tool for clinicians to use when looking at MD. This study examined the reliability and the validity of the MDI. This study shows that the MDI has adequate test-retest reliability, and good internal consistency. The results indicate that the MDI has good concurrent validity when compared to other tests that measure symptoms of MD. Under predictive validity, there was some support to suggest that the MDI can predict MD, however, the predictive validity of the MDI needs to be examined more in-depth. The MDI appears to measure more state symptoms of MD than trait symptoms. This may make it easier for clinicians to detect an emerging problem before it becomes harder for the individual to overcome.

Obesity is an ever-growing concern in the developed world that carries with it a plethora of health issues. For example, obesity increases an individual’s risk for Type 2 Diabetes and cardiovascular disease. Pregnancy is a vital time for a woman to maintain optimal health, both for her own benefit as well as that of her offspring, and yet almost half of women in the United States who are of age to bear children are overweight or obese. In mice, we found that offspring born to dams fed a high fat diet did not have impaired glucose tolerance, contrary to our hypothesis. In addition, we challenged the offspring with a high fat diet, and found no difference in glucose tolerance as a result of maternal diet. Exercise is at the opposite end of the wellness spectrum – individuals who exercise experience many health benefits. Even overweight or obese individuals who exercise without losing weight have improved insulin sensitivity, for example. Studies have previously used voluntary running and found that offspring born to exercised dams have improved glucose tolerance. With the goal of controlling variable running times and distances, we developed a novel model of controlled exercise and have shown that it is a safe intervention that warrants further study. In addition, many individuals choose to take dietary supplements for various reasons. Branched chain amino acids (BCAAs) are a common dietary supplement that have been shown to increase lean mass, and may be implicated in glucose metabolism. We supplemented female mice with BCAAs for 16 weeks and found that exercise plus BCAAs improved body composition compared to sedentary control-diet fed animals, when exercise alone did not. In summary, we herein explore a number of health behaviors in female mice, both negative treatments such as consumption of a high fat diet and positive interventions such as exercise and BCAA supplementation, and the impact that they may have on the female animal and/or her offspring.

Introdução: Beribéri é uma doença causada pela deficiência de tiamina (vitamina B1) que, apesar de facilmente tratável, pode levar a óbito. Há pelo menos setenta anos não se tinha referência de surtos de beribéri no Brasil. Objetivo: Descrever o perfil epidemiológico dos casos de beribéri e óbitos notificados no Estado do Maranhão. Método: Estudo descritivo-retrospectivo que analisou 1.207 casos notificados de beribéri e 40 óbitos ocorridos no Maranhão no período de 2006 a 2008. As informações foram obtidas do banco de dados da Vigilância Epidemiológica e fichas de notificação. Resultados: Os casos distribuíram-se em 434 (36,0%) em 2006, 551 (45,6%) em 2007 e 222 (18,4%) em 2008. Afetou dois terços das Unidades Regionais de Saúde e 26,3% dos municípios localizados nas regiões centro-oeste, noroeste e sudoeste do Estado. As notificações foram maiores nos meses de março a agosto, com pico em junho. O coeficiente de incidência no período foi de 4,32/10.000 hab. Homens foram mais acometidos (81,9%), com concentração de casos na faixa etária de 20-40 anos (57,0%). Predominou a ocorrência do beribéri seco (84,6%) e o tempo decorrido entre os primeiros sintomas e a notificação foi inferior a três meses para dois terços dos casos. A hospitalização ocorreu para 50% dos casos em 2006, 30% em 2007 e 15% em 2008. O consumo de álcool foi referido por 53,2% dos acometidos em 2006, com proporção discretamente menor nos anos subseqüentes, e o hábito de fumar por cerca de um terço dos acometidos. Sintomas mais comuns foram: diminuição da força, dormência e edema das pernas, dificuldade para caminhar e dor na panturrilha. Em relação à escolaridade, constatou-se que mais da metade (57,2%) tinha quatro anos ou menos de estudo, dois terços (66,2%) desempenhava atividade laboral pesada e 72,9% tinham renda familiar inferior a um salário mínimo. Foram registrados 40 óbitos (3,3% do total de casos notificados) apenas em 2006, concentrados no mês de junho (61,9%) e distribuídos em 21 municípios (9,7%). A taxa de mortalidade para o Estado foi de 0,45/10.000 hab. Praticamente a totalidade dos óbitos ocorreu no sexo masculino (97,5%), sendo 72,5% na faixa etária de 20-30 anos. Para dois terços, o tempo decorrido entre os primeiros sintomas e a notificação foi inferior a três meses e a hospitalização ocorreu para 42,5%. Hábito de consumir álcool e fumar foi elevado entre aqueles que foram a óbito, 75,0% e 66,7%, respectivamente. Conclusão: O estudo se destaca por abranger análise de todas as notificações de beribéri do estado do Maranhão. Constatou-se que os casos e óbitos apresentaram distribuição espacial e temporal relacionado à realidade do estado. A ausência de óbitos em 2007 e 2008 e redução dos casos em 2008 sugerem efeitos positivos das ações de enfretamento governamentais implementadas. Esta avaliação descritiva é importante para nortear as atividades e áreas a serem priorizadas no planejamento das ações de combate, tanto no nível central (federal, estadual e municipal), como para os profissionais da atenção básica e especializada, no direcionamento de suas práticas. Os resultados contribuem também para o delineamento de outras pesquisas que possam auxiliar no estudo da determinação do beribéri no Brasil. / Introduction: Beriberi is a disease caused by a deficiency of thiamine (vitamin B1) which, although easily treatable, may lead to death. There had been no register of beriberi outbreaks in Brazil for at least seventy years. Objective: To describe the epidemiological profile of reported beriberi cases in the State of Maranhão. Method: A descriptive retrospective study of 1,207 reported beriberi cases and 40 deaths in the State of Maranhão from 2006 to 2008. The information was obtained from the database of Epidemiological Surveillance and the reporting forms. Results: The cases were distributed in 434 (36.0%) in 2006, 551 (45.6%) in 2007 and 222 (18.4%) in 2008. It affected two thirds of the Regional Health Units and 26.3% of the municipalities located in the Central-Western, Northwestern and Southwestern of the State. The notifications were higher in the months from March to August, peaking in June. The incidence rate in the period was 4.32 / 10,000 inhabitants. Men were more affected (81.9%), with more concentration of cases in the age group 20-40 years (57.0%). Dry beriberi was predominant (84.6%) and the elapsed time between first symptoms and reporting was less than three months in two thirds of cases. Hospitalization occurred for 50.0% of cases in 2006, 30.0% in 2007 and 15.0% in 2008. Alcohol consumption was reported by 53.2% of patients in 2006 and slightly lower proportion in subsequent years, and smoking was reported for about one-third of patients. Main symptoms were loss of strength, numbness and swelling of the legs, difficulty in walking and calf pain. Regarding education it was found that more than half (57.2%) had four or fewer years of study, two thirds (66.2%) performed heavy labor activity and 72.9% had a family income lower than minimum wage. Forty deaths were recorded (3.3% of all reported cases) only in 2006, concentrated in the month of June (61.9%) and distributed in 21 municipalities (9.7%). The mortality rate for the State was 0.45 per 10,000 inhabitants. Almost all the deaths occurred in males (97.5%), and 72.5% aged 20-30 years. For two-thirds of the patients who died, the elapsed time between first symptoms and reporting was less than three months and hospitalization occurred in 42.5%. Alcohol consumption and smoking were higher among those who died, 75.0% and 66.7% respectively. Conclusion: This study stands out for including analysis of all reported beriberi cases in the State of Maranhão. It was found that cases and deaths showed spatial and temporal distribution related to the social reality of the State. The absence of deaths in 2007 and 2008 and reduction of cases in 2008 suggest positive effects of the implemented governmental actions. This descriptive evaluation is important to guide the activities and areas to be prioritized in the planning of actions at the central level (federal, state and municipal), as well as for guiding the practice of primary and specialized healthcare professionals. The results also contribute to the design of other research that may support the study of beriberi in Brazil.

Little attention has been given to differences in obesity risk factors by racial/ethnic groups. Using data from the 2011-2012 California Health Interview Survey, we examined differences in risk factors for obesity among Whites, Latinos, Asians, and African Americans among 42,935 adults (24.8% obese). Estimates were weighted to ensure an unbiased representation of the Californian population. Multiple logistic and linear regression analyses were used to examine the differences in risk factors for obesity. Large ethnic disparities were found in obesity prevalence: Whites (22.0%), Latinos (33.6%), African Americans (36.1%), and Asians (9.8%). Differences in risk factors for obesity were also observed: Whites (gender, age, physical activity, smoking, arthritis, and diabetes medicine intake), Latinos (age, arthritis, and diabetes medicine intake), Asians (age, binge drinking, arthritis, and diabetes medicine intake), and African Americans (gender, physical activity, smoking, binge drinking, and diabetes medicine intake). Females were more likely to be obese among African Americans (odds ratio (OR) = 1.43, 95% confidence interval (CI) = 1.05–1.94), but less likely among Whites (OR = 0.80, 95% CI = 0.74–0.87). Race/ethnicity should be considered in developing obesity prevention strategies.

Sleep problems have been defined using a variety of definitions. No study has assessed the longitudinal association between infant sleep problems and childhood overweight or obesity using existing definitions of sleep problems. This study used longitudinal data (n=895) from the multi-site Study of Early Child Care and Youth Development (SECCYD) to investigate the effects of infant sleep problems on childhood weight status in Grade 6. Infants with sleep problems in Phase I (1991) and with complete data through Phase III (2004) of SECCYD were included. Sleep problems were assessed using maternal reports of night wakings and duration of a waking episode. Sleep problems were defined using Richman (1981), Lozoff et al. (1985), and Zuckerman et al. (1987) definitions. Multinomial logistic regression was used to examine the association between sleep problems during infancy and childhood weight status in Grade 6 while controlling for birth weight, race, sex, breastfeeding, maternal poverty, family structure, and maternal education. After adjusting for all covariates, children with a history of sleep problems were found to be overweight in Grade 6 using Zukerman et al. (Odds ratio (OR)=1.68; 95% confidence interval (CI): 1.11–2.55) and Richman (OR=1.76; 95% CI: 1.05–2.97) definitions, but not using Lozoff et al. definition. Infant sleep problems were not found to be associated with being obese. The study found differential effects of infant sleep problems on childhood overweight in Grade 6 per different definitions of sleep problems. Findings highlight the need to construct a single definition of infant sleep problems.

Type II diabetes mellitus (T2DM) is a chronic disease that has a worldwide prevalence which is expected to rise dramatically over the course of the next thirty years. The disease has reached pandemic stages of development in many cultures, most notably in developing countries, followed somewhat closely by developed countries with access to an overabundance of refined carbohydrates and fat (refined oils). T2DM is a condition that can be prevented or managed, but not cured; therefore a method of stymieing the development of this disease is paramount to halting its progressively increasing morbidity. In this study, bartlett pear and kiowa blackberry were investigated in relation to their ability to modify and improve both glucose metabolism and hypertension management with in vitro assay models. Effectiveness and bioactive functionality was evaluated by various in vitro assays to study the properties of: 100% bartlett pear juice, 100% kiowa blackberry juice and a ratio of 70:30 pear: blackberry juice found to have increased phenolic properties due to synergy in previous studies. These assays aimed at determining: alpha-amylase and alpha-glucosidase inhibition, angiotensin converting enzyme inhibition, total soluble phenolic content and antioxidant capabilities. These juices were also fermented with Lactobacillus helveticus and Bifidobacterium longum, common yogurt culture strains, to investigate if fermentation would improve the bioactive functionality of pear: blackberry synergies. A secondary goal of the experiment was to investigate if these fruit juices could prevent the growth of Helicobacter pylori, which is a common bacterium found in the stomach which can lead to cancer.