Potential for Thermal Enhancement by Quercetin Mediated Mechanisms Targeting p53 Antagonists in Human Melanoma Cells

Introduction: Recently Temozolomide (TMZ) has become the more commonly used analog of DTIC-related oral agents. Although the response rates achieved by TMZ alone are less than satisfactory, there is great interest in identifying compounds that could be used in combination therapy. We have previously demonstrated that the bioflavonoid quercetin (Qct) promotes a p53-mediated response in melanoma and sensitizes melanoma to DTIC. Here we demonstrate that Qct also sensitizes cells to TMZ by a mechanism that involves the modulation of a truncated p53 family member, ΔNp73. Society for Thermal Medicine Annual Meeting April 23-26, Clearwater Beach, FL

Quercetin as an Emerging Anti-Melanoma Agent: A Four-Focus Area Therapeutic Development Strategy

Replacing current refractory treatments for melanoma with new prevention and therapeutic approaches is crucial in order to successfully treat this aggressive cancer form. Melanoma develops from neural crest cells, which express tyrosinase -- a key enzyme in the pigmentation pathway. The tyrosinase enzyme is highly active in melanoma cells and metabolizes polyphenolic compounds; tyrosinase expression thus makes a feasible a target for polyphenol-based therapies. For example, quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. Quercetin has demonstrated anti-proliferative and pro-apoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anti-cancer activity; additionally, given that tyrosinase expression increases during tumorigenesis, and its activity is associated with pigmentation changes in both early- and late-stage melanocytic lesions, it suggests that quercetin can be used to target melanoma. In this review we explore the potential of Quercetin as an anti-melanoma agent utilizing and extrapolating on evidence from previous in vitro studies in various human malignant cell lines and propose a four-focus area strategy to develop quercetin as a targeted anti-melanoma compound for use as either a preventative or therapeutic agent. The four areas of focus include utilizing quercetin to i) modulate cellular bioreduction potential and associated signaling cascades, ii) affect transcription of relevant genes, iii) regulate epigenetic processes, and iv) develop effective combination therapies and delivery modalities/protocols. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects

Postnatal β2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle

Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated β adrenergic receptor (ADRβ) desensitization. Our objectives were to measure insulin-sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRβ2 agonist and ADRβ1/β3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose-stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR-AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole-bodyGUR were not different from controls.Of importance, ADRβ2 stimulation with β1/β3 inhibition increases both insulin sensitivity and whole-body glucose utilization in IUGR lambs. In IUGR and IUGR-AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR-AR skeletal muscle than in controls but GLUT1 was greater in IUGR-AR. ADRβ2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR-AR lambs heart rates were greater, which was independent of cardiac ADRβ1 activation. We conclude that targeted ADRβ2 stimulation improved whole-body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch-up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes

Landowners' perceptions on coordinated wildlife and groundwater management in the Edwards Plateau

Since Texas contains less than 5% public land, private landowners are critical to the success of environmental management initiatives in the state. This has implications for resources that traverse property boundaries, such as wildlife and groundwater. Texas landowners are increasingly capitalizing on the income potential of fee-based hunting, and many have banded together to form Wildlife Management Associations (WMAs). Not only can such landowner associations enhance the coordination of resource management decisions, they also have the potential to increase social capital, which is reflected by interpersonal trust, reciprocity and civic participation. To improve the management of common-pool resources it is important to understand the relationship between social capital and coordinated resource management because long-term community stability and resource sustainability appear to be highly correlated. A 600-landowner mail survey (with 48.1% response) was conducted in the Edwards Plateau region of Texas to compare the land management characteristics and social capital of landowners who are members of WMAs with non-member landowners. The goal of this research was to determine how WMA membership, property size, and location affect levels of social capital and interest in cooperative resource management. It was hypothesized that members, large landowners, and northern landowners would be more interested in cooperative management and exhibit higher social capital. While WMA members and large-property owners were more involved in wildlife management than non-members and small-property owners, this interest in resource management did not carry over to groundwater. These groups were not more involved in groundwater management activities, and all survey groups were disinterested in joining private cooperatives for groundwater marketing. Social capital differences were more evident between large- and small-property owners than between WMA members and non-members. Members scored higher only on community involvement, while large owners scored higher on community involvement as well as trust. These results suggest that WMA membership per se does not significantly increase social capital among Edwards Plateau landowners, but do not necessarily refute the importance of social capital within WMAs. Differences in trust between members were positively correlated with increased communication and meeting frequency, suggesting ways WMAs can improve intra-association social capital

Catecholamines Mediate Multiple Fetal Adaptations during Placental Insufficiency That Contribute to Intrauterine Growth Restriction: Lessons from Hyperthermic Sheep

Placental insufficiency (PI) prevents adequate delivery of nutrients to the developing fetus and creates a chronic state of hypoxemia and hypoglycemia. In response, the malnourished fetus develops a series of stress hormone-mediated metabolic adaptations to preserve glucose for vital tissues at the expense of somatic growth. Catecholamines suppress insulin secretion to promote glucose sparing for insulin-independent tissues (brain, nerves) over insulin-dependent tissues (skeletal muscle, liver, and adipose). Likewise, premature induction of hepatic gluconeogenesis helps maintain fetal glucose and appears to be stimulated by both norepinephrine and glucagon. Reduced glucose oxidation rate in PI fetuses creates a surplus of glycolysis-derived lactate that serves as substrate for hepatic gluconeogenesis. These adrenergically influenced adaptive responses promote in utero survival but also cause asymmetric intrauterine growth restriction and small-for-gestational-age infants that are at greater risk for serious metabolic disorders throughout postnatal life, including obesity and type II diabetes

Real supermodels wear wool: summarizing the impact of the pregnant sheep as an animal model for adaptive fetal programming

• Intrauterine growth restriction (IUGR) continues to be a global epidemic that is associated with high early-life mortality rates and greater risk for developing metabolic disorders that lower length and quality of life in affected individuals. • Fetal programming of muscle growth and metabolic function associated with IUGR is often comparable among nonlitter bearing mammalian species, which allows much of the information learned in domestic animal models to be applicable to humans (and other animals). • Recent studies in sheep models of IUGR have begun to uncover the molecular mechanisms linking adaptive fetal programming and metabolic dysfunction. • Targets of adaptive fetal programming indicated by sheep studies include adrenergic and inflammatory pathways that regulate skeletal muscle growth and glucose metabolism. Adaptive changes in these pathways represent potential focus areas for prenatal interventions or postnatal treatments to improve outcomes in IUGR-born offspring

Changes in myoblast responsiveness to TNFα and IL-6 contribute to decreased skeletal muscle mass in intrauterine growth restricted fetal sheep

Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality (Alisi et al., 2011). Skeletal muscle growth is disproportionately reduced in IUGR fetuses and offspring (Padoan et al. 2004; Yates et al. 2014). These individuals present with reduced muscle mass and increased risk for metabolic disorders at all stages of life (Godfrey and Barker, 2000; Yates et al. 2016.). Muscle growth requires proliferation, differentiation, and fusion of myoblasts (muscle stem cells) to form muscle fibers early in gestation and to increase myonuclear content of existing fibers during late gestation and after birth (Yates et al., 2014). These processes can be disrupted by inflammation, which is a potential factor in impaired muscle development in the IUGR fetus (Yates et al., 2012; Cadaret et al., 2017). Tumor necrosis factor-alpha (TNFα) and interleukin 6 (IL-6) are potent multifunctional cytokines involved in inflammatory and noninflammatory skeletal muscle disorders (Tüzün et al., 2006). We recently found that changes in gene expression of these cytokines and muscle sensitivity to them differed between IUGR and control rats (Cadaret et al., 2017), and that maternal inflammation induced fetal leukocyte adaptations, increasing gene expression of TNFα and its receptor TNFR1, but decreasing gene expression of IL-6 receptor. Both cytokines also regulate myoblast proliferation and differentiation outside of inflammatory states (Al-Shanti et al., 2008). These findings indicate TNFα and IL-6 are essential factors in proper growth and development of muscle, and thus, we postulate that expression and sensitivity changes contribute to decreased muscle growth capacity in IUGR fetuses. The objective of this study was to determine the effects of cytokines on fetal myoblast function and to determine if altered responsiveness is intrinsic in IUGR myoblasts, which would represent a potential adaptive mechanism for reduced muscle mass in IUGR offspring

Suppression of Radiation-Induced Salivary Gland Dysfunction by IGF-1

Radiation is a primary or secondary therapeutic modality for treatment of head and neck cancer. A common side effect of irradiation to the neck and neck region is xerostomia caused by salivary gland dysfunction. Approximately 40,000 new cases of xerostomia result from radiation treatment in the United States each year. The ensuing salivary gland hypofunction results in significant morbidity and diminishes the effectiveness of anti-cancer therapies as well as the quality of life for these patients. Previous studies in a rat model have shown no correlation between induction of apoptosis in the salivary gland and either the immediate or chronic decrease in salivary function following gamma-radiation treatment.A significant level of apoptosis can be detected in the salivary glands of FVB mice following gamma-radiation treatment of the head and neck and this apoptosis is suppressed in transgenic mice expressing an activated mutant of Akt (myr-Akt1). Importantly, this suppression of apoptosis in myr-Akt1 mice preserves salivary function, as measured by saliva output, three and thirty days after gamma-radiation treatment. In order to translate these studies into a preclinal model we found that intravenous injection of IGF1 stimulated activation of endogenous Akt in the salivary glands in vivo. A single injection of IGF1 prior to exposure to gamma-radiation diminishes salivary acinar cell apoptosis and completely preserves salivary gland function three and thirty days following irradiation.These studies suggest that apoptosis of salivary acinar cells underlies salivary gland hypofunction occurring secondary to radiation of the head and neck region. Targeted delivery of IGF1 to the salivary gland of patients receiving head and neck irradiation may be useful in reducing or eliminating xerostomia and restoring quality of life to these patients