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Assessing the Influence of Extracellular Mitochondria on Neuroinflammation

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A prominent aspect of Alzheimer’s disease (AD) is the presence of neuroinflammation is mediated by the activation of microglial cells, which are the immune cells in the central nervous system (CNS) that express an array of cytokines that may promote

A prominent aspect of Alzheimer’s disease (AD) is the presence of neuroinflammation is mediated by the activation of microglial cells, which are the immune cells in the central nervous system (CNS) that express an array of cytokines that may promote an inflammatory response. The main cytokines produced are: tumor necrosis factor-alpha (TNF-), interleukin-1β (IL-1β), and interleukin-6 (IL-6). The presence of these cytokines in the CNS may lead to neuronal death, to the production of toxic chemicals (such as nitric oxide), and to the generation of amyloid beta (a major pathological feature of AD). Previous studies have shown that modulation of the inflammatory response in the nervous system can potentially prevent and/or delay the onset of neurodegenerative diseases such as AD. Therefore, it is important to identify the process that induces CNS inflammation. For example, mitochondrial lysates have been found to produce an inflammatory response due to their ability to stimulate TNF-, Aβ, and APP mRNA [10]. Interestingly, extracellular mitochondria have been detected in the brain due to neurons degrading old mitochondria extracellularly. Therefore, we set out to study the effect of whole mitochondria isolated by differential centrifugation from human neuroblastoma cells (BE(2)-M17 cells) on the neuroinflammatory response in a human microglia model (THP-1 cells). Despite our best efforts, in the end it was unclear whether the mitochondrial fraction or other cellular components induced the inflammatory response we observed. Thus, further work with an improved mitochondrial isolation method should be carried out to address this issue.

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2018-05

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Effects of urbanization on the nutritional physiology and gut microbiome of house sparrows (Passer domesticus)

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The natural habitat as well as the food abundance and food sources of avian species is changing due to urbanization, and such anthropocentric actions could lead to devastating impacts on bird populations. As changes in distribution and nutrition are thought

The natural habitat as well as the food abundance and food sources of avian species is changing due to urbanization, and such anthropocentric actions could lead to devastating impacts on bird populations. As changes in distribution and nutrition are thought to be related to the gut microbiome, the goal of this study was to determine the relationship between nutritional markers, including body mass, gizzard mass, triglycerides, free glycerol and glycogen, and the gut microbiome in urban and rural house sparrows (Passer domesticus), to understand physiological differences between urban and rural house sparrows. We hypothesized that increased access to human refuse, through urbanization, may significantly alter the gut microbiome and thus, the nutritional physiology-the effects of foods on metabolism-of urban birds. Fecal samples were collected from rural (n=13) and urban (n=7) birds to characterize the gut microbiome and plasma samples were collected to measure nutritional markers using commercially available kits. Following euthanasia, liver samples were collected to measure triglycerides, free glycerol and glycogen. While there were no significant differences in circulating triglycerides or free glycerol between populations, urban birds had significantly greater blood glucose (p=0.046) compared to rural birds, when normalized to body mass. Additionally, rural birds had significantly more plasma uric acid (p=0.016) and liver free glycerol (p=0.044). Higher blood glucose suggests greater accessibility to carbohydrates in an urban setting or higher rates of gluconeogenesis. Uric acid is a byproduct of purine catabolism and a potent antioxidant. Thus, higher uric acid suggests that rural birds may utilize more protein for energy. Finally, higher liver free glycerol in rural birds suggests they metabolize more fat but could also indicate that urban birds have greater glycerol gluconeogenesis, which may consume free glycerol resulting in higher glucose concentrations. However, the current study does not provide evidence for this as there were no significant differences in the gluconeogenic enzyme PEPCK-C levels between urban and rural house sparrows (p= 0.165). While triglyceride, glucose, and uric acid levels differed between urban and rural birds, there were additionally no significant differences in the gut microbiome, indicating that although nutritional physiology can be affected by distribution and varying food availability and sources, differences in the gut microbiome are evident at the phyla level.

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2018-05

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Novel Organometallic Complex Mitigates Liver Injury caused by a 10-Week High Fat Diet in Adolescent Male Sprague-Dawley Rats

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Nonalcoholic fatty liver disease is the most common form of chronic liver disease in the United States. Diets high in saturated fats are known to promote obesity and hepatic steatosis. The consumption of a high fat diet (HFD) can increase

Nonalcoholic fatty liver disease is the most common form of chronic liver disease in the United States. Diets high in saturated fats are known to promote obesity and hepatic steatosis. The consumption of a high fat diet (HFD) can increase the risk factors associated with insulin resistance, which can lead to the onset of diabetes and obesity. A prior study of a soil-derived organometallic complex (OMC) showed that supplementation reduces glucose and body mass in diabetic mice. The goal of this study was to test the efficacy of a similar OMC compound on the mitigation of hepatic steatosis induced from a HFD. Six-week-old male Sprague-Dawley rats (n=42) were divided into the following diet groups: standard rodent chow or 60% kcal from fat high fat diet (mainly lard) for 10-weeks. Rats were further divided into OMC treatment groups with OMC added to their drinking water: 0 mg/ml, 0.6 mg/ml or 3.0mg/ml OMC. At 10 weeks, study animals were euthanized with sodium pentobarbital (200 mg/kg, i.p.) and cardiac plasma as well as liver samples were collected and stored at -80° C until further analyses. Plasma ALT and AST as well as liver triglyceride and free glycerol concentrations were measured using commercially available kits. To assess cellular injury, aspartate transaminase (AST; released mainly from injured cardiac and liver cells) and alanine transaminase (ALT; released mainly from injured liver cells) were examined. Rats fed HFD had elevated plasma ALT activity, which was prevented by treatment with the high dose of OMC (p<0.05). No changes in plasma AST activity were detected. Examination of liver triglyceride and free glycerol concentrations showed increased fat accumulation in the liver of rats consuming HFD (Two-Way ANOVA, p<0.001). OMC did not prevent this increase. These findings suggest that, although OMC does not prevent the accumulation of lipids in the liver of rats fed HFD, it does mitigate liver injury resulting from excess dietary intake of saturated fats.

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2019-05

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Effects of Menthol on Weight Regain and Maintenance of Caloric Restriction: A Pilot Study

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The prevalence of excessive weight gain (obesity) has steadily increased since about 1980. Excessive weight gain is associated with many comorbidities; thus, a successful treatment is needed. The most common form of non-surgical treatment for excessive weight gain is caloric

The prevalence of excessive weight gain (obesity) has steadily increased since about 1980. Excessive weight gain is associated with many comorbidities; thus, a successful treatment is needed. The most common form of non-surgical treatment for excessive weight gain is caloric restriction with the intent to reduce body weight by 10%. Though this treatment is successful at reducing body weight, it often fails at maintaining the weight loss. Dietary menthol has been suggested as a possible treatment for excessive weight gain and has produced promising results as a preventative method for excessive weight gain. Our studies aimed at reducing weight regain and maintaining caloric restriction by feeding male Sprague-Dawley rats 0.5% dietary menthol during a period of caloric restriction, aimed at reducing their body weight by 10%, following an experimental period where the rats were fed a high-fat diet (HFD) or low-fat diet (LFD). The effects of the dietary menthol were observed during the weight regain period following the caloric restriction period. Two studies were conducted, and both were unable to achieve a maintenance of weight loss following caloric restriction, although our first study was able to produce a delay in weight regain and did not show any evidence of increased thermogenesis in menthol-treated rats. Our findings differ from the findings of previous studies on dietary menthol which could possibly be due to species effects, differences in procedures, age effects, or effects of different fatty acid compositions. The contrasting results in our studies could be due to genetic differences between litters used or a difference in manufacturing of the menthol diet between studies. Given the partial response to menthol in the first study, it can be suggested that the concentration of 0.5% may be below the threshold of menthol sensitivity for some rats. Future research should focus on increasing the concentration of dietary menthol from 0.5% to 1%, since the current concentration did not yield a reduction in weight regain or maintenance of caloric restriction.

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2019-05

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Hypoxia plus Glucose Deprivation Increases NF-κB Activation and Downstream Pro-Inflammatory Enzyme Levels in Human Brain Vascular Smooth Muscle Cells

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Vascular inflammation is a key component for cerebrovascular disease and ischemic injury is suggested to be a significant contributor, resulting in either myocardial ischemia or stroke. A strong inflammatory response is characterized by the release of inflammatory cytokines, thus producing

Vascular inflammation is a key component for cerebrovascular disease and ischemic injury is suggested to be a significant contributor, resulting in either myocardial ischemia or stroke. A strong inflammatory response is characterized by the release of inflammatory cytokines, thus producing and/or activating pro-inflammatory proteins in the cell. Our previous studies have demonstrated that hypoxia plus glucose deprivation (HGD), an in vitro model of ischemia, increases the proinflammatory mediator, cyclooxygenase-2 levels (COX-2), in vascular tissues. Nuclear factor kappa B (NF-κB) activation is an upstream transcription factor of COX-2 and had been suggested to be involved in “sterile” inflammation in experimental stroke models. Mechanisms underlying the development and progression of inflammation in the cerebrovasculature following ischemic injury in human tissue has not been addressed. Thus, the purpose of this study was to examine the impact of HGD on NF-κB expression and activation in human brain vascular smooth muscle cells (HBVSMC). In addition, we assessed pro-inflammatory mediator levels of downstream NF-κB transcription products, COX-2 and iNOS, and level of its upstream receptor, TLR4. Primary HBVSMC at passage 7 were treated with normoxia (room air) or HGD (1% O2). Following exposure to HGD (3h), cells were isolated, homogenized, and total protein content determined. Lysates, either whole cell or nuclear and cytosolic fractions, were prepped for western blot and analysis. Anti-α-smooth muscle actin was used to verify HBVSMC origin and -actin was used as a loading control. NF-κBp65, phosphorylated NF-κBp65, COX-2, and TLR4 protein levels were all measured post HGD. NF-κBp65 total protein was expressed in HBVSMC and a trend for an increase in levels following HGD was observed. Indirect activation of pNF-kBp65 was assessed via nuclear fractionation studies and was increased following HGD. Lamin AC was used to verify nuclear fractionation. Additional findings suggested that HBVSMC expressed TLR4 however, total protein levels of TLR4 were not altered by HGD. COX-2 and iNOS protein levels were also increased following HGD. In conclusion, these studies indicate that HGD alters proinflammatory enzyme levels, potentially by altering NF-κBp65 activation in human vascular smooth muscle cells. Funding Support: University of Arizona Sarver Heart Center and University of Arizona Valley Research Project Grant VRP P1 (RG).

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2018-12

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Examination of an Organometallic Complex on Insulin Resistance in Periadolescent Male Rats Following a 10-week High Fat Diet

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With the rising prevalence of obesity and diabetes, novel treatments to help mitigate or prevent symptoms of these conditions are warranted. Prior studies have shown that fossilized plant materials found in soil lowers blood sugar in a mouse model of

With the rising prevalence of obesity and diabetes, novel treatments to help mitigate or prevent symptoms of these conditions are warranted. Prior studies have shown that fossilized plant materials found in soil lowers blood sugar in a mouse model of diabetes. The goal of this study is to determine whether a similar organometallic complex (OMC) could prevent insulin resistance in the skeletal muscle brought on by chronic high fat intake by examining the protein expression of key enzymes in the insulin signaling pathway and examining glucoregulatory measures. Six-week-old periadolescent male Sprague-Dawley rats (n=42) were randomly chosen to be fed either a high fat diet (HFD) (20% protein, 20% carbohydrates [6.8% sucrose], 60% fat) or a standard chow diet (18.9% protein, 57.33% carbohydrates, 5% fat) for 10 weeks. Rats from each diet group were then randomly assigned to one of three doses of OMC (0, 0.6, 3.0 mg/mL), which was added to their drinking water and fasting blood glucose was measured at baseline and again at 10 weeks. After 10 weeks, rats were euthanized, and soleus muscle samples were isolated, snap-frozen, and stored at -80°C until analyses. Fasting plasma glucose was measured using a commercially available glucose oxidase kit. Following 6 and 10 weeks, HFD rats developed significant hyperglycemia (p<0.001 and p=0.025) compared to chow controls which was prevented by high dose OMC (p=0.021). After 10 weeks, there were significant differences in fasting serum insulin between diets (p=0.009) where levels were higher in HFD rats. No significant difference was seen in p-PI3K expression between groups. These results suggest that OMC could prevent insulin resistance by reducing hyperglycemia. Further studies are needed to characterize the effects of diet and OMC on the insulin signaling pathway in skeletal muscle, the main site of postprandial glucose disposal. This study was supported by a grant from Isagenix International LLC as well as funds from Barrett, the Honors College at Arizona State University, Tempe Campus.

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2018-12

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Impact of Sumac on Lowering Oxidative stress as it pertains to Dementia

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Background: To determine the effect of sumac on vasodilation and oxidative stress in vascular tissue. This study hypothesized that sumac would increase vasodilation and reduce vascular damage in vascular tissue taken from rats to improve symptoms and risk of vascular

Background: To determine the effect of sumac on vasodilation and oxidative stress in vascular tissue. This study hypothesized that sumac would increase vasodilation and reduce vascular damage in vascular tissue taken from rats to improve symptoms and risk of vascular dementia.
Methods: Male Sprague-Dawley rats were fed a chow diet or a high fat diet (HFD) for ten weeks. Endothelium-dependent vasodilation was measured in isolated mesenteric arterioles that were treated with or without 80 µg/ml sumac in the superfusate throughout the experiment.
Results: Sumac did not improve vasodilation or in ex vivo arteries from rats fed a high fat diet. There were trends of improved vasodilation in sumac treated vessels from high fat diet rats, but sumac did not significantly improve vasodilation. In rats fed a chow diet, sumac prevented phenylephrine (PE) constriction in the vascular tissue. The most likely cause for this is the presence of Gallic acid in sumac. Another possible explanation is the presence of nitrates in sumac which may have prevented PE vasoconstriction.
Conclusions: Sumac did not significantly improve vasodilation in isolated arteries from rats fed a high fat diet. The results are inconclusive for the improvement of symptoms or risk of vascular dementia. In vivo treatment with sumac should be tested as results may differ.

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2018-05

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Effects of an Urban Diet on Glucose, Sodium, and Osmolality in the Mourning Dove, Zenaida macroura

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Prior studies of Mourning Doves have observed no changed in glucose in response to either a high fat “chow” diet or a white bread diet. In the current feeding study, we fed doves an urban diet, high in carbohydrates, fat,

Prior studies of Mourning Doves have observed no changed in glucose in response to either a high fat “chow” diet or a white bread diet. In the current feeding study, we fed doves an urban diet, high in carbohydrates, fat, and sodium, which is representative of typical American nutrition accessible to the avian population in an urbanized environment. Based on studies of other avian species that examined the effects of an urban diet on physiology, I hypothesized that doves fed an urban diet would have increased plasma glucose and sodium, which would promote an increase in plasma osmolality. This hypothesis was based on preliminary data that found birds fed an urban diet developed impaired vasodilation compared to seed diet control birds. Therefore, differences in plasma glucose, sodium, and osmolality were examined as increases may contribute to the impairment. Adult doves of both sexes were captured on the Arizona State University, Tempe campus. Doves were placed in two dietary groups: an urban diet consisting of a 50/50 ratio of French fries and nutritionally-balanced bird seed (n=7) and a control group of only the seed diet (n=6). Following the four-week diets, birds were euthanized, and cardiac plasma samples were collected from birds to measure glucose, sodium, and osmolality. There were no significant differences between the two study groups in plasma glucose concentration (p=0.445), sodium concentration (p=0.731), or osmolality (p=0.692). Sodium concentrations were signficantly more variable in birds consuming a seed diet than those that were provided the mixed French fry and seed diet (p=0.014). These results suggest that glucose, sodium, and osmolality likely do not contribute to the altered vasodilation of doves fed an urban diet and that such a diet may not be as detrimental to the doves health given their phenotypic flexibility.

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2020-05

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An Urban Diet Impairs Tibial Vasodilation in Mourning Doves (Zenaida macroura)

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Birds maintain resting plasma glucose concentrations (pGlu) nearly twice that of comparably sized mammals. Despite this, birds do not incur much of the oxidative tissue damage that might be expected from a high pGlu. Their ability to stave off oxidative

Birds maintain resting plasma glucose concentrations (pGlu) nearly twice that of comparably sized mammals. Despite this, birds do not incur much of the oxidative tissue damage that might be expected from a high pGlu. Their ability to stave off oxidative damage allows birds to serve as a negative model of hyperglycemia-related complications, making them ideal for the development of new diabetes treatments with the potential for human application. Previous studies conducted by the Sweazea Lab at Arizona State University aimed to use diet as a means to raise blood glucose in mourning doves (Zenaida macroura) in order to better understand the mechanisms they utilize to stave off oxidative damage. These protocols used dietary interventions—a 60% high fat (HF) “chow” diet, and a high carbohydrate (HC) white bread diet—but were unsuccessful in inducing pathologies. Based on this research, we hypothesized that a model of an urban diet (high in fat, refined carbohydrates, and sodium) might impair vasodilation, as the effect of this diet on birds is currently unknown. We found that tibial vasodilation was significantly impaired in birds fed an urban diet compared to those fed a seed diet. Unexpectedly, vasodilation in the urban diet group was comparable to data of wild-caught birds from previous research, possibly indicating that the birds had already been eating a diet similar to this study’s urban diet before they were caught. This may constitute evidence that the seed diet improved vasodilation while the urban diet more closely mimicked the diet of the birds before the trial, suggesting that the model of the urban diet acted as the control diet in this context. This study is the first step in elucidating avian mechanisms for dealing with diabetogenic diets and has potential to aid in the development of treatments for humans with metabolic syndrome.

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2020-05

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Doxorubicin Induced Cardiotoxicity and High Intensity Aerobic Exercise

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Doxorubicin (DOX) is a cardiotoxic, anthracycline-based, anti-neoplastic agent that causes pathological cardiac remodeling due to altered protein expression associated with cardiotoxicity. DOX cardiotoxicity causes increased Akt phosphorylation, blunted AMPK phosphorylation and upregulated mTOR phosphorylation. Akt is activated by cellular stress

Doxorubicin (DOX) is a cardiotoxic, anthracycline-based, anti-neoplastic agent that causes pathological cardiac remodeling due to altered protein expression associated with cardiotoxicity. DOX cardiotoxicity causes increased Akt phosphorylation, blunted AMPK phosphorylation and upregulated mTOR phosphorylation. Akt is activated by cellular stress and damage. AMPK is activated by increases in AMP and ADP concentrations and decreased ATP concentration. mTOR is active in cellular growth and remodeling. These proteins are cellular kinases with cascades that are influenced by one another. Exercise preconditioning may diminish the cardiotoxic effects on these proteins. Female, Ovariectomized Sprague-Dawley rats (N=33) were randomized to: Exercise+DOX (EX+DOX, n=9); Exercise+Vehicle (EX+VEH, n=8); Sedentary+DOX (SED+DOX, n=8); and Sedentary+Vehicle (SED+VEH, n=8) groups. DOX (4mg/kg) or VEH (saline) intraperitoneal injections were administered bi-weekly (cumulative dose of 12mg/kg). VEH animals received body weight matched volumes of saline based on dosing in animals receiving DOX. Exercise (EX) animals underwent high intensity (85-95% VO2 peak) interval training (HIIT) (4x4 min bouts) separated by low intensity (50-60% VO2max) intervals (2 min bouts) 5 days per week. Exercise began 1 week prior to the first injection and was continued throughout the study. Rats were euthanized 5 days after the last injection. Left ventricular tissue was isolated, processed into lysate and used for western blot analyses [2x2 ANOVA; (α=0.05)]. DOX induced significant phosphorylation of Akt and mTOR (p=0.035; p=0.032) only in SED+DOX rats, but unchanged in EX+DOX rats. No significant differences (p=0.374) in AMPK phosphorylation were observed between groups. Exercise Preconditioning prevents some DOX-induced changes in the cardiac mTOR signaling pathway implicated in pathological remodeling.

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2017-05