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IMPACT OF 17-BETA ESTRADIOL AND MODERATE-INTENSITY EXERCISE ON MESENTERIC ARTERIAL FUNCTION OF UC DAVIS TYPE-2 DIABETES MELLITUS RATSRazan, Md Rahatullah 01 January 2021 (has links)
The studies in this dissertation were designed to investigate the impacts of estrogen (17-β estradiol/E2) and moderate-intensity exercise (MIE) on the mesenteric arterial (MA) function of the University of California Davis type-2 diabetes mellitus (UCD-T2DM) Rat model. Our recent report suggests that diabetes impairs MA vasorelaxation in both sexes of the UCD-T2DM model. Particularly, we reported that MA from prediabetic male rats showed a greater impairment compared to that in prediabetic females. However, when females become diabetic, they exhibit a greater vascular dysfunction than males. Therefore, the aim of the first study was to investigate whether female sex hormone, specifically E2, preserves the MA vasorelaxation in female UCD-T2DM rats at the early prediabetic state. For this study, age-matched healthy Sprague Dawley (SD) and prediabetic female UCD-T2DM rats were ovariectomized and subcutaneously implanted with either a placebo or E2 pellet for 45 days. Regular aerobic exercise is a well-known therapeutic intervention for endothelial dysfunction, insulin resistance, and cardiovascular disease (CVD) risk in diabetes. However, there are still debates about the duration, intensity, and underlying mechanisms of benefits of exercise against deleterious metabolic consequences in diabetic patients. In the second study outlined in this dissertation, we examined the impact of exercise training on vascular function and wall structure of the UCD-T2DM male rats. Age-matched male diabetic and SD control rats were randomly divided into sedentary and exercise-trained groups. The exercise-trained groups ran on a treadmill for eight weeks (1hr/day, 5days per week). For both studies (Studies I & II), metabolic parameters and MA responses to vasodilator and vasocontractile agents were determined. Furthermore, the expression of molecules associated with vascular signaling were also analyzed.
The specific aims of our studies were to investigate whether E2 and moderate-intensity exercise (MIE) alter the 1) endothelium-dependent vasorelaxation (EDV) and vasoconstriction 2) relative contribution of endothelium-derived relaxing factors (EDRF) to vasorelaxation, and 3) expression of proteins associated with vascular signaling, in MA of UCD-T2DM rats.
In the first study, we demonstrated that acetylcholine (ACh)-induced vasorelaxation was impaired in MA of ovariectomized (OVX) prediabetic UCD-T2DM rats. Our data also showed that E2 replacement improved MA relaxation in OVX prediabetic group to a similar level to that in control groups. Inhibition of cyclooxygenase (COX) by indomethacin (Indo) did not significantly affect the vascular responses in any groups, suggesting a minor role of COX metabolites in MA relaxation in the experimental groups. Inhibition of nitric oxide (NO) synthase (NOS) by L-NAME reduced vasorelaxation to ACh in control groups, but it did not completely abolish the vasorelaxation. We also showed that in control (healthy) groups, both NO and endothelium-derived hyperpolarizing factor (EDHF)-type relaxation were dominant in the MA relaxation of placebo and E2 treated rats. However, in prediabetic groups, L-NAME completely abolished the vasorelaxation, regardless of E2 treatment, suggesting a relative shift from EDHF-type relaxation to only NO-mediated relaxation in these groups. Furthermore, the sensitivity of MA to NO was significantly impaired in OVX prediabetic group, but E2 treatment enhanced the MA sensitivity to NO. Overall, our data suggest that a greater vasorelaxation in the E2 treated OVX prediabetic group could be partly attributed to the elevated role of NO or improved sensitivity of MA to NO in this group.
The second study demonstrated that ACh-induced vasorelaxation of MA was significantly impaired in sedentary diabetic (DS) male rats. MIE significantly enhanced MA vasorelaxation in the exercise-trained diabetic (DE) group compared to the DS. However, no significant differences were observed between the vasorelaxation of control sedentary (CS) and control exercise-trained groups (CE). Inhibition of COX enhanced maximal vasorelaxation response (Rmax) to ACh in DS arteries suggesting an elevated contractile COX contribution in MA of this group which could possibly be due to the observed increase in COX expression in the DS group. Unlike the DS group, inhibition of COX did not affect the vasorelaxation responses to ACh in the DE group. The addition of L-NAME resulted in a reduction in ACh-induced relaxation of MA from both DS and DE groups. However, the effect of L-NAME was more prominent in the DS group compared to the DE group, suggesting a major contribution of NO in DS arteries. On the other hand, a preserved role of NO with an enhanced EDHF-mediated relaxation was observed in the MA vasorelaxation of the DE group. Our data on the elevated small conductance calcium-activated potassium channel (SKCa) expression level in MA taken from the DE group compared to that in the DS group may suggest a role for SKCa in increased EDHF-type relaxation in the DE group. Furthermore, DS arteries exhibited a higher contractile response, myogenic tone, and wall thickness than those in MA of DE. Overall, our data suggest that MIE reduced myogenic tone (DE vs. DS) and improved EDV in mesenteric arteries of diabetic rats, possibly via a shift from contractile COX activity to both NO and EDHF-type relaxation.
In conclusion, the data generated in study-I suggest that estrogen may protect prediabetic female MA from early vascular dysfunction, possibly by elevating the contribution of NO to vasorelaxation as a compensatory mechanism to the loss of EDHF-type relaxation in this group. Although the results of the current study are in agreement with our previous report demonstrating a possible protective effect of female sex hormones in the MA function at prediabetic state, additional studies are needed to establish the specific role of E2 in the progression of vascular dysfunction in the diabetic state.
Lastly, an intriguing observation of study-II was that MIE improved vasorelaxation and prevented the loss of EDHF-type relaxation in diabetic arteries. This was in addition to the changes induced to the wall thickness and myogenic tone in arteries of UCD-T2DM males. Given that sex differences play an important role in cardiovascular physiology, additional studies are needed to establish the specific role of MIE on vascular dysfunction in UCD-T2DM female rats and its underlying mechanisms.
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The effect of cigarette smoking on the virulence of streptococcus mutans caries and cardiovascular diseases-epidemiological analysis and in vitro studiesZheng, Cunge January 2010 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / The impact of tobacco smoking on human health is well documented. The influence of smoking on tooth loss and cardiovascular diseases was investigated in the current study via both epidemiology and in vitro studies.
From analyzing the 2006 Behavioral Risk Factor Surveillance System (2006 BRFSS) database, we confirmed that smoking was significantly associated with the number of teeth lost in a dose-dependent manner and smoking cessation reduced the risk when compared to those subjects continuing to smoke. In addition, the virulence factors related to caries were compared between Streptococcus mutans and Streptococcus gordonii in response to cigarette smoking condensate (CSC) treatment. We observed that S. gordonii was more susceptible to CSC treatment than S. mutans. CSC significantly enhanced S. mutans sucrose-dependent and independent adherence. Western blot assays revealed that several bacterial surface proteins including glucosyltransferase (GTF), glucan-binding proteins and antigen I/II, were significantly upregulated for the treated S. mutans. These findings suggested that the oral environment with CSC may favor a cariogenic dominant composition, which may increase the risk for smokers to develop caries.
We also found that smoking and oral health status modified each other and synergistically increased the risk of CVD and this joint effect was more pronounced among the youngest age group using the 2006 BRFSS database. To further understand the joint effect, we conducted an in vitro study to investigate bacterial attachment to fibronectin and endothelial cells in response to smoking condensate treatment. Our study clearly demonstrated CSC significantly enhanced S. mutans attachment to both soluble and immobilized fibronectin as well as endothelial cells. Furthermore, our data suggested that bacteria possessed several adhesins that bound to host tissues and endothelial cells also had multiple receptors for bacterial attachment. Among these adhesins, antigen I/II seemed essential for bacterial attachment to endothelial cells without CSC. The knowledge of bacterial attachment to host tissues in the presence of CSC may help in developing different preventive or therapeutic strategies against attachment and colonization of the host by S. mutans.
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UNDERSTANDING THE LINK BETWEEN RELIGIOUS SERVICE ATTENDANCE, CORONARY HEART DISEASE AND RELATED RISK FACTORS IN CANADA: A MIXED METHODS STUDY AND FUTURE DIRECTIONS FOR HEALTH PROMOTION.Banerjee, Tina Ananya 10 1900 (has links)
<p>Research examining the relationships between religious indicators and the cardiovascular health of individuals and populations has been relatively understudied in the Canadian context. This thesis contains three main studies, developed from a sequential explanatory mixed method research design.</p> <p>The first study examined the association between the frequency of religious service attendance (RSA) and prevalence of coronary heart disease (CHD), diabetes and high blood pressure in Canada. The Saskatchewan sample of the Canadian Community Health Survey (CCHS-4.1) was used to build multivariable logistic regression models. The analysis revealed participants who attended religious services more than once a week had lower prevalent odds of CHD (OR= 0.82, 95% CI 0.61-1.11, p>0.05), diabetes (OR=0.60, 95% CI 0.45-0.80, p</p> <p>The second study was qualitative and undertaken to help interpret and explain the quantitative results from the CCHS. Twelve semi-structured interviews with ordained pastors and three focus groups with parishioners in Catholic, Anglican and United churches were conducted in Canada. The findings suggest that attending religious services: (1) promotes mental health; (2) provides social support and activities; and (3) promotes health and lifestyle behaviours to lower CHD risk.</p> <p>Qualitative data from the second study was used for the third study, which identified relevant factors associated with the implementation of heart health promotion programs in churches. Among the various factors identified, pastor leadership, funding for a parish nurse, community-focused interventions, secured infrastructure and social support were important to facilitate health promotion programs in churches.</p> / Doctor of Philosophy (PhD)
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FUNCTIONAL FOODS AND WOMEN'S HIGH CHOLESTEROLJovanovic, Maja January 2014 (has links)
<p>This dissertation takes the format of a "three paper model" (i.e. Sandwich Thesis), and all three articles have been submitted for publication.</p> <p>Article 1 (Chapter 4) - appears in <em>Food, Culture & Society (2014).</em></p> <p>Article 2 (Chapter 5) - appears in <em>Social Science & Medicine (2014).</em></p> <p>Article 3 (Chapter 6) - Revise & Resubmit from <em>Sociology of Health & Illness</em></p> / <p>Food and the various aspects surrounding what we eat, what we <em>should</em> eat, and concerns about how to remain healthy and ward off disease and illness is escalating while our choices are endless. In this competitive food market a new type has emerged: the functional food. Functional foods are those that have an added health benefit beyond the basic nutritional content and display physiological benefits in reducing chronic diseases. A popular category of functional foods are those that purport to lower one's cholesterol. In particular, high cholesterol is marketed as a "disease" rather than a risk factor for various cardiovascular diseases, such as heart disease. Little is known about the sociological diagnosis of high cholesterol and the marketing of functional foods, in particular with women. This dissertation address this gap by asking: (1) How is high cholesterol (HC) identified and marketed as a disease rather than a risk factor for cardiovascular diseases in functional food advertising - specifically addressing the Becel® pro.activ® margarine campaign? (2) How do women understand the issue and <em>causes </em>of high cholesterol; and (3) What do women understand the <em>solution </em>to high cholesterol to be and how do they view Becel's<sup>®</sup> high cholesterol solution? --The findings center on 4 key issues: <ol> <li>The construction and marketing of high cholesterol <em>as a disease</em> (i.e. via the sociology of diagnosis), rather than a risk factor for heart disease;</li> <li>The causes of high cholesterol and attribution of blame are placed on women's poor lifestyle choices and seen as an individual responsibility;</li> <li>There are class differences regarding women's knowledge and awareness of the social determinants of health (SDOH); and</li> <li>The solution to high cholesterol is individualized via the 'proactive myopia' repertoire.</li> </ol></p> / Doctor of Philosophy (PhD)
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LIFESTYLE CONTRIBUTORS TO CARDIOVASCULAR DISEASE RISKBerrones, Adam J. 01 January 2016 (has links)
Aortic stiffness is an independent risk factor that has prognostic value regarding future cardiovascular disease (CVD) events such as myocardial infarction, strokes, and heart failure. Although death rates due to coronary heart disease have declined in recent years, the leading global killer remains CVD and prevalence is still high. Understanding lifestyle contributors associated with aortic stiffness would provide the public with insight into targeting key health-related behaviors.
The purpose of this observational study was to examine the association of physical activity, physical function, and dietary quality as independent factors contributing to aortic stiffness in apparently healthy middle aged men. Fifty-two men between the ages of 30 and 59 years were recruited to participate in this study, which required two visits to the Exercise Physiology Laboratory. Aortic stiffness was measured by aortic pulse wave velocity (aPWV) and was not associated with total daily step counts (r=-0.06; P=0.70). However, aortic stiffness was inversely associated with physical function, determined with the sitting-rising test score (r=-0.44; P<0.01) and inversely associated with relative muscular strength, determined with peak handgrip strength in both hands normalized to body mass (r=-0.41; P<0.01). Additionally, aortic stiffness was inversely associated with dietary quality, determined with the Healthy Eating Index score (r=0.51; P<0.01).
In conclusion, key health-related behaviors in this study that explained a large percentage of the variation in aortic stiffness were physical function and dietary quality (Adj r²=0.47; SEE=0.634). Hence, optimizing overall musculoskeletal fitness by focusing on strength, balance, coordination, and flexibility in addition to greater adherence to the U.S. Dietary Guidelines are key lifestyle contributors associated with reduced CVD risk in otherwise healthy middle aged men.
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The responses of endothelium to insult : does endothelial heterogeneity play a role in in vitro cell modelsMthethwa, Mashudu 12 1900 (has links)
Thesis (PhD)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Endothelial injury and dysfunction precede the development of cardiovascular diseases. The endothelium may be regarded as the first line of defence against inflammation / obesity-induced vascular injury, therefore gaining more information on the mechanisms of injury and response to injury, as well as modulating endothelial function may be key in the prevention of cardiovascular diseases. Endothelial cells differ in structure and function, therefore endothelial heterogeneity may be relevant when investigating endothelial function and dysfunction. Understanding endothelial heterogeneity in response to pathophysiological stimuli may be of significance in the prevention of cardiovascular diseases. Oleanolic acid (OA), a plant-derived triterpenoid, has been shown to possess endothelio-protective properties; however, its role in reversing endothelial injury is poorly understood.
This study investigated endothelial heterogeneity between aortic endothelial cells (AECs) and cardiac microvascular endothelial cells (CMECs) at baseline and in response to an inflammatory insult via the cytokine, tumour necrosis factor-alpha (TNF-α). An in vitro model of endothelial injury was developed by treating AECs and CMECs with 20 ng/ml TNF-α for 24 hours. Endothelial heterogeneity was investigated by comparing intracellular nitric oxide (NO) and reactive oxygen species (ROS) production, protein expression and phosphorylation, and large-scale protein expression and regulation in AECs and CMECs. The experimental techniques included flow cytometry, western blots and proteomic analyses. An ex vivo model of endothelial injury was included to investigate vascular function in aortic rings from lean and high fat diet (HFD) rats. The role of OA in reversing TNF-α-induced injury and modulating vascular function in the ex vivo model was investigated. Although baseline NO-levels were similar between AECs and CMECs, heterogeneity was observed with regards to the NO biosynthetic pathway in terms of increased eNOS expression in CMECs. Baseline ROS levels were heterogeneous between AECs and CMECs, interestingly CMECs possessed higher anti-oxidant capacity. An in vitro model of TNF-α-induced injury was confirmed by decreased NO-levels, increased ROS-levels and necrosis, up-regulation of apoptotic proteins and activation of inflammatory pathways in AECs and CMECs. Here, heterogeneity between AECs and CMECs was also observed: endothelial activation was mediated through different proteins in AECs (CD9 molecule, galectin) and CMECs (ICAM-1 and IL-36α). Apoptosis was mediated by caspase 3 in AECs and Bid in CMECs. AECs appeared to advance to a dysfunctional state shown by up-regulation of endothelin-converting enzyme and angiotensin II-converting enzyme, while CMECs maintained an activated state. OA reversed TNF-α-induced injury through restoring NO-production, decreasing ROS-production in both AECs and CMECs, and inhibiting necrosis in AECs. In the ex vivo model of injury, aortic rings from 16-week HFD rats showed a pro-contractile response to phenylephrine-induced contraction, a response that was reversed by OA. In conclusion, we demonstrated novel findings with regards to endothelial heterogeneity between AECs and CMECs under baseline and TNF-α-treated conditions. Although reduced NO-bioavailability may be the hallmark of endothelial dysfunction, signalling pathways mediating endothelial injury may differ between cell types as was shown in this study. We demonstrated that OA possess protective properties in AECs and CMECS, an observation which was translated to the ex vivo model. / AFRIKAANSE OPSOMMING: Endoteelbesering en –disfunksie gaan die ontwikkeling van kardiovaskulêre siektes vooraf. Die endoteel word as die eerste linie van verdediging teen inflammasie / vetsug-geïnduseerde vaskulêre skade beskou; dus is die ontginning van nuwe inligting betreffende die meganismes van en respons tot besering, asook die modulering van endoteelfunksie essensieël in die voorkoming van kardiovaskulêre siektes. Endoteelselle verskil t.o.v. struktuur en funksie, en dus is endoteel-heterogeniteit relevant tydens die ondersoek van endoteelfunksie en –disfunksie. ‘n Beter begrip van endoteel-heterogeniteit in die respons tot patofisiologiese stimuli kan betekenisvol tot die voorkoming van kardiovaskulêre siektes bydra. Oleanoliese suur (OA), ‘n triterpenoïed afkomstig van plante is voorheen bewys om endoteelbeskermende eienskappe te besit; die rol van OA in die omkering van endoteelbesering is egter minder bekend. Hierdie studie het endoteel-heterogeniteit tussen aorta endoteelselle (AECs) en hart mikrovaskulêre endoteeelselle (CMECs) by basislyn en in respons tot ‘n inflammatoriese besering via die sitokien, tumor nekrose faktor-alfa (TNF-α), ondersoek. ‘n In vitro model van endoteelbesering is ontwikkel deur AECs en CMECs met 20 ng/ml TNF-α vir 24 uur te behandel. Endoteel-heterogeniteit was ondersoek deur intrasellulêre stikstofoksied (NO) en reaktiewe suurstofspesies (ROS) produksie, proteïenuitdrukking en fosforilering, en grootskaalse proteïenuitdrukking en regulering in AECs en CMECs te vergelyk. Die eksperimentele tegnieke het ingesluit: vloeisitometrie, western blots en proteomika. ‘n Ex vivo model van endoteelbesering was ook ingesluit deur die vaskulêre funksie in aortaringe van normale en hoë vet dieet-gevoerde (HFD) rotte te meet. Die rol van OA in die omkering van TNF-α-geïnduseerde besering en modulering van vaskulêre funksie was in hierdie model is ondersoek. Alhoewel basislyn NO-vlakke vergelykbaar was in AECs en CMECs, is heterogeniteit wel aangetoon m.b.t. die NO biosintese pad met verhoogde eNOS uitdrukking in die CMECs. Basislyn ROS-vlakke was verskillend in AECs en CMECs en die CMECs het hoër anti-oksidant kapasiteit getoon. ‘n In vitro model van TNF-α-geïnduseerde besering is bevestig met die waarneming van verlaagde NO-vlakke, verhoogde ROS-vlakke en nekrose, opregulering van apoptotiese proteïene en aktivering van inflammatoriese paaie in AECs en CMECs. Hier was heterogeniteit ook opmerkbaar: endoteelaktivering was deur verskillende proteïene in AECs (CD9 molekule, galektien) en CMECs (ICAM-1, IL-36α) bemiddel. Apotose was deur kaspase 3 in AECs en Bid in CMECs bemiddel. Dit het geblyk dat AECs tot ‘n staat van endoteeldisfunksie gevorder het met die opregulering van endotelien-omsettingsensiem en angiotensien II-omsettingsensiem, terwyl CMECs eerder ‘n geaktiveerde staat gehandhaaf het. OA het TNF-α-geïnduseerde besering omgekeer deur NO-produksie te herstel, ROS-produksie te onderdruk in beide AECs en CMECs, en nekrose te inhibeer in AECs. In die ex vivo model van besering, het aortaringe van 16-week HFD rotte ‘n pro-kontraktiele respons tot fenielefrien-geïnduseerde kontraksie getoon, wat deur OA omgekeer is. Ten slotte, nuwe bevindinge is waargeneem m.b.t. endoteel-heterogeniteit tussen AECs en CMECs onder basislyn en TNF-α-behandelde omstandighede. Alhoewel verlaagde NO-biobeskikbaarheid die waarmerk van endoteeldisfunksie is, het hierdie studie getoon dat seintransduksiepaaie wat endoteelbesering medieer verskillend is tussen seltipes. Die studie het verder ook gedemonstreer dat OA beskermende eienskappe toon in AECs en CMECs, ‘n waarneming wat ook in die ex vivo model aangetoon kon word.
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ADHERENCE TO PHYSICAL ACTIVITY AMONG INDIVIDUALS WITH OR WITHOUT CARDIOVASCULAR DISEASESaleh, Zyad T. 01 January 2013 (has links)
Cardiovascular disease (CVD) is a major public health problem and a primary cause of morbidity and mortality in the United States. Regular physical activity is recommended for prevention and management of CVD. Despite the cardiovascular health benefits of physical activity most adults are physically inactive. Therefore, the aim of this dissertation was to examine the factors associated with adherence to physical activity among individuals with or without CVD.
The first paper is a report of a study conducted to examine which baseline demographic (age, gender, marital status, socioeconomic status, and place of residency), psychosocial (social support, depression, anxiety, and fatalism), and clinical (past history of exercising, comorbidity, and health literacy) variables predicted successful adoption of the active lifestyle recommendation of increasing moderate-to-vigorous physical activity by an accumulated 15 minutes or more each day following a CVD risk reduction intervention and 2) to identify which of those same factors predicted dropout from the CVD risk reduction intervention among at-risk individuals in rural America. The study sample consisted of 399 rural Americans. The results revealed that a higher anxiety level was a predictor of active lifestyle modification following a CVD risk reduction intervention. In contrast, younger age and low health literacy were predictors of dropout from a CVD risk reduction intervention.
The second paper is a literature review of studies investigating the factors that affected enrollment in cardiac rehabilitation in patients with heart failure (HF). The aims of this review were to: (a) describe enrollment rates of patients with HF in cardiac rehabilitation programs, (b) review the literature on factors affecting enrollment of patients with HF, and (c) identify areas for future research. It is difficult to draw conclusion about enrollment rates because the period of time after hospital discharge that enrollment was measured varied across studies. A wide array of demographic, psychosocial, and clinical variables have been identified as potential barriers of enrollment in cardiac rehabilitation programs. Additional research including patients with HF is needed.
The third paper is a report of a cross-sectional study of 279 patients with HF. The aims were to determine 1) the amount of variance in the functional status predicted by depressive symptoms, perceived control, self-rated health, HF self-care maintenance behaviors, and serum N-terminal pro-B-type natriuretic peptide ( NT-pro-BNP) biomarker of cardiac dysfunction in patients with HF and 2) whether NT-pro-BNP mediated the relationship between self-care maintenance behaviors and functional status. Depressive symptoms, poor self-rated health, non-adherence to physical activity, and greater serum NT-pro-BNP levels were independently associated with worse perceptions of functional status. Serum NT-pro-BNP levels partially mediated the association between adherence to physical activity and perception of functional status.
The findings from this dissertation provided further evidence of the importance of adherence to physical activity and identify key variables that promote participation in interventions to promote heart healthy lifestyles and adherence to physical activity.
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EXAMINING THE EFFECT OF RACE ON THE RELATIONSHIP BETWEEN POSTTRAUMATIC STRESS DISORDER AND METABOLIC SYNDROME IN WOMENHarper, Leia 01 January 2014 (has links)
Posttraumatic stress disorder (PTSD) is a psychiatric condition affecting approximately 8% of the adult U.S. population with rates twice as high in women than men. Increasingly, evidence has suggested a close relationship between PTSD and increased risk of metabolic diseases. However, the literature on PTSD and metabolic disease risk factors has been limited by the lack of investigation of the potential influence of race on this relation. The current study examined the possible effect of race on the relation between PTSD and metabolic risk. Data for this study were provided from sample of that included 50 African American women and 39 Caucasian women, 56.2% and 43.8% respectively. Results support the importance of race in the relationship between PTSD and metabolic disease risk factors. Future research would benefit from analysis of cultural factors to explain how race might influence the course of metabolic disease risk and development in women with PTSD.
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Vitamin C: A potential regulator of inflammatory responseMohammed, Bassem M 01 January 2015 (has links)
Introduction: Neutrophils (PMNs) and Macrophages are the first responders recruited consecutively to the site of injury/inflammation. PMNs’ response/fate as well as macrophage reprogramming ultimately determine the course of resolution of inflammation. Physiologic wound healing has a significant inflammatory component. An exaggerated inflammation however is self-defeating leading to delayed healing. Parenteral vitamin C (VitC) attenuated inflammation in murine sepsis models and in patients with sepsis. However information about the mechanisms by which VitC regulates these events is limited.
Methods: Humanized mice lacking VitC synthesis capability (Gulo-/-) were used. VitC sufficient and deficient mice were challenged with sterile inflammation, or septic insults. Some VitC deficient mice received parenteral VitC (200mg/kg) following the challenge to give deficient + AscA mice up to 14 days. Using a murine model of excisional wound, two full thickness excisional wounds were created on the back of the different Gulo-/- mice groups. Wound tissues were excised at day 7 and 14 post-wounding for analysis. Cell counts, immunohistochemistry, circulating free DNA, the expression of pro- and anti-inflammatory proteins were investigated. Additional in vitro experiments were carried out using human PMN (huPMNs), THP-1 monocyte/macrophage, and neonatal human dermal fibroblasts (HnDF).
Results: VitC deficiency delayed resolution of lung inflammation and led to exaggerated pro-inflammatory responses. PMNs from VitC deficient mice demonstrated increased autophagy, histone citrullination, and NFκB activation, while inhibiting apoptosis. VitC sufficiency/supplementation restored macrophage phenotype, as well as attenuated neutrophil extracellular trap (NET) formation. VitC attenuated pro-inflammatory responses in THP-1 macrophages. In wound healing model, wounds from VitC sufficient/AscA infused mice had lower gene expression of the pro-inflammatory mediators; higher expression of genes promoting wound healing and resolution. Exposure of HnDF to AscA increased their intracellular VitC levels; promoted fibroblast proliferation and induced expression of fibroblast self-renewal genes.
Conclusion: Our findings identify VitC as a novel regulator of PMN and macrophage responses. In wound healing, VitC favorably impacted the spatiotemporal expression of transcripts associated with early resolution of inflammation and tissue remodeling. Collectively, these results substantiate the protective notion of parenteral VitC and support its clinical use.
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Dual PI3K/mTOR Inhibition with BEZ235 Augments the Therapeutic Efficacy of Doxorubicin in Cancer without Influencing Cardiac FunctionDurrant, David E. 01 January 2015 (has links)
Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. DOX has been very effective at treating several different cancers and is still widely used today however its clinical use is limited due to cumulative dose dependent cardiotoxicity. Therefore, combination therapy targeting survival pathways is utilized to minimize the cumulative dose of DOX without ameliorating its anti-tumor effects.
We investigated the potential anti-cancer effects of combining the dual PI3K/mTOR inhibitor, BEZ235 (BEZ), with DOX in pancreatic, breast and other cancer cells lines as well as its associated effects on the heart. Our results showed that co-treatment of BEZ with DOX increased apoptosis in a manner that was dependent on inhibition of the AKT survival pathway. Moreover, BEZ co-treatment with DOX had additive effects towards cell viability while it significantly enhanced necrotic cell death compared to either drug alone. Furthermore, we observed that physiological concentrations of BEZ inhibited ABCB1 efflux resulting in increased intracellular accumulation of DOX, which led to increased DNA damage. In addition, BEZ in combination with gemcitabine (Gem) reduced cell proliferation but did not enhance necrosis or apoptosis. Treatment with BEZ and DOX in mice bearing tumor xenographs reduced tumor growth as compared to BEZ, DOX or Gem. Moreover, BEZ reduced DOX toxicity in rat myoblast cells and did not potentiate the effects of DOX in tumor-bearing mice. We propose that combining BEZ with DOX could be a novel therapeutic approach for the treatment of patients with cancer in the hope of improving the prognosis of this deadly disease.
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