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- Creators: School of Life Sciences
Description
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).
ContributorsRahman, Sanna (Author) / Sweazea, Karen (Thesis director) / Gonzales, Rayna (Committee member) / Li, Yu-Jing (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
Description
Alzheimer’s disease (AD) is a progressive cognitive and behavior disorder that is characterized by the deposition of extracellular Aβ plaques, intracellular neurofibrillary tangles, and neuroinflammation. Aβ is generated by cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1) and, subsequently, y- secretase. In recent years, there has been an increasing interest in studying and understanding inflammation as a therapeutic target for AD. Inflammation manifests in the brain in the form of activated microglia and astrocytes. These cells are able to release high levels of inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α). TNF-α is a major cytokine, which is involved in early inflammatory events and plays a role in the progression of AD pathology. There are currently no treatments that target chronic neuroinflammation. However, previous work in our laboratory with transgenic mice modeling AD suggested that the anti-cancer drug lenalidomide could lower neuroinflammation and slow AD progression, though the cellular and molecular mechanisms are yet to be elucidated. Here we hypothesized that lenalidomide can modulate TNF-α production in microglia and decrease amyloidogenesis. Using immortal cell lines mimicking several brain cell types, we discovered that lenalidomide is likely to decrease inflammation by modulating microglia cells rather than neurons or astrocytes. In addition, the drug may prevent the overexpression of BACE1 upon inflammation, thus blocking the overproduction of Aβ. If confirmed, these results could lead to a better understanding of how inflammation regulates Aβ synthesis and provide novel cellular and molecular therapeutic targets to control the progression AD.
ContributorsGujju, Manasa (Author) / DeCourt, Boris (Thesis director) / Olive, M. Foster (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Vascular inflammation plays a key role in the development and progression of cardiovascular disease. High fat diet has been associated with cardiovascular risk (1). Therefore, as poor nutrition and poor diet become more widespread, the number of people at risk to cardiovascular disease increases. We hypothesized that using the cancer drug lenalidomide would reverse the inflammation caused by high fat conditions. Human aortic vascular smooth muscle cells were used as an in vitro model to analyze the effect of lenalidomide on high fat diet induced inflammation. Palmitate, a saturated fatty acid was used to induce inflammation. Since lenalidomide has been shown to inhibit cytokine production and attenuate oxidative stress, we investigated whether lenalidomide alters select markers of vascular inflammation in vascular smooth muscle treated with high fat exposure using palmitate. These markers were cyclooxygenase-2 (COX-2) protein levels, TNF-α pro-inflammatory cytokine levels, and superoxide ions. Lenalidomide (5 µM) reversed COX-2 protein expression in cells exposed to high fat conditions (100 µM palmitate). In conclusion, high fat exposure elicits an inflammatory response in cultured primary human vascular smooth muscle, but this response appears to be independent of local cytokine or ROS production. Lenalidomide, although effective at reversing palmitate-induced COX-2, alone augments the pro-inflammatory mediators, COX-2 and TNF-α as well as promotes oxidative stress independent of high fat exposure in human vascular smooth muscle cells.
ContributorsBartel, Robyn Katherine (Author) / Sweazea, Karen (Thesis director) / DeCourt, Boris (Committee member) / Gonzales, Rayna (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
Duchenne Muscular Dystrophy (DMD) is a muscular degenerative disease characterized by striated membrane instability that stimulates continuous cycles of muscle repair. Chronic activation of the innate immune response necessary for muscle repair leads to a pathological accumulation of fibrotic materials that disrupt muscle function. During healthy tissue repair, a balance between pro-inflammatory macrophage (M1) and anti-inflammatory macrophage (M2) promotes clearance of necrotic fibers (myolysis) followed by tissue repair. This is regulated by an intricate feedback loop between muscle, neutrophils and macrophages mediated by Th1 and Th2 cytokines and chemokines. During chronic inflammation, there is an imbalance in an M2 species that produces high levels of extracellular matrix that leads to fibrosis. Finding treatments that ameliorate fibrosis are essential to limiting the muscle pathology that reduces ambulation of DMD patients. Previous studies have shown that Mohawk, (Mkx) a homeobox transcription factor, is essential for the initiation of the inflammation response during acute muscle injury. This study aims to examine whether Mkx regulates inflammation during chronic damage associated with muscular dystrophy. The mdx mouse is a well-studied mouse model that recapitulates muscle necrosis, chronic inflammatory response and fibrosis associated with muscular dystrophy. Utilizing quantitative RT-PCR and histological analysis, the diaphragms and Quadriceps of adult Mkx-/-/mdx and Mkx+/+/mdx mice were analyzed at three critical time points (4 weeks, 3 months and 7 months). In contrast to what was anticipated, there was evidence of increased muscle damage in the absence of Mkx. There was a consistent reduction in the diameter of muscle fibers found in both types of tissue in Mkx-/-/mdx versus Mkx+/+/mdx mice without a difference in the number of fibers with centralized nuclei at 4 weeks and 1 year between the two genotypes, suggesting that the Mkx mutation influences the maturation of fibers forming in response to muscle damage. Fibrosis was higher in the diaphragm of the Mkx-/-/mdx mice at 4 weeks and 3 months, while at1 year there did not appear to be a difference. Overall, the results predict that the absence of Mkx exacerbates the instability of muscle fibers in the mdx mouse. Future studies will be needed to understand the relationship between Mkx and the dystrophin gene.
ContributorsMasson, Samantha Ashley (Author) / Rawls, Alan (Thesis director) / Wilson-Rawls, Jeanne (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
In females, critical hormonal shifts occur during puberty, menstruation, pregnancy, and <br/>menopause. The fluctuating ovarian hormone levels across a woman’s lifespan likely contribute <br/>to inflammatory responses driven by the immune system, which is regulated by a variety of <br/>physiological pathways and microbiological cues. Pregnancy in particular results in drastic <br/>changes in circulating hormone profiles, and involves a variety of physiological changes, <br/>including inflammatory responses of the immune system. There is evidence that these effects are <br/>mediated, in part, by the significant hormone fluctuations that characterize pregnancy and <br/>postpartum periods. This thesis highlights and synthesizes important physiological changes <br/>associated with pregnancy, and their potential implications on cognitive and brain aging in <br/>women. A tertiary model of cognition is presented depicting interactions between hormonal <br/>history, reproductive history, and immune functions. This research is important to create a better <br/>understanding of women’s health and enhance medical care for women throughout pregnancy <br/>and across reproductive hormone shifts across the lifespan.
ContributorsLogan-Robledo, Santiago Rodrigo (Author) / Bimonte-Nelson, Heather A. (Thesis director) / Koebele, Stephanie V. (Committee member) / Simard, Alain (Committee member) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Genistein, a compound found in soy that functions as a phytoestrogen, has been found to play a role in the body’s inflammatory response. By suppressing the expression of inflammatory genes and inhibiting tumor cell growth, genistein is thought to have both anti-inflammatory and cancer fighting properties. This study seeks to demonstrate genistein’s potential to mitigate the negative consequences of consuming a high fat diet specifically as it relates to increased inflammation and changes in the gut microbiome. Using an animal model, the study tested whether supplementing the mice’s diet with soy derived genistein would affect their serum IL-6 levels and the way in which their gut microbiomes responded to their high fat consumption. It was presumed that genistein supplementation would result in a less significant shift from the biomarkers tested in the control group and reduce the impact of the high fat diet. It was also hypothesized that consumption of the high fat diet would raise IL-6 levels and increase the presence of harmful bacteria in the test subjects.
ContributorsPettit, Gabrielle Sofia (Author) / Whisner, Dr. Corrie (Thesis director) / Al-Nakkash, Dr. Layla (Committee member) / Ortega Santos, Carmen (Committee member) / Dean, W.P. Carey School of Business (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Long chain ω-3PUFA fatty acid supplementation in animal models of diet-induced-obesity has consistently shown to improve insulin sensitivity. The same is not always reported in studies with obese, insulin resistant (IR) subjects. We studied whether high-dose ω-3PUFA supplementation for 3 months improves insulin sensitivity and adipose tissue (AT) inflammation in severely obese, IR subjects. Thirteen obese, IR subjects underwent 80 mU/m 2· min euglycemic-hyperinsulinemic clamp with subcutaneous (Sc) AT biopsy before and after three months of ω-3PUFA (DHA & EPA, 4g/daily) supplementation. Cytoadipokine plasma profiles were assessed before and after ω-3PUFA. AT-specific inflammatory gene expression was evaluated on Sc fat biopsies. Microarray analysis was performed on the fat biopsies collected during the program. Palmitic and stearic acid plasma levels were significantly reduced (P<0.05) after ω-3PUFA. Gene expression of pro-inflammatory markers and adipokines were improved after ω-3PUFA (P<0.05). Systemic inflammation was decreased after ω-3PUFA, as shown by cytokine assessment (P<0.05). These changes were associated with a 25% increase in insulin-stimulated glucose disposal (4.67±0.62mg/kg ffm•min vs 5.87±0.79mg/kg ffm•min) despite no change in
body weight. Microarray analysis identified 53 probe sets significantly altered post- ω-3PUFA, with APOE being one of the most upregulated genes. High dose of long chain ω-3PUFA supplementation modulates significant changes in plasma fatty acid profile, AT and systemic inflammation. These findings associate with significant improvement of insulin-stimulated glucose disposal. Unbiased microarray analysis of Sc fat biopsy identified APOE as the most differentially regulated gene after ω-3PUFA 22 supplementation. We speculate that ω-3PUFA increases macrophage-derived APOE mRNA levels with anti-inflammatory properties.
body weight. Microarray analysis identified 53 probe sets significantly altered post- ω-3PUFA, with APOE being one of the most upregulated genes. High dose of long chain ω-3PUFA supplementation modulates significant changes in plasma fatty acid profile, AT and systemic inflammation. These findings associate with significant improvement of insulin-stimulated glucose disposal. Unbiased microarray analysis of Sc fat biopsy identified APOE as the most differentially regulated gene after ω-3PUFA 22 supplementation. We speculate that ω-3PUFA increases macrophage-derived APOE mRNA levels with anti-inflammatory properties.
ContributorsRau, Cassandra (Author) / Kastanos, Christos (Thesis director) / De Filippis, Eleanna (Committee member) / School of Life Sciences (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Spinal cord injury (SCI) is characterized by severe tissue damage and extreme inflammation involving prolonged invasion of inflammatory cells. Following SCI, there is long-term disability and treatment is limited. We previously demonstrated that sustained subdural infusion of the anti-inflammatory protein, Serp-1, significantly improved functional recovery and reduced inflammatory cell invasion following SCI. We hypothesized that sustained delivery of immune-modulating Serp-1 using a chitosan-collagen hydrogel would demonstrate therapeutic benefits and reduce damage following forceps crush-induced SCI. Following the dorsal column crush injury, we observed that for rats treated with high-dose (100 μg/50 μL) Serp-1, functional motor improvement was observed. There was also a more pronounced neuroprotective effect in comparison to the low-dose (10 μg/50 μL) treatment, which was likely attributable to suppression of local inflammation. Conversely, sustained infusion of low-dose Serp-1 CCH did not enhance recovery. Thus, sustained delivery of immune-modulating Serp-1 through a chitosan-collagen hydrogel exhibits neuroprotective potential following acute SCI.
ContributorsSchutz, Lauren (Author) / Lucas, Alexandra R. (Thesis director) / Yaron, Jordan R. (Committee member) / Karis, John P. (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Innate immunity is regulated at both the transcriptional and epigenetic level. However, the complex epigenetic regulation of inflammatory responses in innate immunity remains to be fully characterized. The objective was to characterize the function of a NAD+-dependent lysine deacetylase SIRT7 in regulating polarization and inflammatory responses in bone marrow derived macrophages. In primary bone marrow derived macrophages, LPS induced significant pro-inflammatory responses. LysM-Cre induced SIRT7 knockout (KO) male macrophages exhibited enhanced inflammatory responses compared to WT macrophages. Interestingly, we did not observe a similar trend in female cells. In fact, loss of SIRT7 in female macrophages induced weaker proinflammatory responses when challenged with LPS. As an epigenetic co-factor, SIRT7 is known to interact with multiple inflammation related nuclear hormone receptors, such as glucocorticoid receptor (GR), and vitamin D receptor (VDR). Therefore, we examined whether the glucocorticoid or vitamin D induced anti-inflammatory responses are affected in SIRT7 KO macrophages. Preliminary results suggest that both glucocorticoid and vitamin D are still able to inhibit LPS-induced inflammatory responses in SIRT7 KO cells. Future studies using RNA-seq and epigenetic assays will be needed to determine the sex-specific function of SIRT7 in macrophage activation.
ContributorsMikkilineni, Sneha (Author) / Katsanos, Christos (Thesis director) / Wei, Zong (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2022-05
Description
This thesis is a retrospective study analyzing data from patient implanted cardiac devices in order to determine the effect of SARS-CoV-2 on cardiac arrhythmias. This study is also the first, to the knowledge of the researchers, in which a cohort of undifferentiated hospitalized and non-hospitalized COVID patients were studied using data from cardiac implanted devices. The results from this study has shown that SARS-CoV-2 leads to statistically significant increases in arrhythmic burden, in particular increased overall arrhythmic episodes, increased VT episodes, increased AT Burden percent, and increased SVT Average Ventricular Rate, and a statistically significant decrease in VT Average Ventricular Rate.
ContributorsGomez, Mia (Author) / Ahmed, Aamina (Co-author) / Ross, Heather (Thesis director) / Kleinhans, Amy (Committee member) / Doshi, Rahul (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2022-05