Matching Items (21)

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Lenalidomide modulates high fat diet induced inflammation in human vascular smooth muscle cells

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

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.

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Date Created
  • 2017-12

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Upregulation of Adipose Tissue APOE Expression by ω3PUFA Supplmentation Associates with Decreased Plasma FFA Levels and Improves Insulin Sensitivity in Obese Subjects: A Reflection of My Time Working in Research and Where I Am Now

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

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.

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Date Created
  • 2020-05

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MKX Regulation of Macrophage Recruitment during Chronic Muscle Damage Associated with Muscular Dystrophy

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

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.

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Date Created
  • 2016-05

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Molecular Analysis of Lenalidomide Modulation of Alzheimer's Disease Pathology

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

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.

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Date Created
  • 2018-05

Anti-Inflammatory Cookbook for Diabetic Patients

Description

The purpose of this cookbook is to provide pre-diabetic, type 1 and type 2 diabetics with a foundation of recipes. These recipes have been created with the intent of regulating

The purpose of this cookbook is to provide pre-diabetic, type 1 and type 2 diabetics with a foundation of recipes. These recipes have been created with the intent of regulating inflammation which can be caused by such metabolic abnormalities. I want to educate patients who suffer from these conditions that there are several ingredients that work alongside their condition rather than feeling that they are limited to foods and recipes. I want to increase patients moral and self-efficacy to explore and work with new ingredients. These series of recipes should be used as a guide to trying new foods however patients should know that they are able to add their own ingredients that are suitable to their liking or condition.

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Date Created
  • 2018-12

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Relationships Between the Inflammatory Responses of the Immune System and Periods of Critical Hormonal Shifts in Females Across the Lifespan: A Pregnancy Review

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

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.

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Date Created
  • 2021-05

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Investigating the Effect of a Hyaluronic Acid-Laminin Hydrogel on Inflammation After Traumatic Brain Injury

Description

Traumatic brain injury (TBI) is a leading cause of death in individuals under the age of 45, resulting in over 50,000 deaths each year. Over 80,000 TBI patients report long-term

Traumatic brain injury (TBI) is a leading cause of death in individuals under the age of 45, resulting in over 50,000 deaths each year. Over 80,000 TBI patients report long-term deficits consisting of motor or cognitive dysfunctions due to TBI pathophysiology. The biochemical secondary injury triggers a harmful inflammatory cascade, gliosis, and astrocyte activation surrounding the injury lesion, and no current treatments exist to alleviate these underlying pathologies. In order to mitigate the negative inflammatory effects of the secondary injury, we created a hydrogel comprised of hyaluronic acid (HA) and laminin, and we hypothesized that the anti-inflammatory properties of HA will decrease astrocyte activation and inflammation after TBI. C57/BL6 mice were subjected to mild-to-moderate CCI. Three days following injury, mice were treated with injection of vehicle or HA-Laminin hydrogel. Mice were sacrificed at three and seven days post injection and analyzed for astrocyte and inflammatory responses. In mice treated with vehicle injections, astrocyte activation was significantly increased at three days post-transplantation in the injured cortex and injury lesion. However, mice treated with the HA-Laminin hydrogel experienced significantly reduced acute astrocyte activation at the injury site three days post transplantation. Interestingly, there were no significant differences in astrocyte activation at seven days post treatment in either group. Although the microglial and macrophage response remains to be investigated, our data suggest that the HA-Laminin hydrogel demonstrates potential for TBI therapeutics targeting inflammation, including acute modulation of the astrocyte, microglia, and macrophage response to TBI.

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Date Created
  • 2016-05

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Microglial activation in the amygdala following traumatic brain injury

Description

Neuroinflammation is an important secondary injury response occurring after traumatic brain injury (TBI). Anxiety-like disorders are commonly exacerbated after TBI and are mediated through the amygdala; however, the amygdala remains

Neuroinflammation is an important secondary injury response occurring after traumatic brain injury (TBI). Anxiety-like disorders are commonly exacerbated after TBI and are mediated through the amygdala; however, the amygdala remains understudied despite its important contribution in processing emotional and stressful stimuli. Therefore, we wanted to study neuroinflammation after experimental TBI using midline fluid percussion in rodent models. We assessed microglia morphology over time post-injury in two circuit related nuclei of the amygdala, the basolateral amygdala (BLA) and central amygdala of the nucleus (CeA), using skeletal analysis. We also looked at silver staining and glial fibrillary acidic protein (GFAP) to evaluate the role of neuropathology and astrocytosis to evaluate for neuroinflammation in the amygdala. We hypothesized that experimental diffuse TBI leads to microglial activation in the BLA-CeA circuitry over time post-injury due to changes in microglial morphology and increased astrocytosis in the absence of neuropathology. Microglial cell count was found to decrease in the BLA at 1 DPI before returning to sham levels by 28 DPI. No change was found in the CeA. Microglial ramification (process length/cell and endpoints/cell) was found to decrease at 1DPI compared to sham in the CeA, but not in the BLA. Silver staining and GFAP immunoreactivity did not find any evidence of neurodegeneration or activated astrocytes in the respectively. Together, these data indicate that diffuse TBI does not necessarily lead to the same microglial response in the amygdala nuclei, although an alternative mechanism for a neuroinflammatory response in the CeA likely contributes to the widespread neuronal and circuit dysfunction that occurs after TBI.

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Date Created
  • 2018-05

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Understanding the Role of the Repair Response during Localized Tissue Damage in D. melanogaster

Description

Proper developmental fidelity ensures uninterrupted progression towards sexual maturity and species longevity. However, early development, the time-frame spanning infancy through adolescence, is a fragile state since organisms have limited mobility

Proper developmental fidelity ensures uninterrupted progression towards sexual maturity and species longevity. However, early development, the time-frame spanning infancy through adolescence, is a fragile state since organisms have limited mobility and responsiveness towards their environment. Previous studies have shown that damage during development leads to an onset of developmental delay which is proportional to the extent of damage accrued by the organism. In contrast, damage sustained in older organisms does not delay development in response to tissue damage. In the fruit fly, Drosophila melanogaster, damage to wing precursor tissues is associated with developmental retardation if damage is sustained in young larvae. No developmental delay is observed when damage is inflicted closer to pupariation time. Here we use microarray analysis to characterize the genomic response to injury in Drosophila melanogaster in young and old larvae. We also begin to develop tools to examine in more detail, the role that the neurotransmitter dopamine might play in mediating injury-induced developmental delays.

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Date Created
  • 2016-05

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Hepatic inflammatory response following high fat diet in adolescent male Sprague-Dawley rats

Description

There has long been a link tied between obesity and such pathological conditions as nonalcoholic fatty liver disease and type two diabetes. Studies have shown that feeding rats a diet

There has long been a link tied between obesity and such pathological conditions as nonalcoholic fatty liver disease and type two diabetes. Studies have shown that feeding rats a diet high in fat results in hepatic steatosis and steatohepatitis. Using a novel short term diet of six weeks with male adolescent Sprague-Dawley rats, our laboratory sought to investigate the early effects of high fat intake on the liver. Prior findings in our laboratory found that a high fat diet (HFD) leads to nonalcoholic fatty liver disease as well as other symptoms of metabolic syndrome. This study hypothesized that rats fed a 60% HFD for 6 weeks, unlike a high sucrose or standard chow diet, would have an elevated expression of pro-inflammatory cytokines associated with steatohepatitis. TNF-α, TLR4 and XBP1 were chosen for their link to hepatic inflammation. The results of this study found that contrary to the hypothesis, the high fat diet did not induce significant changes in the expression of any inflammatory marker in comparison to a high sucrose or control chow diet.

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Date Created
  • 2015-05