Obesity, insulin resistance, and type 2 diabetes mellitus are associated with diabetic cognopathy. This study tested the hypothesis that neurovascular unit(s) (NVU) within cerebral cortical gray matter regions may depict abnormal cellular... more
Obesity, insulin resistance, and type 2 diabetes mellitus are associated with diabetic cognopathy. This study tested the hypothesis that neurovascular unit(s) (NVU) within cerebral cortical gray matter regions may depict abnormal cellular remodeling. The monogenic (Leprdb) female diabetic db/db [BKS.CgDock7m +/+Leprdb/J] (DBC) mouse model was utilized for this ultrastructural study. Upon sacrifice (20 weeks), left-brain hemispheres of the DBC and age-matched nondiabetic control C57BL/KsJ (CKC) mice were immediately immersion-fixed. We observed an attenuation/loss of endothelial blood–brain barrier tight/adherens junctions and pericytes, thickened basement membranes, adherent red and white blood cells, neurovascular unit microbleeds and pathologic remodeling of protoplasmic astrocytes. In this second of a three-part series, we focus on the observational ultrastructural remodeling of microglia and mitochondria in relation to the NVU in leptin receptor deficient DBC models. This study ...
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Type 2 diabetes mellitus is a multifactorial disease with polygenic and environmental stressors resulting in multiple metabolic toxicities and islet oxidative stress. We have integrated the role of the islet renin-angiotensin system (RAS)... more
Type 2 diabetes mellitus is a multifactorial disease with polygenic and environmental stressors resulting in multiple metabolic toxicities and islet oxidative stress. We have integrated the role of the islet renin-angiotensin system (RAS) in the pathogenesis of early islet fibrosis utilizing the transgenic (mRen2)27 rodent model of hypertension and tissue RAS overexpression. The Ren2 pancreatic islet tissue was evaluated with transmission electron microscopy to study both early cellular and extracellular matrix remodeling. Four 9- to 10-week-old male Ren2 untreated models and four Sprague Dawley sex and age matched controls were used. Ultrastructural study to compare pancreatic islet tissue. Only qualitative and observational transmission electron microscopy findings are reported. Major remodeling differences in the Ren2 model were found to be located within the islet exocrine interface, including deposition of early fibrillar-banded collagen (fibrosis) and cellular remodeling of th...
Research Interests: Transmission Electron Microscopy, Oxidative Stress, Extracellular Matrix, Blood Glucose, Hypertension, and 15 moreBlood Pressure, Renin Angiotensin Aldosterone System, Animals, Male, Pericytes, Fibrosis, Clinical Sciences, Rats, Body Weight, Rat Model, Cell communication, Type 2 Diabetes Mellitus, Angiotensin II, islets of Langerhans, and Pancreatic islets
Amyloid deposits within the islet of the pancreas have been known for a century. In 1987, the islet amyloid precursor polypeptide (IAPP) amylin (a 37 amino acid) was discovered. Recently there has been an explosion of amylin's... more
Amyloid deposits within the islet of the pancreas have been known for a century. In 1987, the islet amyloid precursor polypeptide (IAPP) amylin (a 37 amino acid) was discovered. Recently there has been an explosion of amylin's importance in the development of type 2 diabetes mellitus (T2DM). This review is intended to share what is understood about amylin derived amyloid and the role it plays in T2DM. Whether islet amyloid is an epiphenomenona, a tombstone, or a trigger it leaves an indelible footprint in greater that 70% of the patients with T2DM. There is current data supporting the damaging role of intermediate sized toxic amyloid particles to the beta cell resulting in a beta cell defect which contributes to a relative deficiency or loss of insulin secretion. Within the islet there is an intense redox stress which may be associated with the unfolding of amylin's native secondary structure compounding its amyloidogenic properties. In addition to the beta cell defect there...
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Remodeling of the endocrine pancreas, caused by the deleterious effects of amylin as it is co-synthesized, co-packaged, and co-secreted with insulin, gives clinicians and researchers cause to ponder. A literature search was done, and... more
Remodeling of the endocrine pancreas, caused by the deleterious effects of amylin as it is co-synthesized, co-packaged, and co-secreted with insulin, gives clinicians and researchers cause to ponder. A literature search was done, and relevant publications and texts on amylin and islet amyloid polypeptide (IAPP) were reviewed. The mechanisms and clinical consequences attributed to the remodeling of the endocrine pancreas, along with proposals for reevaluating the methods of treating patients who have type 2 diabetes are illustrated and discussed. In addition to controlling the devastating effects ofglucotoxicity, lipotoxicity, and hypertension, we should consider the newer hypoglycemic agents with regard to their effects on the remodeling of the endocrine pancreas. This remodeling results in structural and subsequent functional changes, causing continued elevations of hemoglobin A1C. Studies are indicated to determine whether amylin (IAPP) may be implicated in the remodeling of the a...
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Redox stress, reactive oxygen species, reactive nitrogen species, and oxygen free radicals ("toxic oxygen") are increasingly being reported as important cellular signaling mechanisms. It has been known for over a hundred years... more
Redox stress, reactive oxygen species, reactive nitrogen species, and oxygen free radicals ("toxic oxygen") are increasingly being reported as important cellular signaling mechanisms. It has been known for over a hundred years that type 2 diabetes mellitus is a manifold disease, not only in its etiology, but also in its associated manifold toxicities and multiple complications of the diabetic opathies. The presence of islet amyloid has also been described in association with type 2 diabetes mellitus for a century. This review will attempt to remain focused on the relationship between redox stress, the reactive oxygen species and the reactive nitrogen species in the islet, and how these interact with the multiplicative effect of the toxicities of insulin resistance, metabolic syndrome, amylin (hyperamylinemia), amylin derived islet amyloid and type 2 diabetes mellitus. Redox sensitive cellular signaling systems play an important role in the development, progressive nature (...
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Metabolic syndrome, insulin resistance, prediabetes, and overt type 2 diabetes mellitus are associated with an accelerated atherosclerosis (atheroscleropathy). This quartet is also associated with multiple metabolic toxicities resulting... more
Metabolic syndrome, insulin resistance, prediabetes, and overt type 2 diabetes mellitus are associated with an accelerated atherosclerosis (atheroscleropathy). This quartet is also associated with multiple metabolic toxicities resulting in the production of reactive oxygen species. The redox stress associated with these reactive oxygen species contribute to the development, progression, and the final fate of the arterial vessel wall in prediabetic and diabetic atheroscleropathy. The prevention of morbidity and mortality of these intersecting metabolic diseases can be approached through comprehensive global risk reduction.
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Over the past three decades, we have witnessed an improvement of survival in those patients with the trio of metabolic syndrome, prediabetes, and overt type 2 diabetes mellitus. Revolutionary changes in technology and an improved... more
Over the past three decades, we have witnessed an improvement of survival in those patients with the trio of metabolic syndrome, prediabetes, and overt type 2 diabetes mellitus. Revolutionary changes in technology and an improved understanding of the mechanisms involved in acute coronary syndromes have resulted in this observation. Due to advances in coronary care, we are currently at a crossroads, wherein, the mortality from acute cardiovascular events have been declining and the mortality associated with this trio has been increasing due to congestive heart failure (CHF). This intersect between the two causes of death represent a challenge for the future, as the numbers of patients with this deadly trio are undergoing exponential growth not only in the U.S. but also abroad as more countries undergo urbanization and adopt a western-type lifestyle of over nutrition and under exercise. Thus, we live to die another day. There are multiple metabolic toxicities in this toxic trio, which...
Research Interests: Obesity, Oxidative Stress, Extracellular Matrix, Heart Failure, Insulin Resistance, and 9 moreHumans, Reactive Oxygen Species, Nitric Oxide Synthase, Coronary heart disease, Type 2 Diabetes Mellitus, Oxidation-Reduction, Matrix Metalloproteinase, Metabolic Syndrome X, and Medical and Health Sciences
We have described a 35-year-old man with M pneumoniae pneumonia who had severe hemolytic anemia that appeared to respond well to high-dose corticosteroid therapy. Whether corticosteroids have value in decreasing the severity of hemolytic... more
We have described a 35-year-old man with M pneumoniae pneumonia who had severe hemolytic anemia that appeared to respond well to high-dose corticosteroid therapy. Whether corticosteroids have value in decreasing the severity of hemolytic anemia due to cold agglutinin and other protean extrapulmonary manifestations with M pneumoniae infection needs further controlled study. Our experience suggests that corticosteroids may be beneficial.
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Human heart matrix metalloproteinases (MMP) are present in the latent form and activated in the failing heart. To examine whether the MMP activation was due to gene and/or post-translational modification, we analysed tissue from 10... more
Human heart matrix metalloproteinases (MMP) are present in the latent form and activated in the failing heart. To examine whether the MMP activation was due to gene and/or post-translational modification, we analysed tissue from 10 explanted hearts due to coronary heart disease (CHD) and five normal left atrial tissue from donor hearts. Based on in situ immunolabeling MMP-1, tissue inhibitor of metalloproteinase (TIMP-1) and collagen were co-localized in the interstitial tissue. Based on sandwich ELISA, TIMP-1 and MMP-1 levels were 37 +/- 8 ng/mg and 9 +/- 2 ng/mg in normal tissue (P < 0.01) and 12 +/- 5 ng/mg and 75 +/- 11 ng/mg in the infarcted tissue (P < 0.01), respectively. These levels suggest repression of TIMP-1 during myocardial infarction. Northern blot analysis indicated that the mRNAs for both MMP-1 and TIMP-1 were increased three-to four-fold in the infarcted tissue as compared to the normal tissue, suggesting upregulation of MMP and TIMP gene transcription following infarction. Based on in situ tissue overlay zymography, the generalized activation of MMP was observed in the interstitium of the infarcted heart. Zymographic and immunoblot analysis demonstrated the presence of one band at 66 kDa (MMP-2) in the normal tissue and several bands at 92 (MMP-9), 66 (MMP-2) and 54 kDa (MMP-1) in the infarcted heart. Incubation of the zymographic gel with metal chelator (phenanthroline) abolished bands at 92 kDa and 54 kDa but phenanthroline did not abolish the lytic band at 66 kDa. The 66 kDa band was completely abolished in the presence of phenanthroline and phenyl methyl sulfonyl fluoride (PMSF). 2D-zymographic analysis suggested that the lytic band at 66 kDa was a mixture of two neutral proteinases with different isoelectric point. Plasminogen/gelatin zymographic analysis of infarcted tissue extract indicated that the band at 66 kDa was plasmin generated due to increased expression of tissue plasminogen activator (tPA) activity. In relation to increased expression of gelatinase in the infarcted tissue, our data suggest that gelatinase B (92 kDa) is induced in diseased heart. The results suggest that tPA converts plasminogen to plasmin which, in turn, activates MMPs and inactivates TIMP-1 post-translationally following ischemic cardiomyopathy.
Research Interests: Gene expression, Extracellular Matrix, Heart Failure, Molecular, Humans, and 10 moreCollagen, Post-Transcriptional Gene Regulation, Myocardial Infarction, Coronary heart disease, Ischemic Heart Disease, Cardiomyopathies, Tissue Plasminogen Activator, Plasminogen Activator, Matrix Metalloproteinase, and Cardiovascular medicine and haematology
Research Interests: Electron Microscopy, Oxidative Stress, Cell line, Hypertension, Reactive Oxygen Species, and 15 moreMice, Blood Pressure, Renin Angiotensin Aldosterone System, Animals, Male, NADPH oxidase, Clinical Sciences, Rats, Isoenzymes, Biological markers, Albuminuria, Angiotensin II, Podocytes, nicotinamide adenine dinucleotide phosphate, and Cardiovascular medicine and haematology
TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5–8 g of glomerular filtered... more
TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5–8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT1R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6–7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-β-d-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and ×60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systol...
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The statistical association between endurance exercise capacity and cardiovascular disease suggests that impaired aerobic metabolism underlies the cardiovascular disease risk in men and women. To explore this connection, we applied... more
The statistical association between endurance exercise capacity and cardiovascular disease suggests that impaired aerobic metabolism underlies the cardiovascular disease risk in men and women. To explore this connection, we applied divergent artificial selection in rats to develop low-capacity runner (LCR) and high-capacity runner (HCR) rats and found that disease risks segregated strongly with low running capacity. Here, we tested if inborn low aerobic capacity promotes differential sex-related cardiovascular effects. Compared with HCR males (HCR-M), LCR males (LCR-M) were overweight by 34% and had heavier retroperitoneal, epididymal, and omental fat pads; LCR females (LCR-F) were 20% heavier than HCR females (HCR-F), and their retroperitoneal, but not perireproductive or omental, fat pads were heavier as well. Unlike HCR-M, blood pressure was elevated in LCR-M, and this was accompanied by left ventricular (LV) hypertrophy. Like HCR-F, LCR-F exhibited normal blood pressure and LV w...
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The transgenic (mRen2)27 (Ren2) rat overexpresses mouse renin in extrarenal tissues, causing increased local synthesis of ANG II, oxidative stress, and hypertension. However, little is known about the role of oxidative stress induced by... more
The transgenic (mRen2)27 (Ren2) rat overexpresses mouse renin in extrarenal tissues, causing increased local synthesis of ANG II, oxidative stress, and hypertension. However, little is known about the role of oxidative stress induced by the tissue renin-angiotensin system (RAS) as a contributing factor in pulmonary hypertension (PH). Using male Ren2 rats, we test the hypothesis that lung tissue RAS overexpression and resultant oxidative stress contribute to PH and pulmonary vascular remodeling. Mean arterial pressure (MAP), right ventricular systolic pressure (RVSP), and wall thickness of small pulmonary arteries (PA), as well as intrapulmonary NADPH oxidase activity and subunit protein expression and reactive oxygen species (ROS), were compared in age-matched Ren2 and Sprague-Dawley (SD) rats pretreated with the SOD/catalase mimetic tempol for 21 days. In placebo-treated Ren2 rats, MAP and RVSP, as well as intrapulmonary NADPH oxidase activity and subunits (Nox2, p22phox, and Rac-1...
Research Interests: Physiology, Oxidative Stress, Pulmonary Hypertension, Antioxidants, Reactive Oxygen Species, and 15 moreMice, Blood Pressure, Animals, Male, Catalase, American, Medical Physiology, Lung, NADPH oxidase, Rats, Cross Section, Protein Expression, Left ventricular hypertrophy, Pulmonary Artery, and Mean Arterial Pressure
Rac1 is a Rho-family small GTP-ase, when activated is pivotal in NAD(P)H oxidase (NOX) activation and generation of reactive oxygen species (ROS). Evidence links Rac1 activation to receptor-mediated albumin endocytosis in the proximal... more
Rac1 is a Rho-family small GTP-ase, when activated is pivotal in NAD(P)H oxidase (NOX) activation and generation of reactive oxygen species (ROS). Evidence links Rac1 activation to receptor-mediated albumin endocytosis in the proximal tubule cell (PTC). Thus in states of albumin overload, Rac1 activation could lead to NOX activation and ROS formation in the PTC. Furthermore, accumulating evidence supports that HMG-CoA reductase inhibition may reduce oxidative stress and albuminuria. To investigate the role of HMG-CoA reductase inhibition of Rac1 and oxidative stress we used the opossum kidney PTC. ROS generation in the PTC was confirmed using oxidative fluorescent dihydroethidium staining. We observed time-dependent increases in NOX activity with bovine serum albumin (albumin) stimulation (500 microg/dl, maximum at 20 min, p < 0.05) that was inhibited in a concentration-dependent manner with the HMG-CoA reductase inhibitor rosuvastatin (1 microM, p < 0.05). Additionally, the Rac1 inhibitor NSC23766 (100 ng/ml) attenuated albumin activation of NOX. Western blot analysis confirmed Rac1 translocation to plasma membrane in the PTC following albumin stimulation and subsequent inhibition by rosuvastatin and NSC23766. These data demonstrate that albumin-mediated increases in NOX activity and ROS in PTC are reversed by inhibition of Rac1 signaling with the use of rosuvastatin.
Research Interests: Oxidative Stress, Confocal Microscopy, Western blotting, Signal Transduction, Reactive Oxygen Species, and 15 moreEndocytosis, Animals, American, NADPH oxidase, Clinical Sciences, Time Dependent, Western blot, Albuminuria, Bovine Serum Albumin, Opossums, Proximal Tubule, Plasma Membrane, Cell Membrane, HMG CoA Reductase, and Sulfonamides
: Viremia in coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is often only discussed in passing and there are very few references detailing its structural mechanisms. In... more
: Viremia in coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is often only discussed in passing and there are very few references detailing its structural mechanisms. In addition to viremia in the classic closed cardiovascular system, the lymphatic system is discussed in relation to a possible “lympho-viremia”. The cells that comprise each of these separate but interacting systems will be examined and include endothelial cells, erythrocytes, leukocytes (monocytes/monocyte-derived macrophages and resident tissue macrophages) (lymphocytes) (neutrophils) and thrombocytes -platelets. The SARS-CoV-2 virus has been identified in multiple extrapulmonary target organs at autopsy in those with severe COVID-19 requiring intensive care. Vulnerable COVID-19 patients may suffer from multiple storms including viral/virion storm, redox storm, cytokine storm and thrombo-embolic storm. Therefore, it is important that the possible mechanisms of viremia be explored in greater detail and how these mechanisms might affect intravascular blood components, extracellular tissue interstitium and organ structural remodeling and function. While the co-morbidity of T2DM does not increase the risk of acquiring COVID-19, it is commonly accepted that T2DM increases the risk for COVID-19 admissions to hospitals, assisted ventilation, morbidity and mortality. Importantly, the co-existence of T2DM and COVID-19 may have synergistic detrimental outcomes.
Type 2 diabetes is associated with diabetic cognopathy. Anti-hyperglycemic sodium glucose transporter 2 (SGLT2) inhibitors have shown promise in reducing cognitive impairment in mice with type 2 diabetes mellitus. We recently described... more
Type 2 diabetes is associated with diabetic cognopathy. Anti-hyperglycemic sodium glucose transporter 2 (SGLT2) inhibitors have shown promise in reducing cognitive impairment in mice with type 2 diabetes mellitus. We recently described marked ultrastructural (US) remodeling of the neurovascular unit (NVU) in type 2 diabetic db/db female mice. Herein, we tested whether the SGLT-2 inhibitor, empagliflozin (EMPA), protects the NVU from abnormal remodeling in cortical gray and subcortical white matter. Ten-week-old female wild-type and db/db mice were divided into lean controls (CKC, n = 3), untreated db/db (DBC, n = 3), and EMPA-treated db/db (DBE, n = 3). Empagliflozin was added to mouse chow to deliver 10 mg kg−1 day−1 and fed for ten weeks, initiated at 10 weeks of age. Brains from 20-week-old mice were immediately immersion fixed for transmission electron microscopic study. Compared to CKC, DBC exhibited US abnormalities characterized by mural endothelial cell tight and adherens ju...
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Research Interests:
Consumption of a high-fat, high-fructose diet [Western diet (WD)] promotes vascular stiffness, a critical factor in the development of cardiovascular disease (CVD). Obese and diabetic women exhibit greater arterial stiffness than men,... more
Consumption of a high-fat, high-fructose diet [Western diet (WD)] promotes vascular stiffness, a critical factor in the development of cardiovascular disease (CVD). Obese and diabetic women exhibit greater arterial stiffness than men, which contributes to the increased incidence of CVD in these women. Furthermore, high-fructose diets result in elevated plasma concentrations of uric acid via xanthine oxidase (XO) activation, and uric acid elevation is also associated with increased vascular stiffness. However, the mechanisms by which increased xanthine oxidase activity and uric acid contribute to vascular stiffness in obese females remain to be fully uncovered. Accordingly, we examined the impact of XO inhibition on endothelial function and vascular stiffness in female C57BL/6J mice fed a WD or regular chow for 16 wk. WD feeding resulted in increased arterial stiffness, measured by atomic force microscopy in aortic explants (16.19 ± 1.72 vs. 5.21 ± 0.54 kPa, P < 0.05), as well as ...
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Diastolic dysfunction (DD), a hallmark of obesity and primary defect in heart failure with preserved ejection fraction, is a predictor of future cardiovascular events. We previously reported that linagliptin, a dipeptidyl peptidase-4... more
Diastolic dysfunction (DD), a hallmark of obesity and primary defect in heart failure with preserved ejection fraction, is a predictor of future cardiovascular events. We previously reported that linagliptin, a dipeptidyl peptidase-4 inhibitor, improved DD in Zucker Obese rats, a genetic model of obesity and hypertension. Here we investigated the cardioprotective effects of linagliptin on development of DD in western diet (WD)-fed mice, a clinically relevant model of overnutrition and activation of the renin-angiotensin-aldosterone system. Female C56Bl/6 J mice were fed an obesogenic WD high in fat and simple sugars, and supplemented or not with linagliptin for 16 weeks. WD induced oxidative stress, inflammation, upregulation of Angiotensin II type 1 receptor and mineralocorticoid receptor (MR) expression, interstitial fibrosis, ultrastructural abnormalities and DD. Linagliptin inhibited cardiac DPP-4 activity and prevented molecular impairments and associated functional and structu...
Research Interests: Obesity, Oxidative Stress, Signal Transduction, Female, Animals, and 13 moreNF-kappa B, Nitrosative stress, Fibrosis, Myocarditis, Left Ventricular Dysfunction, Myocardium, Time Factors, Cardiomyopathies, Down-Regulation, Recovery of Function, Linagliptin, Diastole, and Cardiovascular medicine and haematology
Obesity is a global epidemic with profound cardiovascular disease (CVD) complications. Obese women are particularly vulnerable to CVD, suffering higher rates of CVD compared to non-obese females. Diastolic dysfunction is the earliest... more
Obesity is a global epidemic with profound cardiovascular disease (CVD) complications. Obese women are particularly vulnerable to CVD, suffering higher rates of CVD compared to non-obese females. Diastolic dysfunction is the earliest manifestation of CVD in obese women but remains poorly understood with no evidence-based therapies. We have shown early diastolic dysfunction in obesity is associated with oxidative stress and myocardial fibrosis. Recent evidence suggests exercise may increase levels of the antioxidant heme oxygenase-1 (HO-1). Accordingly, we hypothesized that diastolic dysfunction in female mice consuming a western diet (WD) could be prevented by daily volitional exercise with reductions in oxidative stress, myocardial fibrosis and maintenance of myocardial HO-1 levels. Four-week-old female C57BL/6J mice were fed a high-fat/high-fructose WD for 16weeks (N=8) alongside control diet fed mice (N=8). A separate cohort of WD fed females was allowed a running wheel for the entire study (N=7). Cardiac function was assessed at 20weeks by high-resolution cardiac magnetic resonance imaging (MRI). Functional assessment was followed by immunohistochemistry, transmission electron microscopy (TEM) and Western blotting to identify pathologic mechanisms and assess HO-1 protein levels. There was no significant body weight decrease in exercising mice, normalized body weight 14.3g/mm, compared to sedentary mice, normalized body weight 13.6g/mm (p=0.38). Total body fat was also unchanged in exercising, fat mass of 6.6g, compared to sedentary mice, fat mass 7.4g (p=0.55). Exercise prevented diastolic dysfunction with a significant reduction in left ventricular relaxation time to 23.8ms for exercising group compared to 33.0ms in sedentary group (p&amp;amp;amp;amp;lt;0.01). Exercise markedly reduced oxidative stress and myocardial fibrosis with improved mitochondrial architecture. HO-1 protein levels were increased in the hearts of exercising mice compared to sedentary WD fed females. This study provides seminal evidence that exercise can prevent diastolic dysfunction in WD-induced obesity in females even without changes in body weight. Furthermore, the reduction in myocardial oxidative stress and fibrosis and improved HO-1 levels in exercising mice suggests a novel mechanism for the antioxidant effect of exercise.
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Research Interests:
Over the past three decades, we have witnessed an improvement of survival in those patients with the trio of metabolic syndrome, prediabetes, and overt type 2 diabetes mellitus. Revolutionary changes in technology and an improved... more
Over the past three decades, we have witnessed an improvement of survival in those patients with the trio of metabolic syndrome, prediabetes, and overt type 2 diabetes mellitus. Revolutionary changes in technology and an improved understanding of the mechanisms involved in acute coronary syndromes have resulted in this observation. Due to advances in coronary care, we are currently at a crossroads, wherein, the mortality from acute cardiovascular events have been declining and the mortality associated with this trio has been increasing due to congestive heart failure (CHF). This intersect between the two causes of death represent a challenge for the future, as the numbers of patients with this deadly trio are undergoing exponential growth not only in the U.S. but also abroad as more countries undergo urbanization and adopt a western-type lifestyle of over nutrition and under exercise. Thus, we live to die another day. There are multiple metabolic toxicities in this toxic trio, which predispose to an increase in reactive oxygen species and resultant redox stress within the vascular intima and myocardium. By aggressively reducing the elevated substrates producing reactive oxygen species we may be able to restore our individual, endogenous, potent, antioxidant (antiredoxidant) network. Appropriately, we need to examine the mechanisms that result in the development and transition from diastolic and systolic dysfunction to the clinical syndrome of overt CHF with its inherent increase in morbidity and mortality.
Research Interests: Obesity, Oxidative Stress, Extracellular Matrix, Heart Failure, Insulin Resistance, and 9 moreHumans, Reactive Oxygen Species, Nitric Oxide Synthase, Coronary heart disease, Type 2 Diabetes Mellitus, Oxidation-Reduction, Matrix Metalloproteinase, Metabolic Syndrome X, and Medical and Health Sciences
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Research Interests: Apoptosis, Echocardiography, Cardiac Hypertrophy, Blood Pressure, Aldosterone, and 15 moreAnimals, Corticosterone, Cytochrome C, Clinical Sciences, Body Weight, Albuminuria, Cell Proliferation, Angiotensin II, Cell Survival, Cardiomegaly, Experimental Group, Arterial pressure, Cardiac output, Cardiovascular Events, and Cardiovascular medicine and haematology
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In 2004, the human islet amyloid polypeptide (HIP) rat model was created by transfecting the Sprague-Dawley rat with the human islet amyloid polypeptide (hIAPP)-amylin gene. The objective of this study is to utilize the transmission... more
In 2004, the human islet amyloid polypeptide (HIP) rat model was created by transfecting the Sprague-Dawley rat with the human islet amyloid polypeptide (hIAPP)-amylin gene. The objective of this study is to utilize the transmission electron microscope to study the longitudinal cellular and extracellular morphological changes within the islets of this model at 4, 8, and 14 months of age. It has been previously demonstrated that the 2-, 5-, and 10-month HIP models have no diabetes, impaired fasting glucose, and diabetes, respectively. The 4-month HIP model (FBS 123 mg/dl) demonstrated an abundance of beta-cells and insulin secretory granules with significant pericapillary and inter-beta-cell islet amyloid deposition. The 8-month model (FBS 187 mg/dl) demonstrated extensive islet amyloid deposition and marked changes of beta-cell apoptosis. The 14-month-old model (FBS 244 mg/dl) demonstrated islet and beta-cell atrophy with even greater amounts of extracellular islet amyloid compared to the 4-month-old and 8-month-old models. Functional beta cells were sparse and were associated with intra islet adipose deposition. These findings of ultrastructure cellular and extracellular morphological longitudinal remodeling changes in this novel animal model of type 2 diabetes may provide investigators with a better understanding regarding the role of islet amyloid in human islet.
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ABSTRACT
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In 1901 Eugene L. Opie, MD, a Dean of Washington University School of Medicine (Figure 1) described the histologic presence of amyloid within the pancreatic islets of patients with type 2 diabetes mellitus. Although amyloid is present in... more
In 1901 Eugene L. Opie, MD, a Dean of Washington University School of Medicine (Figure 1) described the histologic presence of amyloid within the pancreatic islets of patients with type 2 diabetes mellitus. Although amyloid is present in at least 70 percent of type 2 diabetic patients, the subject has not been clinically emphasized. This paper reviews the history of Opie&amp;amp;#39;s discovery and current clinical implications of islet amyloid.
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Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D™), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical... more
Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D™), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5 mg or placebo in addition to their stable glucose-lowering background therapy for 24 weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24 weeks with α = 0.05. MARLINA-T2D™ is the first ...
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The rising obesity rates parallel increased consumption of a Western diet, high in fat and fructose, which is associated with increased uric acid. Population-based data support that elevated serum uric acids are associated with left... more
The rising obesity rates parallel increased consumption of a Western diet, high in fat and fructose, which is associated with increased uric acid. Population-based data support that elevated serum uric acids are associated with left ventricular hypertrophy and diastolic dysfunction. However, the mechanism by which excess uric acid promotes these maladaptive cardiac effects has not been explored. In assessing the role of Western diet-induced increases in uric acid, we hypothesized that reductions in uric acid would prevent Western diet-induced development of cardiomyocyte hypertrophy, cardiac stiffness, and impaired diastolic relaxation by reducing growth and profibrotic signaling pathways. Four-weeks-old C57BL6/J male mice were fed excess fat (46%) and fructose (17.5%) with or without allopurinol (125 mg/L), a xanthine oxidase inhibitor, for 16 weeks. The Western diet-induced increases in serum uric acid along with increases in cardiac tissue xanthine oxidase activity temporally rel...
Research Interests: Oxidative Stress, Signal Transduction, Hypertension, Mice, Animals, and 12 moreMale, Fibrosis, Left Ventricular Dysfunction, Clinical Sciences, Uric Acid, Myocardium, Left ventricular hypertrophy, Biological markers, Allopurinol, Xanthine Oxidase, Dietary fats, and Cardiovascular medicine and haematology
BACKGROUND/AIMS: Childhood-adolescent overweight and obesity have grown to pandemic proportions during the past decade. The onset of obesity in younger adults will likely be manifested as earlier onset of myocardial and renal end-organ... more
BACKGROUND/AIMS: Childhood-adolescent overweight and obesity have grown to pandemic proportions during the past decade. The onset of obesity in younger adults will likely be manifested as earlier onset of myocardial and renal end-organ disease in younger adults. For the first time, it is estimated that the current generation may not live to be as old as their parents. Thus, it is important to develop animal models of childhood obesity to understand fundamental pathological organ changes. METHODS: IN THIS REGARD, WE UTILIZE TRANSMISSION ELECTRON MICROSCOPY EVALUATION TO EVALUATE EARLY REMODELING CHANGES OF TWO ADOLESCENT RODENT OBESITY MODELS: the Zucker obese (fa/fa) rat and the db/db mouse models of obesity. We have concentrated on the initial ultrastructural remodeling (obese adipose tissue, skeletal muscle, and islet remodeling) and the associated changes in target end organs (including the myocardium and kidney) in young rodent models of obesity and insulin resistance, collectiv...
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Obesity has reached epidemic proportions with far-reaching health care and economic implications. Overnutrition, characterized by excess intake of carbohydrates and fats, has been associated with end-organ damage in several tissues,... more
Obesity has reached epidemic proportions with far-reaching health care and economic implications. Overnutrition, characterized by excess intake of carbohydrates and fats, has been associated with end-organ damage in several tissues, including the heart and the kidney. Furthermore, overnutrition is one of the most important modifiable and preventable causes of morbidity and mortality associated with cardiovascular and kidney diseases. Insulin resistance and compensatory hyperinsulinemia as well as associated mechanisms, including enhanced renin-angiotensin-aldosterone system activity, inflammation, and oxidative stress, have been implicated in obesity-related cardiorenal injury. In this review, the effect of overnutrition on heart and kidney disease is assessed in a rodent model of overnutrition and obesity, the Zucker obese rat.
Research Interests:
Calcific uremic arteriolopathy (CUA)/calciphylaxis is an important cause of morbidity and mortality in patients with chronic kidney disease requiring renal replacement. Once thought to be rare, it is being increasingly recognized and... more
Calcific uremic arteriolopathy (CUA)/calciphylaxis is an important cause of morbidity and mortality in patients with chronic kidney disease requiring renal replacement. Once thought to be rare, it is being increasingly recognized and reported on a global scale. The uremic milieu predisposes to multiple metabolic toxicities including increased levels of reactive oxygen species and inflammation. Increased oxidative stress and inflammation promote this arteriolopathy by adversely affecting endothelial function resulting in a prothrombotic milieu and significant remodeling effects on vascular smooth muscle cells. These arteriolar pathological effects include intimal hyperplasia, inflammation, endovascular fibrosis and vascular smooth muscle cell apoptosis and differentiation into bone forming osteoblast-like cells resulting in medial calcification. Systemic factors promoting this vascular condition include elevated calcium, parathyroid hormone, and hyperphosphatemia with consequent incr...