Diseases Commons^™

Asymmetric Dimethylarginine Blocks Nitric Oxide-Mediated Alcohol-Stimulated Cilia Beating., Todd A. Wyatt, S . M. Wells, Z . A. Alsaidi, Jane M. Devasure, E. B. Klein, Kristina L. Bailey, Joseph H. Sisson

Journal Articles: Pulmonary & Critical Care Med

The airway epithelium is exposed to alcohol during drinking through direct exhalation of volatized ethanol from the bronchial circulation. Alcohol exposure leads to a rapid increase in the cilia beat frequency (CBF) of bronchial epithelial cells followed by a chronic desensitization of cilia stimulatory responses. This effect is governed in part by the nitric oxide regulation of cyclic guanosine and adenosine monophosphate-dependent protein kinases (PKG and PKA) and is not fully understood. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is implicated in the pathogenesis of several pulmonary disorders. We hypothesized that the inhibition of nitric oxide synthase …

Bioengineered Lysozyme Reduces Bacterial Burden And Inflammation In A Murine Model Of Mucoid Pseudomonas Aeruginosa Lung Infection, Charlotte C. Teneback, Thomas C. Scanlon, Matthew J. Wargo, Jenna L. Bement, Karl E. Griswold, Laurie W. Leclair

Dartmouth Scholarship

The spread of drug-resistant bacterial pathogens is a growing global concern and has prompted an effort to explore potential adjuvant and alternative therapies derived from nature's repertoire of bactericidal proteins and peptides. In humans, the airway surface liquid layer is a rich source of antibiotics, and lysozyme represents one of the most abundant and effective antimicrobial components of airway secretions. Human lysozyme is active against both Gram-positive and Gram-negative bacteria, ac

Cardiac Fibroblast-Dependent Extracellular Matrix Accumulation Is Associated With Diastolic Stiffness In Type 2 Diabetes., Kirk R. Hutchinson, C. Kevin Lord, T. Aaron West, James A. Stewart

CAS Publications

Cardiovascular complications are a leading cause of death in patients with type 2 diabetes mellitus (T2DM). Diastolic dysfunction is one of the earliest manifestations of diabetes-induced changes in left ventricular (LV) function, and results from a reduced rate of relaxation and increased stiffness. The mechanisms responsible for increased stiffness are not completely understood. Chronic hyperglycemia, advanced glycation endproducts (AGEs), and increased levels of proinflammatory and profibrotic cytokines are molecular pathways known to be involved in regulating extracellular matrix (ECM) synthesis and accumulation resulting in increased LV diastolic stiffness. Experiments were conducted using a genetically-induced mouse model of T2DM generated by …

Id4 Deficiency Attenuates Prostate Development And Promotes Pin-Like Lesions By Regulating Androgen Receptor Activity And Expression Of Nkx3.1 And Pten, Pankaj Sharma, Ashley Knowell, Swathi Chinaranagari, Shravan Komaragiri, Peri Nagappan, Divya Patel, Mathew C. Havrda, Jaideep Chaudhary

Dartmouth Scholarship

Background: Inhibitor of differentiation 4 (Id4), a member of the helix-loop-helix family of transcriptional regulators has emerged as a tumor suppressor in prostate cancer. Id4 is expressed in the normal prostate where its expression is also regulated by androgens. In this study we investigated the effect of loss of Id4 (Id4-/-) on adult prostate morphology. Methods: Histological analysis was performed on prostates from 6-8 weeks old Id4-/-, Id4+/- and Id4+/+ mice. Expression of Id1, Sox9, Myc, androgen receptor, Akt, p-Akt, Pten and Nkx3.1 was investigated by immunohistochemistry. Androgen receptor binding on NKX3.1 promoter was studied by chromatin immuno-precipitation. Id4 was …

Intracranial Injection Of Gammagard, A Human Ivig, Modulates The Inflammatory Response Of The Brain And Lowers AΒ In App/Ps1 Mice Along A Different Time Course Than Anti-AΒ Antibodies, Tiffany L. Sudduth, Abigail Greenstein, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Gammagard IVIg is a therapeutic approach to treat Alzheimer's disease currently in phase 3 clinical trials. Despite the reported efficacy of the approach the mechanism of action is poorly understood. We have previously shown that intracranial injection of anti-Aβ antibodies into the frontal cortex and hippocampus reveals important information regarding the time course of events once the agent is in the brain. In the current study we compared IVIg, mouse-pooled IgG, and the anti-Aβ antibody 6E10 injected intracranially into the frontal cortex and hippocampus of 7-month-old APP/PS1 mice. We established a time course of events ranging from 1 …

Maresin-1 Reduces The Pro-Inflammatory Response Of Bronchial Epithelial Cells To Organic Dust., Tara M. Nordgren, Art J. Heires, Todd A. Wyatt, Jill A. Poole, Tricia D. Levan, D. Roselyn Cerutis, Debra J. Romberger

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Exposure to organic dust causes detrimental airway inflammation. Current preventative and therapeutic measures do not adequately treat resulting disease, necessitating novel therapeutic interventions. Recently identified mediators derived from polyunsaturated fatty acids exhibit anti-inflammatory and pro-resolving actions. We tested the potential of one of these mediators, maresin-1 (MaR1), in reducing organic dust-associated airway inflammation.

METHODS: As bronchial epithelial cells (BECs) are pivotal in initiating organic dust-induced inflammation, we investigated the in vitro effects of MaR1 on a human BEC cell line (BEAS-2B). Cells were pretreated for 1 hour with 0-200 nM MaR1, followed by 1-24 hour treatment with 5% hog …

Intra-Tumoral Heterogeneity In Metastatic Potential And Survival Signaling Between Iso-Clonal Hct116 And Hct116b Human Colon Carcinoma Cell Lines., Sanjib Chowdhury, Melanie Ongchin, Elizabeth Sharratt, Ivan Dominguez, J. Wang, Michael G. Brattain, Ashwani Rajput

Journal Articles: Eppley Institute

BACKGROUND: Colorectal cancer (CRC) metastasis is a leading cause of cancer-related deaths in the United States. The molecular mechanisms underlying this complex, multi-step pathway are yet to be completely elucidated. Recent reports have stressed the importance of intra-tumoral heterogeneity in the development of a metastatic phenotype. The purpose of this study was to characterize the intra-tumoral phenotypic heterogeneity between two iso-clonal human colon cancer sublines HCT116 and HCT116b on their ability to undergo metastatic colonization and survive under growth factor deprivation stress (GFDS).

MATERIALS AND METHODS: HCT116 and HCT116b cells were transfected with green fluorescence protein and subcutaneously injected into …

Cd4 And Cd8 T Cells Directly Recognize Murine Gammaherpesvirus 68-Immortalized Cells And Prevent Tumor Outgrowth, Xiaozhan Liang, Rebecca L. Crepeau, Weijun Zhang, Samuel H. Speck, Edward J. Usherwood

Dartmouth Scholarship

There has been extensive research regarding T cell recognition of Epstein-Barr virus-transformed cells; however, less is known regarding the recognition of B cells immortalized by gamma-2 herpesviruses. Here we show that B cells immortalized by murine gammaherpesvirus 68 (MHV-68, γHV-68) can be controlled by either CD4 or CD8 T cells in vivo. We present evidence for the direct recognition of infected B cells by CD4 and CD8 T cells. These data will help in the development of immunotherapeutic approaches combating gamma-2 herpesvirus-related disease.

Inhibition Of The Host Translation Shutoff Response By Herpes Simplex Virus 1 Triggers Nuclear Envelope-Derived Autophagy, Kerstin Radtke, Luc English, Christiane Rondeau, David Leib

Dartmouth Scholarship

Macroautophagy is a cellular pathway that degrades intracellular pathogens and contributes to antigen presentation. Herpes simplex virus 1 (HSV-1) infection triggers both macroautophagy and an additional form of autophagy that uses the nuclear envelope as a source of membrane. The present study constitutes the first in-depth analysis of nuclear envelope-derived autophagy (NEDA). We established LC3a as a marker that allowed us to distinguish between NEDA and macroautophagy in both immunofluorescence and flow cytometry. NEDA was observed in many different cell types, indicating that it is a general response to HSV-1 infection. This autophagic pathway is known to depend on the …

Mitochondrial Cardiomyopathy: Pathophysiology, Diagnosis, And Management, Deborah E Meyers, Haseeb Ilias Basha, Mary Kay Koenig

The Texas Heart Institute Journal

Mitochondrial disease is a heterogeneous group of multisystemic diseases that develop consequent to mutations in nuclear or mitochondrial DNA. The prevalence of inherited mitochondrial disease has been estimated to be greater than 1 in 5,000 births; however, the diagnosis and treatment of this disease are not taught in most adult-cardiology curricula. Because mitochondrial diseases often occur as a syndrome with resultant multiorgan dysfunction, they might not immediately appear to be specific to the cardiovascular system. Mitochondrial cardiomyopathy can be described as a myocardial condition characterized by abnormal heart-muscle structure, function, or both, secondary to genetic defects involving the mitochondrial respiratory …

Some Thoughts About The Historic Events That Led To The First Clinical Implantation Of A Total Artificial Heart, Denton A Cooley

The Texas Heart Institute Journal

No abstract provided.

Early Hemodynamic And Biochemical Changes In Overloaded Swine Ventricleearly Hemodynamic And Biochemical Changes In Overloaded Swine Ventricle, Sandro Gelsomino, Fabiana Lucà, Chiara Nediani, Sandra Zecchi Orlandini, Daniele Bani, Antonio S Rubino, Attilio Renzulli, Roberto Lorusso, Andrea Consolo, Antonino Lo Cascio, Jos Maessen, Gian Franco Gensini

The Texas Heart Institute Journal

The present study was undertaken to investigate, in an animal model, the relationship between sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity, phospholamban phosphorylation, acylphosphatase activity, and hemodynamic changes that occur in the early phase of pressure overload. In 54 study-group pigs, weighing 40±5 kg each, an aortic stenosis was created with a band of umbilical tape tied around the aorta; 18 sham-operated pigs formed our control group. Eight animals (6 study and 2 control) were randomly assigned to each experimental time (0.5, 3, 6, 12, 24, 48, 72, 96, and 168 hr). All indices of left ventricular function declined significantly, with a …

The Pathobiology Of Acute Coronary Syndromes: Clinical Implications And Central Role Of The Mitochondria, L Maximilian Buja

The Texas Heart Institute Journal

Ongoing investigation has provided new insights into the pathobiology of myocardial ischemic injury. These include an improved understanding of the roles of the major modes of cell injury and death, including oncosis, apoptosis, and unregulated autophagy, as well as the central role of the mitochondria in the progression of myocardial ischemic injury, reperfusion injury, and myocardial conditioning. This understanding is providing insights for developing new pathophysiologic, pharmacologic, and cell-based therapies, alone or in combination with percutaneous coronary interventions, for better preservation of myocardium and reduction of morbidity and mortality rates from ischemic heart disease.

Induction Of Early Biomarkers In A Thrombus-Induced Sheep Model Of Ischemic Heart Failure, Aluganti N Chandrakala, Pawel Kwiatkowski, Chittoor B Sai-Sudhakar, Benjamin Sun, Angela Phillips, Sampath Parthasarathy

The Texas Heart Institute Journal

The levels of brain natriuretic peptide (BNP) and monocyte chemoattractant protein-1 (MCP-1) are known to be increased in the sera of subjects with heart failure. Existing models do not account for the biomass of thrombus that occurs in patients undergoing myocardial infarction. In this study, we compared the expressions of sheep-derived genes for BNP, MCP-1, and atrial natriuretic peptide in a new large-animal model of thrombus-induced heart failure. Thrombus of autologous platelets was injected directly into the left circumflex coronary arteries of sheep. Cardiac ischemic injury was evaluated by troponin I levels, and heart failure progression was monitored with the …

Effects Of Exercise On Ampk Signaling And Downstream Components To Pi3k In Rat With Type 2 Diabetes, Shicheng Cao, Bowen Li, Xuejie Yi, Bo Chang, Beibei Zhu, Zhenzhen Lian, Zhaoran Zhang, Gang Zhao, Huili Liu, He Zhang

Barnstable Brown Diabetes Center Faculty Publications

Exercise can increase skeletal muscle sensitivity to insulin, improve insulin resistance and regulate glucose homeostasis in rat models of type 2 diabetes. However, the potential mechanism remains poorly understood. In this study, we established a male Sprague-Dawley rat model of type 2 diabetes, with insulin resistance and β cell dysfunction, which was induced by a high-fat diet and low-dose streptozotocin to replicate the pathogenesis and metabolic characteristics of type 2 diabetes in humans. We also investigated the possible mechanism by which chronic and acute exercise improves metabolism, and the phosphorylation and expression of components of AMP-activated protein kinase (AMPK) and …

Coronary Artery Remodeling In A Model Of Left Ventricular Pressure Overload Is Influenced By Platelets And Inflammatory Cells, Fanmuyi Yang, Anping Dong, Paul Mueller, Jessica Caicedo, Alyssa Moore Sutton, Juliana Odetunde, Cordelia J. Barrick, Yuri M. Klyachkin, Ahmed Abdel-Latif, Susan S. Smyth

Internal Medicine Faculty Publications

Left ventricular hypertrophy (LVH) is usually accompanied by intensive interstitial and perivascular fibrosis, which may contribute to arrhythmogenic sudden cardiac death. The mechanisms underlying the development of cardiac fibrosis are incompletely understood. To investigate the role of perivascular inflammation in coronary artery remodeling and cardiac fibrosis during hypertrophic ventricular remodeling, we used a well-established mouse model of LVH (transverse aortic constriction [TAC]). Three days after pressure overload, macrophages and T lymphocytes accumulated around and along left coronary arteries in association with luminal platelet deposition. Consistent with these histological findings, cardiac expression of IL-10 was upregulated and in the systemic circulation, …

Murine Gammaherpesvirus 68 Lana Acts On Terminal Repeat Dna To Mediate Episome Persistence, Aline C. Habison, Chantal Beauchemin, J. Pedro Simas, Edward J. Usherwood

Dartmouth Scholarship

Murine gammaherpesvirus 68 (MHV68) ORF73 (mLANA) has sequence homology to Kaposi’s sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA). LANA acts on the KSHV terminal repeat (TR) elements to mediate KSHV episome maintenance. Disruption of mLANA expression severely reduces the ability of MHV68 to establish latent infection in mice, consistent with the possibility that mLANA mediates episome persistence. Here we assess the roles of mLANA and MHV68 TR (mTR) elements in episome persistence. mTR-associated DNA persisted as an episome in latently MHV68-infected tumor cells, demonstrating that the mTR elements can serve as a cis-acting element for MHV68 episome maintenance. In some …

Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction In A Mouse Model That Exhibits Age-Dependent Progression Of Alzheimer's Disease-Related Pathology, Adam D. Bachstetter, Christopher M. Norris, Pradoldej Sompol, Donna M. Wilcock, Danielle Goulding, Janna H. Neltner, Daret St. Clair, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that …

Alcohol Exposure Alters Mouse Lung Inflammation In Response To Inhaled Dust., Michael L. Mccaskill, Debra J. Romberger, Jane M. Devasure, Jessica Boten, Joseph H. Sisson, Kristina L. Bailey, Jill A. Poole, Todd A. Wyatt

Journal Articles: Pulmonary & Critical Care Med

Alcohol exposure is associated with increased lung infections and decreased mucociliary clearance. Occupational workers exposed to dusts from concentrated animal feeding operations (CAFOs) are at risk for developing chronic inflammatory lung diseases. Agricultural worker co-exposure to alcohol and organic dust has been established, although little research has been conducted on the combination effects of alcohol and organic dusts on the lung. Previously, we have shown in a mouse model that exposure to hog dust extract (HDE) collected from a CAFO results in the activation of protein kinase C (PKC), elevated lavage fluid cytokines/chemokines including interleukin-6 (IL-6), and the development of …

Mice Deficient In Gem Gtpase Show Abnormal Glucose Homeostasis Due To Defects In Beta-Cell Calcium Handling, Jenny E. Gunton, Mary Sisavanh, Rebecca A. Stokes, Jon Satin, Leslie S. Satin, Min Zhang, Sue M. Liu, Weikang Cai, Kim Cheng, Gregory J. Cooney, D. Ross Laybutt, Trina So, Juan-Carlos Molero, Shane T. Grey, Douglas A. Andres, Michael S. Rolph, Charles R. Mackay

Physiology Faculty Publications

AIMS AND HYPOTHESIS: Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo.

METHODS: Gem-deficient mice were generated and their metabolic phenotype characterised by in …

Non-Typeable Haemophilus Influenzae Decreases Cilia Beating Via Protein Kinase Cε., Kristina L. Bailey, Tricia D. Levan, Daniel A. Yanov, Jacqueline A. Pavlik, Jane M. Devasure, Joseph H. Sisson, Todd A. Wyatt

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Haemophilus influenzae infection of the nasal epithelium has long been associated with observations of decreased nasal ciliary beat frequency (CBF) and injury to the ciliated epithelium. Previously, we have reported that several agents that slow CBF also have the effect of activating protein kinase C epsilon (PKCε) activity in bronchial epithelial cells. The subsequent auto-downregulation of PKCε or the direct inhibition of PKCε leads to the specific detachment of the ciliated cells.

METHODS: Primary cultures of ciliated bovine bronchial epithelial cells were exposed to filtered conditioned media supernatants from non-typeable H. influenzae (NTHi) cultures. CBF and motile points were …

Transforming Growth Factor-Β Suppresses Metastasis In A Subset Of Human Colon Carcinoma Cells., Neka A.K. Simms, Ashwani Rajput, Elizabeth A. Sharratt, Melanie Ongchin, Carol A. Teggart, J. Wang, Michael G. Brattain

Journal Articles: Eppley Institute

BACKGROUND: TGFβ signaling has typically been associated with suppression of tumor initiation while the role it plays in metastasis is generally associated with progression of malignancy. However, we present evidence here for an anti-metastatic role of TGFβ signaling.

METHODS: To test the importance of TGFβ signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGFβ response (FET), or tumorigenic with TGFβ response (FETα) or tumorigenic with abrogated TGFβ response via introduction of dominant negative TGFβRII (FETα/DN) and their ability to metastasize. Metastatic competency was assessed by orthotopic transplantation. Metastatic colony formation …

Hiv-1 Tat Triggers Nuclear Localization Of Zo-1 Via Rho Signaling And Camp Response Element-Binding Protein Activation, Yu Zhong, Bei Zhang, Sung Yong Eum, Michal Toborek

Neurosurgery Faculty Publications

The human immunodeficiency virus (HIV)-specific protein trans-activator of transcription (Tat) can contribute to the dysfunction of brain endothelial cells and HIV trafficking into the brain by disrupting tight junction (TJ) integrity at the blood–brain barrier (BBB) level. Specific TJ proteins, such as zonula occludens (ZO) proteins, localize not only at the cell–cell borders but are also present in the nuclei. The objective of the present study was to evaluate the mechanisms and significance of Tat-induced nuclear localization of ZO-1. Treatment of a brain endothelial cell line (hCMEC/D3 cells) with Tat resulted in a decrease in total levels of ZO-1 but …

Gentamicin Rapidly Inhibits Mitochondrial Metabolism In High-Frequency Cochlear Outer Hair Cells, Heather Jensen Smith, Richard Hallworth, Michael G. Nichols

Journal Articles: Eppley Institute

Aminoglycosides (AG), including gentamicin (GM), are the most frequently used antibiotics in the world and are proposed to cause irreversible cochlear damage and hearing loss (HL) in 1/4 of the patients receiving these life-saving drugs. Akin to the results of AG ototoxicity studies, high-frequency, basal turn outer hair cells (OHCs) preferentially succumb to multiple HL pathologies while inner hair cells (IHCs) are much more resilient. To determine if endogenous differences in IHC and OHC mitochondrial metabolism dictate differential sensitivities to AG-induced HL, IHC- and OHC-specific changes in mitochondrial reduced nicotinamide adenine dinucleotide (NADH) fluorescence during acute (1 h) GM treatment …

Cellular Retrograde Cardiomyoplasty And Relaxin Therapy For Postischemic Myocardial Repair In A Rat Model, Gabriella Di Lascio, Guy Harmelin, Mattia Targetti, Cristina Nanni, Giacomo Bianchi, Tommaso Gasbarri, Sandro Gelsomino, Daniele Bani, Sandra Zecchi Orlandini, Massimo Bonacchi

The Texas Heart Institute Journal

We sought to determine whether skeletal myoblasts, wild-type or engineered to express relaxin, might improve myocardial viability and performance in a rat model of chronic myocardial infarction. Our purpose was to investigate a potential new therapy for heart failure.

From October 2005 through September 2009, we surgically induced acute myocardial infarction in 80 male Wistar rats. Thirty days after surgery, the rats underwent reoperation for the retrograde coronary venous infusion of skeletal myoblasts, relaxin, or both. The animals were randomly assigned to 4 experimental groups: R1 (the control group, which underwent saline-solution infusion), R2 (systemic relaxin therapy), R3 (myoblast infusion), …

Triterpenoid Modulation Of Il-17 And Nrf-2 Expression Ameliorates Neuroinflammation And Promotes Remyelination In Autoimmune Encephalomyelitis, Tej K. Pareek, Abdelmadjid Belkadi, Sashi Kesavapany, Anita Zaremba, Sook L. Loh, Lianhua Bai, Mark L. Cohen, Colin Meyer, Karen T. Liby, Robert H. Miller, Michael B. Sporn, John J. Letterio

Dartmouth Scholarship

Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of …

Functional Plasticity Of Central Trpv1 Receptors In Brainstem Dorsal Vagal Complex Circuits Of Streptozotocin-Treated Hyperglycemic Mice, Andrea Zsombok, Muthu D. Bhaskaran, Hong Gao, Andrei V. Derbenev, Bret N. Smith

Physiology Faculty Publications

Emerging data indicate that central neurons participate in diabetic processes by modulating autonomic output from neurons in the dorsal motor nucleus of the vagus (DMV). We tested the hypothesis that synaptic modulation by transient receptor potential vanilloid type 1 (TRPV1) receptors is reduced in the DMV in slices from a murine model of type 1 diabetes. The TRPV1 agonist capsaicin robustly enhanced glutamate release onto DMV neurons by acting at preterminal receptors in slices from intact mice, but failed to do so in slices from diabetic mice. TRPV1 receptor protein expression in the vagal complex was unaltered. Brief insulin preapplication …

Renal Thrombotic Microangiopathy In Mice With Combined Deletion Of Endocytic Recycling Regulators Ehd3 And Ehd4., Manju George, Mark A. Rainey, Mayumi Naramura, Kirk W. Foster, Melissa S. Holzapfel, Laura L. Willoughby, Guoguang Ying, Rasna M. Goswami, Channabasavaiah B. Gurumurthy, Vimla Band, Simon C. Satchell, Hamid Band

Journal Articles: Eppley Institute

Eps15 Homology Domain-containing 3 (EHD3), a member of the EHD protein family that regulates endocytic recycling, is the first protein reported to be specifically expressed in the glomerular endothelium in the kidney; therefore we generated Ehd3(-/-) mice and assessed renal development and pathology. Ehd3(-/-) animals showed no overt defects, and exhibited no proteinuria or glomerular pathology. However, as the expression of EHD4, a related family member, was elevated in the glomerular endothelium of Ehd3(-/-) mice and suggested functional compensation, we generated and analyzed Ehd3(-/-); Ehd4(-/-) mice. These mice were smaller, possessed smaller and paler kidneys, were proteinuric and died between …

A Survey Of Oxidative Paracatalytic Reactions Catalyzed By Enzymes That Generate Carbanionic Intermediates: Implications For Ros Production, Cancer Etiology, And Neurodegenerative Diseases, Victoria Bunik, John Schloss, John T. Pinto, Natalia Dudareva, Arthur J L Cooper

NYMC Faculty Publications

Enzymes that generate carbanionic intermediates often catalyze paracatalytic reactions with O2 and other electrophiles not considered “normal” reactants. For example, pyridoxal 5′-phosphate (PLP)—containing pig kidney dopa decarboxylase oxidizes dopamine with molecular O2 to 3,4-dihydroxyphenylacetaldehyde at about 1% of the rate at which it catalyzes nonoxidative dopa decarboxylation. The mutant Y332F enzyme, however, catalyzes stoichiometric conversion of dopa to 3,4-dihydroxyphenylacetaldehyde, suggesting that even minor structural changes may alter or initiate paracatalytic reactions catalyzed by certain enzymes. Carbanions generated by several thiamine diphosphate (ThDP)—dependent enzymes react with different electrophiles, transforming some xenobiotics and endogenous compounds into potentially biologically hazardous products. The detrimental …

The Roles Of Conserved And Nonconserved Cysteinyl Residues In The Oligomerization And Function Of Mammalian Prestin, Benjamin Currall, Danielle Rossino, Heather Jensen Smith, Richard Hallworth

Journal Articles: Eppley Institute

The creation of several prestin knockout and knockin mouse lines has demonstrated the importance of the intrinsic outer hair cell membrane protein prestin to mammalian hearing. However, the structure of prestin remains largely unknown, with even its major features in dispute. Several studies have suggested that prestin forms homo-oligomers that may be stabilized by disulfide bonds. Our phylogenetic analysis of prestin sequences across chordate classes suggested that the cysteinyl residues could be divided into three groups, depending on the extent of their conservation between prestin orthologs and paralogs or homologs. An alanine scan functional analysis was performed of all nine …