Medical Physiology Commons^™

Hydroxyurea In The Sickle Cell Disease Modern Era, Chazmyn Riley, Walter K. Kraft, Robin Miller

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

INTRODUCTION: Sickle cell disease is an inherited disorder characterized by hemoglobin S polymerization leading to vaso-occlusion and hemolytic anemia. These result in a variety of pathological events, causing both acute and chronic complications. Millions around the world are affected by sickle cell disease with predominance in sub-Saharan Africa. Hydroxyurea was the first drug approved for use in sickle cell disease to reduce the occurrence of painful crises and blood transfusions in patients with frequent, moderate to severe painful crises.

AREAS COVERED: With the development of new therapeutics, the role of hydroxyurea is evolving. This narrative review aims to provide clinical …

Fundamental Neurochemistry Review: The Role Of Enteroendocrine Cells In Visceral Pain, Annie Londregan, Tyler D. Alexander, Manuel Covarrubias, Scott A. Waldman

Department of Neuroscience Faculty Papers

While visceral pain is commonly associated with disorders of the gut-brain axis, underlying mechanisms are not fully understood. Dorsal root ganglion (DRG) neurons innervate visceral structures and undergo hypersensitization in inflammatory models. The characterization of peripheral DRG neuron terminals is an active area of research, but recent work suggests that they communicate with enteroendocrine cells (EECs) in the gut. EECs sense stimuli in the intestinal lumen and communicate information to the brain through hormonal and electrical signaling. In that context, EECs are a target for developing therapeutics to treat visceral pain. Linaclotide is an FDA-approved treatment for chronic constipation that …

An Updated Classification Of Meditation Methods Using Principles Of Taxonomy And Systematics, Jonathan D. Nash, Andrew B. Newberg

Marcus Institute of Integrative Health Faculty Papers

This paper revisits the proposal for the classification of meditation methods which we introduced in our initial 2013 publication, “Toward a Universal Taxonomy and Definition of Meditation”. At that time, we advanced the thesis that meditation methods could be effectively segregated into three orthogonal categories by integrating the taxonomic principle of functional essentialism and the paradigm of Affect and Cognition; and we presented relevant research findings which supported that assertion. This iteration expands upon those theoretical and methodological elements by articulating a more comprehensive Three Tier Classification System which accounts for the full range of meditation methods; and demonstrates how …

Capture At The Er-Mitochondrial Contacts Licenses Ip, Máté Katona, Ádám Bartók, Zuzana Nichtova, György Csordás, Elena Berezhnaya, David Weaver, Arijita Ghosh, Péter Várnai, David I. Yule, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP3 receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca2+ coupling, IP3Rs …

Ctpathway: A Crosstalk-Based Pathway Enrichment Analysis Method For Cancer Research, Haizhou Liu, Mengqin Yuan, Ramkrishna Mitra, Xu Zhou, Min Long, Wanyue Lei, Shunheng Zhou, Yu-E Huang, Fei Hou, Christine M. Eischen, Wei Jiang

Department of Cancer Biology Faculty Papers

Background: Pathway enrichment analysis (PEA) is a common method for exploring functions of hundreds of genes and identifying disease-risk pathways. Moreover, different pathways exert their functions through crosstalk. However, existing PEA methods do not sufficiently integrate essential pathway features, including pathway crosstalk, molecular interactions, and network topologies, resulting in many risk pathways that remain uninvestigated.

Methods: To overcome these limitations, we develop a new crosstalk-based PEA method, CTpathway, based on a global pathway crosstalk map (GPCM) with >440,000 edges by combing pathways from eight resources, transcription factor-gene regulations, and large-scale protein-protein interactions. Integrating gene differential expression and crosstalk effects in …

Lysine Methyltransferase Nsd1 And Cancers: Any Role In Melanoma?, Imène Krossa, Thomas Strub, Andrew E Aplin, Robert Ballotti, Corine Bertolotto

Department of Cancer Biology Faculty Papers

Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of NSD1 in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or …

Steap1-4 (Six-Transmembrane Epithelial Antigen Of The Prostate 1-4) And Their Clinical Implications For Prostate Cancer, Michael Xu, Latese Evans, Candice L Bizzaro, Fabio Quaglia, Cecilia E Verrillo, Li Li, Julia Stieglmaier, M J Schiewer, Lucia R Languino, William Kevin Kelly

Department of Urology Faculty Papers

Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP1-4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1-4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1-4 as potential biomarkers and therapeutic …

Identification And Characterization Of Cyps Induced In The Drosophila Antenna By Exposure To A Plant Odorant, Shane R Baldwin, Pratyajit Mohapatra, Monica Nagalla, Rhea Sindvani, Desiree Amaya, Hope A Dickson, Karen Menuz

Department of Medicine Faculty Papers

Degrading Enzymes (ODEs). However, their contribution to olfactory signaling in vivo is poorly understood. This is due in part to the challenge of identifying which of the dozens of antennal-expressed CYPs might inactivate a given odorant. Here, we tested a high-throughput deorphanization strategy in Drosophila to identify CYPs that are transcriptionally induced by exposure to odorants. We discovered three CYPs selectively upregulated by geranyl acetate using transcriptional profiling. Although these CYPs are broadly expressed in the antenna in non-neuronal cells, electrophysiological recordings from CYP mutants did not reveal any changes in olfactory neuron responses to this odorant. Neurons were desensitized …

Coronavirus Disease 2019 (Covid-19): Multisystem Review Of Pathophysiology, Tanveer Mir, Talal Almas, Jasmeet Kaur, Mohammed Faisaluddin, David Song, Waqas Ullah, Sahil Mamtani, Hiba Rauf, Sunita Yadav, Sharaad Latchana, Nara Miriam Michaelson, Michael Connerney, Yasar Sattar

Division of Internal Medicine Faculty Papers & Presentations

Abstract Coronavirus disease-19 (COVID-19) pandemic is associated with high morbidity and mortality. COVID-19, which is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2), affects multiple organ systems through a myriad of mechanisms. Afflicted patients present with a vast constellation of symptoms, from asymptomatic disease to life-threatening complications. The most common manifestations pertain to mild pulmonary symptoms, which can progress to respiratory distress syndrome and venous thromboembolism. However, in patients with renal failure, life-threatening cardiac abnormalities can ensue. Various mechanisms such as viral entry through Angiotensin receptor (ACE) affecting multiple organs and thus releasing pro-inflammatory markers have been postulated. …

Increasing Upstream Chromatin Long-Range Interactions May Favor Induction Of Circular Rnas In Lysopc-Activated Human Aortic Endothelial Cells., Angus Li, Yu Sun, Charles Drummer, Yifan Lu, Daohai Yu, Yan Zhou, Xinyuan Li, Simone J. Pearson, Candice Johnson, Catherine Yu, William Y. Yang, Kevin Mastascusa, Xiaohua Jiang, Jianxin Sun, Thomas Rogers, Wenhui Hu, Hong Wang, Xiaofeng Yang

Center for Translational Medicine Faculty Papers

Circular RNAs (circRNAs) are non-coding RNAs that form covalently closed continuous loops, and act as gene regulators in physiological and disease conditions. To test our hypothesis that proatherogenic lipid lysophosphatidylcholine (LPC) induce a set of circRNAs in human aortic endothelial cell (HAEC) activation, we performed circRNA analysis by searching our RNA-Seq data from LPC-activated HAECs, and found: (1) LPC induces significant modulation of 77 newly characterized cirRNAs, among which 47 circRNAs (61%) are upregulated; (2) 34 (72%) out of 47 upregulated circRNAs are upregulated when the corresponding mRNAs are downregulated, suggesting that the majority of circRNAs are upregulated presumably via …

Causality Analysis And Cell Network Modeling Of Spatial Calcium Signaling Patterns In Liver Lobules., Aalap Verma, Anil Noronha Antony, Babatunde A. Ogunnaike, Jan B. Hoek, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Dynamics as well as localization of Ca2+ transients plays a vital role in liver function under homeostatic conditions, repair, and disease. In response to circulating hormonal stimuli, hepatocytes exhibit intracellular Ca2+ responses that propagate through liver lobules in a wave-like fashion. Although intracellular processes that control cell autonomous Ca2+ spiking behavior have been studied extensively, the intra- and inter-cellular signaling factors that regulate lobular scale spatial patterns and wave-like propagation of Ca2+ remain to be determined. To address this need, we acquired images of cytosolic Ca2+ transients in 1300 hepatocytes situated across several mouse liver lobules over a period of …

Propofol Inhibits The Voltage-Gated Sodium Channel Nachbac At Multiple Sites., Yali Wang, Elaine Yang, Marta M. Wells, Vasyl Bondarenko, Kellie Woll, Vincenzo Carnevale, Daniele Granata, Michael L. Klein, Roderic G. Eckenhoff, William P. Dailey, Manuel Covarrubias, Pei Tang, Yan Xu

Department of Neuroscience Faculty Papers

Voltage-gated sodium (Na_V) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic Na_V channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac. We then strategically place small fluorinated probes at these putative binding sites and experimentally quantify the interaction strengths with a fluorinated propofol analogue, 4-fluoropropofol. In vitro and in vivo measurements show that 4-fluoropropofol and propofol have similar effects …

High Fat Diet Upregulates Fatty Acid Oxidation And Ketogenesis Via Intervention Of Ppar-Γ., Kunal Sikder, Sanket Kumar Shukla, Neel Patel, Harpreet Singh, Khadija Rafiq

Center for Translational Medicine Faculty Papers

BACKGROUND/AIMS: Systemic hyperlipidemia and intracellular lipid accumulation induced by chronic high fat diet (HFD) leads to enhanced fatty acid oxidation (FAO) and ketogenesis. The present study was aimed to determine whether activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) by surplus free fatty acids (FA) in hyperlipidemic condition, has a positive feedback regulation over FAO and ketogenic enzymes controlling lipotoxicity and cardiac apoptosis.

METHODS: 8 weeks old C57BL/6 wild type (WT) or PPAR-γ-/- mice were challenged with 16 weeks 60% HFD to induce obesity mediated type 2 diabetes mellitus (T2DM) and diabetic cardiomyopathy. Treatment course was followed by echocardiographic measurements, glycemic and …

Diversity And Plasticity In Signaling Pathways That Regulate Smooth Muscle Responsiveness: Paradigms And Paradoxes For The Myosin Phosphatase, The Master Regulator Of Smooth Muscle Contraction., Masumi Eto, Toshio Kitazawa

Department of Molecular Physiology and Biophysics Faculty Papers

A hallmark of smooth muscle cells is their ability to adapt their functions to meet temporal and chronic fluctuations in their demands. These functions include force development and growth. Understanding the mechanisms underlying the functional plasticity of smooth muscles, the major constituent of organ walls, is fundamental to elucidating pathophysiological rationales of failures of organ functions. Also, the knowledge is expected to facilitate devising innovative strategies that more precisely monitor and normalize organ functions by targeting individual smooth muscles. Evidence has established a current paradigm that the myosin light chain phosphatase (MLCP) is a master regulator of smooth muscle responsiveness …

Cardiac Specific Overexpression Of Mitochondrial Omi/Htra2 Induces Myocardial Apoptosis And Cardiac Dysfunction., Ke Wang, Yuexing Yuan, Xin Liu, Wayne Bond Lau, Lin Zuo, Xiaoliang Wang, Lu Ma, Kun Jiao, Jianyu Shang, Wen Wang, Xinliang Ma, Huirong Liu

Department of Emergency Medicine Faculty Papers

Myocardial apoptosis is a significant problem underlying ischemic heart disease. We previously reported significantly elevated expression of cytoplasmic Omi/HtrA2, triggers cardiomyocytes apoptosis. However, whether increased Omi/HtrA2 within mitochondria itself influences myocardial survival in vivo is unknown. We aim to observe the effects of mitochondria-specific, not cytoplasmic, Omi/HtrA2 on myocardial apoptosis and cardiac function. Transgenic mice overexpressing cardiac-specific mitochondrial Omi/HtrA2 were generated and they had increased myocardial apoptosis, decreased systolic and diastolic function, and decreased left ventricular remodeling. Transiently or stably overexpression of mitochondria Omi/HtrA2 in H9C2 cells enhance apoptosis as evidenced by elevated caspase-3, -9 activity and TUNEL staining, which …

Neurophysiological Impact And Modeling-Independent Elucidation Of Inactivation Pathways In A-Type K+ Channels, J.D. Fineberg, David Ritter, Manuel Covarrubias

Department of Molecular Physiology and Biophysics Faculty Papers

Poster presented at Society for Neuroscience

Abstract:

A-type voltage-gated K⁺ channels auto-regulate their function by undergoing fast inactivation. Independent of molecular mechanisms, this inactivation can proceed after channel opening (open-state inactivation, OSI) or from a closed state prior to opening (closed-state inactivation, CSI). We hypothesize that the specific neurophysiological roles of A-type Kv channels depend on whether they undergo OSI, CSI or both (CSI+OSI). To explore these possibilities, we introduced Markov kinetic schemes of the A-type Kv4 conductance into a computational model of the hippocamcal CA1 neuron assuming either CSI or CSI+OSI and compared the properties of the somatic …

Increased Susceptibility To Metabolic Syndrome In Adult Offspring Of Angiotensin Type 1 Receptor Autoantibody-Positive Rats., Suli Zhang, Xi Zhang, Lihong Yang, Zi Yan, Li Yan, Jue Tian, Xiaoyu Li, Li Song, Li Wang, Xiaoli Yang, Ronghua Zheng, Wayne Bond Lau, Xinliang Ma, Huirong Liu

Department of Emergency Medicine Faculty Papers

Abstract Aims: Abnormal fetal and early postnatal growth is closely associated with adult-onset metabolic syndrome (MetS). However, the underlying etiological factors remain complex. The presence of the autoantibody against the angiotensin II type 1 receptor (AT1-Ab), a known risk factor for pre-eclampsia, may create a suboptimal intrauterine fetal environment. The current study investigated whether middle-aged offspring of AT1-Ab-positive mothers were prone to metabolic disorder development. Results: The AT1-Abs was detected in placental trophoblastic cells, capillary endothelium, and milk of pregnant rats actively immunized with the second extracellular loop of the AT1 receptor. AT1-Abs in newborn rats induced vasoconstriction, increased intracellular-free …

Perspectives On: Sgp Symposium On Mitochondrial Physiology And Medicine: Molecular Identities Of Mitochondrial Ca2+ Influx Mechanism: Updated Passwords For Accessing Mitochondrial Ca2+-Linked Health And Disease., Jin O-Uchi, Shi Pan, Shey-Shing Sheu

Center for Translational Medicine Faculty Papers

No abstract provided.

Essential Role Of Caveolin-3 In Adiponectin Signalsome Formation And Adiponectin Cardioprotection., Yajing Wang, Xiaoliang Wang, Jean-François Jasmin, Wayne Bond Lau, Rong Li, Yuexin Yuan, Wei Yi, Kurt Chuprun, Michael P. Lisanti, Walter J Koch, Erhe Gao, Xin-Liang Ma

Department of Emergency Medicine Faculty Papers

OBJECTIVE: Adiponectin (APN) system malfunction is causatively related to increased cardiovascular morbidity/mortality in diabetic patients. The aim of the current study was to investigate molecular mechanisms responsible for APN transmembrane signaling and cardioprotection.

METHODS AND RESULTS: Compared with wild-type mice, caveolin-3 knockout (Cav-3KO) mice exhibited modestly increased myocardial ischemia/reperfusion injury (increased infarct size, apoptosis, and poorer cardiac function recovery; P

CONCLUSIONS: Taken together, these results demonstrated for the first time that Cav-3 plays an essential role in APN transmembrane signaling and APN anti-ischemic/cardioprotective actions.

Identification Of The Functional Binding Pocket For Compounds Targeting Small-Conductance Ca²⁺-Activated Potassium Channels., Miao Zhang, John M Pascal, Marcel Schumann, Roger S Armen, Ji-Fang Zhang

Department of Molecular Physiology and Biophysics Faculty Papers

Small- and intermediate-conductance Ca(2+)-activated potassium channels, activated by Ca(2+)-bound calmodulin, have an important role in regulating membrane excitability. These channels are also linked to clinical abnormalities. A tremendous amount of effort has been devoted to developing small molecule compounds targeting these channels. However, these compounds often suffer from low potency and lack of selectivity, hindering their potential for clinical use. A key contributing factor is the lack of knowledge of the binding site(s) for these compounds. Here we demonstrate by X-ray crystallography that the binding pocket for the compounds of the 1-ethyl-2-benzimidazolinone (1-EBIO) class is located at the calmodulin-channel interface. …

Glucose Decouples Intracellular Ca2+ Activity From Glucagon Secretion In Mouse Pancreatic Islet Alpha-Cells., Sylvain J Le Marchand, David W Piston

Farber Institute for Neuroscience Faculty Papers

The mechanisms of glucagon secretion and its suppression by glucose are presently unknown. This study investigates the relationship between intracellular calcium levels ([Ca(2+)](i)) and hormone secretion under low and high glucose conditions. We examined the effects of modulating ion channel activities on [Ca(2+)](i) and hormone secretion from ex vivo mouse pancreatic islets. Glucagon-secreting α-cells were unambiguously identified by cell specific expression of fluorescent proteins. We found that activation of L-type voltage-gated calcium channels is critical for α-cell calcium oscillations and glucagon secretion at low glucose levels. Calcium channel activation depends on K(ATP) channel activity but not on tetrodotoxin-sensitive Na(+) channels. …

Analysis Of The Proteome Of Human Airway Epithelial Secretions., Mehboob Ali, Erik P Lillehoj, Yongsung Park, Yoshiyuki Kyo, K Chul Kim

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Airway surface liquid, often referred to as mucus, is a thin layer of fluid covering the luminal surface that plays an important defensive role against foreign particles and chemicals entering the lungs. Airway mucus contains various macromolecules, the most abundant being mucin glycoproteins, which contribute to its defensive function. Airway epithelial cells cultured in vitro secrete mucins and nonmucin proteins from their apical surface that mimics mucus production in vivo. The current study was undertaken to identify the polypeptide constituents of human airway epithelial cell secretions to gain a better understanding of the protein composition of respiratory mucus.

RESULTS: …

Upa Is Upregulated By High Dose Celecoxib In Women At Increased Risk Of Developing Breast Cancer., Wenyi Qin, Weizhu Zhu, John E Hewett, George Rottinghaus, Yin-Chieh Chen, John T Flynn, Beth Kliethermes, Ferdinando Mannello, Edward R Sauter

Department of Physiology Faculty Papers

BACKGROUND: While increased urokinase-type plasminogen activator (uPA) expression in breast cancer tissue is directly associated with poor prognosis, recent evidence suggests that uPA overexpression may suppress tumor growth and prolong survival. Celecoxib has been shown to have antiangiogenic and antiproliferative properties. We sought to determine if uPA, PA inhibitor (PAI)-1 and prostaglandin (PG)E2 expression in nipple aspirate fluid (NAF) and uPA and PGE2 expression in plasma were altered by celecoxib dose and concentration in women at increased breast cancer risk.

METHODS: NAF and plasma samples were collected in women at increased breast cancer risk before and 2 weeks after taking …