Digital Commons Network^™

Evidence That A Lipolytic Enzyme—Hematopoietic-Specific Phospholipase C-Β2—Promotes Mobilization Of Hematopoietic Stem Cells By Decreasing Their Lipid Raft-Mediated Bone Marrow Retention And Increasing The Promobilizing Effects Of Granulocytes, M. Adamiak, A. Poniewierska-Baran, S. Borkowska, G. Schneider, A. Abdelbaset-Ismail, M. Suszynska, Ahmed Abdel-Latif, M. Kucia, J. Ratajczak, M. Z. Ratajczak

Internal Medicine Faculty Publications

Hematopoietic stem/progenitor cells (HSPCs) reside in the bone marrow (BM) microenvironment and are retained there by the interaction of membrane lipid raft-associated receptors, such as the α-chemokine receptor CXCR4 and the α₄β₁-integrin (VLA-4, very late antigen 4 receptor) receptor, with their respective specific ligands, stromal-derived factor 1 and vascular cell adhesion molecule 1, expressed in BM stem cell niches. The integrity of the lipid rafts containing these receptors is maintained by the glycolipid glycosylphosphatidylinositol anchor (GPI-A). It has been reported that a cleavage fragment of the fifth component of the activated complement cascade, C5a, has an …

Impact Of Individual Acute Phase Serum Amyloid A Isoforms On Hdl Metabolism In Mice, Myung-Hee Kim, Maria C. De Beer, Joanne M. Wroblewski, Richard J. Charnigo, Ailing Ji, Nancy R. Webb, Frederick C. De Beer, Deneys R. Van Der Westhuyzen

Internal Medicine Faculty Publications

The acute phase (AP) reactant serum amyloid A (SAA), an HDL apolipoprotein, exhibits pro-inflammatory activities, but its physiological function(s) are poorly understood. Functional differences between SAA1.1 and SAA2.1, the two major SAA isoforms, are unclear. Mice deficient in either isoform were used to investigate plasma isoform effects on HDL structure, composition, and apolipoprotein catabolism. Lack of either isoform did not affect the size of HDL, normally enlarged in the AP, and did not significantly change HDL composition. Plasma clearance rates of HDL apolipoproteins were determined using native HDL particles. The fractional clearance rates (FCRs) of apoA-I, apoA-II, and SAA were …

Glycine N-Acyltransferase-Like 3 Is Responsible For Long-Chain N-Acylglycine Formation In N18Tg2 Cells, Kristen A Jeffries, Daniel R Dempsey, Emma K Farrell, Ryan L Anderson, Gabrielle J Garbade, Tatyana S Gurina, Imran Gruhonjic, Carly A Gunderson, David J Merkler

Chemistry Faculty Publications

Long-chain fatty acid amides are signaling lipids found in mammals and other organisms; however, details of the metabolic pathways for the N-acylglycines and primary fatty acid amides (PFAMs) have remained elusive. Heavy-labeled precursor and subtraction lipidomic experiments in mouse neuroblastoma N18TG2 cells, a model cell line for the study of fatty acid amide metabolism, establish the biosynthetic pathways for the N-acylglycines and the PFAMs. We provide evidence that the N-acylglycines are formed by a long-chain specific glycine-conjugating enzyme, glycine N-acyltransferase-like 3 (GLYATL3). siRNA knockdown of GLYATL3 in the N18TG2 cells resulted in a decrease in the levels of the N-acylglycines …

Correlation Of Maximal Inspiratory Pressure To Transdiaphragmatic Twitch Pressure In Intensive Care Unit Patients, Gerald S. Supinski, Philip M. Westgate, Leigh Ann Callahan

Internal Medicine Faculty Publications

Background: Respiratory muscle weakness contributes to respiratory failure in ICU patients. Unfortunately, assessment of weakness is difficult since the most objective test, transdiaphragmatic pressure in response to phrenic nerve stimulation (PdiTw), is difficult to perform. While most clinicians utilize maximum inspiratory pressure (Pimax) to assess strength, the relationship of this index to PdiTw has not been evaluated in a large ICU population. The purpose of the present study was to assess both PdiTw and Pimax in ICU patients to determine how these indices correlate with each other, what factors influence these indices, and how well these indices predict outcomes.

Methods: …

Vegfr2 Py949 Signalling Regulates Adherens Junction Integrity And Metastatic Spread, Xiujuan Li, Narendra Padhan, Elisabet O. Sjöström, Francis P. Roche, Chiara Testini, Naoki Honkura, Miguel Sáinz-Jaspeado, Emma Gordon, Katie Bentley, Andrew Philippides, Vladimir Tolmachev, Elisabetta Dejana, Radu V. Stan, Dietmar Vestweber, Kurt Ballmer-Hofer, Christer Betsholtz, Kristian Pietras, Leif Jansson, Lena Claesson-Welsh

Dartmouth Scholarship

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2^Y949F/Y949F leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2^Y949F/Y949F mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2^Y949F/Y949F mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory …

Arf6 Controls Platelet Spreading And Clot Retraction Via Integrin ΑIibΒ3 Trafficking, Yunjie Huang, Smita Joshi, Binggang Xiang, Yasunori Kanaho, Zhenyu Li, Beth A. Bouchard, Carole L. Moncman, Sidney W. Whiteheart

Molecular and Cellular Biochemistry Faculty Publications

Platelet and megakaryocyte endocytosis is important for loading certain granule cargo (ie, fibrinogen [Fg] and vascular endothelial growth factor); however, the mechanisms of platelet endocytosis and its functional acute effects are understudied. Adenosine 5'-diphosphate–ribosylation factor 6 (Arf6) is a small guanosine triphosphate–binding protein that regulates endocytic trafficking, especially of integrins. To study platelet endocytosis, we generated platelet-specific Arf6 knockout (KO) mice. Arf6 KO platelets had less associated Fg suggesting that Arf6 affects α_IIbβ₃-mediated Fg uptake and/or storage. Other cargo was unaffected. To measure Fg uptake, mice were injected with biotinylated- or fluorescein isothiocyanate (FITC)–labeled Fg. Platelets …

Smn Protein Can Be Reliably Measured In Whole Blood With An Electrochemiluminescence (Ecl) Immunoassay: Implications For Clinical Trials, Phillip Zaworski, Katharine M. Von Herrmann, Shannon Taylor, Sara S. Sunshine, Kathleen Mccarthy, Nicole Risher, Tara Newcomb, Marla Weetall, Thomas W. Prior, Kathryn J. Swoboda, Karen S. Chen, Sergey Paushkin

Dartmouth Scholarship

Spinal muscular atrophy (SMA) is caused by defects in the survival motor neuron 1 (SMN1) gene that encodes survival motor neuron (SMN) protein. The majority of therapeutic approaches currently in clinical development for SMA aim to increase SMN protein expression and there is a need for sensitive methods able to quantify increases in SMN protein levels in accessible tissues. We have developed a sensitive electrochemiluminescence (ECL)-based immunoassay for measuring SMN protein in whole blood with a minimum volume requirement of 5μL. The SMN-ECL immunoassay enables accurate measurement of SMN in whole blood and other tissues. Using the assay, …

Myonuclear Transcription Is Responsive To Mechanical Load And Dna Content But Uncoupled From Cell Size During Hypertrophy, Tyler J. Kirby, Rooshil M. Patel, Timothy S. Mcclintock, Esther E. Dupont-Versteegden, Charlotte A. Peterson, John J. Mccarthy

Physiology Faculty Publications

Myofibers increase size and DNA content in response to a hypertrophic stimulus, thus providing a physiological model with which to study how these factors affect global transcription. Using 5-ethynyl uridine (EU) to metabolically label nascent RNA, we measured a sevenfold increase in myofiber transcription during early hypertrophy before a change in cell size and DNA content. The typical increase in myofiber DNA content observed at the later stage of hypertrophy was associated with a significant decrease in the percentage of EU-positive myonuclei; however, when DNA content was held constant by preventing myonuclear accretion via satellite cell depletion, both the number …

Neurogenesis-Mediated Forgetting Minimizes Proactive Interference., Jonathan R Epp, Rudy Silva Mera, Stefan Köhler, Sheena A Josselyn, Paul W Frankland

Brain and Mind Institute Researchers' Publications

Established memories may interfere with the encoding of new memories, particularly when existing and new memories overlap in content. By manipulating levels of hippocampal neurogenesis, here we show that neurogenesis regulates this form of proactive interference. Increasing hippocampal neurogenesis weakens existing memories and, in doing so, facilitates the encoding of new, conflicting (but not non-conflicting) information in mice. Conversely, decreasing neurogenesis stabilizes existing memories, and impedes the encoding of new, conflicting information. These results suggest that reduced proactive interference is an adaptive benefit of neurogenesis-induced forgetting.

Cddo-Me Redirects Activation Of Breast Tumor Associated Macrophages, Michael S. Ball, Emilie P. Shipman, Hyunjung Kim, Karen T. Liby, Patricia A. Pioli

Dartmouth Scholarship

Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression …

Herpes Simplex Virus And Interferon Signaling Induce Novel Autophagic Clusters In Sensory Neurons, Sarah Katzenell, David A. Leib

Dartmouth Scholarship

Herpes simplex virus 1 (HSV-1) establishes lifelong infection in the neurons of trigeminal ganglia (TG), cycling between productive infection and latency. Neuronal antiviral responses are driven by type I interferon (IFN) and are crucial to controlling HSV-1 virulence. Autophagy also plays a role in this neuronal antiviral response, but the mechanism remains obscure. In this study, HSV-1 infection of murine TG neurons triggered unusual clusters of autophagosomes, predominantly in neurons lacking detectable HSV-1 antigen. Treatment of neurons with IFN-β induced a similar response, and cluster formation by infection or IFN treatment was dependent upon an intact IFN-signaling pathway. The autophagic …

Mw151 Inhibited Il-1Β Levels After Traumatic Brain Injury With No Effect On Microglia Physiological Responses, Adam D. Bachstetter, Zhengqiu Zhou, Rachel K. Rowe, Bin Xing, Danielle S. Goulding, Alyssa N. Conley, Pradoldej Sompol, Shelby Meier, Jose F. Abisambra, Jonathan Lifshitz, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

A prevailing neuroinflammation hypothesis is that increased production of proinflammatory cytokines contributes to progressive neuropathology, secondary to the primary damage caused by a traumatic brain injury (TBI). In support of the hypothesis, post-injury interventions that inhibit the proinflammatory cytokine surge can attenuate the progressive pathology. However, other post-injury neuroinflammatory responses are key to endogenous recovery responses. Therefore, it is critical that pharmacological attenuation of detrimental or dysregulated neuroinflammatory processes avoid pan-suppression of inflammation. MW151 is a CNS-penetrant, small molecule experimental therapeutic that restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis without immunosuppression. Post-injury administration of MW151 in a …

Pi(4)P Promotes Phosphorylation And Conformational Change Of Smoothened Through Interaction With Its C-Terminal Tail, Kai Jiang, Yajuan Liu, Junkai Fan, Jie Zhang, Xiang-An Li, B. Mark Evers, Haining Zhu, Jianhang Jia

Markey Cancer Center Faculty Publications

In Hedgehog (Hh) signaling, binding of Hh to the Patched-Interference Hh (Ptc-Ihog) receptor complex relieves Ptc inhibition on Smoothened (Smo). A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulation. In this study, we found that Hh elevates production of phosphatidylinositol 4-phosphate (PI(4)P). Increased levels of PI(4)P promote, whereas decreased levels of PI(4)P inhibit, Hh signaling activity. We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation. Moreover, we identified the pleckstrin homology (PH) domain of G protein-coupled receptor kinase 2 (Gprk2) as an …

The Role Of Pas Kinase And The Gut Microbiome In Metabolism And Diabetes Onset In Mice, Andrew Rees, Laura Bridgewater

Journal of Undergraduate Research

Diabetes and obesity are among the most prevalent health concerns in the modern world. However, prevention of their onset and control of their symptoms are still largely limited by our understanding of how these diseases arise. Recent research has indicated that the composition of the gut microbiome is one of the important factors in development of these diseases (5). However, current thinking is not definitive on the relative importance of genetic factors, diet and the gut microbiome, among other factors (5,6). PAS Kinase provided a model through which we could compare the relative affects of genetics, gut microbiome and diet …

Oncomodulin, An Ef-Hand Ca2+ Buffer, Is Critical For Maintaining Cochlear Function In Mice, Benton Tong, Aubrey J. Hornak, Stéphane F. Maison, Kevin K. Ohlemiller, M Charles Liberman, Dwayne D. Simmons

Open Access Publications

UNLABELLED: Oncomodulin (Ocm), a member of the parvalbumin family of calcium binding proteins, is expressed predominantly by cochlear outer hair cells in subcellular regions associated with either mechanoelectric transduction or electromotility. Targeted deletion of Ocm caused progressive cochlear dysfunction. Although sound-evoked responses are normal at 1 month, by 4 months, mutants show only minimal distortion product otoacoustic emissions and 70-80 dB threshold shifts in auditory brainstem responses. Thus, Ocm is not critical for cochlear development but does play an essential role for cochlear function in the adult mouse.

SIGNIFICANCE STATEMENT: Numerous proteins act as buffers, sensors, or pumps to control …

Gap Junction Mediated Mirna Intercellular Transfer And Gene Regulation: A Novel Mechanism For Intercellular Genetic Communication, Liang Zong, Yan Zhu, Ruqiang Liang, Hong-Bo Zhao

Otolaryngology--Head & Neck Surgery Faculty Publications

Intercellular genetic communication is an essential requirement for coordination of cell proliferation and differentiation and has an important role in many cellular processes. Gap junction channels possess large pore allowing passage of ions and small molecules between cells. MicroRNAs (miRNAs) are small regulatory RNAs that can regulate gene expression broadly. Here, we report that miRNAs can pass through gap junction channels in a connexin-dependent manner. Connexin43 (Cx43) had higher permeability, whereas Cx30 showed little permeability to miRNAs. In the tested connexin cell lines, the permeability to miRNAs demonstrated: Cx43 > Cx26/30 > Cx26 > Cx31 > Cx30 = Cx-null. However, consistent with a uniform …

Estrogen Receptor Alpha (Esr1)-Dependent Regulation Of The Mouse Oviductal Transcriptome, Katheryn L. Cerny, Rosanne A. C. Ribeiro, Myoungkun Jeoung, Chemyong Ko, Phillip J. Bridges

Animal and Food Sciences Faculty Publications

Estrogen receptor-α (ESR1) is an important transcriptional regulator in the mammalian oviduct, however ESR1-dependent regulation of the transcriptome of this organ is not well defined, especially at the genomic level. The objective of this study was therefore to investigate estradiol- and ESR1-dependent regulation of the transcriptome of the oviduct using transgenic mice, both with (ESR1KO) and without (wild-type, WT) a global deletion of ESR1. Oviducts were collected from ESR1KO and WT littermates at 23 days of age, or ESR1KO and WT mice were treated with 5 IU PMSG to stimulate follicular development and the production of ovarian estradiol, and the …

A Comprehensive Behavioral Test Battery To Assess Learning And Memory In 129s6/Tg2576 Mice, Andrea Wolf, Björn Bauer, Erin L. Abner, Tal Ashkenazy-Frolinger, Anika M. S. Hartz

Pharmaceutical Sciences Faculty Publications

Transgenic Tg2576 mice overexpressing human amyloid precursor protein (hAPP) are a widely used Alzheimer’s disease (AD) mouse model to evaluate treatment effects on amyloid beta (Aβ) pathology and cognition. Tg2576 mice on a B6;SJL background strain carry a recessive rd1 mutation that leads to early retinal degeneration and visual impairment in homozygous carriers. This can impair performance in behavioral tests that rely on visual cues, and thus, affect study results. Therefore, B6;SJL/Tg2576 mice were systematically backcrossed with 129S6/SvEvTac mice resulting in 129S6/Tg2576 mice that lack the rd1 mutation. 129S6/Tg2576 mice do not develop retinal degeneration but still show Aβ accumulation …

H2ax Deficiency Is Associated With Erythroid Dysplasia And Compromised Haematopoietic Stem Cell Function, Baobing Zhao, Timothy L. Tan, Yang Mei, Jing Yang, Yiting Yu, Amit Verma, Ying Liang, Juehua Gao, Peng Ji

Toxicology and Cancer Biology Faculty Publications

Myelodysplastic syndromes (MDS) are clonal disorders of haematopoiesis characterised by dysplastic changes of major myeloid cell lines. However, the mechanisms underlying these dysplastic changes are poorly understood. Here, we used a genetically modified mouse model and human patient data to examine the physiological roles of H2AX in haematopoiesis and how the loss of H2AX contributes to dyserythropoiesis in MDS. H2AX knockout mice showed cell-autonomous anaemia and erythroid dysplasia, mimicking dyserythropoiesis in MDS. Also, dyserythropoiesis was increased in MDS patients with the deletion of chromosome 11q23, where H2AX is located. Although loss of H2AX did not affect the early stage of …

Obesity-Induced Colorectal Cancer Is Driven By Caloric Silencing Of The Guanylin-Gucy2c Paracrine Signaling Axis., Jieru E. Lin, Francheska Colon-Gonzalez, Erik S. Blomain, Gilbert W. Kim, Amanda Aing, Brian Stoecker, Justin Rock, Adam E. Snook, Tingting Zhan, Terry M. Hyslop, Michal Tomczak, Richard S. Blumberg, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations …

Effect Of Hydroxychloroquine And Characterization Of Autophagy In A Mouse Model Of Endometriosis, A. Ruiz, S. Rockfield, N. Taran, E. Haller, Robert Engelman, I Flores, P Panina-Bordignon, Meera Nanjundan

Molecular Biosciences Faculty Publications

In endometriosis, the increased survival potential of shed endometrial cells (which normally undergo anoikis) is suggested to promote lesion development. One mechanism that may alter anoikis is autophagy. Using an autophagic flux inhibitor hydroxychloroquine (HCQ), we identified that it reduces the in vitro survival capacity of human endometriotic and endometrial T-HESC cells. We also identified that HCQ could decrease lesion numbers and disrupt lesion histopathology, as well as increase the levels of peritoneal macrophages and the IP-10 (10 kDa interferon-γ-induced protein) chemokine in a mouse model of endometriosis. We noted that RNA levels of a subset of autophagic …

Analyzing Clustered Data: Why And How To Account For Multiple Observations Nested Within A Study Participant?, Erika L. Moen, Catherine J. Fricano-Kugler, Bryan W. Luikart, A. James O’Malley

Dartmouth Scholarship

A conventional study design among medical and biological experimentalists involves col- lecting multiple measurements from a study subject. For example, experiments utilizing mouse models in neuroscience often involve collecting multiple neuron measurements per mouse to increase the number of observations without requiring a large number of mice. This leads to a form of statistical dependence referred to as clustering. Inappropriate analy- ses of clustered data have resulted in several recent critiques of neuroscience research that suggest the bar for statistical analyses within the field is set too low. We compare naïve ana- lytical approaches to marginal, fixed-effect, and mixed-effect models …

Non-Alcoholic Fatty Liver Disease Induces Signs Of Alzheimer’S Disease (Ad) In Wild-Type Mice And Accelerates Pathological Signs Of Ad In An Ad Model, Do-Geun Kim, Antje Krenz, Leon E. Toussaint, Kirk J. Maurer

Dartmouth Scholarship

Background: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world's population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and subsequent liver pathology. Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer's disease (AD). Here, we investigated NAFLD-induced liver inflammation in the pathogenesis of AD.

Methods: WT and APP-Tg mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 2, 5 months, or 1 year to induce NAFLD. Another …

Serum Amyloid A Impairs The Antiinflammatory Properties Of Hdl, Chang Yeop Han, Chongren Tang, Myriam E. Guevara, Hao Wei, Tomasz Wietecha, Baohai Shao, Savitha Subramanian, Mohamed Omer, Shari Wang, Kevin D. O'Brien, Santica M. Marcovina, Thomas N. Wight, Tomas Vaisar, Maria C. De Beer, Frederick C. De Beer, William R. Osborne, Keith B. Elkon, Alan Chait

Physiology Faculty Publications

HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO₃ fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO₃-injected mice lacking Saa1.1 …

Integrative Analysis Of Breast Cancer Reveals Prognostic Haematopoietic Activity And Patient-Specific Immune Response Profiles, Frederick S. Varn, Erik H. Andrews, David W. Mullins, Chao Cheng

Dartmouth Scholarship

Transcriptional programmes active in haematopoietic cells enable a variety of functions including dedifferentiation, innate immunity and adaptive immunity. Understanding how these programmes function in the context of cancer can provide valuable insights into host immune response, cancer severity and potential therapy response. Here we present a method that uses the transcriptomes of over 200 murine haematopoietic cells, to infer the lineage-specific haematopoietic activity present in human breast tumours. Correlating this activity with patient survival and tumour purity reveals that the transcriptional programmes of many cell types influence patient prognosis and are found in environments of high lymphocytic infiltration. Collectively, these …

Paternal Exposure To Low-Dose Lead Acetate: Effect On Implantation Rate,Pregnancy Outcome, And Sex Ratio In Mice, Basima Al-Juboori, Farqad Hamdan, Anam Al-Salihi

Turkish Journal of Medical Sciences

Background/aim: It has been reported from in vivo exposed experimental animals that paternal lead exposure reduces birth rate; however, there is limited evidence to suggest a decrease in the proportion of male births. This study investigated the role of paternal exposure to lower lead acetate doses on early embryonic development (implantation) and the sex ratio of their offspring. Materials and methods: In total 180 Swiss Webster mice were used (60 male and 120 female). The males were divided into 3 groups: G1 (untreated group), G2 (treated daily with 50 μg/kg BW lead acetate), and G3 (treated daily with 100 μg/kg …

Upregulation Of Rgs2: A New Mechanism For Pirfenidone Amelioration Of Pulmonary Fibrosis, Yan Xie, Haihong Jiang, Qian Zhang, Suneet Mehrotra, Peter W. Abel, Myron L. Toews, Dennis W. Wolff, Stephen I. Rennard, Reynold A. Panettieri, Thomas B. Casale, Yaping Tu

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Pirfenidone was recently approved for treatment of idiopathic pulmonary fibrosis. However, the therapeutic dose of pirfenidone is very high, causing side effects that limit its doses and therapeutic effectiveness. Understanding the molecular mechanisms of action of pirfenidone could improve its safety and efficacy. Because activated fibroblasts are critical effector cells associated with the progression of fibrosis, this study investigated the genes that change expression rapidly in response to pirfenidone treatment of pulmonary fibroblasts and explored their contributions to the anti-fibrotic effects of pirfenidone.

METHODS: We used the GeneChip microarray to screen for genes that were rapidly up-regulated upon exposure …

Redox Control Of Antioxidant And Antihepatotoxic Activities Ofcassia Surattensisseed Extract Against Paracetamol Intoxication In Mice: In Vitro And In Vivo Studies Of Herbal Green Antioxidant, U.S. Uthaya Kumar, Y. Chen, J.R. Kanwar, S. Sasidharan

Research Publications (2016 to 2020)

The therapeutic potential of Cassia surattensis in reducing free radical-induced oxidative stress and inflammation particularly in hepatic diseases was evaluated in this study. The polyphenol rich C. surattensis seed extract showed good in vitro antioxidant. C. surattensis seed extract contained total phenolic content of 100.99 mg GAE/g dry weight and there was a positive correlation () between total phenolic content and the antioxidant activities of the seed extract. C. surattensis seed extract significantly () reduced the elevated levels of serum liver enzymes (ALT, AST, and ALP) and relative liver weight in paracetamol-induced liver hepatotoxicity in mice. Moreover, the extract significantly …

The Synergistic Roles Of Cholecystokinin B And Dopamine D5 Receptors On The Regulation Of Renal Sodium Excretion., Xiaoliang Jiang, Wei Chen, Xing Liu, Zihao Wang, Yunpeng Liu, Robin A Felder, John J Gildea, Pedro A. Jose, Chuan Qin, Zhiwei Yang

Medicine Faculty Publications

Renal dopamine D1-like receptors (D1R and D5R) and the gastrin receptor (CCKBR) are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT) cells to promote natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR increase each other's expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was …

Antibodies Against A Secreted Product Of Staphylococcus Aureus Trigger Phagocytic Killing, Lena Thomer, Carla Emolo, Vilasack Thammavongsa, Hwan Keun Kim, Molly E. Mcadow, Wenqi Yu, Matthew Kieffer, Olaf Schneewind, Dominique Missiakas

Molecular Biosciences Faculty Publications

Host immunity against bacteria typically involves antibodies that recognize the microbial surface and promote phagocytic killing. Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of lethal bloodstream infection; however, vaccines and antibody therapeutics targeting staphylococcal surface molecules have thus far failed to achieve clinical efficacy. S. aureus secretes coagulase (Coa), which activates host prothrombin and generates fibrin fibrils that protect the pathogen against phagocytosis by immune cells. Because of negative selection, the coding sequence for the prothrombin-binding D1-D2 domain is highly variable and does not elicit cross-protective immune responses. The R domain, tandem repeats of a 27-residue peptide that bind …