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Gupta M, Das N, Mohanty S, Shunmugam R. Hydrogen Sulfide Induced Unique Twisted-Rod Assemblies from Norbornene-Based Polymer in Aqueous Environment as Gasotransmitter Regulators. Chem Asian J 2025; 20:e202401571. [PMID: 39946149 DOI: 10.1002/asia.202401571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 02/05/2025] [Indexed: 03/14/2025]
Abstract
Hydrogen sulfide, being a poisonous pollutant, (H2S) is known for its pungent smell. Although it is having significant role in the biological and physiological processes as a potential biomarker in the present day. The over-expression of H2S leads to several biological disorders and diseases, therefore, monitoring the level of H2S in the biological pH is important. Optical sensors to detect hydrogen sulfide have gained popularity due to their cost-effectiveness, portability, fast response, etc. Here, we are designing a norbornene-based polymeric bio-sensor for detecting hydrogen sulfide in physiological pH. Hydrophilic and hydrophobic monomers are strategically crafted to permeate polymeric sensors with water solubility and the ability to detect hydrogen sulfide, respectively. These monomers are polymerized by ring-opening metathesis polymerization (ROMP). The probe is characterized by nuclear magnetic resonance (NMR) spectroscopy, fluorescence, and UV-visible absorbance spectra. The polymeric sensor can selectively detect hydrogen sulfide with high sensitivity by turn-on fluorescence responses. Moreover, this probe efficiently conducts the morphological changes associated with sensing phenomena. The collapsed vesicles are nicely converted into twisted rods. One dimentional structures (such as twisted rods, etc.) are becoming very interesting as they have fascinating structural and functional properties. Having application in biomedical fields such as targeted drug delivery, imaging, and scaffolds for tissue engineering, it also can exhibits improved mechanical strength, flexibility, unique optical properties, increased surface area, etc. This probe is biocompatible and has the scopes for bio-imaging. Therefore, this water-soluble polymeric probe can open new bio-medical applications for detecting analytes.
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Affiliation(s)
- Moumita Gupta
- Polymer Research Center, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER), Kolkata, West Bengal, 741246, India
| | - Narayan Das
- Polymer Research Center, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER), Kolkata, West Bengal, 741246, India
| | - Srujana Mohanty
- Polymer Research Center, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER), Kolkata, West Bengal, 741246, India
| | - Raja Shunmugam
- Polymer Research Center, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER), Kolkata, West Bengal, 741246, India
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Liewhiran C, Punginsang M, Inyawilert K, Siriwalai M, Wisitsoraat A. Selectivity toward H2S against various gaseous disease markers in exhaled breath of flame-produced CuOx-loaded SnO2 nanosensors. SENSORS AND ACTUATORS B: CHEMICAL 2025; 424:136856. [DOI: 10.1016/j.snb.2024.136856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Coavoy-Sanchez SA, da Costa Marques LA, Costa SKP, Muscara MN. Role of Gasotransmitters in Inflammatory Edema. Antioxid Redox Signal 2024; 40:272-291. [PMID: 36974358 DOI: 10.1089/ars.2022.0089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
Significance: Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are, to date, the identified members of the gasotransmitter family, which consists of gaseous signaling molecules that play central roles in the regulation of a wide variety of physiological and pathophysiological processes, including inflammatory edema. Recent Advances: Recent studies show the potential anti-inflammatory and antiedematogenic effects of NO-, CO-, and H2S-donors in vivo. In general, it has been observed that the therapeutical effects of NO-donors are more relevant when administered at low doses at the onset of the inflammatory process. Regarding CO-donors, their antiedematogenic effects are mainly associated with inhibition of proinflammatory mediators (such as inducible NO synthase [iNOS]-derived NO), and the observed protective effects of H2S-donors seem to be mediated by reducing some proinflammatory enzyme activities. Critical Issues: The most recent investigations focus on the interactions among the gasotransmitters under different pathophysiological conditions. However, the biochemical/pharmacological nature of these interactions is neither general nor fully understood, although specifically dependent on the site where the inflammatory edema occurs. Future Directions: Considering the nature of the involved mechanisms, a deeper knowledge of the interactions among the gasotransmitters is mandatory. In addition, the development of new pharmacological tools, either donors or synthesis inhibitors of the three gasotransmitters, will certainly aid the basic investigations and open new strategies for the therapeutic treatment of inflammatory edema. Antioxid. Redox Signal. 40, 272-291.
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Affiliation(s)
| | | | - Soraia Katia Pereira Costa
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
| | - Marcelo Nicolas Muscara
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
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Claßen R, Diener M, Pouokam E. Gasotransmitters do not prevent changes in transepithelial ion transport induced by hypoxia followed by reoxygenation. J Basic Clin Physiol Pharmacol 2024; 35:61-70. [PMID: 38263911 DOI: 10.1515/jbcpp-2023-0034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 12/28/2023] [Indexed: 01/25/2024]
Abstract
OBJECTIVES How gaseous signalling molecules affect ion transport processes contributing to the physiological functions of the gastrointestinal tract under hypoxic conditions still needs to be clarified. The objective of the present study was to characterize the impact of gaseous signalling molecules on parameters of colonic ion transport during a hypoxia/reoxygenation cycle and the remaining secretory capacity of the epithelium after such a cycle. METHODS Short-circuit current (Isc) and tissue conductance (Gt) recordings in Ussing chamber experiments were performed on rat colon samples using CORM-2 (putative CO donor; 35 and 350 µM), sodium nitroprusside (NO donor; 100 µM), NaHS (fast H2S donor; 10 - 1,000 µM), GYY 4137 (slow H2S donor; 50 µM) and Angeli's salt (HNO donor; 100 µM) as donors for gasotransmitters. Inhibition of endogenous synthesis of H2S was operated by inhibitors of cystathionin-γ-lyase, i.e. dl-propargylglycine (1 mM) or β-cyano-l-alanine (5 mM), and the inhibitor of cystathionine-β-synthase, amino-oxyacetate (5 mM). RESULTS The fast gasotransmitter donors NaHS, sodium nitroprusside and Angeli's salt, administered 5 min before the onset of hypoxia, induced an increase in Isc. The response to the subsequently applied hypoxia was characterized by a decrease in Isc, which tended to be reduced only in the presence of the lowest concentration of NaHS (10 µM) tested. Reoxygenation resulted in a slow increase in Isc, which was unaffected by all donors or inhibitors tested. The stable acetylcholine derivative carbachol (50 µM) was administered at the end of each hypoxia/reoxygenation cycle to test the secretory capacity of the epithelium. Pretreatment of the tissue with the putative CO donor CORM-2 suppressed the secretory response induced by carbachol. The same was observed when cystathionin-γ-lyase and cystathionin-γ-synthase were inhibited simultaneously. Under both conditions, Gt drastically increased suggesting an impaired tissue integrity. CONCLUSIONS The present results demonstrate that none of the exogenous gasotransmitter releasing drugs significantly ameliorated the changes in epithelial ion transport during the hypoxia/reoxygenation cycle ex vivo. In contrast, the putative CO donor CORM-2 exerted a toxic effect on the epithelium. The endogenous production of H2S, however, seems to have a protective effect on the mucosal integrity and the epithelial transport functions, which - when inhibited - leads to a loss of the secretory ability of the mucosa. This observation together with the trend for improvement observed with a low concentration of the H2S donor NaHS suggests a moderate protective role of low concentrations of H2S under hypoxic conditions.
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Affiliation(s)
- Rebecca Claßen
- Institute for Veterinary Physiology and Biochemistry, Justus-Liebig-Universitat Giessen, Giessen, Germany
| | - Martin Diener
- Institute for Veterinary Physiology and Biochemistry, Justus-Liebig-Universitat Giessen, Giessen, Germany
| | - Ervice Pouokam
- Institute for Veterinary Physiology and Biochemistry, Justus-Liebig-Universitat Giessen, Giessen, Germany
- Department of Human Medicine, MSB Medical School Berlin, Rüdesheimer Str. 50, 14197 Berlin, Germany
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Li X, Ji S, Cipriani G, Hillestad ML, Eisenman ST, Barry MA, Nath KA, Linden DR, Wright A, AlAsfoor S, Grover M, Sha L, Hsi LC, Farrugia G. Adeno-associated virus-9 reverses delayed gastric emptying of solids in diabetic mice. Neurogastroenterol Motil 2023; 35:e14669. [PMID: 37702100 PMCID: PMC10841310 DOI: 10.1111/nmo.14669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 06/07/2023] [Accepted: 08/14/2023] [Indexed: 09/14/2023]
Abstract
BACKGROUND Gastroparesis is defined by delayed gastric emptying (GE) without obstruction. Studies suggest targeting heme oxygenase-1 (HO1) may ameliorate diabetic gastroparesis. Upregulation of HO1 expression via interleukin-10 (IL-10) in the gastric muscularis propria is associated with reversal of delayed GE in diabetic NOD mice. IL-10 activates the M2 cytoprotective phenotype of macrophages and induces expression of HO1 protein. Here, we assess delivery of HO1 by recombinant adeno-associated viruses (AAVs) in diabetic mice with delayed GE. METHODS C57BL6 diabetic delayed GE mice were injected with 1 × 1012 vg scAAV9-cre, scAAV9-GFP, or scAAV9-HO1 particles. Changes to GE were assessed weekly utilizing our [13 C]-octanoic acid breath test. Stomach tissue was collected to assess the effect of scAAV9 treatment on Kit, NOS1, and HO1 expression. KEY RESULTS Delayed GE returned to normal within 2 weeks of treatment in 7/12 mice receiving scAAV9-cre and in 4/5 mice that received the scAAV9-GFP, whereas mice that received scAAV9-HO1 did not respond in the same manner and had GE that took significantly longer to return to normal (6/7 mice at 4-6 weeks). Kit, NOS1, and HO1 protein expression in scAAV9-GFP-treated mice with normal GE were not significantly different compared with diabetic mice with delayed GE. CONCLUSIONS AND INFERENCES Injection of scAAV9 into diabetic C57BL6 mice produced a biological response that resulted in acceleration of GE independently of the cargo delivered by the AAV9 vector. Further research is needed to determine whether use of AAV mediated gene transduction in the gastric muscularis propria is beneficial and warranted.
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Affiliation(s)
- Xiaojie Li
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
| | - Sihan Ji
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
| | - Gianluca Cipriani
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
| | | | - Seth T. Eisenman
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - Michael A. Barry
- Department of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, Mn, USA
| | - Karl A. Nath
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
- Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Mn, USA
| | - David R. Linden
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
| | - Alec Wright
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - Shefaa AlAsfoor
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
| | - Madhusudan Grover
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
| | - Lei Sha
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
| | - Linda C. Hsi
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
| | - Gianrico Farrugia
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
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Reiländer S, Schmehl W, Popp K, Nuss K, Kronen P, Verdino D, Wiezorek C, Gutmann M, Hahn L, Däubler C, Meining A, Raschig M, Kaiser F, von Rechenberg B, Scherf-Clavel O, Meinel L. Oral Use of Therapeutic Carbon Monoxide for Anyone, Anywhere, and Anytime. ACS Biomater Sci Eng 2022. [DOI: 10.1021/acsbiomaterials.2c00464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Simon Reiländer
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Wolfgang Schmehl
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Kevin Popp
- German Plastics Center (SKZ), Friedrich-Bergius-Ring 22, Wuerzburg97076, Germany
| | - Katja Nuss
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
| | - Peter Kronen
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
| | - Dagmar Verdino
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
| | - Christina Wiezorek
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
| | - Marcus Gutmann
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Lukas Hahn
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Christof Däubler
- Department of Internal Medicine II, Gastroenterology, University Hospital Wuerzburg, Oberdürrbacherstr. 6, Wuerzburg97080, Germany
| | - Alexander Meining
- Department of Internal Medicine II, Gastroenterology, University Hospital Wuerzburg, Oberdürrbacherstr. 6, Wuerzburg97080, Germany
| | - Martina Raschig
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Friederike Kaiser
- Department for Functional Materials in Medicine and Dentistry, University of Würzburg, Pleicherwall 2, Würzburg97070, Germany
| | - Brigitte von Rechenberg
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
| | - Oliver Scherf-Clavel
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Lorenz Meinel
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
- Helmholtz Institute for RNA-based Infection Biology (HIRI), Würzburg97070, Germany
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Role of Heme Oxygenase in Gastrointestinal Epithelial Cells. Antioxidants (Basel) 2022; 11:antiox11071323. [PMID: 35883814 PMCID: PMC9311893 DOI: 10.3390/antiox11071323] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 02/04/2023] Open
Abstract
The gastrointestinal tract is a unique organ containing both vascular and luminal routes lined by epithelial cells forming the mucosa, which play an important role in the entry of nutrients and act as a selective barrier, excluding potentially harmful agents. Mucosal surfaces establish a selective barrier between hostile external environments and the internal milieu. Heme is a major nutritional source of iron and is a pro-oxidant that causes oxidative stress. Heme oxygenases (HOs) catalyze the rate-limiting step in heme degradation, resulting in the formation of iron, carbon monoxide, and biliverdin, which are subsequently converted to bilirubin by biliverdin reductase. In gastrointestinal pathogenesis, HO-1, an inducible isoform of HO, is markedly induced in epithelial cells and plays an important role in protecting mucosal cells. Recent studies have focused on the biological effects of the products of this enzymatic reaction, which have antioxidant, anti-inflammatory, and cytoprotective functions. In this review, the essential roles of HO in the gastrointestinal tract are summarized, focusing on nutrient absorption, protection against cellular stresses, and the maintenance and regulation of tight junction proteins, emphasizing the potential therapeutic implications. The biochemical basis of the potential therapeutic implications of glutamine for HO-1 induction in gastrointestinal injury is also discussed.
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Hopper CP, De La Cruz LK, Lyles KV, Wareham LK, Gilbert JA, Eichenbaum Z, Magierowski M, Poole RK, Wollborn J, Wang B. Role of Carbon Monoxide in Host-Gut Microbiome Communication. Chem Rev 2020; 120:13273-13311. [PMID: 33089988 DOI: 10.1021/acs.chemrev.0c00586] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Nature is full of examples of symbiotic relationships. The critical symbiotic relation between host and mutualistic bacteria is attracting increasing attention to the degree that the gut microbiome is proposed by some as a new organ system. The microbiome exerts its systemic effect through a diverse range of metabolites, which include gaseous molecules such as H2, CO2, NH3, CH4, NO, H2S, and CO. In turn, the human host can influence the microbiome through these gaseous molecules as well in a reciprocal manner. Among these gaseous molecules, NO, H2S, and CO occupy a special place because of their widely known physiological functions in the host and their overlap and similarity in both targets and functions. The roles that NO and H2S play have been extensively examined by others. Herein, the roles of CO in host-gut microbiome communication are examined through a discussion of (1) host production and function of CO, (2) available CO donors as research tools, (3) CO production from diet and bacterial sources, (4) effect of CO on bacteria including CO sensing, and (5) gut microbiome production of CO. There is a large amount of literature suggesting the "messenger" role of CO in host-gut microbiome communication. However, much more work is needed to begin achieving a systematic understanding of this issue.
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Affiliation(s)
- Christopher P Hopper
- Institute for Experimental Biomedicine, University Hospital Wuerzburg, Wuerzburg, Bavaria DE 97080, Germany.,Department of Medicinal Chemistry, College of Pharmacy, The University of Florida, Gainesville, Florida 32611, United States
| | - Ladie Kimberly De La Cruz
- Department of Chemistry & Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303, United States
| | - Kristin V Lyles
- Department of Biology, Georgia State University, Atlanta, Georgia 30303, United States
| | - Lauren K Wareham
- The Vanderbilt Eye Institute and Department of Ophthalmology & Visual Sciences, The Vanderbilt University Medical Center and School of Medicine, Nashville, Tennessee 37232, United States
| | - Jack A Gilbert
- Department of Pediatrics, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
| | - Zehava Eichenbaum
- Department of Biology, Georgia State University, Atlanta, Georgia 30303, United States
| | - Marcin Magierowski
- Cellular Engineering and Isotope Diagnostics Laboratory, Department of Physiology, Jagiellonian University Medical College, Cracow PL 31-531, Poland
| | - Robert K Poole
- Department of Molecular Biology and Biotechnology, The University of Sheffield, Firth Court, Sheffield S10 2TN, U.K
| | - Jakob Wollborn
- Department of Anesthesiology and Critical Care, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg DE 79085, Germany.,Department of Anesthesiology, Perioperative and Pain Management, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Binghe Wang
- Department of Chemistry & Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303, United States
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Wang S, Wang R, Zhang Y, Zhang X, Cai B, Lu Y, Xia Y, Chen Q. Therapies for diabetic gastroparesis: A protocol for a systematic review and network meta-analysis. Medicine (Baltimore) 2020; 99:e20461. [PMID: 32481350 PMCID: PMC7249871 DOI: 10.1097/md.0000000000020461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetic gastroparesis (DG) is a common autonomic neuropathy which impacts on nutritional state and quality of life in diabetic patients, and it also adversely affects glycemic control in diabetes. The prevalence of DG is growing with the number of patients with diabetes continues to increase. However, there is no definitive answer as to which of the current therapies is the best for the clinical treatment of the different manifestations of DG. The subject of this study is to answer the following question: what is the best intervention for diabetic patients with gastroparesis? METHODS Comprehensive searches of the Cochrane Library, PubMed, Embase, Medline, Central and Web of Science, and 4 Chinese databases, including China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, Chinese Biomedical Literature Database, and WanFang will be completed using the following keywords DG and therapies and related entry terms. Studies will be included, according to the eligibility criteria (randomized controlled trials and controlled clinical trials, considering specific outcome measures for DG). The reference lists of included studies will be manual searched. Relevant data will be extracted from included studies using a specially designed data extraction sheet. Risk of bias of the included studies will be assessed, and the overall strength of the evidence will be summarized through GRADE. A random effects model will be used for all pairwise meta-analyses (with a 95% confidence interval). A Bayesian network meta-analysis will explore the relative benefits between the various therapies. The review will be reported using the Preferred Reporting Items for Systematic Reviews incorporating Network Meta-Analyses statement. Network meta-analysis will be performed using a Bayesian framework through the Winbugs software. RESULTS This network meta-analysis will identify the best effective therapy for DG. CONCLUSION This study will compare and evaluate current therapies for DG, and find the best treatment of DG.
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Affiliation(s)
- Shengju Wang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine
| | - Ruili Wang
- Diabetes Department, Jintang County Traditional Chinese Medicine Hospital, Chengdu
| | - Yanli Zhang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine
| | - Xu Zhang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine
| | - Baochao Cai
- Endocrinology Department, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing
| | - Yan Lu
- Department of Endocrinology, Third Affiliated Hospital of Chengdu University of TCM, Chengdu, China
| | - Yuguo Xia
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine
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10
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Korbut E, Brzozowski T, Magierowski M. Carbon Monoxide Being Hydrogen Sulfide and Nitric Oxide Molecular Sibling, as Endogenous and Exogenous Modulator of Oxidative Stress and Antioxidative Mechanisms in the Digestive System. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:5083876. [PMID: 32377300 PMCID: PMC7180415 DOI: 10.1155/2020/5083876] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 02/06/2020] [Accepted: 02/13/2020] [Indexed: 12/17/2022]
Abstract
Oxidative stress reflects an imbalance between oxidants and antioxidants in favor of the oxidants capable of evoking tissue damage. Like hydrogen sulfide (H2S) and nitric oxide (NO), carbon monoxide (CO) is an endogenous gaseous mediator recently implicated in the physiology of the gastrointestinal (GI) tract. CO is produced in mammalian tissues as a byproduct of heme degradation catalyzed by the heme oxygenase (HO) enzymes. Among the three enzymatic isoforms, heme oxygenase-1 (HO-1) is induced under conditions of oxidative stress or tissue injury and plays a beneficial role in the mechanism of protection against inflammation, ischemia/reperfusion (I/R), and many other injuries. According to recently published data, increased endogenous CO production by inducible HO-1, its delivery by novel pharmacological CO-releasing agents, or even the direct inhalation of CO has been considered a promising alternative in future experimental and clinical therapies against various GI disorders. However, the exact mechanisms underlying behind these CO-mediated beneficial actions are not fully explained and experimental as well as clinical studies on the mechanism of CO-induced protection are awaited. For instance, in a variety of experimental models related to gastric mucosal damage, HO-1/CO pathway and CO-releasing agents seem to prevent gastric damage mainly by reduction of lipid peroxidation and/or increased level of enzymatic antioxidants, such as superoxide dismutase (SOD) or glutathione peroxidase (GPx). Many studies have also revealed that HO-1/CO can serve as a potential defensive pathway against oxidative stress observed in the liver and pancreas. Moreover, increased CO levels after treatment with CO donors have been reported to protect the gut against formation of acute GI lesions mainly by the regulation of reactive oxygen species (ROS) production and the antioxidative activity. In this review, we focused on the role of H2S and NO molecular sibling, CO/HO pathway, and therapeutic potential of CO-releasing pharmacological tools in the regulation of oxidative stress-induced damage within the GI tract with a special emphasis on the esophagus, stomach, and intestines and also two solid and important metabolic abdominal organs, the liver and pancreas.
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Affiliation(s)
- Edyta Korbut
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Krakow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Krakow, Poland
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Krakow, Poland
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11
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Van Dingenen J, Pieters L, Van Nuffel E, Lefebvre RA. Hemin reduces postoperative ileus in a heme oxygenase 1-dependent manner while dimethyl fumarate does without heme oxygenase 1-induction. Neurogastroenterol Motil 2020; 32:e13624. [PMID: 31121086 DOI: 10.1111/nmo.13624] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 03/28/2019] [Accepted: 04/26/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Postoperative ileus (POI), the impairment of gastrointestinal motility after abdominal surgery, is mainly due to intestinal muscular inflammation. Carbon monoxide (CO)-releasing compounds were shown to exert an anti-inflammatory effect in murine POI partially through induction of heme oxygenase-1 (HO-1). The influence of hemin and dimethyl fumarate (DMF), currently used for multiple sclerosis (MS), was therefore tested in murine POI. METHODS C57BL/6J mice were anesthetized and after laparotomy, POI was induced via intestinal manipulation (IM). Animals were treated with either 30 mg kg-1 hemin intraperitoneally (ip), 30 mg kg-1 DMF ip, or 100 mg kg-1 intragastrically (ig) 24 hours before IM. Intestinal transit was assessed 24 hours postoperatively and mucosa-free muscularis or whole segments of the small intestine were stored for later analysis. Intestinal HO-1 protein expression was studied at 6, 12, and 24 hours after administration of hemin or DMF in non-manipulated mice. KEY RESULTS Pretreatment with hemin and DMF, both ig and ip, prevented the delayed transit seen after IM. Concomitantly, both hemin and DMF significantly reduced the increased interleukin-6 levels and the elevated leukocyte infiltration in the muscularis. Hemin but not DMF caused a significant increase in intestinal HO-1 protein expression and co-administration of the HO-1 inhibitor chromium mesoporphyrin abolished the protective effects of hemin on POI; DMF reduced the IM-induced activation of NF-κB and ERK 1/2. CONCLUSIONS AND INFERENCES Both hemin and DMF improve the delayed transit and inflammation seen in murine POI, but only hemin does so in a HO-1-dependent manner.
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Affiliation(s)
- Jonas Van Dingenen
- Department of Basic and Applied Medical Sciences, Faculty of Medicine & Health Sciences, Ghent University, Ghent, Belgium
| | - Leen Pieters
- Department of Human Structure and Repair, Faculty of Medicine & Health Sciences, Ghent University, Ghent, Belgium
| | - Elien Van Nuffel
- Unit of Molecular Signal Transduction in Inflammation, Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Romain A Lefebvre
- Department of Basic and Applied Medical Sciences, Faculty of Medicine & Health Sciences, Ghent University, Ghent, Belgium
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12
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Głowacka U, Brzozowski T, Magierowski M. Synergisms, Discrepancies and Interactions between Hydrogen Sulfide and Carbon Monoxide in the Gastrointestinal and Digestive System Physiology, Pathophysiology and Pharmacology. Biomolecules 2020; 10:445. [PMID: 32183095 PMCID: PMC7175135 DOI: 10.3390/biom10030445] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/07/2020] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
Endogenous gas transmitters, hydrogen sulfide (H2S), carbon monoxide (CO) and nitric oxide (NO) are important signaling molecules known to exert multiple biological functions. In recent years, the role of H2S, CO and NO in regulation of cardiovascular, neuronal and digestive systems physiology and pathophysiology has been emphasized. Possible link between these gaseous mediators and multiple diseases as well as potential therapeutic applications has attracted great attention from biomedical scientists working in many fields of biomedicine. Thus, various pharmacological tools with ability to release CO or H2S were developed and implemented in experimental animal in vivo and in vitro models of many disorders and preliminary human studies. This review was designed to review signaling functions, similarities, dissimilarities and a possible cross-talk between H2S and CO produced endogenously or released from chemical donors, with special emphasis on gastrointestinal digestive system pathologies prevention and treatment.
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Affiliation(s)
| | | | - Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Cracow, Poland; (U.G.); (T.B.)
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13
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Abstract
This review covers the epidemiology, pathophysiology, clinical features, diagnosis, and management of diabetic gastroparesis, and more broadly diabetic gastroenteropathy, which encompasses all the gastrointestinal manifestations of diabetes mellitus. Up to 50% of patients with type 1 and type 2 DM and suboptimal glycemic control have delayed gastric emptying (GE), which can be documented with scintigraphy, 13C breath tests, or a wireless motility capsule; the remainder have normal or rapid GE. Many patients with delayed GE are asymptomatic; others have dyspepsia (i.e., mild to moderate indigestion, with or without a mild delay in GE) or gastroparesis, which is a syndrome characterized by moderate to severe upper gastrointestinal symptoms and delayed GE that suggest, but are not accompanied by, gastric outlet obstruction. Gastroparesis can markedly impair quality of life, and up to 50% of patients have significant anxiety and/or depression. Often the distinction between dyspepsia and gastroparesis is based on clinical judgement rather than established criteria. Hyperglycemia, autonomic neuropathy, and enteric neuromuscular inflammation and injury are implicated in the pathogenesis of delayed GE. Alternatively, there are limited data to suggest that delayed GE may affect glycemic control. The management of diabetic gastroparesis is guided by the severity of symptoms, the magnitude of delayed GE, and the nutritional status. Initial options include dietary modifications, supplemental oral nutrition, and antiemetic and prokinetic medications. Patients with more severe symptoms may require a venting gastrostomy or jejunostomy and/or gastric electrical stimulation. Promising newer therapeutic approaches include ghrelin receptor agonists and selective 5-hydroxytryptamine receptor agonists.
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Affiliation(s)
- Adil E Bharucha
- Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Yogish C Kudva
- Division of Endocrinology. Mayo Clinic, Rochester, Minnesota
| | - David O Prichard
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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14
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Yu L, Hu P, Chen Y. Gas-Generating Nanoplatforms: Material Chemistry, Multifunctionality, and Gas Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2018; 30:e1801964. [PMID: 30066474 DOI: 10.1002/adma.201801964] [Citation(s) in RCA: 213] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/26/2018] [Indexed: 05/16/2023]
Abstract
The fast advances of theranostic nanomedicine enable the rational design and construction of diverse functional nanoplatforms for versatile biomedical applications, among which gas-generating nanoplatforms (GGNs) have emerged very recently as unique theranostic nanoplatforms for broad gas therapies. Here, the recent developments of the rational design and chemical construction of versatile GGNs for efficient gas therapies by either exogenous physical triggers or endogenous disease-environment responsiveness are reviewed. These gases involve some therapeutic gases that can directly change disease status, such as oxygen (O2 ), nitric oxide (NO), carbon monoxide (CO), hydrogen (H2 ), hydrogen sulfide (H2 S) and sulfur dioxide (SO2 ), and other gases such as carbon dioxide (CO2 ), dl-menthol (DLM), and gaseous perfluorocarbon (PFC) for supplementary assistance of the theranostic process. Abundant nanocarriers have been adopted for gas delivery into lesions, including poly(d,l-lactic-co-glycolic acid), micelles, silica/mesoporous silica, organosilica, MnO2 , graphene, Bi2 Se3 , upconversion nanoparticles, CaCO3 , etc. Especially, these GGNs have been successfully developed for versatile biomedical applications, including diagnostic imaging and therapeutic use. The biosafety issue, challenges faced, and future developments on the rational construction of GGNs are also discussed for further promotion of their clinical translation to benefit patients.
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Affiliation(s)
- Luodan Yu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Ping Hu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China
| | - Yu Chen
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China
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15
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Van Dingenen J, Steiger C, Zehe M, Meinel L, Lefebvre RA. Investigation of orally delivered carbon monoxide for postoperative ileus. Eur J Pharm Biopharm 2018; 130:306-313. [DOI: 10.1016/j.ejpb.2018.07.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 05/22/2018] [Accepted: 07/08/2018] [Indexed: 01/26/2023]
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16
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Wollborn J, Hermann C, Goebel U, Merget B, Wunder C, Maier S, Schäfer T, Heuler D, Müller-Buschbaum K, Buerkle H, Meinel L, Schick MA, Steiger C. Overcoming safety challenges in CO therapy - Extracorporeal CO delivery under precise feedback control of systemic carboxyhemoglobin levels. J Control Release 2018; 279:336-344. [PMID: 29655987 DOI: 10.1016/j.jconrel.2018.04.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 04/04/2018] [Accepted: 04/09/2018] [Indexed: 10/17/2022]
Abstract
Carbon monoxide (CO) has demonstrated therapeutic potential in multiple inflammatory conditions including intensive care applications such as organ transplantation or sepsis. Approaches to translate these findings into future therapies, however, have been challenged by multiple hurdles including handling and toxicity issues associated with systemic CO delivery. Here, we describe a membrane-controlled Extracorporeal Carbon Monoxide Release System (ECCORS) for easy implementation into Extracorporeal Membrane Oxygenation (ECMO) setups, which are being used to treat cardiac and respiratory diseases in various intensive care applications. Functionalities of the ECCORS were investigated in a pig model of veno-arterial ECMO. By precisely controlling CO generation and delivery as a function of systemic carboxyhemoglobin levels, the system allows for an immediate onset of therapeutic CO-levels while preventing CO-toxicity. Systemic carboxyhemoglobin levels were profiled in real-time by monitoring exhaled CO levels as well as by pulse oximetry, enabling self-contained and automatic feedback control of CO generation within ECCORS. Machine learning based mathematical modeling was performed to increase the predictive power of this approach, laying foundation for high precision systemic CO delivery concepts of tomorrow.
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Affiliation(s)
- Jakob Wollborn
- Department of Anesthesiology and Critical Care, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Cornelius Hermann
- Institute for Pharmacy and Food Chemistry, University of Würzburg, Germany
| | - Ulrich Goebel
- Department of Anesthesiology and Critical Care, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Benjamin Merget
- Computational Chemistry and Biology, BASF SE, Ludwigshafen, Germany
| | - Christian Wunder
- Department of Anesthesiology and Critical Care, Robert-Bosch-Krankenhaus, Stuttgart, Germany
| | - Sven Maier
- Department of Cardiovascular Surgery, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Germany
| | - Thomas Schäfer
- Institute for Inorganic Chemistry, University of Würzburg, Germany
| | - Dominik Heuler
- Institute for Inorganic Chemistry, University of Würzburg, Germany
| | | | - Hartmut Buerkle
- Department of Anesthesiology and Critical Care, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Lorenz Meinel
- Institute for Pharmacy and Food Chemistry, University of Würzburg, Germany
| | - Martin A Schick
- Department of Anesthesiology and Critical Care, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Christoph Steiger
- Institute for Pharmacy and Food Chemistry, University of Würzburg, Germany.
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17
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Gibbons SJ, Grover M, Choi KM, Wadhwa A, Zubair A, Wilson LA, Wu Y, Abell TL, Hasler WL, Koch KL, McCallum RW, Nguyen LAB, Parkman HP, Sarosiek I, Snape WJ, Tonascia J, Hamilton FA, Pasricha PJ, Farrugia G. Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis. PLoS One 2017; 12:e0187772. [PMID: 29161307 PMCID: PMC5697813 DOI: 10.1371/journal.pone.0187772] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 10/25/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Idiopathic and diabetic gastroparesis in Homo sapiens cause significant morbidity. Etiology or risk factors have not been clearly identified. Failure to sustain elevated heme oxygenase-1 (HO1) expression is associated with delayed gastric emptying in diabetic mice and polymorphisms in the HO1 gene (HMOX1, NCBI Gene ID:3162) are associated with worse outcomes in other diseases. AIM Our hypothesis was that longer polyGT alleles are more common in the HMOX1 genes of individuals with gastroparesis than in controls without upper gastrointestinal motility disorders. METHODS Repeat length was determined in genomic DNA. Controls with diabetes (84 type 1, 84 type 2) and without diabetes (n = 170) were compared to diabetic gastroparetics (99 type 1, 72 type 2) and idiopathic gastroparetics (n = 234). Correlations of repeat lengths with clinical symptom sub-scores on the gastroparesis cardinal symptom index (GCSI) were done. Statistical analyses of short (<29), medium and long (>32) repeat alleles and differences in allele length were used to test for associations with gastroparesis. RESULTS The distribution of allele lengths was different between groups (P = 0.016). Allele lengths were longest in type 2 diabetics with gastroparesis (29.18±0.35, mean ± SEM) and longer in gastroparetics compared to non-diabetic controls (28.50±0.14 vs 27.64±0.20 GT repeats/allele, P = 0.0008). Type 2 diabetic controls had longer alleles than non-diabetic controls. In all gastroparetic groups, allele lengths were longer in African Americans compared to other racial groups, differences in the proportion of African Americans in the groups accounted for the differences between gastroparetics and controls. Diabetic gastroparetics with 1 or 2 long alleles had worse GCSI nausea sub-scores (3.30±0.23) as compared to those with 0 long alleles (2.66±0.12), P = 0.022. CONCLUSIONS Longer poly-GT repeats in the HMOX1 gene are more common in African Americans with gastroparesis. Nausea symptoms are worse in subjects with longer alleles.
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Affiliation(s)
- Simon J. Gibbons
- Mayo Clinic, Enteric NeuroScience Program, Rochester, Minnesota, United States of America
| | - Madhusudan Grover
- Mayo Clinic, Enteric NeuroScience Program, Rochester, Minnesota, United States of America
| | - Kyoung Moo Choi
- Mayo Clinic, Enteric NeuroScience Program, Rochester, Minnesota, United States of America
| | - Akhilesh Wadhwa
- Mayo Clinic, Enteric NeuroScience Program, Rochester, Minnesota, United States of America
| | - Adeel Zubair
- Mayo Clinic, Enteric NeuroScience Program, Rochester, Minnesota, United States of America
| | - Laura A. Wilson
- Johns Hopkins University Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Yanhong Wu
- Mayo Clinic, Medical Genomics Program, Rochester, Minnesota, United States of America
| | - Thomas L. Abell
- University of Louisville, Louisville, Kentucky, United States of America
| | - William L. Hasler
- University of Michigan, Ann Arbor, Michigan, United States of America
| | - Kenneth L. Koch
- Wake Forest University, Winston-Salem, North Carolina, United States of America
| | | | | | - Henry P. Parkman
- Temple University, Philadelphia, Pennsylvania, United States of America
| | - Irene Sarosiek
- Texas Tech University, El Paso, Texas, United States of America
| | - William J. Snape
- California Pacific Medical Center, San Francisco, California, United States of America
| | - James Tonascia
- Johns Hopkins University Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Frank A. Hamilton
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States of America
| | - Pankaj J. Pasricha
- Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Gianrico Farrugia
- Mayo Clinic, Enteric NeuroScience Program, Rochester, Minnesota, United States of America
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18
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Stakenborg N, Gomez-Pinilla PJ, Boeckxstaens GE. Postoperative Ileus: Pathophysiology, Current Therapeutic Approaches. Handb Exp Pharmacol 2017; 239:39-57. [PMID: 27999957 DOI: 10.1007/164_2016_108] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Postoperative ileus, which develops after each abdominal surgical procedure, is an iatrogenic disorder characterized by a transient inhibition of gastrointestinal motility. Its pathophysiology is complex involving pharmacological (opioids, anesthetics), neural, and immune-mediated mechanisms. The early neural phase, triggered by activation of afferent nerves during the surgical procedure, is short lasting compared to the later inflammatory phase. The latter starts after 3-6 h and lasts several days, making it a more interesting target for treatment. Insight into the triggers and immune cells involved is of great importance for the development of new therapeutic strategies. In this chapter, the pathogenesis and the current therapeutic approaches to treat postoperative ileus are discussed.
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Affiliation(s)
- N Stakenborg
- Division of Gastroenterology and Hepatology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, Leuven, 3000, Belgium
| | - P J Gomez-Pinilla
- Division of Gastroenterology and Hepatology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, Leuven, 3000, Belgium
| | - G E Boeckxstaens
- Division of Gastroenterology and Hepatology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, Leuven, 3000, Belgium. .,Division of Gastroenterology and Hepatology, University Hospital Leuven, Herestraat 49, Leuven, 3000, Belgium.
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19
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Wallace JL, Ianaro A, de Nucci G. Gaseous Mediators in Gastrointestinal Mucosal Defense and Injury. Dig Dis Sci 2017; 62:2223-2230. [PMID: 28733867 DOI: 10.1007/s10620-017-4681-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 07/11/2017] [Indexed: 12/26/2022]
Abstract
Of the numerous gaseous substances that can act as signaling molecules, the best characterized are nitric oxide, carbon monoxide and hydrogen sulfide. Contributions of each of these low molecular weight substances, alone or in combination, to maintenance of gastrointestinal mucosal integrity have been established. There is considerable overlap in the actions of these gases in modulating mucosal defense and responses to injury, and in some instances they act in a cooperative manner. Each also play important roles in regulating inflammatory and repair processes throughout the gastrointestinal tract. In recent years, significant progress has been made in the development of novel anti-inflammatory and cytoprotective drugs that exploit the beneficial activities of one or more of these gaseous mediators.
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Affiliation(s)
- John L Wallace
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada. .,Department of Medicine, Universidade Camilo Castelo Branco, Fernandopolis, SP, Brazil.
| | - Angela Ianaro
- Department of Experimental Pharmacology, University of Naples, Naples, Italy
| | - Gilberto de Nucci
- Department of Medicine, Universidade Camilo Castelo Branco, Fernandopolis, SP, Brazil
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20
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Aucott BJ, Ward JS, Andrew SG, Milani J, Whitwood AC, Lynam JM, Parkin A, Fairlamb IJS. Redox-Tagged Carbon Monoxide-Releasing Molecules (CORMs): Ferrocene-Containing [Mn(C^N)(CO)4] Complexes as a Promising New CORM Class. Inorg Chem 2017; 56:5431-5440. [DOI: 10.1021/acs.inorgchem.7b00509] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Benjamin J. Aucott
- Department of Chemistry, University of York, York, YO10 5DD, United Kingdom
| | - Jonathan S. Ward
- Department of Chemistry, University of York, York, YO10 5DD, United Kingdom
| | - Samuel G. Andrew
- Department of Chemistry, University of York, York, YO10 5DD, United Kingdom
| | - Jessica Milani
- Department of Chemistry, University of York, York, YO10 5DD, United Kingdom
| | - Adrian C. Whitwood
- Department of Chemistry, University of York, York, YO10 5DD, United Kingdom
| | - Jason M. Lynam
- Department of Chemistry, University of York, York, YO10 5DD, United Kingdom
| | - Alison Parkin
- Department of Chemistry, University of York, York, YO10 5DD, United Kingdom
| | - Ian J. S. Fairlamb
- Department of Chemistry, University of York, York, YO10 5DD, United Kingdom
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21
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Kellner M, Noonepalle S, Lu Q, Srivastava A, Zemskov E, Black SM. ROS Signaling in the Pathogenesis of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 967:105-137. [PMID: 29047084 PMCID: PMC7120947 DOI: 10.1007/978-3-319-63245-2_8] [Citation(s) in RCA: 272] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The generation of reactive oxygen species (ROS) plays an important role for the maintenance of cellular processes and functions in the body. However, the excessive generation of oxygen radicals under pathological conditions such as acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) leads to increased endothelial permeability. Within this hallmark of ALI and ARDS, vascular microvessels lose their junctional integrity and show increased myosin contractions that promote the migration of polymorphonuclear leukocytes (PMNs) and the transition of solutes and fluids in the alveolar lumen. These processes all have a redox component, and this chapter focuses on the role played by ROS during the development of ALI/ARDS. We discuss the origins of ROS within the cell, cellular defense mechanisms against oxidative damage, the role of ROS in the development of endothelial permeability, and potential therapies targeted at oxidative stress.
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Affiliation(s)
- Manuela Kellner
- Department of Medicine, Center for Lung Vascular Pathobiology, University of Arizona, 1501 N Campbell Ave., Tucson, AZ, 85719, USA
| | - Satish Noonepalle
- Department of Medicine, Center for Lung Vascular Pathobiology, University of Arizona, 1501 N Campbell Ave., Tucson, AZ, 85719, USA
| | - Qing Lu
- Department of Medicine, Center for Lung Vascular Pathobiology, University of Arizona, 1501 N Campbell Ave., Tucson, AZ, 85719, USA
| | - Anup Srivastava
- Department of Medicine, Center for Lung Vascular Pathobiology, University of Arizona, 1501 N Campbell Ave., Tucson, AZ, 85719, USA
| | - Evgeny Zemskov
- Department of Medicine, Center for Lung Vascular Pathobiology, University of Arizona, 1501 N Campbell Ave., Tucson, AZ, 85719, USA
| | - Stephen M Black
- Department of Medicine, Center for Lung Vascular Pathobiology, University of Arizona, 1501 N Campbell Ave., Tucson, AZ, 85719, USA.
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22
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Magierowski M, Magierowska K, Hubalewska-Mazgaj M, Adamski J, Bakalarz D, Sliwowski Z, Pajdo R, Kwiecien S, Brzozowski T. Interaction between endogenous carbon monoxide and hydrogen sulfide in the mechanism of gastroprotection against acute aspirin-induced gastric damage. Pharmacol Res 2016; 114:235-250. [PMID: 27825819 DOI: 10.1016/j.phrs.2016.11.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/12/2016] [Accepted: 11/02/2016] [Indexed: 02/07/2023]
Abstract
Acetylsalicylic acid (ASA) is mainly recognized as painkiller or anti-inflammatory drug. However, ASA causes serious side effects towards gastrointestinal (GI) tract which limits its usefulness. Carbon monoxide (CO) and hydrogen sulfide (H2S) have been described to act as important endogenous messengers and mediators of gastroprotection but whether they can interact in gastroprotection against acute ASA-induced gastric damage remains unknown. In this study male Wistar rats were pretreated with 1) vehicle (saline, i.g.), 2) tricarbonyldichlororuthenium (II) dimer (CORM-2, 5mg/kg i.g.), 3) sodium hydrosulfide (NaHS, 5mg/kg i.g.), 4) zinc protoporphyrin (ZnPP, 10mg/kg i.p.), 5) D,L-propargylglycine (PAG, 30mg/kg i.g.), 6) ZnPP combined with NaHS, 7) PAG combined with CORM-2 or 8) 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10mg/kg i.p.) combined with CORM-2 or NaHS and 30min later ASA was administered i.g. in a single dose of 125mg/kg. After 1h, gastric blood flow (GBF) was determined by H2 gas clearance technique and gastric lesions were assessed by planimetry and histology. CO content in gastric mucosa and COHb concentration in blood were determined by gas chromatography and H2S production was assessed in gastric mucosa using methylene blue method. Protein and/or mRNA expression for cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), heme oxygenase (HO)-1, HO-2, hypoxia inducible factor-alpha (HIF)-1α, nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX)-1 and COX-2, inducible nitric oxide synthase (iNOS) and interleukin (IL)-1β were determined by Western blot or real-time PCR, respectively. ASA caused hemorrhagic gastric mucosal damage and significantly decreased GBF, H2S production, CO content, mRNA or protein expression for CSE, 3-MST, HO-2 and increased mRNA and/or protein expression for CBS, HO-1, Nrf-2, HIF-1α, iNOS, IL-1β, COX-2 in gastric mucosa and COHb concentration in blood. Pretreatment with CORM-2 or NaHS but not with PAG decreased ASA-damage and increased GBF. ZnPP reversed protective and hyperemic effect of NaHS but PAG failed to affect CORM-2-induced gastroprotection. CORM-2 elevated CO content, mRNA or protein expression for HO-1, Nrf-2, and decreased expression of CBS, HIF-1α, COX-2, IL-1β, iNOS, the H2S production in gastric mucosa and COHb concentration in blood. NaHS raised mRNA or protein expression for CSE, COX-1 and decreased mRNA expression for IL-1β and COHb level in blood. We conclude that CO is involved in gastroprotection induced by H2S while beneficial protective action of CO released from CORM-2 in gastric mucosa seems to be H2S-independent. In contrast to H2S, CO ameliorates hypoxia, regulates Nrf-2 expression but similarly to H2S acts on sGC-dependent manner to restore gastric microcirculation and exhibit anti-inflammatory activity in gastric mucosa compromised by ASA.
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Affiliation(s)
- Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
| | - Katarzyna Magierowska
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Magdalena Hubalewska-Mazgaj
- Department of Genetic Research and Nutrigenomics, Malopolska Centre of Biotechnology, Jagiellonian University, 7A Gronostajowa Street, 30-387 Cracow, Poland
| | - Juliusz Adamski
- Department of Forensic Toxicology, Institute of Forensic Research, 9 Westerplatte Street, 31-033 Cracow, Poland
| | - Dominik Bakalarz
- Department of Forensic Toxicology, Institute of Forensic Research, 9 Westerplatte Street, 31-033 Cracow, Poland
| | - Zbigniew Sliwowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Robert Pajdo
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Slawomir Kwiecien
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
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Nacci C, Fanelli M, Potenza MA, Leo V, Montagnani M, De Salvia MA. Carbon monoxide contributes to the constipating effects of granisetron in rat colon. World J Gastroenterol 2016; 22:9333-9345. [PMID: 27895421 PMCID: PMC5107697 DOI: 10.3748/wjg.v22.i42.9333] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 09/16/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide (HO/CO) pathway in the constipating effects of granisetron.
METHODS For in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous (sc)], zinc protoporphyrin IX [ZnPPIX, 50 μg/kg/intraperitoneal (ip)] and hemin (50 μmol/L/kg/ip), alone or in combination. For in vitro studies, the contractile neurogenic response to electrical field stimulation (EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine (ACh, 0.1-100 μmol/L) were evaluated on colon specimens incubated with granisetron (3 μmol/L, 15 min), ZnPPIX (10 μmol/L, 60 min) or CO-releasing molecule-3 (CORM-3, 100, 200, 400 μmol/L) alone or in combination. These experiments were performed under co-treatment with or without atropine (3 μmol/L, a muscarinic receptor antagonist) or NG-nitro-L-Arginine (L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor).
RESULTS Administration of granisetron (50, 75 μg/kg) in vivo significantly increased the time to first defecation (P = 0.045 vs vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of ZnPPIX or hemin alone had no effect on this gastrointestinal motility parameter, ZnPPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered in vitro, granisetron alone (3 μmol/L) did not significantly modify the colon’s contractile response to either EFS or ACh. Incubation with ZnPPIX alone (10 μmol/L) significantly reduced the colon’s contractile response to EFS (P = 0.016) but had no effect on contractile response to ACh. Co-administration of ZnPPIX and atropine (3 μmol/L) abolished the ZnPPIX-mediated decrease in contractile response to EFS. Conversely, incubation with CORM-3 (400 μmol/L) alone increased both the contractile response to EFS at 10 Hz (10 Hz: 71.02 ± 19.16 vs 116.25 ± 53.70, P = 0.01) and the contractile response to ACh (100 μmol/L) (P = 0.012). Co-administration of atropine abolished the CORM-3-mediated effects on the EFS-mediated response. When granisetron was co-incubated in vitro with ZnPPIX, the ZnPPIX-mediated decrease in colon contractile response to EFS was lost. On the other hand, co-incubation of granisetron and CORM-3 (400 μmol/L) further increased the colon’s contractile response to EFS (at 5 Hz: P = 0.007; at 10 Hz: P = 0.001) and to ACh (ACh 10 μmol/L: P = 0.001; ACh 100 μmol/L: P = 0.001) elicited by CORM-3 alone. L-NNA co-administered with granisetron and CORM-3 abolished the potentiating effect of CORM-3 on granisetron on both the EFS-induced and ACh-induced contractile response.
CONCLUSION Taken together, findings from in vivo and in vitro studies suggest that the HO/CO pathway is involved in the constipating effects of granisetron.
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24
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Steiger C, Hermann C, Meinel L. Localized delivery of carbon monoxide. Eur J Pharm Biopharm 2016; 118:3-12. [PMID: 27836646 DOI: 10.1016/j.ejpb.2016.11.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 10/18/2016] [Accepted: 11/07/2016] [Indexed: 01/18/2023]
Abstract
The heme oxygenase (HO)/carbon monoxide (CO) system is a physiological feedback loop orchestrating various cell-protective effects in response to cellular stress. The therapeutic use of CO is impeded by safety challenges as a result of high CO-Hemoglobin formation following non-targeted, systemic administration jeopardizing successful CO therapies as of this biological barrier. Another caveat is the use of CO-Releasing Molecules containing toxicologically critical transition metals. An emerging number of local delivery approaches addressing these issues have recently been introduced and provide exciting new starting points for translating the fascinating preclinical potential of CO into a clinical setting. This review will discuss these approaches and link to future delivery strategies aiming at establishing CO as a safe and effective medication of tomorrow.
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Affiliation(s)
- Christoph Steiger
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, DE-97074 Wuerzburg, Germany
| | - Cornelius Hermann
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, DE-97074 Wuerzburg, Germany
| | - Lorenz Meinel
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, DE-97074 Wuerzburg, Germany.
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25
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Magierowski M, Magierowska K, Szmyd J, Surmiak M, Sliwowski Z, Kwiecien S, Brzozowski T. Hydrogen Sulfide and Carbon Monoxide Protect Gastric Mucosa Compromised by Mild Stress Against Alendronate Injury. Dig Dis Sci 2016; 61:3176-3189. [PMID: 27541924 PMCID: PMC5067292 DOI: 10.1007/s10620-016-4280-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 08/10/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND Alendronate is an inhibitor of osteoclast-mediated bone resorption, but its clinical utility is limited due to gastrointestinal complications including bleeding erosions. AIMS We studied whether potent vasodilators hydrogen sulfide (H2S) and carbon monoxide (CO) can protect against alendronate-induced gastric lesions in rats exposed to mild stress. METHODS Three series (A, B, and C) of Wistar rats received alendronate (150-700 mg/kg i.g., series A) with or without NaHS (5 mg/kg), H2S donor or CORM-2 (5 mg/kg) releasing CO administered i.g. 30 min before alendronate administration (series B) in rats exposed for 3 days before alendronate administration to mild stress (series C). The area of gastric lesions was assessed by planimetry, the gastric blood flow (GBF) was determined by H2-gas clearance technique, and H2S production via CSE/CBS/3-MST activity and the gastric expression of HO-1, HO-2, HIF-1α, NF-κB, iNOS, COX-2, IL-1β, TNF-α, GPx-1 and SOD-2 were analyzed by qPCR or Western blot. RESULTS Alendronate dose-dependently produced gastric mucosal lesions and significantly decreased GBF, and these effects were exacerbated by mild stress. NaHS and CORM-2 significantly reduced the alendronate-induced gastric lesions in non-stressed and stressed animals, but only NaHS but not CORM-2 raised H2S production. NaHS and CORM-2 inhibited gastric expression of HIF-1α protein and HO-1, HIF-1α, NF-κB, COX-2, iNOS, IL-1β, TNF-α mRNAs but failed to affect those of HO-2, GPx-1, and SOD-2. CONCLUSION Both H2S and CO released from their donors, NaHS and CORM-2, protect gastric mucosa compromised by stress against alendronate-induced gastric damage via mechanism involving downregulation of HIF-1α, NF-κB and proinflammatory factors COX-2, iNOS, IL-1β, and TNF-α.
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Affiliation(s)
- Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Katarzyna Magierowska
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Jakub Szmyd
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Marcin Surmiak
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
- Division of Molecular Biology and Clinical Genetics, Department of Medicine, Jagiellonian University Medical College, 8 Skawinska Street, 31-066 Cracow, Poland
| | - Zbigniew Sliwowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Slawomir Kwiecien
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
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26
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Bharucha AE, Daley SL, Low PA, Gibbons SJ, Choi KM, Camilleri M, Saw EJ, Farrugia G, Zinsmeister AR. Effects of hemin on heme oxygenase-1, gastric emptying, and symptoms in diabetic gastroparesis. Neurogastroenterol Motil 2016; 28:1731-1740. [PMID: 27283929 PMCID: PMC5083191 DOI: 10.1111/nmo.12874] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 05/09/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND Therapeutic options for management of diabetic gastroparesis are limited. Failure to maintain upregulation of heme oxygenase (HO1) leads to loss of interstitial cells of Cajal and delayed gastric emptying (GE) in non-obese diabetic mice. Our hypothesis was that hemin upregulation of HO1 would restore normal GE in humans with gastroparesis. AIMS To compare effects of hemin and placebo infusions on HO1 activity and protein, GE, autonomic function, and gastrointestinal symptoms in diabetic gastroparesis. METHODS In a single-center, double-blind, placebo-controlled, randomized clinical trial, we compared intravenous hemin, prepared in albumin, or albumin alone (placebo) in 20 patients, aged 41 ± 5 (SEM) years with diabetic gastroparesis. After infusions on days 1, 3, and 7, weekly infusions were administered for 7 additional weeks. Assessments included blood tests for HO1 protein and enzyme activity levels, GE with 13 C-spirulina breath test, autonomic functions (baseline and end), and gastrointestinal symptoms every 2 weeks. KEY RESULTS Nine of 11 patients randomized to hemin completed all study procedures. Compared to placebo, hemin increased HO1 protein on days 3 (p = 0.0002) and 7 (p = 0.008) and HO1 activity on day 3 (p = 0.0003) but not after. Gastric emptying, autonomic functions, and symptoms did not differ significantly in the hemin group relative to placebo. CONCLUSIONS & INFERENCES Hemin failed to sustain increased HO1 levels beyond a week and did not improve GE or symptoms in diabetic gastroparesis. Further studies are necessary to ascertain whether more frequent hemin infusions or other drugs would have a more sustained effect on HO1 and improve GE.
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Affiliation(s)
| | - Shannon L. Daley
- Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Simon J. Gibbons
- Department of Physiology and Biomedical Engineering, Mayo Clinic Center for Biomedical Discovery, Rochester, MN
| | - Kyoung Moo Choi
- Department of Physiology and Biomedical Engineering, Mayo Clinic Center for Biomedical Discovery, Rochester, MN
| | - Michael Camilleri
- Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - essica J. Saw
- Mayo Medical School, Mayo Clinic College of Medicine, Rochester, MN
| | - Gianrico Farrugia
- Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Alan R Zinsmeister
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN
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27
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Steiger C, Uchiyama K, Takagi T, Mizushima K, Higashimura Y, Gutmann M, Hermann C, Botov S, Schmalz HG, Naito Y, Meinel L. Prevention of colitis by controlled oral drug delivery of carbon monoxide. J Control Release 2016; 239:128-36. [PMID: 27578097 DOI: 10.1016/j.jconrel.2016.08.030] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 08/22/2016] [Accepted: 08/24/2016] [Indexed: 01/03/2023]
Abstract
Carbon monoxide (CO) is an endogenous signal transmitter involved in numerous physiological processes including the gastrointestinal (GI) homeostasis. CO has been recognized as potential new therapeutic agent for motility related and inflammatory disorders of the GI tract. A therapeutic use, however, is challenged by inappropriate drug delivery modes. Here we describe a micro scale Oral Carbon Monoxide Release System (M-OCORS) designed for localized and controlled exposure of the GI tract with in situ generated CO. M-OCORS allowed for controlled release profiles lasting for several minutes or up to almost one day. These in vitro release profiles translated into a large pharmacokinetic design space following oral administration in mice and measured as CO-hemoglobin (CO-Hb) formation. M-OCORS with a release profile featuring exposure of the intestine was profiled in two independently performed studies demonstrating preventive effects in chemically induced colitis. M-OCORS significantly reduced damage scores and prevented upregulation of colitis biomarkers.
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Affiliation(s)
- Christoph Steiger
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
| | - Kazuhiko Uchiyama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Katsura Mizushima
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yasuki Higashimura
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Marcus Gutmann
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
| | - Cornelius Hermann
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
| | - Svetlana Botov
- Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Koeln, Germany
| | - Hans-Günther Schmalz
- Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Koeln, Germany
| | - Yuji Naito
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Lorenz Meinel
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
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28
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Choi KM, Gibbons SJ, Sha L, Beyder A, Verhulst PJ, Cipriani G, Phillips JE, Bauer AJ, Ordog T, Camp JJ, Ge X, Bharucha AE, Linden DR, Szurszewski JH, Kashyap PC, Farrugia G. Interleukin 10 Restores Gastric Emptying, Electrical Activity, and Interstitial Cells of Cajal Networks in Diabetic Mice. Cell Mol Gastroenterol Hepatol 2016; 2:454-467. [PMID: 27795979 PMCID: PMC5042607 DOI: 10.1016/j.jcmgh.2016.04.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 04/17/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Gastroparesis is a complication of diabetes characterized by delayed emptying of stomach contents and accompanied by early satiety, nausea, vomiting, and pain. No safe and reliable treatments are available. Interleukin 10 (IL10) activates the M2 cytoprotective phenotype of macrophages and induces expression of heme oxygenase 1 (HO1) protein. We investigated whether IL10 administration could improve gastric emptying and reverse the associated cellular and electrical abnormalities in diabetic mice. METHODS Nonobese diabetic mice with delayed gastric emptying were given either IL10 (0.1-1 μg, twice/day) or vehicle (controls). Stomach tissues were isolated, and sharp microelectrode recordings were made of the electrical activity in the gastric muscle layers. Changes to interstitial cells of Cajal (ICC), reduced nicotinamide adenine dinucleotide phosphate diaphorase, and levels and distribution of HO1 protein were determined by histochemical and imaging analyses of the same tissues. RESULTS Gastric emptying remained delayed in vehicle-treated diabetic mice but returned to normal in mice given IL10 (n = 10 mice; P < .05). In mice given IL10, normalization of gastric emptying was associated with a membrane potential difference between the proximal and distal stomach, and lower irregularity and higher frequency of slow-wave activity, particularly in the distal stomach. Levels of HO1 protein were higher in stomach tissues from mice given IL10, and ICC networks were more organized, better connected, and more evenly distributed compared with controls. CONCLUSIONS IL10 increases gastric emptying in diabetic mice and has therapeutic potential for patients with diabetic gastroparesis. This response is associated with up-regulation of HO1 and repair of connectivity of ICC networks.
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Affiliation(s)
- Kyoung Moo Choi
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Simon J. Gibbons
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Lei Sha
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Arthur Beyder
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Pieter-Jan Verhulst
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Gianluca Cipriani
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Jessica E. Phillips
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Anthony J. Bauer
- Department of Integrative Physiology and Pharmacology, Liberty University College of Osteopathic Medicine, Lynchburg, Virginia
| | - Tamas Ordog
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Jon J. Camp
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Xin Ge
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Adil E. Bharucha
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - David R. Linden
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | | | - Purna C. Kashyap
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota
| | - Gianrico Farrugia
- Enteric NeuroScience Program, Mayo Clinic School of Medicine, Rochester, Minnesota,Correspondence Address correspondence to: Gianrico Farrugia, MD, Enteric NeuroScience Program, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. fax: (507) 284–0266.Enteric NeuroScience ProgramMayo Clinic200 First Street SWRochesterMinnesota 55905
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29
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Carbon Monoxide (CO) Released from Tricarbonyldichlororuthenium (II) Dimer (CORM-2) in Gastroprotection against Experimental Ethanol-Induced Gastric Damage. PLoS One 2015; 10:e0140493. [PMID: 26460608 PMCID: PMC4604159 DOI: 10.1371/journal.pone.0140493] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 09/25/2015] [Indexed: 01/29/2023] Open
Abstract
The physiological gaseous molecule, carbon monoxide (CO) becomes a subject of extensive investigation due to its vasoactive activity throughout the body but its role in gastroprotection has been little investigated. We determined the mechanism of CO released from its donor tricarbonyldichlororuthenium (II) dimer (CORM-2) in protection of gastric mucosa against 75% ethanol-induced injury. Rats were pretreated with CORM-2 30 min prior to 75% ethanol with or without 1) non-selective (indomethacin) or selective cyclooxygenase (COX)-1 (SC-560) and COX-2 (celecoxib) inhibitors, 2) nitric oxide (NO) synthase inhibitor L-NNA, 3) ODQ, a soluble guanylyl cyclase (sGC) inhibitor, hemin, a heme oxygenase (HO)-1 inductor or zinc protoporphyrin IX (ZnPPIX), an inhibitor of HO-1 activity. The CO content in gastric mucosa and carboxyhemoglobin (COHb) level in blood was analyzed by gas chromatography. The gastric mucosal mRNA expression for HO-1, COX-1, COX-2, iNOS, IL-4, IL-1β was analyzed by real-time PCR while HO-1, HO-2 and Nrf2 protein expression was determined by Western Blot. Pretreatment with CORM-2 (0.5-10 mg/kg) dose-dependently attenuated ethanol-induced lesions and raised gastric blood flow (GBF) but large dose of 100 mg/kg was ineffective. CORM-2 (5 mg/kg and 50 mg/kg i.g.) significantly increased gastric mucosal CO content and whole blood COHb level. CORM-2-induced protection was reversed by indomethacin, SC-560 and significantly attenuated by celecoxib, ODQ and L-NNA. Hemin significantly reduced ethanol damage and raised GBF while ZnPPIX which exacerbated ethanol-induced injury inhibited CORM-2- and hemin-induced gastroprotection and the accompanying rise in GBF. CORM-2 significantly increased gastric mucosal HO-1 mRNA expression and decreased mRNA expression for iNOS, IL-1β, COX-1 and COX-2 but failed to affect HO-1 and Nrf2 protein expression decreased by ethanol. We conclude that CORM-2 released CO exerts gastroprotection against ethanol-induced gastric lesions involving an increase in gastric microcirculation mediated by sGC/cGMP, prostaglandins derived from COX-1, NO-NOS system and its anti-inflammatory properties.
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30
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Takagi T, Uchiyama K, Naito Y. The therapeutic potential of carbon monoxide for inflammatory bowel disease. Digestion 2015; 91:13-8. [PMID: 25632911 DOI: 10.1159/000368765] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory disorders of the intestinal tract. Because the precise pathogenesis of IBD remains unclear, it is important to investigate the pathogenesis of IBD and to evaluate new anti-inflammatory strategies. Recent accumulating evidence has suggested that carbon monoxide (CO) may act as an endogenous defensive gaseous molecule to reduce inflammation and tissue injury in various organ injury models, including intestinal inflammation. Furthermore, exogenous CO administration at low concentrations is protective against intestinal inflammation. These data suggest that CO may be a novel therapeutic molecule in patients with IBD. In this review, we present what is currently known regarding the therapeutic potential of CO in intestinal inflammation.
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Affiliation(s)
- Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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31
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Abstract
Gastroparesis is a complication of long-standing type 1 and type 2 diabetes mellitus. Symptoms associated with gastroparesis include early satiety, prolonged postprandial fullness, bloating, nausea and vomiting, and abdominal pain. Mortality is increased in patients with diabetic gastroparesis. A subset of patients with diabetic gastroparesis have pylorospasm that results in obstructive gastroparesis. Current treatment approaches include improving glucose control with insulin and prescribing antinauseant drugs, prokinetic agents, and gastric electric stimulation. Future directions include improved diet counseling based on gastric emptying rate, continuous insulin delivery systems with glucose sensor-augmented monitoring, and drugs for correcting gastric neural and electric abnormalities.
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Affiliation(s)
- Kenneth L Koch
- Section on Gastroenterology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
| | - Jorge Calles-Escandón
- Section on Endocrinology, MetroHealth Regional, Case Western Reserve University School of Medicine, 2500 Metrohealth Drive, Cleveland, OH 44109, USA
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32
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Yue X, Zhu Z, Zhang M, Ye Z. Reaction-Based Turn-on Electrochemiluminescent Sensor with a Ruthenium(II) Complex for Selective Detection of Extracellular Hydrogen Sulfide in Rat Brain. Anal Chem 2015; 87:1839-45. [DOI: 10.1021/ac503875j] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Xiaoxiao Yue
- Department
of Chemistry, Renmin University of China, Beijing 100872, China
| | - Ziyu Zhu
- Department
of Chemistry, Renmin University of China, Beijing 100872, China
| | - Meining Zhang
- Department
of Chemistry, Renmin University of China, Beijing 100872, China
| | - Zhiqiang Ye
- State
Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian 116024, China
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33
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Phillips LK, Rayner CK, Jones KL, Horowitz M. Measurement of gastric emptying in diabetes. J Diabetes Complications 2014; 28:894-903. [PMID: 25047170 DOI: 10.1016/j.jdiacomp.2014.06.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 06/10/2014] [Indexed: 02/07/2023]
Abstract
There has been a substantial evolution of concepts related to disordered gastric emptying in diabetes. While the traditional focus has hitherto related to the pathophysiology and management of upper gastrointestinal symptoms associated with gastroparesis, it is now apparent that the rate of gastric emptying is central to the regulation of postprandial glycemia. This recognition has stimulated the development of dietary and pharmacologic approaches to optimize glycemic control, at least in part, by slowing gastric emptying. With the increased clinical interest in this area, it has proved necessary to expand the traditional indications for gastric emptying studies, and consider the relative strengths and limitations of available techniques. Scintigraphy remains the 'gold standard' for the measurement of gastric emptying, however, there is a lack of standardization of the technique, and the optimal test meal for the evaluation of gastrointestinal symptoms may be discordant from that which is optimal to assess impaired glycemic control. The stable isotope breath test provides an alternative to scintigraphy and can be performed in an office-based setting. The effect of glucagon-like peptide-1 (GLP-1) and its agonists to reduce postprandial glycemia is dependent on the baseline rate of gastric emptying, as well as the magnitude of slowing. Because the effect of exogenous GLP-1 to slow gastric emptying is subject to tachyphylaxis with sustained receptor exposure, 'short acting' or 'prandial' GLP-1 agonists primarily target postprandial glycemia through slowing of gastric emptying, while 'long acting' or 'non-prandial' agents lower fasting glucose primarily through insulinotropic and glucagonostatic mechanisms. Accordingly, the indications for the therapeutic use of these different agents are likely to vary according to baseline gastric emptying rate and glycemic profiles.
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Affiliation(s)
- Liza K Phillips
- Discipline of Medicine, The University of Adelaide, Australia; NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia; Endocrine and Metabolic Unit, Royal Adelaide Hospital, Australia
| | - Chris K Rayner
- Discipline of Medicine, The University of Adelaide, Australia; NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Australia
| | - Karen L Jones
- Discipline of Medicine, The University of Adelaide, Australia; NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia
| | - Michael Horowitz
- Discipline of Medicine, The University of Adelaide, Australia; NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia; Endocrine and Metabolic Unit, Royal Adelaide Hospital, Australia.
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Bharucha AE, Choi KM, Saw J, Gibbons SJ, Farrugia G, Carlson D, Zinsmeister AR. Effects of aspirin & simvastatin and aspirin, simvastatin, & lipoic acid on heme oxygenase-1 in healthy human subjects. Neurogastroenterol Motil 2014; 26:1437-42. [PMID: 25093998 PMCID: PMC4177447 DOI: 10.1111/nmo.12404] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Accepted: 06/27/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND Heme oxygenase 1 (HO-1) degrades heme and protects against oxidative stress. In vitro and animal models suggest that HO-1 is beneficial in several diseases (e.g., postoperative ileus, gastroparesis, acute pancreatitis, and colitis). However, the only drugs (i.e., hemin and heme arginate) which pharmacologically upregulate HO-1 in humans are expensive and can only be administered intravenously. Our aims were to compare the effects of placebo, aspirin, and simvastatin alone, and with α-lipoic acid, on HO-1 protein concentration and activity in humans. METHODS This randomized, double-blind, placebo-controlled study compared the effects of three oral regimens administered for 7 days, i.e., placebo; aspirin (325 mg twice daily) and simvastatin (40 mg twice daily); aspirin, simvastatin, and the sodium salt of R- α-lipoic acid (NaRLA, 600 mg three times daily) on markers of HO-1 activation (i.e., plasma HO-1 protein concentration and venous monocyte HO-1 protein activity) in 18 healthy subjects (14 females). Markers of HO-1 activation were evaluated at baseline, days 2, and 7. KEY RESULTS Baseline HO-1 protein concentrations and activity were similar among the three groups. Compared to placebo, aspirin and simvastatin combined, or together with NaRLA did not affect HO-1 protein concentration or activity at 2 or 7 days. HO-1 protein concentrations and activity were correlated on day 7 (r = 0.75, p = 0.0004) but not at baseline and on day 2. CONCLUSIONS & INFERENCES At therapeutic doses, aspirin, simvastatin, and α-lipoic acid do not increase plasma HO-1 protein concentration or venous monocyte HO-1 activity in healthy humans.
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Affiliation(s)
- Adil E. Bharucha
- Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
| | - Kyoung Moo Choi
- Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
| | - Jessica Saw
- Mayo Medical School, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
| | - Simon J. Gibbons
- Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
| | - Gianrico Farrugia
- Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
| | | | - Alan R Zinsmeister
- Division of Biomedical Statistics and Informatics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
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Oral drug delivery of therapeutic gases — Carbon monoxide release for gastrointestinal diseases. J Control Release 2014; 189:46-53. [DOI: 10.1016/j.jconrel.2014.06.025] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Revised: 06/14/2014] [Accepted: 06/16/2014] [Indexed: 01/27/2023]
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Farrugia G, Szurszewski JH. Carbon monoxide, hydrogen sulfide, and nitric oxide as signaling molecules in the gastrointestinal tract. Gastroenterology 2014; 147:303-13. [PMID: 24798417 PMCID: PMC4106980 DOI: 10.1053/j.gastro.2014.04.041] [Citation(s) in RCA: 134] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 04/16/2014] [Accepted: 04/24/2014] [Indexed: 12/24/2022]
Abstract
Carbon monoxide (CO) and hydrogen sulfide (H2S) used to be thought of simply as lethal and (for H2S) smelly gaseous molecules; now they are known to have important signaling functions in the gastrointestinal tract. CO and H2S, which are produced in the gastrointestinal tract by different enzymes, regulate smooth muscle membrane potential and tone, transmit signals from enteric nerves, and can regulate the immune system. The pathways that produce nitric oxide, H2S, and CO interact; each can inhibit and potentiate the level and activity of the other. However, there are significant differences between these molecules, such as in half-lives; CO is more stable and therefore able to have effects distal to the site of production, whereas nitric oxide and H2S are short lived and act only close to sites of production. We review their signaling functions in the luminal gastrointestinal tract and discuss how their pathways interact. We also describe other physiological functions of CO and H2S and how they might be used as therapeutic agents.
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Affiliation(s)
- Gianrico Farrugia
- Enteric NeuroScience Program, Division of Gastroenterology and Hepatology and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
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Babu D, Motterlini R, Lefebvre RA. CO and CO-releasing molecules (CO-RMs) in acute gastrointestinal inflammation. Br J Pharmacol 2014; 172:1557-73. [PMID: 24641722 DOI: 10.1111/bph.12632] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 01/30/2014] [Accepted: 02/05/2014] [Indexed: 12/13/2022] Open
Abstract
Carbon monoxide (CO) is enzymatically generated in mammalian cells alongside the liberation of iron and the production of biliverdin and bilirubin. This occurs during the degradation of haem by haem oxygenase (HO) enzymes, a class of ubiquitous proteins consisting of constitutive and inducible isoforms. The constitutive HO2 is present in the gastrointestinal tract in neurons and interstitial cells of Cajal and CO released from these cells might contribute to intestinal inhibitory neurotransmission and/or to the control of intestinal smooth muscle cell membrane potential. On the other hand, increased expression of the inducible HO1 is now recognized as a beneficial response to oxidative stress and inflammation. Among the products of haem metabolism, CO appears to contribute primarily to the antioxidant and anti-inflammatory effects of the HO1 pathway explaining the studies conducted to exploit CO as a possible therapeutic agent. This article reviews the effects and, as far as known today, the mechanism(s) of action of CO administered either as CO gas or via CO-releasing molecules in acute gastrointestinal inflammation. We provide here a comprehensive overview on the effect of CO in experimental in vivo models of post-operative ileus, intestinal injury during sepsis and necrotizing enterocolitis. In addition, we will analyse the in vitro data obtained so far on the effect of CO on intestinal epithelial cell lines exposed to cytokines, considering the important role of the intestinal mucosa in the pathology of gastrointestinal inflammation.
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Affiliation(s)
- D Babu
- Heymans Institute of Pharmacology, Ghent University, Gent, Belgium
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Libardi SH, Skibsted LH, Cardoso DR. Oxidation of carbon monoxide by perferrylmyoglobin. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2014; 62:1950-5. [PMID: 24506496 DOI: 10.1021/jf4053176] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Perferrylmyoglobin is found to oxidize CO in aerobic aqueous solution to CO2. Tryptophan hydroperoxide in the presence of tetra(4-sulfonatophenyl)-porphyrinate-iron(III) or simple iron(II)/(III) salts shows similar reactivity against CO. The oxidation of CO is for tryptophan hydroperoxide concluded to depend on the formation of alkoxyl radicals by reductive cleavage by iron(II) or on the formation of peroxyl radicals by oxidative cleavage by iron(III). During oxidation of CO, the tryptophan peroxyl radical was depleted with a rate constant of 0.26 ± 0.01 s(-1) for CO-saturated aqueous solution of pH 7.4 at 25 °C without concomitant reduction of the iron(IV) center. Carbon monoxide is as a natural metabolite accordingly capable of scavenging tryptophan radicals in myoglobin activated by peroxides with a second-order rate constant of (3.3 ± 0.6) × 10(2) L mol(-1) s(-1), a reaction that might be of importance in cellular membranes of the intestine for protection of tissue against radical damage during meat digestion.
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Affiliation(s)
- Silvia H Libardi
- Instituto de Quı́mica de São Carlos, Universidade de São Paulo , Av. Trabalhador São Carlense 400, CP 780, CEP 13560-970 São Carlos, SP, Brazil
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