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Jebahi S, Ben Salah G, Jarray S, Naffati M, Ahmad MA, Brahmi F, Saeed M, Siddiqui AJ, Abdelmajid K, Badraoui R. Chitosan-Based Gastric Dressing Materials Loaded with Pomegranate Peel as Bioactive Agents: Pharmacokinetics and Effects on Experimentally Induced Gastric Ulcers in Rabbits. Metabolites 2022; 12:metabo12121158. [PMID: 36557196 PMCID: PMC9784949 DOI: 10.3390/metabo12121158] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/07/2022] [Accepted: 11/17/2022] [Indexed: 11/25/2022] Open
Abstract
This study reported the fabrication and characterization of gastric dressing, composed of gelatine (GEL), chitosan (CH), and pomegranate peel (PP) extract. The structural changes occurring after γ-irradiation of GEL−CH−PP dressing were reported. The results showed that the electron paramagnetic resonance (EPR) spectroscopy of un-irradiated GEL−CH−PP showed two paramagnetic centers, which corresponded to g = 2.19 and g = 2.002. After irradiation, a new active centre appeared at g = 2.0035 at 10 kGy. The Fourier transform infrared spectroscopy (FTIR) analyses revealed an increase in peak intensity at C−H chains, as well as the C=O carboxyl groups at 10 kGy, due to the cross-linking phenomenon. The X-ray diffraction analysis showed a low change of crystallinity between the range of 2θ (15−30°). Moreover, γ-rays enhanced scavenging DPPH radical activity (51±%) and chelating power activities 79.12%. A significant inhibition of antibacterial and anti-biofilm activities (p < 0.01) was noticed. The hemolysis rates showed 0.42%, suggesting a high hemocompatibility, and exhibited significant anti-inflammatory activity in vitro (48%). In vivo, the healing effects of GEL−CH−PP dressing showed that the incidence and severity of gastric histopathological lesions decreased, compared with the ulcerated group, which could explain the bioavailability and the pharmacokinetic findings. The results highlight the loading of bioactive agents into polymer-based gastric dressings, with promising pharmacokinetics properties and effects on the induced ulcera in rabbits.
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Affiliation(s)
- Samira Jebahi
- Energy and Matter Research Laboratory, National Center for Sciences and Nuclear Technologies, BiotechPole, Ariana 2020, Tunisia
| | - Ghada Ben Salah
- Department of Pharmacology and Toxicology, Unaizah College of Pharmacy, Qassim University, Buraidah 51452, Saudi Arabia
| | - Soufien Jarray
- Higher Institute of Applied Biology of Mednine, Route El Jorf-Km 22.5-4119 Medenine, University of Gabes, Medenine 4119, Tunisia
| | - Mounir Naffati
- Higher Institute of Applied Biology of Mednine, Route El Jorf-Km 22.5-4119 Medenine, University of Gabes, Medenine 4119, Tunisia
| | - Mohammad Ayaz Ahmad
- Department of Mathematics, Physics & Statistics, University of Guyana, Turkeyen Campus, Georgetown P.O. Box 10-1110, Guyana
| | - Faten Brahmi
- Laboratory of General Biology, Department of Biology, University of Ha’il, Ha’il 81451, Saudi Arabia
| | - Mohd Saeed
- Laboratory of General Biology, Department of Biology, University of Ha’il, Ha’il 81451, Saudi Arabia
| | - Arif J. Siddiqui
- Laboratory of General Biology, Department of Biology, University of Ha’il, Ha’il 81451, Saudi Arabia
| | - Khabir Abdelmajid
- Higher Institute of Applied Biology of Mednine, Route El Jorf-Km 22.5-4119 Medenine, University of Gabes, Medenine 4119, Tunisia
- Laboratory of Histo-Embryology & Cytogenetics, Medicine Faculty of Sfax, University of Sfax, Sfax 3029, Tunisia
| | - Riadh Badraoui
- Laboratory of General Biology, Department of Biology, University of Ha’il, Ha’il 81451, Saudi Arabia
- Laboratory of Histo-Embryology & Cytogenetics, Medicine Faculty of Sfax, University of Sfax, Sfax 3029, Tunisia
- Section of Histology-Cytology, Medicine Faculty of Tunis, University of Tunis El Manar, La Rabta, Tunis 1007, Tunisia
- Correspondence: ; Tel.: +216-98-587-492 or +966-531-334-541
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Yin YC, Li XH, Rao X, Li YJ, Du J. Involvement of microRNA/cystine/glutamate transporter in cold-stressed gastric mucosa injury. Front Pharmacol 2022; 13:968098. [PMID: 36249798 PMCID: PMC9554746 DOI: 10.3389/fphar.2022.968098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/08/2022] [Indexed: 11/18/2022] Open
Abstract
Stress ulcers are complicated by severe trauma and other critical diseases, the mechanism of which remains unclear. An increasing number of studies have shown that microRNAs (miRNAs) are important regulators of stress responses such as hypoxia, abnormal temperature, and inflammation. The evidence indicates that miRNAs are also involved in regulating stress-induced ulcers. Recently, we demonstrated that gastric mucosal injury induced by aspirin is related to the reduction of glutamate levels by inhibition of cystine/glutamate transporter (xCT) activity. In the present study, the effect of a miRNA/xCT on gastric mucosal injury induced by cold stimulation was investigated. We found that cold stimulation induced gastric mucosa injury with a reduction in glutamate levels and xCT activity and upregulation of miR-143, miR-152, and miR-181 expression. Exogenous glutamate significantly alleviated gastric mucosa injury by cold stimulation. In vitro experiments demonstrated that treatment with miR-143, miR-152, or miR-181 mimics directly induced cell damage. The effects of these mimics were alleviated by exogenous glutamate. The present study suggests that miR-143, miR-152, and miR-181 are involved in cold stimulation-induced acute gastric mucosal injury. Furthermore, the regulatory effect of miRNAs on gastric mucosa injury induced by cold stimulation is related to a decrease in glutamate release by reduction of cystine/glutamate transporter activity.
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Affiliation(s)
- You-Cong Yin
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China
- Department of Pharmacy, The Central Hospital of Shaoyang, Shaoyang, China
| | - Xiao-hui Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Xuan Rao
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Yuan-Jian Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China
- *Correspondence: Jie Du, ; Yuan-Jian Li,
| | - Jie Du
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (XIANGYA), Central South University, Changsha, China
- *Correspondence: Jie Du, ; Yuan-Jian Li,
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Mohamed YT, Naguib IA, Abo-Saif AA, Elkomy MH, Alghamdi BS, Mohamed WR. Role of ADMA/DDAH-1 and iNOS/eNOS signaling in the gastroprotective effect of tadalafil against indomethacin-induced gastric injury. Biomed Pharmacother 2022; 150:113026. [PMID: 35658250 DOI: 10.1016/j.biopha.2022.113026] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/16/2022] [Accepted: 04/20/2022] [Indexed: 11/02/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcers represent a significant clinical concern and adversely affect the quality of life. Inducible nitric oxide synthase/endothelial nitric oxide synthase (iNOS/eNOS) and asymmetric dimethylarginine/ dimethylarginine dimethylaminohydrolase-1 (ADMA/DDAH-1) signaling are key players in gastric ulcer pathogenesis. This work was planned to explore the role of iNOS/eNOS and ADMA/DDAH-1 signaling in rats with indomethacin-induced gastric ulcer, as potential pathways for the gastro-protective effect of tadalafil. Split into 5 separate groups, rats were assigned to control, tadalafil (10 mg/kg, p.o), indomethacin (single oral dose of 60 mg/kg), indomethacin + pantoprazole (40 mg/kg, p.o), and indomethacin + tadalafil (10 mg/kg, p.o). The results indicated that pretreatment with tadalafil significantly reduced ulcer index (UI), increased preventive index (PI), and counteracted indomethacin-induced histopathological aberrations. Tadalafil significantly reduced the gastric content of NO while it significantly elevated that of GSH and enhanced SOD activity. It significantly reduced the gastric expression of TNF-α and ADMA while it significantly elevated that of COX-2, PGE-2, and DDAH-1. Western blot analysis revealed that pretreatment with tadalafil significantly reduced iNOS protein expression while it significantly elevated that of eNOS. Collectively, these data suggest that tadalafil exerts potential protective effect against indomethacin-induced ulcer through suppression of inflammation, attenuation of oxidative stress, and boosting of antioxidants. Moreover, tadalafil protective effects are mediated via upregulation of PGE-2 with modulating the signaling pathways of ADMA/DDAH-1, and iNOS/eNOS. As a result, the current evidence corroborates the use of tadalafil in controlling gastric ulcers and preventing NSAID gastric side effects.
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Affiliation(s)
- Yasmin T Mohamed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef 62514, Egypt.
| | - Ibrahim A Naguib
- Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
| | - Ali A Abo-Saif
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef 62514, Egypt.
| | - Mohammed H Elkomy
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
| | - Badrah S Alghamdi
- Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia; Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
| | - Wafaa R Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
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Mohamed YT, Naguib IA, Abo-Saif AA, Mohamed WR. Protective effects of perindopril against indomethacin-induced gastric mucosal damage through modulation of DDAH-1/ADMA and ACE-2/ANG-(1-7) signaling pathways. Drug Chem Toxicol 2021; 45:2509-2518. [PMID: 34384315 DOI: 10.1080/01480545.2021.1962672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Indomethacin is a widely used nonsteroidal anti-inflammatory drug; however, its clinical utility is accompanied by serious adverse reactions including peptic ulcers. The current study aims to investigate the protective potential of perindopril against indomethacin-induced gastric injury in rats. Perindopril (4 mg/kg) was administered orally for 7 days and indomethacin (60 mg/kg, single oral dose) was administered on the 7th day, 1 h after perindopril administration. Pantoprazole was used as a standard agent. Ulcer index (UI), preventive index ratio (PI), histopathological examination, oxidative stress, and inflammatory biomarkers were investigated. Perindopril significantly decreased UI while increased PI and counteracted histopathological aberrations induced by indomethacin. It alleviated indomethacin-induced oxidative stress by lowering NO while increasing GSH content and superoxide dismutase activity. Perindopril significantly downregulated TNF-α and asymmetric dimethylarginine (ADMA), while significantly upregulated COX-2, PGE-2, dimethylarginine dimethylaminohydrolase-1 (DDAH-1), ANG-(1-7), and ACE-2 expression. Together, these findings suggest the gastroprotective effects of perindopril through modulation of DDAH-1/ADMA and ACE-2/ANG-(1-7) signaling.HIGHLIGHTSPerindopril attenuated gastric histopathological damage.It increased GSH content and SOD activity while decreased NO content.It modulated gastric ADMA and DDAH-1 activity.It reduced TNF-α, while increased COX-2 and PGE-2 expression.It upregulated ACE-2 activity and ANG-(1-7) protein expression.
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Affiliation(s)
- Yasmin T Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | - Ibrahim A Naguib
- Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Ali A Abo-Saif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | - Wafaa R Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
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Bednarz-Misa I, Fleszar MG, Fortuna P, Lewandowski Ł, Mierzchała-Pasierb M, Diakowska D, Krzystek-Korpacka M. Altered L-Arginine Metabolic Pathways in Gastric Cancer: Potential Therapeutic Targets and Biomarkers. Biomolecules 2021; 11:biom11081086. [PMID: 34439753 PMCID: PMC8395015 DOI: 10.3390/biom11081086] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
There is a pressing need for molecular targets and biomarkers in gastric cancer (GC). We aimed at identifying aberrations in L-arginine metabolism with therapeutic and diagnostic potential. Systemic metabolites were quantified using mass spectrometry in 293 individuals and enzymes’ gene expression was quantified in 29 paired tumor-normal samples using qPCR and referred to cancer pathology and molecular landscape. Patients with cancer or benign disorders had reduced systemic arginine, citrulline, and ornithine and elevated symmetric dimethylarginine and dimethylamine. Citrulline and ornithine depletion was accentuated in metastasizing cancers. Metabolite diagnostic panel had 91% accuracy in detecting cancer and 70% accuracy in differentiating cancer from benign disorders. Gastric tumors had upregulated NOS2 and downregulated ASL, PRMT2, ORNT1, and DDAH1 expression. NOS2 upregulation was less and ASL downregulation was more pronounced in metastatic cancers. Tumor ASL and PRMT2 expression was inversely related to local advancement. Enzyme up- or downregulation was greater or significant solely in cardia subtype. Metabolic reprogramming in GC includes aberrant L-arginine metabolism, reflecting GC subtype and pathology, and is manifested by altered interplay of its intermediates and enzymes. Exploiting L-arginine metabolic pathways for diagnostic and therapeutic purposes is warranted. Functional studies on ASL, PRMT2, and ORNT1 in GC are needed.
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Affiliation(s)
- Iwona Bednarz-Misa
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
| | - Mariusz G. Fleszar
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
| | - Paulina Fortuna
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
| | - Łukasz Lewandowski
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
| | - Magdalena Mierzchała-Pasierb
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
| | - Dorota Diakowska
- Department of Gastrointestinal and General Surgery, Wroclaw Medical University, 50-368 Wroclaw, Poland;
- Department of Nervous System Diseases, Wroclaw Medical University, 51-618 Wroclaw, Poland
| | - Małgorzata Krzystek-Korpacka
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
- Correspondence:
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Mitchell JA, Kirkby NS, Ahmetaj-Shala B, Armstrong PC, Crescente M, Ferreira P, Lopes Pires ME, Vaja R, Warner TD. Cyclooxygenases and the cardiovascular system. Pharmacol Ther 2021; 217:107624. [DOI: 10.1016/j.pharmthera.2020.107624] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023]
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Elshamy AI, Farrag ARH, Ayoub IM, Mahdy KA, Taher RF, Gendy AENGEI, Mohamed TA, Al-Rejaie SS, EI-Amier YA, Abd-EIGawad AM, Farag MA. UPLC-qTOF-MS Phytochemical Profile and Antiulcer Potential of Cyperus conglomeratus Rottb. Alcoholic Extract. Molecules 2020; 25:E4234. [PMID: 32942704 PMCID: PMC7570889 DOI: 10.3390/molecules25184234] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/10/2020] [Accepted: 09/13/2020] [Indexed: 02/07/2023] Open
Abstract
Cyperus has been commonly used as a multi-use medicinal plant in folk medicine worldwide. The objectives of our study were to determine the different metabolites in the Cyperus conglomeratus Rottb. methanol extract, and to assess its in vivo gastroprotective effect in ethanol-induced gastric ulcer model in rats. Serum levels of galactin-3 and TNF-α were employed as biochemical markers. To pinpoint for active agents, comprehensive metabolites profiling of extract via UPLC-qTOF-MS/MS was employed. A total of 77 chromatographic peaks were detected, of which 70 were annotated. The detected metabolites were categorized into phenolic acids and their derivatives, flavonoids, stilbenes, aurones, quinones, terpenes, and steroids. Rats were divided into six groups; healthy control, ulcer control, standard drug group, and 25, 50, 100 mg/kg of C. conglomeratus treated rats. Pre-treatment with C. conglomeratus alcohol extract significantly reduced galactin-3, and TNF-α in ethanol-induced ulcer model at 25, 50, and 100 mg/kg. Further histopathological and histochemical studies revealed moderate erosion of superficial epithelium, few infiltrated inflammatory cells, and depletion of gastric tissue glycoprotein in the ulcer group. Treatment with the extract protected the gastric epithelial cells in a dose-dependent manner. It could be concluded that C. conglomeratus extract provides significant gastroprotective activity in ethanol-induced gastric ulcer and ought to be included in nutraceuticals in the future for ulcer treatment.
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Affiliation(s)
- Abdelsamed I. Elshamy
- Department of Natural Compounds Chemistry, National Research Center, 33 El Bohouth St., Dokki, Giza 12622, Egypt;
| | - Abdel Razik H. Farrag
- Pathology Department, National Research Centre, 33 El Bohouth St., Dokki, Giza 12622, Egypt;
| | - Iriny M. Ayoub
- Pharmacognosy Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt;
| | - Karam A. Mahdy
- Medical Biochemistry Department, National Research Centre, 33 El Bohouth St., Dokki, Giza 12622, Egypt;
| | - Rehab F. Taher
- Department of Natural Compounds Chemistry, National Research Center, 33 El Bohouth St., Dokki, Giza 12622, Egypt;
| | - Abd El-Nasser G. EI Gendy
- Medicinal and Aromatic Plants Research Department, National Research Centre, 33 El Bohouth St., Dokki, Giza 12622, Egypt;
| | - Tarik A. Mohamed
- Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt;
| | - Salim S. Al-Rejaie
- Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Yasser A. EI-Amier
- Department of Botany, Faculty of Science, Mansoura University, Mansoura 35516, Egypt;
| | - Ahmed M. Abd-EIGawad
- Department of Botany, Faculty of Science, Mansoura University, Mansoura 35516, Egypt;
- Plant Production Department, College of Food & Agriculture Sciences, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia
| | - Mohamed A. Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr el Aini St., Cairo P.B. 11562, Egypt;
- Chemistry Department, School of Sciences & Engineering, The American University in Cairo, New Cairo 11835, Egypt
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Zhao DQ, Xue H, Sun HJ. Nervous mechanisms of restraint water-immersion stress-induced gastric mucosal lesion. World J Gastroenterol 2020; 26:2533-2549. [PMID: 32523309 PMCID: PMC7265141 DOI: 10.3748/wjg.v26.i20.2533] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 04/07/2020] [Accepted: 04/28/2020] [Indexed: 02/06/2023] Open
Abstract
Stress-induced gastric mucosal lesion (SGML) is one of the most common visceral complications after trauma. Exploring the nervous mechanisms of SGML has become a research hotspot. Restraint water-immersion stress (RWIS) can induce GML and has been widely used to elucidate the nervous mechanisms of SGML. It is believed that RWIS-induced GML is mainly caused by the enhanced activity of vagal parasympathetic nerves. Many central nuclei, such as the dorsal motor nucleus of the vagus, nucleus of the solitary tract, supraoptic nucleus and paraventricular nucleus of the hypothalamus, mediodorsal nucleus of the thalamus, central nucleus of the amygdala and medial prefrontal cortex, are involved in the formation of SGML in varying degrees. Neurotransmitters/neuromodulators, such as nitric oxide, hydrogen sulfide, vasoactive intestinal peptide, calcitonin gene-related peptide, substance P, enkephalin, 5-hydroxytryptamine, acetylcholine, catecholamine, glutamate, γ-aminobutyric acid, oxytocin and arginine vasopressin, can participate in the regulation of stress. However, inconsistent and even contradictory results have been obtained regarding the actual roles of each nucleus in the nervous mechanism of RWIS-induced GML, such as the involvement of different nuclei with the time of RWIS, the different levels of involvement of the sub-regions of the same nucleus, and the diverse signalling molecules, remain to be further elucidated.
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Affiliation(s)
- Dong-Qin Zhao
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| | - Hua Xue
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| | - Hai-Ji Sun
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
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A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling. Sci Rep 2018. [PMID: 29523851 PMCID: PMC5844881 DOI: 10.1038/s41598-018-22727-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The advent of angiotensin II type 1 receptor blockers (ARBs) as intriguing gastroprotective candidates and the superior pharmacokinetics and pharmacodynamics displayed by irbesartan compared to many other ARBs raised the interest to investigate its gastroprotective potential in a rat model of gastric injury. Irbesartan (50 mg/Kg) was orally administered to male Wistar rats once daily for 14 days; thereafter gastric injury was induced by indomethacin (60 mg/Kg, p.o). Irbesartan reduced gastric ulcer index, gastric acidity, and ameliorated indomethacin-induced gastric mucosal apoptotic and inflammatory aberrations, as demonstrated by hampering caspase-3, prostaglandin E2 and tumor necrosis factor-alpha levels and cyclooxygenase-2 mRNA expression. This ARB increased mucosal dimethylarginine dimethylaminohydrolase-1 (DDAH-1) gene expression and decreased elevated levels of matrix metalloproteinase-9, asymmetric dimethylarginine (ADMA), epidermal growth factor receptor (EGFR) mRNA and phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Histopathological evaluation corroborated biochemical findings. Overall efficacy of irbesartan was comparable to ranitidine, the widely used H2 receptor blocker. In conclusion, irbesartan exerts significant gastroprotection against indomethacin-induced mucosal damage via acid-inhibitory, anti-inflammatory, anti-apoptotic and extracellular matrix remodeling mechanisms that are probably mediated, at least partly, by down-regulating DDAH/ADMA and EGFR/ERK1/2 signaling.
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Gastroprotective Mechanism and Ulcer Resolution Effect of Cyrtocarpa procera Methanolic Extract on Ethanol-Induced Gastric Injury. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:2862706. [PMID: 29507589 PMCID: PMC5817374 DOI: 10.1155/2018/2862706] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 11/29/2017] [Indexed: 12/30/2022]
Abstract
Gastric ulcers are a worldwide health problem and their poor healing is one of the most important causes for their recurrence. We have previously reported the remarkable gastroprotective and anti-Helicobacter pylori activities of the methanolic extract (CpMet) of Cyrtocarpa procera bark. This work investigates, in a murine model, the CpMet gastroprotective mechanism and establishes its preclinical efficacy in the resolution of ethanol-induced gastric ulcers. The results showed that the gastroprotective activity of CpMet is mainly associated with endogenous NO and prostaglandins, followed by sulfhydryl groups and KATP channels. Furthermore, CpMet (300 mg/kg, twice a day) orally administered during 20 consecutive days promoted an ulcer area reduction of 62.65% at the 20th day of the treatment. The effect was confirmed macroscopically by the alleviation of gastric mucosal erosions and microscopically by an increase in mucin content and a reduction in the inflammatory infiltration at the site of the ulcer. No clinical symptoms or signs of toxicity were observed in the treated animals. The results indicate the safety and efficacy of CpMet in promoting high quality of ulcer healing by different mechanisms, but mostly through cytoprotective and anti-inflammatory effects, making it a promising phytodrug for ulcer treatment.
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Gastroprotective effects of sulforaphane and thymoquinone against acetylsalicylic acid-induced gastric ulcer in rats. J Surg Res 2016; 203:348-59. [PMID: 27363643 DOI: 10.1016/j.jss.2016.03.027] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 02/29/2016] [Accepted: 03/11/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) commonly cause gastric ulcers (GUs). We investigated the effects of sulforaphane (SF) and thymoquinone (TQ) in rats with acetylsalicylic acid (ASA)-induced GUs. MATERIALS AND METHODS Thirty-five male Wistar-Albino rats were divided into five groups: control; ASA; ASA with vehicle; ASA + SF; and ASA + TQ. Compounds were administered by oral gavage before GU induction. GUs were induced by intragastric administration of ASA. Four hours after GU induction, rats were killed and stomachs excised. Total oxidant status, total antioxidant status, total thiol, nitric oxide, asymmetric dimethylarginine, tumor necrosis factor-alpha levels, superoxide dismutase activity, and glutathione peroxidase activity in tissue were measured. Messenger RNA expression of dimethylarginine dimethylaminohydrolases, heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2, and nuclear factor kappa-light-chain-enhancer of activated B cells were analyzed. Renal tissues were evaluated by histopathologic and immunohistochemical means. RESULTS SF and TQ reduced GU indices, apoptosis, total oxidant status, asymmetric dimethylarginine, and tumor necrosis factor-alpha levels, nuclear factor kappa-light-chain-enhancer of activated B cells, and inducible nitric oxide synthase expressions (P < 0.001, P = 0.001). Both examined compounds increased superoxide dismutase activity, glutathione peroxidase activity, total antioxidant status, total thiol, nitric oxide levels, endothelial nitric oxide synthase, dimethylarginine dimethylaminohydrolases, HO-1, nuclear factor erythroid 2-related factor 2, and HO-1 expressions (P < 0.001). CONCLUSIONS These results suggest that pretreatment with SF or TQ can reduce ASA-induced GUs via anti-inflammatory, antioxidant, and antiapoptotic effects. These compounds may be useful therapeutic strategies to prevent the gastrointestinal adverse effects that limit nonsteroidal anti-inflammatory drugs use.
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Magierowski M, Jasnos K, Sliwowski Z, Surmiak M, Krzysiek-Maczka G, Ptak-Belowska A, Kwiecien S, Brzozowski T. Exogenous asymmetric dimethylarginine (ADMA) in pathogenesis of ischemia-reperfusion-induced gastric lesions: interaction with protective nitric oxide (NO) and calcitonin gene-related peptide (CGRP). Int J Mol Sci 2014; 15:4946-4964. [PMID: 24658439 PMCID: PMC3975433 DOI: 10.3390/ijms15034946] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 03/03/2014] [Accepted: 03/04/2014] [Indexed: 12/26/2022] Open
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthesis inhibitor and pro-inflammatory factor. We investigated the role of ADMA in rat gastric mucosa compromised through 30 min of gastric ischemia (I) and 3 h of reperfusion (R). These I/R animals were pretreated with ADMA with or without the combination of L-arginine, calcitonin gene-related peptide (CGRP) or a small dose of capsaicin, all of which are known to afford protection against gastric lesions, or with a farnesoid X receptor (FXR) agonist, GW 4064, to increase the metabolism of ADMA. In the second series, ADMA was administered to capsaicin-denervated rats. The area of gastric damage was measured with planimetry, gastric blood flow (GBF) was determined by H2-gas clearance, and plasma ADMA and CGRP levels were determined using ELISA and RIA. ADMA significantly increased I/R-induced gastric injury while significantly decreasing GBF, the luminal NO content, and the plasma level of CGRP. This effect of ADMA was significantly attenuated by pretreatment with CGRP, L-arginine, capsaicin, or a PGE2 analogue. In GW4064 pretreated animals, the I/R injury was significantly reduced and this effect was abolished by co-treatment with ADMA. I/R damage potentiated by ADMA was exacerbated in capsaicin-denervated animals with a further reduction of CGRP. Plasma levels of IL-10 were significantly decreased while malonylodialdehyde (MDA) and plasma TNF-α contents were significantly increased by ADMA. In conclusion, ADMA aggravates I/R-induced gastric lesions due to a decrease of GBF, which is mediated by a fall in NO and CGRP release, and the enhancement of lipid peroxidation and its pro-inflammatory properties.
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Affiliation(s)
- Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, Grzegorzecka Street 16, Cracow 31-531, Poland.
| | - Katarzyna Jasnos
- Department of Physiology, Jagiellonian University Medical College, Grzegorzecka Street 16, Cracow 31-531, Poland.
| | - Zbigniew Sliwowski
- Department of Physiology, Jagiellonian University Medical College, Grzegorzecka Street 16, Cracow 31-531, Poland.
| | - Marcin Surmiak
- Department of Physiology, Jagiellonian University Medical College, Grzegorzecka Street 16, Cracow 31-531, Poland.
| | - Gracjana Krzysiek-Maczka
- Department of Physiology, Jagiellonian University Medical College, Grzegorzecka Street 16, Cracow 31-531, Poland
| | - Agata Ptak-Belowska
- Department of Physiology, Jagiellonian University Medical College, Grzegorzecka Street 16, Cracow 31-531, Poland
| | - Slawomir Kwiecien
- Department of Physiology, Jagiellonian University Medical College, Grzegorzecka Street 16, Cracow 31-531, Poland.
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, Grzegorzecka Street 16, Cracow 31-531, Poland.
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13
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Caldas GFR, Oliveira ARDS, Araújo AV, Quixabeira DCA, Silva-Neto JDC, Costa-Silva JH, de Menezes IRA, Ferreira F, Leite ACL, da Costa JGM, Wanderley AG. Gastroprotective and ulcer healing effects of essential oil of Hyptis martiusii Benth. (Lamiaceae). PLoS One 2014; 9:e84400. [PMID: 24454726 PMCID: PMC3893125 DOI: 10.1371/journal.pone.0084400] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 11/19/2013] [Indexed: 11/19/2022] Open
Abstract
Hyptis martiusii Benth. is an aromatic plant found in abundance in northeastern Brazil that is used in ethnomedicine to treat gastric disorders. The aim of this study was to elucidate the mechanisms of action involved in the gastroprotection of the essential oil of Hyptis martiusii (EOHM) and to evaluate its healing capacity. Wistar rats were exposed to different protocols and subsequently were treated with 1% Tween-80 aqueous solution (negative control), pantoprazole, carbenoxolone, N-acetylcysteine (depending on the specificity of each model) or EOHM. The antisecretory activity (basal or stimulated) was determined using the pyloric ligature method. The gastroprotective action of nitric oxide and sulphydryl groups (–SH groups), as well as the quantification of adherent mucus and the levels of malondialdehyde and –SH groups in gastric mucosa, were evaluated using ethanol-induced gastric ulcer model. The healing ability was evaluated using the acetic acid-induced gastric ulcer model and histological and immunohistochemical analysis (HE, PAS and PCNA). EOHM (400 mg/kg) reduced the volume and acidity of gastric secretion stimulated by histamine and pentagastrin. The gastroprotective effect of EOHM involves the participation of endogenous sulfhydryl groups. EOHM increased mucus production (54.8%), reduced levels of MDA (72.5%) and prevented the depletion of –SH groups (73.8%) in the gastric mucosa. The treatment with EOHM reduced in 70.3% the gastric lesion area, promoting significant regeneration of the gastric mucosa, as confirmed by histological analysis and analysis of proliferating cell nuclear antigen. The results show that gastroprotective effect of EOHM is mediated by cytoprotective and antioxidant mechanisms and by their antisecretory activity, and suggest that the essential oil of Hyptis martiusii is a promising candidate for the treatment of gastric ulcers.
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Affiliation(s)
| | | | - Alice Valença Araújo
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, Pernambuco, Brazil
| | | | | | - João Henrique Costa-Silva
- Department of Physical Education and Sport Sciences, Federal University of Pernambuco, Vitória de Santo Antão, Pernambuco, Brazil
| | | | - Fabiano Ferreira
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, Pernambuco, Brazil
| | - Ana Cristina Lima Leite
- Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife, Pernambuco, Brazil
| | | | - Almir Gonçalves Wanderley
- Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife, Pernambuco, Brazil
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, Pernambuco, Brazil
- * E-mail:
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14
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Zhu J, Wang P, He Q, Zhou J, Luo C. Evidence of an anti-apoptotic effect of qinghuobaiduyin on intestinal mucosa following burn injury. Exp Ther Med 2013; 6:1390-1396. [PMID: 24255668 PMCID: PMC3829758 DOI: 10.3892/etm.2013.1314] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Accepted: 09/13/2013] [Indexed: 11/10/2022] Open
Abstract
Burn injuries are common in wartime and in times of peace. The prevention and therapy of ischemia-reperfusion injury to the organs, in particular the intestine, during the burn shock and recovery process has become a popular yet challenging area of research. Studies concerning the apoptosis of the cells of the burned intestinal mucosa have gained considerable attention. Qinghuobaiduyin (QHBDY) is a traditional Chinese medicine that has been used as a clinical prescription since 1995 to treat burn patients due to its opsonization function in the immune system and favorable clinical therapeutic effect. The aim of this study was to investigate the effect of QHBDY on the apoptosis of intestinal mucosa following burn injury. An animal model was constructed comprising severely burned rats that were treated with various dosages of QHBDY. Tissues from the small intestine were collected to investigate the apoptosis rate by TUNEL assay and the protein expression levels of heat shock protein 70 (Hsp70) and caspase-3 by immunohistochemistry. In addition, IEC-18 cells treated with QHBDY and burn serum were investigated. The cell apoptosis rate was analyzed by flow cytometry (FCM), the protein expression levels of Hsp70 were measured by western blot analysis and caspase-3 activity was analyzed by a colorimetric assay. The results showed that in animal experiments, compared with the burned group, the apoptosis rates in the treatment group was decreased, the protein expression level of Hsp70 was increased while Caspase-3 was decreased. In cell experiments, after treatment with QHBDY, the cell apoptosis rate was lower than that of the burn serum group. In addition, Hsp70 protein expression was upregulated and caspase-3 activity was decreased. QHBDY may play an important role in the prevention of apoptosis at the whole animal and cellular levels.
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Affiliation(s)
- Jie Zhu
- Department of Burn and Plastics Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
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15
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He W, Zhang Y, Wang X, Guo L, Han L, Liu E, Wang T. Zhizhu Decoction Promotes Gastric Emptying and Protects the Gastric Mucosa. J Med Food 2013; 16:306-11. [DOI: 10.1089/jmf.2012.2438] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Wei He
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Ministry of Education, Tianjin, China
| | - Yi Zhang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Ministry of Education, Tianjin, China
| | - Xinrui Wang
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Ministry of Education, Tianjin, China
| | - Lingling Guo
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Ministry of Education, Tianjin, China
| | - Lifeng Han
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Ministry of Education, Tianjin, China
| | - Erwei Liu
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Ministry of Education, Tianjin, China
| | - Tao Wang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Ministry of Education, Tianjin, China
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16
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Abdel-Sater KA, Abdel-Daiem WM, Sayyed Bakheet M. The gender difference of selective serotonin reuptake inhibitor, fluoxetine in adult rats with stress-induced gastric ulcer. Eur J Pharmacol 2012; 688:42-8. [PMID: 22546225 DOI: 10.1016/j.ejphar.2012.04.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 04/11/2012] [Accepted: 04/11/2012] [Indexed: 11/16/2022]
Abstract
We investigated the gender difference of selective serotonin reuptake inhibitor, fluoxetine in adult rats with stress-induced gastric ulcer. The rats were randomly divided into six groups: Group I, control males and group II, control females; group III, acute cold restraint stressed males and group IV, acute cold restraint stressed females; group V, fluoxetine-treated stressed males and group VI, fluoxetine-treated stressed females. Acute cold restraint stress was established by fixing the four limbs of the rat and placing it in a refrigerator at 4°C for 3h. Fluoxetine was given intraperitoneal in a single dose of 10mg/kg/day. After 2 weeks, stomach and brain tissues were collected for the assay of gastric malonaldehyde (MDA), catalase, nitric oxide (NO) and cortical gamma aminobutyric acid (GABA). Stressed animals exhibited increased total acidity in association with decreased gastric secretion volume. Gastric MDA was increased while gastric catalase, NO, and cortical GABA were decreased in stressed male rats when compared to stressed females. However, fluoxetine administration attenuated these stress-induced changes especially in stressed male animals. Stressed male rats were more responsive to the antiulcer effect of fluoxetine more than stressed females. However, fluoxetine might be considered to be the first-choice drug in depressive patients with gastric ulcers in the future.
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Affiliation(s)
- Khaled A Abdel-Sater
- Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Al-Azher Faculty of Medicine, Assiut, Egypt.
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17
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Zhang Z, Zou YY, Li FJ, Hu CP. Asymmetric dimethylarginine: A novel biomarker of gastric mucosal injury? World J Gastroenterol 2011; 17:2178-80. [PMID: 21633526 PMCID: PMC3092868 DOI: 10.3748/wjg.v17.i17.2178] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 12/13/2010] [Accepted: 12/20/2010] [Indexed: 02/06/2023] Open
Abstract
Nitric oxide (NO), a multifunctional endogenous gas molecule, is metabolized from L-arginine by enzymatic reaction in the presence of nitric oxide synthase. NO, an important gas signaling molecule, is a gastric mucosa protective factor that contributes significantly to maintain normal gastric mucosa integrity. NO increases gastric mucosa blood flow, regulates the secretion of mucus and bicarbonate, and inhibits the secretion of gastric juice. Asymmetric dimethylarginine (ADMA) has been identified as the major endogenous inhibitor of nitric oxide synthase. The function of ADMA is to decrease NO production via inhibiting nitric oxide synthase activity. Besides inhibiting NO synthesis, ADMA also directly induces oxidative stress and cell apoptosis, and participates in inflammation reaction. Its systemic accumulation was observed in conjunction with several cardiovascular and metabolic diseases. ADMA also mediates gastric ulcer injury induced by ethanol, stress, helicobacter pylori and indomethacin. The mechanism of ADMA directly producing adverse effect in gastric mucosa is incompletely understood. It is widely accepted that NO bioavailability decrease is the majority reason. Promotion of apoptosis and aggravation of inflammation may be other important mechanisms of ADMA-induced gastric injury. ADMA might be a novel clinical and experimental biomarker related to gastric mucosa disorder. Although therapeutic tool targeting to ADMA is available in multiple cardiovascular diseases, it is unknown in gastrointestinal disease. The strategy to inhibit ADMA is beneficial to gastric ulcer induced by ethanol in rats. Thus, ADMA might be a candidate of therapeutic target in gastric mucosa damage.
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18
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Li L, Luo XJ, Liu YZ, Zhang YS, Yuan Q, Tan N, Xiang DX, Peng J. The role of the DDAH-ADMA pathway in the protective effect of resveratrol analog BTM-0512 on gastric mucosal injury. Can J Physiol Pharmacol 2010; 88:562-7. [PMID: 20555425 DOI: 10.1139/y10-027] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A recent study showed that resveratrol, a polyphenol found in many plant species, exerts dual effects on gastric mucosal injury. By using the model of ethanol-induced gastric mucosal injury in the present study, we explored the effect of trans-3,5,4'-trimethoxystilbene (BTM-0512), a novel analog of resveratrol, on gastric mucosal injury and the possible underlying mechanisms. Gastric mucosal injury in the rat was induced by oral administration of acidified ethanol. The gastric tissues were collected for determination of the gastric ulcer index, asymmetric dimethylarginine (ADMA) and nitric oxide (NO) contents, the activity of dimethylarginine dimethylaminohydrolase (DDAH) and superoxide anion (O2(-)) or hydroxyl radical (OH*) formation. The results showed that acute administration of ethanol significantly increased the gastric ulcer index concomitantly with the decrease in DDAH activity and NO content as well as the increase in ADMA content, effects that were reversed by pretreatment with BTM-0512 (100 mg/kg) or L-arginine (300 mg/kg). Administration of BTM-0512 did not show a significant effect on O2(-) or OH. formation. The results suggest that BTM-0512 could protect the gastric mucosa against ethanol-induced injury, which is mainly related to an increase in DDAH activity and subsequent decrease in ADMA content.
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Affiliation(s)
- Li Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, P.R. China
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19
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Yuan Q, Peng J, Liu SY, Wang CJ, Xiang DX, Xiong XM, Hu CP, Li YJ. Inhibitory effect of resveratrol derivative BTM-0512 on high glucose-induced cell senescence involves dimethylaminohydrolase/asymmetric dimethylarginine pathway. Clin Exp Pharmacol Physiol 2010; 37:630-5. [DOI: 10.1111/j.1440-1681.2010.05368.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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20
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Zinkievich JM, George S, Jha S, Nandi J, Levine RA. Gastric acid is the key modulator in the pathogenesis of non-steroidal anti-inflammatory drug-induced ulceration in rats. Clin Exp Pharmacol Physiol 2010; 37:654-61. [PMID: 20082628 DOI: 10.1111/j.1440-1681.2010.05357.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
1. In the present study, we investigated the role of gastric acid (GA) secretion on non-steroidal anti-inflammatory drug (NSAID)-induced ulcerogenesis in vivo. Rats were administered single oral doses of selective cyclo-oxygenase (COX)-1 (SC-560; 2.5 mg/kg), COX-2 (DFU; 25 mg/kg) or non-selective COX (indomethacin; 25 mg/kg) inhibitors. Three groups (basal, histamine-stimulated and histamine with lansoprazole) were pylorus ligated 2 h after inhibitor administration and killed 2 h later. Another group without pylorus ligation received only inhibitors and was killed after 18 h. 2. At 4 h, indomethacin increased the ulcer index (UI) and myeloperoxidase (MPO) activity in basal and histamine-stimulated states, whereas SC-560 only increased MPO activity. Histamine-stimulated, but not basal, GA was further enhanced by indomethacin and SC-560 via increased proton pump expression. Lansoprazole (10 mg/kg) reduced the UI, MPO activity and GA to basal levels with SC-560 and DFU and to near basal with indomethacin. Indomethacin and SC-560 significantly inhibited prostaglandin (PG) E(2), without significantly affecting COX-1 and COX-2 expression. Although DFU inhibited PGE(2) by one-third, it did not affect COX expression. 3. At 18 h, indomethacin significantly increased the UI and MPO activity, whereas PGE(2) synthesis was less inhibited, indicating a return to control levels. In contrast, PGE(2) synthesis was higher than control with SC-560. Furthermore, COX-2 expression was significantly elevated with indomethacin and SC-560, explaining the source of augmented PGE(2) synthesis. Proton pump expression remained elevated, comparable with 4 h levels, with indomethacin and SC-560. However, DFU had no significant effect on the aforementioned parameters. 4. The data suggest that NSAID-induced ulcerogenesis is dependent on the amount of GA secretion derived from increased proton pump expression and requires inhibition of both COX-1 and COX-2.
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Affiliation(s)
- J Michael Zinkievich
- Division of Gastroenterology, Department of Medicine, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA
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21
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Zhang S, Liu HF, Zhang CG. Research progress in mechanism of stress-induced gastric mucosal lesions. Shijie Huaren Xiaohua Zazhi 2009; 17:1697-1701. [DOI: 10.11569/wcjd.v17.i17.1697] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The stress-induced gastric mucosal lesions, appearing as a consequence of surgical trauma, shocks and burns, are serious clinical complication that results in the imbalance between the aggressive factors promoting mucosal damage and the gastric mucosal defense mechanisms. The pathology of stress-induced gastric mucosal lesions show extensive and superficial erosion. Recent studies indicate that stress ulceration is a complex process, and it may be caused by many factors, such as neuroendocrine disorders, gastric mucosal barrier damage, injury factors increase, apoptosis, etc. This paper reviews the pathogenesis of stress-induced gastric mucosal lesions.
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22
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Wadham C, Mangoni AA. Dimethylarginine dimethylaminohydrolase regulation: a novel therapeutic target in cardiovascular disease. Expert Opin Drug Metab Toxicol 2009; 5:303-19. [PMID: 19331593 DOI: 10.1517/17425250902785172] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Asymmetric dimethylarginine (ADMA), an endogenous methylated form of the amino acid L-arginine, inhibits the activity of the enzyme endothelial nitric oxide synthase, with consequent reduced synthesis of nitric oxide. ADMA is metabolised to L-citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The modulation of DDAH activity and expression plays a pivotal role in regulating intracellular ADMA concentrations, with important effects on vascular homeostasis. For example, impairment in DDAH activity, resulting in elevated ADMA concentrations and reduced nitric oxide synthesis, can promote the onset and progression of atherosclerosis in experimental models. This review discusses the current role of ADMA and DDAH in vascular health and disease, the techniques used to assess DDAH activity and expression, and the results of recent studies on pharmacological and biological agents modulating DDAH activity and expression. Suggestions for future basic and clinical research directions are also discussed.
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Affiliation(s)
- Carol Wadham
- Flinders University, Flinders Medical Centre, Department of Clinical Pharmacology, Adelaide, Australia
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Zhang Z, Zhou Y, Zou YY, Wang L, Yang ZC, Guo R, Li D, Peng J, Li YJ. Detrimental effects of nicotine on the acute gastric mucosal injury induced by ethanol: role of asymmetric dimethylarginine. Can J Physiol Pharmacol 2009; 86:835-40. [PMID: 19088804 DOI: 10.1139/y08-093] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The aim of this study was to determine whether asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is responsible for the detrimental effects of nicotine on ethanol-induced gastric mucosal injury and its underlying mechanisms. Gastric mucosal injury was induced by an injection of ethanol in the stomach in rats. Animals were pretreated with nicotine for 28 days before ethanol injection. The gastric mucosal ulcer index (UI) and the levels of ADMA and NO in gastric juice were determined. In vitro, the cultured mucosal epithelial cells were treated with nicotine in the presence or absence of ethanol. The concentration of ADMA in the culture medium and the ratio of cell apoptosis were measured, and the effect of nicotine or ADMA alone on cell apoptosis was also examined. In rats treated with ethanol, the UI and ADMA levels were increased and the NO level was decreased, and these effects of ethanol were augmented by pretreatment with nicotine. Administration of nicotine alone did not show significant impact on UI, ADMA level, or NO level. In vitro, incubation of human epithelial cells with ethanol induced cell injury accompanied by increased ADMA levels in the culture medium, an effect which was amplified in the presence of nicotine. Similarly, ethanol was able to induce epithelial cell apoptosis that was exacerbated by nicotine. Incubation of epithelial cells with nicotine alone did not induce cell apoptosis, but administration of ADMA alone did induce cell apoptosis. The results suggest that the gastric mucosal injury induced by ethanol is augmented by nicotine, which is related to the increased ADMA level.
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Affiliation(s)
- Zhe Zhang
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, No.110 Xiang-Ya Road, Changsha 410078, China
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Liu YZ, Zhou Y, Li D, Wang L, Hu GY, Peng J, Li YJ. Reduction of asymmetric dimethylarginine in the protective effects of rutaecarpine on gastric mucosal injury. Can J Physiol Pharmacol 2009; 86:675-81. [PMID: 18841172 DOI: 10.1139/y08-073] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Our recent study has shown that asymmetric dimethylarginine (ADMA) plays an important role in facilitating gastric mucosal injury by multiple factors. To explore whether the protection of rutaecarpine against gastric mucosal injury is related to reduction of ADMA content, a model of ethanol-induced gastric mucosal injury in rats was selected for this study. The ulcer index, the content of ADMA and NO, and the activity of dimethylarginine dimethylaminohydrolase (DDAH) in gastric tissues were measured in vivo after pretreatment with rutaecarpine. The in vitro effect of rutaecarpine on the release of calcitonin gene-related peptide (CGRP) and NO from isolated gastric tissues was also determined. The results showed that ethanol significantly increased the ulcer index, decreased the DDAH activity and the NO level, and elevated the ADMA level, which was attenuated by pretreatment with rutaecarpine (0.6 mg/kg or 1.2 mg/kg). In the isolated gastric tissues, rutaecarpine significantly increased the release of both CGRP and NO; the release of NO, but not CGRP, was abolished in the presence of l-NAME (10(-4) mol/L). The present results suggest that rutaecarpine protects the gastric mucosa against injury induced by ethanol and that the gastroprotection of rutaecarpine is related to reduction of ADMA levels through stimulating the release of CGRP.
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Affiliation(s)
- Ying-Zi Liu
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, No.110 Xiang-Ya Road, Changsha 410078, China
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Heeba GH, Hassan MKA, Amin RS. Gastroprotective effect of simvastatin against indomethacin-induced gastric ulcer in rats: role of nitric oxide and prostaglandins. Eur J Pharmacol 2009; 607:188-93. [PMID: 19217901 DOI: 10.1016/j.ejphar.2009.02.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2008] [Revised: 01/19/2009] [Accepted: 02/09/2009] [Indexed: 12/19/2022]
Abstract
This study investigated the possible mechanisms underlying the gastroprotective effect of simvastatin against indomethacin-induced gastric ulcer in rats. Rats were randomly assigned to vehicle-, simvastatin-, simvastatin+L-arginine- and simvastatin+N(G)-nitro-L-arginine methyl ester (L-NAME)-pretreated groups for two weeks. Pyloric ligation was performed for the collection of gastric juice, and gastric ulceration was induced by a single intraperitoneal injection of indomethacin (30 mg/kg). Gastric juice parameters (total acid output, pepsin activity and mucin concentration) were determined. The stomachs tissues were used for determination of gastric mucosal lipid peroxides, superoxide dismutase, catalase, total nitrites and prostaglandin E(2) levels. Pretreatment with simvastatin (10 mg/kg, orally, for 2 weeks) caused significant reduction in gastric mucosal lesions and lipid peroxides associated with a significant increase in gastric juice mucin concentration. Simvastatin significantly increased the gastric mucosal total nitrite and prostaglandin E(2) levels. Additionally, simvastatin attenuated the elevations in gastric mucosal superoxide dismutase observed with indomethacin. The gastroprotective effect afforded by simvastatin was significantly augmented by coadministration with L-arginine (a nitric oxide precursor) and inhibited by coadministration with L-NAME (a nitric oxide synthase inhibitor). Results confirm a gastroprotective effect for simvastatin, and indicate that the anti-ulcer effect of simvastatin is mediated by scavenging free radicals, increasing nitric oxide and prostaglandin E(2) levels, and increasing gastric juice mucin production. We conclude that simvastatin represents a more suitable antihyperlipidemic therapy for patients who are at risk of gastric ulcers that were induced by the use of nonsteroidal anti-inflammatory drugs (NSAIDs).
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Affiliation(s)
- Gehan H Heeba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, 6111, Egypt.
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