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Wang H, Jin H, Dong Y, Wang Z, Wang Y, Wei F. Structural characterization of Dendrobium huoshanense polysaccharides and its gastroprotective effect on acetic acid-induced gastric ulcer in mice. Int J Biol Macromol 2025; 311:143361. [PMID: 40268013 DOI: 10.1016/j.ijbiomac.2025.143361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 04/11/2025] [Accepted: 04/18/2025] [Indexed: 04/25/2025]
Abstract
Dendrobium huoshanense (DH) is a medicinal plant known for its efficacy in improving gastrointestinal diseases. In this study, a novel polysaccharide, DHPs-1, was isolated and purified from DH, and its structural characteristics were analyzed using advanced methodologies, including monosaccharide composition analysis, methylation, FT-IR spectroscopy, and NMR. The gastroprotective effect of DHPs-1 was assessed using a mouse model of chronic gastric ulcers induced by acetic acid. The results revealed that DHPs-1 is primarily composed of mannose (Man) and glucose (Glc) with a molecular weight of 3.137 × 106 Da. The purified polysaccharide DHPs-1 is primarily composed of →4)-β-D-Glcp-(1 → and →4)-β-D-Manp-(1→, with an acetyl substitution at the C-2 position of Man. DHPs-1 exhibited a pronounced protective effect against acetic acid-induced chronic gastric ulcers in mice by modulating gastric defense factors and inflammatory mediators. Furthermore, DHPs-1 downregulated the expression of p-p65/p-IκBα in gastric tissues, thereby mitigating gastric mucosal injury. These findings suggest that DHPs-1 has the potential to serve as an effective gastric mucosal protective agent and could be developed into functional foods and dietary supplements.
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Affiliation(s)
- Haonan Wang
- State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing 102629, China; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Hongyu Jin
- State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing 102629, China
| | - Yuan Dong
- Yunnan Provincial lnstitute for Drug Control, Kunming 650011, China
| | - Zhao Wang
- State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing 102629, China
| | - Ying Wang
- State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing 102629, China.
| | - Feng Wei
- State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing 102629, China
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Ellagic acid (EA), a tannin was isolated from Eucalyptus citriodora leaves and its anti-inflammatory activity. Med Chem Res 2021. [DOI: 10.1007/s00044-021-02806-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Jedidi S, Aloui F, Rtibi K, Sammari H, Selmi H, Rejeb A, Toumi L, Sebai H. Individual and synergistic protective properties of Salvia officinalis decoction extract and sulfasalazine against ethanol-induced gastric and small bowel injuries. RSC Adv 2020; 10:35998-36013. [PMID: 35517119 PMCID: PMC9056994 DOI: 10.1039/d0ra03265d] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
The present study was carried out to determine the phytochemical composition of Salvia officinalis flowers decoction extract (SOFDE) as well as its individual and/or synergistic actions with sulfasalazine against ethanol (EtOH)-induced peptic ulcer in Wistar rats. In this respect, rats were divided into six groups of eight animals each: control, EtOH, EtOH + sulfasalazine (SULF, 100 mg kg-1, b.w., p.o.), mixture: MIX (SOFDE, 50 mg kg-1 b.w., p.o. + SULF, 50 mg kg-1, b.w., p.o.) and EtOH + two doses of SOFDE (100 and 200 mg kg-1 b.w., p.o.). In vitro, the phytochemical and the antioxidant properties were determined using colorimetric analysis. HPLC-PDA/ESI-MS assay was used to identify the distinctive qualitative profile of phenolic compounds. Our results firstly indicated that SOFDE is rich in total tannins, flavonols, anthocyanins and a moderate concentration of total carotenoids. Chromatographic techniques allowed the identification of 13 phenolic compounds and the major ones are quinic acid, protocatechuic acid, gallic acid and salviolinic acid. SOFDE also exhibited an important in vitro antioxidant activity using the β-carotene bleaching method. In vivo, SOFDE and the mixture provide significant protection against ethanol-induced gastric and duodenal macroscopic and histological alterations. Also, SOFDE alone or in combination with SULF, showed a significant protection against the secretory profile disturbances, lipid peroxidation, antioxidant enzyme activities and non-enzymatic antioxidant level depletion induced by alcohol administration. Importantly, we showed that EtOH acute intoxication increased gastric and intestinal calcium, free iron, magnesium and hydrogen peroxide (H2O2) levels, while SOFDE/MIX treatment protected against all these intracellular mediators' deregulation. We also showed that alcohol treatment significantly increased the C-reactive protein (CRP) and alkaline phosphatase (ALP) activities in plasma. The SOFDE and MIX treatment significantly protected against alcohol-induced inflammation. More importantly, we showed in the present work that the mixture exerted a more important effect than SOFDE and SULF each alone indicating a possible synergism between these two molecules. In conclusion, our data suggests that SOFDE and SULF exerted a potential synergistic protective effect against all the macroscopic, histological and biochemical disturbances induced by EtOH intoxication. This protection might be related in part to its antioxidant and anti-inflammatory properties as well as by negatively regulating Fenton reaction components such as H2O2 and free iron.
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Affiliation(s)
- Saber Jedidi
- Unité de Physiologie Fonctionnelle et Valorisation des Bio-Ressources, Université de Jendouba, Institut Superieur de Biotechnologie de Beja Avenue Habib Bourguiba, B.P. 382 9000 Beja Tunisia +216 78 459 098 +216 97 249 486.,Laboratoire des Ressources Sylvo-Pastorales, Université de Jendouba, Institut Sylvo-Pastoral de Tabarka B.P. 345 8110 Tabarka Tunisia.,Universite de Carthage, Faculté des Sciences de Bizerte 7021 Jarzouna Tunisia
| | - Foued Aloui
- Laboratoire des Ressources Sylvo-Pastorales, Université de Jendouba, Institut Sylvo-Pastoral de Tabarka B.P. 345 8110 Tabarka Tunisia
| | - Kais Rtibi
- Unité de Physiologie Fonctionnelle et Valorisation des Bio-Ressources, Université de Jendouba, Institut Superieur de Biotechnologie de Beja Avenue Habib Bourguiba, B.P. 382 9000 Beja Tunisia +216 78 459 098 +216 97 249 486
| | - Houcem Sammari
- Laboratoire des Ressources Sylvo-Pastorales, Université de Jendouba, Institut Sylvo-Pastoral de Tabarka B.P. 345 8110 Tabarka Tunisia
| | - Houcine Selmi
- Laboratoire des Ressources Sylvo-Pastorales, Université de Jendouba, Institut Sylvo-Pastoral de Tabarka B.P. 345 8110 Tabarka Tunisia
| | - Ahmed Rejeb
- Laboratoire d'Anatomie Pathologique, Université de Manouba, Ecole Nationale de Médecine Vétérinaire de Sidi Thabet 2020 Sidi Thabet Tunisia
| | - Lamjed Toumi
- Laboratoire des Ressources Sylvo-Pastorales, Université de Jendouba, Institut Sylvo-Pastoral de Tabarka B.P. 345 8110 Tabarka Tunisia
| | - Hichem Sebai
- Unité de Physiologie Fonctionnelle et Valorisation des Bio-Ressources, Université de Jendouba, Institut Superieur de Biotechnologie de Beja Avenue Habib Bourguiba, B.P. 382 9000 Beja Tunisia +216 78 459 098 +216 97 249 486
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Hashemzaei M, Mamoulakis C, Tsarouhas K, Georgiadis G, Lazopoulos G, Tsatsakis A, Shojaei Asrami E, Rezaee R. Crocin: A fighter against inflammation and pain. Food Chem Toxicol 2020; 143:111521. [DOI: 10.1016/j.fct.2020.111521] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/07/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023]
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5
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Zhang C, Gao F, Gan S, He Y, Chen Z, Liu X, Fu C, Qu Y, Zhang J. Chemical characterization and gastroprotective effect of an isolated polysaccharide fraction from Bletilla striata against ethanol-induced acute gastric ulcer. Food Chem Toxicol 2019; 131:110539. [PMID: 31158404 DOI: 10.1016/j.fct.2019.05.047] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 05/04/2019] [Accepted: 05/27/2019] [Indexed: 02/07/2023]
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Xie W, Huang X, Chen R, Chen R, Li T, Wu W, Huang Z. Esomeprazole alleviates the damage to stress ulcer in rats through not only its antisecretory effect but its antioxidant effect by inactivating the p38 MAPK and NF-κB signaling pathways. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:2969-2984. [PMID: 31686780 PMCID: PMC6709796 DOI: 10.2147/dddt.s193641] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 05/16/2019] [Indexed: 12/14/2022]
Abstract
Background Stress ulcer is a severe complication in critically ill patients and causes a high mortality. The proton pump inhibitor esomeprazole is widely applied in the treatment of stress ulcers because of its powerful acid suppression ability. However, the mechanism of stress ulcer and the precise gastroprotective effect of esomeprazole in stress ulcer remain unclear. Purpose In the present study, the rats with water-immersed and restraint (WIR)-induced stress ulcer were used to further elucidate the anti-ulcerogenic capacity of esomeprazole in stress ulcer in addition to its anti-acid secreting ability. Methods and results The rats were randomly divided into 5 groups: control group (NS), water-immersed and restraint group (WIR), high-dose application of esomeprazole plus stress ulcer-induced group (HE+WIR), low-dose application of esomeprazole plus stress ulcer-induced group (LE+WIR), and high-dose application of esomeprazole without stress ulcer-induced group (HE). Our study showed that the pretreatment of esomeprazole alleviated gastric tissue damage in both macroscopic and histopathological manifestations. Pretreatment of esomeprazole elevated the decline in PEG2 level affected by WIR; and it inhibited the secretion of gastric acid, gastrin and pepsin. Moreover, esomeprazole exerted its antioxidant effects by reducing malondialdehyde levels, enhancing the expressions of antioxidant factors like glutathione and superoxide dismutase (SOD) and reducing the compensatory transcriptional elevation of SOD1 gene. Esomeprazole also reduced the levels of MPO (myeloperoxidase), tumor necrosis factor (TNF)-α and interleukin (IL)-1β according to its anti-inflammatory effects. We further explored the possible mechanism of esomeprazole pretreatment on stress ulcer and demonstrated that esomeprazole attenuated the high phosphorylation levels of nuclear factor kappa B (NF-κB) p65 and p38 MAPK, and decreased the NF-κB p65 nuclear translocation induced by WIR related stress ulcer. Conclusion Our study provides some evidence that the esomeprazole pretreatment exerts gastroprotective effects in WIR-induced stress ulcer through not only its antisecretory effect but also its antioxidant effect by inactivating the p38 MAPK and NF-κB signaling pathways.
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Affiliation(s)
- Wei Xie
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Xielin Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Renpin Chen
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Ruru Chen
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Tang Li
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Wei Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Zhiming Huang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
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A modified pectic polysaccharide from turmeric (Curcuma longa) with antiulcer effects via anti–secretary, mucoprotective and IL–10 mediated anti–inflammatory mechanisms. Int J Biol Macromol 2018; 118:864-880. [PMID: 29924982 DOI: 10.1016/j.ijbiomac.2018.06.053] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/03/2018] [Accepted: 06/11/2018] [Indexed: 12/15/2022]
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8
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Salem NA, Wahba MA, Eisa WH, El-Shamarka M, Khalil W. Silver oxide nanoparticles alleviate indomethacin-induced gastric injury: a novel antiulcer agent. Inflammopharmacology 2017; 26:1025-1035. [DOI: 10.1007/s10787-017-0424-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 11/21/2017] [Indexed: 12/20/2022]
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9
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Ohta Y, Kubo H, Yashiro K, Ohashi K, Tsuzuki Y, Wada N, Yamamoto Y, Saito K. Effect of water-immersion restraint stress on tryptophan catabolism through the kynurenine pathway in rat tissues. J Physiol Sci 2017; 67:361-372. [PMID: 27364617 PMCID: PMC10717894 DOI: 10.1007/s12576-016-0467-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/20/2016] [Indexed: 12/12/2022]
Abstract
The aim of this study was to clarify the effect of water-immersion restraint stress (WIRS) on tryptophan (Trp) catabolism through the kynurenine (Kyn) pathway in rat tissues. The tissues of rats subjected to 6 h of WIRS (+WIRS) had increased tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) activities and increased TDO and IDO1 (one of two IDO isozymes in mammals) mRNA expression levels, with decreased Trp and increased Kyn contents in the liver. +WIRS rats had unchanged TDO and IDO activities in the kidney, decreased TDO activity and unchanged IDO activity in the brain, and unchanged IDO activity in the lung and spleen, with increased Kyn content in all of these tissues. Pretreatment of stressed rats with RU486, a glucocorticoid antagonist, attenuated the increased TOD activity, but not the increased IDO activity, with partial recoveries of the decreased Trp and increased Kyn contents in the liver. These results indicate that WIRS enhances hepatic Trp catabolism by inducing both IDO1 and TDO in rats.
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Affiliation(s)
- Yoshiji Ohta
- Department of Chemistry, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan.
| | - Hisako Kubo
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, 666-8507, Japan
| | - Koji Yashiro
- Department of Chemistry, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan
| | - Koji Ohashi
- Department of Clinical Biochemistry, Faculty of Medical Technology, Fujita Health University School of Health Sciences, Toyoake, Aichi, 470-1192, Japan
| | - Yuji Tsuzuki
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, 666-8507, Japan
| | - Naoya Wada
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, 666-8507, Japan
| | - Yasuko Yamamoto
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, 666-8507, Japan
- Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, 470-1192, Japan
| | - Kuniaki Saito
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, 666-8507, Japan
- Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, 470-1192, Japan
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10
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Ohta Y, Yashiro K, Kobayashi T, Inui K, Yoshino J. Protective effect ofN,N’-dimethylthiourea against stress-induced gastric mucosal lesions in rats. Fundam Clin Pharmacol 2017; 31:319-328. [DOI: 10.1111/fcp.12268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 01/11/2017] [Indexed: 01/01/2023]
Affiliation(s)
- Yoshiji Ohta
- Department of Chemistry; Fujita Health University School of Medicine; Toyoake Aichi 470-1192 Japan
| | - Koji Yashiro
- Department of Chemistry; Fujita Health University School of Medicine; Toyoake Aichi 470-1192 Japan
| | - Takashi Kobayashi
- Department of Internal Medicine; Second Teaching Hospital; Fujita Health University School of Medicine; Nagoya Aichi 454-0012 Japan
| | - Kazuo Inui
- Department of Internal Medicine; Second Teaching Hospital; Fujita Health University School of Medicine; Nagoya Aichi 454-0012 Japan
| | - Junji Yoshino
- Dainagoya building Central Clinic; Nagoya Aichi 450-6409 Japan
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11
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Golyshkin D, Kobyliak N, Virchenko O, Falalyeyeva T, Beregova T, Ostapchenko L, Caprnda M, Skladany L, Opatrilova R, Rodrigo L, Kruzliak P, Shcherbokov A, Spivak M. Nanocrystalline cerium dioxide efficacy for prophylaxis of erosive and ulcerative lesions in the gastric mucosa of rats induced by stress. Biomed Pharmacother 2016; 84:1383-1392. [PMID: 27802899 DOI: 10.1016/j.biopha.2016.10.060] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 10/18/2016] [Accepted: 10/18/2016] [Indexed: 02/07/2023] Open
Abstract
In our previous works, the important therapeutic properties of nanocrystalline cerium dioxide such as strong antioxidant ability, prebiotical and antibiotic activity were shown. Such properties were obtained due to stabilization of nanoparticles with precise size 3-7nm. Such modification of nanocrystalline cerium dioxide has contributed to its remarkable efficacy and low toxicity. We have carried out the investigation of toxicity of the nanodrug and revealed that in the condition of the acute toxicity test, LD 50 was 2000mg/kg when it was administered per os. This indicator is approximately 1000 times greater than effective dose of the compound that proved the possibility of its usage for humans. Considering the strong antioxidant properties of this substance, we have performed the investigation of the influence of nanocrystalline cerium dioxide on the erosive-ulcerative lesions in gastric mucosa of rats induced by Selye's restraint stress. It was established that the studied compound significantly reduced the lesions area by 58.3% (p<0.05) induced by Selye's restraint stress. The attenuation of inflammation and decrease of lipid peroxidation in the conditions of gastric lesions and prophylactic administration of nanocrystalline cerium dioxide were shown. That was confirmed by the decrease of pro-inflammatory cytokines content (interleukin (IL) 1β, 12B p40) and raise of anti-inflammatory cytokines content (IL-10 and transforming growth factor β). Measurement of lipid peroxidation products has proved the antioxidant properties of nanocrystalline cerium dioxide as it decreased the content of conjugated dienes and thiobarbituric acid active products in the conditions of gastric ulceration induced by stress.
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Affiliation(s)
- Dmytro Golyshkin
- Institute of Biology, Taras Shevchenko National University, Kyiv, Ukraine
| | - Nazarii Kobyliak
- Department of Endocrinology, Bogomolets National Medical University, Kyiv, Ukraine
| | | | | | - Tetyana Beregova
- Institute of Biology, Taras Shevchenko National University, Kyiv, Ukraine
| | | | - Martin Caprnda
- 2nd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Lubomir Skladany
- Department of Internal Medicine, F. D. Roosvelt Hospital, Banska Bytrica, Slovakia
| | - Radka Opatrilova
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czechia
| | - Luis Rodrigo
- Department of Gastroenterology, Faculty of Medicine, University of Oviedo, Central University Hospital of Asturias (HUCA), Oviedo, Spain
| | - Peter Kruzliak
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czechia.
| | | | - Mykola Spivak
- Zabolotny Institute of Microbiology and Virology, Kyiv, Ukraine
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Ohta Y, Yashiro K, Ohashi K, Horikoshi Y, Kusumoto C, Matsura T, Fukuzawa K. Effect of Dietary Vitamin E Supplementation on Liver Oxidative Damage in Rats with Water-Immersion Restraint Stress. J Nutr Sci Vitaminol (Tokyo) 2016; 61:113-22. [PMID: 26052141 DOI: 10.3177/jnsv.61.113] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
We examined how dietary supplementation of vitamin E protects against liver oxidative damage in rats with water-immersion restraint stress (WIRS). Before WIRS exposure, rats received a normal diet (ND) or vitamin E-supplemented diet (VESD) (500 IU α-tocopherol/kg diet) at a mean dose of 15 g/animal/d for 4 wk. The two diet groups had serum transaminases and lactate dehydrogenase activities and adrenocorticotropic hormone, corticosterone, and glucose levels to a similar extent. VESD-fed rats had higher liver α-tocopherol concentrations and lower liver ascorbic acid, total coenzyme Q9 (CoQ9), reduced CoQ9, reduced CoQ10, and lipid peroxide (LPO) concentrations than ND-fed rats. When the two diet groups were exposed to 6 h of WIRS, the serum liver cell damage index enzyme activities increased more greatly in ND-fed rats than in VESD-fed rats but the serum stress marker levels increased to a similar extent. The WIRS exposure caused no change in liver LPO concentration with the further increase in liver α-tocopherol concentration in VESD-fed rats but increased liver LPO concentration without changing liver α-tocopherol concentration in ND-fed rats. Upon the WIRS exposure, liver reduced glutathione concentration decreased with the further decrease in liver ascorbic acid concentration in VESD-fed rats and those concentrations decreased in ND-fed rats. The WIRS exposure recovered the decreased liver total CoQ9 and reduced CoQ9 concentrations in VESD-fed rats but decreased liver total CoQ9, reduced CoQ9, and reduced CoQ10 concentrations in ND-fed rats. These results indicate that dietary vitamin E supplementation protects against liver oxidative damage without affecting the stress response in rats with WIRS.
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Affiliation(s)
- Yoshiji Ohta
- Department of Chemistry, Fujita Health University School of Medicine
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Zheng HM, Choi MJ, Kim JM, Cha KH, Lee KW, Park YH, Hong SS, Lee DH. Centella asiaticaLeaf Extract Protects Against Indomethacin-Induced Gastric Mucosal Injury in Rats. J Med Food 2016; 19:38-46. [PMID: 26469560 DOI: 10.1089/jmf.2015.3464] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Affiliation(s)
- Hong-Mei Zheng
- Department of New Drug Development, College of Medicine, Inha University Hospital, Incheon, Korea
| | - Myung-Joo Choi
- Department of New Drug Development, College of Medicine, Inha University Hospital, Incheon, Korea
| | - Jae Min Kim
- National Center of Efficacy Evaluation for the Development of Health Products Targeting Digestive Disorder, Inha University Hospital, Incheon, Korea
| | | | - Kye Wan Lee
- R&D Center, Dongkook Pharmaceutical, Seoul, Korea
| | - Yu Hwa Park
- R&D Center, Dongkook Pharmaceutical, Seoul, Korea
| | - Soon-Sun Hong
- Department of New Drug Development, College of Medicine, Inha University Hospital, Incheon, Korea
- National Center of Efficacy Evaluation for the Development of Health Products Targeting Digestive Disorder, Inha University Hospital, Incheon, Korea
| | - Don Haeng Lee
- Department of New Drug Development, College of Medicine, Inha University Hospital, Incheon, Korea
- National Center of Efficacy Evaluation for the Development of Health Products Targeting Digestive Disorder, Inha University Hospital, Incheon, Korea
- Division of Gastroenterology and Hepatology, Inha University Hospital, Incheon, Korea
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Anti-Ulcerogenic Properties of Lycium chinense Mill Extracts against Ethanol-Induced Acute Gastric Lesion in Animal Models and Its Active Constituents. Molecules 2015; 20:22553-64. [PMID: 26694339 PMCID: PMC6332331 DOI: 10.3390/molecules201219867] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 12/10/2015] [Accepted: 12/10/2015] [Indexed: 12/25/2022] Open
Abstract
The objective of this study was to explore the gastroprotective properties of the aerial part of Lycium chinense Mill (LCA) against ethanol-induced gastric mucosa lesions in mice models. Administration of LCA at doses of 50, 100, 200 and 400 mg/kg body weight prior to ethanol consumption dose dependently inhibited gastric ulcers. The gastric mucosal injury was analyzed by gastric juice acidity, glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO) activities. Furthermore, the levels of the inflammatory mediators, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in serum were also analyzed using ELISA. Pathological changes were also observed with the aid of hematoxylin-eosin (HE) staining. Our results indicated that LCA significantly reduced the levels of MPO, MDA and increased SOD and GSH activities. Furthermore, LCA also significantly inhibited the levels of TNF-α, IL-6, and IL-1β in the serum of ulcerated mice in a dose dependent manner. Immunohistological analysis indicated that LCA also significantly attenuated the overexpression of nuclear factor-κB in pretreated mice models. This findings suggests Lycium chinense Mill possesses gastroprotective properties against ethanol-induced gastric injury and could be a possible therapeutic intervention in the treatment and management of gastric ulcers.
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Hussein SA, Hassanein MRR, Amin A, Hussein AHM. Alpha-Lipoic Acid Protects Rat Kidney Against Oxidative Stress-Mediated DNA Damage and Apoptosis Induced by Lead. ACTA ACUST UNITED AC 2015. [DOI: 10.3923/ajbmb.2016.1.14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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16
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Tominaga K, Arakawa T. Clinical application of kampo medicine (rikkunshito) for common and/or intractable symptoms of the gastrointestinal tract. Front Pharmacol 2015; 6:7. [PMID: 25688209 PMCID: PMC4311617 DOI: 10.3389/fphar.2015.00007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 01/10/2015] [Indexed: 12/14/2022] Open
Abstract
Gastroenterological reflux disease and functional dyspepsia are usually treatable using Western medical practices. Nonetheless, some cases present with intractable symptoms that are not amenable to these therapies. Treatment with kampo, a traditional Japanese medicine, recently has been proposed as an alternative therapy for use in combination with the Western practices. In general, traditional Japanese medicines have been used empirically for intractable symptoms correctively designated as “general malaises.” Accumulating lines of evidence, including basic and clinical researches, have demonstrate detailed mechanisms where traditional Japanese medicines exert pharmacological action to improve symptoms. Therefore, traditional Japanese medicines have been gaining use by various medical doctors as the specific modes of pharmacological action are recognized. This review covers both the pharmacological functions and the clinical efficacies of rikkunshito for use in treating disorders of the gastrointestinal tract.
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Affiliation(s)
- Kazunari Tominaga
- Department of Gastroenterology, Osaka City University Graduate School of Medicine , Osaka, Japan
| | - Tetsuo Arakawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine , Osaka, Japan
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El-Maraghy SA, Rizk SM, Shahin NN. Gastroprotective effect of crocin in ethanol-induced gastric injury in rats. Chem Biol Interact 2015; 229:26-35. [PMID: 25637687 DOI: 10.1016/j.cbi.2015.01.015] [Citation(s) in RCA: 110] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 11/16/2014] [Accepted: 01/09/2015] [Indexed: 12/29/2022]
Abstract
The present study investigated the gastroprotective effect of crocin in ethanol-induced gastric injury in rats. Rats were allocated into a normal group, an ulcer group, a crocin-treated group, an ulcer group pretreated with crocin, and an ulcer group pretreated with omeprazole as a reference anti-ulcer drug. Rats were sacrificed 3h after ethanol administration. Prophylactic administration of crocin (50mg/kg/day, i.p.) for 3 consecutive days before the administration of 70% ethanol (10 ml/kg, orally) resulted in significant gastroprotection compared to ethanol-ulcerated rats as manifested by significant reduction in the gastric ulcer index. Crocin pretreatment increased ethanol-lowered levels of gastric juice mucin and mucosal prostaglandin E2 (PGE2) and interleukin-6 (IL-6). Moreover, crocin significantly decreased ethanol-elevated tumor necrosis factor-alpha (TNF-α) level, myeloperoxidase activity and heat shock protein 70 mRNA and protein levels. It also restored ethanol-altered mucosal levels of glutathione, malondialdehyde and superoxide dismutase activity. Furthermore, crocin-pretreatment alleviated ethanol-induced mucosal apoptosis as revealed by significant down-regulation of cytochrome c and caspase-3 mRNA expression, significant decrease in caspase-3 activity and mitigated DNA fragmentation as indicated by significant decrements in comet parameters. The protective efficacy of crocin was further supported by histological assessment. No significant difference was observed between crocin and omeprazole (20mg/kg orally 1h before ethanol administration) regarding their mucin-secretagogue and antioxidant effects, as well as their effects on TNF-α, IL-6 and cytochrome c. On the other hand, omeprazole was superior in enhancing PGE2 level and in alleviating neutrophil infiltration, caspase-3 activation and DNA fragmentation. Conclusively, crocin protects rat gastric mucosa against ethanol-induced injury via anti-inflammatory, anti-oxidative, anti-apoptotic and mucin-secretagogue mechanisms that are probably mediated by enhanced PGE2 release.
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Affiliation(s)
- Shohda A El-Maraghy
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street, Cairo 11562, Egypt
| | - Sherine M Rizk
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street, Cairo 11562, Egypt
| | - Nancy N Shahin
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street, Cairo 11562, Egypt.
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Gomathy G, Venkatesan D, Palani S. Gastroprotective potentials of the ethanolic extract ofMukia maderaspatanaagainst indomethacin-induced gastric ulcer in rats. Nat Prod Res 2014; 29:2107-11. [DOI: 10.1080/14786419.2014.986726] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Nakamura T, Ohta Y, Ikeno K, Ohashi K, Ikeno T. Protective Effect of Repeatedly Preadministered Brazilian Propolis Ethanol Extract against Stress-Induced Gastric Mucosal Lesions in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2014; 2014:383482. [PMID: 24639881 PMCID: PMC3930185 DOI: 10.1155/2014/383482] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 12/20/2013] [Indexed: 11/17/2022]
Abstract
The present study was conducted to clarify the protective effect of Brazilian propolis ethanol extract (BPEE) against stress-induced gastric mucosal lesions in rats. The protective effect of BPEE against gastric mucosal lesions in male Wistar rats exposed to water-immersion restraint stress (WIRS) for 6 h was compared between its repeated preadministration (50 mg/kg/day, 7 days) and its single preadministration (50 mg/kg). The repeated BPEE preadministration attenuated WIRS-induced gastric mucosal lesions and gastric mucosal oxidative stress more largely than the single BPEE preadministration. In addition, the repeated BPEE preadministration attenuated neutrophil infiltration in the gastric mucosa of rats exposed to WIRS. The protective effect of the repeated preadministration of BPEE against WIRS-induced gastric mucosal lesions was similar to that of a single preadministration of vitamin E (250 mg/kg) in terms of the extent and manner of protection. From these findings, it is concluded that BPEE preadministered in a repeated manner protects against gastric mucosal lesions in rats exposed to WIRS more effectively than BPEE preadministered in a single manner possibly through its antioxidant and anti-inflammatory actions.
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Affiliation(s)
| | - Yoshiji Ohta
- Department of Chemistry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | | | - Koji Ohashi
- Department of Clinical Biochemistry, Faculty of Medical Technology, Fujita Health University School of Health Sciences, Toyoake, Aichi 470-1192, Japan
| | - Takeyuki Ikeno
- Faculty of Health and Nutrition, Shubun University, Ichinomiya, Aichi 491-0938, Japan
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Rozza AL, Meira de Faria F, Souza Brito AR, Pellizzon CH. The gastroprotective effect of menthol: involvement of anti-apoptotic, antioxidant and anti-inflammatory activities. PLoS One 2014; 9:e86686. [PMID: 24466200 PMCID: PMC3897732 DOI: 10.1371/journal.pone.0086686] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 12/17/2013] [Indexed: 12/19/2022] Open
Abstract
The aim of this research was to investigate the anti-apoptotic, antioxidant and anti-inflammatory properties of menthol against ethanol-induced gastric ulcers in rats. Wistar rats were orally treated with vehicle, carbenoxolone (100 mg/kg) or menthol (50 mg/kg) and then treated with ethanol to induce gastric ulcers. After euthanasia, stomach samples were prepared for histological slides and biochemical analyses. Immunohistochemical analyses of the cytoprotective and anti-apoptotic heat-shock protein-70 (HSP-70) and the apoptotic Bax protein were performed. The neutrophils were manually counted. The activity of the myeloperoxidase (MPO) was measured. To determine the level of antioxidant functions, the levels of glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and superoxide dismutase (SOD) were measured using ELISA. The levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the anti-inflammatory cytokine interleukin-10 (IL-10) were assessed using ELISA kits. The menthol treated group presented 92% gastroprotection compared to the vehicle-treated group. An increased immunolabeled area was observed for HSP-70, and a decreased immunolabeled area was observed for the Bax protein in the menthol treated group. Menthol treatment induced a decrease in the activity of MPO and SOD, and the protein levels of GSH, GSH-Px and GR were increased. There was also a decrease in the levels of TNF-α and IL-6 and an increase in the level of IL-10. In conclusion, oral treatment with menthol displayed a gastroprotective activity through anti-apoptotic, antixidant and anti-inflammatory mechanisms.
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Affiliation(s)
- Ariane Leite Rozza
- Pharmacology Department, Biosciences Institute, Universidade Estadual Paulista - UNESP, Botucatu, Brazil
| | - Felipe Meira de Faria
- Pharmacology Department, Faculty of Medical Sciences, University of Campinas - UNICAMP, Campina, Brazil
| | - Alba Regina Souza Brito
- Department of Structural and Functional Biology, Biology Institute, University of Campinas - UNICAMP, Campinas, Brazil
| | - Cláudia Helena Pellizzon
- Morphology Department, Biosciences Institute, UNESP – Universidade Estadual Paulista - UNESP, Botucatu, Brazil
- * E-mail:
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Upregulation of the proinflammatory cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1 in rats' intestinal anastomotic wound healing--does it matter? Asian J Surg 2013; 37:86-92. [PMID: 24060212 DOI: 10.1016/j.asjsur.2013.07.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Revised: 07/13/2013] [Accepted: 07/23/2013] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The proinflammatory cytokines and growth-promoting factor are essential components of the wound healing process. We hypothesized that under healthy conditions, faster healing of intestinal anastomotic wound is due to an early upregulation of proinflammatory cytokines, cytokine-induced neutrophil chemoattractant-1 (CINC-1) that is followed by a quicker upregulation of homeostatic chemokine, monocyte chemoattractant protein-1 (MCP-1) and late upregulation of transforming growth factor (TGF-β). METHODS We characterized the time course of CINC-1, MCP-1 and TGF-β release at four wounds (skin, muscle, small bowel, and colonic anastomosis) after surgery on 38 juvenile male Sprague Dawley rats. The tissue samples of each site were harvested at 0 (control), 1, 3, 5, 7 and 14 days postoperatively (n = 6-8/group) and analyzed by ELISA kits for CINC-1, MCP-1 and TGF-β. RESULTS CINC-1 expression peaked earlier in muscle and colonic wounds when compared to skin and small bowel. MCP-1 levels were elevated early in skin and muscle wounds, but later expression of MCP-1 was shown in colonic wounds. TGF-β levels were unchanged in all wound sites. CONCLUSION An earlier peak in CINC-1 levels and later expression of MCP-1 were seen in colonic wounds, but no significant increase in TGF-β levels was observed. These findings support the early healing process in intestinal anastomotic wounds.
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Protective effect of 3,4-methylenedioxyphenol (sesamol) on stress-related mucosal disease in rats. BIOMED RESEARCH INTERNATIONAL 2013; 2013:481827. [PMID: 23984371 PMCID: PMC3741923 DOI: 10.1155/2013/481827] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 06/14/2013] [Accepted: 06/19/2013] [Indexed: 12/13/2022]
Abstract
Stress-related mucosal disease (SRMD) causes considerable morbidity and mortality in critically ill patients. 3,4-Methylenedioxyphenol (sesamol) has been reported to have potent antioxidative and anti-inflammatory properties. The aim of this study was to investigate the effect of sesamol on water immersion restraint- (WIR-) induced SRMD in rats. Rat gastric ulcer and hemorrhage were induced by WIR. Rats were pretreated orally with various doses of sesamol (0.1, 0.3, and 1 mg/kg, resp.) 30 min before WIR. Gastric mucosal ulceration, hemoglobin, lipid peroxidation, mucus secretion, proinflammatory cytokines, and nuclear factor (NF)-κB levels were determined 4 h after WIR. In addition, the infiltration of neutrophil and macrophage into gastric mucosa was also determined after WIR. Water immersion restraint increased gastric mucosal ulcer and hemorrhage, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels but failed to affect mucosal lipid peroxidation and mucus secretion compared with non-WIR. Sesamol significantly decreased gastric ulceration and hemorrhage and inhibited mucosal TNF-α, IL-1β, and IL-6 production and NF-κB activity in WIR-treated rats. In addition, increased myeloperoxidase and CD68 levels in gastric mucosa were found in WIR-treated rats compared to non-WIR rats. Sesamol did not affect myeloperoxidase but decreased CD68 levels in mucosa in WIR-treated rats. Sesamol may protect against SRMD by inhibiting gastric mucosal proinflammatory cytokines in rats.
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Absence of NF-κB subunit p50 ameliorates cold immobilization stress-induced gastric ulcers. Biochem Biophys Res Commun 2013; 434:547-51. [PMID: 23583384 DOI: 10.1016/j.bbrc.2013.03.112] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Accepted: 03/27/2013] [Indexed: 11/22/2022]
Abstract
Stress ulcers are a common complication in critically ill patients, but the underlying mechanism is little known. This study characterized the function of the p50 subunit of NF-κB in an experimental model of cold immobilization stress-induced gastric ulcers. Stress-induced gastric mucosal inflammation and gastric injury were examined in wild-type and NF-κB p50-deficient mice. When subjected to cold immobilization stress, NF-κB was rapidly activated in the gastric mucosa in WT mice whereas the majority of κB DNA-binding activity was abrogated from p50(-/-) mice. Deficiency of p50 ameliorated stress-induced expression of TNF-α, MIP-2, and ICAM-1, resulting in reduced mucosal accumulation of neutrophils and gastric injury. These data indicated a critical role for the p50 in the gastric mucosal inflammatory response to cold restraint stress.
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Kampo medicines for gastrointestinal tract disorders: a review of basic science and clinical evidence and their future application. J Gastroenterol 2013; 48:452-62. [PMID: 23503839 PMCID: PMC3698434 DOI: 10.1007/s00535-013-0788-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Accepted: 02/20/2013] [Indexed: 02/04/2023]
Abstract
Treatment with kampo, the Japanese traditional medicine, is a form of pharmacological therapy that combines modern Western and traditional Asian medical practices. In Japan, various traditional medicines are often combined with Western medicines and prescribed for patients with diseases such as gastroesophageal reflux disease, functional dyspepsia, chronic gastritis, irritable bowel syndrome, and post-operative ileus. Based on numerous past observations, Japanese traditional medicines are thought to be particularly useful in the treatment of medically unexplained physical symptoms such as nausea, abdominal discomfort, and anorexia. However, the detailed mechanism by which they mediate their pharmacological action is yet unknown. In addition, the clinical evidence to support their use is insufficient. This review focuses on the basic evidence of the pharmacological action and the clinical efficacies of kampo medicines accumulated over several past decades. In addition, we introduce both the current novel insights into kampo medicines and the therapeutic approach employed when they are used to treat various disorders of the gastrointestinal tract.
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Abbas AM, Sakr HF. Effect of selenium and grape seed extract on indomethacin-induced gastric ulcers in rats. J Physiol Biochem 2013; 69:527-37. [PMID: 23456451 DOI: 10.1007/s13105-013-0241-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 01/23/2013] [Indexed: 12/16/2022]
Abstract
Indomethacin (IND) is a non-steroid anti-inflammatory agent that is known to induce severe gastric mucosal lesions. In this study, we investigated the protective effect of selenium (SEL), grape seed extract (GSE), and both on IND-induced gastric mucosal ulcers in rats. Sprague-Dawley rats (200-250 g) were given SEL, GSE, and both by oral gavage for 28 days, and then gastric ulcers were induced by oral administration of 25 mg/kg IND. Malondialdehyde (MDA), non-enzymatic (reduced glutathione, GSH) and enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) antioxidants, prostaglandin E2 (PGE2) in gastric mucosa, and serum tumor necrosis factor alpha (TNF-α) were measured. Moreover, gastric ulcer index and preventive index were determined. Indomethacin increased the gastric ulcer index, MDA, TNF-α, and decreased PGE2 and non-enzymatic (GSH) and enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) antioxidants. Pretreatment with SEL, GSE, and both significantly decreased the gastric ulcer index, MDA, and TNF and increased antioxidants and PGE2. Histopathological observations confirm the gastric ulcer index and biochemical parameters. Selenium and GSE have a protective effect against IND-induced gastric ulcers through prevention of lipid peroxidation, increase of GSH, activation of radical scavenging enzymes, PGE2 generation, and anti-inflammatory activity. Co-administration of GSE and SEL is more effective than GSE or SEL alone.
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Affiliation(s)
- Amr M Abbas
- Medical Physiology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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26
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Investigation of gastro protective activity of Xanthium strumarium L. by modulation of cellular and biochemical marker. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/s13596-012-0090-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Kamel R, El Morsy EM, Awad AS. Immunomodulatory effect of candesartan on indomethacin-induced gastric ulcer in rats. Immunopharmacol Immunotoxicol 2012; 34:956-61. [DOI: 10.3109/08923973.2012.698283] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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The protective of hydrogen on stress-induced gastric ulceration. Int Immunopharmacol 2012; 13:197-203. [PMID: 22543062 DOI: 10.1016/j.intimp.2012.04.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 03/24/2012] [Accepted: 04/09/2012] [Indexed: 02/08/2023]
Abstract
Stress ulceration frequently occurs as a result of major stressful events and hydroxyl radical (⋅OH) is one of the major causative factors for it. Recently, it has been proved that hydrogen, a potent selectively ⋅OH scavenger, can effectively protect animals against ROS-induced tissue damage. In like manner, we hypothesize that hydrogen may have a protective effect against stress ulceration. Gastric ulceration was induced by the method of cold restraint stress. Rats in the hydrogen treatment group received hydrogen-rich saline (10 mL/kg body weight) 5 min before the stress. At 6h post-stress, gastric corpus mucosa was harvested for the measurement of malondialdehyde, protein carbonyl, 8-hydroxy-desoxyguanosine, glutathione, superoxide dismutase, myeloperoxidase, TNF-α, IL-1β and cytokine-induced neutrophils chemoattractant-1. In addition, western blotting was used to determine the expression of p38 MAPK, P-p38 MAPK, P-JNk, JNK, Bcl-xl, Bax and cleaved caspase-3. Nuclear translocation of NF-κB was assessed by electrophoretic mobility shift assay. Gastric mucosa structure and mucosal epithelial cells apoptosis were measured at 12h post-stress. Our present study showed that hydrogen treatment lessened the stress-induced lipid peroxidation, protein carbonyl and DNA oxidant and improved tissue antioxidant potential. In addition, hydrogen mitigated inflammatory response and neutrophils infiltration with suppressing the activity of P-p38 MAPK, P-JNk and NF-κB. Importantly, hydrogen ameliorated gastric mucosa damage with preventing cell apoptosis. Furthermore, the up-regulation of cleaved caspase-3, Bax and down-regulation of Bcl-xl expression were blocked by hydrogen treatment. In conclusion, hydrogen treatment effectively ameliorated stress-associated gastric mucosa damage via its anti-oxidant, anti-inflammatory and anti-apoptotic effects.
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Murakami S, Takayama F, Egashira T, Imao M, Mori A. Protective effect of fermented papaya preparation on stress-induced acute gastric mucosal lesion. ACTA ACUST UNITED AC 2012. [DOI: 10.4236/jbpc.2012.34038] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Ock CY, Hong KS, Choi KS, Chung MH, Kim YS, Kim JH, Hahm KB. A novel approach for stress-induced gastritis based on paradoxical anti-oxidative and anti-inflammatory action of exogenous 8-hydroxydeoxyguanosine. Biochem Pharmacol 2011; 81:111-22. [DOI: 10.1016/j.bcp.2010.08.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 08/22/2010] [Accepted: 08/24/2010] [Indexed: 01/07/2023]
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Elseweidy MM, Taha MM, Younis NN, Ibrahim KS, Hamouda HA, Eldosouky MA, Soliman H. Gastritis induced by Helicobacter pylori infection in experimental rats. Dig Dis Sci 2010; 55:2770-2777. [PMID: 20094782 DOI: 10.1007/s10620-009-1103-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2009] [Accepted: 12/10/2009] [Indexed: 02/08/2023]
Abstract
BACKGROUND Gastritis, an inflammation of gastric mucosa, may be due to many pathological factors and infection, such as with Helicobacter pylori. The use of experimental models of gastritis is important to evaluate the biochemical changes and study chemotherapeutic intervention. In a previous study we demonstrated an acute gastritis model induced by iodoacetamide. AIMS Our objective in this study was to evaluate a new gastritis model induced by H. pylori infection in experimental rats in terms of certain biomarkers in serum and mucosal tissues in addition to histopathological examination. METHODS Gastritis was induced in 20 albino Wistar rats by H. pylori isolated from antral biopsy taken from a 49-year-old male patient endoscopically diagnosed as having H. pylori infection. Another ten rats were used as controls. Serum gastrin, pepsinogen I activity, interleukin-6 (IL-6) and gastric mucosal myeloperoxidase (MPO) activity and prostaglandin E(2) (PGE(2)) were measured. Immunostaining for inducible nitric oxide synthase (iNOS), nitrotyrosine and DNA fragmentation were used to further evaluate H. pylori-induced gastritis. RESULTS Serum gastrin, IL-6, mucosal MPO activity, and PGE(2) demonstrated significant increases joined with a decreased serum pepsinogen I activity (P < 0.001). Immunohistochemistry demonstrated positive reaction for iNOS, nitrotyrosine and DNA fragmentation. CONCLUSIONS Helicobacter pylori-induced gastritis models demonstrated massive oxidative stress and pronounced injury in mucosal tissue. Since our model in rats reflected the clinical picture of H. pylori infection, it can be considered as a consistent model to study chemotherapeutic intervention for this type of gastritis.
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Affiliation(s)
- Mohamed M Elseweidy
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
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Ohta Y, Imai Y, Kaida S, Kamiya Y, Kawanishi M, Hirata I. Vitamin E protects against stress-induced gastric mucosal lesions in rats more effectively than vitamin C. Biofactors 2010; 36:60-9. [PMID: 20091802 DOI: 10.1002/biof.73] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In this study, we examined the protective effects of vitamin E (VE) against gastric mucosal lesions induced by water immersion restraint stress (WIRS) in rats in comparison with that of vitamin C (VC). The gastric mucosa of rats with 6 h of WIRS showed lesions with bleeding, decrease in nonprotein SH, VC, VE, and adherent mucus concentrations and constitutive nitric oxide synthase activity, and increase in lipid peroxide and NOx (nitrite/nitrate) concentrations and myeloperoxidase, xanthine oxidase, and inducible nitric oxide synthase activities. Either VE (0.05 or 0.5 mmol/kg) or VC (0.5 or 1.5 mmol/kg) was orally administered to rats with 6 h of WIRS just before the onset of the stress. Both doses of pre-administered VE prevented gastric mucosal lesion development and attenuated all these changes in gastric mucosal components and enzymes studied, whereas only the higher dose of pre-administered VC suppressed the changes in all parameters studied. These results indicate that orally administered VE protects against WIRS-induced gastric mucosal lesions in rats more effectively than orally administered VC. These results also suggest that the administered VE protects against gastric mucosal lesions in rats with WIRS through its antioxidant and anti-inflammatory actions in the gastric mucosa in the same way as the administered VC.
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Affiliation(s)
- Yoshiji Ohta
- Department of Chemistry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
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Tomita M, Okuyama T, Nata M, Katsuyama H, Hidaka K, Watanabe Y, Otsuki T, Moriya F, Ishizu H. Methamphetamine protects against stress-induced gastric mucosal lesions in mice. Leg Med (Tokyo) 2009; 11 Suppl 1:S437-9. [DOI: 10.1016/j.legalmed.2009.01.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2008] [Accepted: 01/08/2009] [Indexed: 11/25/2022]
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Mohamadin AM, Ashour OM, El-Sherbeny NA, Alahdal AM, Morsy GM, Abdel-Naim AB. MELATONIN PROTECTS AGAINST HYDROGEN PEROXIDE-INDUCED GASTRIC INJURY IN RATS. Clin Exp Pharmacol Physiol 2009; 36:367-72. [DOI: 10.1111/j.1440-1681.2008.05072.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Koizumi S, Odashima M, Otaka M, Jin M, Linden J, Watanabe S, Ohnishi H. Attenuation of gastric mucosal inflammation induced by indomethacin through activation of the A2A adenosine receptor in rats. J Gastroenterol 2009; 44:419-25. [PMID: 19333545 PMCID: PMC3328190 DOI: 10.1007/s00535-009-0028-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2008] [Accepted: 12/15/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce gastric mucosal lesions in part by the activation of inflammatory cells and the production of proinflammatory cytokines. The activation of adenosine A(2A) receptors inhibits inflammation by increasing cyclic AMP in leukocytes and reducing both the production of various proinflammatory cytokines and neutrophil chemotaxis. The aim of present study was to determine whether administration of an orally active adenosine A(2A) receptor agonist (4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester; ATL-313) ameliorated indomethacin-induced gastric mucosal lesions in rats. METHODS Gastric lesions were produced by oral gavage of indomethacin (30 mg/kg). ATL-313 (1-10 microg/kg) was given orally just before the indomethacin administration. RESULTS The ulcer index induced by indomethacin was significantly (>50%) reduced by pretreatment with ATL-313 and this effect was blocked completely by the addition of equimolar ZM241385, a selective A(2A) receptor antagonist. The gastric content of myeloperoxidase (MPO) and proinflammatory cytokines was significantly reduced by 10 microg/kg ATL-313, but gastric mucosal prostaglandin 2 (PGE2) was not affected. CONCLUSION We conclude that ATL-313 does not inhibit the mucosal damaging effect of indomethacin, but it does block secondary injury due to stomach inflammation. A(2A) agonists may represent a class of new therapeutic drugs for NSAID-induced gastric ulcers.
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Affiliation(s)
- Shigeto Koizumi
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
| | - Masaru Odashima
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
| | - Michiro Otaka
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | - Mario Jin
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
| | - Joel Linden
- Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
| | - Sumio Watanabe
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | - Hirohide Ohnishi
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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Protective Effect of Taurine against Nitrosative Stress in the Stomach of Rat with Water Immersion Restraint Stress. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 643:273-83. [DOI: 10.1007/978-0-387-75681-3_28] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
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El-Moselhy MA, Abdel-Hamid NM, Abdel-Raheim SR. Gastroprotective effect of nicorandil in indomethacin and alcohol-induced acute ulcers. Appl Biochem Biotechnol 2008; 152:449-59. [PMID: 18931948 DOI: 10.1007/s12010-008-8384-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2008] [Accepted: 09/23/2008] [Indexed: 12/24/2022]
Abstract
Despite the fact that dietary habits and lifestyles are incredibly advancing, gastric ulceration is still a terrible complaint. Extensive use of non-steroidal anti-inflammatory drugs (NSAIDs) and alcohol, in addition to stress, are all predisposing factors for ulcers. Most medical treatments are always time consuming and not efficient or satisfactory to the patients. Cardiovascular patients always need NSAIDs, or mostly cannot quit alcohols, while using many cardiovascular drugs. We aim to study a possible benefit of a common nitrogen oxide donor, anti-anginal drug, nicorandil [N-(2-hydroxyethyl) nicotinamide nitrate ester], in managing acute gastric ulcers through studying its effect on some relevant intermediates to ulcerogenesis as lipid peroxidation, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO). In addition, gastric mucosal histology was studied to pursue the drug effects on tissue level. Our study revealed that both indomethacin and alcohol induced gastric ulcer mainly through up-regulation of gastric mucosal lipid peroxidation, local tissue inflammation, leukocytic infiltration, and necrosis. Both ulcerogens significantly elevated TNF-alpha and decreased NO, initiating ulcer formation. Nicorandil pretreatment depicted a higher preventive index in indomethacin- (89.8%) and alcohol-induced (77.7%) acute ulceration. On the tissue level, it also protected the gastric mucosa combating leukocyte infiltration and tissue congestion. Nicorandil protected tissue necrosis through decreasing oxidative stress, elevating NO levels, and down-regulating the ulcerogen-induced TNF-alpha elevation and improved sub-mucosal blood supply. We conclude that nicorandil may be a suitable bimodal treatment for cardiovascular patients who are at high risk of gastric ulcers by using variable analgesics to alleviate possible cardiac pain episodes, and probably frequent doses will offer a more established and long-lasting protection.
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Affiliation(s)
- M A El-Moselhy
- Department of Pharmacology, Minia University, Minia, Egypt
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Xu Y, Hunt NH, Bao S. The effect of restraint stress on experimental colitis is IFN-gamma independent. J Neuroimmunol 2008; 200:53-61. [PMID: 18662832 DOI: 10.1016/j.jneuroim.2008.06.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2008] [Revised: 06/03/2008] [Accepted: 06/04/2008] [Indexed: 12/21/2022]
Abstract
Stress, a protective reaction to external threats, may be deleterious if linked to an inflammatory stimulus. Stress may influence intestinal immunity, thereby contributing to the development of colitis. Less severe histological abnormalities and clinical scores were detected in dextran sulphate sodium (DSS)-induced colitis in IFN-gamma(-/-), compared to Wt, mice. Disease severity was increased by restraint stress in DSS-treated IFN-gamma(-/-) and Wt mice, accompanied by suppressed colonic pro and anti inflammatory cytokine responses. Our data suggest that IFN-gamma is important in the development of acute colitis. Stress increases the severity of colitis, but is independent of the IFN-gamma pathway.
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Affiliation(s)
- Yinghua Xu
- Discipline of Pathology (D06), Bosch Institute and School of Medical Sciences, University of Sydney, NSW 2006, Australia
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Elseweidy MM, Younis NN, Amin RS, Abdallah FR, Fathy AM, Yousif ZA. Effect of some natural products either alone or in combination on gastritis induced in experimental rats. Dig Dis Sci 2008; 53:1774-1784. [PMID: 18368490 DOI: 10.1007/s10620-008-0246-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2004] [Accepted: 07/12/2005] [Indexed: 02/08/2023]
Abstract
Gastritis, an inflammatory state in gastric mucosa, can be induced experimentally in various ways. The present study considered the iodoacetamide model (Iodo). Omega-3 fatty acids (fish oil), black seed oil, and curcuminoids (natural products) in addition to omeprazole (synthetic proton-pump inhibitor) were tested. Supplementation of 0.1% iodoacetamide to drinking water of experimental rats for two consecutive weeks resulted in: (i) increased serum nitric oxide (NO) and gastrin, and decreased pepsinogen, (ii) depletion of gastric mucosal glutathione (GSH), and (iii) increased gastric mucosal lipid peroxidation (MDA), but failed to affect gastric mucosal myeloperoxidase (MPO) activity. Histological examination showed marked neutrophilic infiltration after 1 week of iodoacetamide administration and shedding of apical cell layer with pale edematous vacuolated gastric gland cells and thickening of muscularis mucosa after 2 weeks of iodoacetamide intake. Individual administration of omega-3 fatty acids 12 mg/kg, black seed oil 50 mg/kg, and curcuminoids 50 mg/kg body weight orally daily for 3 weeks decreased MDA, gastrin, and NO, and normalized mucosal GSH but failed to affect serum pepsinogen level. Combined administration of these natural products for 3 weeks normalized MPO activity, and other effects were nearly the same as with individual use. Omeprazole administration 30 mg/kg body weight orally daily for 3 weeks induced a similar response except for an observed increase in serum gastrin and pepsinogen levels.
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Affiliation(s)
- Mohamed M Elseweidy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
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Jia YT, Wei W, Ma B, Xu Y, Liu WJ, Wang Y, Lv KY, Tang HT, Wei D, Xia ZF. Activation of p38 MAPK by reactive oxygen species is essential in a rat model of stress-induced gastric mucosal injury. THE JOURNAL OF IMMUNOLOGY 2008; 179:7808-19. [PMID: 18025227 DOI: 10.4049/jimmunol.179.11.7808] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Stress ulceration is a common complication in critically ill patients and can result in significant upper gastrointestinal bleeding associated with a high morbidity and mortality. At present, little is known of the molecular mechanisms underlying the incidence of this type of gastric damage. In the present study, we investigated the temporal activation of the redox-sensitive p38 signaling transduction cascade and its roles in a well-defined experimental model of cold immobilization stress-induced gastric ulceration. Exposure of Sprague-Dawley rats to 6 h of cold immobilization stress led to a rapid activation of p38 in the gastric mucosa at as early as 15 min after stress, and this activation was maximal after 1.5 h of stress and still persisted until the end of stress. Selectively blocking p38 by pretreatment with SB 239063, a potent and selective p38 inhibitor, suppressed the stress-promoted TNF-alpha, IL-1beta, and CINC-1 production and then prevented the subsequent neutrophil infiltration, gastric mucosal epithelial necrosis and apoptosis, and the ulcerative lesions formation. Prior administration of the free radical scavengers, tempol and N-acetyl-L-cysteine, abolished the stress induction of p38 activation and the resulting mucosal inflammation and gastric injury. These results demonstrate that reactive oxygen species-mediated p38 activation plays an essential role in the pathogenesis of stress-induced gastric inflammatory damage in the rat model of cold immobilization stress. Our findings suggested that inhibition of p38 activation might be a potential strategy for the prophylaxis and treatment of stress ulceration.
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Affiliation(s)
- Yi-Tao Jia
- Burn Institute of Chinese People's Liberation Army and Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
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Yamato M, Watanabe T, Higuchi K, Taira K, Tanigawa T, Shiba M, Tominaga K, Fujiwara Y, Oshitani N, Takeuchi K, Arakawa T. Anti-inflammatory effects of pravastatin on Helicobacter pylori-induced gastritis in mice. Dig Dis Sci 2007; 52:2833-9. [PMID: 17404852 DOI: 10.1007/s10620-006-9638-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2006] [Accepted: 10/01/2006] [Indexed: 12/11/2022]
Abstract
Pravastatin, an HMG-CoA reductase inhibitor, exerts anti-inflammatory effects via several mechanisms including induction of endothelial nitric oxide synthase (eNOS). We investigated the effect of pravastatin on Helicobacter pylori-induced gastritis in mice. Mice with or without H. pylori infection received intraperitoneal pravastatin daily for 1 week. Expression of eNOS mRNA and tumor necrosis factor-alpha mRNA and myeloperoxidase activity in gastric tissue was determined. Myeloperoxidase activity was reduced in a dose-dependent manner by pravastatin, with activity inhibited by 53.5 and 73.7% at doses of 0.3 and 1 mg/kg, respectively. At a dose of 1 mg/kg, pravastatin reduced the level of tumor necrosis factor-alpha mRNA by 52.7%, while it did not affect eNOS expression. Pravastatin had no effects on these inflammatory parameters in uninfected mice. Pravastatin did not affect the viability of H. pylori. In conclusion, pravastatin exerts an anti-inflammatory effect on H. pylori-induced gastritis in mice without affecting eNOS expression.
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Affiliation(s)
- Masanori Yamato
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
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Jia YT, Ma B, Wei W, Xu Y, Wang Y, Tang HT, Xia ZF. Sustained activation of nuclear factor-kappaB by reactive oxygen species is involved in the pathogenesis of stress-induced gastric damage in rats. Crit Care Med 2007; 35:1582-91. [PMID: 17452936 DOI: 10.1097/01.ccm.0000266824.82280.17] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Stress ulceration is a common complication in critically ill patients, but the mechanisms involved are poorly understood. In this study we investigated the temporal activation of the redox-sensitive transcription factor nuclear factor-kappaB and its roles in an experimental model of cold immobilization stress-induced gastric mucosal lesions. DESIGN Prospective, controlled, and randomized animal study. SETTING University research laboratory. SUBJECTS Male Sprague-Dawley rats. INTERVENTIONS The rats were subjected to cold immobilization stress for a total of 6 hrs. The temporal profiles of nuclear factor-kappaB activation and expression of tumor necrosis factor-alpha, interleukin-1beta, cytokine-induced neutrophil chemoattractant-1 (CINC-1), intercellular adhesion molecule-1 (ICAM-1), and inducible nitric oxide synthase (iNOS) were determined in the gastric corpus mucosa of stressed rats. To study the roles of nuclear factor-kappaB activation, rats received an intravenous bolus of a specific nuclear factor-kappaB inhibitor Bay 11-7082 (20 mg/kg) 1 hr before stress. For antioxidant administration, rats were treated with intravenous injection of a free radical scavenger pyrrolidine dithiocarbamate (50, 100, and 200 mg/kg) 1 hr before stress. MEASUREMENTS AND MAIN RESULTS Exposure of rats to 6 hrs of stress led to a rapid and persistent activation of nuclear factor-kappaB, which was associated with transient degradation of inhibitory protein IkappaBalpha and slower but sustained degradation of IkappaBbeta. Nuclear factor-kappaB activation preceded the induction of tumor necrosis factor-alpha, interleukin-1beta, CINC-1, ICAM-1, and iNOS messenger RNAs, all of which were linearly increased with the duration of stress. Bay 11-7082 selectively blocked the stress-induced nuclear factor-kappaB activation and up-regulation of tumor necrosis factor-alpha, interleukin-1beta, CINC-1, ICAM-1, and iNOS messenger RNAs. Inhibition of expression of these proinflammatory genes prevented the increases in myeloperoxidase activity (an indicator of neutrophil infiltration) in gastric mucosa and the development of gastric damage. Pyrrolidine dithiocarbamate dose-dependently inhibited the stress-induced nuclear factor-kappaB pathway activation and consequential proinflammatory gene expression, neutrophil infiltration, and gastric damage, suggesting the involvement of reactive oxygen species in these processes. CONCLUSIONS Sustained activation of nuclear factor-kappaB by reactive oxygen species is an important in vivo mechanism mediating stress-induced gastric inflammatory damage in rats.
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Affiliation(s)
- Yi-Tao Jia
- Chinese PLA Institute of Burn Surgery & Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
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Abstract
Angiotensin II (Ang II), the active principle of the renin-angiotensin system (RAS), was discovered as a vasoconstrictive, fluid retentive circulating hormone. It was revealed later that there are local RAS in many organs, including the brain. The physiological receptor for Ang II, the AT(1) receptor type, was found to be highly expressed in many tissues and brain areas involved in the hypothalamic-pituitary-adrenal axis response to stress and in the sympathoadrenal system. The production of circulating and local Ang II, and the expression of AT(1) receptors increase during stress. Blockade of peripheral and brain AT(1) receptors with receptor antagonists administered peripherally prevented the hormonal and sympathoadrenal response to isolation stress, the stress-related alterations in cortical CRF(1) and benzodiazepine receptors, part of the GABA(A) complex, and reduced anxiety in rodents. AT(1) receptor blockade prevented the ulcerations of the gastric mucosa produced by cold-restraint stress, by preservation of the gastric blood flow, prevention of the stress-induced inflammatory response of the gastric mucosa, and partial blockade of the sympathoadrenal response to the stress. Our observations demonstrate that Ang II is an important stress hormone, and that blockade of AT(1) receptors could be proposed as a potentially useful therapy for stress-induced disorders.
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Affiliation(s)
- Juan M Saavedra
- Section on Pharmacology, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
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Odashima M, Otaka M, Ohba R, Jin M, Wada I, Horikawa Y, Matsuhashi T, Hatakeyama N, Oyake J, Watanabe S. Attenuation of gastric mucosal inflammation induced by aspirin through inhibition of selective type III phospshodiesterase in rats. Dig Dis Sci 2007; 52:1355-9. [PMID: 17372821 DOI: 10.1007/s10620-006-9553-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2006] [Accepted: 07/31/2006] [Indexed: 12/09/2022]
Abstract
Cilostazol, a selective type III phosphodiesterase inhibitor, is widely used for treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The activation of inflammatory cells and pro-inflammatory cytokine production play critical roles in the pathogenesis of aspirin-induced gastric irritation. The aim of the present study was to determine whether cilostazol can ameliorate aspirin-induced gastric mucosal lesions in rats, reduce neutrophil accumulation, and reduce the production of pro-inflammatory cytokines. Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 N, 8.0 ml/kg). Cilostazol (1-10 mg/kg, IP) was injected 30 min before aspirin administration. Also, we measured the gastric mucosal concentrations of myeloperoxidase and interleukin-1 beta, tumor necrosis factor-alpha, and cytokine-induced neutrophil chemoattractants-1, as an index of neutrophil accumulation, and the pro-inflammatory cytokines. Cilostazol ameliorated the gastric mucosal lesions induced by aspirin administration (P<0.01). The gastric contents of myeloperoxidase and pro-inflammatory cytokines were all increased after aspirin administration and significantly reduced by cilostazol treatment. In this study, we demonstrated that a selective type III phosphodiesterase inhibitor, cilostazol, reduced aspirin-induced gastric inflammation and damage via suppression of the production of proinflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions induced by aspirin.
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Affiliation(s)
- Masaru Odashima
- Department of Gastroenterology, Akita University of Medicine, 1-1-1, Hondo, Akita City, 010-8543, Akita, Japan.
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Wang J. Role of tumor necrosis factor-α in acute gastric mucosal injury in rats after acute brain trauma. Shijie Huaren Xiaohua Zazhi 2007; 15:1437-1440. [DOI: 10.11569/wcjd.v15.i12.1437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [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
AIM: To detect the content of tumor necrosis factor-α (TNF-α) in acute gastric mucosal injury in rats after acute brain trauma and explore its significance.
METHODS: Modified Allen's method was used to induce the rat model of acute gastric mucosal injury after acute brain trauma. Meanwhile, the sham operation group was also designed. The content of TNF-α and ulcer index of gastric mucosa were determined at different time points (1, 3, 6, 24 h), and the pathological changes were also observed under light microscope.
RESULTS: The content of TNF-α in model group was significantly higher than that in control group at the 1st, 3rd, 6th and 24th hour (t = 16.45, P = 0.000; t = 5.252, P = 0.000; t = 9.099, P = 0.000; t = 12.028, P = 0.000). More severe injury occurred in model group and the ulcer index of gastric mucosa was markedly higher than that in control group at the 6th and 24th hour (t = 7.275, P = 0.000; t = 10.579, P = 0.000). TNF-α content was positively correlated with the ulcer index of gastric mucosa (r = 0.68, P = 0.004).
CONCLUSION: TNF-α plays a certen role in acute gastric mucosal injury after acute brain trauma.
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Takekawa S, Matsui T, Arakawa Y. The protective effect of the soybean polyphenol genistein against stress-induced gastric mucosal lesions in rats, and its hormonal mechanisms. J Nutr Sci Vitaminol (Tokyo) 2006; 52:274-80. [PMID: 17087054 DOI: 10.3177/jnsv.52.274] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The present study investigated the effect of the soybean polyphenol genistein on the stomach using a water immersion restraint (WIR) stress model. Male Wistar rats were administered 50 or 100 mg/kg/d of genistein for 2 wk or were not given any drug. Rats were subjected to WIR stress for 4 h. At the end of the WIR period, rats were sacrificed. Subsequently, rats underwent measurement of the ratio of the mucosal hemorrhagic erosion area to the whole stomach body area, myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, thiobarbituric acid reactive substances (TBARS) level, and proinflammatory cytokines (tumor necrosis factor (TNF)-a and cytokine-induced neutrophil chemoattractant (CINC)-1) levels in the gastric tissue. Furthermore, an isolated rat stomach infusion model was employed for the endocrinological investigation of the effect of genistein. The extracted stomach canal and the vascular system, which comprised the experimental model, were subjected to perfusion. After 20 min of perfusion, the perfusate from the portal vein was collected, and the concentrations of histamine, gastrin, and somatostatin in the perfusate were measured. Experiments demonstrated that genistein administration resulted in significant suppression of WIR stress-induced gastric mucosal injury and MPO activity, Further, genistein significantly elevated SOD activity and significantly suppressed the TBARS level, production of TNF-alpha and CINC-1, and secretion of gastrin, histamine, and somatostatin. These data suggest that genistein protected against gastric mucosal injury, likely via its ability to inhibit oxidation, inflammation, and secretion of gastrin and histamine.
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Affiliation(s)
- Sachio Takekawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Kamimachi, Ooyaguchi, Itabashi-ku, Tokyo 173-8610, Japan
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Konishi N, Otaka M, Odashima M, Jin M, Wada I, Komatsu K, Sato T, Kato S, Matsuhashi T, Watanabe S. Systemic stress increases serum leptin level. J Gastroenterol Hepatol 2006; 21:1099-102. [PMID: 16824059 DOI: 10.1111/j.1440-1746.2006.04132.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIM Leptin, the product of the obese (ob) gene, is a circulating peptide mainly synthesized by adipocytes. Leptin inhibits food intake and decreases body weight. A recent report has suggested that the gastric mucosa is also the source of leptin, and that the stomach leptin also contributes to the regulation of the serum leptin level. The aim of the present study was to investigate the effect of water-immersion stress on serum, stomach and adipose tissue leptin levels to understand the relationship between stress and eating behavior. METHODS Male Sprague-Dawley rats were used in this experiment. The leptin level in the serum, gastric mucosa and adipose tissue was measured using ELISA system before and after the initiation of water-immersion stress. RESULTS The serum leptin level was significantly increased by water-immersion stress. The peak was observed 9 h after the initiation of the stress (P < 0.01). However, the gastric leptin level significantly decreased 6 and 9 h after the stress. The adipose tissue leptin level significantly increased 3 h after the stress. CONCLUSIONS The results suggest that changes in serum leptin levels could be associated with stimulation of leptin secretion from the gastric mucosa and leptin production in the adipose tissue by systemic stress and that leptin might be regulated by stress-related events.
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Affiliation(s)
- Noriaki Konishi
- Department of Internal Medicine, Akita University School of Medicine, Akita, Japan
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Odashima M, Otaka M, Jin M, Komatsu K, Wada I, Horikawa Y, Matsuhashi T, Hatakeyama N, Oyake J, Ohba R, Watanabe S, Linden J. Attenuation of gastric mucosal inflammation induced by aspirin through activation of A 2A adenosine receptor in rats. World J Gastroenterol 2006; 12:568-73. [PMID: 16489670 PMCID: PMC4066089 DOI: 10.3748/wjg.v12.i4.568] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether a specific adenosine A2A receptor agonist (ATL-146e) can ameliorate aspirin-induced gastric mucosal lesions in rats, and reduce neutrophil accumulation and production of pro-inflammatory cytokines.
METHODS: Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 mol/L, 8.0 mL/kg). 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL-146e, 2.5-5 μg/kg, IP) was injected 30 min before the administration of aspirin. Tissue myeloperoxidase (MPO) concentration in gastric mucosa was measured as an index of neutrophil infiltration. Gastric mucosal concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined by ELISA. Also, we examined the effect of ATL-146e on tissue prostaglandin E2 (PGE2) production and gastric secretion.
RESULTS: Intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. The total length of gastric erosions (ulcer index) in control rats was 29.8±7.75 mm and was reduced to 3.8±1.42 mm after pretreatment with 5.0 g/kg ATL-146e (P< 0.01). The gastric contents of MPO and pro-inflammatory cytokines were all increased after the administration of aspirin and reduced to nearly normal levels by ATL-146e. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of ATL-146e.
CONCLUSION: The specific adenosine A2A receptor agonist, ATL-146e, has potent anti-ulcer effects presumably mediated by its anti-inflammatory properties.
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Affiliation(s)
- Masaru Odashima
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita City 010-8543, Japan.
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Ohba R, Otaka M, Odashima M, Jin M, Komatsu K, Konishi N, Wada I, Horikawa Y, Matsuhashi T, Oyake J, Hatakeyama N, Watanabe S. Effect of cilostazol, a selective type-III phosphodiesterase inhibitor, on water-immersion stress-induced gastric mucosal injury in rats. J Gastroenterol 2006; 41:34-40. [PMID: 16501855 DOI: 10.1007/s00535-005-1686-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2005] [Accepted: 06/23/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND Cilostazol, a specific type-III phosphodiesterase inhibitor, is widely used for the treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to the suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The pathogenesis of stress-induced gastric mucosal lesions is characterized by the activation of inflammatory cells and the production of inflammatory cytokines. The effects of cilostazol on the development of gastric mucosal lesions have not been reported. In the present study, we examined the effect of a cilostazol on water-immersion stress-induced gastric mucosal lesions. METHODS Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of the selective type-III phosphodiesterase inhibitor, cilostazol. We measured the gastric mucosal lesion and the concentrations of myeloperoxidase (MPO), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1), as an index of neutrophil accumulation and pro-inflammatory cytokine production. RESULTS Cilostazol ameliorated the gastric mucosal injury induced by water-immersion stress (P<0.001). The gastric contents of MPO, TNF-alpha, IL-1beta, and CRO/CINC-1 were all increased after water-immersion stress and were reduced to almost normal levels by cilostazol. CONCLUSIONS In this study, we demonstrated that a selective type-III phosphodiesterase inhibitor, cilostazol, inhibited stress-induced gastric inflammation and damage via suppressing the production of pro-inflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions.
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Affiliation(s)
- Reina Ohba
- Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
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Saavedra JM, Ando H, Armando I, Baiardi G, Bregonzio C, Juorio A, Macova M. Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists. ACTA ACUST UNITED AC 2005; 128:227-38. [PMID: 15837532 DOI: 10.1016/j.regpep.2004.12.015] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The brain and the peripheral (hormonal) angiotensin II systems are stimulated during stress. Activation of brain angiotensin II AT(1) receptors is required for the stress-induced hormone secretion, including CRH, ACTH, corticoids and vasopressin, and for stimulation of the central sympathetic activity. Long-term peripheral administration of the angiotensin II AT(1) antagonist candesartan blocks not only peripheral but also brain AT(1) receptors, prevents the hormonal and sympathoadrenal response to isolation stress and prevents the formation of stress-induced gastric ulcers. The mechanisms responsible for the prevention of stress-induced ulcers by the AT(1) receptor antagonist include protection from the stress-induced ischemia and inflammation (neutrophil infiltration and increase in ICAM-1 and TNF-alpha) in the gastric mucosa and a partial blockade of the stress-induced sympathoadrenal stimulation, while the protective effect of the glucocorticoid release during stress is maintained. AT(1) receptor antagonism prevents the stress-induced decrease in cortical CRH(1) and benzodiazepine binding and is anxiolytic. Blockade of brain angiotensin II AT(1) receptors offers a novel therapeutic opportunity for the treatment of anxiety and other stress-related disorders.
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Affiliation(s)
- Juan M Saavedra
- Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-1514, USA.
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