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Heeba GH, Morsy MA, Mahmoud ME, Abdel-Latif R. Gastro-protective effect of l-arginine against nitric oxide deficiency-related mucosal injury induced by indomethacin: Does age matter? J Biochem Mol Toxicol 2023; 37:e23479. [PMID: 37483153 DOI: 10.1002/jbt.23479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 07/09/2023] [Accepted: 07/13/2023] [Indexed: 07/25/2023]
Abstract
Gastric ulcer is a common disease with increased prevalence in the aged population. Aged gastric mucosa has increased susceptibility to injury along with nonsteroidal anti-inflammatory drugs use due to impaired mucosal defense and decreased vasodilator release. We investigated whether l-arginine could protect against age-related gastric ulceration induced by indomethacin. Aged and adult male Wistar rats were administered sole and combined treatment of l-arginine and Nω -nitro-l-arginine methyl ester ( l-NAME) before induction of gastric ulceration by indomethacin. The gastroprotective effect of l-arginine was displayed only in adult rats with indomethacin-induced gastric ulceration, as evidenced by a significant decrease in ulcer index, oxidative stress parameters, and mucosal myeloperoxidase activity along with increased mucosal PGE2 levels. Interestingly, the mucosal gene expressions of NF-кB, iNOS, and COX-2 were significantly suppressed by l-arginine pretreatment and aggregated upon pretreatment with l-NAME in both adult and aged rats treated with indomethacin. In conclusion, l-arginine protected the rats' gastric mucosa against indomethacin-induced gastric ulceration, possibly, at least in part, by enhancement of mucosal nitric oxide/PGE2 content along with suppressing gastric inflammation and oxidative stress. This study supposed that the gastroprotective effect of l-arginine depends on aging, and even so, the adoption of a new approach to gastric ulcer treatment for the aged population is warranted.
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Affiliation(s)
- Gehan H Heeba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Mohamed A Morsy
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, Egypt
| | - Magda E Mahmoud
- Department of Agricultural Chemistry, Faculty of Agriculture, Minia University, El-Minia, Egypt
| | - Rania Abdel-Latif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
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Campos-Vidal Y, Zamilpa A, Jiménez-Ferrer E, Jiménez-Aparicio AR, Camacho-Díaz BH, Trejo-Tapia G, Tapia-Maruri D, Monterrosas-Brisson N, Herrera-Ruiz M. A Mixture of Kaempferol-3- O-sambubioside and Kaempferol-3- O-sophoroside from Malvaviscus arboreus Prevents Ethanol-Induced Gastric Inflammation, Oxidative Stress, and Histologic Changes. PLANTS (BASEL, SWITZERLAND) 2022; 11:plants11212951. [PMID: 36365404 PMCID: PMC9654347 DOI: 10.3390/plants11212951] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 05/30/2023]
Abstract
Malvaviscus arboreus is used in traditional Mexican medicine to treat gastrointestinal diseases. Therefore, a mixture of Kaempferol-O-sambubioside and Kaempferol-O-sophoroside (MaSS) isolated from flowers of this species was tested as a preventive treatment on gastric lesions induced with ethanol in rats. MaSS was obtained by chromatographic methods and administered by oral pathway to male Sprague Dawley rats with ethanol-induced gastric lesions. Pretreatment with MaSS at doses of 30, 90, 120, and 180 mg/kg significantly prevents gastric lesions, inhibits the increment in relative stomach weight (%) in gastric IL-6, and also provokes an increment of IL-10 concentration and catalase activity. Finally, MaSS prevented edema in the mucosa and submucosa and diminished microscopic gastric lesions provoked by ethanol.
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Affiliation(s)
- Yrvinn Campos-Vidal
- Centro de Investigación Biomédica del Sur, Instituto Mexicano Del Seguro Social, Argentina # 1, Centro, Xochitepec 62790, Mexico
- Centro de Desarrollo de Productos Bióticos, Instituto Politécnico Nacional, Col. San Isidro, Yautepec 62731, Mexico
| | - Alejandro Zamilpa
- Centro de Investigación Biomédica del Sur, Instituto Mexicano Del Seguro Social, Argentina # 1, Centro, Xochitepec 62790, Mexico
| | - Enrique Jiménez-Ferrer
- Centro de Investigación Biomédica del Sur, Instituto Mexicano Del Seguro Social, Argentina # 1, Centro, Xochitepec 62790, Mexico
| | | | | | - Gabriela Trejo-Tapia
- Centro de Desarrollo de Productos Bióticos, Instituto Politécnico Nacional, Col. San Isidro, Yautepec 62731, Mexico
| | - Daniel Tapia-Maruri
- Centro de Desarrollo de Productos Bióticos, Instituto Politécnico Nacional, Col. San Isidro, Yautepec 62731, Mexico
| | | | - Maribel Herrera-Ruiz
- Centro de Investigación Biomédica del Sur, Instituto Mexicano Del Seguro Social, Argentina # 1, Centro, Xochitepec 62790, Mexico
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Campos-Vidal Y, Herrera-Ruiz M, Trejo-Tapia G, Gonzalez-Cortazar M, Aparicio AJ, Zamilpa A. Gastroprotective activity of kaempferol glycosides from Malvaviscus arboreus Cav. JOURNAL OF ETHNOPHARMACOLOGY 2021; 268:113633. [PMID: 33253829 DOI: 10.1016/j.jep.2020.113633] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/25/2020] [Accepted: 11/23/2020] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Malvaviscus arboreus is traditionally used in Mexico and Central America for culinary and medicinal purposes. Leaves and flowers of this species are commonly used for preparation of salads, herbal teas and herbal dyes. Panamanian, Guatemalan and Mexican healers use this medicinal plant for the management of fever, respiratory complications, dysentery, liver and gallbladder problems, stomachache and gastritis between other health troubles. AIM OF THE STUDY Considering the traditional use of M. arboreous as well as its content in flavonoids and other polyphenols, the objective of this work was to evaluate the gastroprotective effect of an aqueous extract and identify the potential bio-active principles from flowers of this species. MATERIAL AND METHODS Fresh flowers of Malvaviscus arboreus were collected, dried, and macerated with water. The aqueous extract (ExAq) was partitioned using an immiscible mixture of water and ethyl acetate, giving an aqueous (MaAq) and organic (MaEA) fractions. The gastroprotective effect was carried out using an ethanol-induced gastric ulcer experimental test in male rats. While tween 20 was used as a negative control, famotidine (10 mg/kg) and L-arginine (300 mg/kg) were used as positive controls. Compounds 1 and 2 were isolated by several chromatographic techniques and the chemical characterization was carried out by means of the analysis of the NMR spectra in one and two dimensions. RESULTS The integrate extract (ExAq) to 250, 500 and 750 mg/kg showed gastroprotective effect with high levels of 97.8%, 79.5% and 91.1% respectively. The organic fraction (MaEA) displayed a protection of 91.2%, 96.0% and 99.4% when it was evaluated at 125, 250 and 500 mg/kg respectively. Comparison of these results with famotidine at 10 mg/kg (83% of gastroprotection) indicated that ethyl acetate fraction showed a better gastroprotection. The bio-guided separation of this organic mixture, allowed obtaining the most active fraction (C1F4, 60 mg/kg) which was finally purified to obtain two glycosylated flavonols: kaempferol 3-O-D-sophoroside (1) and kaempferol 3-O-D-sambubioside (2). This mixture of flavonoids (40 y 60 mg/kg) showed 93.7 and 92% of gastroprotective activity respectively. CONCLUSION This study allowed demonstrating that an aqueous extract and its organic fraction (MaEA) from M. arboreous contain glycosylated flavonoids (1 and 2) which are responsible of the gastroprotective properties of M. arboreous. These results will be used in the future development of a standardized treatment useful in the therapeutic management of gastric ulcers.
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Affiliation(s)
- Yrvinn Campos-Vidal
- Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Argentina No. 1, Col. Centro, Xochitepec, Morelos, C.P. 62790, Mexico; Centro de Desarrollo de Productos Bióticos, Instituto Politécnico Nacional, Col. San Isidro, Yautepec, Morelos, C.P. 62731, Mexico
| | - Maribel Herrera-Ruiz
- Centro de Desarrollo de Productos Bióticos, Instituto Politécnico Nacional, Col. San Isidro, Yautepec, Morelos, C.P. 62731, Mexico
| | - Gabriela Trejo-Tapia
- Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Argentina No. 1, Col. Centro, Xochitepec, Morelos, C.P. 62790, Mexico.
| | - Manases Gonzalez-Cortazar
- Centro de Desarrollo de Productos Bióticos, Instituto Politécnico Nacional, Col. San Isidro, Yautepec, Morelos, C.P. 62731, Mexico
| | - Antonio Jiménez Aparicio
- Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Argentina No. 1, Col. Centro, Xochitepec, Morelos, C.P. 62790, Mexico
| | - Alejandro Zamilpa
- Centro de Desarrollo de Productos Bióticos, Instituto Politécnico Nacional, Col. San Isidro, Yautepec, Morelos, C.P. 62731, Mexico.
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Cajaraville JP. Ibuprofen Arginate for Rapid-Onset Pain Relief in Daily Practice: A Review of Its Use in Different Pain Conditions. J Pain Res 2021; 14:117-126. [PMID: 33531831 PMCID: PMC7846824 DOI: 10.2147/jpr.s280571] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 11/11/2020] [Indexed: 01/22/2023] Open
Abstract
Ibuprofen is one of the most frequently used analgesics. One of the concerns related with the oral administration of conventional ibuprofen is the relatively slow absorption, which is clinically a relative inconvenience when rapid-onset analgesic effect is required in patients suffering from acute moderate/severe pain. A new oral dosage formulation of ibuprofen containing the L-arginine salt of ibuprofen (ibuprofen arginate) has been commercialized for more than two decades, but data reported in the literature are relatively scarce. This article presents salient findings on pharmacokinetics, pharmacological activity, clinical efficacy and tolerability of ibuprofen arginate, with the purpose to provide clinicians with a summary overview of some frequent acute pain conditions, such as dental pain, dysmenorrhea, headache or postoperative pain in which ibuprofen arginate may be considered the drug of choice in individual patients.
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Lebda MA, El-Far AH, Noreldin AE, Elewa YHA, Al Jaouni SK, Mousa SA. Protective Effects of Miswak ( Salvadora persica) against Experimentally Induced Gastric Ulcers in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:6703296. [PMID: 30116487 PMCID: PMC6079327 DOI: 10.1155/2018/6703296] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 04/26/2018] [Accepted: 05/24/2018] [Indexed: 12/11/2022]
Abstract
Gastric ulcers are among the most broadly perceived illnesses affecting individuals. Alcohol consumption is the main cause of gastric ulceration. This study assessed the protective effects of Salvadora persica (SP) extract against ethanol-induced gastric ulcer and elucidated the conceivable underlying mechanisms involved. For this purpose, 40 rats were allotted into 4 equal groups (control, ethanol- (EtOH-) treated, and SP-treated "SP200 and SP400" groups). The control and EtOH-treated groups were given phosphate buffer saline (PBS), and both the SP200 and SP400 groups were given SP extract dissolved in PBS at doses of 200 and 400 mg/kg b.w., respectively. All treatments were given orally for 7 constitutive days. On the 8th day, all rats were fasted for 24 h followed by oral gavage of PBS in the control group and chilled absolute ethanol solution (5 ml/kg b.w.) in the EtOH- and SP-treated groups to induce gastric lesions. One hour later, the rats were sacrificed and the stomachs were harvested. Gross and microscopic examinations of the EtOH-treated group showed severe gastric hemorrhagic necrosis, submucosal edema, destruction of epithelial cells, and reduced glycoprotein content at the mucus surface. These pathological lesions were defeated by SP extract treatment. Administration of SP extract modulated the oxidative stress and augmented the antioxidant defenses. The elevated ethanol-expressed tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) genes, as well as bcl-2-like protein 4 (Bax) and inducible nitric oxide synthase (iNOS), were diminished in the SP-treated group. Curiously, SP extract upregulated endothelial nitric oxide synthase (eNOS) and transforming growth factor-β1 (TGF-β1) gene expression comparable to that of the EtOH-treated rats. Aggregately, SP exerted antiulcer activities in ethanol-induced gastric ulcer rat models via modulation of oxidant/antioxidant status, mitigation of proinflammatory cytokines, and apoptosis, as well as remodeling of both NOS isoforms.
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Affiliation(s)
- Mohamed A. Lebda
- Biochemistry Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria 22758, Egypt
| | - Ali H. El-Far
- Biochemistry Department, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt
| | - Ahmed E. Noreldin
- Histology and Cytology Department, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt
| | - Yaser H. A. Elewa
- Histology and Cytology Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
- Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary, Hokkaido University, Sapporo, Japan
| | - Soad K. Al Jaouni
- Department of Pediatric Hematology/Oncology, King Abdulaziz University Hospital and Scientific Chair of Yousef Abdul Latif Jameel of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Shaker A. Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA
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Sáenz JB, Mills JC. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat Rev Gastroenterol Hepatol 2018; 15:257-273. [PMID: 29463907 PMCID: PMC6016373 DOI: 10.1038/nrgastro.2018.5] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Subjected to countless daily injuries, the stomach still functions as a remarkably efficient digestive organ and microbial filter. In this Review, we follow the lead of the earliest gastroenterologists who were fascinated by the antiseptic and digestive powers of gastric secretions. We propose that it is easiest to understand how the stomach responds to injury by stressing the central role of the most important gastric secretion, acid. The stomach follows two basic patterns of adaptation. The superficial response is a pattern whereby the surface epithelial cells migrate and rapidly proliferate to repair erosions induced by acid or other irritants. The stomach can also adapt through a glandular response when the source of acid is lost or compromised (that is, the process of oxyntic atrophy). We primarily review the mechanisms governing the glandular response, which is characterized by a metaplastic change in cellular differentiation known as spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that the stomach, like other organs, exhibits marked cellular plasticity: the glandular response involves reprogramming mature cells to serve as auxiliary stem cells that replace lost cells. Unfortunately, such plasticity might mean that the gastric epithelium undergoes cycles of differentiation and de-differentiation that increase the risk of accumulating cancer-predisposing mutations.
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Affiliation(s)
- José B. Sáenz
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
| | - Jason C. Mills
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
- Department of Developmental Biology, Washington University School of Medicine
- Department of Pathology and Immunology, Washington University School of Medicine
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El-Lithy GM, El-Bakly WM, Matboli M, Abd-Alkhalek HA, Masoud SI, Hamza M. Prophylactic L-arginine and ibuprofen delay the development of tactile allodynia and suppress spinal miR-155 in a rat model of diabetic neuropathy. Transl Res 2016; 177:85-97.e1. [PMID: 27392937 DOI: 10.1016/j.trsl.2016.06.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 06/11/2016] [Accepted: 06/14/2016] [Indexed: 02/08/2023]
Abstract
Diabetic neuropathy (DN) is a common complication of diabetes mellitus that is hardly reversible at the late stages. Since treatment of neuropathic pain is predominantly symptomatic, a prophylactic measure would be useful. Both ibuprofen and L-arginine exert antiallodynic effects on chronic constriction injury (CCI)-induced cold allodynia. Furthermore, ibuprofen is effective in CCI-induced mechanical allodynia. The aim of the study was to assess the antiallodynic effect of prophylactic ibuprofen and L-arginine in streptozotocin-induced DN in rats and to further investigate the role of spinal miR-155 and nitric oxide (NO) in this effect. Tactile allodynia was assessed weekly by von Frey filaments. Oral daily administration of ibuprofen, L-arginine and their combination, for 4 weeks starting 1 week after streptozotocin injection (ie, before the development of tactile allodynia), resulted in a significant decrease of tactile allodynia compared with the control diabetic group. This was evident in the fifth week of the experiment. The 3 treatments prevented the decrease in muscle fiber diameter and epidermal thickness, seen in the control diabetic group. Furthermore, ibuprofen, L-arginine and their combination prevented the increase in the spinal NO level and miRNA-155, seen in the control diabetic group. In conclusion, both ibuprofen and L-arginine delayed the development of behavioral and histologic changes of DN, with concomitant suppression of spinal miR-155 and NO level. L-arginine being tolerable may be useful prophylactically in diabetic patients.
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Affiliation(s)
- Ghada M El-Lithy
- Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Wesam M El-Bakly
- Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Marwa Matboli
- Department of Biochemistry, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hadwa A Abd-Alkhalek
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Somaia I Masoud
- Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - May Hamza
- Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
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Ribeiro ARS, Diniz PBF, Pinheiro MS, Albuquerque-Júnior RLC, Thomazzi SM. Gastroprotective effects of thymol on acute and chronic ulcers in rats: The role of prostaglandins, ATP-sensitive K(+) channels, and gastric mucus secretion. Chem Biol Interact 2015; 244:121-8. [PMID: 26689173 DOI: 10.1016/j.cbi.2015.12.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/25/2015] [Accepted: 12/10/2015] [Indexed: 12/13/2022]
Abstract
Thymol, a monoterpene phenol derivative of cymene, is found in abundance in the essential oils of Thymus, Origanum, and Lippia species. The present study investigated the gastroprotective actions of thymol (10, 30, and 100 mg/kg, p.o.) in the acute (ethanol- and nonsteroidal anti-inflammatory drug-induced ulcers) and chronic (acetic acid-induced ulcers) ulcer models in rats. Some of the mechanisms underlying to the gastroprotective effect of thymol were investigated in the ethanol-induced ulcer model. Gastric secretion parameters (volume, pH, and total acidity) were also evaluated by the pylorus ligature model, and the mucus in the gastric content was determined. The anti-Helicobacter pylori activity of thymol was performed using the agar-well diffusion method. Thymol (10, 30, and 100 mg/kg) produced dose dependent reduction (P < 0.01) on the total lesion area in the ethanol-induced ulcer model. The gastroprotective response caused by thymol (30 mg/kg) was significantly attenuated (P < 0.001) by intraperitoneal treatment of rats with indomethacin (a non-selective inhibitor of cyclo-oxygenase, 10 mg/kg) and glibenclamide (ATP-sensitive K(+) channel blocker, 10 mg/kg), but not by DL-Propargylglycine (PAG, a cystathionine-γ-lyase inhibitor, 25 mg/kg) and Nw-nitro-L-arginine methyl ester hydrochloride (L-NAME, a non-selective inhibitor of nitric oxide synthase, 70 mg/kg). Thymol (30 and 100 mg/kg) also reduced the ulcer index (P < 0.05) and the total lesion area (P < 0.001) in the indomethacin- and acetic-acid-induced ulcer models, respectively. In the model pylorus ligature, the treatment with thymol failed to significantly change the gastric secretion parameters. However, after treatment with thymol (30 and 100 mg/kg), there was a significant increase (P < 0.01) in mucus production. Thymol no showed anti-H. pylori activity in vitro. Collectively, the present results provide convincing evidence that thymol displays gastroprotective actions on the acute and chronic ulcer models through mechanisms that involve increased in the amount of mucus, prostaglandins, and ATP-sensitive K(+) channels.
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Affiliation(s)
- Ana Roseli S Ribeiro
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil
| | - Polyana B F Diniz
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil
| | - Malone S Pinheiro
- Unit Lab - Laboratório Central de Biomedicina, Universidade Tiradentes, Rua Laranjeiras, 710, CEP 49010-000 Aracaju, Sergipe, Brazil
| | - Ricardo L C Albuquerque-Júnior
- Instituto de Tecnologia e Pesquisa-ITP, Universidade Tiradentes, Av. Murilo Dantas, 300, CEP 49032-490 Aracaju, Sergipe, Brazil
| | - Sara M Thomazzi
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil.
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Wang S, Zhao Y, Zhang J, Huang X, Wang Y, Xu X, Zheng B, Zhou X, Tian H, Liu L, Mei Q. Antidiarrheal effect of Alpinia oxyphylla Miq. (Zingiberaceae) in experimental mice and its possible mechanism of action. JOURNAL OF ETHNOPHARMACOLOGY 2015; 168:182-190. [PMID: 25861952 DOI: 10.1016/j.jep.2015.03.066] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 02/12/2015] [Accepted: 03/30/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The fructus Alpinia oxyphylla Miq. (AOM) has been used for treating diarrhea with spleen deficiency and gastralgia for thousands of years. A number of traditional Chinese medicine formulae provide AOM as an alternative herbal treatment for diarrhea, but the scientific basis for this usage has not been well defined. AIM OF THE STUDY In this study, we tried to investigate the antidiarrheal activity and possible mechanisms of Fructus AOM, aiming to enrich our understanding to the scientific meanings and theoretical significance of Fructus AOM in clinical practice. MATERIALS AND METHODS The fructus of AOM collected from Hainan province in China were macerated in the 95% ethanol to obtain the crude 95% ethanol extract, followed by subjected to chromatographic separation over a Diaion HP20 column to obtain 90% and 50% ethanol eluted fractions. The activities of the crude extract and fractions on castor oil induced acute diarrhea, rhubarb induced chronic diarrhea, gastrointestinal transit (GIT) in mice, and contractions of isolated guinea-pig ileum were evaluated. Additionally, nitric oxide (NO), gastrointestinal peptides gastrin (GAS), motilin (MTL) and somatostatin (SS) levels that related to gastrointestinal motilities were detected to demonstrate the potential mechanisms. Ultimately, LC-MS/MS method was utilized to ensure the chemical consistency. RESULTS The 95% ethanol extract and 90% ethanol eluted fraction significantly delayed the onset time and decreased the wet faeces proportion compared with control group in the castor oil induced acute diarrhea mice. In terms of further evaluation of antidiarrheal activity, the 95% ethanol extract and 90% ethanol elution displayed significant inhibition of the intestinal propulsion at the two highest oral doses of 20 g crude drug/kg and 1g/kg. Moreover the 95% ethanol extract (10 and 20 g crude drug/kg) and 90% ethanol elution (0.5 and 1g/kg) could significantly inhibit the GIT, which was partially attributed to the increase in NO and SS levels, and the decreased MTL. In vitro spontaneous contractions of the isolated guinea pig ileum induced by carbachol, neostigmine and histamine were attenuated by both the extract and elution. Phytochemical analysis of 95% ethanol extract and its fractions identified the presence of diphenylheptanes, sesquiterpenes, and flavones as the major components. CONCLUSIONS Our in vivo and in vitro data could partly support and justify the traditional usage of Fructus AOM on the treatment of diarrhea in traditional medicine.
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Affiliation(s)
- Sheng Wang
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Yang Zhao
- Vascular Biology Program, Centenary Institute, The University of Sydney, Shanghai 2042, NSW, Australia.
| | - Junqing Zhang
- Hainan Provincial Key Laboratory of Research and Development of Tropical Medicinal Plants, Hainan Medical University, Haikou 571199, China.
| | - Xiaoxing Huang
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Yifei Wang
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Xiaotao Xu
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Bin Zheng
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Xue Zhou
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Huajie Tian
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Li Liu
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Qibing Mei
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
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Damasceno SR, Rodrigues JC, Silva RO, Nicolau LA, Chaves LS, Freitas AL, Souza MH, Barbosa AL, Medeiros JVR. Role of the NO/KATP pathway in the protective effect of a sulfated-polysaccharide fraction from the algae Hypnea musciformis against ethanol-induced gastric damage in mice. REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY 2013. [DOI: 10.1590/s0102-695x2013005000003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Tang RS, Chan FKL. Mechanisms behind the increased vulnerability of the aging stomach to NSAID-related injury: perhaps not as simple as we may think. Dig Dis Sci 2013; 58:11-2. [PMID: 23086120 DOI: 10.1007/s10620-012-2443-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Morsy MA, Heeba GH, Abdelwahab SA, Rofaeil RR. Protective effects of nebivolol against cold restraint stress-induced gastric ulcer in rats: Role of NO, HO-1, and COX-1,2. Nitric Oxide 2012; 27:117-22. [DOI: 10.1016/j.niox.2012.06.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Revised: 05/30/2012] [Accepted: 06/02/2012] [Indexed: 01/22/2023]
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Hata S, Abe M, Suzuki H, Kitamura F, Toyama-Sorimachi N, Abe K, Sakimura K, Sorimachi H. Calpain 8/nCL-2 and calpain 9/nCL-4 constitute an active protease complex, G-calpain, involved in gastric mucosal defense. PLoS Genet 2010; 6:e1001040. [PMID: 20686710 PMCID: PMC2912385 DOI: 10.1371/journal.pgen.1001040] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2010] [Accepted: 06/23/2010] [Indexed: 11/23/2022] Open
Abstract
Calpains constitute a superfamily of Ca2+-dependent cysteine proteases, indispensable for various cellular processes. Among the 15 mammalian calpains, calpain 8/nCL-2 and calpain 9/nCL-4 are predominantly expressed in the gastrointestinal tract and are restricted to the gastric surface mucus (pit) cells in the stomach. Possible functions reported for calpain 8 are in vesicle trafficking between ER and Golgi, and calpain 9 are implicated in suppressing tumorigenesis. These highlight that calpains 8 and 9 are regulated differently from each other and from conventional calpains and, thus, have potentially important, specific functions in the gastrointestinal tract. However, there is no direct evidence implicating calpain 8 or 9 in human disease, and their properties and physiological functions are currently unknown. To address their physiological roles, we analyzed mice with mutations in the genes for these calpains, Capn8 and Capn9. Capn8−/− and Capn9−/− mice were fertile, and their gastric mucosae appeared normal. However, both mice were susceptible to gastric mucosal injury induced by ethanol administration. Moreover, the Capn8−/− stomach showed significant decreases in both calpains 9 and 8, and the same was true for Capn9−/−. Consistent with this finding, in the wild-type stomach, calpains 8 and 9 formed a complex we termed “G-calpain,” in which both were essential for activity. This is the first example of a “hybrid” calpain complex. To address the physiological relevance of the calpain 8 proteolytic activity, we generated calpain 8:C105S “knock-in” (Capn8CS/CS) mice, which expressed a proteolytically inactive, but structurally intact, calpain 8. Although, unlike the Capn8−/− stomach, that of the Capn8CS/CS mice expressed a stable and active calpain 9, the mice were susceptible to ethanol-induced gastric injury. These results provide the first evidence that both of the gastrointestinal-tract-specific calpains are essential for gastric mucosal defense, and they point to G-calpain as a potential target for gastropathies caused by external stresses. The continuous or improper ingestion of irritants, including alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), and Helicobacter pylori, often leads to serious gastropathies, affecting a wide range of people. A complex gastric defense system helps protect against these threats, for example by secreting mucus. Here we report that two gastrointestinal-tract-specific calpains, calpain 8/nCL-2 and calpain 9/nCL-4, are involved in the mucosal defense against stress-induced gastropathies. Calpains are Ca2+-dependent cytosolic proteases that are indispensable for various cellular processes. Improper calpain activities can result in death or serious disorders, such as muscular dystrophies and lissencephaly, although no role for calpains in gastrointestinal diseases has been reported. Here we show that mice with mutations in the genes for calpains 8 and 9 are susceptible to alcohol-induced gastric injury. Moreover, these calpains form a stable complex, in which both molecules are essential for activity. Thus, human calpains 8 and 9 may contribute to the stomach's susceptibility to stress caused by irritants such as alcohol. Indeed, some reported human single nucleotide polymorphisms (SNPs) in these calpains are predicted to compromise their proteolytic activity. Our mutant mice provide unique animal models for potential human gastropathies caused by such SNPs.
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Affiliation(s)
- Shoji Hata
- Calpain Project, The Tokyo Metropolitan Institute of Medical Science (Rinshoken), Tokyo, Japan
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Ortiz-Masiá D, Hernández C, Quintana E, Velázquez M, Cebrián S, Riaño A, Calatayud S, Esplugues JV, Barrachina MD. iNOS-derived nitric oxide mediates the increase in TFF2 expression associated with gastric damage: role of HIF-1. FASEB J 2009; 24:136-45. [PMID: 19741170 DOI: 10.1096/fj.09-137489] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Trefoil (TFF) peptides are involved in gastrointestinal mucosal restitution. An hypoxia inducible factor 1 (HIF-1)-dependent induction of TFF genes has been reported in gastric epithelial cells. Nitric oxide (NO) is associated with mucosal damage and modulates HIF-1 activity. The aim of the present study was to analyze the role of iNOS-derived NO in HIF-1alpha stabilization and TFF gene expression in damaged gastric mucosa. Aspirin caused gastric injury that peaked 6 h after dosing and returned to normality at 24 h. iNOS mRNA expression occurs in the corpus in parallel with damage. Blockade of iNOS activity did not modify gastric lesions induced by aspirin but delayed mucosal healing. Aspirin induced HIF-1alpha stabilization and TFF2 mRNA up-regulation in the mucosa, but these effects were diminished when iNOS activity was inhibited. Results obtained using a coculture setup showed that iNOS-derived NO from activated macrophages induced HIF-1alpha stabilization, TFF gene expression, and accelerated wound healing in cultured epithelial cells. Finally, transient silencing of endogenous HIF-1alpha in epithelial cells significantly undermined activated macrophage-induced TFF gene expression. Evidence suggests that the iNOS-derived NO associated with NSAID-induced gastric injury is implicated in mucosal restitution via the HIF-1-mediated induction of TFF genes.
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Affiliation(s)
- Dolores Ortiz-Masiá
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Avda. Blasco Ibáñez 15-17, Valencia, Spain
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Kwasniewski FH, Landgraf RG, Jancar S. Small bowel injury associated to allergy is triggered by platelet-activating factor, mast cells, neutrophils and protected by nitric oxide. Int Immunopharmacol 2008; 8:371-8. [DOI: 10.1016/j.intimp.2007.10.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2007] [Revised: 10/24/2007] [Accepted: 10/25/2007] [Indexed: 11/30/2022]
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Mechanisms of increased gastric protection after NSAID-administration in rats consuming virgin olive oil diets. ACTA ACUST UNITED AC 2008. [DOI: 10.1016/j.eclnm.2007.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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A neonatal mouse model of intestinal perforation: investigating the harmful synergism between glucocorticoids and indomethacin. J Pediatr Gastroenterol Nutr 2007; 45:509-19. [PMID: 18030227 DOI: 10.1097/mpg.0b013e3181558591] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Early postnatal steroids and indomethacin in combination have been shown to increase the risk of spontaneous intestinal perforation (SIP) in infants with extremely low birth weight (ELBW), but the mechanism behind this synergistic effect is unknown. MATERIALS AND METHODS Based on literature in a variety of models suggesting that glucocorticoids and nonsteroidal antiinflammatory agents diminish complementary isoforms of nitric oxide synthase (NOS), we hypothesized that perturbations in NO metabolism contribute to SIP. RESULTS Our results using newborn wild-type (WT) and endothelial NOS-knockout (eNOS KO) mice treated with dexamethasone and/or indomethacin indicate that indomethacin treatment diminishes ileal eNOS abundance; dexamethasone treatment diminishes ileal inducible NOS and neuronal NOS (nNOS); 100% of dexamethasone-treated eNOS KO mice die after 3 days; eNOS KO mice treated for 2 days with dexamethasone develop acute pyloric stenosis in association with reduced expression of pyloric nNOS; and isolated ileum from eNOS KO mice treated for 2 days with dexamethasone exhibit a significant decrease in spontaneous peristalsis, decreased circumference, and decreased capacitance for forced volume before ileal perforation compared with ileum from untreated controls. CONCLUSIONS Our findings suggest that eNOS and nNOS display functional overlap in the newborn mouse gastrointestinal tract and that simultaneous reduction in the activity of both NOS isoforms may be a risk factor for neonatal ileal perforation. If this holds true in human infants, then it provides a plausible etiologic explanation for the strong temporal association between SIP and the simultaneous treatment of ELBW infants with glucocorticoids and indomethacin.
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Pan LR, Tang Q, Fu Q, Hu BR, Xiang JZ, Qian JQ. Roles of nitric oxide in protective effect of berberine in ethanol-induced gastric ulcer mice. Acta Pharmacol Sin 2005; 26:1334-8. [PMID: 16225755 DOI: 10.1111/j.1745-7254.2005.00186.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
AIM To investigate the protective effects of berberine on ethanol-induced gastric ulcer in mice. METHODS Gastric ulcers were induced by oral ingestion of ethanol. Nitric oxide (NO) content was measured, and mRNA expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS The ulcer index (UI) at 1 h, 2 h, 3 h and 6 h after oral administration of ethanol was 23.8+/-1.4, 23.3+/-2.2, 22.3+/-1.2 and 20.8+/-1.1, respectively. The UI in the berberine-treated groups (5 mg/kg and 50 mg/kg) was less than the control group. The content of NO in the control group was 73.3+/-7.3 microL/L, 94.0+/-9.2 microL/L, 109.6+/-6.4 microL/L and 138.2+/-10.2 microL/L in gastric juice and 5.8+/-1.1 micromol/g protein, 8.3+/-1.1 micromol/g protein, 9.8+/-1.1 micromol/g protein and 11.9+/-1.2 micromol/g protein in gastric tissue at 1 h, 2 h, 3 h and 6 h, respectively, after the oral administration of ethanol. The content of NO in the berberine-treated groups (5 mg/kg and 50 mg/kg) was higher than the control group at 1 h after the oral administration of ethanol (P<0.05), and was lower at 6 h (P<0.05). Analysis by RT-PCR showed that expression of eNOS was inhibited but iNOS expression was enhanced by ethanol. However, the expression of eNOS could be enhanced and iNOS expression could be inhibited by berberine (P<0.01). CONCLUSION Berberine could significantly protect gastric mucosa from damage by ethanol. This effect may be related to the increased expression of eNOS mRNA and inhibited expression of iNOS mRNA.
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Affiliation(s)
- Long-rui Pan
- Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Jiménez MD, Martín MJ, Alarcón de la Lastra C, Bruseghini L, Esteras A, Herrerías JM, Motilva V. Role of L-arginine in ibuprofen-induced oxidative stress and neutrophil infiltration in gastric mucosa. Free Radic Res 2005; 38:903-11. [PMID: 15621707 DOI: 10.1080/10715760410001705168] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
It has been proposed that neutrophil and oxygen dependent microvascular injuries may be important prime events in gastrointestinal (GI) toxicity of non-steroidal antiinflammatory drugs (NSAIDs). L-arginine (L-ARG) is an essential amino acid which participates in many important biochemical reactions associated to the normal physiology of the organism. In these experimentations, we studied the role of L-ARG, aminoacid precursor of NO synthesis, on ibuprofen (IB) induced gastric lesions, and also on the inflammatory and oxidative mechanisms related to mucosal damage. Oral administration of IB (100 mg kg(-1)), produced severe damage on gastric mucosa, which was more important after 6 h test-period, and was accompanied by a significant increment in myeloperoxidase (MPO) activity, as index of neutrophil activation, as well as lipid peroxidation (LP) levels and xanthine oxidase (XO) activity. However, no changes were observed in total mucosal glutathione (tGSH), nor glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activity. Simultaneous treatment with equimolar doses of L-ARG (oral and i.p.), considerably reduced the number and intensity of lesions, and at the same time (6 h) the maximum protection was also observed. In addition, L-ARG inhibited the IB-induced LP and XO enhancement, but did not produce changes in leukocyte infiltration, tGSH, GSH-Px and SOD activity. These findings suggest that (1) L-ARG protective effect on gastric mucosa against IB-induced mucosal lesions could be explained by a local effect and also might be due to the systemic action of the aminoacid; (2) the active oxygen species, derived both from XO and activated neutrophils, could play a role in the pathogenesis of gastric injury induced by IB, (3) L-ARG exhibit a protective effect against IB-induced mucosal damage, probably through the inhibition of oxidative stress derived via xanthine-XO, but it does not block the oxygen free radical production through polymorphe nuclear leukocytes.
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Affiliation(s)
- M D Jiménez
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
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Abraham P, K I, K D. Nitro-arginine methyl ester, a non-selective inhibitor of nitric oxide synthase reduces ibuprofen-induced gastric mucosal injury in the rat. Dig Dis Sci 2005; 50:1632-40. [PMID: 16133962 DOI: 10.1007/s10620-005-2908-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2004] [Accepted: 01/13/2004] [Indexed: 02/07/2023]
Abstract
Ibuprofen is a commonly used non-steroidal anti-inflammatory drug. Gastrointestinal adverse drug reactions from ibuprofen usage include gastric mucosal ulcers and bleeding. The mechanism by which ibuprofen induces gastric mucosal damage is not clear. The present study is an attempt to examine the role of nitric oxide in the pathogenesis of ibuprofen-induced gastric mucosal damage. Ibuprofen administered orally at the dose of 100 mg/kg body weight for 6 days to the rats resulted in gastric mucosal injury. Serum nitrite and nitrosothiol were increased significantly as compared with the controls, which were treated with the vehicle alone. In the gastric mucosa, lipid peroxidation and protein thiols were increased, and the activity of glyceraldehyde 3-phosphate dehydrogenase, a nitric oxide sensitive enzyme was decreased significantly. Pretreatment of the rats daily with nitric oxide synthase inhibitor, nitro-arginine methyl ester (30 mg/kg body weight) 1 hr before treatment with ibuprofen reduced the gastric mucosal injury. Biochemically, it prevented the rise in serum nitrite levels and the increase in lipid peroxidation and protein thiol levels and the loss of glyceraldehyde 3-phosphate dehydrogenase activity in the gastric mucosa. The results of the present study suggest that increased nitric oxide production may be one of the mechanisms by which ibuprofen produces gastric mucosal injury and that inhibition of nitric oxide synthase reduces gastric mucosal injury.
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Affiliation(s)
- Premila Abraham
- Department of Biochemistry, Christian Medical College, Bagayam, Vellore, India.
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Sánchez-Fidalgo S, Martín-Lacave I, Illanes M, Motilva V. Angiogenesis, cell proliferation and apoptosis in gastric ulcer healing. Effect of a selective cox-2 inhibitor. Eur J Pharmacol 2005; 505:187-94. [PMID: 15556152 DOI: 10.1016/j.ejphar.2004.10.019] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2004] [Accepted: 10/04/2004] [Indexed: 02/08/2023]
Abstract
To elucidate the role of cyclooxygenase-2, we compared the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, and ibuprofen, a nonselective cyclooxygenase inhibitor, on the evolution of acetic-acid-induced gastric ulcers in rats, evaluating growth factor expression, the angiogenic process, cell proliferation and cell apoptosis. Levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), angiogenesis and cell proliferation were analysed by immunohistochemical methods, and apoptosis was evaluated by an enzyme immunoassay. Both growth factors and microvessels appeared to be abundant in the granulation tissue of the ulcer bed. Rofecoxib (2.5 mg/kg/day) and ibuprofen (100 mg/kg/day) delayed ulcer healing, but only rofecoxib treatment provoked a reduction of bFGF expression and inhibition of the development of new microvessels. No changes in VEGF expression were detected. Results also showed that proliferation and apoptosis were increased in control ulcerated animals. Rofecoxib reduced significantly both processes. These findings demonstrate that a reduction of bFGF expression and an antiangiogenic action, as well as proliferation/apoptosis inhibition, are some of the mechanisms possibly implicated in the delay in ulcer healing seen after the administration of the highly selective COX-2 inhibitor rofecoxib.
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Motilva V, Alarcón de la Lastra C, Bruseghini L, Manuel Herrerias J, Sánchez-Fidalgo S. COX expression and PGE2 and PGD2 production in experimental acute and chronic gastric lesions. Int Immunopharmacol 2005; 5:369-79. [PMID: 15652766 DOI: 10.1016/j.intimp.2004.10.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2004] [Revised: 09/14/2004] [Accepted: 10/15/2004] [Indexed: 10/26/2022]
Abstract
Prostaglandin E(2) and D(2) (PGE(2) and PGD(2)) production and cyclooxygenase-2 (COX-2) expression during the resolution of acute and chronic gastric inflammatory lesions in Wistar rats have been investigated. Differences between ibuprofen, nonselective COX inhibitor, and rofecoxib, specific COX-2 inhibitor, on the development of the induced responses were also analysed. In an acute model, by instillation of HCL, the greatest injury was observed early with a rapid and progressive restoration. Maximal up-regulation of COX-2 protein was detected at 6 h and was accompanied by increase of PGE(2) synthesis but not PGD(2). Both drugs stimulated COX-2 expression in accordance to their capacity of inhibiting this enzymatic activity, driving to delay in the healing. In a chronic model, by acetic acid-induced gastric ulcers, COX-2 was expressed at 7 days and was also associated with PGE(2) increase. Ibuprofen and rofecoxib also augmented COX-2 protein and inhibited PGE(2) levels. However, PGD(2) production was augmented when none signal of COX-2 protein could be detected. Together, this study confirms the role played by COX-2 enzyme in the resolution of acute and chronic gastric inflammatory process, PGE(2) being the principal product. The antiinflammatory effect of nonsteroidal antiinflammatory drugs (NSAIDs) could be mediated not only through the inhibition of COX activity but also through the induction of antiinflammatory PGs production-such as PGD(2)-although further studies would be needed to clarify the mechanisms of this activity and the possible implicated processes.
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Affiliation(s)
- Virginia Motilva
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, Spain.
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Liang YC, Liu HJ, Chen SH, Chen CC, Chou LS, Tsai LH. Effect of lipopolysaccharide on diarrhea and gastrointestinal transit in mice: Roles of nitric oxide and prostaglandin E 2. World J Gastroenterol 2005; 11:357-61. [PMID: 15637744 PMCID: PMC4205337 DOI: 10.3748/wjg.v11.i3.357] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [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 investigate the effect of lipopolysaccharide (LPS) on the diarrheogenic activity, gastrointestinal transit (GIT), and intestinal fluid content and the possible role of nitric oxide (NO) and prostaglandin E2 (PGE2) in gastrointestinal functions of endotoxin-treated mice.
METHODS: Diarrheogic activity, GIT, and intestinal fluid content as well as nitric oxide and PGE2 products were measured after intraperitoneal administration of LPS in mice.
RESULTS: LPS dose-dependently accumulated abundant fluid into the small intestine, induced diarrhea, but decreased the GIT. Both nitric oxide and PGE2 were found to increase in LPS-treated mice. Western blot analysis indicated that LPS significantly induced the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 in mice intestines. Pretreatment with NG-nitro-L-arginine-methyl ester (L-NAME, a non-selective NOS inhibitor) or indomethacin (an inhibitor of prostaglandin synthesis) significantly attenuated the effects of LPS on the diarrheogenic activity and intestine content, but reversed the GIT.
CONCLUSION: The present study suggests that the pathogenesis of LPS treatment may mediate the stimulatory effect of LPS on nitric oxide and PGE2 production and NO/prostaglandin pathway may play an important role on gastrointestinal function.
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Affiliation(s)
- Yu-Chih Liang
- Graduate Institute of Biomedical Technology, Taipei Medical University, Taipei, Taiwan, China
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Alderman BM, McCaffrey GJ, Yeomans ND. Nonsteroidal antiinflammatory drugs and the stomach. Curr Opin Gastroenterol 2002; 18:658-62. [PMID: 17033344 DOI: 10.1097/00001574-200211000-00004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
We review papers on nonsteroidal antiinflammatory drugs (NSAID) and the stomach published in the 12 months ending April 2002. During this period, some further developments occurred in the ongoing search for safer antiinflammatory drugs. The highly selective COX-2 inhibitors (COX-2i) have again exhibited some toxicity in animal models of repair, but continue to seem a safer alternative than nonselective inhibitors from the standpoint of the production of human ulcers. Some data on the gastrointestinal safety of valdecoxib and parecoxib are available, while co-therapies with acid suppressants to reduce the risk of conventional NSAID also remain an option (a study comparing lansoprazole with misoprostol is now published). Whether co-prescribing a proton pump inhibitor with a COX-2i in patients at higher risk is effective or justified awaits the results of yet to be completed studies. The nitric oxide (NO)-donating NSAID and NO-donating aspirin show some distinct promise in animal studies and early-phase clinical trials.
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Affiliation(s)
- Barbara M Alderman
- Department of Medicine, University of Melbourne at Western Hospital, Footscray, Victoria, Australia
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Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2002; 11:421-36. [PMID: 12271887 DOI: 10.1002/pds.661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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