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Liu Y, Miao R, Xia J, Zhou Y, Yao J, Shao S. Infection of Helicobacter pylori contributes to the progression of gastric cancer through ferroptosis. Cell Death Discov 2024; 10:485. [PMID: 39622791 PMCID: PMC11612470 DOI: 10.1038/s41420-024-02253-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 12/06/2024] Open
Abstract
Helicobacter pylori (H. pylori) is a gram-negative pathogen that colonizes gastric epithelial cells, and its chronic infection is the primary risk factor for the development of gastric cancer (GC). Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and reactive oxygen species (ROS) imbalance. There is evidence suggesting that pathogens can manipulate ferroptosis to facilitate their replication, transmission, and pathogenesis. However, the interaction between ferroptosis and H. pylori infection requires further elucidation. We reviewed the mechanism of ferroptosis and found that H. pylori virulence factors such as cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), neutrophil-activating protein A (NapA), superoxide dismutase B (SodB), γ-glutamyl transpeptidase (gGT), lipopolysaccharide (LPS), and outer inflammatory protein A (OipA) affected glutathione (GSH), ROS, and lipid oxidation to regulate ferroptosis. It also affected the progression of GC by regulating ferroptosis-related indicators through abnormal gene expression after H. pylori infected gastric mucosa cells. Finally, we discuss the potential application value of ferroptosis inducers, inhibitors and other drugs in treating H. pylori-infected GC patients while acknowledging that their interactions are still not fully understood.
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Affiliation(s)
- Yun Liu
- Department of Gastroenterology, Institute of Digestive Disease, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, China
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Renjie Miao
- Department of Clinical laboratory, Affiliated Third Hospital of Zhenjiang to Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jinxuan Xia
- Zhenjiang Mental Health Center, Jiangsu, China
| | - Yong Zhou
- Department of Gastroenterology, Institute of Digestive Disease, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, China.
| | - Jun Yao
- Department of Gastroenterology, Institute of Digestive Disease, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, China.
| | - Shihe Shao
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
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Gupta PC, Sharma N, Kar A, Kumar J, Sharma AK, Kalani A. Protective effect of
Phlogacanthus thyrsiflorus
Nees against experimentally induced gastric mucosal lesions in rats: Experimental evidence from biochemical and histological analysis. JOURNAL OF BIOLOGICALLY ACTIVE PRODUCTS FROM NATURE 2024; 14:427-442. [DOI: 10.1080/22311866.2024.2398611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/24/2024] [Accepted: 08/24/2024] [Indexed: 01/02/2025]
Affiliation(s)
- Prakash Chandra Gupta
- School of Pharmaceutical Sciences, Chhatrapati Shahu Ji Maharaj University, Kanpur-208024, India
| | - Nisha Sharma
- School of Pharmaceutical Sciences, Chhatrapati Shahu Ji Maharaj University, Kanpur-208024, India
| | - Ashish Kar
- The Energy and Resources Institute (TERI), Northeastern Regional Centre, Guwahati-781036, India
| | - Jay Kumar
- School of Pharmaceutical Sciences, Chhatrapati Shahu Ji Maharaj University, Kanpur-208024, India
| | - Ajay Kumar Sharma
- Department of Pharmacy, Ganesh Shankar Vidyarthi Memorial Medical College, Kanpur-208002, India
| | - Anuradha Kalani
- Disease Biology Lab, School of Life Sciences and Biotechnology, Chhatrapati Shahu Ji Maharaj University, Kanpur-208024, India
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Kumar S, Dhiman M. Helicobacter pylori secretary Proteins-Induced oxidative stress and its role in NLRP3 inflammasome activation. Cell Immunol 2024; 399-400:104811. [PMID: 38518686 DOI: 10.1016/j.cellimm.2024.104811] [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: 07/12/2023] [Revised: 01/09/2024] [Accepted: 01/15/2024] [Indexed: 03/24/2024]
Abstract
Helicobacter pylori-associated stomach infection is a leading cause of gastric ulcer and related cancer. H. pylori modulates the functions of infiltrated immune cells to survive the killing by reactive oxygen and nitrogen species (ROS and RNS) produced by these cells. Uncontrolled immune responses further produce excess ROS and RNS which lead to mucosal damage. The persistent oxidative stress is a major cause of gastric cancer. H. pylori regulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), nitric oxide synthase 2 (NOS2), and polyamines to control ROS and RNS release through lesser-known mechanisms. ROS and RNS produced by these pathways differentiate macrophages and T cells from protective to inflammatory phenotype. Pathogens-associated molecular patterns (PAMPs) induced ROS activates nuclear oligomerization domain (NOD), leucine rich repeats (LRR) and pyrin domain-containing protein 3 (NLRP3) inflammasome for the release of pro-inflammatory cytokines. This study evaluates the role of H. pylori secreted concentrated proteins (HPSCP) related oxidative stress role in NLRP3 inflammasome activation and macrophage differentiation. To perceive the role of ROS/RNS, THP-1 and AGS cells were treated with 10 μM diphenyleneiodonium (DPI), 50 μM salicyl hydroxamic acid (SHX), 5 μM Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), which are specific inhibitors of NADPH oxidase (NOX), Myeloperoxidase (MPO), and mitochondrial oxidative phosphorylation respectively. Cells were also treated with 10 μM of NOS2 inhibitor l-NMMA and 10 μM of N-acetyl cysteine (NAC), a free radical scavenger·H2O2 (100 μM) treated and untreated cells were used as positive controls and negative control respectively. The expression of gp91phox (NOX2), NOS2, NLRP3, CD86 and CD163 was analyzed through fluorescent microscopy. THP-1 macrophages growth was unaffected whereas the gastric epithelial AGS cells proliferated in response to higher concentration of HPSCP. ROS and myeloperoxidase (MPO) level increased in THP-1 cells and nitric oxide (NO) and lipid peroxidation significantly decreased in AGS cells. gp91phox expression was unchanged, whereas NOS2 and NLRP3 downregulated in response to HPSCP, but increased after inhibition of NO, ROS and MPO in THP-1 cells. HPSCP upregulated the expression of M1 and M2 macrophage markers, CD86 and CD163 respectively, which was decreased after the inhibition of ROS. This study concludes that there are multiple pathways which are generating ROS during H. pylori infection which further regulates other cellular processes. NO is closely associated with MPO and inhibition of NLRP3 inflammasome. The low levels of NO and MPO regulates gastrointestinal tract homeostasis and overcomes the inflammatory response of NLRP3. The ROS also plays crucial role in macrophage polarization hence alter the immune responses duing H. pylori pathogenesis.
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Affiliation(s)
- Sandeep Kumar
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Bathinda, 151 401 Punjab, India
| | - Monisha Dhiman
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Bathinda, 151 401 Punjab, India.
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Baskerville MJ, Kovalyova Y, Mejías-Luque R, Gerhard M, Hatzios SK. Isotope tracing reveals bacterial catabolism of host-derived glutathione during Helicobacter pylori infection. PLoS Pathog 2023; 19:e1011526. [PMID: 37494402 PMCID: PMC10406306 DOI: 10.1371/journal.ppat.1011526] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 08/07/2023] [Accepted: 07/01/2023] [Indexed: 07/28/2023] Open
Abstract
Mammalian cells synthesize the antioxidant glutathione (GSH) to shield cellular biomolecules from oxidative damage. Certain bacteria, including the gastric pathogen Helicobacter pylori, can perturb host GSH homeostasis. H. pylori infection significantly decreases GSH levels in host tissues, which has been attributed to the accumulation of reactive oxygen species in infected cells. However, the precise mechanism of H. pylori-induced GSH depletion remains unknown, and tools for studying this process during infection are limited. We developed an isotope-tracing approach to quantitatively monitor host-derived GSH in H. pylori-infected cells by mass spectrometry. Using this method, we determined that H. pylori catabolizes reduced GSH from gastric cells using γ-glutamyl transpeptidase (gGT), an enzyme that hydrolyzes GSH to glutamate and cysteinylglycine (Cys-Gly). gGT is an established virulence factor with immunomodulatory properties that is required for H. pylori colonization in vivo. We found that H. pylori internalizes Cys-Gly in a gGT-dependent manner and that Cys-Gly production during H. pylori infection is coupled to the depletion of intracellular GSH from infected cells. Consistent with bacterial catabolism of host GSH, levels of oxidized GSH did not increase during H. pylori infection, and exogenous antioxidants were unable to restore the GSH content of infected cells. Altogether, our results indicate that H. pylori-induced GSH depletion proceeds via an oxidation-independent mechanism driven by the bacterial enzyme gGT, which fortifies bacterial acquisition of nutrients from the host. Additionally, our work establishes a method for tracking the metabolic fate of host-derived GSH during infection.
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Affiliation(s)
- Maia J. Baskerville
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, United States of America
- Microbial Sciences Institute, Yale University, West Haven, Connecticut, United States of America
| | - Yekaterina Kovalyova
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, United States of America
- Microbial Sciences Institute, Yale University, West Haven, Connecticut, United States of America
- Department of Chemistry, Yale University, New Haven, Connecticut, United States of America
| | - Raquel Mejías-Luque
- Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, School of Medicine, Munich, Germany
- German Centre for Infection Research, Munich, Germany
| | - Markus Gerhard
- Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, School of Medicine, Munich, Germany
- German Centre for Infection Research, Munich, Germany
| | - Stavroula K. Hatzios
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, United States of America
- Microbial Sciences Institute, Yale University, West Haven, Connecticut, United States of America
- Department of Chemistry, Yale University, New Haven, Connecticut, United States of America
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Xi Y, Zhang XL, Luo QX, Gan HN, Liu YS, Shao SH, Mao XH. Helicobacter pylori regulates stomach diseases by activating cell pathways and DNA methylation of host cells. Front Cell Dev Biol 2023; 11:1187638. [PMID: 37215092 PMCID: PMC10192871 DOI: 10.3389/fcell.2023.1187638] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 04/25/2023] [Indexed: 05/24/2023] Open
Abstract
One of the most prevalent malignant tumors of the digestive tract is gastric cancer (GC). Age, high salt intake, Helicobacter pylori (H. pylori) infection, and a diet deficient in fruits and vegetables are risk factors for the illness. A significant risk factor for gastric cancer is infection with H. pylori. Infecting gastric epithelial cells with virulence agents secreted by H. pylori can cause methylation of tumor genes or carcinogenic signaling pathways to be activated. Regulate downstream genes' aberrant expression, albeit the precise mechanism by which this happens is unclear. Oncogene, oncosuppressor, and other gene modifications, as well as a number of different gene change types, are all directly associated to the carcinogenesis of gastric cancer. In this review, we describe comprehensive H. pylori and its virulence factors, as well as the activation of the NF-κB, MAPK, JAK/STAT signaling pathways, and DNA methylation following infection with host cells via virulence factors, resulting in abnormal gene expression. As a result, host-related proteins are regulated, and gastric cancer progression is influenced. This review provides insight into the H. pylori infection, summarizes a series of relevant papers, discusses the complex signaling pathways underlying molecular mechanisms, and proposes new approach to immunotherapy of this important disease.
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Affiliation(s)
- Yue Xi
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xiao-Li Zhang
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, China
| | - Qing-Xin Luo
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hai-Ning Gan
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yu-Shi Liu
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Shi-He Shao
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xu-Hua Mao
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, China
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Potential Active Constituents from Opophytum forsskalii (Hochst. ex Boiss.) N.E.Br against Experimental Gastric Lesions in Rats. Pharmaceuticals (Basel) 2022; 15:ph15091089. [PMID: 36145310 PMCID: PMC9502456 DOI: 10.3390/ph15091089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/26/2022] [Accepted: 08/27/2022] [Indexed: 11/17/2022] Open
Abstract
Opophytum forsskalii (O. forsskalii) is a desert plant that belongs to the Aizoaceae family. Although it is a natural food source for Bedouin tribes in northern Saudi Arabia, there is little information on its active metabolites. Therefore, the secondary metabolites of the hydroalcoholic extract from the leaves of this species were analyzed by liquid chromatography-mass chromatography (LC-MS). LC-MS identified a total of 30 secondary metabolites. These compounds represented two main categories among sixteen classes. Among them, flavonoids represented the largest proportion with eleven metabolites while fatty acids provided seven compounds. In addition, the extract was evaluated for its gastroprotective effect against gastric lesions induced by different models, such as indomethacin, stress, and necrotizing agents (80% ethanol, 0.2 mol/L NaOH, and 25% NaCl), in rats. For each method, group 1 was used as the control group while groups 2 and 3 received the leaf extract at doses of 200 and 400 mg/kg, respectively. The ulcer index (UI) and intraluminal bleeding score (IBS) were measured for each method. In addition, gastric tissue from the ethanol method was used for the analysis of nonprotein sulfhydrates (NP-SH), malondialdehyde (MDA), total protein (TP), and histopathologic evaluation. Pretreatment with O. forsskalii significantly decreased UI (p < 0.01) and IBS (p < 0.01) at 400 mg/kg. Pretreatment with O. forsskalii significantly improved total protein levels (p < 0.01) and NP-SH (p < 0.001) compared to the ethanol ulcer groups. MDA levels increased from 0.5 to 5.8 nmol/g in the normal groups compared to the ethanol groups and decreased to 2.34 nmol/g in the O. forsskalii pretreatment. In addition to the gastroprotective markers, histopathological examination of gastric tissue confirmed the gastroprotective potential of O. forsskalii extract against ethanol.
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Evaluation of Antiulcer and Cytotoxic Potential of the Leaf, Flower, and Fruit Extracts of Calotropis procera and Isolation of a New Lignan Glycoside. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:8086791. [PMID: 28951762 PMCID: PMC5603131 DOI: 10.1155/2017/8086791] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 07/09/2017] [Accepted: 07/24/2017] [Indexed: 11/18/2022]
Abstract
Calotropis procera is traditionally used for treating many diseases including ulcers and tumors. It was thus deemed of interest to investigate and compare the antiulcer and cytotoxic activities of C. procera leaf, flower, and fruit extracts in an attempt to verify its traditional uses. Phytochemical studies on the fruits, flowers, and leaves of C. procera, collected from the desert of Saudi Arabia, led to the isolation of one new lignan 7′-methoxy-3′-O-demethyl-tanegool-9-O-β-d-glucopyranoside and five known compounds from the flowers, four compounds from leaves, and a flavonoid glycoside and a lignan glycoside from the fruits. The structures of compounds were determined by spectroscopic techniques. Ethanol extracts of the three parts of C. procera were evaluated for their antiulcer activity and we found that the leaf extract possessed a powerful antiulcer activity which could be considered as a promising drug candidate. All the extracts and the isolated compounds were evaluated for their cytotoxic activity against MCF-7, HCT-116, HepG-2, and A-549 human cancer cell lines. Compound 2 was highly active on all the cell lines, whereas compounds 5 and 11 were more selective on colon and liver cell lines. Compound 10 demonstrated a significant activity on liver and lung cancer cell lines.
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Pérez S, Taléns-Visconti R, Rius-Pérez S, Finamor I, Sastre J. Redox signaling in the gastrointestinal tract. Free Radic Biol Med 2017; 104:75-103. [PMID: 28062361 DOI: 10.1016/j.freeradbiomed.2016.12.048] [Citation(s) in RCA: 195] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 12/20/2016] [Accepted: 12/31/2016] [Indexed: 12/16/2022]
Abstract
Redox signaling regulates physiological self-renewal, proliferation, migration and differentiation in gastrointestinal epithelium by modulating Wnt/β-catenin and Notch signaling pathways mainly through NADPH oxidases (NOXs). In the intestine, intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells. Furthermore, commensal bacteria contribute to intestine epithelial homeostasis through NOX1- and dual oxidase 2-derived reactive oxygen species (ROS). The loss of redox homeostasis is involved in the pathogenesis and development of a wide diversity of gastrointestinal disorders, such as Barrett's esophagus, esophageal adenocarcinoma, peptic ulcer, gastric cancer, ischemic intestinal injury, celiac disease, inflammatory bowel disease and colorectal cancer. The overproduction of superoxide anion together with inactivation of superoxide dismutase are involved in the pathogenesis of Barrett's esophagus and its transformation to adenocarcinoma. In Helicobacter pylori-induced peptic ulcer, oxidative stress derived from the leukocyte infiltrate and NOX1 aggravates mucosal damage, especially in HspB+ strains that downregulate Nrf2. In celiac disease, oxidative stress mediates most of the cytotoxic effects induced by gluten peptides and increases transglutaminase levels, whereas nitrosative stress contributes to the impairment of tight junctions. Progression of inflammatory bowel disease relies on the balance between pro-inflammatory redox-sensitive pathways, such as NLRP3 inflammasome and NF-κB, and the adaptive up-regulation of Mn superoxide dismutase and glutathione peroxidase 2. In colorectal cancer, redox signaling exhibits two Janus faces: On the one hand, NOX1 up-regulation and derived hydrogen peroxide enhance Wnt/β-catenin and Notch proliferating pathways; on the other hand, ROS may disrupt tumor progression through different pro-apoptotic mechanisms. In conclusion, redox signaling plays a critical role in the physiology and pathophysiology of gastrointestinal tract.
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Affiliation(s)
- Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Raquel Taléns-Visconti
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Isabela Finamor
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain.
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Beta-cyclodextrin enhanced gastroprotective effect of (−)-linalool, a monoterpene present in rosewood essential oil, in gastric lesion models. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:1245-1251. [PMID: 27629579 DOI: 10.1007/s00210-016-1298-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 09/02/2016] [Indexed: 12/18/2022]
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Cover TL, Holland RL, Blanke SR. Helicobacter pylori Vacuolating Toxin. HELICOBACTER PYLORI RESEARCH 2016:113-141. [DOI: 10.1007/978-4-431-55936-8_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Yahiro K, Hirayama T, Moss J, Noda M. Helicobacter pylori VacA toxin causes cell death by inducing accumulation of cytoplasmic connexin 43. Cell Death Dis 2015; 6:e1971. [PMID: 26561781 PMCID: PMC4670933 DOI: 10.1038/cddis.2015.329] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- K Yahiro
- Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - T Hirayama
- Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan
| | - J Moss
- Cardiovascular and Pulmonary Branch, NHLBI, National Institutes of Health, Bethesda, MD 20892, USA
| | - M Noda
- Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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Helicobacter pylori VacA induces apoptosis by accumulation of connexin 43 in autophagic vesicles via a Rac1/ERK-dependent pathway. Cell Death Discov 2015; 1:15035. [PMID: 27551466 PMCID: PMC4979424 DOI: 10.1038/cddiscovery.2015.35] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 08/16/2015] [Accepted: 08/19/2015] [Indexed: 12/15/2022] Open
Abstract
Helicobacter pylori (H. pylori) produces vacuolating cytotoxin (VacA), a potent protein toxin, which is associated with gastric inflammation and ulceration. Recent studies demonstrated that connexins (Cxs), which are responsible for intracellular communication at gap junctions (GJs) as well as cell homeostasis, participate in VacA-induced cell death. We now demonstrate in AZ-521 cells that VacA increased cytoplasmic Cx43, accompanied by LC3-II generation in a time- and dose-dependent manner without induction of Cx43 mRNA expression. Inhibition of VacA-induced Rac1 activity prevented ERK phosphorylation and the increase in Cx43. Suppression of ERK activity and addition of N-acetyl-cysteine inhibited VacA-dependent increase in Cx43 and LC3-II. DIDS, an anion-selective inhibitor, suppressed VacA-dependent increase in Cx43, suggesting that VacA channel activity was involved in this pathway. By confocal microscopy, Cx43 increased by VacA was predominately localized in cholesterol-rich, detergent-resistant membranes including GJs, and a fraction of Cx43 was incorporated in endocytotic vesicles and autophagolysosomes. Accumulation of Cx43 was also observed in gastric mucosa from H. pylori-infected patients compared with healthy controls, suggesting that the pathogen caused a similar effect in vivo. Our findings show that VacA-mediated effects on autophagy inhibits turnover of Cx43, resulting in increased levels in the cytoplasm, leading eventually to apoptotic cell death.
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Carrasco V, Pinto LA, Cordeiro KW, Cardoso CAL, Freitas KDC. Antiulcer activities of the hydroethanolic extract of Sedum dendroideum Moc et Sessé ex DC. (balsam). JOURNAL OF ETHNOPHARMACOLOGY 2014; 158 Pt A:345-351. [PMID: 25446587 DOI: 10.1016/j.jep.2014.10.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2014] [Revised: 10/06/2014] [Accepted: 10/21/2014] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The leaves of Sedum dendroideum, commonly known as balsam, have long been employed for the treatment of gastric ulcers. The aim of study was to evaluate the antiulcer activity and toxicological properties of Sedum dendroideum using induced gastric ulcer models in Wistar rats. MATERIALS AND METHODS The hydroethanolic extract of Sedum dendroideum (ESD) was analyzed using an acute ulcer model using ethanol and indomethacin and a chronic ulcer model using acetic acid. The toxicity was evaluated with acute and subacute toxicity tests. The gastric secretion was assessed by the performance of pyloric ligation and the gastric volume, pH, and hydrogen ion concentration. The mechanism of the gastroprotective activity of ESD through the involvement of nitric oxide and sulfhydryl compounds was assessed. Moreover, a phytochemical screening and antioxidant assays were performed. RESULTS No signs of toxicity were observed. In the ethanol-induced ulceration model, ESD doses of 25, 50, and 100mg/kg significantly reduced the gastric lesions by 66.03%, 71.11%, and 70.82%, respectively. In the indomethacin-induced ulceration model, ESD doses of 25, 50, and 100mg/kg significantly reduced the gastric lesions by 89.88%, 94.36%, and 90.64%, respectively. Treatment with ESD at 50mg/kg and cimetidine at 200mg/kg significantly reduced acetic acid-induced ulcerations and resulted in 92.99% and 77.16% cure, respectively. ESD doses of 25, 50, and 100mg/kg inhibited oxidation by 79.7%, 82.4%, and 82.3%, respectively. The antiulcer activity of ESD may involve sulfhydryl compounds, considering that this activity was inhibited in the animals treated with sulfhydryl compound blockers. Furthermore, ESD increased mucus secretion and reduced gastric acidity and volume. CONCLUSIONS The leaf extract of Sedum dendroideum exhibited gastroprotective activity, potentially due to sulfhydryl compounds and antioxidant activity. Therefore, other studies are warranted to elucidate the antiulcer properties of these compounds.
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Affiliation(s)
- Viviane Carrasco
- Federal University of Grande Dourados, School of Health Sciences, Dourados (Universidade Federal da Grande Dourados, Faculdade de Ciências da Saúde), Mato Grosso do Sul, Brazil
| | - Lorraine Aparecida Pinto
- Federal University of Grande Dourados, School of Health Sciences, Dourados (Universidade Federal da Grande Dourados, Faculdade de Ciências da Saúde), Mato Grosso do Sul, Brazil
| | - Kátia Wolff Cordeiro
- Federal University of Mato Grosso do Sul, Medical School, (Universidade Federal de Mato Grosso do Sul, Faculdade de Medicina), Campo Grande, Mato Grosso do Sul, Brazil
| | - Claudia Andrea Lima Cardoso
- State University of Mato Grosso do Sul, School of Chemistry (Universidade Estadual de Mato Grosso do Sul, Curso de Química), Dourados, Mato Grosso do Sul, Brazil
| | - Karine de Cássia Freitas
- Federal University Federal de Mato Grosso do Sul, Center of Biological and Health Sciences (Universidade Federal de Mato Grosso do Sul, Centro de Ciências Biológicas e da Saúde), Campo Grande, Mato Grosso do Sul, Brazil.
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14
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Semper RP, Mejías-Luque R, Groß C, Anderl F, Müller A, Vieth M, Busch DH, Prazeres da Costa C, Ruland J, Groß O, Gerhard M. Helicobacter pylori-induced IL-1β secretion in innate immune cells is regulated by the NLRP3 inflammasome and requires the cag pathogenicity island. THE JOURNAL OF IMMUNOLOGY 2014; 193:3566-76. [PMID: 25172489 DOI: 10.4049/jimmunol.1400362] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Infection with the gram-negative bacterium Helicobacter pylori is the most prevalent chronic bacterial infection, affecting ∼50% of the world's population, and is the main risk factor of gastric cancer. The proinflammatory cytokine IL-1β plays a crucial role in the development of gastric tumors and polymorphisms in the IL-1 gene cluster leading to increased IL-1β production have been associated with increased risk for gastric cancer. To be active, pro-IL-1β must be cleaved by the inflammasome, an intracellular multiprotein complex implicated in physiological and pathological inflammation. Recently, H. pylori was postulated to activate the inflammasome in murine bone marrow-derived dendritic cells; however, the molecular mechanisms as well as the bacterial virulence factor acting as signal 2 activating the inflammasome remain elusive. In this study, we analyzed the inflammasome complex regulating IL-1β upon H. pylori infection as well as the molecular mechanisms involved. Our results indicate that H. pylori-induced IL-1β secretion is mediated by activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 inflammasome. We also show that reactive oxygen species, potassium efflux, and lysosomal destabilization are the main cellular mechanisms responsible of nucleotide-binding oligomerization domain family, pyrin domain-containing 3 inflammasome activation upon H. pylori infection, and identify vacuolating cytotoxin A and cag pathogenicity island as the bacterial virulence determinants involved. Moreover, in vivo experiments indicate an important role for the inflammasome in the onset and establishment of H. pylori infection and in the subsequent inflammatory response of the host.
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Affiliation(s)
- Raphaela P Semper
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany
| | - Raquel Mejías-Luque
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany
| | - Christina Groß
- Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany
| | - Florian Anderl
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany
| | - Anne Müller
- Institute of Molecular Cancer Research, University of Zürich, 8057 Zürich, Switzerland
| | - Michael Vieth
- Institut für Pathologie, Klinikum Bayreuth, 95445 Bayreuth, Germany; and
| | - Dirk H Busch
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany; German Centre for Infection Research, Partner Site Munich, 81675 Munich, Germany
| | - Clarissa Prazeres da Costa
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany
| | - Jürgen Ruland
- Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany; German Centre for Infection Research, Partner Site Munich, 81675 Munich, Germany
| | - Olaf Groß
- Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany
| | - Markus Gerhard
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany; German Centre for Infection Research, Partner Site Munich, 81675 Munich, Germany
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Bhattacharyya A, Chattopadhyay R, Mitra S, Crowe SE. Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol Rev 2014; 94:329-54. [PMID: 24692350 DOI: 10.1152/physrev.00040.2012] [Citation(s) in RCA: 1539] [Impact Index Per Article: 139.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.
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Rahimian G, Sanei MH, Shirzad H, Azadegan-Dehkordi F, Taghikhani A, Salimzadeh L, Hashemzadeh-Chaleshtori M, Rafieian-Kopaei M, Bagheri N. Virulence factors of Helicobacter pylori vacA increase markedly gastric mucosal TGF-β1 mRNA expression in gastritis patients. Microb Pathog 2014; 67-68:1-7. [PMID: 24462401 DOI: 10.1016/j.micpath.2013.12.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2013] [Revised: 12/14/2013] [Accepted: 12/30/2013] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Helicobacter pylori (H. pylori) infection is the main cause of gastric inflammation. Regulatory T cells (Treg cells) suppress the activation and proliferation of antigen-specific T cells and mediate immunologic tolerance. TGF-β1 was shown to be secreted in a subset of Treg cells known as 'Th3 cells'. These cells have not been sufficiently studied in context to H. pylori-induced inflammation in human gastric mucosa. In this study we therefore, aimed to investigate the expression of TGF-β1 in the context of H. pylori colonization in chronic gastritis, to examine the relationship between it and histopathologic findings and to compare it with virulence factors. PATIENTS AND METHODS Total RNA was extracted from gastric biopsies of 48 H. pylori-infected patients and 38 H. pylori-negative patients with gastritis. Mucosal TGF-β1 mRNA expression in H. pylori-infected and uninfected gastric biopsies was determined by real-time PCR. Presence of vacA, cagA, iceA, babA2 and oipA virulence factors was evaluated using PCR. RESULTS TGF-β1 mRNA expression was significantly increased in biopsies of H. pylori-infected patients compared to H. pylori-uninfected patients. There was association between virulence factors and TGF-β1 mRNA expression. TGF-β1 mRNA expression in mucosa was significantly higher in patients with vacA s1 and s1m1. CONCLUSIONS TGF-β1 may play an important role in the inflammatory response and promote the chronic and persistent inflammatory changes in the gastric. This may ultimately influence the outcome of H. pylori-associated diseases that arise within the context of gastritis and vacA may suffice to induce expression of TGF-β1 mRNA.
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Affiliation(s)
- Ghorbanali Rahimian
- Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | | | - Hedayatollah Shirzad
- Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | | | - Afshin Taghikhani
- Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Loghman Salimzadeh
- Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | | | | | - Nader Bagheri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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Bagheri N, Taghikhani A, Rahimian G, Salimzadeh L, Azadegan Dehkordi F, Zandi F, Chaleshtori MH, Rafieian-Kopaei M, Shirzad H. Association between virulence factors of helicobacter pylori and gastric mucosal interleukin-18 mRNA expression in dyspeptic patients. Microb Pathog 2013; 65:7-13. [DOI: 10.1016/j.micpath.2013.08.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 08/17/2013] [Accepted: 08/30/2013] [Indexed: 12/30/2022]
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Prostaglandin analogous and antioxidant activity mediated gastroprotective action of Tabernaemontana divaricata (L.) R. Br. flower methanolic extract against chemically induced gastric ulcers in rats. BIOMED RESEARCH INTERNATIONAL 2013; 2013:185476. [PMID: 24350249 PMCID: PMC3856123 DOI: 10.1155/2013/185476] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Revised: 05/23/2013] [Accepted: 06/12/2013] [Indexed: 11/29/2022]
Abstract
The present study was conducted to evaluate the antiulcerogenic effect and recognize the basic mechanism of action of Tabernaemontana divaricata (L.) R. Br. flowers. T. divaricata flower methanolic extract (TDFME) was screened for antiulcer activity versus aspirin and ethanol induced gastric ulcers at three doses—125, 250, and 500 mg/kg—orally using misoprostol as a standard. Besides histopathological examination, seven parameters, that is, ulcer index, total protein, nonprotein sulphhydryls, mucin, catalase, malondialdehyde, and superoxide dismutase levels, were estimated. In addition to HPLC profiling, GC-MS analysis and electrospray ionization—high resolution mass spectral (ESI-HRMS) analysis of crude TDFME were carried out in an attempt to identify known phytochemicals present in the extract on the basis of m/z value. The results revealed a significant increase in the levels of catalase, superoxide dismutase, mucin, and nonprotein sulphhydryls, while they revealed a reduction in ulcer index, the levels of total protein, and malondialdehyde. Histopathological observations also demonstrated the protective effect. Though all the doses of TDFME exhibited gastroprotective function, higher doses were found to be more effective. Mass spectral analysis gave a few characteristic m/z values suggesting the presence of a few known indole alkaloids, while HPLC profiling highlighted the complexity of the extract. TDFME was found to exhibit its gastroprotective effect through antioxidant mechanism and by enhancing the production of gastric mucous.
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Khan MI, Khan MR. Gastroprotective Potential of Dalbergia sissoo Roxb. Stem Bark against Diclofenac-Induced Gastric Damage in Rats. Osong Public Health Res Perspect 2013; 4:271-7. [PMID: 24298443 PMCID: PMC3845230 DOI: 10.1016/j.phrp.2013.09.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 09/04/2013] [Accepted: 09/05/2013] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Dalbergia sissoo Roxb. stem bark possesses anti-inflammatory, antipyretic, and antioxidant properties. This plant is used traditionally in the Indian system of medicine to treat emesis, ulcers, leucoderma, dysentery, stomach complaints, and skin disorders. This study was conducted to evaluate the antiulcer effects of D. sissoo stem bark methanol extract (DSME) against the diclofenac sodium-induced ulceration in rat. METHODS The DSME (200 mg/kg and 400 mg/kg body weight) was orally administered to rats once a day for 10 days in diclofenac-treated rats. The gastroprotective effects of DSME were determined by assessing gastric-secretory parameters such as volume of gastric juice, pH, free acidity, and total acidity. Biochemical studies of gastric mucosa were conducted to estimate the levels of nonprotein sulfhydryls (NP-SHs), lipid peroxidation [thiobarbituric acid reactive substances (TBARSs)], reduced glutathione (GSH), hydrogen peroxide (H2O2), levels of scavenging antioxidants, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST), and myeloperoxidase (MPO). Moreover, adherent mucus content and histological studies were performed on stomach tissues. RESULTS Administration of DSME significantly decreased the ulcer index, TBARSs, H2O2, and MPO activity in gastric mucosa of the ulcerated rats. Activities of enzymic antioxidants, CAT, SOD, GSH-Px, GST and GSH, and NP-SH contents were significantly increased with DSME administration in the gastric mucosa of diclofenac-treated rats. Volume of gastric juice, total and free acidity were decreased, whereas pH of the gastric juice was increased with the administration of DSME + diclofenac. Our results show that DSME administration is involved in the prevention of ulcer through scavenging of free radicals. Results of histopathological studies supported the gastroprotective activities of DSME. CONCLUSION The results of this study showed that DSME exhibit potential gastroprotective activity probably due to its antioxidant and cytoprotection ability.
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Affiliation(s)
| | - Muhammad Rashid Khan
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
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Luiz-Ferreira A, Cola M, Barbastefano V, de-Faria FM, de Almeida ABA, Farias-Silva E, Calvo TR, Hiruma-Lima CA, Vilegas W, Souza-Brito ARM. Healing, antioxidant and cytoprotective properties of Indigofera truxillensis in different models of gastric ulcer in rats. Int J Mol Sci 2012. [PMID: 23203107 PMCID: PMC3509623 DOI: 10.3390/ijms131114973] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The present study evaluated the antiulcerogenic activity and mechanisms of the aqueous (AqF 100 mg/kg) and ethyl acetate (AcF 50 mg/kg) fractions from Indigofera truxillensis leaves. This dose was selected to assess its activity on ulcer healing and its action on gastric acid and mucus secretion, prostaglandin production and antioxidant enzyme activity (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd)). Gastric ulcer was induced by absolute ethanol. Antisecretory action, mucus and prostaglandin production, healing and antioxidant enzyme activities were evaluated for both fractions. AqF and AcF significantly inhibited the gastric mucosal damage caused by ethanol. This effect was statistically significant at 100 and 50 mg/kg compared with the vehicle. Neither fraction interfered with gastric secretion. AcF increased the PGE(2) production, and both fractions increased mucus production. l-NAME did not alter the gastroprotection exerted by the fractions, but N-ethylmaleimide attenuated only AcF. In the ischemia/reperfusion model both fractions inhibited the mucosal damage. AcF increased SOD, GSH-Px and GSH-Rd activity, but AqF increased only SOD and GSH-Px. In the acetic acid-induced ulcer model AcF only accelerated ulcer healing. These results showed that Indigofera truxillensis acted as a gastroprotective agent, stimulating protective factors and antioxidants enzymes.
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Affiliation(s)
- Anderson Luiz-Ferreira
- Department of Biological Sciences, Federal University of Goiás, 75704-020, Catalão, Goiás, Brazil
- Department of Structural and Functional Biology, Biology Institute, Campinas University, 13083-865, Campinas, São Paulo, Brazil; E-Mails: (V.B.); (A.B.A.A.); (E.F.-S.); (A.R.M.S.-B.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +55-64-34415348
| | - Maira Cola
- Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, 13083-887, Campinas, São Paulo, Brazil; E-Mails: (M.C.); (F.M.F.)
| | - Victor Barbastefano
- Department of Structural and Functional Biology, Biology Institute, Campinas University, 13083-865, Campinas, São Paulo, Brazil; E-Mails: (V.B.); (A.B.A.A.); (E.F.-S.); (A.R.M.S.-B.)
| | - Felipe Meira de-Faria
- Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, 13083-887, Campinas, São Paulo, Brazil; E-Mails: (M.C.); (F.M.F.)
| | - Ana Beatriz A. de Almeida
- Department of Structural and Functional Biology, Biology Institute, Campinas University, 13083-865, Campinas, São Paulo, Brazil; E-Mails: (V.B.); (A.B.A.A.); (E.F.-S.); (A.R.M.S.-B.)
| | - Elisângela Farias-Silva
- Department of Structural and Functional Biology, Biology Institute, Campinas University, 13083-865, Campinas, São Paulo, Brazil; E-Mails: (V.B.); (A.B.A.A.); (E.F.-S.); (A.R.M.S.-B.)
| | - Tamara Regina Calvo
- Department of Organic Chemistry, Institute of Chemistry, São Paulo State University, 14800-900, Araraquara, São Paulo, Brazil; E-Mails: (T.R.C.); (W.V.)
| | - Clélia A. Hiruma-Lima
- Department of Physiology, Institute of Biosciences, São Paulo State University, 18618-000, Botucatu, São Paulo, Brazil; E-Mail:
| | - Wagner Vilegas
- Department of Organic Chemistry, Institute of Chemistry, São Paulo State University, 14800-900, Araraquara, São Paulo, Brazil; E-Mails: (T.R.C.); (W.V.)
| | - Alba Regina M. Souza-Brito
- Department of Structural and Functional Biology, Biology Institute, Campinas University, 13083-865, Campinas, São Paulo, Brazil; E-Mails: (V.B.); (A.B.A.A.); (E.F.-S.); (A.R.M.S.-B.)
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Luiz-Ferreira A, Cola M, Barbastefano V, Farias-Silva E, Calvo TR, de Almeida ABA, Pellizzon CH, Hiruma-Lima CA, Vilegas W, Souza-Brito ARM. Indigofera suffruticosa Mill as new source of healing agent: involvement of prostaglandin and mucus and heat shock proteins. JOURNAL OF ETHNOPHARMACOLOGY 2011; 137:192-198. [PMID: 21600972 DOI: 10.1016/j.jep.2011.05.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Revised: 05/03/2011] [Accepted: 05/04/2011] [Indexed: 05/30/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Indigofera suffruticosa is specie typical of the "Cerrado" or Brazilian savannah; it is a member of the Fabaceae family - in folkmedicine is used for gastric disorders, infection and inflammation. AIM OF THE STUDY Ethyl acetate fraction (AcF) and aqueous fraction (AqF) of the methanolic extract of I. suffruticosa leaves were evaluated against acute gastric ulcer. The AcF fraction was selected to assess its activity in ulcer healing and its gastroprotective effects via mucus and gastric secretion. MATERIALS AND METHODS The gastroprotective action of AcF and AqF fractions were evaluated in a rodent experimental model. The action mechanisms, involvements of the antisecretory action, mucus and prostaglandin production, toxicological and healing activity of the AcF (100mg/kg, p.o.) were evaluated. We also used histological analysis (HE and PAS) and immunohistochemical (PCNA and HSP-70) assays to evaluate the effects of I. suffruticosa. RESULTS AcF significantly inhibited the gastric mucosal damage caused by ethanol. This effect was statistically significant in 100mg/kg group compared vehicle. AcF did not interfered with gastric secretion, significantly increased the PGE(2) and mucus production (validated in PAS technique). The gastroprotection was attenuated by pretreatment with N-ethylmaleimide, but not L-NAME. In acid-acetic-induced ulcer model AcF accelerated ulcer healing. Immunohistochemistry analysis showed induction of proliferating cell (PCNA) and heat shock protein (HSP 70). CONCLUSIONS These results showed that AcF acted as gastroprotective agent stimulating prostaglandin, mucus and HSP70.
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Affiliation(s)
- Anderson Luiz-Ferreira
- Departamento de Anatomia, Biologia Celular, Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, SP, Brazil.
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Huang XW, Luo RH, Zhao Q, Shen ZZ, Huang LL, An XY, Zhao LJ, Wang J, Huang YZ. Helicobacter pylori induces mitochondrial DNA mutation and reactive oxygen species level in AGS cells. Int J Med Sci 2011; 8:56-67. [PMID: 21234270 PMCID: PMC3020393 DOI: 10.7150/ijms.8.56] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Accepted: 01/01/2011] [Indexed: 01/04/2023] Open
Abstract
To investigate the role of ROS in the helicobacter pylori (Hp) induced mtDNA mutations, AGS cells were treated by extracts of Hp11638 or Hp11638M. The ROS levels, cytochrome C reductions, and intracellular ATP levels were measured. The coding region and the D-Loop region were amplified and sequenced. Results showed the ROS levels, cytochrome C reduction and mtDNA mutations were markedly increased and cell viability decreased after treatment with both Hp extracts, and 616 mutations were detected in D-Loop region and 3 heteroplasmic point mutations in the Cytb gene. No mutations were found in the coding region. The mutation rates of mtDNA D-Loop region were positively correlated with the ROS levels and negatively to the ATP levels.
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Affiliation(s)
- Xue-Wen Huang
- Department of Clinical Laboratory, Huadong Sanatorium, Wuxi, Jiangsu Province 214065, China.
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Al-Howiriny T, Alsheikh A, Alqasoumi S, Al-Yahya M, ElTahir K, Rafatullah S. Gastric antiulcer, antisecretory and cytoprotective properties of celery (Apium graveolens) in rats. PHARMACEUTICAL BIOLOGY 2010; 48:786-793. [PMID: 20645778 DOI: 10.3109/13880200903280026] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
In the present investigation, an ethanol extract of celery [Apium graveolens L. (Apiaceae/Umbelliferae)], at doses of 250 and 500 mg/kg body weight, was evaluated for antigastric ulcer activity using various experimental gastric ulcer models in rats. Ulcers were induced by indomethacin, cytodestructive agents (80% ethanol, 0.2 M NaOH and 25% NaCl) and cold restraint stress. Gastric secretory studies were undertaken by using pylorus ligation (Shay rat model). In addition to gastric wall mucus (GWM), non-protein sulfhydryl (NP-SH) and malondialdehyde (MDA) were also estimated in gastric tissues after 80% ethanol treatment. Pretreatment of celery extract produced dose-dependent reduction in all experimentally induced gastric lesions. Ethanol (80%) decreased the levels of GWM, NP-SH and increase in MDA concentration in gastric tissue. Celery extract showed the ability to significantly replenish the ethanol-induced depleted levels of GWM and gastric mucosal NP-SH. The gastric mucosal MDA level was also significantly lowered in extract pretreated rats. The celery extract showed stomach protection against the models used for ulcerogenesis. Results were further confirmed by using histopathological assessment. The phytochemical screening showed the presence of various chemical constituents such as flavonoids, tannins, volatile oils, alkaloids, sterols and/or triterpenes. Acute toxicity test revealed no deleterious or toxic symptoms or mortality over a period of 14 days. However, the LD(50) was found to be 7.55 g/kg, and showed a large margin of safety. The results suggest that Apium graveolens extract significantly protects the gastric mucosa and suppresses the basal gastric secretion in rats, possibly through its antioxidant potential.
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Affiliation(s)
- Tawfeq Al-Howiriny
- Departments of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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Kushima H, Nishijima CM, Rodrigues CM, Rinaldo D, Sassá MF, Bauab TM, Stasi LCD, Carlos IZ, Brito ARMS, Vilegas W, Hiruma-Lima CA. Davilla elliptica and Davilla nitida: gastroprotective, anti-inflammatory immunomodulatory and anti-Helicobacter pylori action. JOURNAL OF ETHNOPHARMACOLOGY 2009; 123:430-438. [PMID: 19501275 DOI: 10.1016/j.jep.2009.03.031] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2008] [Revised: 03/20/2009] [Accepted: 03/21/2009] [Indexed: 05/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Davilla elliptica and Davilla nitida are species commonly found in the Brazilian Cerrado biome. AIM OF THE STUDY Based on ethnopharmacological and phytochemical analyses, methanolic extracts from leaves of Davilla elliptica (EDE) and Davilla nitida (EDN) were evaluated for their anti-ulcer, anti-inflammatory, immunological and anti-Helicobacter pylori activities. MATERIALS AND METHODS The gastroprotective action of both extracts was evaluated in rodent experimental models (HCl/ethanol, ethanol or NSAID). We also evaluated anti-inflammatory (carrageenin-induced rat hind paw edema), immunomodulatory (murine peritoneal macrophages) and antibacterial action of both extracts against a standard strain of Helicobacter pylori. RESULTS EDE and EDN (500 mg/kg) were able to protect gastric mucosa against HCl/ethanol solution (EDE 63%; EDN 59%), absolute ethanol (EDE 95%; EDN 88%), and also against injurious effect of NSAID (EDE 77%; EDN 67%). When EDE and EDN were challenged with sulfhydryl depleter compound, the gastroprotective action of both extracts was completely abolished. EDE had gastroprotective effect related to increase of glutathione bioavailability and stimulated higher levels of NO, H2O2 and TNF-alpha production. Otherwise EDN showed better anti-Helicobacter pylori action than EDE. Neither extracts presented anti-inflammatory activity by oral route. CONCLUSION The phytochemical investigation showed that both extracts possess phenolic acid derivatives, acylglycoflavonoids and condensed tannins with evident quantitative variations that probably influenced the pharmacological differences between extracts.
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Affiliation(s)
- Hélio Kushima
- Physiology Department, Biosciences Institute, São Paulo State University, C.P. 510, 18618-000 UNESP, Botucatu, SP, Brazil
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Alqasoumi S, Al-Sohaibani M, Al-Howiriny T, Al-Yahya M, Rafatullah S. Rocket “ Eruca sativa”: A salad herb with potential gastric anti-ulcer activity. World J Gastroenterol 2009; 15:1958-65. [PMID: 19399927 PMCID: PMC2675085 DOI: 10.3748/wjg.15.1958] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [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 validate gastric anti-ulcer properties of Rocket “Eruca sativa” on experimentally-induced gastric secretion and ulceration in albino rats.
METHODS: Gastric acid secretion studies were undertaken using pylorus-ligated rats. Gastric lesions in the rats were induced by noxious chemicals including ethanol, strong alkalis, indomethacin and hypothermic restraint stress. The levels of gastric wall mucus (GWM), nonprotein sulfhydryls (NP-SH) and malondialdehyde (MDA) were also measured in the glandular stomach of rats following ethanol administration. The gastric tissue was also examined histologically. The extract was used in two doses (250 and 500 mg/kg body weight) in all experiments.
RESULTS: In pylorus-ligated Shay rats, the ethanolic extract of Rocket “Eruca sativa L.” (EER) significantly and dose-dependently reduced the basal gastric acid secretion, titratable acidity and ruminal ulceration. Rocket extract significantly attenuated gastric ulceration induced by necrotizing agents (80% ethanol, 0.2 mol/L NaOH, 25% NaCl), indomethacin and hypothermic restraint stress. The anti-ulcer effect was further confirmed histologically. On the other hand, the extract significantly replenished GWM and NP-SH levels, as well as the MDA level significantly reduced by extract pretreatment.
CONCLUSION: Rocket extract possesses anti-secretory, cytoprotective, and anti-ulcer activities against experimentally-induced gastric lesions. The anti-ulcer effect is possibly through prostaglandin-mediated activity and/or through its anti-secretory and antioxidant properties.
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Lima ZP, dos Santos RDC, Torres TU, Sannomiya M, Rodrigues CM, dos Santos LC, Pellizzon CH, Rocha LRM, Vilegas W, Souza Brito ARM, Cardoso CRP, Varanda EA, de Moraes HP, Bauab TM, Carli C, Carlos IZ, Hiruma-Lima CA. Byrsonima fagifolia: an integrative study to validate the gastroprotective, healing, antidiarrheal, antimicrobial and mutagenic action. JOURNAL OF ETHNOPHARMACOLOGY 2008; 120:149-160. [PMID: 18761075 DOI: 10.1016/j.jep.2008.07.047] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2008] [Revised: 07/25/2008] [Accepted: 07/31/2008] [Indexed: 05/26/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ethnopharmacological survey indicated leaves of Byrsonima fagifolia Nied. (Malpighiaceae) against gastrointestinal disorders. AIM OF THE STUDY The methanolic extract from the leaves of Byrsonima fagifolia (denominated BF) was evaluated for toxic, mutagenic, gastroprotective, antidiarrheal, antibacterial and immunomodulatory activities. MATERIALS AND METHODS The preventive and healing action of BF against gastric ulcer was evaluated in experimental models in rodents. We evaluated immunomodulatory (by murine peritoneal macrophages), antidiarrheal (by induced diarrhea with castor oil and intestinal motility) and antibacterial action of BF against standard strain of Escherichia coli, Staphylococcus aureus and Helicobacter pylori. The safety of use of BF was also evaluated by mutagenic (Ames assay) and by analyses of toxicity parameters. RESULTS Phytochemical BF profile indicated the presence of phenolic compounds with antioxidant and radical-scavenging properties. BF significantly inhibited gastric lesions induced by ethanol and HCl/ethanol and endogenous mucosal sulphydryl groups (SHs) participated efficaciously in BF gastroprotection. BF blocked development of inflammation process and also has antidiarrheal actions. This extract accelerated the healing of the gastric ulcerated mucosa by stimulating proliferative factors and by increasing production of gastric mucus with no toxic action. The substances responsible for the protective action are concentrated in the ethyl acetate fraction that demonstrated no mutagenic action in vitro. CONCLUSIONS Byrsonima fagifolia presents gastroprotective, healing and antidiarrheal activities supporting previous claims that its traditional use by Brazilians can treat these gastrointestinal ailments.
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Affiliation(s)
- Zeila Pinheiro Lima
- São Paulo State University, Departamento de Fisiologia, Instituto de Biociências, cp 610, CEP 18618-000, UNESP, Botucatu, SP, Brazil
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Chitcholtan K, Hampton MB, Keenan JI. Outer membrane vesicles enhance the carcinogenic potential of Helicobacter pylori. Carcinogenesis 2008; 29:2400-5. [PMID: 18784355 DOI: 10.1093/carcin/bgn218] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Chronic Helicobacter pylori infection is associated with an increased risk of gastric carcinogenesis. These non-invasive bacteria colonize the gastric mucosa and constitutively shed small outer membrane vesicles (OMV). In this study, we investigated the direct effect of H.pylori OMV on cellular events associated with carcinogenesis. We observed increased micronuclei formation in AGS human gastric epithelial cells treated with OMV isolated from a toxigenic H.pylori strain (60190). This effect was absent in OMV from strain 60190v:1 that has a mutant vacA, indicating VacA-dependent micronuclei formation. VacA induces intracellular vacuolation, and reduced acridine orange staining indicated disruption in the integrity of these vacuoles. This was accompanied by an alteration in iron metabolism and glutathione (GSH) loss, suggesting a role for oxidative stress in genomic damage. Increasing intracellular GSH levels with a GSH ester abrogated the VacA-mediated increase in micronuclei formation. In conclusion, OMV-mediated delivery of VacA to the gastric epithelium may constitute a new mechanism for H.pylori-induced gastric carcinogenesis.
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Affiliation(s)
- Kenny Chitcholtan
- Department of Surgery, University of Otago Christchurch, Christchurch, New Zealand
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Affiliation(s)
- Toshiya Hirayama
- Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University
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Hisatsune J, Yamasaki E, Nakayama M, Shirasaka D, Kurazono H, Katagata Y, Inoue H, Han J, Sap J, Yahiro K, Moss J, Hirayama T. Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells. Infect Immun 2007; 75:4472-81. [PMID: 17591797 PMCID: PMC1951161 DOI: 10.1128/iai.00500-07] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E(2) (PGE(2)) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE(2) production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-kappaB or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE(2) production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter.
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Affiliation(s)
- Junzo Hisatsune
- Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 8528523, Japan
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Al Mofleh IA, Alhaider AA, Mossa JS, Al-Soohaibani MO, Rafatullah S. Aqueous suspension of anise “ Pimpinella anisum” protects rats against chemically induced gastric ulcers. World J Gastroenterol 2007; 13:1112-8. [PMID: 17373749 PMCID: PMC4146877 DOI: 10.3748/wjg.v13.i7.1112] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [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 substantiate the claims of Unani and Arabian traditional medicine practitioners on the gastroprotective potential effect of a popular spice anise, “Pimpinella anisum L.” on experimentally-induced gastric ulceration and secretion in rats.
METHODS: Acute gastric ulceration in rats was produced by various noxious chemicals including 80% ethanol, 0.2 mol/L NaOH, 25% NaCl and indomethacin. Anti-secretory studies were undertaken using pylorus-ligated Shay rat technique. Levels of gastric non-protein sulfhydryls (NP-SH) and wall mucus were estimated and gastric tissue was also examined histologically. Anise aqueous suspension was used in two doses (250 and 500 mg/kg body weight) in all experiments.
RESULTS: Anise significantly inhibited gastric mu-cosal damage induced by necrotizing agents and indomethacin. The anti-ulcer effect was further confirmed histologically. In pylorus-ligated Shay rats, anise suspension significantly reduced the basal gastric acid secretion, acidity and completely inhibited the rumenal ulceration. On the other hand, the suspension significantly replenished ethanol-induced depleted levels of gastric mucosal NP-SH and gastric wall mucus concentration.
CONCLUSION: Anise aqueous suspension possesses significant cytoprotective and anti-ulcer activities against experimentally-induced gastric lesions. The anti-ulcer effect of anise is possibly prostaglandin-mediated and/or through its anti-secretory and antioxidative properties.
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Affiliation(s)
- Ibrahim A Al Mofleh
- Department of Medicine, College of Medicine, King Saud University, PO Box 2925 (59), Riyadh 11461, Saudi Arabia.
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Natale G, Lazzeri G, Lubrano V, Colucci R, Vassalle C, Fornai M, Blandizzi C, Del Tacca M. Mechanisms of gastroprotection by lansoprazole pretreatment against experimentally induced injury in rats: role of mucosal oxidative damage and sulfhydryl compounds. Toxicol Appl Pharmacol 2004; 195:62-72. [PMID: 14962506 DOI: 10.1016/j.taap.2003.10.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2003] [Accepted: 10/17/2003] [Indexed: 01/03/2023]
Abstract
This study investigated the mechanisms involved in the protective actions exerted by lansoprazole against experimental gastric injury. Following the intraluminal injection of ethanol-HCl, the histomorphometric analysis of rat gastric sections demonstrated a pattern of mucosal lesions associated with a significant increase in the mucosal contents of malondialdehyde and 8-iso-prostaglandin F(2alpha) (indices of lipid peroxidation), as well as a decrease in the levels of mucosal sulfhydryl compounds, assayed as reduced glutathione (GSH). Pretreatment with lansoprazole 90 micromol/kg, given intraduodenally as single dose or once daily by intragastric route for 8 days, significantly prevented ethanol-HCl-induced gastric damage. The concomitant changes in the mucosal levels of malondialdehyde, 8-iso-prostaglandin F(2alpha) and GSH elicited by ethanol-HCl were also counteracted by lansoprazole. In separate experiments, performed on animals undergoing 2-h pylorus ligation, lansoprazole did not enhance the concentration of prostaglandin E(2), bicyclo-prostaglandin E(2), or nitric oxide (NO) metabolites into gastric juice. Western blot analysis revealed the expression of both type 1 and 2 cyclooxygenase (COX) isoforms in the gastric mucosa of pylorus-ligated rats. These expression patterns were not significantly modified by single-dose or repeated treatment with lansoprazole. Lansoprazole also exhibited direct antioxidant properties by reducing 8-iso-prostaglandin F(2alpha) generation in an in vitro system where human native low-density lipoproteins were subjected to oxidation upon exposure to CuSO(4). The present results suggest that the protective effects of lansoprazole can be ascribed to a reduction of gastric oxidative injury, resulting in an increased bioavailability of mucosal sulfhydryl compounds. It is also proposed that lansoprazole does not exert modulator effects on the gastric expression of COX isoforms as well as on the activity of NO pathways.
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Affiliation(s)
- Gianfranco Natale
- Department of Human Morphology and Applied Biology, University of Pisa, Pisa, Italy
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Naito Y, Yoshikawa T. Molecular and cellular mechanisms involved in Helicobacter pylori-induced inflammation and oxidative stress. Free Radic Biol Med 2002; 33:323-36. [PMID: 12126754 DOI: 10.1016/s0891-5849(02)00868-7] [Citation(s) in RCA: 157] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori (H. pylori)-infection leads to different clinical and pathological outcomes in humans, including chronic gastritis, peptic ulcer disease, and gastric neoplasia. The key determinants of these outcomes are the severity and distribution of the H. pylori-induced inflammation. Antral-type gastritis is associated with excessive acid secretion and a high risk of duodenal ulcer. In contrast, gastritis that involves the acid-secreting corpus region leads to hypochlorhydria, progressive gastric atrophy, and an increased risk of gastric cancer. The key pathophysiological event in H. pylori infection is initiation and continuance of an inflammatory response. Bacteria or their products trigger this inflammatory process and the main mediators are cytokines. Identification of both host- and bacterial-factors that mediate is an intense area of interest in current researches. Recent data indicates that the cag pathogenicity island plays a crucial role in H. pylori-induced gastric inflammation via the activation of gene transcription. It has been demonstrated that oxidative and nitrosative stress associated with inflammation plays an important role in gastric carcinogenesis as a mediator of carcinogenic compound formation, DNA damage, and cell proliferation. Genetic information regulating such stress would be one of the host factors determining the outcome--particularly when the outcome is gastric cancer--of H. pylori infection, and the compound that attenuates such stress may be a candidate for use in chemoprevention. This review highlights recent advances in understanding of the mechanisms underlying chronic inflammation following infection with H. pylori.
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Affiliation(s)
- Yuji Naito
- First Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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