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Tang W, Guan M, Li Z, Pan W, Wang Z. A2BR facilitates the pathogenesis of H. pylori-associated GU by inducing oxidative stress through p38 MAPK phosphorylation. Heliyon 2023; 9:e21004. [PMID: 38027590 PMCID: PMC10660004 DOI: 10.1016/j.heliyon.2023.e21004] [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: 05/19/2023] [Revised: 09/25/2023] [Accepted: 10/12/2023] [Indexed: 12/01/2023] Open
Abstract
Gastric ulcers significantly impact the quality of life of patients, the pathogenesis of which is closely associated with Helicobacter pylori (HP) infection. Oxidative stress is involved in the pathological mechanism of gastric ulcers. Recently, adenosine A2B Receptor (A2BR) was reported to activate the p38MAPK pathway. However, the role of A2BR in gastric ulcers remains unknown. In the present study, the biological function of A2BR in HP-induced gastric ulcers was investigated to explore novel targets for gastric ulcers. GES-1 cells were infected with HP, followed by incubation with 10 μM BAY60-6583 (A2BR agonist) and 25 nM PSB1115 (A2BR antagonist). In HP-infected GES-1 cells, an increased apoptotic rate, enhanced migration ability, excessive release of reactive oxygen species (ROS), increased malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity were observed, accompanied by the activation of p38MAPK signaling, which were dramatically aggravated by BAY60-6583 and alleviated by PSB1115. In animal experiments, rats were treated with 2 mg/kg BAY60-6583 and 10 mg/kg PSB1115, followed by gastric ulcer modeling 30 min later. In HP-infected rats, increased ulcer area, elevated pepsin activity, increased hematoxylin and eosin (HE) pathological scores, increased MDA levels, and decreased SOD activity were observed, which were further aggravated by BAY60-6583 and ameliorated by PSB1115. Finally, the effects of A2BR activation on apoptosis, migration, oxidative stress, and p38MAPK signaling in HP-infected GES-1 cells were reversed by an inhibitor of the p38MAPK pathway. Collectively, A2BR facilitated the pathogenesis of HP-induced gastric ulcers by inducing oxidative stress through p38MAPK activation.
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Affiliation(s)
- Weihong Tang
- Department of Gastroenterology. Hangzhou Children's Hospital, No.195, Wenhui Road, Xiacheng District, Hangzhou, Zhejiang, 310014, China
| | - Minchang Guan
- Department of Pediatrics. Hangzhou Hospital of Traditional Chinese Medicine, No. 1630, Huanding Road, Hangzhou, Zhejiang, 310014, China
| | - Ze Li
- Department of Gastroenterology. Hangzhou Children's Hospital, No.195, Wenhui Road, Xiacheng District, Hangzhou, Zhejiang, 310014, China
| | - Wei Pan
- Department of Gastroenterology. Hangzhou Children's Hospital, No.195, Wenhui Road, Xiacheng District, Hangzhou, Zhejiang, 310014, China
| | - Zhongmin Wang
- Department of Gastroenterology. Hangzhou Children's Hospital, No.195, Wenhui Road, Xiacheng District, Hangzhou, Zhejiang, 310014, China
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Nakayama M, Naito M, Omori K, Ono S, Nakayama K, Ohara N. Porphyromonas gingivalis Gingipains Induce Cyclooxygenase-2 Expression and Prostaglandin E 2 Production via ERK1/2-Activated AP-1 (c-Jun/c-Fos) and IKK/NF-κB p65 Cascades. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1146-1154. [PMID: 35110422 DOI: 10.4049/jimmunol.2100866] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/13/2021] [Indexed: 06/14/2023]
Abstract
Porphyromonas gingivalis is commonly known as one of the major pathogens contributing to periodontitis, and its persistent infection may increase the risk for the disease. The proinflammatory mediators, including IL-6, TNF-α, and cyclooxygenase-2 (COX-2)/PGE2, are closely associated with progression of periodontitis. In this study, we focused on the cysteine protease "gingipains," lysine-specific gingipain, arginine-specific gingipain (Rgp) A, and RgpB, produced by P. gingivalis, and used the wild-type strain and several gene-deletion mutants (rgpA, rgpB, kgp, and fimA) to elucidate the involvement of gingipains in COX-2 expression and PGE2 production. We infected human monocytes, which are THP-1 cells and primary monocytes, with these bacterial strains and found that gingipains were involved in induction of COX-2 expression and PGE2 production. We have shown that the protease activity of gingipains was crucial for these events by using gingipain inhibitors. Furthermore, activation of ERK1/2 and IκB kinase was required for gingipain-induced COX-2 expression/PGE2 production, and these kinases activated two transcription factors, c-Jun/c-Fos (AP-1) and NF-κB p65, respectively. In particular, these data suggest that gingipain-induced c-Fos expression via ERK is essential for AP-1 formation with c-Jun, and activation of AP-1 and NF-κB p65 plays a central role in COX-2 expression/PGE2 production. Thus, we show the (to our knowledge) novel finding that gingipains with the protease activity from P. gingivalis induce COX-2 expression and PGE2 production via activation of MEK/ERK/AP-1 and IκB kinase/NF-κB p65 in human monocytes. Hence it is likely that gingipains closely contribute to the inflammation of periodontal tissues.
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Affiliation(s)
- Masaaki Nakayama
- Department of Oral Microbiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Advanced Research Center for Oral and Craniofacial Sciences, Dental School, Okayama University, Okayama, Japan
| | - Mariko Naito
- Department of Microbiology and Oral Infection, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan; and
| | - Kazuhiro Omori
- Department of Periodontics and Endodontics, Okayama University Hospital, Okayama, Japan
- Advanced Research Center for Oral and Craniofacial Sciences, Dental School, Okayama University, Okayama, Japan
| | - Shintaro Ono
- Department of Periodontics and Endodontics, Okayama University Hospital, Okayama, Japan
| | - Koji Nakayama
- Department of Microbiology and Oral Infection, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan; and
| | - Naoya Ohara
- Department of Oral Microbiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan;
- Advanced Research Center for Oral and Craniofacial Sciences, Dental School, Okayama University, Okayama, Japan
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Ma S, Wu Q, Zhao Z, Xiong J, Niu J, Liu C, Liu T, Chai Y, Qu X, Ma Z, Zhang L, Pu X. Mechanisms of Dendrobium officinale polysaccharides in repairing gastric mucosal injuries based on mitogen-activated protein kinases (MAPK) signaling pathway. Bioengineered 2021; 13:71-82. [PMID: 34898361 PMCID: PMC8805811 DOI: 10.1080/21655979.2021.2006951] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The present study aimed to investigate the protective effects and molecular mechanisms of Dendrobium officinale polysaccharides on gastric mucosal injuries. Following one week of continuous intragastric administration, a gastric mucosal injury model was established using intragastric administration of anhydrous ethanol. The area of gastric ulcer was measured, the contents of interleukin- 6 (IL-6), epidermal growth factor receptor (EGFR), and thyroid transcription factor 1 (TFF-1) in serum were detected by enzyme linked immunosorbent assay (ELISA), and the expressions of EGFR, TFF-1, IL-6, Raf-2, MAP kinase kinase 1 (MEK1), MEK2, and ERK1 in the gastric tissue were determined utilizing qPCR, Western blotting and immunohistochemistry. Simultaneously, Dendrobium officinale polysaccharides and anhydrous ethanol were added to the gastric mucosal cells (GES1) cultured in vitro, and the protective effects of Dendrobium officinale polysaccharides on cell viability was detected using Cell Counting Kit (CCK)-8. The addition of Dendrobium officinale polysaccharides markedly improved the gastric epithelial defect, inflammatory cell infiltration, and redness and swelling stemmed from gastric mucosal injuries and greatly reduced the area of gastric ulcer. The inhibition rates of gastric ulcer were 48.12 ± 2.98, 42.95 ± 1.52, and 27.96 ± 2.05% in the high, medium, and low concentration Dendrobium officinale polysaccharide groups, respectively. Dendrobium officinale polysaccharides could increase the expressions of EGFR and TFF-1 and decrease the expressions of IL-6, Raf-2, MEK1, MEK2, and ERK1. Dendrobium officinale polysaccharides could reduce the level of inflammatory factors and protect gastric mucosa by inhibiting the expression of MAPK pathway genes and proteins.
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Affiliation(s)
- Sibu Ma
- College of Humanities and Management, Guizhou University of Traditional Chinese Medicine, China
| | - Qiong Wu
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, China
| | - Zelin Zhao
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, China
| | - Jiangyan Xiong
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, China
| | - Jianjun Niu
- Dejiang Nation Hospital of Traditional Chinese Medicine, Dejiang County, Tongren City, Guizhou Province, China
| | - Chunyan Liu
- Dejiang Nation Hospital of Traditional Chinese Medicine, Dejiang County, Tongren City, Guizhou Province, China
| | - Tingjiang Liu
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, China
| | - Yihui Chai
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, China
| | - Xiangling Qu
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, China
| | - Zili Ma
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, China
| | - Liyan Zhang
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, China
| | - Xiang Pu
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, China
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Kugler TE, Taradin GG, Pellicano R. The role of <i>Helicobacter pylori</i> in metabolic and cardiovascular diseases. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021:86-95. [DOI: 10.31146/1682-8658-ecg-193-9-86-95] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Helicobacter pylori (H. pylori) infection is one of the most common in the world. More than 50% of the world’s population is infected and infection rates are especially high in countries with poor socio-economic conditions. H. pylori causes gastroduodenal and extra-gastroduodenal diseases including such metabolic disorders as obesity, diabetes mellitus and non-alcoholic fatty liver disease. Recent epidemiological and clinical studies showed that the long-term persistence of H. pylori infection is associated with the development and progression of atherosclerosis and consequently cardiovascular diseases. However, the correlation between these conditions is ambiguous and there is not enough evidence to confirm it. The lack of consensus might be related to differences in diagnostic methods used for H. pylori and the variety of its genotypes. Considering high prevalence of H. pylori infection as well as high incidence of metabolic and cardiovascular diseases, a verified correlation between these can be of great epidemiological, prophylactic and clinical significance.
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Kountouras J, Papaefthymiou A, Polyzos SA, Deretzi G, Vardaka E, Soteriades ES, Tzitiridou-Chatzopoulou M, Gkolfakis P, Karafyllidou K, Doulberis M. Impact of Helicobacter pylori-Related Metabolic Syndrome Parameters on Arterial Hypertension. Microorganisms 2021; 9:microorganisms9112351. [PMID: 34835476 PMCID: PMC8618184 DOI: 10.3390/microorganisms9112351] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/28/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Arterial hypertension is a risk factor for several pathologies, mainly including cardio-cerebrovascular diseases, which rank as leading causes of morbidity and mortality worldwide. Arterial hypertension also constitutes a fundamental component of the metabolic syndrome. Helicobacter pylori infection is one of the most common types of chronic infection globally and displays a plethora of both gastric and extragastric effects. Among other entities, Helicobacter pylori has been implicated in the pathogenesis of the metabolic syndrome. Within this review, we illustrate the current state-of-the-art evidence, which may link several components of the Helicobacter pylori-related metabolic syndrome, including non-alcoholic fatty liver disease and arterial hypertension. In particular, current knowledge of how Helicobacter pylori exerts its virulence through dietary, inflammatory and metabolic pathways will be discussed. Although there is still no causative link between these entities, the emerging evidence from both basic and clinical research supports the proposal that several components of the Helicobacter pylori infection-related metabolic syndrome present an important risk factor in the development of arterial hypertension. The triad of Helicobacter pylori infection, the metabolic syndrome, and hypertension represents a crucial worldwide health problem on a pandemic scale with high morbidity and mortality, like COVID-19, thereby requiring awareness and appropriate management on a global scale.
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Affiliation(s)
- Jannis Kountouras
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (A.P.); (M.T.-C.); (M.D.)
- Correspondence:
| | - Apostolis Papaefthymiou
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (A.P.); (M.T.-C.); (M.D.)
- Department of Gastroenterology, University Hospital of Larisa, 41110 Larisa, Greece
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Stergios A. Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Georgia Deretzi
- Multiple Sclerosis Unit, Department of Neurology, Papageorgiou General Hospital, 56403 Thessaloniki, Greece;
| | - Elisabeth Vardaka
- Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece;
| | - Elpidoforos S. Soteriades
- Healthcare Management Program, School of Economics and Management, Open University of Cyprus, Nicosia 2252, Cyprus;
- Department of Environmental Health, Environmental and Occupational Medicine and Epidemiology (EOME), Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Maria Tzitiridou-Chatzopoulou
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (A.P.); (M.T.-C.); (M.D.)
- School of Healthcare Sciences, Midwifery Department, University of West Macedonia, Koila, 50100 Kozani, Greece
| | - Paraskevas Gkolfakis
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, 1070 Brussels, Belgium;
- Department of Medical Oncology, Institut Jules Bordet, 1000 Brussels, Belgium
| | - Kyriaki Karafyllidou
- Department of Pediatrics, University Children’s Hospital of Zurich, 8032 Zurich, Switzerland;
| | - Michael Doulberis
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (A.P.); (M.T.-C.); (M.D.)
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
- Division of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, 5001 Aarau, Switzerland
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Furuto Y, Kawamura M, Yamashita J, Yoshikawa T, Namikawa A, Isshiki R, Takahashi H, Shibuya Y. Relationship Between Helicobacter pylori Infection and Arteriosclerosis. Int J Gen Med 2021; 14:1533-1540. [PMID: 33935515 PMCID: PMC8079247 DOI: 10.2147/ijgm.s303071] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 04/01/2021] [Indexed: 12/19/2022] Open
Abstract
It is reported that Helicobacter pylori (H. pylori) infection may be linked to non-digestive tract diseases, such as arteriosclerosis including dyslipidemia, diabetes, obesity, hypertension, and cardiovascular disease. Therefore, we reviewed recent studies available in PubMed dealing with the mechanisms of arteriosclerosis due to H. pylori infection and the effects of H. pylori eradication. Conventional studies suggested that H. pylori infection may increase the risk of arteriosclerosis. A large interventional study is required to clarify the causal relationships and the effects of bacterial eradication.
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Affiliation(s)
- Yoshitaka Furuto
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Mariko Kawamura
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Jumpei Yamashita
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Takahiro Yoshikawa
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Akio Namikawa
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Rei Isshiki
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Hiroko Takahashi
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Yuko Shibuya
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
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Park HS, Jeong HY, Kim YS, Seo CS, Ha H, Kwon HJ. Anti-microbial and anti-inflammatory effects of Cheonwangbosim-dan against Helicobacter pylori-induced gastritis. J Vet Sci 2020; 21:e39. [PMID: 32476313 PMCID: PMC7263912 DOI: 10.4142/jvs.2020.21.e39] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/26/2020] [Accepted: 01/26/2020] [Indexed: 12/11/2022] Open
Abstract
Background There are various Helicobacter species colonizing the stomachs of animals. Although Helicobacter species usually cause asymptomatic infection in the hosts, clinical signs can occur due to gastritis associated with Helicobacter in animals. Among them, Helicobacter pylori is strongly associated with chronic gastritis, gastric ulcers, and gastric cancers. As the standard therapies used to treat H. pylori have proven insufficient, alternative options are needed to prevent and eradicate the diseases associated with this bacterium. Cheonwangbosim-dan (CBD), a traditional herbal formula that is popular in East Asia, has been commonly used for arterial or auricular flutter, neurosis, insomnia, and cardiac malfunction-induced disease. Objectives The present study investigated the antimicrobial effect of CBD on H. pylori-infected human gastric carcinoma AGS cells and model mice. Methods AGS cells were infected with H. pylori and treated with a variety of concentrations of CBD or antibiotics. Mice were given 3 oral inoculations with H. pylori and then dosed with CBD (100 or 500 mg/kg) for 4 weeks or with standard antibiotics for 1 week. One week after the last treatment, gastric samples were collected and examined by histopathological analysis, real-time quantitative polymerase chain reaction, and immunoblotting. Results Our results showed that CBD treatment of AGS cells significantly reduced the H. pylori-induced elevations of interleukin-8, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In the animal model, CBD treatment inhibited the colonization of H. pylori and the levels of malondialdehyde, inflammation, proinflammatory cytokines, iNOS, and COX-2 in gastric tissues. CBD also decreased the phosphorylation levels of p38 mitogen-activated protein kinase family. Conclusions This study suggests that CBD might be a prospective candidate for treating H. pylori-induced gastric injury.
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Affiliation(s)
- Hee Seon Park
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
| | - Hye Yun Jeong
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
| | - Young Suk Kim
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
| | - Chang Seob Seo
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea
| | - Hyekyung Ha
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea
| | - Hyo Jung Kwon
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.
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Sumatriptan alleviates radiation-induced oral mucositis in rats by inhibition of NF-kB and ERK activation, prevention of TNF-α and ROS release. Arch Oral Biol 2020; 119:104919. [PMID: 32977152 DOI: 10.1016/j.archoralbio.2020.104919] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 09/05/2020] [Accepted: 09/07/2020] [Indexed: 11/21/2022]
Abstract
OBJECTIVES Oral mucositis caused by radiation therapy is a common problem in cancer patients, especially those with head and neck cancer. Numerous experimental and clinical studies have attempted to find a drug to alleviate oral mucositis. Sumatriptan, is conventionally used to treat migraine attack and cluster headache. Recently, low doses have been shown to have anti-inflammatory properties. In this study we aimed to measure the effect of sumatriptan on experimental radiotherapy-induced oral mucositis. MATERIAL AND METHODS This study evaluates the use of sumatriptan 0.3 and 1 mg/kg in radiation-induced oral mucositis. In order to induce oral mucositis, six rats from each group received 8-Gy of X-ray in a single session. Likewise, three rats from each group received 26-Gy of X-ray. The latter dose of X-ray was used for inducing severe mucositis and apoptosis evaluation by TUNEL assay, while the first dose was used for histopathological and molecular assessments. On 8th day after irradiation, specimens were collected from their tongues for histology, TUNEL and molecular assessments. RESULTS Radiation caused mucosal atrophy, derangement of the tissue and vasodilation. Sumatriptan significantly decreased histopathological score and alleviated mucosal atrophy. As well, there was no evidence of vasodilation in the sumatriptan group. Likewise, sumatriptan decreased the increased level of NF-kB and prevented its activation as well as ERK phosphorylation. In addition, Sumatriptan-treated rats had lower tissue level of TNF-α, reactive oxygen species and fewer apoptotic cells in TUNEL assay. CONCLUSION Based on study results, sumatriptan mitigate radiation-induced oral mucositis by inhibiting NF-kB, ERK and limiting the release of TNF-α, oxidative stress factor and apoptosis.
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Ren Q, Li X, Li Q, Yang H, Wang H, Zhang H, Zhao L, Jiang‐yong S, Meng X, Zhang Y, Shen X. Total flavonoids from sea buckthorn ameliorates lipopolysaccharide/cigarette smoke‐induced airway inflammation. Phytother Res 2019; 33:2102-2117. [PMID: 31209984 DOI: 10.1002/ptr.6404] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 05/01/2019] [Accepted: 05/18/2019] [Indexed: 12/16/2022]
Affiliation(s)
- Qing‐cuo Ren
- College of Ethnic MedicineChengdu University of Traditional Chinese Medicine Chengdu China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University HospitalSichuan University Chengdu China
| | - Xuan‐hao Li
- College of Ethnic MedicineChengdu University of Traditional Chinese Medicine Chengdu China
| | - Qiu‐yue Li
- College of Ethnic MedicineChengdu University of Traditional Chinese Medicine Chengdu China
| | - Hai‐ling Yang
- College of Ethnic MedicineChengdu University of Traditional Chinese Medicine Chengdu China
| | - Hong‐ling Wang
- College of Ethnic MedicineChengdu University of Traditional Chinese Medicine Chengdu China
| | - Hai Zhang
- College of PharmacyChengdu University of Traditional Chinese Medicine Chengdu China
| | - Lin Zhao
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University HospitalSichuan University Chengdu China
| | - Si‐lang Jiang‐yong
- College of Ethnic MedicineChengdu University of Traditional Chinese Medicine Chengdu China
| | - Xian‐li Meng
- College of PharmacyChengdu University of Traditional Chinese Medicine Chengdu China
| | - Yi Zhang
- College of Ethnic MedicineChengdu University of Traditional Chinese Medicine Chengdu China
| | - Xiao‐fei Shen
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University HospitalSichuan University Chengdu China
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Slomiany BL, Slomiany A. Syk: a new target for attenuation of Helicobacter pylori-induced gastric mucosal inflammatory responses. Inflammopharmacology 2019; 27:203-211. [PMID: 30820719 DOI: 10.1007/s10787-019-00577-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 02/19/2019] [Indexed: 02/07/2023]
Abstract
The magnitude of gastric mucosal inflammatory response to H. pylori relies primarily on the extent of its key endotoxin, LPS, engagement of Toll-like receptor-4 (TLR4) and the initiation of signal transduction events converging on mitogen-activated protein kinase (MAPK) and IκB complex (IKK) cascades. These cascades, in turn, exert their control over the assembly of transcription factors, NFκB and AP1, implicated in the induction of the expression of iNOS and COX-2 proinflammatory genes. The LPS-induced TLR4 activation and the ensuing phosphorylation of its intracellular tyrosine domain by Src-family kinases not only leads to recruitment to the cytoplasmic domain of TLR4 of adaptor molecules directly involved in propagation of the signaling cascades converging on MAPK and IKK, but also provides a propitious docking site for a non-receptor tyrosine kinase, spleen tyrosine kinase (Syk), the activation of which apparently leads to upregulation in the expression of proinflammatory genes. Here, we review the pathways engaged by H. pylori in the recruitment and interaction of Syk with TLR4 in gastric mucosa, and discuss the cascades involved in Syk-mediated amplification in proinflammatory signaling. We focus, moreover, on the potential role of drugs targeting Syk and TLR4 in the treatment of H. pylori-related gastric disease.
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Affiliation(s)
- Bronislaw L Slomiany
- Research Center, C855, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA.
| | - Amalia Slomiany
- Research Center, C855, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA
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Zhang LN, Gong WD, Luo J, Yu YJ, Qi SH, Yue ZY. Exogenous ghrelin ameliorates acute lung injury by modulating the nuclear factor κB inhibitor kinase/nuclear factor κB inhibitor/nuclear factor κB pathway after hemorrhagic shock. Int Immunopharmacol 2019; 69:95-102. [PMID: 30690345 DOI: 10.1016/j.intimp.2019.01.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 01/06/2019] [Accepted: 01/10/2019] [Indexed: 01/22/2023]
Abstract
Previous studies have shown that ghrelin, a peptide produced in the stomach, attenuates acute lung injury (ALI) in various animal models, and that some of these effects are associated with inhibition of the nuclear factor κB signaling pathway. This study investigated whether ghrelin exerts beneficial effects on hemorrhagic shock (HS)-induced ALI by modulating nuclear factor κB inhibitor kinase/nuclear factor κB inhibitor/nuclear factor κB (IKK/IκBα/NF-κB) pathway activity. HS was induced in male SD rats by withdrawing blood to a mean arterial pressure (MAP) of 40 mm Hg for 1 h; rats then received ghrelin (10 nmol/kg) or vehicle intravenously and were resuscitated with the shed blood and an equal volume of Ringer lactate solution followed by observation for 2 h. After resuscitation, samples were collected and analyzed for lung histopathology, wet to dry weight ratio (W/D), bronchoalveolar lavage fluid (BALF) protein, neutrophil infiltration, plasma inflammatory cytokines (TNF-α and IL-6), and cytoplasmic phosphorylated IKKβ, IκBα, phosphorylated IκBα and nuclear NF-κB expression. Compared to those in the two sham groups, lung injury, W/D, BALF protein, neutrophil infiltration, plasma TNF-α and IL-6 levels, and IKK/IκBα/NF-κB pathway activation were significantly increased in HS rats. After ghrelin administration, all parameters analyzed were decreased compared to those without ghrelin in HS rats. Moreover, ghrelin alleviated the decreased MAP after resuscitation compared to that in HS rats. Exogenous ghrelin attenuates the inflammatory response and acute lung injury after HS. These beneficial effects appear to be mediated through inhibition of IKK/IκBα/NF-κB signaling.
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Affiliation(s)
- Li-Na Zhang
- Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, 37 Yiyuan Street, Nangang District, Harbin 150001, China
| | - Wei-Dong Gong
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150001, China
| | - Juan Luo
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150001, China
| | - Yong-Jing Yu
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150001, China
| | - Si-Hua Qi
- Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, 37 Yiyuan Street, Nangang District, Harbin 150001, China
| | - Zi-Yong Yue
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150001, China.
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Mechanisms of Antiulcer Effect of an Active Ingredient Group of Modified Xiao Chaihu Decoction. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:5498698. [PMID: 29849711 PMCID: PMC5932449 DOI: 10.1155/2018/5498698] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 02/26/2018] [Accepted: 03/12/2018] [Indexed: 01/30/2023]
Abstract
The present study aimed to investigate the antiulcer activities and mechanisms of action of an active ingredient group (AIG) of Modified Xiao Chaihu Decoction (MXCD). The gastroprotective action of the AIG was studied in ethanol-induced, pylorus ligature-induced, and acetic acid-induced in vivo gastric ulcer models. The enzyme-linked immunoadsorbent assay (tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), and epidermal growth factor (EGF)), nitrate reductase assay (nitric oxide (NO)), western blot analysis (Bax, Bcl-2, cleaved-caspase-3, and cleaved-PARP (poly (ADP-Ribose) polymerase)), histological analysis (HE), and immunohistochemical analysis (HSP-70, p-AKT, and PCNA) were used to evaluate the anti-inflammatory, antiapoptotic, and healing properties of AIG. Numerous mechanisms are involved in the antiulcer activity of AIG, including the increase of PGE2, NO, and EGF content and a reduction in TNF-α levels. The upregulation of HSP-70, p-AKT, and PCNA seems to be directly linked to the healing effect of AIG. Bax, Bcl-2, cleaved-caspase-3, and cleaved-PARP also play a key role in this process. The AIG exerted gastroprotective effects by reducing antisecretory, anti-inflammatory, and antiapoptotic mechanisms. In addition, it promotes cell proliferation. Therefore, activation of the PI3K/AKT signaling pathway may play an important role in cell proliferation.
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Alhasani RH, Biswas L, Tohari AM, Zhou X, Reilly J, He JF, Shu X. Gypenosides protect retinal pigment epithelium cells from oxidative stress. Food Chem Toxicol 2018; 112:76-85. [DOI: 10.1016/j.fct.2017.12.037] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 12/06/2017] [Accepted: 12/19/2017] [Indexed: 02/07/2023]
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Mantero P, Matus GS, Corti RE, Cabanne AM, Zerbetto de Palma GG, Marchesi Olid L, Piskorz MM, Zubillaga MB, Janjetic MA, Goldman CG. Helicobacter pylori and corpus gastric pathology are associated with lower serum ghrelin. World J Gastroenterol 2018; 24:397-407. [PMID: 29391762 PMCID: PMC5776401 DOI: 10.3748/wjg.v24.i3.397] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 11/30/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the association of Helicobacter pylori (H. pylori), cagA genotype, and type of gastric pathology with ghrelin, leptin and nutritional status.
METHODS Fasted dyspeptic adults (18-70 years) referred for an upper digestive endoscopy were enrolled in this cross-sectional study. Height and weight were assessed for body mass index (BMI) calculation. A sociodemographic survey was administered and nutrient intake was evaluated with 24 h dietary recalls. Serum total ghrelin and leptin levels were analyzed by enzyme-linked immunosorbent assay. 13C-Urea Breath Test was performed and four gastric biopsies were obtained during endoscopy for histopathology and H. pylori DNA amplification and genotyping. Data analysis was performed using χ2, Mann-Whitney U, Kruskal-Wallis tests, Spearman’s correlation and linear regression.
RESULTS One hundred and sixty-three patients (40.8 ± 14.0 years), 98/65 females/males, were included. Overall, persistent H. pylori prevalence was 53.4% (95%CI: 45.7%-65.8%). Neither nutrient intake nor BMI differed significantly between H. pylori positive and negative groups. Serum ghrelin was significantly lower in infected patients [median 311.0 pg/mL (IQR 230.0-385.5)] than in uninfected ones [median 355.0 pg/mL (IQR 253.8-547.8)] (P = 0.025), even after adjusting for BMI and gender (P = 0.03). Ghrelin levels tended to be lower in patients carrying cagA positive strains both in the antrum and the corpus; however, differences with those carrying cagA negative strains did not reach statistical significance (P = 0.50 and P = 0.49, respectively). In addition, the type and severity of gastric pathology in the corpus was associated with lower serum ghrelin (P = 0.04), independently of H. pylori status. Conversely, leptin levels did not differ significantly between infected and uninfected patients [median 1.84 ng/mL (0.80-4.85) vs 1.84 ng/mL (0.50-5.09), (P = 0.51)].
CONCLUSION H. pylori infection and severity of gastric corpus pathology are associated with lower serum ghrelin. Further studies could confirm a lower ghrelin prevalence in cagA-positive patients.
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Affiliation(s)
- Paula Mantero
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Física, Buenos Aires C1113AAD, Argentina
| | - Gonzalo Sebastián Matus
- Hospital de Gastroenterología “Dr. Carlos Bonorino Udaondo”, Sección Esófago-Estómago, Buenos Aires C1264AAA, Argentina
| | - Rodolfo Ernesto Corti
- Hospital de Gastroenterología “Dr. Carlos Bonorino Udaondo”, Sección Esófago-Estómago, Buenos Aires C1264AAA, Argentina
| | - Ana María Cabanne
- Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo”, Unidad Patología, Buenos Aires C1264AAA, Argentina
| | - Gerardo Gabriel Zerbetto de Palma
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Física, Buenos Aires C1113AAD, Argentina
- Universidad de Buenos Aires - CONICET, Facultad de Medicina, Instituto de Microbiología y Parasitología Médica (IMPAM), Buenos Aires C1121ABG, Argentina
| | - Liliana Marchesi Olid
- Universidad de Buenos Aires, Facultad de Medicina, Escuela de Nutrición, Buenos Aires C1121ABG, Argentina
| | - María Marta Piskorz
- Hospital de Clínicas “José de San Martín”, División Gastroenterología, Buenos Aires C1120AAR, Argentina
| | - Marcela Beatriz Zubillaga
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Física, Buenos Aires C1113AAD, Argentina
- National Scientific and Technical Research Council (CONICET), Buenos Aires C1425FQB, Argentina
| | - Mariana Andrea Janjetic
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Física, Buenos Aires C1113AAD, Argentina
- Universidad de Buenos Aires, Facultad de Medicina, Escuela de Nutrición, Buenos Aires C1121ABG, Argentina
- National Scientific and Technical Research Council (CONICET), Buenos Aires C1425FQB, Argentina
| | - Cinthia Gabriela Goldman
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Física, Buenos Aires C1113AAD, Argentina
- National Scientific and Technical Research Council (CONICET), Buenos Aires C1425FQB, Argentina
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Helicobacter pylori LPS-induced gastric mucosal spleen tyrosine kinase (Syk) recruitment to TLR4 and activation occurs with the involvement of protein kinase Cδ. Inflammopharmacology 2018; 26:805-815. [PMID: 29353412 DOI: 10.1007/s10787-017-0430-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 11/28/2017] [Indexed: 12/15/2022]
Abstract
Spleen tyrosine kinase (Syk) has emerged recently as a major effector of proinflammatory genes expression induced by LPS-elicited TLR4 activation, and manifested by the up-amplification in the production of inflammatory mediators, including PGE2 and NO. Here, we investigated the nature of factors involved in the recruitment and interaction of Syk with TLR4 in gastric mucosa in response to H. pylori LPS. We show that stimulation of gastric mucosal cells with the LPS leads to localization of Syk with the membrane-associated TLR4 complex and its activation through phosphorylation on Tyr. Furthermore, we reveal that the membrane translocation of Syk upon the LPS stimulation occurs with the involvement of protein kinase Cδ (PKCδ)-mediated phosphorylation of Syk on Ser. Thus, our findings demonstrate that H. pylori LPS-induced up-regulation in Syk activity proceeds through the stage of PKCδ-mediated Syk phosphorylation on Ser, required for its recruitment to the membrane-anchored TLR4, followed by the kinase activation through phosphorylation on Tyr. Hence, the phase of PKCδ-mediated Syk phosphorylation on Ser affects the extent of amplification in gastric mucosal inflammatory response to H. pylori.
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16
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Zhao J, Wen S, Wang X, Zhang Z. Helicobacter pylori modulates cyclooxygenase-2 and 15-hydroxy prostaglandin dehydrogenase in gastric cancer. Oncol Lett 2017; 14:5519-5525. [PMID: 29113180 DOI: 10.3892/ol.2017.6843] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 02/13/2017] [Indexed: 01/05/2023] Open
Abstract
Persistent infection with Helicobacter pylori may contribute to the carcinogenesis of gastric cancer through modulating local prostaglandin E2 (PGE2) levels. Cyclooxygenase-2 (COX-2) and 15-hydroxy prostaglandin dehydrogenase (15-PGDH) are two key enzymes that regulate PGE2 synthesis and inactivation, respectively. The present study was designed to investigate the expression of COX-2 and 15-PGDH in gastric cancer specimens (n=66) in comparison to that of control specimens (n=70) and, furthermore, to semi-quantitatively assess the level of COX-2 and 15-PGDH mRNA and protein in tissues with or without H. pylori infection by reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. It was revealed that COX-2 was expressed in almost all gastric cancer specimens infected with H. pylori (32 out of 33 specimens), but it was also expressed in 2/3 gastric cancers without H. pylori infection (22 out of 33 specimens). By contrast, COX-2 was expressed in <1/6 control subjects regardless of H. pylori infection. Furthermore, 15-PGDH was expressed in control samples but significantly downregulated in gastric cancer specimens. H. pylori infection resulted in slight inhibition of 15-PGDH in control subjects, but significant inhibition of 15-PGDH mRNA expression and protein synthesis in the gastric cancer specimens. These findings indicated that COX-2 and 15-PGDH, the two enzymes that regulate PGE2 levels, were significantly altered in gastric cancer, and that H. pylori may contribute to gastric carcinogenesis through modulating COX-2 and 15-PGDH mRNA expression and protein synthesis.
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Affiliation(s)
- Jianqiu Zhao
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Shujun Wen
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Xingfen Wang
- Department of Pathology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Zhiguang Zhang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
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赵 丽, 冯 志. 幽门螺杆菌感染与心血管疾病. Shijie Huaren Xiaohua Zazhi 2017; 25:1255-1264. [DOI: 10.11569/wcjd.v25.i14.1255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
随着社会经济的发展与生活方式的改变, 心血管疾病的发生率明显上升, 相关的危险因素包括年龄、吸烟、肥胖、糖尿病、高血压和血脂异常等, 但仍有一部分心血管疾病尚未发现确切病因. 近年来, 随着幽门螺杆菌(Helicobacter pylori, H. pylori)研究的不断深入, 发现其与多种胃肠外疾病的发生发展密切相关. 目前国内外多项研究探讨了H. pylori感染与心血管疾病的相关性, 多数研究认为心血管疾病患者H. pylori感染率明显增加, 联合H. pylori根除治疗有益于心血管疾病的防治, 但也有结果并不完全一致. 本文就心血管疾病中H. pylori感染的研究现状, 根除H. pylori对心血管疾病的影响以及H. pylori感染诱导心血管疾病的机制等方面的相关研究作一综述.
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Slomiany BL, Slomiany A. Role of LPS-elicited signaling in triggering gastric mucosal inflammatory responses to H. pylori: modulatory effect of ghrelin. Inflammopharmacology 2017; 25:415-429. [PMID: 28516374 DOI: 10.1007/s10787-017-0360-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 05/05/2017] [Indexed: 12/14/2022]
Abstract
Infection with Helicobacter pylori is a primary culprit in the etiology of gastric disease, and its cell-wall lipopolysaccharide (LPS) is recognized as a potent endotoxin responsible for triggering a pattern of the mucosal inflammatory responses. The engagement by the LPS of gastric mucosal Toll-like receptor 4 (TLR4) leads to initiation of signal transduction events characterized by the activation of mitogen-activated protein kinase (MAPK) cascade, induction of phosphoinositide-specific phospholipase C (PLC)/protein kinase C (PKC)/phosphatidylinositol 3-kinase (PI3K) pathway, and up-regulation in Src/Akt. These signaling events in turn exert their influence over H. pylori-elicited excessive generation of NO and PGE2 caused by the disturbances in nitric oxide synthase and cyclooxygenase isozyme systems, increase in epidermal growth factor receptor transactivation, and the induction in matrix metalloproteinase-9 (MMP-9) release. Interestingly, the extent of gastric mucosal inflammatory response to H. pylori is influenced by a peptide hormone, ghrelin, the action of which relays on the growth hormone secretagogue receptor type 1a (GHS-R1a)-mediated mobilization of G-protein dependent transduction pathways. Yet, the signals triggered by TLR-4 activation as well as those arising through GHS-R1a stimulation converge at MAPK and PLC/PKC/PI3K pathways that form a key integration node for proinflammatory signals generated by H. pylori LPS as well as for those involved in modulation of inflammation by ghrelin. Hence, therapeutic targeting these signals' convergence and integration node could provide a novel and attractive opportunities for developing more effective treatments of H. pylori-related gastric disease.
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Affiliation(s)
- B L Slomiany
- Research Center, C855, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA
| | - A Slomiany
- Research Center, C855, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA.
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19
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Zhu CZ, Liu D, Kang WM, Yu JC, Ma ZQ, Ye X, Li K. Ghrelin and gastrointestinal stromal tumors. World J Gastroenterol 2017; 23:1758-1763. [PMID: 28348480 PMCID: PMC5352915 DOI: 10.3748/wjg.v23.i10.1758] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 11/28/2016] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
Ghrelin, as a kind of multifunctional protein polypeptide, is mainly produced in the fundus of the stomach and can promote occurrence and development of many tumors, including gastrointestinal tumors, which has been proved by the relevant researches. Most gastrointestinal stromal tumors (GISTs, about 80%), as the most common mesenchymal tumor, also develop in the fundus. Scientific research has confirmed that ghrelin, its receptors and mRNA respectively can be found in GISTs, which demonstrated the existence of a ghrelin autocrine/paracrine loop in GIST tissues. However, no reports to date have specified the mechanism whether ghrelin can promote the occurrence and development of GISTs. Studies of pulmonary artery endothelial cells in a low-oxygen environment and cardiac muscle cells in an ischemic environment have shown that ghrelin can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Moreover, some studies of GISTs have confirmed that activation of the PI3K/AKT/mTOR pathway can indeed promote the growth and progression of GISTs. Whether ghrelin is involved in the development or progression of GISTs through certain pathways remains unknown. Can we find a new target for the treatment of GISTs? This review explores and summaries the relationship among ghrelin, the PI3K/AKT/mTOR pathway and the development of GISTs.
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20
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Slomiany BL, Slomiany A. Helicobacter pylori-induced changes in microtubule dynamics conferred by α-tubulin phosphorylation on Ser/Tyr mediate gastric mucosal secretion of matrix metalloproteinase-9 (MMP-9) and its modulation by ghrelin. Inflammopharmacology 2016; 24:197-205. [PMID: 27613723 DOI: 10.1007/s10787-016-0278-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 08/27/2016] [Indexed: 12/18/2022]
Abstract
Regulation of matrix metalloproteinase-9 (MMP-9) secretion in response to proinflammatory challenge remains under a strict control of factors that affect the stability dynamics of the major cytoskeleton polymeric structures, microtubules (MTs). In this study, we report that H. pylori LPS-elicited induction gastric mucosal MMP-9 secretion is accompanied by the enhancement in MT stabilization as evidenced by the increase in α-tubulin acetylation and detyrosination while the modulatory influence of hormone, ghrelin, is associated with MT destabilization and reflected in a decrease in α-tubulin acetylation and detyrosination. Further, we reveal that the LPS-induced enhancement in MT stabilization and up-regulation in MMP-9 secretion as well as the modulatory influence of ghrelin occur with the involvement of PKCδ and SFK. The LPS effect is reflected in a marked increase in PKCδ-mediated α-tubulin phosphorylation on Ser, while the modulatory effect of ghrelin on MT dynamics and MMP-9 secretion is manifested by the SFK-dependent phosphorylation of α-tubulin on Tyr. Moreover, the changes in α-tubulin phosphorylation and MT stabilization dynamics occur in concert with the Golgi recruitment and activation of PKD2 and Arf-GEF. The findings demonstrate that the enhancement in gastric mucosal MMP-9 secretion in response to H. pylori and its modulation by ghrelin are the result of changes in MT dynamics conferred by PKCδ/SFK- mediated α-tubulin Ser/Tyr phosphorylation.
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Affiliation(s)
- B L Slomiany
- Research Center, C875 Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA.
| | - A Slomiany
- Research Center, C875 Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA
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21
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Yu H, Shi L, Qi G, Zhao S, Gao Y, Li Y. Gypenoside Protects Cardiomyocytes against Ischemia-Reperfusion Injury via the Inhibition of Mitogen-Activated Protein Kinase Mediated Nuclear Factor Kappa B Pathway In Vitro and In Vivo. Front Pharmacol 2016; 7:148. [PMID: 27313532 PMCID: PMC4887463 DOI: 10.3389/fphar.2016.00148] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 05/19/2016] [Indexed: 11/13/2022] Open
Abstract
Gypenoside (GP) is the major effective component of Gynostemma pentaphyllum and has been shown to encompass a variety of pharmacological activities. In this study, we investigated whether GP is able to protect cardiomyocytes against injury myocardial ischemia-reperfusion (I/R) injury by using in vitro oxygen-glucose deprivation-reoxygenation (OGD/R) H9c2 cell model and in vivo myocardial I/R rat model. We found that GP pre-treatment alleviated the impairments on the cardiac structure and function in I/R injured rats. Moreover, pre-treatment with GP significantly inhibited IκB-α phosphorylation and nuclear factor (NF)-κB p65 subunit translocation into nuclei. GP and the MAPK pathway inhibitors also reduced the phosphorylation of ERK, JNK, and p38 in vitro. Specific inhibition of ERK, JNK, and p38 increased the cell viability of OGD/R injured cells. Taken together, our data demonstrated that GP protects cardiomyocytes against I/R injury by inhibiting NF-κB p65 activation via the MAPK signaling pathway both in vitro and in vivo. These findings suggest that GP may be a promising agent for the prevention or treatment of myocardial I/R injury.
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Affiliation(s)
- Haijie Yu
- Department of Cardiology, The First Affiliated Hospital of China Medical University Shenyang, China
| | - Liye Shi
- Department of Geriatrics, The First Affiliated Hospital of China Medical University Shenyang, China
| | - Guoxian Qi
- Department of Geriatrics, The First Affiliated Hospital of China Medical University Shenyang, China
| | - Shijie Zhao
- Department of Geriatrics, The First Affiliated Hospital of China Medical University Shenyang, China
| | - Yuan Gao
- Department of Cardiology, The First Affiliated Hospital of China Medical University Shenyang, China
| | - Yuzhe Li
- Department of Cardiology, The First Affiliated Hospital of China Medical University Shenyang, China
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22
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Role of protein kinase D2 phosphorylation on Tyr in modulation by ghrelin of Helicobacter pylori-induced up-regulation in gastric mucosal matrix metalloproteinase-9 (MMP-9) secretion. Inflammopharmacology 2016; 24:119-26. [PMID: 27209313 DOI: 10.1007/s10787-016-0267-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 05/10/2016] [Indexed: 01/26/2023]
Abstract
Matrix metalloproteinas-9 (MMP-9) is a glycosylated endopeptidase associated with host reaction to microbial endotoxins and also characterizes gastric mucosal inflammatory response to H. pylori infection. Here, we report on the factors involved in gastric mucosal MMP-9 secretion in response to H. pylori LPS, and the effect of hormone, ghrelin. We show that both the LPS-elicited induction in MMP-9 secretion and also the modulatory influence of ghrelin occur at the level of MMP-9 processing between the endoplasmic reticulum (ER) and Golgi. Further, we demonstrate that the LPS effect is associated with up-regulation in the activation of Arf1, a small GTPase of the ADP-ribosylation factor family, and the recruitment and phosphorylation of protein kinase D2 (PKD2), involved in the secretory cargo processing in the Golgi. Moreover, we reveal that the LPS-induced up-regulation in MMP-9 secretion is reflected in a marked increase in PKCδ-mediated PKD2 phosphorylation on Ser, while the modulatory effect of ghrelin is manifested by the SFK-PTKs-dependent phosphorylation of PKD2 on Tyr. Thus, our findings demonstrate the role of Arf1/PKD2 in mediation of H. pylori LPS-induced up-regulation in gastric mucosal MMP-9 secretion and suggest the modulatory mechanism of ghrelin action.
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Natarajan K, Abraham P. Methotrexate administration induces differential and selective protein tyrosine nitration and cysteine nitrosylation in the subcellular organelles of the small intestinal mucosa of rats. Chem Biol Interact 2016; 251:45-59. [PMID: 27038877 DOI: 10.1016/j.cbi.2016.03.032] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 03/11/2016] [Accepted: 03/29/2016] [Indexed: 12/26/2022]
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24
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Apaya MK, Lin CY, Chiou CY, Yang CC, Ting CY, Shyur LF. Simvastatin and a Plant Galactolipid Protect Animals from Septic Shock by Regulating Oxylipin Mediator Dynamics through the MAPK-cPLA 2 Signaling Pathway. Mol Med 2016; 21:988-1001. [PMID: 26701313 DOI: 10.2119/molmed.2015.00082] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 12/12/2015] [Indexed: 02/02/2023] Open
Abstract
Sepsis remains a major medical issue despite decades of research. Identification of important inflammatory cascades and key molecular mediators are crucial for developing intervention and prevention strategies. In this study, we conducted a comparative oxylipin metabolomics study to gain a comprehensive picture of lipid mediator dynamics during the initial hyperinflammatory phase of sepsis, and demonstrated, in parallel, the efficacy of simvastatin and plant galactolipid, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG) in the homeostatic regulation of the oxylipin metabolome using a lipopolysaccharide (LPS)-induced sepsis C57BL/6J mouse model. LPS increased the systemic and organ levels of proinflammatory metabolites of linoleic acid including leukotoxin diols (9-,10-DHOME, 12-,13-DHOME) and octadecadienoic acids (9-HODE and 13-HODE) and arachidonic acid-derived prostanoid, PGE2, and hydroxyeicosatetraenoic acids (8-, 12- and 15-HETE). Treatment with either compound decreased the levels of proinflammatory metabolites and elevated proresolution lipoxin A4, 5(6)-EET, 11(12)-EET and 15-deoxy-PGJ2. dLGG and simvastatin ameliorated the effects of LPS-induced mitogen-activated protein kinase (MAPK)-dependent activation of cPLA2, cyclooxygenase-2, lipoxygenase, cytochrome P450 and/or epoxide hydrolase lowered systemic TNF-α and IL-6 levels and aminotransferase activities and decreased organ-specific infiltration of inflammatory leukocytes and macrophages, and septic shock-induced multiple organ damage. Furthermore, both dLGG and simvastatin increased the survival rates in the cecal ligation and puncture (CLP) sepsis model. This study provides new insights into the role of oxylipins in sepsis pathogenesis and highlights the potential of simvastatin and dLGG in sepsis therapy and prevention.
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Affiliation(s)
- Maria Karmella Apaya
- Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan.,Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.,Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan
| | - Chih-Yu Lin
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
| | - Ching-Yi Chiou
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
| | - Chung-Chih Yang
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.,Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Chen-Yun Ting
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
| | - Lie-Fen Shyur
- Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan.,Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.,Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.,Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan
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Helicobacter pylori-elicited induction in gastric mucosal matrix metalloproteinase-9 (MMP-9) release involves ERK-dependent cPLA2 activation and its recruitment to the membrane-localized Rac1/p38 complex. Inflammopharmacology 2016; 24:87-95. [PMID: 26886372 DOI: 10.1007/s10787-016-0261-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 02/04/2016] [Indexed: 01/23/2023]
Abstract
Matrix metalloproteinases (MMPs) are a family of endopeptidases implicated in a wide rage of degenerative and inflammatory diseases, including Helicobacter pylori-associated gastritis, and gastric and duodenal ulcer. As gastric mucosal inflammatory responses to H. pylori are characterized by the rise in MMP-9 production, as well as the induction in mitogen-activated protein kinase (MAPK) and Rac1 activation, we investigated the role of Rac1/MAPK in the processes associated with the release of MMP-9. We show that H. pylori LPS-elicited induction in gastric mucosal MMP-9 release is associated with MAPK, ERK and p38 activation, and occurs with the involvement of Rac1 and cytosolic phospholipase A2 (cPLA2). Further, we demonstrate that the LPS-induced MMP-9 release requires ERK-mediated phosphorylation of cPLA2 on Ser(505) that is essential for its membrane localization with Rac1, and that this process necessitates p38 participation. Moreover, we reveal that the activation and membrane translocation of p38 to the Rac1-GTP complex plays a pivotal role in cPLA2-dependent enhancement in MMP-9 release. Hence, our findings provide a strong evidence for the role of ERK/cPLA2 and Rac1/p38/cPLA2 cascade in H. pylori LPS-induced up-regulation in gastric mucosal MMP-9 release.
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Slomiany BL, Slomiany A. Helicobacter pylori-induced gastric mucosal TGF-α ectodomain shedding and EGFR transactivation involves Rac1/p38 MAPK-dependent TACE activation. Inflammopharmacology 2015; 24:23-31. [PMID: 26658844 DOI: 10.1007/s10787-015-0254-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 11/11/2015] [Indexed: 01/26/2023]
Abstract
Infection of gastric mucosa by H. pylori triggers a pattern of inflammatory responses characterized by the rise in proinflammatory cytokine production, up-regulation in mitogen-activated protein kinase (MAPK) cascade, and the induction in epidermal growth factor receptor (EGFR) activation. In this study, we report on the role of MAPK/p38 and Rac1 in the regulation of H. pylori LPS-induced TGF-α ectodomain shedding and EGFR transactivation. We show that stimulation of gastric mucosal cells with the LPS, reflected in p38 phosphorylation, guanine nucleotide exchange factor Dock180 activation and the rise in Rac1-GTP level, is accompanied by the activation of membrane-associated metalloprotease, (TACE) also known as ADAM17, responsible for soluble TGF-α release. Further, we reveal that the LPS-induced TGF-α shedding and EGFR transactivation involves the TACE activation through phosphorylation by p38 that requires Rac1 participation. Moreover, we demonstrate that up-regulation in H. pylori LPS-elicited Rac1-GTP membrane translocation plays a pivotal role in recruitment of the activated p38 to the membrane for TACE activation through phosphorylation on Thr(735). Taken together, our findings provide strong evidence as to the essential function of Rac1 in TACE activation, TGF-α ectodomain shedding, and the EGFR transactivation.
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Affiliation(s)
- B L Slomiany
- Research Center, C875, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103 2400, USA.
| | - A Slomiany
- Research Center, C875, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103 2400, USA
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Waluga M, Kukla M, Żorniak M, Bacik A, Kotulski R. From the stomach to other organs: Helicobacter pylori and the liver. World J Hepatol 2015; 7:2136-2146. [PMID: 26328025 PMCID: PMC4550868 DOI: 10.4254/wjh.v7.i18.2136] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 07/23/2015] [Accepted: 08/21/2015] [Indexed: 02/06/2023] Open
Abstract
Many recent studies have examined the importance of Helicobacter pylori (H. pylori) infection in the pathogenesis of the diseases outside the stomach and explored the significance of this bacterium in the pathogenesis of some metabolic and cardiovascular diseases. Recent studies have provided evidence that H. pylori is also involved in the pathogenesis of some liver diseases. Many observations have proved that H. pylori infection is important in the development of insulin resistance, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis and cirrhosis. The worsening of liver inflammation of different origins also occurs during H. pylori infection. Some studies have indicated that H. pylori infection induces autoimmunological diseases in the liver and biliary tract. The potential significance of this bacterium in carcinogenesis is unclear, but it is within the scope of interest of many studies. The proposed mechanisms through which H. pylori impacts the development of hepatobiliary diseases are complex and ambiguous. The importance of other Helicobacter species in the development of hepatobiliary diseases is also considered because they could lead to the development of inflammatory, fibrotic and necrotic injuries of the liver and, consequently, to hepatocellular carcinoma. However, many contrary viewpoints indicate that some evidence is not convincing, and further studies of the subject are needed. This review presents the current knowledge about the importance of H. pylori in the pathogenesis of liver and in biliary diseases.
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Regulatory role of guanine nucleotide exchange factor (GEF) Dock180 phosphorylation on Tyr/Ser in mediation of gastric mucosal Rac1 activation in response to Helicobacter pylori and ghrelin. Inflammopharmacology 2015; 23:111-8. [PMID: 25957600 DOI: 10.1007/s10787-015-0235-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 04/28/2015] [Indexed: 01/26/2023]
Abstract
A small GTPase, Rac1, is recognized as an important modulator of the inflammatory responses to bacterial lipopolysaccharide (LPS) by affecting the processes of phospholipase C activation. The activation of Rac1 involves the exchange of GDP for GTP and is catalyzed by the guanine nucleotide exchange factors (GEFs). Here, we report on the gastric mucosal GEF, Dock180, activation in response to H. pylori PS, and the hormone, ghrelin. We show that stimulation of gastric mucosal cells with the LPS leads to up-regulation in Dock180 phosphorylation on Tyr and Ser that is accompanied by a massive rise in Rac1-GTP level, while the effect of ghrelin, manifested by a drop in Dock180 phosphorylation on Ser, is associated with a decrease in Rac1-GTP formation. Furthermore, we demonstrate that phosphorylation on Tyr remains under the control of the Src family protein tyrosine kinases (SFK-PTKs), and is accompanied by Dock180 membrane translocation, while phosphorylation of the membrane-localized Dock180 on Ser represents the stimulatory contribution of protein kinase Cδ (PKCδ) to Dock180 activation. Moreover, we reveal that the interaction between Dock180 and PKCδ is dependent on Dock180 Tyr phosphorylation as well as the activity of PKCδ. Thus, our findings point to the involvement of PKCδ in the LPS-induced up-regulation of Dock180 activation, and suggest the modulatory mechanism of ghrelin influence on the gastric mucosal inflammatory responses to H. pylori.
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Vijayvergiya R, Vadivelu R. Role of Helicobacter pylori infection in pathogenesis of atherosclerosis. World J Cardiol 2015; 7:134-143. [PMID: 25810813 PMCID: PMC4365310 DOI: 10.4330/wjc.v7.i3.134] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023] Open
Abstract
Though a century old hypothesis, infection as a cause for atherosclerosis is still a debatable issue. Epidemiological and clinical studies had shown a possible association but inhomogeneity in the study population and study methods along with potential confounders have yielded conflicting results. Infection triggers a chronic inflammatory state which along with other mechanisms such as dyslipidemia, hyper-homocysteinemia, hypercoagulability, impaired glucose metabolism and endothelial dysfunction, contribute in pathogenesis of atherosclerosis. Studies have shown a positive relations between Cytotoxic associated gene-A positive strains of Helicobacter pylori and vascular diseases such as coronary artery disease and stroke. Infection mediated genetic modulation is a new emerging theory in this regard. Further large scale studies on infection and atherosclerosis focusing on multiple pathogenetic mechanisms may help in refining our knowledge in this aspect.
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Slomiany BL, Slomiany A. Mechanism of Rac1-induced amplification in gastric mucosal phospholipase Cγ2 activation in response to Helicobacter pylori: modulatory effect of ghrelin. Inflammopharmacology 2015; 23:101-9. [PMID: 25796615 DOI: 10.1007/s10787-015-0231-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 03/04/2015] [Indexed: 12/27/2022]
Abstract
Membrane recruitment followed by targeted phosphorylation of specific Tyr and Ser residues and the interaction with Rac GTPases are the crucial parts of an elaborate mechanism of PLCγ2 activation essential for its role in linking the specific receptor responses to a variety of hormones and bacterial endotoxins with the intended intracellular targets. Here, we explored the involvement of Rac in mediation of PLCγ2 activation associated with gastric mucosal inflammatory responses to H. pylori LPS and the hormone, ghrelin. We show that stimulation of gastric mucosal cells with the LPS leads to the membrane translocation of Rac1 as well as PLCγ2, while the effect of ghrelin is manifested by elevation in the membrane PLCγ2 activation and suppression in Rac1 translocation. However, blocking the LPS-induced Rac1 translocation, while detrimental to the PLCγ2 activation, has no effect on its membrane translocation. We reveal further that PLCγ2, localized in the membrane in association with Rac1 following the LPS stimulation, exhibits a marked increase in phosphorylation on Ser, while the modulatory effect of ghrelin, manifested by a drop in Rac1 translocation, is associated with a distinct decrease in PLCγ2 phosphorylation on Ser. Thus, the results suggest that H. pylori-elicited increase in gastric mucosal PLCγ2 phosphorylation on Ser serves as an essential platform for Rac1 colocalization and amplification in PLCγ2 activation.
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Affiliation(s)
- B L Slomiany
- Research Center C875, Rutgers School of Dental Medicine Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA,
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Role of amplification in phospholipase Cγ2 activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori: effect of ghrelin. Inflammopharmacology 2014; 23:37-45. [PMID: 25362585 DOI: 10.1007/s10787-014-0220-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 10/18/2014] [Indexed: 12/21/2022]
Abstract
Phosphoinositide-specific phospholipase C (PLC) enzymes are crucial elements of signal transduction pathways that provide a common link of communication integrating specific receptor responses to a variety of hormones, growth factors, and bacterial endotoxins with the intended intracellular targets. Here, we examined the involvement of PLC in modulation of gastric mucosal inflammatory responses to Helicobacter pylori LPS by peptide hormone, ghrelin. We show that stimulation of gastric mucosal cells with the LPS leads to the activation and membrane translocation of the γ2 isoform of PLC, phosphorylated on Tyr as well as Ser, while the effect of ghrelin is reflected in the translocation and phosphorylation of membrane-associated PLCγ2 on Tyr mainly. Moreover, we demonstrate that PLCγ2 phosphorylation on Tyr remains under the control of the Src family protein tyrosine kinases (SFK-PTKs), and is intimately linked to PLCγ2 membrane localization, while the LPS-induced phosphorylation of membrane-recruited PLCγ2 on Ser displays dependence on protein kinase Cδ (PKCδ) and leads to the amplification in PLCγ2 activation. Thus, our findings link the extent of H. pylori-elicited gastric mucosal inflammatory involvement to the PKCδ-mediated amplification in PLCγ2 activation through phosphorylation on Ser.
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Slomiany BL, Slomiany A. Modulation of gastric mucosal inflammatory responses to Helicobacter pylori via ghrelin-induced protein kinase Cδ tyrosine phosphorylation. Inflammopharmacology 2014; 22:251-62. [PMID: 24840386 DOI: 10.1007/s10787-014-0206-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 04/29/2014] [Indexed: 12/13/2022]
Abstract
A peptide hormone, ghrelin, plays a key role in modulation of gastric mucosal inflammatory responses to Helicobacter pylori by controlling the activation of constitutive nitric oxide synthase via Src/Akt-dependent phosphorylation that requires phosphatidylinositol 3-kinase (PI3K) participation. Here, we examined the relationship among PI3K; its upstream effector, protein kinase C (PKC); and cSrc. We show that stimulation of gastric mucosal cells with H. pylori LPS leads to the activation and membrane translocation of Ser-phosphorylated PKCδ, while the effect of ghrelin is reflected in the phosphorylation of membrane-associated PKCδ on Tyr. Further, we demonstrate that in response to the LPS-induced PKCδ activation both PI3K and Src show a marked increase in their Ser phosphorylation, while the effect of ghrelin is manifested in the phosphorylation of PI3K and cSrc at Tyr. Moreover, whereas Tyr phosphorylation of PKCδ exhibited susceptibility to cSrc inhibitor (PP2), the inhibitor of PKC (GF109203X) but not that of cSrc (PP2) blocked the Tyr phosphorylation of PI3K, while ghrelin-induced cSrc phosphorylation at Tyr was subject to inhibition by the inhibitors of PKC and PI3K. Thus, our findings stipulate the prerequisite of PKCδ in the activation of PI3K as well as cSrc, and imply that PI3K activation provides an essential platform for ghrelin-induced cSrc activation through autophosphorylation at Tyr(416). We also reveal that ghrelin-elicited up-regulation in PKCδ activation by Tyr phosphorylation shows dependence on cSrc activity.
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Affiliation(s)
- B L Slomiany
- Research Center, C875, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA,
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Role of ghrelin-induced phosphatidylinositol 3-kinase activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori. Inflammopharmacology 2013; 22:169-77. [PMID: 24057979 DOI: 10.1007/s10787-013-0190-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 09/10/2013] [Indexed: 12/14/2022]
Abstract
A peptide hormone, ghrelin, is recognized as an important modulator of gastric mucosal inflammatory responses to Helicobacter pylori through the regulation of Src/Akt-dependent activation of constitutive nitric oxide synthase (cNOS) by phosphorylation. In this study, we report on the role of phosphatidylinositol 3-kinase (PI3K) in the processes of Src/Akt activation in gastric mucosal cells exposed to H. pylori LPS. We demonstrate that cNOS activation through phosphorylation induced by ghrelin is associated with PI3K activation which occurs upstream of cSrc, and that PI3K is required for cSrc activation of Akt. We show further that ghrelin-induced activation of PI3K, as well as that of Src and Akt, was susceptible to suppression by the inhibitors of phospholipase C (U73122) and protein kinase C (BIM). Both these inhibitors also blocked the ghrelin-induced membrane translocation of PI3K and cSrc, whereas the inhibitor of PI3K (LY294002) blocked only the membrane translocation of cSrc. Collectively, our findings suggest that the modulatory influence of ghrelin in countering gastric mucosal responses to H. pylori LPS relies on PI3K activation that depends on PLC/PKC signaling pathway, and that PI3K activity is required for the induction of cSrc/Akt activation.
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