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Sikiric P, Boban Blagaic A, Krezic I, Zizek H, Kalogjera L, Smoday IM, Vukovic V, Oroz K, Chiddenton HM, Buric S, Antunovic M, Gojkovic S, Strbe S, Skocic M, Sikiric S, Milavic M, Beketic Oreskovic L, Kokot A, Koprivanac A, Dobric I, Sever M, Staresinic M, Batelja Vuletic L, Skrtic A, Seiwerth S. From Selye's and Szabo's Cysteamine-Duodenal Ulcer in Rats to Dopamine in the Stomach: Therapy Significance and Possibilities. Pharmaceuticals (Basel) 2023; 16:1699. [PMID: 38139825 PMCID: PMC10748240 DOI: 10.3390/ph16121699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/30/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
We reviewed gastric ulcer healing by dopamine considering several distinctive duodenal key points. Selye and Szabo describe the cysteamine-induced duodenal ulcer in rats as a duodenal stress ulcer in patients. Szabo's cysteamine duodenal ulcer as the dopamine duodenal healing and cysteamine as a dopamine antagonist signifies the dopamine agonists anti-ulcer effect and dopamine antagonists ulcerogenic effect. From these viewpoints, we focused on dopamine and gastric ulcer healing. We mentioned antecedent studies on the dopamine presence in the stomach and gastric juice. Then we reviewed, in the timeline, therapy significance arising from the anti-ulcer potency of the various dopamine agonists, which is highly prevailing over the quite persistent beneficial evidence arising from the various dopamine antagonists. Meanwhile, the beneficial effects of several peptides (i.e., amylin, cholecystokinin, leptin, and stable gastric pentadecapeptide BPC 157, suggested as an acting mediator of the dopamine brain-gut axis) were included in the dopamine gastric ulcer story. We attempt to resolve dopamine agonists/antagonists issue with the dopamine significance in the stress (cysteamine as a prototype of the duodenal stress ulcer), and cytoprotection (cysteamine in small dose as a prototype of the cytoprotective agents; cysteamine duodenal ulcer in gastrectomized rats). Thereby, along with dopamine agonists' beneficial effects, in special circumstances, dopamine antagonists having their own ulcerogenic effect may act as "mild stress (or)" or "small irritant" counteracting subsequent strong alcohol or stress procedure-induced severe lesions in this particular tissue. Finally, in the conclusion, as a new improvement in further therapy, we emphasized the advantages of the dopamine agents' application in lower gastrointestinal tract therapy.
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Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Luka Kalogjera
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Vlasta Vukovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Katarina Oroz
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Helen Marie Chiddenton
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Sara Buric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Marko Antunovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Milena Skocic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (M.M.); (L.B.V.); (S.S.)
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (M.M.); (L.B.V.); (S.S.)
| | - Lidija Beketic Oreskovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
| | - Antun Koprivanac
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Ivan Dobric
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.D.); (M.S.)
| | - Marko Sever
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.D.); (M.S.)
| | - Mario Staresinic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.D.); (M.S.)
| | - Lovorka Batelja Vuletic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (M.M.); (L.B.V.); (S.S.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (M.M.); (L.B.V.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (M.M.); (L.B.V.); (S.S.)
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Hayashi H, Yamakado M, Yamaguchi M, Kozakai T. Leptin and ghrelin expressions in the gastrointestinal tracts of calves and cows. J Vet Med Sci 2020; 82:475-478. [PMID: 32092743 PMCID: PMC7192723 DOI: 10.1292/jvms.19-0680] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
This study aims to investigate and compare the expressions of leptin and ghrelin in the
gastrointestinal tracts of calves and cows. The mRNA expression of leptin in the rumen,
abomasum, and jejunum of calves was significantly higher than that in cows. In both calves
and cows, abomasum ghrelin mRNA expression was significantly higher than that in other
gastrointestinal tracts. In calves, leptin protein expression in the abomasum was the
highest. In addition, leptin protein expression in the abomasum and jejunum of calves was
significantly higher than that in cows. Results indicated that leptin in the abomasum and
jejunum plays an important role during the suckling period in a ruminant.
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Affiliation(s)
- Hideaki Hayashi
- School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan
| | - Mutsumi Yamakado
- School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan
| | - Mana Yamaguchi
- School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan
| | - Takaharu Kozakai
- National Agricultural Research Center for Hokkaido Region, National Agriculture and Food Research Organization, Sapporo, Hokkaido 062-8555, Japan.,Faculty of Education, Art, and Science, Yamagata University, 1-4-12 Kojirakawa-machi, Yamagata-shi, Yamagata 990-8560, Japan
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Zuluaga AM, Silveira A GE, Martìnez A JR. Nitric oxide and malondialdehyde in gastric contents and blood in an equine model of gastric ulcer induced by phenylbutazone. REV COLOMB CIENC PEC 2016. [DOI: 10.17533/udea.rccp.v29n1a05] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Sgambato D, Capuano A, Sullo MG, Miranda A, Federico A, Romano M. Gut-Brain Axis in Gastric Mucosal Damage and Protection. Curr Neuropharmacol 2016; 14:959-966. [PMID: 26903151 PMCID: PMC5333589 DOI: 10.2174/1570159x14666160223120742] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 11/18/2015] [Accepted: 02/07/2016] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND The gut-brain axis plays a potential role in numerous physiological and pathological conditions. Several substances link stomach with central nervous system. In particular, hypothalamo-pituitary-adrenocortical axis, thyrotropinreleasing factor-containing nerve fibers and capsaicin-sensitive nerves are principal mediators of the harmful and protective central nervous system-mediated effects on gastric mucosa. Also, existing evidence indicates that nitric oxide, prostaglandins and calcitonin gene-related peptide play a role as final effectors of gastric protection. METHODS We undertook a structured search of bibliographic databases for peerreviewed research literature with the aim of focusing on the role of gut-brain axis in gastric damage and protection. In particular, we examined manuscripts dealing with the role of steroids, thyrotropin-releasing hormone, prostaglandins, melatonin, hydrogen sulfide and peptides influencing food intake (i.e. leptin, cholecystokinin, peptide YY, central glucagon-like peptide-1, and ghrelin). Also, the role of GABAergic and glutamatergic pathways in gastric mucosal protection have been examined. RESULTS We found and reviewed 61 peer-reviewed papers dealing with the major aspects related to the role of gut brain axis in gastric mucosal damage and protection. CONCLUSIONS A dense neuronal network links stomach with central nervous system and a number of neurotransmitters and peptides functionally and anatomically related to central nervous system play a major role in contributing to gastric mucosal integrity. Exploiting the mechanisms underlying the connection between brain and gut may lead to a better understanding of the pathophysiology of gastric mucosal injury and to an improvement in the prevention and, eventually, management of gastric damage.
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Affiliation(s)
| | | | | | | | | | - Marco Romano
- Address correspondence to this author at the Division of Hepato-Gastroenterology, Department of Clinical and Experimental Medicine, Second University of Naples, Via Pansini 5, 80131 Naples, Italy; Tel: +390815666718; Fax: +390815666714; E-mail:
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Gyires K, Zádori ZS. Brain neuropeptides in gastric mucosal protection. Curr Opin Pharmacol 2014; 19:24-30. [PMID: 24971914 DOI: 10.1016/j.coph.2014.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 05/29/2014] [Accepted: 06/01/2014] [Indexed: 01/15/2023]
Abstract
The centrally induced gastroprotective effect of neuropeptides has been intensively studied. Besides many similarities, however, differences can also be observed in their gastroprotective actions. The gastroprotective dose-response curve proved to be either sigmoid, or bell-shaped. Additional gastrointestinal effects of neuropeptides can contribute to their mucosal protective effect. Part of the neuropeptides induces gastroprotection by peripheral administration as well. Besides vagal nerve the sympathetic nervous system may also be involved in conveying the central effect to the periphery. Better understanding of the complex mechanism of the maintenance of gastric mucosal integrity may result in the development of new strategy to enhance gastric mucosal resistance against injury.
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Affiliation(s)
- Klára Gyires
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, 1089, Budapest, Hungary.
| | - Zoltán S Zádori
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, 1089, Budapest, Hungary
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Júnior FEB, de Oliveira DR, Boligon AA, Athayde ML, Kamdem JP, Macedo GE, da Silva GF, de Menezes IRA, Costa JGM, Coutinho HDM, Kerntopf MR, Posser T. Protective effects of Croton campestris A. St-Hill in different ulcer models in rodents: evidence for the involvement of nitric oxide and prostaglandins. JOURNAL OF ETHNOPHARMACOLOGY 2014; 153:469-477. [PMID: 24625391 DOI: 10.1016/j.jep.2014.03.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 02/17/2014] [Accepted: 03/01/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Croton campestris A. St.-Hill., popularly known as "velame do campo", is a species native from savannah area of Northeast Brazil, which is used by traditional communities in folk medicine for a variety of health problems, especially detoxification, inflammation and gastritis. The present study investigates the possible gastric antiulcer activity of Croton campestris root extract (CCRE) and mechanisms of action underlying this effect. MATERIALS AND METHODS Gastric lesions were induced in mice by ethanol, acidified ethanol and indomethacin. CCRE was previously administered orally in doses ranging from 50 to 750 mg/kg. Stomach lesions were measured. The involvement of Nitric Oxide (NO), prostaglandins (PGEs), ATP-dependent K+ channel and adrenergic receptor was investigated through specific inhibitors. RESULTS CCRE produced significant antiulcer activity against absolute ethanol, acidified ethanol and indomethacin induced gastric lesions. The pretreatment with L-NAME (10 mg/kg, p.o.), an inhibitor of nitric oxide synthesis and indomethacin (10 mg/kg, s.c.), an inhibitor of prostaglandin production, reversed the antiulcer action of CCRE. CONCLUSION Taking together, these results suggest that the antiulcer activity of CCRE is dependent of NO and prostaglandin pathways possibly due to its ability to stimulate the synthesis of NO, and activation of endogenous prostaglandin production. Therefore, the use of CCRE in traditional Brazilian medicine against gastric disorders has a scientific basis.
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Affiliation(s)
- Francisco E B Júnior
- Laboratório de Farmacologia e Química Medicinal, Departamento de Química Biológica, Universidade Regional do Cariri, CE 63100-000, Brazil; Campus São Gabriel, Universidade Federal do Pampa, São Gabriel, Rio Grande do Sul 97300-000, Brazil.
| | - Dayanne R de Oliveira
- Laboratório de Farmacologia e Química Medicinal, Departamento de Química Biológica, Universidade Regional do Cariri, CE 63100-000, Brazil
| | - Aline Augusti Boligon
- Laboratório de Pesquisa em Fitoquímica, Departamento de Farmácia Industrial, Universidade Federal de Santa Maria, Prédio 26, Sala 1115, Santa Maria, CEP 97105-900, Brazil
| | - Margareth Linde Athayde
- Laboratório de Pesquisa em Fitoquímica, Departamento de Farmácia Industrial, Universidade Federal de Santa Maria, Prédio 26, Sala 1115, Santa Maria, CEP 97105-900, Brazil
| | - Jean Paul Kamdem
- Departamento de Química, Programa de Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS 97105-900, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS CEP 90035-003, Brazil
| | | | - Gustavo Felipe da Silva
- Campus São Gabriel, Universidade Federal do Pampa, São Gabriel, Rio Grande do Sul 97300-000, Brazil
| | - Irwin R A de Menezes
- Laboratório de Farmacologia e Química Medicinal, Departamento de Química Biológica, Universidade Regional do Cariri, CE 63100-000, Brazil
| | - José G M Costa
- Laboratório de Farmacologia e Química Medicinal, Departamento de Química Biológica, Universidade Regional do Cariri, CE 63100-000, Brazil
| | - Henrique Douglas Melo Coutinho
- Laboratório de Farmacologia e Química Medicinal, Departamento de Química Biológica, Universidade Regional do Cariri, CE 63100-000, Brazil
| | - Marta R Kerntopf
- Laboratório de Farmacologia e Química Medicinal, Departamento de Química Biológica, Universidade Regional do Cariri, CE 63100-000, Brazil
| | - Thaís Posser
- Campus São Gabriel, Universidade Federal do Pampa, São Gabriel, Rio Grande do Sul 97300-000, Brazil.
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Kenny S, Steele I, Lyons S, Moore AR, Murugesan SV, Tiszlavicz L, Dimaline R, Pritchard DM, Varro A, Dockray GJ. The role of plasminogen activator inhibitor-1 in gastric mucosal protection. Am J Physiol Gastrointest Liver Physiol 2013; 304:G814-22. [PMID: 23494120 PMCID: PMC3652002 DOI: 10.1152/ajpgi.00017.2013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gastric mucosal health is maintained in response to potentially damaging luminal factors. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) disrupt protective mechanisms leading to bleeding and ulceration. The plasminogen activator system has been implicated in fibrinolysis following gastric ulceration, and an inhibitor of this system, plasminogen activator inhibitor (PAI)-1, is expressed in gastric epithelial cells. In Helicobacter pylori-negative patients with normal gastric histology taking aspirin or NSAIDs, we found elevated gastric PAI-1 mRNA abundance compared with controls; the increase in patients on aspirin was independent of whether they were also taking proton pump inhibitors. In the same patients, aspirin tended to lower urokinase plasminogen activator mRNA. Immunohistochemistry indicated PAI-1 localization to epithelial cells. In a model system using MKN45 or AGS-GR cells transfected with a PAI-1 promoter-luciferase reporter construct, we found no evidence for upregulation of PAI-1 expression by indomethacin, and, in fact, cyclooxygenase products such as PGE2 and PGI2 weakly stimulated expression. Increased gastric PAI-1 mRNA was also found in mice following gavage with ethanol or indomethacin, but plasma PAI-1 was unaffected. In PAI-1(-/-) mice, gastric hemorrhagic lesions in response to ethanol or indomethacin were increased compared with C57BL/6 mice. In contrast, in PAI-1-H/Kβ mice in which PAI-1 is overexpressed in parietal cells, there were decreased lesions in response to ethanol and indomethacin. Thus, PAI-1 expression is increased in gastric epithelial cells in response to mucosal irritants such as aspirin and NSAIDs probably via an indirect mechanism, and PAI-1 acts as a local autoregulator to minimize mucosal damage.
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Affiliation(s)
- Susan Kenny
- 1Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Islay Steele
- 1Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Suzanne Lyons
- 1Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Andrew R. Moore
- 1Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Senthil V. Murugesan
- 1Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | | | - Rod Dimaline
- 1Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - D. Mark Pritchard
- 1Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Andrea Varro
- 1Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Graham J. Dockray
- 1Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
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The Role of Cholecystokinin Receptors in the Short-Term Control of Food Intake. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2013; 114:277-316. [DOI: 10.1016/b978-0-12-386933-3.00008-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Santos Cerqueira G, dos Santos e Silva G, Rios Vasconcelos E, Fragoso de Freitas AP, Arcanjo Moura B, Silveira Macedo D, Lopes Souto A, Barbosa Filho JM, de Almeida Leal LK, de Castro Brito GA, Souccar C, de Barros Viana GS. Effects of hecogenin and its possible mechanism of action on experimental models of gastric ulcer in mice. Eur J Pharmacol 2012; 683:260-9. [DOI: 10.1016/j.ejphar.2012.02.043] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 02/18/2012] [Accepted: 02/26/2012] [Indexed: 10/28/2022]
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Baudry C, Reichardt F, Marchix J, Bado A, Schemann M, des Varannes SB, Neunlist M, Moriez R. Diet-induced obesity has neuroprotective effects in murine gastric enteric nervous system: involvement of leptin and glial cell line-derived neurotrophic factor. J Physiol 2011; 590:533-44. [PMID: 22124147 DOI: 10.1113/jphysiol.2011.219717] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Nutritional factors can induce profound neuroplastic changes in the enteric nervous system (ENS), responsible for changes in gastrointestinal (GI) motility. However, long-term effects of a nutritional imbalance leading to obesity, such as Western diet (WD), upon ENS phenotype and control of GI motility remain unknown. Therefore, we investigated the effects of WD-induced obesity (DIO) on ENS phenotype and function as well as factors involved in functional plasticity. Mice were fed with normal diet (ND) or WD for 12 weeks. GI motility was assessed in vivo and ex vivo. Myenteric neurons and glia were analysed with immunohistochemical methods using antibodies against Hu, neuronal nitric oxide synthase (nNOS), Sox-10 and with calcium imaging techniques. Leptin and glial cell line-derived neurotrophic factor (GDNF) were studied using immunohistochemical, biochemical or PCR methods in mice and primary culture of ENS. DIO prevented the age-associated decrease in antral nitrergic neurons observed in ND mice. Nerve stimulation evoked a stronger neuronal Ca(2+) response in WD compared to ND mice. DIO induced an NO-dependent increase in gastric emptying and neuromuscular transmission in the antrum without any change in small intestinal transit. During WD but not ND, a time-dependent increase in leptin and GDNF occurred in the antrum. Finally, we showed that leptin increased GDNF production in the ENS and induced neuroprotective effects mediated in part by GDNF. These results demonstrate that DIO induces neuroplastic changes in the antrum leading to an NO-dependent acceleration of gastric emptying. In addition, DIO induced neuroplasticity in the ENS is likely to involve leptin and GDNF.
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Affiliation(s)
- Charlotte Baudry
- Inserm, U913, Institut F´ed´eratif de Recherche Th´erapeutique, IFR26 Nantes, France
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Bradford EM, Miller ML, Prasad V, Nieman ML, Gawenis LR, Berryman M, Lorenz JN, Tso P, Shull GE. CLIC5 mutant mice are resistant to diet-induced obesity and exhibit gastric hemorrhaging and increased susceptibility to torpor. Am J Physiol Regul Integr Comp Physiol 2010; 298:R1531-42. [PMID: 20357015 DOI: 10.1152/ajpregu.00849.2009] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chloride intracellular channel 5 (CLIC5) and other CLIC isoforms have been implicated in a number of biological processes, but their specific functions are poorly understood. The association of CLIC5 with ezrin and the actin cytoskeleton led us to test its possible involvement in gastric acid secretion. Clic5 mutant mice exhibited only a minor reduction in acid secretion, Clic5 mRNA was expressed at only low levels in stomach, and Clic5 mutant parietal cells were ultrastructurally normal, negating the hypothesis that CLIC5 plays a major role in acid secretion. However, the mutants exhibited gastric hemorrhaging in response to fasting, reduced monocytes and granulocytes suggestive of immune dysfunction, behavioral and social disorders suggestive of neurological dysfunction, and evidence of a previously unidentified metabolic defect. Wild-type and mutant mice were maintained on normal and high-fat diets; plasma levels of various hormones, glucose, and lipids were determined; and body composition was studied by quantitative magnetic resonance imaging. Clic5 mutants were lean, hyperphagic, and highly resistant to diet-induced obesity. Plasma insulin and glucose levels were reduced, and leptin levels were very low; however, plasma triglycerides, cholesterol, phospholipids, and fatty acids were normal. Indirect calorimetry revealed increased peripheral metabolism and greater reliance on carbohydrate metabolism. Because Clic5 mutants were unable to maintain energy reserves, they also exhibited increased susceptibility to fasting-induced torpor, as indicated by telemetric measurements showing episodes of reduced body temperature and heart rate. These data reveal a requirement for CLIC5 in the maintenance of normal systemic energy metabolism.
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Affiliation(s)
- Emily M Bradford
- Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524, USA
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Abstract
The aim of the present review is to synthesise and summarise our recent knowledge on the involvement of cholecystokinin (CCK) and gastrin peptides and their receptors in the control of digestive functions and more generally their role in the field of nutrition in mammals. First, we examined the release of these peptides from the gut, focusing on their molecular forms, the factors regulating their release and the signalling pathways mediating their effects. Second, general physiological effects of CCK and gastrin peptides are described with regard to their specific receptors and the role of CCK on vagal mucosal afferent nerve activities. Local effects of CCK and gastrin in the gut are also reported, including gut development, gastrointestinal motility and control of pancreatic functions through vagal afferent pathways, including NO. Third, some examples of the intervention of the CCK and gastrin peptides are exposed in diseases, taking into account intervention of the classical receptor subtypes (CCK1 and CCK2 receptors) and their heterodimerisation as well as CCK-C receptor subtype. Finally, applications and future challenges are suggested in the nutritional field (performances) and in therapy with regards to the molecular forms or in relation with the type of receptor as well as new techniques to be utilised in detection or in therapy of disease. In conclusion, the present review underlines recent developments in this field: CCK and gastrin peptides and their receptors are the key factor of nutritional aspects; a better understanding of the mechanisms involved may increase the efficiency of the nutritional functions and the treatment of abnormalities under pathological conditions.
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Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage--mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. Mediators Inflamm 2009; 2009:345838. [PMID: 19688109 PMCID: PMC2726438 DOI: 10.1155/2009/345838] [Citation(s) in RCA: 165] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2009] [Accepted: 06/04/2009] [Indexed: 12/14/2022] Open
Abstract
Obesity is an important risk factor for osteoarthritis (OA) in weight-bearing joints, but also in hand joints, pointing to an obesity-related metabolic factor that influences on the pathogenesis of OA. Leptin is an adipokine regulating energy balance, and it has recently been related also to arthritis and inflammation as a proinflammatory factor. In the present paper, the effects of leptin on human OA cartilage were studied. Leptin alone or in combination with IL-1 enhanced the expression of iNOS and COX-2, and production of NO, PGE2, IL-6, and IL-8. The results suggest that the effects of leptin are mediated through activation of transcription factor nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway c-Jun NH2-terminal kinase (JNK). Interestingly, inhibition of leptin-induced NO production with a selective iNOS inhibitor 1400 W inhibited also the production of IL-6, IL-8, and PGE2, and this was reversed by exogenously added NO-donor SNAP, suggesting that the effects of leptin on IL-6, IL-8, and PGE2 production are dependent on NO. These findings support the idea of leptin as a factor enhancing the production of proinflammatory factors in OA cartilage and as an agent contributing to the obesity-associated increased risk for osteoarthritis.
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Yoshizawa N, Yamaguchi H, Yamamoto M, Shimizu N, Furihata C, Tatematsu M, Seto Y, Kaminishi M. Gastric carcinogenesis by N-Methyl-N-nitrosourea is enhanced in db/db diabetic mice. Cancer Sci 2009; 100:1180-5. [PMID: 19432903 PMCID: PMC11158018 DOI: 10.1111/j.1349-7006.2009.01157.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2008] [Revised: 02/25/2009] [Accepted: 03/03/2009] [Indexed: 12/13/2022] Open
Abstract
In 2005, a Japanese epidemiological study showed that increase in plasma glucose levels is a risk factor for gastric cancer. However, no animal model has hitherto shown any association between diabetes mellitus and neoplasia in the stomach. Diabetic (db/db) mice have obese and diabetic phenotypes, including hyperglycemia, because of disruption of the leptin receptor. In the present study, effects of hyperglycemia and/or hyperinsulinemia on the development of proliferative lesions were therefore examined in db/db mice given N-methyl-N-nitrosourea (MNU). A total of 120 mice were assigned to four groups: Group A, 40 db/db mice with MNU; Group B, 40 + /db mice with MNU; Group C, 30 misty (wild-type) mice with MNU; Group D, 10 db/db mice without MNU. MNU was given at 60 ppm in drinking water for 20 weeks. Subgroups of animals were sacrificed at weeks 21 and 30 and blood samples were collected to measure glucose, insulin, leptin, and adiponectin concentrations. The removed stomachs were fixed in formalin, and embedded in paraffin for histological examination and immunohistochemistry. At week 30 in Groups A, B, C and D, hyperplasia was observed in 100, 79, 57, and 0%, and dysplasia in 91, 43, 71, and 0%, respectively. Adenocarcinomas and pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were observed only in Group A, at an incidence of 45%. The serum levels of insulin and leptin were also elevated in Group A. Gastric carcinogenesis by MNU was enhanced in db/db mice, possibly in association with hyperinsulinemia and hyperleptinemia.
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Affiliation(s)
- Nao Yoshizawa
- Department of Gastrointestinal Surgery, The University of Tokyo, Tokyo 113-8655, Japan.
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15
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The effect of intraperitoneal administration of leptin on short-term food intake in rats. Eur J Pharmacol 2008; 580:143-52. [DOI: 10.1016/j.ejphar.2007.10.046] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2007] [Revised: 10/10/2007] [Accepted: 10/16/2007] [Indexed: 11/23/2022]
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Gastroprotective effect of leptin in indomethacin-induced gastric injury. J Biomed Sci 2008; 15:405-12. [PMID: 18181030 DOI: 10.1007/s11373-007-9227-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2007] [Accepted: 12/03/2007] [Indexed: 10/22/2022] Open
Abstract
This study investigated the involvement of neutrophil infiltration, disturbances in nitric oxide (NO) generation and oxidative stress in indomethacin-induced gastric ulcer, and the possible gastroprotective potentials of leptin, known for its angiogenic effect. Male Wistar albino rats (180-220 g) were allocated into a normal control group, ulcer control group (received a single dose of indomethacin 40 mg/kg p.o.) and an ulcer group pretreated with leptin (10 microg/kg i.p. 30 min before ulcer induction). The animals were killed 6 h after indomethacin administration and their gastric juice, serum and mucosal tissue were used for gastric injury evaluation. Indomethacin produced multiple lesions in glandular mucosa, evidenced by marked increase in gastric ulcer index (GUI) accompanied by significant increases in gastric juice acidity, tissue myeloperoxidase (MPO) activity, serum NO and tissue conjugated diene (CD), and marked decreases in tissue NO and glutathione (GSH) as well as glutathione reductase (GR) and superoxide dismutase (SOD) activities, while gastric juice mucin and tissue glutathione peroxidase (GPx) were not affected. Leptin exerted significant gastroprotection as evidenced by significantly decreased GUI and attenuated neutrophil infiltration. Leptin significantly increased mucin and tissue NO, restored GR and SOD activities and up-regulated GPx activity. It failed to affect acidity, serum NO, GSH and CD. These results suggest that leptin confers significant gastroprotection against indomethacin-induced injury through interfering with neutrophil infiltration, NO production and oxidative stress.
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Midha S, Singh S, Sachdev V, Misra A, Garg PK. Leptin and its correlation with exocrine and endocrine pancreatic function in idiopathic chronic pancreatitis: implications for pathophysiology. Pancreas 2007; 35:262-6. [PMID: 17895848 DOI: 10.1097/01.rmr.0000248671.22330.b0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Leptin alters pancreatic exocrine and beta-cell secretion in animal studies. We hypothesized that leptin might be important in the pathogenesis of idiopathic chronic pancreatitis (ICP) and/or the development of diabetes in ICP. METHODS Fifty patients with ICP (25 with diabetes, 25 without diabetes) and 25 healthy controls were included in a prospective, case-control study. Fasting plasma leptin concentration was measured by enzyme-linked immunosorbent assay. Exocrine and endocrine pancreatic functions were assessed by fecal chymotrypsin and serum C-peptide, respectively. Anthropometric parameters and body fat mass (FM) were measured. RESULTS Patients with ICP (mean age, 30 years; 33 men) had significantly lower body mass index (19.5 +/- 2.6 kg/m2) and FM (10.6 +/- 4.2 kg) as compared with controls (body mass index, 21.7 +/- 4.1 kg/m2; FM, 19.0 +/- 16.6 kg; P < 0.01). Fecal chymotrypsin (median, 5.2 [range, 0.3-42.6] U/kg) and C-peptide (median, 1.7 [range, 0.2-9.5] ng/mL) were significantly lower in patients than in controls (12.9 [range, 2.5-33.0] U/kg and 3.5 [range, 0.3-10.3] ng/mL; P < 0.01). Plasma leptin concentration was slightly lower but statistically insignificant in patients with ICP (median, 4.0 [range, 2.0-62.5] ng/mL) as compared with controls (median, 5.0 [range, 2.0-63.0] ng/mL). Patients with and those without diabetes were also comparable with regard to their leptin concentration, pancreatic functions, and anthropometric parameters. CONCLUSIONS Leptin does not seem to have a pathophysiological role in either ICP or the development of diabetes in ICP.
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Affiliation(s)
- Shallu Midha
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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Abstract
AIM: To examine the expression of leptin and its receptor, OB-R, in normal gastric mucosa and neoplasia.
METHODS: By immunohistochemical staining using specific antibodies, we evaluated the expression of leptin and OB-R in 207 gastric carcinomas (100 early and 107 advanced carcinomas) and analyzed their relationship with clinicopathological features.
RESULTS: Both normal gastric epithelium and carcinoma cells expressed a significant level of leptin. In cases with OB-R staining, carcinoma cells showed OB-R-positive expression, but the intensity was weaker than that in normal mucosa. The expression of OB-R showed a significant correlation with the level of leptin expression. The expression levels of both leptin and OB-R tended to increase as the depth of tumor invasion or TMN stage increased (P < 0.01). Lymph node metastasis was detected in 49.5% (47/95) of leptin-strong cases and in 50.5% (48/95) of OB-R-positive cases, and the rate was 33% (37/112) in leptin-weak cases and 17% (19/112) in OB-R-negative cases. Both venous and lymphatic invasion also tended to be observed frequently in positive tumors as compared with negative tumors. Interestingly, in the 96 leptin- or OB-R-positive tumors, hematogenous metastasis was detected preoperatively in 3 (3.1%) patients. In contrast, none of the carcinomas that lacked expression of leptin and OB-R showed hematogenous metastasis.
CONCLUSION: Overexpression of leptin and expression of OB-R may play a positive role in the process of progression in gastric cancer. Functional upregulation of leptin/OB-R may have a positive role in the development and initial phase of progression in gastric cancer.
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Affiliation(s)
- Makoto Ishikawa
- Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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Abstract
Cholecystokinin and gastrin receptors (CCK1R and CCK2R) are G protein-coupled receptors that have been the subject of intensive research in the last 10 years with corresponding advances in the understanding of their functioning and physiology. In this review, we first describe general properties of the receptors, such as the different signaling pathways used to exert short- and long-term effects and the structural data that explain their binding properties, activation, and regulation. We then focus on peripheral cholecystokinin receptors by describing their tissue distribution and physiological actions. Finally, pathophysiological peripheral actions of cholecystokinin receptors and their relevance in clinical disorders are reviewed.
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Affiliation(s)
- Marlène Dufresne
- Institut National de la Santé et de la Recherche Médicale U. 531, Institut Louis Bugnard, Centre Hospitalier Universitaire Rangueil, France
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Konishi N, Otaka M, Odashima M, Jin M, Wada I, Komatsu K, Sato T, Kato S, Matsuhashi T, Watanabe S. Systemic stress increases serum leptin level. J Gastroenterol Hepatol 2006; 21:1099-102. [PMID: 16824059 DOI: 10.1111/j.1440-1746.2006.04132.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIM Leptin, the product of the obese (ob) gene, is a circulating peptide mainly synthesized by adipocytes. Leptin inhibits food intake and decreases body weight. A recent report has suggested that the gastric mucosa is also the source of leptin, and that the stomach leptin also contributes to the regulation of the serum leptin level. The aim of the present study was to investigate the effect of water-immersion stress on serum, stomach and adipose tissue leptin levels to understand the relationship between stress and eating behavior. METHODS Male Sprague-Dawley rats were used in this experiment. The leptin level in the serum, gastric mucosa and adipose tissue was measured using ELISA system before and after the initiation of water-immersion stress. RESULTS The serum leptin level was significantly increased by water-immersion stress. The peak was observed 9 h after the initiation of the stress (P < 0.01). However, the gastric leptin level significantly decreased 6 and 9 h after the stress. The adipose tissue leptin level significantly increased 3 h after the stress. CONCLUSIONS The results suggest that changes in serum leptin levels could be associated with stimulation of leptin secretion from the gastric mucosa and leptin production in the adipose tissue by systemic stress and that leptin might be regulated by stress-related events.
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Affiliation(s)
- Noriaki Konishi
- Department of Internal Medicine, Akita University School of Medicine, Akita, Japan
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Brzozowski T, Konturek PC, Pajdo R, Kwiecień SN, Konturek S, Targosz A, Burnat G, Cieszkowski J, Pawlik WW, Hahn EG. Agonist of peroxisome proliferator-activated receptor gamma (PPAR-gamma): a new compound with potent gastroprotective and ulcer healing properties. Inflammopharmacology 2006; 13:317-30. [PMID: 16259750 DOI: 10.1163/156856005774423908] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Pioglitazone, a specific ligand for peroxisome proliferator-activated receptor gamma (PPAR-gamma), was recently implicated in the control of inflammatory processes and in the modulation of the expression of various cytokines such as tumor necrosis factor alpha (TNF-alpha), but its role in the mechanism of gastric mucosal integrity has not been studied extensively. This study was designed to determine the effect of pioglitazone on gastric mucosal lesions induced in rats by topical application of 100% ethanol and by 3.5 h of water immersion and restraint stress (WRS) with or without pretreatment with indomethacin (5 mg/kg i.p.) to inhibit cyclooxygenase-1 (COX-1) and COX-2 enzyme activities and L-NNA (20 mg/kg i.p.) to suppress nitric oxide (NO)-synthase. In addition, the effect of pioglitazone on ulcer healing in rats with chronic acetic acid ulcers (ulcer area 28 mm2) was determined. Rats were killed 1 h and 3.5 h after ethanol administration or WRS exposure or at day 9 upon ulcer induction, and the number and area of gastric lesions were measured by planimetry, the gastric blood flow (GBF) was determined by H2-gas clearance technique and the mucosal PGE2 generation and gene expression and plasma concentration of TNF-alpha and IL-1beta were also evaluated. Pre-treatment with pioglitazone dose-dependently attenuated gastric lesions induced by 100% ethanol and WRS; the dose reducing these lesions by 50% (ID50) being 10 mg/kg and 7 mg/kg, respectively. The protective effect of pioglitazone was accompanied by the significant rise in the GBF, an increase in PGE2 generation and the significant fall in the plasma TNF-alpha and IL-1beta levels. Strong signals for IL-1beta- and TNF-alpha mRNA were recorded in gastric mucosa exposed to ethanol or WRS, and these effects were significantly decreased by pioglitazone. Indomethacin which suppressed PG generation by about 90%, while augmenting WRS damage, and L-NNA, that suppressed NO-synthase activity, significantly attenuated the protective and hyperaemic activity of this PPAR-gamma ligand. In the chronic study, pioglitazone significantly reduced the area of gastric ulcers on day 9 and significantly raised the GBF at the ulcer margin. The acceleration of ulcer healing by PPAR-gamma ligand was accompanied by a significant increase in the expression of PECAM-1 protein, a marker of angiogenesis. We conclude that (1) pioglitazone exerts a potent gastroprotective and hyperaemic actions on the stomach involving endogenous PG and NO and attenuation of the expression and release of proinflammatory cytokines TNF-alpha and IL-1beta, and (2) PPAR-gamma ligand accelerates ulcer healing, possibly due to the enhancement in angiogenesis at ulcer margin.
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Affiliation(s)
- Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
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Lin T, Sakata H, Ootani A, Fujise T, Tsunada S, Amemori S, Danjo A, Yokoyama F, Sakata Y, Iwakiri R, Toda S, Fujimoto K. Apoptosis in rat jejunal mucosa is regulated partly through the central nervous system, which controls feeding behavior. J Gastroenterol Hepatol 2005; 20:1285-91. [PMID: 16048579 DOI: 10.1111/j.1440-1746.2005.03921.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
AIM The aim of this study was to investigate whether central nervous system-related feeding behavior regulates mucosal apoptosis in rat small intestines. METHODS The test solutions used in this study were an H(1) receptor antagonist (chlorpheniramine maleate), 2-deoxy-D-glucose, leptin, and 1-deoxy-D-glucosamine (2-amino-1,5-anhydro-2-deoxy-D-glucitol). Test solutions were injected into the third cerebroventricles of rats. Feeding behavior and jejunal apoptosis were evaluated both with and without truncal vagotomy. Intestinal apoptosis was evaluated by percentage fragmented DNA, electrophoresis, and TUNEL staining. RESULTS Chlorpheniramine and 2-deoxy-D-glucose elicited feeding, whereas leptin and 1-deoxy-D-glucosamine suppressed feeding. The test solutions, which elicited feeding (0.24 and 24 micromol/rat of chlorpheniramine and 2-deoxy-D-glucose, respectively), suppressed mucosal apoptosis in the rat jejunum 1 h after cerebroventricular infusion. In contrast, the test solutions, which suppressed feeding (8 and 24 micromol/rat of leptin and 1-deoxy-D-glucosamine, respectively), induced jejunal mucosal apoptosis 3 h after infusion. The effects of the test solutions on feeding behavior and changes in apoptosis were not affected by truncal vagotomy. CONCLUSION The central nervous system, which regulates feeding behavior, might control intestinal function through the regulation of intestinal apoptosis.
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Affiliation(s)
- Taisan Lin
- Department of Internal Medicine, Saga Medical School, Nabeshima, Saga 849-8501, Japan
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Cammisotto PG, Renaud C, Gingras D, Delvin E, Levy E, Bendayan M. Endocrine and exocrine secretion of leptin by the gastric mucosa. J Histochem Cytochem 2005; 53:851-60. [PMID: 15995144 DOI: 10.1369/jhc.5a6620.2005] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Leptin is a hormone that plays important roles in nutritional status and in obesity. By means of immunocytochemistry, two populations of leptin-secreting cells were found in the lower half of the gastric mucosa. One consists of numerous large cells located around the gastric pits, the Chief epithelial cells, whereas the second refers to much smaller cells, strongly stained, few in number, and scattered between the gastric pits, the endocrine cells. By double immunostaining, leptin and pepsinogen were colocalized in the Chief cells, whereas the endocrine cells were positive only for leptin. Immunoelectron microscopy showed that leptin is present along the rough endoplasmic reticulum-Golgi-granules secretory pathways of the Chief and endocrine cells. On the other hand, leptin-receptor (long and short forms) immunolabelings, although absent in the gastric epithelial cell plasma membranes, were present in enterocytes at the level of their apical and basolateral membranes. Duodenal, jejunal, and ileal enterocytes displayed similar labelings for the leptin receptor. Thus, exocrine and endocrine secretions of leptin together with the presence of leptin receptors on enterocyte plasma membranes constitute a gastroenteric axis that coordinates the role played by leptin in the digestive tract.
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Affiliation(s)
- Philippe G Cammisotto
- Département de Pathologie et Biologie Cellulaire, Université de Montréal, C.P. 6128, Succursale Centre Ville, Montréal, Québec, Canada H3C 3J7
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Adeyemi EO, Bastaki SA, Chandranath IS, Hasan MY, Fahim M, Adem A. Mechanisms of action of leptin in preventing gastric ulcer. World J Gastroenterol 2005; 11:4154-60. [PMID: 16015682 PMCID: PMC4615435 DOI: 10.3748/wjg.v11.i27.4154] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of leptin (1-20 μg/kg) on acidified ethanol (AE)- and indomethacin (Indo)-induced gastric lesions in rats and compare it with ranitidine, lanso-prazole, and omeprazole and to determine its mechanisms of actions.
METHODS: Gastric ulcers, which were approximately 1 mm in width, formed in the glandular portion of the gastric mucosa produced by oral administration of either AE or Indo were taken as ulcer index. The inhibitory effect of subcutaneous administration of leptin, two proton pump inhibitors (PPIs) lansoprazole and omeprazole, or H2-receptor antagonist ranitidine 30 min before AE or Indo was evaluated. A radioimmunoassay was used to determine the PGE2 concentration in the homogenate of the glandular portion of the stomach. We performed histological study of the glandular stomach for the evaluation of total, acidic, and sulfated mucus content.
RESULTS: Subcutaneous administration of leptin, two PPIs lansoprazole and omeprazole or H2-receptor antagonist ranitidine 30 min before AE or Indo produced a dose-dependent and reproducible inhibition of gastric ulcers (GUs). This inhibition was found to be more potent than other antagonists used. In NG-nitro L-arginine methyl ester (L-NAME)-pretreated animals, the ulcer prevention ability of leptin in AE-induced ulcer was significantly reduced, compared to rats without L-NAME pretreatment. However, the ulcer prevention ability of leptin was not altered by L-NAME treatment in Indo-induced ulcers. Leptin produced a dose-dependent increase in PGE2 level in the gastric glandular tissues. Leptin also increased mucus secretion.
CONCLUSION: The results of the present study show that leptin inhibits GU formation by AE or Indo in a dose-dependent and reproducible manner in rats. The results also suggest that leptin prevents ulcer formation by increasing the activities of the cyclo-oxygenase and/or nitric oxide pathways and by increasing mucus secretion.
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Affiliation(s)
- Edward O Adeyemi
- Department of Internal Medicine, UAE University, Al Ain, United Arab Emirates
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Groeben H, Meier S, Brown RH, O'Donnell CP, Mitzner W, Tankersley CG. The effect of leptin on the ventilatory responseto hyperoxia. Exp Lung Res 2005; 30:559-70. [PMID: 15371092 DOI: 10.1080/01902140490489144] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Leptin-deficient mice show a blunted response to hypercapnia explained by central nervous system effects. The impact of leptin on peripheral chemoreceptor function is unclear. Therefore, 9 mutant (ob/ob) and 9 wild-type (+/+) mice were exposed to room air or 100% oxygen and respiratory rate (RR) and tidal volume (Vt) were measured. Subsequently, ob/ob mice received either leptin or vehicle and measurements were repeated. Compared to baseline, for +/+ mice, RR decreased significantly by 9.4% +/- 3.0% (means +/- SD), whereas Vt remained unchanged. Transition from normoxia to hyperoxia did not change RR and Vt in untreated ob/ob mice, whereas after leptin treatment, RR and Vt decreased significantly. Leptin deficiency abolishes the response to hyperoxia, which is restored by leptin replacement. Thus, leptin seems to be influential for a competent peripheral chemoreceptor function.
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Affiliation(s)
- Harald Groeben
- Department of Anesthesiology and Critical Care Medicine, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
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Bełtowski J, Jochem J, Wójcicka G, Zwirska-Korczala K. Influence of intravenously administered leptin on nitric oxide production, renal hemodynamics and renal function in the rat. REGULATORY PEPTIDES 2004; 120:59-67. [PMID: 15177921 DOI: 10.1016/j.regpep.2004.02.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2004] [Revised: 02/13/2004] [Accepted: 02/19/2004] [Indexed: 10/26/2022]
Abstract
We investigated the effect of leptin on systemic nitric oxide (NO) production, arterial pressure, renal hemodynamics and renal excretory function in the rat. Leptin (1 mg/kg) was injected intravenously and mean arterial pressure (MAP), heart rate (HR), renal blood flow (RBF) and renal cortical blood flow (RCBF), were measured for 210 min after injection. Urine was collected for seven consecutive 30-min periods and blood samples were withdrawn at 15, 45, 75, 105, 135, 165 and 195 min after leptin administration. Leptin had no effect on MAP, HR, RBF, RCBF and creatinine clearance, but increased urine output by 37.8% (0-30 min), 32.4% (31-60 min) and 27.0% (61-90 min), as well as urinary sodium excretion by 175.8% (0-30 min), 136.4% (31-60 min) and 124.2% (61-90 min). In contrast, leptin had no effect on potassium and phosphate excretion. Plasma concentration of NO metabolites, nitrites + nitrates (NOx), increased following leptin injection at 15, 45, 75 and 105 min by 27.7%, 178.1%, 156.4% and 58.7%, respectively. Leptin increased urinary NOx excretion by 241.6% (0-30 min), 552.6% (31-60 min), 430.7% (61-90 min) and 88.9% (91-120 min). This was accompanied by increase in plasma and urinary cyclic GMP. These data indicate that leptin stimulates systemic NO production but has no effect on arterial pressure and renal hemodynamics.
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Affiliation(s)
- Jerzy Bełtowski
- Department of Pathophysiology, Medical University, ul. Jaczewskiego 8 20-090 Lublin, Poland.
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Brzozowski T, Konturek PC, Moran AP, Pajdo R, Kwiecien S, Konturek SJ, Sliwowski Z, Drozdowicz D, Pawlik WW, Hahn EG. Involvement of capsaicin-sensitive afferent nerves and cholecystokinin 2/gastrin receptors in gastroprotection and adaptation of gastric mucosa to Helicobacter pylori-lipopolysaccharide. J Pharmacol Exp Ther 2004; 310:116-25. [PMID: 15024038 DOI: 10.1124/jpet.104.065128] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Lipopolysaccharide (LPS) is one of the virulence factors in the Helicobacter pylori (Hp)-infected stomach, but it remains unknown whether single and prolonged pretreatment with Hp-LPS can affect the course of gastric damage induced by aspirin (ASA). We compared the effects of Hp-LPS with those induced by LPSs isolated from intestinal Bacteroides fragilis, Yersinia enterocolitica, and Campylobacter jejuni applied for 4 days on acute ASA-induced gastric lesions in rats. The area of ASA-induced gastric lesions, gastric blood flow (GBF), expression of mRNA and protein of leptin and plasma leptin, gastrin, interleukin-1beta, and tumor necrosis factor-alpha levels were examined. Single (once) or repeated (five times) i.p. injections of Hp-LPS (1 mg/kg) or intestinal LPSs failed to produce macroscopic gastric damage and did not affect the GBF when compared with vehicle. Hp-LPS injected repeatedly suppressed the gastric acid secretion, up-regulated leptin mRNA and protein, and increased plasma leptin and gastrin levels. Hp-LPS significantly reduced the ASA-induced gastric damage and the accompanying decline in the GBF, and these effects were significantly attenuated by capsaicin denervation and selective antagonism of cholecystokinin-B (CCK2) receptors by RPR-102681 [N-(metoxy-3 phenyl) N-(N-methyl N-phenyl-carbamylmethyl) carbamoylmethyl]-3 ureido]-3 phenyl]-2 propronique] but not by loxiglumide, an antagonist of CCK1 receptors. We conclude that 1) daily application of Hp-LPS enhances gastric mucosal resistance against ASA damage due to the increase of GBF and the expression and release of leptin and gastrin exerting trophic and gastroprotective effects, and 2) this enhanced resistance to ASA damage in Hp-LPS-adapted stomach is mediated by the sensory afferents and specific CCK2/gastrin receptors.
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Affiliation(s)
- Tomasz Brzozowski
- Department of Physiology, Jagiellonian University School of Medicine, Cracow, Poland.
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Utsumi H, Iwakiri R, Wu B, Fujise T, Sakata H, Shimoda R, Amemori S, Tsunada S, Ootani A, Fujimoto K. Intracerebroventricular administration of leptin-induced apoptosis in the rat small intestinal mucosa. Exp Biol Med (Maywood) 2003; 228:1239-44. [PMID: 14610267 DOI: 10.1177/153537020322801022] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The localization of leptin and leptin receptors in the stomach and small intestine has been reported. Their function is still unknown, although leptin is a hormone that regulates appetite and fat-related metabolism. The small intestine is one of the important organs for regulating metabolism. The purpose of the present study was to investigate whether leptin regulates apoptosis in the small intestinal mucosa. Intestinal apoptosis was evaluated by percent fragmented DNA, electrophoresis, TUNEL staining, and western blotting analysis of caspase-3. Mucosal apoptosis in the rat jejunum and ileum was evaluated at 0, 3, 6, 12, and 24 hrs after injection. Rats were tested after ad libitum feeding and 24-hr fasting to exclude the anorectic effect of leptin. Leptin was injected intraperitoneally (ip) at a dose of 200 microg/rat and infused into the rat third cerebroventricle (icv) at a dose of 8 microg/rat. Leptin at a dose of 8 microg/rat significantly induced intestinal apoptosis in the small intestine at 3 and 6 hrs after icv administration in both ad libitum feeding and 24-hr fasted rats. This increase in apoptosis was not attenuated by vagotomy. Intestinal apoptosis increased 12 and 24 hrs after ip injection of leptin at a dose of 200 microg/rat. The peak of the increase in apoptosis in icv rats appeared earlier than that in ip rats. Leptin induced jejunal and ileal mucosal apoptosis in the rat, indicating that leptin might control intestinal function through the regulation of intestinal apoptosis.
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Affiliation(s)
- Hiroyoshi Utsumi
- Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan
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Matyjek R, Herzig KH, Kato S, Zabielski R. Exogenous leptin inhibits the secretion of pancreatic juice via a duodenal CCK1-vagal-dependent mechanism in anaesthetized rats. REGULATORY PEPTIDES 2003; 114:15-20. [PMID: 12763635 DOI: 10.1016/s0167-0115(03)00064-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Leptin originally described as product of the ob gene has been shown to be expressed in various tissues including the gastrointestinal tract. In this study, we investigated the influence of leptin on the secretion of pancreatic juice in biliary-pancreatic duct cannulated anaesthetised rats and in dispersed rat pancreatic acini in vitro. Exogenous leptin was given in boluses intravenously with or without CCK-8 (12 pmol kg(-1) body weight) in the presence or absence pharmacological CCK(1) receptor blockade, cervical vagotomy, and capsaicin pre-treatment. Administration of leptin (0.1, 1 and 10 microg kg(-1) body weight) did not affect the volume of bile and pancreatic juice while the protein and trypsin outputs were reduced in a dose-dependent manner. In the rats, leptin inhibited CCK-8 stimulated protein and trypsin outputs stronger than the basal pancreatic secretion. The inhibition by leptin was abolished by the pharmacological CCK(1) receptor blockade, cervical vagotomy, and capsaicin pre-treatment. In contrast, leptin did not affect basal and CCK-8-stimulated amylase release from the dispersed rat pancreatic acini in vitro. In conclusion, the results of the present study suggest that leptin does not act directly on the rat pancreatic acinar cells but inhibits the secretion of pancreatic enzymes acting indirectly via a neurohormonal CCK-vagal-dependent mechanism.
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Affiliation(s)
- R Matyjek
- The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110 Jablonna, Poland
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Konturek PC, Brzozowski T, Kania J, Kukharsky V, Bazela K, Kwiecien S, Harsch I, Konturek SJ, Hahn EG. Pioglitazone, a Specific Ligand of the Peroxisome Proliferator-Activated Receptor Gamma Reduces Gastric Mucosal Injury Induced by Ischaemia/Reperfusion in Rat. Scand J Gastroenterol 2003; 38:468-476. [PMID: 28443766 DOI: 10.1080/00365520310002904] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear receptor that has been implicated in the control of metabolism and numerous cellular processes, including cell cycle control, carcinogenesis, and inflammation. The present study was designed to investigate the effect of the specific PPARγ ligand, pioglitazone, on the mucosal lesions induced by ischaemia and reperfusion (I/R) in rats. METHODS I/R lesions were induced in Wistar rats by applying a small clamp to the coeliac artery for 30 min (ischaemic phase), followed by the removal of the clamp for 3 h (reperfusion phase). Vehicle (saline) or increasing doses of pioglitazone (2.5, 10, and 30 mg/kg i.g.) were given 30 min before exposure to I/R. The animals were killed immediately after the end of the reperfusion phase (time 0) and at 12 and 24 h after I/R. The area of gastric lesions was measured by planimetry, and the gastric blood flow was determined by the H[Formula: See Text] gas clearance method. The gastric mucosal gene expressions of PPARγ, interleukin-1beta (IL-1β), tumour necrosis factor alpha (TNF-α), leptin, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were examined by RT-PCR. In addition, protein expression of COX-2 and leptin was assessed by Western blot. RESULTS The pretreatment with pioglitazone reduced in a dose-dependent manner the mean lesion area induced by I/R, and this effect was accompanied by a significant increase in the gastric blood flow. The decrease in gastric ulcerations by pioglitazone was also observed 12 and 24 h after the I/R. The PPARγ mRNA was weakly expressed in the intact gastric mucosa, but significantly up-regulated after exposure to I/R at each time interval studied. The expression of IL-1β was not changed significantly after pioglitazone applied i.g. at doses 2.5 and 10 mg/kg, but it was down-regulated at the dose 30 mg/kg. TNFα mRNA was strongly increased after the exposure to I/R, but it was down-regulated after pioglitazone pretreatment. In contrast, both leptin and COX-2 mRNA and protein expression were increased in the gastric mucosa after exposure to I/R. The pretreatment with pioglitazone caused a significant up-regulation of mRNA and protein expression of leptin, reaching its peak at the dose 30 mg/kg i.g. In contrast, COX-2 expression did not change significantly after the 2.5 and 10 mg/kg of pioglitazone, but it significantly decreased after pioglitazone at dose 30 mg/kg given to rats before exposure to I/R. CONCLUSIONS Pioglitazone reduces the acute erosions and deeper gastric lesions induced by I/R. The beneficial effect of this PPARγ ligand on I/R-induced gastric damage may be due to its anti-inflammatory properties, especially to the reduction in TNF-α expression and to up-regulation of leptin mRNA in the gastric mucosa. The inhibition of COX-2 expression by pioglitazone may reflect the anti-inflammatory properties of this compound.
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Affiliation(s)
- P C Konturek
- a Dept. of Medicine I University Erlangen-Nuremberg Erlangen Germany
| | - T Brzozowski
- b Dept. of Physiology Jagiellonian University Medical College Cracow Poland
| | - J Kania
- a Dept. of Medicine I University Erlangen-Nuremberg Erlangen Germany
| | - V Kukharsky
- b Dept. of Physiology Jagiellonian University Medical College Cracow Poland
| | - K Bazela
- a Dept. of Medicine I University Erlangen-Nuremberg Erlangen Germany
| | - S Kwiecien
- b Dept. of Physiology Jagiellonian University Medical College Cracow Poland
| | - I Harsch
- a Dept. of Medicine I University Erlangen-Nuremberg Erlangen Germany
| | - S J Konturek
- b Dept. of Physiology Jagiellonian University Medical College Cracow Poland
| | - E G Hahn
- a Dept. of Medicine I University Erlangen-Nuremberg Erlangen Germany
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Jaworek J, Bonior J, Pierzchalski P, Tomaszewska R, Stachura J, Sendur R, Leja A, Jachimczak B, Konturek PC, Bielański W, Pawlik W, Konturek SJ. Leptin protects the pancreas from damage induced by caerulein overstimulation by modulating cytokine production. Pancreatology 2002; 2:89-99. [PMID: 12123099 DOI: 10.1159/000055897] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recent identification of specific leptin receptors in the pancreas suggests that this peptide may also play some role in this gland. AIM To examine the effect of intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of leptin in rats on caerulein-induced pancreatitis (CIP), pancreatic gene expression of leptin and inflammatory cytokine production. METHODS Caerulein (25 micrograms/kg) was infused subcutaneously into conscious rats over 5 h to produce CIP. Leptin (1, 5, or 10 micrograms/kg) was injected i.p. or i.c.v. 30 min prior to the CIP induction. The plasma level of TNF alpha and IL-4 was determined by ELISA, while plasma leptin was measured by RIA and leptin gene expression in pancreas by RT-PCR. RESULTS CIP was characterized by the usual pancreatic edema, reduction in pancreatic blood flow (PBF) and an increase in serum levels of amylase, TNF alpha and IL-4. Pretreatment with i.p. or i.c.v. leptin of the CIP rats partially reversed the harmful effects of CIP on the pancreas, and reduced pancreatic inflammation and the fall in PBF. This was accompanied by a dose-dependent reduction in serum levels of amylase and TNF alpha, while serum IL-4 in the CIP rats pretreated with leptin rose dose-dependently as compared to control rats with CIP alone. Pretreatment with leptin resulted in the dose-dependent rise in plasma leptin level over that observed in vehicle-treated controls. Leptin mRNA expression in the pancreas was dose-dependently increased after infusion of caerulein. Leptin content in isolated pancreatic acini was also increased dose-dependently by caerulein added to the incubation medium bathing these acini. CONCLUSIONS (1) Exogenous leptin protects the pancreas against damage by CIP; (2) endogenous leptin seems to limit the extend of pancreatic damage, and (3) these protective effects of leptin could be attributed to the reduction in TNF alpha and to the increase in IL-4 production.
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Affiliation(s)
- Jolanta Jaworek
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
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Guilmeau S, Nagain-Domaine C, Buyse M, Tsocas A, Rozé C, Bado A. Modulation of exocrine pancreatic secretion by leptin through CCK(1)-receptors and afferent vagal fibres in the rat. Eur J Pharmacol 2002; 447:99-107. [PMID: 12106809 DOI: 10.1016/s0014-2999(02)01887-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
In this report, we determined whether leptin could modify the exocrine pancreatic secretion of anaesthetized rats in vivo. Intravenous injection of recombinant murine leptin resulted in a time- and dose-dependent stimulation of exocrine pancreatic secretion, maximally observed with 30 nmol/kg of leptin. This stimulation of pancreatic water, bicarbonate, and protein output was abolished by atropine, hexamethonium, L364,718 ([3S(-)-N-(1,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine]), a cholecystokinin CCK(1) receptor antagonist or perivagal capsaicin pretreatment, but unaffected by the CCK(2) receptor antagonist L365,260 ([3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3yl)-N'-(3-methylphenyl)urea]). In addition, the physiological dose of 3 nmol/kg leptin, ineffective per se, potentiated the secretory effect of 45 pmol/kg of cholecystokinin octapeptide (CCK-8) on exocrine pancreatic secretion. Furthermore, intraperitoneal leptin induced a rapid increase in plasma CCK levels in vivo in the rat. In conclusion, exogenous leptin can modulate exocrine pancreatic secretion through mechanisms involving CCK(1) receptors and capsaicin-sensitive afferent fibres in the rat. Whether this may have a physiological relevance in the postprandial regulation of exocrine pancreatic secretion and thus in nutrient digestion will require further investigations.
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Affiliation(s)
- Sandra Guilmeau
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 410, IFR 02 Claude Bernard, Faculté de Médecine Xavier Bichat, 16 Rue H. Huchard, BP 416, 75870 Cedex 18, Paris, France
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Abstract
Hyperphagia (overeating) is often associated with energy over-storage and obesity, which may lead to a myriad of serious health problems, including heart disease, hypertension, and type 2 diabetes. Thus, understanding the complex pathological mechanisms underlying hyperphagia and obesity has an important clinical significance. Leptin, or ob protein, is a key element in the long-term regulation of food intake and body weight homeostasis. It circulates in the blood at levels correlated with body fat mass. Leptin binds to specific receptors in the hypothalamus to mediate events that regulate feeding behavior. In light of new evidence, the initial view that leptin is an adipocyte-derived signal, which acts centrally to decrease body weight, has been modified. It has been shown that leptin may also have specific functions in the gastrointestinal tract, suggesting that feeding and energy homeostasis is regulated by both central and peripheral signals. Evidence supports the view that leptin integrates short-term, meal-related signals from the gut into long-term regulation of energy balance. In addition, the gastric leptin level is altered by the nutritional state and the administration of cholecystokinin. This commentary aims to review the evidence of the role of leptin as a peripherally acting signal in the gut in the regulation of nutrient intake, adiposity, and body weight. Based on currently available data, some potential future studies are suggested.
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Affiliation(s)
- Anoja S Attele
- Department of Anesthesia and Critical Care, The University of Chicago, 5841 S. Maryland Avenue, MC 4028, Chicago, IL 60637, USA
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Konturek PC, Jaworek J, Maniatoglou A, Bonior J, Meixner H, Konturek SJ, Hahn EG. Leptin modulates the inflammatory response in acute pancreatitis. Digestion 2002; 65:149-60. [PMID: 12138320 DOI: 10.1159/000064935] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Leptin is a pleiotropic hormone that is involved in the regulation of food intake and body weight. Recent findings demonstrated that leptin receptors are present in the pancreas but the involvement of leptin in pancreatitis remains unknown. The aim of the present study was: (1) to assess plasma leptin levels in rats with caerulein-induced pancreatitis (CIP) and humans with acute pancreatitis; and (2) to determine the effects of exogenous leptin on the course of acute CIP in rats. METHODS CIP was produced in Wistar rats by s.c. infusion of 5 microg of caerulein for 5 h. Plasma leptin was measured by specific RIA and leptin expression in the pancreas was determined at the transcriptional and protein levels. In addition, the effects of exogenous leptin at the doses of 1 or 10 microg/kg i.p. on the course of CIP and the plasma levels and mRNA expression in pancreas of cytokines TNFalpha and IL-4 were studied. Furthermore, pancreatic cNOS and iNOS expression at mRNA level were measured in rats with CIP and pretreated with leptin. Parallel to these studies, the plasma levels of leptin were measured in 15 patients with acute edematous pancreatitis and in 30 healthy controls of comparable age and body mass index. RESULTS In rats, plasma leptin rose significantly from the median of 0.14 (0.03-0.3 ng/ml) in the control group to 0.56 (0.2-3.2 ng/ml) in rats with CIP. The CIP was associated with an upregulation of mRNA and protein for leptin in the pancreas. The administration of exogenous leptin significantly reduced the weight of pancreas, histological manifestations of pancreatitis, plasma TNFalpha and mRNA expression for iNOS in the pancreatic tissue. The assessment of leptin plasma level in humans demonstrated significantly higher median values of plasma leptin in patients with acute pancreatitis [7.5 (4.3-18.4 ng/ml)] than in healthy controls [2.1 (1.0-11.8 ng/ml)]. CONCLUSIONS (1) Acute pancreatitis in rats and in humans is associated with a marked increase in the plasma level of leptin. (2) The transcriptional upregulation of leptin in the pancreas after induction of pancreatitis indicates that the inflamed pancreas could be the source of local production of leptin. (3) Exogenous leptin protects the pancreas against development of acute CIP in rats and one possible mechanism of action of leptin might be attributed to the activation of nitric oxide pathway.
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Affiliation(s)
- P C Konturek
- First Department of Medicine, University Erlangen-Nuremberg, Erlangen, Germany.
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Chapter 11 Gut regulatory peptides and hormones of the small intestine. ACTA ACUST UNITED AC 2002. [DOI: 10.1016/s1877-1823(09)70127-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Goïot H, Attoub S, Kermorgant S, Laigneau JP, Lardeux B, Lehy T, Lewin MJ, Bado A. Antral mucosa expresses functional leptin receptors coupled to STAT-3 signaling, which is involved in the control of gastric secretions in the rat. Gastroenterology 2001; 121:1417-27. [PMID: 11729121 DOI: 10.1053/gast.2001.29581] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Leptin is a circulating hormone that communicates the peripheral nutritional status to the hypothalamus, which controls food intake, energy expenditure, and body weight. This study characterizes leptin receptors and leptin-sensitive STAT proteins in the antrum and investigates the effects of leptin on gastric secretions. METHODS The effects of leptin on gastrin messenger RNA (mRNA), plasma gastrin, gastric acid in vivo in the rat, and on somatostatin and gastrin secretions by isolated antral cells were determined in vitro. Leptin receptors were investigated in isolated rat antral cells by reverse transcription-polymerase chain reaction and binding of [(125)I]-leptin studies. The effects of in vivo and in vitro leptin on transduction signal STAT proteins were investigated by immunoblotting antral extracts. RESULTS Peripheral injection of leptin inhibited in a dose-dependent manner, basal gastric secretion, gastrinemia, and mucosal gastrin mRNA in vivo. mRNAs encoding the long (Ob-Rb) and short (Ob-Ra) receptor forms were detected in rat antral mucosa, as were STAT-1, -3, and -5b immunoreactive proteins. Isolated antral cells specifically bound [(125)I]-leptin, and addition of leptin to these cells inhibited the release of somatostatin and increased the release of gastrin. These effects were associated with an increase in nuclear STAT-3 proteins in vitro and in vivo. CONCLUSIONS This study provides the first molecular evidence for the coexpression of leptin receptors and STAT-3 in antral mucosa. It provides further evidence for the involvement of leptin in the control of gastric secretions.
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Affiliation(s)
- H Goïot
- INSERM Unité 410, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 75870 Paris Cedex 18, France
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Gröschl M, Rauh M, Wagner R, Neuhuber W, Metzler M, Tamgüney G, Zenk J, Schoof E, Dörr HG, Blum WF, Rascher W, Dötsch J. Identification of leptin in human saliva. J Clin Endocrinol Metab 2001; 86:5234-9. [PMID: 11701683 DOI: 10.1210/jcem.86.11.7998] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Leptin is produced predominantly in adipose tissue but has recently also been found in gastric mucosa. It has been shown that the oral application of leptin induces neuronal activity in the brain stem of rodents. The objective of the present study was to identify this hormone in human saliva and to examine the production and stability of salivary leptin. We have demonstrated production of leptin in salivary glands and oral mucosa by RT-PCR, its storage by immunocytochemistry, and the release of the peptide by RIA. Chromatographic analysis and immunoblotting confirmed the identity of leptin. There is a strong linear correlation (r2 = 0.78) between leptin concentrations from simultaneously collected saliva and plasma samples (n = 61). Stimulation of saliva flow increases total leptin secretion up to 3-fold (P < 0.001). As to the stability of leptin in gastric fluid, we found the peptide was not degraded above pH 3.5. Additionally, salivary leptin remains stable up to 5 d at 4 C. With regard to the presence of leptin receptors in gastric mucosa, we suggest salivary leptin as being a possible ligand for gastric leptin receptors. Furthermore, the determination of leptin in saliva allows for noninvasive sample collection.
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Affiliation(s)
- M Gröschl
- Klinik mit Poliklinik für Kinder und Jugendliche, Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
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Calatayud S, Barrachina D, Esplugues JV. Nitric oxide: relation to integrity, injury, and healing of the gastric mucosa. Microsc Res Tech 2001; 53:325-35. [PMID: 11376493 DOI: 10.1002/jemt.1100] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Nitric oxide (NO) plays a multifaceted role in mucosal integrity. The numerous functions of NO and the double-edged role played by NO in most of them provide a great complexity to the NO action. The three enzymatic sources of NO, neuronal NO-synthase (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), have been characterised in the gastrointestinal tract. The protective properties of the NO derived from constitutive NO-synthases (eNOS and nNOS) have already been well established. Less clear is the role assigned to iNOS. The simplistic initial view of low levels of NO synthesised by constitutive NOS being protective while exaggerated NO levels after iNOS induction leading irremediably to cytotoxicity is being questioned by new evidence. As initially reported for constitutive NOS, iNOS activity may be associated to reduced leukocyte-endothelium interaction and platelet aggregation as well as protection of mucosal microcirculation. Moreover, iNOS activity may be important to resolve inflammation by increasing apoptosis in inflammatory cells. It is entirely possible that a low level of expression of iNOS will reflect a positive host-defense response to challenge, but that exaggerated or uncontrolled expression of iNOS itself becomes detrimental. There is no doubt about the protective role of NO in physiological conditions. However, when the mucosa is threatened, the role of NO becomes multiple and the final effect will probably depend on the nature of the insult, the environment involved, and the interaction with other mediators.
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Affiliation(s)
- S Calatayud
- Departmento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
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40
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Abstract
The recent discovery of gastric leptin has initiated several investigations on the possible role of leptin in digestive physiology. The following clues are currently suggested: leptin might control meal size in cooperation with Cholecystokinin, help cytoprotection of the gastric mucosa, play a role in gut inflammatory processes, regulate secretion of gastric hormones such as gastrin and somatostatin, and modulate intestinal transport of small peptides. The present review is a brief survey of the most significant advances in these issues.
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Affiliation(s)
- M J Lewin
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 410, Paris, France.
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Brzozowski T, Konturek PC, Konturek SJ, Pierzchalski P, Bielanski W, Pajdo R, Drozdowicz D, Kwiecień S, Hahn EG. Central leptin and cholecystokinin in gastroprotection against ethanol-induced damage. Digestion 2001; 62:126-42. [PMID: 11025360 DOI: 10.1159/000007805] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Leptin, a product of the ob gene controlling food intake, has recently been detected in the stomach and shown to be released by cholecystokinin (CCK) and to induce gastroprotection against various noxious agents, but it is not known whether centrally applied leptin influences gastric secretion and mucosal integrity. AIMS In this study we compared the effects of leptin and CCK-8 applied intracerebroventricularly (i.c.v.) on gastric secretion and gastric mucosal lesions induced by topical application of 75% ethanol. METHODS Several major series of Wistar rats were used in this study. The effects of leptin or CCK applied i.c.v. on gastric secretion were examined using conscious rats with gastric fistulas. For the studies on gastroprotection the following series of rats were used to determine the effects of: (A) leptin and CCK applied centrally on this protection and the blockade of CCK(A) with loxiglumide (30 mg/kg i.p.) and CCK(B) receptors with RPR 102681 (30 mg/kg i.p.); (B) cutting of vagal nerves; (C) inactivation of sensory nerves by capsaicin (125 mg/kg s.c.); (D) inhibition of calcitonin gene-related peptide (CGRP) receptors with CGRP(8-37) (100 microg/kg i.p.), and (E) suppression of nitric oxide synthase (NOS) with N(G)-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg i.v. ) on ethanol-induced gastric lesions in rats with or without the i.c.v. pretreatment with leptin or CCK-8. Rats were anesthetized 1 h after ethanol administration to measure the gastric blood flow (GBF) and then to determine the area of gastric lesions by planimetry. Blood was withdrawn for the measurement of plasma leptin and gastrin levels by radioimmunoassay and gastric biopsy samples were collected for the determination of cNOS and iNOS mRNA by RT-PCR. RESULTS Leptin and CCK-8 (0.01-5 microg/kg i.c.v.) dose dependently attenuated gastric lesions induced by 75% ethanol; the doses reducing these lesions by 50% (ED(50)) were 0.8 and 1.2 microg/kg, respectively. The protective effects of leptin and CCK-8 applied i.c. v. were accompanied by a significant rise in plasma leptin level and an increase in GBF. Blockade of CCK(A) receptors with loxiglumide abolished the protective and hyperemic effects of CCK but not those of leptin, while RPR 10268, a specific antagonist of CCK(B) receptors, counteracted leptin-induced protection and the rise in the GBF but failed to influence those afforded by CCK-8. For comparison, pretreatment with peripheral CCK-8 or leptin (10 microg/kg i.p.) causing a similar rise in the plasma leptin level also significantly reduced gastric lesions induced by 75% ethanol. The protective and hyperemic effects of centrally administered leptin were abolished by vagotomy, producing a fall in plasma leptin levels, and significantly attenuated by sensory denervation with capsaicin, by pretreatment with the CGRP antagonist, CGRP(8-37), or with L-NAME. A strong signal for iNOS mRNA was recorded in the gastric mucosa of leptin- and CCK-8-treated animals, whereas cNOS mRNA was unaffected. CONCLUSIONS (1) Central leptin exerts a potent gastroprotective action at a dose that has no influence on gastric secretion; (2) this protection depends upon CCK(B) receptors, vagal activity and sensory nerves, and involves hyperemia probably mediated by NO, and (3) leptin mimics the gastroprotective effect of CCK and may be implicated in the protective and hyperemic actions of this peptide on the rat stomach.
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Affiliation(s)
- T Brzozowski
- Department of Physiology, Jagiellonian University School of Medicine, Cracow, Poland
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Konturek PC, Brzozowski T, Sulekova Z, Brzozowska I, Duda A, Meixner H, Hahn EG, Konturek SJ. Role of leptin in ulcer healing. Eur J Pharmacol 2001; 414:87-97. [PMID: 11230999 DOI: 10.1016/s0014-2999(01)00748-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Leptin was shown to exhibit similar to cholecystokinin (CCK) cytoprotective activity against acute gastric lesions, but its role in ulcer healing has not been examined. The aims of this study were: (1) to compare the effects of exogenous leptin to those of CCK on the course of healing of chronic gastric ulcers; (2) to study the gene and protein expression of leptin at the ulcer margin during ulcer healing; and (3) to assess the effects of leptin administration on the mucosal gene expression of main growth factor such as transforming growth factor alpha (TGFalpha). Gastric ulcers were produced in rats by the acetic acid method. Rats with ulcers were divided in following treatment groups: (1) vehicle; (2) leptin (10 microg/kg i.p.); (3) CCK (10 microg/kg s.c.); and (4) leptin or CCK with or without tyrphostin A46 (200 microg/kg i.p.), an inhibitor of epidermal growth factor (EGF)-receptor tyrosine kinase or NG-nitro-L-arginine (20 mg/kg i.g.), a blocker of nitric oxide synthase. Animals were euthanized 9 days after ulcer induction. The area of gastric ulcers and the gastric blood flow at the ulcer area were determined. In addition, mucosal biopsy samples were taken from the ulcer area for histological evaluation as well as for the determination of mRNA and protein expression for leptin and constitutive nitric oxide synthase (cNOS) and inducibile nitric oxide synthase (iNOS) by reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot, respectively. In addition, the gene expression for TGFalpha was analyzed by RT-PCR. Both leptin and CCK reduced significantly the ulcer area as compared to vehicle-treated group by approximately 50%. The treatment with tyrphostin or N(G)-nitro-L-arginine reversed in part the acceleration of ulcer healing by leptin and CCK. The expression of leptin mRNA and protein was significantly increased at the ulcer edge. The leptin-induced acceleration of ulcer healing was associated with increased expression of transcripts for TGFalpha as well as increased mRNA and protein expression for cNOS and iNOS at the ulcer margin. We conclude that leptin accelerates ulcer healing by mechanisms involving the up-regulation of TGFalpha and increased production of nitric oxide due to up-regulation of cNOS and iNOS in the ulcer area.
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Affiliation(s)
- P C Konturek
- Department of Medicine I, University Erlangen-Nuremberg, Krankenhausstr. 12, D-91054, Erlangen, Germany.
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Konturek PC, Konturek SJ, Brzozowski T, Jaworek J, Hahn EG. Role of leptin in the stomach and the pancreas. JOURNAL OF PHYSIOLOGY, PARIS 2001; 95:345-54. [PMID: 11595459 DOI: 10.1016/s0928-4257(01)00047-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Leptin, a 16 kDa protein encoded by the ob gene, is known mainly for its role in the regulation of food intake, body composition and energy expenditure through a central feedback mechanism. Initially leptin was considered as an ob gene product of adipocytes but recently the presence of leptin and its receptors have been revealed in other organs including gastric mucosa and the pancreas and found to be released from these organs by cholecystokinin (CCK), gastrin and ordinary feeding. Furthermore, leptin was found to mimic the action of CCK on gastric and pancreatic integrity, while reducing the food intake and to affect gastric and pancreatic secretion. This report emphasizes the role of leptin originating from the gastrointestinal tract acting synergistically with CCK at the hypothalamus level on the mechanism of food intake and locally on the protection of gastric mucosa and the pancreas against noxious agents and to maintain tissue integrity.
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Affiliation(s)
- P C Konturek
- Department of Medicine, University of Erlangen-Nuremberg, Erlangen, Germany
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Abstract
The gastroduodenal mucosa is a model system of defense with several structural levels and biologic strategies that are closely interrelated with each other to cope with the harmful ingredients of ingested food and the potentially deleterious effects of gastric acid and pepsin. Experimental and clinical research carried out during the review period added to the understanding of each component of the multiple mechanisms of gastroduodenal mucosal protection. In the first place, mucosal integrity is defended by the mucus gel barrier, the epithelial cell barrier, and the immune barrier. The properties of these barriers are maintained by adequate regulation of mucus production, bicarbonate secretion, mucosal microcirculation, and motor activity. These regulatory systems are alarmed by nociceptive neurons and the mucosal immune system which includes chemokine-secreting epithelial cells. The ultimate defense system is rapid repair of the injured mucosa under the control of several growth factors. Progressing insight into the network of mucosal defense not only will improve existing therapies of inflammation and ulceration but also will provide new leads for the management of functional diseases in the gastroduodenal region.
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Affiliation(s)
- P Holzer
- Department of Experimental and Clinical Pharmacology, University of Graz, Austria.
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Brzozowski T, Konturek PC, Konturek SJ, Sliwowski Z, Drozdowicz D, Kwiecień S, Pajdo R, Ptak A, Pawlik M, Hahn E. Gastroprotective and ulcer healing effects of nitric oxide-releasing non-steroidal anti-inflammatory drugs. Dig Liver Dis 2000; 32:583-94. [PMID: 11142556 DOI: 10.1016/s1590-8658(00)80840-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIM New class of nitric oxide-releasing non-steroidal anti-inflammatory drugs was shown to inhibit cyclooxygenase and prostaglandin generation without causing mucosal damage but whether these agents are capable of affecting gastric mucosal damage induced by strong irritants and healing of chronic gastric ulcers remains to be studied. In this investigation, effects of nitric oxide-releasing aspirin and nitric oxide-releasing naproxen were compared with those of native agents on gastric lesions provoked by 100% ethanol and on healing of chronic acetic acid ulcers. RESULTS Both, nitric oxide-releasing aspirin and naproxen dose-dependently attenuated ethanol-induced damage and produced a significant rise in gastric blood flow but did not delay healing of gastric ulcers while native aspirin and naproxen had no influence on ethanol-induced gastric damage but significantly prolonged ulcer healing, reduced gastric blood flow and suppressed mucosal generation of prostaglandin E2. The gastroprotective and hyperaemic effects of both nitric oxide-non-steroidal anti-inflammatory drugs were completely abolished by ODQ, an inhibitor of guanylyl cyclase-cGMP system but not influenced by suppression of nitric oxide-synthase with L-NNA. The damaging effects of native acetyl salicylate acid or naproxen were aggravated by acidification of these non-steroidal anti-inflammatory drugs but the exogenous acid added to nitric oxide-acetyl salicylate acid or nitric oxide-naproxen failed to influence their effect. Despite inhibiting of PGE2 generation, both nitric oxide-releasing derivatives and native aspirin and naproxen failed to affect expression of cyclooxygenase-1 mRNA but upregulated the cyclooxygenase-2 mRNA. Concurrent inhibition of cyclooxygenase-2 by selective inhibitor NS-398 which by itself delayed ulcer healing and attenuated the gastric blood flow at ulcer margin, significantly worsened the effects of these nitric oxide-non-steroidal anti-inflammatory drugs and their parent drugs on ulcer healing and the gastric blood flow at the ulcer margin. CONCLUSIONS 1) Coupling of nitric oxide to aspirin or naproxen attenuates ethanol-induced damage, possibly due to an increase in gastric microcirculation mediated by excessive release and action of nitric oxide that probably compensates for PG deficiency induced by non-steroidal anti-inflammatory drugs; and 2) nitric oxide-non-steroidal anti-inflammatory drug, unlike classic non-steroidal anti-inflammatory drugs, does not affect intact gastric mucosa and fails to delay the healing of pre-existing ulcers.
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Affiliation(s)
- T Brzozowski
- Department of Physiology, Jagiellonian University School of Medicine, Cracow, Poland
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Wang L, Barachina MD, Martínez V, Wei JY, Taché Y. Synergistic interaction between CCK and leptin to regulate food intake. REGULATORY PEPTIDES 2000; 92:79-85. [PMID: 11024569 DOI: 10.1016/s0167-0115(00)00153-1] [Citation(s) in RCA: 95] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Leptin administered (either intracerebroventricularly, icv, or intraperitoneally, ip) acts in synergy with CCK to suppress food intake and body weight in lean mice or rats. The potentiating effect induced by the co-injection of ip CCK and leptin to inhibit food consumption in mice is mediated by the CCK-A receptor and capsaicin sensitive afferents. In vitro, studies in rats showed that a subset of gastric vagal afferent fibers responded to leptin injected directly into the gastric artery only after a prior intra-arterial CCK injection. Moreover, the tonic activity of gastric-related neurons in the nucleus tractus solitarius (NTS) increased when leptin was delivered into the gastric chamber of an in vitro stomach-brainstem preparation. CCK co-injected with leptin potentiated Fos expression selectively in the area postrema, NTS and paraventricular nucleus of the hypothalamus (PVN), which points to the PVN as part of the afferent and efferent limbs of the circuitry involved in the synergistic interaction between leptin and CCK. The dampening of CCK or leptin inhibitory action on ingestive behavior when either factor is not present or their receptors are non functional supports the notion that such leptin-CCK interaction may have a physiological relevance. These observations provide a mean through which leptin and CCK integrate short- and mid-term meal-related input signals into long-term control of energy balance.
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Affiliation(s)
- L Wang
- CURE, Digestive Diseases Research Center, University of California at Los Angeles, USA.
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Abstract
The discovery of leptin in 1990 was the culmination of earlier work which recognized that communication between the adipocyte and the hypothalamus was important in maintaining body weight. Leptin, which is a 16 kilodalton protein-encoded by the OB gene, is involved in the regulation of food intake, body composition, and energy expenditure through a central feedback mechanism. Initially thought to be adipocyte-specific, the OB gene, as well as the leptin receptor, have been found in a variety of other tissues. Relevant to this review, the leptin gene and its receptor have been identified in the stomach, intestine, liver, and pancreas. Recent data also suggest that leptin may act locally within the gastrointestinal tract to influence intestinal function. This review emphasizes the concept that leptin may be a new gastrointestinal hormone and the need to expand the focus of leptin research to include all phases of weight maintenance, such as nutrient absorption and utilization, in addition to food intake.
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Affiliation(s)
- C Raguso
- MetroHealth Medical Center, Cleveland, Ohio 44109, USA
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