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  1 / 2652 MEDLINE  
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[PMID]:29307825
[Au] Autor:Shi Q; Hong YP; Zhang XY; Tao J; Wang CY; Zhao L; Mei FC; You YD; Xia H; Xiong XC; Wang GR; Wang WX
[Ad] Endereço:Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
[Ti] Título:ß cells can be generated from cytokeratin 5-positive cells after cerulein-induced pancreatitis in adult mice.
[So] Source:Biochem Biophys Res Commun;496(1):114-119, 2018 01 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Clinical studies have revealed that some patients will develop glucose tolerance dysfunction after recovering from acute pancreatitis (AP), which indicated the importance of investigating the potential therapies for restoration of islet ß cell function. Cytokeratin 5 (Krt5)-positive cells are considered to function as stem or progenitor cells in the regeneration of lung and salivary gland following injury. In the present study, AP was induced by six hourly intraperitoneal injections of 100 µg/kg cerulein for 4 consecutive days in adult mice, in order to determine the role of Krt5-positive cells in pancreatic regeneration, especially in the restoration of ß cell function and the underlying mechanisms. Results showed that glucose homeostasis were deteriorated partly during the recovery process after AP. Furthermore, clusters of Krt5-positive cells were significantly increased in the damaged pancreas marked by inflammatory cells infiltration and acinar cell eradication. In addition, cells co-labelling insulin and Krt5 were found in the injured region after cerulein administration, part of these cells were immunopositive for GLUT2. Taken together, our data demonstrated that Krt5-expressing cells could be involved in the natural pancreas self-healing process and the renewal of ß cells after AP in adult mice. It is promising that promoting conversion of Krt5-expressing cells into functional ß cells may be a novel method to mitigate the development of diabetes mellitus after AP in vivo.
[Mh] Termos MeSH primário: Células Secretoras de Insulina/metabolismo
Células Secretoras de Insulina/patologia
Queratina-5/metabolismo
Pancreatite/metabolismo
Pancreatite/patologia
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Células Cultivadas
Ceruletídeo
Feminino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Pancreatite/induzido quimicamente
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Keratin-5); 888Y08971B (Ceruletide)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180109
[St] Status:MEDLINE


  2 / 2652 MEDLINE  
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[PMID]:28468316
[Au] Autor:Bonior J; Ceranowicz P; Gajdosz R; Kusnierz-Cabala B; Pierzchalski P; Warzecha Z; Dembinski A; Pedziwiatr M; Kot M; Leja-Szpak A; Nawrot-Porabka K; Link-Lenczowski P; Olszanecki R; Bartus K; Jaworek J
[Ad] Endereço:Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 12 Michalowskiego St., 31-126 Krakow, Poland. joanna.bonior@uj.edu.pl.
[Ti] Título:Molecular Ghrelin System in the Pancreatic Acinar Cells: The Role of the Polypeptide, Caerulein and Sensory Nerves.
[So] Source:Int J Mol Sci;18(5), 2017 May 02.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Ghrelin (GHRL) is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Experimental studies showed that GHRL protects the stomach and pancreas against acute damage, but the effect of GHRL on pancreatic acinar cells was still undetermined. AIM: To investigate the effect of GHRL and caerulein on the functional ghrelin system in pancreatic acinar cells taking into account the role of sensory nerves (SN). METHODS: Experiments were carried out on isolated pancreatic acinar cells and AR42J cells. Before acinar cells isolation, GHRL was administered intraperitoneally at a dose of 50 µg/kg to rats with intact SN or with capsaicin deactivation of SN (CDSN). After isolation, pancreatic acinar cells were incubated in caerulein-free or caerulein containing solution. AR42J cells were incubated under basal conditions and stimulated with caerulein, GHRL or a combination of the above. RESULTS: Incubation of isolated acinar cells with caerulein inhibited GHS-R and GHRL expression at the level of mRNA and protein in those cells. Either in rats with intact SN or with CDSN, administration of GHRL before isolation of acinar cells increased expression of GHRL and GHS-R in those cells and reversed the caerulein-induced reduction in expression of those parameters. Similar upregulation of GHS-R and GHRL was observed after administration of GHRL in AR42J cells. CONCLUSIONS: GHRL stimulates its own expression and expression of its receptor in isolated pancreatic acinar cells and AR42J cells on the positive feedback pathway. This mechanism seems to participate in the pancreatoprotective effect of GHRL in the course of acute pancreatitis.
[Mh] Termos MeSH primário: Células Acinares/metabolismo
Ceruletídeo/farmacologia
Grelina/metabolismo
Receptores de Grelina/metabolismo
Células Receptoras Sensoriais/fisiologia
[Mh] Termos MeSH secundário: Células Acinares/efeitos dos fármacos
Animais
Linhagem Celular
Células Cultivadas
Retroalimentação Fisiológica
Grelina/genética
Masculino
Pâncreas/citologia
Pâncreas/inervação
Ratos
Ratos Wistar
Receptores de Grelina/genética
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ghrelin); 0 (Receptors, Ghrelin); 888Y08971B (Ceruletide)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


  3 / 2652 MEDLINE  
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[PMID]:28988112
[Au] Autor:Jia R; Ma J; Xiang S; Meng W; Wang N
[Ad] Endereço:Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
[Ti] Título:Caerulin-induced pro-inflammatory response in macrophages requires TRAF3-p38 signaling activation.
[So] Source:Biochem Biophys Res Commun;494(1-2):358-364, 2017 Dec 09.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acute pancreatitis is a common threat to human health. Caerulin provokes severe inflammations, causing injuries to surrounding pancreatic cells. TNF receptor-associated factor 3 (TRAF3) is a highly versatile regulator of immune response. The current study aims to understand the potential effect of TRAF3 on caerulin-induced pro-inflammatory responses. In the primary-cultured mouse bone marrow-derived macrophages (BMDMs), caerulin induced TRAF3 protein stabilization, which formed a complex with mitogen-activated protein kinase kinase 3 (MKK3) to mediate downstream p38 activation. Lentiviral shRNA-mediated TRAF3 stable knockdown significantly attenuated caerulin-induced MKK3-p38 activation and production of several key pro-inflammatory cytokines, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and IL-17. Remarkably, TRAF3 knockdown in caerulin-stimulated BMDMs also alleviated cytotoxicity to Panc02 and primary mouse pancreatic cells. Thus, TRAF3 is required for caerulin-induced p38 activation and macrophage-mediated pro-inflammatory responses. TRAF3 expression in macrophages could be a novel therapeutic target protein for the treatment of acute pancreatitis.
[Mh] Termos MeSH primário: Ceruletídeo/farmacologia
Células Epiteliais/efeitos dos fármacos
Macrófagos/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Fator 3 Associado a Receptor de TNF/genética
Proteínas Quinases p38 Ativadas por Mitógeno/genética
[Mh] Termos MeSH secundário: Animais
Técnicas de Cocultura
Células Epiteliais/citologia
Células Epiteliais/imunologia
Regulação da Expressão Gênica
Interleucina-17/genética
Interleucina-17/imunologia
Interleucina-1beta/genética
Interleucina-1beta/imunologia
Lentivirus/genética
Lentivirus/imunologia
MAP Quinase Quinase 3/genética
MAP Quinase Quinase 3/imunologia
Macrófagos/citologia
Macrófagos/imunologia
Camundongos
Pâncreas/citologia
Pâncreas/efeitos dos fármacos
Pâncreas/imunologia
Cultura Primária de Células
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/imunologia
Fator 3 Associado a Receptor de TNF/antagonistas & inibidores
Fator 3 Associado a Receptor de TNF/imunologia
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/imunologia
Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL1B protein, mouse); 0 (Interleukin-17); 0 (Interleukin-1beta); 0 (RNA, Small Interfering); 0 (TNF Receptor-Associated Factor 3); 0 (Tumor Necrosis Factor-alpha); 888Y08971B (Ceruletide); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); EC 2.7.12.2 (MAP Kinase Kinase 3); EC 2.7.12.2 (Map2k3 protein, mouse)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171009
[St] Status:MEDLINE


  4 / 2652 MEDLINE  
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[PMID]:28709869
[Au] Autor:Sharmila GR; Venkateswaran G
[Ad] Endereço:Academy of Scientific and Innovative Research, CSIR-Central Food Technological Research Institute, Mysuru 570020, India; Microbiology and Fermentation Technology Department, CSIR-Central Food Technological Research Institute, Mysuru 570020, India.
[Ti] Título:Protective effect of bacillopeptidase CFR5 from Bacillus subtilis CFR5 on cerulein-induced pancreatitis.
[So] Source:Biochem Biophys Res Commun;491(2):455-462, 2017 Sep 16.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bacillopeptidase is a serine peptidase, known for its fibrinolytic activity. However, a very little information is known about its in vivo inflammatory and/or anti-inflammatory properties. Thus, to understand whether bacillopeptidase incorporation can regulate pancreatitis or not, the cerulein-induced pancreatitis model was used, and the role of bacillopeptidase on pancreatitis was studied. In this study, 46 kDa protein was purified from Bacillus subtilis and identified as bacillopeptidase CFR5 (BPC) through MS/MS analysis. The nutritional prophylactic group was orally fed with two doses of BPC (100 µg/Kg/BW of rat) 6 h before cerulein administration and analyzed for its effect on intestine and pancreas inflammation, cytokines, and pancreatitis marker gene expression. BPC administration significantly reduced the severity of pancreatitis by decreasing serum amylase, lipase, pancreatic edema and myeloperoxidase activity. The pretreatment with BPC suppressed the pancreatic pro-inflammatory and inflammatory cytokines production including IL-6, IL-1ß, TNF-α, IL-2, IL-4, IL-5, IL-10, and IL-13 in both pancreas and serum samples. Moreover, BPC supplementation restored pancreatitis mediated disruption of intestinal barrier integrity by upregulating tight junction proteins (ZO-1, occludin), antimicrobial peptides (DEFB1, CRAMP), MUC-2, TFF3 expression and by enhancing SCFA's production. Pretreatment with BPC suppressed the intestinal inflammation with reduced cytokines production in the colon and ileal region of cerulein-induced pancreatitis. Thus, BPC based pretreatment protocol is a novel intervention to prevent acute pancreatitis.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/farmacologia
Bacillus subtilis/química
Proteínas de Bactérias/farmacologia
Edema/tratamento farmacológico
Pancreatite/tratamento farmacológico
Serina Endopeptidases/farmacologia
[Mh] Termos MeSH secundário: Administração Oral
Animais
Anti-Inflamatórios não Esteroides/isolamento & purificação
Proteínas de Bactérias/isolamento & purificação
Catelicidinas/genética
Catelicidinas/metabolismo
Ceruletídeo
Citocinas/biossíntese
Defensinas/genética
Defensinas/metabolismo
Edema/induzido quimicamente
Edema/genética
Edema/patologia
Regulação da Expressão Gênica
Masculino
Mucina-2/genética
Mucina-2/metabolismo
Ocludina/genética
Ocludina/metabolismo
Pâncreas/efeitos dos fármacos
Pâncreas/metabolismo
Pâncreas/patologia
Pancreatite/induzido quimicamente
Pancreatite/genética
Pancreatite/patologia
Ratos
Ratos Wistar
Serina Endopeptidases/isolamento & purificação
Fator Trefoil-3/genética
Fator Trefoil-3/metabolismo
Proteína da Zônula de Oclusão-1/genética
Proteína da Zônula de Oclusão-1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Bacterial Proteins); 0 (Cathelicidins); 0 (Cytokines); 0 (Defb1 protein, rat); 0 (Defensins); 0 (Muc2 protein, rat); 0 (Mucin-2); 0 (Occludin); 0 (Ocln protein, rat); 0 (TFF3 protein, rat); 0 (Tjp1 protein, rat); 0 (Trefoil Factor-3); 0 (Zonula Occludens-1 Protein); 0 (cathelicidin antimicrobial peptide); 888Y08971B (Ceruletide); EC 3.4.21.- (Serine Endopeptidases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170716
[St] Status:MEDLINE


  5 / 2652 MEDLINE  
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[PMID]:28639695
[Au] Autor:Ding L; Liou GY; Schmitt DM; Storz P; Zhang JS; Billadeau DD
[Ad] Endereço:Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA.
[Ti] Título:Glycogen synthase kinase-3ß ablation limits pancreatitis-induced acinar-to-ductal metaplasia.
[So] Source:J Pathol;243(1):65-77, 2017 Sep.
[Is] ISSN:1096-9896
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3ß) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3ß promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3ß attenuates caerulein-induced ADM formation and PanIN progression in Kras transgenic mice. Furthermore, we demonstrate that GSK-3ß ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3ß regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3ß participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Células Acinares/enzimologia
Carcinoma in Situ/prevenção & controle
Transdiferenciação Celular
Glicogênio Sintase Quinase 3 beta/deficiência
Pâncreas Exócrino/enzimologia
Ductos Pancreáticos/enzimologia
Neoplasias Pancreáticas/prevenção & controle
Pancreatite/enzimologia
[Mh] Termos MeSH secundário: Células Acinares/efeitos dos fármacos
Células Acinares/patologia
Animais
Carcinoma in Situ/enzimologia
Carcinoma in Situ/genética
Carcinoma in Situ/patologia
Proliferação Celular
Transdiferenciação Celular/efeitos dos fármacos
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/metabolismo
Transformação Celular Neoplásica/patologia
Células Cultivadas
Ceruletídeo
Modelos Animais de Doenças
Progressão da Doença
Predisposição Genética para Doença
Glicogênio Sintase Quinase 3 beta/genética
Proteínas de Homeodomínio/genética
Masculino
Metaplasia
Camundongos Knockout
Pâncreas Exócrino/efeitos dos fármacos
Pâncreas Exócrino/patologia
Ductos Pancreáticos/efeitos dos fármacos
Ductos Pancreáticos/patologia
Neoplasias Pancreáticas/enzimologia
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/patologia
Pancreatite/induzido quimicamente
Pancreatite/genética
Pancreatite/patologia
Fenótipo
Proteínas Proto-Oncogênicas p21(ras)/genética
Proteínas Quinases S6 Ribossômicas/metabolismo
Transdução de Sinais
Serina-Treonina Quinases TOR/metabolismo
Fatores de Tempo
Transativadores/genética
Fator de Necrose Tumoral alfa/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Homeodomain Proteins); 0 (Trans-Activators); 0 (Tumor Necrosis Factor-alpha); 0 (pancreatic and duodenal homeobox 1 protein); 888Y08971B (Ceruletide); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 2.7.11.1 (Gsk3b protein, mouse); EC 2.7.11.1 (Ribosomal Protein S6 Kinases); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1002/path.4928


  6 / 2652 MEDLINE  
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[PMID]:28480430
[Au] Autor:Shao Z
[Ad] Endereço:Department of Emergency, Beijing Tongren hospital, Affiliated to the Capital Medical University Beijing 100176, China.
[Ti] Título: STEM EXTRACT IMPROVES THE PROTECTIVE EFFECT OF HEPARIN ON CERULEIN-INDUCED PANCREATITIS.
[So] Source:Afr J Tradit Complement Altern Med;14(3):187-193, 2017.
[Is] ISSN:2505-0044
[Cp] País de publicação:Nigeria
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The present study evaluates the effect of stem extract (SS) in the management of pancreatitis alone and in combination with heparin. MATERIAL AND METHODS: Pancreatitis was induced pancreatitis by cerulean (50µg/kg, i.p.) five times at an interval of 1 h without any pretreatment of drug. Rats were treated with SS (100 and 200 mg/kg, p. o.) and heparin (150 U/kg, i.p.) alone and in combination for the duration of a week. Later pancreatic weight and blood flow was estimated and different biochemical parameters like concentration of D-dimer and Interleukin 1ß (IL-Ιß) and activity of amylase and lipase were determined in blood of pancreatitis rats. Moreover effect of drug treatment on DNA synthesis and histopathology was also estimated on cerulean induced pancreatitis rats. RESULT: Results of this study suggest that treatment with SS alone and in combination with heparin significantly increase in prothrombin time and pancreatic blood flow than negative control group. There was significant decrease in concentration of IL-Ιß and D-dimer and activity of amylase and lipase in SS and heparin treated group than negative control group. Pancreatic DNA synthesis was also found to be reduced in SS and heparin alone and in combination treated group. Histopathology study also reveals that treatment with SS and heparin alone and in combination reduces edema, hemorrhages, leukocyte infiltration in the TS of pancreatic tissues. CONCLUSION: Present study concludes that treatment with SS alone effectively manages the pancreatitis by ceasing the inflammatory pathway and potentiates the effect of heparin in the management of pancreatitis.
[Mh] Termos MeSH primário: Anticoagulantes/administração & dosagem
Fabaceae/química
Heparina/administração & dosagem
Pancreatite/tratamento farmacológico
Fitoterapia/métodos
Extratos Vegetais/administração & dosagem
Caules de Planta/química
Substâncias Protetoras/administração & dosagem
[Mh] Termos MeSH secundário: Amilases/metabolismo
Animais
Ceruletídeo
Quimioterapia Combinada
Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo
Interleucina-1beta/metabolismo
Lipase/metabolismo
Masculino
Inibidores da Síntese de Ácido Nucleico/administração & dosagem
Pâncreas/efeitos dos fármacos
Pâncreas/metabolismo
Pâncreas/patologia
Pancreatite/induzido quimicamente
Pancreatite/metabolismo
Tempo de Protrombina
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticoagulants); 0 (Fibrin Fibrinogen Degradation Products); 0 (Interleukin-1beta); 0 (Nucleic Acid Synthesis Inhibitors); 0 (Plant Extracts); 0 (Protective Agents); 0 (fibrin fragment D); 888Y08971B (Ceruletide); 9005-49-6 (Heparin); EC 3.1.1.3 (Lipase); EC 3.2.1.- (Amylases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170815
[Lr] Data última revisão:
170815
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170509
[St] Status:MEDLINE
[do] DOI:10.21010/ajtcam.v14i3.20


  7 / 2652 MEDLINE  
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[PMID]:28315674
[Au] Autor:Wu J; Mulatibieke T; Ni J; Han X; Li B; Zeng Y; Wan R; Wang X; Hu G
[Ad] Endereço:Department of Gastroenterology and the Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
[Ti] Título:Dichotomy between Receptor-Interacting Protein 1- and Receptor-Interacting Protein 3-Mediated Necroptosis in Experimental Pancreatitis.
[So] Source:Am J Pathol;187(5):1035-1048, 2017 May.
[Is] ISSN:1525-2191
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pancreatic acinar cell necrosis and inflammatory responses are two key pathologic processes in acute pancreatitis (AP), which determines the severity and outcome of the disease. Recent studies suggest that necroptosis, a programed form of necrosis, is involved in the pathogenesis of AP, but the underlying mechanisms remain unknown. We investigated the expression of necrosome components, including receptor-interacting protein (RIP) 1, RIP3, and mixed lineage kinase domain-like (MLKL), and the molecular mechanisms in pancreatitis-associated necroptosis. We found that RIP3 and phosphorylated MLKL expression was positively related to the degree of necrosis, whereas RIP1 expression was negatively related to the degree of necrosis. Pharmacologic inhibition of RIP1 kinase activity exerted no protection against caerulein/cholecystokinin-8-induced AP, but knockdown of RIP1 with siRNA increased acinar cell necrosis and inhibition of NF-κB activation. RIP1 inhibition led to enhanced RIP3 expression. RIP3 and MLKL inhibition decreased acinar cell necrosis, in which the inhibition of RIP3 reduced the phosphorylation level of MLKL. RIP3 inhibition had no effect on trypsinogen activation but partly inhibited inflammasome activation. Our study strongly suggests that the imbalance between RIP1 and RIP3 shifts the cell death to necrosis, which unravels a new molecular pathogenesis of mechanism of AP and may provide insight into the development of novel therapeutic agent for other necrosis-related diseases.
[Mh] Termos MeSH primário: Pancreatite/patologia
Proteína Serina-Treonina Quinases de Interação com Receptores/fisiologia
[Mh] Termos MeSH secundário: Células Acinares/fisiologia
Doença Aguda
Animais
Apoptose/fisiologia
Ceruletídeo/toxicidade
Colecistocinina/toxicidade
Irritantes/toxicidade
Masculino
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Necrose/fisiopatologia
Fragmentos de Peptídeos/toxicidade
Fosforilação/fisiologia
Inibidores de Proteínas Quinases/farmacologia
Ratos Sprague-Dawley
Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores
Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Irritants); 0 (Peptide Fragments); 0 (Protein Kinase Inhibitors); 0 (cholecystokinin 8); 888Y08971B (Ceruletide); 9011-97-6 (Cholecystokinin); EC 2.7.11.1 (RIPK1 protein, human); EC 2.7.11.1 (RIPK3 protein, human); EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170320
[St] Status:MEDLINE


  8 / 2652 MEDLINE  
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[PMID]:28300832
[Au] Autor:Liu Y; Chen XD; Yu J; Chi JL; Long FW; Yang HW; Chen KL; Lv ZY; Zhou B; Peng ZH; Sun XF; Li Y; Zhou ZG
[Ad] Endereço:Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
[Ti] Título:Deletion Of XIAP reduces the severity of acute pancreatitis via regulation of cell death and nuclear factor-κB activity.
[So] Source:Cell Death Dis;8(3):e2685, 2017 Mar 16.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Severe acute pancreatitis (SAP) still remains a clinical challenge, not only for its high mortality but the uncontrolled inflammatory progression from acute pancreatitis (AP) to SAP. Cell death, including apoptosis and necrosis are critical pathology of AP, since the severity of pancreatitis correlates directly with necrosis and inversely with apoptosis Therefore, regulation of cell death from necrosis to apoptosis may have practicably therapeutic value. X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the inhibitor of apoptosis proteins (IAP) family, but its function in AP remains unclear. In the present study, we investigated the potential role of XIAP in regulation of cell death and inflammation during acute pancreatitis. The in vivo pancreatitis model was induced by the administration of cerulein with or without lipopolysaccharide (LPS) or by the administration of l-arginine in wild-type or XIAP-deficient mice, and ex vivo model was induced by the administration of cerulein+LPS in AR42J cell line following XIAP inhibition. The severity of acute pancreatitis was determined by serum amylase activity and histological grading. XIAP deletion on cell apoptosis, necrosis and inflammatory response were examined. Caspases activities, nuclear factor-κB (NF-κB) activation and receptor-interacting protein kinase1 (RIP1) degradation were assessed by western blot. Deletion of XIAP resulted in the reduction of amylase activity, decrease of NF-κB activation and less release of TNF-α and IL-6, together with increased caspases activities and RIP1 degradation, leading to enhanced apoptosis and reduced necrosis in pancreatic acinar cells and ameliorated the severity of acute pancreatitis. Our results indicate that deletion of XIAP switches cell death away from necrosis to apoptosis and decreases the inflammatory response, effectively attenuating the severity of AP/SAP. The critical role of XIAP in cell death and inflammation suggests that inhibition of XIAP represents a potential therapeutic strategy for the treatment of acute pancreatitis.
[Mh] Termos MeSH primário: Morte Celular/fisiologia
Proteínas Inibidoras de Apoptose/metabolismo
NF-kappa B/metabolismo
Pancreatite/metabolismo
Pancreatite/patologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Apoptose/fisiologia
Arginina/metabolismo
Caspases/metabolismo
Morte Celular/efeitos dos fármacos
Linhagem Celular
Ceruletídeo/farmacologia
Inflamação/metabolismo
Interleucina-6/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Necrose/metabolismo
Necrose/patologia
Pâncreas/diagnóstico por imagem
Pâncreas/metabolismo
Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
Fator de Necrose Tumoral alfa/metabolismo
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Birc4 protein, mouse); 0 (Inhibitor of Apoptosis Proteins); 0 (Interleukin-6); 0 (NF-kappa B); 0 (Tumor Necrosis Factor-alpha); 0 (X-Linked Inhibitor of Apoptosis Protein); 888Y08971B (Ceruletide); 94ZLA3W45F (Arginine); EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases); EC 3.4.22.- (Caspases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2017.70


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[PMID]:28254412
[Au] Autor:Leal AS; Williams CR; Royce DB; Pioli PA; Sporn MB; Liby KT
[Ad] Endereço:Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, NH, USA; Michigan State University, Department of Pharmacology & Toxicology, East Lansing, MI, USA.
[Ti] Título:Bromodomain inhibitors, JQ1 and I-BET 762, as potential therapies for pancreatic cancer.
[So] Source:Cancer Lett;394:76-87, 2017 May 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Bromodomain inhibitors (JQ1 and I-BET 762) are a new generation of selective, small molecule inhibitors that target BET (bromodomain and extra terminal) proteins. By impairing their ability to bind to acetylated lysines on histones, bromodomain inhibitors interfere with transcriptional initiation and elongation. BET proteins regulate several genes responsible for cell cycle, apoptosis and inflammation. In this study, JQ1 and I-BET 762 decreased c-Myc and p-Erk 1/2 protein levels and inhibited proliferation in pancreatic cancer cells. The tumor microenvironment is known to play an important role in pancreatic cancer, and these drugs suppressed the production of nitric oxide and a variety of inflammatory cytokines, including IL-6, CCL2, and GM-CSF, in both immune and pancreatic cancer cells in vitro. Notably, the bromodomain inhibitors also reduced protein levels of p-Erk 1/2 and p-STAT3 in mouse models of pancreatic cancer. All of these proteins are essential for tumor promotion, progression and metastasis. In conclusion, the bromodomain inhibitors JQ1 and I-BET 762 targeted and suppressed multiple pathways in pancreatic cancer. I-BET 762 and a number of other bromodomain inhibitors are currently being tested in several clinical trials, making them potentially promising drugs for the treatment of pancreatic cancer, an often-fatal disease.
[Mh] Termos MeSH primário: Anti-Inflamatórios/farmacologia
Antineoplásicos/farmacologia
Azepinas/farmacologia
Benzodiazepinas/farmacologia
Neoplasias Pancreáticas/tratamento farmacológico
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Ceruletídeo
Citocinas/metabolismo
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Seres Humanos
Mediadores da Inflamação/metabolismo
Macrófagos/efeitos dos fármacos
Macrófagos/imunologia
Macrófagos/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Óxido Nítrico/metabolismo
Neoplasias Pancreáticas/imunologia
Neoplasias Pancreáticas/metabolismo
Neoplasias Pancreáticas/patologia
Pancreatite/induzido quimicamente
Pancreatite/tratamento farmacológico
Pancreatite/imunologia
Pancreatite/metabolismo
Fosforilação
Proteínas Proto-Oncogênicas c-myc/metabolismo
Células RAW 264.7
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((+)-JQ1 compound); 0 (Anti-Inflammatory Agents); 0 (Antineoplastic Agents); 0 (Azepines); 0 (Cytokines); 0 (GSK525762A); 0 (Inflammation Mediators); 0 (MYC protein, human); 0 (Myc protein, mouse); 0 (Proto-Oncogene Proteins c-myc); 0 (Triazoles); 12794-10-4 (Benzodiazepines); 31C4KY9ESH (Nitric Oxide); 888Y08971B (Ceruletide); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE


  10 / 2652 MEDLINE  
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[PMID]:28253495
[Au] Autor:Terada Y; Tsubota M; Sugo H; Wakitani K; Sekiguchi F; Wada K; Takada M; Oita A; Kawabata A
[Ad] Endereço:Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-osaka, Japan.
[Ti] Título:Tacrolimus Triggers Transient Receptor Potential Vanilloid-1-Dependent Relapse of Pancreatitis-Related Pain in Mice.
[So] Source:Pharmacology;99(5-6):281-285, 2017.
[Is] ISSN:1423-0313
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Transient receptor potential vanilloid-1 (TRPV1) expressed in nociceptors is directly phosphorylated and activated by protein kinase C, and involved in the signaling of pancreatic pain. On the other hand, Cav3.2 T-type Ca2+ channels expressed in nociceptors are functionally upregulated by phosphorylation with protein kinase A and also play a role in pancreatitis-related pain. Calcineurin, a phosphatase, negatively regulates various channel functions including TRPV1, and calcineurin inhibitor-induced pain syndrome by tacrolimus, a calcineurin inhibitor, used as an immunosuppressant, has been a clinical problem. We thus examined the effect of tacrolimus on pancreatitis-related pain in mice. Repeated treatment with cerulein caused referred hyperalgesia accompanying acute pancreatitis, which was unaffected by tacrolimus. Pancreatitis-related symptoms disappeared in 24 h, whereas the referred hyperalgesia recurred following the administration of tacrolimus, which was abolished by the blockers of TRPV1 but not T-type Ca2+ channels. Thus, tacrolimus appears to cause the TRPV1-dependent relapse of pancreatitis-related pain, suggesting the involvement of calcineurin in the termination of pancreatic pain.
[Mh] Termos MeSH primário: Hiperalgesia/induzido quimicamente
Dor/fisiopatologia
Canais de Cátion TRPV/fisiologia
Tacrolimo/farmacologia
[Mh] Termos MeSH secundário: Anilidas/farmacologia
Animais
Benzimidazóis/farmacologia
Ceruletídeo/efeitos adversos
Cinamatos/farmacologia
Ciclopropanos/farmacologia
Masculino
Camundongos
Naftalenos/farmacologia
Dor/complicações
Pancreatite/induzido quimicamente
Pancreatite/complicações
Recidiva
Tacrolimo/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((1S,2S)-2-(2-(N-((3-benzimidazol-2-yl)propyl)-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride); 0 (Anilides); 0 (Benzimidazoles); 0 (Cinnamates); 0 (Cyclopropanes); 0 (N-(3-methoxyphenyl)-4-chlorocinnamanilide); 0 (Naphthalenes); 0 (TRPV Cation Channels); 0 (TRPV1 protein, mouse); 888Y08971B (Ceruletide); WM0HAQ4WNM (Tacrolimus)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170516
[Lr] Data última revisão:
170516
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170303
[St] Status:MEDLINE
[do] DOI:10.1159/000454816



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