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Almutary KH, Zaghloul MS, Nader MA, Elsheakh AR. Mechanistic insights into the protective potential of ambrisentan against L-arginine induced acute pancreatitis and multiorgan damage (role of NRF2/HO-1 and TXNIP/NLRP3 pathways). Biomed Pharmacother 2025; 187:118119. [PMID: 40319659 DOI: 10.1016/j.biopha.2025.118119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025] Open
Abstract
Acute pancreatitis (AP) is an abrupt inflammation of the pancreatic tissue. The severity of AP varies from mild and self-limiting to severe, potentially fatal, and can affect several organ systems. The most severe type of AP causes multiple organ damage (MOD) due to systemic inflammation. In this study, ambrisentan (AMB), an endothelin A receptor antagonist (ETA), was investigated for its potential to ameliorate L-arginine (L-Arg) induced AP and MOD in rats. AP was induced using L-Arg (100 mg/100 g). Two doses of AMB were tested and compared to N-acetylcystiene (NAC) effect. AMB restored the normal structure of the pancreatic, hepatic, pulmonary, and renal tissues. In addition, it normalized the levels of pancreatic enzymes, lactate dehydrogenase (LDH), serum liver enzymes, and kidney biomarkers. Furthermore, AMB corrected the imbalance in the levels of oxidants/antioxidants caused by L-Arg. In contrast, AMB (5 mg/kg) significantly upregulated the protein levels of adenosine monophosphate protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxidase-1(HO-1) and thioredoxin reductase 1 (TXNRD1) by approximately 69.59 %, 85.14 %, 688 % and 96 % respectively, compared with those in rats treated with L-Arg. Furthermore, AMB (5 mg/kg) significantly lowered the thioredoxin-interacting protein (TXNIP), nod-like Receptor Protein 3 (NLRP3), glycogen synthase kinase-3β (GSK-3β), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), CD68, autophagic markers (P62 and LC3) and apoptotic marker caspase 3 by around 62.43 %, 73.56 %, 62.5 %,70 %, 80.3 %, 93 %, 96.7 %, 95 %, 39.6 % respectively, compared to the group treated with L-Arg. AMB effectively improved the AP and MOD produced by L-Arg through its anti-inflammatory and antioxidant properties. NRF2/HO-1 and TXNIP/NLRP3 pathways play major roles in these protective effects.
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Affiliation(s)
- Khaled H Almutary
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Majmaah University, P.O.Box 66, Majmaah 11952, Saudi Arabia
| | - Marwa S Zaghloul
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt.
| | - Manar A Nader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt
| | - Ahmed R Elsheakh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt; Future Studies and Risks Management & National Committee of Drugs, Academy of Scientific Research, Ministry of Higher Education, Elsayeda Zeinab, Egypt
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Sharma MK, Priyam K, Kumar P, Garg PK, Roy TS, Jacob TG. Effect of chloroquine on autophagy and the severity of caerulein-induced acute pancreatitis in mice. Acta Histochem 2025; 127:152234. [PMID: 39913992 DOI: 10.1016/j.acthis.2025.152234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 01/23/2025] [Accepted: 01/31/2025] [Indexed: 03/01/2025]
Abstract
Impaired autophagy is implicated in the pathogenesis of caerulein-induced model of acute pancreatitis (AP). Chloroquine blocks the fusion of autophagosome and lysosome and affects completion of the cellular autophagic flux. Adult, male, Swiss albino mice (20-25 g) were divided into four groups- 1, 2, 3 and 4 of 6 mice each. Mice in Group1 were given 8, hourly intraperitoneal injections of normal saline. Group 2 was also given intraperitoneal injections of chloroquine (60 mg/Kg) at 14 h and 30-min prior to first injection of normal saline. Mice in Groups 3 and 4 given 8, hourly intraperitoneal injections of caerulein (50 µg /Kg/dose). Group 4 also received chloroquine as Group 2. After sacrifice at the 9th hour in CO2-chamber, blood was drawn for amylase activity and cytokines estimation (IL-6, TNF-α, GM-CSF, IL-1β and IL-10) and pancreas was harvested for histopathology, transmission electron microscopy (TEM) and immunoblotting (LC3II, Beclin 1, SQSTM1, RIPK1, P65, Caspase-3, RIPK3, HMGB1). The relative expression of SQSTM1 and the autophagic vacuole area was higher in groups 2, 3 and 4 (p < 0.05), suggestive of increased impairment of autophagic flux. Autolysosome count was significantly increased in group 3 in comparison to group 1 (p = 0.0049). Autolysosome area was also increased in group 4 in comparison to group 3 (p = 0.031), which suggested impairment of autophagy. Total histopathological score and amylase activity were equivalent in groups 3 and 4. RIPK1 in pancreas and TNF-α level in plasma were more in group 4 than 3 (p = 0.014, 0.02, respectively). Expression of Caspase-3, was lesser in group 4 than 3 (p < 0.001). Expression of HMGB1was more in group 4 than 3 (p = 0.046). Chloroquine enhances necrosis and inflammation in caerulein-induced pancreatitis.
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Affiliation(s)
| | - Kumari Priyam
- Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
| | - Punit Kumar
- Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
| | - Pramod Kumar Garg
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Tara Sankar Roy
- Department of Anatomy, North DMC Medical College & Hindu Rao Hospital, New Delhi, India
| | - Tony George Jacob
- Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
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Li MM, Huang Y, Sumathipala M, Liang MQ, Valdeolivas A, Ananthakrishnan AN, Liao K, Marbach D, Zitnik M. Contextual AI models for single-cell protein biology. Nat Methods 2024; 21:1546-1557. [PMID: 39039335 PMCID: PMC11310085 DOI: 10.1038/s41592-024-02341-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 06/10/2024] [Indexed: 07/24/2024]
Abstract
Understanding protein function and developing molecular therapies require deciphering the cell types in which proteins act as well as the interactions between proteins. However, modeling protein interactions across biological contexts remains challenging for existing algorithms. Here we introduce PINNACLE, a geometric deep learning approach that generates context-aware protein representations. Leveraging a multiorgan single-cell atlas, PINNACLE learns on contextualized protein interaction networks to produce 394,760 protein representations from 156 cell type contexts across 24 tissues. PINNACLE's embedding space reflects cellular and tissue organization, enabling zero-shot retrieval of the tissue hierarchy. Pretrained protein representations can be adapted for downstream tasks: enhancing 3D structure-based representations for resolving immuno-oncological protein interactions, and investigating drugs' effects across cell types. PINNACLE outperforms state-of-the-art models in nominating therapeutic targets for rheumatoid arthritis and inflammatory bowel diseases and pinpoints cell type contexts with higher predictive capability than context-free models. PINNACLE's ability to adjust its outputs on the basis of the context in which it operates paves the way for large-scale context-specific predictions in biology.
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Affiliation(s)
- Michelle M Li
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Yepeng Huang
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Marissa Sumathipala
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Man Qing Liang
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Alberto Valdeolivas
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Ashwin N Ananthakrishnan
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Katherine Liao
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA
| | - Daniel Marbach
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Marinka Zitnik
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
- Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University, Allston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Harvard Data Science Initiative, Cambridge, MA, USA.
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Li MM, Huang Y, Sumathipala M, Liang MQ, Valdeolivas A, Ananthakrishnan AN, Liao K, Marbach D, Zitnik M. Contextual AI models for single-cell protein biology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.07.18.549602. [PMID: 37503080 PMCID: PMC10370131 DOI: 10.1101/2023.07.18.549602] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Understanding protein function and developing molecular therapies require deciphering the cell types in which proteins act as well as the interactions between proteins. However, modeling protein interactions across biological contexts remains challenging for existing algorithms. Here, we introduce Pinnacle, a geometric deep learning approach that generates context-aware protein representations. Leveraging a multi-organ single-cell atlas, Pinnacle learns on contextualized protein interaction networks to produce 394,760 protein representations from 156 cell type contexts across 24 tissues. Pinnacle's embedding space reflects cellular and tissue organization, enabling zero-shot retrieval of the tissue hierarchy. Pretrained protein representations can be adapted for downstream tasks: enhancing 3D structure-based representations for resolving immuno-oncological protein interactions, and investigating drugs' effects across cell types. Pinnacle outperforms state-of-the-art models in nominating therapeutic targets for rheumatoid arthritis and inflammatory bowel diseases, and pinpoints cell type contexts with higher predictive capability than context-free models. Pinnacle's ability to adjust its outputs based on the context in which it operates paves way for large-scale context-specific predictions in biology.
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Affiliation(s)
- Michelle M. Li
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Yepeng Huang
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Marissa Sumathipala
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Man Qing Liang
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Alberto Valdeolivas
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Ashwin N. Ananthakrishnan
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Katherine Liao
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, MA, USA
| | - Daniel Marbach
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Marinka Zitnik
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University, Allston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Data Science Initiative, Cambridge, MA, USA
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Yang DJ, Chen KL, Lv ZY, Zhou B, Zhou ZG, Li Y. PD-L1 blockade in mitigating severe acute pancreatitis induced pancreatic damage through modulation of immune cell apoptosis. Int Immunopharmacol 2024; 133:112081. [PMID: 38652963 DOI: 10.1016/j.intimp.2024.112081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 04/07/2024] [Accepted: 04/10/2024] [Indexed: 04/25/2024]
Abstract
Acute pancreatitis (AP) is a prevalent gastrointestinal disorder. The immune response plays a crucial role in AP progression. However, the impact of immune regulatory checkpoint PD-L1 on severe acute pancreatitis (SAP) remains uncertain. Hence, this study aimed to examine the influence of PD-L1 on SAP. We assessed PD-L1 expression in neutrophils and monocytes obtained from SAP patients. We induced SAP in C57BL/6J mice, PD-L1 gene-deficient mice, and PD-L1 humanized mice using intraperitoneal injections of cerulein plus lipopolysaccharide. Prior to the initial cerulein injection, a PD-L1 inhibitor was administered. Pancreatic tissues were collected for morphological and immunohistochemical evaluation, and serum levels of amylase, lipase, and cytokines were measured. Flow cytometry analysis was performed using peripheral blood cells. The expression of PD-L1 in neutrophils and monocytes was significantly higher in SAP patients compared to healthy individuals. Likewise, the expression of PD-L1 in inflammatory cells in the peripheral blood of SAP-induced C57BL/6J mice was notably higher than in the control group. In mice with PD-L1 deficiency, SAP model exhibited lower pancreatic pathology scores, amylase, lipase, and cytokine levels compared to wild-type mice. PD-L1 deletion resulted in reduced neutrophil apoptosis, leading to an earlier peak in neutrophil apoptosis. Furthermore, it decreased early monocyte apoptosis and diminished the peak of T lymphocyte apoptosis. Within the SAP model, administration of a PD-L1 inhibitor reduced pancreatic pathology scores, amylase, lipase, and cytokine levels in both C57BL/6J mice and PD-L1 humanized mice. These findings suggest that inhibiting PD-L1 expression can alleviate the severity of SAP.
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Affiliation(s)
- Du-Jiang Yang
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China; Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu 610041, Sichuan Province, China
| | - Ke-Ling Chen
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China
| | - Zhao-Ying Lv
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China
| | - Bin Zhou
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China
| | - Zong-Guang Zhou
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China
| | - Yuan Li
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China.
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Bi YW, Li LS, Ru N, Zhang B, Lei X. Nicotinamide adenine dinucleotide phosphate oxidase in pancreatic diseases: Mechanisms and future perspectives. World J Gastroenterol 2024; 30:429-439. [PMID: 38414585 PMCID: PMC10895600 DOI: 10.3748/wjg.v30.i5.429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/17/2023] [Accepted: 01/12/2024] [Indexed: 01/31/2024] Open
Abstract
Pancreatitis and pancreatic cancer (PC) stand as the most worrisome ailments affecting the pancreas. Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases, yet their true nature continues to elude their grasp. Within this realm, oxidative stress is often believed to play a causal and contributory role in the development of pancreatitis and PC. Excessive accumulation of reactive oxygen species (ROS) can cause oxidative stress, and the key enzyme responsible for inducing ROS production in cells is nicotinamide adenine dinucleotide phosphate hydrogen oxides (NOX). NOX contribute to pancreatic fibrosis and inflammation by generating ROS that injure acinar cells, activate pancreatic stellate cells, and mediate macrophage polarization. Excessive ROS production occurs during malignant transformation and pancreatic carcinogenesis, creating an oxidative microenvironment that can cause abnormal apoptosis, epithelial to mesenchymal transition and genomic instability. Therefore, understanding the role of NOX in pancreatic diseases contributes to a more in-depth exploration of the exact pathogenesis of these diseases. In this review, we aim to summarize the potential roles of NOX and its mechanism in pancreatic disorders, aiming to provide novel insights into understanding the mechanisms underlying these diseases.
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Affiliation(s)
- Ya-Wei Bi
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Long-Song Li
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Nan Ru
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Bo Zhang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Xiao Lei
- Department of Radiation Oncology, Chinese PLA General Hospital, Beijing 100853, China
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Hussein MM, Sayed RKA, Mokhtar DM. Structural and immunohistochemical characterization of pancreas of Molly fish (Poecilia sphenops), with a special reference to its immune role. Microsc Res Tech 2023; 86:1667-1680. [PMID: 37610072 DOI: 10.1002/jemt.24407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/12/2023] [Accepted: 08/12/2023] [Indexed: 08/24/2023]
Abstract
Recently, teleost species have been considered important model systems for investigating different research areas including immunologic one. The available literature provides poor data about the localization and the structure of pancreas in Molly fish. Moreover, little attention has been paid to the immunologic role of pancreatic tissue of teleost, particularly Molly fish; therefore, this study aimed to highlights the description of pancreatic tissue in Molly fish using light- and electron- microscopy, focusing on the role of pancreatic immune cells and pancreatic acinar cells in immune responses. Microscopic analysis revealed that the pancreas of Molly fish was composed of intrahepatic, disseminated and compact parts. Exocrine pancreatic tissue was diffusely extended within the hepatic tissue forming hepatopancreas. The disseminated pancreas appeared as several irregular nodules of pancreatic tissue localized within the mesenteric adipose tissue. The compact pancreas appeared as an oval shaped body embedded within the mesenteric adipose tissue between the spleen and the intestinal loops. Several telocytes and melanomacrophages were detected within the disseminated pancreatic nodules. Moreover, dendritic cells were found in a close association to the exocrine pancreatic acini. The pancreatic acinar cells showed strong immunoreactivity to APG5, TGF-β, IL-1β, NF-κB, Nrf2, and SOX9 in both hepatopancreas and disseminated pancreas of Molly fish. S100 protein revealed a strong expression in the exocrine pancreatic acinar cells of disseminated pancreas and also in the endocrine cells of the compact pancreas. In conclusion, findings of this study suggest the potential role of the pancreas of the Molly fish in cell proliferation and differentiation, proinflammatory cytokines stimulation, and regulation of both innate and adaptive immunity. RESEARCH HIGHLIGHTS: Telocytes and melanomacrophages were detected in the disseminated pancreatic nodules of the Molly fish. In Molly fish, dendritic cells were found in a close association to the exocrine pancreatic acini. Strong immunoreactivity of the pancreatic acinar cells of the Molly fish to APG5, TGF-β, IL-1β, NF-κB, Nrf2, SOX9, and S100.
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Affiliation(s)
- Marwa M Hussein
- Department of Cell and Tissues, Faculty of Veterinary Medicine, Assuit University, Assiut, Egypt
| | - Ramy K A Sayed
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt
| | - Doaa M Mokhtar
- Department of Cell and Tissues, Faculty of Veterinary Medicine, Assuit University, Assiut, Egypt
- Department of Histology and Anatomy, School of Veterinary Medicine, Badr University in Assuit, Assiut, Egypt
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Lv J, Fang M, Sun S, Wang G, Fu S, Sun B, Tong J. Blockade of the Arid5a/IL-6/STAT3 axis underlies the anti-inflammatory effect of Rbpjl in acute pancreatitis. Cell Biosci 2022; 12:95. [PMID: 35725649 PMCID: PMC9208186 DOI: 10.1186/s13578-022-00819-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 05/19/2022] [Indexed: 01/07/2024] Open
Abstract
Background The microarray data analysis predicted that Rbpjl is poorly expressed in acute pancreatitis (AP). Activated IL-6/STAT3 signaling is further known to contribute to the progression of AP through immune regulation, and both IL-6 and STAT3 were bioinformatically predicted to interact with Arid5a. Accordingly, we aimed to investigate the potential involvement of the Arid5a/IL-6/STAT3 axis in the regulatory role of Rbpjl in the inflammation of AP. Methods Pancreatic acinar cells were exposed to lipopolysaccharide (LPS) to induce the pancreatic cell damage, and mice were subjected to supramaximal cerulein stimulation to induce AP. Expression patterns of Rbpjl and the Arid5a/IL-6/STAT3 axis were measured in mouse and cell models. Their expression was further manipulated to explore their effects on pancreatic cell injury and inflammation, as reflected by cell viability and apoptosis as well as reactive oxygen species (ROS) accumulation and proinflammatory cytokine secretion. Moreover, ChIP, EMSA, and dual-luciferase reporter assays were carried out to identify the interactions between Rbpjl and Arid5a. Results Rbpjl was found to be down-regulated in pancreatic tissues of AP mice and LPS-induced pancreatic acinar cells, while re-expression of Rbpjl led to enhanced cell viability, suppressed LPS-induced inflammation and ROS accumulation, and alleviation of AP-induced damage. Mechanistically, Rbpjl could bind to the promoter region of Arid5a and down-regulated its expression, thus repressing the activation of the IL-6/STAT3 signal axis. Furthermore, Rbpjl impaired Arid5a-dependent IL-6/STAT3 activation, hence alleviating pancreatic acinar cell inflammation. Furthermore, these effects were validated with in vivo experiments. Conclusion Collectively, our findings highlight that Rbpjl attenuates AP by down-regulating Arid5a and inactivating the IL-6/STAT3 pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00819-1.
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Kaplan M, Tanoğlu A, Çakır Güney B, Yeniçeri M, Çırak Z, Taştan YÖ, Sade AG, Sade AG, Department of Gastroenterology, Sultan 2. Abdulhamid Han Training and Research Hospital, Istanbul, Turkey, Department of Internal Medicine, Sultan 2. Abdulhamid Han Training and Research Hospital, Istanbul, Turkey, Department of Internal Medicine, Sultan 2. Abdulhamid Han Training and Research Hospital, Istanbul, Turkey, Department of Internal Medicine, Sultan 2. Abdulhamid Han Training and Research Hospital, Istanbul, Turkey, Department of Internal Medicine, Sultan 2. Abdulhamid Han Training and Research Hospital, Istanbul, Turkey, Department of Pathology, Sultan 2. Abdulhamid Han Training and Research Hospital, Istanbul, Turkey. Golimumab Ameliorates Pancreatic Inflammatory Response in the Cerulein-Induced Acute Pancreatitis in Rats. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2022; 33:918-924. [PMID: 36262104 PMCID: PMC9797786 DOI: 10.5152/tjg.2022.21456] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND The aim of the study was to evaluate whether a new and successful treatment opportunity can be provided in acute pancreatitis and may prevent symptomatic treatments and show its effect through etiopathogenesis. Therefore, we want to investigate the efficacy of golimumab in an experimental rat model of cerulein-induced acute pancreatitis. METHODS A total of 35 rats, including 7 rats in each group, were distributed into 5 groups (sham, acute pancreatitis, placebo, acute pancreatitis+golimumab 5 mg/kg, and acute pancreatitis+golimumab 10 mg/kg). An experimental cerulein-induced acute pancreatitis model was accomplished by intraperitoneal cerulein injections. After sacrification, rat blood samples were collected for amylase, IL-6, and IL-1beta measurements. Histopathological analysis of the pancreas was performed with Tunel and hematoxylin and eosin staining. RESULTS Amylase, IL-6, and IL-1beta levels were found to be increased in the acute pancreatitis group. IL-1beta, amylase, IL-6 levels, and pancreatic inflammation were all significantly decreased in golimumab groups (P < .01). Moreover, in both golimumab groups, golimumab treatment significantly reduced apoptosis in pancreatic tissues (P < .05). Golimumab treatment was found to significantly reduce edema formation, inflammation, vacuolization, and fat necrosis of pancreatic tissues (P < .05). CONCLUSION Firstly in the literature, we investigated the efficacy of golimumab in the experimental acute pancreatitis model. In the light of our findings, it could be suggested that golimumab may be an effective and safe therapeutic option in the treatment of patients with acute pancreatitis.
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Affiliation(s)
- Mustafa Kaplan
- Department of Internal Medicine, Sultan 2. Abdulhamid Han Training and Research Hospital, İstanbul, Turkey,Corresponding author: Mustafa Kaplan, e-mail:
| | - Alpaslan Tanoğlu
- Department of Gastroenterology, Sultan 2. Abdulhamid Han Training and Research Hospital, İstanbul, Turkey
| | - Başak Çakır Güney
- Department of Pathology, Sultan 2. Abdulhamid Han Training and Research Hospital, İstanbul, Turkey
| | - Murat Yeniçeri
- Department of Pathology, Sultan 2. Abdulhamid Han Training and Research Hospital, İstanbul, Turkey
| | - Zafer Çırak
- Department of Pathology, Sultan 2. Abdulhamid Han Training and Research Hospital, İstanbul, Turkey
| | - Yeşim Önal Taştan
- Department of Pathology, Sultan 2. Abdulhamid Han Training and Research Hospital, İstanbul, Turkey
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Sun S, Han Y, Zhang C, Liu H, Wang B, Cao S, Yuan Q, Wei S, Chen Y. Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis. Front Cell Dev Biol 2022; 10:827714. [PMID: 35281076 PMCID: PMC8904929 DOI: 10.3389/fcell.2022.827714] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/07/2022] [Indexed: 12/14/2022] Open
Abstract
Background: Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored. Methods: To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 μg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the in vitro effects of ADK inhibition on cerulein–induced inflammation and necroptotic cell death. Results: ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein–treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both in vivo and in vitro. Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A2A receptor antagonist. Conclusion: ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP via the adenosine A2A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.
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Affiliation(s)
- Shukun Sun
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Yu Han
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Chuanxin Zhang
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Han Liu
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Bailu Wang
- Clinical Trial Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shengchuan Cao
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Qiuhuan Yuan
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Shujian Wei
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- *Correspondence: Shujian Wei, ; Yuguo Chen,
| | - Yuguo Chen
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- *Correspondence: Shujian Wei, ; Yuguo Chen,
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Mesna Alleviates Cerulein-Induced Acute Pancreatitis by Inhibiting the Inflammatory Response and Oxidative Stress in Experimental Rats. Dig Dis Sci 2020; 65:3583-3591. [PMID: 32088797 DOI: 10.1007/s10620-020-06072-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 01/12/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Acute pancreatitis (AP) is a sudden inflammation of the pancreas that may be life-threatening disease with high mortality rates, particularly in the presence of systemic inflammatory response and multiple organ failure. Oxidative stress has been shown to be involved in the pathophysiology of acute pancreatitis. AIM This study is designed to investigate the possible effect of mesna on an experimental model of cerulein-induced acute pancreatitis. METHODS Animals were divided into five groups: Group 1 served as a control group given the saline; group II (mesna group) received mesna at a dose of (100 mg/kg per dose, i.p.) four times; group III (acute pancreatitis group) received cerulein at a dose of (20 µg/kg/dose, s.c.) four times with 1-h intervals; group VI, cerulein + mesna, was treated with mesna at a dose of (100 mg/kg, i.p.) 15 min before each cerulein injection. RESULTS Animals with acute pancreatitis showed elevated serum amylase and lipase levels. Biochemical parameters showed increased pancreatic tumor necrosis factors-α (TNF-α) and interleukin-1β (IL-1β) levels. A disturbance in oxidative stress markers was evident by elevated pancreatic lipid peroxides (TBARS) and decline in pancreatic antioxidants' concentrations including reduced glutathione (GSH); superoxide dismutase (SOD); and glutathione peroxidase (GSH-Px). Histological examination confirmed pancreatic injury. Pre-treatment with mesna was able to abolish the changes in pancreatic enzymes, oxidative stress markers (TBARS, SOD, GSH and GSH-Px), pancreatic inflammatory markers (TNF-α, IL-1β) as well as histological changes. CONCLUSIONS Mesna mitigates AP by alleviating pancreatic oxidative stress damage and inhibiting inflammation.
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12
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McMahon DB, Carey RM, Kohanski MA, Tong CCL, Papagiannopoulos P, Adappa ND, Palmer JN, Lee RJ. Neuropeptide regulation of secretion and inflammation in human airway gland serous cells. Eur Respir J 2020; 55:13993003.01386-2019. [PMID: 32029445 DOI: 10.1183/13993003.01386-2019] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 01/13/2020] [Indexed: 12/14/2022]
Abstract
Airway submucosal gland serous cells are sites of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and are important for fluid secretion in conducting airways. To elucidate how neuropeptides regulate serous cells, we tested if human nasal turbinate serous cells secrete bicarbonate (HCO3 -), important for mucus polymerisation and antimicrobial peptide function, during stimulation with cAMP-elevating vasoactive intestinal peptide (VIP) and if this requires CFTR. Serous cells stimulated with VIP exhibited a ∼15-20% cAMP-dependent decrease in cell volume and a ∼0.15 unit decrease in intracellular pH (pHi), reflecting activation of Cl- and HCO3 - secretion, respectively. HCO3 - secretion was directly dependent on CFTR and was absent in cells from CF patients. In contrast, neuropeptide Y (NPY) reduced VIP-evoked cAMP increases, CFTR activation, and Cl-/HCO3 - secretion. Culture of primary serous cells in a model that maintained a serous phenotype confirmed the activating and inhibiting effects of VIP and NPY, respectively, on fluid and HCO3 - secretion. Moreover, VIP enhanced antimicrobial peptide secretion and antimicrobial efficacy of secretions while NPY reduced antimicrobial efficacy. In contrast, NPY enhanced cytokine release while VIP reduced cytokine release through a mechanism requiring CFTR. As levels of VIP and NPY are up-regulated in diseases like allergy, asthma, and chronic rhinosinusitis, the balance of these two peptides in the airway may control mucus rheology and inflammatory responses in serous cells. Furthermore, the loss of CFTR conductance in serous cells may contribute to CF pathophysiology by increasing serous cells inflammatory responses in addition to directly impairing Cl- and HCO3 - secretion.
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Affiliation(s)
- Derek B McMahon
- Dept of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Ryan M Carey
- Dept of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Michael A Kohanski
- Dept of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Charles C L Tong
- Dept of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Peter Papagiannopoulos
- Dept of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Nithin D Adappa
- Dept of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - James N Palmer
- Dept of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Robert J Lee
- Dept of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.,Dept of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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13
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Pasari LP, Khurana A, Anchi P, Aslam Saifi M, Annaldas S, Godugu C. Visnagin attenuates acute pancreatitis via Nrf2/NFκB pathway and abrogates associated multiple organ dysfunction. Biomed Pharmacother 2019; 112:108629. [PMID: 30798137 DOI: 10.1016/j.biopha.2019.108629] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 01/13/2019] [Accepted: 01/28/2019] [Indexed: 12/14/2022] Open
Abstract
Acute pancreatitis (AP) is an exocrine dysfunction of the pancreas where oxidative stress and inflammatory cytokines play a key role in induction and progression of the disease. Studies have demonstrated that antioxidant phytochemicals have been effective in improving pancreatitis condition, but there are no clinically approved drugs till date. Our study aims to assess the preventive activity of visnagin, a novel phytochemical isolated from Ammi visnaga against cerulein induced AP. Male Swiss albino mice were divided into six groups (n = 6, each group) comprising of normal control, cerulein control, seven day pre-treatment with visnagin at three dose levels; visnagin low dose (10 mg/kg), visnagin mid dose (30 mg/kg), visnagin high dose (60 mg/kg) and visnagin control (60 mg/kg). AP was induced by six injections of cerulein (50 μg/kg, i.p.) on the 7th day and the animals were sacrificed after 6 h of last cerulein dose. Various markers of pancreatic function, oxidative stress and inflammation were assessed. Visnagin was found to be effective in reducing plasma amylase and lipase levels, reduced cerulein induced oxidative stress. Visnagin dose dependently decreased the expression of IL-1β, IL-6, TNF-α and IL-17. It attenuated the levels of nuclear p65-NFκB. Visnagin improved the antioxidant defence by improving Nrf2 expression and halted pancreatic inflammation by suppressing NFκB and nitrotyrosine expression in the acinar cells. Further, it attenuated the expression of markers of multiple organ dysfunction syndrome and reduced inflammatory cytokines in lungs and intestine. Cumulatively, these findings indicate that visnagin has substantial potential to prevent cerulein induced AP.
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Affiliation(s)
- Lakshmi Priya Pasari
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana State, India
| | - Amit Khurana
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana State, India
| | - Pratibha Anchi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana State, India
| | - Mohd Aslam Saifi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana State, India
| | - Shivaraju Annaldas
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana State, India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana State, India.
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14
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Zhao JY, Wang JQ, Wu L, Zhang F, Chen ZP, Li WD, Cai H, Liu X. Emodin attenuates cell injury and inflammation in pancreatic acinar AR42J cells. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2019; 21:186-195. [PMID: 29182014 DOI: 10.1080/10286020.2017.1408594] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 11/20/2017] [Indexed: 06/07/2023]
Abstract
The study was intended to investigate the protective effects of emodin against cell injury and inflammation in AR42J cells. We determined trypsin and lipase activity, intracellular ROS and MMP using specific assay kits. The related protein expression and TNF-α and IL-6 in the medium were assayed by Western blot and ELISA kits. Results showed that emodin could protect AR42J cells against cell injury caused by cerulein and lipopolysaccharide which were possibly associated with inhibition of mitochondrial damage, ROS production, and then significantly inhibited ROS-mediated pathway, and ameliorated pancreatic cells injury by depleting the levels of inflammatory cytokines.
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Affiliation(s)
- Jia-Yu Zhao
- a Department of Pharmacology, College of Pharmacy , Nanjing University of Chinese Medicine , Nanjing 210023 , China
- b National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine , Nanjing 210023 , China
| | - Jia-Qi Wang
- a Department of Pharmacology, College of Pharmacy , Nanjing University of Chinese Medicine , Nanjing 210023 , China
| | - Li Wu
- a Department of Pharmacology, College of Pharmacy , Nanjing University of Chinese Medicine , Nanjing 210023 , China
- b National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine , Nanjing 210023 , China
| | - Feng Zhang
- a Department of Pharmacology, College of Pharmacy , Nanjing University of Chinese Medicine , Nanjing 210023 , China
- b National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine , Nanjing 210023 , China
| | - Zhi-Peng Chen
- a Department of Pharmacology, College of Pharmacy , Nanjing University of Chinese Medicine , Nanjing 210023 , China
- b National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine , Nanjing 210023 , China
| | - Wei-Dong Li
- a Department of Pharmacology, College of Pharmacy , Nanjing University of Chinese Medicine , Nanjing 210023 , China
- b National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine , Nanjing 210023 , China
| | - Hao Cai
- a Department of Pharmacology, College of Pharmacy , Nanjing University of Chinese Medicine , Nanjing 210023 , China
- b National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine , Nanjing 210023 , China
| | - Xiao Liu
- a Department of Pharmacology, College of Pharmacy , Nanjing University of Chinese Medicine , Nanjing 210023 , China
- b National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine , Nanjing 210023 , China
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15
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Shaalan A, Carpenter G, Proctor G. Epithelial disruptions, but not immune cell invasion, induced secretory dysfunction following innate immune activation in a novel model of acute salivary gland injury. J Oral Pathol Med 2017; 47:211-219. [PMID: 29160910 DOI: 10.1111/jop.12663] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2017] [Indexed: 11/30/2022]
Abstract
BACKGROUND Salivary gland (SG) injurious agents are all translated into loss of salivation (xerostomia). An association has been established between activation of innate immunity and SG injury and dysfunction. However, it remains unclear how the secretory epithelia respond by halting saliva production. METHODS C57BL/6 submandibular glands (SMGs) were acutely challenged using a single dose of the innate immune stimulant: polyinosinic-polycytidylic acid (poly (I:C)). Secretory capacity of the infected SMGs was substantiated by assessing the flow rate in response to pilocarpine stimulation. Depletion of the acute inflammatory cells was achieved by pre-treating mice with RB6-8C5 depletion antibody. Flow cytometry, histology and immunohistochemistry were conducted to verify the immune cell depletion. Epithelial expression of saliva-driving molecules: muscarinic 3 receptor (M3R), aquaporin 5 water channel (AQP5), Na-K-CL-Cotransporter 1 (NKCC1) and transmembrane member 16A (TMEM16A), was characterized using RT-qPCR and immunohistochemistry. Tight junction (TJ) protein; zonula occludens (ZO-1) and basement membrane (BM) protein; and laminin were assessed by immunohistochemistry. RESULTS Innate immune challenge prompted dysfunction in the exocrine SGs. Dysregulated gene and protein expression of molecules that drive saliva secretion was substantiated. Aberrant expression of TJ and BM proteins followed innate immune activation. Hyposalivation in the current model was independent of myeloperoxidase (MPO)-positive, acute inflammatory cells. CONCLUSIONS In this study, we developed a novel injury model of the SGs, featuring acute secretory dysfunction and immediate structural disruptions. Our results ruled out the injurious role of aggressively infiltrating inflammatory cells.
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Affiliation(s)
- Abeer Shaalan
- Mucosal and Salivary Biology Division, Dental Institute, King's College London, Guy's Hospital, London, UK
| | - Guy Carpenter
- Mucosal and Salivary Biology Division, Dental Institute, King's College London, Guy's Hospital, London, UK
| | - Gordon Proctor
- Mucosal and Salivary Biology Division, Dental Institute, King's College London, Guy's Hospital, London, UK
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Tritschler S, Theis FJ, Lickert H, Böttcher A. Systematic single-cell analysis provides new insights into heterogeneity and plasticity of the pancreas. Mol Metab 2017; 6:974-990. [PMID: 28951822 PMCID: PMC5605721 DOI: 10.1016/j.molmet.2017.06.021] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 06/13/2017] [Accepted: 06/19/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Diabetes mellitus is characterized by loss or dysfunction of insulin-producing β-cells in the pancreas, resulting in failure of blood glucose regulation and devastating secondary complications. Thus, β-cells are currently the prime target for cell-replacement and regenerative therapy. Triggering endogenous repair is a promising strategy to restore β-cell mass and normoglycemia in diabetic patients. Potential strategies include targeting specific β-cell subpopulations to increase proliferation or maturation. Alternatively, transdifferentiation of pancreatic islet cells (e.g. α- or δ-cells), extra-islet cells (acinar and ductal cells), hepatocytes, or intestinal cells into insulin-producing cells might improve glycemic control. To this end, it is crucial to systematically characterize and unravel the transcriptional program of all pancreatic cell types at the molecular level in homeostasis and disease. Furthermore, it is necessary to better determine the underlying mechanisms of β-cell maturation, maintenance, and dysfunction in diabetes, to identify and molecularly profile endocrine subpopulations with regenerative potential, and to translate the findings from mice to man. Recent approaches in single-cell biology started to illuminate heterogeneity and plasticity in the pancreas that might be targeted for β-cell regeneration in diabetic patients. SCOPE OF REVIEW This review discusses recent literature on single-cell analysis including single-cell RNA sequencing, single-cell mass cytometry, and flow cytometry of pancreatic cell types in the context of mechanisms of endogenous β-cell regeneration. We discuss new findings on the regulation of postnatal β-cell proliferation and maturation. We highlight how single-cell analysis recapitulates described principles of functional β-cell heterogeneity in animal models and adds new knowledge on the extent of β-cell heterogeneity in humans as well as its role in homeostasis and disease. Furthermore, we summarize the findings on cell subpopulations with regenerative potential that might enable the formation of new β-cells in diseased state. Finally, we review new data on the transcriptional program and function of rare pancreatic cell types and their implication in diabetes. MAJOR CONCLUSION Novel, single-cell technologies offer high molecular resolution of cellular heterogeneity within the pancreas and provide information on processes and factors that govern β-cell homeostasis, proliferation, and maturation. Eventually, these technologies might lead to the characterization of cells with regenerative potential and unravel disease-associated changes in gene expression to identify cellular and molecular targets for therapy.
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Affiliation(s)
- Sophie Tritschler
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Am Parkring 11, 85748 Garching-Hochbrück, Germany
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Fabian J. Theis
- Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Am Parkring 11, 85748 Garching-Hochbrück, Germany
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Anika Böttcher
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Am Parkring 11, 85748 Garching-Hochbrück, Germany
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany
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17
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Xiong Y, Yepuri G, Necetin S, Montani JP, Ming XF, Yang Z. Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging. Diabetes 2017; 66:1636-1649. [PMID: 28356309 DOI: 10.2337/db16-1190] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 03/21/2017] [Indexed: 11/13/2022]
Abstract
Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-II L-arginine-ureahydrolase, is highly expressed in pancreas. However, its role in regulation of pancreatic β-cell function is not known. Here we show that female (not male) mice deficient in Arg-II (Arg-II-/-) are protected from age-associated glucose intolerance and reveal greater glucose induced-insulin release, larger islet size and β-cell mass, and more proliferative and less apoptotic β-cells compared with the age-matched wild-type (WT) controls. Moreover, Arg-II is mainly expressed in acinar cells and is upregulated with aging, which enhances p38 mitogen-activated protein kinase (p38 MAPK) activation and release of tumor necrosis factor-α (TNF-α). Accordingly, conditioned medium of isolated acinar cells from old WT (not Arg-II-/-) mice contains higher TNF-α levels than the young mice and stimulates β-cell apoptosis and dysfunction, which are prevented by a neutralizing anti-TNF-α antibody. In acinar cells, our study demonstrates an age-associated Arg-II upregulation, which promotes TNF-α release through p38 MAPK leading to β-cell apoptosis, insufficient insulin secretion, and glucose intolerance in female rather than male mice.
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Affiliation(s)
- Yuyan Xiong
- Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
- Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland
| | - Gautham Yepuri
- Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
| | - Sevil Necetin
- Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
| | - Jean-Pierre Montani
- Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
- Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland
| | - Xiu-Fen Ming
- Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
- Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland
| | - Zhihong Yang
- Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
- Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland
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Kaur J, Sidhu S, Chopra K, Khan MU. Protective effect of Mimosa pudica L. in an l-arginine model of acute necrotising pancreatitis in rats. J Nat Med 2016; 70:423-34. [DOI: 10.1007/s11418-016-0991-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Accepted: 03/25/2016] [Indexed: 01/22/2023]
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Bläuer M, Laaninen M, Sand J, Laukkarinen J. Reciprocal stimulation of pancreatic acinar and stellate cells in a novel long-term in vitro co-culture model. Pancreatology 2016; 16:570-7. [PMID: 27075041 DOI: 10.1016/j.pan.2016.03.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Revised: 03/16/2016] [Accepted: 03/18/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND/OBJECTIVES Pancreatic stellate cells (PSCs) are the key fibrogenic cells in the pancreas. Acinar cell injury is known to trigger PSC activation. To facilitate the experimental analysis of the crosstalk between acinar cells and PSCs, an in vitro system for their long-term co-cultivation was developed. MATERIALS AND METHODS PSCs and acinar cells capable of retaining their secretory phenotype in long-term in vitro culture were obtained from mouse pancreata. A dual-chamber co-culture model was built in 24-well format with acinar cells seeded in the wells and PSCs in tissue culture inserts. Acinar cell-3T3 fibroblast co-cultures served as controls. After 4-day maintenance, the acinar compartment was analyzed for cell morphology, secretory capability, necrosis (HMGB1), apoptosis (TUNEL) and inflammation (NFκB). PSCs were analyzed for migratory activity and extracellular matrix (ECM) protein expression. The results were compared to parallel monocultures. RESULTS Acinar cells in monoculture and in co-culture with fibroblasts exhibited a healthy monolayer arrangement and an ability to respond to 0.1 nM caerulein stimulus by increased amylase release. Co-culture with PSCs caused marked changes in acinar cell morphology and rendered them insensitive to secretagogue stimulus. Activation of NFκB and necrotic changes, but not apoptosis, were identified in co-cultured acinar cells. Co-culture increased the migratory activity and ECM protein expression of PSCs. CONCLUSIONS Humoral interactions between acinar and PSCs in co-culture were shown to reciprocally affect their cellular functions. With its two separable cell compartments the co-culture system provides a versatile culture setting that allows independent manipulation and analysis of both cell types.
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Affiliation(s)
- Merja Bläuer
- Tampere Pancreas Laboratory, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland
| | - Matias Laaninen
- Tampere Pancreas Laboratory, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland
| | - Juhani Sand
- Tampere Pancreas Laboratory, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland; Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland
| | - Johanna Laukkarinen
- Tampere Pancreas Laboratory, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland; Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland.
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Inman KS, Francis AA, Murray NR. Complex role for the immune system in initiation and progression of pancreatic cancer. World J Gastroenterol 2014; 20:11160-11181. [PMID: 25170202 PMCID: PMC4145756 DOI: 10.3748/wjg.v20.i32.11160] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/27/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.
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21
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Difference in Early Activation of NF-κB and MCP-1 in Acinar-Cell-Rich versus Fibrotic Human Pancreas Exposed to Surgical Trauma and Hypoxia. Gastroenterol Res Pract 2014; 2014:460363. [PMID: 25147563 PMCID: PMC4131420 DOI: 10.1155/2014/460363] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 07/13/2014] [Accepted: 07/15/2014] [Indexed: 01/23/2023] Open
Abstract
Objectives. Previously we have shown that a pancreas with over 40% acinar cells is exposed to postoperative pancreatitis and other complications after pancreaticoduodenectomy (PD). Our aim was to analyze the expression of NF-κB and MCP-1 in the cut edge of human pancreas after PD in both acinar-cell-rich and fibrotic pancreata. Methods. Several pancreatic samples from six patients, three with acinar-cell-rich and three with fibrotic pancreata, were exposed to surgical trauma in PD, and thereafter to hypoxemia for 15 minutes, 2-2.5 hours, 4 hours, or 6 hours, to mimic postoperative conditions of the pancreatic remnant in a patient. Immunohistochemical analysis of inflammation markers (NF-κB, MCP-1) was performed. Results. In the acinar-cell-rich pancreata, intra-acinar NF-κB and MCP-1 expression increased from mild at 15 minutes to high during the first 4 hours, whereas in ductal cells MCP-1 staining was highly intense at both time points. Acinar cell NF-κB and MCP-1 expression and ductal cell MCP-1 expression were also observed in the fibrotic pancreata, but the activation remained low throughout the 6 hours. Conclusions. In acinar-cell-rich pancreas, an extensive inflammatory cascade begins almost immediately after surgical trauma. Fibrosis may limit the progression of inflammatory process in pancreas.
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Jiang CY, Wang W, Tang JX, Yuan ZR. The adipocytokine resistin stimulates the production of proinflammatory cytokines TNF-α and IL-6 in pancreatic acinar cells via NF-κB activation. J Endocrinol Invest 2013; 36:986-92. [PMID: 23765438 DOI: 10.3275/9002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Resistin, an adipocytokine secreted by fat tissues, has been associated with the inflammatory response, though its role in inflammation during acute pancreatitis (AP) remains unclear. OBJECTIVE The proinflammatory response following acinar cell injury impacts pancreatitis severity, necessitating better understanding of functional consequences associated with pancreatic acinar cell resistin exposure and resultant effects on proinflammatory signaling. METHODS Amylase-secreting rat pancreatic acinar AR42J cells were subjected to 1, 10, or 100 ng/ml recombinant rat resistin treatments. Cytotoxicity was evaluated by amylase secretion and lactate dehydrogenase (LDH) release. Tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) mRNA and protein expressions were determined by real-time real time-PCR and enzyme-linked immunosorbent assay, respectively. Nuclear NF-κB p65 subunit protein level was measured by western blotting. RESULTS Significantly increased amylase secretion and LDH release was observed in the 100 ng/ml resistin treatment (p<0.01). Both TNF-α and IL-6 protein expression levels increased in a concentration-dependent manner when treated with resistin. Pretreatment of resistin- treated AR42J cells with the NF-κB inhibitor PDTC, which decreases the NF-κB p65 subunit protein expression levels in the nuclei, produced significantly lower mRNA expression levels for both TNF-α and IL-6 compared with those produced by resistin-treated cells (p<0.01). CONCLUSIONS Resistin exhibits some cytotoxic activity in rat pancreatic acinar AR42J cells and stimulates proinflammatory cytokine TNF-α and IL-6 production via NF-κB activation. Thus, overproduction of obesity-related circulating resistin and associated lowgrade inflammation may result in mild injury to pancreatic acini, increasing AP severity and risk.
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Affiliation(s)
- C Y Jiang
- Department of General Surgery, Huadong Hospital Affiliated To Fudan University, Shanghai 200040, China
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Chen C, Xu P, Wang J, Lou XL. Effect of PI3K inhibitor wortmannin on cytokine levels and pancreatic histopathological scores in rats with severe acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2012; 20:3663-3669. [DOI: 10.11569/wcjd.v20.i36.3663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of the PI3K/Akt signaling transduction pathway inhibitor wortmannin on the levels of cytokines [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6] and pancreatic histopathological changes in rats with severe acute pancreatitis (SAP).
METHODS: Sixty male Sprague-Dawley (SD) rats were randomly divided into five groups, including SAP group, sham operation group, normal saline group, DMSO control group, and wortmannin group. The modified Aho's method was used to reproduce the SAP model. The rats were sacrificed 3 and 6 h after treatment. The levels of inflammatory cytokines TNF-α, IL-1β and IL-6 in serum were determined by ELISA. Transcription levels of these inflammatory cytokines in pancreatic tissue were determined by real-time PCR. In addition, the amount of ascites, the activities of serum amylase and ascites amylase, and the pathological scores of pancreatic tissue were also measured.
RESULTS: At 3 and 6 h after treatment, all parameters tested, including the amount of ascites, the levels of serum and ascites amylase, the pathological scores of pancreatic tissue, serum levels of TNF-α, IL-1β and IL-6, and the transcription levels of TNF-α, IL-1β and IL-6 mRNAs in the pancreatic tissue, in the SAP group and DMSO group were significantly higher than those in the normal saline group and sham operation group (all P < 0.05). Compared to the SAP group and DMSO group, the above parameters decreased significantly in the wortmannin group (all P < 0.05).
CONCLUSION: Wortmannin exerts a protective effect against SAP possibly by down-regulating the levels of TNF-α, IL-1β and IL-6 and reducing pathological injury of pancreatic tissue in rats.
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Santana DG, Santos CA, Santos ADC, Nogueira PCL, Thomazzi SM, Estevam CS, Antoniolli AR, Camargo EA. Beneficial effects of the ethanol extract of Caesalpinia pyramidalis on the inflammatory response and abdominal hyperalgesia in rats with acute pancreatitis. JOURNAL OF ETHNOPHARMACOLOGY 2012; 142:445-455. [PMID: 22626927 DOI: 10.1016/j.jep.2012.05.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Revised: 05/05/2012] [Accepted: 05/06/2012] [Indexed: 06/01/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Caesalpinia pyramidalis Tul. (Fabaceae) is a plant found in the Northeast of Brazil that is popularly used to treat inflammation. Acute pancreatitis (AP) is an inflammatory disease for which abdominal pain is a relevant symptom. As there is no specific therapy for AP, we investigated the effect of the ethanol extract from the inner bark of C. pyramidalis (EECp) on the AP induced by common bile duct obstruction (CBDO) in rats. MATERIAL AND METHODS AP was induced in male Wistar rats (200-250 g, n=6-8) through laparotomy and subsequent CBDO. Animals were euthanized after 6 (G6h) or 24 h (G24h) of induction. In the G6h protocol, animals were pretreated with EECp (100-400 mg/kg, p.o.) or vehicle (Tween 80; 0.2%) 1h before CBDO or sham surgery. For the G24h protocol, rats were pretreated with EECp (400mg/kg, 1h before CBDO or 1 h before and 12 h after CBDO) or vehicle. The following parameters were measured: inflammatory/oxidative (myeloperoxidase activity and malondialdehyde formation in the pancreas and lung, leukocyte counts in the blood and serum nitrate/nitrite), enzymatic (serum amylase and lipase levels) and nociceptive (abdominal hyperalgesia). RESULTS Induction of AP by CBDO significantly increased all the parameters evaluated in both G6h and G24h protocols when compared with the respective sham group. In the G6h protocol, the EECp pretreatment (400 mg/kg) significantly reduced all these parameters, besides completely inhibiting abdominal hyperalgesia. The same profile of reduction was observed from two administrations of EECp in the G24h protocol, while one single dose of EECp was able to significantly reduce pancreatic MDA, serum lipase levels, leukocyte counts in the blood and abdominal hyperalgesia without affecting the other parameters in the G24h protocol. Furthermore, rutin was found in the EECp. CONCLUSIONS Our results demonstrated that EECp decreases inflammation, lipoperoxidation and hyperalgesia in CBDO-induced AP, making it of interest in future approaches to treat this condition.
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Affiliation(s)
- Danielle G Santana
- Department of Physiology, Federal University of Sergipe (UFS), São Cristóvão, 49100-000 SE, Brazil
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