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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [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: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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Oikonomou P, Nikolaou C, Papachristou F, Sovatzidis A, Lambropoulou M, Giouleka C, Kontaxis V, Linardoutsos D, Papalois A, Pitiakoudis M, Tsaroucha A. Eugenol Reduced ΜPO, CD45 and HMGB1 Expression and Attenuated the Expression of Leukocyte Infiltration Markers in the Intestinal Tissue in Biliopancreatic Duct Ligation-Induced Pancreatitis in Rats. MEDICINA (KAUNAS, LITHUANIA) 2023; 60:74. [PMID: 38256335 PMCID: PMC10820626 DOI: 10.3390/medicina60010074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/30/2023] [Accepted: 12/26/2023] [Indexed: 01/24/2024]
Abstract
Background and Objectives: Inflammation and dysregulation in the intestinal barrier function in acute pancreatitis (AP) trigger pancreatic lesions, systemic inflammatory response, and multiple organ dysfunction. Eugenol, as the main component of clove (Syzygium aromaticum), is known for its antioxidant and anti-inflammatory properties. We studied the potentially beneficial effect of eugenol in a rodent model of biliopancreatic duct ligation-induced AP. Materials and Methods: Rats were randomly divided into three groups: Sham, AP, and AP + eugenol (15 mg/kg/day). Serum TNFα, IL-6, IL-18, and resistin levels, as well as IL-6, TNFα, MPO, HMGB1, and CD45 tissue expression, were determined at various timepoints after the induction of AP. Results: Eugenol attenuated hyperemia and inflammatory cell infiltration in the intestinal mucosal, submucosal, and muscular layers. IL-6 and resistin serum levels were significantly reduced in the AP + eugenol group, while serum TNFα and IL-18 levels remained unaffected overall. TNFα pancreatic and intestinal expression was attenuated by eugenol at 72 h, while IL-6 expression was affected only in the pancreas. MPO, CD45, and HMGB1 intestinal expression was significantly reduced in eugenol-treated rats. Conclusions: Eugenol managed to attenuate the inflammatory response in the intestine in duct ligation-induced AP in rats.
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Affiliation(s)
- Panagoula Oikonomou
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Christina Nikolaou
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Fotini Papachristou
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Apostolos Sovatzidis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Maria Lambropoulou
- Laboratory of Histology-Embryology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Charikleia Giouleka
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Vasileios Kontaxis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Dimitrios Linardoutsos
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Apostolos Papalois
- Experimental Research Center, ELPEN Pharmaceuticals, Pikermi, 19009 Athens, Greece;
| | - Michael Pitiakoudis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Alexandra Tsaroucha
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
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Al-Hashem F. Metformin Ameliorates Infiltration of Inflammatory Cells and Pancreatic Injury Biomarkers Induced by L-Arginine. INT J PHARMACOL 2022. [DOI: 10.3923/ijp.2022.1038.1046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Fu Q, Colgan SP, Shelley CS. Hypoxia: The Force that Drives Chronic Kidney Disease. Clin Med Res 2016; 14:15-39. [PMID: 26847481 PMCID: PMC4851450 DOI: 10.3121/cmr.2015.1282] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 09/30/2015] [Indexed: 12/15/2022]
Abstract
In the United States the prevalence of end-stage renal disease (ESRD) reached epidemic proportions in 2012 with over 600,000 patients being treated. The rates of ESRD among the elderly are disproportionally high. Consequently, as life expectancy increases and the baby-boom generation reaches retirement age, the already heavy burden imposed by ESRD on the US health care system is set to increase dramatically. ESRD represents the terminal stage of chronic kidney disease (CKD). A large body of evidence indicating that CKD is driven by renal tissue hypoxia has led to the development of therapeutic strategies that increase kidney oxygenation and the contention that chronic hypoxia is the final common pathway to end-stage renal failure. Numerous studies have demonstrated that one of the most potent means by which hypoxic conditions within the kidney produce CKD is by inducing a sustained inflammatory attack by infiltrating leukocytes. Indispensable to this attack is the acquisition by leukocytes of an adhesive phenotype. It was thought that this process resulted exclusively from leukocytes responding to cytokines released from ischemic renal endothelium. However, recently it has been demonstrated that leukocytes also become activated independent of the hypoxic response of endothelial cells. It was found that this endothelium-independent mechanism involves leukocytes directly sensing hypoxia and responding by transcriptional induction of the genes that encode the β2-integrin family of adhesion molecules. This induction likely maintains the long-term inflammation by which hypoxia drives the pathogenesis of CKD. Consequently, targeting these transcriptional mechanisms would appear to represent a promising new therapeutic strategy.
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Affiliation(s)
- Qiangwei Fu
- Kabara Cancer Research Institute, La Crosse, WI
| | - Sean P Colgan
- Mucosal Inflammation Program and University of Colorado School of Medicine, Aurora, CO
| | - Carl Simon Shelley
- University of Wisconsin School of Medicine and Public Health, Madison, WI
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5
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Abstract
Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF-VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis.
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Moreno ML, Escobar J, Izquierdo-Álvarez A, Gil A, Pérez S, Pereda J, Zapico I, Vento M, Sabater L, Marina A, Martínez-Ruiz A, Sastre J. Disulfide stress: a novel type of oxidative stress in acute pancreatitis. Free Radic Biol Med 2014; 70:265-77. [PMID: 24456905 DOI: 10.1016/j.freeradbiomed.2014.01.009] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 12/26/2013] [Accepted: 01/07/2014] [Indexed: 11/25/2022]
Abstract
Glutathione oxidation and protein glutathionylation are considered hallmarks of oxidative stress in cells because they reflect thiol redox status in proteins. Our aims were to analyze the redox status of thiols and to identify mixed disulfides and targets of redox signaling in pancreas in experimental acute pancreatitis as a model of acute inflammation associated with glutathione depletion. Glutathione depletion in pancreas in acute pancreatitis is not associated with any increase in oxidized glutathione levels or protein glutathionylation. Cystine and homocystine levels as well as protein cysteinylation and γ-glutamyl cysteinylation markedly rose in pancreas after induction of pancreatitis. Protein cysteinylation was undetectable in pancreas under basal conditions. Targets of disulfide stress were identified by Western blotting, diagonal electrophoresis, and proteomic methods. Cysteinylated albumin was detected. Redox-sensitive PP2A and tyrosine protein phosphatase activities diminished in pancreatitis and this loss was abrogated by N-acetylcysteine. According to our findings, disulfide stress may be considered a specific type of oxidative stress in acute inflammation associated with protein cysteinylation and γ-glutamylcysteinylation and oxidation of the pair cysteine/cystine, but without glutathione oxidation or changes in protein glutathionylation. Two types of targets of disulfide stress were identified: redox buffers, such as ribonuclease inhibitor or albumin, and redox-signaling thiols, which include thioredoxin 1, APE1/Ref1, Keap1, tyrosine and serine/threonine phosphatases, and protein disulfide isomerase. These targets exhibit great relevance in DNA repair, cell proliferation, apoptosis, endoplasmic reticulum stress, and inflammatory response. Disulfide stress would be a specific mechanism of redox signaling independent of glutathione redox status involved in inflammation.
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Affiliation(s)
- Mari-Luz Moreno
- Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot (Valencia), Spain
| | - Javier Escobar
- Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot (Valencia), Spain; Division of Neonatology, University Hospital Materno-Infantil La Fe, 46026 Valencia, Spain
| | - Alicia Izquierdo-Álvarez
- Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
| | - Anabel Gil
- Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot (Valencia), Spain
| | - Salvador Pérez
- Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot (Valencia), Spain
| | - Javier Pereda
- Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot (Valencia), Spain
| | - Inés Zapico
- Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain; Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Madrid, Spain
| | - Máximo Vento
- Division of Neonatology, University Hospital Materno-Infantil La Fe, 46026 Valencia, Spain
| | - Luis Sabater
- Department of Surgery, University Clinic Hospital, University of Valencia, 46010 Valencia, Spain
| | - Anabel Marina
- Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Madrid, Spain
| | - Antonio Martínez-Ruiz
- Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
| | - Juan Sastre
- Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot (Valencia), Spain.
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Kuban-Jankowska A, Tuszynski JA, Winter P, Gorska M, Knap N, Wozniak M. Activation of hydrogen peroxide to peroxytetradecanoic acid is responsible for potent inhibition of protein tyrosine phosphatase CD45. PLoS One 2012; 7:e52495. [PMID: 23300686 PMCID: PMC3531430 DOI: 10.1371/journal.pone.0052495] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2012] [Accepted: 11/19/2012] [Indexed: 11/19/2022] Open
Abstract
Hydrogen peroxide induces oxidation and consequently inactivation of many protein tyrosine phosphatases. It was found that hydrogen peroxide, in the presence of carboxylic acids, was efficiently activated to form even more potent oxidant - peroxy acid. We have found that peroxytetradecanoic acid decreases the enzymatic activity of CD45 phosphatase significantly more than hydrogen peroxide. Our molecular docking computational analysis suggests that peroxytetradecanoic acid has a higher binding affinity to the catalytic center of CD45 than hydrogen peroxide.
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Affiliation(s)
- Alicja Kuban-Jankowska
- Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland
- * E-mail: (AKJ); (MW)
| | - Jack A. Tuszynski
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Philip Winter
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Magdalena Gorska
- Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland
| | - Narcyz Knap
- Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland
| | - Michal Wozniak
- Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland
- College of Health, Beauty Care and Education in Poznan, Faculty in Gdynia, Gdynia, Poland
- * E-mail: (AKJ); (MW)
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Esrefoglu M. Experimental and clinical evidence of antioxidant therapy in acute pancreatitis. World J Gastroenterol 2012; 18:5533-41. [PMID: 23112545 PMCID: PMC3482639 DOI: 10.3748/wjg.v18.i39.5533] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Revised: 06/13/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress has been shown to play an important role in the pathogenesis of acute pancreatitis (AP). Antioxidants, alone or in combination with conventional therapy, should improve oxidative-stress-induced organ damage and therefore accelerate the rate of recovery. In recent years, substantial amounts of data about the efficiency of antioxidants against oxidative damage have been obtained from experiments with rodents. Some of these antioxidants have been found beneficial in the treatment of AP in humans; however, at present there is insufficient clinical data to support the benefits of antioxidants, alone or in combination with conventional therapy, in the management of AP in humans. Conflicting results obtained from experimental animals and humans may represent distinct pathophysiological mechanisms mediating tissue injury in different species. Further detailed studies should be done to clarify the exact mechanisms of tissue injury in human AP. Herein I tried to review the existing experimental and clinical studies on AP in order to determine the efficiency of antioxidants. The use of antioxidant enriched nutrition is a potential direction of clinical research in AP given the lack of clues about the efficiency and safety of antioxidant usage in patients with AP.
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Pereda J, Pérez S, Escobar J, Arduini A, Asensi M, Serviddio G, Sabater L, Aparisi L, Sastre J. Obese rats exhibit high levels of fat necrosis and isoprostanes in taurocholate-induced acute pancreatitis. PLoS One 2012; 7:e44383. [PMID: 23028532 PMCID: PMC3445528 DOI: 10.1371/journal.pone.0044383] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 08/02/2012] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Obesity is a prognostic factor for severity in acute pancreatitis in humans. Our aim was to assess the role of oxidative stress and abdominal fat in the increased severity of acute pancreatitis in obese rats. METHODOLOGY Taurocholate-induced acute pancreatitis was performed in lean and obese Zucker rats. Levels of reduced glutathione, oxidized glutathione, L-cysteine, cystine, and S-adenosylmethionine were measured in pancreas as well as the activities of serine/threonine protein phosphatases PP1 and PP2A and tyrosin phosphatases. Isoprostane, malondialdehyde, triglyceride, and free fatty acid levels and lipase activity were measured in plasma and ascites. Lipase activity was measured in white adipose tissue with and without necrosis and confirmed by western blotting. FINDINGS Under basal conditions obese rats exhibited lower reduced glutathione levels in pancreas and higher triglyceride and free fatty acid levels in plasma than lean rats. S-adenosyl methionine levels were markedly increased in pancreas of obese rats. Acute pancreatitis in obese rats led to glutathione oxidation and lower reduced glutathione levels in pancreas together with decreased activities of redox-sensitive phosphatases PP1, and PP2A. S-adenosyl methionine levels decreased but cystine levels increased markedly in pancreas upon pancreatitis. Acute pancreatitis triggered an increase in isoprostane levels in plasma and ascites in obese rats. Free fatty acid levels were extremely high in pancreatitis-associated ascitic fluid from obese rats and lipase was bound with great affinity to white adipose tissue, especially to areas of necrosis. CONCLUSIONS Our results show that oxidative stress occurs locally and systemically in obese rats with pancreatitis favouring inactivation of protein phosphatases in pancreas, which would promote up-regulation of pro-inflammatory cytokines, and the increase of isoprostanes which might cause powerful pulmonary and renal vasoconstriction. Future studies are needed to confirm the translational relevance of the present findings obtained in a rat model of taurocholate-induced pancreatic damage and necrosis.
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Affiliation(s)
- Javier Pereda
- Department of Physiology, School of Pharmacy, University of Valencia, Burjasot, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, School of Pharmacy, University of Valencia, Burjasot, Valencia, Spain
| | - Javier Escobar
- Department of Physiology, School of Pharmacy, University of Valencia, Burjasot, Valencia, Spain
- Division of Neonatology, University Hospital Materno-Infantil La Fe, Valencia, Spain
| | - Alessandro Arduini
- Department of Physiology, School of Pharmacy, University of Valencia, Burjasot, Valencia, Spain
| | - Miguel Asensi
- Department of Physiology, School of Pharmacy, University of Valencia, Burjasot, Valencia, Spain
| | - Gaetano Serviddio
- Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy
| | - Luis Sabater
- Department of Surgery, University of Valencia, Universitary Clinic Hospital, Valencia, Spain
| | - Luis Aparisi
- Laboratory of Pancreatic Function, Universitary Clinic Hospital, Valencia, Spain
| | - Juan Sastre
- Department of Physiology, School of Pharmacy, University of Valencia, Burjasot, Valencia, Spain
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Zhang Z, Wang Y, Dong M, Cui J, Rong D, Dong Q. Oxymatrine ameliorates L-arginine-induced acute pancreatitis in rats. Inflammation 2012; 35:605-13. [PMID: 21633783 DOI: 10.1007/s10753-011-9352-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The aim of this study was to determine whether oxymatrine has a protective effect against acute pancreatitis (AP) in a rat model of L-arginine-induced AP. AP was induced by two intraperitoneal injections of L-arginine (250 mg/100 g) at a 1-h interval. Oxymatrine (50 mg/kg) was administered every 6 h after the induction of AP. Oxymatrine significantly reduced the plasma amylase, D-lactic acid and tumor necrosis factor alpha concentration, serum diamine oxidase and lipase activity, and pancreatic myeloperoxidase activity, which were increased in AP rats (P < 0.05). In addition, the pancreatic CD45 expression and the expression of claudin-1, but not zonula occludens-1 (ZO-1) and occludin, in the intestinal tissues were significantly reduced after the induction of AP. However, oxymatrine increased the expression of claudin-1 and CD45, but did not alter the expression of ZO-1 and occludin. In conclusion, our results demonstrated that oxymatrine is potentially capably of protecting against L-arginine-induced AP and attenuating AP-associated intestinal barrier injury by up-regulation of claudin-1.
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Affiliation(s)
- Zhiqiang Zhang
- Department of General Surgery, The People's Hospital of Liaoning Province, 33 Wenyi Road, Shenyang 110016, People's Republic of China
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Escobar J, Pereda J, López-Rodas G, Sastre J. Redox signaling and histone acetylation in acute pancreatitis. Free Radic Biol Med 2012; 52:819-37. [PMID: 22178977 DOI: 10.1016/j.freeradbiomed.2011.11.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 11/08/2011] [Accepted: 11/09/2011] [Indexed: 12/22/2022]
Abstract
Histone acetylation via CBP/p300 coordinates the expression of proinflammatory cytokines in the activation phase of inflammation, particularly through mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB), and signal transducers and activators of transcription (STAT) pathways. In contrast, histone deacetylases (HDACs) and protein phosphatases are mainly involved in the attenuation phase of inflammation. The role of reactive oxygen species (ROS) in the inflammatory cascade is much more important than expected. Mitochondrial ROS act as signal-transducing molecules that trigger proinflammatory cytokine production via inflammasome-independent and inflammasome-dependent pathways. The major source of ROS in acute inflammation seems to be NADPH oxidases, whereas NF-κB, protein phosphatases, and HDACs are the major targets of ROS and redox signaling in this process. There is a cross-talk between oxidative stress and proinflammatory cytokines through serine/threonine protein phosphatases, tyrosine protein phosphatases, and MAPKs that greatly contributes to amplification of the uncontrolled inflammatory cascade and tissue injury in acute pancreatitis. Chromatin remodeling during induction of proinflammatory genes would depend primarily on phosphorylation of transcription factors and their binding to gene promoters together with recruitment of histone acetyltransferases. PP2A should be considered a key modulator of the inflammatory cascade in acute pancreatitis through the ERK/NF-κB pathway and histone acetylation.
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Affiliation(s)
- Javier Escobar
- Department of Physiology, School of Pharmacy, University of Valencia, Burjasot, Valencia, Spain
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12
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Escobar J, Pereda J, Arduini A, Sandoval J, Moreno ML, Pérez S, Sabater L, Aparisi L, Cassinello N, Hidalgo J, Joosten LAB, Vento M, López-Rodas G, Sastre J. Oxidative and nitrosative stress in acute pancreatitis. Modulation by pentoxifylline and oxypurinol. Biochem Pharmacol 2011; 83:122-30. [PMID: 22000995 DOI: 10.1016/j.bcp.2011.09.028] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Revised: 09/29/2011] [Accepted: 09/30/2011] [Indexed: 12/17/2022]
Abstract
Reactive oxygen species are considered mediators of the inflammatory response and tissue damage in acute pancreatitis. We previously found that the combined treatment with oxypurinol - as inhibitor of xanthine oxidase- and pentoxifylline - as inhibitor of TNF-α production-restrained local and systemic inflammatory response and decreased mortality in experimental acute pancreatitis. Our aims were (1) to determine the time-course of glutathione depletion and oxidation in necrotizing pancreatitis in rats and its modulation by oxypurinol and pentoxifylline; (2) to determine whether TNF-α is responsible for glutathione depletion in acute pancreatitis; and (3) to elucidate the role of oxidative stress in the inflammatory cascade in pancreatic AR42J acinar cells. We report here that oxidative stress and nitrosative stress occur in pancreas and lung in acute pancreatitis and the co-treatment with oxypurinol and pentoxifylline prevents oxidative stress in both tissues. Oxypurinol was effective in preventing glutathione oxidation, whereas pentoxifylline abrogated glutathione depletion. This latter effect was independent of TNF-α since glutathione depletion occurred in mice deficient in TNF-α or its receptors after induction of pancreatitis. The beneficial effects of oxypurinol in the inflammatory response may also be ascribed to a partial inhibition of MEK1/2 activity. Pentoxifylline markedly reduced the expression of Icam1 and iNos induced by TNF-α in vitro in AR42J cells. Oxidative stress significantly contributes to the TNF-α-induced up-regulation of Icam and iNos in AR42J cells. These results provide new insights into the mechanism of action of oxypurinol and pentoxifylline as anti-inflammatory agents in acute pancreatitis.
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Affiliation(s)
- Javier Escobar
- Department of Physiology, School of Pharmacy, University of Valencia, Spain.
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Dios ID. Inflammatory role of the acinar cells during acute pancreatitis. World J Gastrointest Pharmacol Ther 2010; 1:15-20. [PMID: 21577290 PMCID: PMC3091137 DOI: 10.4292/wjgpt.v1.i1.15] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 01/07/2010] [Accepted: 01/14/2010] [Indexed: 02/06/2023] Open
Abstract
Pancreatic acinar cells are secretory cells whose main function is to synthesize, store and finally release digestive enzymes into the duodenum. However, in response to noxious stimuli, acinar cells behave like real inflammatory cells because of their ability to activate signalling transduction pathways involved in the expression of inflammatory mediators. Mediated by the kinase cascade, activation of Nuclear factor-κB, Activating factor-1 and Signal transducers and activators of transcription transcription factors has been demonstrated in acinar cells, resulting in overexpression of inflammatory genes. In turn, kinase activity is down-regulated by protein phosphatases and the final balance between kinase and phosphatase activity will determine the capability of the acinar cells to produce inflammatory factors. The kinase/phosphatase pair is a redox-sensitive system in which kinase activation overwhelms phosphatase activity under oxidant conditions. Thus, the oxidative stress developed within acinar cells at early stages of acute pancreatitis triggers the activation of signalling pathways involved in the up-regulation of cytokines, chemokines and adhesion molecules. In this way, acinar cells trigger the release of the first inflammatory signals which can mediate the activation and recruitment of circulating inflammatory cells into the injured pancreas. Accordingly, the role of acinar cells as promoters of the inflammatory response in acute pancreatitis may be considered. This concept leads to amplifying the focus from leukocyte to acinar cells themselves, to explain the local inflammation in early pancreatitis.
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Affiliation(s)
- Isabel De Dios
- Isabel De Dios, Department of Physiology and Pharmacology, University of Salamanca, Salamanca 37007, Spain
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Sandoval J, Escobar J, Pereda J, Sacilotto N, Rodriguez JL, Sabater L, Aparisi L, Franco L, López-Rodas G, Sastre J. Pentoxifylline prevents loss of PP2A phosphatase activity and recruitment of histone acetyltransferases to proinflammatory genes in acute pancreatitis. J Pharmacol Exp Ther 2009; 331:609-17. [PMID: 19671881 DOI: 10.1124/jpet.109.157537] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Mitogen-activated protein kinases (MAPKs) are considered major signal transducers early during the development of acute pancreatitis. Pentoxifylline is a phosphodiesterase inhibitor with marked anti-inflammatory properties through blockade of extracellular signal regulated kinase (ERK) phosphorylation and tumor necrosis factor alpha production. Our aim was to elucidate the mechanism of action of pentoxifylline as an anti-inflammatory agent in acute pancreatitis. Necrotizing pancreatitis induced by taurocholate in rats and taurocholate-treated AR42J acinar cells were studied. Phosphorylation of ERK and ERK kinase (MEK1/2), as well as PP2A, PP2B, and PP2C serine/threonine phosphatase activities, up-regulation of proinflammatory genes (by reverse transcription-polymerase chain reaction and chromatin immunoprecipitation), and recruitment of transcription factors and histone acetyltransferases/deacetylases to promoters of proinflammatory genes (egr-1, atf-3, inos, icam, il-6, and tnf-alpha) were determined in the pancreas during pancreatitis. Pentoxifylline did not reduce MEK1/2 phosphorylation but prevented the marked loss of serine/threonine phosphatase PP2A activity induced by taurocholate in vivo without affecting PP2B and PP2C activities. The rapid loss in PP2A activity induced by taurocholate in acinar cells was due to a decrease in cAMP levels that was prevented by pentoxifylline. Pentoxifylline also reduced the induction of early (egr-1, atf-3) responsive genes and abrogated the up-regulation of late (inos, icam, il-6, tnf-alpha) responsive genes and recruitment of transcription factors (nuclear factor kappaB and C/EBPbeta) and histone acetyltransferases to their gene promoters during pancreatitis. In conclusion, the beneficial effects of pentoxifylline--and presumably of other phosphodiesterase inhibitors--in this disease seem to be mediated by abrogating the loss of cAMP levels and PP2A activity as well as chromatin-modifying complexes very early during acute pancreatitis.
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Affiliation(s)
- Juan Sandoval
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Valencia, Spain.
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Malleo G, Mazzon E, Siriwardena AK, Cuzzocrea S. Role of tumor necrosis factor-alpha in acute pancreatitis: from biological basis to clinical evidence. Shock 2007; 28:130-40. [PMID: 17529903 DOI: 10.1097/shk.0b013e3180487ba1] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tumor necrosis factor (TNF)-alpha is a pleiotropic cytokine that exerts host-damaging effects in different autoimmune and inflammatory diseases. It is a key regulator of other proinflammatory cytokines and of leukocyte adhesion molecules, and it is a priming activator of immune cells. In recent years, several research lines-mostly derived from animal models and in vitro studies-suggested that TNF-alpha plays a pivotal role in the pathogenesis of acute pancreatitis. In particular, it contributes to the systemic progression of the inflammatory response and to the end-organ dysfunction often observed in severe disease. Current clinical applications of TNF-alpha in acute pancreatitis include the assessment of blood concentrations to predict disease severity and to identify individuals prone to develop complications such as multiple organ failure and septic shock. However, TNF-alpha is rapidly cleared from the bloodstream, and sensitivity and overall accuracy of its measurement seem strictly time dependent, thereby being of potential prognostic value only in the first days after the onset of the disease. In parallel, TNF-alpha has been evaluated as a novel pharmacologic target for treating pancreatitis. Although promising results have been observed in the laboratory, transition to clinical practice seems problematic, in particular, in the light of divergent results obtained in sepsis trials. Therefore, in future clinical trials pertaining to TNF-alpha neutralization in acute pancreatitis, timing of intervention should be related to changes in TNF-alpha serum levels, and inclusion and exclusion criteria should be accurately selected to better define the population most likely to benefit.
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Affiliation(s)
- Giuseppe Malleo
- Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Via C. Valeria-Gazzi, 98100 Messina, Italy
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