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Rius-Pérez S, Pérez S, Torres-Cuevas I, Martí-Andrés P, Taléns-Visconti R, Paradela A, Guerrero L, Franco L, López-Rodas G, Torres L, Corrales F, Sastre J. Blockade of the trans-sulfuration pathway in acute pancreatitis due to nitration of cystathionine β-synthase. Redox Biol 2020; 28:101324. [PMID: 31539805 PMCID: PMC6811996 DOI: 10.1016/j.redox.2019.101324] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/03/2019] [Accepted: 09/07/2019] [Indexed: 02/07/2023] Open
Abstract
Acute pancreatitis is an inflammatory process of the pancreatic gland that may lead to dysregulation of the trans-sulfuration pathway. The aims of this work were firstly to study the methionine cycle as well as the trans-sulfuration pathway using metabolomic and proteomic approaches identifying the causes of this dysregulation in an experimental model of acute pancreatitis; and secondly to reveal the effects of S-adenosylmethionine administration on these pathways. Acute pancreatitis was induced by cerulein in mice, and a group of animals received S-adenosylmethionine treatment. Cerulein-induced acute pancreatitis rapidly caused marked depletion of methionine, S-adenosylmethionine, 5'-methylthioadenosine, cystathionine, cysteine, and glutathione levels in pancreas, but S-adenosylhomocysteine and homocysteine remained unchanged. Protein steady-state levels of S-adenosylhomocysteine-hydrolase and cystathionine gamma-lyase diminished but methylthioadenosine phosphorylase levels increased in pancreas with acute pancreatitis. Although cystathionine β-synthase protein levels did not change with acute pancreatitis, Nos2 mRNA and protein levels were markedly up-regulated and caused tyrosine nitration of cystathionine β-synthase in pancreas. S-adenosylmethionine administration enhanced Nos2 mRNA expression and cystathionine β-synthase nitration and triggered homocysteine accumulation in acute pancreatitis. Furthermore, S-adenosylmethionine administration promoted enrichment of the euchromatin marker H3K4me3 in the promoters of Tnf-α, Il-6, and Nos2 and enhanced the mRNA up-regulation of these genes. Accordingly, S-adenosylmethionine administration increased inflammatory infiltrate and edema in pancreas with acute pancreatitis. In conclusion, tyrosine-nitration of cystathionine β-synthase blockades the trans-sulfuration pathway in acute pancreatitis promoting homocysteine accumulation upon S-adenosylmethionine treatment.
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Affiliation(s)
- Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100, Burjassot, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100, Burjassot, Valencia, Spain
| | | | - Pablo Martí-Andrés
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100, Burjassot, Valencia, Spain
| | - Raquel Taléns-Visconti
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46100, Burjassot, Valencia, Spain
| | - Alberto Paradela
- Proteomics Unit, Centro Nacional de Biotecnología, CSIC, 28049, Madrid, Spain
| | - Laura Guerrero
- Proteomics Unit, Centro Nacional de Biotecnología, CSIC, 28049, Madrid, Spain
| | - Luis Franco
- Department of Biochemistry and Molecular Biology, University of Valencia, 46100, Burjassot, Valencia, Spain; Institute of Health Research, INCLIVA, Valencia, Spain
| | - Gerardo López-Rodas
- Department of Biochemistry and Molecular Biology, University of Valencia, 46100, Burjassot, Valencia, Spain; Institute of Health Research, INCLIVA, Valencia, Spain
| | - Luis Torres
- Department of Biochemistry and Molecular Biology, University of Valencia, 46100, Burjassot, Valencia, Spain; Institute of Health Research, INCLIVA, Valencia, Spain
| | - Fernando Corrales
- Proteomics Unit, Centro Nacional de Biotecnología, CSIC, 28049, Madrid, Spain
| | - Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100, Burjassot, Valencia, Spain.
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Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Alsanea S, Al-Hosaini KA, Mahmood HM, Alzahrani MZ, Attia SM. Inhibition of tyrosine kinase signaling by tyrphostin AG126 downregulates the IL-21/IL-21R and JAK/STAT pathway in the BTBR mouse model of autism. Neurotoxicology 2019; 77:1-11. [PMID: 31811869 DOI: 10.1016/j.neuro.2019.12.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 12/02/2019] [Accepted: 12/03/2019] [Indexed: 01/01/2023]
Abstract
Autism spectrum disorder (ASD) comprises a broad range of neurodevelopmental disorders that are associated with deficits in social interaction and communication. The tyrosine kinase inhibitor tyrphostin AG126 represents a promising therapeutic agent for several neuroinflammatory disorders. There are currently no treatments available that can improve ASD and we previously showed that AG126 treatment exerts beneficial effects on BTBR T+ Itpr3tf/J (BTBR) mice, a model for autism that shows the core features of ASD; however, the immunological mechanisms and molecular targets associated with this effect were previously unclear. This study was undertaken to delineate the neuroprotective effect of AG126 on BTBR mice. Here, using this mouse model, we investigated the effects of AG126 administration on IL-21R, IL-21, IL-22, TNF-α, NOS2, STAT3, IL-27, and Foxp3 production by CD8+ T cells in the spleen by flow cytometry. We further explored the mRNA and protein expression of IL-21, IL-22, IL-1β, TNF-α, NOS2, JAK1, STAT3, IL-27, and Foxp3 in brain tissue by RT-PCR, and western blotting. We found that BTBR mice treated with AG126 exhibited significant decreases in IL-21R-, IL-21-, IL-22-, TNF-α-, NOS2-, STAT3-producing, and increases in IL-27- and Foxp3-producing, CD8+ T cells. Our results further demonstrated that AG126 treatment effectively decreased IL-21, IL-22, IL-1β, TNF-α, NOS2, JAK1, and STAT3, and increased IL-27 and Foxp3 mRNA and protein expression in brain tissues. Our findings suggest that AG126 elicits a neuroprotective response through downregulation of the IL-21/IL-21R and JAK/STAT pathway in BTBR mice, which could represent a promising novel therapeutic target for ASD treatment.
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Affiliation(s)
- Sheikh F Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
| | - Mushtaq A Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed Nadeem
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Saleh A Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sary Alsanea
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Khaled A Al-Hosaini
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hafiz M Mahmood
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammad Z Alzahrani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sabry M Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Nilotinib, a tyrosine kinase inhibitor exhibits protection against acute pancreatitis-induced lung and liver damage in rats. Naunyn Schmiedebergs Arch Pharmacol 2016; 390:291-300. [PMID: 27975299 DOI: 10.1007/s00210-016-1327-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 11/29/2016] [Indexed: 12/20/2022]
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Menzfeld C, John M, van Rossum D, Regen T, Scheffel J, Janova H, Götz A, Ribes S, Nau R, Borisch A, Boutin P, Neumann K, Bremes V, Wienands J, Reichardt HM, Lühder F, Tischner D, Waetzig V, Herdegen T, Teismann P, Greig I, Müller M, Pukrop T, Mildner A, Kettenmann H, Brück W, Prinz M, Rotshenker S, Weber MS, Hanisch UK. Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. Glia 2015; 63:1083-99. [PMID: 25731696 DOI: 10.1002/glia.22803] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 01/20/2015] [Indexed: 01/17/2023]
Abstract
The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll-like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR-induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti-inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN-sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions.
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Karaguzel E, Sivrikaya A, Mentese A, Yulug E, Turkmen S, Kutlu O, Guler Y, Us D, Turedi S, Alver A, Kazaz IO. Investigation of tyrphostin AG 556 for testicular torsion-induced ischemia reperfusion injury in rat. J Pediatr Urol 2014; 10:223-9. [PMID: 24070787 DOI: 10.1016/j.jpurol.2013.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Accepted: 08/15/2013] [Indexed: 12/27/2022]
Abstract
OBJECTIVE To investigate the effects of tyrphostin AG 556, a tyrosine kinase inhibitor (TKI) in an experimental model of testicular ischemia-reperfusion (I/R) injury. MATERIAL AND METHODS Twenty-four adult male rats were randomly divided into four groups (n = 6): sham, torsion/detorsion (T/D), T/D + dimethylsulfoxide (DMSO) (vehicle group), and T/D + DMSO + tyrphostin AG 556. Testicular torsion was achieved by rotating the left testis 720° clockwise for 4 h. Thirty minutes before detorsion, 3 mg/kg tyrphostin AG 556 was injected transperitoneally in the AG 556 group and DMSO was injected transperitoneally in the DMSO group. After 2 h of reperfusion arterial blood samples were collected for biochemical analysis for malondialdehyde (MDA), ischemia modified albumin (IMA), SCUBE1 (signal peptide-CUB [complement C1r/C1s, Uegf, and Bmp1] and EGF [epidermal growth factor] like domain-containing protein 1), total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) parameters, and ipsilateral orchiectomies were performed for histopathological examination based on the semi-quantitative Johnsen's mean testicular biopsy score (MTBS) in all groups. RESULTS Tyrphostin AG 556 exhibited a protective effect against I/R injury in testicular torsion. Of the biochemical parameters evaluated as a result of testicular I/R, IMA, MDA, and TOS levels were significantly elevated. There was no significant difference in terms of these biochemical parameters between the sham and AG 556 groups. Significant histopathological injury was determined by comparing the T/D and sham groups. According to histopathological injury scores, significant differences were determined between T/D and AG 556 groups and between AG 556 and sham groups. AG 556 had a superior improving effect on Johnsen's scores than DMSO. CONCLUSIONS Our results suggest that the use of tyrphostin AG 556 prior to testicular reperfusion has a protective effect against testicular I/R injury.
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Affiliation(s)
- Ersagun Karaguzel
- Department of Urology, Karadeniz Technical University, Faculty of Medicine, Trabzon 61080, Turkey.
| | - Abdullah Sivrikaya
- Department of Urology, Karadeniz Technical University, Faculty of Medicine, Trabzon 61080, Turkey
| | - Ahmet Mentese
- Department of Medical Biochemistry, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| | - Esin Yulug
- Department of Histology and Embryology, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| | - Suha Turkmen
- Department of Emergency Medicine, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| | - Omer Kutlu
- Department of Urology, Karadeniz Technical University, Faculty of Medicine, Trabzon 61080, Turkey
| | - Yavuz Guler
- Department of Urology, Karadeniz Technical University, Faculty of Medicine, Trabzon 61080, Turkey
| | - Diler Us
- Department of Medical Biochemistry, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| | - Suleyman Turedi
- Department of Emergency Medicine, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| | - Ahmet Alver
- Department of Medical Biochemistry, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| | - Ilke O Kazaz
- Department of Urology, Karadeniz Technical University, Faculty of Medicine, Trabzon 61080, Turkey
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Hegyi P, Rakonczay Z. The role of nitric oxide in the physiology and pathophysiology of the exocrine pancreas. Antioxid Redox Signal 2011; 15:2723-2741. [PMID: 21777142 DOI: 10.1089/ars.2011.4063] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
SIGNIFICANCE Nitric oxide (NO), a ubiquitous gaseous signaling molecule, contributes to both pancreatic physiology and pathophysiology. RECENT ADVANCES The present review provides a general overview of NO synthesis, signaling, and function. Further, it specifically discusses NO metabolism and its effects in the exocrine pancreas and focuses on the role of NO in the pathogenesis of acute pancreatitis and pancreatic ischemia/reperfusion injury. CRITICAL ISSUES Unfortunately, the role of NO in pancreatic physiology and pathophysiology remains controversial in numerous areas. Many questions regarding the messenger molecule still remain unanswered. FUTURE DIRECTIONS Probably the least is known about the downstream targets of NO, which need to be identified, especially at the molecular level.
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Affiliation(s)
- Péter Hegyi
- First Department of Medicine, University of Szeged, Szeged, Hungary
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Turpaev K, Ermolenko M, Cresteil T, Drapier JC. Benzylidenemalononitrile compounds as activators of cell resistance to oxidative stress and modulators of multiple signaling pathways. A structure–activity relationship study. Biochem Pharmacol 2011; 82:535-47. [DOI: 10.1016/j.bcp.2011.05.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Revised: 05/24/2011] [Accepted: 05/25/2011] [Indexed: 10/18/2022]
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Olson DM, Christiaens I, Gracie S, Yamamoto Y, Mitchell BF. Emerging tocolytics: challenges in designing and testing drugs to delay preterm delivery and prolong pregnancy. Expert Opin Emerg Drugs 2009; 13:695-707. [PMID: 19046135 DOI: 10.1517/14728210802568764] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The global rate of preterm delivery (before 37 completed weeks of pregnancy) is increasing and there are no effective means available to prevent this rise. Prematurity is the principal cause of neonatal mortality and a major cause of pediatric morbidity and long-term disability. Current strategies to prolong pregnancy are based on inhibiting the mechanisms that effect uterine smooth muscle (myometrium) contractions in women who are in preterm labor. Most drugs in this group were developed for other purposes. Newer strategies are designed to maintain a state of uterine quiescence and pregnancy, preventing the myometrium from initiating contractions and entering preterm labor. Again, it may be possible to use existing drugs for pregnancy maintenance. Several financial and practical barriers exist for developing completely new drugs to delay labor. Designing clinical trials to test tocolytics is complicated, as the health of two patients must be considered and the nature of preterm birth and its outcomes are different at early preterm labor (< 28 weeks) and late preterm labor (34 - 36 weeks).
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Affiliation(s)
- David M Olson
- University of Alberta, AHFMR Interdisciplinary Team in Preterm Birth and Healthy Outcomes, Department of Obstetrics and Gynecology, 220 HMRC, Edmonton, T6G 2S2, Alberta, Canada.
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Dimitrova P, Ivanovska N. Tyrphostin AG-490 inhibited the acute phase of zymosan-induced inflammation. Int Immunopharmacol 2008; 8:1567-77. [DOI: 10.1016/j.intimp.2008.06.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2008] [Revised: 06/26/2008] [Accepted: 06/30/2008] [Indexed: 01/07/2023]
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10
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Inflammatory processes in preterm and term parturition. J Reprod Immunol 2008; 79:50-7. [PMID: 18550178 DOI: 10.1016/j.jri.2008.04.002] [Citation(s) in RCA: 377] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2006] [Revised: 02/20/2008] [Accepted: 04/15/2008] [Indexed: 11/22/2022]
Abstract
A role for the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor alpha (TNF-alpha) is evident in term and preterm delivery, and this is independent of the presence of infection. All uterine tissues progress through a staged transformation near the end of pregnancy that leads from relative uterine quiescence and maintenance of pregnancy to the activation of the uterus that prepares it for the work of labour and production of stimulatory molecules that trigger the onset of labour and delivery. The uterus is activated by pro-inflammatory cytokines through stimulation of the expression and production of uterine activation proteins (UAPs). One of these actions is the stimulation of prostaglandin (PG) synthesis. Particularly important for labour is PGF(2alpha) and its receptor, PTGFR. In addition, pro-inflammatory cytokines are able to increase the synthesis of matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF) and the progesterone receptor C isoform, which leads to decreased tissue progesterone responsiveness. Some of these effects are replicated by PGF(2alpha), suggesting that it may act via its receptor to amplify the direct actions of cytokines. In turn, VEGF may enhance leukocyte recruitment to the uterus, and MMP-9 may promote activation of inactive pro-form cytokines. Pro-inflammatory cytokines also decrease the activity of 11beta-hydroxysteroid dehydrogenase, which likely increases intrauterine cortisol concentrations. In turn, cortisol may drive PG synthesis. Together these feed-forward mechanisms activate the uterus, trigger the production of uterine contractile stimulants and lead to labour and delivery.
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Effects of glycogen synthase kinase-3beta inhibition on the development of cerulein-induced acute pancreatitis in mice. Crit Care Med 2007; 35:2811-21. [PMID: 18074481 DOI: 10.1097/01.ccm.0000295303.62996.9f] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVE Glycogen synthase kinase (GSK)-3 is a ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and signal transduction pathways. It also plays an important role in the pathophysiology of a number of diseases characterized by an enhanced or unregulated inflammatory response. Here we investigate the effects of GSK-3beta inhibition on the development of experimental acute pancreatitis induced by cerulein in mice. DESIGN Prospective, randomized study. SETTING University-based research laboratory. SUBJECTS One-hundred and sixty anesthetized male CD mice. INTERVENTIONS Pancreatitis was induced by intraperitoneal injection of cerulein (hourly x5, 50 microg/kg). In the treatment group, the potent and selective GSK-3beta inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was administered 1 hr and 6 hrs after the first injection of cerulein (10 mg/kg, intraperitoneally). Sham groups were treated with vehicle (0.1 mL of 0.9% NaCl, intraperitoneally) and TDZD-8. In another set of experiments, mice were monitored for 24 days to determine their mortality rate. MEASUREMENTS AND MAIN RESULTS The injection of cerulein resulted in acute necrotizing pancreatitis. TDZD-8 significantly reduced the degree of pancreas injury, amylase, and lipase serum levels (p < .01); nuclear factor-kappaB activation (p < .01); the production of tumor necrosis factor-alpha and interleukin-1beta (p < .01); the expression of adhesion molecules and neutrophil accumulation (p < .01); the formation of oxygen and nitrogen-derived radicals (p < .01); the degree of lipid peroxidation (p < .01); the expression of transforming growth factor-beta and vascular endothelial growth factor (p < .01); and-ultimately-the mortality rate (p < .01). CONCLUSIONS Inhibition of GSK-3beta reduces the degree of cerulein-induced acute pancreatitis and the associated mortality rate in mice. Blocking protein kinase activity may be a novel approach to treatment of this inflammatory condition.
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Cuzzocrea S, Malleo G, Genovese T, Mazzon E, Esposito E, Muià C, Abdelrahman M, Di Paola R, Thiemermann C. Effects of glycogen synthase kinase-3[beta] inhibition on the development of cerulein-induced acute pancreatitis in mice *. Crit Care Med 2007. [DOI: 10.1097/00003246-200712000-00021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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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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Zhang XP, Ye Q, Jiang XG, Ma ML, Zhu FB, Zhang RP, Cheng QH. Preparation method of an ideal model of multiple organ injury of rat with severe acute pancreatitis. World J Gastroenterol 2007; 13:4566-73. [PMID: 17729407 PMCID: PMC4611828 DOI: 10.3748/wjg.v13.i34.4566] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish an ideal model of multiple organ injury of rats with severe acute pancreatitis (SAP).
METHODS: SAP models were induced by retrograde injection of 0.1 mL/100 g 3.5% sodium taurocholate into the biliopancreatic duct of Sprague-Dawley rats. The plasma and samples of multiple organ tissues of rats were collected at 3, 6 and 12 h after modeling. The ascites volume, ascites/body weight ratio, and contents of amylase, endotoxin, endothelin-1 (ET-1), nitrogen monoxidum (NO), phospholipase A2 (PLA2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) in plasma were determined. The histological changes of multiple organs were observed under light microscope.
RESULTS: The ascites volume, ascites/body weight ratio, and contents of various inflammatory mediators in blood were higher in the model group than in the sham operation group at all time points [2.38 (1.10), 2.58 (0.70), 2.54 (0.71) vs 0.20 (0.04), 0.30 (0.30), 0.22 (0.10) at 3, 6 and 12 h in ascites/body weight ratio; 1582 (284), 1769 (362), 1618 (302) (U/L) vs 5303 (1373), 6276 (1029), 7538 (2934) (U/L) at 3, 6 and 12 h in Amylase; 0.016 (0.005), 0.016 (0.010), 0.014 (0.015) (EU/mL) vs 0.053 (0.029), 0.059 (0.037), 0.060 (0.022) (EU/mL) at 3, 6 and 12 h in Endotoxin; 3.900 (3.200), 4.000 (1.700), 5.300 (3.000) (ng/L) vs 41.438 (37.721), 92.151 (23.119), 65.016 (26.806) (ng/L) at 3, 6 and 12 h in TNF-α, all P < 0.01]. Visible congestion, edema and lamellar necrosis and massive leukocytic infiltration were found in the pancreas of rats of model group. There were also pathological changes of lung, liver, kidney, ileum, lymphonode, thymus, myocardium and brain.
CONCLUSION: This rat model features reliability, convenience and a high achievement ratio. Complicated with multiple organ injury, it is an ideal animal model of SAP.
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Affiliation(s)
- Xi-Ping Zhang
- Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, Zhejiang Province, China.
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15
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Genovese T, Mazzon E, Esposito E, Muià C, Di Paola R, Crisafulli C, Bramanti P, Cuzzocrea S. Inhibition of tyrosine kinase-mediated cellular signalling by Tyrphostins AG126 and AG556 modulates secondary damage in experimental spinal cord trauma. Neuropharmacology 2007; 52:1454-71. [PMID: 17418876 DOI: 10.1016/j.neuropharm.2007.01.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2006] [Revised: 01/12/2007] [Accepted: 01/23/2007] [Indexed: 11/21/2022]
Abstract
Protein tyrosine kinases help to regulate the expression of many genes, which play an important role in the pathophysiology of a number of diseases. Here we investigate the effects of the tyrosine kinase inhibitors, AG126 and AG556 on the degree of experimental spinal cord trauma induced by the application of vascular clips to the dura via a four-level T4-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by oedema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with AG126 and AG556 significantly reduced the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) iNOS, nitrotyrosine, and PARP expression and (4) apoptosis (TUNEL staining and Bax and Bcl-2 expression). In a separate set of experiments, AG126 and AG556 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). This study provides an experimental evidence that (1) prevention of the activation of protein tyrosine kinases reduces the development of inflammation and tissue injury associated with spinal cord trauma, and (2) inhibition of the activity of certain tyrosine kinases may represent a novel approach for the therapy of spinal cord trauma.
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Affiliation(s)
- Tiziana Genovese
- Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy
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Mazzon E, Genovese T, Di Paola R, Muià C, Crisafulli C, Malleo G, Esposito E, Meli R, Sessa E, Cuzzocrea S. Effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase, in a mouse model of acute pancreatitis induced by cerulein. Eur J Pharmacol 2006; 549:149-56. [PMID: 16979620 DOI: 10.1016/j.ejphar.2006.08.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2006] [Revised: 07/25/2006] [Accepted: 08/02/2006] [Indexed: 11/17/2022]
Abstract
Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the colon injury associated with experimental colitis. The aim of the present study was to examine the effects of 3-aminobenzamide (3-AB), an inhibitor of PARP activity, in the development of acute pancreatitis caused by cerulein in mice. Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by oedema, neutrophil infiltration and necrosis and elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced expression of the intercellular adhesion molecule-1 (ICAM-1) and P-selectin. Immunohistochemical examination demonstrated a marked increase in the staining (immunoreactivity) for transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) in the pancreas of cerulein-treated mice in comparison to sham-treated mice. Acute pancreatitis in vehicle-treated mice was also associated with a significant mortality (40% survival at 5 days after cerulein administration). In contrast, (1) the degree of pancreatic inflammation and tissue injury (histological score), (2) upregulation/formation of ICAM-1 and P-selectin, (4) neutrophils infiltration and (5) the expression of TGF-beta and VEGF was markedly reduced in pancreatic tissue obtained from cerulein-treated mice which have been treated with 3-AB. These findings provide the evidence that PARP inhibition reduce the degree of pancreas injury caused by acute pancreatitis induced by cerulein administration.
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Affiliation(s)
- Emanuela Mazzon
- Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di Messina, Italy
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Genovese T, Mazzon E, Di Paola R, Muià C, Crisafulli C, Malleo G, Esposito E, Cuzzocrea S. Role of peroxisome proliferator-activated receptor-alpha in acute pancreatitis induced by cerulein. Immunology 2006; 118:559-70. [PMID: 16764691 PMCID: PMC1782323 DOI: 10.1111/j.1365-2567.2006.02393.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The aim of the present study was to examine the effects of endogenous PPAR-alpha ligand on the development of acute pancreatitis caused by cerulein in mice. Intraperitoneal injection of cerulein into PPAR-alpha wild-type (WT) mice resulted in severe, acute pancreatitis characterized by oedema, neutrophil infiltration and necrosis and by elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as an increase in myeloperoxidase activity) was associated with enhanced expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and P-selectin. Immunohistochemical examination demonstrated a marked increase in the staining (immunoreactivity) for transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) in the pancreas of cerulein-treated PPAR-alpha wild-type (WT) mice in comparison to sham-treated mice. Acute pancreatitis in PPAR-alphaWT mice was also associated with a significant mortality (20% survival at 5 days after cerulein administration). In contrast, the degree of pancreatic inflammation and tissue injury (histological score), up-regulation/formation of ICAM-1 and P-selectin, infiltration of neutrophils, and the expression of TGF-beta and VEGF was markedly enhanced in pancreatic tissue obtained from cerulein-treated PPAR-alpha knockout (KO) mice. Thus, endogenous PPAR-alpha ligands reduce the degree of pancreas injury caused by acute pancreatitis induced by cerulein administration.
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Affiliation(s)
- Tiziana Genovese
- Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di MessinaItaly
- Centro per lo Studio ed il Trattamento dei Neurolesi Lungodegenti, Facoltà di Medicina e Chirurgia, Università di MessinaItaly
| | - Emanuela Mazzon
- Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di MessinaItaly
- Centro per lo Studio ed il Trattamento dei Neurolesi Lungodegenti, Facoltà di Medicina e Chirurgia, Università di MessinaItaly
| | - Rosanna Di Paola
- Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di MessinaItaly
| | - Carmelo Muià
- Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di MessinaItaly
| | - Concetta Crisafulli
- Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di MessinaItaly
| | - Giuseppe Malleo
- Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di MessinaItaly
| | - Emanuela Esposito
- Dipartimento di Farmacologia Sperimentale, Università di Napoli ‘Federico II’, NapoliItaly
| | - Salvatore Cuzzocrea
- Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di MessinaItaly
- Centro per lo Studio ed il Trattamento dei Neurolesi Lungodegenti, Facoltà di Medicina e Chirurgia, Università di MessinaItaly
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