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Xue QM, Pan H, Huang L, Li N. Effects of Acupuncture at St25 on Inflammatory Mediators and Nuclear Factor κB Activation in a Rat Model of Severe Acute Pancreatitis. Acupunct Med 2015; 33:299-304. [PMID: 25979864 DOI: 10.1136/acupmed-2014-010609] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2015] [Indexed: 02/05/2023]
Abstract
Objective To observe the effect of electroacupuncture (EA) and manual acupuncture (MA) at ST25 on inflammatory mediators and nuclear factor κ-B (NF-κB) activation in rats with sodium taurocholate-induced severe acute pancreatitis (SAP). Methods Eighty-eight male Sprague–Dawley rats were randomly divided into four groups: control (sham-operated), SAP, SAP+EA and SAP+MA (n=22 each). A SAP model was established by injecting 3.5% sodium taurocholate 1 mL/kg into the pancreatic duct. In each group, animals were killed at t=3 h (n=7), 6 h (n=7) and 12 h (n=8) after the procedure. Pancreatic expression of NF-κB was examined by immunohistochemical staining. The levels of tumour necrosis factor α (TNF-α) and interleukin 6 (IL-6) in serum were determined by ELISA. Pathological changes in the pancreas were examined microscopically. Results Serum levels of TNF-α and IL-6 increased and morphological changes consistent with tissue damage were observed in the pancreas of SAP rats. NF-κB p65 expression was significantly higher in the SAP group than in the sham-operated group (p<0.05). Treatment with acupuncture at ST25 attenuated morphological damage and reduced levels of TNF-α and IL-6 in serum. NF-κB p65 expression was also significantly reduced by acupuncture at ST25 in the pancreas at 6 and 12 h after the procedure (p<0.05). There were no significant differences between the SAP+EA and SAP+MA groups. Conclusions Acupuncture at ST25 might have a therapeutic effect on rats with SAP through inhibition of NF-κB expression and a reduction in the release of pro-inflammatory cytokines.
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Affiliation(s)
- Qi-Ming Xue
- Department of Integrated Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Hui Pan
- Department of Integrated Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Lu Huang
- Department of Integrated Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Ning Li
- Department of Integrated Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
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Gamrekelashvili J, Greten TF, Korangy F. Immunogenicity of necrotic cell death. Cell Mol Life Sci 2014; 72:273-83. [PMID: 25274062 DOI: 10.1007/s00018-014-1741-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 09/03/2014] [Accepted: 09/22/2014] [Indexed: 12/20/2022]
Abstract
The mode of tumor cell death has significant effects on anti-tumor immunity. Although, previously it was thought that cell death is an inert effect, different investigators have clearly shown that dying tumors can attract, activate and mature professional antigen presenting cells and dendritic cells. In addition, others and we have shown that the type of tumor cell death not only controls the presence or absence of specific tumor antigens, but also can result in immunological responses ranging from immunosuppression to anti-tumor immunity. More importantly, it is possible to enhance anti-tumor immunity both in vitro and in vivo by targeting specific molecular mechanisms such as oligopeptidases and the proteasome. These studies not only extend our knowledge on basic immunological questions and the induction of anti-tumor immunity, but also have implications for all types of cancer treatments, in which rapid tumor cell death is induced. This review is a comprehensive summary of cell death and particularly necrosis and the pivotal role it plays in anti-tumor immunity.
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Zhang M, Zhu DZ, Li ZS, Zhan XB. [Red peony root decoction in treatment of severe acute pancreatitis: a randomized controlled trial]. ACTA ACUST UNITED AC 2010; 6:569-75. [PMID: 18559232 DOI: 10.3736/jcim20080605] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To compare the therapeutic effects of red peony root decoction, a compound traditional Chinese herbal medicine, and rhubarb in treating severe acute pancreatitis (SAP). METHODS A total of 96 consecutive patients with objectively-graded SAP were randomly divided into treatment and control groups. There were 48 cases in each group. The patients in the treatment and control groups were assigned to receive red peony root decoction and rhubarb treatment 1-2 times a day via a gastric tube respectively. Comparisons in the time needed for the disappearance of abdominal tenderness, fever and abdominal distension were made between the two groups. The total days of using antibiotics, enzyme inhibitor, protease inhibitor, and nasojejunal feeding start, nasojejunal feeding, gastrointestinal decompression, fasting diet were also compared. And comparison also included hospital stays and hospitalization costs. RESULTS The durations of abdominal tenderness, fever and abdominal distension in the treatment group were less than those in the control group (P<0.05). Compared with the control group, the time length for antibiotics (including anti-bacteria drug and antifungal agent) use, nasojejunal feeding start, nasojejunal feeding, gastrointestinal decompression, fasting diet, hospital stays and hospitalization costs were decreased in the treatment group (P<0.05). There were no significant differences between the two groups in enzyme inhibitor and protease inhibitor requirement, mortality and adverse reactions. CONCLUSION Red peony root decoction is more effective than rhubarb alone for SAP patients.
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Affiliation(s)
- Min Zhang
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
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James FE, Mansfield CS, Steiner JM, Williams DA, Robertson ID. Pancreatic response in healthy dogs fed diets of various fat compositions. Am J Vet Res 2009; 70:614-8. [DOI: 10.2460/ajvr.70.5.614] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Letoha T, Fehér LZ, Pecze L, Somlai C, Varga I, Kaszaki J, Tóth G, Vizler C, Tiszlavicz L, Takács T. Therapeutic proteasome inhibition in experimental acute pancreatitis. World J Gastroenterol 2007; 13:4452-7. [PMID: 17724800 PMCID: PMC4611577 DOI: 10.3748/wjg.v13.i33.4452] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [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 the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 (Z-Leu-Leu-Leu-aldehyde) in an experimental model of acute pancreatitis.
METHODS: Pancreatitis was induced in rats by two hourly intraperitoneal (ip) injections of cholecystokinin octapeptide (CCK; 2 × 100 μg/kg) and the proteasome inhibitor MG132 (10 mg/kg ip) was administered 30 min after the second CCK injection. Animals were sacrificed 4 h after the first injection of CCK.
RESULTS: Administering the proteasome inhibitor MG132 (at a dose of 10 mg/kg, ip) 90 min after the onset of pancreatic inflammation induced the expression of cell-protective 72 kDa heat shock protein (HSP72) and decreased DNA-binding of nuclear factor-κB (NF-κB).
Furthermore MG132 treatment resulted in milder inflammatory response and cellular damage, as revealed by improved laboratory and histological parameters of pancreatitis and associated oxidative stress.
CONCLUSION: Our findings suggest that proteasome inhibition might be beneficial not only for the prevention, but also for the therapy of acute pancreatitis.
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Affiliation(s)
- Tamás Letoha
- Department of Medical Chemistry, University of Szeged, Dom ter 8, H-6720, Szeged, Hungary.
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Abstract
Acute pancreatitis represents a spectrum of disease, ranging from a mild, transitory illness to a severe, rapidly progressive hemorrhagic form, with massive necrosis and mortality rates of up to 24%. The reported incidence of acute pancreatitis diagnosed first at clinicopathologic autopsy ranges between 30% and 42%. To better describe outpatient fatalities due to acute pancreatitis that present as sudden, unexpected death, we retrospectively reviewed the autopsy files at the Institute of Legal Medicine, University of Hamburg, Germany, from 2000-2004. Individual cases were analyzed for sex, age, race, circumstances of death, social background of the deceased and previous medical history, seasonal occurrence of the disease, blood alcohol concentration at the time of death, body mass index, autopsy findings, histopathology, and etiology of acute pancreatitis. Among the 6178 autopsies carried out during the 5-year period evaluated, there were 27 cases of acute pancreatitis that presented as sudden, unexpected death. In all cases, the diagnosis was first made at autopsy. The male:female ratio was 1.7:1 and the mean age was 52 years (range, 30-91 years). Etiologies of acute pancreatitis included alcohol (n=19), gall stones (n=2), other identified etiologic factors (n=3), and idiopathic (n=3). Complications of acute pancreatitis included lung edema and/or acute respiratory distress syndrome, peritonitis, disseminated intravascular coagulation, and sepsis. At least 20 subjects (74%) had lived isolated, with no social contacts. Contrary to the clinical observations of a clear seasonal variation in the onset of acute pancreatitis, we found no correlation between death due to acute pancreatitis and a specific month or season. Many prior studies have suggested that the majority of deaths in severe acute pancreatitis occur in the late phase of the disease as a result of pancreatic sepsis. Conversely, in the present study, the majority of affected individuals died during the very early phase of the disease. While gallstones represent the main etiologic factor in most larger clinical series, biliary etiology seems to play only a minor role in outpatient deaths undergoing medicolegal autopsies. Data derived from medicolegal autopsy studies should be included in future population-based studies of acute pancreatitis.
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Affiliation(s)
- Michael Tsokos
- Institute of Legal Medicine and Forensic Sciences, Berlin, Germany.
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Kerem M, Bedirli A, Pasaoglu H, Unsal C, Yilmaz TU, Ofluoglu E, Sahin TT. Role of ghrelin and leptin in predicting the severity of acute pancreatitis. Dig Dis Sci 2007; 52:950-955. [PMID: 17333355 DOI: 10.1007/s10620-006-9150-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2005] [Accepted: 11/13/2005] [Indexed: 02/05/2023]
Abstract
Ghrelin and leptin are the hormones that influence endocrine and exocrine functions of the pancreas and regulate feeding behaviors and energy metabolism. The aim of this study was to investigate the levels of ghrelin and leptin in pancreatitis of different severities and the relation of these hormones with blood glucose level and proinflammatory cytokines. The study was performed on 90 Wistar Albino rats. Three experimental groups composed of 30 rats were established: control group, 0.9% NaCl solution was injected intraperitoneally (i.p); acute edematous pancreatitis (AEP) group, 1 microg/100 g cerulein was injected i.p. five times, at 1-hr intervals; and acute necrotizing pancreatitis (ANP) group, 500 mg/100 g L-arginine was injected i.p. Ten animals in each group were sacrificed under anesthesia 12, 24 and 48 hr after the last injection. After blood withdrawal, the pancreas was totally excised. The levels of blood sugar, lipase, serum tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), ghrelin, and leptin were investigated and histopathologic examination was performed. Following pancreatitis induction, serum ghrelin levels increased at 24 hr and reached the peak level at 48 hr. Its level in the AEP group was higher than in the ANP group. Serum leptin levels in the AEP and ANP groups increased after 12 hr and stayed at high levels until 48 hr compared with the control group. Similarly to ghrelin and leptin, blood glucose levels increased in both pancreatitis groups, but the increase was more prominent in the ANP group, with levels >200 mg/ml at 48 hr. The levels of TNF-alpha and IL-1beta in the AEP and ANP groups reached the peak level at 24 hr and then decreased to a level close to that of the control group at 48 hr. We conclude that serum leptin and ghrelin levels increase in the first 48 hr of AEP and ANP. As the serum ghrelin levels in ANP are higher than in AEP, it can be used as a marker to show the severity of pancreatitis. While TNF-alpha and IL-1beta can be used as a prognostic factor in the first 24 hr, ghrelin and leptin can be used subsequently.
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Affiliation(s)
- Mustafa Kerem
- Department of General Surgery, Gazi University, Medical Faculty, 06510 Besevler, Ankara, Turkey.
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Zhang XP, Zhang L, Chen LJ, Cheng QH, Wang JM, Cai W, Shen HP, Cai J. Influence of dexamethasone on inflammatory mediators and NF-kappaB expression in multiple organs of rats with severe acute pancreatitis. World J Gastroenterol 2007; 13:548-56. [PMID: 17278220 PMCID: PMC4065976 DOI: 10.3748/wjg.v13.i4.548] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2006] [Revised: 09/27/2006] [Accepted: 12/12/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To observe the therapeutic effects of dexamethasone on rats with severe acute pancreatitis (SAP) and investigate the influences of dexamethasone on the inflammatory mediators and NF-kappaB expression in multiple organs of SAP rats as well as the mechanisms involved. METHODS Ninety Sprague-Dawley (SD) rats with SAP were randomly divided into the model group (n = 45) and dexamethasone treatment group (n = 45), and another 45 rats were selected for the sham operation group. All groups were randomly subdivided into the 3 h, 6 h and 12 h groups, each group containing 15 rats. The survival of all groups and pathological changes of multiple organs (liver, kidney and lung) were observed at different time points after the operation. The pathological score of multiple organs was carried out, followed by the determination of amylase, endotoxin and TNF-alpha contents in blood. The tissue microarray was used to detect the expression levels of NF-kappaB p65 protein in multiple organs. RESULTS There was no marked difference between the model group and treatment group in the survival rate. The amylase content of the treatment group was significantly lower compared to the model group at 12 h (P < 0.01, 7791.00 vs 9195.00). Moreover, the endotoxin and TNF-alpha levels of the treatment group were significantly lower than that of the model group at 6 h and 12 h (P < 0.01, 0.040 vs 0.055, 0.042 vs 0.059 and P < 0.05, 58.30 vs 77.54, 38.70 vs 67.30, respectively). Regarding the changes in liver NF-kappaB expression, the model group significantly exceeded the sham operation group at 3 h (P < 0.01, 1.00 vs 0.00), and the treatment group significantly exceeded the sham operation group at 12 h (P < 0.01, 1.00 vs 0.00), whereas no marked difference was observed between the model group and treatment group at all time points. The kidney NF-kappaB expression level in the treatment group significantly exceeded the model group (P < 0.05, 2.00 vs 0.00) and the sham operation group (P < 0.01, 2.00 vs 0.00) at 12 h. No NF-kappaB expression in the lung was found in any group. CONCLUSION Dexamethasone can lower the amylase, endotoxin and TNF-alpha levels as well as mortality of SAP rats. NF-kappaB plays an important role in multiple organ injury. Further studies should be conducted to determine whether dexamethasone can ameliorate the pathological changes of multiple organs by reducing the NF-kappaB expression in the liver and kidney. The advantages of tissue microarrays in pancreatitis pathological examination include time- and energy- saving, and are highly efficient and representative. The restriction of tissue microarrays on the representation of tissues to various extents due to small diameter may lead to the deviation of analysis.
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Affiliation(s)
- Xi-Ping Zhang
- Department of General Surgery, Hangzhou First People's Hospital, 261 Huansha Road, Hangzhou 310006, Zhejiang Province, China.
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Miralles F, Hebrard S, Lamotte L, Durel B, Gilgenkrantz H, Li Z, Daegelen D, Tuil D, Joshi RL. Conditional inactivation of the murine serum response factor in the pancreas leads to severe pancreatitis. J Transl Med 2006; 86:1020-36. [PMID: 16894357 DOI: 10.1038/labinvest.3700457] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The Serum Response Factor (SRF) is widely expressed transcription factor acting at the confluence of multiple signaling pathways and has been implicated in the control of differentiation, growth, and cell death. In the present study, we found that SRF is expressed in the developing and adult pancreas. To explore the possible role of SRF in this organ, we have generated mutant mice with conditional disruption of the Srf gene. Such mutants presented normal development of both the exocrine and endocrine pancreas indicating that SRF is dispensable for pancreas ontogenesis. However, after weaning, these mice developed profound morphological alterations of the exocrine pancreas, which were reminiscent of severe pancreatitis. In these mice, massive acinar injury, Nuclear Factor Kappa B activation and proinflammatory cytokines release led to complete destruction of the exocrine pancreas and its replacement by adipose tissue. Despite these changes, the organization and function of the endocrine islets of Langerhans remained well-preserved. This new animal model of spontaneous pancreatitis could prove a valuable tool to gain further insight into the physiopathology of this disease.
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Affiliation(s)
- Francisco Miralles
- Departement de Génétique et Développement, Institut Cochin, INSERM U567, CNRS UMR8104, Université René Descartes Paris V, Paris, France.
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Magaña-Gómez J, López-Cervantes G, Calderón de la Barca AM. Caerulin-induced pancreatitis in rats: Histological and genetic expression changes from acute phase to recuperation. World J Gastroenterol 2006; 12:3999-4003. [PMID: 16810747 PMCID: PMC4087709 DOI: 10.3748/wjg.v12.i25.3999] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [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 study the histological and pancreatitis-associated protein mRNA accumulation changes of pancreas from acute phase of caerulin-induced pancreatitis to recuperation in rats.
METHODS: Acute pancreatitis was induced by caerulein in male Wistar rats and followed up for 90 d by histological and mRNA analyses of pancreas. Pancreases were dissected at 0, 9, 24 h and 3, 5, 15, 30, 60, 90 d post-induction. Edema (E), polymorphonuclear neutrophil (PMN) infiltration, cytoplasmic vacuolization (V), zymogen granule depletion (ZD) and acinar disorganization (AD) were microscopically evaluated. Accumulation of pancreatitis-associated protein (PAP) and L13A mRNAs were quantified by real-time PCR.
RESULTS: The main histological changes appeared at 9 h post-induction for PMN infiltration and cytoplasmic V, while at 24 h and 3 d for E and ZD, respectively. All the parameters were recovered after 5 d, except for ZD which delayed more than 30 d. The main AD was observed after 15 d and values returned to normal after 30 d. Similarly to histological changes, accumulation of the PAP mRNA was increased at 9 h with the highest accumulation at 24 h and differences disappeared after 5 d.
CONCLUSION: From the acute phase to recuperation of pancreatitis, regeneration and re-differentiation of pancreas occur and PAP expression is exclusively an acute response of pancreatitis.
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Affiliation(s)
- Javier Magaña-Gómez
- Departamento de Nutrición, Centro de Investigación en Alimentación y Desarrollo, A.C. PO BOX 1735, Hermosillo 83000, Sonora, México
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Hernández-Barbáchano E, San Román JI, López MA, Coveñas R, López-Novoa JM, Calvo JJ. Beneficial effects of vasodilators in preventing severe acute pancreatitis shock. Pancreas 2006; 32:335-42. [PMID: 16670614 DOI: 10.1097/01.mpa.0000220856.47754.c4] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVES To investigate the effect of treatment with several vasodilatory substance on the changes in mean arterial pressure (MAP) of severe acute pancreatitis. METHODS Pancreatitis was induced in rats by 5% sodium taurocholate retrograde infusion through the pancreatic duct, which produces a significant decrease in arterial blood pressure. RESULTS Three hours after the induction of pancreatitis, a fall of approximately 25 mm Hg in MAP was observed, with no changes of MAP in untreated controls. The administration of the nitric oxide synthesis inhibitor, N-nitro-L-arginine methyl ester (25 mg/kg), previously to the induction of pancreatitis, produced a marked fall in MAP leading to the death of all the animals. When several vasodilatory substances, S-nitroso-N-acetylpenicillamine (200 microg x kg x h), calcitonin gene-related peptide (10 microg/kg), and vasoactive intestinal polypeptide (8 microg x kg x h) were administered previously to the induction of pancreatitis, the MAP fall induced by pancreatitis was not observed. The improvement of physiological conditions observed in vasodilator-treated animals is in agreement with histological data, which show only minor structural changes in the pancreas from these animals, in contrast with the severe alterations observed in untreated pancreatitic rats. CONCLUSION : Vasodilation confers protection against the systemic circulatory derangement derived from the development of severe acute pancreatitis.
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Letoha T, Somlai C, Takács T, Szabolcs A, Rakonczay Z, Jármay K, Szalontai T, Varga I, Kaszaki J, Boros I, Duda E, Hackler L, Kurucz I, Penke B. The proteasome inhibitor MG132 protects against acute pancreatitis. Free Radic Biol Med 2005; 39:1142-51. [PMID: 16214030 DOI: 10.1016/j.freeradbiomed.2005.06.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2005] [Revised: 06/07/2005] [Accepted: 06/09/2005] [Indexed: 02/06/2023]
Abstract
The cell-permeant MG132 tripeptide (Z-Leu-Leu-Leu-aldehyde) is a peptide aldehyde proteasome inhibitor that also inhibits other proteases, including calpains and cathepsins. By blocking the proteasome, this tripeptide has been shown to induce the expression of cell-protective heat shock proteins (HSPs) in vitro. Effects of MG132 were studied in an in vivo model of acute pancreatitis. Pancreatitis was induced in male Wistar rats by injecting 2 x 100 microug/kg cholecystokinin octapeptide intraperitoneally (ip) at an interval of 1 h. Pretreating the animals with 10 mg/kg MG132 ip before the induction of pancreatitis significantly inhibited IkappaB degradation and subsequent activation of nuclear factor-kappaB (NF-kappaB). MG132 also increased HSP72 expression. Induction of HSP72 and inhibition of NF-kappaB improved parameters of acute pancreatitis. Thus MG132 significantly decreased serum amylase, pancreatic weight/body weight ratio, pancreatic myeloperoxidase activity, proinflammatory cytokine concentrations, and the expression of pancreatitis-associated protein. Parameters of oxidative stress (GSH, MDA, SOD, etc.) were improved in both the serum and the pancreas. Histopathological examinations revealed that pancreatic specimens of animals pretreated with the peptide demonstrated milder edema, cellular damage, and inflammatory activity. Our findings show that simultaneous inhibition of calpains, cathepsins, and the proteasome with MG132 prevents the onset of acute pancreatitis.
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Affiliation(s)
- Tamás Letoha
- Department of Medical Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.
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