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Eltahir HM, Elbadawy HM, Almikhlafi MA, Alalawi AM, Aldhafiri AJ, Alahmadi YM, Al thagfan SS, Albadrani M, M Eweda S, Abouzied MM. Sitagliptin ameliorates L-arginine-induced acute pancreatitis via modulating inflammatory cytokines expression and combating oxidative stress. Front Pharmacol 2024; 15:1389670. [PMID: 38910880 PMCID: PMC11190672 DOI: 10.3389/fphar.2024.1389670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 04/26/2024] [Indexed: 06/25/2024] Open
Abstract
Background Acute pancreatitis (AP) is an inflammatory condition that resolves spontaneously, but occasionally, develops into systemic inflammation, organ failure and mortality. Oxidative stress and activation of inflammatory pathways represent major players in AP pathogenesis. Current management of AP relies on attenuating injuries to the pancreas and putting the inflammatory process under control. In this study, we investigated the role of sitagliptin in modulating L-arginine-induced AP in rats. Methods Swiss rats were subdivided into a healthy control group, AP group (a single dose of L-arginine 250 mg/100 g, intraperitoneal), and sitagliptin + L-arginine-treated group (10 mg sitagliptin/kg body weight/day, orally). Sitagliptin treatment started 1 hour after L-arginine injection and continued for 3days. Biochemical and histopathological investigations were performed on serum and tissue samples collected from test animals. Results L-arginine increased pancreatic meyloperoxidase and serum amylase- and lipase activities and serum levels of TNF-α, LT-α, IFN-γ, IL-1α/β, IL-6, IL-10, IL-12, and IL-15. AP animals showed elevated MDA and NO and decreased GSH and serum calcium levels. Histopathological changes were observed by H&E staining. Sitagliptin treatment significantly ameliorated these biochemical and histological changes diminishing the signs of AP. Conclusion Sitagliptin treatment was effective in ameliorating L-arginine-induced AP which can be regarded to its anti-inflammatory and antioxidant effect.
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Affiliation(s)
- Heba M. Eltahir
- Department of Pharmacology and Toxicology (Biochemistry Subdivision), College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Hossein M. Elbadawy
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Mohannad A. Almikhlafi
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Ali M. Alalawi
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Ahmed J. Aldhafiri
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Yaser M. Alahmadi
- Department of Clinical and Hospital Pharmacy, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Sultan S. Al thagfan
- Department of Clinical and Hospital Pharmacy, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Muayad Albadrani
- Department of Family and Community Medicine, College of Medicine, Taibah University, Medina, Saudi Arabia
| | - Saber M Eweda
- 5Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Mekky M. Abouzied
- Department of Pharmacology and Toxicology (Biochemistry Subdivision), College of Pharmacy, Taibah University, Medina, Saudi Arabia
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt
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Wang WJ, Zhang LW, Feng SY. Diagnostic performance of acoustic radiation force impulse for acute pancreatitis: A meta-analysis. Medicine (Baltimore) 2024; 103:e38035. [PMID: 38728451 PMCID: PMC11081614 DOI: 10.1097/md.0000000000038035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 04/05/2024] [Indexed: 05/12/2024] Open
Abstract
OBJECTIVE The objective of this meta-analysis is to evaluate the diagnostic performance of acoustic radiation force impulse (ARFI) in acute pancreatitis (AP) patients. METHODS PubMed, Web of Science, Embase, Wanfang, Chinese Biological Medicine databases, and Chinese Biomedical Literature Service System were searched for relevant studies to explore the potential diagnostic performance of ARFI in AP from inception to November 2023. STATA 14.0 was used to analyze the standardized mean difference (SMD) with 95% confidence interval (CI), pooled sensitivity, specificity, area under the curve, meta-regression analysis, sensitivity analysis, and publication bias. RESULTS Nine studies, involving 533 AP patients and 585 healthy controls, were included. AP patients had significantly higher ARFI levels than healthy controls (SMD: 3.13, 95% CI: 1.88-4.39, P = .001). The area under the curve of ARFI for diagnosing AP was 0.99 (95% CI: 0.98-1.00), with 98% sensitivity and 94% specificity. Meta-regression identified the study region and study period as the sources of heterogeneity. Sensitivity analysis showed that the exclusion of any single study did not materially alter the overall combined effect. No evidence of publication bias was observed in the included studies. CONCLUSION This meta-analysis demonstrated that ARFI exerted satisfactory diagnostic performance in AP.
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Affiliation(s)
- Wen Jie Wang
- Emergency Department, Cangzhou Central Hospital, Yunhe Qu, Cangzhou, China
| | - Li Wei Zhang
- Emergency Department, Cangzhou Central Hospital, Yunhe Qu, Cangzhou, China
| | - Shun Yi Feng
- Emergency Department, Cangzhou Central Hospital, Yunhe Qu, Cangzhou, China
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Coavoy-Sanchez SA, da Costa Marques LA, Costa SKP, Muscara MN. Role of Gasotransmitters in Inflammatory Edema. Antioxid Redox Signal 2024; 40:272-291. [PMID: 36974358 DOI: 10.1089/ars.2022.0089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
Significance: Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are, to date, the identified members of the gasotransmitter family, which consists of gaseous signaling molecules that play central roles in the regulation of a wide variety of physiological and pathophysiological processes, including inflammatory edema. Recent Advances: Recent studies show the potential anti-inflammatory and antiedematogenic effects of NO-, CO-, and H2S-donors in vivo. In general, it has been observed that the therapeutical effects of NO-donors are more relevant when administered at low doses at the onset of the inflammatory process. Regarding CO-donors, their antiedematogenic effects are mainly associated with inhibition of proinflammatory mediators (such as inducible NO synthase [iNOS]-derived NO), and the observed protective effects of H2S-donors seem to be mediated by reducing some proinflammatory enzyme activities. Critical Issues: The most recent investigations focus on the interactions among the gasotransmitters under different pathophysiological conditions. However, the biochemical/pharmacological nature of these interactions is neither general nor fully understood, although specifically dependent on the site where the inflammatory edema occurs. Future Directions: Considering the nature of the involved mechanisms, a deeper knowledge of the interactions among the gasotransmitters is mandatory. In addition, the development of new pharmacological tools, either donors or synthesis inhibitors of the three gasotransmitters, will certainly aid the basic investigations and open new strategies for the therapeutic treatment of inflammatory edema. Antioxid. Redox Signal. 40, 272-291.
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Affiliation(s)
| | | | - Soraia Katia Pereira Costa
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
| | - Marcelo Nicolas Muscara
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
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Shu J, Liao Y, Wang J, Zhang Y, Zhou W, Zhang H. Synthesis of Selenium Nanoparticles and Their Effect on Pancreatic Functions and Acute Pancreatitis in Rats. J Oleo Sci 2024; 73:351-358. [PMID: 38432999 DOI: 10.5650/jos.ess23190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2024] Open
Abstract
Acute pancreatitis (AP) have been documented to have severe impact on pancreatic function. Frequent incidence of AP can result in chronic pancreatitis and thereby it can increase the probability of pancreatic cancers. This study intended to examine the effect of selenium nanoparticles (Se-NPs) synthesized from Coleus forskohlii leaf extract on pancreatic function and AP in rat. Primarily, Se-NPs was fabricated using the C. forskohlii leaf extract. The synthesized nanomaterial was characterized through UV-visible, XRD, and FTIR spectroscopies. Notably, the zeta potential of Se-NPs was found to be -32.8 mV with a polydispersity index (PDI) of 0.18. Morphological analysis on SEM unveiled the spherical shape of Se-NP with an average particle size of 12.69 nm. Strikingly, cytotoxicity analysis on pancreatic cancer and normal cells unveiled the concentration-dependent toxicity profile. However, IC 50 value is lower in normal pancreatic cell lines in comparison to pancreatic cancer cells lines. Assessment of Se-NPs on AP rats revealed the positive impact of Se-NPs. It effectively decreased the amount of lipase, amylase, IL-1β, MDA, NO, and Bcl-2 while increased the glucose, insulin, HOMA-β and antioxidant potential in AP rats. In addition, an evaluation of Se-NPs in the pancreatic functions revealed the non-harmful effect of Se-NPs.
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Affiliation(s)
- Juan Shu
- Department of Gastroenterology, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology
| | - Yusheng Liao
- Department of Gastroenterology, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology
| | - Jian Wang
- Department of Gastroenterology, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology
| | - Yuanjie Zhang
- Department of Gastroenterology, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology
| | - Weilai Zhou
- Department of Gastroenterology, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology
| | - Heng Zhang
- Department of Gastroenterology, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology
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Omayone TP, Ijomone OM, Oloyede SB, Okunola ST, Aigoro ZO, Esukpa VU, Dinakin SO. Modulatory action of Moringa oleifera Lam. on L-arginine induced acute pancreatitis. J Basic Clin Physiol Pharmacol 2023; 34:707-715. [PMID: 34606706 DOI: 10.1515/jbcpp-2021-0149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/08/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Acute pancreatitis (AP) is an inflammatory disease of the pancreas with high morbidity and mortality. This study investigates the effect of Moring oleifera (MO) on L-arginine-induced AP in Wistar rats. METHODS Male Wistar rats were randomly divided into seven groups. Control, AP, Magnesium groups, all fed with standard rat diet, MO leaf groups (5% MLF and 15% MLF), and MO seed groups (5% MSD and 15% MSD) were fed with five or 15% MO leaf or seed supplemented diet for four weeks prior to induction of AP. AP was induced by administration of double doses of L-arginine (320 mg/100 g i.p.) at 1 h interval. All animals were sacrificed 72 h thereafter. RESULTS Weekly mean feed consumption and body weight were significantly higher in MO groups compared to the control. Amylase level, MDA, MPO, and NO were significantly higher in the AP group than in the control but decreased in Mg and MO groups. While CAT, SOD, GSH, and SH-group were significantly depleted in AP groups, which was attenuated in MO groups. Rats in AP groups showed severe inflammation, necrosis, and edema. These effects were significantly improved in MO groups resulting in lower histological scores compared to the AP group. CONCLUSIONS Pretreatment with MO could attenuate AP via its antioxidant and anti-inflammatory action.
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Affiliation(s)
- Tosan Peter Omayone
- Department of Physiology, School of Health and Health Technology, Federal University of Technology Akure, Akure, Nigeria
| | - Omamuyovwi Meashack Ijomone
- Department of Anatomy, School of Health and Health Technology, Federal University of Technology Akure, Akure, Nigeria
| | - Solomon Babatunde Oloyede
- Department of Physiology, School of Health and Health Technology, Federal University of Technology Akure, Akure, Nigeria
| | - Salihaat Toyin Okunola
- Department of Physiology, School of Health and Health Technology, Federal University of Technology Akure, Akure, Nigeria
| | - Zainab Oluwabukola Aigoro
- Department of Physiology, School of Health and Health Technology, Federal University of Technology Akure, Akure, Nigeria
| | - Victory Uwuma Esukpa
- Department of Physiology, School of Health and Health Technology, Federal University of Technology Akure, Akure, Nigeria
| | - Samuel Oluwaseun Dinakin
- Department of Physiology, School of Health and Health Technology, Federal University of Technology Akure, Akure, Nigeria
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Ridha M, Rivera Gonzalez G, Seenivasagam M. Pre-Workout-Induced Pancreatitis. Cureus 2023; 15:e44609. [PMID: 37795059 PMCID: PMC10547118 DOI: 10.7759/cureus.44609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2023] [Indexed: 10/06/2023] Open
Abstract
The use of dietary supplements, including pre-workout formulations, has gained widespread popularity among individuals engaged in sports and fitness. This case report presents a unique instance of pre-workout-induced pancreatitis in a previously healthy young adult. The patient, a 35-year-old male, presented to the emergency department with abdominal pain, elevated pancreatic enzymes, and characteristic radiological findings indicative of acute pancreatitis. The patient's history revealed no prior predisposing factors for pancreatitis such as alcohol consumption or gallstone disease. Extensive diagnostic evaluation excluded other potential causes leading to the suspicion of his pre-workout supplement as the source. Pre-workout supplements contain a blend of stimulants, amino acids, and other metabolic ingredients designed to enhance exercise and muscle performance. Research shows that some of these ingredients, such as amino acids, induce metabolic chain reactions which may damage pancreatic cells. However, there is extremely limited literature regarding these amino acids in combination such as in workout supplements. This case prompts an examination of the potential adverse effects of pre-workout supplements, highlighting the need for increased vigilance among healthcare providers and consumers alike. As the use of these products grows, further research is warranted to allow for safe commercial distribution and to protect consumers from serious harm.
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Werawatganon D, Vivatvakin S, Somanawat K, Tumwasorn S, Klaikeaw N, Siriviriyakul P, Chayanupatkul M. Effects of probiotics on pancreatic inflammation and intestinal integrity in mice with acute pancreatitis. BMC Complement Med Ther 2023; 23:166. [PMID: 37217916 DOI: 10.1186/s12906-023-03998-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 05/14/2023] [Indexed: 05/24/2023] Open
Abstract
BACKGROUND Severe acute pancreatitis is a potentially life-threatening disease. Despite being a common disorder, acute pancreatitis lacks a specific treatment. The present study aimed to examine the effects of probiotics on pancreatic inflammation and intestinal integrity in mice with acute pancreatitis. METHODS Male ICR mice were randomly divided into 4 groups (n = 6 per group). The control group received two intraperitoneal (i.p.) injections of normal saline as a vehicle control. The acute pancreatitis (AP) group received two i.p. injections of L-arginine 450 mg/100 g body weight. AP plus probiotics groups received L-arginine to induce acute pancreatitis as above. In the single-strain and mixed-strain groups, mice received 1 mL of Lactobacillus plantarum B7 1 × 108 CFU/mL and 1 mL of Lactobacillus rhamnosus L34 1 × 108 CFU/mL and Lactobacillus paracasei B13 1 × 108 CFU/mL by oral gavage, respectively for 6 days starting 3 days prior to the AP induction. All mice were sacrificed 72 h after L-arginine injection. Pancreatic tissue was obtained for histological evaluation and immunohistochemical studies for myeloperoxidase, whereas ileal tissue was used for immunohistochemical studies for occludin, and claudin-1. Blood samples were collected for amylase analysis. RESULTS Serum amylase levels and pancreatic myeloperoxidase levels in the AP group were significantly higher than in controls and significantly decreased in probiotic groups compared with the AP group. Ileal occludin and claudin-1 levels were significantly lower in the AP group than in controls. Ileal occludin levels significantly increased, whereas ileal claudin-1 levels did not significantly change in both probiotic groups as compared with the AP group. The pancreatic histopathology showed significantly higher degree of inflammation, edema, and fat necrosis in the AP group, and these changes improved in mixed-strained probiotic groups. CONCLUSIONS Probiotics, particularly the mixed-strain ones, attenuated AP via the reduction of inflammation and the maintenance of intestinal integrity.
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Affiliation(s)
- Duangporn Werawatganon
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sarocha Vivatvakin
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kanjana Somanawat
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Somying Tumwasorn
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Naruemon Klaikeaw
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Prasong Siriviriyakul
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Maneerat Chayanupatkul
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
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Clinical Significance of Serum Nitric Oxide, Urine Nitric Oxide, and Urinary Nitric Oxide-to-Creatinine Ratio in Acute Pancreatitis. Indian J Surg 2022. [DOI: 10.1007/s12262-022-03580-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
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Wang L, Xu T, Wang R, Wang X, Wu D. Hypertriglyceridemia Acute Pancreatitis: Animal Experiment Research. Dig Dis Sci 2022; 67:761-772. [PMID: 33939144 DOI: 10.1007/s10620-021-06928-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/26/2021] [Indexed: 12/09/2022]
Abstract
In recent years, the number of acute pancreatitis cases caused by hypertriglyceridemia has increased gradually, which has caught the attention of the medical community. However, because the exact mechanism of hypertriglyceridemic acute pancreatitis (HTG-AP) is not clear, treatment and prevention in clinical practice face enormous challenges. Animal models are useful for elucidating the pathogenesis of diseases and developing and testing novel interventions. Therefore, animal experiments have become the key research means for us to understand and treat this disease. We searched almost all HTG-AP animal models by collecting many studies and finally collated common animals such as rats, mice and included some rare animals that are not commonly used, summarizing the methods to model spontaneous pancreatitis and induce pancreatitis. We sorted them on the basis of three aspects, including the selection of different animals, analyzed the characteristics of different animals, different approaches to establish hypertriglyceridemic pancreatitis and their relative advantages and disadvantages, and introduced the applications of these models in studies of pathogenesis and drug therapy. We hope this review can provide relevant comparisons and analyses for researchers who intend to carry out animal experiments and will help researchers to select and establish more suitable animal experimental models according to their own experimental design.
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Affiliation(s)
- Lu Wang
- Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ting Xu
- Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ruifeng Wang
- Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Xiaobing Wang
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Dong Wu
- Department of Gastroenterology, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China
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Abdel Hafez SMN, Allam FAFA, Elbassuoni E. Sex differences impact the pancreatic response to chronic immobilization stress in rats. Cell Stress Chaperones 2021; 26:199-215. [PMID: 32986228 PMCID: PMC7736456 DOI: 10.1007/s12192-020-01169-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/21/2020] [Accepted: 09/24/2020] [Indexed: 12/27/2022] Open
Abstract
Chronic stress has been related to multiple diseases. Inflammation is proposed strongly to link stress to stress-related diseases in different organs, such as small intestine, colon, and brain. However, stress cellular effect on the pancreatic tissue, especially the exocrine one, had received relatively little attention. This work aimed to evaluate the cellular effect of chronic immobilization stress on the pancreatic tissue function and structure along with evaluating the sex role in this type of pancreatic injury. Thirty rats were equally divided into 5 groups: control male, control female, stressed male, stressed female, and stressed female with bilateral ovariectomy. Stressed rats were exposed to immobilization for 1 h/day, 6 days/week, for 3 weeks. Rats were then decapitated for further biochemical, histological, histo-morphometric, and immunohistochemical study. The results showed that, in male and female rats, chronic immobilization stress produced hypoinsulinemia and hyperglycemia, with increasing exocrine pancreatic injury markers by increasing oxidative and inflammatory status of the pancreatic tissue, and exhibited a degenerative effect on the pancreatic tissue. However, the stress-induced pancreatic effects were more obvious in male rats and female rats with bilateral ovariectomy than that in female rats. It could be concluded that male animals were more susceptible to stress-induced pancreatic damage than females. The ovarian hormones are responsible, at least partly, for pancreatic tissue protection since the stress-induced pancreatic injury in females was exacerbated by ovariectomy. In this study, inflammatory and oxidative stress differences in both sexes could provide a plausible explanation for sex differences.
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Affiliation(s)
| | | | - Eman Elbassuoni
- Physiology Department, Faculty of Medicine, Minia University, Minia, Egypt
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Yang X, Yao L, Fu X, Mukherjee R, Xia Q, Jakubowska MA, Ferdek PE, Huang W. Experimental Acute Pancreatitis Models: History, Current Status, and Role in Translational Research. Front Physiol 2020; 11:614591. [PMID: 33424638 PMCID: PMC7786374 DOI: 10.3389/fphys.2020.614591] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 11/30/2020] [Indexed: 02/05/2023] Open
Abstract
Acute pancreatitis is a potentially severe inflammatory disease that may be associated with a substantial morbidity and mortality. Currently there is no specific treatment for the disease, which indicates an ongoing demand for research into its pathogenesis and development of new therapeutic strategies. Due to the unpredictable course of acute pancreatitis and relatively concealed anatomical site in the retro-peritoneum, research on the human pancreas remains challenging. As a result, for over the last 100 years studies on the pathogenesis of this disease have heavily relied on animal models. This review aims to summarize different animal models of acute pancreatitis from the past to present and discuss their main characteristics and applications. It identifies key studies that have enhanced our current understanding of the pathogenesis of acute pancreatitis and highlights the instrumental role of animal models in translational research for developing novel therapies.
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Affiliation(s)
- Xinmin Yang
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Linbo Yao
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xianghui Fu
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Rajarshi Mukherjee
- Liverpool Pancreatitis Research Group, Liverpool University Hospitals National Health Service Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Qing Xia
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | | | - Pawel E. Ferdek
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Wei Huang
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
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Zhang Z, Liu Q, Zang H, Shao Q, Sun T. Oxymatrine protects against l-arginine-induced acute pancreatitis and intestine injury involving Th1/Th17 cytokines and MAPK/NF-κB signalling. PHARMACEUTICAL BIOLOGY 2019; 57:595-603. [PMID: 31496325 PMCID: PMC6746280 DOI: 10.1080/13880209.2019.1657906] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Context: Oxymatrine (OMT) has various pharmacological effects, including immune reaction regulation, anti-inflammation and anti-hypersensitive reaction. Objective: This is the first report to investigate the molecular mechanism of OMT function in l-arginine (Arg)-induced acute pancreatitis (AP) involving intestinal injury. Materials and methods: Rat pancreatic AR42J and small intestinal IEC-6 cells were treated with Arg (200-800 µM) for 48 h plus OMT (4 mg/mL) treatment. Thirty adult Wistar rats were randomly assigned to control (saline), AP (i.p. of 250 mg/100 g body weight Arg) and OMT (i.p. injection of 50 mg/kg b.w. OMT every 6 h following Arg). Both cells and rats were harvested at 48 h. Results: Arg-induced cell proliferation in both rats AR42J (EC50 633.9 ± 31.4 µM) and IEC-6 cells (EC50 571.3 ± 40.4 µM) in a dose-dependent manner, which was significantly inhibited by OMT (4 mg/mL). Meanwhile, Arg (600 µM) induced expression of proinflammatory cytokines (TNF-α, IL-6, IL-1β, NF-κB, IL-17A/IL-17F and IFN-γ) and activation of p-p38/p-ERK in vitro, which was reversed by OMT. In vivo, OMT (50 mg/kg) inhibited 250 mg/100 g of Arg-induced AP involving intestinal injury, including inhibiting Arg-induced inflammatory in pancreas and intestine, inhibiting Arg-induced increase of TNF-α, IL-6, IL-1β, NF-κB and p-p38/p-ERK-MAPK signalling, and inhibiting Arg-induced increase of IL-17A/IL-17F, IFN-γ, ROR-γt and T-bet. Meanwhile, OMT inhibited Arg-induced expression of CD44 and CD55 in intestinal injury. Discussion and conclusions: OMT protects against Arg-induced AP involving intestinal injury via regulating Th1/Th17 cytokines and MAPK/NF-κB signalling, which is a promising therapeutic agent in clinics.
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Affiliation(s)
- Zhiqiang Zhang
- Department of General Surgery, The People's Hospital of Liaoning Province, Shenyang, China
| | - Qingfeng Liu
- Department of General Surgery, The People's Hospital of Liaoning Province, Shenyang, China
| | - Hui Zang
- Department of General Surgery, The People's Hospital of Liaoning Province, Shenyang, China
| | - Qingliang Shao
- Department of General Surgery, The People's Hospital of Liaoning Province, Shenyang, China
- CONTACT Qingliang Shao Department of General Surgery, The Peoples’ Hospital of Liaoning Province, Shenyang 110016, China
| | - Tian Sun
- Department of General Surgery, The People's Hospital of China Medical University, Shenyang, China
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Stojanović NM, Stevanović M, Randjelović P, Mitić K, Petrović V, Sokolović D, Mladenović B, Lalić J, Radulović NS. Low dose of carvacrol prevents rat pancreas tissue damage after L-arginine application, while higher doses cause pancreatic tissue impairment. Food Chem Toxicol 2019; 128:280-285. [DOI: 10.1016/j.fct.2019.04.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 04/06/2019] [Accepted: 04/08/2019] [Indexed: 02/07/2023]
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14
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Elbassuoni EA, Abdel Hafez SM. Impact of chronic exercise on counteracting chronic stress-induced functional and morphological pancreatic changes in male albino rats. Cell Stress Chaperones 2019; 24:567-580. [PMID: 30903523 PMCID: PMC6527668 DOI: 10.1007/s12192-019-00988-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 03/02/2019] [Accepted: 03/08/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic stress has been linked to many diseases resulted from dysfunction of both the nervous system and peripheral organ systems. Yet, the effects of chronic stress on the pancreas have received relatively little attention. This work aims to investigate the influence of chronic stress exposure on both the endocrine and exocrine pancreatic function and morphology and its possible mechanism of action, and also to evaluate the impact of chronic exercise with moderate intensity on ameliorating the stress-induced pancreatic changes. Forty adult male albino rats were used and divided into four groups: control group, exercised group (3 weeks of swimming exercise), stressed group (3 weeks of immobilization stress), and stressed group practicing exercise (3 weeks of exercise, concomitant with 21 daily sessions of stress). On the final day of the experiment, all rats were sacrificed. Biochemical, immunohistochemical, and histological studies were conducted. The results showed that chronic immobilization stress produced hyperglycemia, hyperinsulinemia, and increased homeostatic model assessment of insulin resistance index (HOMA-IR) with increasing exocrine pancreatic injury markers by increasing oxidative and inflammatory status of the pancreatic tissue. Histological study showed the injurious effect of stress on the morphology of pancreatic tissue. Physical exercise protected the pancreas from the negative effects of stress through its anti-inflammatory and anti-oxidative effects, evidenced by increasing pancreatic interleukin 10 and total antioxidant capacity and decreasing pancreatic tumor necrosis factor-alpha, and malondialdehyde with ameliorating most of the histological changes induced by stress exposure. Physical exercise effectively counteracts chronic stress-induced pancreatic changes through different mechanisms.
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Affiliation(s)
- Eman A. Elbassuoni
- Physiology Department, Faculty of Medicine, Minia University, Minia, 61111 Egypt
| | - Sara M. Abdel Hafez
- Histology and Cell Biology Department, Faculty of Medicine, Minia University, Minia, 61111 Egypt
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15
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Martinelli P, Real FX. Animal Modeling of Pancreatitis-to-Cancer Progression. PANCREATIC CANCER 2018:313-347. [DOI: 10.1007/978-1-4939-7193-0_66] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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16
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Csonka C, Baranyai T, Tiszlavicz L, Fébel H, Szűcs G, Varga ZV, Sárközy M, Puskás LG, Antal O, Siska A, Földesi I, Ferdinandy P, Czakó L, Csont T. Isolated hypercholesterolemia leads to steatosis in the liver without affecting the pancreas. Lipids Health Dis 2017; 16:144. [PMID: 28750643 PMCID: PMC5532767 DOI: 10.1186/s12944-017-0537-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 07/13/2017] [Indexed: 02/06/2023] Open
Abstract
Background Lipid accumulation in the liver and pancreas is primarily caused by combined hyperlipidemia. However, the effect of isolated hypercholesterolemia without hypertriglyceridemia is not fully described. Therefore, our aim was to investigate whether hypercholesterolemia alone leads to alterations both in hepatic and pancreatic lipid panel and histology in rats. Methods Male Wistar rats were fed with 2% cholesterol +0.25% cholate-supplemented diet or standard chow for 12 weeks. Blood was collected at weeks 0, 4, 8 and 12 to measure serum cholesterol and triglyceride levels. At week 12, both the pancreas and the liver were isolated for further histological and biochemical analysis. Hepatic and plasma fatty acid composition was assessed by gas chromatography. Expression of mRNA of major enzymes involved in saturated/unsaturated fatty acid synthesis was analyzed by qPCR. In separate experiments serum enzyme activities and insulin levels were measured at week 9. Results At week 12, rats fed with 2% cholesterol +0.25% cholate-supplemented diet were characterized by elevated serum cholesterol (4.09 ± 0.20 vs. 2.89 ± 0.22 mmol/L, *p < 0.05) while triglyceride (2.27 ± 0.05 vs. 2.03 ± 0.03 mmol/L) and glucose levels (5.32 ± 0.14 vs. 5.23 ± 0.10 mmol/L) remained unchanged. Isolated hypercholesterolemia increased hepatic lipid accumulation, hepatic cholesterol (5.86 ± 0.22 vs. 1.60 ± 0.15 ng/g tissue, *p < 0.05) and triglyceride contents (19.28 ± 1.42 vs. 6.78 ± 0.71 ng/g tissue, *p < 0.05), and hepatic nitrotyrosine level (4.07 ± 0.52 vs. 2.59 ± 0.31 ng/mg protein, *p < 0.05). The histology and tissue lipid content of the pancreas was not affected. Serum total protein level, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities remained unchanged in response to isolated hypercholesterolemia while serum alkaline phosphatase activity (ALP) significantly increased. Plasma insulin levels did not change in response to isolated hypercholesterolemia suggesting an intact endocrine function of the pancreas. Isolated hypercholesterolemia caused a significantly increased hepatic and serum fatty acid level associated with a marked alteration of fatty acid composition. Hepatic expression of Δ9-desaturase (SCD1) was increased 4.92×, while expression of Δ5-desaturase and Δ6-desaturase were decreased (0.447× and 0.577×, respectively) due to isolated hypercholesterolemia. Conclusions Isolated hypercholesterolemia leads to hepatic steatosis and marked alterations in the hepatic lipid profile without affecting the pancreas. Altered fatty acid profile might mediate harmful effects of cholesterol in the liver.
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Affiliation(s)
- Csaba Csonka
- Metabolic Diseases and Cell Signaling Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - Tamás Baranyai
- Metabolic Diseases and Cell Signaling Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary.,1st Department of Internal Medicine, University of Szeged, Szeged, Hungary.,Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | | | - Hedvig Fébel
- Research Institute for Animal Breeding, Nutrition and Meat Science, Herceghalom, Szeged, Hungary
| | - Gergő Szűcs
- Metabolic Diseases and Cell Signaling Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary.,Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
| | - Zoltán V Varga
- Metabolic Diseases and Cell Signaling Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary.,Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Márta Sárközy
- Metabolic Diseases and Cell Signaling Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - László G Puskás
- Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary
| | - Otilia Antal
- Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary
| | - Andrea Siska
- Department of Laboratory Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Imre Földesi
- Department of Laboratory Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - László Czakó
- 1st Department of Internal Medicine, University of Szeged, Szeged, Hungary
| | - Tamás Csont
- Metabolic Diseases and Cell Signaling Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary.
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Zhan X, Wang F, Bi Y, Ji B. Animal models of gastrointestinal and liver diseases. Animal models of acute and chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2016; 311:G343-55. [PMID: 27418683 PMCID: PMC5076005 DOI: 10.1152/ajpgi.00372.2015] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 07/06/2016] [Indexed: 01/31/2023]
Abstract
Animal models of pancreatitis are useful for elucidating the pathogenesis of pancreatitis and developing and testing novel interventions. In this review, we aim to summarize the most commonly used animal models, overview their pathophysiology, and discuss their strengths and limitations. We will also briefly describe common animal study procedures and refer readers to more detailed protocols in the literature. Although animal models include pigs, dogs, opossums, and other animals, we will mainly focus on rodent models because of their popularity. Autoimmune pancreatitis and genetically engineered animal models will be reviewed elsewhere.
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Affiliation(s)
- Xianbao Zhan
- 1Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida and
| | - Fan Wang
- 1Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida and
| | - Yan Bi
- 2Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida and
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18
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Cremades A, Del Rio-Garcia J, Lambertos A, López-Garcia C, Peñafiel R. Tissue-specific regulation of potassium homeostasis by high doses of cationic amino acids. SPRINGERPLUS 2016; 5:616. [PMID: 27330882 PMCID: PMC4870509 DOI: 10.1186/s40064-016-2224-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 04/22/2016] [Indexed: 01/19/2023]
Abstract
The administration of l-arginine hydrochloride has been used for testing pituitary secretion in humans, and as an experimental model for induction of acute pancreatitis in rats and mice. Whereas in the first case, the administration of the amino acid is associated with hiperkalemia, in the model of acute pancreatitis no data are available on possible changes in potassium homeostasis. The present study shows that the acute administration to mice of l-arginine hydrochloride or other cationic amino acids almost duplicate plasma potassium levels. This effect was associated to a marked decrease of tissue potassium in both pancreas and liver. No changes were found in other tissues. These changes cannot be ascribed to the large load of chloride ions, since similar effects were produced when l-ornithine aspartate was administered. The changes in potassium levels were dependent on the dose. The displacement of intracellular potassium from the liver and pancreas to the extracellular compartment appears to be dependent on the entry of the cationic amino acid, since the administration of an equivalent dose of alfa-difluoromethyl ornithine HCl (DFMO), a non physiological analog of l-ornithine, which is poorly taken by the tissues in comparison with the physiological cationic amino acids, did not produce any change in potassium levels in pancreas and liver. The analyses of the expression of cationic amino acid transporters (CAT) suggest that the CAT-2 transporter may be implicated in the potassium/cationic amino acid interchange in liver and pancreas. The possible physiological or pathological relevance of these findings is discussed.
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Affiliation(s)
- Asunción Cremades
- Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain ; Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Jesús Del Rio-Garcia
- Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain
| | - Ana Lambertos
- Department of Biochemistry, Molecular Biology B and Immunology, School of Medicine, University of Murcia, 30100 Murcia, Spain
| | - Carlos López-Garcia
- Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain
| | - Rafael Peñafiel
- Department of Biochemistry, Molecular Biology B and Immunology, School of Medicine, University of Murcia, 30100 Murcia, Spain ; Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
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Gorenko ZA, Grinchenko OA, Veselsky SP, Baban VM. [COMPOSITION OF GASTRIC JUICE AND BILE IN RATS AT THE EXPERIMENTAL CHRONIC PANCREATITIS]. ACTA ACUST UNITED AC 2015; 61:86-95. [PMID: 27025049 DOI: 10.15407/fz61.06.086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Chronic pancreatitis is an inflammatory disease of the pancreas, which is characterized by destruction of pancreatic secretory parenchyma and progressing exocrine and endocrine insufficiency. Usually these patients have complications as cardiovascular, renal, respiratory and liver failure, and various gastric dysfunctions. The data of clinical observations do not reveal fully the functional state of the stomach and liver in chronic pancreatitis also remains an open question about the quality of the gastric juices and bile by this pathology. Therefore our aim was to investigate the secretory functions of the stomach and liver features in rats at the experimental chronic pancreatitis. This pathology modeled using L-arginine. Basal gastric secretion was investigated in chronic experiment by aspiration method for 10th and 63rd days, and pancreas and liver--in acute experiments at 13th and 68th days after the last administration of L-arginine. It was established that the character of the secretory response of the digestive tract depends on the duration of the pathology course. On the 10th day the functional state of the gastric secretory glands in rats with chronic pancreatitis characterized by twice increase of gastric acid production but decrease the level of hexosamines on 23.8% (P < 0.001) that indicate a increase of gastric content aggressiveness and mucus producing cells secretory insufficiency. In these animals the rate of total protein decreased on 61.7% (P < 0.05). On the 13th day observed the increase of pancreatic juice on 332% (P < 0.01), hepatic secret volume on 74.9% (P < 0.001) and redistribution in the cholates spectrum: glycocholates level increased but tauro-, free and total dehydroxylated bile acids decreased. These changes suggest deterioration of bile detergent properties, inhibition of acidic pathway of bile acids biosynthesis and conjugation of cholates with taurine. In two months total deficit of amino acids in gastric juice correlated with exocrine pancreatic insufficiency. Herein the acidity of gastric content partially restored, while the level of protein and mucus secretion proceed to decline. Consequently gastric mucosa is more vulnerable. In these rats the rates of free bile acids greatly increased while tauro- and glycocholates significantly decreased. Thus the processes of hydroxylation and conjugation of bile acids with amino acids inhibited suggesting interruption of synthetic and detoxification functions of the liver. The present work is important for comprehension the pathophysiological aspects of chronic pancreatitis particularly the digestive system functioning features at this pathology. These data could be considered in the appointment of treatment to avoid complications.
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20
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Robles L, Vaziri ND, Li S, Masuda Y, Takasu C, Takasu M, Vo K, Farzaneh SH, Stamos MJ, Ichii H. Dimethyl fumarate protects pancreatic islet cells and non-endocrine tissue in L-arginine-induced chronic pancreatitis. PLoS One 2014; 9:e107111. [PMID: 25198679 PMCID: PMC4157838 DOI: 10.1371/journal.pone.0107111] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Accepted: 08/06/2014] [Indexed: 12/12/2022] Open
Abstract
Background Chronic pancreatitis (CP) is a progressive disorder resulting in the destruction and fibrosis of the pancreatic parenchyma which ultimately leads to impairment of the endocrine and exocrine functions. Dimethyl Fumarate (DMF) was recently approved by FDA for treatment of patients with multiple sclerosis. DMF's unique anti-oxidant and anti-inflammatory properties make it an interesting drug to test on other inflammatory conditions. This study was undertaken to determine the effects of DMF on islet cells and non-endocrine tissue in a rodent model of L-Arginine-induced CP. Methods Male Wistar rats fed daily DMF (25 mg/kg) or vehicle by oral gavage were given 5 IP injections of L-Arginine (250 mg/100 g×2, 1 hr apart). Rats were assessed with weights and intra-peritoneal glucose tolerance tests (IPGTT, 2 g/kg). Islets were isolated and assessed for islet mass and viability with flow cytometry. Non-endocrine tissue was assessed for histology, myeloperoxidase (MPO), and lipid peroxidation level (MDA). In vitro assessments included determination of heme oxygenase (HO-1) protein expression by Western blot. Results Weight gain was significantly reduced in untreated CP group at 6 weeks. IPGTT revealed significant impairment in untreated CP group and its restoration with DMF therapy (P <0.05). Untreated CP rats had pancreatic atrophy, severe acinar architectural damage, edema, and fatty infiltration as well as elevated MDA and MPO levels, which were significantly improved by DMF treatment. After islet isolation, the volume of non-endocrine tissue was significantly smaller in untreated CP group. Although islet counts were similar in the two groups, islet viability was significantly reduced in untreated CP group and improved with DMF treatment. In vitro incubation of human pancreatic tissue with DMF significantly increased HO-1 expression. Conclusion Administration of DMF attenuated L-Arginine-induced CP and islet function in rats. DMF treatment could be a possible strategy to improve clinical outcome in patients with CP.
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Affiliation(s)
- Lourdes Robles
- Departments of Surgery and Medicine, University of California Irvine, Irvine, CA, United States of America
| | - Nosratola D. Vaziri
- Departments of Surgery and Medicine, University of California Irvine, Irvine, CA, United States of America
| | - Shiri Li
- Departments of Surgery and Medicine, University of California Irvine, Irvine, CA, United States of America
| | - Yuichi Masuda
- Departments of Surgery and Medicine, University of California Irvine, Irvine, CA, United States of America
| | - Chie Takasu
- Departments of Surgery and Medicine, University of California Irvine, Irvine, CA, United States of America
| | - Mizuki Takasu
- Departments of Surgery and Medicine, University of California Irvine, Irvine, CA, United States of America
| | - Kelly Vo
- Departments of Surgery and Medicine, University of California Irvine, Irvine, CA, United States of America
| | - Seyed H. Farzaneh
- Departments of Surgery and Medicine, University of California Irvine, Irvine, CA, United States of America
| | - Michael J. Stamos
- Departments of Surgery and Medicine, University of California Irvine, Irvine, CA, United States of America
| | - Hirohito Ichii
- Departments of Surgery and Medicine, University of California Irvine, Irvine, CA, United States of America
- * E-mail:
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21
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Autophagy in alcohol-induced multiorgan injury: mechanisms and potential therapeutic targets. BIOMED RESEARCH INTERNATIONAL 2014; 2014:498491. [PMID: 25140315 PMCID: PMC4124834 DOI: 10.1155/2014/498491] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Accepted: 06/29/2014] [Indexed: 12/21/2022]
Abstract
Autophagy is a genetically programmed, evolutionarily conserved intracellular degradation pathway involved in the trafficking of long-lived proteins and cellular organelles to the lysosome for degradation to maintain cellular homeostasis. Alcohol consumption leads to injury in various tissues and organs including liver, pancreas, heart, brain, and muscle. Emerging evidence suggests that autophagy is involved in alcohol-induced tissue injury. Autophagy serves as a cellular protective mechanism against alcohol-induced tissue injury in most tissues but could be detrimental in heart and muscle. This review summarizes current knowledge about the role of autophagy in alcohol-induced injury in different tissues/organs and its potential molecular mechanisms as well as possible therapeutic targets based on modulation of autophagy.
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22
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Synthesis and evaluation of (−)-Massoialactone and analogues as potential anticancer and anti-inflammatory agents. Eur J Med Chem 2014; 76:291-300. [DOI: 10.1016/j.ejmech.2014.02.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 01/06/2014] [Accepted: 02/08/2014] [Indexed: 12/31/2022]
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Recent advances in the investigation of pancreatic inflammation induced by large doses of basic amino acids in rodents. J Transl Med 2014; 94:138-49. [PMID: 24365745 DOI: 10.1038/labinvest.2013.143] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 11/13/2013] [Accepted: 11/19/2013] [Indexed: 12/16/2022] Open
Abstract
It has been known for approximately 30 years that large doses of the semi-essential basic amino acid L-arginine induce severe pancreatic inflammation in rats. Recently, it has been demonstrated that L-arginine can also induce pancreatitis in mice. Moreover, other basic amino acids like L-ornithine and L-lysine can cause exocrine pancreatic damage without affecting the endocrine parenchyma and the ducts in rats. The utilization of these noninvasive severe basic amino acid-induced pancreatitis models is becoming increasingly popular and appreciated as these models nicely reproduce most laboratory and morphological features of human pancreatitis. Consequently, the investigation of basic amino acid-induced pancreatitis may offer us a better understanding of the pathogenesis and possible treatment options of the human disease.
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Nelson TS, Akin RE, Weiler MJ, Kassis T, Kornuta JA, Dixon JB. Minimally invasive method for determining the effective lymphatic pumping pressure in rats using near-infrared imaging. Am J Physiol Regul Integr Comp Physiol 2014; 306:R281-90. [PMID: 24430884 DOI: 10.1152/ajpregu.00369.2013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The ability to quantify collecting vessel function in a minimally invasive fashion is crucial to the study of lymphatic physiology and the role of lymphatic pump function in disease progression. Therefore, we developed a highly sensitive, minimally invasive research platform for quantifying the pumping capacity of collecting lymphatic vessels in the rodent tail and forelimb. To achieve this, we have integrated a near-infrared lymphatic imaging system with a feedback-controlled pressure cuff to modulate lymph flow. After occluding lymphatic flow by inflating a pressure cuff on the limb or tail, we gradually deflate the cuff while imaging flow restoration proximal to the cuff. Using prescribed pressure applications and automated image processing of fluorescence intensity levels in the vessels, we were able to noninvasively quantify the effective pumping pressure (P(eff), pressure at which flow is restored after occlusion) and vessel emptying rate (rate of fluorescence clearance during flow occlusion) of lymphatics in the rat. To demonstrate the sensitivity of this system to changes in lymphatic function, a nitric oxide (NO) donor cream, glyceryl trinitrate ointment (GTNO), was applied to the tails. GTNO decreased P(eff) of the vessels by nearly 50% and the average emptying rate by more than 60%. We also demonstrate the suitability of this approach for acquiring measurements on the rat forelimb. Thus, this novel research platform provides the first minimally invasive measurements of P(eff) and emptying rate in rodents. This experimental platform holds strong potential for future in vivo studies that seek to evaluate changes in lymphatic health and disease.
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Affiliation(s)
- Tyler S Nelson
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia
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25
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Araújo LCC, Aguiar JS, Napoleão TH, Mota FVB, Barros ALS, Moura MC, Coriolano M, Coelho LCBB, Silva TG, Paiva PMG. Evaluation of cytotoxic and anti-inflammatory activities of extracts and lectins from Moringa oleifera seeds. PLoS One 2013; 8:e81973. [PMID: 24349164 PMCID: PMC3857229 DOI: 10.1371/journal.pone.0081973] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 10/18/2013] [Indexed: 01/03/2023] Open
Abstract
Background The extract from Moringa oleifera seeds is used worldwide, especially in rural areas of developing countries, to treat drinking water. M. oleifera seeds contain the lectins cmol and WSMoL, which are carbohydrate-binding proteins that are able to reduce water turbidity because of their coagulant activity. Studies investigating the ability of natural products to damage normal cells are essential for the safe use of these substances. This study evaluated the cytotoxic and anti-inflammatory properties of the aqueous seed extract, the extract used by population to treat water (named diluted seed extract in this work), and the isolated lectins cmol and WSMoL. Methodology/Principal Findings The data showed that the aqueous seed extract and cmol were potentially cytotoxic to human peripheral blood mononuclear cells, while WSMoL and diluted seed extract were not cytotoxic. The M. oleifera aqueous seed extract and the lectins cmol and WSMoL were weakly/moderately cytotoxic to the NCI-H292, HT-29 and HEp-2 cancer cell lines and were not hemolytic to murine erythrocytes. Evaluation of acute toxicity in mice revealed that the aqueous seed extract (2.000 mg/kg) did not cause systemic toxicity. The aqueous seed extract, cmol and WSMoL (6.25 µg/mL) and diluted seed extract at 50 µg/mL exhibited anti-inflammatory activity on lipopolyssaccharide-stimulated murine macrophages by regulating the production of nitric oxide, TNF-α and IL-1β. The aqueous seed extract reduced leukocyte migration in a mouse model of carrageenan-induced pleurisy; the myeloperoxidase activity and nitric oxide, TNF-α and IL-1β levels were similarly reduced. Histological analysis of the lungs showed that the extract reduced the number of leukocytes. Conclusion/Significance This study shows that the extract prepared according to folk use and WSMoL may be non-toxic to mammalian cells; however, the aqueous seed extract and cmol may be cytotoxic to immune cells which may explain the immunosuppressive potential of the extract.
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Affiliation(s)
- Larissa Cardoso Corrêa Araújo
- Departamento de Antibióticos, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco, Brazil
- Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco, Brazil
| | - Jaciana Santos Aguiar
- Departamento de Antibióticos, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco, Brazil
| | - Thiago Henrique Napoleão
- Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco, Brazil
| | - Fernanda Virgínia Barreto Mota
- Departamento de Antibióticos, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco, Brazil
| | - André Luiz Souza Barros
- Departamento de Antibióticos, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco, Brazil
| | - Maiara Celine Moura
- Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco, Brazil
| | - Marília Cavalcanti Coriolano
- Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco, Brazil
| | | | - Teresinha Gonçalves Silva
- Departamento de Antibióticos, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco, Brazil
- * E-mail:
| | - Patrícia Maria Guedes Paiva
- Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco, Brazil
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Abstract
The nonneoplastic diseases of the human pancreas generally comprise the inflammatory and degenerative conditions that include acute and chronic pancreatitis, with cystic fibrosis being arguably one of the most important diseases that induce the condition. Both acute and chronic conditions vary in severity, but both can be life threatening; and because of this fact, the study of their progression, and their responsiveness to therapy, is largely conducted by indirect means using serum markers of damage and repair such as amylase and lipase activities that normally occur at very low levels in the circulation but can be significantly increased during inflammatory episodes. Progress in the understanding the pathogenesis of both conditions has therefore been largely due to time course studies in animal models of pancreatitis, and it is in this context that animal model development has been so significant. In general terms, the animal models can be divided into the invasive, surgical procedures, and those induced by the administration of chemical secretagogues that induce hypersecretion of the pancreatic enzymes. The former include ligation and/or cannulation of the biliopancreatic ducts with infusion of solutions of various kinds, or the formation of closed duodenal loops. Secretagogue administration includes administration of caerulein or l-arginine in various protocols. An additional model involves administration of dibutyltin dichloride, which induces a partial blockage of the pancreatic ducts to induce pancreatic disease through enzymic reflux into the gland. The models have been invaluable in generating testable hypotheses for the human diseases. These hypotheses for the production of cellular damage as the initiating events in the disease include (1) intracellular chemical activation, (2) pancreatic secretion reflux, (3) intracellular production of reactive oxygen species, and (4) intracellular production of free radicals.
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Affiliation(s)
- John R Foster
- 1AstraZeneca Pharmaceuticals, Cheshire, United Kingdom
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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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Khan MW, Priyamvada S, Khan SA, Khan S, Naqshbandi A, Yusufi ANK. Protective effect of ω-3 polyunsaturated fatty acids onL-arginine-induced nephrotoxicity and oxidative damage in rat kidney. Hum Exp Toxicol 2012; 31:1022-34. [DOI: 10.1177/0960327112440110] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- MW Khan
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - S Priyamvada
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - SA Khan
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - S Khan
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - A Naqshbandi
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - ANK Yusufi
- Department of Biochemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
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Aghdassi AA, Mayerle J, Christochowitz S, Weiss FU, Sendler M, Lerch MM. Animal models for investigating chronic pancreatitis. FIBROGENESIS & TISSUE REPAIR 2011; 4:26. [PMID: 22133269 PMCID: PMC3274456 DOI: 10.1186/1755-1536-4-26] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 12/01/2011] [Indexed: 02/06/2023]
Abstract
Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed.
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Affiliation(s)
- Alexander A Aghdassi
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
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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; 15:2723-41. [PMID: 21777142 DOI: 10.1089/ars.2011.4063] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [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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Therapeutic effect of pentoxifylline versus losartan on experimentally induced acute pancreatitis in adult albino rats. ACTA ACUST UNITED AC 2011. [DOI: 10.1097/01.ehx.0000401367.91216.9d] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Zou XP, Chen M, Wei W, Cao J, Chen L, Tian M. Effects of enteral immunonutrition on the maintenance of gut barrier function and immune function in pigs with severe acute pancreatitis. JPEN J Parenter Enteral Nutr 2011; 34:554-66. [PMID: 20852186 DOI: 10.1177/0148607110362691] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND This study evaluated the effects of enteral immunonutrition (EIN) supplemented with glutamine, arginine, and probiotics on gut barrier function and immune function in pigs with severe acute pancreatitis (SAP). METHODS The model was induced by retrograde injection of 5% sodium taurocholate and trypsin via the pancreatic duct. After induction of SAP, 18 pigs were randomly divided into 3 groups, in which either parenteral nutrition (PN), control enteral nutrition (CEN), or EIN was applied for 8 days. Serum and pancreatic fluid amylase concentration was determined. Intestinal permeability (lactulose to mannitol ratio) was measured by high-performance liquid chromatography, and plasma endotoxin was quantified by the chromogenic limulus amebocyte lysate technique. Samples of venous blood and organs were cultured using standard techniques. Pancreatitis severity and villi of ileum were scored according to histopathologic grading. Plasma T-lymphocyte subsets were measured by flow cytometry, and immunoglobulins (Igs) were determined via enzyme-linked immunosorbent assay. RESULTS There were no significant differences in serum and pancreatic fluid amylases concentrations or in pancreatitis severity between any 2 of the 3 groups. Compared with PN and CEN, EIN significantly decreased intestinal permeability, plasma endotoxin concentration, and the incidence and magnitudes of bacterial translocation, but increased ileal mucosal thickness, villous height, crypt depth, and percentage of normal intestinal villi. Significant differences were found in CD3+, CD4+ lymphocyte subsets, the ratio of CD4+: CD8+ lymphocyte subsets, and serum IgA and IgG, but not IgM, between any 2 of the 3 groups. CONCLUSIONS EIN maintained gut barrier function and immune function in pigs with SAP.
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Affiliation(s)
- Xiao-Ping Zou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, P.R. China.
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Melo CM, Carvalho KMMB, Neves JCDS, Morais TC, Rao VS, Santos FA, Brito GADC, Chaves MH. α,β-amyrin, a natural triterpenoid ameliorates L-arginine-induced acute pancreatitis in rats. World J Gastroenterol 2010; 16:4272-80. [PMID: 20818810 PMCID: PMC2937107 DOI: 10.3748/wjg.v16.i34.4272] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the beneficial effects of triterpene α,β-amyrin and the underlying mechanisms in an experimental pancreatitis model.
METHODS: Acute pancreatitis was induced in five groups of rats (n = 8) by L-arginine (2 × 2.5 g/kg, intraperitoneal, 1 h apart) and 1 h later, they received a single oral dose of α,β-amyrin (10, 30 and 100 mg/kg), methylprednisolone (30 mg/kg) and vehicle (3% Tween 80). A saline (0.9% NaCl) treated group served as a normal control. Efficacy was assessed at 24 h by determination of serum levels of amylase, lipase and pro-inflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin (IL)-6], pancreatic myeloperoxidase (MPO) activity, lipid peroxidation [thiobarbituric acid reactive substances (TBARS)], nitrate/nitrite levels, and the wet weight/body weight ratio. Tissue histology and the immunoreactivity for TNF-α and inducible nitric oxide synthetase (iNOS) were performed.
RESULTS: α,β-amyrin and methylprednisolone treatments significantly (P < 0.05) attenuated the L-arginine-induced increases in pancreatic wet weight/body weight ratio, and decreased the serum levels of amylase and lipase, and TNF-α and IL-6, as compared to the vehicle control. Also, pancreatic levels of MPO activity, TBARS, and nitrate/nitrite were significantly lower. Histological findings and TNF-α and iNOS immunostaining further confirmed the amelioration of pancreatic injury by α,β-amyrin.
CONCLUSION: α,β-amyrin has the potential to combat acute pancreatitis by acting as an anti-inflammatory and antioxidant agent.
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Abstract
OBJECTIVES Intraperitoneal (IP) injection of 3.5 g/kg L-arginine (known to induce acute pancreatitis) in rats will result in much greater increases in serum ornithine versus citrulline concentration (Crit Care Med. 2008;36:2117-2127). These data indicate a major role of arginase in the catabolism of L-arginine. Therefore, we tested the effects of the irreversible arginase inhibitor (+)-S-2-amino-6-iodoacetamidohexanoic acid (AIHA) on L-arginine-induced acute pancreatitis. METHODS The inhibitory effect of AIHA on arginase activity was tested on rat liver homogenate and purified bovine arginase. Male Wistar rats were administered 15 mg/kg AIHA or its vehicle IP 1 hour before the injection of physiological saline or 3.5 g/kg L-arginine IP. Laboratory and histological parameters of pancreatitis were determined 24 hours after the last injection. RESULTS Sixty micromolars of AIHA (equimolar to an in vivo dose of 15 mg/kg) significantly inhibited arginase activity by about 25%. Pretreatment with AIHA significantly ameliorated pancreatic damage caused by L-arginine administration. It decreased pancreatic weight/body weight ratio, pancreatic glutathione peroxidase and myeloperoxidase activities, and histological damage. Administration of AIHA in itself significantly increased levels of pancreatic heat shock proteins. CONCLUSIONS Pretreatment with AIHA reduces the severity of L-arginine-induced pancreatitis most likely by inhibiting arginase activity.
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Abdin AA, El-Hamid MAA, El-Seoud SHA, Balaha MFH. Effect of pentoxifylline and/or alpha lipoic acid on experimentally induced acute pancreatitis. Eur J Pharmacol 2010; 643:289-96. [PMID: 20599924 DOI: 10.1016/j.ejphar.2010.06.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2009] [Revised: 06/01/2010] [Accepted: 06/11/2010] [Indexed: 12/17/2022]
Abstract
Acute pancreatitis is a sudden inflammation of the pancreas that may be life threatening disease with high mortality rates; particularly in presence of systemic inflammatory response and multiple organ failure despite of the conventional antibiotic and symptomatic treatment. Oxidative stress has been shown to be involved in the pathophysiology of acute pancreatitis. This study was designed to investigate the possible effect of pentoxifylline and alpha lipoic acid respectively and in combination on rats with L-arginine induced acute pancreatitis. Rats were divided as follow; Group 1: served as control, Group 2 and Group 3: sacrificed after 24h and 7 days; respectively, from induction of acute pancreatitis by L-arginine 250 mg/100g, Group 4 and Group 5: rats treated by pentoxifylline (12 mg/kg) and sacrificed after 24h and 7 days; respectively, from induction of acute pancreatitis, Group 6 and Group 7: treated by alpha lipoic acid (1mg/kg) and sacrificed after 24h and 7 days; respectively, from induction of acute pancreatitis, Group 8 and Group 9: treated by pentoxifylline and alpha lipoic acid and sacrificed after 24h and 7 days; respectively, from induction of acute pancreatitis. Serum samples were collected to assay levels of amylase enzyme, C-reactive protein, IL-6, catalase enzyme activity, malondialdehyde and pancreases were excised for histopathological examination and assay of pancreatic myeloperoxidase. L-arginine induced-acute pancreatitis was evident by increased in serum marker enzymes and by histopathological findings compared to control group. Pentoxifylline and alpha lipoic acid respectively provided protection against L-arginine induced acute pancreatitis possibly by their antioxidant and anti-inflammatory effect. Treatment with alpha lipoic acid exhibited pronounced improvement in the course of pancreatitis when compared to treatment with pentoxifylline. Moreover, the combination of pentoxifylline and alpha lipoic acid offered the most evident protection when compared to groups that received monotherapy; pointing to the effectiveness of such combination therapy.
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Affiliation(s)
- Amany A Abdin
- Department of Pharmacology, Faculty of medicine, Tanta University, Egypt.
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36
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Batcioglu K, Gul M, Uyumlu AB, Esrefoglu M. Liver lipid peroxidation and antioxidant capacity in cerulein-induced acute pancreatitis. Braz J Med Biol Res 2010; 42:776-82. [PMID: 19738983 DOI: 10.1590/s0100-879x2009000900001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2008] [Accepted: 06/15/2009] [Indexed: 01/27/2023] Open
Abstract
The aim of this study was to evaluate the role of oxidative damage in pancreatitis-induced hepatic injury. Thirty-five rats were divided into five groups (each of 7 rats): control, cerulein (100 microg/kg body weight), cerulein and pentoxifylline (12 mg/kg body weight), cerulein plus L-NAME (10 mg/kg body weight) and cerulein plus L-arginine (160 mg/kg body weight). The degree of hepatic cell degeneration differed significantly between groups. Mean malondialdehyde levels were 7.00 +/- 2.29, 20.89 +/- 10.13, 11.52 +/- 4.60, 18.69 +/- 8.56, and 8.58 +/- 3.68 nmol/mg protein for the control, cerulein, pentoxifylline, L-NAME, and L-arginine groups, respectively. Mean catalase activity was 3.20 +/- 0.83, 1.09 +/- 0.35, 2.05 +/- 0.91, 1.70 +/- 0.60, and 2.85 +/- 0.47 U/mg protein for the control, cerulein, pentoxifylline, L-NAME, and L-arginine groups, respectively, and mean glutathione peroxidase activity was 0.72 +/- 0.25, 0.33 +/- 0.09, 0.37 +/- 0.04, 0.34 +/- 0.07 and 0.42 +/- 0.1 U/mg protein for the control, cerulein, pentoxifylline, L-NAME, and L-arginine groups, respectively. Cerulein-induced liver damage was accompanied by a significant increase in tissue malondialdehyde levels (P < 0.05) and a significant decrease in catalase (P < 0.05) and GPx activities (P < 0.05). L-arginine and pentoxifylline, but not L-NAME, protected against this damage. Oxidative injury plays an important role not only in the pathogenesis of AP but also in pancreatitis-induced hepatic damage.
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Affiliation(s)
- K Batcioglu
- Department of Biochemistry, Inonu University, Malatya, Turkey.
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37
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Shi Cheng, Yan WM, Bin Yang, Shi JD, Song MM, Yuqian Zhao. A crucial role of nitric oxide in acute lung injury secondary to the acute necrotizing pancreatitis. Hum Exp Toxicol 2010; 29:329-37. [PMID: 20144956 DOI: 10.1177/0960327110361760] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
To investigate the role of nitric oxide (NO) in acute lung inflammation and injury secondary to acute necrotizing pancreatitis (ANP), 5% sodium taurocholate was retrogradely injected into the biliopancreatic duct of rats to ANP model. These ANP rats were given L-Arginine (L-Arg, 100 mg/kg), L-NAME (10 mg/kg), or their combination by intraperitoneal injection 30 min prior to ANP induction. At 1, 3, 6, and 12 hours after ANP induction, lung NO production, and inducible NO synthase (iNOS) expression were measured. Lung histopathological changes, bronchoalveolar lavage (BAL) protein concentration, proinflammatory mediators tumor necrotic factor alpha (TNF-α), and lung tissue myeloperoxidase (MPO) activity were examined. Results showed that NO production and iNOS mRNA expression in alveolar macrophages (AMs) were significantly increased along with significant increases in lung histological abnormalities and BAL proteins in the ANP group, all of which were further enhanced by pretreatment with L-Arg and attenuated by pretreatment with L-NAME, respectively. These markers were slightly attenuated by pretreatment with combination of L-Arg + L-NAME, suggesting that NO is required for initiating the acute lung damage in ANP rats, and also that L-Arg-enhanced lung injury is mediated by its NO generation rather than its direct effect. MPO activity and TNF-α expression in lung were upregulated in the ANP rats and further enhanced by pretreatment with L-Arg and attenuated by pretreatment with L-NAME, respectively. These results suggest that overproduction of NO mediated by iNOS in the lung is required for the acute lung inflammation and damage secondary to ANP.
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Affiliation(s)
- Shi Cheng
- Department of General Surgery, Affiliated Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
| | - Wen-Mao Yan
- Department of General Surgery, Affiliated Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
| | - Bin Yang
- Department of General Surgery, Affiliated Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
| | - Jing-dong Shi
- Department of General Surgery, Affiliated Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
| | - Mao-min Song
- Department of General Surgery, Affiliated Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
| | - Yuqian Zhao
- Department of General Surgery, Affiliated Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
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Abstract
Reactive oxygen and reactive nitrogen species (ROS/RNS) have been implicated in the pathogenesis of acute and chronic pancreatitis. Clinical and basic science studies have indicated that ROS/RNS formation processes are intimately linked to the development of the inflammatory disorders. The detrimental effects of highly reactive ROS/RNS are mediated by their direct actions on biomolecules (lipids, proteins, and nucleic acids) and activation of proinflammatory signal cascades, which subsequently lead to activation of immune responses. The present article summarizes the possible sources of ROS/RNS formation and the detailed signaling cascades implicated in the pathogenesis of pancreatic inflammation, as observed in acute and chronic pancreatitis. A therapeutic ROS/RNS-scavenging strategy has been advocated for decades; however, clinical studies examining such approaches have been inconsistent in their results. Emerging evidence indicates that pancreatitis-inducing ROS/RNS generation may be attenuated by targeting ROS/RNS-generating enzymes and upstream mediators.
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Affiliation(s)
- Po Sing Leung
- Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
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Bohus E, Coen M, Keun HC, Ebbels TMD, Beckonert O, Lindon JC, Holmes E, Noszál B, Nicholson JK. Temporal metabonomic modeling of l-arginine-induced exocrine pancreatitis. J Proteome Res 2008; 7:4435-45. [PMID: 18710274 DOI: 10.1021/pr800407j] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The time-related metabolic responses to l-arginine (ARG)-induced exocrine pancreatic toxicity were investigated using single ip doses of 1,000 and 4,000 mg/kg body weight over a 7 day experimental period in male Sprague-Dawley rats. Sequential timed urine and plasma samples were analyzed using high resolution (1)H NMR spectroscopy together with complementary clinical chemistry and histopathology analyses. Principal components analysis (PCA) and orthogonal projection on latent structures discriminant analysis (O-PLS-DA) were utilized to analyze the (1)H NMR data and to extract and identify candidate biomarkers and to construct metabolic trajectories post ARG administration. Low doses of ARG resulted in virtually no histopathological damage and distinct reversible metabolic response trajectories. High doses of ARG caused pancreatic acinar degeneration and necrosis and characteristic metabolic trajectory profiles with several distinct phases. The initial trajectory phase (0-8 h) involved changes in the urea cycle and transamination indicating a homeostatic response to detoxify excess ammonia generated from ARG catabolism. By 48 h, there was a notable enhancement of the excretion of the gut microbial metabolites, phenylacetylglycine (PAG), 4-cresol-glucuronide and 4-cresol-sulfate, suggesting that compromised pancreatic function impacts on the activity of the gut microbiota giving potential rise to a novel class of surrogate extragenomic biomarkers of pancreatic injury. The implied compromise of microbiotal function may also contribute to secondary hepatic and pancreatic toxic responses. We show here for the first time the value of metabonomic studies in investigating metabolic disruption due to experimental pancreatitis. The variety of observed systemic responses suggests that this approach may be of general value in the assessment of other animal models or human pancreatitis.
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Affiliation(s)
- Eszter Bohus
- Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes Endre u. 9, Budapest 1092, Hungary
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Rakonczay Z, Hegyi P, Dósa S, Iványi B, Jármay K, Biczó G, Hracskó Z, Varga IS, Karg E, Kaszaki J, Varró A, Lonovics J, Boros I, Gukovsky I, Gukovskaya AS, Pandol SJ, Takács T. A new severe acute necrotizing pancreatitis model induced by L-ornithine in rats. Crit Care Med 2008; 36:2117-27. [PMID: 18594222 DOI: 10.1097/ccm.0b013e31817d7f5c] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Intraperitoneal administration of large doses of L-arginine is known to induce severe acute pancreatitis in rats. We therefore set out to determine whether metabolites of L-arginine (L-ornithine, L-citrulline, and nitric oxide) cause pancreatitis. DESIGN The authors conducted an in vivo animal study. SETTING This study was conducted at a university research laboratory. SUBJECTS Study subjects were male Wistar rats. INTERVENTIONS Dose-response and time course changes of laboratory and histologic parameters of pancreatitis were determined after L-arginine, L-ornithine, L-citrulline, or sodium nitroprusside (nitric oxide donor) injection. MEASUREMENTS AND MAIN RESULTS Intraperitoneal injection of 3 g/kg L-ornithine but not L-citrulline or nitroprusside caused severe acute pancreatitis; 4 to 6 g/kg L-ornithine killed the animals within hours. Serum and ascitic amylase activities were significantly increased, whereas pancreatic amylase activity was decreased after intraperitoneal injection of 3 g/kg L-ornithine. The increase in pancreatic trypsin activity (9-48 hrs) correlated with the degradation of IkappaB proteins and elevated interleukin-1beta levels. Oxidative stress in the pancreas was evident from 6 hrs; HSP72 synthesis was increased from 4 hrs after L-ornithine administration. Morphologic examination of the pancreas showed massive interstitial edema, apoptosis, and necrosis of acinar cells and infiltration of neutrophil granulocytes and monocytes 18 to 36 hrs after 3 g/kg L-ornithine injection. One month after L-ornithine injection, the pancreas appeared almost normal; the destructed parenchyma was partly replaced by fat. Equimolar administration of L-arginine resulted in lower pancreatic weight/body weight ratio, pancreatic myeloperoxidase activity, and histologic damage compared with the L-ornithine-treated group. L-ornithine levels in the blood were increased 54-fold after intraperitoneal administration of L-arginine. CONCLUSIONS We have developed a simple, noninvasive model of acute necrotizing pancreatitis in rats by intraperitoneal injection of 3 g/kg L-ornithine. Interestingly, we found that, compared with L-arginine, L-ornithine was even more effective at inducing pancreatitis. Large doses of L-arginine produce a toxic effect on the pancreas, at least in part, through L-ornithine.
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Affiliation(s)
- Zoltán Rakonczay
- First Department of Medicine, University of Szeged, Szeged, Hungary.
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The better the model, the nearer the cure*. Crit Care Med 2008; 36:2208-9. [DOI: 10.1097/ccm.0b013e31817c0994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Li BF, Liu YF, Cheng Y, Zhang KZ, Li TM, Zhao N. Protective effect of inducible nitric oxide synthase inhibitor on pancreas transplantation in rats. World J Gastroenterol 2008; 13:6066-71. [PMID: 18023101 PMCID: PMC4250892 DOI: 10.3748/wjg.v13.45.6066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of inducible nitric oxide synthase inhibitor, aminoguanidine, on pancreas transplantation in rats. METHODS A model of pancreas transplantation was established in rats. Streptozotocin-induced diabetic male Wistar rats were randomly assigned to sham-operation control group (n = 6), transplant control group (n = 6), and aminoguanidine (AG) treatment group (n = 18). In the AG group, aminoguanidine was added to intravascular infusion as the onset of reperfusion at the dose of 60 mg/kg, 80 mg/kg, 100 mg/kg body weight, respectively. Serum nitric oxide (NO) level, blood sugar and amylase activity were detected. Nitric oxide synthase (NOS) test kit was used to detect the pancreas cNOS and inducible NOS (iNOS) activity. Pancreas sections stained with HE and immunohistochemistry were evaluated under a light microscope. RESULTS As compared with the transplant control group, the serum NO level and amylase activity decreased obviously and the evidence for pancreas injury was much less in the AG group. The AG (80 mg/kg body weight) group showed the most significant difference in NO and amylase (NO: 66.0 +/- 16.6 vs 192.3 +/- 60.0, P < 0.01 and amylase: 1426 +/- 177 vs 4477 +/- 630, P < 0.01). The expression and activity of tissue iNOS, and blood sugar in the AG (80 mg/kg body weight) group were much lower than those in the transplant control group (iNOS: 2.01 +/- 0.23 vs 26.59 +/- 5.78, P < 0.01 and blood sugar: 14.2 +/- 0.9 vs 16.8 +/- 1.1, P < 0.01). CONCLUSION Selective iNOS inhibitor, aminoguanidine as a free radical, has a protective effect on pancreas transplantation in rats by inhibiting NO and reducing its toxicity.
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Affiliation(s)
- Bai-Feng Li
- Department of Surgery and Organ Transplant Unit, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
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Czakó L, Szabolcs A, Vajda A, Csáti S, Venglovecz V, Rakonczay Z, Hegyi P, Tiszlavicz L, Csont T, Pósa A, Berkó A, Varga C, Varga Ilona S, Boros I, Lonovics J. Hyperlipidemia induced by a cholesterol-rich diet aggravates necrotizing pancreatitis in rats. Eur J Pharmacol 2007; 572:74-81. [PMID: 17628538 DOI: 10.1016/j.ejphar.2007.05.064] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2007] [Revised: 05/21/2007] [Accepted: 05/23/2007] [Indexed: 11/28/2022]
Abstract
The aim of the present study was to investigate whether hyperlipidemia can cause acute pancreatitis or alter its severity. Male Wistar rats were fed a 3% cholesterol-enriched diet or a normal diet for 16 weeks. Edematous and necrotizing pancreatitis was induced with 3x75 mug/kg body weight of cholecystokinin s.c. and 2x2 g/kg body weight of L-arginine i.p., respectively, in separate groups of normal and hyperlipidemic rats. The severity of the pancreatitis was assessed. We studied the influence of hyperlipidemia on the formation of oxygen-derived free radicals, endogenous scavengers, nitric oxide synthases (NOS), peroxynitrite (ONOO(-)), heat shock protein 72 (HSP72) and nuclear factor-kappa B (NF-kappaB) activation in the pancreas during acute edematous and necrotizing pancreatitis. Hyperlipidemia did not worsen edematous, but aggravated necrotizing pancreatitis. The cholesterol-enriched diet significantly reduced the catalase and Mn-superoxide dismutase (SOD) and constitutive NOS (cNOS) activities and increased the inducible NOS (iNOS) in the pancreas relative to those in the rats on the normal diet. The pancreatic nitrotyrosine level, as a marker of ONOO(-), and the NF-kappaB DNA-binding activity in the pancreas, were significantly elevated in the cholesterol-fed rats. The pancreatic HSP72 expression during necrotizing pancreatitis was not influenced by the hyperlipidemia. The pancreatic Mn-SOD, Cu, Zn-SOD, glutathione peroxidase, total glutathione and cNOS activities were significantly reduced, while the catalase, iNOS and NF-kappaB DNA-binding activities were significantly increased in the animals with necrotizing pancreatitis on the cholesterol diet as compared with those with pancreatitis and receiving the normal diet. Hyperlipidemia induced with this cholesterol-enriched diet leads to decreases in endogenous scavenger and cNOS activities, results in iNOS and NF-kappaB activation and stimulates ONOO(-) generation in the pancreas, which may be responsible for the aggravation of acute necrotizing pancreatitis.
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Affiliation(s)
- László Czakó
- First Department of Medicine, University of Szeged, Hungary.
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Dawra R, Sharif R, Phillips P, Dudeja V, Dhaulakhandi D, Saluja AK. Development of a new mouse model of acute pancreatitis induced by administration of L-arginine. Am J Physiol Gastrointest Liver Physiol 2007; 292:G1009-18. [PMID: 17170029 DOI: 10.1152/ajpgi.00167.2006] [Citation(s) in RCA: 137] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The pathogenesis of acute pancreatitis is not fully understood. Experimental animal models that mimic human disease are essential to better understand the pathophysiology of the disease and to evaluate potential therapeutic agents. Given that the mouse genome is known completely and that a large number of strains with various genetic deletions are available, it is advantageous to have multiple reliable mouse models of acute pancreatitis. Presently, there is only one predominant model of acute pancreatitis in mice, in which hyperstimulatory doses of cholecystokinin or its analog caerulein are administered. Therefore, the aim of this study was to develop another mouse model of acute pancreatitis. In this study, C57BL/6 mice were injected intraperitoneally with L-arginine in two doses of 4 g/kg each, 1 h apart. Serum amylase, myeloperoxidase, and histopathology were examined at varying time points after injection to assess injury to the pancreas and lung. We found that injection of L-arginine was followed by significant increases in plasma amylase and pancreatic myeloperoxidase accompanied by marked histopathological changes. The injury to the pancreas was slow to develop and peaked at 72 h. Subsequent to peak injury, the damaged areas contained collagen fibers as assessed by increased Sirius red staining. In contrast, D-arginine or other amino acids did not cause injury to the pancreas. In addition, acute inflammation in the pancreas was associated with lung injury. Our results indicate that administration of L-arginine to mice results in severe acute pancreatitis. This model should help in elucidating the pathophysiology of pancreatitis.
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Affiliation(s)
- Rajinder Dawra
- Department of Surgery, University of Minnesota, MMC 195, 420 Delaware St. SE, Minneapolis, MN 55416, USA
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Abstract
Acute pancreatitis (AP) is characterized by edema, acinar cell necrosis, hemorrhage, and severe inflammation of the pancreas. Patients with AP present with elevated blood and urine levels of pancreatic digestive enzymes, such as amylase and lipase. Severe AP may lead to systemic inflammatory response syndrome and multiorgan dysfunction syndrome, which account for the high mortality rate of AP. Although most (>80%) cases of AP are associated with gallstones and alcoholism, some are idiopathic. Although the pathogenesis of AP has not yet been elucidated, a common feature is the premature activation of trypsinogen within pancreatic tissues, which triggers autodigestion of the gland. Recent advances in basic research suggest that etiologic factors including cyclooxygenase-2, substance P, and angiotensin II may have novel roles in this disease. Basic research data obtained thus far have been based on animal models of AP ranging from mild edematous pancreatitis to severe necrotizing pancreatitis. In view of this, an adequate selection of experimental animal models is of paramount importance. Notwithstanding these animal models, it should be emphasized that none of these models mimic the clinical situation where varying degrees of severity usually occur. In this review, commonly used animal models of AP will be critically evaluated. A discussion of recent advances in our knowledge about AP risk factors is also included.
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Affiliation(s)
- Yuk Cheung Chan
- Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
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Shields CJ, Delaney CP, Winter DC, Young L, Gorey TF, Fitzpatrick JM. Induction of Nitric Oxide Synthase is a Key Determinant of Progression to Pulmonary Injury in Experimental Pancreatitis. Surg Infect (Larchmt) 2006; 7:501-11. [PMID: 17233567 DOI: 10.1089/sur.2006.7.501] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND The immunomodulatory potential of nitric oxide provides prospective strategies to attenuate inappropriate inflammatory reactions. This study tested the hypothesis that inhibition of nitric oxide synthase (NOS) reduces end-organ injury in pancreatitis. METHODS Pancreatitis was induced in male Sprague-Dawley rats by intraperitoneal (i.p.) injection of 20% L-arginine (500 mg/100 g of body weight). Animals were randomized into four groups of 45: Pancreatitis without intervention; pre-treatment with i.p. aminoguanidine (AMG) (50 mg/kg), an isoform-specific inhibitor of inducible NOS; post-treatment with AMG (50 mg/kg); and controls. Pancreatic and pulmonary pathology, neutrophil infiltration (myeloperoxidase activity), endothelial permeability (bronchoalveolar lavage, wet:dry weight ratio), NOS expression, and concentrations of pro-inflammatory cytokines (tumor necrosis factor-alpha; interleukin-6) were assessed. RESULTS Inhibition of iNOS significantly reduced end-organ injury. Pancreatic and pulmonary injury scores were markedly attenuated in the AMG treatment groups compared with no intervention (p < 0.05). Increased endothelial permeability (2,411.1 +/- 47.9) and neutrophil sequestration (1.99 +/- 0.01) were manifest in the untreated animals compared with AMG pretreatment (1,286.8 +/- 35.1 and 1,548.0 +/- 0.1; p < 0.05). In addition, a significant reduction in inflammatory cytokine concentrations was observed (p < 0.05). CONCLUSIONS Inhibition of inducible NOS encourages a more benign immunologic profile, minimizing the deleterious effects of unrestrained neutrophil sequestration subsequent to pancreatitis.
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Affiliation(s)
- Conor J Shields
- Department of Surgery, Mater Misericordiae Hospital, and University College, Dublin, Ireland.
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Bouffard L, Papirakis ME, Maheux P. Enalapril increases the local extravasation of macromolecules and nitric oxide synthase in pancreas of the fructose-fed insulin-resistant rat model. Pancreas 2006; 33:418-24. [PMID: 17079949 DOI: 10.1097/01.mpa.0000236729.01123.7d] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Angiotensin-converting enzyme (ACE) inhibitors have been associated with an increased risk of acute pancreatitis. The pathogenesis of this condition remains unclear, but an activation of the kinin system and a resultant localized angioedema have been implicated in the initial step leading to acute pancreatic damage. The goal of the present study was to explore the impact of ACE inhibition on pancreatic microcirculation and capillary permeability in normal and insulin-resistant rats. METHODS Chow- or fructose-fed Sprague-Dawley rats were treated with enalapril (dosage, 10 mg.kg.d) or vehicle for 4 weeks before measuring in vivo the extravasation of Evans blue (EB) dye in pancreas. Unanesthetized animals (n = 10-17 per group) were injected with EB 20 mg.kg in the caudal vein 10 minutes before killing, and EB dye was extracted from each pancreas by using formamide. RESULTS Relative to controls, enalapril-treated animals showed a 5-fold increase in pancreatic extravasation of EB in the fructose-fed rat model (P < 0.001); smaller changes (2-fold) were observed in the chow-fed animals treated with enalapril (P < 0.001). The increase in pancreatic vasopermeability observed with enalapril in the fructose-fed animals was accompanied by a significant increase in total pancreatic nitric oxide synthase (NOS) activity compared to controls (Delta = +128%; P < 0.001). This increase in NOS activity seemed to be solely attributable to an upregulation of the endothelial NOS isoform because only the eNOS immunoreactive mass (as opposed to nNOS) seemed to be increased in the pancreas of these animals. Treatment with enalapril was not associated with any increase in serum amylase concentrations in either animal subgroup. CONCLUSIONS Enalapril increases capillary permeability (extravasation of macromolecules) in the pancreas of the fructose-fed rat model. This suggests that ACE inhibition upregulates the eNOS isoform locally, increases vasopermeability of the pancreas, and can therefore result in local edema in the fructose-fed insulin-resistant rat model.
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Affiliation(s)
- Lucie Bouffard
- Department of Medicine, Division of Endocrinology & Metabolism, Université de Sherbrooke, Quebec, Canada
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Chvanov M, Petersen OH, Tepikin A. Free radicals and the pancreatic acinar cells: role in physiology and pathology. Philos Trans R Soc Lond B Biol Sci 2006; 360:2273-84. [PMID: 16321797 PMCID: PMC1569596 DOI: 10.1098/rstb.2005.1757] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Reactive oxygen and nitrogen species (ROS and RNS) play an important role in signal transduction and cell injury processes. Nitric oxide synthase (NOS)-the key enzyme producing nitric oxide (NO)-is found in neuronal structures, vascular endothelium and, possibly, in acinar and ductal epithelial cells in the pancreas. NO is known to regulate cell homeostasis, and its effects on the acinar cells are reviewed here. ROS are implicated in the early events within the acinar cells, leading to the development of acute pancreatitis. The available data on ROS/RNS involvement in the apoptotic and necrotic death of pancreatic acinar cells will be discussed.
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Affiliation(s)
- M Chvanov
- The University of Liverpool The Physiological Laboratory Crown Street, Liverpool L69 3BX, UK.
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Hyvönen MT, Herzig KH, Sinervirta R, Albrecht E, Nordback I, Sand J, Keinänen TA, Vepsäläinen J, Grigorenko N, Khomutov AR, Krüger B, Jänne J, Alhonen L. activated polyamine catabolism in acute pancreatitis: alpha-methylated polyamine analogues prevent trypsinogen activation and pancreatitis-associated mortality. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 168:115-22. [PMID: 16400014 PMCID: PMC1592678 DOI: 10.2353/ajpath.2006.050518] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Polyamines are essential for normal cellular growth and function. Activation of polyamine catabolism in transgenic rats overexpressing spermidine/spermine N(1)-acetyltransferase, the key enzyme in polyamine catabolism, results in severe acute pancreatitis. Here, we investigated the role of polyamine catabolism in pancreatitis and studied the effect of polyamine analogues on the outcome of the disease. Polyamine depletion was associated with arginine- and cerulein-induced pancreatitis as well as with human acute necrotizing and chronic secondary pancreatitis. Substitution of depleted polyamine pools with methylspermidine partially prevented arginine-induced necrotizing pancreatitis whereas cerulein-induced edematous pancreatitis remained unaffected. Transgenic rats receiving methylated polyamine analogues after the induction of pancreatitis showed less pancreatic damage than the untreated rats. Most importantly, polyamine analogues dramatically rescued the animals from pancreatitis-associated mortality. Induction of spermidine/spermine N(1)-acetyltransferase in acinar cells isolated from transgenic rats resulted in increased trypsinogen activation. Pretreatment of acini with bismethylspermine prevented trypsinogen activation, indicating that premature proteolytic activation is one of the effects triggered by polyamine depletion. Our data suggest that activation of polyamine catabolism is a general pathway in the pathogenesis of acute pancreatitis and that experimental disease can be ameliorated with stable polyamine analogues.
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Affiliation(s)
- Mervi T Hyvönen
- Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland
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Frossard JL, Quadri R, Hadengue A, Morel P, Pastor CM. Endothelial nitric oxide synthase regulation is altered in pancreas from cirrhotic rats. World J Gastroenterol 2006; 12:228-33. [PMID: 16482622 PMCID: PMC4066031 DOI: 10.3748/wjg.v12.i2.228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [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 determine whether biliary cirrhosis could induce pancreatic dysfunction such as modifications in endothelial nitric oxide synthase(eNOS) expression and whether the regulation of eNOS could be altered by the regulatory proteins caveolin and heat shock protein 90 (Hsp90), as well as by the modifications of calmodulin binding to eNOS.
METHODS: Immunoprecipitations and Western blotting analysis were performed in pancreas isolated from sham and cirrhotic rats.
RESULTS: Pancreatic injury was minor in cirrhotic rats but eNOS expression importantly decreased with the length (and the severity) of the disease. Because co-immunoprecipitation of eNOS with both Hsp90 and caveolin similarly decreased in cirrhotic rats, eNOS activity was not modified by this mechanism. In contrast, cirrhosis decreased the calmodulin binding to eNOS with a concomitant decrease in eNOS activity.
CONCLUSION: In biliary cirrhosis, pancreatic injury is minor but the pancreatic nitric oxide (NO) production is significantly decreased by two mechanisms: a decreased expression of the enzyme and a decreased binding of calmodulin to eNOS.
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Affiliation(s)
- Jean-Louis Frossard
- Division de Gastroenterologie, Hôpitaux Universitaires de GenevePhilippe Morel, Departement de Chirurgie, Hopitaux Universitaires de Geneve, Switzerland
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