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Chen Y, Xiang Q, Peng F, Gao S, Yu L, Tang Y, Yang Z, Pu W, Xie X, Peng C. The mechanism of action of safflower total flavonoids in the treatment of endometritis caused by incomplete abortion based on network pharmacology and 16S rDNA sequencing. JOURNAL OF ETHNOPHARMACOLOGY 2023:116639. [PMID: 37201664 DOI: 10.1016/j.jep.2023.116639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 05/10/2023] [Accepted: 05/14/2023] [Indexed: 05/20/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Safflower is a traditional Chinese medicine used for treating gynaecological diseases. However, its material basis and mechanism of action in the treatment of endometritis induced by incomplete abortion are still unclear. AIM OF THE STUDY This study aimed to reveal the material basis and mechanism of action of safflower in the treatment of endometritis induced by incomplete abortion through comprehensive methods, including network pharmacology and 16S rDNA sequencing. MATERIALS AND METHODS Network pharmacology and molecular docking methods were used to screen the main active components and potential mechanisms of action of safflower in the treatment of endometritis induced by incomplete abortion in rats. A rat model of endometrial inflammation by incomplete abortion was established. The rats were treated with safflower total flavonoids (STF) based on forecasting results, serum levels of inflammatory cytokines were analysed, and immunohistochemistry, Western blots, and 16S rDNA sequencing were performed to investigate the effects of the active ingredient and the treatment mechanism. RESULTS The network pharmacology prediction results showed 20 active components with 260 targets in safflower, 1007 targets related to endometritis caused by incomplete abortion, and 114 drug-disease intersecting targets, including TNF, IL6, TP53, AKT1, JUN, VEGFA, CASP3 and other core targets, PI3K/AKT, MAPK and other signalling pathways may be closely related to incomplete abortion leading to endometritis. The animal experiment results showed that STF could significantly repair uterine damage and reduce the amount of bleeding. Compared with the model group, STF significantly down-regulated the levels of pro-inflammatory factors (IL-6, IL-1β, NO, TNF-α) and the expression of JNK, ASK1, Bax, caspase3, and caspase11 proteins. At the same time, the levels of anti-inflammatory factors (TGF-β and PGE2) and the protein expression of ERα, PI3K, AKT, and Bcl2 were up-regulated. Significant differences in the intestinal flora were seen between the normal group and the model group, and the intestinal flora of the rats was closer to the normal group after the administration of STF. CONCLUSIONS The characteristics of STF used in the treatment of endometritis induced by incomplete abortion were multi-targeted and involved multiple pathways. The mechanism may be related to the activation of the ERα/PI3K/AKT signalling pathway by regulating the composition and ratio of the gut microbiota.
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Affiliation(s)
- Yan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, 611137, Chengdu, China; College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; School of Public Health, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China
| | - Qiwen Xiang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China
| | - Fu Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, 611137, Chengdu, China; School of Pharmacy, West China School of Pharmacy, Sichuan University, 610041, Chengdu, China
| | - Song Gao
- School of Public Health, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China
| | - Lei Yu
- State Key Laboratory of Southwestern Chinese Medicine Resources, 611137, Chengdu, China; College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yunli Tang
- State Key Laboratory of Southwestern Chinese Medicine Resources, 611137, Chengdu, China; College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Zhou Yang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China
| | - Wei Pu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China
| | - Xiaofang Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, 611137, Chengdu, China; College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, 611137, Chengdu, China; College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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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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Wu X, Yao J, Hu Q, Kang H, Miao Y, Zhu L, Li C, Zhao X, Li J, Wan M, Tang W. Emodin Ameliorates Acute Pancreatitis-Associated Lung Injury Through Inhibiting the Alveolar Macrophages Pyroptosis. Front Pharmacol 2022; 13:873053. [PMID: 35721108 PMCID: PMC9201345 DOI: 10.3389/fphar.2022.873053] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 05/13/2022] [Indexed: 02/05/2023] Open
Abstract
Objective: To investigate the protective effect of emodin in acute pancreatitis (AP)-associated lung injury and the underlying mechanisms. Methods: NaT-AP model in rats was constructed using 3.5% sodium taurocholate, and CER+LPS-AP model in mice was constructed using caerulein combined with Lipopolysaccharide. Animals were divided randomly into four groups: sham, AP, Ac-YVAD-CMK (caspase-1 specific inhibitor, AYC), and emodin groups. AP-associated lung injury was assessed with H&E staining, inflammatory cytokine levels, and myeloperoxidase activity. Alveolar macrophages (AMs) pyroptosis was evaluated by flow cytometry. In bronchoalveolar lavage fluid, the levels of lactate dehydrogenase and inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Pyroptosis-related protein expressions were detected by Western Blot. Results: Emodin, similar to the positive control AYC, significantly alleviated pancreas and lung damage in rats and mice. Additionally, emodin mitigated the pyroptotic process of AMs by decreasing the level of inflammatory cytokines and lactate dehydrogenase. More importantly, the protein expressions of NLRP3, ASC, Caspase1 p10, GSDMD, and GSDMD-NT in AMs were significantly downregulated after emodin intervention. Conclusion: Emodin has a therapeutic effect on AP-associated lung injury, which may result from the inhibition of NLRP3/Caspase1/GSDMD-mediated AMs pyroptosis signaling pathways.
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Affiliation(s)
- Xiajia Wu
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Jiaqi Yao
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Qian Hu
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Hongxin Kang
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yifan Miao
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lv Zhu
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Cong Li
- Research Core Facility, West China Hospital, Sichuan University, Chengdu, China
| | - Xianlin Zhao
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Juan Li
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Meihua Wan
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Wenfu Tang
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
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Forman MA, Steiner JM, Armstrong PJ, Camus MS, Gaschen L, Hill SL, Mansfield CS, Steiger K. ACVIM consensus statement on pancreatitis in cats. J Vet Intern Med 2021; 35:703-723. [PMID: 33587762 PMCID: PMC7995362 DOI: 10.1111/jvim.16053] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 12/16/2022] Open
Abstract
Background Pancreatitis in cats, although commonly diagnosed, still presents many diagnostic and management challenges. Objective To summarize the current literature as it relates to etiology, pathogenesis, diagnosis, and management of pancreatitis in cats and to arrive at clinically relevant suggestions for veterinary clinicians that are based on evidence, and where such evidence is lacking, based on consensus of experts in the field. Animals None. Methods A panel of 8 experts in the field (5 internists, 1 radiologist, 1 clinical pathologist, and 1 anatomic pathologist), with support from a librarian, was formed to assess and summarize evidence in the peer reviewed literature and complement it with consensus clinical recommendations. Results There was little literature on the etiology and pathogenesis of spontaneous pancreatitis in cats, but there was much in the literature about the disease in humans, along with some experimental evidence in cats and nonfeline species. Most evidence was in the area of diagnosis of pancreatitis in cats, which was summarized carefully. In contrast, there was little evidence on the management of pancreatitis in cats. Conclusions and Clinical Importance Pancreatitis is amenable to antemortem diagnosis by integrating all clinical and diagnostic information available, and recognizing that acute pancreatitis is far easier to diagnose than chronic pancreatitis. Although both forms of pancreatitis can be managed successfully in many cats, management measures are far less clearly defined for chronic pancreatitis.
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Affiliation(s)
- Marnin A Forman
- Cornell University Veterinary Specialists, Stamford, Connecticut, USA
| | - Joerg M Steiner
- Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - P Jane Armstrong
- College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, USA
| | - Melinda S Camus
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Lorrie Gaschen
- Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Louisiana, USA
| | - Steve L Hill
- Flagstaff Veterinary Internal Medicine Consulting, Flagstaff, Arizona, USA
| | | | - Katja Steiger
- Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
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Animal models to study the role of pulmonary intravascular macrophages in spontaneous and induced acute pancreatitis. Cell Tissue Res 2020; 380:207-222. [DOI: 10.1007/s00441-020-03211-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 03/30/2020] [Indexed: 12/14/2022]
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Chen Y, Xie CL, Hu R, Shen CY, Zeng M, Wu CQ, Chen TW, Chen C, Tang MY, Xue HD, Jin ZY, Zhang XM. Genetic Polymorphisms: A Novel Perspective on Acute Pancreatitis. Gastroenterol Res Pract 2017; 2017:5135172. [PMID: 29333155 PMCID: PMC5733231 DOI: 10.1155/2017/5135172] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 08/10/2017] [Indexed: 12/15/2022] Open
Abstract
Acute pancreatitis (AP) is a complex disease that results in significant morbidity and mortality. For many decades, it has compelled researchers to explore the exact pathogenesis and the understanding of the pathogenesis of AP has progressed dramatically. Currently, premature trypsinogen activation and NF-κB activation for inflammation are two remarkable hypotheses for the mechanism of AP. Meanwhile, understanding of the influence of genetic polymorphisms has resulted in tremendous development in the understanding of the advancement of complex diseases. Now, genetic polymorphisms of AP have been noted gradually and many researchers devote themselves to this emerging area. In this review, we comprehensively describe genetic polymorphisms combined with the latest hypothesis of pathogenesis associated with AP.
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Affiliation(s)
- Yong Chen
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Chao Lian Xie
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Ran Hu
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Cheng Yi Shen
- Sichuan Key Laboratory of Medical Imaging and Department of Pathophysiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Mei Zeng
- Biology Group, North Sichuan Medical College, Nanchong, China
| | - Chang Qiang Wu
- Sichuan Key Laboratory of Medical Imaging, North Sichuan Medical College, Nanchong, China
| | - Tian Wu Chen
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Chen Chen
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Meng Yue Tang
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Hua Dan Xue
- Radiology Department, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Zheng Yu Jin
- Radiology Department, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao Ming Zhang
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
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Zhao X, Jin B, Yang B, Yan W, Wu X, Jiang C, Cheng S. Gadolinium chloride ameliorates acute lung injury associated with severe acute pancreatitis in rats by regulating CYLD/NF-κB signaling. Biochem Biophys Res Commun 2017; 492:255-261. [PMID: 28823916 DOI: 10.1016/j.bbrc.2017.08.061] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 08/16/2017] [Indexed: 11/18/2022]
Abstract
The present study was embarked on an investigation of the mechanisms behind the effects of Gadolinium chloride (GdCl3) on lung injury associated with severe acute pancreatitis (SAP) in rats. Rats were randomly distributed into three groups: sham operation group (SO), SAP group and SAP treated with GdCl3 group (SAP + GdCl3). Retrograde injection of 5% sodium taurocholate into the biliopancreatic duct was adopted to induce SAP. Lung tissue specimens were harvested for histological study, wet-to-dry weight ratio calculation and myeloperoxidase examination. Meanwhile, bronchoalveolar lavage fluid was analyzed for TNF-α and IL-1β activity and proteins content. Then the apoptosis ratio of alveolar macrophages (AMs) was detected. NF-κB activation and cylindromatosis (CYLD) expression in AMs were measured respectively. Results showed that GdCl3 treatment notably ameliorated lung injury induced by SAP, and simultaneously, the apoptosis ratio of AMs was significantly promoted. The NF-κB activation was obviously inhibited when CYLD expression was markedly up-regulated in AMs of SAP + GdCl3. Negative correlation was analyzed between CYLD and NF-κB in both SAP and SAP + GdCl3. These data demonstrate that GdCl3 ameliorates lung injury secondary to SAP in rats mainly by up-regulating CYLD expression and inhibiting NF-κB activation in AMs, which may play a vital role in lung injury.
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Affiliation(s)
- Xiuhao Zhao
- Department of General Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, PR China
| | - Bei Jin
- Department of Pediatric Surgery, Central Hospital of Handan City, Hebei, PR China
| | - Bin Yang
- Department of Vascular Surgery, Jining No.1 People's Hospital, Shandong, PR China
| | - Wenmao Yan
- Department of General Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, PR China
| | - Xianjia Wu
- Department of General Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, PR China
| | - Cuinan Jiang
- Department of General Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, PR China
| | - Shi Cheng
- Department of General Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, PR China.
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Vrolyk V, Wobeser BK, Al-Dissi AN, Carr A, Singh B. Lung Inflammation Associated With Clinical Acute Necrotizing Pancreatitis in Dogs. Vet Pathol 2016; 54:129-140. [DOI: 10.1177/0300985816646432] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Although dogs with acute necrotizing pancreatitis (ANP) can develop respiratory complications, there are no data describing lung injury in clinical cases of ANP in dogs. Therefore, we conducted a study to characterize lung injury and determine if pulmonary intravascular macrophages (PIMs) are induced in dogs with ANP ( n = 21) compared with control dogs ( n = 6). Two pathologists independently graded histologic sections of pancreas from clinical cases to characterize the severity of ANP (total scores of 3–10) compared with controls showing histologically normal pancreas (total scores of 0). Based on histological grading, lungs from dogs with ANP showed inflammation (median score, 1.5; range, 0–3), but the scores did not differ statistically from the control lungs (median score, 0.5; range, 0–2). A grid intersects-counting method showed an increase in the numbers of MAC387-positive alveolar septal mononuclear phagocyte profiles in lungs of dogs with ANP (ratio median, 0.0243; range, 0.0093–0.0734, with 2 outliers at 0.1523 and 0.1978) compared with controls (ratio median, 0.0019; range, 0.0017–0.0031; P < .0001). Only dogs with ANP showed labeling for von Willebrand factor in alveolar septal capillary endothelial cells, septal inflammatory cells, and alveolar macrophages. Toll-like receptor 4 and interleukin 6 were variably expressed in alveolar macrophages and septal inflammatory cells in lungs from both ANP and control dogs. Inducible nitric oxide synthase was detected in alveolar macrophages of dogs with ANP only. These data show that dogs with ANP have lung inflammation, including the recruitment of PIMs and expression of inflammatory mediators.
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Affiliation(s)
- V. Vrolyk
- Departments of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - B. K. Wobeser
- Veterinary Pathology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - A. N. Al-Dissi
- Veterinary Pathology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - A. Carr
- Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - B. Singh
- Departments of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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Ateyya H, Wagih HM, El-Sherbeeny NA. Effect of tiron on remote organ injury in rats with severe acute pancreatitis induced by L-arginine. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:873-85. [PMID: 27118662 DOI: 10.1007/s00210-016-1250-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 04/19/2016] [Indexed: 12/11/2022]
Abstract
Acute pancreatitis (AP) is an acute inflammatory disorder of the pancreas that can be complicated by involvement of other remote organs. Oxidative stress is known to have a crucial role in the development of pancreatic acinar damage and one of the main causes in multisystem organ failure in experimental AP. The aim of the study was to determine the effect of tiron on pancreas and remote organ damage in L-arginine (L-Arg) induced AP rat model. Thirty-two male rats were divided in random into four groups: control, tiron, L-Arg, and tiron with L-Arg. At the end of the experiment, blood samples were withdrawn for biochemical analysis. The pancreas, lung, kidney, and liver were collected for histopathological examination. Estimation of pancreatic water content was done. Analysis of pulmonary, hepatic, renal, and pancreatic lipid peroxide levels (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) were carried out. Finally, nuclear factor kappa B (NF-κB) and transforming growth factor β1 (TGF-β1) expression in pancreatic tissue was determined. Results indicated that treatment with tiron significantly decreased lipid peroxide levels and markedly increased both SOD activity and GSH level. Moreover, histopathological analysis further confirmed that administration of tiron relatively ameliorates pancreatic acinar cells and remote organ damage. Increased immunoreactivity of NF-κB and TGF-β1 were reduced also by tiron treatment. These findings pointed out the protective role of the mitochondrial antioxidant, tiron against AP induced by L-Arg.
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Affiliation(s)
- Hayam Ateyya
- College of Pharmacy, Taibah University, El-Madinah, El-Munawarah, Saudi Arabia. .,Department of Clinical Pharmacology, Faculty of Medicine, Cairo University, Giza, Egypt.
| | - Heba M Wagih
- Medical Laboratories Technology Department, Faculty of Applied Medical Sciences, Taibah University, El-Madinah El-Munawarah, Saudi Arabia.,Pathology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Nagla A El-Sherbeeny
- College of Pharmacy, Taibah University, El-Madinah, El-Munawarah, Saudi Arabia.,Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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Caria CREP, Moscato CH, Tomé RBG, Pedrazzoli J, Ribeiro ML, Gambero A. Nitric oxide interferes with hypoxia signaling during colonic inflammation. ARQUIVOS DE GASTROENTEROLOGIA 2015; 51:302-8. [PMID: 25591158 DOI: 10.1590/s0004-28032014000400007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 07/08/2014] [Indexed: 01/24/2023]
Abstract
CONTEXT Intestinal inflammation can induce a local reduction in oxygen levels that triggers an adaptive response centered on the expression of hypoxia-inducible factors (HIFs). Nitric oxide, a well-described inflammatory mediator, may interfere with hypoxia signaling. OBJECTIVES We aimed to evaluate the role of nitric oxide in hypoxia signaling during colonic inflammation. METHODS Colitis was induced by single (acute) or repeated (reactivated colitis) trinitrobenzenosulfonic acid administration in rats. In addition, one group of rats with reactivated colitis was also treated with Nw-Nitro-L-arginine methyl ester hydrochloride to block nitric oxide synthase. Colitis was assessed by macroscopic score and myeloperoxidase activity in the colon samples. Hypoxia was determined using the oxygen-dependent probe, pimonidazole. The expression of HIF-1α and HIF-induced factors (vascular endothelial growth factor - VEGF and apelin) was assessed using Western blotting. RESULTS The single or repeated administration of trinitrobenzenosulfonic acid to rats induced colitis which was characterized by a high macroscopic score and myeloperoxidase activity. Hypoxia was observed with both protocols. During acute colitis, HIF-1α expression was not increased, but VEGF and apelin were increased. HIF-1α expression was inhibited during reactivated colitis, and VEGF and apelin were not increased. Nw-Nitro-L-arginine methyl ester hydrochloride blockade during reactivated colitis restored HIF-1α, VEGF and apelin expression. CONCLUSIONS Nitric oxide could interfere with hypoxia signaling during reactivated colitis inflammation modifying the expression of proteins regulated by HIF-1α.
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Affiliation(s)
- Cintia Rabelo e Paiva Caria
- Unidade Integrada de Farmacologia e Gastroenterologia (Unifag), Faculdade de Medicina da Universidade São Francisco, São Paulo, SP, Brasil
| | - Camila Henrique Moscato
- Unidade Integrada de Farmacologia e Gastroenterologia (Unifag), Faculdade de Medicina da Universidade São Francisco, São Paulo, SP, Brasil
| | - Renata Bortolin Guerra Tomé
- Unidade Integrada de Farmacologia e Gastroenterologia (Unifag), Faculdade de Medicina da Universidade São Francisco, São Paulo, SP, Brasil
| | - José Pedrazzoli
- Unidade Integrada de Farmacologia e Gastroenterologia (Unifag), Faculdade de Medicina da Universidade São Francisco, São Paulo, SP, Brasil
| | - Marcelo Lima Ribeiro
- Unidade Integrada de Farmacologia e Gastroenterologia (Unifag), Faculdade de Medicina da Universidade São Francisco, São Paulo, SP, Brasil
| | - Alessandra Gambero
- Unidade Integrada de Farmacologia e Gastroenterologia (Unifag), Faculdade de Medicina da Universidade São Francisco, São Paulo, SP, Brasil
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Pérez S, Pereda J, Sabater L, Sastre J. Pancreatic ascites hemoglobin contributes to the systemic response in acute pancreatitis. Free Radic Biol Med 2015; 81:145-55. [PMID: 25157787 DOI: 10.1016/j.freeradbiomed.2014.08.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 07/31/2014] [Accepted: 08/03/2014] [Indexed: 02/08/2023]
Abstract
Upon hemolysis extracellular hemoglobin causes oxidative stress and cytotoxicity due to its peroxidase activity. Extracellular hemoglobin may release free hemin, which increases vascular permeability, leukocyte recruitment, and adhesion molecule expression. Pancreatitis-associated ascitic fluid is reddish and may contain extracellular hemoglobin. Our aim has been to determine the role of extracellular hemoglobin in the local and systemic inflammatory response during severe acute pancreatitis in rats. To this end we studied taurocholate-induced necrotizing pancreatitis in rats. First, extracellular hemoglobin in ascites and plasma was quantified and the hemolytic action of ascitic fluid was tested. Second, we assessed whether peritoneal lavage prevented the increase in extracellular hemoglobin in plasma during pancreatitis. Third, hemoglobin was purified from rat erythrocytes and administered intraperitoneally to assess the local and systemic effects of ascitic-associated extracellular hemoglobin during acute pancreatitis. Extracellular hemoglobin and hemin levels markedly increased in ascitic fluid and plasma during necrotizing pancreatitis. Peroxidase activity was very high in ascites. The peritoneal lavage abrogated the increase in extracellular hemoglobin in plasma. The administration of extracellular hemoglobin enhanced ascites; dramatically increased abdominal fat necrosis; upregulated tumor necrosis factor-α, interleukin-1β, and interleukin-6 gene expression; and decreased expression of interleukin-10 in abdominal adipose tissue during pancreatitis. Extracellular hemoglobin enhanced the gene expression and protein levels of vascular endothelial growth factor (VEGF) and other hypoxia-inducible factor-related genes in the lung. Extracellular hemoglobin also increased myeloperoxidase activity in the lung. In conclusion, extracellular hemoglobin contributes to the inflammatory response in severe acute pancreatitis through abdominal fat necrosis and inflammation and by increasing VEGF and leukocyte infiltration into the lung.
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Affiliation(s)
- Salvador Pérez
- Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot, Valencia, Spain
| | - Javier Pereda
- Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot, Valencia, Spain
| | - Luis Sabater
- Department of Surgery, University of Valencia, University Clinic Hospital, 46010 Valencia, Spain
| | - Juan Sastre
- Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot, Valencia, Spain.
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Zayed AA, Khorshied MM, Hussein MF. Inducible nitric oxide synthase promoter polymorphism: a molecular susceptibility marker for vitiligo in Egyptians. Int J Dermatol 2014; 54:675-9. [PMID: 25556582 DOI: 10.1111/ijd.12716] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 03/01/2014] [Accepted: 03/08/2014] [Indexed: 12/28/2022]
Abstract
BACKGROUND Vitiligo is a depigmentary disease characterized by loss of melanocytes from the skin and mucous membranes. The pathomechanism of vitiligo is still obscure. Inducible nitric oxide synthase (iNOS) produces very large amounts of nitric oxide (NO). Promotor polymorphisms within iNOS gene have been reported to be associated with overproduction of NO, which may induce melanocyte destruction. AIM The current study aimed at investigating the possible association between iNOS gene polymorphism (-954 G/C and Ex 16+14 C/T) and susceptibility to non-segmental vitiligo in a cohort of Egyptians. METHODS The study was conducted on 200 participants: 100 patients with vitiligo and 100 aged matched healthy controls. Polymerase chain reaction using restriction fragment length polymorphism method (PCR-RFLP) was used to identify the genotypes. RESULTS Our results showed that iNOS -954 G/C heteromutant genotype (GC) was associated with increased risk of vitiligo (OR = 3.35, 95% CI = 1.77-6.33), and the risk increased when confined to females (OR = 7.4, 95% CI = 2.80-19.40). iNOS Ex 16 + 14 C/T heteromutant genotype (CT) conferred two folds increased risk of vitiligo (OR = 2.47, 95% CI = 1.39-4.37). Furthermore, the risk of vitiligo increased when the heteromutant genotype of iNOS -954 G/C (GC) was co-inherited with the wild genotype of iNOS Ex16+14 C/T (CC) (OR = 23.2, 95% CI = 3.04-177.21). CONCLUSIONS Inducible nitric oxide synthase -954 G/C and Ex 16+14 C/T might be considered as genetic susceptibility markers for non-segmental vitiligo among Egyptians.
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Affiliation(s)
- Amira A Zayed
- Faculty of Medicine, Kasr Al Ainy University Hospital, Cairo, Egypt
| | | | - Marwa F Hussein
- Faculty of Medicine, Kasr Al Ainy University Hospital, Cairo, Egypt
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Determination of iNOS-2087A>G Polymorphism in Acute Pancreatitis Patients. CURRENT HEALTH SCIENCES JOURNAL 2014; 40:249-52. [PMID: 26793321 PMCID: PMC4709709 DOI: 10.12865/chsj.40.04.03] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Accepted: 10/15/2014] [Indexed: 12/22/2022]
Abstract
PURPOSE To determine whether single nucleotide polymorphism (SNP) of inducible nitric oxide synthase (iNOS) is involved in susceptibility for acute pancreatitis. MATERIAL AND METHODS Genomic DNA was extracted from blood samples collected from cases of acute pancreatitis (n=110) and normal population controls frequency matched for age and sex (n=232). iNOS - 2087A>G polymorphism was genotyped using TaqMan allelic discrimination assays. The association of the genetic polymorphism with clinical and pathological data of the patients was evaluated. RESULTS We have found no significant statistical association between this polymorphism and an increased risk of developing acute pancreatitis. CONCLUSION In Romanian population, the risk of developing acute pancreatitis is not increased by the presence of iNOS-2087A>G polymorphism.
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Pleurotus eryngii Ameliorates Lipopolysaccharide-Induced Lung Inflammation in Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:532389. [PMID: 24799939 PMCID: PMC3995096 DOI: 10.1155/2014/532389] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 02/17/2014] [Accepted: 03/04/2014] [Indexed: 11/22/2022]
Abstract
Pleurotus eryngii (P. eryngii) is consumed as a fresh cultivated mushroom worldwide and demonstrated to have multiple beneficial effects. We investigated the anti-inflammatory effect of P. eryngii in mice with acute lung injury (ALI). Intranasal instillation of lipopolysaccharide (LPS) (10 μg/site/mouse) induced marked lung inflammation (increase in the number of inflammatory cells, protein leakage, and production of nitric oxide in bronchoalveolar lavage fluid) as well as histopathological damage in the lung, 6 h after treatment. Mice administered heat-treated P. eryngii (0.3–1 g/kg, p.o. (HTPE)) 1 h before LPS challenge showed decreased pulmonary inflammation and ameliorated histopathological damage. These results suggest that HTPE has anti-inflammatory effects against ALI. Thus, P. eryngii itself may also have anti-inflammatory effects and could be a beneficial food for the prevention of ALI induced by bacterial infection.
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15
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Treatment with ginkgo biloba extract protects rats against acute pancreatitis-associated lung injury by modulating alveolar macrophage. GASTROENTEROLOGY REVIEW 2014; 9:43-8. [PMID: 24868298 PMCID: PMC4027842 DOI: 10.5114/pg.2014.40850] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 08/16/2013] [Accepted: 11/21/2013] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Acute pancreatitis (AP) protease release induces lung parenchymal destruction via inflammatory mediators. Ginkgo biloba has been reported to have anti-inflammatory effects. AIM To evaluate the effect of ginkgo biloba extract on experimental acute pancreatitis-associated lung injury in the rat and to investigate the underlying mechanisms. MATERIAL AND METHODS Acute pancreatitis was induced in rats by injection of 5% sodium taurocholate into the biliary pancreatic duct. Ginkgo biloba extract (GBE) was administered and pancreas and lung injury were assessed by histological examination. Alveolar macrophages were harvested by bronchoalveolar lavage. Specificity fluorescent probe DAF-FM-DA was applied to observe nitric oxide (NO) bioavailability in alveolar macrophage. The expression of tumour necrosis factor α (TNF-α) and macrophage migration inhibitory factor (MIF) protein in alveolar macrophage was studied by ELISA. RESULTS In sodium taurocholate-induced acute pancreatitis, treatment with GBE significantly protected rats against lung injury associated with pancreatitis in histological sections. Ginkgo biloba extract had a tendency to down-regulate NO bioavailability compared with the AP group, but without statistical significance. Moreover, TNF-α and MIF at protein levels in alveolar macrophage with GBE treatment were decreased compared with the AP group. CONCLUSIONS These results suggest that GBE could effectively protect rats against acute pancreatitis-associated lung injury. The GBE may inhibit excessive activation of alveolar macrophages from acute pancreatitis-associated lung injury through down-regulation of generation of NO, TNF-α and MIF. These findings suggest that ginkgo biloba extract is a suitable candidate as an effective strategy against acute pancreatitis-associated lung injury.
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Abstract
There is a convincing body of evidence that oxidative stress is involved in the pathogenesis of acute pancreatitis. The effects of different radical scavengers suggested that reactive oxygen metabolites are generated at very early stage of disease and contribute to amplify the pancreatic damage. Oxidative stress is also involved in the progression of the disease from a local damage to a systemic organ failure. However, therapeutic use of antioxidants failed to clearly show a clinical benefit in different trials. Therefore, although antioxidants alone seem to be not enough for the treatment of severe acute pancreatitis, future combined therapeutic strategies should include antioxidants in its composition.
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Affiliation(s)
- Daniel Closa
- Department of Experimental Pathology, IIBB-CSIC-IDIBAPS, CIBEREHD , Barcelona , Spain
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17
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Akbarshahi H, Rosendahl AH, Westergren-Thorsson G, Andersson R. Acute lung injury in acute pancreatitis--awaiting the big leap. Respir Med 2012; 106:1199-1210. [PMID: 22749752 DOI: 10.1016/j.rmed.2012.06.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Revised: 05/09/2012] [Accepted: 06/01/2012] [Indexed: 12/12/2022]
Abstract
Acute lung injury is a severe complication to acute pancreatitis and a significant health problem associated with a considerable mortality. Underlying mechanisms are complex and poorly understood, although recent insights have identified several inflammatory profiles and cellular components involved to varying degrees during different phases of pancreatitis exacerbation and acute lung injury. This review aims to highlight the current understanding of the inflammatory and cellular components involved in and responsible for the associations of acute pancreatitis and acute lung injury, with the hope of thereby providing an increased understanding of the underlying mechanisms. In addition, novel experimental models of modulating the pancreatitis-associated acute lung injury are presented, interventions that may be of potential future clinical value.
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Affiliation(s)
- Hamid Akbarshahi
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund, Sweden
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Honokiol attenuates the severity of acute pancreatitis and associated lung injury via acceleration of acinar cell apoptosis. Shock 2012; 37:478-84. [PMID: 22258232 DOI: 10.1097/shk.0b013e31824653be] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Severe acute pancreatitis remains a life-threatening disease with a high mortality rate among a defined proportion of those affected. Apoptosis has been hypothesized to be a beneficial form of cell death in acute pancreatitis. Honokiol, a low-molecular-weight natural product, possesses the ability of anti-inflammation and apoptosis induction. Here, we investigate whether honokiol can ameliorate severe acute pancreatitis and the associated acute lung injury in a mouse model. Mice received six injections of cerulein at 1-h intervals, then given one intraperitoneal injection of bacterial lipopolysaccharide for the induction of severe acute pancreatitis. Moreover, mice were intraperitoneally given vehicle or honokiol 10 min after the first cerulein injection. Honokiol protected against the severity of acute pancreatitis in terms of increased serum amylase and lipase levels, pancreas pathological injury, and associated acute lung injury. Honokiol significantly reduced the increases in serum tumor necrosis factor-α, interleukin 1, and nitric oxide levels 3 h and serum high-mobility group box 1 24 h after acute pancreatitis induction. Honokiol also significantly decreased myeloperoxidase activities in the pancreas and the lungs. Endoplasmic reticulum stress-related molecules eIF2α (phosphorylated) and CHOP protein expressions, apoptosis, and caspase-3 activity were increased in the pancreas of mice with severe acute pancreatitis, which was unexpectedly enhanced by honokiol treatment. These results suggest that honokiol protects against acute pancreatitis and limits the spread of inflammatory damage to the lung in a severe acute pancreatitis mouse model. The acceleration of pancreatic cell apoptosis by honokiol may play a pivotal role.
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Mansfield C. Pathophysiology of acute pancreatitis: potential application from experimental models and human medicine to dogs. J Vet Intern Med 2012; 26:875-87. [PMID: 22676262 DOI: 10.1111/j.1939-1676.2012.00949.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Revised: 04/05/2012] [Accepted: 04/24/2012] [Indexed: 12/18/2022] Open
Abstract
The cellular events leading to pancreatitis have been studied extensively in experimental models. Understanding the cellular events and inciting causes of the multisystem inflammatory cascades that are activated with this disease is of vital importance to advance diagnosis and treatment of this condition. Unfortunately, the pathophysiology of pancreatitis in dogs is not well understood, and extrapolation from experimental and human medicine is necessary. The interplay of the inflammatory cascades (kinin, complement, cytokine) is extremely complex in both initiating leukocyte migration and perpetuating disease. Recently, nitric oxide (NO) and altered microcirculation of the pancreas have been proposed as major initiators of inflammation. In addition, the role of the gut is becoming increasingly explored as a cause of oxidative stress and potentiation of systemic inflammation in pancreatitis.
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Affiliation(s)
- Caroline Mansfield
- Faculty of Veterinary Science, The University of Melbourne, Werribee, Vic., Australia.
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Hegyi P, Rakonczay Z. The role of nitric oxide in the physiology and pathophysiology of the exocrine pancreas. Antioxid Redox Signal 2011; 15:2723-2741. [PMID: 21777142 DOI: 10.1089/ars.2011.4063] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
SIGNIFICANCE Nitric oxide (NO), a ubiquitous gaseous signaling molecule, contributes to both pancreatic physiology and pathophysiology. RECENT ADVANCES The present review provides a general overview of NO synthesis, signaling, and function. Further, it specifically discusses NO metabolism and its effects in the exocrine pancreas and focuses on the role of NO in the pathogenesis of acute pancreatitis and pancreatic ischemia/reperfusion injury. CRITICAL ISSUES Unfortunately, the role of NO in pancreatic physiology and pathophysiology remains controversial in numerous areas. Many questions regarding the messenger molecule still remain unanswered. FUTURE DIRECTIONS Probably the least is known about the downstream targets of NO, which need to be identified, especially at the molecular level.
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Affiliation(s)
- Péter Hegyi
- First Department of Medicine, University of Szeged, Szeged, Hungary
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Rubini A. The Effect of N G-Nitro- L-Arginine Methyl Ester, a Nitric Oxide Synthase Inhibitor, on Respiratory Mechanics in Rats. Respiration 2011; 82:468-75. [DOI: 10.1159/000329562] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Accepted: 05/23/2011] [Indexed: 12/29/2022] Open
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Du Y, Wang T, Jiang N, Ren RT, Zhao DL, Li C, Fu FH. Protective effect of sodium aescinate on lung injury induced by methyl parathion. Hum Exp Toxicol 2010; 30:1584-91. [DOI: 10.1177/0960327110393764] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Methyl parathion (MP) is a high venenosus insecticide. It has been used in pest control of agriculture for several years. The present study is performed to investigate the protective effect of sodium aescinate (SA) on lung injury induced by MP. Forty male Sprague-Dawley rats are randomly divided into five groups, with 8 animals in each group: control group, MP administration group, MP plus SA at doses of 0.45 mg/kg, 0.9 mg/kg and 1.8 mg/kg groups. Acetylcholinesterase (AChE) activity and nitric oxide (NO) level in plasma, myeloperoxidase (MPO) activity, NO level, and antioxidative parameters in lung tissue are assayed. Histopathological examination of lung is also performed. The results show that SA has no effect on AChE. Treatment with SA decreases the activity of MPO in lung and the level of NO in plasma and lung. The level of malondialdehyde in lung is decreased after SA treatments. SA increases the activities of superoxide dismutase, glutathione peroxidase and the content of glutathione in lung. SA administration also ameliorates lung injury induced by MP. The findings indicate that SA could protect lung injury induced by MP and the mechanism of action is related to the anti-inflammatory and anti-oxidative effect of SA.
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Affiliation(s)
- Yuan Du
- Department of Pharmacology, School of Pharmacy, Yantai University, NO. 32, Qingquan Road, Yantai 264005, Shandong, China
| | - Tian Wang
- Department of Pharmacology, School of Pharmacy, Yantai University, NO. 32, Qingquan Road, Yantai 264005, Shandong, China
| | - Na Jiang
- Department of Pharmacology, School of Pharmacy, Yantai University, NO. 32, Qingquan Road, Yantai 264005, Shandong, China
| | - Ru-Tong Ren
- Department of Pharmacology, School of Pharmacy, Yantai University, NO. 32, Qingquan Road, Yantai 264005, Shandong, China
| | - De-Lu Zhao
- Institute of Pharmacology & Toxicology, Taiping Road, Beijing, China
| | - Chong Li
- Department of Pharmacology, School of Pharmacy, Yantai University, NO. 32, Qingquan Road, Yantai 264005, Shandong, China
| | - Feng-Hua Fu
- Department of Pharmacology, School of Pharmacy, Yantai University, NO. 32, Qingquan Road, Yantai 264005, Shandong, China
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