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Chen J, Jiang M, Ying Y, Ji Y, Chi Y, Tao L, Wu F, Chen M. Network pharmacological mechanism analysis and evidence-based medical validation of Dahuang Mudan Decoction in the treatment of acute pancreatitis. Medicine (Baltimore) 2024; 103:e39679. [PMID: 39287237 PMCID: PMC11404899 DOI: 10.1097/md.0000000000039679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024] Open
Abstract
BACKGROUND Dahuang Mudan Decoction is commonly used in China for the treatment of acute pancreatitis. Nevertheless, the therapeutic efficacy of the drug remains a subject of debate, and its active ingredients and potential therapeutic targets remain to be determined. The present study used a network pharmacological approach to investigate the active ingredients and possible targets of the drug, and illustrated the clinical effectiveness of Dahuang Mudan Decoction in the treatment of acute pancreatitis by meta-analysis. METHODS The present study investigated the active ingredients of the constituent herbs of Dahuang Mudan Decoction using the TCMID database. In order to further identify molecular targets, Swiss Target Prediction, OMIM and Genecards databases was be used. The present study used metascape database for gene ontology function enrichment analysis and Kyoto Genome Encyclopedia pathway enrichment analysis. A gene interaction network diagram was established for predicting the main targets and mechanism of action to Dahuang Mudan Decoction for acute pancreatitis. To further illustrate the validity of the gene targets and the clinical efficacy of the drug, 13 relevant studies were included for meta-analysis and analyzed using the Cochrane Collaboration's Review Manager 5.4 software. RESULT After a thorough screening process, the present study identified three main components of Dahuang Mudan Decoction: kaempferol, quercetin and eupatin. These three major components have the potential to target 5 important proteins: AKT1, TNF-a, IL-6, TP53, HIF1A. In addition, pathway analyses by the Kyoto Genome Encyclopedia showed that Dahuang Mudan Decoction is active through the Pathways in cancer, AGE-RAGE signaling pathway in diabetic complications, PI3K-Akt signaling pathway, etc signaling pathway to act on acute pancreatitis. The results of meta-analysis showed that compared with the control group, the experimental group had superior performance in terms of overall treatment efficacy, reduction of hospital stays and inflammatory factor levels after treatment. CONCLUSION In summary, network pharmacological studies have shown that Dahuang Mudan Decoction affects acute pancreatitis through different components, targets, and mechanisms. In addition, the meta-analysis study strongly supported the effectiveness of Dahuang Mudan Decoction in the treatment of acute pancreatitis.
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Affiliation(s)
- Jinhan Chen
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Mengjie Jiang
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuou Ying
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuan Ji
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuying Chi
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Linghui Tao
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Fuping Wu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Mingxian Chen
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, China
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Wang J, Wang Y, Chen Z, Liu B, Wang W, Li Y. Study on the mechanism of Shugan Lidan Xiaoshi granule in preventing acute pancreatitis based on network pharmacology and molecular docking. Heliyon 2024; 10:e27365. [PMID: 38486764 PMCID: PMC10938120 DOI: 10.1016/j.heliyon.2024.e27365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 02/21/2024] [Accepted: 02/28/2024] [Indexed: 03/17/2024] Open
Abstract
Background Shugan Lidan Xiaoshi granules (SLXG) is a herbal granule formulation developed by extensively modifying multiple traditional Chinese medicine compound prescriptions known for their ability to dissolve stones. It is primarily used for the prevention and treatment of cholelithiasis and possesses significant therapeutic potential in both preventing and treating acute pancreatitis. However, the preventive effects of SLXG on cholelithiasis-related complications, such as acute pancreatitis (AP), have been inadequately researched. Methods TCMSP database was searched to identify the active components and targets of SLXG's action. The disease gene databases (GeneCards, OMMI, PharmGKB, DrugBank) were used to retrieve the targets associated with AP. A TCM ingredient target network was then constructed by using the intersection of these two datasets. The overlapping targets underwent network analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG)and Protein-Protein Interaction (PPI) analyses. Molecular docking was performed to examine the interaction patterns between the active ingredients and central targets. Results A "Traditional Chinese Medicine-Component-Target" complex network consisting of 10 traditional Chinese medicines, 114 compounds, and 164 targets was constructed. GO and KEGG analysis showed that SLXG has the potential to regulate the response of oxygen-containing compounds, apoptosis, and inflammatory factors. Nine central genes were identified by the PPI network and subnetwork. IL6 was chosen as the most significant gene for molecular docking. The three active compounds of SLXG: quercetin, luteolin, and paeoniflorin, along with the active site of IL6 have a good binding ability and thus play a preventive role in AP. Conclusion This study provides evidence of the effective preventive role of SLXG against AP, as indicated by bioinformatics analysis. The preventive effect of SLXG is attributed to its multi-component, multi-target, and multi-pathway mechanisms. This finding provides a solid foundation for future research on the clinical application and mechanism of action of drugs.
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Affiliation(s)
- Jiaxing Wang
- Department of Interventional Medicine and Microinvasive Oncology, The Second Hospital, Cheello College of Medicine, Shandong University, Jinan, China
- Institute of Interventional Oncology, Shandong University, Jinan, China
| | - Yang Wang
- Department of Interventional Medicine and Microinvasive Oncology, The Second Hospital, Cheello College of Medicine, Shandong University, Jinan, China
- Institute of Interventional Oncology, Shandong University, Jinan, China
| | - Zitong Chen
- Department of Interventional Medicine and Microinvasive Oncology, The Second Hospital, Cheello College of Medicine, Shandong University, Jinan, China
- Institute of Interventional Oncology, Shandong University, Jinan, China
| | - Bin Liu
- Department of Interventional Medicine and Microinvasive Oncology, The Second Hospital, Cheello College of Medicine, Shandong University, Jinan, China
- Institute of Interventional Oncology, Shandong University, Jinan, China
| | - Wujie Wang
- Department of Interventional Medicine and Microinvasive Oncology, The Second Hospital, Cheello College of Medicine, Shandong University, Jinan, China
- Institute of Interventional Oncology, Shandong University, Jinan, China
| | - Yuliang Li
- Department of Interventional Medicine and Microinvasive Oncology, The Second Hospital, Cheello College of Medicine, Shandong University, Jinan, China
- Institute of Interventional Oncology, Shandong University, Jinan, China
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Huang QY, Zhang R, Zhang QY, Dai C, Yu XY, Yuan L, Liu YY, Shen Y, Huang KL, Lin ZH. Disulfiram reduces the severity of mouse acute pancreatitis by inhibiting RIPK1-dependent acinar cell necrosis. Bioorg Chem 2023; 133:106382. [PMID: 36716580 DOI: 10.1016/j.bioorg.2023.106382] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/12/2023] [Accepted: 01/15/2023] [Indexed: 01/22/2023]
Abstract
Acute pancreatitis (AP) is a frequent abdominal inflammatory disease. Despite the high morbidity and mortality, the management of AP remains unsatisfactory. Disulfiram (DSF) is an FDA-proved drug with potential therapeutic effects on inflammatory diseases. In this study, we aim to investigate the effect of DSF on pancreatic acinar cell necrosis, and to explore the underlying mechanisms. Cell necrosis was induced by sodium taurocholate or caerulein, AP mice model was induced by nine hourly injections of caerulein. Network pharmacology, molecular docking, and molecular dynamics simulation were used to explore the potential targets of DSF in protecting against cell necrosis. The results indicated that DSF significantly inhibited acinar cell necrosis as evidenced by a decreased ratio of necrotic cells in the pancreas. Network pharmacology, molecular docking, and molecular dynamics simulation identified RIPK1 as a potent target of DSF in protecting against acinar cell necrosis. qRT-PCR analysis revealed that DSF decreased the mRNA levels of RIPK1 in freshly isolated pancreatic acinar cells and the pancreas of AP mice. Western blot showed that DSF treatment decreased the expressions of RIPK1 and MLKL proteins. Moreover, DSF inhibited NF-κB activation in acini. It also decreased the protein expression of TLR4 and the formation of neutrophils extracellular traps (NETs) induced by damage-associated molecular patterns released by necrotic acinar cells. Collectively, DSF could ameliorate the severity of mouse acute pancreatitis by inhibiting RIPK-dependent acinar cell necrosis and the following formation of NETs.
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Affiliation(s)
- Qiu-Yang Huang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054 Chongqing, China
| | - Rui Zhang
- Department of Pharmacy, Guizhou Provincial People's Hospital, 550002 Guiyang, China
| | - Qing-Yu Zhang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054 Chongqing, China
| | - Chen Dai
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054 Chongqing, China
| | - Xiu-Yan Yu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054 Chongqing, China
| | - Lu Yuan
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054 Chongqing, China
| | - Yi-Yuan Liu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054 Chongqing, China
| | - Yan Shen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054 Chongqing, China.
| | - Kui-Long Huang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054 Chongqing, China
| | - Zhi-Hua Lin
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054 Chongqing, China.
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Alcohol Aggravates Acute Pancreatitis by Impairing Autophagic Flux Through Activation of AMPK Signaling Pathway. Dig Dis Sci 2022; 67:524-535. [PMID: 33555515 DOI: 10.1007/s10620-021-06870-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 01/20/2021] [Indexed: 12/09/2022]
Abstract
OBJECTIVE Alcohol consumption is always the main cause of acute pancreatitis (AP). It has been reported that alcohol exerts direct damage to the pancreas. However, the specific role of alcohol during AP needs to be investigated. This study aims to examine the effects of alcohol in cerulein-induced AP and the role of the AMPK pathway. METHODS Human subjects from operations, cerulein-induced AP rat, and cerulein-stimulated AR42J cell line were enrolled in this study. Electron microscopy was employed for observation of cell morphology, immunohistochemistry for identification of cells, ELISA for detection of inflammation factors, Annexin V/PI double staining for evaluation of cell apoptosis, immunofluorescence for assessment of autophagic flux, oil red O staining for examination of lipid droplet accumulation, and Western blot for measurement of expressions of proteins related to autophagy, apoptosis, and AMPK signal pathway. PI3K inhibitor 3-MA and AMPK inhibitor BML-275 were utilized for investigation of the relationship between impaired autophagic flux and the AMPK pathway by inhibiting or stimulating the formation of autophagosome. RESULTS Alcohol consumption caused lipid droplet accumulation in the pancreas, and it also activated AMPK signaling pathway, thus aggravating the autophagic flux during AP. Alcohol up-regulated the expressions of anti-apoptotic proteins during the induction of AP to inhibit cell apoptosis and enhance cell necrosis. Inhibition of autophagosome formation by AMPK inhibitor BML-275 ameliorated the decreased cell viability caused by alcohol and cerulein in vitro. CONCLUSION Alcohol aggravates AP progression by impairing autophagic flux and enhancing cell autophagy through the AMPK signaling pathway.
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Zhang J, Huang W, He Q, Deng T, Wu B, Huang F, Bi J, Jin Y, Sun H, Zhang Q, Shi K. PINK1/PARK2 dependent mitophagy effectively suppresses NLRP3 inflammasome to alleviate acute pancreatitis. Free Radic Biol Med 2021; 166:147-164. [PMID: 33636335 DOI: 10.1016/j.freeradbiomed.2021.02.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/12/2021] [Accepted: 02/13/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND Acute pancreatitis (AP) is a clinically common acute inflammatory disease in digestive system, leading to systemic inflammatory response syndrome (SIRS) and severe acute pancreatitis (SAP). It was reported that PINK1/PARK2 dependent mitophagy played an important role in various inflammatory diseases. However, its role in AP has not been elucidated. Herein, we explore the effect of mitophagy in the pathogenesis of AP. METHODS Firstly, we established cerulein-induced AP group and arginine-induced SAP group based on wild, PINK1-/- and PARK2-/- mice. Pancreatic samples were harvested for further investing the mitochondrial dynamics, mitophagy alterations, NLRP3 inflammatory pathway etc. Furthermore, peripheral blood mononuclear cells from SAP patients were collected to examine the expression of mitophagy-related indicators. Additionally, the interrelationship between mitophagy and NLRP3 inflammasome was also explored in AP. RESULTS It was confirmed that mitochondria were damaged in both AP and SAP models. The expressions of PINK1, PARK2 and mitochondrial autophagosomes were elevated in wild AP group, which were decreased in SAP group over time. Similarly, the expressions of PINK1 and PAKR2 in peripheral blood mononuclear cells were significantly lower in SAP patients. Besides, in PINK1-/- and PARK2-/- mice AP groups, more pronounced inflammatory infiltration, increased apoptotic and necrotic levels and upregulated NLRP3 inflammasome pathway were detected. After injection with MCC950, NLRP3 inflammasome production was notably reduced in PINK1-/-and PARK2-/-mice, which effectively alleviated the pancreatic damage and inflammatory cell infiltration. CONCLUSION Our study suggested that mitochondrial dysfunction activated PINK1/PARK2-mediated mitophagy in AP, while mitophagy was impaired in SAP. PINK1-/- and PARK2-/- mice were more sensitive to onset of SAP and the deficiency of mitophagy could lead to the formation of NLRP3 inflammasome.
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Affiliation(s)
- Jie Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, PR China.
| | - Weiguo Huang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, PR China.
| | - Qikuan He
- Department of General Surgery, Ningbo First Hospital, Ningbo, Zhejiang, 315000, PR China.
| | - Tuo Deng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, PR China.
| | - Boda Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, PR China.
| | - Feifei Huang
- The Ultrasonic Department of the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, PR China.
| | - Jiayang Bi
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, PR China.
| | - Yuepeng Jin
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, PR China.
| | - Hongwei Sun
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, PR China.
| | - Qiyu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, PR China.
| | - Keqing Shi
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, PR China.
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Abdominal paracentesis drainage attenuates severe acute pancreatitis by enhancing cell apoptosis via PI3K/AKT signaling pathway. Apoptosis 2021; 25:290-303. [PMID: 32100210 PMCID: PMC7181427 DOI: 10.1007/s10495-020-01597-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Our previous studies have shown that abdominal paracentesis drainage (APD) is a safe and effective strategy for patients with severe acute pancreatitis (SAP). However, the underlying mechanisms behind APD treatment remain poorly understood. Given that apoptosis is a critical pathological response of SAP, we here aim to investigate the effect of APD on cell apoptosis in pancreatic tissues during SAP and to explore its potential molecular mechanism. SAP was induced by 5% sodium-taurocholate retrograde while APD group was inserted a drainage tube into the right lower abdomen of rats immediately after SAP induction. Histopathological staining, serum amylase, endotoxin and inflammatory mediators were measured. Cell apoptosis, apoptosis-related proteins and signaling pathway were also evaluated. Our results demonstrated that APD treatment significantly attenuated pancreatic damage and decreased the serum levels of amylase, endotoxin, TNF-α, IL-1 and IL-6 in rats with SAP. Notably, APD treatment enhanced cell apoptosis and reduced necrosis in pancreatic tissues, as evidenced by Tunnel staining, the increased pro-apoptosis proteins (Cleaved-caspase-3 and bax) and decreased anti-apoptosis protein (Bcl-2). Moreover, the effect of APD on cell apoptosis was further confirmed by the regulatory pathway of PI3K/AKT and NF-kB signaling pathway. These results suggest that APD attenuates the severity of SAP by enhancing cell apoptosis via suppressing PI3K/AKT signaling pathway. Our findings provide new insights for understanding the effectiveness of APD in patients with SAP.
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Manandhar S, Sinha P, Ejiwale G, Bhatia M. Hydrogen Sulfide and its Interaction with Other Players in Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1315:129-159. [PMID: 34302691 DOI: 10.1007/978-981-16-0991-6_6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hydrogen sulfide (H2S) plays a vital role in human physiology and in the pathophysiology of several diseases. In addition, a substantial role of H2S in inflammation has emerged. This chapter will discuss the involvement of H2S in various inflammatory diseases. Furthermore, the contribution of reactive oxygen species (ROS), adhesion molecules, and leukocyte recruitment in H2S-mediated inflammation will be discussed. The interrelationship of H2S with other gasotransmitters in inflammation will also be examined. There is mixed literature on the contribution of H2S to inflammation due to studies reporting both pro- and anti-inflammatory actions. These apparent discrepancies in the literature could be resolved with further studies.
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Affiliation(s)
- Sumeet Manandhar
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Priyanka Sinha
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Grace Ejiwale
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
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Luo Y, Liu LM, Xie L, Zhao HL, Lu YK, Wu BQ, Wu ZY, Zhang ZL, Hao YL, Ou WH, Liu RS, Xu WM, Chen XH. Activation of the CaR-CSE/H2S pathway confers cardioprotection against ischemia-reperfusion injury. Exp Cell Res 2020; 398:112389. [PMID: 33221316 DOI: 10.1016/j.yexcr.2020.112389] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/27/2020] [Accepted: 11/17/2020] [Indexed: 01/21/2023]
Abstract
Ischemia-reperfusion (I/R) injury is a multifactorial process triggered when an organ is subjected to transiently reduced blood supply. The result is a cascade of pathological complications and organ damage due to the production of reactive oxygen species following reperfusion. The present study aims to evaluate the role of activated calcium-sensing receptor (CaR)-cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway in I/R injury. Firstly, an I/R rat model with CSE knockout was constructed. Transthoracic echocardiography, TTC and HE staining were performed to determine the cardiac function of rats following I/R Injury, followed by TUNEL staining observation on apoptosis. Besides, with the attempt to better elucidate how CaR-CSE/H2S affects I/R, in-vitro culture of human coronary artery endothelial cells (HCAECs) was conducted with gadolinium chloride (GdCl3, a CaR agonist), H2O2, siRNA against CSE (siCSE), or W7 (a CaM inhibitor). The interaction between CSE and CaM was subsequently detected. Plasma oxidative stress indexes, H2S and CSE, and apoptosis-related proteins were all analyzed following cell apoptosis. We found that H2S elevation led to the improvement whereas CSE knockdown decreased cardiac function in rats with I/R injury. Moreover, oxidative stress injury in I/R rats with CSE knockout was aggravated, while the increased expression of H2S and CSE in the aortic tissues resulted in alleviated the oxidative stress injury. Moreover, increased H2S and CSE levels were found to inhibit cell apoptotic ability in the aortic tissues after I/R injury, thus attenuating oxidative stress injury, accompanied by inhibited expression of apoptosis-related proteins. In HCAECs following oxidative stress treatment, siCSE and CaM inhibitor were observed to reverse the protection of CaR agonist. Coimmunoprecipitation assay revealed the interaction between CSE and CaM. Taken together, all above-mentioned data provides evidence that activation of the CaR-CSE/H2S pathway may confer a potent protective effect in cardiac I/R injury.
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Affiliation(s)
- Ying Luo
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Li-Mei Liu
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Li Xie
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Hong-Lei Zhao
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Yong-Kang Lu
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Bao-Quan Wu
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Zhi-Ye Wu
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Zhi-Ling Zhang
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Yun-Ling Hao
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Wu-Hua Ou
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Rui-Shuang Liu
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China
| | - Wen-Min Xu
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, PR China.
| | - Xie-Hui Chen
- Department of Geriatrics and Cardiovascular Medicine, ShenZhen Hospital, Fuwai Hospital China Academy of Medical Sciences (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, 518112, PR China.
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Comparing the preventive effect of sodium hydrosulfide, leptin, and curcumin against L-arginine induced acute pancreatitis in rats: role of corticosterone and inducible nitric oxide synthase. Endocr Regul 2020; 53:221-230. [PMID: 31734652 DOI: 10.2478/enr-2019-0022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVES Acute pancreatitis (AP) is a life-threatening condition. Using antioxidants in AP is insufficient and conflicting. Therefore, this study compared the effect of hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS), leptin or curcumin pretreatment on AP induced by L-arginine. METHODS Forty adult male rats were used and classified into: 1) control; 2) AP group [each rat was intraperitoneally (i.p.) injected with 2 doses of L-arginine of 250 mg/100 g body weight (b.w.) with an interval of 1 h]; 3) NaHS+AP group (each rat was i.p. injected with 10 mg/kg b.w. of NaHS 1 h before induction of AP); 4) leptin+AP group (each rat was pretreated with 10 μg/kg b.w. of leptin 30 min before induction of AP; and 5) curcumin+AP group (in which rats were i.p. injected with 150 mg/kg b.w. of curcumin 30 min before induction of AP). Serum amylase, lipase, nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and corticosterone (CORT) levels were assayed. In addition, pancreatic tissues were obtained for histopathological examination and malondialde-hyde (MDA), total antioxidant capacity (TAC), and inducible nitric oxide synthase (iNOS) levels were measured. RESULTS All AP treated groups showed significant decrease in serum levels of pancreatic enzymes, NO, and TNF-α, and pancreatic MDA and iNOS levels, while TAC levels were significantly increased. NaHS caused more limitation of inflammation than leptin and curcumin by affecting iNOS. Leptin was more potent than curcumin due to the stimulatory effect of leptin on glucocorticoid release to counteract inflammation. CONCLUSIONS NaHS was more effective in AP amelioration than the leptin and curcumin.
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Liao R, Xue L, Qiang Z, Zhang C, Liu Y. Release of endogenous hydrogen sulfide in enteric nerve cells suppresses intestinal motility during severe acute pancreatitis. Acta Biochim Biophys Sin (Shanghai) 2020; 52:64-71. [PMID: 31889183 DOI: 10.1093/abbs/gmz139] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Indexed: 12/13/2022] Open
Abstract
Previous studies have shown that during severe acute pancreatitis (SAP) attacks, hydrogen sulfide (H2S) is released in the colon. However, the roles played by H2S in regulating enteric nerves remain unclear. In this study, we examined the association between SAP-induced H2S release and loss of intestinal motility, and also explored the relevant mechanism in enteric nerve cells. A rat SAP model was constructed and enteric nerve cells were prepared. Intestinal mobility was evaluated by measuring the number of bowel movements at indicated time points and by performing intestinal propulsion tests. The production of inflammatory cytokines during a SAP attack was quantified by ELISA, and the levels of cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) were examined by immunohistochemistry and western blot analysis. In vivo studies showed that PI3K/Akt/Sp1 signaling in enteric nerve cells was blocked, confirming the mechanism of endogenous H2S formation by western blot analysis and immunofluorescence. Our results also showed that rats with SAP symptoms had reduced intestinal motility. Furthermore, PI3K/Akt/Sp1 signaling was triggered and CSE expression was up-regulated, and these changes were associated with H2S formation in the colon. In addition, propargylglycine reduced the levels of inflammatory cytokines and suppressed the release of H2S. Enteric nerve cells that were incubated with LY294002 and transfected with a Sp1-knockdown vector displayed decreased levels of CSE production, which led to a decrease in H2S production. These results suggest that SAP symptoms suppressed the intestinal motility of rats via the release of H2S in enteric nerve cells, which was dependent on the inflammation-induced PI3K/Akt/Sp1 signaling pathway.
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Affiliation(s)
- Ribin Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Guilin Medical University, Guilin 541100, China
| | - Liwei Xue
- Department of Gastroenterology, The Second Affiliated Hospital of Guilin Medical University, Guilin 541100, China
| | - Zhanrong Qiang
- Department of Gastroenterology, The Second Affiliated Hospital of Guilin Medical University, Guilin 541100, China
| | - Cheng Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Guilin Medical University, Guilin 541100, China
| | - Ying Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Guilin Medical University, Guilin 541100, China
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11
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Seok AE, Son BK, Lee J, Chung KH, Lee YR, Kim D, Cha BH, Kang HG. Screening of Sera from Patients with Pancreatitis by an Apoptosis Assay of Skin-derived Cells. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 74:219-226. [PMID: 31650798 DOI: 10.4166/kjg.2019.74.4.219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 08/01/2019] [Accepted: 08/14/2019] [Indexed: 01/29/2023]
Abstract
Background/Aims An excessive inflammatory response is typical in acute pancreatitis and a significant cause of early mortality in severe acute pancreatitis. This is believed to be caused by inflammatory molecules or upregulated cytokine levels in the serum of patients. The aim of this study was to identify the serum-mediated apoptosis-inducing effects in acute pancreatitis patients. Methods A skin tissue-derived cell line, BJ, was treated for 24 hours with the sera of 22 healthy volunteers (control) and 71 acute pancreatitis patients (22 with gallstone pancreatitis, 16 with alcoholic pancreatitis, and 11 with pancreatitis with other causes) collected at the time of hospital admission (active) and discharge (resolved). Apoptosis was analyzed by flow cytometry. Results The average percentage of living cells, early apoptotic cells, and late apoptotic cells ranged from 78.8% to 85.0%, 5.5% to 7.3%, and 7.7% to 13.1%, respectively. The number of live cells increased significantly using the serum from the resolved state of gallstone-induced pancreatitis. In addition, the number of early apoptotic cells increased significantly using the serum from the resolved state of pancreatitis with other causes. The number of late apoptotic cells decreased significantly with the serum from the resolved state compared to the active state of gallstone- and alcohol-induced pancreatitis. Conclusions Serum samples from patients with pancreatitis induced a change in the apoptosis profiles of skin-derived cells. These results indicate changes in the serum components in patients with acute pancreatitis.
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Affiliation(s)
- Ae Eun Seok
- Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon, Korea
| | - Byoung Kwan Son
- Division of Gastroenterology, Department of Internal Medicine, Eulji University Eulji Hospital, Seoul, Korea
| | - Jiyeong Lee
- Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam, Korea
| | - Kwang Hyun Chung
- Division of Gastroenterology, Department of Internal Medicine, Eulji University Eulji Hospital, Seoul, Korea
| | - You-Rim Lee
- Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon, Korea
| | - Doojin Kim
- Department of Laboratory Medicine, Seongnam Central Hospital, Seongnam, Korea
| | - Byung Heun Cha
- Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam, Korea
| | - Hee-Gyoo Kang
- Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon, Korea.,Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam, Korea
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12
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Cen ME, Wang F, Su Y, Zhang WJ, Sun B, Wang G. Gastrointestinal microecology: a crucial and potential target in acute pancreatitis. Apoptosis 2019; 23:377-387. [PMID: 29926313 DOI: 10.1007/s10495-018-1464-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In the early stage of acute pancreatitis (AP), abundant cytokines induced by local pancreatic inflammation enter the bloodstream, further cause systemic inflammatory response syndrome (SIRS) by "trigger effect", which eventually leads to multiple organ dysfunction syndrome (MODS). During SIRS and MODS, the intestinal barrier function was seriously damaged accompanied by the occurrence of gut-derived infection which forms a "second hit summit" by inflammatory overabundance. Gastrointestinal microecology, namely the biologic barrier, could be transformed into a pathogenic state, which is called microflora dysbiosis when interfered by the inflammatory stress during AP. More and more evidences indicate that gastrointestinal microflora dysbiosis plays a key role in "the second hit" induced by AP gut-derived infection. Therefore, the maintenance of gastrointestinal microecology balance is likely to provide an effective method in modulating systemic infection of AP. This article reviewed the progress of gastrointestinal microecology in AP to provide a reference for deeply understanding the pathogenic mechanisms of AP and identifying new therapeutic targets.
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Affiliation(s)
- Meng-Er Cen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.,Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Nephropathy, Hangzhou, Zhejiang, China
| | - Feng Wang
- Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ying Su
- Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Wang-Jun Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
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13
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Duan PY, Ma Y, Li XN, Qu FZ, Ji L, Guo XY, Zhang WJ, Xiao F, Li L, Hu JS, Sun B, Wang G. Inhibition of RIPK1-dependent regulated acinar cell necrosis provides protection against acute pancreatitis via the RIPK1/NF-κB/AQP8 pathway. Exp Mol Med 2019; 51:1-17. [PMID: 31375658 PMCID: PMC6802613 DOI: 10.1038/s12276-019-0278-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 01/22/2019] [Accepted: 03/06/2019] [Indexed: 12/20/2022] Open
Abstract
Currently, preliminary results have confirmed the existence of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis of pancreatic acinar cells during early acute pancreatitis (AP), which might be a potential target for the effective regulation of necroinflammatory injury. However, the exact effect of receptor-interacting protein kinase 1 (RIPK1)-dependent regulated acinar cell necrosis on AP is still uncertain. In our study, we first explored the changes in the degree of local and systemic inflammation in AP rats when the activation of acinar cell RIPK1 was inhibited. The RIPK1 inhibitor Nec-1 was used to treat rats, and the levels of related inflammatory markers, necrosis indicators and apoptotic indicators were measured. Changes in pancreatic nuclear factor κB (NF-κB) and aquaporin 8 (AQP8) expression were noted. Next, the expression of AQP8 in AR42J cells was inhibited, and the degree of cell necrosis and inflammatory damage was found to be significantly reduced. Most importantly, we demonstrated that the RIPK1/NF-ĸB/AQP8 axis might be a potential regulatory pathway mediating RIPK1-dependent regulated acinar cell necrosis in early AP. Finally, we used the NF-κB inhibitor PDTC and Nec-1 to treat rats in different groups and measured the degree of pathological pancreatic injury, the activation of RIPK1, and the expression of NF-κB and AQP8. In summary, we hypothesized that there might be a RIPK1/NF-ĸB/AQP8 pathway controlling RIPK1-dependent regulated necrosis of acinar cells in AP, which might be a promising therapeutic target against AP-related injury.
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Affiliation(s)
- Peng-Yu Duan
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Yuan Ma
- Department of Medical Administration, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Xi-Na Li
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Feng-Zhi Qu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Liang Ji
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Xiao-Yu Guo
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Wang-Jun Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Fan Xiao
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Le Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Ji-Sheng Hu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
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Hypoxia-Inducible Factor-1 α Knockdown Plus Glutamine Supplementation Attenuates the Predominance of Necrosis over Apoptosis by Relieving Cellular Energy Stress in Acute Pancreatitis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4363672. [PMID: 31281575 PMCID: PMC6589200 DOI: 10.1155/2019/4363672] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Accepted: 05/09/2019] [Indexed: 12/25/2022]
Abstract
The present study was conducted to investigate the effect and potential mechanism of hypoxia-inducible factor-1α (HIF-1α) genetic inhibition plus glutamine (Gln) supplementation on necrosis-apoptosis imbalance during acute pancreatitis (AP), with a specific focus on the regulations of intracellular energy metabolism status. Wistar rats and AR42J cells were used to establish AP models. When indicated, a HIF-1α knockdown with or without a Gln supplementation was administered. In vivo, local and systemic inflammatory injuries were assessed by serum cytokine measurement, H&E staining, and transmission electron microscope (TEM) observation of pancreatic tissue. In vitro, intracellular energy metabolism status was evaluated by measuring the intracellular adenosine triphosphate (ATP), lactic acid, and Ca2+ concentrations and the mitochondrial potential. In addition, changes in the apoptotic activity were analyzed using TUNEL staining in vivo and an apoptosis assay in vitro. HIF-1α knockdown alleviated AP-related inflammatory injury as indicated by the measurements of serum cytokines and examinations of TEM and H&E staining of pancreatic tissues. HIF-1α knockdown played an antioxidative role against AP-related injuries by preventing the increase in the intracellular Ca2+ concentration and the decrease in the mitochondrial membrane potential and subsequently by suppressing the glycolysis pathway and increasing energy anabolism in AR42J cells after AP induction. Apoptosis was significantly upregulated when HIF-1α was knocked down before AP induction due to an attenuation of the translocation of nuclear factor-kappa B to the nuclei. Furthermore, these merits of HIF-1α knockdown in the relief of the metabolic stress and upregulation of apoptosis were more significant when Gln was administered concomitantly. In conclusion, Gln-supplemented HIF-1α knockdown might be promising for the future management of AP by relieving the intracellular energy stress, thereby attenuating the predominance of necrosis over apoptosis.
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15
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Abstract
Acinar cell death is the most important pathophysiological change in the early stage of acute pancreatitis, and it has been the emphasis of the research. The mode of acinar cell death includes apoptosis, necrosis, necroptosis, autophagy, and pyroptosis. Some scholars have shown that acinar cell death affects the outcome of acute pancreatitis. Therefore, studying the mode of acinar cell death has great value in the assessment of the severity of acute pancreatitis. Apoptosis can reduce inflammatory response, and necrosis aggravates inflammatory response. In recent years, research on the effect of necroptosis and pyroptosis on acute pancreatitis has been carried out. This article will review the effect of apoptosis, necrosis, necroptosis, and pyroptosis on acute pancreatitis.
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Affiliation(s)
- Mei-Feng Zhang
- Department of Cadre Ward, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xiang-Ren Jin
- Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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Jinhong Tablet Reduces Damage of Intestinal Mucosal Barrier in Rats with Acute Biliary Infection via Bcl-2/Bax mRNA and Protein Regulation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:4985926. [PMID: 29234407 PMCID: PMC5646335 DOI: 10.1155/2017/4985926] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Accepted: 08/23/2017] [Indexed: 12/22/2022]
Abstract
Objective To explore the effects and mechanism of Jinhong Tablet on intestinal mucosal barrier function and SIRS in rats with acute biliary infection. Methods 36 SD male rats were divided into three groups: sham operation (control), acute biliary infection (ABI) model, and Jinhong Tablet (Jinhong) group. Jinhong group were force-fed with Jinhong Tablet, while the other two groups received oral saline. At days 3 and 5, morphological changes of intestinal mucosa were assessed. Serum diamine oxidase (DAO), D-lactate, and endotoxin levels were measured. And the genes bcl-2 and bax in intestinal tissues were tested by real-time PCR and Western blotting. Results Intestinal damage was significantly less severe in Jinhong group compared with ABI group, as indicated by Chiu's scoring, TUNEL analysis, and serum DAO, D-lactic acid, and endotoxin levels. Additionally, the expression of bax mRNA and protein was decreased and the ratio of bcl-2/bax mRNA and protein was increased compared with ABI group. Conclusion Jinhong Tablet had a positive intervention on acute biliary infection through improving inflammation and intestinal mucosal barrier, inhibiting excessive apoptosis of intestinal epithelial cells via bax and bcl-2 gene, and protein regulation.
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17
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Magierowski M, Magierowska K, Hubalewska-Mazgaj M, Adamski J, Bakalarz D, Sliwowski Z, Pajdo R, Kwiecien S, Brzozowski T. Interaction between endogenous carbon monoxide and hydrogen sulfide in the mechanism of gastroprotection against acute aspirin-induced gastric damage. Pharmacol Res 2016; 114:235-250. [PMID: 27825819 DOI: 10.1016/j.phrs.2016.11.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/12/2016] [Accepted: 11/02/2016] [Indexed: 02/07/2023]
Abstract
Acetylsalicylic acid (ASA) is mainly recognized as painkiller or anti-inflammatory drug. However, ASA causes serious side effects towards gastrointestinal (GI) tract which limits its usefulness. Carbon monoxide (CO) and hydrogen sulfide (H2S) have been described to act as important endogenous messengers and mediators of gastroprotection but whether they can interact in gastroprotection against acute ASA-induced gastric damage remains unknown. In this study male Wistar rats were pretreated with 1) vehicle (saline, i.g.), 2) tricarbonyldichlororuthenium (II) dimer (CORM-2, 5mg/kg i.g.), 3) sodium hydrosulfide (NaHS, 5mg/kg i.g.), 4) zinc protoporphyrin (ZnPP, 10mg/kg i.p.), 5) D,L-propargylglycine (PAG, 30mg/kg i.g.), 6) ZnPP combined with NaHS, 7) PAG combined with CORM-2 or 8) 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10mg/kg i.p.) combined with CORM-2 or NaHS and 30min later ASA was administered i.g. in a single dose of 125mg/kg. After 1h, gastric blood flow (GBF) was determined by H2 gas clearance technique and gastric lesions were assessed by planimetry and histology. CO content in gastric mucosa and COHb concentration in blood were determined by gas chromatography and H2S production was assessed in gastric mucosa using methylene blue method. Protein and/or mRNA expression for cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), heme oxygenase (HO)-1, HO-2, hypoxia inducible factor-alpha (HIF)-1α, nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX)-1 and COX-2, inducible nitric oxide synthase (iNOS) and interleukin (IL)-1β were determined by Western blot or real-time PCR, respectively. ASA caused hemorrhagic gastric mucosal damage and significantly decreased GBF, H2S production, CO content, mRNA or protein expression for CSE, 3-MST, HO-2 and increased mRNA and/or protein expression for CBS, HO-1, Nrf-2, HIF-1α, iNOS, IL-1β, COX-2 in gastric mucosa and COHb concentration in blood. Pretreatment with CORM-2 or NaHS but not with PAG decreased ASA-damage and increased GBF. ZnPP reversed protective and hyperemic effect of NaHS but PAG failed to affect CORM-2-induced gastroprotection. CORM-2 elevated CO content, mRNA or protein expression for HO-1, Nrf-2, and decreased expression of CBS, HIF-1α, COX-2, IL-1β, iNOS, the H2S production in gastric mucosa and COHb concentration in blood. NaHS raised mRNA or protein expression for CSE, COX-1 and decreased mRNA expression for IL-1β and COHb level in blood. We conclude that CO is involved in gastroprotection induced by H2S while beneficial protective action of CO released from CORM-2 in gastric mucosa seems to be H2S-independent. In contrast to H2S, CO ameliorates hypoxia, regulates Nrf-2 expression but similarly to H2S acts on sGC-dependent manner to restore gastric microcirculation and exhibit anti-inflammatory activity in gastric mucosa compromised by ASA.
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Affiliation(s)
- Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
| | - Katarzyna Magierowska
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Magdalena Hubalewska-Mazgaj
- Department of Genetic Research and Nutrigenomics, Malopolska Centre of Biotechnology, Jagiellonian University, 7A Gronostajowa Street, 30-387 Cracow, Poland
| | - Juliusz Adamski
- Department of Forensic Toxicology, Institute of Forensic Research, 9 Westerplatte Street, 31-033 Cracow, Poland
| | - Dominik Bakalarz
- Department of Forensic Toxicology, Institute of Forensic Research, 9 Westerplatte Street, 31-033 Cracow, Poland
| | - Zbigniew Sliwowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Robert Pajdo
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Slawomir Kwiecien
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
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Qureshi IN, David D, Thangaraj KR, Kurien RT, Chowdhury SD, Goel A, Dutta AK, Simon EG, Ramachandran A, Balasubramanian KA, Joseph AJ. Plasma hydrogen sulphide does not predict severity of acute pancreatitis in humans. Indian J Gastroenterol 2016; 35:478-481. [PMID: 27796938 DOI: 10.1007/s12664-016-0703-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 10/01/2016] [Indexed: 02/04/2023]
Abstract
The primary aim of this study was to assess the usefulness of plasma hydrogen sulphide (H2S) level at admission as a predictor of severity of acute pancreatitis. The secondary aims were to examine whether the level of H2S after 48 h correlated with severity and whether level of H2S correlated with pulmonary, renal or infectious complications. Plasma hydrogen sulphide was measured within 24 h of admission and 48 h later, in patients with acute pancreatitis. Patients were classified as having mild or severe pancreatitis, and H2S levels in the two groups were compared. A total of 55 patients had H2S estimation carried out within 24 h of admission. H2S levels were similar in patients with mild (mean 31.8 ± 18.8, range 7.1 to 81.4 µmol/L) and severe pancreatitis (mean 28.2 ± 21.6, range 6.1 to 74.4 µmol/L; p = 0.339). There was no difference found between the groups after 48 h (mild n = 28, mean 26.8 ± 19.4 µmol/L, and severe n = 20, mean 34.6 ± 21.0 µmol/L; p = 0.127). There was also no difference in the levels between patients with or without lung injury, kidney injury or sepsis. Performing H2S estimation to predict severity in acute pancreatitis is not beneficial.
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Affiliation(s)
- Iqbal N Qureshi
- Department of Gastroenterology, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India
| | - Deepu David
- Department of Gastroenterology, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India.
| | - Kavitha R Thangaraj
- Wellcome Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India
| | - Reuben T Kurien
- Department of Gastroenterology, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India
| | - Sudipta D Chowdhury
- Department of Gastroenterology, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India
| | - Ashish Goel
- Department of Gastroenterology, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India
| | - Amit K Dutta
- Department of Gastroenterology, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India
| | - Ebby G Simon
- Department of Gastroenterology, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India
| | - Anup Ramachandran
- Wellcome Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India
| | - Kunissery A Balasubramanian
- Wellcome Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India
| | - Anjilivelil J Joseph
- Department of Gastroenterology, Division of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, 632 004, India
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Gaddam RR, Fraser R, Badiei A, Chambers S, Cogger VC, Le Couteur DG, Ishii I, Bhatia M. Cystathionine-Gamma-Lyase Gene Deletion Protects Mice against Inflammation and Liver Sieve Injury following Polymicrobial Sepsis. PLoS One 2016; 11:e0160521. [PMID: 27518439 PMCID: PMC4982653 DOI: 10.1371/journal.pone.0160521] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Accepted: 07/19/2016] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Hydrogen sulfide (H2S), produced by the activity of cystathionine-gamma-lyase (CSE), is a key mediator of inflammation in sepsis. The liver sinusoidal endothelial cells (LSECs) are important target and mediator of sepsis. The aim of this study was to investigate the role of CSE-derived H2S on inflammation and LSECs fenestrae in caecal-ligation and puncture (CLP)-induced sepsis using CSE KO mice. METHODS Sepsis was induced by CLP, and mice (C57BL/6J, male) were sacrificed after 8 hours. Liver, lung, and blood were collected and processed to measure CSE expression, H2S synthesis, MPO activity, NF-κB p65, ERK1/2, and cytokines/chemokines levels. Diameter, frequency, porosity and gap area of the liver sieve were calculated from scanning electron micrographs of the LSECs. RESULTS An increased CSE expression and H2S synthesizing activity in the liver and lung of wild-type mice following CLP-induced sepsis. This was associated with an increased liver and lung MPO activity, and increased liver and lung and plasma levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and the chemokines MCP-1 and MIP-2α. Conversely, CSE KO mice had less liver and lung injury and reduced inflammation following CLP-induced sepsis as evidenced by decreased levels of H2S synthesizing activity, MPO activity, and pro-inflammatory cytokines/chemokines production. Extracellular-regulated kinase (ERK1/2) and nuclear factor-κB p65 (NF-κB) became significantly activated after the CLP in WT mice but not in CSE KO mice. In addition, CLP-induced damage to the LSECs, as indicated by increased defenestration and gaps formation in the LSECs compared to WT sham control. CSE KO mice showed decreased defenestration and gaps formation following sepsis. CONCLUSIONS Mice with CSE (an H2S synthesising enzyme) gene deletion are less susceptible to CLP-induced sepsis and associated inflammatory response through ERK1/2-NF-κB p65 pathway as evidenced by reduced inflammation, tissue damage, and LSECs defenestration and gaps formation.
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Affiliation(s)
| | - Robin Fraser
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Alireza Badiei
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Stephen Chambers
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Victoria C Cogger
- Centre for Education and Research on Ageing, Alzheimers and Ageing Institute, Biogerentology, ANZAC Research Institute, University of Sydney, Sydney and Concord Hospital, Sydney, Australia
| | - David G Le Couteur
- Centre for Education and Research on Ageing, Alzheimers and Ageing Institute, Biogerentology, ANZAC Research Institute, University of Sydney, Sydney and Concord Hospital, Sydney, Australia
| | - Isao Ishii
- Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan
| | - Madhav Bhatia
- Department of Pathology, University of Otago, Christchurch, New Zealand
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20
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Ji L, Li L, Qu F, Zhang G, Wang Y, Bai X, Pan S, Xue D, Wang G, Sun B. Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway. J Cell Mol Med 2016; 20:2349-2361. [PMID: 27419805 PMCID: PMC5134374 DOI: 10.1111/jcmm.12928] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 06/12/2016] [Indexed: 01/14/2023] Open
Abstract
Previously, we have shown that hydrogen sulphide (H2 S) might be pro-inflammatory during acute pancreatitis (AP) through inhibiting apoptosis and subsequently favouring a predominance of necrosis over apoptosis. In this study, we sought to investigate the detrimental effects of H2 S during AP specifically with regard to its regulation on the impaired autophagy. The incubated levels of H2 S were artificially intervened by an administration of sodium hydrosulphide (NaHS) or DL-propargylglycine (PAG) after AP induction. Accumulation of autophagic vacuoles and pre-mature activation of trypsinogen within acini, which indicate the impairment of autophagy during AP, were both exacerbated by treatment with NaHS but attenuated by treatment with PAG. The regulation that H2 S exerted on the impaired autophagy during AP was further attributed to over-activation of autophagy rather than hampered autophagosome-lysosome fusion. To elucidate the molecular mechanism that underlies H2 S-mediated over-activation of autophagy during AP, we evaluated phosphorylations of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR). Furthermore, Compound C (CC) was introduced to determine the involvement of mTOR signalling by evaluating phosphorylations of downstream effecters including p70 S6 kinase (P70S6k) and UNC-51-Like kinase 1 (ULK1). Our findings suggested that H2 S exacerbated taurocholate-induced AP by over-activating autophagy via activation of AMPK and subsequently, inhibition of mTOR. Thus, an active suppression of H2 S to restore over-activated autophagy might be a promising therapeutic approach against AP-related injuries.
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Affiliation(s)
- Liang Ji
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Le Li
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fengzhi Qu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guangquan Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongwei Wang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuewei Bai
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shangha Pan
- Central Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Gang Wang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bei Sun
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Plasma Citrulline, Glycans, and Hydrogen Sulfide in Patients With Acute Pancreatitis: Possible Markers of Intestinal Damage. Pancreas 2016; 45:e27-9. [PMID: 27295536 DOI: 10.1097/mpa.0000000000000593] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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Han B, Zhou H, Jia G, Wang Y, Song Z, Wang G, Pan S, Bai X, Lv J, Sun B. MAPKs and Hsc70 are critical to the protective effect of molecular hydrogen during the early phase of acute pancreatitis. FEBS J 2016; 283:738-56. [PMID: 26683671 DOI: 10.1111/febs.13629] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 11/15/2015] [Accepted: 12/14/2015] [Indexed: 12/14/2022]
Abstract
Molecular hydrogen (H2 ) has been proven to be an effective agent that can cure multiple organ diseases by reducing oxidative stress. Although the protective effect of hydrogen on acute pancreatitis (AP) has been confirmed, its molecular mechanism is still unclear. In this article, we aimed to investigate the changes in pancreatic cell protein expression associated with the protective effect of H2 against AP and attempted to uncover the molecular mechanism underlying this process. A proteomic analysis identified 73 differentially expressed proteins and generated the protein-protein interaction networks of these proteins. The results triggered our interest in mitogen-activated protein kinase (MAPK) and heat shock cognate 71 kDa protein (Hsc70). The subsequent in vitro experiments showed that H2 treatment inhibited the phosphorylation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAPK, and activated NF-κB and the expression of tumor necrosis factor α and interleukin-1β, while simultaneously preventing the translocation of phospho-ERK, phospho-JNK, and phospho-p38 from the cytoplasm to the nucleus. Furthermore, Hsc70 expression was upregulated by H2 administration. The animal experimental results were consistent with those of the in vitro experiments. In conclusion, H2 treatment can ameliorate the inflammatory response and reduce the expression of inflammatory mediators during the early phase of AP by inhibiting the MAPK pathways and increasing Hsc70 expression.
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Affiliation(s)
- Bing Han
- Department of Hepatobiliary Surgery, Yantai Yuhuangding Hospital of Qingdao University Medical College, China.,Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, China
| | - Haoxin Zhou
- Department of Emergency Surgery, First Affiliated Hospital of Harbin Medical University, China
| | - Guang Jia
- Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, China
| | - Yongwei Wang
- Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, China
| | - Zengfu Song
- Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, China
| | - Shangha Pan
- Central Laboratory, First Affiliated Hospital of Harbin Medical University, China
| | - Xuewei Bai
- Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, China
| | - Jiachen Lv
- Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, China
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Zhou HX, Han B, Hou LM, An TT, Jia G, Cheng ZX, Ma Y, Zhou YN, Kong R, Wang SJ, Wang YW, Sun XJ, Pan SH, Sun B. Protective Effects of Hydrogen Gas on Experimental Acute Pancreatitis. PLoS One 2016; 11:e0154483. [PMID: 27115738 PMCID: PMC4845997 DOI: 10.1371/journal.pone.0154483] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 04/14/2016] [Indexed: 12/24/2022] Open
Abstract
Acute pancreatitis (AP) is an inflammatory disease mediated by damage to acinar cells and pancreatic inflammation. In patients with AP, subsequent systemic inflammatory responses and multiple organs dysfunction commonly occur. Interactions between cytokines and oxidative stress greatly contribute to the amplification of uncontrolled inflammatory responses. Molecular hydrogen (H2) is a potent free radical scavenger that not only ameliorates oxidative stress but also lowers cytokine levels. The aim of the present study was to investigate the protective effects of H2 gas on AP both in vitro and in vivo. For the in vitro assessment, AR42J cells were treated with cerulein and then incubated in H2-rich or normal medium for 24 h, and for the in vivo experiment, AP was induced through a retrograde infusion of 5% sodium taurocholate into the pancreatobiliary duct (0.1 mL/100 g body weight). Wistar rats were treated with inhaled air or 2% H2 gas and sacrificed 12 h following the induction of pancreatitis. Specimens were collected and processed to measure the amylase and lipase activity levels; the myeloperoxidase activity and production levels; the cytokine mRNA expression levels; the 8-hydroxydeoxyguanosine, malondialdehyde, and glutathione levels; and the cell survival rate. Histological examinations and immunohistochemical analyses were then conducted. The results revealed significant reductions in inflammation and oxidative stress both in vitro and in vivo. Furthermore, the beneficial effects of H2 gas were associated with reductions in AR42J cell and pancreatic tissue damage. In conclusion, our results suggest that H2 gas is capable of ameliorating damage to the pancreas and AR42J cells and that H2 exerts protective effects both in vitro and in vivo on subjects with AP. Thus, the results obtained indicate that this gas may represent a novel therapy agent in the management of AP.
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Affiliation(s)
- Hao-xin Zhou
- Department of Emergency Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Bing Han
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Li-Min Hou
- Department of Emergency Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Ting-Ting An
- Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Guang Jia
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Zhuo-Xin Cheng
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Yong Ma
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Yi-Nan Zhou
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Rui Kong
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Shuang-Jia Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Yong-Wei Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Xue-Jun Sun
- Department of Diving Medicine, Second Military Medical University, Shanghai, People’s Republic of China
| | - Shang-Ha Pan
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
- * E-mail:
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Hu YY, Zhou CH, Dou WH, Feng H, Wang SF. TUNEL staining combined with cell morphologic characteristics for identifying acinar cell death mode in rats with acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2015; 23:3259-3264. [DOI: 10.11569/wcjd.v23.i20.3259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [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 detect acinar cell death in rats with acute pancreatitis (AP) by TdT-mediated dUTP nick labeling (TUNEL) staining and to study the correlation between the morphology of TUNEL positive cells and their death modes.
METHODS: Acute necrotizing pancreatitis (ANP) was induced in rats by injection of 4% sodium taurocholate in the pancreaticobiliary duct, and the pathological changes in pancreatic tissue were observed. Pancreatic tissue sections were stained by TUNEL, and the morphological changes of TUNEL positive cells were evaluated under a light microscope.
RESULTS: Compared to the sham operated group, the pancreas of ANP rats exhibited typical pathological changes of AP, and had a large number of TUNEL positive acinar cells. The TUNEL positive cells showed various morphologic characteristics, which included the manifestations of both apoptosis and necrosis. The apoptotic morphology was characterized by nuclear condensation and karyorrhexis followed by the formation of apoptotic bodies, while necrotic cells demonstrated nuclear swelling, karyolysis and cytoplasmic vacuolization. There were significant differences between the morphologic characteristics of the two cell death modes.
CONCLUSION: TUNEL staining itself cannot well differentiate the apoptosis and necrosis of acinar cells in AP. However, when combined with the morphologic characteristics of TUNEL positive cells, TUNEL staining can preliminarily identify the two modes of cell death.
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Li Y, Zhao Q, Fan LQ, Wang LL, Tan BB, Leng YL, Liu Y, Wang D. Zinc finger protein 139 expression in gastric cancer and its clinical significance. World J Gastroenterol 2014; 20:18346-18353. [PMID: 25561801 PMCID: PMC4277971 DOI: 10.3748/wjg.v20.i48.18346] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 05/30/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of zinc finger protein 139 (ZNF139) in gastric cancer (GC), and to analyze its clinical significance.
METHODS: A total of 108 patients who were diagnosed with GC and underwent surgery between January 2005 and March 2007 were enrolled in this study. Gastric tumor specimens and paired tumor-adjacent tissues were collected and paraffin-embedded, and the clinicopathologic characteristics and prognosis were recorded. The expression of ZNF139, Bcl-2, Bax, and caspase-3 were determined by immunohistochemistry, and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. SPSS 13.0 software was used for data processing and analyses, and significance was determined at P < 0.05.
RESULTS: The expression of ZNF139 was stronger in tumors than in tumor-adjacent tissues (66.67% vs 44.44%; P < 0.01). Overexpression of ZNF139 correlated with tumor differentiation, invasion depth, clinical stage, lymphatic metastasis, and blood vessel invasion (all Ps < 0.05). Patients with overexpression of ZNF139 had a poorer prognosis (P < 0.01), and overexpression of ZNF139 was an independent factor for the prognosis of GC patients by a Cox survival analysis (P = 0.02). A negative relationship between ZNF139 and the apoptosis index was observed (r = -0.686; P < 0.01). The expression of Bcl-2 in GC was stronger than in tumor-adjacent tissues (66.67% vs 41.67%), whereas the expression levels of Bax and caspase-3 were lower in primary tumors (54.63% and 47.22%, respectively) than in tumor-adjacent tissues (73.15% and 73.15%, respectively) (all Ps < 0.05). The expression of ZNF139 negatively correlated with caspase-3 (r = -0.370; P < 0.01). The expressions of Bcl-2 and Bax were also negatively correlated (r = -0.231; P = 0.02). The expressions of caspase-3 and Bax protein were positively correlated (r = 0.217; P = 0.024).
CONCLUSION: ZNF139 is related to clinicopathologic characteristics and prognosis of GC. Furthermore, it is overexpressed and involved in apoptosis in GC tissues by regulating caspase-3.
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Lv JC, Wang G, Pan SH, Bai XW, Sun B. Lycopene protects pancreatic acinar cells against severe acute pancreatitis by abating the oxidative stress through JNK pathway. Free Radic Res 2014; 49:151-63. [PMID: 25410533 DOI: 10.3109/10715762.2014.988150] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This study investigated the anti-oxidative and anti-inflammatory effects of lycopene on severe acute pancreatitis (SAP) in both in vivo and in vitro models. Utilizing a rat model, we found that lycopene administration protected against SAP, as indicated by the decreased levels of serum amylase and C-reactive protein. Pathological changes were alleviated by pretreatment with lycopene. The serum levels of tumor necrosis factor-α, interleukin-6, macrophage inflammatory protein-1α, and monocyte chemotactic protein-1 were decreased by lycopene. The decreased reactive oxygen species (ROS) content in the pancreatic tissues of the lycopene-treated group were indirectly evaluated by measuring the levels of myeloperoxidase, lipid peroxidase, and superoxide dismutase. Lycopene protected acinar cells against necrosis and apoptosis by relieving the mitochondrial and endoplasmic stress caused by ROS which was shown in electron microscopy and immunohistochemistry staining of active nuclear factor-κB p65. The protective effect was also observed in a simulated SAP model in a rat acinar cell line. ROS and apoptotic staining were compared between groups. Lycopene exerts protective effects against SAP in rats that may be related to its anti-inflammatory property through inhibiting the expression of damage-associated molecular patterns, and anti-oxidative property which can thus maintain cellular homeostasis and prevent the phosphorylation of JNK pathway.
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Affiliation(s)
- J C Lv
- Department of Pancreatic and Biliary Surgery, the First Affiliated Hospital of Harbin Medical University , Harbin, Heilongjiang , P. R. China
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Olson KR, DeLeon ER, Liu F. Controversies and conundrums in hydrogen sulfide biology. Nitric Oxide 2014; 41:11-26. [PMID: 24928561 DOI: 10.1016/j.niox.2014.05.012] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Revised: 05/28/2014] [Accepted: 05/30/2014] [Indexed: 01/10/2023]
Abstract
Hydrogen sulfide (H2S) signaling has been implicated in physiological processes in practically all organ systems studied to date. At times the excitement of this new field has outpaced the technical expertise or practical knowledge with which to accurately assess these advancements. Recently, the myriad of proposed H2S actions has spawned interest in using indicators of H2S metabolism, especially plasma H2S concentrations, as a means of identifying a variety of pathophysiological conditions or to predict clinical outcomes. While this is a noteworthy endeavor, there are a number of contraindications to this practice at this time. First, there is little consensus regarding normal, i.e., "physiological" concentrations of H2S in either plasma or tissue. In fact, it has been shown that the methods most often employed for these measurements are associated with substantial artifact. Second, interactions, or presumed lack thereof, of H2S with other biomolecules (e.g., O2, H2O2, pH, etc.) or analytical reagents (e.g., reducing reagents, N-ethylmaleimide, phenylarsine, etc.) are often assumed but not evaluated. Third, the experimental design and/or statistical analyses may not be sufficient to justify using H2S concentration in tissue or blood as a predictive biomarker of pathophysiology. In this study, we first briefly review the problems associated with plasma and tissue H2S measurements and the associated errors and we provide some simple methods to evaluate whether the data obtained is physiologically relevant. Second we provide a brief analysis of H2S interactions with the above biomolecules. Third, we provide a statistical tool with which to determine the clinical applicability of H2S measurements. It is hoped that these points will provide a rational background for future work.
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Affiliation(s)
- Kenneth R Olson
- Indiana University School of Medicine - South Bend, South Bend, IN 46617, United States.
| | - Eric R DeLeon
- Indiana University School of Medicine - South Bend, South Bend, IN 46617, United States; Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, United States
| | - Fang Liu
- Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556, United States
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Tang QQ, Su SY, Fang MY. Zinc supplement modulates oxidative stress and antioxidant values in rats with severe acute pancreatitis. Biol Trace Elem Res 2014; 159:320-4. [PMID: 24771310 DOI: 10.1007/s12011-014-9971-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 04/08/2014] [Indexed: 02/08/2023]
Abstract
Oxidative stress is a main factor in the pathogenesis of severe acute pancreatitis (SAP). The ability of zinc (Zn) to retard oxidative processes has been recognized for many years. This study aims to examine the levels of free oxygen radicals and antioxidant enzyme in SAP rats and know the effect of Zn supplementation on free oxygen radicals and antioxidant system in rats with SAP. Forty-five male Wistar rats were divided into three groups-the SAP group (n=15), the Zn-treated group (n=15), and the controlled group (n=15). For the SAP group, sodium taurocholate is injected into the pancreatic duct to induce SAP; for the Zn-treated group, Zn (5 mg/kg) is subcutaneously injected immediately after injection of 5% sodium taurocholate. Firstly, the activity of erythrocyte glutathione peroxidase (GSH-Px), erythrocyte superoxide dismutase (SOD), and the content of plasma malondialdehyde (MDA), which are the toxic products of oxidative stress, is measured. Secondly, the levels of free oxygen radicals in the liver and kidney are detected. The result showed that the activity of GSH-Px and SOD was lower in the SAP group than that in the controlled group, although the content of plasma MDA increased. However, the activity of SOD and GSH-Px in the Zn-treated group was not significantly decreased after comparing with the controlled group; in the mean time, the content of MDA was not significantly increased either. Moreover, the content of free radical in liver and kidney was higher in the SAP group compared with the controlled group, but the content of free radical in the Zn-treated group was not higher than that in the controlled group (p>0.05). All of the above indicated that Zn may recover the activity of free radical-scavenging enzymes and decrease the content of free radical for the SAP group rats. In conclusion, the content of free radical increase may be one of the reasons that SAP rats are injured, and it is possible for Zn to be used to treat SAP through scavenging free radical and increasing the activity of SOD and GSH-Px of erythrocyte.
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Affiliation(s)
- Qin-qing Tang
- Department of Emergency Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China, 230022
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From nitric oxide to hyperbaric oxygen: invisible and subtle but nonnegligible gaseous signaling molecules in acute pancreatitis. Pancreas 2014; 43:511-7. [PMID: 24713669 DOI: 10.1097/mpa.0000000000000062] [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] [Indexed: 12/23/2022]
Abstract
Nitric oxide (NO), carbon monoxide, and hydrogen sulfide in addition to hydrogen are well established as gaseous signal molecules throughout the body. Although the role of gasotransmitters in acute pancreatitis (AP) has been explored for many years, many details remain to be elucidated. The physiologic effect of NO in AP mainly relies on induced NO synthase, which stimulates the production of cytokines in the blood. Carbon monoxide inhibits nuclear factor-κB activation, which leads to amelioration of the inflammatory response. Hydrogen sulfide displays a dual role in the mechanism of AP according to its concentration in the system. Hydrogen is a newly discovered gaseous signaling molecule, and currently, there is little evidence that it has any function in alleviating inflammation. We discovered that hyperbaric oxygen is a novel gasotransmitter that has potential use in the treatment of AP. The correlation among hyperbaric oxygen, hypoxia inducible factor 1α, and other signaling pathways should be further studied. We also discuss some prospects and issues that remain to be resolved in this review. In summary, the discovery of gaseous signal molecules has established a new platform for deep investigation of the mechanism of AP, and our knowledge of the role of gasotransmitters in AP will increase with further research.
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Ang AD, Rivers-Auty J, Hegde A, Ishii I, Bhatia M. The effect of CSE gene deletion in caerulein-induced acute pancreatitis in the mouse. Am J Physiol Gastrointest Liver Physiol 2013; 305:G712-G721. [PMID: 24008358 DOI: 10.1152/ajpgi.00044.2013] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hydrogen sulfide (H2S) has been reported to be involved in the signaling of the inflammatory response; however, there are differing views as to whether it is pro- or anti-inflammatory. In this study, we sought to determine whether endogenously synthesized H2S via cystathionine-γ-lyase (CSE) plays a pro- or anti-inflammatory role in caerulein-induced pancreatitis. To investigate this, we used mice genetically deficient in CSE to elucidate the function of CSE in caerulein-induced acute pancreatitis. We compared the inflammatory response and tissue damage of wild-type (WT) and CSE knockout (KO) mice following 10 hourly administrations of 50 μg/kg caerulein or saline control. From this, we found that the CSE KO mice showed significantly less local pancreatic damage as well as acute pancreatitis-associated lung injury compared with the WT mice. There were also lower levels of pancreatic eicosanoid and cytokines, as well as reduced acinar cell NF-κB activation in the CSE KO mice compared with WT mice. Additionally, in WT mice, there was a greater level of pancreatic CSE expression and sulfide-synthesizing activity in caerulein-induced pancreatitis compared with the saline control. When comparing the two saline-treated control groups, we noted that the CSE KO mice showed significantly less pancreatic H2S-synthesizing activity relative to the WT mice. These results indicate that endogenous H2S generated by CSE plays a key proinflammatory role via NF-κB activation in caerulein-induced pancreatitis, and its genetic deletion affords significant protection against acute pancreatitis and associated lung injury.
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Affiliation(s)
- Abel D Ang
- Dept. of Pathology, Univ. of Otago, Christchurch, 2 Riccarton Ave., PO Box 4345, Christchurch 8140, New Zealand.
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