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1
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Shokr MM, Eladawy RM. HMGB1: Different secretion pathways with pivotal role in epilepsy and major depressive disorder. Neuroscience 2025; 570:55-67. [PMID: 39970982 DOI: 10.1016/j.neuroscience.2025.02.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/10/2024] [Accepted: 02/12/2025] [Indexed: 02/21/2025]
Abstract
High-mobility group box 1 (HMGB1) protein is a highly prevalent protein that, once it is translocated to an extracellular site, can contribute to the pathogenesis of autoimmune and inflammatory responses, including epilepsy and depression. The conditions needed for release are associated with the production of multiple isoforms, and this translocation may occur in response to both immune cell activation and cell death. HMGB1 has been shown to interact with different mediators, including exportin 1, notch receptors, mitogen-activated protein kinase, STAT, tumor protein 53, and inflammasomes. Furthermore, as a crucial inflammatory mediator, HMGB1 has demonstrated upregulated expression and a higher percentage of translocation from the nucleus to the cytoplasm, acting on downstream receptors such as toll-like receptor 4 and receptor for advanced glycation end products, thereby activating interleukin-1 beta and nuclear factor kappa-B, intensifying inflammatory responses. In this review, we aim to discuss the different molecular interactions for the secretion of HMGB1 along with its pivotal role in epilepsy and major depressive disorder.
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Affiliation(s)
- Mustafa M Shokr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University - Arish Branch, 45511 Arish, Egypt.
| | - Reem M Eladawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University - Arish Branch, 45511 Arish, Egypt
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2
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Cai Y, Yang F, Huang X. Oxidative stress and acute pancreatitis (Review). Biomed Rep 2024; 21:124. [PMID: 39006508 PMCID: PMC11240254 DOI: 10.3892/br.2024.1812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/06/2024] [Indexed: 07/16/2024] Open
Abstract
Acute pancreatitis (AP) is a common inflammatory disorder of the exocrine pancreas that causes severe morbidity and mortality. Although the pathophysiology of AP is poorly understood, a substantial body of evidence suggests some critical events for this disease, such as dysregulation of digestive enzyme production, cytoplasmic vacuolization, acinar cell death, edema formation, and inflammatory cell infiltration into the pancreas. Oxidative stress plays a role in the acute inflammatory response. The present review clarified the role of oxidative stress in the occurrence and development of AP by introducing oxidative stress to disrupt cellular Ca2+ balance and stimulating transcription factor activation and excessive release of inflammatory mediators for the application of antioxidant adjuvant therapy in the treatment of AP.
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Affiliation(s)
- Yongxia Cai
- Department of Emergency Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Feng Yang
- Department of Emergency Medicine, The First People's Hospital of Wuyi County, Jinhua, Zhejiang 321200, P.R. China
| | - Xizhu Huang
- Department of Emergency Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
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Tsomidis I, Voumvouraki A, Kouroumalis E. The Pathogenesis of Pancreatitis and the Role of Autophagy. GASTROENTEROLOGY INSIGHTS 2024; 15:303-341. [DOI: 10.3390/gastroent15020022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. In this review, the current evidence indicating that several mechanisms act in concert to induce and perpetuate pancreatitis were presented. As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. The various aspects of pathogenesis, including trypsinogen activation, ER stress and mitochondrial dysfunction, the implications of inflammation, and macrophage involvement in innate immunity, as well as the significance of pancreatic stellate cells in the development of fibrosis, were also analyzed. Recent findings on exosomes and the miRNA regulatory role were also presented. Finally, the role of autophagy in the protection and aggravation of pancreatitis and possible therapeutic implications were reviewed.
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Affiliation(s)
- Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
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4
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Oikonomou P, Nikolaou C, Papachristou F, Sovatzidis A, Lambropoulou M, Giouleka C, Kontaxis V, Linardoutsos D, Papalois A, Pitiakoudis M, Tsaroucha A. Eugenol Reduced ΜPO, CD45 and HMGB1 Expression and Attenuated the Expression of Leukocyte Infiltration Markers in the Intestinal Tissue in Biliopancreatic Duct Ligation-Induced Pancreatitis in Rats. MEDICINA (KAUNAS, LITHUANIA) 2023; 60:74. [PMID: 38256335 PMCID: PMC10820626 DOI: 10.3390/medicina60010074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/30/2023] [Accepted: 12/26/2023] [Indexed: 01/24/2024]
Abstract
Background and Objectives: Inflammation and dysregulation in the intestinal barrier function in acute pancreatitis (AP) trigger pancreatic lesions, systemic inflammatory response, and multiple organ dysfunction. Eugenol, as the main component of clove (Syzygium aromaticum), is known for its antioxidant and anti-inflammatory properties. We studied the potentially beneficial effect of eugenol in a rodent model of biliopancreatic duct ligation-induced AP. Materials and Methods: Rats were randomly divided into three groups: Sham, AP, and AP + eugenol (15 mg/kg/day). Serum TNFα, IL-6, IL-18, and resistin levels, as well as IL-6, TNFα, MPO, HMGB1, and CD45 tissue expression, were determined at various timepoints after the induction of AP. Results: Eugenol attenuated hyperemia and inflammatory cell infiltration in the intestinal mucosal, submucosal, and muscular layers. IL-6 and resistin serum levels were significantly reduced in the AP + eugenol group, while serum TNFα and IL-18 levels remained unaffected overall. TNFα pancreatic and intestinal expression was attenuated by eugenol at 72 h, while IL-6 expression was affected only in the pancreas. MPO, CD45, and HMGB1 intestinal expression was significantly reduced in eugenol-treated rats. Conclusions: Eugenol managed to attenuate the inflammatory response in the intestine in duct ligation-induced AP in rats.
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Affiliation(s)
- Panagoula Oikonomou
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Christina Nikolaou
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Fotini Papachristou
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Apostolos Sovatzidis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Maria Lambropoulou
- Laboratory of Histology-Embryology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Charikleia Giouleka
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Vasileios Kontaxis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Dimitrios Linardoutsos
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Apostolos Papalois
- Experimental Research Center, ELPEN Pharmaceuticals, Pikermi, 19009 Athens, Greece;
| | - Michael Pitiakoudis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Alexandra Tsaroucha
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
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5
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Wang X, Tang G, Liu Y, Zhang L, Chen B, Han Y, Fu Z, Wang L, Hu G, Ma Q, Sheng S, Wang J, Hu X, Shao S. The role of IL-6 in coronavirus, especially in COVID-19. Front Pharmacol 2022; 13:1033674. [PMID: 36506506 PMCID: PMC9727200 DOI: 10.3389/fphar.2022.1033674] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/02/2022] [Indexed: 11/25/2022] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects both people and animals and may cause significant respiratory problems, including lung illness: Corona Virus Disease 2019 (COVID-19). Swabs taken from the throat and nose of people who have the illness or are suspected of having it have shown this pathogenic virus. When SARS-CoV-2 infects the upper and lower respiratory tracts, it may induce moderate to severe respiratory symptoms, as well as the release of pro-inflammatory cytokines including interleukin 6 (IL-6). COVID-19-induced reduction of IL-6 in an inflammatory state may have a hitherto undiscovered therapeutic impact. Many inflammatory disorders, including viral infections, has been found to be regulated by IL-6. In individuals with COVID-19, one of the primary inflammatory agents that causes inflammatory storm is IL-6. It promotes the inflammatory response of virus infection, including the virus infection caused by SARS-CoV-2, and provides a new diagnostic and therapeutic strategy. In this review article, we highlighted the functions of IL-6 in the coronavirus, especially in COVID-19, showing that IL-6 activation plays an important function in the progression of coronavirus and is a rational therapeutic goal for inflammation aimed at coronavirus.
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Affiliation(s)
- Xinyi Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Guozheng Tang
- Department of Orthopaedics, Lu’an Hospital of Anhui Medical University, Lu’an, Anhui, China
| | - Yuchen Liu
- Department of Otolaryngology, Head and Neck Surgery, The First Affifiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lizhi Zhang
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Bangjie Chen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yanxun Han
- Department of Otolaryngology, Head and Neck Surgery, The First Affifiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Ziyue Fu
- Second Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Liuning Wang
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Guangzhi Hu
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Qing Ma
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Shuyan Sheng
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Jianpeng Wang
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Xinyang Hu
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Song Shao
- Department of Orthopaedics, Lu’an Hospital of Anhui Medical University, Lu’an, Anhui, China,*Correspondence: Song Shao,
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6
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Zhou X, Jin S, Pan J, Lin Q, Yang S, Ambe PC, Basharat Z, Zimmer V, Wang W, Hong W. Damage associated molecular patterns and neutrophil extracellular traps in acute pancreatitis. Front Cell Infect Microbiol 2022; 12:927193. [PMID: 36034701 PMCID: PMC9411527 DOI: 10.3389/fcimb.2022.927193] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 07/21/2022] [Indexed: 11/15/2022] Open
Abstract
Previous researches have emphasized a trypsin-centered theory of acute pancreatitis (AP) for more than a century. With additional studies into the pathogenesis of AP, new mechanisms have been explored. Among them, the role of immune response bears great importance. Pro-inflammatory substances, especially damage-associated molecular patterns (DAMPs), play an essential role in activating, signaling, and steering inflammation. Meanwhile, activated neutrophils attach great importance to the immune defense by forming neutrophil extracellular traps (NETs), which cause ductal obstruction, premature trypsinogen activation, and modulate inflammation. In this review, we discuss the latest advances in understanding the pathological role of DAMPs and NETs in AP and shed light on the flexible crosstalk between these vital inflammatory mediators. We, then highlight the potentially promising treatment for AP targeting DAMPs and NETs, with a focus on novel insights into the mechanism, diagnosis, and management of AP.
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Affiliation(s)
- Xiaoying Zhou
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shengchun Jin
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Jingyi Pan
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qingyi Lin
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shaopeng Yang
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Peter C. Ambe
- Department of General Surgery, Visceral Surgery and Coloproctology, Vinzenz-Pallotti-Hospital Bensberg, Bensberg, Germany
| | - Zarrin Basharat
- Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Vincent Zimmer
- Department of Medicine, Marienhausklinik St. Josef Kohlhof, Neunkirchen, Germany
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Wei Wang
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Wandong Hong, ; Wei Wang,
| | - Wandong Hong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Wandong Hong, ; Wei Wang,
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7
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Chen R, Kang R, Tang D. The mechanism of HMGB1 secretion and release. Exp Mol Med 2022; 54:91-102. [PMID: 35217834 PMCID: PMC8894452 DOI: 10.1038/s12276-022-00736-w] [Citation(s) in RCA: 411] [Impact Index Per Article: 137.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/13/2021] [Accepted: 11/04/2021] [Indexed: 02/08/2023] Open
Abstract
High mobility group box 1 (HMGB1) is a nonhistone nuclear protein that has multiple functions according to its subcellular location. In the nucleus, HMGB1 is a DNA chaperone that maintains the structure and function of chromosomes. In the cytoplasm, HMGB1 can promote autophagy by binding to BECN1 protein. After its active secretion or passive release, extracellular HMGB1 usually acts as a damage-associated molecular pattern (DAMP) molecule, regulating inflammation and immune responses through different receptors or direct uptake. The secretion and release of HMGB1 is fine-tuned by a variety of factors, including its posttranslational modification (e.g., acetylation, ADP-ribosylation, phosphorylation, and methylation) and the molecular machinery of cell death (e.g., apoptosis, pyroptosis, necroptosis, alkaliptosis, and ferroptosis). In this minireview, we introduce the basic structure and function of HMGB1 and focus on the regulatory mechanism of HMGB1 secretion and release. Understanding these topics may help us develop new HMGB1-targeted drugs for various conditions, especially inflammatory diseases and tissue damage. A nuclear protein that gets released after cell death or is actively secreted by immune cells offers a promising therapeutic target for treating diseases linked to excessive inflammation. Daolin Tang from the University of Texas Southwestern Medical Center in Dallas, USA, and colleagues review how cellular stresses can trigger the accumulation of HMGB1, a type of alarm signal protein that promotes the recruitment and activation of inflammation-promoting immune cells. The researchers discuss various mechanisms that drive both passive and active release of HMGB1 into the space around cells. These processes, which include enzymatic modifications of the HMGB1 protein, cell–cell interactions and molecular pathways of cell death, could be targeted by drugs to lessen tissue damage and inflammatory disease caused by HMGB1-induced immune responses
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Affiliation(s)
- Ruochan Chen
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. .,Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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8
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Gao Y, Wang L, Niu Z, Feng H, Liu J, Sun J, Gao Y, Pan L. miR-340-5p inhibits pancreatic acinar cell inflammation and apoptosis via targeted inhibition of HMGB1. Exp Ther Med 2022; 23:140. [PMID: 35069821 PMCID: PMC8756431 DOI: 10.3892/etm.2021.11063] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/04/2021] [Indexed: 02/05/2023] Open
Abstract
Acute pancreatitis (AP) is a common gastrointestinal disease that affects 1 million individuals worldwide. Inflammation and apoptosis are considered to be important pathogenic mechanisms of AP, and high mobility group box 1 (HMGB1) has been shown to play a particularly important role in the etiology of this disease. MicroRNAs (miRs) are emerging as critical regulators of gene expression and, as such, they represent a promising area of therapeutic target identification and development for a variety of diseases, including AP. Using the online database query (microRNA.org), the current study identified a site in the 3' untranslated region of HMGB1 mRNA that was a viable target for miR-340-5p. The present study aimed to investigate the association between miR-340-5p and HMGB1 expression in pancreatic acinar cells following lipopolysaccharide (LPS) treatment by performing luciferase, western blotting and reverse transcription-quantitative PCR assays. The results suggest that miR-340-5p attenuates the induction of HMGB1 by LPS, thereby inhibiting inflammation and apoptosis via blunted activation of Toll-like receptor 4 and enhanced AKT signaling. Thus, the therapeutic application of miR-340-5p may be a useful strategy in AP via upregulation of HMGB1 and subsequent promotion of inflammation and apoptosis.
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Affiliation(s)
- Yazhou Gao
- Department of Emergency Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Liming Wang
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Zequn Niu
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Hui Feng
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Jie Liu
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Jiangli Sun
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Yanxia Gao
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Longfei Pan
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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9
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Abdelmageed ME, Nader MA, Zaghloul MS. Targeting HMGB1/TLR4/NF-κB signaling pathway by protocatechuic acid protects against l-arginine induced acute pancreatitis and multiple organs injury in rats. Eur J Pharmacol 2021; 906:174279. [PMID: 34197778 DOI: 10.1016/j.ejphar.2021.174279] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 12/16/2022]
Abstract
Acute pancreatitis (AP) is a common pancreatic inflammation associated with substantial morbidity and mortality. AP may be mild or severe which can spread systemically causing multiple organs failure (MOF) and even death. In the current study, protocatechuic acid (PCA), a natural phenolic acid, was investigated for its possible protective potential against L-arginine induced AP and multiple organs injury (MOI) in rats. AP was induced by L-arginine (500 mg/100 g, ip). Two dose levels of PCA were tested (50 and 100 mg/kg, oral, 10 days before L-arginine injection). PCA successfully protected against L-arginine induced AP and MOI that was manifested by normalizing pancreatic, hepatic, pulmonary, and renal tissue architecture and restoring the normal values of pancreatic enzymes (amylase and lipase), serum total protein, liver enzymes (alanine transaminase (ALT) and aspartate transaminase (AST)) and kidney function biomarkers (blood urea nitrogen (BUN) and serum creatinine (Cr)) that were significantly elevated upon L-arginine administration. Additionally, PCA restored balanced oxidant/antioxidants status that was disrupted by L-arginine and normalized pancreatic levels of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) content. Moreover, PCA significantly decreased L-arginine induced elevation in pancreatic high motility group box protein 1 (HMGB1), toll like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), tumor necrosis factor- α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) expression. PCA significantly ameliorated L-arginine-induced AP and MOI through its anti-inflammatory and antioxidant effects. HMGB1/TLR4/NF-κB was the major pathway involved in the observed protective potential.
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Affiliation(s)
- Marwa E Abdelmageed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Manar A Nader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Marwa S Zaghloul
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
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10
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High-mobility group box protein-1 induces acute pancreatitis through activation of neutrophil extracellular trap and subsequent production of IL-1β. Life Sci 2021; 286:119231. [PMID: 33600865 DOI: 10.1016/j.lfs.2021.119231] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 02/01/2021] [Accepted: 02/10/2021] [Indexed: 12/22/2022]
Abstract
PURPOSE The aim of this study is to evaluate acute pancreatitis (AP)-associated NET activation mediated by a novel inflammatory mediator (high-mobility group box protein-1 [HMGB1]) and proinflammatory cytokine responses. METHODS In this study, primary neutrophils, monocytes, and monocytic cell line Thp-1-derived macrophages were isolated and treated with HMGB1, lipopolysaccharide (LPS), adenosine triphosphate (ATP), and ATP + ATP inhibitor. The effects of HMGB1, ATP, and deoxyribonuclease (DNAse) were then examined for their in vivo effects using a newly established AP mouse model. RESULTS The mRNA and protein levels of inflammasome and interleukin IL-1β in cells, blood, and pancreatic tissues were examined. Within-cell nuclear DNA signal, cell-free DNA concentration, and pancreatic tissue damage were investigated. Our study showed that HMGB1 triggers NET formation in neutrophils and promotes the activation of inflammasome complexes (the NLR family, pyrin domain containing 3, and NLRP3; ASC; and caspase-1); therefore, the production of IL-1β is induced in human monocytes/macrophages. HMGB1 and NET cooperatively stimulate IL-1β processing in macrophages. Furthermore, the AP mouse model confirmed these HMGB1-mediated molecular mechanisms in vivo and indicated that HMGB1 is required for NET activation. CONCLUSIONS We found that NET inhibition reverses HMGB1-stimulated inflammasome activation and IL-1β production. HMGB1 thus leads to pancreatic injury through the activation of NET and subsequently induces IL-1β processing from neutrophils to pancreatic tissues. These findings demonstrate that HMGB1 and NET are new therapeutic targets for inflammation suppression in severe AP.
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11
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Ferrero-Andrés A, Panisello-Roselló A, Roselló-Catafau J, Folch-Puy E. NLRP3 Inflammasome-Mediated Inflammation in Acute Pancreatitis. Int J Mol Sci 2020; 21:5386. [PMID: 32751171 PMCID: PMC7432368 DOI: 10.3390/ijms21155386] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/17/2020] [Accepted: 07/28/2020] [Indexed: 12/11/2022] Open
Abstract
The discovery of inflammasomes has enriched our knowledge in the pathogenesis of multiple inflammatory diseases. The NLR pyrin domain-containing protein 3 (NLRP3) has emerged as the most versatile and well-characterized inflammasome, consisting of an intracellular multi-protein complex that acts as a central driver of inflammation. Its activation depends on a tightly regulated two-step process, which includes a wide variety of unrelated stimuli. It is therefore not surprising that the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Inflammasome-mediated inflammation has become increasingly important in acute pancreatitis, an inflammatory disorder of the pancreas that is one of the fatal diseases of the gastrointestinal tract. This review presents an update on the progress of research into the contribution of the NLRP3 inflammasome to acute pancreatic injury, examining the mechanisms of NLRP3 activation by multiple signaling events, the downstream interleukin 1 family of cytokines involved and the current state of the literature on NLRP3 inflammasome-specific inhibitors.
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Affiliation(s)
- Ana Ferrero-Andrés
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
| | - Emma Folch-Puy
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
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Gu H, Liu A, Ma W, Ni J, Ma C, Zhou X, Liu Z, Xia D, Tian X, Shi L, Zhu L. Berberine hydrochloride mitigates acute pancreatitis by suppressing the TLR4/IκBα/NFκB pathway. ALL LIFE 2020. [DOI: 10.1080/26895293.2020.1765885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Affiliation(s)
- Huali Gu
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Aiguo Liu
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Weiping Ma
- Department of Editorial, Medical College of Qingdao University, Qingdao, People’s Republic of China
| | - Jianmin Ni
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Chengtai Ma
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Xiumei Zhou
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Zhenfang Liu
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Di Xia
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Xintao Tian
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Lei Shi
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Liang Zhu
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
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14
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Zhao S, Yang J, Liu T, Zeng J, Mi L, Xiang K. Dexamethasone inhibits NF‑кBp65 and HMGB1 expression in the pancreas of rats with severe acute pancreatitis. Mol Med Rep 2018; 18:5345-5352. [PMID: 30365121 PMCID: PMC6236277 DOI: 10.3892/mmr.2018.9595] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 08/23/2018] [Indexed: 12/11/2022] Open
Abstract
Severe acute pancreatitis (SAP) starts as a local inflammation of pancreatic tissue that induces the development of multiple extra-pancreatic organ dysfunction; however, the underlying mechanisms remain unclear. The present study was designed to evaluate the effect of dexamethasone (DXM) on pancreatic damage and to investigate the role of high-mobility group box-1 (HMGB1) and nuclear factor-κB (NF-κBp65) in the development of SAP in animal and cell models. For the in vivo experiment, 35 Sprague-Dawley rats were randomly assigned to three groups: The sham-operation control group, the SAP group and the DXM treatment group. Histological analysis revealed that, when DXM was infused into SAP rats, edema formation and structural alterations with necrosis were reduced, and the number of apoptotic cells was markedly reduced. In addition, compared with the SAP group, the expression level of HMGB1 was significantly decreased in the nucleus and the expression level of NF-κBp65 was significantly decreased in the cytoplasm from rats treated with DXM. In vitro, DXM was able to suppress the apoptosis and cell death induced by caerulein (CAE), and DXM could suppress the expression of NF-κBp65 and HMGB1 induced by CAE, as demonstrated by western blotting and immunofluorescence analysis. Therefore, these results provide an experimental basis for investigating the underlying therapeutic mechanisms of DXM treatment for SAP.
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Affiliation(s)
- Shangping Zhao
- ICU, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Jinming Yang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Ting Liu
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Juanxian Zeng
- Department of General Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Liangliang Mi
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Kaimin Xiang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
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15
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Pan LF, Yu L, Wang LM, He JT, Sun JL, Wang XB, Wang H, Bai ZH, Feng H, Pei HH. Augmenter of liver regeneration (ALR) regulates acute pancreatitis via inhibiting HMGB1/TLR4/NF-κB signaling pathway. Am J Transl Res 2018; 10:402-410. [PMID: 29511434 PMCID: PMC5835805 DOI: pmid/29511434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 01/17/2018] [Indexed: 02/08/2023]
Abstract
This research aimed to explore the effect of augmenter of liver regeneration (ALR) in acute pancreatitis (AP) of mice and the underlying mechanism. Caerulein were given to mice to get AP models. AP mice were given saline, ALR plasmids or negative control plasmids. Then, pancreas tissues were fixed and stained for histological examination. The levels of serum amylase, serum lipase, MPO, HMGB1, TNF-α, IL-1β as well as MCP-1 were detected by ELISA assay. The mRNA levels of TLR4, p65, IκBα, iNOS, COX-2 and GAPDH were examined by RT-qPCR. The protein levels of HMGB1, TLR4, MD2, MyD88, IκBα and GAPDH were detected by western blotting. ALR decreased serum amylase as well as lipase levels and alleviated the histopathological alterations of the pancreas in AP mice. ALR decreased the MPO activity of pancreas in AP Mice. ALR decreased the HMGB1/TLR4 signaling pathway in AP Mice. ALR decreased pancreas IL-1β and MCP-1 in AP mice, and also decreased plasma TNF-α and IL-1β in AP mice. ALR attenuated the cerulein-caused increase in p65 mRNA and protein levels, but had no effects on mRNA and protein levels of IκBα. The AP mice significantly promoted the mRNA levels of iNOS and COX-2 that was inhibited by ALR. HNE formation was also increased in AP mice, but it was decreased by ALR. ALR alleviates acute pancreatitis by inhibiting HMGB1/TLR4/NF-κB signaling pathway. It is promising to alleviate the syndromes of patients with acute via targeting ALR.
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Affiliation(s)
- Long-Fei Pan
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong UniversityXi’an 710004, Shaanxi, China
| | - Lei Yu
- Xi’an Medical CollegeXi’an 710021, Shaanxi, China
| | - Li-Ming Wang
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong UniversityXi’an 710004, Shaanxi, China
| | - Jun-Tao He
- Department of Clinical Laboratory, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong UniversityXi’an 710004, Shaanxi, China
| | - Jiang-Li Sun
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong UniversityXi’an 710004, Shaanxi, China
| | - Xiao-Bo Wang
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong UniversityXi’an 710004, Shaanxi, China
| | - Hai Wang
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong UniversityXi’an 710004, Shaanxi, China
| | - Zheng-Hai Bai
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong UniversityXi’an 710004, Shaanxi, China
| | - Hui Feng
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong UniversityXi’an 710004, Shaanxi, China
| | - Hong-Hong Pei
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong UniversityXi’an 710004, Shaanxi, China
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Cui H, Li S, Xu C, Zhang J, Sun Z, Chen H. Emodin alleviates severe acute pancreatitis-associated acute lung injury by decreasing pre-B-cell colony-enhancing factor expression and promoting polymorphonuclear neutrophil apoptosis. Mol Med Rep 2017; 16:5121-5128. [PMID: 28849044 PMCID: PMC5647045 DOI: 10.3892/mmr.2017.7259] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 04/20/2017] [Indexed: 12/16/2022] Open
Abstract
The present study aimed to evaluate the protective effects of emodin on severe acute pancreatitis (SAP)‑associated acute lung injury (ALI), and investigated the possible mechanism involved. SAP was induced in Sprague‑Dawley rats by retrograde infusion of 5% sodium taurocholate (1 ml/kg), after which, rats were divided into various groups and were administered emodin, FK866 [a competitive inhibitor of pre‑B‑cell colony‑enhancing factor (PBEF)] or dexamethasone (DEX). DEX was used as a positive control. Subsequently, PBEF expression was detected in polymorphonuclear neutrophils (PMNs) isolated from rat peripheral blood by reverse transcription‑quantitative polymerase chain reaction and western blotting. In addition, histological alterations, apoptosis in lung/pancreatic tissues, apoptosis of peripheral blood PMNs and alterations in the expression of apoptosis‑associated proteins were examined by hematoxylin and eosin staining, terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assay, Annexin V/propidium iodide (PI) assay and western blotting, respectively. Serum amylase activity and wet/dry (W/D) weight ratios were also measured. An in vitro study was also conducted, in which PMNs were obtained from normal Sprague‑Dawley rats and were incubated with emodin, FK866 or DEX in the presence of lipopolysaccharide (LPS). Apoptosis of PMNs and the expression levels of apoptosis‑associated proteins were examined in cultured PMNs in vitro by Annexin V/PI assay and western blotting, respectively. The results demonstrated that emodin, FK866 and DEX significantly downregulated PBEF expression in peripheral blood PMNs. In addition, emodin, FK866 and DEX reduced serum amylase activity, decreased lung and pancreas W/D weight ratios, alleviated lung and pancreatic injuries, and promoted PMN apoptosis by regulating the expression of apoptosis‑associated proteins: Fas, Fas ligand, B‑cell lymphoma (Bcl)‑2‑associated X protein, cleaved caspase‑3 and Bcl‑extra‑large. In addition, the in vitro study demonstrated that emodin, FK866 and DEX significantly reversed the LPS‑induced decrease of apoptosis in PMNs by regulating the expression of apoptosis‑associated proteins. In conclusion, the present study demonstrated that emodin may protect against SAP‑associated ALI by decreasing PBEF expression, and promoting PMN apoptosis via the mitochondrial and death receptor apoptotic pathways.
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Affiliation(s)
- Hongzhang Cui
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Shu Li
- Department of Chinese Medicine, Dalian Municipal Central Hospital, Dalian, Liaoning 116033, P.R. China
| | - Caiming Xu
- Department of Chinese Medicine, Dalian Obstetrics and Gynecology Hospital, Dalian, Liaoning 116083, P.R. China
| | - Jingwen Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Zhongwei Sun
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Hailong Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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Yu C, Yu X, Zhu HW, Li X, Huang LH, Li ZQ, Han D, Huang H. Expression pattern of HMGB1 and its association with autophagy in acute necrotizing pancreatitis. Mol Med Rep 2016; 14:5507-5513. [PMID: 27878276 PMCID: PMC5355707 DOI: 10.3892/mmr.2016.5945] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 07/27/2016] [Indexed: 12/12/2022] Open
Abstract
High-motility group box protein 1 (HMGB1) has an important role in autophagy; however, its exact role in acute necrotizing pancreatitis (ANP) remains unknown. The present study aimed to investigate the expression pattern of HMGB1 in ANP, and to determine its association with autophagy. Sprague Dawley rats (weight, 350±30 g, n=48) were randomly divided into control (n=12) and experimental (n=36) groups. Experimental rats were retrogradely injected with 5% sodium taurocholate into the biliopancreatic duct to induce ANP. Control rats received an equal amount of saline. Serum amylase levels were used to determine whether the model had been successfully generated. Autophagosomes in pancreatic acinar cells were observed under electron microscopy. The expression levels of HMGB1 and Beclin 1 were detected in pancreatic tissues by western blotting, quantitative polymerase chain reaction and immunohistochemistry. HMGB1 levels were also determined in the serum and in isolated nuclei. The results demonstrated that autophagy was detected at 3 h post-ANP induction; however, HMGB1 expression remained unaltered during the early stage (0–6 h; P>0.05). HMGB1 expression was significantly increased at 12 h, and was still increasing at 24 h (P<0.05). Notably, HMGB1 was increased in the nuclei compared with in the cytoplasm at 3–6 h. Furthermore, serum HMGB1 levels began to increase at 3 h, and reached the highest levels at 24 h in the ANP group. In conclusion, in an ANP model, HMGB1 was initially increased in the nuclei to initiate autophagy. Subsequently, it moved into the cytoplasm, where it interacted with Beclin 1 to enhance autophagy, and HMGB1 was released into the blood, leading to the deterioration of ANP.
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Affiliation(s)
- Can Yu
- Department of Hepatobiliary and Pancreatic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Xiao Yu
- Department of Hepatobiliary and Pancreatic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Hong-Wei Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Xia Li
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Li-Hua Huang
- Center for Medical Experiments, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Zhi-Qiang Li
- Department of Hepatobiliary and Pancreatic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Duo Han
- Department of Hepatobiliary and Pancreatic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Hui Huang
- Department of Hepatobiliary and Pancreatic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
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18
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Li G, Wu X, Yang L, He Y, Liu Y, Jin X, Yuan H. TLR4-mediated NF-κB signaling pathway mediates HMGB1-induced pancreatic injury in mice with severe acute pancreatitis. Int J Mol Med 2015; 37:99-107. [PMID: 26719855 PMCID: PMC4687439 DOI: 10.3892/ijmm.2015.2410] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 11/11/2015] [Indexed: 12/21/2022] Open
Abstract
Severe acute pancreatitis (SAP) is an extremely dangerous acute abdominal disorder which causes multiple complications and has a high mortality rate. Previous research has suggested that high-mobility group box 1 (HMGB1) plays an important role in the pathogenesis of SAP; however, the mechanisms underlying this strong correlation remain unclear. In this study, to further investigate whether HMGB1 acts as a stimulating factor, and whether Toll-like receptor 4 (TLR4) acts as its major mediator in the development of pancreatic injury during SAP, recombinant human HMGB1 (rhHMGB1) and TLR4-deficient mice were used. We found that HMGB1 and TLR4 were highly expressed, and nuclear factor-κB (NF-κB) was activated in our mouse model of SAP. We noted that the rhHMGB1 pancreas-targeted injection activated the TLR4-mediated NF-κB signaling pathway and induced pancreatic injury in wild-type mice. In TLR4-deficient mice, the rhHMGB1-induced activation of NF-κB and pathological changes in the pancreas were less evident than in wild-type mice. Therefore, this study provides evidence that HMGB1 promotes the pathogenesis of pancreatitis, and its downstream TLR4-mediated NF-κB signaling pathway is a potential important mediator in the development of this form of pancreatic injury.
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Affiliation(s)
- Gang Li
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xuejun Wu
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Le Yang
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Yuxiang He
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Yang Liu
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xing Jin
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Hai Yuan
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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Li G, Wu X, Yang L, He Y, Liu Y, Jin X, Yuan H. TLR4-mediated NF-κB signaling pathway mediates HMGB1-induced pancreatic injury in mice with severe acute pancreatitis. Int J Mol Med 2015; 38:1313. [PMID: 27573568 PMCID: PMC5029970 DOI: 10.3892/ijmm.2016.2707] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 11/11/2015] [Indexed: 12/17/2022] Open
Affiliation(s)
- Gang Li
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xuejun Wu
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Le Yang
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Yuxiang He
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Yang Liu
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xing Jin
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Hai Yuan
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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Sodium Butyrate Reduces Organ Injuries in Mice with Severe Acute Pancreatitis Through Inhibiting HMGB1 Expression. Dig Dis Sci 2015; 60:1991-9. [PMID: 25686746 DOI: 10.1007/s10620-015-3586-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 02/09/2015] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The present study was designed to evaluate the effect of sodium butyrate on pancreas damage and to investigate the role of high-mobility group box-1 (HMGB1) and nuclear factor-κB (NF-κB) in the development of severe acute pancreatitis (SAP) in a mouse model. METHODS The SAP model was established by intraperitoneal injection of two doses of 20 % L-2 arginine (200 mg/g). Female Sprague-Dawley mice were randomly allocated into three groups (n = 48/group): the control, untreated SAP, and sodium butyrate-treated SAP groups. The animals were euthanized at 0, 12, 24, and 48 h after the establishment of the SAP. Histopathology of the pancreas was performed, and the NF-κB levels were determined by immunohistochemistry. The serum levels of tumor necrosis factor (TNFα), interleukin-6 (IL-6), and HMGB1 were measured by ELISA. The HMGB1 mRNA levels were determined by qRT-PCR. RESULTS The sodium butyrate-treated SAP animals showed significantly improved pancreas histopathology and lower serum amylase levels than the untreated SAP animals. In the SAP group, the mRNA levels of HMGB1 were remarkably increased at the 12 h, peaked at 24 h, and remained at a high level up to 48 h after L-2 arginine injection. The levels of TNFα and IL-6 were decreased at 48 h. Treatment with sodium butyrate reduced the pathological lesions, the serum levels of HMGB1, TNFα, and IL-6, the HMGB1 mRNA levels, and NF-κB activity. CONCLUSION Sodium butyrate inhibits the NF-κB activation and reduces pancreas injury in SAP through the modulation of HMGB1 and other inflammatory cytokine responses.
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Hu H, Zhai C, Qian G, Gu A, Liu J, Ying F, Xu W, Jin D, Wang H, Hu H, Zhang Y, Tang G. Protective effects of tanshinone IIA on myocardial ischemia reperfusion injury by reducing oxidative stress, HMGB1 expression, and inflammatory reaction. PHARMACEUTICAL BIOLOGY 2015; 53:1752-1758. [PMID: 25864557 DOI: 10.3109/13880209.2015.1005753] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
CONTEXT Although there were reports on the protective functions of tanshinone IIA (TSA) on rat myocardial ischemia, the exerting mechanism has not been completely clarified. OBJECTIVE An attempt was made to further verify the protective effect of TSA on myocardial ischemia reperfusion injury and elucidate its underlying mechanism. MATERIALS AND METHODS The rats were given TSA (10, 20, and 40 mg/kg bw per day) in intraperitoneal injection for 15 d. Rami anterior descending branch of coronary artery was ligated for 30 min and then re-perfused for 120 min to establish a reperfusion model. Effects of TSA on the infarct area, creatine kinase (CK), aspartate aminotransferase (AST), high mobility group box B1 protein (HMGB1), and inflammation and oxidation were investigated. RESULTS Compared with those in the IR group, infarct size percentages of rats' myocardium in L-TSA, M-TSA, and H-TSA groups were reduced by 1.21, 4.26, and 12.50%, respectively, CK activities by 7.4, 11.2, and 12.5%, respectively, and AST activities also declined (p < 0.05). Furthermore, compared with those in the IR group, SOD and GSH-Px activities increased, and MDA, TNF-α, IL-6, and iNOS levels decreased in L-TSA, M-TSA, and H-TSA groups (p < 0.05). Meanwhile, compared with those in the IR group, HMGB1 expressions in L-TSA, M-TSA, and H-TSA groups were lowered by 21.9, 32.4, and 35.6%, respectively. DISCUSSION AND CONCLUSION The protective function of TSA on myocardial ischemia reperfusion injury may be possibly exerted by inhibiting the increase of ROS caused by the reperfusion to attenuate the expression of HMGB1 and inhibit inflammation.
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Affiliation(s)
- Huilin Hu
- Department of Cardiology, First Affiliated Hospital of Jiaxing University , Jiaxing, Zhejiang , PR China
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Shen X, Li WQ. High-mobility group box 1 protein and its role in severe acute pancreatitis. World J Gastroenterol 2015; 21:1424-1435. [PMID: 25663762 PMCID: PMC4316085 DOI: 10.3748/wjg.v21.i5.1424] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Revised: 10/07/2014] [Accepted: 11/11/2014] [Indexed: 02/06/2023] Open
Abstract
The high mobility group box 1 (HMGB1), which belongs to the subfamily of HMG-1/-2, is a highly conserved single peptide chain consisting of 215 amino acid residues with a molecular weight of approximately 24894 Da. HMGB1 is a ubiquitous nuclear protein in mammals and plays a vital role in inflammatory diseases. Acute pancreatitis is one of the most common causes of acute abdominal pain with a poor prognosis. Acute pancreatitis is an acute inflammatory process of the pancreas (duration of less than six months), for which the severe form is called severe acute pancreatitis (SAP). More and more studies have shown that HMGB1 has a bidirectional effect in the pathogenesis of SAP. Extracellular HMGB1 can aggravate the pancreatic inflammatory process, whereas intracellular HMGB1 has a protective effect against pancreatitis. The mechanism of HMGB1 is multiple, mainly through the nuclear factor-κB pathway. Receptors for advanced glycation end-products and toll-like receptors (TLR), especially TLR-2 and TLR-4, are two major types of receptors mediating the inflammatory process triggered by HMGB1 and may be also the main mediators in the pathogenesis of SAP. HMGB1 inhibitors, such as ethyl pyruvate, pyrrolidine dithiocarbamate and Scolopendra subspinipes mutilans, can decrease the level of extracellular HMGB1 and are the promising targets in the treatment of SAP.
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Correlation between serum levels of high mobility group box-1 protein and pancreatitis: a meta-analysis. BIOMED RESEARCH INTERNATIONAL 2015; 2015:430185. [PMID: 25695079 PMCID: PMC4324490 DOI: 10.1155/2015/430185] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 10/30/2014] [Indexed: 12/12/2022]
Abstract
Background. Aberrant expression of high mobility group box-1 protein (HMGB1) contributes to the progression of various inflammatory diseases. This meta-analysis focused on the clinical significance of serum HMGB1 levels in pancreatitis patients, with the goal of building a novel diagnostic score model. Method. We conducted a meta-analysis by searching in the PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine (CBM), and China National Knowledge Infrastructure (CNKI) databases without any language restrictions. Studies were pooled and standard mean difference (SMD) and its corresponding 95% confidence intervals (95% CIs) were calculated. Version 12.0 STATA software was used for statistical analysis. Results. We performed a final analysis of 841 subjects from 12 clinical case-control studies. The meta-analysis results showed a positive association between serum HMGB1 levels and the progression of pancreatitis. In the subgroup analysis by country, high serum level of HMGB1 may be related to pancreatitis progression in China, Korea, Hungary, and Japan populations (all P < 0.05). Conclusion. The present meta-analysis indicated that serum HMGB1 level was statistically elevated in patients with pancreatitis, and thus serum levels of HMGB1 could be determined to be a useful biomarker for pancreatitis patients.
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Xiang K, Cheng L, Luo Z, Ren J, Tian F, Tang L, Chen T, Dai R. Glycyrrhizin suppresses the expressions of HMGB1 and relieves the severity of traumatic pancreatitis in rats. PLoS One 2014; 9:e115982. [PMID: 25541713 PMCID: PMC4277455 DOI: 10.1371/journal.pone.0115982] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 12/02/2014] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND High mobility group box 1 (HMGB1) plays important roles in a large variety of diseases; glycyrrhizin (GL) is recognized as an HMGB1 inhibitor. However, few studies have focused on whether glycyrrhizin can potentially improve the outcome of traumatic pancreatitis (TP) by inhibiting HMGB1. METHODS A total of 60 male Wistar rats were randomly divided into three groups (n = 20 in each): Control group, TP group and TP-GL group. Pancreatic trauma was established with a custom-made biological impact machine-III, and GL was administered at 15 minutes after the accomplishment of operation. To determine survival rates during the first 7 days after injury, another 60 rats (n = 20 in each) were grouped and treated as mentioned above. At 24 hours of induction of TP, the histopathological changes in pancreas were evaluated and serum amylase levels were tested. Serum tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and HMGB1 were measured using enzyme linked immunosorbent assay. HMGB1 expressions in pancreas were measured using immunohistochemical staining, Western blot and Real-Time PCR analysis. RESULTS Serum levels of HMGB1, TNF-α and IL-6 were increased dramatically in TP group at 24 hours after induction of TP. However, these indicators were reduced significantly by GL administration in TP-GL group comparing with TP group (P < 0.05). Meanwhile, survival analysis showed that the seven-day survival rate in TP-GL group was significantly higher than that in TP group (85% versus 65%, P < 0.05). GL treatment significantly decreased the pancreatic protein and mRNA expressions of HMGB1 and ameliorated the pancreatic injury in rats with TP. CONCLUSIONS Glycyrrhizin might play an important role in improving survival rates and ameliorating pancreatic injury of TP by suppression of the expressions of HMGB1 and other proinflammatory cytokine.
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Affiliation(s)
- Ke Xiang
- The Third Military Medical University, Chongqing, P. R. China
- Department of General Surgery, Chengdu Military General Hospital, Chengdu, P. R. China
| | - Long Cheng
- Department of General Surgery, Chengdu Military General Hospital, Chengdu, P. R. China
| | - Zhulin Luo
- Department of General Surgery, Chengdu Military General Hospital, Chengdu, P. R. China
| | - Jiandong Ren
- Department of Pharmacy, Chengdu Military General Hospital, Chengdu, P. R. China
| | - Fuzhou Tian
- Department of General Surgery, Chengdu Military General Hospital, Chengdu, P. R. China
| | - Lijun Tang
- Department of General Surgery, Chengdu Military General Hospital, Chengdu, P. R. China
| | - Tao Chen
- Department of General Surgery, Chengdu Military General Hospital, Chengdu, P. R. China
| | - Ruiwu Dai
- Department of General Surgery, Chengdu Military General Hospital, Chengdu, P. R. China
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Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ, Lotze MT, Tang D. HMGB1 in health and disease. Mol Aspects Med 2014; 40:1-116. [PMID: 25010388 PMCID: PMC4254084 DOI: 10.1016/j.mam.2014.05.001] [Citation(s) in RCA: 731] [Impact Index Per Article: 66.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 05/05/2014] [Indexed: 12/22/2022]
Abstract
Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
| | - Ruochan Chen
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Qiuhong Zhang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Wen Hou
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Sha Wu
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jin Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yan Yu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xue-Gong Fan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhengwen Yan
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA; Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Xiaofang Sun
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Experimental Department of Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Haichao Wang
- Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Qingde Wang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Michael T Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
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Park JM, Lee S, Chung MK, Kwon SH, Kim EH, Ko KH, Kwon CI, Hahm KB. Antioxidative phytoceuticals to ameliorate pancreatitis in animal models: An answer from nature. World J Gastroenterol 2014; 20:16570-16581. [PMID: 25469025 PMCID: PMC4248200 DOI: 10.3748/wjg.v20.i44.16570] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 03/10/2014] [Accepted: 05/14/2014] [Indexed: 02/06/2023] Open
Abstract
Despite enthusiastic efforts directed at elucidating critical underlying mechanisms towards the identification of novel therapeutic targets for severe acute pancreatitis (SAP), the disease remains without a specific therapy to be executed within the first hours to days after onset of symptoms. Although earlier management for SAP should aim to either treat organ failure or reduce infectious complications, the current standard of care for the general management of AP in the first hours to days after onset of symptoms include intravenous fluid replacement, nutritional changes, and the use of analgesics with a close monitoring of vital signs. Furthermore, repeated evaluation of severity is very important, as the condition is particularly unstable in the early stages. In cases where biliary pancreatitis is accompanied by acute cholangitis or in cases where biliary stasis is suspected, an early endoscopic retrograde cholangiopancreatography is recommended. However, practice guidelines regarding the treatment of pancreatitis are suboptimal. In chronic pancreatitis, conservative management strategies include lifestyle modifications and dietary changes followed by analgesics and pancreatic enzyme supplementation. Recently, attention has been focused on phytoceuticals or antioxidants as agents that could surpass the limitations associated with currently available therapies. Because oxidative stress has been shown to play an important role in the pathogenesis of pancreatitis, antioxidants alone or combined with conventional therapy may improve oxidative-stress-induced organ damage. Interest in phytoceuticals stems from their potential use as simple, accurate tools for pancreatitis prognostication that could replace older and more tedious methods. Therefore, the use of antioxidative nutrition or phytoceuticals may represent a new direction for clinical research in pancreatitis. In this review article, recent advances in the understanding of the pathogenesis of pancreatitis are discussed and the paradigm shift underway to develop phytoceuticals and antioxidants to treat it is introduced. Despite the promise of studies evaluating the effects of antioxidants/phytoceuticals in pancreatitis, translation to the clinic has thus far been disappointing. However, it is expected that continued research will provide solid evidence to justify the use of antioxidative phytoceuticals in the treatment of pancreatitis.
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Kang R, Lotze MT, Zeh HJ, Billiar TR, Tang D. Cell death and DAMPs in acute pancreatitis. Mol Med 2014; 20:466-77. [PMID: 25105302 PMCID: PMC4277549 DOI: 10.2119/molmed.2014.00117] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 08/04/2014] [Indexed: 12/18/2022] Open
Abstract
Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP. Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP. DAMPs might be an attractive therapeutic target in AP.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Michael T Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
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Wang YF, Wu M, Ma BJ, Cai DA, Yin BB. Role of high mobility group box-1 and protection of growth hormone and somatostatin in severe acute pancreatitis. ACTA ACUST UNITED AC 2014; 47:1075-84. [PMID: 25387675 PMCID: PMC4244674 DOI: 10.1590/1414-431x20143165] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Accepted: 05/27/2014] [Indexed: 01/24/2023]
Abstract
In this study, we investigated the potential role of high-mobility group box 1
(HMGB1) in severe acute pancreatitis (SAP) and the effects of growth hormone (G) and
somatostatin (S) in SAP rats. The rats were randomly divided into 6 groups of 20
each: sham-operated, SAP, SAP+saline, SAP+G, SAP+S and SAP+G+S. Ileum and pancreas
tissues of rats in each group were evaluated histologically. HMGB1 mRNA expression
was measured by reverse transcription-PCR. Levels of circulating TNF-α, IL-1, IL-6,
and endotoxin were also measured. In the SAP group, interstitial congestion and
edema, inflammatory cell infiltration, and interstitial hemorrhage occurred in ileum
and pancreas tissues. The levels of HMGB1, TNF-α, IL-1, IL-6 and endotoxin were
significantly up-regulated in the SAP group compared with those in the sham-operated
group, and the 7-day survival rate was 0%. In the SAP+G and SAP+S groups, the
inflammatory response of the morphological structures was alleviated, the levels of
HMGB1, TNF-α, IL-1, IL-6, and endotoxin were significantly decreased compared with
those in the SAP group, and the survival rate was increased. Moreover, in the SAP+G+S
group, all histological scores were significantly improved and the survival rate was
significantly higher compared with the SAP group. In conclusion, HMGB1 might
participate in pancreas and ileum injury in SAP. Growth hormone and somatostatin
might play a therapeutic role in the inflammatory response of SAP.
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Affiliation(s)
- Y F Wang
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - M Wu
- Department of Surgery, Jinshan Pavilion Forest Hospital, Shanghai, China
| | - B J Ma
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - D A Cai
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - B B Yin
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China
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Hu X, Zhang K, Xu C, Chen Z, Jiang H. Anti-inflammatory effect of sodium butyrate preconditioning during myocardial ischemia/reperfusion. Exp Ther Med 2014; 8:229-232. [PMID: 24944626 PMCID: PMC4061237 DOI: 10.3892/etm.2014.1726] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Accepted: 05/07/2014] [Indexed: 12/23/2022] Open
Abstract
High mobility group box 1 protein (HMGB1) has an important role in myocardial ischemia/reperfusion (I/R) injury. Sodium butyrate, an inhibitor of histone deacetylase, has been shown to inhibit HMGB1 expression. In the present study, the effect of sodium butyrate on myocardial I/R injury in rats was investigated. Anesthetized male rats were intraperitoneally administered sodium butyrate (100 or 300 mg/kg) 30 min prior to the induction of ischemia. The rats were then subjected to ischemia for 30 min followed by reperfusion for 4 h. Infarct size, lactate dehydrogenase (LDH), creatine kinase (CK) and superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels were then measured. The expression of HMGB1 was assessed using western blot analysis. The results demonstrated that pretreatment with sodium butyrate (300 mg/kg) significantly reduced the infarct size, as well as the levels of LDH and CK (P<0.05). In addition, sodium butyrate (300 mg/kg) was shown to significantly inhibit the I/R-induced increase in the level of MDA and reduction in the level of SOD (P<0.05). Furthermore, treatment with sodium butyrate (300 mg/kg) was found to significantly inhibit the expression of TNF-α, IL-6 and HMGB1 induced by I/R injury (P<0.05). In conclusion, the results from the present study suggest that preconditioning with sodium butyrate may attenuate myocardial I/R injury by inhibition of the expression of inflammatory mediators during myocardial I/R.
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Affiliation(s)
- Xiaorong Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Kai Zhang
- Department of Cardiology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, Hubei 435000, P.R. China
| | - Changwu Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zhiqaing Chen
- Department of Cardiology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, Hubei 435000, P.R. China
| | - Hong Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Anti-inflammatory Effect of B-Type Natriuretic Peptide Postconditioning During Myocardial Ischemia–Reperfusion: Involvement of PI3K/Akt Signaling Pathway. Inflammation 2014; 37:1669-74. [DOI: 10.1007/s10753-014-9895-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Luan ZG, Ma XC, Zhang H, Zhang C, Guo RX. Protective effect of ethyl pyruvate on pancreas injury in rats with severe acute pancreatitis. J Surg Res 2013; 181:76-84. [DOI: 10.1016/j.jss.2012.05.066] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2012] [Revised: 04/20/2012] [Accepted: 05/22/2012] [Indexed: 12/22/2022]
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Jo IJ, Bae GS, Park KC, Choi SB, Jung WS, Jung SY, Cho JH, Choi MO, Song HJ, Park SJ. Scolopendra subspinipes mutilans protected the cerulein-induced acute pancreatitis by inhibiting high-mobility group box protein-1. World J Gastroenterol 2013; 19:1551-1562. [PMID: 23539679 PMCID: PMC3602472 DOI: 10.3748/wjg.v19.i10.1551] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 10/15/2012] [Accepted: 10/30/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the inhibitory effects of Scolopendra subspinipes mutilans (SSM) on cerulein-induced acute pancreatitis (AP) in a mouse model.
METHODS: SSM water extract (0.1, 0.5, or 1 g/kg) was administrated intraperitoneally 1 h prior to the first injection of cerulein. Once AP developed, the stable cholecystokinin analogue, cerulein was injected hourly, over a 6 h period. Blood samples were taken 6 h later to determine serum amylase, lipase, and cytokine levels. The pancreas and lungs were rapidly removed for morphological examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction. To specify the role of SSM in pancreatitis, the pancreatic acinar cells were isolated using collagenase method. Then the cells were pre-treated with SSM, then stimulated with cerulein. The cell viability, cytokine productions and high-mobility group box protein-1 (HMGB-1) were measured. Furthermore, the regulating mechanisms of SSM action were evaluated.
RESULTS: The administration of SSM significantly attenuated the severity of pancreatitis and pancreatitis associated lung injury, as was shown by the reduction in pancreatic edema, neutrophil infiltration, vacuolization and necrosis. SSM treatment also reduced pancreatic weight/body weight ratio, serum amylase, lipase and cytokine levels, and mRNA expression of multiple inflammatory mediators such as tumor necrosis factor-α and interleukin-1β. In addition, treatment with SSM inhibited HMGB-1 expression in the pancreas during AP. In accordance with in vivo data, SSM inhibited the cerulein-induced acinar cell death, cytokine, and HMGB-1 release. SSM also inhibited the activation of c-Jun NH2-terminal kinase, p38 and nuclear factor (NF)-κB.
CONCLUSION: These results suggest that SSM plays a protective role during the development of AP and pancreatitis associated lung injury via deactivating c-Jun NH2-terminal kinase, p38 and NF-κB.
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Kong X, Zhang C, Jin X, Wu X, Zhang S, Zhong Z, Feng Q, Liu T, Yuan H. The effect of HMGB1 A box on lung injury in mice with acute pancreatitis. Biofactors 2011; 37:323-7. [PMID: 21915938 DOI: 10.1002/biof.177] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The objective of this study is to observe the effect of high-mobility group protein B1 A Box (HMGB1 A) box on lung injury in mice with acute pancreatitis and its effect on the level of high-mobility group protein B1 (HMGB1) in lung, to explore the mechanism. A total of 60 male Institute of Cancer Research mice were randomly divided into control group (n = 30) and treatment group (n = 30). Severe acute pancreatitis mice model was induced by 20% L-Arg intraperitoneal injection. The recombination HMGB1 A box was used in treatment after modeling. All the mice were killed under anesthesia at 24 and 48 h after the modeling injection. The level of HMGB1 and activity of myeloperoxidase (MPO) in lung were measured. The pathological changes of lung were observed. The level of HMGB1 in lung of A box treatment group decreased more significantly 24 h and 48 h after modeling compared with control group. The activity of MPO in lung of A box treatment group decreased more significantly 24 h after modeling compared with control group. The lung tissue pathologic score of A box treatment group decreased more significantly 48 h after modeling compared with control group. HMGB1 expression levels in the lungs were positively related to histological score of injured lung in acute pancreatitis. It indicates that HMGB1 A box is remarkably protective to lung injury induced by acute pancreatitis.
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Affiliation(s)
- Xiangqian Kong
- Department of General Surgery, Provincial Hospital affiliated to Shandong University, Jinan, China
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Hu X, Cui B, Zhou X, Xu C, Lu Z, Jiang H. Ethyl pyruvate reduces myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats. Mol Biol Rep 2011; 39:227-31. [PMID: 21556772 DOI: 10.1007/s11033-011-0730-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 04/23/2011] [Indexed: 01/13/2023]
Abstract
High mobility group box 1 protein (HMGB1) plays an important role in myocardial ischemia and reperfusion (I/R) injury. Ethyl pyruvate (EP), a potent reactive oxygen species scavenger, has been reported to inhibit myocardial apoptosis and reduce myocardial I/R injury. The aim of this study was to investigate the mechanism by which EP reduces myocardial I/R injury in rats. Anesthetized male rats were once treated with EP (50 mg/kg, i.p.) before ischemia, and then subjected to ischemia for 30 min followed by reperfusion for 4 h. Lactate dehydrogenase (LDH), creatine kinase (CK), malondialdehyde (MDA), superoxide dismutase (SOD) activity and infarct size were measured. HMGB1 expression was assessed by immunoblotting. The results showed that pretreatment of EP (50 mg/kg) could significantly reduce the infarct size and the levels of LDH and CK after 4 h reperfusion (all P<0.05). EP could also significantly inhibit the increase of the MDA level, the decrease of the SOD level (both P<0.05). Meanwhile, EP could significantly inhibit the expression of HMGB1 induced by I/R. The present study suggested that ethyl pyruvate could attenuate myocardial I/R injury by inhibiting HMGB1 expression.
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Affiliation(s)
- Xiaorong Hu
- Department of Cardiology, Renmin Hospital of Wuhan University and Cardiovascular Research Institute of Wuhan University, 238 Jiefang Road, Wuchang, 430060, Wuhan, People's Republic of China
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