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El-Maddawy ZK, Mashalla AWA, Alnasser SM, El-Sawy AESF, Abdo W, Kamel MA, Alotaibi M, Khormi MA, Aborasain AM, Abd-El-Hafeez HH, Awad AA. Mitigation of hepatic and gastric impairments induced by flunixin meglumine through co-administration with alpha lipoic acid in male rats. BMC Vet Res 2025; 21:382. [PMID: 40426177 PMCID: PMC12117845 DOI: 10.1186/s12917-025-04751-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 04/11/2025] [Indexed: 05/29/2025] Open
Abstract
Long term use of Flunixin meglumine produces many gastric and hepatic hazards. The current study aimed to investigate using Alpha lipoic acid (ALA) for treating flunixin meglumine (FM)-induced liver and gastrointestinal problems in male rats. FM alternated with ALA for 14 and 56 days in the experiment. This study divided 72 male rats into six groups, 12 rats for each group. Group 1 (control) received saline and distilled water, Group 2 (ALA) received alpha lipoic acid orally at 100 mg/kg bwt, Group 3 (FM-2.5) received Flunixin meglumine subcutaneously at 2.5 mg/kg bwt, Group 4 (FM-5) received Flunixin meglumine subcutaneously, Group 5 (FM-2.5 and ALA) received FM and ALA, and Group 6 received FM and ALA. Elevated white blood cell (WBC) concentrations, ALT, AST, ALP, pro-inflammatory cytokines (NF-κB, TNF-α, HMG), malonaldehyde (MDA), and significant reductions in hepatic and gastric total antioxidant capacity (TAC) were observed. At weeks 4 and 8, FM-5-treated groups had a lower stomach index weight. These changes improved when Groups 5 and 6 used ALA and FM. ALA treatment reduced WBCs, ALT, AST, ALP, NF-κB, TNF-α, HMG, MDA, TAC, and stomach index weight gains in FM-5-treated groups. Finally, biochemical markers and stomach index volume showed liver and stomach dysfunctions in male rats after FM injections. The simultaneous administration of ALA greatly reduced these deficits, suggesting it may prevent FM-related hepatic and gastrointestinal diseases.
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Affiliation(s)
- Zeynab Kh El-Maddawy
- Veterinary Pharmacology Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt
| | - Abdel-Wahed A Mashalla
- Toxicology and Forensic Medicine Department, Faculty of Veterinary Medicine, Omar Al-Moukhtar University, El-Bedia, Libya
| | - Sulaiman Mohammed Alnasser
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, 51452, Qassim, Saudi Arabia
| | - Abd El-Salam F El-Sawy
- Veterinary Pharmacology Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt
| | - Walied Abdo
- Department of Pathology -Faculty of Veterinary Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Maher A Kamel
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
- Research Projects unit, Pharos University in Alexandria, Alexandria, 21648, Egypt
| | - Meshal Alotaibi
- Department of Pharmacy Practice, College of Pharmacy, University of Hafr Albatin, Hafer Al Batin, 39524, Saudi Arabia
| | - Mohsen A Khormi
- Department of Biology, College of Science, Kingdom of Saudi Arabia, Jazan University, P.O. Box. 114, Jazan, 45142, Saudi Arabia
| | - Ali M Aborasain
- Department of Biology, College of Science, Kingdom of Saudi Arabia, Jazan University, P.O. Box. 114, Jazan, 45142, Saudi Arabia
| | - Hanan H Abd-El-Hafeez
- Department of Cell and Tissues, Faculty of Veterinary Medicine, Assiut University, Assiut, 71526, Egypt.
| | - Amal A Awad
- Veterinary Pharmacology Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt.
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Zhen M, Zhu Y, Wang P, Liu X, Zhu J, Liu H, Li J, Zhao J, Shu B. HMGB1 Accelerates Wound Healing by Promoting the Differentiation of Epidermal Stem Cells via the "HMGB1-TLR4-Wnt/Notch" Axis. Adv Wound Care (New Rochelle) 2024. [PMID: 39694535 DOI: 10.1089/wound.2023.0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024] Open
Abstract
Objective: Impairments in the differentiation and migratory capacity of epidermal stem cells (ESCs) are pivotal factors contributing to delayed wound healing. High mobility group box1 (HMGB1) has recently emerged as a potential target for tissue repair. Therefore, we aimed to investigate the role and molecular mechanisms of HMGB1 in ESCs during the wound-healing process. Approach: Initially, we examined the expression of HMGB1 and the differentiation of ESCs in normal skin, normal wounds and chronic wounds. Then, we assessed the ESC migration and differentiation, and the key markers in the Wnt/Notch signaling pathways, after treatment of HMGB1 and inhibitor, and the knockdown of toll-like receptor 4 (TLR4), using scratch assay, qPCR, western blotting, and immunofluorescence. Finally, we conducted mice models to analyze the healing rates and quality in vivo. Results: HMGB1 was decreased across all epidermal layers, and the differentiation of ESCs was hindered in diabetic foot ulcer. In vitro, HMGB1 enhanced both the migration and differentiation of ESCs while stimulating the expression of the Wnt/Notch pathway within ESCs. However, the downregulation of TLR4 negated these effects. Finally, our in vivo experiments provided evidence that HMGB1 facilitates wound healing and epidermis differentiation via TLR4 and Wnt/Notch signaling pathways. Innovation: This study innovatively introduces HMGB1 as a novel target for skin wound healing and elucidates its mechanisms of action. Conclusions: HMGB1 accelerated wound healing by promoting the differentiation of epidermal stem cells through the "HMGB1-TLR4-Wnt/Notch" axis, which reveals a new potential mechanism and target to expedite wound healing.
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Affiliation(s)
- Miao Zhen
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yongkang Zhu
- Department of Burn and Plastic Surgery, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Peng Wang
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaogang Liu
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Junyou Zhu
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hengdeng Liu
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jingting Li
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jingling Zhao
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bin Shu
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Morioka N, Nakamura Y, Hisaoka-Nakashima K, Nakata Y. High mobility group box-1: A therapeutic target for analgesia and associated symptoms in chronic pain. Biochem Pharmacol 2024; 222:116058. [PMID: 38367818 DOI: 10.1016/j.bcp.2024.116058] [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: 11/24/2023] [Revised: 01/16/2024] [Accepted: 02/12/2024] [Indexed: 02/19/2024]
Abstract
The number of patients with chronic pain continues to increase against the background of an ageing society and a high incidence of various epidemics and disasters. One factor contributing to this situation is the absence of truly effective analgesics. Chronic pain is a persistent stress for the organism and can trigger a variety of neuropsychiatric symptoms. Hence, the search for useful analgesic targets is currently being intensified worldwide, and it is anticipated that the key to success may be molecules involved in emotional as well as sensory systems. High mobility group box-1 (HMGB1) has attracted attention as a therapeutic target for a variety of diseases. It is a very unique molecule having a dual role as a nuclear protein while also functioning as an inflammatory agent outside the cell. In recent years, numerous studies have shown that HMGB1 acts as a pain inducer in primary sensory nerves and the spinal dorsal horn. In addition, HMGB1 can function in the brain, and is involved in the symptoms of depression, anxiety and cognitive dysfunction that accompany chronic pain. In this review, we will summarize recent research and discuss the potential of HMGB1 as a useful drug target for chronic pain.
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Affiliation(s)
- Norimitsu Morioka
- Department of Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
| | - Yoki Nakamura
- Department of Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Kazue Hisaoka-Nakashima
- Department of Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Yoshihiro Nakata
- Department of Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
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Paudel YN, Khan SU, Othman I, Shaikh MF. Naturally Occurring HMGB1 Inhibitor, Glycyrrhizin, Modulates Chronic Seizures-Induced Memory Dysfunction in Zebrafish Model. ACS Chem Neurosci 2021; 12:3288-3302. [PMID: 34463468 DOI: 10.1021/acschemneuro.0c00825] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Glycyrrhizin (GL) is a well-known pharmacological inhibitor of high mobility group box 1 (HMGB1) and is abundantly present in the licorice root (Glycyrrhiza radix). HMGB1 protein, a key mediator of neuroinflammation, has been implicated in several neurological disorders, including epilepsy. Epilepsy is a devastating neurological disorder with no effective disease-modifying treatment strategies yet, suggesting a pressing need for exploring novel therapeutic options. In the current investigation, using a second hit pentylenetetrazol (PTZ) induced chronic seizure model in adult zebrafish, regulated mRNA expression of HMGB1 was inhibited by pretreatment with GL (25, 50, and 100 mg/kg, ip). A molecular docking study suggests that GL establishes different binding interactions with the various amino acid chains of HMGB1 and Toll-like receptor-4 (TLR4). Our finding suggests that GL pretreatment reduces/suppresses second hit PTZ induced seizure, as shown by the reduction in the seizure score. GL also regulates the second hit PTZ induced behavioral impairment and rescued second hit PTZ related memory impairment as demonstrated by an increase in the inflection ratio (IR) at the 3 h and 24 h T-maze trial. GL inhibited seizure-induced neuronal activity as demonstrated by reduced C-fos mRNA expression. GL also modulated mRNA expression of BDNF, CREB-1, and NPY. The possible mechanism underlying the anticonvulsive effect of GL could be attributed to its anti-inflammatory activity, as demonstrated by the downregulated mRNA expression level of HMGB1, TLR4, NF-kB, and TNF-α. Overall, our finding suggests that GL exerts an anticonvulsive effect and ameliorates seizure-related memory disruption plausibly through regulating of the HMGB1-TLR4-NF-kB axis.
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Affiliation(s)
- Yam Nath Paudel
- Neuropharmacology Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia
| | - Shafi Ullah Khan
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Selangor, Malaysia
- Department of Pharmacy, Abasyn University, Ring Road, Peshawar 25120, Pakistan
| | - Iekhsan Othman
- Neuropharmacology Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia
- Liquid Chromatography-Mass Spectrometry (LCMS) Platform, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Malaysia
| | - Mohd. Farooq Shaikh
- Neuropharmacology Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia
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Galbiati V, Maddalon A, Iulini M, Marinovich M, Corsini E. Human keratinocytes and monocytes co-culture cell system: An important contribution for the study of moderate and weak sensitizers. Toxicol In Vitro 2020; 68:104929. [DOI: 10.1016/j.tiv.2020.104929] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 06/10/2020] [Accepted: 06/30/2020] [Indexed: 12/17/2022]
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Wang M, Gauthier A, Daley L, Dial K, Wu J, Woo J, Lin M, Ashby C, Mantell LL. The Role of HMGB1, a Nuclear Damage-Associated Molecular Pattern Molecule, in the Pathogenesis of Lung Diseases. Antioxid Redox Signal 2019; 31:954-993. [PMID: 31184204 PMCID: PMC6765066 DOI: 10.1089/ars.2019.7818] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 06/07/2019] [Indexed: 12/11/2022]
Abstract
Significance: High-mobility group protein box 1 (HMGB1), a ubiquitous nuclear protein, regulates chromatin structure and modulates the expression of many genes involved in the pathogenesis of lung cancer and many other lung diseases, including those that regulate cell cycle control, cell death, and DNA replication and repair. Extracellular HMGB1, whether passively released or actively secreted, is a danger signal that elicits proinflammatory responses, impairs macrophage phagocytosis and efferocytosis, and alters vascular remodeling. This can result in excessive pulmonary inflammation and compromised host defense against lung infections, causing a deleterious feedback cycle. Recent Advances: HMGB1 has been identified as a biomarker and mediator of the pathogenesis of numerous lung disorders. In addition, post-translational modifications of HMGB1, including acetylation, phosphorylation, and oxidation, have been postulated to affect its localization and physiological and pathophysiological effects, such as the initiation and progression of lung diseases. Critical Issues: The molecular mechanisms underlying how HMGB1 drives the pathogenesis of different lung diseases and novel therapeutic approaches targeting HMGB1 remain to be elucidated. Future Directions: Additional research is needed to identify the roles and functions of modified HMGB1 produced by different post-translational modifications and their significance in the pathogenesis of lung diseases. Such studies will provide information for novel approaches targeting HMGB1 as a treatment for lung diseases.
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Affiliation(s)
- Mao Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Alex Gauthier
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - LeeAnne Daley
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Katelyn Dial
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Jiaqi Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Joanna Woo
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Mosi Lin
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Charles Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
| | - Lin L. Mantell
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York
- Center for Inflammation and Immunology, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York
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Wu CZ, Zheng JJ, Bai YH, Xia P, Zhang HC, Guo Y. HMGB1/RAGE axis mediates the apoptosis, invasion, autophagy, and angiogenesis of the renal cell carcinoma. Onco Targets Ther 2018; 11:4501-4510. [PMID: 30122942 PMCID: PMC6078191 DOI: 10.2147/ott.s167197] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background High mobility group box 1 protein (HMGB1) is a sort of non-histone protein in chromatin, which plays an important role in tumor proliferation, invasion, and immune escape. HMGB1-RAGE (receptor for advanced glycation end products) interactions have been reported to be important in a number of cancers. Methods CCK8, flow cytometry and qRT-PCR were used to detected cell viability, apoptosis and gene expression, respectively. Results In the present study, we demonstrated that HMGB1/RAGE axis regulated the cell proliferation, apoptosis, and invasion of the renal cell carcinoma (RCC). Further, we discovered that HMGB1/RAGE axis increased the expression of autophagic proteins LC3 and Beclin-1 in RCC. Finally, we used a coculture model of human umbilical vein endothelial cells with RCC cell lines to find out that HMGB1 also increased the expression of VEGF and VEGFR2 in human umbilical vein endothelial cells. An in vivo study further confirmed that HMGB1 knockdown inhibited RCC tumor growth. Conclusion Our results illustrated that HMGB1/RAGE axis mediated RCC cell viability, apoptosis, invasion, autophagy, and angiogenesis, which provides a novel theoretical basis for using HMGB1 as the target in RCC.
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Affiliation(s)
- Cun-Zao Wu
- Department of Transplantation Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Jian-Jian Zheng
- Department of Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yong-Heng Bai
- Department of Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Peng Xia
- Department of Transplantation Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Hai-Cong Zhang
- Department of Pathology, The Fifth Hospital of Shijiazhuang, Shijiazhuang, China
| | - Yong Guo
- Department of Transplantation Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China,
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Yagmur E, Buendgens L, Herbers U, Beeretz A, Weiskirchen R, Koek GH, Trautwein C, Tacke F, Koch A. High mobility group box 1 as a biomarker in critically ill patients. J Clin Lab Anal 2018; 32:e22584. [PMID: 29862569 DOI: 10.1002/jcla.22584] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 05/15/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Extracellular release of high mobility group box 1 (HMGB1) acts as a danger-associated molecular pattern, thereby "alarming" the immune system and promoting systemic inflammation. We investigated plasma HMGB1 concentrations as a potential diagnostic and prognostic biomarker in critical illness. METHODS Our study included 218 critically ill patients (145 with sepsis, 73 without sepsis), of whom blood samples were obtained at the time-point of admission to the medical intensive care unit (ICU). RESULTS High mobility group box 1 levels were significantly elevated in critically ill patients (n = 218) compared with healthy controls (n = 66). Elevated HMGB1 plasma levels were independent from the presence of sepsis. Moreover, HMGB1 was not associated with disease severity, organ failure, or mortality in the ICU. We observed a trend toward lower HMGB1 levels in ICU patients with pre-existing obesity, type 2 diabetes and end-stage renal disease patients on chronic hemodialysis. CONCLUSION In conclusion, our study did not reveal significant associations between HMGB1 levels at ICU admission and clinical outcomes in critically ill patients. Due to the pathogenic role of HMGB1 in the late phases of experimental sepsis, future studies might assess the potential value of HMGB1 by measuring its plasma concentrations at later time points during the course of critical illness.
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Affiliation(s)
- Eray Yagmur
- Medical Care Centre, Dr Stein and Colleagues, Mönchengladbach, Germany
| | - Lukas Buendgens
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
| | - Ulf Herbers
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
| | - Anne Beeretz
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH-University Hospital Aachen, Aachen, Germany
| | - Ger H Koek
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
| | - Christian Trautwein
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
| | - Alexander Koch
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
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Jiang M, Li X, Quan X, Li X, Zhou B. Single Nucleotide Polymorphisms in HMGB1 Correlate with Lung Cancer Risk in the Northeast Chinese Han Population. Molecules 2018; 23:E832. [PMID: 29617336 PMCID: PMC6017634 DOI: 10.3390/molecules23040832] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 03/26/2018] [Accepted: 04/01/2018] [Indexed: 12/18/2022] Open
Abstract
Lung cancer is the principal cause of cancer-associated deaths. HMGB1 has been reported to be associated with tumorigenesis. This study aimed to investigate the relationship between rs1412125 and rs1360485 polymorphisms in HMGB1 and the risk and survival of lung cancer. 850 cases and 733 controls were included. Logistic regression analysis and survival analysis were performed to investigate the association between SNPs and the risk and survival of lung cancer. Crossover analysis was used to analyze the interaction between SNPs and tobacco exposure. Results indicated that rs1412125 polymorphism was associated with lung cancer risk, especially with the risk of lung adenocarcinoma and small cell lung cancer. Carriers with CT and CC genotypes had a decreased risk of lung cancer (CT + CC vs.TT: adjusted OR = 0.736, p = 0.004). Similar results were obtained in the stratification analysis for non-smokers and female population. For rs1360485 polymorphism, AG and GG genotypes could decrease the risk of lung adenocarcinoma and female lung cancer by 0.771-fold and 0.789-fold. However, no significant interaction between polymorphisms and tobacco exposure or association between SNPs and the survival of lung cancer was observed. This study indicated polymorphisms in HMGB1 may be a novel biomarker for female lung adenocarcinoma risk.
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Affiliation(s)
- Min Jiang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang 110122, China.
| | - Xuelian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang 110122, China.
| | - Xiaowei Quan
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang 110122, China.
| | - Xiaoying Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang 110122, China.
| | - Baosen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang 110122, China.
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A functional variant at the miRNA binding site in HMGB1 gene is associated with risk of oral squamous cell carcinoma. Oncotarget 2018; 8:34630-34642. [PMID: 28423715 PMCID: PMC5470997 DOI: 10.18632/oncotarget.16120] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 02/15/2017] [Indexed: 12/12/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a common malignancy that has been causally associated with both hereditary and acquired factors. The high mobility group box 1 (HMGB1) gene plays an important role as a DNA chaperone to help maintain nuclear homeostasis. Altered expression of HMGB1 has been implicated in a wide range of pathological processes, including inflammation and cancer. The present study explores the impact of HMGB1 gene polymorphisms, combined with environmental risks regarding susceptibility to oral tumorigenesis. Four single-nucleotide polymorphisms (SNPs) of the HMGB1 gene, rs1412125, rs2249825, rs1045411, and rs1360485, were evaluated in 1,200 normal controls and 772 patients with OSCC. We found an association between the wild-type allele of rs1045411 and genotypes CT and CT/TT (AOR=0.754, 95% CI=0.582-0.978 and AOR=0.778, 95% CI=0.609-0.995, respectively). Additionally, bioinformatics analysis was used to characterize the functional relevance of these variants for the miRNA-505-5p binding site and transcriptional regulation by the HMGB1 3’-UTR and promoter regions. Moreover, in considering behavioral exposure to environmental carcinogens, the presence of the four HMGB1 SNPs, combined with/without betel quid chewing and smoking showed, profoundly synergistic effects on the risk of OSCC. In conclusion, we present a potential clinical relevance for HMGB1 variants in OSCC, as well as associations between HMGB1 polymorphisms, haplotypes and environmental risk factors. The finding may help in development of optimal therapeutic approaches for OSCC patients.
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Hung SC, Wang SS, Li JR, Chen CS, Yang CK, Chiu KY, Cheng CL, Ou YC, Ho HC, Yang SF. Effect of HMGB1 Polymorphisms on Urothelial Cell Carcinoma Susceptibility and Clinicopathological Characteristics. Int J Med Sci 2018; 15:1731-1736. [PMID: 30588197 PMCID: PMC6299401 DOI: 10.7150/ijms.27901] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/18/2018] [Indexed: 12/29/2022] Open
Abstract
The high mobility group box 1 gene (HMGB1) plays a prominent role in cancer progression, angiogenesis, invasion, and metastasis. This study explored the effect of HMGB1 polymorphisms on clinicopathological characteristics of urothelial cell carcinoma (UCC). In total, 1293 participants (431 patients with UCC and 862 healthy controls) were recruited. Four single-nucleotide polymorphisms (SNPs) of HMGB1 (rs1412125, rs1360485, rs1045411, and rs2249825) were assessed using TaqMan real-time polymerase chain reaction assay. The results indicated that individuals carrying at least one T allele at rs1045411 had a lower risk of UCC than those with the wild-type allele [adjusted odds ratio = 0.722, 95% confidence interval (CI) = 0.565-0.924]. Furthermore, female patients with UCC carrying at least one T allele at rs1045411 were at a lower invasive tumor stage than those with the wild-type allele [odds ratio (OR) = 0.396, 95% CI = 0.169-0.929], similar to nonsmoking patients (OR = 0.607, 95% CI = 0.374-0.985). In conclusion, this is the first report on correlation between HMGB1 polymorphisms and UCC risk. Individuals carrying at least one T allele at rs1045411 are associated with a lower risk of UCC and a less invasive disease in women and nonsmokers.
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Affiliation(s)
- Sheng-Chun Hung
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Shian-Shiang Wang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan
| | - Jian-Ri Li
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Medicine and Nursing, Hungkuang University, Taichung, Taiwan Taiwan
| | - Chuan-Shu Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chun-Kuang Yang
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Kun-Yuan Chiu
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan
| | - Chen-Li Cheng
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yen-Chuan Ou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Urology, Tung's Taichung MetroHarbor Hospital, Taichung, Taiwan
| | - Hao-Chung Ho
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
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12
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Kargı A, Demirpençe Ö, Gündüz Ş, Göktaş S, Alikanoǧlu AS, Yıldırım M. Serum levels of HMGB1 have a diagnostic role in metastatic renal cell cancer. Cancer Biomark 2017; 17:17-20. [PMID: 27062570 DOI: 10.3233/cbm-160611] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
RCC constitutes approximately 90% of all renal malignancies and 2-3% of all malignant tumours in adults. In spite of the improvement in radiologic methods, nearly 30% of the early metastatic RCC patients are incidentally diagnosed. HMGB1 is an extracellular signalling molecule that plays a role both in inflammation and carcinogenesis. Patients who were followed in Medical Oncology Departments of Denizli Government Hospital and Antalya Education and Research Hospital with a histopathological diagnosis of RCC between years 2010-2012 were enrolled in this study. HMGB1 levels were also assessed in a manually performed quantitative sandwich-enzyme-linked immunosorbent assay (ELISA) assay kit. In our study, we showed that the serum level of HMGB1, whether 149.9 pg/ml or not is important in differential diagnosis between patient and control group.
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13
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Ding J, Cui X, Liu Q. Emerging role of HMGB1 in lung diseases: friend or foe. J Cell Mol Med 2016; 21:1046-1057. [PMID: 28039939 PMCID: PMC5431121 DOI: 10.1111/jcmm.13048] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 10/30/2016] [Indexed: 12/11/2022] Open
Abstract
Lung diseases remain a serious problem for public health. The immune status of the body is considered to be the main influencing factor for the progression of lung diseases. HMGB1 (high‐mobility group box 1) emerges as an important molecule of the body immune network. Accumulating data have demonstrated that HMGB1 is crucially implicated in lung diseases and acts as independent biomarker and therapeutic target for related lung diseases. This review provides an overview of updated understanding of HMGB1 structure, release styles, receptors and function. Furthermore, we discuss the potential role of HMGB1 in a variety of lung diseases. Further exploration of molecular mechanisms underlying the function of HMGB1 in lung diseases will provide novel preventive and therapeutic strategies for lung diseases.
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Affiliation(s)
- Junying Ding
- Beijing Key Lab of Basic Study on Traditional Chinese Medicine (TCM) Infectious Diseases, Beijing Research Institute of TCM, Beijing Hospital of TCM affiliated to Capital Medical University, Beijing, China
| | - Xuran Cui
- Beijing Key Lab of Basic Study on Traditional Chinese Medicine (TCM) Infectious Diseases, Beijing Research Institute of TCM, Beijing Hospital of TCM affiliated to Capital Medical University, Beijing, China
| | - Qingquan Liu
- Beijing Key Lab of Basic Study on Traditional Chinese Medicine (TCM) Infectious Diseases, Beijing Research Institute of TCM, Beijing Hospital of TCM affiliated to Capital Medical University, Beijing, China
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14
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Wu HH, Liu YF, Yang SF, Lin WL, Chen SC, Han CP, Wang HL, Lin LY, Wang PH. Association of single-nucleotide polymorphisms of high-mobility group box 1 with susceptibility and clinicopathological characteristics of uterine cervical neoplasia in Taiwanese women. Tumour Biol 2016; 37:15813–15823. [PMID: 27704361 DOI: 10.1007/s13277-016-5408-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 09/13/2016] [Indexed: 12/14/2022] Open
Abstract
To date, no study associated the genetic polymorphisms of high-mobility group box 1 protein (HMGB1) with the development of uterine cervical cancer. We therefore conducted this study to investigate the associations of HMGB1 single-nucleotide polymorphisms (SNPs) with cervical carcinogenesis and clinicopathological characteristics of cancer patients. Five hundred two women, including 112 with invasive cancer, 85 with precancerous lesions of the uterine cervix, and 305 normal controls, were consecutively enrolled into this study. Analysis of HMGB1 SNPs was done by real-time polymerase chain reaction and genotyping. Our results found that the risk of susceptibility to cervical invasive cancer was 1.85 (95 % CI 1.12-3.04; p = 0.016) in women with TC and 1.99 (95 % CI 1.24-3.23; p = 0.005) in women with TC/CC after adjusting for age, using TT as a comparison reference in HMGB1 SNP rs1412125. In rs2249825, the increased risk was also seen for the development of cervical invasive cancer in women with CG [adjusted odds ratio (AOR) 2.04, 95 % CI 1.22-3.40; p = 0.006] or CG/GG (AOR 2.02, 95 % CI 1.22-3.32; p = 0.006) using CC as a comparison reference. An additional integrated in silico analysis confirmed that rs2249825 creates a binding site for v-Myb, which may affect HMGB1 expression. In conclusion, Taiwanese women with TC or TC/CC in HMGB1 SNP rs1412125 as well as CG or CG/GG in rs2249825 were susceptible to the development of cervical invasive cancer.
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Affiliation(s)
- Hsin-Hung Wu
- Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo North Road, Taichung, 40201, Taiwan
- Infertility Center, Xiamen EMBO Hospital Xiamen, Fujian, China
- Reproductive Medicine Center, Kinmen Hospital, Kinmen, Taiwan
| | - Yu-Fan Liu
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo North Road, Taichung, 40201, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Wea-Lung Lin
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shiuan-Chih Chen
- Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo North Road, Taichung, 40201, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Family and Community Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Ping Han
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan
- Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Hsiang-Ling Wang
- Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo North Road, Taichung, 40201, Taiwan
- Department of Beauty Science, National Taichung University of Science and Technology, Taichung, Taiwan
| | - Long-Yau Lin
- Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo North Road, Taichung, 40201, Taiwan.
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
- Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan.
| | - Po-Hui Wang
- Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo North Road, Taichung, 40201, Taiwan.
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
- Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan.
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15
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Liu Y, Hu X, Xia D, Zhang S. MicroRNA-181b is downregulated in non-small cell lung cancer and inhibits cell motility by directly targeting HMGB1. Oncol Lett 2016; 12:4181-4186. [PMID: 27895789 DOI: 10.3892/ol.2016.5198] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 08/19/2016] [Indexed: 12/21/2022] Open
Abstract
The expression of microRNA-181b (miR-181b) has been investigated in various human cancers. However, the expression and functions of miR-181b in non-small cell lung cancer (NSCLC) are yet to be studied. In the present study, miR-181b expression in NSCLC tissues and cell lines was analyzed by quantitative polymerase chain reaction, and was shown to be recurrently downregulated. Following transfection of the H23 and H522 NSCLC cells lines with miR-181b, cell migration and cell invasion assays were performed to evaluate the effect of miR-181b overexpression on the cell motility. It was demonstrated that overexpression of miR-181b inhibited the migration and invasion of NSCLC cells. Subsequently, bioinformatics analysis, western blotting and luciferase reporter assays were conducted to investigate the mechanism underlying the miR-181b-mediated inhibition of NSCLC cell motility. It was found that miR-181b directly targeted high-mobility group box-1 (HMGB1) in NSCLC cells. These results reveal a novel therapeutic target, the miR-181b/HMGB1 axis, in NSCLC. Treatment approaches targeting this axis will be beneficial to prevent NSCLC from becoming invasive.
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Affiliation(s)
- Yun Liu
- Department of Cardiothoracic Surgery, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei 443000, P.R. China; Department of Cardiothoracic Surgery, Yichang Central People's Hospital, Yichang, Hubei 443000, P.R. China
| | - Xu Hu
- Department of Cardiothoracic Surgery, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei 443000, P.R. China; Department of Cardiothoracic Surgery, Yichang Central People's Hospital, Yichang, Hubei 443000, P.R. China
| | - Daokui Xia
- Department of Cardiothoracic Surgery, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei 443000, P.R. China; Department of Cardiothoracic Surgery, Yichang Central People's Hospital, Yichang, Hubei 443000, P.R. China
| | - Songlin Zhang
- Department of Cardiothoracic Surgery, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei 443000, P.R. China; Department of Cardiothoracic Surgery, Yichang Central People's Hospital, Yichang, Hubei 443000, P.R. China
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16
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PPAR Ligands Function as Suppressors That Target Biological Actions of HMGB1. PPAR Res 2016; 2016:2612743. [PMID: 27563308 PMCID: PMC4985574 DOI: 10.1155/2016/2612743] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 06/21/2016] [Accepted: 06/28/2016] [Indexed: 01/12/2023] Open
Abstract
High mobility group box 1 (HMGB1), which has become one of the most intriguing molecules in inflammatory disorders and cancers and with which ligand-activated peroxisome proliferator-activated receptors (PPARs) are highly associated, is considered as a therapeutic target. Of particular interest is the fact that certain PPAR ligands have demonstrated their potent anti-inflammatory activities and potential anticancer effects. In this review article we summarize recent experimental evidence that PPAR ligands function as suppressors that target biological actions of HMGB1, including intracellular expression, receptor signaling cascades, and extracellular secretion of HMGB1 in cell lines and/or animal models. We also propose the possible mechanisms underlying PPAR involvement in inflammatory disorders and discuss the future therapeutic value of PPAR ligands targeting HMGB1 molecule for cancer prevention and treatment.
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17
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Sohun M, Shen H. The implication and potential applications of high-mobility group box 1 protein in breast cancer. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:217. [PMID: 27386491 PMCID: PMC4916368 DOI: 10.21037/atm.2016.05.36] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 04/14/2016] [Indexed: 01/09/2023]
Abstract
High-mobility group box 1 protein (HMGB1) is a highly conserved, non-histone and ubiquitous chromosomal protein found enriched in active chromatin forming part of the high mobility group family of proteins and is encoded by the HMGB1 gene (13q12) in human beings. It has various intranuclear and extracellular functions. It plays an important role in the pathogenesis of many diseases including cancer. In 2012, there was approximately 1.67 million new breast cancer cases diagnosed which makes it the second most frequent cancer in the world after lung cancer (25% of all cancers) and the commonest cancer among women. Both pre-clinical and clinical studies have suggested that HMGB1 might be a useful target in the management of breast cancer. This review summarises the structure and functions of HMGB1 and its dual role in carcinogenesis both as a pro-tumorigenic and anti-tumorigenic factor. It also sums up evidence from in vitro and in vivo studies using breast cancer cell lines and samples which demonstrate its influence in radiotherapy, chemotherapy and hormonal therapy in breast cancer. It may have particular importance in HER2 positive and metastatic breast cancer. It might pave the way for new breast cancer treatments through development of novel drugs, use of microRNAs (miRNAs), targeting breast cancer stem cells (CSCs) and breast cancer immunotherapy. It may also play a role in determining breast cancer prognosis. Thus HMGB1 may open up novel avenues in breast cancer management.
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Affiliation(s)
- Moonindranath Sohun
- Department of Oncology, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212013, China
| | - Huiling Shen
- Department of Oncology, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212013, China
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18
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Singh MK, Singh L, Pushker N, Sen S, Sharma A, Chauhan FA, Kashyap S. Correlation of High Mobility Group Box-1 Protein (HMGB1) with Clinicopathological Parameters in Primary Retinoblastoma. Pathol Oncol Res 2015; 21:1237-42. [PMID: 26118980 DOI: 10.1007/s12253-015-9951-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 05/14/2015] [Indexed: 11/29/2022]
Abstract
HMGB1 is considered to be DNA chaperone as it binds without any specificity. It is the structural protein which alters nuclear homeostasis and genomic stability of chromatin. Its role in retinoblastoma (Rb) remains unclear. The aim of the present study was to evaluate the expression of HMGB1 protein in primary enucleated retinoblastomas. Expression of HMGB1 in 69 prospective cases of primary retinoblastoma were assessed by immunohistochemistry and reverse transcriptase PCR (RT-PCR) technique and correlated with clinicopathological parameters. Immunohistochemical staining revealed expression of HMGB1 in 55.07 % (38/69) cases. Semi-quantitative RT-PCR was performed on 31 fresh tumor tissues. mRNA expression was observed in 77.41 % (24/31) cases. Expression of HMGB1 was statistically significant with poor tumor differentiation (p = 0.0440) & optic nerve invasion (p = 0.0128). HMGB1 expression was frequently seen in poorly differentiated tumors and those with histopathological high risk factors. Therefore, HMGB1 may contribute to tumor invasiveness and could serve as a poor prognostic marker in Rb.
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Affiliation(s)
- Mithalesh Kumar Singh
- Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
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19
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Circulating HMGB1 and RAGE as Clinical Biomarkers in Malignant and Autoimmune Diseases. Diagnostics (Basel) 2015; 5:219-53. [PMID: 26854151 PMCID: PMC4665591 DOI: 10.3390/diagnostics5020219] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 06/01/2015] [Accepted: 06/05/2015] [Indexed: 12/18/2022] Open
Abstract
High molecular group box 1 (HMGB1) is a highly conserved member of the HMG-box-family; abundantly expressed in almost all human cells and released in apoptosis; necrosis or by activated immune cells. Once in the extracellular space, HMGB1 can act as a danger associated molecular pattern (DAMP), thus stimulating or inhibiting certain functions of the immune system; depending on the “combinatorial cocktail” of the surrounding milieu. HMGB1 exerts its various functions through binding to a multitude of membrane-bound receptors such as TLR-2; -4 and -9; IL-1 and RAGE (receptor for advanced glycation end products); partly complex-bound with intracellular fragments like nucleosomes. Soluble RAGE in the extracellular space, however, acts as a decoy receptor by binding to HMGB1 and inhibiting its effects. This review aims to outline today’s knowledge of structure, intra- and extracellular functions including mechanisms of release and finally the clinical relevance of HMGB1 and RAGE as clinical biomarkers in therapy monitoring, prediction and prognosis of malignant and autoimmune disease.
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20
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Supic G, Kozomara R, Zeljic K, Stanimirovic D, Magic M, Surbatovic M, Jovic N, Magic Z. HMGB1 genetic polymorphisms in oral squamous cell carcinoma and oral lichen planus patients. Oral Dis 2015; 21:536-43. [PMID: 25639284 DOI: 10.1111/odi.12318] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 01/16/2015] [Indexed: 01/05/2023]
Abstract
OBJECTIVES This study examined the single nucleotide polymorphisms (SNPs) in high-mobility group box 1 (HMGB1) gene in patients with oral squamous cell carcinoma (OSCC) and oral lichen planus (OLP). MATERIALS AND METHODS The study was conducted on 93 patients with OSCC, 53 patients with OLP, and 100 controls, all Caucasians of the same ethnicity, matched by age. HMGB1 genotypes for 4 SNPs, 2262G/A (rs1045411), 1177G/C (rs3742305), 3814C/G (rs2249825), and rs4540927, were assessed using TaqMan SNP Genotyping Assays, Applied Biosystems. RESULTS The HMGB1 1177GG genotype was associated with lymph-node metastasis and tumor stage in OSCCs (P = 0.016 and P = 0.030, respectively). Genotype 1177GG resulted in poorer recurrence-free survival (RFS), P = 0.000. The 1177G/C polymorphism was an independent predictor of RFS compared to GG genotype, P = 0.001. The three polymorphisms were in linkage disequilibrium (LD). The AGC and GGC haplotypes were associated with an increased oral cancer risk, determined over the haplotype odds ratios (HOR = 13.316, P = 0.015, and HOR = 5.769, P = 0.029, respectively). The AGC haplotype was related to erosive OLP progression to OSCC (HOR = 12.179, P = 0.001). CONCLUSIONS HMGB1 polymorphism 1177G/C could be associated with tumor progression and recurrence-free survival in patients with OSCC. The haplotypes of HMGB1 gene might be associated with susceptibility to OSCC and OLP progression to OSCC.
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Affiliation(s)
- G Supic
- Faculty of Medicine, Military Medical Academy, University of Defense, Belgrade, Serbia; Institute for Medical Research, Military Medical Academy, Belgrade, Serbia
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21
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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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22
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Galbiati V, Papale A, Galli CL, Marinovich M, Corsini E. Role of ROS and HMGB1 in Contact Allergen–Induced IL-18 Production in Human Keratinocytes. J Invest Dermatol 2014; 134:2719-2727. [DOI: 10.1038/jid.2014.203] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 03/18/2014] [Accepted: 04/07/2014] [Indexed: 12/25/2022]
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23
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HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA. Nat Commun 2014; 4:2388. [PMID: 24005720 PMCID: PMC4005793 DOI: 10.1038/ncomms3388] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 08/02/2013] [Indexed: 12/14/2022] Open
Abstract
Upon muscle injury, the high mobility group box 1 (HMGB1) protein is upregulated and secreted to initiate reparative responses. Here we show that HMGB1 controls myogenesis both in vitro and in vivo during development and after adult muscle injury. HMGB1 expression in muscle cells is regulated at the translational level: the miRNA miR-1192 inhibits HMGB1 translation and the RNA-binding protein HuR promotes it. HuR binds to a cis-element, HuR binding sites (HuRBS), located in the 3'UTR of the HMGB1 transcript, and at the same time miR-1192 is recruited to an adjacent seed element. The binding of HuR to the HuRBS prevents the recruitment of Argonaute 2 (Ago2), overriding miR-1192-mediated translation inhibition. Depleting HuR reduces myoblast fusion and silencing miR-1192 re-establishes the fusion potential of HuR-depleted cells. We propose that HuR promotes the commitment of myoblasts to myogenesis by enhancing the translation of HMGB1 and suppressing the translation inhibition mediated by miR-1192.
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24
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Zhang C, Ge S, Hu C, Yang N, Zhang J. MiRNA-218, a new regulator of HMGB1, suppresses cell migration and invasion in non-small cell lung cancer. Acta Biochim Biophys Sin (Shanghai) 2013; 45:1055-61. [PMID: 24247270 DOI: 10.1093/abbs/gmt109] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
MicroRNAs (miRNAs) function as negative regulators of gene expression involved in cancer metastasis. The aim of this study is to investigate the potential roles of miR-218 in non-small cell lung cancer and validate its regulation mechanism. Functional studies showed that miR-218 overexpression inhibited cell migration and invasion, but had no effect on cell viability. Enhanced green fluorescent protein reporter assay, real-time polymerase chain reaction and western blot analysis confirmed that miR-218 suppressed the expression of high mobility group box-1 (HMGB1) by directly targeting its 3'-untranslated region. Accordingly, silencing of HMGB1 accorded with the effects of miR-218 on cell migration and invasion, and overexpression of HMGB1 can restore cell migration and invasion which were reduced by miR-218. In conclusion, these findings demonstrate that miR-218 functions as a tumor suppressor in lung cancer. Furthermore, miR-218 may act as a potential therapeutic biomarker for metastatic lung cancer patients.
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Affiliation(s)
- Cailian Zhang
- Department of Geriatrics, The Affiliated Hospital of Yan'an University, Yan'an 716000, China
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25
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Zhu P, Xie L, Ding HS, Gong Q, Yang J, Yang L. High mobility group box 1 and kidney diseases (Review). Int J Mol Med 2013; 31:763-768. [PMID: 23440289 DOI: 10.3892/ijmm.2013.1286] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 01/18/2013] [Indexed: 11/10/2022] Open
Abstract
High mobility group box 1 (HMGB1), a non-histone DNA-binding protein, regulates nucleosome function and transcription in the nuclei of all metazoans and plants. However, extracellular HMGB1, which is actively or passively released under different conditions, can act as a key inflammatory mediator through MyD88/mitogen-activated protein kinase signaling by binding to its receptors including the receptor for advanced glycation end products or Toll-like receptors. A growing body of evidence indicates that HMGB1 plays an important role in kidney diseases, such as glomerulonephritis, lupus nephritis, antineutrophilic cytoplasmatic antibody-associated vaculitis, diabetic nephropathy, renal allograft rejection and acute kidney injury. In this review, we focus on the biology of HMGB1 and the association of HMGB1 with kidney diseases.
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Affiliation(s)
- Ping Zhu
- Department of Nephrology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, PR China.
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26
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ZHANG XIAOJUAN, LUAN ZHENGGANG, MA XIAOCHUN. shRNAs targeting high-mobility group box-1 inhibit E-selectin expression via homeobox A9 in human umbilical vein endothelial cells. Mol Med Rep 2013; 7:1251-6. [DOI: 10.3892/mmr.2013.1314] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Accepted: 01/30/2013] [Indexed: 11/05/2022] Open
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27
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Ratliff BB, Rabadi MM, Vasko R, Yasuda K, Goligorsky MS. Messengers without borders: mediators of systemic inflammatory response in AKI. J Am Soc Nephrol 2013; 24:529-36. [PMID: 23349311 DOI: 10.1681/asn.2012060633] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The list of signals sent by an injured organ to systemic circulation, so-called danger signals, is growing to include multiple metabolites and secreted moieties, thus revealing a highly complex and integrated network of interlinked systemic proinflammatory and proregenerative messages. Emerging new data indicate that, apart from the well established local inflammatory response to AKI, danger signaling unleashes a cascade of precisely timed, interdependent, and intensity-gradated mediators responsible for development of the systemic inflammatory response. This fledgling realization of the importance of the systemic inflammatory response to the localized injury and inflammation is at the core of this brief overview. It has a potential to explain the additive effects of concomitant diseases or preexisting chronic conditions that can prime the systemic inflammatory response and exacerbate it out of proportion to the actual degree of acute kidney damage. Although therapies for ameliorating AKI per se remain limited, a potentially powerful strategy that could reap significant benefits in the future is to modulate the intensity of danger signals and consequently the systemic inflammatory response, while preserving its intrinsic proregenerative stimuli.
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Affiliation(s)
- Brian B Ratliff
- Department of Medicine, Renal Research Institute, New York Medical College, 15 Dana Road, BSB C-06, Valhalla, NY 10595, USA.
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Role of high mobility group box 1 in inflammatory disease: focus on sepsis. Arch Pharm Res 2012; 35:1511-23. [PMID: 23054707 DOI: 10.1007/s12272-012-0901-5] [Citation(s) in RCA: 158] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Revised: 07/16/2012] [Accepted: 07/18/2012] [Indexed: 12/20/2022]
Abstract
High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types. In response to infection or injury, HMGB1 is actively secreted by innate immune cells and/or released passively by injured or damaged cells. Thus, serum and tissue levels of HMGB1 are elevated during infection, and especially during sepsis. Sepsis is a systemic inflammatory response to disease and the most severe complication of infections, and HMGB1 acts as a potent proinflammatory cytokine and is involved in delayed endotoxin lethality and sepsis. Furthermore, the targeting of HMGB1 with antibodies or specific antagonists has been found to have protective effects in established preclinical inflammatory disease models, including models of lethal endotoxemia and sepsis. In the present study, emerging evidence supporting the notion that extracellular HMGB1 acts as a proinflammatory danger signal is reviewed, and the potential therapeutic effects of a wide array of HMGB1 inhibitors agents in sepsis and ischemic injury are discussed.
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Bitto A, Polito F, Bagnato G, Talotta R, Atteritano M, Irrera N, Ientile R, Ferlazzo N, Caccamo D, Bagnato G, Caliri A, Squadrito F, Altavilla D. Influence of Polymorphism −308 G/A of the Tnf-α Gene on High Mobility Group Box-1 Protein in Rheumatoid and Spondylo-Arthritis Patients. EUR J INFLAMM 2012. [DOI: 10.1177/1721727x1201000316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Single nucleotide polymorphism (SNP) in the human Tumor Necrosis Factor-α(TNF-α) gene promoter, the −308 G/A variant, has been associated with increased TNF-α levels that may amplify the severity of rheumatoid arthritis (RA) and a poor responsiveness to TNF-α blockade therapy. High mobility group box protein (HMGB-1) is a pro-inflammatory cytokine that plays a pivotal role in the pathogenesis of RA and may be an original target of therapy. The aim of this study is to investigate whether the −308 G/A variant of the TNF-α gene is associated with altered expression of HMBG-1. A total of 110 consecutive patients with rheumatoid arthritis and spondylo-arthritis (ankylosing spondylitis, psoriatic arthritis and spondylitis associated with inflammatory bowel disease) referring to the Rheumatology Unit of Messina University Hospital were enrolled. Patients were genotyped for the −308 TNF-α gene promoter polymorphism. Clinical status was also assessed. HMGB-1 and TNF-α mRNA(Real Time PCR) from total blood and plasmatic HMGB-1 (Western Blot analysis) and TNF-α (ELISA) protein were also evaluated. Irrespective of the underlying disease, patients carrying the G/A genotype showed enhanced HMGB-1 and TNF-α mRNA levels and increased circulating concentration of the inflammatory cytokines when compared to patients with G/G genotype. The data suggest that subjects carrying the TNF-α −308G/A genotype have enhanced expression of HMGB-1 protein that may explain, at least in part, the increased severity of the disease.
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Affiliation(s)
- A. Bitto
- Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Italy
| | - F. Polito
- Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, Italy
| | - G. Bagnato
- Department of Internal Medicine, Rheumatology Unit, University of Messina, Italy
| | - R. Talotta
- Department of Internal Medicine, Rheumatology Unit, University of Messina, Italy
| | - M. Atteritano
- Department of Internal Medicine, Rheumatology Unit, University of Messina, Italy
| | - N. Irrera
- Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Italy
| | - R. Ientile
- Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, Italy
| | - N. Ferlazzo
- Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, Italy
| | - D. Caccamo
- Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, Italy
| | - G. Bagnato
- Department of Internal Medicine, Rheumatology Unit, University of Messina, Italy
| | - A. Caliri
- Department of Internal Medicine, Rheumatology Unit, University of Messina, Italy
| | - F. Squadrito
- Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Italy
| | - D. Altavilla
- Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Italy
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Rosu-Myles M, She YM, Fair J, Muradia G, Mehic J, Menendez P, Prasad SS, Cyr TD. Identification of a candidate proteomic signature to discriminate multipotent and non-multipotent stromal cells. PLoS One 2012; 7:e38954. [PMID: 22719999 PMCID: PMC3374805 DOI: 10.1371/journal.pone.0038954] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Accepted: 05/14/2012] [Indexed: 01/09/2023] Open
Abstract
Bone marrow stromal cell cultures contain multipotent cells that may have therapeutic utility for tissue restoration; however, the identity of the cell that maintains this function remains poorly characterized. We have utilized a unique model of murine bone marrow stroma in combination with liquid chromatography mass spectrometry to compare the nuclear, cytoplasmic and membrane associated proteomes of multipotent (MSC) (CD105+) and non-multipotent (CD105-) stromal cells. Among the 25 most reliably identified proteins, 10 were verified by both real-time PCR and Western Blot to be highly enriched, in CD105+ cells and were members of distinct biological pathways and functional networks. Five of these proteins were also identified as potentially expressed in human MSC derived from both standard and serum free human stromal cultures. The quantitative amount of each protein identified in human stromal cells was only minimally affected by media conditions but varied highly between bone marrow donors. This study provides further evidence of heterogeneity among cultured bone marrow stromal cells and identifies potential candidate proteins that may prove useful for identifying and quantifying both murine and human MSC in vitro.
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Affiliation(s)
- Michael Rosu-Myles
- Centre for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Canada.
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31
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Watanabe T, Asai K, Fujimoto H, Tanaka H, Kanazawa H, Hirata K. Increased levels of HMGB-1 and endogenous secretory RAGE in induced sputum from asthmatic patients. Respir Med 2010; 105:519-25. [PMID: 21041074 DOI: 10.1016/j.rmed.2010.10.016] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Revised: 10/12/2010] [Accepted: 10/13/2010] [Indexed: 10/18/2022]
Abstract
BACKGROUND High mobility group box 1 (HMGB-1), a ligand of the receptor for advanced glycation end products (RAGE), is an inflammatory mediator in various disorders. Its endogenous decoy inhibitor, endogenous secretory RAGE (esRAGE), prevents the activation of RAGE signaling, and imbalance between HMGB-1 and esRAGE is known to be a factor determining progression of chronic inflammatory diseases. METHODS We measured HMGB-1 and esRAGE levels in induced sputum from 44 asthmatic patients and 15 normal controls, and examined their correlations with asthma indices including pulmonary function test values and induced sputum indices. RESULTS HMGB-1 levels in induced sputum were significantly higher in asthmatic patients than in normal controls (p < 0.001). Similarly, esRAGE levels were significantly higher in asthmatic patients than in normal controls (p < 0.001). In asthmatic patients, HMGB-1 levels were inversely correlated with percentage of predicted forced expiratory volume in 1 s (%FEV(1)) and FEV(1)/forced vital capacity (FEV(1)/FVC). There was a significant increase in HMGB-1 level associated with severity of asthma (p < 0.001). However, there was no significant increase in esRAGE level associated with severity of asthma. In asthmatic patients, HMGB-1 levels were significantly correlated with percentage of neutrophils in induced sputum. CONCLUSIONS Our findings suggest that the HMGB-1 is a mediator of neutrophilic airway inflammation in asthma and that imbalance between HMGB-1 and esRAGE is related to the severity of asthma. Combined measurement of HMGB-1 and esRAGE may be novel biomarkers in asthma with severe airflow limitation.
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Affiliation(s)
- Tetsuya Watanabe
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
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Kornblit B, Masmas T, Petersen SL, Madsen HO, Heilmann C, Schejbel L, Sengeløv H, Müller K, Garred P, Vindeløv L. Association of HMGB1 polymorphisms with outcome after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2009; 16:239-52. [PMID: 19819342 DOI: 10.1016/j.bbmt.2009.10.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2009] [Accepted: 10/03/2009] [Indexed: 12/18/2022]
Abstract
Several studies have demonstrated that genetic variation in cytokine genes can modulate the immune reactions after allogeneic hematopoietic cell transplantation (HCT). High mobility group box 1 protein (HMBG1) is a pleiotropic cytokine that functions as a pro-inflammatory signal, important for the activation of antigen presenting cells (APCs) and propagation of inflammation. HMGB1 is implicated in the pathophysiology of a variety of inflammatory diseases, and we have recently found the variation in the HMGB1 gene to be associated with mortality in patients with systemic inflammatory response syndrome. To assess the impact of the genetic variation in HMGB1 on outcome after allogeneic HCT, we genotyped 276 and 146 patient/donor pairs treated with allogeneic HCT for hematologic malignancies following myeloablative (MA) or nonmyeloablative (NMA) conditioning. Associations between genotypes and outcome were only observed in the cohort treated with MA conditioning. Patient homozygosity or heterozygosity for the-1377delA minor allele was associated with increased risk of relapse (hazard ratio [HR] 2.11, P = .02) and increased relapse related mortality (RRM) (P = .03). Furthermore, patient homozygosity for the 3814C > G minor allele was associated with increased overall survival (OS; HR 0.13, P = .04), progression free survival (PFS; HR 0.30, P = .05) and decreased probability of RRM (P = .03). Patient carriage of the 2351insT minor allele reduced the risk of grade II to IV acute graft-versus-host disease (aGVHD) (HR 0.60, P = .01), whereas donor homozygosity was associated with chronic GVHD (cGVHD) (HR 1.54, P = .01). Our findings suggest that the inherited variation in HMGB1 is associated with outcome after allogeneic HCT following MA conditioning. None of the polymorphisms were associated with treatment-related mortality (TRM).
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Affiliation(s)
- Brian Kornblit
- Laboratory of Molecular Medicine, Department of Clinical Immunology, University of Copenhagen, Denmark.
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Pan HF, Wu GC, Li WP, Li XP, Ye DQ. High Mobility Group Box 1: a potential therapeutic target for systemic lupus erythematosus. Mol Biol Rep 2009; 37:1191-5. [PMID: 19247800 DOI: 10.1007/s11033-009-9485-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2008] [Accepted: 02/19/2009] [Indexed: 11/26/2022]
Abstract
High Mobility Group Box 1 (HMGB1) is a nuclear protein participating in chromatin architecture and transcriptional regulation. Recently, there is increasing evidence that HMGB1 contributes to the pathogenesis of chronic inflammatory and autoimmune diseases due to its pro-inflammatory and immunostimulatory properties. Elevated expression of HMGB1 was found in the sera of patients and mice with systemic lupus erythematosus (SLE). In addition, it has been shown that HMGB1 may act as a proinflammatory mediator in antibody-induced kidney damage in SLE. All theses findings suggest that HMGB1 have important biological effects in autoimmunity that might be a promising therapeutic target for SLE. In this review, we will briefly discuss the biological features of HMGB1 and summarize recent advances on the role of HMGB1 in the pathogenesis and treatment of SLE.
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Affiliation(s)
- Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui, People's Republic of China.
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Stros M, Polanská E, Struncová S, Pospísilová S. HMGB1 and HMGB2 proteins up-regulate cellular expression of human topoisomerase IIalpha. Nucleic Acids Res 2009; 37:2070-86. [PMID: 19223331 PMCID: PMC2673423 DOI: 10.1093/nar/gkp067] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Topoisomerase IIα (topo IIα) is a nuclear enzyme involved in several critical processes, including chromosome replication, segregation and recombination. Previously we have shown that chromosomal protein HMGB1 interacts with topo IIα, and stimulates its catalytic activity. Here we show the effect of HMGB1 on the activity of the human topo IIα gene promoter in different cell lines. We demonstrate that HMGB1, but not a mutant of HMGB1 incapable of DNA bending, up-regulates the activity of the topo IIα promoter in human cells that lack functional retinoblastoma protein pRb. Transient over-expression of pRb in pRb-negative Saos-2 cells inhibits the ability of HMGB1 to activate the topo IIα promoter. The involvement of HMGB1 and its close relative, HMGB2, in modulation of activity of the topo IIα gene is further supported by knock-down of HMGB1/2, as evidenced by significantly decreased levels of topo IIα mRNA and protein. Our experiments suggest a mechanism of up-regulation of cellular expression of topo IIα by HMGB1/2 in pRb-negative cells by modulation of binding of transcription factor NF-Y to the topo IIα promoter, and the results are discussed in the framework of previously observed pRb-inactivation, and increased levels of HMGB1/2 and topo IIα in tumors.
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Affiliation(s)
- Michal Stros
- Laboratory of Analysis of Chromosomal Proteins, Academy of Sciences of the Czech Republic, Institute of Biophysics, Brno, Czech Republic.
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35
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Kornblit B, Munthe-Fog L, Madsen HO, Strøm J, Vindeløv L, Garred P. Association of HMGB1 polymorphisms with outcome in patients with systemic inflammatory response syndrome. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2008; 12:R83. [PMID: 18577209 PMCID: PMC2481482 DOI: 10.1186/cc6935] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2008] [Revised: 05/13/2008] [Accepted: 06/24/2008] [Indexed: 11/23/2022]
Abstract
Introduction High mobility group box 1 protein (HMGB1) is a pleiotropic cytokine, recently implicated in the pathophysiology of the systemic inflammatory response syndrome (SIRS) and sepsis. Data from experimental sepsis models show that administration of anti-HMGB1 antibodies significantly decreased mortality, even when administration was delayed for 24 hours, providing a window of opportunity for therapeutic intervention if transferred into a clinical setting. Whether genetic variation in the human HMGB1 gene is associated with disease susceptibility is unknown. Methods We sequenced the HMGB1 gene in 239 prospectively monitored patients with SIRS admitted to an intensive care unit and we measured the corresponding HMGB1 serum concentrations. Blood donors served as control individuals. Outcome parameters according to different HMGB1 genotypes were compared. Results Homozygosity and heterozygosity for a promoter variant (-1377delA) was associated with a decreased overall 4-year survival (15% versus 44%, hazard ratio = 1.80; P = 0.01) and with a decreased number of SIRS criteria. Carriage of an exon 4 variant (982C>T) was significantly associated with an increased number of SIRS criteria, a higher Simplified Acute Physiology Score II score, a lower PaO2/FiO2 ratio and lower serum HMGB1 levels (P = 0.01), and with a significantly higher probability of early death due to infection (P = 0.04). HMGB1 was undetectable in the control individuals. Conclusion The present article is the first report of clinical implications of variation in the human HMGB1 gene. Two polymorphisms were determined as significant risk factors associated with early and late mortality, which may provide insight into the molecular background of SIRS and sepsis, suggesting a possible role for HMGB1 genetics in future prognostic evaluation.
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Affiliation(s)
- Brian Kornblit
- Department of Clinical Immunology - 7631, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen O, Denmark.
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36
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Kornblit B, Munthe-Fog L, Petersen SL, Madsen HO, Vindeløv L, Garred P. The genetic variation of the human HMGB1 gene. ACTA ACUST UNITED AC 2007; 70:151-6. [PMID: 17610420 DOI: 10.1111/j.1399-0039.2007.00854.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
High-mobility group box 1 protein (HMGB1) is a nuclear DNA-binding protein, which also functions as a pleiotropic cytokine, implicated in the pathology of several different immune-mediated diseases. The purpose of this study was to examine the HMGB1 gene for putative polymorphisms in 103 healthy Caucasian Danish blood donors. A total of six polymorphisms and four mutations were identified in the HMGB1 gene. Subsequent MatInspector estimation revealed that several polymorphisms might have a potential regulatory impact on HMGB1 transcription. This study has characterized genetic variations in the HMGB1 gene locus, which may have a regulating role in the expression of HMGB1, providing the basis for molecular investigations of the HMGB1 gene in different disease settings.
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Affiliation(s)
- B Kornblit
- Tissue Typing Laboratory-7631, Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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37
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Ellerman JE, Brown CK, de Vera M, Zeh HJ, Billiar T, Rubartelli A, Lotze MT. Masquerader: High Mobility Group Box-1 and Cancer. Clin Cancer Res 2007; 13:2836-48. [PMID: 17504981 DOI: 10.1158/1078-0432.ccr-06-1953] [Citation(s) in RCA: 285] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Since its identification a third of a century ago, the high-mobility group box-1 (HMGB1) protein has been linked to varied diverse cellular processes, including release from necrotic cells and secretion by activated macrophages engulfing apoptotic cells. Initially described as solely chromatin-associated, HMGB1 was additionally discovered in the cytoplasm of several types of cultured mammalian cells 6 years later. In addition to its intracellular role, HMGB1 has been identified extracellularly as a putative leaderless cytokine and differentiation factor. In the years since its discovery, HMGB1 has also been implicated in disease states, including Alzheimer's, sepsis, ischemia-reperfusion, arthritis, and cancer. In cancer, overexpression of HMGB1, particularly in conjunction with its receptor for advanced glycation end products, has been associated with the proliferation and metastasis of many tumor types, including breast, colon, melanoma, and others. This review focuses on current knowledge and speculation on the role of HMGB1 in the development of cancer, metastasis, and potential targets for therapy.
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Affiliation(s)
- Jessica E Ellerman
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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38
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Jiang W, Pisetsky DS. Mechanisms of Disease: the role of high-mobility group protein 1 in the pathogenesis of inflammatory arthritis. ACTA ACUST UNITED AC 2007; 3:52-8. [PMID: 17203009 DOI: 10.1038/ncprheum0379] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2006] [Accepted: 11/07/2006] [Indexed: 11/09/2022]
Abstract
High-mobility group protein 1 (HMG1) is a nonhistone nuclear protein that is a prototype of a dual-function alarmin whose immune activity is dependent upon its cellular location. Inside the cell, HMG1 binds to DNA and has a role in transcriptional regulation. Outside the cell, HMG1 acts as a cytokine and has activities that resemble those of tumor necrosis factor. The cytokine activities of HMG1 become manifest when this protein translocates from the nucleus to the cytoplasm and, eventually, into the external milieu; this translocation occurs during cell activation and cell death. Given its cytokine activity, HMG1 has been implicated in the pathogenesis of a broad range of immune-mediated diseases including arthritis. The role for this protein in arthritis was established by observations of the expression of HMG1 in synovial tissue of patients with rheumatoid arthritis as well as in the joints of animals used to model arthritis. Furthermore, in the mouse model of collagen-induced arthritis, treatment with antibodies to HMG1 or to an inhibitory domain of HMG1 can attenuate joint inflammation and damage. These studies identify a novel pathway in the pathogenesis of inflammatory arthritis, as well as a new target for biologic therapy.
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Affiliation(s)
- Weiwen Jiang
- Department of Medicine, Duke University Medical Center, Durham, NC 27705, USA
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Jeon EJ, Kwak HW, Song JH, Lee YW, Chung JW, Choi JC, Shin JW, Park IW, Choi BW, Kim JY. Proinflammatory Effects of High Mobility Group B1 (HMGB1) Versus LPS and the Mechanism of IL-8 Promoter Stimulation by HMGB1. Tuberc Respir Dis (Seoul) 2007. [DOI: 10.4046/trd.2007.62.4.299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Eun Ju Jeon
- Department of Internal Medicine, ChungAng University College of Medicine, Seoul, Korea
| | - Hee Won Kwak
- Department of Internal Medicine, ChungAng University College of Medicine, Seoul, Korea
| | - Ju Han Song
- Department of Internal Medicine, ChungAng University College of Medicine, Seoul, Korea
| | - Young Woo Lee
- Department of Internal Medicine, ChungAng University College of Medicine, Seoul, Korea
| | - Jae Woo Chung
- Department of Internal Medicine, ChungAng University College of Medicine, Seoul, Korea
| | - Jae Chul Choi
- Department of Internal Medicine, ChungAng University College of Medicine, Seoul, Korea
| | - Jong Wook Shin
- Department of Internal Medicine, ChungAng University College of Medicine, Seoul, Korea
| | - In Won Park
- Department of Internal Medicine, ChungAng University College of Medicine, Seoul, Korea
| | - Byoung Whui Choi
- Department of Internal Medicine, ChungAng University College of Medicine, Seoul, Korea
| | - Jae Yeol Kim
- Department of Internal Medicine, ChungAng University College of Medicine, Seoul, Korea
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40
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de Oliveira FMB, de Abreu da Silva IC, Rumjanek FD, Dias-Neto E, Guimarães PEM, Verjovski-Almeida S, Stros M, Fantappié MR. Cloning the genes and DNA binding properties of High Mobility Group B1 (HMGB1) proteins from the human blood flukes Schistosoma mansoni and Schistosoma japonicum. Gene 2006; 377:33-45. [PMID: 16644144 DOI: 10.1016/j.gene.2006.03.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2005] [Revised: 03/02/2006] [Accepted: 03/03/2006] [Indexed: 11/18/2022]
Abstract
The parasitic helminth Schistosoma mansoni contains three HMGB proteins, HMGB1, HMGB2 and HMGB3, of primary amino acid sequences highly similar to vertebrate proteins. In this report we describe the characterization of the HMGB1 proteins and their genes from S. mansoni and Schistosoma japonicum. The deduced amino acid sequences of HMGB1 proteins from both schistosome species are identical, and comprise 176 residues. The proteins contain the two evolutionarily highly conserved HMG-box domains, A and B, exhibiting 60% similarity to mammalian HMGB1. Unlike the human HMGB1 which contains an unbroken run of 30 glutamic or aspartic residues, the SmHMGB1 or SjHMGB1 proteins possess unusually short acidic C-terminal tails (5 acidic residues interrupted by 2 serines). Southern hybridization and DNA sequencing revealed a single copy HMGB1 gene, composed of 3 exons and two introns, in S. mansoni. The exon/intron boundaries are identical to those of the human HMGB1 gene, with the exception that the second exon of the SmHMGB1 gene which is not split into two exons as in the human HMGB1 gene. RNA blot analysis revealed that the SmHMGB1 gene is constitutively expressed in similar levels both in male and female worms. The single-sized mRNA for SmHMGB1 is consistent with the size derived from the cDNA. Although DNA binding properties of SmHMGB1 (or SjHMGB1) protein seem to be similar to those previously reported with human HMGB1, i.e., preferential binding to supercoiled DNA over linear DNA, specific recognition of DNA four-way junctions, DNA-induced supercoiling in the presence of topoisomerase I, and DNA bending, we have observed two important differences relative to those observed with the human HMGB1: (i) the inability of the isolated SmHMGB1 domain A to bend DNA (as revealed by T4 ligase-mediated circularization assay), and (ii) higher DNA supercoiling and bending potential of the SmHMGB1 protein as compared to its human counterpart. The latter finding may indicate that the long acidic C-tail of human HMGB1 has much stronger repressive role on DNA bending or DNA supercoiling by topoisomerase I at physiological ionic strength than the short C-tail of the SmHMGB1 protein. Considering the important role of HMGB1 in DNA replication, transcription, recombination, and in particularly, the mediation of inflammation responses in mammalian cells, further studies on schistosome HMGB proteins may provide valuable information related to schistosomiasis, where inflammation plays a critical role in this disease.
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MESH Headings
- Amino Acid Sequence
- Animals
- Base Sequence
- Cloning, Molecular
- DNA, Complementary/genetics
- DNA, Helminth/chemistry
- DNA, Helminth/genetics
- DNA, Helminth/metabolism
- DNA, Superhelical/chemistry
- DNA, Superhelical/genetics
- DNA, Superhelical/metabolism
- Genes, Helminth
- HMGB1 Protein/genetics
- HMGB1 Protein/metabolism
- Helminth Proteins/genetics
- Helminth Proteins/metabolism
- Humans
- Molecular Sequence Data
- Nucleic Acid Conformation
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Schistosoma japonicum/genetics
- Schistosoma japonicum/metabolism
- Schistosoma japonicum/pathogenicity
- Schistosoma mansoni/genetics
- Schistosoma mansoni/metabolism
- Schistosoma mansoni/pathogenicity
- Sequence Homology, Amino Acid
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O'Callaghan A, Wang J, Redmond HP. HMGB1 as a key mediator of tissue response to injury: roles in inflammation and tissue repair. Eur Surg 2006. [DOI: 10.1007/s10353-006-0255-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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42
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Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, Sohn JW, Yamada S, Maruyama I, Banerjee A, Ishizaka A, Abraham E. High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 2005; 290:C917-24. [PMID: 16267105 DOI: 10.1152/ajpcell.00401.2005] [Citation(s) in RCA: 739] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
High mobility group box 1 (HMGB1), originally described as a DNA-binding protein, can also be released extracellularly and functions as a late mediator of inflammatory responses. Although recent reports have indicated that the receptor for advanced glycation end products (RAGE) as well as Toll-like receptor (TLR)2 and TLR4 are involved in cellular activation by HMGB1, there has been little evidence of direct association between HMGB1 and these receptors. To examine this issue, we used fluorescence resonance energy transfer (FRET) and immunoprecipitation to directly investigate cell surface interactions of HMGB1 with TLR2, TLR4, and RAGE. FRET images in RAW264.7 macrophages demonstrated association of HMGB1 with TLR2 and TLR4 but not RAGE. Transient transfections into human embryonic kidney-293 cells showed that HMGB1 induced cellular activation and NF-kappaB-dependent transcription through TLR2 or TLR4 but not RAGE. Coimmunoprecipitation also found interaction between HMGB1 and TLR2 as well as TLR4, but not with RAGE. These studies provide the first direct evidence that HMGB1 can interact with both TLR2 and TLR4 and also supply an explanation for the ability of HMGB1 to induce cellular activation and generate inflammatory responses that are similar to those initiated by LPS.
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Affiliation(s)
- Jong Sung Park
- Division of Pulmonary Sciences and Critical Care Medicine, Box C272, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262, USA
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43
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Müller S, Ronfani L, Bianchi ME. Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function. J Intern Med 2004; 255:332-43. [PMID: 14871457 DOI: 10.1111/j.1365-2796.2003.01296.x] [Citation(s) in RCA: 292] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
High mobility group box protein 1 (HMGB1) has been considered as a ubiquitous nuclear protein with an architectural function, but even early reports have described its presence outside of the nucleus. Today, we have only started to understand the extranuclear and extracellular functions of HMGB1: we know that it participates in developmental and differentiation processes, triggers and modulates many of the inflammatory cascades in the body, and may even be involved in the metastatic invasion programme of cancer cells. Given such diverse roles, it is important to know which cells express HMGB1, where, and how much. The present review deals with the expression pattern of HMGB1 and provides evidence that, far from being housekeeping, the HMGB1 gene is tightly regulated. This can have implications for therapeutic intervention on inflammatory diseases as well as cancer.
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Affiliation(s)
- S Müller
- San Raffaele Scientific Institute, San Raffaele University, Milan, Italy
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Abstract
High mobility group box 1 (HMGB1), a 30 kDa nuclear and cytosolic protein widely studied as a transcription factor and growth factor, has recently been identified as a cytokine mediator of lethal systemic inflammation (e.g. endotoxaemia and sepsis), arthritis and local inflammation. It is released by activated macrophages, and serum levels increase significantly during endotoxaemia, sepsis and arthritis with significant delayed kinetics in comparison with tumour necrosis factor (TNF) and interleukin-1beta. Recently identified biological activities of HMGB1 include activation of macrophages/monocytes to release proinflammatory cytokines, upregulation of endothelial adhesion molecules, stimulation of epithelial cell barrier failure, and mediation of fever and anorexia. Passive immunization with anti-HMGB1 antibodies confers significant protection against lethal endotoxaemia, sepsis, arthritis and lipopolysaccharide-induced acute lung injury, even when antibody administration is delayed until after the early TNF responses have resolved. Strategies to inhibit HMGB1 activity and release are being investigated in these and other preclinical models of acute and chronic inflammation.
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Affiliation(s)
- H Wang
- Laboratory of Emergency Medicine, North Shore-LIJ Research Institute, Manhasset, NY 11030, USA.
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45
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Abstract
HMGB1 is a member of the high-mobility group protein superfamily that has been widely studied as nuclear proteins that bind DNA, stabilize nucleosomes and facilitate gene transcription. A series of recent discoveries revealed a cytokine activity of HMGB1, that when secreted into the extracellular milieu, mediates downstream inflammatory responses in endotoxemia, arthritis and sepsis. HMGB1 is properly defined as a cytokine because it stimulates proinflammatory responses in monocytes/macrophages, is produced during inflammatory responses in vivo in standardized models of systemic and local inflammation, mediates delayed endotoxin lethality, and is required for the full expression of inflammation in animal models of endotoxemia, sepsis and arthritis. HMGB1 is either actively secreted by monocytes/macrophages or passively released from necrotic cells from any tissue. These pathways are central for the biology of HMGB1 as a cytokine, since they provide key mechanisms that integrate the inflammatory response to infectious and non-infectious cell injuries. Receptor signal transduction of HMGB1 occurs in part through the receptor for advanced glycation end-products (RAGE) expressed on monocytes/macrophages, endothelial cells, neurons and smooth-muscle cells. HMGB1 is a late-acting cytokine, because it first appears in the extracellular milieu 8-12 h after the initial macrophage response to proinflammatory stimuli. Knowledge of the cytokine role of HMGB1 has implications for understanding downstream cytokine cascades, regulation of delayed innate immune responses and targeting treatment towards these processes. Effectiveness of delayed treatment with HMGB1 blockade up to 24 h after induction of experimental sepsis offers a unique window of opportunities to allow rescue from lethal sepsis.
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Affiliation(s)
- Ulf Andersson
- Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden.
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46
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Abstract
Sepsis, a lethal systemic inflammatory response to infection, affects nearly 750,000 patients in the United States annually and has a mortality of 30%. Mounting evidence has implicated cytokines, circulating factors produced by the innate immune system, as critical mediators of sepsis-related tissue injury and death. Many resources have been expended to elucidate the pathologic mechanisms that underlie sepsis and to develop appropriate and effective therapeutics. To date, no anti-inflammatory agent has been clinically approved for the treatment of sepsis because even a slight delay in administration of therapeutics that target inflammatory mediators renders most approaches ineffective. These and other findings, described in part in this review, suggest that successful clinical management of sepsis may be dependent on identification of late-acting, downstream lethal mediators that can be targeted in a broader therapeutic window. A candidate mediator of delayed lethality is high mobility group box 1, a cellular and nuclear protein that is now recognized as a cytokine and experimental therapeutic target.
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Affiliation(s)
- Christopher J Czura
- Laboratory of Biomedical Science, North Shore-LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030, USA
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47
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Andersson U, Erlandsson‐Harris H, Yang H, Tracey KJ. HMGB1 as a DNA‐binding cytokine. J Leukoc Biol 2002. [DOI: 10.1189/jlb.72.6.1084] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Ulf Andersson
- Department of Medicine, Rheumatology Research Unit, Karolinska Hospital, Stockholm, Sweden
- Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children’s Hospital, Stockholm, Sweden
| | | | - Huan Yang
- Laboratory of Biomedical Science, North Shore–Long Island Jewish Research Institute, Manhasset, New York
| | - Kevin J. Tracey
- Laboratory of Biomedical Science, North Shore–Long Island Jewish Research Institute, Manhasset, New York
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48
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Czura CJ, Wang H, Tracey KJ. Dual roles for HMGB1: DNA binding and cytokine. JOURNAL OF ENDOTOXIN RESEARCH 2002; 7:315-21. [PMID: 11717586 DOI: 10.1177/09680519010070041401] [Citation(s) in RCA: 89] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Effective therapies against overwhelming Gram-negative bacteremia, or sepsis, have eluded successful development. The discovery that tumor necrosis factor (TNF), a host-derived inflammatory mediator, was both necessary and sufficient to recapitulate Gram-negative sepsis raised cautious optimism for developing a targeted therapeutic. However, the rapid kinetics of the TNF response to infection defined an extremely narrow window of opportunity during which anti-TNF therapeutics could be successfully administered. HMGB1 was previously studied as a DNA-binding protein involved in DNA replication, repair, and transcription; and as a membrane-associated protein that mediates neurite outgrowth. A decade-long search has culminated in our identification of HMGB1 as a late mediator of endotoxemia. HMGB1 is released by macrophages upon exposure to endotoxin, activates many other pro-inflammatory mediators, and is lethal to otherwise healthy animals. Elevated levels of HMGB1 are observed in the serum of patients with sepsis, and the highest levels were found in those patients that died. The delayed kinetics of HMGB1 release indicate that it may be useful to target this toxic cytokine in the development of future therapies.
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Affiliation(s)
- C J Czura
- Laboratory of Biomedical Science, North Shore/Long Island Jewish Research Institute, Manhasset, New York 11030, USA
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49
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Ronfani L, Ferraguti M, Croci L, Ovitt CE, Schöler HR, Consalez GG, Bianchi ME. Reduced fertility and spermatogenesis defects in mice lacking chromosomal protein Hmgb2. Development 2001; 128:1265-73. [PMID: 11262228 DOI: 10.1242/dev.128.8.1265] [Citation(s) in RCA: 146] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
High mobility group 2 protein (Hmgb2) is a member of the HMGB protein family, which includes the ubiquitous Hmgb1 and the embryo-specific Hmgb3. The three proteins are more than 80% identical at the amino acid level and their biochemical properties are indistinguishable. Hmgb1 is an abundant component of all mammalian nuclei and acts as an architectural factor that bends DNA and promotes protein assembly on specific DNA targets. Cells that lack Hmgb1 can survive, although mutant mice die shortly after birth. As Hmgb2 is present in all cultured cells and is abundant in thymus, the preferred source for HMGB proteins, it was considered a ubiquitous variant of Hmgb1. We show that in adult mice Hmgb2 is restricted mainly to lymphoid organs and testes, although it is widely expressed during embryogenesis. Mice that lack Hmgb2 are viable. However, male Hmgb2(−)(/)(−) mice have reduced fertility, that correlates with Sertoli and germ cell degeneration in seminiferous tubules and immotile spermatozoa. Significantly, Hmgb2 is expressed at very high levels in primary spermatocytes, while it is barely detectable in spermatogonia and elongated spermatids. This peculiar pattern of expression and the phenotype of mutants indicate that Hmgb2 has a specialised role in germ cell differentiation.
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Affiliation(s)
- L Ronfani
- DIBIT, Istituto Scientifico San Raffaele, via Olgettina 58, Italy
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50
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Charbonneau A, The VL. Genomic organization of a human 5beta-reductase and its pseudogene and substrate selectivity of the expressed enzyme. BIOCHIMICA ET BIOPHYSICA ACTA 2001; 1517:228-35. [PMID: 11342103 DOI: 10.1016/s0167-4781(00)00278-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The enzyme 5beta-reductase catalyzes the reduction of the 4-ene of 3-ketosteroids, converting them into 5beta-dihydro-3-ketosteroids and, thus, could be involved in the metabolism of 4-cholestene-3-one, progesterone, 17~-hydroxyprogesterone, aldosterone, corticosterone, cortisol, 4-androstenedione, and testosterone. In this study, we report the genomic structure of a human 5beta-reductase gene, its tissue distribution, the characterization of an intronless pseudogene and the substrate selectivity of the enzyme. The gene coding for the active 5beta-reductase contains nine exons like most members of the aldo-keto reductase family, but the sequence covered by the gene, more than 42 kb, is much longer than the sequence of other members of this family. There are many large introns, especially introns 3, 4 and 7 that span approx. 7 kb, and intron 1 that contains more than 10 kb. Northern blot analysis showed three band sizes of 1.3, 2.2 and 2.7 kb. The 1.3 and 2.7 kb bands are highly expressed in the liver while weaker 2.2 and 1.3 kb bands have been observed in the testis and colon, respectively. We also identified an intronless gene having 86% homology with the 5beta-reductase cDNA sequence. Since its sequence contains many stop codons, this gene is most probably a pseudogene. To determine more precisely the substrate selectivity of the enzyme, we established a stable cell line expressing human 5beta-reductase in transformed embryonic kidney (HEK-293) cells. The transfected cells efficiently catalyze the transformation of progesterone, androstenedione, 17alpha-hydroxyprogesterone and testosterone. However, they catalyze much less efficiently the transformation of compounds containing an 11beta-hydroxy group, such as aldosterone, corticosterone and cortisol. In addition to its role in cholesterol catabolism, it is well recognized that 5beta-reductase inactivates active androgens. Indeed, 5beta-dihydrotestosterone (5beta-DHT), the product of the reduction of testosterone by 5beta-reductase, is not active while its 5~-isomer (DHT) is the most potent natural androgen. Recent findings show that 5beta-pregnanes are active ligands in the induction of CYP3A through the orphan receptor hPAR. Our results thus open an opportunity for studying the new role of 5beta-reductase in the formation of a new type of active steroids.
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Affiliation(s)
- A Charbonneau
- Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), 2705 Laurier Boulevard, Quebec, G1V 4G2, Canada
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