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Datta S, Rahman MA, Koka S, Boini KM. High Mobility Group Box 1 (HMGB1): Molecular Signaling and Potential Therapeutic Strategies. Cells 2024; 13:1946. [PMID: 39682695 PMCID: PMC11639863 DOI: 10.3390/cells13231946] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/19/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
High Mobility Group Box 1 (HMGB1) is a highly conserved non-histone chromatin-associated protein across species, primarily recognized for its regulatory impact on vital cellular processes, like autophagy, cell survival, and apoptosis. HMGB1 exhibits dual functionality based on its localization: both as a non-histone protein in the nucleus and as an inducer of inflammatory cytokines upon extracellular release. Pathophysiological insights reveal that HMGB1 plays a significant role in the onset and progression of a vast array of diseases, viz., atherosclerosis, kidney damage, cancer, and neurodegeneration. However, a clear mechanistic understanding of HMGB1 release, translocation, and associated signaling cascades in mediating such physiological dysfunctions remains obscure. This review presents a detailed outline of HMGB1 structure-function relationship and its regulatory role in disease onset and progression from a signaling perspective. This review also presents an insight into the status of HMGB1 druggability, potential limitations in understanding HMGB1 pathophysiology, and future perspective of studies that can be undertaken to address the existing scientific gap. Based on existing paradigm of various studies, HMGB1 is a critical regulator of inflammatory cascades and drives the onset and progression of a broad spectrum of dysfunctions. Studies focusing on HMGB1 druggability have enabled the development of biologics with potential clinical benefits. However, deeper understanding of post-translational modifications, redox states, translocation mechanisms, and mitochondrial interactions can potentially enable the development of better courses of therapy against HMGB1-mediated physiological dysfunctions.
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Affiliation(s)
- Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Mohammad Atiqur Rahman
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA;
| | - Krishna M. Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
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Zheng X, Wang Q, Xu X, Huang X, Chen J, Huo X. Associations of insulin sensitivity and immune inflammatory responses with child blood lead (Pb) and PM 2.5 exposure at an e-waste recycling area during the COVID-19 lockdown. ENVIRONMENTAL GEOCHEMISTRY AND HEALTH 2024; 46:296. [PMID: 38980420 DOI: 10.1007/s10653-024-02066-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/04/2024] [Indexed: 07/10/2024]
Abstract
Fine particular matter (PM2.5) and lead (Pb) exposure can induce insulin resistance, elevating the likelihood of diabetes onset. Nonetheless, the underlying mechanism remains ambiguous. Consequently, we assessed the association of PM2.5 and Pb exposure with insulin resistance and inflammation biomarkers in children. A total of 235 children aged 3-7 years in a kindergarten in e-waste recycling areas were enrolled before and during the Corona Virus Disease 2019 (COVID-19) lockdown. Daily PM2.5 data was collected and used to calculate the individual PM2.5 daily exposure dose (DED-PM2.5). Concentrations of whole blood Pb, fasting blood glucose, serum insulin, and high mobility group box 1 (HMGB1) in serum were measured. Compared with that before COVID-19, the COVID-19 lockdown group had lower DED-PM2.5 and blood Pb, higher serum HMGB1, and lower blood glucose and homeostasis model assessment of insulin resistance (HOMA-IR) index. Decreased DED-PM2.5 and blood Pb levels were linked to decreased levels of fasting blood glucose and increased serum HMGB1 in all children. Increased serum HMGB1 levels were linked to reduced levels of blood glucose and HOMA-IR. Due to the implementation of COVID-19 prevention and control measures, e-waste dismantling activities and exposure levels of PM2.5 and Pb declined, which probably reduced the association of PM2.5 and Pb on insulin sensitivity and diabetes risk, but a high level of risk of chronic low-grade inflammation remained. Our findings add new evidence for the associations among PM2.5 and Pb exposure, systemic inflammation and insulin resistance, which could be a possible explanation for diabetes related to environmental exposure.
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Affiliation(s)
- Xiangbin Zheng
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, 855 East Xingye Avenue, Guangzhou, 511443, Guangdong, China
- Center for Reproductive Medicine, Clinical Research Center, Shantou Central Hospital, Shantou, 515041, Guangdong, China
| | - Qihua Wang
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, 855 East Xingye Avenue, Guangzhou, 511443, Guangdong, China
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands
| | - Xijin Xu
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Xiaofan Huang
- Center for Reproductive Medicine, Clinical Research Center, Shantou Central Hospital, Shantou, 515041, Guangdong, China
| | - Jiaxue Chen
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Xia Huo
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, 855 East Xingye Avenue, Guangzhou, 511443, Guangdong, China.
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Assessment of metabolic syndrome predictors in relation to inflammation and visceral fat tissue in older adults. Sci Rep 2023; 13:89. [PMID: 36596839 PMCID: PMC9810713 DOI: 10.1038/s41598-022-27269-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 12/29/2022] [Indexed: 01/04/2023] Open
Abstract
The diagnosis of metabolic syndrome (MetS) focuses on the assessment of risk factors such as insulin resistance, dyslipidemia, central adiposity and elevated blood pressure. Evidence suggests that markers of systemic inflammation may also be included in the definition of MetS and play some role in its pathogenesis. The study was designed to evaluate low-grade inflammation status in older adults with MetS in relation to increased body fat tissue and an attempt was made to evaluate new predictors for MetS through the analysis of the ROC Curve. Ninety-six middle-aged (69.2 ± 4.9) individuals from University of Third Age (women n = 75 and men n = 21) were allocated to two groups: without metabolic syndrome (n = 37) and with metabolic syndrome (n = 59) according to International Diabetes Federation criteria in agreement with American Heart Association/National Heart, Lung and Blood Institute 2009. Participants' current health status was assessed using medical records from a routine follow-up visit to a primary care physician. Statistical analysis was performed using R studio software. Depending on the normal distribution, ANOVA or the Kruskal-Wallis test was used. The optimal threshold value for clinical stratification (cut-off value) was obtained by calculating the Youden index. The AUC was observed to be the highest for a new anthropometric index i.e. lipid accumulation product (0.820). Low-grade inflammation dominated in MetS group (BMI 28.0 ± 4.4 kg/m2, WHR 0.9 ± 0.1, FM 24.7 ± 7.9 kg) where significantly higher values of TNF-α (p = 0.027) and HGMB-1 protein (p = 0.011) were recorded.The optimal threshold values for immunological indices assessed as new predictors of the metabolic syndrome were: 93.4 for TNF-α, 88.2 for HGMB-1 protein and 1992.75 for ghrelin. High AUC values for these indices additionally confirmed their high diagnostic usefulness in MetS.
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Al-Hakeim HK, Al-Kaabi QJ, Maes M. High mobility group box 1 and Dickkopf-related protein 1 as biomarkers of glucose toxicity, atherogenicity, and lower β cell function in patients with type 2 diabetes mellitus. Growth Factors 2022; 40:240-253. [PMID: 36165005 DOI: 10.1080/08977194.2022.2126317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is associated with increased atherogenicity and inflammatory responses, which may be related to high mobility group box 1 (HMGB1) and Dickkopf-related protein 1 (DKK1). The role of HMGB1 and DKK1 in T2DM is examined in association with lipid and insulin profiles. Serum HMGB1 and DKK1 were measured in T2DM with and without hypertension and compared with controls. The results showed that HMGB1 and DKK1 are higher in T2DM irrespective of hypertension. A large part of the variance in the β-cell index and glucose toxicity was explained by the combined effects of HMGB1 and DKK1. In conclusion, both HMGB1 and DKK1 may contribute to increased atherogenicity in T2DM. Moreover, both biomarkers may cause more deficits in β-cell function and increase glucose toxicity leading to the development of more inflammation and diabetic complications. HMGB1 and the Wnt pathways are other drug targets in treating T2DM.
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Affiliation(s)
| | | | - Michael Maes
- Faculty of Medicine, Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
- School of Medicine, IMPACT Strategic Research Centre, Deakin University, Geelong, Australia
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Liu S, Wang X, Kai Y, Tian C, Guo S, He L, Zhai D, Song X. Clinical significance of high mobility group box 1/toll-like receptor 4 in obese diabetic patients. Endocr J 2022; 69:235-242. [PMID: 34657898 DOI: 10.1507/endocrj.ej21-0381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
High mobility group box 1 (HMGB1) is an alarmin that may link to obesity and type 2 diabetes mellitus (T2DM). The present study analyzed the correlation between HMGB1/ Toll-like receptor 4 (TLR4) and certain biochemical parameters in obese (OB) diabetic patients. 40 normal glucose tolerant subjects (NGT) and 40 patients with newly diagnosed T2DM were enrolled. All patients were further divided into non-obese NGT (NGT-NOB), obese NGT (NGT-OB), non-obese T2DM (T2DM-NOB) and obese T2DM (T2DM-OB) groups according to body mass index (BMI).The levels of HMGB1 in serum were quantified using ELISA, whereas the mRNA expression levels of TLR4 in peripheral blood mononuclear cells were assessed using reverse transcription-quantitative PCR. The results suggested that the levels of HMGB1 and TLR4 were higher in NGT-OB and T2DM-NOB groups compared with those in NGT-NOB group. Similarly, the levels of these two markers were higher in T2DM-OB group compared with those in NGT-OB group. Correlation analysis indicated that the levels of HMGB1 and TLR4 were positively correlated with triglyceride (TG), fasting plasma glucose (FPG) levels and BMI, whereas a negative correlation between HMGB1 and high density lipoprotein (HDL) was noted. Linear regression analysis suggested that HMGB1 was associated with FPG and TG levels, whereas TLR4 was strongly associated with TG levels and BMI. The results demonstrated that the expression levels of HMGB1 and TLR4 in patients with T2DM or obesity were increased, which were associated with glycolipid metabolism disorders. Therefore, the HMGB1/TLR4 may serve a role in inflammatory process associated with obesity and T2DM.
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Affiliation(s)
- Shuai Liu
- Department of Blood Transfusion, the Third Affiliated Hospital of Xinxiang Medical University, Henan Xinxiang, 453003, China
| | - Xianchun Wang
- Clinical laboratory, the Third Affiliated Hospital of Xinxiang Medical University, Henan Xinxiang, 453003, China
| | - Yue Kai
- Department of Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Henan Xinxiang, 453003, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Henan Xinxiang, 453000, China
| | - Chenrui Tian
- Department of Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Henan Xinxiang, 453003, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Henan Xinxiang, 453000, China
| | - Sheng Guo
- Department of Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Henan Xinxiang, 453003, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Henan Xinxiang, 453000, China
| | - Ling He
- Department of Ophthalmology, the 371 Affiliated Hospital of Xinxiang Medical University, Henan Xinxiang, 453003, China
| | - Desheng Zhai
- Department of Epidemiology and Biostatistics, School of Public Health, Xinxiang Medical University, Henan Xinxiang, 453003, China
| | - Xiangfeng Song
- Department of Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Henan Xinxiang, 453003, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Henan Xinxiang, 453000, China
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The influence of gastric bypass surgery on the concentration of high mobility group box 1, nuclear factor erythroid 2-related factor 2 and the genes expression of high mobility group box 1, nuclear factor erythroid2-related factor 2, interleukin 6, and tumor necrosis factor-alpha in the peripheral blood mononuclear cells of patients with morbid obesity. Mol Biol Rep 2022; 49:3745-3755. [PMID: 35107739 DOI: 10.1007/s11033-022-07214-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/27/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND AND OBJECTIVES Obesity is known as a disease with a chronic low-grade state of inflammation and high levels of oxidative stress. Given the challenges and consequences caused by obesity, obesity therapy is an essential subject to address. For sustainable weight loss, gastric bypass surgery is the most successful and essential option. METHODS This prospective cohort study was performed on 35 patients aged (18-54) with morbid obesity (BMI: 42.06 kg/m2). Volunteers blood was taken, and peripheral blood mononuclear cells (PBMCs) were isolated, high mobility group box 1(HMGB1), nuclear factor erythroid2-related factor 2(Nrf2), Interleukin 6(IL-6), tumor necrosis factor-alpha (TNF-α), and biochemical factors were determined one day before and 4 months after surgery. RESULTS Four months following surgery, the BMI, hip and waist circumferences, and waist-to-hip ratio (WHR) all decreased significantly. The lipid profile and antioxidant power were dramatically enhanced after surgery. IL-6 and TNF-α expression in PBMC patients showed a significant decrease after surgery. HMGB1 and Nrf2 expression in PBMC of postoperative patients decreased compared to before surgery, and HMGB1, and Nrf2 protein levels also decreased after surgery. CONCLUSION Weight loss indicated the significant function of adipose tissue in the induction of oxidative stress and inflammatory factors. Gastric bypass reduced the inflammation conditions and improved the metabolic status and living situations in the patients with morbid obesity.
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Chimenz R, Chirico V, Basile P, Carcione A, Conti G, Monardo P, Lacquaniti A. HMGB-1 and TGFβ-1 highlight immuno-inflammatory and fibrotic processes before proteinuria onset in pediatric patients with Alport syndrome. J Nephrol 2021; 34:1915-1924. [PMID: 33761123 DOI: 10.1007/s40620-021-01015-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 03/02/2021] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Alport syndrome (ALP) is a rare genetic condition characterized by progressive involvement of the basal membranes and renal dysfunction. The purpose of the study was to evaluate urinary (u) and serum (s) levels of tumor growth factor (TGF)-beta(β) and high mobility group box (HMGB)-1 in ALP patients with normal renal function, albuminuria and proteinuria. METHODS A prospective, single-center study was performed with a follow-up period of 12 months, enrolling 11 pediatric ALP patients and 10 healthy subjects (HS). Normal values of serum creatinine, albuminuria and proteinuria, as well as unaltered estimated glomerular filtration rate (eGFR) were required at enrollment. RESULTS ALP patients had significantly higher levels of serum and urinary HMGB1 compared to HS. The same trend was observed for TGF-β1, with higher values in ALP patients than in HS. HMGB1 and TGF-β1 correlated with each other and with markers of renal function and damage. Urinary biomarkers did not correlate with eGFR, whereas sHMGB1 and sTGF-β1 were negatively related to filtration rate (r: - 0.66; p = 0.02, r: - 0.96; p < 0.0001, respectively). Using proteinuria as a dependent variable in a multiple regression model, only the association with sTGF-β1 (β = 0.91, p < 0.0001) remained significant. CONCLUSIONS High levels of HMGB1 and TGF-β1 characterized ALP patients with normal renal function, highlighting the subclinical pro-fibrotic and inflammatory mechanisms triggered before the onset of proteinuria. Further studies are needed to evaluate the role of HMGB1 and TGFβ-1 in ALP patients.
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Affiliation(s)
- R Chimenz
- Pediatric Nephrology and Dialysis Unit, University Hospital "G. Martino", Messina, Italy.
| | - V Chirico
- Pediatric Nephrology and Dialysis Unit, University Hospital "G. Martino", Messina, Italy
| | - P Basile
- Pediatric Nephrology and Dialysis Unit, University Hospital "G. Martino", Messina, Italy
| | - A Carcione
- Pediatric Nephrology and Dialysis Unit, University Hospital "G. Martino", Messina, Italy
| | - G Conti
- Pediatric Nephrology and Dialysis Unit, University Hospital "G. Martino", Messina, Italy
| | - P Monardo
- Nephrology and Dialysis Unit, Papardo Hospital, Messina, Italy
| | - A Lacquaniti
- Nephrology and Dialysis Unit, Papardo Hospital, Messina, Italy
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Yahia S, El-Farahaty R, El-Gilany AH, Shoaib R, Ramadan R, Salem N. Serum adiponectin, body adiposity and metabolic parameters in obese Egyptian children with Down syndrome. J Pediatr Endocrinol Metab 2021; 34:1401-1410. [PMID: 34348423 DOI: 10.1515/jpem-2021-0324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 07/19/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Children with Down syndrome (DS) have a higher risk for obesity. Adiponectin plays a crucial role in obesity-related cardiometabolic comorbidities. The study aimed to explore whether body adiposity indicators, the frequency of metabolic syndrome (MetS) and its components, serum adiponectin and insulin resistance indices as well as the validity of serum adiponectin as a biomarker for MetS are different in prepubertal obese-DS children compared to matched obese-controls. METHODS Cross-sectional study included 150 prepubertal children classfied into three groups; obese-DS (n=50), obese-control (n=50) and normal-weight-control (n=50). Participants were evaluated for waist-circumference (WC), body adiposity, serum triglycerides, HDL-C, adiponectin and Homeostasis-Model-Assessment of Insulin-Resistance (HOMA-IR). MetS was defined using modified Adult Treatment Panel III-criteria. RESULTS Obese-DS had significantly higher WC, %body fat, total-fat mass, trunk-fat mass, trunk/appendicular-fat mass ratio, triglycerides, insulin and HOMA-IR and significantly lower HDL-C values compared to obese-control. Higher prevalence of MetS and its components were observed in obese-DS that was evident at younger age. Adiponectin was significantly lower in obese-DS compared with obese-control and in obese-DS children with MetS compared to obesecontrol with MetS. The decrease in adiponectin with increasing grades of obesity was pronounced in obese-DS. Adiponectin exhibited strong correlations with body adiposity, several MetS components and HOMA-IR in obese-DS. Adiponectin performed better as a biomarker for MetS among obese-DS (AUC=0.808) than obese-control (AUC=0.674). CONCLUSIONS Prepubertal obese-DS displayed excess body adiposity with pronounced central fat distribution, atherogenic lipid profile and higher insulin resistance compared to matched obese-control. Adiponectin performed better as potential biomarker of MetS in obese-DS than obese-control.
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Affiliation(s)
- Sohier Yahia
- Department of Pediatrics, Genetics Unit, Faculty of Medicine, Mansoura, Egypt
| | - Reham El-Farahaty
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Abdel-Hady El-Gilany
- Public Health Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rasha Shoaib
- Biochemistry Department, Faculty of Science, Damietta University, New Damietta, Egypt
| | | | - Nanees Salem
- Department of Pediatrics, Endocrinology Unit, Faculty of Medicine, Mansoura, Egypt
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Frisardi V, Matrone C, Street ME. Metabolic Syndrome and Autophagy: Focus on HMGB1 Protein. Front Cell Dev Biol 2021; 9:654913. [PMID: 33912566 PMCID: PMC8072385 DOI: 10.3389/fcell.2021.654913] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/18/2021] [Indexed: 12/11/2022] Open
Abstract
Metabolic syndrome (MetS) affects the population worldwide and results from several factors such as genetic background, environment and lifestyle. In recent years, an interplay among autophagy, metabolism, and metabolic disorders has become apparent. Defects in the autophagy machinery are associated with the dysfunction of many tissues/organs regulating metabolism. Metabolic hormones and nutrients regulate, in turn, the autophagy mechanism. Autophagy is a housekeeping stress-induced degradation process that ensures cellular homeostasis. High mobility group box 1 (HMGB1) is a highly conserved nuclear protein with a nuclear and extracellular role that functions as an extracellular signaling molecule under specific conditions. Several studies have shown that HMGB1 is a critical regulator of autophagy. This mini-review focuses on the involvement of HMGB1 protein in the interplay between autophagy and MetS, emphasizing its potential role as a promising biomarker candidate for the early stage of MetS or disease's therapeutic target.
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Affiliation(s)
- Vincenza Frisardi
- Clinical and Nutritional Laboratory, Department of Geriatric and NeuroRehabilitation, Arcispedale Santa Maria Nuova (AUSL-IRCCS), Reggio Emilia, Italy
| | - Carmela Matrone
- Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Maria Elisabeth Street
- Division of Paediatric Endocrinology and Diabetology, Paediatrics, Department of Mother and Child, Arcispedale Santa Maria Nuova (AUSL-IRCCS), Reggio Emilia, Italy
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Li B, Peng X, Li H, Chen F, Chen Y, Zhang Y, Le K. The performance of the alarmin HMGB1 in pediatric diseases: From lab to clinic. Immun Inflamm Dis 2021; 9:8-30. [PMID: 33140586 PMCID: PMC7860603 DOI: 10.1002/iid3.370] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/10/2020] [Accepted: 10/21/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION The ubiquitously expressed nonhistone nuclear protein high-mobility group box protein 1 (HMGB1) has different functions related to posttranslational modifications and cellular localization. In the nucleus, HMGB1 modulates gene transcription, replication and DNA repair as well as determines chromosomal architecture. When the post-transcriptional modified HMGB1 is released into the extracellular space, it triggers several physiological and pathological responses and initiates innate immunity through interacting with its reciprocal receptors (i.e., TLR4/2 and RAGE). The effect of HMGB1-mediated inflammatory activation on different systems has received increasing attention. HMGB1 is now considered to be an alarmin and participates in multiple inflammation-related diseases. In addition, HMGB1 also affects the occurrence and progression of tumors. However, most studies involving HMGB1 have been focused on adults or mature animals. Due to differences in disease characteristics between children and adults, it is necessary to clarify the role of HMGB1 in pediatric diseases. METHODS AND RESULTS Through systematic database retrieval, this review aimed to first elaborate the characteristics of HMGB1 under physiological and pathological conditions and then discuss the clinical significance of HMGB1 in the pediatric diseases according to different systems. CONCLUSIONS HMGB1 plays an important role in a variety of pediatric diseases and may be used as a diagnostic biomarker and therapeutic target for new strategies for the prevention and treatment of pediatric diseases.
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Affiliation(s)
- Bo Li
- Department of CardiologyChildren's Hospital of Hebei Province Affiliated to Hebei Medical UniversityShijiazhuangHebeiChina
| | - Xin Peng
- Department of OtolaryngologyThe Affiliated Children's Hospital of Nanchang UniversityNanchangJiangxiChina
| | - He Li
- Department of Urology SurgeryQilu Children's Hospital of Shandong UniversityJinanShandongChina
| | - Fei Chen
- Department of Child Health CareQilu Children's Hospital of Shandong UniversityJinanShandongChina
| | - Yuxia Chen
- Ministry of Education Key Laboratory of Child Development and Disorders, and Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, and Rehabilitation Centre, Children's HospitalChongqing Medical UniversityChongqingYuzhongChina
| | - Yingqian Zhang
- Department of CardiologyChildren's Hospital of Hebei Province Affiliated to Hebei Medical UniversityShijiazhuangHebeiChina
| | - Kai Le
- Department of Rehabilitation MedicineThe First Affiliated Hospital of Nanchang UniversityNanchangJiangxiChina
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Behl T, Sharma E, Sehgal A, Kaur I, Kumar A, Arora R, Pal G, Kakkar M, Kumar R, Bungau S. Expatiating the molecular approaches of HMGB1 in diabetes mellitus: Highlighting signalling pathways via RAGE and TLRs. Mol Biol Rep 2021; 48:1869-1881. [PMID: 33479829 DOI: 10.1007/s11033-020-06130-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/24/2020] [Indexed: 12/16/2022]
Abstract
Diabetes mellitus (DM) has become one of the major healthcare challenges worldwide in the recent times and inflammation being one of its key pathogenic process/mechanism affect several body parts including the peripheral and central nervous system. High-mobility group box 1 (HMGB1) is one of the major non-histone proteins that plays a key role in triggering the inflammatory response. Upon its release into the extracellular milieu, HMGB1 acts as an "alarmin" for the immune system to initiate tissue repair as a component of the host defense system. Furthermore, HMGB1 along with its downstream receptors like Toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE) serve as the suitable target for DM. The forthcoming research in the field of diabetes would potentially focus on the development of alternative approaches to target the centre of inflammation that is primarily mediated by HMGB1 to improve diabetic-related complications. This review covers the therapeutic actions of HMGB1 protein, which acts by activating the RAGE and TLR molecules to constitute a functional tripod system, in turn activating NF-κB pathway that contributes to the production of mediators for pro-inflammatory cytokines associated with DM. The interaction between TLR2 and TLR4 with ligands present in the host and the activation of RAGE stimulates various immune and metabolic responses that contribute to diabetes. This review emphasizes to elucidate the role of HMGB1 in the initiation and progression of DM and control over the inflammatory tripod as a promising therapeutic approach in the management of DM.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
| | - Eshita Sharma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Ishnoor Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Arun Kumar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Rashmi Arora
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Giridhari Pal
- Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
| | - Munish Kakkar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Ravinder Kumar
- Cardiovascular Research Institute, Icahn School of Medicine, New York, USA
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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Chen L, Zhu H, Su S, Harshfield G, Sullivan J, Webb C, Blumenthal JA, Wang X, Huang Y, Treiber FA, Kapuku G, Li W, Dong Y. High-Mobility Group Box-1 Is Associated With Obesity, Inflammation, and Subclinical Cardiovascular Risk Among Young Adults: A Longitudinal Cohort Study. Arterioscler Thromb Vasc Biol 2020; 40:2776-2784. [PMID: 32814439 PMCID: PMC7578115 DOI: 10.1161/atvbaha.120.314599] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVE We aimed to characterize circulating HMGB1 (high-mobility group box-1) levels, one of the better-characterized damage-associated molecular patterns, with respect to age, sex, and race in the general population, and investigate the longitudinal associations of HMGB1 with inflammatory markers, obesity, and preclinical markers of cardiovascular disease. Approach and Results: The analyses included 489 participants (50% Blacks, aged 24.6±3.3 years at the first visit) with up to 4 follow-up visits (1149 samples) over a maximum of 8.5 years. Systolic blood pressure, diastolic blood pressure, carotid-femoral pulse wave velocity, and carotid intima-media thickness together with plasma HMGB1, hs-CRP (high-sensitivity C-reactive protein), IFN-γ (interferon-γ), IL-6 (interleukin-6), IL-10 (interleukin-10), and TNF-α (tumor necrosis factor-α) were measured at each visit. At baseline, plasma HMGB1 concentrations were higher in Blacks compared with Whites (3.86 versus 3.20 ng/mL, P<0.001), and in females compared with males (3.75 versus 3.30 ng/mL, P=0.005). HMGB1 concentrations increased with age (P=0.007), and higher levels of obesity measures (P<0.001). Without adjustment for age, sex, race, and body mass index, HMGB1 concentrations were positively associated with hs-CRP, IL-6, TNF-α, systolic blood pressure, diastolic blood pressure, and carotid-femoral pulse wave velocity (P<0.05) but not IL-10, IFN-γ or carotid intima-media thickness. After covariate adjustments, the associations of HMGB1 with hs-CRP, and carotid-femoral pulse wave velocity remained statistically significant (P<0.05). CONCLUSIONS This study demonstrates the age, sex, and race differences in circulating HMGB1. The increasing circulating concentrations of HMGB1 with age suggest a potential role of HMGB1 in the pathogenesis of chronic low-grade inflammation, obesity, and subclinical cardiovascular disease risk.
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Affiliation(s)
- Li Chen
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Haidong Zhu
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Shaoyong Su
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Gregory Harshfield
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Jennifer Sullivan
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Clinton Webb
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - James A. Blumenthal
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
| | - Xiaoling Wang
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Ying Huang
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Frank A. Treiber
- College of Nursing, Medical University of South Carolina, Charleston, SC, USA
- College of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Gaston Kapuku
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Wenjun Li
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Yanbin Dong
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
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13
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Peek V, Neumann E, Inoue T, Koenig S, Pflieger FJ, Gerstberger R, Roth J, Matsumura K, Rummel C. Age-Dependent Changes of Adipokine and Cytokine Secretion From Rat Adipose Tissue by Endogenous and Exogenous Toll-Like Receptor Agonists. Front Immunol 2020; 11:1800. [PMID: 32973755 PMCID: PMC7466552 DOI: 10.3389/fimmu.2020.01800] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 07/06/2020] [Indexed: 01/04/2023] Open
Abstract
White adipose tissue but recently also brown adipose tissue have emerged as endocrine organs. Age-associated obesity is accompanied by prolonged and elevated lipopolysaccharide (LPS)-induced sickness symptoms and increased cytokine and adipokine levels in the circulation partially originating from adipose tissue. In the present study, ex vivo fat explants were used to investigate how the exogenous pathogen-associated molecular pattern (PAMP) LPS or the endogenous danger-associated molecular patterns (DAMPs) high mobility group box-1 protein (HMGB1) and biglycan modulate the release of cytokines and adipokines/batokines and, thus, could influence systemic and/or local inflammation. The response of adipose tissue (epididymal, retroperitoneal, subcutaneous, and brown) was compared between young lean and old obese rats (2 vs. 24 months old). LPS induced a strong interleukin (IL)-6 and tumor necrosis factor (TNF) alpha release into the supernatant of all adipose tissue types investigated. HMGB1 (subcutaneous) and biglycan (retroperitoneal) led to an increased release of IL-6 and TNFalpha (HMGB1) and decreased visfatin and adiponectin (biglycan) secretion from epididymal adipose tissue (young rats). Visfatin was also decreased by HMGB1 in retroperitoneal adipose tissue of old rats. We found significantly higher leptin (all fat pads) and adiponectin (subcutaneous) levels in supernatants of adipose tissue from old compared to young rats, whereas visfatin secretion showed the opposite. The expression of the biglycan receptor Toll-like receptor (TLR) 2 as well as the LPS and HMGB1 receptors TLR4 and receptor for advanced glycation end products (RAGE) were reduced with age (TLR4/RAGE) and by stimulation with their ligands (subcutaneous). Overall, we revealed that adipokines/adipose-tissue released cytokines show some modulation of their release caused by mediators of septic (batokines) and sterile inflammation with potential implication for acute and chronic disease. Moreover, aging may increase or decrease the release of fat-derived mediators. These data show that DAMPS and LPS locally modulate cytokine secretion while only DAMPS but not LPS can locally alter adipokine secretion during inflammation.
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Affiliation(s)
- Verena Peek
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany
| | - Elena Neumann
- Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus Liebig University Gießen, Bad Nauheim, Germany
| | - Tomohiro Inoue
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, Japan
| | - Sandy Koenig
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany
| | - Fabian Johannes Pflieger
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany
| | - Rüdiger Gerstberger
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany
| | - Joachim Roth
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany.,Joachim Roth and Christoph Rummel, Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Marburg, Germany
| | - Kiyoshi Matsumura
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, Japan
| | - Christoph Rummel
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany.,Joachim Roth and Christoph Rummel, Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Marburg, Germany
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14
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Zhu Z, Peng X, Li X, Tu T, Yang H, Teng S, Zhang W, Xing Z, Tang J, Hu X, Fang Z, Zhou S. HMGB1 impairs endothelium‐dependent relaxation in diabetes through TLR4/eNOS pathway. FASEB J 2020; 34:8641-8652. [PMID: 32359123 DOI: 10.1096/fj.202000242r] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/07/2020] [Accepted: 04/17/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Zhaowei Zhu
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
| | - Xiaofan Peng
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
| | - Xuping Li
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
| | - Tao Tu
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
| | - Hui Yang
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
| | - Shuai Teng
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
| | - Wei Zhang
- Department of Internal Medicine Wake Forest University School of Medicine NC USA
| | - Zhenhua Xing
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
| | - Jianjun Tang
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
| | - Xinqun Hu
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
| | - Zhenfei Fang
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
| | - Shenghua Zhou
- Cardiovascular Department The Second Xiangya Hospital Central South University Changsha China
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15
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Cuppari C, Colavita L, Miraglia Del Giudice M, Chimenz R, Salpietro C. Recurrent respiratory infections between immunity and atopy. Pediatr Allergy Immunol 2020; 31 Suppl 24:19-21. [PMID: 32017215 DOI: 10.1111/pai.13160] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/10/2019] [Indexed: 11/30/2022]
Abstract
Recurrent respiratory infections (RRIs) are frequent in children and are characterized by more than 6 airway infections in 1 year or more than 1 upper airway infection per month in the period between September and April or more than 3 lower airway infections in 1 year. Often pediatric RRIs are related to predisposing factors, such as reduced airway size, poor tussive reflex, and immaturity of the immune system. RRIs due to immature immune system are a transient condition, with spontaneous resolution in the school age. However, some RRIs are expression of more complex diseases. Red flags are the onset of symptoms in the first year of life, the involvement of other systems, unusual pathogens, slowing of growth, severe infections of the lower airways, and recurrence of the infection site. To help the pediatrician in the RRI differential diagnosis, we have created a roadmap based on scientific literature data and clinical practice that identifies 6 macro areas: immunodeficiencies, simple minimal genetic immunodeficiency, atopy, obesity, nutritional deficiencies, autoinflammatory diseases, and complex diseases.
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Affiliation(s)
- Caterina Cuppari
- Unit of Pediatric Emergency, Department of Adult and Childhood Human Pathology, University Hospital of Messina, Messina, Italy
| | - Laura Colavita
- Unit of Pediatric Emergency, Department of Adult and Childhood Human Pathology, University Hospital of Messina, Messina, Italy
| | - Michele Miraglia Del Giudice
- Department of Woman, Child and of General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Roberto Chimenz
- Unit of Pediatric Nephrology, Department of Adult and Childhood Human Pathology, University Hospital of Messina, Messina, Italy
| | - Carmelo Salpietro
- Unit of Pediatric Emergency, Department of Adult and Childhood Human Pathology, University Hospital of Messina, Messina, Italy
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16
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Calmasini FB, McCarthy CG, Wenceslau CF, Priviero FBM, Antunes E, Webb RC. Toll-like receptor 9 regulates metabolic profile and contributes to obesity-induced benign prostatic hyperplasia in mice. Pharmacol Rep 2020; 72:179-187. [PMID: 32016843 DOI: 10.1007/s43440-019-00010-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 08/27/2019] [Accepted: 09/10/2019] [Indexed: 01/24/2023]
Abstract
BACKGROUND Benign prostatic hyperplasia (BPH) is associated with obesity and prostatic inflammation. The present study investigated the participation of toll-like receptor 9 (TLR9) in obesity-induced BPH, focusing on metabolic impairments, damage-associated molecular patterns (DAMP) levels and prostatic oxidative stress generation. METHODS C57BL/6 (WT) and TLR9 mutant male mice were fed with regular or high-fat diet for 12 weeks. Metabolic profile, functional protocols, reactive-oxygen species (ROS) generation, prostatic histological analysis and DAMP levels were analyzed. Western blotting for prostatic TLR9 signaling pathway was also performed. RESULTS BPH in WT obese animals was characterized by increased prostate weight, smooth muscle hypercontractility and prostatic epithelial hyperplasia. Higher epididymal fat weight and prostatic ROS generation along with increased fasting glucose, triglyceride and circulating DAMP levels were also observed in WT obese group. Conversely, TLR9 mutant obese animals exhibited lower epididymal fat weight, fasting glucose and triglyceride levels associated with reduced prostate hypercontractility, prostatic ROS and circulating DAMP levels. However, TLR9 mutant obese mice were not protected from obesity-associated prostatic overgrowth and epithelial hyperplasia. Interestingly, TLR9 mutant lean mice exhibited augmented fasting glucose and prostatic ROS levels compared with WT lean mice. Despite increased prostatic expression of TLR9 in WT obese mice, no differences were seen in MyD88 expression between groups. CONCLUSION Improved obesity-induced BPH-related prostatic smooth muscle hypercontractility in TLR9 obese mice may be associated with amelioration in the metabolic profile, ROS and DAMP generation. Therefore, TLR9 could be a valuable target to improve obesity-associated metabolic disorders and prostate smooth muscle hypercontractility in BPH.
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Affiliation(s)
- Fabiano B Calmasini
- Department of Physiology, Augusta University, 1120 15th Street, Augusta, GA, USA. .,Department of Pharmacology, Faculty of Medical Science, University of Campinas (UNICAMP), Campinas, Brazil.
| | - Cameron G McCarthy
- Department of Physiology, Augusta University, 1120 15th Street, Augusta, GA, USA.,Department of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of Toledo, Toledo, USA
| | - Camilla F Wenceslau
- Department of Physiology, Augusta University, 1120 15th Street, Augusta, GA, USA.,Department of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of Toledo, Toledo, USA
| | | | - Edson Antunes
- Department of Pharmacology, Faculty of Medical Science, University of Campinas (UNICAMP), Campinas, Brazil
| | - R Clinton Webb
- Department of Physiology, Augusta University, 1120 15th Street, Augusta, GA, USA
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17
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Increased plasma levels of high mobility group box 1 protein in patients with bipolar disorder: A pilot study. J Neuroimmunol 2019; 334:576993. [DOI: 10.1016/j.jneuroim.2019.576993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 06/05/2019] [Accepted: 06/06/2019] [Indexed: 12/21/2022]
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18
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Cao D, Wang W, Li S, Lai W, Huang X, Zhou J, Chen X, Li X. TLR2-Deficiency Promotes Prenatal LPS Exposure-Induced Offspring Hyperlipidemia. Front Physiol 2019; 10:1102. [PMID: 31507457 PMCID: PMC6713936 DOI: 10.3389/fphys.2019.01102] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 08/08/2019] [Indexed: 12/15/2022] Open
Abstract
Toll-like receptor 2 (TLR2), which recognizes several lipopeptides and transduces inflammatory signaling, promotes the pathogenesis of diet-induced dyslipidemia and obesity. TLR2-deficient mice were shown to have improved insulin sensitivity and reduced diet-induced metabolic syndrome. Previous studies demonstrated that prenatal lipopolysaccharide (LPS) exposure causes dyslipidemia accompanied by increased body weight and insulin resistance in offspring. To determine whether TLRs are involved in this complex abnormal phenotype, we analyzed TLR2 and TLR4 expression levels in adipose tissues from offspring with prenatal LPS-exposure (offspring-pLPS) and compared these levels to those of control offspring with prenatal saline-exposure (offspring-pSaline). TLR2 expression was specifically upregulated in the adipose tissue of offspring-pLPS mice. However, unexpectedly, TLR2-deficient offspring-pLPS mice not only presented with an abnormal phenotype comparable to that of wild-type offspring-pLPS mice but also exhibited significantly more severe hyperlipidemia. Our further analyses revealed a dramatic upregulation of TLR4 expression and overactivation of the TLR4/Myd88 signaling pathway in TLR2-deficient offspring-pLPS adipose tissue. Our finding suggests a compensatory genetic interaction between TLR2 and TLR4 in the context of prenatal inflammatory stimulation, and this interaction likely contributes to the prenatal inflammation-induced hyperlipidemia and lipid overload-induced obesity, thus providing a potential mechanism for the fetal origin of adult metabolic diseases.
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Affiliation(s)
- Dayan Cao
- Institute of Materia Medica, Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing, China
| | - Wenjia Wang
- Institute of Materia Medica, Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing, China
| | - Shuhui Li
- Department of Clinical Biochemistry, College of Pharmacy, Army Medical University, Chongqing, China
| | - Wenjing Lai
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xiaoyong Huang
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Jianzhi Zhou
- Institute of Materia Medica, Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing, China
| | - Xin Chen
- Institute of Materia Medica, Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing, China
| | - Xiaohui Li
- Institute of Materia Medica, Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing, China
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19
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Serum levels of the high-mobility group box 1 protein (HMGB1) in children with type 1 diabetes mellitus: case-control study. Cent Eur J Immunol 2019; 44:33-37. [PMID: 31114434 PMCID: PMC6526583 DOI: 10.5114/ceji.2019.84012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Accepted: 03/15/2018] [Indexed: 01/13/2023] Open
Abstract
Introduction The involvement of the high-mobility group box 1 protein (HMGB1) in various autoimmune and inflammatory diseases has been documented; however, the role of this proinflammatory molecule in children with diabetes type 1 (T1DM) has not been addressed. The aim of this case-control study is to compare the serum level of HMGB1 in children with newly diagnosed T1DM (group 1) and a control group composed of healthy children. Material and methods This case-control study included 136 children: group 1 (n = 96) and a control group (n = 40). Measurements were taken from serum for the following: HMGB1, white blood cell count, C-reactive protein, glucose, haemoglobin A1C, and β-cell autoantibodies (GADA-65, IA-2, ICA). HMGB1 was determined using enzyme-linked immunosorbent assay on a Labsystems iEMS Reader MF analyser (Labsystems Diagnostics Oy, Helsinki, Finland). Results The level (median and interquartile range) of HMGB1 was statistically higher (p < 0.001) in children with T1DM: 8.7 (5.0-9.8) µg/l, in comparison with the control group: 1.0 (0.6-1.4) µg/l. No correlation was found between HMGB1 and HbA1c in group 1, or between HMGB1 and BMI. A statistically higher percentage of positive children for autoantibodies were present in group 1 compared to the control group (p ≤ 0.001). HMGB1 serum levels were also tested and the presence of autoantibodies, and none of those antibodies correlated with the level of HMGB1. Conclusions The higher level of HMGB1 in children with T1DM, compared to the control group, indicates that this proinflammatory molecule is a good candidate marker of inflammation in children with T1DM.
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20
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Erdal M, Altunkaynak BZ, Kocaman A, Alkan I, Öztas E. The role of HMGB1 in liver inflammation in obese rats. Biotech Histochem 2019; 94:449-458. [PMID: 30916587 DOI: 10.1080/10520295.2019.1589573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Obesity is a chronic disease that is characterized by increased body fat owing to imbalance between consumed and expended energy. Inflammation generally is accompanied by accumulation of excess lipid in adipose tissue and liver. High mobility group box-1 (HMGB1) participates in the pathogenesis of inflammatory diseases. We investigated the relation of the number of HMGB1 positive cells to body mass index (BMI), liver inflammation and the number of Kupffer cells. We divided 18 female Wistar albino rats into two groups: group 1, untreated control fed normal commercial rat diet and group 2, obese rats fed a special diet containing 40% fat. The plasma concentrations of cholesterol, glucose, superoxide dismutase enzyme (SOD) and catalase activities were measured for all animals. The numbers of hepatocytes, Kupffer cells and HMGB1 positive cells were counted using stereological methods. The mean numbers of Kupffer cells and HMGB1 positive cells were higher for group 2 than for group 1. The concentrations of plasma cholesterol and glucose levels also were higher in group 2. Plasma levels of SOD and catalase were significantly lower in group 2 compared to group 1. The number of HMGB1 cells was related directly to BMI and inflammation. The role of HMGB1 was demonstrated for the liver of the obese group. We demonstrated the relations among HMGB1, BMI, obesity and inflammation.
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Affiliation(s)
- M Erdal
- Department of Histology and Embryology, Gulhane Medical School, Ankara, Turkey
| | - B Z Altunkaynak
- Department of Histology and Embryology, Medical School, Istanbul Okan University , Istanbul , Turkey
| | - A Kocaman
- Department of Histology and Embryology, Medical School, Ondokuz Mayis University , Samsun , Turkey
| | - I Alkan
- Department of Histology and Embryology, Medical School, Ondokuz Mayis University , Samsun , Turkey
| | - E Öztas
- Department of Histology and Embryology, Gulhane Medical School, Ankara, Turkey
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21
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Jabalie G, Ahmadi M, Koushaeian L, Eghbal‐Fard S, Mehdizadeh A, Kamrani A, Abdollahi‐Fard S, Farzadi L, Hojjat‐ Farsangi M, Nouri M, Yousefi M. Metabolic syndrome mediates proinflammatory responses of inflammatory cells in preeclampsia. Am J Reprod Immunol 2019; 81:e13086. [DOI: 10.1111/aji.13086] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 12/17/2018] [Accepted: 12/28/2018] [Indexed: 01/21/2023] Open
Affiliation(s)
- Gisoo Jabalie
- Stem Cell Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Majid Ahmadi
- Student’s Research CommitteeTabriz University of Medical Sciences Tabriz Iran
- Reproductive Biology Department Tabriz University of Medical Sciences Tabriz Iran
| | - Ladan Koushaeian
- Stem Cell Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Shadi Eghbal‐Fard
- Stem Cell Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Amir Mehdizadeh
- Endocrine Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Amin Kamrani
- Stem Cell Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Sedigheh Abdollahi‐Fard
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Laya Farzadi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Mohammad Hojjat‐ Farsangi
- Department of Oncology‐Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK)Karolinska University Hospital Solna and Karolinska Institute Stockholm Sweden
| | - Mohammad Nouri
- Reproductive Biology Department Tabriz University of Medical Sciences Tabriz Iran
| | - Mehdi Yousefi
- Drug Applied Research CenterTabriz University of Medical Sciences Tabriz Iran
- Aging Research Institute Tabriz University of Medical Sciences Tabriz Iran
- Department of Immunology Tabriz University of Medical Sciences Tabriz Iran
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22
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Elfeky M, Yoneshiro T, Okamatsu-Ogura Y, Kimura K. Adiponectin suppression of late inflammatory mediator, HMGB1-induced cytokine expression in RAW264 macrophage cells. J Biochem 2018; 163:143-153. [PMID: 29048484 DOI: 10.1093/jb/mvx069] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 09/02/2017] [Indexed: 12/27/2022] Open
Abstract
High-mobility group protein B1 (HMGB1) is a late inflammatory mediator released from inflammatory cells when stimulated, resulting in exaggerating septic symptoms. We recently demonstrated that full-length adiponectin, a potent anti-inflammatory adipokine, inhibits lipopolysaccharide-induced HMGB1 release. However, the effects of adiponectin on HMGB1-induced exaggerating signals currently remain unknown. This study aimed to investigate the effects of adiponectin on the pro-inflammatory function of HMGB1 in RAW264 macrophage cells. The treatment of RAW264 cells with HMGB1 significantly up-regulated the mRNA expression of tumour necrosis factor-α, interleukin-1β and C-X-C motif chemokine 10. HMGB1-induced cytokine expression was markedly suppressed by a toll-like receptor 4 (TLR4) antagonist and slightly suppressed by an antagonist of the receptor for advanced glycation end products. A prior treatment with full-length or globular adiponectin dose-dependently suppressed all types of HMGB1-induced cytokine expression, and this suppression was abolished by compound C, an AMPK inhibitor, but not by the haem oxygenase (HO)-1 inhibitor, zinc protoporphyrin IX. Both forms of adiponectin also reduced the mRNA expression of TLR4. These results suggest that full-length and globular adiponectin suppress HMGB1-induced cytokine expression through an AMPK-mediated HO-1-independent pathway.
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Affiliation(s)
- Mohamed Elfeky
- Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi9, Kita-ku, Sapporo 060-0818, Japan.,Department of Biochemistry, Faculty of Veterinary Medicine, Alexandria University, Edfina, Rosetta-Line, Rashid, Behera Governate 22758, Egypt
| | - Takeshi Yoneshiro
- Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi9, Kita-ku, Sapporo 060-0818, Japan
| | - Yuko Okamatsu-Ogura
- Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi9, Kita-ku, Sapporo 060-0818, Japan
| | - Kazuhiro Kimura
- Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi9, Kita-ku, Sapporo 060-0818, Japan
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23
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VanPatten S, Al-Abed Y. High Mobility Group Box-1 (HMGb1): Current Wisdom and Advancement as a Potential Drug Target. J Med Chem 2018; 61:5093-5107. [PMID: 29268019 DOI: 10.1021/acs.jmedchem.7b01136] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
High mobility group box-1 (HMGb1) protein, a nuclear non-histone protein that is released or secreted from the cell in response to damage or stress, is a sentinel for the immune system that plays a critical role in cell survival/death pathways. This review highlights key features of the endogenous danger-associated molecular pattern (DAMP) protein, HMGb1 in the innate inflammatory response along with various cofactors and receptors that regulate its downstream effects. The evidence demonstrating increased levels of HMGb1 in human inflammatory diseases and conditions is presented, along with a summary of current small molecule or peptide-like antagonists proven to specifically target HMGb1. Additionally, we delineate the measures needed toward validating this protein as a clinically relevant biomarker or bioindicator and as a relevant drug target.
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Affiliation(s)
- Sonya VanPatten
- Center for Molecular Innovation , The Feinstein Institute for Medical Research , 350 Community Drive , Manhasset , New York 11030 , United States
| | - Yousef Al-Abed
- Center for Molecular Innovation , The Feinstein Institute for Medical Research , 350 Community Drive , Manhasset , New York 11030 , United States
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Zhang J, Zhang L, Zhang S, Yu Q, Xiong F, Huang K, Wang CY, Yang P. HMGB1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity. Mol Cell Endocrinol 2017; 454:103-111. [PMID: 28619625 DOI: 10.1016/j.mce.2017.06.012] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 05/17/2017] [Accepted: 06/12/2017] [Indexed: 12/12/2022]
Abstract
Obesity has emerged as an imminent global public health concern over the past several decades. It has now become evident that obesity is characterized by the persistent and low-grade inflammation in the adipose tissue, and serves as an independent risk factor for many metabolic disorders such as diabetes and cardiovascular disease. Particularly, adipocytes originated from obese mice and humans likely predominate necrosis upon stressful insults, leading to passive release of cellular contents including the high mobility group box 1 (HMGB1) into the extracellular milieu. Extracellular HMGB1 acts as an innate alarmin to stimulate the activation of resident immune cells in the adipose tissue. Upon activation, those resident immune cells actively secrete additional HMGB1, which in turn activates/recruits additional immune cells, and induces adipocyte death. This review summarizes those novel discoveries in terms of HMGB1 in the initiation and maintenance of chronic inflammatory state in adipose tissue in obesity, and discusses its potential application in clinical settings.
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Affiliation(s)
- Jing Zhang
- The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Lei Zhang
- The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Shu Zhang
- The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Qilin Yu
- The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Fei Xiong
- The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Kun Huang
- Tongji School of Pharmacy, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Cong-Yi Wang
- The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Ave., Wuhan, 430030, China.
| | - Ping Yang
- The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Ave., Wuhan, 430030, China.
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Rider P, Voronov E, Dinarello CA, Apte RN, Cohen I. Alarmins: Feel the Stress. THE JOURNAL OF IMMUNOLOGY 2017; 198:1395-1402. [PMID: 28167650 DOI: 10.4049/jimmunol.1601342] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 09/27/2016] [Indexed: 12/20/2022]
Abstract
Over the last decade, danger-associated molecular pattern molecules, or alarmins, have been recognized as signaling mediators of sterile inflammatory responses after trauma and injury. In contrast with the accepted passive release models suggested by the "danger hypothesis," it was recently shown that alarmins can also directly sense and report damage by signaling to the environment when released from live cells undergoing physiological stress, even without loss of subcellular compartmentalization. In this article, we review the involvement of alarmins such as IL-1α, IL-33, IL-16, and high-mobility group box 1 in cellular and physiological stress, and suggest a novel activity of these molecules as central initiators of sterile inflammation in response to nonlethal stress, a function we denote "stressorins." We highlight the role of posttranslational modifications of stressorins as key regulators of their activity and propose that targeted inhibition of stressorins or their modifiers could serve as attractive new anti-inflammatory treatments for a broad range of diseases.
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Affiliation(s)
- Peleg Rider
- Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, 84105 Beer-Sheva, Israel
| | - Elena Voronov
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben Gurion University of the Negev, 84105 Beer-Sheva, Israel
| | | | - Ron N Apte
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben Gurion University of the Negev, 84105 Beer-Sheva, Israel
| | - Idan Cohen
- Faculty of Medicine, Galilee Medical Center, Nahariya Hospital, 22100 Nahariya, Israel
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Li N, Wang B, Cai S, Liu P. The Role of Serum High Mobility Group Box 1 and Interleukin‐6 Levels in Acute Pancreatitis: A Meta‐Analysis. J Cell Biochem 2017; 119:616-624. [PMID: 28618057 DOI: 10.1002/jcb.26222] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 06/14/2017] [Indexed: 12/14/2022]
Affiliation(s)
- Nuo Li
- Department of GastroenterologyThe Fourth Affiliated Hospital of China Medical UniversityShenyang110032P.R. China
| | - Bao‐Ming Wang
- Department of InterventionThe Fourth Affiliated Hospital of China Medical UniversityShenyang110032P.R. China
| | - Shuang Cai
- Department of GastroenterologyThe Fourth Affiliated Hospital of China Medical UniversityShenyang110032P.R. China
| | - Peng‐Liang Liu
- Department of GastroenterologyThe Fourth Affiliated Hospital of China Medical UniversityShenyang110032P.R. China
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Koborová I, Gurecká R, Csongová M, Volkovová K, Szökő É, Tábi T, Šebeková K. Association between metabolically healthy central obesity in women and levels of soluble receptor for advanced glycation end products, soluble vascular adhesion protein-1, and the activity of semicarbazide-sensitive amine oxidase. Croat Med J 2017; 58:106-116. [PMID: 28409494 PMCID: PMC5410733 DOI: 10.3325/cmj.2017.58.106] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
AIM To determine the levels of circulating soluble receptor for advanced glycation end products (sRAGE), as a biomarker of risk of metabolic syndrome and cardiovascular disease development in centrally obese (CO) women considered metabolically healthy (COH) in comparison with those metabolically unhealthy (COU). METHODS 47 lean healthy, 17 COH (presenting waist-to-height ratio ≥0.5 but not elevated blood pressure, atherogenic lipid profile, and insulin resistance), and 50 COU (CO presenting ≥2 risk factors) women aged 40-45 years were included. Anthropometric characteristics, blood chemistry and hematology data, adipokines, markers of inflammation, sRAGE, soluble vascular adhesion protein-1 (sVAP-1), and the activity of semicarbazide sensitive amine oxidase (SSAO) were determined. RESULTS Central obesity associated with low sRAGE levels (lean healthy: 1503±633 pg/mL; COH: 1103±339 pg/mL, P<0.05; COU: 1106±367 ng/mL, P<0.0.1), hyperleptinemia, and elevated markers of inflammation irrespective of the presence or absence of cardiometabolic risk factors. COU women presented high adiponectin levels. SVAP-1 concentrations and the activity of SSAO were similar in all 3 groups. CONCLUSION COH women present abnormalities in non-standard markers of cardiometabolic risk (sRAGE, leptin, high sensitive C-reactive protein), supporting the view that there is no healthy pattern of obesity. The clinical impact of our findings for future prognosis of metabolically healthy obese subjects remains to be elucidated in longitudinal studies.
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Affiliation(s)
- Ivana Koborová
- Ivana Koborová, Institute of Molecular BioMedicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia,
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Manti S, Cuppari C, Tardino L, Parisi G, Spina M, Salpietro C, Leonardi S. HMGB1 as a new biomarker of celiac disease in children: A multicenter study. Nutrition 2017; 37:18-21. [PMID: 28359357 DOI: 10.1016/j.nut.2016.12.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 12/03/2016] [Accepted: 12/17/2016] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Despite the availability of specific sierology and point-of-care tests, the phenotypic heterogeneity and the symptoms fluctuation as well as the "open-window" existing among the late and silent forms cause often a delayed celiac disease (CD) diagnosis. Recently, it has been reported that high mobility group box 1 (HMGB1) mediates inflammation and gastrointestinal barrier failure. The aim of this study was to detect serum HMGB1 levels at CD diagnosis and to evaluate the relationship between serum HMGB1 levels and clinical and histologic phenotypes. METHODS 49 CD children and 44 healthy children were enrolled. Specific antitissue transglutaminase type 2, antideaminated form of gliadin antibodies, serum HMGB1 levels, and typical histopathological changes in duodenal mucosa were performed in all patients. Mucosal lesions were classified according to Marsh classification. In relation to clinical presentation, we classified patients into: typical, atypical and silent forms. RESULTS Serum HMGB1 levels were significantly higher in those with CD than those in the healthy control group (P < 0.001). Significant differences in serum HMGB1 levels were detected in children with typical CD form compared to both children with atypical CD form (P < 0.001) and children with silent CD form (P < 0.001). By using the Marsh classification, significant differences were found between subjects with grade 3 B-B1 and 3 C-B2 and villous atrophy, respectively (P < 0.05). On the contrary, no significant differences in serum HMGB1 levels in subgroups of children with grade 3 A compared to grade 3 B-B1 were detected. CONCLUSIONS HMGB1 is upregulated at diagnosis in all CD children, especially in typical form, and reflecting the histologic severity of disease.
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Affiliation(s)
- Sara Manti
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Caterina Cuppari
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Lucia Tardino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Giuseppe Parisi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Massimo Spina
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Carmelo Salpietro
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Salvatore Leonardi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
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Wang Y, Zhong J, Zhang X, Liu Z, Yang Y, Gong Q, Ren B. The Role of HMGB1 in the Pathogenesis of Type 2 Diabetes. J Diabetes Res 2016; 2016:2543268. [PMID: 28101517 PMCID: PMC5215175 DOI: 10.1155/2016/2543268] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 11/08/2016] [Accepted: 11/29/2016] [Indexed: 12/17/2022] Open
Abstract
Significance. With an alarming increase in recent years, diabetes mellitus has become a global challenge. Despite advances in treatment of diabetes mellitus, currently, medications available are unable to control the progression of diabetes and its complications. Growing evidence suggests that inflammation is an important pathogenic mediator in the development of diabetes mellitus. The perspectives including suggestions for new therapies involving the shift from metabolic stress to inflammation should be taken into account. Critical Issues. High-mobility group box 1 (HMGB1), a nonhistone nuclear protein regulating gene expression, was rediscovered as an endogenous danger signal molecule to trigger inflammatory responses when released into extracellular milieu in the late 1990s. Given the similarities of inflammatory response in the development of T2D, we will discuss the potential implication of HMGB1 in the pathogenesis of T2D. Importantly, we will summarize and renovate the role of HMGB1 and HMGB1-mediated inflammatory pathways in adipose tissue inflammation, insulin resistance, and islet dysfunction. Future Directions. HMGB1 and its downstream receptors RAGE and TLRs may serve as potential antidiabetic targets. Current and forthcoming projects in this territory will pave the way for prospective approaches targeting the center of HMGB1-mediated inflammation to improve T2D and its complications.
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Affiliation(s)
- Yanan Wang
- Department of Immunology, Medical School, Yangtze University, Jingzhou 434023, China
| | - Jixin Zhong
- Department of Immunology, Medical School, Yangtze University, Jingzhou 434023, China
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Xiangzhi Zhang
- Department of Medicine, Hospital of Yangtze University, Jingzhou 434000, China
| | - Ziwei Liu
- Department of Immunology, Medical School, Yangtze University, Jingzhou 434023, China
| | - Yuan Yang
- Department of Immunology, Medical School, Yangtze University, Jingzhou 434023, China
| | - Quan Gong
- Department of Immunology, Medical School, Yangtze University, Jingzhou 434023, China
| | - Boxu Ren
- Department of Immunology, Medical School, Yangtze University, Jingzhou 434023, China
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Gunasekaran MK, Virama-Latchoumy AL, Girard AC, Planesse C, Guérin-Dubourg A, Ottosson L, Andersson U, Césari M, Roche R, Hoareau L. TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte. Adipocyte 2016; 5:384-388. [PMID: 27994953 PMCID: PMC5160392 DOI: 10.1080/21623945.2016.1245818] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 10/03/2016] [Accepted: 10/03/2016] [Indexed: 10/20/2022] Open
Abstract
Chronic low grade inflammation is one of the major metabolic disorders in case of obesity and associated pathologies. By its important secretion function, the role of adipose tissue in this metabolic low grade inflammation is well known. Recently, it was demonstrated that the alarmin high mobility group box protein 1 (HMGB1) is involved in obesity-related pathologies by its increased serum levels in obese compared to normal weight individuals, and by its pro-inflammatory effects. However, the role of HMGB1 on adipocytes inflammation is poorly documented and we propose to investigate this point. Primary culture of human subcutaneous adipocytes were performed from human adipose tissue samples. Cells were treated with recombinant HMGB1 with/without anti-TLR4 antibody and inhibitors of NF-κB and P38 MAPK. Supernatants were collected for IL-6 and MCP-1 ELISA. HMGB1 initiates Toll-like receptor 4 (TLR4)-dependent activation of inflammation through the downstream NF-κB and P38 MAPK signaling pathway to upregulate the secretion of the pro-inflammatory cytokine IL-6. HMGB1 has pro-inflammatory effects on adipocytes. This reinforces the role of TLR4 in adipose tissue inflammation and antagonizing the HMGB1 inflammatory pathway could bring on new therapeutic targets to counteract obesity-associated pathologies.
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Affiliation(s)
- Manoj Kumar Gunasekaran
- Inserm, UMR 1188, Diabéte athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, Sainte-Clotilde, France
- Université de La Réunion, UMR 1188, Sainte-Clotilde, France
| | - Anne-Laurence Virama-Latchoumy
- Inserm, UMR 1188, Diabéte athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, Sainte-Clotilde, France
- Université de La Réunion, UMR 1188, Sainte-Clotilde, France
| | - Anne-Claire Girard
- Inserm, UMR 1188, Diabéte athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, Sainte-Clotilde, France
- Université de La Réunion, UMR 1188, Sainte-Clotilde, France
- Centre Hospitalier Universitaire (CHU) de La Réunion
| | - Cynthia Planesse
- Inserm, UMR 1188, Diabéte athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, Sainte-Clotilde, France
- Université de La Réunion, UMR 1188, Sainte-Clotilde, France
- Stemcis, plateforme CYROI, Sainte-Clotilde, France
| | | | - Lars Ottosson
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stokholm, Sweden
| | - Ulf Andersson
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stokholm, Sweden
| | - Maya Césari
- Inserm, UMR 1188, Diabéte athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, Sainte-Clotilde, France
- Université de La Réunion, UMR 1188, Sainte-Clotilde, France
| | - Régis Roche
- Stemcis, plateforme CYROI, Sainte-Clotilde, France
| | - Laurence Hoareau
- Inserm, UMR 1188, Diabéte athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, Sainte-Clotilde, France
- Université de La Réunion, UMR 1188, Sainte-Clotilde, France
- Stemcis, plateforme CYROI, Sainte-Clotilde, France
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Chimenz R, Lacquaniti A, Colavita L, Chirico V, Fede C, Buemi M, Fede C. High mobility group box 1 and tumor growth factor β: useful biomarkers in pediatric patients receiving peritoneal dialysis. Ren Fail 2016; 38:1370-1376. [DOI: 10.1080/0886022x.2016.1216711] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Azzarà A, Pirillo C, Giovannini C, Federico G, Scarpato R. Different repair kinetic of DSBs induced by mitomycin C in peripheral lymphocytes of obese and normal weight adolescents. Mutat Res 2016; 789:9-14. [PMID: 27174706 DOI: 10.1016/j.mrfmmm.2016.05.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 03/21/2016] [Accepted: 05/01/2016] [Indexed: 01/13/2023]
Abstract
In 2013, 42 million children under the age of 5 years were overweight or obese. In the context of obesity, we recently showed that (1) peripheral lymphocytes of obese children/adolescents had an 8-fold increase in double strand breaks (DSBs), expressed as g-H2AX foci, than normal weight adolescents, and (2) 30% of the damage was retained into chromosome mutations. Thus, we investigated DSBs repair efficiency in a group of obese adolescents assessing the kinetic of H2AX phosphorylation in mitomycin C (MMC)-treated lymphocytes harvested 2 h- or 4 h-post mutagen treatment. According to our previous studies, these harvesting times represent the peak of DSBs induction and the time in which an appreciable DSBs reduction was observed. In addition, we evaluated the expression of the high mobility group box-1 protein (HMGB1), a chromatin remodelling protein involved in DSBs repair and obesity. Compared to normal weight adolescents, obese subjects 1) showed higher levels of g-H2AX foci at either 2 h- (0.239±0.041 vs. 0.473±0.048, P=0.0016) or 4 h- (0.150±0.026 vs. 0.255±0.030, P=0.0198) post mutagen treatment, and 2) have repaired a greater amount of the initial lesions (0.088±0.033 vs. 0.218±0.045, P=0.0408). Concordantly, 1) HMGB1 levels of obese individuals increased and decreased at 2h- or 4 h-post mutagen treatment, respectively, and 2) the opposite occurred for the normal weight adolescents where the protein was down-expressed at 2h and over-expressed at 4h. In conclusion, lymphocytes of obese and normal weight adolescents showed a distinct temporal kinetic of repairing MMC-induced DSBs, together with a different expression of HMGB1. The finding that obesity may modulate the repair of DNA damage induced in lymphocytes by genotoxic agents should be confirmed by further experiments.
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Affiliation(s)
- Alessia Azzarà
- Unità di Genetica, Dipartimento di Biologia, Pisa University, Pisa, Italy
| | - Chiara Pirillo
- Unità di Genetica, Dipartimento di Biologia, Pisa University, Pisa, Italy
| | | | - Giovanni Federico
- Unità di Endocrinologia Pediatrica e Diabete, Dipartimento di Medicina Clinica e Sperimentale Pisa University, Pisa, Italy
| | - Roberto Scarpato
- Unità di Genetica, Dipartimento di Biologia, Pisa University, Pisa, Italy; Research Center of Nutraceuticals and Food for Health, University of Pisa, Pisa, Italy.
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Giacobbe A, Granese R, Grasso R, Salpietro V, Corrado F, Giorgianni G, Foti G, Amadore D, Triolo O, Giunta L, Di Benedetto A. Association between maternal serum high mobility group box 1 levels and pregnancy complicated by gestational diabetes mellitus. Nutr Metab Cardiovasc Dis 2016; 26:414-418. [PMID: 27089978 DOI: 10.1016/j.numecd.2016.02.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 12/03/2015] [Accepted: 02/05/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Gestational diabetes mellitus (GDM), is characterized by chronic, low-grade subclinical inflammation with altered production of cytokines and mediators. Recently, a new protein acting as a "danger signal", high mobility group box 1 (HMGB1), that migrates quickly during electrophoresis, has been identified. The aim of our study was to analyze serum levels of HMGB1 in pregnant women, with or without GDM, in the third trimester of pregnancy to evaluate correlation with insulin resistance and other risk factors for GDM. METHODS AND RESULTS Seventy five pregnant women positive to the 75 g oral glucose tolerance test (OGTT) were included in the study group and 48 pregnant women who were negative to the screening test, were randomly selected using a computer-generated randomisation table. A significant positive univariate correlation was observed between serum HMGB1 levels, HOMA-IR index, glycaemia values at OGTT and pre-pregnancy BMI. Moreover, logistic regression analysis showed that serum HMGB1 was independent linked to GDM. CONCLUSION Our study demonstrated that HMGB1, a marker of chronic inflammation, is associated to GDM and insulin resistance level, in the third trimester of pregnancy.
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Affiliation(s)
- A Giacobbe
- Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, via Consolare Valeria 1, 98125 Messina, Italy
| | - R Granese
- Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, via Consolare Valeria 1, 98125 Messina, Italy.
| | - R Grasso
- Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, via Consolare Valeria 1, 98125 Messina, Italy
| | - V Salpietro
- Department of Clinical and Experimental Medicine University Hospital, via Consolare Valeria 1, 98125 Messina, Italy
| | - F Corrado
- Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, via Consolare Valeria 1, 98125 Messina, Italy
| | - G Giorgianni
- Department of Clinical and Experimental Medicine University Hospital, via Consolare Valeria 1, 98125 Messina, Italy
| | - G Foti
- Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, via Consolare Valeria 1, 98125 Messina, Italy
| | - D Amadore
- Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, via Consolare Valeria 1, 98125 Messina, Italy
| | - O Triolo
- Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, via Consolare Valeria 1, 98125 Messina, Italy
| | - L Giunta
- Department of Clinical and Experimental Medicine University Hospital, via Consolare Valeria 1, 98125 Messina, Italy
| | - A Di Benedetto
- Department of Clinical and Experimental Medicine University Hospital, via Consolare Valeria 1, 98125 Messina, Italy
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miR-155 Deletion in Female Mice Prevents Diet-Induced Obesity. Sci Rep 2016; 6:22862. [PMID: 26953132 PMCID: PMC4782173 DOI: 10.1038/srep22862] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 02/22/2016] [Indexed: 12/28/2022] Open
Abstract
Obesity is a growing epidemic in developed countries. Obese individuals are susceptible to comorbidities, including cardiovascular disease and metabolic disorder. Increasing the ability of adipose tissue to expend excess energy could improve protection from obesity. One promising target is microRNA (miR)-155-5p. We demonstrate that deletion of miR-155 (-5p and -3p) in female mice prevents diet-induced obesity. Body weight gain did not differ between wild-type (WT) and miR-155 knockout (KO) mice fed control diet (CD); however, miR-155 KO mice fed high-fat diet (HFD) gained 56% less body weight and 74% less gonadal white adipose tissue (WAT) than WT mice. Enhanced WAT thermogenic potential, brown adipose tissue differentiation, and/or insulin sensitivity might underlie this obesity resistance. Indeed, miR-155 KO mice on HFD had 21% higher heat release than WT HFD mice. Compared to WT adipocytes, miR-155 KO adipocytes upregulated brown (Ucp1, Cidea, Pparg) and white (Fabp4, Pnpla2, AdipoQ, Fasn) adipogenic genes, and glucose metabolism genes (Glut4, Irs1). miR-155 deletion abrogated HFD-induced adipocyte hypertrophy and WAT inflammation. Therefore, miR-155 deletion increases adipogenic, insulin sensitivity, and energy uncoupling machinery, while limiting inflammation in WAT, which together could restrict HFD-induced fat accumulation. Our results identify miR-155 as a novel candidate target for improving obesity resistance.
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Chirico V, Lacquaniti A, Piraino B, Cutrupi M, Cuppari C, Grasso L, Rigoli L, David A, Arrigo T, Salpietro C. Thalassaemia major and infectious risk: High Mobility Group Box-1 represents a novel diagnostic and prognostic biomarker. Br J Haematol 2015; 171:130-136. [PMID: 26058743 DOI: 10.1111/bjh.13530] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 03/18/2015] [Indexed: 11/30/2022]
Abstract
High mobility group box -1 (HMGB1) represents a common causal agent for various types of diseases, including infective pathologies. This study aimed to investigate the role of HMGB1 in β-thalassemia major (TM) by evaluating its diagnostic and prognostic role. Fifty-one TM patients and 30 healthy subjects (HS) were enrolled. Receiver operating characteristics (ROC) analysis was employed to calculate the area under the curve (AUC) for HMGB1 to determine the best cut-off values capable of identifying infectious episodes. Adjusted risk estimates for infective events were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. Serum HMGB1 levels were higher in TM patients than in HS (14·6 ± 8·7 vs. 2·08 ± 0·9 ng/ml, P < 0·0001). Patients who underwent splenectomy were characterized by lower levels of HMGB1, when compared with patients with an intact spleen (10·2 ± 8 vs. 19·1 ± 7 ng/ml, P = 0·004). ROC analyses revealed an AUC for serum HMGB1 of 0·801, with a sensitivity and specificity of 92·3% and 68·2% to detect an infectious episode. Low HMGB1 levels predicted high risk of infective events (HR: 0·81; P = 0·006). HMGB1 represents a prognostic marker for TM patients and a predictive factor for infectious events.
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Affiliation(s)
- Valeria Chirico
- Department of Paediatric Sciences, University of Messina, Messina, Italy
| | | | - Basilia Piraino
- Department of Paediatric Sciences, University of Messina, Messina, Italy
| | - Maricia Cutrupi
- Department of Paediatric Sciences, University of Messina, Messina, Italy
| | - Caterina Cuppari
- Department of Paediatric Sciences, University of Messina, Messina, Italy
| | - Luisa Grasso
- Department of Paediatric Sciences, University of Messina, Messina, Italy
| | - Luciana Rigoli
- Department of Paediatric Sciences, University of Messina, Messina, Italy
| | - Antonio David
- Department of Neuroscience and Anesthesiology, University of Messina, Messina, Italy
| | - Teresa Arrigo
- Department of Paediatric Sciences, University of Messina, Messina, Italy
| | - Carmelo Salpietro
- Department of Paediatric Sciences, University of Messina, Messina, Italy
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Wang H, Qu H, Deng H. Plasma HMGB-1 Levels in Subjects with Obesity and Type 2 Diabetes: A Cross-Sectional Study in China. PLoS One 2015; 10:e0136564. [PMID: 26317615 PMCID: PMC4552731 DOI: 10.1371/journal.pone.0136564] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 08/05/2015] [Indexed: 12/22/2022] Open
Abstract
Object To detect the levels of plasma High-Mobility Group Box-1(HMGB1) in Chinese subject with obesity and type 2 diabetes mellitus (T2DM), and to investigate the correlations between plasma HMGB1 concentration and parameters of body fat, insulin resistance (IR) metabolism and inflammation. Methods This study recruited 79 normal glucose tolerance (NGT) subjects and 76 newly diagnosed T2DM patients. NGT and T2DM groups were divided into normal weight (NW) and obese (OB)subgroups respectively. Anthropometric parameters such as height, weight, waist circumference, hip circumference and blood pressure were measured. Plasma concentrations of HMGB1, IL-6, fasting plasma glucose (FPG), 2 hours post challenge plasma glucose (2hPG), serum lipid, glycated hemoglobin (HbA1C) and fasting insulin (FINS) were examined. The homeostasis model assessment (HOMA) was performed to assess IR status. Results Plasma HMGB1 levels were higher in T2DM group than that in NGT group. The concentrations of serum HMGB1 were also higher in subjects with OB than those in subjects with NW both in NGT and T2DM groups. Plasma levels of HMGB1 were positively correlated with waist hip ratio (WHR), blood pressure, FPG, FINS, HOMA-IR, TG, IL-6 and negatively correlated with HOMA-βand high-density lipoprotein-cholesterol (HDL-c) independent of age, gender and BMI. Plasma levels of HMGB1 were significantly correlated with diabetes in fully adjusted models. Conclusion Plasma HMGB1 levels were increased in Chinese subjects with pure T2DM, which might be caused by IR. Serum HMGB1 participated in the pathological process of obesity and T2DM via its proinflammatory effect.
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Affiliation(s)
- Hang Wang
- M.D. Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hua Qu
- M.D. Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huacong Deng
- M.D. Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- * E-mail:
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Cuppari C, Manti S, Chirico V, Caruso R, Salpietro V, Giacchi V, Laganà F, Arrigo T, Salpietro C, Leonardi S. Sputum high mobility group box-1 in asthmatic children: a noninvasive sensitive biomarker reflecting disease status. Ann Allergy Asthma Immunol 2015; 115:103-107. [PMID: 26250770 DOI: 10.1016/j.anai.2015.06.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 06/04/2015] [Accepted: 06/08/2015] [Indexed: 11/28/2022]
Abstract
BACKGROUND The monitoring of asthma is based mainly on clinical history, physical examination, and lung function test evaluation. To improve knowledge of the disease, new biomarkers of airway inflammation, including high mobility group box-1 (HMGB1), are being developed. OBJECTIVE To evaluate sputum HMGB1 levels in children with stable, off-therapy, allergic asthma and to evaluate the relation between HMGB1 levels and lung function parameters. METHODS Fifty children with asthma (28 boys and 22 girls, median age 11.56 ± 1.41 years) and 44 healthy children (22 boys and 22 girls, median age 11.07 ± 2.12 years) were enrolled. Sputum HMGB1 was assessed in the cohort study. Lung function (predicted percentage of forced expiratory volume in 1 second [FEV1%] and forced expiratory flow between 25% and 75% [FEF25%-75%]), serum total IgE levels, and asthma severity by validated Global Initiative for Asthma criteria were recorded. RESULTS Sputum HMGB1 levels were higher in children with asthma than in healthy controls (100.68 ± 10.03 vs 9.60 ± 3.76 ng/mL, P < .0001). Sputum HMGB1 levels also were positively related to total IgE levels in children with asthma (r = 0.6567, P < .0001). An inverse and strict correlation between sputum HMGB1 levels and pulmonary function indices also were observed in children with mild (FEV1%, r = -0.86544, P < .0001; FEF25%-75%, r = -0.53948, P < .05), moderate (FEV1%, r = -0.99548, P < .0001; FEF25%-75%, r = -0.48668, P < .05), and severe (FEV1%, r = -0.90191, P < .0001; FEF25%-75%, r = -0.66777, P < .05) asthma. CONCLUSION The present study provides evidence that sputum HMGB1 is a sensitive biomarker of allergic asthma in children because it was increased and correlated directly with asthma severity and inversely with lung function indices.
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Affiliation(s)
- Caterina Cuppari
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Sara Manti
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Valeria Chirico
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Rosangela Caruso
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Vincenzo Salpietro
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Valentina Giacchi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Francesca Laganà
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Teresa Arrigo
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Carmelo Salpietro
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy.
| | - Salvatore Leonardi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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Marseglia L, Manti S, D'Angelo G, Cuppari C, Salpietro V, Filippelli M, Trovato A, Gitto E, Salpietro C, Arrigo T. Obesity and breastfeeding: The strength of association. Women Birth 2015; 28:81-86. [PMID: 25595034 DOI: 10.1016/j.wombi.2014.12.007] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 12/14/2014] [Accepted: 12/30/2014] [Indexed: 02/08/2023]
Abstract
UNLABELLED Obesity and attendant co-morbidities are an emergent problem in public health. Much attention has focused on prevention, especially during the perinatal period. Breastfeeding is considered a possible protective factor for obesity in childhood, influencing gene-neuroendocrine-environment-lifestyle interaction. Therefore, breastfeeding and its longer duration are probably associated with lower development of childhood obesity. Through human milk, but not formula, the child assumes greater bioactive factors contributing to immunological, endocrine, development, neural and psychological benefits. Contrarily, other studies did not confirm a critical role of breast milk. Confounding factors, especially maternal pre-pregnancy overweight, may influence breastfeeding effects. This review summarises what is known about the possible relationship between breastfeeding and prevention of obesity development. CONCLUSION Breastfeeding appears to represent a protective factor for obesity in childhood, although evidence is still controversial and underlying mechanisms unclear. Further research is needed to improve knowledge on overweight/obesity and breastfeeding.
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Affiliation(s)
- Lucia Marseglia
- Department of Pediatrics, University of Messina, Messina, Italy.
| | - Sara Manti
- Department of Pediatrics, University of Messina, Messina, Italy.
| | | | - Caterina Cuppari
- Department of Pediatrics, University of Messina, Messina, Italy.
| | | | | | - Antonio Trovato
- Department of Pediatrics, University of Catania, Catania, Italy.
| | - Eloisa Gitto
- Department of Pediatrics, University of Messina, Messina, Italy.
| | | | - Teresa Arrigo
- Department of Pediatrics, University of Messina, Messina, Italy.
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Chang CJ, Jian DY, Lin MW, Zhao JZ, Ho LT, Juan CC. Evidence in obese children: contribution of hyperlipidemia, obesity-inflammation, and insulin sensitivity. PLoS One 2015; 10:e0125935. [PMID: 26011530 PMCID: PMC4444301 DOI: 10.1371/journal.pone.0125935] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 03/19/2015] [Indexed: 11/20/2022] Open
Abstract
Background Evidence shows a high incidence of insulin resistance, inflammation and dyslipidemia in adult obesity. The aim of this study was to assess the relevance of inflammatory markers, circulating lipids, and insulin sensitivity in overweight/obese children. Methods We enrolled 45 male children (aged 6 to 13 years, lean control = 16, obese = 19, overweight = 10) in this study. The plasma total cholesterol, HDL cholesterol, triglyceride, glucose and insulin levels, the circulating levels of inflammatory factors, such as TNF-α, IL-6, and MCP-1, and the high-sensitive CRP level were determined using quantitative colorimetric sandwich ELISA kits. Results Compared with the lean control subjects, the obese subjects had obvious insulin resistance, abnormal lipid profiles, and low-grade inflammation. The overweight subjects only exhibited significant insulin resistance and low-grade inflammation. Both TNF-α and leptin levels were higher in the overweight/obese subjects. A concurrent correlation analysis showed that body mass index (BMI) percentile and fasting insulin were positively correlated with insulin resistance, lipid profiles, and inflammatory markers but negatively correlated with adiponectin. A factor analysis identified three domains that explained 74.08% of the total variance among the obese children (factor 1: lipid, 46.05%; factor 2: obesity-inflammation, 15.38%; factor 3: insulin sensitivity domains, 12.65%). Conclusions Our findings suggest that lipid, obesity-inflammation, and insulin sensitivity domains predominantly exist among obese children. These factors might be applied to predict the outcomes of cardiovascular diseases in the future.
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Affiliation(s)
- Chi-Jen Chang
- Division of Pediatric Surgery, Department of Surgery, Shin-Kong Wu Ho-Su Hospital, Taipei, Taiwan
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Deng-Yuan Jian
- Institutes of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Division of Nephrology, Wen-Lin Hemodialysis Unit, Taipei, Taiwan
| | - Ming-Wei Lin
- Institute of Public Health, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jun-Zhi Zhao
- Division of Pediatric Surgery, Department of Surgery, Shin-Kong Wu Ho-Su Hospital, Taipei, Taiwan
| | - Low-Tone Ho
- Institutes of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chi-Chang Juan
- Institutes of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Education and Research, Taipei City Hospital, Taipei, Taiwan
- * E-mail:
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Giacobbe A, Grasso R, Imbesi G, Salpietro CD, Grasso L, Laganà AS, Triolo O, Di Benedetto A. High mobility group protein B1: a new biomarker of obesity in pregnant women? Gynecol Endocrinol 2015; 31:113-5. [PMID: 25356847 DOI: 10.3109/09513590.2014.964637] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Obesity is associated with an increased risk of an adverse pregnancy outcome. The aim of this study was to analyze the serum levels of high mobility group protein B1 (HMGB1) in obese pregnant women, to assess the role of this protein in the pathogenesis of this disease and to evaluate its possible function as a diagnostic marker for obesity-related complications in obese women. Study participants were randomly selected, from a cohort of pregnant women afferent to our department. A total of 120 women were enrolled in this study: 60 pregnant women had normal body mass index (BMI) and 60 women resulted obese. Pre-pregnancy BMI, weight increase and HMGB1 levels were evaluated for each pregnant woman enrolled. Matching serum HMGB1 levels in two groups, our data evidenced higher levels in the obese women, with a statistically significant difference (p = 0.0023). A significant positive univariate correlation was observed between serum HMGB1 levels and BMI in obese women. HMGB1 serum levels may therefore represent a predictive marker of disease in pregnant women (r = 20.9 and p = 0.0001). Further studies are needed in order to validate the role of this cytokine, with the aim of making it possible to use in clinical practice not only for diagnostic purposes, but especially for the early recognition of complications related to it.
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Affiliation(s)
- A Giacobbe
- Department of Pediatric Gynecological, Microbiological and Biomedical Sciences and
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Arrigo T, Leonardi S, Cuppari C, Manti S, Lanzafame A, D’Angelo G, Gitto E, Marseglia L, Salpietro C. Role of the diet as a link between oxidative stress and liver diseases. World J Gastroenterol 2015; 21:384-395. [PMID: 25593454 PMCID: PMC4292270 DOI: 10.3748/wjg.v21.i2.384] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 10/24/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress is caused by an imbalance between the production of reactive oxygen (free radicals) and the body's ability (antioxidant capacity) to readily detoxify the reactive intermediates or easily repair the resulting damage. An adequate diet, characterized by daily intake of foods associated with improvements in the total antioxidant capacity of individuals and reduced incidence of diseases related to oxidation, can modulate the degree of oxidative stress. In fact, diet-derived micronutrients may be direct antioxidants, or are components of antioxidant enzymes, leading to improvement of some indicators of hepatic function. However, although their increased dietary intake might be beneficial, literature data are still controversial. This review summarizes what is known about the effects of diet nutrients on oxidative stress, inflammation and liver function. Moreover, we have analyzed: (1) the main nutritional components involved in the production and/or removal of free radicals; and (2) the role of free radicals in the pathogenesis of several hepatic diseases and related comorbidities.
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Wagner M, Samdal Steinskog ES, Wiig H. Adipose tissue macrophages: the inflammatory link between obesity and cancer? Expert Opin Ther Targets 2014; 19:527-38. [DOI: 10.1517/14728222.2014.991311] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ, Lotze MT, Tang D. HMGB1 in health and disease. Mol Aspects Med 2014; 40:1-116. [PMID: 25010388 PMCID: PMC4254084 DOI: 10.1016/j.mam.2014.05.001] [Citation(s) in RCA: 742] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 05/05/2014] [Indexed: 12/22/2022]
Abstract
Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
| | - Ruochan Chen
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Qiuhong Zhang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Wen Hou
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Sha Wu
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jin Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yan Yu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xue-Gong Fan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhengwen Yan
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA; Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Xiaofang Sun
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Experimental Department of Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Haichao Wang
- Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Qingde Wang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Michael T Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
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Chirico V, Lacquaniti A, Leonardi S, Grasso L, Rotolo N, Romano C, Di Dio G, Lionetti E, David A, Arrigo T, Salpietro C, La Rosa M. Acute pulmonary exacerbation and lung function decline in patients with cystic fibrosis: high-mobility group box 1 (HMGB1) between inflammation and infection. Clin Microbiol Infect 2014; 21:368.e1-9. [PMID: 25658530 DOI: 10.1016/j.cmi.2014.11.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Revised: 11/02/2014] [Accepted: 11/02/2014] [Indexed: 12/21/2022]
Abstract
Airway inflammation plays a central role in cystic fibrosis (CF) lung disease, and biomarkers of inflammation, such as high-mobility group box 1 (HMGB1) could be used to monitor disease activity. The main aim of this study was to confirm the role of HMGB1 in CF patients, correlating its serum and sputum levels with pulmonary function and inflammation. Serum and sputum HMGB1 were evaluated in a cohort of 31 CF patients and 30 non-smoking healthy subjects (HS group). Acute pulmonary exacerbation events and lung function decline have been also evaluated during a 3-year follow-up period. Serum HMGB1 levels were significantly higher than those measured in HS, such as sputum HMGB1. Kaplan-Meier survival curves revealed that patients with high HMGB1 values experienced a significantly faster evolution to decline of lung function. A multiple Cox regression analysis assessed that an increase of serum HMGB1 was associated with 5% increased risk of pulmonary disease progression, whereas elevated sputum HMGB1 was related to a 10% increased risk of lung function decline. In CF patients, HMGB1 closely reflects the entity of pulmonary impairment and represents a strong and independent risk marker for progression of lung function decline.
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Affiliation(s)
- V Chirico
- Department of Pediatric Sciences, Genetics and Immunology Paediatrics Unit, University of Messina, Messina, Italy.
| | - A Lacquaniti
- Department of Internal Medicine, Nephrology and Dialysis Unit, University of Messina, Messina, Italy
| | - S Leonardi
- Pediatric Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - L Grasso
- Department of Pediatric Sciences, Genetics and Immunology Paediatrics Unit, University of Messina, Messina, Italy
| | - N Rotolo
- Pediatric Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - C Romano
- Department of Pediatric Sciences, Genetics and Immunology Paediatrics Unit, University of Messina, Messina, Italy
| | - G Di Dio
- Pediatric Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - E Lionetti
- Pediatric Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - A David
- Department of Neuroscience and Anesthesiology, University of Messina, Italy
| | - T Arrigo
- Department of Pediatric Sciences, Genetics and Immunology Paediatrics Unit, University of Messina, Messina, Italy
| | - C Salpietro
- Department of Pediatric Sciences, Genetics and Immunology Paediatrics Unit, University of Messina, Messina, Italy
| | - M La Rosa
- Pediatric Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
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Salpietro V, Polizzi A, Di Rosa G, Romeo AC, Dipasquale V, Morabito P, Chirico V, Arrigo T, Ruggieri M. Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications. Int J Endocrinol 2014; 2014:282489. [PMID: 25276129 PMCID: PMC4167812 DOI: 10.1155/2014/282489] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 08/12/2014] [Indexed: 01/27/2023] Open
Abstract
Various neurological and psychiatric manifestations have been recorded in children with adrenal disorders. Based on literature review and on personal case-studies and case-series we focused on the pathophysiological and clinical implications of glucocorticoid-related, mineralcorticoid-related, and catecholamine-related paediatric nervous system involvement. Childhood Cushing syndrome can be associated with long-lasting cognitive deficits and abnormal behaviour, even after resolution of the hypercortisolism. Exposure to excessive replacement of exogenous glucocorticoids in the paediatric age group (e.g., during treatments for adrenal insufficiency) has been reported with neurological and magnetic resonance imaging (MRI) abnormalities (e.g., delayed myelination and brain atrophy) due to potential corticosteroid-related myelin damage in the developing brain and the possible impairment of limbic system ontogenesis. Idiopathic intracranial hypertension (IIH), a disorder of unclear pathophysiology characterised by increased cerebrospinal fluid (CSF) pressure, has been described in children with hypercortisolism, adrenal insufficiency, and hyperaldosteronism, reflecting the potential underlying involvement of the adrenal-brain axis in the regulation of CSF pressure homeostasis. Arterial hypertension caused by paediatric adenomas or tumours of the adrenal cortex or medulla has been associated with various hypertension-related neurological manifestations. The development and maturation of the central nervous system (CNS) through childhood is tightly regulated by intrinsic, paracrine, endocrine, and external modulators, and perturbations in any of these factors, including those related to adrenal hormone imbalance, could result in consequences that affect the structure and function of the paediatric brain. Animal experiments and clinical studies demonstrated that the developing (i.e., paediatric) CNS seems to be particularly vulnerable to alterations induced by adrenal disorders and/or supraphysiological doses of corticosteroids. Physicians should be aware of potential neurological manifestations in children with adrenal dysfunction to achieve better prevention and timely diagnosis and treatment of these disorders. Further studies are needed to explore the potential neurological, cognitive, and psychiatric long-term consequences of high doses of prolonged corticosteroid administration in childhood.
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Affiliation(s)
- Vincenzo Salpietro
- Department of Pediatric Neurology, Chelsea and Westminster Hospital NHS Foundation Trust, 369 Fulham Road, London SW10 9NH, UK
- Unit of Genetics and Paediatric Immunology, Department of Pediatrics, University of Messina, Italy
| | - Agata Polizzi
- National Center for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy
- Institute of Neurological Sciences, National Research Council, Catania, Italy
| | - Gabriella Di Rosa
- Infantile Neuropsychiatry Unit, Department of Pediatrics, University of Messina, Italy
| | - Anna Claudia Romeo
- Unit of Genetics and Paediatric Immunology, Department of Pediatrics, University of Messina, Italy
| | - Valeria Dipasquale
- Unit of Genetics and Paediatric Immunology, Department of Pediatrics, University of Messina, Italy
| | - Paolo Morabito
- Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Italy
| | - Valeria Chirico
- Unit of Genetics and Paediatric Immunology, Department of Pediatrics, University of Messina, Italy
| | - Teresa Arrigo
- Unit of Genetics and Paediatric Immunology, Department of Pediatrics, University of Messina, Italy
| | - Martino Ruggieri
- Chair of Pediatrics, Department of Educational Sciences, University of Catania, Italy
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High-mobility group box 1 (HMGB1) in childhood: from bench to bedside. Eur J Pediatr 2014; 173:1123-36. [PMID: 24809802 DOI: 10.1007/s00431-014-2327-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 04/13/2014] [Accepted: 04/22/2014] [Indexed: 02/08/2023]
Abstract
UNLABELLED High-mobility group box protein 1 (HMGB1) is a nonhistone nuclear protein that has a dual function. Inside the cell, HMGB1 binds DNA, regulating transcription and determining chromosomal architecture. Outside the cell, HMGB1 activates the innate system and mediates a wide range of physiological and pathological responses. HMGB1 exerts these actions through differential engagement of multiple surface receptors, including Toll-like receptor (TLR)2, TLR4, and receptor for advanced glycation end products (RAGE). HMGB1 is implicated as a late mediator of sepsis and is also involved in inflammatory and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Interestingly, HMGB1 was associated with tumor progression, becoming a potential therapeutic target, due to its involvement in the resistance to chemotherapy. Its implication on the pathogenesis of systemic vasculitis and inflammatory bowel diseases has also been evaluated. Moreover, it regulates neuroinflammation after traumatic brain injuries or cerebral infectious diseases. The aim of this review is to analyze these different roles of HMGB1, both in physiological and pathological conditions, discussing clinical and scientific implications in the field of pediatrics. CONCLUSION HMGB1 plays a key role in several pediatric diseases, opening new scenarios for diagnostic biomarkers and therapeutic strategies development.
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Manti S, Marseglia L, D'Angelo G, Filippelli M, Cuppari C, Gitto E, Romano C, Arrigo T, Salpietro C. Portal hypertension as immune mediate disease. HEPATITIS MONTHLY 2014; 14:e18625. [PMID: 24976841 PMCID: PMC4071352 DOI: 10.5812/hepatmon.18625] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 04/13/2014] [Indexed: 12/11/2022]
Abstract
CONTEXT Portal Hypertension (PH) is a progressive complication due to chronic liver disease. In addition to pathophysiologic changes in the micro-circulation, in PH are established fibrous tissue (periportal fibrous septal) and regenerative hyperplastic nodules (from micro- to macro-nodules) promoting hepatic architectural distortion. EVIDENCE ACQUISITION A literature search of electronic databases was undertaken for the major studies published from 1981 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the keywords: "portal hypertension, children, immune system, endocrine system, liver fibrosis". RESULTS It is believed that PH results from three "phenotype": ischemia-reperfusion, involving nervous system (NS); edema and oxidative damage, involving immune system; inflammation and angiogenesis, involving endocrine system. However, its exact cause still underdiagnosed and unknown. CONCLUSIONS PH is a dynamic and potentially reversible process. Researchers have tried to demonstrate mechanisms underlying PH and its related-complications. This review focuses on the current knowledge regarding the pathogenesis, and immune, endocrine-metabolic factors of disease. The strong positive association between immune system and development of PH could be efficient to identify non-invasive markers of disease, to modify prognosis of PH, and to development and application of specific and individual anti-inflammatory therapy.
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Affiliation(s)
- Sara Manti
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Lucia Marseglia
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Gabriella D'Angelo
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Martina Filippelli
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Caterina Cuppari
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Eloisa Gitto
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Claudio Romano
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Teresa Arrigo
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Carmelo Salpietro
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
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Manti S, Romano C, Chirico V, Filippelli M, Cuppari C, Loddo I, Salpietro C, Arrigo T. Nonalcoholic Fatty liver disease/non-alcoholic steatohepatitis in childhood: endocrine-metabolic "mal-programming". HEPATITIS MONTHLY 2014; 14:e17641. [PMID: 24829591 PMCID: PMC4013495 DOI: 10.5812/hepatmon.17641] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 02/13/2014] [Accepted: 02/19/2014] [Indexed: 02/08/2023]
Abstract
CONTEXT Nonalcoholic Fatty Liver Disease (NAFLD) is the major chronic liver disease in the pediatric population. NAFLD includes a broad spectrum of abnormalities (inflammation, fibrosis and cirrhosis), ranging from accumulation of fat (also known as steatosis) towards non-alcoholic steatohepatitis (NASH). The development of NAFLD in children is significantly increased. EVIDENCE ACQUISITION A literature search of electronic databases was undertaken for the major studies published from 1998 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the key words: "non-alcoholic fatty liver disease, children, non-alcoholic steatohepatitis and fatty liver". RESULTS NAFLD/NASH is probably promoted by "multiple parallel hits": environmental and genetic factors, systemic immunological disorders (oxidative stress, persistent-low grade of inflammation) as well as obesity and metabolic alterations (insulin resistance and metabolic syndrome). However its exact cause still underdiagnosed and unknown. CONCLUSIONS Pediatric NAFLD/NASH is emerging problem. Longitudinal follow-up studies, unfortunately still insufficient, are needed to better understand the natural history and outcome of NAFLD in children. This review focuses on the current knowledge regarding the epidemiology, pathogenesis, environmental, genetic and metabolic factors of disease. The review also highlights the importance of studying the underlying mechanisms of pediatric NAFLD and the need for complete and personalized approach in the management of NAFLD/NASH.
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Affiliation(s)
- Sara Manti
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Claudio Romano
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Valeria Chirico
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Martina Filippelli
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Caterina Cuppari
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Italia Loddo
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Carmelo Salpietro
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Teresa Arrigo
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
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Chang JS, Bai CH, Huang ZC, Owaga E, Chao KC, Chang CC, Chiou HY. Interleukin 10 and clustering of metabolic syndrome components in pediatrics. Eur J Clin Invest 2014; 44:384-94. [PMID: 24467774 DOI: 10.1111/eci.12247] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 01/23/2014] [Indexed: 01/29/2023]
Abstract
BACKGROUND Interleukin 10 (IL-10) has multifaceted anti-inflammatory properties that are known to regulate insulin sensitivity and atherosclerotic development. However, studies in children are limited and have yielded conflicting results. The aim of this study was to evaluate whether changes in this circulating anti-inflammatory cytokine is a marker for metabolic syndrome. MATERIALS AND METHODS This cross-sectional study involved children and young adolescents from eight elementary schools and two junior high schools located in Taipei and New Taipei City. A total of 553 children ages 8, 11 and 13 years old were included in the analysis. Parameters for obesity, anti- and pro-inflammatory cytokines, and metabolic risk profiles were evaluated. RESULTS Overweight/obese children had lower serum IL-10 concentrations compared with normal weight children in the same age group (all P < 0·001). IL-10 quartiles were negatively associated with body mass index (BMI) and percentage (%) body fat (all P < 0·05). Multivariate regression analysis showed significant inverse relationship between IL-10 concentrations and % body fat (β = -0·009, P < 0·0001), and total cholesterol (β = -0·726, P = 0·003), and a small positive correlation between IL-10 and systolic blood pressure (β = 0·980, P = 0·027). In normal weight children, IL-10 concentrations were independently associated with fasting plasma insulin (β = 0·2912, P = 0·001) and waist circumference (β = 0·0069, P = 0·022). By contrast, % body fat (β = -0·016, P = 0·0009) was independently associated with IL-10 concentrations in overweight and obese children. Association between IL-10 and fasting plasma insulin concentrations was weaker in overweight/obese children compared with normal weight (β = 0·283, P = 0·011 vs. β = 0·2912, P = 0·001). CONCLUSION Our data indicate that changes in circulating IL-10 concentrations are marker of metabolic risk in children.
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Affiliation(s)
- Jung-Su Chang
- School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
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