RAGE and HMGB1 Expression in Orbital Tissue Microenvironment in Graves’ Ophthalmopathy

Graves’ ophthalmopathy (GO) is a chronic autoimmune inflammatory disorder involving orbital tissues. A receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 (HMGB1) protein trigger inflammation and cell proliferation and are involved in the pathogenesis of various chronic inflammatory diseases. This study was aimed to evaluate RAGE and HMGB1 expression in GO to determine its potential clinical significance. To the best of our knowledge, this is the first study showing RAGE and HMGB1 expression in orbital tissue using immunohistochemistry. Sections of orbital adipose tissue obtained from patients diagnosed with GO (23 patients; 36 orbits) and normal controls (NC) (15 patients; 15 orbits) were analyzed by immunohistochemistry for RAGE and HMGB1 expression. Expression profiles were then correlated with clinical data of the study group. RAGE and HMGB1 expression were elevated in GO patients in comparison with NC ( p = 0.001 and p = 0.02 , respectively). We observed a correlation between RAGE expression and occurrence of dysthyroid optic neuropathy (DON) ( p = 0.05 ) and levels of TSH Receptor Antibodies (TRAb) ( p = 0.01 ). Overexpression of RAGE and HMGB1 might be associated with GO pathogenesis. In addition, RAGE and HMGB1 proteins may be considered as promising therapeutic targets, but this requires further research.

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The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review

Current Neuropharmacology ◽

10.2174/1570159x20666220114153308 ◽

2022 ◽

Vol 20 ◽

Author(s):

Fathimath Zaha Ikram ◽

Alina Arulsamy ◽

Thaarvena Retinasamy ◽

Mohd. Farooq Shaikh

Keyword(s):

Systematic Review ◽

Tissue Injury ◽

High Mobility ◽

High Mobility Group ◽

Hmgb1 Protein ◽

Toll Like Receptor 4 ◽

Neuroinflammatory Response ◽

Molecular Pattern ◽

Glycation End Products

Background: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) molecule that plays an important role in the repair and regeneration of tissue injury. It also acts as a pro-inflammatory cytokine through the activation of toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), to elicit the neuroinflammatory response. HMGB1 may aggravate several cellular responses which may lead to pathological inflammation and cellular death. Thus, there have been a considerable amount of research into the pathological role of HMGB1 in diseases. However, whether the mechanism of action of HMGB1 is similar in all neurodegenerative disease pathology remains to be determined. Objective: Therefore, this systematic review aimed to critically evaluate and elucidate the role of HMGB1 in the pathology of neurodegeneration based on the available literature. Methods: A comprehensive literature search was performed on four databases; EMBASE, PubMed, Scopus, and CINAHL Plus. Results: A total of 85 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that HMGB1 levels were found elevated in most neurodegeneration except in Huntington’s disease and Spinocerebellar ataxia, where the levels were found decreased. This review also showcased that HMGB1 may act on distinctive pathways to elicit its pathological response leading to the various neurodegeneration processes/diseases. Conclusion: While there have been promising findings in HMGB1 intervention research, further studies may still be required before any HMGB1 intervention may be recommended as a therapeutic target for neurodegenerative diseases.

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High-mobility group box-1 protein from CC10+ club cells promotes type 2 response in the later stage of respiratory syncytial virus infection

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00552.2017 ◽

2019 ◽

Vol 316 (1) ◽

pp. L280-L290 ◽

Cited By ~ 4

Author(s):

Sisi Chen ◽

Guangyuan Yu ◽

Jun Xie ◽

Wei Tang ◽

Leiqiong Gao ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

High Mobility ◽

Clinical Severity ◽

High Mobility Group ◽

Hmgb1 Protein ◽

Club Cells ◽

Hmgb1 Expression ◽

Syncytial Virus ◽

Tract Infections

The type 2 immune response, induced by infection of respiratory syncytial virus (RSV), has been linked to asthma development, but it remains unclear how the response is initiated. Here, we reported that the high-mobility group box-1 (HMGB1) protein promotes the type 2 response in the later stage of RSV infection. In mice, we found that type 2 cytokines were elevated in the later stages, which were strongly diminished after administration of anti-HMGB1 antibodies. Further investigation revealed that HMGB1 expression was localized to CC10+ club cells in the lung. In the clinic, levels of HMGB1 in nasopharyngeal aspirates in hospitalized infants with RSV bronchiolitis [median (interquartile range) 161.20 ng/ml (68.06–221.30)] were significantly higher than those without lower respiratory tract infections [21.94 ng/ml (12.12–59.82); P < 0.001]. Moreover, higher levels of HMGB1 correlated with clinical severity. These results reveal a link between viral infection and the asthma-like type 2 responses that are associated with long-term consequences.

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MiR-142-3p Overexpression Increases Chemo-Sensitivity of NSCLC by Inhibiting HMGB1-Mediated Autophagy

Cellular Physiology and Biochemistry ◽

10.1159/000467896 ◽

2017 ◽

Vol 41 (4) ◽

pp. 1370-1382 ◽

Cited By ~ 28

Author(s):

Yuqing Chen ◽

Xin Zhou ◽

Jianou Qiao ◽

Aihua Bao

Keyword(s):

Drug Resistance ◽

Therapeutic Potential ◽

High Mobility ◽

In Silico Analysis ◽

Luciferase Reporter ◽

Hmgb1 Protein ◽

Drug Induced ◽

Hmgb1 Expression

Background: Non-small-cell lung cancer (NSCLC) is a deadly cancer with high mortality rate. Drug resistance represents a main obstacle in NSCLC treatment. High mobility group box-1 (HMGB1) protein promotes drug resistance in NSCLC cells by activating protective autophagy. Methods: In the current study, we investigated the regulatory role of microRNA-142-3p (miR-142-3p) in HMGB1-mediated autophagy of NSCLC cells and its impact on drug resistance of NSCLC in vitro and in vivo. HMGB1 was identified as a putative target gene of miR-142-3p by in silico analysis. Our luciferase reporter assay results confirmed that miR-142-3p directly targets the 3’-UTR of HMGB1 in NSCLC cells. Results: MiR-142-3p overexpression suppressed while miR-142-3p knockdown increased HMGB1 mRNA and protein expression. Starvation induced HMGB1 expression and activated autophagy in NSCLC cells. The starvation-induced autophagy was inhibited by miR-142-3p overexpression or HMGB1 knockdown. Moreover, miR-142-3p overexpression or HMGB1 knockdown increased PI3K, Akt, and mTOR phosphorylation. Inhibition of PI3K or mTOR restored starvation-induced autophagy inhibited by miR-142-3p overexpression or HMGB1 knockdown. Conclusions: These results demonstrated that miR-142-3p regulates starvation-induced autophagy of NSCLC cells by directly downregulating HMGB1 and subsequently activating the PI3K/Akt/mTOR pathway. Further, miR-142-3p overexpression inhibited anticancer drug-induced autophagy and increased chemo-sensitivity of NSCLC in vitro and in vivo. These findings shed light on the therapeutic potential of miR-142-3p in combating acquired NSCLC chemo-resistance.

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Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves’ Ophthalmopathy through the Regulation of FoxO3a Signaling

Mediators of Inflammation ◽

10.1155/2021/8888913 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yi-Hsuan Wei ◽

Shu-Lang Liao ◽

Chia-Chun Wang ◽

Sen-Hsu Wang ◽

Wan-Chun Tang ◽

...

Keyword(s):

Inflammatory Diseases ◽

Protective Effects ◽

Cellular Mechanisms ◽

Graves Ophthalmopathy ◽

Potential Biomarker ◽

Tnf Α ◽

Orbital Tissue ◽

Proinflammatory Role ◽

And Migration ◽

Orbital Fibroblasts

Graves’ ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves’ disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1β, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue ( n = 4 ) and serum specimens ( n = 6 ) obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO.

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Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

Cells ◽

10.3390/cells9020383 ◽

2020 ◽

Vol 9 (2) ◽

pp. 383 ◽

Cited By ~ 16

Author(s):

Yam Nath Paudel ◽

Efthalia Angelopoulou ◽

Christina Piperi ◽

Iekhsan Othman ◽

Khurram Aamir ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

High Mobility ◽

Health Concern ◽

Hmgb1 Protein ◽

Therapeutic Targeting ◽

Beneficial Effects ◽

Molecular Pattern ◽

Glycation End Products

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

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Computational Analysis of the Messenger RNA Variants Encoding Two Isoforms of the High-mobility Group box 1 Protein

Natural Science and Advanced Technology Education ◽

10.53656/nat2021-3.02 ◽

2021 ◽

Vol 30 (3) ◽

pp. 243-252

Author(s):

Luchezar Karagyozov ◽

◽

Jordana Todorova ◽

Keyword(s):

Messenger Rna ◽

Computational Analysis ◽

Splice Variants ◽

Inflammatory Diseases ◽

High Mobility ◽

High Mobility Group ◽

Dual Function ◽

Chromosomal Protein ◽

Hmgb1 Protein ◽

Gene Encoding

High-mobility group box 1 protein (HMGB1) is a multifunctional nonhistone chromosomal protein. This widespread nuclear protein has a dual function-in the nucleus - it binds DNA and participates in practically all DNA-dependent processes. On the other hand, the protein plays an important role in the extracellular matrix as an “alarmin”, which interacts with certain receptors and stimulates biochemical pathways, associated with carcinogenesis and metastasis. HMGB1 is a critical damage-associated molecular pattern molecule, has been implicated in several inflammatory diseases and cancer types. This universality makes it an attractive target for innovative therapeutic strategies in the treatment of various diseases. The updated database for the HMGB1 gene, encoding the high-mobility group box 1 protein, was used for computational analysis of the annotated mRNA splice variants. Results showed that five of the splice variants encode an HMGB1 protein, containing 215 amino acid residues. However, two of the splice variants encode a shorter HMGB1 protein with 158 residues. Presently, the existence of a shorter HMGB1 protein is not registered in the protein databanks. This inconsistency is not yet resolved.

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Immunogene Zelltodmarker HMGB1 und sRAGE als neue prädiktive und prognostische Serum Biomarker bei Tumorerkrankungen/Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

LaboratoriumsMedizin ◽

10.1515/labmed-2013-0005 ◽

2013 ◽

Vol 37 (1) ◽

Cited By ~ 1

Author(s):

Christin Wittwer ◽

Stefan Holdenrieder

Keyword(s):

High Mobility ◽

Serum Biomarkers ◽

Serum Biomarker ◽

Advanced Glycation ◽

Hmgb1 Protein ◽

Cancer Disease ◽

Glycation End Products ◽

End Products ◽

Sind Eine ◽

Molecular Patterns

ZusammenfassungImmunogene Zelltodmarker sind eine inhomogene Gruppe von Molekülen, die während Zelltodprozessen wie Apoptose, Nekrose oder weiteren Formen freigesetzt werden. Je nach Zusammensetzung des extrazellulären Milieus können diese „Danger associated molecular patterns“ (DAMPs) wie das „High mobility group box 1“ (HMGB1) Protein das Immunsystem stimulierend oder inhibierend beeinflussen. Bei Tumorerkrankungen scheint eine kontinuierliche Freisetzung von HMGB1, u.a. über eine Vermittlung durch den zellulären Bindungspartner „Receptor of advanced glycation end products“ (RAGE), zu einer Förderung des Tumorwachstums zu führen, während die pulsatile Freisetzung während zytotoxischer Therapie zu einer verbesserten antitumorösen Immunantwort beitragen könnte. Lösliches RAGE (sRAGE) kann hingegen die Effekte von extrazellulärem HMGB1 abpuffern. In diesem Review werden die strukturellen und funktionalen Charakteristika dieser immunogenen Zelltodmarker sowie ihre Rolle in der Pathophysiologie von nicht-malignen und malignen Erkrankungen vorgestellt; sodann wird ihre Relevanz als Serum-Biomarker für die Diagnose, die Prognoseabschätzung, die Prädiktion und das Monitoring des Ansprechens einer zytotoxischen Therapie bei Tumorpatienten beleuchtet. Bei Patienten mit verschiedenen Tumorerkrankungen wurden im Vergleich zu gesunden Personen erhöhte Serumkonzentrationen von HMGB1 und niedrigere sRAGE-Werte gefunden. Zudem waren hohe HMGB1- und niedrige sRAGE-Serumwerte vor und während einer zytotoxischen Therapie mit einem unzureichenden Ansprechen auf die Behandlung und einem kürzeren Überleben assoziiert. Diese Ergebnisse weisen die immunogenen Zelltodmarker HMGB1 und sRAGE als neue, vielversprechende Biomarker zur Abschätzung der Prognose, Stratifikation der Patienten und zum Therapiemonitoring bei Tumorpatienten aus.

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Ethyl Pyruvate Inhibits Retinal Pathogenic Neovascularization by Downregulating HMGB1 Expression

Journal of Diabetes Research ◽

10.1155/2013/245271 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 12

Author(s):

Yun Mi Lee ◽

Junghyun Kim ◽

Kyuhyung Jo ◽

So Dam Shin ◽

Chan-Sik Kim ◽

...

Keyword(s):

Ethyl Pyruvate ◽

High Mobility ◽

Fluorescein Isothiocyanate ◽

Causative Factor ◽

Age Related Macular Degeneration ◽

In Vivo Studies ◽

Hmgb1 Protein ◽

Age Related ◽

Hmgb1 Expression

Retinal pathogenic angiogenesis in the eyes is a causative factor in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. This study was designed to examine the pathogenic role of the high-mobility group box-1 (HMGB1) protein and the inhibitory effect of ethyl pyruvate (EP), a well-known antioxidant substance, in retinal pathogenic angiogenesis in mice with oxygen-induced retinopathy (OIR), one of the animal models of proliferative ischemic retinopathy. The OIR mouse model was used for our in vivo studies. The mice were exposed to 75% oxygen from postnatal day 7 (P7) to P11, after which the mice were brought to room air and intraperitoneally injected with EP (50 mg/kg, or 100 mg/kg) for five days. At P17, the mice were perfused with fluorescein isothiocyanate-dextran, and flat-mounted retinas were used to measure nonperfused and neovascular tufts. In OIR mice, an intraperitoneal injection of EP reduced the nonperfused retinal area in the treatment group and significantly reduced the retinal neovascular tufts. In addition, EP inhibited the overexpression of HMGB1 in the retinas of OIR mice. These data suggest that EP could serve as an innovative pharmaceutical agent to prevent retinal neovascularization through inhibiting HMGB1 expression.

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HMGB1-Mediated Neuroinflammatory Responses in Brain Injuries: Potential Mechanisms and Therapeutic Opportunities

International Journal of Molecular Sciences ◽

10.3390/ijms21134609 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4609 ◽

Cited By ~ 3

Author(s):

Yam Nath Paudel ◽

Efthalia Angelopoulou ◽

Christina Piperi ◽

Iekhsan Othman ◽

Mohd. Farooq Shaikh

Keyword(s):

Brain Injury ◽

Brain Injuries ◽

High Mobility ◽

Early Brain Injury ◽

Advanced Glycation ◽

Hmgb1 Protein ◽

Neuroprotective Effects ◽

Mortality And Morbidity ◽

Glycation End Products

Brain injuries are devastating conditions, representing a global cause of mortality and morbidity, with no effective treatment to date. Increased evidence supports the role of neuroinflammation in driving several forms of brain injuries. High mobility group box 1 (HMGB1) protein is a pro-inflammatory-like cytokine with an initiator role in neuroinflammation that has been implicated in Traumatic brain injury (TBI) as well as in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Herein, we discuss the implication of HMGB1-induced neuroinflammatory responses in these brain injuries, mediated through binding to the receptor for advanced glycation end products (RAGE), toll-like receptor4 (TLR4) and other inflammatory mediators. Moreover, we provide evidence on the biomarker potential of HMGB1 and the significance of its nucleocytoplasmic translocation during brain injuries along with the promising neuroprotective effects observed upon HMGB1 inhibition/neutralization in TBI and EBI induced by SAH. Overall, this review addresses the current advances on neuroinflammation driven by HMGB1 in brain injuries indicating a future treatment opportunity that may overcome current therapeutic gaps.

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Overexpression of Receptor for Advanced Glycation End Products and High-Mobility Group Box 1 in Human Dental Pulp Inflammation

Mediators of Inflammation ◽

10.1155/2014/754069 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 12

Author(s):

Salunya Tancharoen ◽

Tassanee Tengrungsun ◽

Theeralaksna Suddhasthira ◽

Kiyoshi Kikuchi ◽

Nuttavun Vechvongvan ◽

...

Keyword(s):

Advanced Glycation End Products ◽

Dental Pulp ◽

High Mobility ◽

High Mobility Group ◽

Dependent Manner ◽

Advanced Glycation ◽

Pulp Inflammation ◽

Glycation End Products ◽

End Products ◽

Hmgb1 Expression

High mobility group box 1 (HMGB1), a nonhistone DNA-binding protein, is released into the extracellular space and promotes inflammation. HMGB1 binds to related cell signaling transduction receptors, including receptor for advanced glycation end products (RAGE), which actively participate in vascular and inflammatory diseases. The aim of this study was to examine whether RAGE and HMGB1 are involved in the pathogenesis of pulpitis and investigate the effect of Prevotella intermedia (P. intermedia) lipopolysaccharide (LPS) on RAGE and HMGB1 expression in odontoblast-like cells (OLC-1). RAGE and HMGB1 expression levels in clinically inflamed dental pulp were higher than those in healthy dental pulp. Upregulated expression of RAGE was observed in odontoblasts, stromal pulp fibroblasts-like cells, and endothelial-like cell lining human pulpitis tissue. Strong cytoplasmic HMGB1 immunoreactivity was noted in odontoblasts, whereas nuclear HMGB1 immunoreactivity was seen in stromal pulp fibroblasts-like cells in human pulpitis tissue. LPS stimulated OLC-1 cells produced HMGB1 in a dose-dependent manner through RAGE. HMGB1 translocation towards the cytoplasm and secretion from OLC-1 in response to LPS was inhibited by TPCA-1, an inhibitor of NF-κB activation. These findings suggest that RAGE and HMGB1 play an important role in the pulpal immune response to oral bacterial infection.

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