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  1. Exploring the role of high-mobility group box 1 (HMGB1) protein in the pathogenesis of Huntington's disease
    Angelopoulou E, Paudel YN, Piperi C
    J Mol Med (Berl), 2020 03;98(3):325-334.
    PMID: 32036391 DOI: 10.1007/s00109-020-01885-z
    Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by an increased and unstable CAG DNA expansion in the Huntingtin (HTT) gene, resulting in an elongated polyglutamine tract in huntingtin protein. Despite its monogenic cause, HD pathogenesis remains elusive and without any approved disease-modifying therapy as yet. A growing body of evidence highlights the emerging role of high-mobility group box 1 (HMGB1) protein in HD pathology. HMGB1, being a nuclear protein, is primarily implicated in DNA repair, but it can also translocate to the cytoplasm and participate into numerous cellular functions. Cytoplasmic HMGB1 was shown to directly interact with huntingtin under oxidative stress conditions and induce its nuclear translocation, a key process in the HD pathogenic cascade. Nuclear HMGB1 acting as a co-factor of ataxia telangiectasia mutated and base excision repair (BER) complexes can exert dual roles in CAG repeat instability and affect the final DNA repair outcome. HMGB1 can inhibit mutant huntingtin aggregation, protecting against polyglutamine-induced neurotoxicity and acting as a chaperon-like molecule, possibly via autophagy regulation. In addition, HMGB1 being a RAGE and TLR-2, TLR-3, and TLR-4 ligand may further contribute to HD pathogenesis by triggering neuroinflammation and apoptosis. Furthermore, HMGB1 participates at the unfolded protein response (UPR) system and can induce protein degradation and apoptosis associated with HD. In this review, we discuss the multiple role of HMGB1 in HD pathology, providing mechanistic insights that could direct future studies towards the development of targeted therapeutic approaches.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor/metabolism
  2. The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review
    Ikram FZ, Arulsamy A, Retinasamy T, Shaikh MF
    Curr Neuropharmacol, 2022;20(11):2221-2245.
    PMID: 35034598 DOI: 10.2174/1570159X20666220114153308
    BACKGROUND: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) 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.

    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor
  3. Fulltext Impact of HMGB1, RAGE, and TLR4 in Alzheimer's Disease (AD): From Risk Factors to Therapeutic Targeting
    Paudel YN, Angelopoulou E, Piperi C, Othman I, Aamir K, Shaikh MF
    Cells, 2020 02 07;9(2).
    PMID: 32046119 DOI: 10.3390/cells9020383
    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.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor/metabolism*
  4. Fulltext Lack of association between Gly82Ser, 1704G/T and 2184A/G of RAGE gene polymorphisms and retinopathy susceptibility in Malaysian diabetic patients
    Ng ZX, Kuppusamy UR, Poh R, Tajunisah I, Koay AC, Fong KC, et al.
    Genet. Mol. Res., 2012 Mar 01;11(1):455-61.
    PMID: 22427038 DOI: 10.4238/2012.March.1.2
    Diabetic retinopathy is the most common diabetic eye disease, occurring in about 60% of type 2 diabetic patients. Other than known clinical risk factors, the influence of genes has been suggested as part of the development of diabetic retinopathy. We investigated the association of Gly82Ser, 1704G/T and 2184A/G polymorphisms in the RAGE gene with retinopathy in type 2 diabetic patients in Malaysia. Ninety-eight unrelated retinopathy patients and 185 unrelated healthy controls from all over Malaysia were recruited in this study. The allele and genotype frequencies of the three gene polymorphisms were investigated using PCR-RFLP. The allele frequency of the three polymorphisms did not differ significantly between the control and the retinopathy group (P > 0.05). Analysis of the frequency of GA+AA, GT+TT and AG+GG in the retinopathy group did not reveal significant differences (P > 0.05) compared to the control group. We conclude that RAGE gene Gly82Ser, 1704G/T and 2184A/G polymorphisms are not associated with retinopathy development in the Malaysian population.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor/genetics*
  5. Potential Neuroprotective Effect of the HMGB1 Inhibitor Glycyrrhizin in Neurological Disorders
    Paudel YN, Angelopoulou E, Semple B, Piperi C, Othman I, Shaikh MF
    ACS Chem Neurosci, 2020 02 19;11(4):485-500.
    PMID: 31972087 DOI: 10.1021/acschemneuro.9b00640
    Glycyrrhizin (glycyrrhizic acid), a bioactive triterpenoid saponin constituent of Glycyrrhiza glabra, is a traditional medicine possessing a plethora of pharmacological anti-inflammatory, antioxidant, antimicrobial, and antiaging properties. It is a known pharmacological inhibitor of high mobility group box 1 (HMGB1), a ubiquitous protein with proinflammatory cytokine-like activity. HMGB1 has been implicated in an array of inflammatory diseases when released extracellularly, mainly by activating intracellular signaling upon binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). HMGB1 neutralization strategies have demonstrated disease-modifying outcomes in several preclinical models of neurological disorders. Herein, we reveal the potential neuroprotective effects of glycyrrhizin against several neurological disorders. Emerging findings demonstrate the therapeutic potential of glycyrrhizin against several HMGB1-mediated pathological conditions including traumatic brain injury, neuroinflammation and associated conditions, epileptic seizures, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Glycyrrhizin's effects in neurological disorders are mainly attributed to the attenuation of neuronal damage by inhibiting HMGB1 expression and translocation as well as by downregulating the expression of inflammatory cytokines. A large number of preclinical findings supports the notion that glycyrrhizin might be a promising therapeutic alternative to overcome the shortcomings of the mainstream therapeutic strategies against neurological disorders, mainly by halting disease progression. However, future research is warranted for a deeper exploration of the precise underlying molecular mechanism as well as for clinical translation.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor/metabolism
  6. Implication of HMGB1 signaling pathways in Amyotrophic lateral sclerosis (ALS): From molecular mechanisms to pre-clinical results
    Paudel YN, Angelopoulou E, Piperi C, Othman I, Shaikh MF
    Pharmacol Res, 2020 06;156:104792.
    PMID: 32278047 DOI: 10.1016/j.phrs.2020.104792
    Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressing neurodegenerative disorder with no effective disease-modifying treatment up to date. The underlying molecular mechanisms of ALS are not yet completely understood. However, the critical role of the innate immune system and neuroinflammation in ALS pathogenesis has gained increased attention. High mobility group box 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, acting as a pro-inflammatory cytokine mainly through activation of its principal receptors, the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) which are crucial components of the innate immune system. HMGB1 is an endogenous ligand for both RAGE and TLR4 that mediate its biological effects. Herein, on the ground of pre-clinical findings we unravel the underlying mechanisms behind the plausible contribution of HMGB1 and its receptors (RAGE and TLR4) in the ALS pathogenesis. Furthermore, we provide an account of the therapeutic outcomes associated with inhibition/blocking of HMGB1 receptor signalling in preventing motor neuron's death and delaying disease progression in ALS experimental models. There is strong evidence that HMGB1, RAGE and TLR4 signaling axes might present potential targets against ALS, opening a novel headway in ALS research that could plausibly bridge the current treatment gap.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor/metabolism*
  7. Fulltext The Ameliorative Effects of a Tocotrienol-Rich Fraction on the AGE-RAGE Axis and Hypertension in High-Fat-Diet-Fed Rats with Metabolic Syndrome
    Cheng HS, Ton SH, Tan JBL, Abdul Kadir K
    Nutrients, 2017 Sep 07;9(9).
    PMID: 28880217 DOI: 10.3390/nu9090984
    The clinical value of tocotrienols is increasingly appreciated because of the unique therapeutic effects that are not shared by tocopherols. However, their effect on metabolic syndrome is not well-established. This study aimed to investigate the effects of a tocotrienol-rich fraction (TRF) from palm oil in high-fat-diet-treated rats. Male, post-weaning Sprague Dawley rats were provided high-fat (60% kcal) diet for eight weeks followed by a TRF (60 mg/kg) treatment for another four weeks. Physical, metabolic, and histological changes were compared to those on control and high-fat diets respectively. High-fat feeding for eight weeks induced all hallmarks of metabolic syndrome. The TRF reversed systolic and diastolic hypertension, hypercholesterolemia, hepatic steatosis, impaired antioxidant defense, and myeloperoxidase hyperactivity triggered by the high-fat diet. It also conferred an inhibitory effect on protein glycation to reduce glycated hemoglobin A1c and advanced glycation end products (AGE). This was accompanied by the suppression of the receptor for advanced glycation end product (RAGE) expression in the liver. The treatment effects on visceral adiposity, glycemic control, triglyceride level, as well as peroxisome proliferator-activated receptor α and γ expression were negligible. To conclude, treatment with a TRF exhibited protective effects on the cardiovascular and liver health in addition to the amelioration of plasma redox imbalance and AGE-RAGE activation. Further investigation as a therapy for metabolic syndrome is therefore worthwhile.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor/metabolism*
  8. Association analysis of -429T/C and -374T/A polymorphisms of receptor of advanced glycation end products (RAGE) gene in Malaysian with type 2 diabetic retinopathy
    Ng ZX, Kuppusamy UR, Tajunisah I, Fong KC, Chua KH
    Diabetes Res Clin Pract, 2012 Mar;95(3):372-7.
    PMID: 22154374 DOI: 10.1016/j.diabres.2011.11.005
    Conflicting results have been reported in different populations on the association between two particular RAGE gene polymorphisms (-429T/C and -374T/A) and retinopathy in diabetic patients. Therefore this study was designed to assess the association between both gene polymorphisms with retinopathy in Malaysian diabetic patients. A total of 342 type 2 diabetic patients [171 without retinopathy (DNR) and 171 with retinopathy (DR)] and 235 healthy controls were included in this study. Genomic DNA was obtained from blood samples and the screening for the gene polymorphisms was done using polymerase chain reaction-restriction fragment length polymorphism approach. Overall, the genotype distribution for both polymorphisms was not statistically different (p>0.05) among the control, DNR and DR groups. The -429C minor allele frequency of DR group (12.0%) was not significantly different (p>0.05) when compared to DNR group (16.1%) and healthy controls (11.3%). The -374A allele frequency also did not differ significantly between the control and DNR (p>0.05), control and DR (p>0.05) as well as DNR and DR groups (p>0.05). This is the first study report on RAGE gene polymorphism in Malaysian DR patients. In conclusion, -429T/C and -374T/A polymorphisms in the promoter region of RAGE gene were not associated with Malaysian type 2 DR patients.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor
  9. Unraveling the Role of Receptor for Advanced Glycation End Products (RAGE) and Its Ligands in Myasthenia Gravis
    Angelopoulou E, Paudel YN, Piperi C
    ACS Chem Neurosci, 2020 03 04;11(5):663-673.
    PMID: 32017530 DOI: 10.1021/acschemneuro.9b00678
    Myasthenia gravis (MG) is an autoimmune T cell-dependent B cell-mediated disorder of the neuromuscular junction (NMJ) characterized by fluctuating skeletal muscle weakness, most commonly attributed to pathogenic autoantibodies against postsynaptic nicotinic acetylcholine receptors (AChRs). Although MG pathogenesis is well-documented, there are no objective biomarkers that could effectively correlate with disease severity or MG clinical subtypes, and current treatment approaches are often ineffective. The receptor for advanced glycation end products (RAGE) is a multiligand cell-bound receptor highly implicated in proinflammatory responses and autoimmunity. Preclinical evidence demonstrates that RAGE and its ligand S100B are upregulated in rat models of experimental autoimmune myasthenia gravis (EAMG). S100B-mediated RAGE activation has been shown to exacerbate EAMG, by enhancing T cell proinflammatory responses, aggravating T helper (Th) subset imbalance, increasing AChR-specific T cell proliferative capacity, and promoting the production of antibodies against AChRs from the spleen. Soluble sRAGE and esRAGE, acting as decoys of RAGE ligands, are found to be significantly reduced in MG patients. Moreover, MG has been associated with increased serum levels of S100A12, S100B and HMGB1. Several studies have shown that the presence of thymic abnormalities, the onset age of MG, and the duration of the disease may affect the levels of these proteins in MG patients. Herein, we discuss the emerging role of RAGE and its ligands in MG immunopathogenesis, their clinical significance as promising biomarkers, as well as the potential therapeutic implications of targeting RAGE signaling in MG treatment.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor
  10. Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats
    Ismail N, Ismail M, Azmi NH, Bakar MFA, Yida Z, Abdullah MA, et al.
    Biomed Pharmacother, 2017 Nov;95:780-788.
    PMID: 28892789 DOI: 10.1016/j.biopha.2017.08.074
    Though the causes of Alzheimer's disease (AD) are yet to be understood, much evidence has suggested that excessive amyloid-β (Aβ) accumulation due to abnormal amyloid-β precursor protein (APP) processing and Aβ metabolism are crucial processes towards AD pathogenesis. Hence, approaches aiming at APP processing and Aβ metabolism are currently being actively pursued for the management of AD. Studies suggest that high cholesterol and a high fat diet have harmful effects on cognitive function and may instigate the commencement of AD pathogenesis. Despite the neuropharmacological attributes of black cumin seed (Nigella sativa) extracts and its main active compound, thymoquinone (TQ), limited records are available in relation to AD research. Nanoemulsion (NE) is exploited as drug delivery systems due to their capacity of solubilising non-polar active compounds and is widely examined for brain targeting. Herewith, the effects of thymoquinone-rich fraction nanoemulsion (TQRFNE), thymoquinone nanoemulsion (TQNE) and their counterparts' conventional emulsion in response to high fat/cholesterol diet (HFCD)-induced rats were investigated. Particularly, the Aβ generation; APP processing, β-secretase 1 (BACE1), γ-secretases of presenilin 1 (PSEN1) and presenilin 2 (PSEN2), Aβ degradation; insulin degrading enzyme (IDE), Aβ transportation; low density lipoprotein receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) were measured in brain tissues. TQRFNE reduced the brain Aβ fragment length 1-40 and 1-42 (Aβ40 and Aβ42) levels, which would attenuate the AD pathogenesis. This reduction could be due to the modulation of β- and γ-secretase enzyme activity, and the Aβ degradation and transportation in/out of the brain. The findings show the mechanistic actions of TQRFNE in response to high fat and high cholesterol diet associated to Aβ generation, degradation and transportation in the rat's brain tissue.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor/metabolism*
  11. Fulltext 2245G/A polymorphism of the receptor for advanced glycation end-products (RAGE) gene is associated with diabetic retinopathy in the Malaysian population
    Ng ZX, Kuppusamy UR, Tajunisah I, Fong KC, Koay AC, Chua KH
    Br J Ophthalmol, 2012 Feb;96(2):289-92.
    PMID: 22116960 DOI: 10.1136/bjophthalmol-2011-300658
    The receptor for advanced glycation end-products (RAGE) has been implicated in the pathogenesis of diabetic microvascular complications. The aim of this study was to investigate the association between 2245G/A gene polymorphism of the RAGE gene and retinopathy in Malaysian type 2 diabetic patients.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor
  12. RAGE and TLRs: relatives, friends or neighbours?
    Ibrahim ZA, Armour CL, Phipps S, Sukkar MB
    Mol Immunol, 2013 Dec;56(4):739-44.
    PMID: 23954397 DOI: 10.1016/j.molimm.2013.07.008
    The innate immune system forms the first line of protection against infectious and non-infectious tissue injury. Cells of the innate immune system detect pathogen-associated molecular patterns or endogenous molecules released as a result of tissue injury or inflammation through various innate immune receptors, collectively termed pattern-recognition receptors. Members of the Toll-like receptor (TLR) family of pattern-recognition receptors have well established roles in the host immune response to infection, while the receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of infection, physiological stress or chronic inflammation. RAGE and TLRs share common ligands and signaling pathways, and accumulating evidence points towards their co-operative interaction in the host immune response. At present however, little is known about the mechanisms that result in TLR versus RAGE signalling or RAGE-TLR cross-talk in response to their shared ligands. Here we review what is known in relation to the physicochemical basis of ligand interactions between TLRs and RAGE, focusing on three shared ligands of these receptors: HMGB1, S100A8/A9 and LPS. Our aim is to discuss what is known about differential ligand interactions with RAGE and TLRs and to highlight important areas for further investigation so that we may better understand the role of these receptors and their relationship in host defense.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor
  13. Receptor for advanced glycation end-product (RAGE) gene polymorphism 2245G/A is associated with pro-inflammatory, oxidative-glycation markers and sRAGE in diabetic retinopathy
    Ng ZX, Kuppusamy UR, Iqbal T, Chua KH
    Gene, 2013 Jun 1;521(2):227-33.
    PMID: 23545311 DOI: 10.1016/j.gene.2013.03.062
    Receptor for advanced glycation end-product (RAGE) gene polymorphism 2245G/A is associated with diabetic retinopathy (DR). However, the mechanism on how it affects the disease development is still unclear.
    Matched MeSH terms: Advanced Glycosylation End Product-Specific Receptor
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