High-mobility group box 1 (HMGB1) protein: friend and foe.
ABSTRACT HMGB1 was originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be "passively released" into the extracellular milieu by necrotic and damaged somatic cells. Extracellular HMGB1 represents an optimal "necrotic marker" selected by the innate immune system to recognize tissue damage and initiate reparative responses. HMGB1 in the extracellular milieu promotes maturation of myeloid and plasmacytoid dendritic cells, and induces myocardial regeneration after infarction. However, extracellular HMGB1 also acts as a potent pro-inflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. A growing number of studies indicate that HMGB1 is a successful therapeutic target in experimental models of ischemia/reperfusion, acute respiratory distress syndrome, rheumatoid arthritis, sepsis, and cancer. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses while preventing its pathological potential. This article focus on the immuno-regulatory role of HMGB1 and its contribution to infectious and inflammatory disorders.
- SourceAvailable from: Maja Surbatovic[Show abstract] [Hide abstract]
ABSTRACT: Objectives The current study examined the single nucleotide polymorphisms (SNPs) in High Mobility Group Box 1 (HMGB1) gene in patients with Oral Squamous Cell Carcinoma (OSCC) and Oral Lichen Planus (OLP).Materials and methodsThe study was conducted on 93 OSCC patients, 53 OLP patients, and 100 controls, all Caucasians of the same ethnicity, matched by age. HMGB1 genotypes for 4 SNPs, 2262G/A (rs1045411), 1177G/C (rs3742305), 3814C/G (rs2249825), and rs4540927, were assessed using TaqMan SNP Genotyping Assays, Applied Biosystems.ResultsThe HMGB1 1177GG genotype was associated with lymph-node metastasis and tumor stage in OSCCs (p=0.016 and p=0.030, respectively). Genotype 1177GG resulted in poorer recurrence-free survival (RFS), p=0.000. The 1177G/C polymorphism was an independent predictor of RFS compared to GG genotype, p=0.001. The three polymorphisms were in linkage disequilibrium (LD). The AGC and GGC haplotypes were associated with an increased oral cancer risk, determined over the Haplotype Odds Ratios, (HOR=13.316, p=0.015, and HOR=5.769, p=0.029, respectively). The AGC haplotype was related to erosive OLP progression to OSCC (HOR=12.179, p=0.001).ConclusionsHMGB1 polymorphism 1177G/C could be associated with tumor progression and recurrence-free survival in OSCC patients. The haplotypes of HMGB1 gene might be associated with susceptibility to OSCC and OLP progression to OSCC.This article is protected by copyright. All rights reserved.Oral Diseases 01/2015; 21(4). DOI:10.1111/odi.12318 · 2.40 Impact Factor
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ABSTRACT: Fasting and calorie restriction are associated with a prolonged life span and an increased resistance to stress. The protective effects of fasting have been exploited for the mitigation of ischemic organ injury, yet the underlying mechanisms remain incompletely understood. Here, we investigated whether fasting protects liver against ischemia reperfusion (IR) through energy-preserving or anti-inflammatory mechanisms. Fasted C57BL6 mice were subjected to partial hepatic IR. Injury was assessed by liver enzymes and histology. Raw 264-7 macrophage-like cells were investigated in vitro. Sirt1 and Hmgb1 were inhibited using Ex527 and neutralizing antibodies, respectively. Fasting for one, but not two or three days, protected from hepatic IR injury. None of the investigated energy parameters correlated with the protective effects. Instead, inflammatory responses were dampened in one-day-fasted mice and in starved macrophages. Fasting alone led to a reduction in circulating Hmgb1 associated with cytoplasmic Hmgb1 translocation, aggregate formation and autophagy. Inhibition of autophagy re-elevated circulating Hmgb1 and abolished protection in fasted mice, as did supplementation with Hmgb1. In vitro, Sirt1 inhibition prevented Hmgb1 translocation, leading to elevated Hmgb1 in the supernatant. In vivo, Sirt1 inhibition abrogated the fasting-induced protection, but had no effect in the presence of neutralizing Hmgb1 antibody. Fasting for one day protects from hepatic IR injury via Sirt1-dependent downregulation of circulating Hmgb1. The reduction in serum Hmgb1 appears to be mediated by its engagement in the autophagic response. These findings integrate Sirt1, Hmgb1 and autophagy into a common framework that underlies the anti-inflammatory properties of short-term fasting.Journal of Hepatology 04/2014; 61(2). DOI:10.1016/j.jhep.2014.04.010 · 10.40 Impact Factor
Article: Autofagia – proces o dwóch obliczach[Show abstract] [Hide abstract]
ABSTRACT: Autophagy is a process that is involved in the pathogenesis of cancer but also in the development of resistance or sensitivity to cytostatic treatment applied. Until now, the issue is still unresolved if we should stimulate or inhibit the process of autophagy in cancer treatment through the use of appropriate anticancer therapy so that it is beneficial for the patient and induce remission of the disease. On the one hand autophagy as a mechanism of programmed cell death may also cause the death of tumor cells. On the other hand, as a defense mechanism is the process of cell survival strategy in stress situations such as hypoxia in the peripheral parts of the tumor or using cytostatic drugs. It would be good to find an answer if the autophagy is the process increasing the effectiveness of therapy or increasing resistance to treatment in a case of specific tumor.Acta haematologica Polonica 10/2013; 44(4):383–391. DOI:10.1016/j.achaem.2013.05.003