An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies

Musumeci, Domenica; Roviello, Giovanni N.; Montesarchio, Daniela

doi:10.1016/j.pharmthera.2013.11.001

Cited by 286 publications

(264 citation statements)

References 132 publications

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“…Glycyrrhizin treatment attenuated HMGB1 as well as circulating proinflammatory cytokine levels and alleviated renal pathology. However, for glycyrrhizin, a range of biological effects were reported, including antiinflammatory, antioxidant, free radical-scavenging, antiulcer, antihepatotoxic, antimicrobial, cytoprotective and cytotoxic activities (34,35). Therefore, it is unclear whether glycyrrhizin exerts its beneficial effects solely via blocking of HMGB1 in this ALD-DNA-induced lupus mouse model.…”

Section: Discussionmentioning

confidence: 90%

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Schaper

Timmeren

Petersen

et al. 2016

Mol Med

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High mobility group box 1 (HMGB1) is a nuclear DNA binding protein that acts as an alarmin when secreted. HMGB1 is increased in systemic lupus erythematosus and might represent a potential therapeutic target. We investigated whether treatment with an anti-HMGB1 antibody affects the development of lupus nephritis in MRL/lpr mice. Seven-week-old MRL/lpr mice were injected intraperitoneally twice weekly for 10 wks with 50 μg monoclonal anti-HMGB1 (2G7, mouse IgG2b) (n = 12) or control antibody (n = 11). Control MRL/MPJ mice (n = 10) were left untreated. Every 2 wks, blood was drawn and urine was collected at wk 7, 11 and 17. Mice were sacrificed at 17 wks for complete disease evaluation. Plasma HMGB1 and anti-HMGB1 levels were increased in MRL/lpr mice compared with control MRL/MPJ mice. There were no differences in albuminuria, urine HMGB1 and plasma levels of complement C3, anti-dsDNA and proinflammatory cytokines between untreated and treated mice at any time point. Lupus nephritis of mice treated with anti-HMGB1 monoclonal antibody (mAb) was classified as class III (n = 3) and class IV (n = 9), while mice treated with control mAb were classified as class II (n = 4), class III (n = 2) and class IV (n = 5). IgG and C3 deposits in kidneys were similar in mice treated with anti-HMGB1 mAb or control mAb. In conclusion, treatment with monoclonal anti-HMGB-1 antibody 2G7 does not affect development of lupus nephritis, disease progression or proinflammatory cytokine levels in MRL/lpr mice. This result indicates that blocking of HMGB1 by this neutralizing antibody does not affect lupus nephritis in MRL/lpr mice.

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Section: Discussionmentioning

confidence: 90%

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Schaper

Timmeren

Petersen

et al. 2016

Mol Med

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“…Extracellular HMGB1 can activate NF-κB and induce the translocation of other nuclear translocation, which results in increased release of additional pro-inflammatory cytokines, such as TNF-α, IL-6, and HMGB1 itself via a positive feedback loop that involves NF-κB acting on its own target receptors 8 . The signaling pathways upstream and downstream of HMGB1 remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Allopurinol preconditioning attenuates renal ischemia/reperfusion injury by inhibiting HMGB1 expression in a rat model

et al. 2016

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PURPOSE:To investigate the potential effects of pretreatment with allopurinol on renal ischemia/reperfusion injury (IRI) in a rat model. METHODS:Twenty four rats were subjected to right kidney uninephrectomy were randomly distributed into the following three groups (n=8): Group A (sham-operated group); Group B (ischemic group) with 30 min of renal ischemia after surgery; and Group C (allopurinol + ischemia group) pretreated with allopurinol at 50 mg/kg for 14 days. At 72 h after renal reperfusion, the kidney was harvested to assess inflammation and apoptosis. RESULTS:Pretreatment with allopurinol significantly improved renal functional and histological grade scores following I/R injury (p<0.05). Compared with Group B, the expression levels of caspase-3 and Bax were markedly reduced in Group C, meanwhile, whereas expression of bcl-2 was clearly increased (p<0.05). A newly described marker of inflammation, High Mobility Group Box 1(HMGB1), showed reduced expression in Group C (p<0.05). CONCLUSION:Pretreatment with allopurinol had a protective effect on kidney ischemia/reperfusion injury, which might be related to the inhibition of HMGB1 expression.Key words: Inflammation. Ischemia. Reperfusion. Allopurinol. Apoptosis. Rats. Allopurinol preconditioning attenuates renal ischemia/reperfusion injury by inhibiting HMGB1 expression in a rat model

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“…This question is relevant to efforts to develop, for example, monoclonal antibodies that bind selectively to HMGB1 isoforms depending on redox state, acetylation and other posttranslational modifications. In this regard, as there are now approaches to block specific forms of cell death (e.g., caspase inhibitors for apoptosis, necrostatin for necrosis), agents that prevent pyroptosis or NETosis can also be considered, but the design and application of these agents require delineation of the processes leading to HMGB1 release (67,68).…”

Section: Implications For Therapymentioning

confidence: 99%

The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases

Magna

Pisetsky

2014

Mol Med

295

199

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High-mobility group box 1 (HMGB1) protein is a highly abundant protein that can promote the pathogenesis of inflammatory and autoimmune diseases once it is in an extracellular location. This translocation can occur with immune cell activation as well as cell death, with the conditions for release associated with the expression of different isoforms. These isoforms result from posttranslational modifications, with the redox states of three cysteines at positions 23, 45 and 106 critical for activity. Depending on the redox states of these residues, HMGB1 can induce cytokine production via toll-like receptor 4 (TLR4) or promote chemotaxis by binding the chemokine CXCL12 for stimulation via CXCR4. Fully oxidized HMGB1 is inactive. During the course of inflammatory disease, HMGB1 can therefore play a dynamic role depending on its redox state. As a mechanism to generate alarmins, cell death is an important source of HMGB1, although each major cell death form (necrosis, apoptosis, pyroptosis and NETosis) can lead to different isoforms of HMGB1 and variable levels of association of HMGB1 with nucleosomes. The association of HMGB1 with nucleosomes may contribute to the pathogenesis of systemic lupus erythematosus by producing nuclear material whose immunological properties are enhanced by the presence of an alarmin. Since HMGB1 levels in blood or tissue are elevated in many inflammatory and autoimmune diseases, this molecule can serve as a unique biomarker as well as represent a target of novel therapies to block its various activities.

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An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies

Cited by 286 publications

References 132 publications

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Allopurinol preconditioning attenuates renal ischemia/reperfusion injury by inhibiting HMGB1 expression in a rat model

The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases

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