HMGB1 inhibitors(University of North Carolina System)

High-mobility group box (HMGB) 1, a nuclear protein that acts as an inflammatory mediator, exacerbates injury following intracerebral hemorrhage (ICH). Glycyrrhizin, a natural HMGB1 inhibitor derived from licorice, alleviates ICH-induced inflammatory responses, including brain edema formation. In our previous study, inspired by the bioconversion of endophytes living symbiotically in licorice, we discovered a glycyrrhizin derivative with more potent anti-HMGB1 activity than glycyrrhizin. However, this derivative is poorly soluble in water, and some issues remain to be resolved when applying it to treat ICH. The aim of this study was to develop an injectable formulation of a water-insoluble glycyrrhizin derivative (WIGLD) to treat acute ICH. Screening of Pluronic surfactants revealed that Pluronic P103 significantly improved the solubility of WIGLD. The micelles had a particle size of approximately 20 nm; therefore, this formulation was considered suitable for intravenous injection. Thus, we investigated the therapeutic efficacy of an intravenously injected solubilized WIGLD formulation in a murine model of ICH induced by intrastriatal collagenase injection. The injected WIGLD formulation increased brain penetration compared to that after oral administration. Additionally, it inhibited microglial activation by HMGB1, decreased brain edema, and ameliorated neurological deficits. These findings suggested that the injectable WIGLD formulation, with its potent anti-HMGB1 activity, represents a promising therapeutic strategy for managing ICH-related brain edema and associated injuries.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, primarily driven by inflammatory processes within the disc, particularly involving the infiltration and activity of macrophages. High Mobility Group Box 1 (HMGB1) has been identified as a crucial mediator in this inflammatory cascade, yet its precise role in macrophage-induced disc degeneration remains unclear. In this study, we employed a combination of in vivo and in vitro models, including genetically engineered mice with macrophage-specific overexpression of HMGB1, a rat model of IVDD, and cultured macrophages and nucleus pulposus cells (NPCs), to elucidate the role of HMGB1 in IVDD. Our findings reveal that HMGB1 overexpression in macrophages significantly accelerates IVDD progression by enhancing NF-κB activation and upregulating MMP3 expression in NPCs. Furthermore, the administration of glycyrrhizin (GL), an HMGB1 inhibitor, effectively mitigated these effects, delaying IVDD progression. This study not only uncovers the critical mechanisms by which HMGB1 regulates the interactions between macrophages and NPCs in the inflammatory microenvironment but also provides a theoretical framework for targeting HMGB1 as a potential therapeutic strategy for IVDD. Thus, our findings suggest a promising novel approach for the treatment of this condition.