BackgroundMicroglia activation is a crucial event in neurodegenerative disease. The depression of microglial inflammatory response is considered a promising therapeutic strategy. NFκB signaling, including IKK/IκB phosphotylation, p65 nucelus relocalization and NFκB-related genes transcription are prevalent accepted to play important role in microglial activation. (+)-JQ1, a BRD4 inhibitor firstly discovered as an anti-tumor agent, was later confirmed to be an anti-inflammatory compound. However, its anti-inflammatory effect in microglia and central neural system remains unclear.ResultsIn the current work, microglial BV2 cells were applied and treatment with lipopolysaccharide (LPS) to induce inflammation and later administered with (+)-JQ1. In parallel, LPS and (+)-JQ1 was intracerebroventricular injected in IL-1β-luc transgenic mice, followed by fluorescence evaluation and brain tissue collection. Results showed that (+)-JQ1 treatment could significantly reduce LPS induced transcription of inflammatory cytokines both in vitro and in vivo. (+)-JQ1 could inhibit LPS induced MAPK but not PI3K signaling phosphorylation, NFκB relocalization and transcription activity. In animal experiments, (+)-JQ1 postponed LPS induced microglial and astrocytes activation, which was also dependent on MAPK/NFκB signaling.ConclusionsThus, our data demonstrated that (+)-JQ1 could inhibit LPS induced microglia associated neuroinflammation, via the attenuation of MAPK/NFκB signaling.
Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.
Multiple sclerosis (MS) is an autoimmune inflammatory disease. Inflammatory infiltrates and demyelination of the CNS are the major characteristics of MS and its related animal model-experimental autoimmune encephalomyelitis (EAE). Immoderate autoimmune responses of Th17 cells and dysfunction of Treg cells critically contribute to the pathogenesis of MS and EAE. Our previous study showed that Ginsenoside Rd effectively ameliorated the clinical severity in EAE mice, but the mechanism remains unclear. In this study, we investigated the therapeutic effect of Ginsenoside Rd on EAE in vivo and in vitro and also explored the potential mechanisms for alleviating the injury of EAE. The results indicated that Ginsenoside Rd was effective for the treatment of EAE in mice and splenocytes. Ginsenoside Rd treatment on EAE mice ameliorated the severity of EAE and attenuated the characteristic signs of disease. Ginsenoside Rd displayed the therapeutic function to EAE by modulating inflammation and autoimmunity, via the downregulation of related proinflammatory cytokines IL-6 and IL-17, upregulation of inhibitory cytokines TGF-β and IL-10, and modulation of Treg/Th17 imbalance. And the Foxp3/RORγt/JAK2/STAT3 signaling was found to be associated with this protective function. In addition, analysis of gut microbiota showed that Ginsenoside Rd also had modulation potential on gut microbiota in EAE mice. Based on this study, we hypothesize that Ginsenoside Rd could be a potential and promising agent for the treatment of MS.
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