Multiple sclerosis (MS) is an incurable and progressive inflammatory disease of the central nervous system (CNS) characterized by inflammatory demyelination, chronic axonal damage, and neurodegeneration. Carabrone (CA), a sesquiterpene lactone from the traditional Chinese herb Carpesium abrotanoides L., demonstrates diverse pharmacological properties. However, its therapeutic effects on MS and the underlying mechanisms remain unexplored. In the present study, we reported the beneficial effects of CA on experimental autoimmune encephalomyelitis (EAE), a well-established mouse model of MS, for the first time. Treatment with CA markedly attenuated disease progression induced by myelin oligodendrocyte glycoprotein (MOG35-55) peptide, as evidenced by reduced clinical severity, diminished inflammatory cell infiltration into the CNS, and a decrease in demyelinated lesions. Mechanistically, CA could covalently bind to the cysteine 85 (Cys85) residue of ubiquitin conjugating enzyme E2 D3 (UBE2D3), thereby inhibiting the phosphorylation of inhibitor of nuclear factor-kappa B alpha (IκBα) and its subsequent ubiquitin-mediated degradation, ultimately leading to suppression of the nuclear factor-κB (NF-κB) signaling pathway. These findings were further confirmed in macrophages via siRNA-mediated knockdown of UBE2D3. Taken together, our results revealed that CA is a novel UBE2D3 inhibitor and provided a promising therapeutic candidate for MS.
Huai-Ping Tang, Liang Sun, Bin Jia et al.· European Journal of Pharmaco...· 0 citations
Excessive activation of microglia exacerbates secondary brain injury after ischemic stroke, yet the upstream mechanisms governing this response remain incompletely understood. This study aimed to investigate the role of RIO kinase 3 (RIOK3) in microglia-mediated neuroinflammation after ischemic stroke and to explore the underlying molecular mechanisms. RIOK3 expression was examined in mice subjected to transient middle cerebral artery occlusion and in primary microglia exposed to lipopolysaccharide or oxygen-glucose deprivation/reoxygenation. Microglia-targeted RIOK3 knockdown was achieved using a Cre-dependent adeno-associated virus-shRNA strategy in Tmem119-CreERT2 mice. RIOK3 was markedly upregulated in microglia after cerebral ischemia and in primary microglia following LPS or OGD/R stimulation. Microglia-targeted RIOK3 knockdown reduced infarct volume, improved early neurological and sensorimotor outcomes, preserved microglial process complexity, and reduced post-ischemic inflammation. In vitro, RIOK3 knockdown reduced microglial inflammatory responses and microglia-mediated neurotoxicity. Transcriptomic and biochemical analyses further showed that RIOK3 knockdown suppressed NF-κB-related transcriptional programs and decreased the phosphorylation of IκBα and p65. Mechanistically, immunoprecipitation assays identified Y-box-binding protein 1 (YBX1) as a RIOK3-interacting protein and mapped this interaction to the C-terminal kinase domain-containing region of RIOK3. RIOK3 enhanced YBX1 Ser102 phosphorylation and nuclear accumulation, whereas YBX1 knockdown attenuated NF-κB activation and the pro-inflammatory effects of RIOK3 overexpression. These findings identify microglial RIOK3 as an important driver of post-ischemic neuroinflammation and highlight the RIOK3-YBX1 axis as a potential therapeutic target for ischemic stroke.
Yang Geng, Ningning Zong, Chao Zhou et al.· Experimental Neurology· 0 citations
The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in host defense; however, its aberrant activation leads to excessive release of pro-inflammatory cytokines, triggering inflammatory responses and tissue damage in human diseases. In this study, the inhibitory effect and anti-inflammatory potential of carabrone on the NLRP3 inflammasome were systematically evaluated. Carabrone suppressed lipopolysaccharide (LPS) + ATP/Nigericin-induced IL-1β secretion, Caspase-1 activation, and apoptosis-associated speck-like protein (ASC) speck formation. Mechanistic investigations revealed that carabrone inhibited the NLRP3-NEK7 interaction and bound to Gln 624 and Ser 658 within the NACHT domain of NLRP3, thereby stabilizing the local conformation and inhibiting inflammasome activation. In addition, carabrone showed protective effects in Alzheimer's disease (AD) models, which were associated with NLRP3 inflammasome inhibition. Similar effects were also observed in other NLRP3 inflammasome-related disease models, including sepsis, gouty arthritis, and acute peritonitis. Collectively, these results indicate that carabrone might act as a modulator of NLRP3 inflammasome activation across multiple inflammatory disease contexts.
Bin Jia, Abuduwaili Zulalai, Huai-Ping Tang et al.· European Journal of Pharmaco...· 0 citations
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