MiR-372-3p alleviates isoflurane-induced cognitive dysfunction by targeting STAT3 to mitigate neuroinflammation and oxidative stress.

New biphenyl derivatives from Garcinia yunnanensis.

Copper depletion ameliorates neuronal damage after intracerebral hemorrhage.

CM-TRAP: A chemoproteomic workflow for profiling circulating metabolites and their protein targets in Alzheimer's disease.

The H2S donor sulforaphane inhibits NLRP3 inflammasome activation by inducing mitochondrial autophagy and mitigating CBS-H2S axis damage in in-vitro and in-vivo models of Parkinson's disease.

UPLC-PDA-MS guided isolation of lindenane sesquiterpene oligomers with anti-neuroinflammatory activity from two rare Chloranthus species.

The active ingredient Monotropein in Morinda officinalis alleviates neuroinflammation via inhibiting cGAS/STING signaling pathway.

Resveratrol modulates inflammatory gene expression in Toxoplasma gondii-infected microglia and shows structurally plausible interactions with parasite virulence proteins.

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by focal inflammation, demyelination, axonal injury, and neuronal damage. Microglia-mediated neuroinflammation plays a critical role in its pathogenesis. Fucoxanthin (Fx), a compound abundant in various algae, exhibits antioxidant, anti-tumor, and anti-inflammatory properties. This study aimed to investigate the therapeutic effects and underlying mechanisms of Fx in ameliorating experimental autoimmune encephalomyelitis (EAE), a well-established animal model of MS. Our results demonstrated that Fx significantly attenuated inflammatory cell infiltration, demyelination, and activation of pro-inflammatory M1-polarized microglia in the spinal cords of EAE mice. Moreover, we found that Fx exerted anti-inflammatory effects by inhibiting the activation of the NLRP3 inflammasome and subsequent pyroptosis in microglia, both in EAE mice and in BV2 microglial cells. In summary, Fx exhibited a promising therapeutic effect on EAE by suppressing neuroinflammation through inhibition of microglial M1 polarization and NLRP3 inflammasome-mediated pyroptosis. Thus, Fx may represent a potential therapeutic agent for the treatment of MS.

Phenanthrenes from Bletilla formosana and their anti-neuroinflammatory activity.

Gut microbiota dysbiosis is implicated in Alzheimer's disease (AD), but causal evidence and mechanisms linking it to microglial dysfunction remain unclear. This study aimed to determine whether gut microbiota drives neuroinflammation and cognitive impairment via the microglial TREM2/SYK signaling axis in early AD. Using six-month-old APP/PS1 mice, fecal microbiota transplantation (FMT) was performed between AD and wild-type mice. Cognitive function, gut microbiota composition (16S rRNA sequencing), serum metabolites, hippocampal neuroinflammation, microglial polarization, and TREM2/SYK/NF-κB pathway activity were assessed. BV2 microglial cells were treated with Aβ oligomers, a TREM2 agonist, or a SYK inhibitor for mechanistic validation. AD mice exhibited cognitive decline, reduced microbial diversity (e.g., decreased Bacteroidetes and Lactobacillus), and altered circulating metabolites, including decreased butyrate and elevated LPS. Their hippocampi exhibited heightened glial activation, elevated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and a shift toward pro-inflammatory activation markers (M1-associated). At the molecular level, TREM2 expression was downregulated, whereas SYK phosphorylation and NF-κB activation were enhanced, concomitant with synaptic protein loss. Critically, FMT from healthy donors reversed these abnormalities and improved cognition, whereas AD microbiota induced mild pathology in wild-type mice. In vitro, TREM2 activation or SYK inhibition attenuated Aβ-induced M1 polarization and cytokine release in microglia. Gut microbiota dysbiosis promotes early AD pathogenesis by dysregulating the microglial TREM2/SYK/NF-κB pathway, thereby driving neuroinflammation and synaptic dysfunction. Targeting this microbiota-signaling axis may offer novel therapeutic strategies.

The TLR4/NF-κB/NLRP3 pathway is involved in levofloxacin-induced alleviation of neuroinflammation in Parkinson's disease.

Exploring the mechanism of ropivacaine in alleviating neuropathic pain via the mTOR-PKM2/STAT3-H4K12 lactylation axis.

Indole-3-Carbinol (I3C) suppression of IgG2b-triggered signaling in innate cells involves early suppression of p-Akt.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory loss, spatial disorientation, and a marked decline in cognitive capacity. Colchicine, a microtubule-disrupting agent, is widely used to model cognitive dysfunction in animals. This study aimed to assess the therapeutic potential of Diosgenin against AD utilizing an integrated in silico, in vitro, and in vivo approach. The in silico analyses, molecular docking and molecular dynamics simulations demonstrated strong binding affinity of Diosgenin with key AD-associated proteins LRP5, MME, and NOS2, indicating modulation of oxidative stress, apoptosis, and neuroinflammation. Computational studies also indicated favourable pharmacokinetic properties, supporting its blood-brain barrier permeability. In vitro assays in BV2 microglial cells demonstrated the antioxidant potential of Diosgenin by reducing oxidative stress markers such as MDA while preserving key antioxidant enzymes SOD and GSH. In vivo studies in a colchicine-induced rat model of AD showed that Diosgenin significantly improved cognitive and memory functions, as evidenced by enhanced performance in radial arm maze and novel object recognition tasks. Brain tissue analysis showed that diosgenin improved cholinergic function by lowering AChE and BChE activity. It also enhanced the brain's antioxidant defence (SOD and GSH) and reduced lipid peroxidation (MDA), thereby limiting oxidative stress. Microscopic studies further confirmed fewer degenerating neurons, reduced plaques, and less inflammation. Taken together, these findings suggest that diosgenin offers multi-faceted protection in AD-supporting memory-related neurotransmission, reducing oxidative damage, and dampening inflammation. Nevertheless, further investigation into advanced formulation strategies to overcome its limited bioavailability is warranted to enable clinical translation.

Vascular dementia (VaD) is a debilitating cognitive disorder with limited pharmacological treatments. Naokang II decoction (NKII) is a traditional Chinese medicine (TCM) formula for VaD with significant efficacy, but its mechanisms remain unclear. This study integrated chemical profiling, network pharmacology, single-nucleus RNA sequencing (snRNA-seq) analysis, molecular docking, and in vitro validation to elucidate NKII's mechanisms against VaD. LC-MS/MS identified 412 components in NKII, of which 45 compounds were screened as active constituents. Their 1081 predicted targets overlapped with 1592 VaD-related dysregulated genes, yielding 73 common targets. Network analysis identified 10 core targets, including NLRP3, CASP1, and TLR2. snRNA-seq data localized these core targets predominantly to microglia. Molecular docking revealed that the coumarin Herniarin, a component newly identified in NKII, exhibited the strongest binding affinity to NLRP3. In vitro experiments on BV2 and HMC3 microglial cells showed that Herniarin inhibited cell proliferation and migration, induced apoptosis, arrested the cell cycle at the G2/M phase, and downregulated TLR2, NLRP3, ASC, and CASP1 at both mRNA and protein levels, exerting antineuroinflammatory effects by inhibiting the microglial NLRP3 inflammasome pathway. This study established a multidimensional research paradigm and identified Herniarin as a novel NLRP3 inhibitor with therapeutic potential for VaD and other neuroinflammatory diseases.

Growing evidence supports a strong association between periodontitis and Alzheimer's disease (AD), yet the mechanisms linking these conditions remain poorly defined. In neurodegenerative disorders, including AD, microglia are often characterized by increased lipid droplet (LD) accumulation, heightened activation, and impaired function. In this study, we examined whether Porphyromonas gingivalis ( Pg ), a keystone periodontal pathogen, promotes LD accumulation in microglia and disrupts their function. We found that Pg infection induces robust LD accumulation in BV2 microglial cells and in microglia from Pg -infected App KI mice. This Pg -driven LD buildup was closely associated with elevated reactive oxygen species (ROS) production, impaired phagocytic ability, and altered activation. Notably, pharmacological inhibition of LD with a triglyceride synthesis inhibitor effectively reversed Pg -induced LD accumulation, mitigated ROS production, and restored phagocytic function, thus underscoring the critical role of lipid metabolism in regulating microglial function. These findings support a model in which, in the context of periodontitis, systemic dissemination of periodontal pathogens promotes LD accumulation in microglia, and this metabolic alteration exacerbates microglia dysfunction via a self-reinforcing cycle of excessive oxidative stress and impaired phagocytosis, potentially accelerating AD progression.

Divergent mechanisms, unified therapy: saracatinib targets Src/HIF signaling in endothelial and microglial cells to treat retinopathy.

Buyang Huanwu Decoction alleviates vascular cognitive impairment by inhibiting neuroinflammation via regulation of the p53/cGAS/STING pathway.

Microglia are the resident immune cells of the brain; they respond rapidly to inflammatory stimuli and contribute to the progression of neurodegenerative diseases. Receptor-interacting protein kinase 3 (RIPK3) is known to mediate pro-inflammatory signaling and necroptosis, a form of regulated necrotic cell death. However, the role of RIPK3 in microglial activation remains unclear. This study aimed to investigate the role of RIPK3 in both in vitro and in vivo models of neuroinflammation and necroptosis using a selective RIPK3 inhibitor, GSK872. In lipopolysaccharide (LPS)-injected mice, GSK872 attenuated microglial activation, decreased the expression of pro-inflammatory mediators, and reduced the phosphorylation of RIPK3 and mixed lineage kinase domain-like protein (MLKL). In BV2 microglial cells, GSK872 suppressed the production of inflammatory mediators under both inflammatory and necroptotic conditions induced by LPS or LPS/Z-VAD. In particular, GSK872 reduced necroptosis-associated cell death and the release of HMGB1 and IL-1β in LPS/Z-VAD-treated cells. Detailed mechanistic studies revealed that GSK872 inhibits the c-Jun N-terminal kinase (JNK) pathway, while pharmacological inhibition of JNK using SP600125 recapitulates the effects of GSK872 on inflammatory and necroptotic markers. These results indicate that JNK plays a critical role in mediating the effects of GSK872. Notably, IL-1β released during necroptosis appears to contribute modestly to the phosphorylation of JNK and MLKL, indicating a potential feedback mechanism that reinforces necroptotic signaling. Our findings provide compelling evidence that the inhibition of RIPK3 by GSK872 alleviates neuroinflammatory responses and necroptotic cell death by modulating JNK signaling in activated microglia, offering a promising therapeutic strategy for neurodegenerative diseases.