Galbanic acid

Ischemic stroke (IS), the predominant clinical stroke subtype, is increasingly linked to dysregulation of the gut-brain axis (GBA)-a bidirectional neuroendocrine-immune interface connecting intestinal homeostasis with cerebrovascular pathophysiology. Xinqingning Tablet (XQNT) demonstrates neuroprotective potential in IS complicated by gut dysbiosis (GD), yet its mechanisms of GBA modulation remain unclear.

A dual-hit IS-GD mouse model was established via fecal slurry transplantation and permanent middle cerebral artery occlusion (pMCAO) surgery. Gut function was evaluated by constipation indices and histopathological changes, while the neuroprotective efficacy of XQNT (0.36, 0.48, and 0.61 g kg⁻¹) was assessed via TTC staining, neurological deficit scores, cerebral water content, and Evans blue (EB) extravasation assays. Additionally, Western blot was employed to quantify blood-brain barrier (BBB) and inflammation-associated proteins. microRNA sequencing was used to screen the differentially expressed miRNAs. miR-126 expression levels were measured by RT-qPCR, while concentrations of LPS, IL-6 and IL-10 were determined by ELISA. Finally, mechanistic validation employed intravenous miR-126 agonism/antagonism coupled with phenotypic rescue experiments.

XQNT conferred robust survival benefits, while concurrently ameliorating intestinal dysfunction and neurovascular injury. Mechanistically, XQNT elevated miR-126 expression, suppressing NF-κB-driven neuroinflammation. Additionally, miR-126 agonism phenocopied XQNT efficacy, whereas miR-126 inhibition abrogated therapeutic benefits.

This study provides early evidence that XQNT functions as a dual-target GBA modulator that alleviates IS with GD via regulation of the miR-126/NF-κB axis. By simultaneously promoting barrier restoration and inflammatory resolution, XQNT offers a promising therapeutic approach that links regulation of the gastrointestinal system with cerebrovascular protection.

While genome-wide association studies have identified GBA1 as a key gene contributing to disease severity and cognitive decline in PD, its molecular effects remain poorly understood.

We used integrative bulk ATAC-seq across six brain regions from autopsied individuals with PD and varying genetic risk to characterize region- and cell type-specific molecular differences. Using Cellformer, an AI-based bulk ATAC-seq-deconvolution tool, we determined cell type-specific effects of GBA1 on PD disease progression and then validated our findings using whole transcriptome data from blood samples.

Epigenomic differences between PD with ("GBA+"; n = 15) and without ("GBA-", n = 15) GBA1 variants were localized in substantia nigra. Nineteen chromatin-accessible regions strictly separated GBA+ from GBA-, including the promoter sites of key genes such as CACNA1C, EHMT1, and SLC25A48. The effect in GBA + spanned the main cell types in brain, and chromatin differences between GBA- and GBA + increased with neuropathologic progression of disease. Significant differences in the epigenomic profile in GBA+ were observed in neuronal cells (AUROC = 0.8, AUPRC = 0.8, P-value<0.0001). Validation in blood samples distinguished between GBA+ and GBA-subtypes, achieving AUROC values of 0.99. Over 5000 transcripts in blood cells distinguished GBA+ from GBA-, validating key genes and pathways from our epigenomic analysis of brain regions.

Our study provides novel insights into the cell type-specific epigenomic and transcriptomic landscape of GBA+ and its molecular divergence from other PD subtypes, and highlights potential therapeutic targets for this genetically defined subset of PD.