Biology subjects

Zhang, J.-Q.

Publications and source records attributed to Zhang, J.-Q..

3 recordsLinked to original sources

bioRxiv2026

Paraspeckles translate microbial insult-induced inflammation into neurovascular remodeling by enhancing CYR61-FGF2 signaling via RBM14 sequestration

BackgroundSystemic inflammation triggered by microbial insults can disrupt endothelial homeostasis, impair blood-brain and blood-retinal barriers, leading to neurovascular remodeling in the central nervous system (CNS). Subnuclear condensates, paraspeckles, play a substantial role in stress-induced gene regulation, yet their contribution to the inflammatory relay from microbial insults to neurovascular remodeling remains unelucidated. ResultsOur comparative transcriptomic analysis followed by experimental validation identified a cross-species NEAT1_2/CYR61/FGF2 signature in the CNS positively associated with neurovascular remodeling across human disease cohorts and multiple mouse models. Notably, systemic inflammation triggered by microbial insults, including sepsis or gut dysbiosis, enhanced NEAT1_2 expression in the brain and retina with neurovascular remodeling. Microbial insults induced hyper-assembly of paraspeckles and the expression of CYR61 and FGF2 in vascular endothelial cells. Paraspeckle assembly and its required NEAT1_2 Domain C, rather than NEAT1_2 expression levels, play a pivotal role in endothelial homeostasis control and neurovascular remodeling by sequestering the RNA-binding protein RBM14 from the CYR61 promoter, thereby relieving its repression of CYR61 transcription. Moreover, secreted CYR61 enhanced FGF2-mediated endothelial remodeling signals in a paracrine manner. Disrupting paraspeckle assembly by targeting Domain C intercepts neurovascular remodeling, restoring endothelial homeostasis in vivo. ConclusionsOur results demonstrate an essential and conserved role for paraspeckles in the inflammatory relay from microbial insults to neurovascular remodeling by sequestering RBM14 to enhance CYR61-FGF2 signaling. Furthermore, our study underscores paraspeckle assembly as a promising therapeutic target for neurovascular remodeling and related diseases.

molecular biology↗

bioRxiv2025

Caffeic acid promoted deep vein thrombosis resolution in mice by suppressed macrophage M1 polarization through Keap1/Nrf2 pathwayv

BackgroundDeep vein thrombosis (DVT) carries significant health risks, with macrophages playing a key role in thrombus resolution. Caffeic acid (CA) has been shown to inhibit thrombosis, but its role in DVT resolution remains unclear. PurposeThis study aimed to investigates the effects and mechanisms of CA in accelerating DVT resolution. MethodsA stasis-type DVT model was established in mice via inferior vena cava ligation. The effects of CA were analyzed. Thrombus resolution was assessed using histological staining, gelatin zymography, immunoblotting, and immunofluorescence. Macrophage depletion was conducted with chlorophosphate liposomes, and bone marrow-derived macrophages (BMDMs) were used for polarization studies. RNA sequencing identified potential molecular pathways. Nrf2 gene-deficient mice were used to verify the role of Nrf2 in deep vein thrombus resolution. ResultsCaffeic acid reduced thrombus size, enhanced collagenolysis via increased MMP-2 activity, promoted neovascularization, increased macrophage infiltration, and suppressed M1 polarization and inflammation. CA activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by inhibiting Keap1, leading to enhanced antioxidant responses in both BMDMs and thrombus tissue. Macrophage depletion negated CAs benefits, confirming the central role macrophages. ConclusionCA promoted early thrombus resolution via macrophage recruitment, M1 polarization suppression, and Nrf2 activation, highlighting its potential as a preventive strategy for DVT.

pharmacology and toxicology↗

bioRxiv2024

Comprehensive profiling of transcriptional regulation in cartilage reveals pathogenesis of osteoarthritis

Cartilage damage is a leading cause of osteoarthritis (OA) etiology, however, the underlying mechanism governing gene expression regulation in this progress is poorly understood. Here, we described a comprehensive profiling of transcriptional regulation of 235 primary human cartilage samples. We identified 3,352 independent significant expression quantitative trait loci (eQTLs) for 3,109 genes. We explored the candidate casual SNP and its underlying regulatory mechanism using our established functional fine-mapping pipeline by integrating the cartilage-specific ATAC-seq data. We identified 117 causal eQTLs that display allele-specific open chromatin (ASoC) and 547 transcription factor binding-disruption (TBD) eQTLs. We conducted cell type-interaction eQTL (ci-eQTL) analyses based on speculated chondrocyte subtype proportions and revealed the regulation relationship of 120 eQTL-gene pairs showed cell type dependency. Further, by integrating with genome-wide association studies (GWASs) data of OA, we nominated 43 candidate effector genes for OA risk loci. We verified that the T allele of the OA risk variant rs11750646 increased the AR binding affinity to an open chromatin region and promoted the expression of an OA-related gene PIK3R1. Altogether, our findings provide new insights into the unique regulatory landscape of cartilage and elucidate potential mechanisms underlying the OA pathogenesis.

genetics↗