Abstract Background Moyamoya disease (MMD) is a rare and complex cerebrovascular disorder characterized by the progressive narrowing of the internal carotid arteries and the formation of compensatory collateral vessels. The etiology of MMD remains enigmatic, making diagnosis and management challenging. The MOYAOMICS project was initiated to investigate the molecular underpinnings of MMD and explore potential diagnostic and therapeutic strategies. Methods The MOYAOMICS project employs a multidisciplinary approach, integrating various omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, to comprehensively examine the molecular signatures associated with MMD pathogenesis. Additionally, we will investigate the potential influence of gut microbiota and brain-gut peptides on MMD development, assessing their suitability as targets for therapeutic strategies and dietary interventions. Radiomics, a specialized field in medical imaging, is utilized to analyze neuroimaging data for early detection and characterization of MMD-related brain changes. Deep learning algorithms are employed to differentiate MMD from other conditions, automating the diagnostic process. We also employ single-cellomics and mass cytometry to precisely study cellular heterogeneity in peripheral blood samples from MMD patients. Conclusions The MOYAOMICS project represents a significant step toward comprehending MMD’s molecular underpinnings. This multidisciplinary approach has the potential to revolutionize early diagnosis, patient stratification, and the development of targeted therapies for MMD. The identification of blood-based biomarkers and the integration of multiple omics data are critical for improving the clinical management of MMD and enhancing patient outcomes for this complex disease.
Here we aimed to investigate the effects of atorvastatin on accelerated reendothelialization after carotid balloon injury. A mouse model of carotid arterial injury was established, followed by intragastric administration of atorvastatin at a dose of 0.6 mg·(kg body mass)(-1)·d(-1). Pathological sections of carotid artery stained with hematoxylin and eosin were observed under light microscopy. Expression levels of eNOS mRNA and protein were detected with real-time quantitative PCR and Western blot analysis, respectively. Proliferation and differentiation of endothelial progenitor cells (EPCs) were observed after treatment, in vitro. Reendothelialization appeared on the neovascular surface, while intimal hyperplasia was inhibited after treatment with atorvastatin. Numbers of CD31-positive cells increased after atorvastatin treatment, as did the number of leucocyte antigen positive cells. The expression of cell markers, such as CD34, eNOS, and VEGF-R, were higher in the atorvastatin-treated group of mononuclear cells. EPC numbers increased with the concentration of atorvastatin. The expression of eNOS mRNA was reduced in the mice with carotid artery injury that were treated with normal saline. The expression levels of eNOS protein were increased in atorvastatin treatment group. In conclusion, atorvastatin stimulates EPCs to differentiate into endothelial cells and promotes the repair of carotid arterial injury.
Ischemic stroke results in blood-brain barrier (BBB) disruption, during which the reciprocal interaction between ischemic neurons and components of the BBB appears to play a critical role. However, the underlying mechanisms for BBB protection remain largely unknown. In this study, we found that Serpina3n, a serine protease inhibitor, was significantly upregulated in the ischemic brain, predominantly in ischemic neurons from 6 hours to 3 days after stroke. Using neuron-specific adeno-associated virus (AAV), intranasal delivery of recombinant protein, and immune-deficient Rag1-/- mice, we demonstrated that Serpina3n attenuated BBB disruption and immune cell infiltration following stroke by inhibiting the activity of granzyme B (GZMB) and neutrophil elastase (NE) secreted by T cells and neutrophils. Furthermore, we found that intranasal delivery of rSerpina3n significantly attenuated the neurologic deficits after stroke. In conclusion, Serpina3n is a novel ischemic neuron-derived proteinase inhibitor that counterbalances BBB disruption induced by peripheral T cell and neutrophil infiltration after ischemic stroke. These findings reveal a novel endogenous protective mechanism against BBB damage with Serpina3n being a potential therapeutic target in ischemic stroke.
ABSTRACT Aim Hyperlipidemia is a common comorbidity of stroke patients, elucidating the mechanism that underlies the exacerbated ischemic brain injury after stroke with hyperlipidemia is emerging as a significant clinical problem due to the growing proportion of hyperlipidemic stroke patients. Methods Mice were fed a high‐fat diet for 12 weeks to induce hyperlipidemia. Transient middle cerebral artery occlusion was induced as a mouse model of ischemic stroke. Emx1 Cre mice were crossed with Mef2c fl/fl mice to specifically deplete Mef2c in neurons. Results We reported that hyperlipidemia significantly aggravated neuronal necroptosis and exacerbated long‐term neurological deficits following ischemic stroke in mice. Mechanistically, Cflar, an upstream necroptotic regulator, was alternatively spliced into pro‐necroptotic isoform (Cflar R ) in ischemic neurons of hyperlipidemic mice. Neuronal Mef2c was a transcription factor modulating Cflar splicing and upregulated by hyperlipidemia following stroke. Neuronal specific Mef2c depletion reduced cerebral level of Cflar R and cFLIP R (translated by Cflar R ), while mitigated neuron necroptosis and neurological deficits following stroke in hyperlipidemic mice. Conclusions Our study highlights the pathogenic role of Cflar R splicing mediated by neuronal Mef2c, which aggravates neuron necroptosis following stroke with comorbid hyperlipidemia and proposes Cflar R splicing as a potential therapeutic target for hyperlipidemic stroke patients.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)