Shared metabolic shifts in endothelial cells in stroke and Alzheimer's disease revealed by integrated analysis.

Since metabolic dysregulation is a hallmark of both stroke and Alzheimer's disease (AD), mining shared metabolic patterns in these diseases will help to identify their possible pathogenic mechanisms and potential intervention targets. However, a systematic integration analysis of the metabolic networks of the these diseases is still lacking. In this study, we integrated single-cell RNA sequencing datasets of ischemic stroke (IS), hemorrhagic stroke (HS) and AD models to construct metabolic flux profiles at the single-cell level. We discovered that the three disorders cause shared metabolic shifts in endothelial cells. These altered metabolic modules were mainly enriched in the transporter-related pathways and were predicted to potentially lead to a decrease in metabolites such as pyruvate and fumarate. We further found that Lef1, Elk3 and Fosl1 may be upstream transcriptional regulators causing metabolic shifts and may be possible targets for interventions that halt the course of neurodegeneration.

The association of arterial stiffness index with cerebrovascular and cardiometabolic disease: A Mendelian randomization study.

BACKGROUND: Arterial stiffness index (ASI) is a potential risk factor for cerebrovascular and cardiometabolic diseases, but the causal links between them are inconclusive. The aim is to evaluate the causal effects of ASI on cerebrovascular and cardiometabolic diseases by Mendelian randomization (MR). METHODS: Two-sample MR analysis was performed to infer causal links. Genetic variants significantly associated with ASI were extracted. The inverse variance weighted method was used for estimating the effects. Sensitivity analysis was performed to test heterogeneity or pleiotropy. RESULTS: MR analysis indicated an effect of genetically predicted ASI on the risk of ischemic stroke (IS) of all causes (OR = 1.894, 95% CI 1.210-2.965, p = 0.005). No links were identified between genetically predicted ASI and other cerebrovascular or cardiometabolic diseases (all p > 0.05). Subgroup analysis of IS etiologies found a suggestive association between genetically predicted ASI and large artery atherosclerosis stroke (LAS) (OR = 3.726, 95% CI 1.230-11.286, p = 0.020). There were no effects of ASI on IS due to cardioembolism or small vessel occlusion. CONCLUSION: The current MR analysis suggested that genetically predicted ASI was associated with higher risk of IS of all causes. The results and the underlying pathways or mechanisms between ASI and IS needs further investigation.

Spatial transcriptome profiling of normal human liver.

The comprehensive study of the spatial-cellular anatomy of the human liver is critical to addressing the cellular origins of liver disease. Here we conducted spatial transcriptomics on normal human liver tissue sections, providing detailed information of liver zonation at the transcriptional level. We present 6581 high-quality spots from normal livers of two human donors. In this dataset, cells were mainly hepatocytes, and we classified them into four sub-groups. Collectively, these data provide a reliable reference for studies on spatial heterogeneity of liver lobules.

Lipid-related protein NECTIN2 is an important marker in the progression of carotid atherosclerosis: An intersection of clinical and basic studies.

BACKGROUND: The nectin cell adhesion molecule 2 (NECTIN2) protein is a cell adhesion molecule involved in lipid metabolism. We aimed to explore the potential role of NECTIN2 in carotid atherosclerosis (CA). MATERIALS AND METHODS: Patients who underwent carotid endarterectomy (CEA) at the First Affiliated Hospital of Zhengzhou University were enrolled in this study. APOE-/- rats fed western or normal diet were used to model early pathological changes in CA. The relationship between patients' lipid indices and plaque severity was assessed using ordinal regression analysis. Mendelian randomisation (MR) analysis was used to determine the causal links between low-density lipoprotein cholesterol (LDL-C) and atherosclerosis. After matching analysis of the single-cell transcriptome and microarray data of carotid plaques, NECTIN2 was identified as a key factor affecting CA. The importance of NECTIN2 was further verified by immunofluorescence staining of CEA and APOE-/- rat specimens. RESULTS: A total of 108 patients were included. The traditional lipid indices did not correlate significantly with the plaque severity (P > 0.05). NECTIN2 provided a strong causal link between LDL-C level and CA (MR effect size >0). Deep-sequencing data illustrated that NECTIN2 expression was cell specific. In early-stage CA, NECTIN2 expression was increased in endothelial cells; however, in advanced-stage CA, NECTIN2 was overexpressed in macrophages located in fibrous caps. APOE-/- rat carotid artery and human carotid plaques modelled the entire atherosclerotic process, showing an upregulation of NECTIN2 expression in CA. CONCLUSIONS: Lipid-related protein NECTIN2 is a potential marker in CA progression and can potentially be a new therapeutic target for clinical prevention.