The fibrinogen-to-albumin ratio is associated with intracranial atherosclerosis plaque enhancement on contrast-enhanced high-resolution magnetic resonance imaging

BackgroundContrast-enhanced high-resolution magnetic resonance imaging (CE-HR-MRI) is a useful imaging modality to assess vulnerable plaques in intracranial atherosclerotic stenosis (ICAS) patients. We studied the relationship between the fibrinogen-to-albumin ratio (FAR) and plaque enhancement in patients with ICAS.MethodsWe retrospectively enrolled consecutive ICAS patients who had undergone CE-HR-MRI. The degree of plaque enhancement on CE-HR-MRI was evaluated both qualitatively and quantitatively. Enrolled patients were classified into no enhancement, mild enhancement, and obvious enhancement groups. An independent association of the FAR with plaque enhancement was identified by multivariate logistic regression and receiver operating characteristic (ROC) curve analyses.ResultsOf the 69 enrolled patients, 40 (58%) were classified into the no/mild enhancement group, and 29 (42%) into the obvious enhancement group. The obvious enhancement group had a significantly higher FAR than the no/mild enhancement group (7.36 vs. 6.05, p = 0.001). After adjusting for potential confounders, the FAR was still significantly independently associated with obvious plaque enhancement in multiple regression analysis (odds ratio: 1.399, 95% confidence interval [CI]: 1.080–1.813; p = 0.011). ROC curve analysis revealed that FAR >6.37 predicted obvious plaque enhancement with 75.86% sensitivity and 67.50% specificity (area under the ROC curve = 0.726, 95% CI: 0.606–0.827, p < 0.001).ConclusionThe FAR can serve as an independent predictor of the degree of plaque enhancement on CE-HR-MRI in patients with ICAS. Also, as an inflammatory marker, the FAR has potential as a serological biomarker of intracranial atherosclerotic plaque vulnerability

The ZAR1 resistosome is a calcium-permeable channel triggering plant immune signaling

Nucleotide-binding, leucine-rich repeat receptors (NLRs) are major immune receptors in plants and animals. Upon activation, the Arabidopsis NLR protein ZAR1 forms a pentameric resistosome in vitro and triggers immune responses and cell death in plants. In this study, we employed single-molecule imaging to show that the activated ZAR1 protein can form pentameric complexes in the plasma membrane, The ZAR1 resistosome displayed ion channel activity in Xenopus oocytes in a manner dependent on a conserved acidic residue Glu11 situated in the channel pore. Pre-assembled ZAR1 resistosome was readily incorporated into planar lipid-bilayers and displayed calcium-permeable cation-selective channel activity. Furthermore, we show that activation of ZAR1 in the plant cell led to Glu11 -dependent Ca2+ influx, perturbation of subcellular structures, production of reactive oxygen species, and cell death. The results thus support that the ZAR1 resisto-some acts as a calcium-permeable cation channel to trigger immunity and cell death

PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons

Abstract Ischemic stroke is a neurological disorder caused by vascular stenosis or occlusion, accounting for approximately 87% of strokes. Clinically, the most effective therapy for ischemic stroke is vascular recanalization, which aims to rescue neurons undergoing ischemic insults. Although reperfusion therapy is the most effective treatment for ischemic stroke, it still has limited benefits for many patients, and ischemia-reperfusion (I/R) injury is a widely recognized cause of poor prognosis. Here, we aim to investigate the mechanism of protein phosphatase Mg2+/Mn2+ dependent 1 K (PPM1K) mediates metabolic disorder of branched-chain amino acids (BCAA) by promoting fatty acid oxidation led to ferroptosis after cerebral I/R injury. We established the I/R model in mice and used BT2, a highly specific BCAA dehydrogenase (BCKD) kinase inhibitor to promote BCAA metabolism. It was further verified by lentivirus knocking down PPM1K in neurons. We found that BCAA levels were elevated after I/R injury due to dysfunctional oxidative degradation caused by phosphorylated BCKD E1α subunit (BCKDHA). Additionally, the level of phosphorylated BCKDHA was determined by decreased PPM1K in neurons. We next demonstrated that BCAA could induce oxidative stress, lipid peroxidation, and ferroptosis in primary cultured cortical neurons in vitro. Our results further showed that BT2 could reduce neuronal ferroptosis by enhancing BCAA oxidation through inhibition of BCKDHA phosphorylation. We further found that defective BCAA catabolism could induce neuronal ferroptosis by PPM1K knockdown. Furthermore, BT2 was found to alleviate neurological behavior disorders after I/R injury in mice, and the effect was similar to ferroptosis inhibitor ferrostatin-1. Our findings reveal a novel role of BCAA in neuronal ferroptosis after cerebral ischemia and provide a new potential target for the treatment of ischemic stroke

Image1_Association of methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C>T) gene polymorphism with ischemic stroke risk in different populations: An updated meta-analysis.TIF

Background: Recently, increasing evidence has implicated methylenetetrahydrofolate reductase (MTHFR) gene mutation as a risk factor for ischemic stroke (IS) in the general population. However, studies have been inconclusive and lack evidence on specific populations. We aim to determine whether the rs1801133 (NC_000001.11 (MTHFR):g. 677C>T (p.Ala222Val) variant, we termed as MTHFR rs1801133 (677 C>T), is linked to an increased risk of IS in different age groups and ancestry groups.Methods: The literature relevant to our study was found by searching the PubMed, Cochrane Library, Web of Science, EMBASE, and CNKI databases. A random effect model analysis was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate any possible association. We conducted a subgroup analysis based on the age and ancestry groups of the included populations.Results: As of March 2022, 1,925 citations had been identified in electronic databases, of which 96 studies involving 34,814 subjects met our eligibility criteria. A strong link was found between IS and the MTHFR gene rs1801133 (677C>T) polymorphism in all genetic models [dominant genetic model (OR = 1.47; 95%CI = 1.33–1.61; p T) variant may increase the risk of IS in Asian, Hispanic, or Latin population, middle-aged, and elderly populations (p Conclusion: Our results implied that mutation of the T allele of MTHFR rs1801133 (677C>T) could be a risk factor for IS. A significant association was found among Asian, Hispanic, or Latin population, middle-aged, and elderly people.</p