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Schwartz Dudley posted an update 6 months, 4 weeks ago
Neuroinflammation-induced neurodegeneration and immune cell infiltration are two features of Alzheimer disease (AD). This study aimed to identify potential peripheral biomarkers that interact with cerebrospinal fluid (CSF) and infiltrating immune cells in AD. Blood and CSF data were downloaded from the Alzheimer’s disease Neuroimaging Initiative database. We identified differentially expressed genes (DEGs) in AD and assessed infiltrating immune cells using the Immune Cell Abundance Identifier (ImmuCellAI) algorithm. Blood-brain barrier (BBB) and immune-related genes were identified from medical databases, and common genes were used to construct a protein-protein interaction network (PPI). Potential biomarkers reflecting the clinical features of AD were screened using Pearson correlations and logistic regression analysis. We identified 210 DEGs in the AD group. selleck ImmuCellAI indicated that blood samples from patients with AD had a higher abundance of exhausted T (Tex; 0.196 vs. 0.132) and induced regulatory T (iTreg; 0.180 vs. 0.137) cells than controls. Thirty-two genes overlapped between the BBB and immune-related genes, and 27 genes in the PPI network were associated with eight pathways, including the cytokine-cytokine receptor interaction pathway (hsa04060) and the chemokine signaling pathway (hsa04062). Pearson correlations showed that five genes were associated with the CSF biomarkers, Aβ, total, and phosphorylated tau. Logistics analysis showed that the B cell-associated genes, CXCL12 and TNFRSF13C, were independent risk factors for AD diagnosis. Peripheral CXCL12 and TNFRSF13C genes that correlated with immune cell infiltration in AD might serve as easily accessible biomarkers for the early diagnosis of AD.Toll-like receptors (TLRs) belong to a pattern recognition receptor class which is an integral part of innate immunity. During Parkinson’s disease (PD), activation of the immune response is a well-established feature in both, the periphery and the brain. The role of TLR is considered to be a salient part of the established framework during inflammation and neurodegenerative disease such as PD. The link between inflammation-mediated TLR expression and the molecular hallmark of PD pathogenesis is well established. Various evidence in support of the review has proved the presence of α-synuclein-positive inclusions, inciting the activated microglia to promote the expression of microglial and neuronal TLRs. Thus, the long-established inflammatory environment is considered as the pivotal element in the progression of the PD pathology. This review aims to delineate the importance of TLRs (TLR2/4) and their altered signaling in the pathogenesis of PD via cascade of proinflammatory pathways and the new therapeutic propositions to modulate the TLR expression. The microglia-mediated inflammatory pathway and aggregated α-synuclein potentiates multiple mechanisms through which inflammation contributes to progression of neurodegeneration in PD via upregulation of TLR2 and TLR4. TLR targeting is a site of interest to facilitate effective treatment for PD.Vanishing white matter disease (VWM) is a rare autosomal recessive leukodystrophy caused by a mutation in any of the five gene encoding subunits of the translation initiation factors eIF2B1 to eIF2B5. Whole-exome sequencing was performed on a 7-year-old boy with prenatal symptoms, including intrauterine-growth retardation, decreased movements, and oligohydramnios as well as mild intellectual disability, optic atrophy, macrocephaly, mild ataxia, and white matter lesions after birth. Analysis of WES data revealed a homozygous missense variant, c.C590T (p.Thr197Met) in the EIF2B3 gene (NM_0203650). The candidate variant was confirmed by Sanger sequencing and found to co-segregate with disease in family members. Pathogenicity analysis, 3D protein modeling, and stability assessment showed the deleterious effects of this nucleotide change. Previous studies suggest a direct relationship between the onset of symptoms and the progression rate and severity of the disease. All described cases of EIF2B deficiency with antenatal-onset led prenatal death; if they were born, they experienced clinical exacerbation, seizure, severe encephalopathy, and consequent infantile death ( less then 1 year). The patient of this study had never had seizure, which could be a potential explanation for the observed mild clinical picture, chronic state, and long-term survival until the age of seven. This study reported the first VWM due to EIF2B gene deficiency with antenatal-onset but mild symptoms and long-term survival. The result of this study showed that stressor factors, particularly seizure, could have a substantial role in poor prognosis and early neonatal death.Non-small cell lung cancer (NSCLC) is a common cancer with an unfavorable 5-year survival rate. We intended to explore the role of circular RNA_0074027 (circ_0074027) in NSCLC progression. The levels of circ_0074027, messenger RNA (mRNA) of its linear form paired like homeodomain 1 (PITX1), microRNA-2467-3p (miR-2467-3p) and ras homolog family member A (RHOA) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK8) assay and plate colony assay were conducted to measure the proliferation ability of NSCLC cells. Transwell assays were used to assess cell migration and invasion abilities. Flow cytometry was utilized to analyze cell apoptosis rate. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to test the interaction between miR-2467-3p and circ_0074027 or RHOA. Western blot assay was performed to evaluate the protein level of RHOA in NSCLC cells. Murine xenograft model was built to evaluate the role of circ_0074027 in tumor growth in vivo. Circ_0074027 expression was prominently elevated in NSCLC tissues and cell lines. Circ_0074027 knockdown or miR-2467-3p overexpression suppressed cell proliferation, migration and invasion and facilitated cell apoptosis of NSCLC cells. Circ_0074027 interacted with miR-2467-3p, and RHOA was a target of miR-2467-3p in NSCLC cells. RHOA silencing blocked the malignant potential of NSCLC cells. Circ_0074027 silencing restrained the malignant phenotypes of NSCLC cells largely through up-regulating miR-2467-3p. Circ_0074027 knockdown notably blocked xenograft tumor growth in vivo. In conclusion, circ_0074027 accelerated NSCLC progression by binding to miR-2467-3p to induce RHOA expression.