Linking Disulfide Levels and NAD+ Metabolism with Alzheimer's Disease for Diagnostic Modeling and Target Drug Analysis.

BACKGROUND: Alzheimer's disease (AD) is a condition that affects the nervous system and that requires considerably more in-depth study. Abnormal Nicotinamide Adenine Dinucleotide (NAD+) metabolism and disulfide levels have been demonstrated in AD. This study investigated novel hub genes for disulfide levels and NAD+ metabolism in relation to the diagnosis and therapy of AD. METHODS: Data from the gene expression omnibus (GEO) database were analyzed. Hub genes related to disulfide levels, NAD+ metabolism, and AD were identified from overlapping genes for differentially expressed genes (DEGs), genes in the NAD+ metabolism or disulfide gene sets, and module genes obtained by weighted gene co-expression network analysis (WGCNA). Pathway analysis of these hub genes was performed by Gene Set Enrichment Analysis (GSEA). A diagnostic model for AD was constructed based on the expression level of hub genes in brain samples. CIBERSORT was used to evaluate immune cell infiltration and immune factors correlating with hub gene expression. The DrugBank database was also used to identify drugs that target the hub genes. RESULTS: We identified 3 hub genes related to disulfide levels in AD and 9 related to NAD+ metabolism in AD. Pathway analysis indicated these 12 genes were correlated with AD. Stepwise regression analysis revealed the area under the curve (AUC) for the predictive model based on the expression of these 12 hub genes in brain tissue was 0.935, indicating good diagnostic performance. Additionally, analysis of immune cell infiltration showed the hub genes played an important role in AD immunity. Finally, 33 drugs targeting 10 hub genes were identified using the DrugBank database. Some of these have been clinically approved and may be useful for AD therapy. CONCLUSION: Hub genes related to disulfide levels and NAD+ metabolism are promising biomarkers for the diagnosis of AD. These genes may contribute to a better understanding of the pathogenesis of AD, as well as to improved drug therapy.

Identification of a lncRNA/circRNA-miRNA-mRNA ceRNA Network in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) occurs in the elderly and pre-elderly, characterized by decline of memory, cognitive dysfunction, impairment of learning capacity, and motor dysfunction. Recently a competitive endogenous RNA (ceRNA) network has been found to be related to AD progression, but there is still little understanding of the ceRNA regulatory network in AD. This study aims to explore the important regulatory mechanisms of ceRNA regulatory networks containing long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in AD. METHODS: Data from the gene expression omnibus (GEO) database were used for the analysis. To study enrichment function for the upregulated and downregulated mRNAs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the Metascape database, respectively. Based on the STRING database and Cytoscape software 3.9.1, a protein-protein interaction (PPI) network was constructed. The hub genes in this network were identified utilizing the CytoHubba plugin in Cytoscape. The TargetScan, miRWalk, and miRDB were selected to calculate the regulatory interaction between miRNAs and the hub genes. LncRNAs were predicted using RNA22. Additionally, circRNA prediction was executed using the circBank database. RESULTS: 711 downregulated and 670 upregulated overlapping mRNAs were identified between AD and control samples. 32 downregulated and 340 upregulated miRNAs were obtained from AD samples compared with control samples. 78 upregulated and 205 downregulated circRNAs were screened. 275 upregulated lncRNAs and 209 downregulated lncRNAs were found between AD samples and control samples. The PPI network constructed consists of 1016 nodes and 13,946 edges. Ten hub genes were selected to identify target miRNAs and ceRNAs. On the basis of the ceRNA hypothesis, a circRNA/lncRNA-miRNA-mRNA network was established. It included five lncRNAs (TRHDE-AS1, SNHG10, OIP5-AS, LINC00926 and LINC00662), 26 circRNAs, five miRNAs (hsa-miR-3158-3p, hsa-miR-4435, hsa-let-7d-3p, hsa-miR-330-5p and hsa-miR-3605-3p), and ten mRNAs (RPL11, RPL34, RPL21, RPL22, RPL6, RPL32, RPL24, RPL35, RPL31, and RPL35A). RPL35 and RPL35A were found to be significantly associated with AD pathology in tau and Aß line AD models by the AlzData database. The study discovered the significance of several lncRNA-miRNA-mRNA axes and circRNA-miRNA-mRNA axes that included RPL35A and RPL35. CONCLUSIONS: ceRNAs were found to be important regulators in the development of AD and provide potential biological therapy targets for AD management.

miR-148a and miR-551b-5p regulate inflammatory responses via regulating autophagy in acute pancreatitis.

Acute pancreatitis (AP) is a common inflammatory response that occurs in the pancreas with mortality rates as high as 30 %. However, there is still no consistent and effective treatment for AP now. MicroRNA-148 was reported to be involved in AP through IL-6 signaling pathway. Therefore, we aimed to further explore the detailed mechanisms of AP, to develop more therapeutic approach for AP. Exosomes were isolated from peripheral blood mononuclear cells of 20 AP patients and 20 healthy volunteers to evaluate the abnormally expressed miRNA. Then pancreatic acinar cells (PACs) were transfected with retrovirus to overexpress miR-148a/miR-551b-5p to evaluate their function. Both miR-148a and miR-551b-5p were highly expressed in AP patients than these in healthy cases. Then overexpressing miR-551b-5p in PACs could regulate autophagy through directly binding to Baculoviral IAP Repeat Containing 6, leading to the increased secretions of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) through interleukin-1 (IL-1) signaling pathway. Moreover, overexpressing miR-148a in PACs could decrease the secretions of IL-1ß and IL-18 to modulate autophagy. The exosomal miRNA-148a and miRNA-551b-5p derived from peripheral blood mononuclear cells of AP patients may two-way mediate autophagy damage through IL-6/STAT3 signaling pathway, which participated in the AP pathogenesis. Our findings may provide new targets for the diagnosis and treatment of AP.