ABSTRACT
Alzheimer's disease (AD) is a prevalent type of dementia and threatens the health of most elderly people and poses a huge burden to families and society. The fibroblast growth factor 23 (FGF23)/α-Klotho axis is associated with multiple aging-related diseases. Hence, this study explored the mechanism of the FGF23/α-Klotho axis in AD. FGF23/α-Klotho protein contents and levels of inflammatory cytokines in AD patients were measured, and the correlation between FGF23/α-Klotho protein contents and inflammatory cytokines was analyzed. FGF23 and α-Klotho expressions were blocked in peripheral blood mononuclear cells (PBMCs) in AD patients (AD-PBMCs) to assess the effects on cell inflammation and the Wnt/ß-catenin pathway activation. The Wnt/ß-catenin pathway was inhibited to evaluate cell inflammation. Combined treatments of the cells were conducted to verify the role of the FGF23/α-Klotho axis and the Wnt/ß-catenin pathway in inflammation in AD-PBMCs. Increased FGF23 protein concentration and reduced α-Klotho protein concentration were observed in AD patients and correlated with inflammatory cytokine levels. FGF23 inhibition or α-Klotho overexpression reduced the production of inflammatory cytokines and activated the Wnt/ß-catenin pathway in AD-PBMCs. Blocking the Wnt/ß-catenin pathway increased inflammatory cytokine production in AD-PBMCs and annulled the effects of the FGF23/α-Klotho axis on AD-induced cell inflammation. We concluded that the FGF23/α-Klotho axis can regulate the AD-induced cell inflammation through the Wnt/ß-catenin pathway.
Subject(s)
Alzheimer Disease , Fibroblast Growth Factor-23/metabolism , Klotho Proteins/metabolism , beta Catenin , Aged , Cytokines , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Glucuronidase/genetics , Glucuronidase/metabolism , Glucuronidase/pharmacology , Humans , Inflammation , Leukocytes, Mononuclear/metabolism , beta Catenin/metabolismABSTRACT
Genistein is a type of isoflavone, which has been widely described as an antitumor agent in many cancers. The present study aimed to provide information on the mechanisms of genistein's activity and thus enable a wider range of targeted therapies in hepatitis B virus (HBV)-related liver cancer. We searched the DrugBank database for direct targets of genistein, which were then analyzed through the STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) database to predict their secondary protein targets. Thirteen primary protein targets of genistein and 209 secondary protein targets-associated genes were identified. The data were integrated into the network of protein targets-associated genes and visualized with the Cytoscape software. We further carried out GO (Gene Ontology) analysis and KEGG (Kyoto Encyclopedia of Gene and Genome) pathway analysis using DAVID (database for annotation, visualization, and integrated discovery) tool. The top 14 KEGG pathways were further assessed, and 19 overlapping genes derived from pathways of hepatitis B and cancer were discovered. The overlapping targets were further mapped in the online tool UALCAN to evaluate the survival rate of hepatocellular carcinoma (HCC) patients. We found that the overexpression of Grb2 (growth factor receptor-binding protein 2) (p < 0.0001) was linked to poor overall survival for liver HCC patients, followed by AKT1 (p = 0.0015) and PIK3CA (p = 0.0088). The present study analyzes the drug-target-disease network and may prove to be a useful tool in gene-phenotype connectivity for genistein in HBV-related liver cancer. Our data also pave the way for further research on Grb2 during the development of chronic HBV infection in liver cancer.
