title: Humic Acid Increases Amyloid β-Induced Cytotoxicity by Induction of ER Stress in Human SK-N-MC Neuronal Cells.
abstract: Humic acid (HA) is a possible etiological factor associated with for several vascular diseases. It is known that vascular risk factors can directly increase the susceptibility to Alzheimer's disease (AD), which is a neurodegenerative disorder due to accumulation of amyloid β (Aβ) peptide in the brain. However, the role that HA contributes to Aβ-induced cytotoxicity has not been demonstrated. In the present study, we demonstrate that HA exhibits a synergistic effect enhancing Aβ-induced cytotoxicity in cultured human SK-N-MC neuronal cells. Furthermore, this deterioration was mediated through the activation of endoplasmic reticulum (ER) stress by stimulating PERK and eIF2α phosphorylation. We also observed HA and Aβ-induced cytotoxicity is associated with mitochondrial dysfunction caused by down-regulation of the Sirt1/PGC1α pathway, while in contrast, treating the cells with the ER stress inhibitor Salubrinal, or over-expression of Sirt1 significantly reduced loss of cell viability by HA and Aβ. Our findings suggest a new mechanism by which HA can deteriorate Aβ-induced cytotoxicity through modulation of ER stress, which may provide significant insights into the pathogenesis of AD co-occurring with vascular injury.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. vivid529@hotmail.com.
authors.forename: Hsin-Hua
authors.initials: HH
authors.lastname: Li
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. fjlu@csmu.edu.tw.
authors.forename: Fung-Jou
authors.initials: FJ
authors.lastname: Lu
authors.affiliation: Department of Life Sciences and Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 40227, Taiwan. hchung@dragon.nchu.edu.tw.
authors.forename: Hui-Chih
authors.initials: HC
authors.lastname: Hung
authors.affiliation: Institute of Microbiology & Immunology, Chung Shan Medical University, Taichung 40201, Taiwan. liugy@csmu.edu.tw.
authors.forename: Guang-Yaw
authors.initials: GY
authors.lastname: Liu
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. ltj3123@ms2.hinet.net.|Department of Psychiatry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. ltj3123@ms2.hinet.net.
authors.forename: Te-Jen
authors.initials: TJ
authors.lastname: Lai
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. dll@csmu.edu.tw.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. dll@csmu.edu.tw.
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Lin
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D006812:Humic Substances / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056564:Sirtuin 1 / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002934:Cinnamates; D006812:Humic Substances; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056564:Sirtuin 1; D013890:Thiourea; D014157:Transcription Factors; D019892:eIF-2 Kinase; C486497:PPARGC1A protein, human; C496827:salubrinal; C447939:SIRT1 protein, human