博士 / 中山醫學大學 / 醫學研究所 / 104 / Impaired insulin signaling was known to be linked to diabetes and aging-related diseases such as vascular disease, Alzheimer’s disease (AD) and non-alcoholic fatty liver disease (NAFLD). In the present study, we demonstrated the possible pathogenic mechanism of aging-associated disease and neurodegeneration via affecting insulin-related signaling. In the part I, the results showed that humic acid (HA) exhibits a synergistic effect enhancing Aβ-induced neurotoxicity in SK-N-MC neuronal cells. Furthermore, this deterioration was mediated through activation of endoplasmic reticulum (ER) stress by stimulating phosphorylation of PERK and Eukaryotic Initiation Factor 2 α (eIF2α). Our results also observed HA and Aβ-induced oxidative stress was associated with mitochondrial dysfunction caused by down-regulation of Silent information regulator-mammalian ortholog 1 (Sirt1)/peroxisome proliferators-activated receptor γ co-activator 1α (PGC-1α) pathway. However, treating with the ER stress inhibitor salubrinal, or overexpression of Sirt1 significantly restored cell viability affected by HA and Aβ. These findings suggested a new mechanism by which HA can deteriorate Aβ-induced neurotoxicity through modulation of ER stress, which may provide significant insights into the pathogenesis of AD co-occurring with vascular injury. Part II demonstrated a specific microRNA, miR-302, silenced phosphatase and tensin homolog (PTEN) activated Akt signaling, which subsequently stimulated Nanog expression to suppress Aβ-induced p-Ser307 insulin receptor substrate 1 (IRS-1) expression and thus enhanced tyrosine phosphorylation and p-Ser 473-Akt/p-Ser 9-GSK3β formation. In addition, we also found that miR-302-mediated Akt signaling further stimulated nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) elevation and hence inhibited Aβ-induced oxidative stress. Furthermore, our in vivo studies revealed that the expression of Nanog and La ribonucleoprotein domain family member 7 (LARP7) mRNA levels were significantly reduced in AD patients'' blood cells, providing a novel potential diagnosis marker for AD. Part III demonstrated a possible mechanism of miR-302 regulated fatty acid formation and hepatic insulin resistance in NAFLD. Our results demonstrated that miR-302 targeted elongation of very long chain fatty acids protein 6 (Elovl6), mainly elongated C16-18 aliphatic acid, which attenuated high fatty acid-induced hepatic lipid accumulation, oxidative stress and insulin resistance. The above-listed observations reveal that oxidative stress indeed exhibits aging-related diseases such as vascular disease, Alzheimer’s disease (AD) and Non-alcoholic fatty liver disease (NAFLD) and display an important risk factor. Our results suggest that reducing oxidative stress or preventing insulin signaling show protection effects in aging-related diseases, and may help to provide novel therapeutic strategies or drug targets in future.
| Identifer | oai:union.ndltd.org:TW/104CSMU5534058 |
| Date | January 2016 |
| Creators | Hsin-Hua Li, 李欣樺 |
| Contributors | , 賴德仁, 林志立 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 166 |
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