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Endogenous ω-3 fatty acid production in fat-1 transgenic mice protects against experimentally induced inflammation and carcinogenesis
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 서영준 | - |
dc.contributor.author | 염혜원 | - |
dc.date.accessioned | 2017-10-27T17:01:16Z | - |
dc.date.available | 2017-10-27T17:01:16Z | - |
dc.date.issued | 2017-08 | - |
dc.identifier.other | 000000145382 | - |
dc.identifier.uri | https://hdl.handle.net/10371/137020 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 약학대학 약학과, 2017. 8. 서영준. | - |
dc.description.abstract | Omega-6 (ω-6) and omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are known to have opposite effects on the inflammatory and carcinogenesis processes. In general, ω-6 PUFAs promote inflammation and tumor development, whereas ω-3 PUFAs possess anti-inflammatory as well as anti-oxidative activity and enhance host immune response.
In the present study, I investigated the protective effects of ω-3 PUFAs on experimentally induced inflammation and carcinogenesis using fat-1 transgenic mice harboring ω-3 desaturase gene capable of converting ω-6 to ω-3 PUFAs. The ω-3/ω-6 PUFA ratio was significantly higher in the dorsal skin of fat-1 mice than that in the wild-type (WT) C57BL/6 mice. fat-1 mice expressed heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 and their mRNA transcripts to a greater extent than did WT mice, which was attributable to the elevated activation of nuclear factor erythroid-related factor 2 (Nrf2) responsible for upregulation of cytoprotective and stress-responsive proteins. Exposure to solar radiation, especially ultraviolet B (UVB), is the most prevalent cause of skin photocarcinogenesis. Upon single exposure to UVB (500 mJ/cm2) irradiation, fat¬-1 mice exhibited a significantly lower degree of skin inflammation and phototoxicity and the expression of the pro-inflammatory enzyme, cyclooxygenases-2 (COX-2) as compared to those observed in WT mouse skin. The protection of fat-1 mice from UVB-induced skin inflammation was associated with decreased phosphorylation of signal transducer and activator of transcription 3 (STAT3), one of the major pro-inflammatory transcription factors. To determine whether the elevated ω-3 PUFA level also protects against UVB-induced skin papillomagenesis, hairless fat-1−/− and fat-1+/− mice were generated by cross-breeding of male fat-1+/− transgenic mice with female SKH-1 hairless mice. After repeated UVB irradiation (180 mJ/cm2) thrice a week for 23 weeks, the incidence and the multiplicity of papillomas were markedly reduced in the fat-1+/− group as compared to the fat-1−/− group. Moreover, the expression of COX-2 and activation of STAT3 in papillomas from fat-1+/− mice were significantly lower than those found in UVB-irradiated fat-1−/− mice. In another study, I also found that an increased ω-3 PUFA tissue status in the fat-1 mice led to effective protection against inflammatory tissue injury in colitis induced by 2,4,6-trinitrobenzene sulfonic acid. The endogenous increase in ω-3 PUFAs in fat-1 mice lso attenuated lipid peroxidation (malondialdehyde) and protein oxidation (4-hydroxy-2-nonenal). The observed protection against inflammatory and oxidative tissue damages in the fat-1 mouse colon was associated with decreased nuclear factor kappa B (NF-kappaB) activity and expression of COX-2 and with elevated activation of Nrf2 and expression of its target gene, ho-1. Taken together, these observations indicate that functional fat-1 potentiates cellular defense against experimentally induced inflammation and tumor development through elevated activation of Nrf2 and subsequent upregulation of cytoprotective gene expression as well as suppression of pro-inflammatory signaling mediated by STAT3 and/or NF-kappaB. | - |
dc.description.tableofcontents | Chapter Ⅰ 1
1. Introduction 2 2. The health beneficial effects associated with ω-3 PUFAs 6 3. The fat-1 transgenic mouse 10 Statement of Purpose 12 Chapter Ⅱ 13 1. Abstract 14 2. Introduction 16 3. Materials and Methods 20 4. Results 26 5. Discussion 41 Chapter Ⅲ 45 1. Abstract 46 2. Introduction 48 3. Materials and Methods 51 4. Results 61 5. Discussion 86 Chapter Ⅳ 92 1. Abstract 93 2. Introduction 95 3. Materials and Methods 98 4. Results 104 5. Discussion 118 Conclusion 121 References 123 Abstract in Korean 151 | - |
dc.format | application/pdf | - |
dc.format.extent | 3621370 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | 2 | - |
dc.subject | 4 | - |
dc.subject | 6-Trinitrobenzene sulfonic acid | - |
dc.subject | Colitis | - |
dc.subject | fat-1 transgenic mice | - |
dc.subject | Inflammation | - |
dc.subject | NF-kappaB | - |
dc.subject | Nrf2 | - |
dc.subject | Omega-3 polyunsaturated fatty acids | - |
dc.subject | Photocarcinogenesis | - |
dc.subject | STAT3 | - |
dc.subject | Ultraviolet B | - |
dc.subject.ddc | 615 | - |
dc.title | Endogenous ω-3 fatty acid production in fat-1 transgenic mice protects against experimentally induced inflammation and carcinogenesis | - |
dc.type | Thesis | - |
dc.description.degree | Doctor | - |
dc.contributor.affiliation | 약학대학 약학과 | - |
dc.date.awarded | 2017-08 | - |
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