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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 龔秀妮(Hsiu-Ni Kung) | |
dc.contributor.author | Pei-Yu Wu | en |
dc.contributor.author | 吳珮羽 | zh_TW |
dc.date.accessioned | 2021-06-08T03:36:43Z | - |
dc.date.copyright | 2019-08-26 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-07-24 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/21523 | - |
dc.description.abstract | 高脂飲食(High fat, HF)所誘導的第二型糖尿病(Diabetes mellitus, DM)是急劇增加的現代疾病。在所有糖尿病併發症中,糖尿病心肌病(Diabetic cardiomyopathy, DC)是糖尿病患者死亡的主要原因,然而,預防或治療DC的具體策略尚未闡明。DC的損害通常是由ROS,發炎和細胞凋亡的增加所引起的,找尋減少ROS和發炎的方法可以保護心肌細胞免受DM所誘導的損傷和死亡。HN242是從植物中提取的天然化合物,可提高各種組織的抗氧化能力,但是HN242是否能保護DC對心臟的傷害目前仍不清楚,因此本實驗旨在探討HN242對DC的影響。
首先,在體內實驗中,C57BL/6小鼠隨機被分成4組,CTL組:普通飲食餵食10週;HF組:高脂飲食餵食10週;HF+HN242組:高脂飲食與HN242同時餵食10週;HF→HN242組:高脂飲食先餵食5週後,再加HN242與高脂飲食同時餵食5週。小鼠餵食HF 10週,血糖達到第二型DM的標準,HF小鼠的心臟大且重於CTL小鼠的心臟,HN242降低了HF組心臟的重量和大小。HN242透過降低c-caspase 3的表現量以減少心肌細胞死亡,降低γH2A、ST2和Galectin 3減少心肌細胞損傷,並透過降低H2O2和O2-含量減少氧化壓力,藉由增加抗氧化調節因子與酵素,包括p-Nrf2,NQO1和SOD1的表現量提高抗氧化能力,並透過降低發炎因子來抑制發炎反應,包括p-P65,TNFα和TGF-β,HN242也可恢復粒線體形態,藉由增加電子傳遞鏈酶COXⅣ,和粒線體生物合成的指標PGC1α的表現量來增加粒線體數量,透過抑制粒線體分裂的指標FIS1和p-DRP1 (ser 637)減少粒線體分裂。而在體外實驗中,棕櫚酸(Palmitic acid, PA)用於模擬HF對H9c2心肌細胞的作用,實驗結果也顯示出HN242減少心肌細胞死亡和損傷,降低ROS含量,增加抗氧化能力,並抑制發炎反應,增加粒線體數量、提高粒線體活性、增加ATP製造,並抑制粒線體過度分裂。NQO1是HN242功能的關鍵,經由抑制劑與siRNA等方法,本研究發現,HN242可透過活化NQO1增加抗氧化能力、增加線粒體活性,並減少發炎,進而改善糖尿病小鼠的心臟損傷,保護心肌細胞免於死亡。可見,HN242具有預防和治療高脂引發DC新型治療劑的潛力。 | zh_TW |
dc.description.abstract | High fat diet (HF) induced type 2 diabetes mellitus (DM) is a modern disease increased dramatically nowadays. Within all the DM complications, diabetic cardiomyopathy (DC) is a major cause of mortality in diabetic patients, however, specific strategies for preventing or treating DC have not been clarified yet. The damages of heart in DM usually caused by the increase of the oxidative stress and inflammation. Finding methods to reduce reactive oxygen species (ROS) and inflammation may protect cardiomyocytes from DM-induced damage and death. HN242 is a natural compound extracted from plants that increased the antioxidant ability in various tissues. However, whether HN242 could protect heart from DC is not understood. This study aims to investigate the effects of HN242 on DC.
First, in the in vivo model, C57BL/6 mice were randomly separated into 4 groups: CTL: normal diet for 10 weeks; HF: high fat diet for 10 weeks; HF+HN242: high fat diet with HN242 feeding for 10 weeks; HF→HN242: After 5 weeks of high fat diet, feeding mice with HN242 for 5 weeks combined with high fat diet. After 10 week feeding, the blood glucose reached the standard of type 2 DM. The hearts in HF mice were larger and heavier than those in mice with normal CTL diet, and HN242 decreased the weight and size of heart under HF. HN242 also reduced cardiomyocyte death by decreasing the expression of c-caspase 3 and reduced damage by decreasing the expression of γH2A, ST2 and Galectin 3, reduced oxidative stress by decreasing the H2O2 and O2- levels, increased antioxidant ability by increasing the expression of anti-oxidant for regulator and enzymes, including p-Nrf2, NQO1, and SOD1, inhibited inflammation by decreasing the expression of inflammation factors, including p-P65, TNFα and TGF-β, restored mitochondrial morphology, elevated mitochondrial content by increasing the expression of electron transport chain enzyme, COXⅣ, and the mitochondrial biogenesis marker, PGC1α, decreased mitochondrial fission by decreasing mitochondrial fission marker, FIS1 and p-DRP1 (ser 637). In the following in vitro model, palmitic acid (PA) was used to mimic the effects of HF on cardiomyocytes, H9c2. The results also demonstrated that HN242 reduced cardiomyocyte death and damage, reduced ROS, increased antioxidant ability, inhibited inflammation, increased mitochondrial content and activity, increased ATP production, and decreased mitochondrial fission. With specific inhibitor and siRNA targeting NQO1, NQO1 was found to be the key for the function of HN242. These data suggested that HN242 may ameliorate cardiac damages in DM mice by increasing the antioxidant ability and mitochondrial activity, decreasing inflammation, and protecting cells from death through the activation of NQO1. HN242 has the potential as a novel therapeutic agent for both the prevention and the treatment of DC. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T03:36:43Z (GMT). No. of bitstreams: 1 ntu-108-R06446006-1.pdf: 12734343 bytes, checksum: d71d7402d88e6a9743ab06cb18274253 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 致謝 i
摘要 iii Abstract v 縮寫表 vii I.Introduction - 1 - 1.Foreword - 1 - 2.Heart - 2 - 3.Diabetes mellitus (DM) - 4 - A.Type 1 DM: - 4 - B.Type 2 DM: - 4 - 4.Diagnosis for diabetes (DM) - 5 - 5.Diabetic cardiomyopathy (DC) - 5 - 6.Relationship between diabetic cardiomyopathy (DC) and oxidative stress - 6 - 7.Relationship between oxidative stress and mitochondrial damage - 7 - 8.Relationship between oxidative stress and inflammatory response - 8 - 9.Development of the DM animal model - 9 - 10.Research purposes - 9 - II. Materials and Methods - 11 - 1.Experimental animal, drug and reagent sources - 11 - 2.Animal experiment process - 13 - A.Experimental group: - 13 - B.Blood glucose measurement: - 14 - C.Formulation of HN242 and feeding method: - 14 - D.High fat diet formula: - 15 - 3.Cardiac ultrasound detection - 15 - 4.Tissue paraffin embedding and sectioning - 16 - 5.Immunohistochemistry (IHC) - 17 - 6.Nonyl acridine orange (NAO) stain - 18 - 7.Tissue freeze embedding and cryo-sectioning - 19 - 8.Reactive oxygen species (ROS) assay - 19 - 9.Epon tissue embedding, sectioning and staining for transmission electron microscope (TEM) - 20 - 10.Cell culture - 22 - A.H9c2 culture medium: - 22 - B.Subculture (100 mm dish): - 22 - C.Differentiation - 23 - 11.Cell treatment - 23 - 12.Cell transfection - 24 - 13.Western blot - 24 - A.SDS PAGE eletrophoresis: - 24 - B.Transfer: - 25 - C.Blocking, and detecting the protein specific antibodies: - 25 - D.Developing: - 25 - 14.ATP assay - 27 - 15.Mitochondria stain - 27 - 16.Flow cytometry - 28 - A.Propidium iodide (PI): - 28 - B.Reactive oxygen species (ROS) assay: - 29 - C.Mitochondrial activity assay: - 30 - 17.Statistical analysis - 30 - III.Result - 31 - 1.HN242 decreased body weight and blood glucose in HF mice. - 31 - 2.HN242 restored size, weight, and cardiac function in hearts of HF mice. - 31 - 3.HN242 decreased cardiomyocyte death in HF mice.- 32 - 4.HN242 decreased cardiomyocyte damage in HF mice.- 32 - 5.HN242 restored gap junction in hearts of HF mice.- 33 - 6.HN242 decreased ROS production in hearts of HF mice. -33- 7.HN242 increased antioxidant ability in hearts of HF mice. - 34 - 8.HN242 inhibited inflammation in hearts of HF mice. - 34 - 9.HN242 increased mitochondrial content in hearts of HF mice. - 35 - 10.HN242 decreased mitochondrial fission in hearts of HF mice. - 36 - 11.HN242 decreased PA induced cell death in H9c2 cardiomyocytes. - 36 - 12.HN242 decreased PA induced damages and restored gap junction in H9c2 cardiomyocytes. - 37 - 13.HN242 decreased ROS production, increased antioxidant ability and inhibited inflammation in PA treated H9c2 cardiomyocytes. - 37 - 14.HN242 increased mitochondrial content, activity and mitochondrial ATP production in PA treated H9c2 cardiomyocytes. - 38 - 15.HN242 decreased mitochondrial ROS production and decreased mitochondrial fission in PA treated H9c2 cardiomyocytes. - 39 - 16.ROS chelator, DTT, decreased cardiomyocyte death, improved cardiac function and antioxidant ability, decreased inflammation, increased mitochondrial content and biogenesis, and decreased mitochondrial fission in PA treated H9c2 cardiomyocytes. - 40 - 17.NQO1 may be an important key to the HN242 effect.-40- 18.Inhibition of NQO1 with dicumarol blocked the protection effects of HN242 in PA treated H9c2 cardiomyocytes. - 41 - 19.Knockdown NQO1 with siRNA blocked the protection effects of HN242 in PA treated H9c2 cardiomyocytes.- 41 - IV.Discussion - 43 - 1.Brief summary - 43 - 2.High fat diet induces diabetes (DM) - 43 - 3.Palmitate acid (PA) mimics the effect of a high-fat diet - 44 - 4.Drugs for treating diabetes (DM) and insulin sensitization - 45 - 5.Treatments and researches for diabetic cardiomyopathy (DC) - 45 - A.Sulfonylurea - 45 - B.Biguanid - 46 - C.Thiazolidinedione (TZD) - 46 - 6.Relationship between diabetic cardiomyopathy (DC) and oxidative stress - 47 - 7.Mitochondrial content and activity in PA treated H9c2 cardiomyocytes - 48 - 8.Mitochondrial fission and fusion - 48 - 9.HN242 may be served as a prevention or treatment drug for diabetic cardiomyopathy (DC) - 49 - 10.The mechanism of HN242 - 50 - 11.Effect of cardiomyocytes in high glucose (HG) environment - 51 - 12.Endocrine hormones of constant blood glucose other than insulin and glucagon - 51 - V. Conclusion - 53 - VI.Figures - 54 - VII. Reference - 103 - VIII. Supplementary figures - 112 - | |
dc.language.iso | zh-TW | |
dc.title | HN242藉由減少氧化壓力、抑制發炎反應和恢復心臟粒線體進而改善糖尿病心肌病 | zh_TW |
dc.title | HN242 ameliorates diabetic cardiomyopathy through reducing oxidative stress, inhibiting inflammation, and restoring mitochondria | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳瀅(Ying Chan),陳玉怜(YUH-LIEN CHEN),楊鎧鍵(KAI-CHIEN YANG) | |
dc.subject.keyword | HN242,高脂飲食,糖尿病心肌病,抗氧化,抗發炎,粒線體,分裂/融合, | zh_TW |
dc.subject.keyword | HN242,high fat diet,diabetic cardiomyopathy,antioxidant,anti-inflammation,mitochondria,fission/fusion, | en |
dc.relation.page | 119 | |
dc.identifier.doi | 10.6342/NTU201901822 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2019-07-25 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
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