Chia Nan University of Pharmacy & Science Institutional Repository:Item 310902800/24938
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    標題: 懈皮酮對外源性給予s-腺核同半胱胺酸合併同半胱胺酸加重熱中風傷害之影響
    Effects of Quercetin on Aggravation of Heatstroke-Induced Damage by Exogenous S-Adenosylhomocysteine Together with Homocysteine Treatment
    作者: 楊彩秀
    溫義嗣
    貢獻者: 保健營養系
    日期: 2011
    上傳時間: 2012-01-03 13:57:16 (UTC+8)
    摘要: 證據顯示Hcy是心血管疾病和神經損傷相關疾病的危險因子之一，同時學者也發現罹患心血管和中風疾病患者血漿中會伴隨有SAH(Hcy生合成的前驅物)濃度增加的情形。但較新的細胞試驗研究指出，當SAH和Hcy同時存在下分別比單獨作用對細胞傷害更大，SAH和Hcy之間可能存在互補或協同的作用，因此SAH和Hcy極有可能共同合併參與形成心血管或神經損傷相關疾病的病理作用影響。目前的研究卻鮮少將SAH和Hcy合併在同一試驗模式下觀察討論。在熱中風大鼠動物模式中，循環性休克和腦部缺氧缺血被認為是熱中風發展的主因；透過大鼠全身性細胞介質素增加產生的發炎作用和血管內皮與心臟功能損傷，促使腦部神經傷害和循環性休克形成，同時近期研究發現，大鼠體內高自由基生成(特別是氫氧自由基和超氧自由基)和低酵素性抗氧化防禦，也參與了生成熱中風傷害的病理作用，最終導致縮短動物體存活時間。根據我們預實驗初步結果顯示，合併給予SAH和Hcy確實明顯更縮短熱中風存活時間，因此，現今的研究計畫中，(一)我們將利用大鼠熱中風動物模式來觀察，同時合併給予SAH和Hcy對熱中風損傷病理發展的影響，並試圖闡述可能的作用機制。(二)同時，研究發現槲皮酮(quercetin)可抑制內皮因子的釋放、抑制活性氮生成、保護血管和抗血小板凝集等作用，可有效改善腦缺血缺氧實驗動物的傷害。我們也將評估給予槲皮酮處理，是否可改善SAH合併Hcy加重惡化熱中風所致傷害的影響。(三)最後，為了更確認槲皮酮的影響作用，我們利用神經膠細胞缺氧模式來觀察，槲皮酮是否對SAH合併Hcy可能引發的高細胞介質素和高自由基表現與細胞DNA損傷的情形有改善，藉此來確認其可能的作用機制。於是在未來三年的研究計畫中，我們將進行以下研究。第一年：探討同時外加給予SAH合併Hcy對大鼠熱中風損傷參數之影響及可能作用機制---我們將外加給予SAH合併Hcy，監測熱中風動物體病理生理參數的變化。本實驗主要的目的在於觀察，是否給予SAH合併Hcy處理會加重惡化熱中風所造成病理生理參數變化，而導致減短動物體存活時間。並觀察腦與心臟細胞損傷程度、自由基生成、發炎反應和DNA甲基轉移酶表現的情形，以探討可能的作用機制。第二年：探討餵食或靜脈注射懈皮酮處理對SAH合併Hcy促進大鼠熱中風病理生成之影響---利用餵食或靜脈注射方式給予槲皮酮處理後，探討槲皮酮是否具預防或治療因SAH合併Hcy加重惡化熱中風所造成的病理作用。擬给予動物體餵食或靜脈注射槲皮酮處理後，觀測對SAH合併Hcy所致熱中風損傷參數的影響，而達到預防或治療SAH合併Hcy促進熱中風所造成的傷害。第三年：探討缺氧下懈皮酮對SAH合併Hcy誘導神經膠細胞傷害之保護作用及可能作用機制--利用小鼠微神經膠細胞培養處理於低氧槽下的細胞試驗，來模擬活體熱中風神經細胞缺氧缺血狀態。我們將先評估在培養於缺氧槽的小鼠神經微膠細胞株(BV-2 cells)中，外加給予SAH合併Hcy處理，對細胞介質素和自由基表現與細胞DNA損傷程度的影響。此實驗目的主要強調，額外給予SAH合併Hcy處理且在缺氧狀況下的BV-2 cells，是否會促使更多細胞介質素和氧化壓力增加，而加重惡化細胞和DNA損傷情形。再者，槲皮酮是否會經由降低細胞內細胞介質素、發炎物質和自由基生成，進而達到保護細胞和改善DNA傷害的效果。我們預實驗初步結果發現，動物體給予急性SAH合併Hcy處理後明顯更縮短熱中風存活時間。本計畫值得繼續進行研究探討。
    Many evidences revealed that Hcy was one of the high risk factors for cardiovascular diseases and neurodegenerative diseases. Additionally, patients of these diseases frequently followed by SAH accumulation. However, the latter study in cells indicated that SAH with Hcy caused the cell damage worse than one alone. SAH and Hcy might have some possible interaction of complement or coordination in the pathological development of these diseases. So far, little attention has been given to observe and discuss the effects of both SAH with Hcy on the same experimental model. Circulatory shock, cerebral hypoxia and ischemia were thought to the main causes to form heatstroke in the heatstroke model of rats. It might evoke the brain neuronal damage and circulatory shock formation by means of high systemic cytokines-induced inflammatory response, vascular endothelial injury and cardiac dysfunction. The latest research found that high radicals products and low enzymatic antioxidant defense were also involved in pathological formation of the heatstroke-induced damage, and led to shorten survival time in rats. Consequently, in present project, (1)we will use the heatstroke animal model of rats to observe effects of SAH together with Hcy on pathological development in heatstroke-induce damage, and attempt to clarify the possible influence mechanism. (2)Additionally, studies found that quercetin could effectively ameliorate the damage in many cerebral hypoxia and ischemia experiments via inhibition of endothelial factors releasing, inhibition of reactive oxygen species, protection of vascular endothelium, and anti-coagulation of platelets. We will also assess whether treatment with quercetin can improve that effects of SAH together with Hcy on aggravating the heatstroke-induced damage. (3)Finally, in order to further confirm quercetin influence, we will use the hypoxia model in microglia cell to investigate whether administration of quercetin can ameliorate the SAH with Hcy-induced increment of cytokines, radicals, and cellular DNA damage. Therefore, we are the first to address hypotheses in this 3-year project and plan to conduct the following studies. 1st year: Investigation of effects of treatment SAH together with Hcy on parameters changes of heatstroke-induced damage and probable underlying mechanism. The purpose of this study is mainly to observe whether exogenous treatment SAH together with Hcy can aggravate the pathological parameters of heatstroke-induced damage, and results in shrinkage of survival time. Meanwhile, we will try to investigate probable underlying mechanism by acquiring the situations of cerebral and cardiac cell damage, products of radicals and cytokines, and expression of DNA methyltransferase in heatstroke rats, after treatment SAH with Hcy. 2nd year: Investigation of effects of SAH together with Hcy on pathological formation during heatstroke, after feeding or intravenous injection with quercetin. We will investigate whether feeding or intravenous injection with quercetin can prevent o therapy the aggravated heatstroke-induced damage, which is evoked by exogenous treatment SAH together with Hcy. 3rd year: Investigation of the protective effects of quercetin on aggravating microglia cell injury under hypoxia condition by giving SAH together with Hcy, and trying to find probable working mechanism. We will firstly evaluate that effects of exogenous SAH with Hcy treatment on expression of cytokines and radicals, and the extent of cellular and DNA damage in the mouse microglia cell line (BV-2 cells) with incubation in hypoxic incubator chamber (mimicking the heatstroke hypoxic and ischemic condition in vivo). The purpose of this study mainly emphasis on whether exogenous SAH with Hcy treatment under hypoxic conditions in BV-2 cells can enhance increment of cytokines, radicals, and lead to cell and DNA damage; however, whether these increment of parameters can be diminished by quercetin, and lead to protect the cell and DNA from injury. According our preliminary results in advance experiment, treatment of SAH together with Hcy apparently revealed the shrinkage in the survival time of heatstroke. This study will be worthy to investigate further more closely.
    關聯: 計畫編號：NSC99-2320-B041-003-MY3
    計畫年度：100；起迄日期：2011-08-01~2012-07-31
    核定金額：1,189,000元
    显示于类别:[保健營養系(所) ] 科技部計畫

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