臺灣博碩士論文加值系統

1.Minocycline在軟骨、神經與牙周組織中具有抗發炎與抗細胞凋亡 (antiapoptotic) 之功效；而此二特性在肝臟疾病之治療製藥學發展上實扮演著樞紐性之角色。因此，我們評估minocycline對於C57BL/6J小鼠經由投予致死劑量之作用型anti-Fas單株抗體 (Jo2)所引起之猛爆性肝炎的影響。
2.藉由腹腔注射每克體重零點六微克之Jo2 抗體導致小鼠發生猛爆性肝炎，其血清中之丙氨酸轉胺酶和天門冬氨酸鹽轉胺酶（alanine/aspartate transaminase）活性因而上升，肝臟之組織結構隨之改變，進而使生物體產生死亡。不過，小鼠經預處理三劑之minocycline（每公斤體重五毫克）卻能有效地減緩此致死效應。此外，若在給予小鼠致死劑量之Jo2抗體的同時，或是延遲三十分鐘後投予minocycline，雖然不若預處理般效果明顯，仍然可以改善小鼠之存活曲線。
3.Jo2抗體所誘發之小鼠肝臟中caspase-3與caspase-9的活化，能被minocycline預處理所抑制。然而，直接將minocycline 加入到從Jo2抗體注射後之小鼠所分離出的肝臟萃取物中，並無法阻斷生物體外（in vitro）caspase之活化。 此外， minocycline能有效地抑制Jo2抗體所引發之小鼠肝臟粒腺體cytochrome c的釋放。然而，minocycline預處理並無法緩解Jo2抗體所觸發之caspase-8之活化與Bid蛋白質的裂解。
4.我們的結果顯示minocycline對於Fas接受體媒介之猛爆性肝炎的保護作用牽涉到粒腺體之細胞凋亡路徑，可能藉由阻斷cytochrome c之釋放，因而避免下游caspase之活化。

1.Minocycline has anti-inflammatory and anti-apoptotic effects on cartilage, neurons and periodontal tissues, and both properties are central to the pharmaceutical treatment of liver diseases. We investigated the effects of minocycline on fulminant hepatitis in C57BL/6J mice induced by lethal challenge of the activating anti-Fas antibody, Jo2.
2.Intraperitoneal injection of Jo2 (0.6ug g-1) to mice resulted in fulminant hepatitis, as evidenced by increase of serum alanine/aspartate transaminase activities and histopathological alterations in liver sections, as well as animal death. Nevertheless, mice pretreated with three doses of minocycline (5 mg kg -1) resisted this lethal effect significantly. Minocycline treatment improved the survival kinetics, although to a lesser extent, when mice were challenged simultaneously with Jo2 or even treated 30 min after the lethal challenge.
3.Jo2-induced activation of caspase-3 or -9 in liver tissues was inhibited by minocycline pretreatment, and yet the direct addition of minocycline to liver extracts from Jo2-challenged mice failed to block caspase activation in vitro. Moreover, minocycline efficiently suppressed the release of cytochrome c from mitochondria of the liver tissues from Jo2-challenged mice. In contrast, the activation of caspase-8 or truncation of Bid by Jo2 was not mitigated with minocycline pretreatment in mouse livers.
4.Our results suggest that easing of Fas-triggered fulminant hepatitis by minocycline may involve a mitochondrial apoptotic pathway, probably through preventing cytochrome c release and thereby blocking downstream caspase activation.

Full Article
General Pharmacology and Pharmacy
Division of Gastroenterology and Hepatology

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