白藜芦醇改善大鼠肝纤维化/肝内的内皮中的功能障碍

StephenW

白藜芦醇改善大鼠肝纤维化/肝内的内皮中的功能障碍
Subject: NATAP: Resveratrol Improves Liver Fibrosis/Intrahepatic Endothelial Dysfunction in Rats


Article in Press
Resveratrol Improves Intrahepatic Endothelial Dysfunction and Reduces Hepatic Fibrosis and Portal Pressure in Cirrhotic Rats - pdf attachedJournal of Hepatology 4 December 2012Marco Di Pascoli, Marta Div., Aina Rodr.guez-Vilarrupla, Eugenio Rosado,
Jorge Gracia-Sancho, Marina Vilaseca, Jaume Bosch, Joan Carles Garc.a-
Pagn

"Resveratrol administration reduces portal pressure, hepatic stellate cell activation and liver fibrosis, and improves hepatic endothelial dysfunction in cirrhotic rats, suggesting it may be a useful dietary supplement in the treatment of portal hypertension in patients with cirrhosis.......In conclusion, our data show that chronic resveratrol administration to cirrhotic rats reduces portal pressure both by causing a regression of liver fibrosis and by correcting hepatic endothelial dysfunction, without affecting systemic hemodynamics. Due to these properties and its low toxicity, resveratrol, which is widely available, may be a useful supplement in the treatment of patients with cirrhosis and portal hypertension.”"we could speculate that in our setting the antifibrotic effect of resveratrol may be due, at least partly, to its anti-oxidant activity [35]. Indeed, it has been shown that resveratrol inhibits the activation of NF-kappaB, which promotes the transcription of several cytokines including the pro-fibrogenic TGF-β [18, 36, 37]. In that regard, we have also demonstrated that resveratrol treatment produces a significant reduction in the NFB and TGF gene expression, suggesting that resveratrol is able to reduce fibrosis by reducing profibrogenic stimuli in cirrhotic rat livers"


"Resveratrol (3,5,4’-trihydroxystilbene) is a natural polyphenolic flavonoid found in a large amount of plant species, including grapes and their derivatives, berries and nuts. It has been suggested to have important health benefits attributed to its demonstrated anti-oxidant, anti-neoplastic, anti-inflammatory and anti-platelet aggregation activities [8-11]. Specifically, in different experimental models resveratrol improves vascular dysfunction"
Abstract Background and AimsResveratrol, a polyphenol found in a variety of fruits, exerts a wide range of beneficial effects on the endothelium, regulates multiple vasoactive substances and decreases oxidative stress, factors involved in the pathophysiology of portal hypertension. Our study aimed at evaluating the effects of resveratrol on hepatic and systemic hemodynamics, hepatic endothelial dysfunction and hepatic fibrosis in CCl4-cirrhotic rats.
MethodsResveratrol (10 and 20 mg/kg/day) or its vehicle were administered to cirrhotic rats for two weeks and hepatic and systemic hemodynamics were measured. Moreover, we evaluated endothelial function by dose-relaxation curves to acetylcholine, hepatic NO bioavailability and TXA2 production. We also evaluated liver fibrosis by Sirius Red staining of liver sections, collagen-1, NFkB, TGFβ mRNA expression, and desmin and α-smooth muscle actin (α-SMA) protein expression, as a surrogate of hepatic stellate cell activation.
ResultsResveratrol administration significantly decreased portal pressure compared to vehicle (12.1±0.9 vs 14.3±2.2 mmHg; p<0.05) without significant changes in systemic hemodynamics. Reduction in portal pressure was associated with an improved vasodilatory response to acetylcholine, with decreased TXA2 production, increased endothelial NO and with a significant reduction in liver fibrosis. The decrease in hepatic fibrosis was associated with a reduced collagen-1, TGFβ, NFкB mRNA expression and desmin and α-SMA protein expression.
ConclusionsResveratrol administration reduces portal pressure, hepatic stellate cell activation and liver fibrosis, and improves hepatic endothelial dysfunction in cirrhotic rats, suggesting it may be a useful dietary supplement in the treatment of portal hypertension in patients with cirrhosis.
Introduction:
In cirrhosis, the initial factor determining the onset of portal hypertension is the increase in intrahepatic vascular resistance. This is not only due to
morphological changes resulting from the chronic liver inflammation and fibrosis, but also to reversible functional alterations, including an exaggerated
response of the porto-hepatic vascular bed to vasoconstrictors and a deficient response to vasodilators [1]. A decreased nitric oxide (NO) availability and an
increase in cyclooxygenase-1 (COX-1)-derived prostanoids within the liver play a major role in the pathogenesis of these dynamic alterations [2-5].
Reduced NO availability has been shown to be in part due to an increase scavenging by superoxide (O2-) and different strategies aimed to reduce O2-
levels [6, 7] such as superoxide dismutase (SOD) gene transfer are able to reduce portal pressure in experimental models of cirrhosis in the rat.
Resveratrol (3,5,4’-trihydroxystilbene) is a natural polyphenolic flavonoid found in a large amount of plant species, including grapes and their derivatives, berries and nuts. It has been suggested to have important health benefits attributed to its demonstrated anti-oxidant, anti-neoplastic, anti-inflammatory and anti-platelet aggregation activities [8-11]. Specifically, in different experimental models resveratrol improves vascular dysfunction, an effect that is attributed to its ability to reduce oxidative stress, to upregulate endothelial nitric oxide synthase (eNOS) expression and activity, and to inhibit COX-1 activity [12-15].

Resveratrol has been shown to exert anti-oxidant effects in experimental models of liver injury induced by ischemia/reperfusion and ethanol by inducing the enzymatic activity of SOD and catalase [16, 17], and to attenuate fibrosis development when co–administrated with CCl4 to rats [18]. Additionally, resveratrol reduces the hepatotoxicity induced by acetaminophen, ethanol and carbone tetrachloride (CCl4), and prevents liver damage due to ischemiareperfusion, irradiation and high fat diet [19]. Overall, we hypothesized that resveratrol may exert beneficial effects in the pathophysiological mechanisms involved in the development of portal hypertension in cirrhosis
Therefore, the aim of the present study was to investigate the effects of chronic administration of resveratrol in CCl4-cirrhotic rats with portal hypertension.

Discussion:
In cirrhosis, an increase in hepatic vascular resistance to portal blood flow is the primary factor in the development of portal hypertension [3]. Therefore, it is of great interest to develop therapeutic strategies aimed at decreasing portal pressure by reducing hepatic vascular resistance. Resveratrol is a natural substance with many biologic functions; among others, it induces antioxidant enzymes, increases NO bioavailability and inhibits the production of inflammatory factors [33].


The main finding of the present study is that in established cirrhotic rats with severe portal hypertension, the oral administration of resveratrol for two weeks reduces portal pressure, without affecting portal blood flow, indicating an effective reduction in hepatic vascular resistance. This beneficial effect on portal pressure was confirmed when a double dose of resveratrol was used. Remarkably, the beneficial effect of resveratrol on portal pressure occurred in the absence of deleterious effects on systemic hemodynamics, as shown by the absence of significant changes in mean arterial pressure, heart rate and superior mesenteric artery blood flow.


Our results further suggest that the reduction in hepatic resistance induced by resveratrol was the result of both amelioration of the liver architectural abnormalities and an improvement in endothelial dysfunction. Indeed, resveratrol significantly reduced liver fibrosis, as shown by the reduction in fibrosis area on Sirius Red stained liver sections and the decrease in collagen I mRNA expression, an effect that was not observed in cirrhotic rats treated with vehicle, demonstrating that this was due to an enhancement by resveratrol of the regression of fibrosis that occurs after ceasing CCl4 administration. Our results showing a decline in both desmin and SMA expression in liver tissue suggests that a decrease in HSC activation may be mostly due to the consequence of apoptosis of activated HSC. This suggestion is further supported by our findings in LX2 cells showing that resveratrol significantly decreases collagen I and SMA gene expression in association with an increase in Bad protein expression, a marker of apoptosis induction.


It has been well documented that a reduction of oxidative stress can deactivate mechanisms leading to liver fibrosis [34]. Therefore, we could speculate that in our setting the antifibrotic effect of resveratrol may be due, at least partly, to its anti-oxidant activity [35]. Indeed, it has been shown that resveratrol inhibits the activation of NF-kappaB, which promotes the transcription of several cytokines including the pro-fibrogenic TGF-β [18, 36, 37]. In that regard, we have also demonstrated that resveratrol treatment produces a significant reduction in the NFB and TGF gene expression, suggesting that resveratrol is able to reduce fibrosis by reducing profibrogenic stimuli in cirrhotic rat livers. Whatever the mechanism, these effects on liver fibrosis were not boosted by higher doses of resveratrol, since similar reductions in fibrosis were observed with 10 and 20 mg/kg bw/day.


Cirrhotic livers of rats treated with resveratrol had a reduction in O2- levels. Resveratrol itself, as a polyphenolic compound, has been shown to scavenge hydroxyl, O2- and other radicals [38, 39]. Moreover, resveratrol have also indirect antioxidant effects by upregulating different endogenous cellular antioxidant systems, such as SOD, catalase, glutathione peroxidase,….and by inhibition of enzymatic systems involved in ROS formation, like NAPDH oxidase [40, 41]. Although decreased scavenging of O2- by diminished SOD activity has been reported as one of the causes of the increased oxidative stress in cirrhotic livers [24], we did not find any effect of resveratrol treatment on SOD activity. Therefore, we think that the observed is a direct antioxidant effect of resveratrol although we can not discard that other mechanisms different from SOD activity increase could be implicated.


Resveratrol administration also improved endothelial dysfunction. We have previously demonstrated that reduced NO bioavailability and a COX-1-dependent increase in TXA2 are the main factors mediating the endothelial dysfunction of cirrhotic rat livers [5, 42, 43]. Resveratrol has been shown to act as a peroxidase-mediated inactivator of COX-1 [15] and, in agreement with that, we found that resveratrol markedly inhibited TXA2 production in whole tissue. We also observed that resveratrol could attenuate the increase in TXA2 levels induced by AA administration in SEC-CH, confirming the role of COX-1-derived prostanoids in the improvement of endothelial dysfunction by resveratrol. In addition, resveratrol treatment promoted a significant increase in NO bioavailability in endothelial cells isolated from cirrhotic livers. Taken together, these results suggest that resveratrol may improve endothelial dysfunction by increasing endothelial NO and reducing endothelial TXA2. Besides, it is highly likely that the improvement in liver fibrosis produced by resveratrol itself may play a major role in the recovery of endothelial function. Furthermore, we herein show that resveratrol reduces the number of CD68- positive cells (34% decrease) in cirrhotic livers. This finding is in agreement with a published study showing that resveratrol may attenuate inflammatory infiltration [37], an effect that may represent an additional benefit of resveratrol treatment.


In conclusion, our data show that chronic resveratrol administration to cirrhotic rats reduces portal pressure both by causing a regression of liver fibrosis and by correcting hepatic endothelial dysfunction, without affecting systemic hemodynamics. Due to these properties and its low toxicity, resveratrol, which is widely available, may be a useful supplement in the treatment of patients with cirrhosis and portal hypertension.

StephenW

主题：NATAP：白藜芦醇改善肝纤维化/肝内大鼠模型的内皮Dysfunction中的

文章在出版中
白藜芦醇提高肝内血管内皮功能障碍和降低肝硬化大鼠的肝纤维化及门脉高压 -  PDF附
-  2012年中华肝脏病杂志4月12日
马可·迪帕斯科利，玛塔息，艾娜Rodr.guez-Vilarrupla，欧金尼奥·罗萨多，
豪尔赫·格拉西亚桑丘，滨海Vilaseca，乌梅博世，琼普约尔Garc.a
Pagn
“白藜芦醇管理降低门静脉压力，肝星状细胞的活化和肝纤维化，改善肝硬化大鼠的肝血管内皮功能障碍，这表明它可能是一个有用的膳食补充剂在肝硬化患者的门静脉高压症的治疗.......在总之，我们的数据显示，肝硬化大鼠慢性白藜芦醇管理，降低门静脉压力，导致肝纤维化的回归和纠正肝血管内皮功能障碍，不影响全身血流动力学的情况下，由于这些属性和它的低毒性，白藜芦醇，这是广在治疗肝硬化门脉高压症患者可能是一个有益的补充。“
“我们可以推测，在我们的设置白藜芦醇的抗纤维化效果可能是由于，至少部分地，它的抗氧化剂活性[35]事实上，已表明，白藜芦醇抑制NF-κB的活化，促进了多种细胞因子的转录，包括亲纤维化转化生长因子-β[18，36，37]，在这方面，我们还表明，白藜芦醇处理产生一个NFB和转化生长因子的基因的表达显着降低，提示，白藜芦醇是能够减少纤维化的减少肝硬化大鼠肝纤维化刺激“

“白藜芦醇（3,5,4' - 三羟基）是一种天然的多酚类，黄酮类化合物中发现了大量的植物物种，包括葡萄和它们的衍生物，，浆果和螺母的。有人曾建议有重要的健康益处归于其证明反氧化剂，抗肿瘤，抗炎和抗血小板聚集活性[8-11]具体而言，在不同的实验模型中白藜芦醇改善血管功能障碍“
抽象
背景与目的

白藜芦醇，多酚发现在各种水果中，产生广泛的有益作用在血管内皮细胞，调节多种血管活性物质，降低氧化应激，门静脉高压症的病理生理因素。我们的研究旨在评估白藜芦醇对肝及全身血流动力学，肝血管内皮功能障碍和四氯化碳肝硬化大鼠肝纤维化的影响。
方法

白藜芦醇（10和20毫克/公斤/天）或它的车辆的两个星期，肝，肝硬化大鼠给药全身血流动力学测定。此外，我们评估血管内皮功能的剂量松弛曲线的乙酰胆碱，肝NO生物利用度和TXA2生产。我们也评估肝纤维化天狼星红染色的肝，胶原蛋白1，核转录，TGFβmRNA的表达，和结蛋白和α-平滑肌肌动蛋白（α-SMA）的蛋白表达，对肝星状细胞活化的替代品。
结果

白藜芦醇管理显着降低门静脉压力相比，没有显着变化，全身血流动力学的车辆（12.1±0.9比14.3±2.2毫米汞柱，P <0.05）。门脉压力减少与一种改进的血管舒张响应于乙酰胆碱，与减少TXA2的生产，增加内皮NO和具有显着降低在肝纤维化。减少胶原-1，TGFβ，NFкBmRNA表达和desmin和α-SMA的表达与肝纤维化的减少。
结论

白藜芦醇管理降低门静脉压力，肝星状细胞的活化和肝纤维化，改善肝硬化大鼠的肝血管内皮功能障碍，这表明它可能是一个有用的治疗门静脉高压症，肝硬化患者的膳食补充剂。
简介：
肝硬化，门静脉高压症的发病的始动因素是肝内血管阻力增加。这不仅是由于
导致从慢性肝脏炎症和纤维化的形态学变化，但也可逆的功能的改变，包括夸张
波尔图肝血管床的血管收缩剂和有缺陷的血管扩张剂[1]的反应的响应。降低一氧化氮（NO）的可用性和
环氧合酶-1（COX-1）衍生肝脏内的前列腺素，这些动态改变的发病机制中发挥了重要作用[2-5]。
减少NO可用性已经被证明是部分由于增加的超氧清除（O2-）和不同的策略，旨在减少O2
水平的影响[6,7]，如超氧化物歧化酶（SOD）的基因转移在大鼠能减少肝硬化门脉压力的实验模型。
白藜芦醇（3,5,4' - 三羟基）是一种天然的多酚类，黄酮类化合物中发现了大量的植物物种，包括葡萄，浆果和坚果及其衍生物。有人已提出有重要的健康益处归于其表现出抗氧化剂，抗肿瘤，抗炎和抗血小板聚集活性[8-11]。具体而言，在不同的实验模型，白藜芦醇改善血管功能障碍，是由于其能力，以减少氧化应激，上调内皮型一氧化氮合酶（eNOS）的表达和活性，抑制COX-1的活性[12〜15]的效果。

白藜芦醇已被证明发挥抗氧化作用，在缺血/再灌注损伤和乙醇诱导酶和过氧化氢酶超氧化物歧化酶（SOD）的活性[16，17]，减轻纤维化的发展时给药四氯化碳肝损伤的实验模​​型影响[18]。此外，白藜芦醇减少了对乙酰氨基酚，乙醇和Carbone的四氯化碳（CCl4）肝损伤，肝功能损害，并防止因缺血再灌注，辐射和高脂肪的饮食[19]。整体而言，我们推测白藜芦醇可能参与肝硬化门静脉高压症的发展的病理生理机制发挥有益的作用
因此，本研究的目的是探讨长期服用白藜芦醇四氯化碳肝硬化门静脉高压症大鼠的影响。

讨论：
肝硬化，肝血管阻力增加，门脉血流量是发展的首要因素，门静脉高压症[3]。因此，这是极大的兴趣来制定治疗策略，旨在通过降低肝血管阻力降低门静脉压力。白藜芦醇是一种天然物质，与许多生物功能，其中包括诱导抗氧化酶活性，增加NO的生物利用度，抑制了生产的炎性细胞因子[33]。

本研究的主要发现是，在肝硬化大鼠严重的门脉高压症，口服白藜芦醇降低门静脉压力，在不影响门静脉血流，说明肝血管阻力有效地减少了两个星期。这种有益的作用门户网站上的压力时，使用双倍剂量的白藜芦醇。值得注意的是，发生在门户网站上的压力白藜芦醇的有益作用的有害影响全身血流动力学的情况下，平均动脉血压，心跳率和肠系膜上动脉的血流量显着变化的情况下。

我们的研究结果还表明，白藜芦醇诱导肝电阻减少，改善肝脏的建筑异常和改善血管内皮功能障碍的结果都。事实上，白藜芦醇显着降低肝纤维化的天狼星红染色的肝纤维化面积的减少和胶原蛋白的减少，如图I mRNA的表达，未观察到的效果，在治疗肝硬化大鼠与车辆，这表明，这是由于提高白藜芦醇的回归纤维化发生后停止四氯化碳管理。我们的研究结果显示结蛋白和SMA在肝组织中的表达下降，减少HSC活化，可能主要是由于活化HSC凋亡的结果。建议进一步支持了我们的研究结果显示，白藜芦醇在LX2细胞显着降低I型胶原和协会SMA基因表达的增加Bad蛋白的表达，诱导细胞凋亡的一个标志。

有据可查，减少氧化应激可以停用机制，导致肝纤维化[34]。因此，我们可以推测，在我们的设置白藜芦醇的抗肝纤维化作用的可能是由于，至少部分，其抗氧化活性[35]。事实上，它已被证明，白藜芦醇抑制NF-κB的活化，从而促进多种细胞因子的转录，包括亲纤维形成的转化生长因子-β[18，36，37]。在这方面，我们还表明，白藜芦醇治疗产生的非专营巴士和转化生长因子基因的表达显着减少，这表明，白藜芦醇能减轻纤维化，减少肝硬化大鼠肝脏纤维化刺激。不管是什么机制，这些对肝纤维化的影响并没有受惠于高剂量的白藜芦醇，因为类似的削减纤维化观察10和20毫克/公斤体重/天。

与白藜芦醇治疗大鼠肝硬化肝脏减少O2-的水平。白藜芦醇本身，作为一种多酚类化合物，已经显示出清除羟基，氧气和其它基团[38，39]的。此外，白藜芦醇还具有间接的抗氧化作用，通过上调不同的内源性细胞抗氧化系统，如超氧化物歧化酶，过氧化氢酶，谷胱甘肽过氧化物酶，......通过抑制酶系统的活性氧的形成，，像NAPDH氧化酶[40，41]。虽然下降已清除O2-的超氧化物歧化酶活性降低肝硬化肝脏的氧化应激增加的原因之一[24]，我们没有找到任何超氧化物歧化酶活性的白藜芦醇治疗效果。因此，我们认为，所观察到的是一个直接的抗氧化作用的白藜芦醇，虽然我们不能放弃，可能会牵连其他不同的超氧化物歧化酶活性增加的机制。

白藜芦醇政府还改善血管内皮功能障碍。之前我们已经证实，NO生物利用度降低和COX-1依赖的增加，TXA2的主要因素介导的内皮功能障碍，肝硬化大鼠肝[5，42，43]。白藜芦醇已被证明的过氧化物酶COX-1介导的灭活[15]，在与该协议中，我们发现，白藜芦醇能显着抑制的TXA2生产在整个组织。我们还发现，白藜芦醇能减轻TXA2水平的增加引起的AA行政SEC-CH，证实白藜芦醇改善血管内皮功能障碍中的COX-1源性前列腺素的作用。此外，白藜芦醇治疗促进了肝硬化肝脏内皮细胞NO的生物利用度显着增加。两者合计，这些结果表明，白藜芦醇可改​​善血管内皮功能障碍，增加血管内皮NO和减少内皮细胞TXA2。此外，它极有可能白藜芦醇本身所产生的肝纤维化，改善发挥了重要作用，血管内皮功能的恢复。此外，我们在此表明​​，白藜芦醇肝硬化肝CD68阳性细胞的数量减少（减少34％）。这一发现是一致的，与发表的一项研究显示，白藜芦醇可以减轻炎症细胞浸润[37]，可能是一个额外的好处白藜芦醇治疗的效果。

总之，我们的数据显示，肝硬化大鼠慢性白藜芦醇管理，降低门静脉压力，导致肝纤维化的回归和纠正肝血管内皮功能障碍，不影响全身血流动力学。由于这些属性和它的低毒性，白藜芦醇，这是广泛使用的，可能是肝硬化门脉高压症的患者在治疗的有益补充。

StephenW

白藜芦醇（Trans-3,5,4'-trihydroxystilbene）resveratrol 是一种非黄酮类的酚类物质。天然的白藜芦醇在很多植物中存在，是植物为了抵御病菌入侵而产生的一种抗毒型物质。
红酒和白藜芦醇康乃尔大学的克雷西博士(Dr. Creasy) 化验了上千种葡萄酒，发现葡萄种类是白藜芦醇含量的决定性因素。黑皮诺所含白藜芦醇最多，其次是美乐以及赤霞珠。另外，葡萄酒的产地也很重要，来自低温高湿地区的葡萄酒，平均含有更多的白藜芦醇。
克雷西1997年的一项研究结果表明，收获季节潮湿寒冷的美国芬格湖地区，其黑皮诺葡萄酒拥有全球最高的白藜芦醇含量。
从红酒中得到白藜芦醇的好处是，其白藜芦醇和溶解媒介酒精都是纯粹天然，像法国人那样让红酒在下颚中停留，来吸收白藜芦醇的同时，还可以享受红酒

天行健君

乙人不能喝酒

StephenW

回复 天行健君 的帖子

是的.
白藜芦醇是在红葡萄皮
中找到的. 红葡萄酒中含有很少白藜芦醇.白藜芦醇是一种很常见的保健品. 应该是值得做一些临床试验.