酗酒及慢性酒精攝取是全球公共衛生問題，酒精的過量攝取會造成酒精性肝臟疾病 (Alcoholic liver disease, ALD)，然而，一些用於治療ALD的藥物具有許多副作用，最近已有研究指出白藜蘆醇可以改善酒精性肝臟損傷，但由於白藜蘆醇的生物可利用率差，阻礙了白藜蘆醇的巨大潛力，因此在本研究中欲將白藜蘆醇包覆於奈米載體來改善其生物可利用率，奈米載體的運輸系統可能可以作為一個有效改善藥物生物可利用率的方法，幫助藥物穿透至腦、肝和腎等器官。近幾年來有研究發現二氧化鈦奈米粒子可以透過誘導內皮細胞滲漏 (Nanoparticle-induced endothelial leakiness ,NanoEL)，促進藥物的穿透及攝取。因此在本篇研究中，我們將嘗試把白藜蘆醇包覆於奈米載體後，改善白藜蘆醇之生物可利用率及攝取量，另外，我們想要探討酒精是否會透過上調galectin-3及抑制自噬作用去活化NLRP3發炎體，並且評估奈米載體包覆白藜蘆醇對酒精性肝臟損傷的保護作用機制。
在動物實驗中，C57BL/6公鼠以酒精液態飼料進行實驗，收集血清及肝臟組織進行生化分析、組織染色、qPCR和western blotting。在細胞實驗中，本研究使用小鼠正常肝臟細胞 (AML-12) 及人類肝竇內皮細胞 (HHSEC) 進行試驗，以細胞存活率來探討酒精對其引起的損傷，並使用western blotting分析酒精性肝臟發炎機制中相關蛋白質的表現量，此外我們亦會探討nRes對於酒精誘導的脂肪累積和發炎之保護機制；而我們將另外以Fe3O4載體及nRes處理HHSEC，並以免疫螢光染色觀察NanoEL的現象。
在餵食酒精液態飼料的小鼠血清中，其AST、ALT、及TCHO水平及肝臟中的TG含量顯著上升，由肝臟組織的H&E和masson trichrome染色結果圖可以看到顯著的脂肪變性及纖維化特徵，NLRP3發炎體及Galectin-3的蛋白表現量亦上升，證實在連續給予10週的酒精餵食後，老鼠的肝臟已經呈現酒精性肝炎的特徵。而給予奈米載體包覆白藜蘆醇後，有效地改善酒精造成的肝臟脂肪累積、發炎和纖維化。細胞實驗結果顯示，在酒精處理後，AML-12的細胞存活率顯著降低。我們將AML-12以不同濃度酒精處理24及48小時，結果顯示在處理24小時後，galectin-3、caspase-1和SREBP-1蛋白表現量隨著劑量上升而增加，且p62和LC3-II的蛋白表現量下降；另外在處理48小時後，NLRP3、ASC、caspase-1和SREBP-1的蛋白表現量隨著劑量增加而升高。另外，我們使用免疫螢光染色標記VE-cadherin以探討以Fe3O4載體處理的HHSEC是否會誘導NanoEL，結果顯示2 g/mL Fe3O4載體會誘導NanoEL現象，促進藥物穿透，並且可同時觀察到有包覆白藜蘆醇的Fe3O4載體 (6.5 g/mL nRes) 能有效回復因Fe3O4載體造成的NanoEL。
綜合本研究結果，我們可以證實酒精會造成肝臟的脂肪累積、發炎及纖維化，並造成相關蛋白的表現量改變，例如galectin-3、NLRP3和TGF-等蛋白，同時亦證實了奈米載體包覆白藜蘆醇透過NanoEL現象可以改善其本身的生物可利用率，以增進對於酒精性肝臟脂肪累積、發炎及纖維化的治療效果，未來奈米載體包覆白藜蘆醇將可以做為具有潛力來治療酒精性肝臟疾病的治療策略。

SUMMARY
Alcohol abuse and chronic alcohol consumption remain as a global public health problem. The excessive intake of alcohol will cause alcoholic liver disease (ALD). ALD is a major cause of liver-related mortality not only in developed but also in developing countries. Currently, some drugs such as corticosteroids was used to treat ALD. Corticosteroids were main drugs to treat severe alcoholic hepatitis, but it can associate with some risk and side effects such as infection. In this study, we investigated the new mechanisms of ALD and developed resveratrol-loaded nanoparticles as a new therapeutic strategy. We used standard alcoholic liver disease model to conduct our experiments. Also, we used AML-12 cell and HHSEC to explore the detailed mechanisms. The results showed the protein expression of galectin-3, NLRP3 were induced by ethanol and the expression of autophagy-related protein were inhibited by ethanol. The mRNA expression of keratin-8 and keratin-18 which were related to alcoholic hepatitis were significantly induced by ethanol. Furthermore, resveratrol-loaded nanoparticles could reverse ethanol-induced steatosis, inflammation and fibrosis including mRNA levels and protein levels. Taken together, our findings demonstrated that ethanol would regulate galectin-3-autophagy-NLRP3 inflammasome pathway to cause lipid accumulation and inflammation. The new mechanisms may be a new target to treat ALD. Otherwise, the treatment of resveratrol-loaded nanoparticles also could rescue those ethanol-induced damages by inhibiting galectin-3-NLRP3 inflammasome pathway. In the future, resveratrol-loaded nanoparticles could be a potential drug to treat ALD.

INTRODUCTION
Alcohol abuse and chronic alcohol consumption remain as a global public health problem. Alcoholic liver disease (ALD) caused by the excessive intake of alcohol. According to the degree of damage is divided into alcoholic fatty liver, steatohepatitis, liver fibrosis and cirrhosis, with subsequent risk of hepatocellular carcinoma. However, some of drugs used to treat ALD possess many side effects. Recent studies have showed that resveratrol (Res) could ameliorate alcoholic liver injury. Nevertheless, resveratrol has poor bioavailability, which hinders its immense potential. Nano-sized delivery systems may provide satisfactory drug permeability into many organs such as brain, liver and kidney. Recently, Tee et al showed that TiO2 nanoparticles have the potential to modulate endothelial permeability and promote drug uptake by inducing nanoparticle-induced endothelial leakiness (NanoEL). Therefore, we attempt to used resveratrol-loaded nanoparticles (nRes) for improving the bioavailability and uptake of resveratrol. In this study, we investigate whether alcohol activates NLRP3 inflammasome by upregulating galectin-3 and suppressing autophagy and evaluate the protective mechanisms of nRes against ALD.
MATERIALS AND METHODS
In vivo study, C57BL/6 male mice were treated with ethanol liquid diet alone or combined with Res or nRes. We fed mice with control liquid diet or ethanol liquid diet for 10 weeks. From the seventh week, we treated Res and nRes twice a week in drug treatment groups. The liver tissues and serum were collected for biochemical analysis, histological staining, qPCR and western blotting. These results were used to investigate the mechanisms of alcoholic liver injury and the protective effect of nRes. In vitro study, normal mouse hepatocytes (AML-12 cells) and human hepatic sinusoidal endothelial cells (HHSECs) were used to mimic liver organ exposure. When AML-12 cells were stimulated with ethanol, we used cell viability assay to investigate the damage that caused by ethanol. Then, we applied western blotting to explore the related protein expressions of the alcoholic liver inflammation mechanisms such as galectin-3 and NLRP3 inflammasome-related pathway. We also explore the protective mechanisms of nRes against ethanol-induced lipid accumulation and inflammation. When HHSECs were treated with Fe3O4 carriers and nRes, we used immunofluorescence staining of VE-cadherin to observe the NanoEL.
RESULTS AND DISCUSSION
In vivo study, ethanol significantly increased the relative liver weights over the 10 weeks treatment period. In addition, the mice treated ethanol liquid diet also significantly elevated serum AST, ALT and TCHO levels and hepatic TG contents. H&E staining and masson trichrome of liver tissues showed that significant feature of steatosis and liver fibrosis. The expression of NLRP3 inflammasome and galectin-3 proteins in ethanol liquid diet group were higher than control liquid diet group. The results of immunohistochemistry staining also showed that the protein expressions of NLRP3, galectin-3 and TGF- were increased in ethanol liquid diet group. The mRNA expression of keratin-8 and keratin-18 which were related to alcoholic hepatitis were significantly induced by ethanol. Moreover, administration of nRes effectively improved the lipid accumulation, inflammation and fibrosis which caused by ethanol and downregulated the expression of galectin-3 and NLRP3 inflammasome and promoted autophagy. In vitro study, the cell viability of AML-12 cells significantly decreased after the treatment of ethanol in a dose-dependent manner. Then, AML-12 cells were treated with ethanol for 24 and 48h. The results of western blotting showed that the protein expression of galectin-3, caspase-1 and SREBP-1 were induced and the expression of autophagy-related protein such as p62 and LC3-II were inhibited by ethanol for 24h. Otherwise, the protein expression of NLRP3, ASC, caspase-1 and SREBP-1 were also induced by ethanol for 48h. Then, we applied immunofluorescence staining to detect VE-cadherin for observing the NanoEL which induced by Fe3O4 carriers. Fe3O4 carriers (2 g/mL) could induce NanoEL to promote drug permeability. Interestingly, Fe3O4 carriers which carried resveratrol (6.5 g/mL nRes) could reverse Fe3O4 carriers-induced NanoEL.
CONCLUSION
Our findings demonstrated that ethanol would cause hepatic lipid accumulation, inflammation and fibrosis. The inflammation and fibrosis-related protein such as galectin-3, NLRP3 and TGF- would also induce by ethanol. We also confirmed the protective effect of resveratrol loaded nanoparticles against hepatic lipid accumulation, inflammation and fibrosis of alcoholic liver disease through NanoEL induced by Fe3O4 carriers to promote drug permeability. In the future, resveratrol loaded nanoparticles could be a potential protective strategy to treat alcoholic liver disease.

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