全世界超過4億人口感染B型肝炎病毒，大約20％的受感染的病人會導致慢性肝炎、肝硬化以及肝癌。在臨床上，治療慢性肝炎患者的藥物主要為alpha干擾素(INF-□)以及病毒反轉錄脢抑制劑-類核苷酸藥物（如3TC、adefovir、entecavir），但是病人對藥物的低反應性以及抗藥性突變株的產生是目前治療B型肝炎上最大的瓶頸。苧麻(Boehmeria nivea (L.) Gaudich)在大陸以及台灣長久以來被用來作為利尿、退熱、保肝的治療用途。在本篇研究，苧麻根水萃物（BNE）被用來研究其抗B型肝炎病毒的功效以及其抗病毒作用的機制探討。
在in vivo HepG2 2.2.15細胞研究結果顯示，100 □g/ml BNE能顯著的抑制HBeAg以及HBV virion分泌到組織培養液，但HBsAg的分泌則不受影響。在BNE不同劑量處理下，HBeAg的減少和抑制HBV DNA的分泌有關聯性。此外，BNE抗HBV的效應並非是由於其對細胞本身的毒性或是抑制病毒DNA的複製以及RNA的表現。在in vitro動物實驗，BNE也能有效的抑制HBV病毒血免疫缺陷鼠HBsAg以及HBV DNA的分泌但並不影響能產生病毒的腫瘤細胞生長，顯示BNE的潛在抗B型肝炎病毒的能力。
在BNE抗病毒機制的研究中，病毒核蛋白鞘(nucleocapsid)的形成以及病毒外套膜蛋白(envelope proteins)包覆的過程並不受到BNE的影響；然而，病毒核蛋白(core)和外套膜蛋白伴隨其包裹內含的HBV DNA都被觀察到在細胞中有累積的現象。病毒外套膜蛋白正確的折疊及組合需要透過宿主保護子(chaperone)蛋白的幫忙。在之前研究報導指出在HBV morphogenesis過程中病毒large-envelope protein需要在內質網進行translocation，而內質網內保護子78 kDa葡萄糖調控蛋白(GRP78)可以和large-envelope protein preS1 domain結合並幫助其正確折疊。為了要研究BNE的作用標靶，分析內質網中相關的保護子是否受到BNE的影響。實驗結果顯示GRP94以及calnexin皆不受BNE的影響，但GRP78卻受到BNE的抑制。受到抑制的GRP78對病毒顆粒分泌的影響其原因可能造成以下兩種反應：(1)無法幫助large-envelope protein正確的折疊，導致病毒外套膜蛋白包覆過程受到影響；(2)累積的large-envelope protein無法藉由引起內質網逆境反應增加middle-和small-envelope protein的表現，來維持適當的外套膜蛋白比例來增加病毒顆粒的分泌。此外，在BNE處理下再同時加入可刺激內質網逆境反應之促進劑thapsigargin以增加細胞內GRP78的總量時，能夠抵消BNE抑制HBV病毒顆粒分泌的能力，更進一步證實BNE抗HBV的機制是透過降低胞內GRP78的量。BNE抑制HBV分泌是可逆的；將BNE聯合3TC處理HepG2 2.2.15細胞時，有增加抗病毒的效果，顯示BNE以不同於類核苷酸藥物的作用機制能結合其他抗HBV的藥物用於治療B型肝炎。總而言之，BNE抗HBV的能力在體外以及體內模式都受到一致性的結果，BNE有潛力被用來發展成新一代抗HBV的藥物。

Hepatitis B virus (HBV) has infected more than 400 million people worldwide. About 20% of patients infected with HBV may lead to chronic hepatitis, liver cirrhosis, and hepatocarcinoma. Chronic hepatitis type-B patients are clinically treated with interferon alpha (INF-□) and nucleoside analogue such as lamivudine (3TC), adefovir or entecavir, which are analogues of reverse-transcriptase inhibitors; however, low responsiveness and drug-resistant mutant are major problems in treatment with chronic hepatitis B. Boehmeria nivea (B. nivea) has been distributed and used therapeutically in China and Taiwan for diuretic, antipyretic, and hepatoprotective purposes. In this thesis, the Chinese herbal medicine, the root extract of B. nivea (BNE) was studied for its anti-human HBV effects and its mechanism of action mode.
In HepG2 2.2.15 cells, HBeAg and particle-associated HBV DNA secretion into supernatant were significantly inhibited by BNE at a dose of 100 μg/mL, whereas the HBsAg was not inhibited. With different doses of BNE, the reduced HbeAg was correlated with the inhibition of HBV DNA. The anti-HBV effect of BNE was not caused by its cytotoxicity to cells or inhibition of viral DNA replication and RNA expression. In an in vivo animal experiment, BNE also showed a potential anti-HBV activity in HBV-viremia SCID mice model. BNE was effective to inhibit the production of HBsAg and HBV DNA, while virus-producing tumor growth was not affected.
Although, both nucleocapsid formation and envelopment by viral surface proteins were not altered by BNE; however, viral core and large-surface proteins accompanied with their encapsidated viral DNA were observed to accumulate within the cells. The proper folding and assembly of viral surface proteins are mediated by host chaperones. It has been reported that viral large- but not small- and middle-surface protein is required for the translocation process in endoplasmic reticulum (ER) during HBV morphogenesis and an ER luminal chaperone 78 kDa glucose-regulated protein (GRP78) bound to preS1 domain of large-surface protein to assist in proper folding. For investigating the target site of BNE, ER-related chaperone proteins were assessed. The ER chaperones such as GRP78, 94 kDa glucose-regulated protein (GRP94) and calnexin were not induced by BNE, BNE specifically decreased the intracellular GRP78 protein amounts. The possible mechanism of blockage of virions secretion by reduced GRP78 might be resulted from (1) mis-folded large-surface protein leading to failure of assembly of virus particle (2) failure to induce the ER stress response by accumulated large-surface protein, which turns to activate the synthesis of middle- and small-surface proteins, GRP78 and GRP94 in assistance of virions envelopment. Furthermore, the antiviral ability of BNE was observed reversible and the HBV DNA was restored by thapsigargin. By combining BNE and 3TC, it revealed an apparently additive anti-HBV effect, suggesting that BNE exploited different anti-HBV action mode from nucleoside analogues could combine other drugs for chronic hepatitis B therapy. In conclusion, the anti-HBV ability of BNE was evaluated and validated in in vitro and in vivo assay systems, and BNE has a potential to be developed as an anti-HBV drug.

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