背景:乙型肝炎病毒(HBV)感染仍然是全球主要的健康负担,由于并发症的风险增加,如肝硬化和肝细胞癌。新型抗HBV药物是至关重要的。我们先前的研究表明,艾蒿精油(AAEO)显着抑制HBVDNA的复制,尤其是在体外乙型肝炎抗原的分泌。
目的:本研究的目的是制备负载AAEO的纳米结构脂质载体(AAEO-NLC),用于将AAEO递送至肝脏,在鸭HBV(DHBV)模型中研究了AAEO-NLCs对HBV的治疗益处,并探讨了其潜在机制。
方法:采用热均质法和超声法制备AAEO-NLC。DHBV感染的鸭子用AAEO(4mg/kg)治疗,AAEO-NLC(0.8、4和20mg/kg的AAEO),和拉米夫定(20mg/kg)15天。通过定量实时PCR测量血清和肝脏中的DHBVDNA水平。口服AAEO-NLC和AAEO混悬液后,在大鼠中进行药代动力学和肝脏分布。通过网络药理学和分子对接研究了AAEO潜在的抗病毒机制和活性化合物。
结果:AAEO-NLCs以剂量依赖性方式显着抑制DHBVDNA的复制,并在DHBV感染的鸭子停药后表现出低病毒学反弹。此外,AAEO-NLC导致比AAEO悬浮液更显著的病毒DNA水平降低。对大鼠的药代动力学和肝脏分布的进一步研究证实,NLCs改善了口服生物利用度并增加了AAEO的肝脏暴露。通过网络药理学探索的AAEO抗HBV的潜在机制与免疫应答相关的信号通路有关,如肿瘤坏死因子,核因子κB,和鞘脂信号通路。此外,总共获得了16个潜在目标,包括前列腺素-内过氧化物合酶-2(PTGS2),caspase-3孕激素受体,等。化合物-靶标对接结果证实了AAEO的四种活性化合物与PTGS2的活性位点具有强的结合相互作用。
结论:AAEO-NLCs显示出有效的抗HBV活性,改善了AAEO的口服生物利用度和肝脏暴露。因此,它可能是治疗HBV感染的潜在治疗策略。
BACKGROUND: Hepatitis B virus (HBV) infection remains a major global health burden, due to the increasing risk of complications, such as cirrhosis and hepatocellular carcinoma. Novel anti-HBV agents are critical required. Our previous
study suggested that Artemisia argyi essential oil (AAEO) significantly inhibited the replication of HBV DNA and especially the secretion of hepatitis B antigen in vitro.
OBJECTIVE: The aim of this
study was to prepare AAEO loaded nanostructured lipid carriers (AAEO-NLCs) for the delivery of AAEO to the liver, investigated the therapeutic benefits of AAEO-NLCs against HBV in a duck HBV (DHBV) model and explored its potential mechanism.
METHODS: AAEO-NLCs were prepared by hot homogenization and ultrasonication method. The DHBV-infected ducks were treated with AAEO (4 mg/kg), AAEO-NLCs (0.8, 4, and 20 mg/kg of AAEO), and lamivudine (20 mg/kg) for 15 days. The DHBV DNA levels in the serum and liver were measured by quantitative Real-Time PCR. Pharmacokinetics and liver distribution were performed in rats after oral administration of AAEO-NLCs and AAEO suspension. The potential antiviral mechanism and active compounds of AAEO were investigated by network pharmacology and molecular docking.
RESULTS: AAEO-NLCs markedly inhibited the replication of DHBV DNA in a dose-dependent manner and displayed a low virologic rebound following withdrawal the treatment in DHBV-infected ducks. Moreover, AAEO-NLCs led to a more pronounced reduction in viral DNA levels than AAEO suspension. Further investigations of pharmacokinetics and liver distribution in rats confirmed that NLCs improved the oral bioavailability and increased the liver exposure of AAEO. The potential mechanisms of AAEO against HBV explored by network pharmacology were associated with signaling pathways related to immune response, such as tumor necrosis factor, nuclear factor kappa B, and sphingolipid signaling pathways. Furthermore, a total of 16 potential targets were obtained, including prostaglandin-endoperoxide synthase-2 (PTGS2), caspase-3, progesterone receptor, etc. Compound-target docking results confirmed that four active compounds of AAEO had strong binding interactions with the active sites of PTGS2.
CONCLUSIONS: AAEO-NLCs displayed potent anti-HBV activity with improved oral bioavailability and liver exposure of AAEO. Thus, it may be a potential therapeutic strategy for the treatment of HBV infection.