Luteolin-7-O-Glucoside Present in Lettuce Extracts Inhibits Hepatitis B Surface Antigen Production and Viral Replication by Human Hepatoma Cells in Vitro

Abstract

Hepatitis B virus (HBV) infection is endemic in Asia and chronic hepatitis B (CHB) is a major public health issue worldwide. Current treatment strategies for CHB are not satisfactory as they induce a low rate of hepatitis B surface antigen (HBsAg) loss. Extracts were prepared from lettuce hydroponically cultivated in solutions containing glycine or nitrate as nitrogen sources. The lettuce extracts exerted potent anti-HBV effects in HepG2 cell lines in vitro, including significant HBsAg inhibition, HBV replication and transcription inhibition, without exerting cytotoxic effects. When used in combination interferon-alpha 2b (IFNα-2b) or lamivudine (3TC), the lettuce extracts synergistically inhibited HBsAg expression and HBV replication. By using differential metabolomics analysis, Luteolin-7-O-glucoside was identified and confirmed as a functional component of the lettuce extracts and exhibited similar anti-HBV activity as the lettuce extracts in vitro. The inhibition rate on HBsAg was up to 77.4%. Moreover, both the lettuce extracts and luteolin-7-O-glucoside functioned as organic antioxidants and, significantly attenuated HBV-induced intracellular reactive oxygen species (ROS) accumulation. Luteolin-7-O-glucoside also normalized ROS-induced mitochondrial membrane potential damage, which suggests luteolin-7-O-glucoside inhibits HBsAg and HBV replication via a mechanism involving the mitochondria. Our findings suggest luteolin-7-O-glucoside may have potential value for clinical application in CHB and may enhance HBsAg and HBV clearance when used as a combination therapy.

HIF‐1α/VEGF signaling‐mediated epithelial–mesenchymal transition and angiogenesis is critically involved in anti‐metastasis effect of luteolin in melanoma cells

“…Luteolin (3′, 4′, 5, 7‐terahydroxyflavone) is a common effective dietary flavonoid that is present in fruits, vegetables, and medicinal herbs (Liu, Xu, Yan, Cheng, & Liu, ; Song et al, ). Furthermore, accumulating evidences have suggested that luteolin possesses multiple pharmacological activities such as anti‐inflammation, anti‐hypertension, antioxidant, and antitumor, which are also supposed to be the basis of these biological properties (Aziz, Kim, & Cho, ; Cui et al, ). Previous studies indicate that luteolin suppress cancer cell growth through multiple mechanisms including promoting cancer cell apoptosis and cell cycle arrest, inhibiting cell proliferation and tumor growth, improving drug resistance, and mitigating invasiveness and metastasis of cancer cells (Cook, Liang, Besch‐Williford, & Hyder, ; Wang et al, ).…”

An Overview of Hepatitis B Virus Surface Antigen Secretion Inhibitors

“…Active compound, Luteolin-7- O -glucoside, extracted from leafy vegetable lettuce ( Latuca satica L. ) has been shown to significantly reduce HBsAg production (>82%; Cui et al, 2017 ). The plant extract had no cellular toxicities at lower concentrations.…”

“…The plant extract had no cellular toxicities at lower concentrations. The viral RNA is a biomarker for activity of HBV transcription ( Cui et al, 2017 ). Accordingly, the viral RNA was significantly reduced (43.9%), which was consistent with reduced HBV replication ( Cui et al, 2017 ).…”

“…The viral RNA is a biomarker for activity of HBV transcription ( Cui et al, 2017 ). Accordingly, the viral RNA was significantly reduced (43.9%), which was consistent with reduced HBV replication ( Cui et al, 2017 ). Inoculation of Luteolin-7- O -glucoside along with 3TC or IFN-α has been shown to have synergistic anti-HBsAg production effects.…”

Ebb-and-flow Subirrigation Strategies Increase Biomass and Nutrient Contents and Reduce Nitrate Levels in Lettuce

“…Lettuce is a significant source of many nutrients and has been reported to exert antioxidant (Yang et al, 2017), antihepatitis B virus (Cui et al, 2017), anti-inflammatory (Pepe et al, 2015), and antidiabetic (Cheng et al, 2014) effects. However, leafy vegetables, such as spinach and lettuce, represent significant sources of nitrate in the human diet, providing 40% to 92% of the average daily intake of nitrate and its metabolite nitrite (14% to 43% of daily dietary intake) (Liu et al, 2014;Qadir et al, 2017).…”