PMID- 31958713 OWN - NLM STAT- MEDLINE DCOM- 20200507 LR - 20200507 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 67 DP - 2020 Feb TI - Flavonoids from Houttuynia cordata attenuate H1N1-induced acute lung injury in mice via inhibition of influenza virus and Toll-like receptor signalling. PG - 153150 LID - S0944-7113(19)30466-0 [pii] LID - 10.1016/j.phymed.2019.153150 [doi] AB - BACKGROUND: Influenza virus is one of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. Houttuynia cordata is a traditionally used medicinal plant for the treatment of pneumonia. Flavonoids are one of the major bioactive constituents of Houttuynia cordata. PURPOSE: This study was designed to investigate the therapeutic effect and mechanism of flavonoid glycosides from H. cordata on influenza A virus (IAV)-induced acute lung injury (ALI) in mice. METHODS: Flavonoids from H. cordata (HCF) were extracted from H. cordata and identified by high-performance liquid chromatography. Mice were infected intranasally with influenza virus H1N1 (A/FM/1/47). HCF (50, 100, or 200 mg/kg) or Ribavirin (100 mg/kg, the positive control) were administered intragastrically. Survival rates, life spans, weight losses, lung indexes, histological changes, inflammatory infiltration, and inflammatory markers in the lungs were measured. Lung virus titers and neuraminidase (NA) activities were detected. The expression of Toll-like receptors (TLRs) and levels of NF-kappaB p65 phosphorylation (NF-kappaB p65(p)) in the lungs were analysed. The effects of HCF on viral replication and TLR signalling were further evaluated in cells. RESULTS: HCF contained 78.5% flavonoid glycosides. The contents of rutin, hyperin, isoquercitrin, and quercitrin in HCF were 8.8%, 26.7%, 9.9% and 31.7%. HCF (50, 100 and 200 mg/kg) increased the survival rate and life span of mice infected with the lethal H1N1 virus. In H1N1-induced ALI, mice treated with HCF (50, 100 and 200 mg/kg) showed lesser weight loss and lower lung index than the model group. The lungs of HCF-treated ALI mice presented more intact lung microstructural morphology, milder inflammatory infiltration, and lower levels of monocyte chemotactic protein 1 (MCP-1), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and malondialdehyde (MDA) than in the model group. Further investigation revealed that HCF exerted antiviral and TLR-inhibitory effects in vivo and in vitro. HCF (50, 100 and 200 mg/kg) reduced lung H1N1 virus titers and inhibited viral NA activity in mice. HCF (100 and 200 mg/kg) elevated the levels of interferon-beta in lungs. HCF also decreased the expression of TLR3/4/7 and level of NF-kappaB p65(p) in lung tissues. In vitro experiments showed that HCF (50, 100 and 200 mug/ml) significantly inhibited viral proliferation and suppressed NA activity. In RAW 264.7 cells, TLR3, TLR4, and TLR7 agonist-stimulated cytokine secretion, NF-kappaB p65 phosphorylation, and nuclear translocation were constrained by HCF treatment. Furthermore, among the four major flavonoid glycosides in HCF, hyperin and quercitrin inhibited both viral replication and TLR signalling in cells. CONCLUSION: HCF significantly alleviated H1N1-induced ALI in mice, which were associated with its dual antiviral and anti-inflammatory effects via inhibiting influenzal NA activity and TLR signalling. among the four major flavonoid glycosides in HCF, hyperin and quercitrin played key roles in the therapeutic effect of HCF. CI - Copyright (c) 2019 Elsevier GmbH. All rights reserved. FAU - Ling, Li-Jun AU - Ling LJ AD - Department of Pharmacognosy, School of Pharmacy, Fudan University, Shanghai 201203, China. FAU - Lu, Yan AU - Lu Y AD - Department of Pharmacognosy, School of Pharmacy, Fudan University, Shanghai 201203, China. FAU - Zhang, Yun-Yi AU - Zhang YY AD - Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. FAU - Zhu, Hai-Yan AU - Zhu HY AD - Department of Microbiological and Biochemical Pharmacy, School of Pharmacy, Fudan University, Shanghai 201203, China. FAU - Tu, Peng AU - Tu P AD - Department of Pharmacognosy, School of Pharmacy, Fudan University, Shanghai 201203, China. FAU - Li, Hong AU - Li H AD - Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: lxzhang@shmu.edu.cn. FAU - Chen, Dao-Feng AU - Chen DF AD - Department of Pharmacognosy, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: dfchen@shmu.edu.cn. LA - eng PT - Journal Article DEP - 20191216 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (Antiviral Agents) RN - 0 (Flavonoids) RN - 0 (Toll-Like Receptors) RN - 0 (Transcription Factor RelA) RN - EC 3.2.1.18 (Neuraminidase) SB - IM MH - Acute Lung Injury/*drug therapy/metabolism/*virology MH - Animals MH - Antiviral Agents/chemistry/*pharmacology MH - Dogs MH - Flavonoids/chemistry/*pharmacology MH - Houttuynia/*chemistry MH - Influenza A Virus, H1N1 Subtype/drug effects/*pathogenicity/physiology MH - Madin Darby Canine Kidney Cells MH - Mice, Inbred BALB C MH - Neuraminidase/metabolism MH - Orthomyxoviridae Infections/drug therapy/metabolism MH - Toll-Like Receptors/metabolism MH - Transcription Factor RelA/metabolism MH - Virus Replication/drug effects OTO - NOTNLM OT - Acute lung injury OT - Antiviral activity OT - Flavonoid glycosides OT - Houttuynia cordata OT - Influenza A virus OT - TLRs signalling COIS- Conflict of interest The authors have declared no conflict of interest. EDAT- 2020/01/21 06:00 MHDA- 2020/05/08 06:00 CRDT- 2020/01/21 06:00 PHST- 2019/08/05 00:00 [received] PHST- 2019/12/03 00:00 [revised] PHST- 2019/12/11 00:00 [accepted] PHST- 2020/01/21 06:00 [pubmed] PHST- 2020/05/08 06:00 [medline] PHST- 2020/01/21 06:00 [entrez] AID - S0944-7113(19)30466-0 [pii] AID - 10.1016/j.phymed.2019.153150 [doi] PST - ppublish SO - Phytomedicine. 2020 Feb;67:153150. doi: 10.1016/j.phymed.2019.153150. Epub 2019 Dec 16.