lignans and Influenza--Human

Eucommia ulmoides Oliver (Du-Zhong) is an ancient Chinese herbal remedy used for the treatment of various diseases. To date, the effects of its constituent lignans on influenza viruses remain to be elucidated. In the present study, a lignan glycoside was isolated and purified from Eucommia ulmoides Oliver. Its structures were identified via extensive spectroscopic analysis, and its antiviral and anti‑inflammatory activities, specifically against influenza viruses, were determined via a cytopathic effect (CPE) assay, plaque‑reduction assays, a progeny virus yield reduction assay, reverse transcription‑quantitative polymerase chain reaction analysis and a Luminex assay. Additionally, western blot analysis was performed to investigate the underlying mechanisms of its effects against influenza viruses. The chemical and spectroscopic methods determined the structure of lignan glycoside to be (+)‑pinoresinol‑O‑β‑D‑glucopyranoside. The CPE assay showed that (+)‑pinoresinol‑O‑β‑D‑glucopyranoside exerted inhibitory activities with 50% inhibition concentration values of 408.81±5.24 and 176.24±4.41 µg/ml against the influenza A/PR/8/34 (H1N1) and A/Guangzhou/GIRD07/09 (H1N1) strains, respectively. Its antiviral properties were confirmed by plaque reduction and progeny virus yield reduction assays. Additional mechanistic analyses indicated that the anti‑H1N1 virus‑induced effects of (+)‑pinoresinol‑O-β‑D-glucopyranoside were likely due to inactivation of the nuclear factor‑κB, p38 mitogen‑activated protein kinase and AKT signaling pathways. Furthermore, (+)‑pinoresinol‑O‑β‑D‑glucopyranoside exhibited pronounced inhibitory effects on the expression of influenza H1N1 virus‑induced pro‑inflammatory mediators, including tumor necrosis factor‑α, interleukin (IL)‑6, IL‑8 and monocyte chemoattractant protein 1. The data obtained suggest that (+)‑pinoresinol‑O‑β‑D-glucopyranoside may be a candidate drug for treating influenza H1N1 virus infection.

Topics: A549 Cells; Animals; Anti-Inflammatory Agents; Antiviral Agents; Cell Line; Cell Line, Tumor; Dogs; Eucommiaceae; Furans; Glycosides; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Lignans; Madin Darby Canine Kidney Cells; Orthomyxoviridae Infections; Plant Extracts; Signal Transduction

Honokiol, a natural polyphenol, which was reported to have satisfactory influenza neuraminidase (NA) inhibitory activity, was structurally modified. Twenty-three compounds were synthesized and the

Topics: Antiviral Agents; Biphenyl Compounds; Drug Design; Humans; Influenza, Human; Lignans; Molecular Structure; Neuraminidase

Influenza virus infections are a major public health concern worldwide. Conventional treatments against the disease are designed to target viral proteins. However, the emergence of viral variants carrying drug-resistant mutations can outpace the development of pathogen-targeting antivirals. Diphyllin and bafilomycin are potent vacuolar ATPase (V-ATPase) inhibitors previously shown to have broad-spectrum antiviral activity. However, their poor water solubility and potential off-target effect limit their clinical application.. In this study, we report that nanoparticle encapsulation of diphyllin and bafilomycin improves the drugs' anti-influenza applicability.. Using PEG-PLGA diblock copolymers, sub-200 nm diphyllin and bafilomycin nanoparticles were prepared, with encapsulation efficiency of 42% and 100%, respectively. The drug-loaded nanoparticles have sustained drug release kinetics beyond 72 hours and facilitate intracellular drug delivery to two different influenza virus-permissive cell lines. As compared to free drugs, the nanoparticulate V-ATPase inhibitors exhibited lower cytotoxicity and greater. These results demonstrate the potential of the nanoparticulate V-ATPase inhibitors for host-targeted treatment against influenza.

Topics: Animals; Antiviral Agents; Benzodioxoles; Cell Line; Dogs; Drug Liberation; Enzyme Inhibitors; Humans; Influenza, Human; Inhibitory Concentration 50; Kinetics; Lignans; Macrolides; Mice; Nanoparticles; Orthomyxoviridae; Orthomyxoviridae Infections; Vacuolar Proton-Translocating ATPases; Viral Proteins; Virus Replication

In 2009, swine flu (H1N1) had spread significantly to levels that threatened pandemic influenza. There have been many treatments that have arisen for patients since the WHO first reported the disease. Although some progress in controlling influenza has taken place during the last few years, the disease is not yet under control. The development of new and less expensive anti-influenza drugs is still needed. Here, we show that sesamin from the seeds of the Thai medicinal plant Sesamum indicum has anti-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) induced by 2009 influenza virus type A H1N1. In this study, the combinatorial screening method combined with the computational approach was applied to investigate the new molecular binding structures of sesamin against the 2009 influenza virus type A H1N1 (p09N1) crystallized structure. Experimental methods were applied to propose the mechanisms of sesamin against cytokine production from H1N1-induced human PBMC model. The molecular dynamics simulation of sesamin binding with the p09N1 crystallized structure showed new molecular binding structures at ARG118, ILE222, ARG224, and TYR406, and it has been proposed that sesamin could potentially be used to produce anti-H1N1 compounds. Furthermore, the mechanisms of sesamin against cytokine production from influenza type A H1N1-induced PBMCs by ELISA and signaling transduction showed that sesamin exhibits the ability to inhibit proinflammatory cytokines, IL-1β and TNF-α, and to enhance the activity of the immune cell cytokine IL-2 via downregulating the phosphorylated JNK, p38, and ERK1/2 MAPK signaling pathways. This information might very well be useful in the prevention and treatment of immune-induced inflammatory disorders.

Topics: Animals; Crystallography, X-Ray; Dioxoles; Humans; Inflammation; Influenza A Virus, H1N1 Subtype; Influenza, Human; Interleukin-1beta; Interleukin-2; Leukocytes, Mononuclear; Lignans; Models, Molecular; Molecular Dynamics Simulation; Orthomyxoviridae Infections; Signal Transduction; Swine; Swine Diseases; Tumor Necrosis Factor-alpha

An influenza pandemic poses a serious threat to humans and animals. Conventional treatments against influenza include two classes of pathogen-targeting antivirals: M2 ion channel blockers (such as amantadine) and neuraminidase inhibitors (such as oseltamivir). Examination of the mechanism of influenza viral infection has shown that endosomal acidification plays a major role in facilitating the fusion between viral and endosomal membranes. This pathway has led to investigations on vacuolar ATPase (v-ATPase) activity, whose role as a regulating factor on influenza virus replication has been verified in extensive genome-wide screenings. Blocking v-ATPase activity thus presents the opportunity to interfere with influenza viral infection by preventing the pH-dependent membrane fusion between endosomes and virions. This study aims to apply diphyllin, a natural compound shown to be as a novel v-ATPase inhibitor, as a potential antiviral for various influenza virus strains using cell-based assays. The results show that diphyllin alters cellular susceptibility to influenza viruses through the inhibition of endosomal acidification, thus interfering with downstream virus replication, including that of known drug-resistant strains. In addition, combinatorial treatment of the host-targeting diphyllin with pathogen-targeting therapeutics (oseltamivir and amantadine) demonstrates enhanced antiviral effects and cell protection in vitro.

Topics: Amantadine; Animals; Antiviral Agents; Benzodioxoles; Drug Therapy, Combination; Drugs, Chinese Herbal; Endosomes; Enzyme Inhibitors; Humans; Influenza, Human; Lignans; Magnoliopsida; Membrane Fusion; Orthomyxoviridae; Oseltamivir; Vacuolar Proton-Translocating ATPases; Virus Replication