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Rheum Emodin Inhibits Enterovirus 71 Viral Replication and Affects the Host Cell Cycle Environment

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Rheum Emodin Inhibits Enterovirus 71 Viral Replication and Affects the Host Cell Cycle Environment Acta Pharmacologica Sinica (2017) 38: 392–401 © 2017 CPS and SIMM All rights reserved 1671-4083/17 www.nature.com/aps Original Article Rheum emodin inhibits enterovirus 71 viral replication and affects the host cell cycle environment Ting ZHONG1, 2, #, Li-ying ZHANG3, #, Zeng-yan WANG4, Yue WANG5, Feng-mei SONG6, Ya-hong ZHANG7, Jing-hua YU1, * 1Institute of Virology and AIDS Research, The First Hospital of Jilin University, Jilin University, Changchun 130000, China; 2Medicinal Chemistry, College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130000, China; 3Department of Biotechnology, College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130000, China; 4Department of Internal Medicine, The First Hospital of Jilin University, Jilin University, Changchun 130000, China; 5Chemistry of Traditional Chinese Medicine, College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130000, China; 6Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Changchun 130000, China; 7Key Laboratory of Natural Medicines and Immunotechnology of Henan Province, Henan University, Kaifeng 475004, China Abstract Human enterovirus 71 (EV71) is the primary causative agent of recent large-scale outbreaks of hand, foot, and mouth disease (HFMD) in Asia. Currently, there are no drugs available for the prevention and treatment of HFMD. In this study, we compared the anti-EV71 activities of three natural compounds, rheum emodin, artemisinin and astragaloside extracted from Chinese herbs Chinese rhubarb, Artemisia carvifolia and Astragalus, respectively, which have been traditionally used for the treatment and prevention of epidemic diseases. Human lung fibroblast cell line MRC5 was mock-infected or infected with EV71, and treated with drugs. The cytotoxicity of the drugs was detected with MTT assay. The cytopathic effects such as cell death and condensed nuclei were morphologically observed. The VP1-coding sequence required for EV71 genome replication was assayed with qRT-PCR. Viral protein expression was analyzed with Western blotting. Viral TCID50 was determined to evaluate EV71 virulence. Flow cytometry analysis of propidium iodide staining was performed to analyze the cell cycle distribution of MRC5 cells. Rheum emodin (29.6 µmol/L) effectively protected MRC5 cells from EV71-induced cytopathic effects, which resulted from the inhibiting viral replication: rheum emodin treatment decreased viral genomic levels by 5.34-fold, viral protein expression by less than 30-fold and EV71 virulence by 0.33107-fold. The fact that inhibition of rheum emodin on viral virulence was much stronger than its effects on genomic levels and viral protein expression suggested that rheum emodin inhibited viral maturation. Furthermore, rheum emodin treatment markedly diminished cell cycle arrest at S phase in MRC5 cells, which was induced by EV71 infection and favored the viral replication. In contrast, neither astragaloside (50 µmol/L) nor artemisinin (50 µmol/L) showed similar anti-EV71 activities. Among the three natural compounds tested, rheum emodin effectively suppressed EV71 viral replication, thus is a candidate anti-HFMD drug. Keywords: enterovirus 71; hand, foot, and mouth disease (HFMD); MRC5 cells; rheum emodin; astragaloside; astragaloside; viral replication; cell cycle arrest Acta Pharmacologica Sinica (2017) 38: 392–401; doi: 10.1038/aps.2016.110; published online 14 Nov 2016 Introduction and in severe cases, acute flaccid paralysis, pulmonary edema, Hand, Foot, and Mouth Disease (HFMD) is a febrile exanthem- myocarditis, encephalitis and even death[1, 2]. Recently, several atous disease that occurs in children <5 years of age. The clini- large outbreaks of HFMD have been reported in Asia. These cal signs include vesicles on the palmar and plantar surfaces include outbreaks in the Fuyang[3], Henan[4], Nanchang[5], of the hands and feet, buccal mucosa, tongue, and buttocks, Hubei[6], Jilin[1] and Taiwan of China, as well as in Japan, and Malaysia[7, 8]. Currently, there are no drugs available for the # prevention and treatment of HFMD. These authors contributed equally to this work. *To whom correspondence should be addressed. Human enterovirus 71 (EV71) is the causative agent for E-mail [email protected] HFMD outbreaks in Asia[1, 2, 5, 9]. In a previous study, we dem- Received 2016-07-06 Accepted 2016-09-02 onstrated that EV71 virus induces cell cycle arrest at S phase www.chinaphar.com Zhong T et al 393 to promote viral replication, while G0/G1 or G2/M synchroni- and incubated at 37 °C for 24 h. Virus-containing supernatant zation inhibits viral replication[10]. This indicates a possibility was serially diluted 10-fold and 100 µL was added per well for developing cell cycle-modifying agents (especially those in octuplicate. The cytopathic effects were observed once per that induce G0/G1 or G2/M arrest) as a novel strategy to treat day until the experimental endpoint was reached. The TCID50 HFMD. was determined by the Reed-Muench method[23], which is Natural products have played pivotal roles in the drug based on the assumption that 1×105 TCID50/mL will produce discovery and development process. It has been noted that 0.7×105 plaque forming units/mL (www.protocol-online.org/ natural products embody more ‘‘privileged structures’’[11] than biology-forums/posts/1664.html). purely synthetic chemical libraries and possess the charac- teristics and therapeutic effects of Chinese herbs[12]. Natural Infection product-based drug discovery research programs represent Cells were mock-infected or infected with EV71 at an MOI of 1 important avenues for drug development[13], including anti- for 2 h. Aafter 2 h of virus adsorption, cells were washed with viral drugs[14, 15]. For example, emodin (1,3,8-tri-hydroxy- PBS once and then fresh culture medium was added. 6-methylanthraquinone) is an active ingredient sourced from herbs belonging to genera Rheum, Polygonum, Rhamnus and Cell growth inhibition test Senna. Extracts from these herbs have been used for the treat- Inhibition of cell growth was determined by MTT (Sigma, St ment of epidemic-prone diseases[16]. Emodin has been shown Louis, MO, USA) assay. MRC5 cells (1.0×104 cells/well) were to inhibit the replication of severe acute respiratory syndrome seeded onto 96-well culture plates (Nunc, Roskilde, Denmark). (SARS) virus[17], hepatitis B (HBV)[18], and herpes simplex After a 24 h incubation, different concentrations of Rheum viruses (HSV)[19]. emodin (Rheu), Artemisinin (Arte) and Astragaloside (Astra), Artemisinin, a drug obtained from the plant Artemisia annua, which were purchased from the National Institute for the is recommended by the WHO for the treatment of infections, Control of Pharmaceutical and Biological Products (Beijing, such as drug-resistant Plasmodium falciparum strains, cerebral China), were added individually to the plates. Following malaria and malaria in children[20]. A major saponin of this incubation, cell growth was measured at 48 h by the addition herb, astragaloside, has been shown to possess anti-cancer, of 20 µL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium anti-fatigue, anti-coxsackie B virus, and anti-inflammatory bromide (MTT, 5 mg/mL) at 37 °C for 2 h; DMSO (150 µL) effects[21]. However, to date, its anti-EV71 activity has not been was added to dissolve the formazan crystals. Absorbance was well investigated. measured at 492 nm with an enzyme-linked immunosorbent In the present study, we aimed to elucidate the anti-EV71 assay plate (ELISA) reader (Bio-Rad, Hercules, CA, USA). The activity of the natural active components from Rheum emo- percentage of inhibition was calculated as follows: din, Astragaloside and Artemisinin. We observed that Rheum Inhibitory ratio (%)= emodin protects host cells against EV71 infection, decreases [A492(control)–A492(sample)]/[A492(control)–A492(blank)]×100%. viral genomic levels and viral protein expressions, and decreases EV71 virulence by intervening in the cell cycle envi- Cytopathic effect ronment that favors viral replication; however, Astragaloside For observing the cytopathic effects, cells were grown on a and Artemisinin did not show similar abilities. These results culture dish and infected by EV71 for 24 h. The morphologi- reinforce our model of the EV71 viral pathogenic mechanisms cal changes were observed and microscopic photographs were that require regulation of the cell cycle environment and sug- taken (Olympus, Tokyo, Japan). gest that Rheum emodin is a potential candidate for the treat- ment and prevention of HMDF disease. Immunofluorescence assay and Hoechst 33258 staining The nuclear stain Hoechst 33258 (Sigma, St Louis, MO, USA) Materials and methods was used to visualize nuclear changes by fluorescence micros- Viruses and cells copy. Briefly, MRC5 cells were plated onto 6-well plastic The Changchun077 strain of EV71 has been reported previ- culture dishes (4×105 cells/well) and infected with EV71 for ously[1]. This virus strain was propagated in African green 2 h; treated with drugs for 22 h; washed with PBS and fixed in monkey kidney cells (Vero). Vero (No CCL-81) and MRC5 3.7% formaldehyde for 1 h; washed with PBS and then stained (No CCL-171) were purchased from the ATCC (Manassas, VA, with 5 mg/L Hoechst 33258 for 30 min. Nuclear changes were USA) and were maintained in Dulbecco’s modified Eagle’s observed under a fluorescence microscope at an excitation medium (DMEM) (HyClone, Logan, UT, USA) supplemented wavelength of 350 nm
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