Corydaline inhibits enterovirus 71 replication by regulating COX-2 expression

Enterovirus 71 (EV71) is a huge threat to the worldwide public health and there is no approved antiviral drug for EV71-induced disease therapy. Corydaline exists antiallergic and antinociceptive activities, but the anti-EV71 activity of corydaline is still not reported. In this study, corydaline could suppress the expression of viral structural and non-structural proteins. Furthermore, corydaline inhibits EV71 replication by suppressing the COX-2 expression and the phosphorylation of JNK MAPK and P38 MAPK but not ERK MAPK in vitro. Based on these findings, corydaline could be a potential lead or supplement for the development of new anti-EV71 agents in the future.     

Curcumin inhibits the replication of enterovirus 71 in vitro

Human enterovirus 71 (EV71) is the main causative pathogen of hand, foot, and mouth disease (HFMD) in children. The epidemic of HFMD has been a public health problem in Asia-Pacific region for decades, and no vaccine and effective antiviral medicine are available. Curcumin has been used as a traditional medicine for centuries to treat a diversity of disorders including viral infections. In this study, we demonstrated that curcumin showed potent antiviral effect again EV71. In Vero cells infected with EV71, the addition of curcumin significantly suppressed the synthesis of viral RNA, the expression of viral protein, and the overall production of viral progeny. Similar with the previous reports, curcumin reduced the production of ROS induced by viral infection. However, the antioxidant property of curcumin did not contribute to its antiviral activity, since N-acetyl-l-cysteine, the potent antioxidant failed to suppress viral replication. This study also showed that extracellular signal-regulated kinase (ERK) was activated by either viral infection or curcumin treatment, but the activated ERK did not interfere with the antiviral effect of curcumin, indicating ERK is not involved in the antiviral mechanism of curcumin. Unlike the previous reports that curcumin inhibited protein degradation through ubiquitin–proteasome system (UPS), we found that curcumin had no impact on UPS in control cells. However, curcumin did reduce the activity of proteasomes which was increased by viral infection. In addition, the accumulation of the short-lived proteins, p53 and p21, was increased by the treatment of curcumin in EV71-infected cells. We further probed the antiviral mechanism of curcumin by examining the expression of GBF1 and PI4KB, both of which are required for the formation of viral replication complex. We found that curcumin significantly reduced the level of both proteins. Moreover, the decreased expression of either GBF1 or PI4KB by the application of siRNAs was sufficient to suppress viral replication. We also demonstrated that curcumin showed anti-apoptotic activity at the early stage of viral infection. The results of this study provide solid evidence that curcumin has potent anti-EV71 activity. Whether or not the down-regulated GBF1 and PI4KB by curcumin contribute to its antiviral effect needs further studies.KEY WORDS: Curcumin, Enterovirus 71, Viral replication, GBF1, PI4KB, Ubiquitin–proteasome system, ApoptosisAbbreviations: CVB, coxsackieviurs B; DCFH-DA, dichloro-dihydro-fluorescein diacetate; ERK, extracellular signal-regulated kinase; EV71, enterovirus 71; GBF1, Golgi brefeldin A resistant guanine nucleotide exchange factor 1; GEF, guanine nucleotide exchange factor; HBV, hepatitis B virus; HCV, hepatitis C virus; HFMD, hand, foot, and mouth disease; HIV, human immunodeficiency virus; HPV, human papillomavirus; NAC, N-acetyl-l-cysteine; PARP-1, poly(ADP-ribose) polymerase; PGC-1α, peroxisome proliferator-activated receptor-gamma co-activator 1 alpha; p.i., post-infection; PI4KB, phosphatidylinositol 4-kinase class III catalytic subunit β; PI4P, phosphatidylinositol 4-phosphate; ROS, reactive oxygen species; siRNA, small interfering RNA; SLLVY-AMC, succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin; UPS, ubiquitin–proteasome system     

肠道病毒71型与宿主相互作用

肠道病毒71型(enterovirus 71,EV71)是引起手足口病的主要病原体之一.EV71传播广泛,感染后可引发中枢神经系统疾病,并导致重症手足口病,给公共卫生安全带来极大挑战.EV71的致病机制与病毒和宿主间的相互作用关系密切,涉及EV71病毒复制、微RNA等多个环节.此文就近年来这些方面的研究进展做一综述.     

Prevention of human enterovirus 71 infection by kappa carrageenan

Enterovirus 71 (EV 71), the newest member of Enteroviridae, is notorious for its etiological role in epidemics of the hand-foot-and-mouth disease, particularly in association with fatal neurological complications in young children. Searching for new and more effective agents against EV 71 infections has never relented as corresponding vaccines or antiviral drugs remain unavailable. Sulfated polysaccharides from seaweed are known to possess a broad range of biological activities across anti-virus, anti-tumor, immunomodulation, anti-coagulation, etc. In this study, we report kappa carrageenan also has a strong and effective anti-EV 71 activity able to reduce plaque formation, prevent viral replication before or during viral adsorption, as well as inhibit EV 71-induced apoptosis. In virus binding assay, kappa carrageenan was shown able to bind EV 71 firmly, forming carrageenan-viruses complexes, whereby the virus-receptor interaction is likely disrupted. Added together, kappa carrageenan may be an ideal candidate worthwhile to develop into anti-EV 71 agents.     

肠道病毒71型疫苗研究进展

 肠道病毒71型（enterovirus 71,EV71）是引起手足口病（hand, foot and mouth disease,HFMD）的主要病原体之一,HFMD可并发神经系统疾病,甚至导致死亡。对于EV71感染,目前尚无有效的治疗药物和措施,因此研制有效的疫苗是控制EV71流行的最佳方法。此文就EV71疫苗的研究进展进行综述。     

肠道病毒71型的生物学特征及研究进展

近年来,肠道病毒71型(enterovirus 71,EV71)的流行在亚太地区呈逐渐上升趋势.EV71导致的手足口病已引起社会各界广泛关注,并成为医学预防和基础科研的挑战.此文就EV71的生物学特性、流行病学、致病机制、临床和实验室诊断、预防及治疗等方面的研究进展作一综述.     

肠道病毒71型的研究进展

肠道病毒71型(enterovirus 71,EV71)是引起手足口病(hand,foot and mouth disease,HFMD)的主要病原体之一,HFMD可并发严重神经系统疾病,甚至导致死亡.事实上,EV71一直被视为继脊髓灰质炎病毒消灭后最重要的嗜神经病毒.此文就EV71感染的易感因素以及疫苗的研究进展进行综述,从而为EV71感染的防控指明方向.     

肠道病毒71型疫苗的研究进展

肠道病毒71型(enterovirus 71,EV71)是近年来我国流行的手足口病的主要病原体之一,并且由其感染引发的重症和死亡病例的比例较大.目前尚无治疗手足口病的特效药物.我国大陆有3家单位完成了EV71灭活疫苗的Ⅲ期临床试验,国家食品药品监督管理总局批准了其中两家单位的灭活疫苗.目前,减毒活疫苗、病毒样颗粒疫苗、亚单位疫苗和DNA疫苗等已开展动物研究.     

肠道病毒71型的研究进展

肠道病毒71型(enterovirus 71,EV71)是引起手足口病(hand,foot and mouth disease,HFMD)的主要病原体之一,HFMD可并发严重神经系统疾病,甚至导致死亡.事实上,EV71一直被视为继脊髓灰质炎病毒消灭后最重要的嗜神经病毒.此文就EV71感染的易感因素以及疫苗的研究进展进行综述,从而为EV71感染的防控指明方向.     

EV71疫苗研制新进展

肠道病毒71型（enterovirus 71,EV71）是引起手足口病和神经系统并发症的重要病原体。近几年,世界多个地区发生了由EV71感染引起的手足口病。由于目前尚无有效的抗病毒药物对患者进行治疗,因而疫苗的研制成为预防和控制EV71传播的关键。此文主要就近年EV71疫苗的研制进展做一综述。     

Ozone exposure in the culture medium inhibits enterovirus 71 virus replication and modulates cytokine production in rhabdomyosarcoma cells

In the present study, the effects of ozone exposure on enterovirus 71 (EV71) replication and related cytokine production were investigated. Rhabdomyosarcoma cells (RD) were exposed to 0.5, 1, 1.5 and 2 ppm ozone or filtered air under different exposure regimens before or after infection for 1 or 2 h. The results revealed that at a proper concentration of ozone, e.g., 1.5 or 2 ppm, ozone exposure restricted virus production, prolonged survival time of cells and modulated cytokine production related to EV71 infection. Upon exposure of non-infected cells to ozone at 1.5 or 2 ppm for 1 h, the production of IL-1β, IL-6 and TNF-α was primed and boosted by the subsequent EV71 infection, generating an inhibitory effect on EV71 replication during the post-infection period of 48 h. While infected cells were exposed to ozone for 2 h at 1.5 or 2 ppm, ozone did not affect cytokine production by RD cells in response to EV71 infection. The data showed that ozone effect on induction of cytokine was only found in uninfected cells. The ozone-induced cytokines produced prior to the onset of EV71 infection generated antiviral effects, which proved beneficial in suppressing the subsequent EV71 infection.     

Ozone exposure in the culture medium inhibits enterovirus 71 virus replication and modulates cytokine production in rhabdomyosarcoma cells

In the present study, the effects of ozone exposure on enterovirus 71 (EV71) replication and related cytokine production were investigated. Rhabdomyosarcoma cells (RD) were exposed to 0.5, 1, 1.5 and 2 ppm ozone or filtered air under different exposure regimens before or after infection for 1 or 2 h. The results revealed that at a proper concentration of ozone, e.g., 1.5 or 2 ppm, ozone exposure restricted virus production, prolonged survival time of cells and modulated cytokine production related to EV71 infection. Upon exposure of non-infected cells to ozone at 1.5 or 2 ppm for 1h, the production of IL-1beta, IL-6 and TNF-alpha was primed and boosted by the subsequent EV71 infection, generating an inhibitory effect on EV71 replication during the post-infection period of 48 h. While infected cells were exposed to ozone for 2 h at 1.5 or 2 ppm, ozone did not affect cytokine production by RD cells in response to EV71 infection. The data showed that ozone effect on induction of cytokine was only found in uninfected cells. The ozone-induced cytokines produced prior to the onset of EV71 infection generated antiviral effects, which proved beneficial in suppressing the subsequent EV71 infection.     

Developments towards antiviral therapies against enterovirus 71

Enterovirus 71 (EV71) has emerged as a clinically important neurotropic virus that can cause acute flaccid paralysis and encephalitis, leading to cardiopulmonary failure and death. Recurring outbreaks of EV71 have been reported in several countries. The current lack of approved anti-EV71 therapy has prompted intense research into antiviral development. Several strategies--ranging from target-based chemical design to compound library screenings--have been employed, while others revisited compound series generated from antiviral developments against poliovirus and human rhinoviruses. These efforts have given rise to a diversity of antiviral candidates that include small molecules and non-conventional nucleic-acid-based strategies. This review aims to highlight candidates with potential for further clinical development based on their putative modes of action.     

人肠道病毒71型实验室检测新进展

近年来,人肠道病毒71型(emerevims 71,EV71)感染在世界各地特别是亚太地区呈上升趋势.EV71感染主要引起手足口病,但所致的神经系统并发症可导致死亡或永久性肌麻痹,因此受到医学界的广泛关注.此文主要就EV71的实验室检测做一综述.     

肠道病毒71型病毒样颗粒疫苗研究进展

肠道病毒71型(enterovirus 71,EV71)是引起儿童手足口病的主要病原体之一.由于尚无有效的抗病毒药物,故研发安全有效的疫苗是控制手足口病的有效措施.目前研发的EV71疫苗以灭活疫苗和病毒样颗粒(virus-like particle,VLP)疫苗为主,研究表明,VLP具有良好的免疫原性和稳定性.此文对目前EV71 VLP疫苗的研究进展做一综述,以期为预防EV71相关手足口病及其他手足口病的新型疫苗的研制提供思路.     

杨梅素体外抗EV71病毒作用的研究

目的初步探究杨梅素抗肠道病毒71型(EV71)的活性及其机制。方法采用EV71感染非洲绿猴肾细胞(Vero细胞)模型,采用致细胞病变(CPE)法和空斑实验观察杨梅素的抗病毒效果。以不同浓度的杨梅素处理细胞,结合结晶紫染色的方法检测杨梅素的细胞毒性。以免疫印迹法检测杨梅素对VP1蛋白表达的影响。应用RT-PCR的方法评价杨梅素对VP1基因表达的影响。结果杨梅素在2.5~20μmol·L^-1的浓度下预处理病毒能够显著抑制EV71感染诱导的细胞死亡,且这种抑制作用具有剂量依赖性,IC50为5.6μmol·L^-1。与病毒组相比,杨梅素在2.5~20μmol·L^-1的浓度下还能够显著降低病毒滴度。免疫印迹和RT-PCR的结果显示,杨梅素还能够明显降低病毒衣壳蛋白VP1的基因和蛋白表达。结论杨梅素具有显著的体外抗EV71病毒活性。     

Inhibition of HBV replication by theophylline

We have suggested recently that ATM-Rad3-Related (ATR) DNA damage signaling pathway, which responds to single-strand breaks in DNA, was activated in response to HBV infection. ATR knockdown cells showed decreased HBV DNA yields, implying HBV infection and replication activate and exploit the activated DNA damage response. Host cell proteins may constitute an attractive target for anti-HBV-1 therapeutics, since development of drug resistance against compounds targeting these cellular cofactor proteins is unlikely. In this study, we show that one of the clinically used compounds of ATR and ataxia telangiectasia-mutated (ATM) kinases inhibitor, theophylline (Tp), significantly reduced the yield of HBV DNA, HBsAg and HBeAg in HepG2215 cell culture system, furthermore, Tp could also suppress serum HBV DNA and HBsAg levels in the HBV-transgenic mice. Consistent with this result, immunohistology also showed reduced intensity of HBsAg staining on livers from Tp-treatment group. Taken together, these data indicated the feasibility of therapeutic approaches that target host cell proteins by inhibiting a cellular gene that was required for HBV replication and provided a potential approach for the prevention and treatment of HBV infection.     

肠道病毒71型疫苗研究进展及质量标准

肠道病毒71型(enterovirus 71,EV71)是导致手足口病的主要病原体之一,近年来在我国持续流行,对婴幼儿的健康造成了严重威胁.安全有效的疫苗是控制EV71流行的重要手段.全球有多家研究机构正在开展EV71疫苗的相关研究,目前由我国自主研发的3种EV71疫苗已获准上市.同时,为保证疫苗的安全性、有效性和质量可控性,已在研发中建立了合适且规范的质量标准.