Relationship between HBV genotypes and anti-viral therapeutic efficacy of interferon-alpha

BACKGROUND: Much evidence demonstrates that the genotypes of hepatitis B virus (HBV) present differences in pathogenicity and outcomes owing to differences in genetic structure. This study aimed to investigate the influences of HBV genotypes on the anti-viral therapeutic efficacy of interferon-alpha (IFN-alpha) in chronic hepatitis B patients, and to determine the relationship between HBV genotypes and levels of viral replication or gene variations. METHODS: The chronic hepatitis B patients who were treated with IFN-alpha were selected randomly. Anti-viral therapeutic efficacy was monitored in these patients. The HBV genotypes were detected by PCR microplate hybridization ELISA. The levels of serum HBV-DNA were determined by fluorescence quantitative PCR. HBV gene variation at pre-C and basic core promoter (BCP) regions were assayed by gene chip technology. RESULTS: Genotypes B and C were predominant in 94 chronic hepatitis B patients. A, E and F genotypes were not found in these patients. The HBV-DNA levels of genotype C and mixed genotypes were significantly higher than those of genotype B. The response to IFN-alpha in patients with genotype B was markedly better than in those with genotypes C and D, and the complete response to IFN-alpha was only observed in genotype B. The response to IFN-alpha in patients with mixed genotypes was the least sensitive. The negative transition of HBeAg was correlated with variations in the HBV pre-C and BCP regions in patients with partial or no response to IFN-alpha. The variation rates of HBV pre-C and BCP regions were clearly higher in genotype C than in genotype B. CONCLUSIONS: The results suggest that HBV genotype is correlated with the serum levels of HBV-DNA, HBV gene variations and therapeutic efficacy of IFN-alpha. The regular detection of HBV genotypes in the clinic will be of benefit for disease prognosis and planning of anti-viral therapeutic strategies.

Era of direct acting anti-viral agents for the treatment of hepatitis C

Hepatitis C infection is universal and the most common indication of liver transplantation in the United States. The period of less effective interferon therapy with intolerable side effects has gone. Now we have stepped into the era of direct acting anti-viral agents(DAAs) against hepatitis C virus. Treatment of hepatitis C is now extremely effective, tolerable and requires a short duration of intake of oral agents. Less monitoring is required with the current therapy and drug-drug interactions are less than the previous regimen. The current treatment options of chronic hepatitis C with various DAAs are discussed in this article.

Anti-viral Effect of Caulis Tripterygii Wilfordii

There have appeared more and more antibiotics to antagonize against causative organism, but in comparison few antivirals have. Hence, many viral diseases remain refractory and fatal due to lack of effective medicine.Caulis Tripterygii wilfordii (TW) is a specific and potent Chinese medicine, and its effect in treating various intractable diseases, such as systemic lupus erythematosus, dermatomyositis, scleroderma, psoriasis and eczema has been confirmed by many medical researches. Pharmacological researches also proved that TW has anti-inflammatory and immunomodulatory actions. It is interesting that some effective components isolated from TW have an antiviral effect and more and more intention has been paid to related achievements at home and abroad.

EV713C protease cleaves host anti-viral factor OAS3 and enhances virus replication

The global spread of enteroviruses(EVs)has become more frequent,severe and life-threatening.Intereron(IFN)I has been proved to control EVs by regulating IFN-stimulated genes(ISG)expression.20-50-oligoadenylate synthetases 3(OAS3)is an important ISG in the OAS/RNase L antiviral system.The relationship between OAS3 and EVs is still unclear.Here,we reveal that OAS3,superior to OAS1 and OAS2,significantly inhibited EV71 replication in vitro.However,EV71 utilized autologous 3C protease(3C^(pro))to cleave intracellular OAS3 and enhance viral replication.Rupintrivir,a human rhinovirus 3C protease inhibitor,completely abolished the cleavage of EV713C^(pro)on OAS3.And the proteolytically deficient mutants H40G,E71A,and C147G of EV713C^(pro)also lost the ability of OAS3 cleavage.Mechanistically,the Q982-G983 motif in C-terminal of OAS3 was identified as a crucial 3C^(pro)cutting site.Further investigation indicated that OAS3 inhibited not only EV71 but also Coxsackievirus B3(CVB3),Coxsackievirus A16(CA16),Enterovirus D68(EVD68),and Coxsackievirus A6(CA6)subtypes.Notably,unlike other four subtypes,CA163C^(pro)could not cleave OAS3.Two key amino acids variation Ile36 and Val86 in CA163C^(pro)might result in weak and delayed virus replication of CA16 because of failure of OAS and 3AB cleavage.Our works elucidate the broad anti-EVs function of OAS3,and illuminate a novel mechanism by which EV71 use 3C^(pro)to escape the antiviral effect of OAS3.These findings can be an important entry point for developing novel therapeutic strategies for multiple EVs infection.

Hepatocellular carcinoma following direct anti-viral for hepatitis C treatment: a report of an Egyptian case series

Egypt had been vexed by the highest load of chronic hepatitis C in the world. It represents a vast market of the new direct-acting anti-viral drugs (DAAs);effectively treating chronic hepatitis C virus (HCV) infection. Eradication of HCV in Egypt has been challenged by the observed increased diagnosis of hepatocellular carcinoma (HCC) in relation to DAAs therapy. This is the first Egyptian report annotating to a series of sixteen chronic HCV infected cases without a diagnosis of HCC before DAAs therapy and unexpected development of HCC during or after completion of DAAs therapy.

COVID-19 vaccination produces exercise-responsive SARS-CoV-2 specific T-cells regardless of infection history

Background:The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)specific T-cells and neutralizing antibodies(nAbs)during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019(COVID-19).We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter nAb titers.Methods:Eighteen healthy participants completed a 20-min bout of graded cycling exercise before and/or after receiving a COVID-19 vaccine.All major leukocyte subtypes were enumerated before,during,and after exercise by flow cytometry,and immune responses to SARS-CoV-2 were determined using whole blood peptide stimulation assays,T-cell receptor(TCR)-βsequencing,and SARS-CoV-2 nAb serology.Results:COVID-19 vaccination had no effect on the mobilization or egress of major leukocyte subsets in response to intensity-controlled graded exercise.However,non-infected participants had a significantly reduced mobilization of CD4+and CD8+naive T-cells,as well as CD4+central memory T-cells,after vaccination(synthetic immunity group);this was not seen after vaccination in those with prior SARS-CoV-2 infection(hybrid immunity group).Acute exercise after vaccination robustly mobilized SARS-CoV-2 specific T-cells to blood in an intensity-dependent manner.Both groups mobilized T-cells that reacted to spike protein;however,only the hybrid immunity group mobilized T-cells that reacted to membrane and nucleocapsid antigens.nAbs increased significantly during exercise only in the hybrid immunity group.Conclusion:These data indicate that acute exercise mobilizes SARS-CoV-2 specific T-cells that recognize spike protein and increases the redistribution of nAbs in individuals with hybrid immunity.

Predictions in Clinical Efficiency of SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp) Inhibitors by Molecular Docking

This study utilizes the enzyme-substrate complex theory to predict the clinical efficacy of COVID-19 treatments at the biological systems level, using molecular docking stability indicators. Experimental data from the Protein Data Bank and molecular structures generated by AlphaFold 3 were used to create macromolecular complex templates. Six templates were developed, including the holo nsp7-nsp8-nsp12 (RNA-dependent RNA polymerase) complex with dsRNA primers (holo-RdRp-RNA). The study evaluated several ligands—Favipiravir-RTP, Remdesivir, Abacavir, Ribavirin, and Oseltamivir—as potential viral RNA polymerase inhibitors. Notably, the first four of these ligands have been clinically employed in the treatment of COVID-19, allowing for comparative analysis. Molecular docking simulations were performed using AutoDock 4, and statistical differences were assessed through t-tests and Mann-Whitney U tests. A review of the literature on COVID-19 treatment outcomes and inhibitors targeting RNA polymerase enzymes was conducted, and the inhibitors were ranked according to their clinical efficacy: Remdesivir > Favipiravir-RTP > Oseltamivir. Docking results obtained from the second and third templates aligned with clinical observations. Furthermore, Abacavir demonstrated a predicted efficacy comparable to Favipiravir-RTP, while Ribavirin exhibited a predicted efficacy similar to that of Remdesivir. This research, focused on inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase, establishes a framework for screening AI-generated drug templates based on clinical outcomes. Additionally, it develops a drug screening platform based on molecular docking binding energy, enabling the evaluation of novel or repurposed drugs and potentially accelerating the drug development process.

自身免疫性肝炎临床误诊分析

目的探讨自身免疫性肝炎(AIH)的诊治措施及误诊原因、防范措施。方法回顾性分析2020年1月—2022年5月收治的AIH误诊为病毒性肝炎21例的临床资料。结果21例主要症状为食欲缺乏、乏力、黄疸、发热,伴腹胀12例,恶心5例,胸闷和胸痛4例,呕吐及关节痛各3例。体形消瘦,巩膜及皮肤黏膜黄染明显。查血丙氨酸转氨酶和天冬氨酸转氨酶升高;7例γ-谷氨酰转肽酶升高,碱性磷酸酶和总胆红素升高各6例。腹部B超检查示肝大18例,肝内回声不均。初期外院诊断为病毒性肝炎,予相应治疗15 d无好转,遂转我院。查血抗平滑肌抗体(SMA)、抗核抗体(ANA)阳性,血γ-球蛋白、IgG升高,结合肝炎病毒血清学检测阴性及相关病史,遂明确诊断为AIH。误诊时间18~21 d。确诊后,18例予泼尼松单独治疗,3例予泼尼松联合硫唑嘌呤治疗。治疗1年后随访,患者病情稳定,无复发。结论AIH发病较隐匿,以年轻女性高发,临床表现多样且无特异性,易误诊为病毒性肝炎,行肝炎病毒血清学检查及ANA、SMA、抗肝肾微粒体、免疫球蛋白或肝组织病理检查可区分二者,确诊后应及时予有效治疗,以改善患者预后。

疏风解毒胶囊预防给药对流感病毒感染小鼠模型TLR4介导肺组织炎性损伤的影响

目的探究疏风解毒胶囊预防给药对甲型流感病毒肺炎小鼠的影响及可能的干预机制。方法采用甲型H1N1流感病毒(FM1株)滴鼻感染ICR小鼠,构建病毒性肺炎模型。每日固定时间观察各组小鼠一般状态,计算各组小鼠肺指数、抑制率和病毒载量;采用Micro-CT、苏木精-伊红染色(HE)法观察小鼠肺组织病理形态变化;采用酶联免疫吸附法(ELISA)检测肺组织中肿瘤坏死因子(TNF-α)、白介素-6(IL-6)的含量;蛋白免疫印迹法(Western blot)检测肺组织中TLR4、MyD88蛋白的表达含量。结果预防性给予疏风解毒胶囊可降低小鼠的肺指数,降低肺组织中病毒载量,修复流感小鼠肺部损伤,减轻肺部病变,降低肺组织中TNF-α和IL-6含量。Western blot结果显示疏风解毒胶囊可下调肺组织TLR4、MyD88蛋白的表达。结论疏风解毒胶囊预防性给药对甲型流感病毒肺炎小鼠具有保护作用,其机制与抑制病毒复制、改善肺组织病变、抑制炎症因子释放和下调肺组织中TLR4、MyD88蛋白的表达有关。

羊栖菜多糖抗A型塞内卡病毒感染PK-15细胞活性和机制探究

研究羊栖菜多糖抗A型塞内卡病毒(Senecavirus A,SVA)感染PK-15细胞的活性及机制。首先采用水提法提取羊栖菜粗多糖,然后用不同孔径超滤膜将粗多糖分为不同分子量段;通过荧光定量PCR测定不同分子量粗多糖抗SVA活性,采用水提醇沉法将抗SVA活性最高分子量段的粗多糖进行纯化并测定其细胞毒性及抗SVA活性;通过在SVA感染周期不同阶段给药研究纯化多糖的抗SVA机制。结果表明,分子量越大的粗多糖抗SVA活性越强;多糖浓度和SVA浓度均与抗SVA活性呈现量效关系,纯化后的多糖对SVA(MOI=0.1)感染PK-15细胞的治疗指数为412,1 mg/mL的多糖对SVA(MOI=10-1~104)感染PK-15细胞病毒载量的抑制率在90%~99.999%之间;不同给药时间试验结果表明,多糖能在SVA吸附或穿入细胞以及病毒复制过程发挥抗病毒作用,其中抑制SVA吸附或穿入的活性最强。本研究分离纯化得到的羊栖菜多糖有很强的抗SVA活性,可为后续抗SVA药物的研发提供参考。

连翘半日花烷型二萜和生物碱类化合物及其抗病毒活性

研究连翘抗炎、抗病毒活性部位中的化学成分及其抗病毒活性。通过综合运用硅胶柱色谱、Sephadex LH-20柱色谱及高效制备色谱等方法对连翘中的化合物进行分离纯化,并根据理化性质和波谱数据对化合物的结构进行鉴定,采用MTT法对得到的部分化合物进行抗病毒活性研究。结果表明,从连翘体积分数95%乙醇提取物的氯仿部位和乙酸乙酯部位分离得到9个半日花烷型二萜和6个生物碱类化合物。9个半日花烷型二萜分别为:19-hydroxy-ent-labda-8(17),13 E-dien-15-oic acid(1);ent-labda-8(17),13 Z-dien-15,19-dioic acid(2);ent-labda-8(17),13 E-dien-15,19-dioic acid(3);3β-hydroxy-8(17),13 E-labdadien-15-oic acid(4);enantio-labda-8(20),13 E-dien-15,18-dioic acid(5);Forsyshiyanin A(6);Forsyshiyanin B(7);18-hydroxy-7-oxolabda-8(9),13 E-diene-15-oic acid(8);3-hydroxy-8(17),13 E-labdadien-15-oic acid(9)。6个生物碱类化合物分别为:Forsyshiyanine A(10);(7 R)-6,7-dihydro-7-methyl-5H-cyclopenta[c]pyridine(11);Forsyshiyanine B(12);(-)-bicuculline(13);(-)-egenine(14);(-)-7′-O-methylegenine(15)。其中化合物10、12为首次从连翘中发现,也是首次从连翘属植物中发现。MTT结果显示,化合物1、2、10、12对于H1N1流感病毒及呼吸道合胞病毒的增长具有抑制作用。

龙胆泻肝汤加减对慢性乙型肝炎低病毒血症期抗纤维化改善、病毒载量及血清HBsAg、ADA的影响

[目的]观察龙胆泻肝汤加减对慢性乙型肝炎低病毒血症期抗纤维化改善、病毒载量及血清乙型肝炎表面抗原(HBsAg)、腺苷脱氨酶(ADA)的影响。[方法]选择2020年1月——2023年1月于医院治疗的102例慢性乙型肝炎患者,随机数字表法分为西医组和中西医组。西医组52例,给予患者恩替卡韦片治疗,中西医组50例,西医组治疗同时给予患者龙胆泻肝汤加减治疗,比较西医组及中西医组临床疗效,治疗前、后给予患者身目俱黄、脘闷腹胀、胁肋疼痛、小便黄赤、烦热、口干而苦、困倦乏力、食欲不振、皮肤瘙痒、恶心呕吐、大便秘结或稀溏评价,检测患者乙型肝炎病毒(HBV)-DNA、HBsAg、ADA、总胆红素、CD4^(+)/CD8^(+)、Ⅲ型胶原、透明质酸、白细胞介素-27(IL-27)水平,计算HBV-DNA、HBsAg转阴率。[结果]中西医组患者总有效率为96.00%,西医组总有效率为80.77%,中西医组患者总有效率较西医组高(P<0.05);中西医组身目俱黄、脘闷腹胀、胁肋疼痛、小便黄赤、烦热、口干而苦、困倦乏力、食欲不振、皮肤瘙痒、恶心呕吐、大便秘结或稀溏评分较西医组降低(P<0.05);中西医组HBV-DNA、HBsAg水平较西医组低(P<0.05),中西医组HBV-DNA、HBsAg转阴率较西医组高(P<0.05);中西医组ADA、总胆红素、Ⅲ型胶原、透明质酸水平较西医组低(P<0.05);中西医组CD4^(+)/CD8^(+)较西医组高(P<0.05),中西医组IL-27水平较西医组低(P<0.05)。[结论]龙胆泻肝汤加减治疗慢性乙型肝炎低病毒血症患者,可改善免疫功能,抑制炎症,提升抗纤维化能力,减少病毒载量及血清HBsAg、ADA水平,缓解病情,提升临床疗效。

倍半萜类化合物生物活性研究进展

倍半萜类化合物在植物、动物、海洋生物及微生物中分布广泛,尤其在菊科植物中分布最多,具有抗肿瘤细胞毒活性、抗菌、抗炎、抗病毒、抗氧化等多种生物活性,也具有保护肝脏、保护神经、预防和治疗糖尿病及提高免疫抑制功能等作用。但是,倍半萜类化合物在抗过敏、抗溃疡、强心、镇痛等方面的生物活性研究较少,并且主要以动物实验、体外研究为主,且在临床应用中的成品较少。今后,需进一步发现新的成分并研究其生物活性,并逐渐深入进行体内研究,并研发成品,在临床中推广应用。

抗冠状呼吸道病毒草药的类别和分子机制概述

在抗击严重急性呼吸综合征(SARS)、中东呼吸综合征(MERS)和新型冠状病毒感染(COVID-19)过程中,国内外利用草药减轻患者病证,降低感染人数,并丰富相关机制。该文综述了公开报道的可能有或初步证明有临床防疫效果的71个科157种草药,包括甘草等传统中药。这些草药的抗病毒机制包括抑制病毒生活周期、减缓感染后血液细胞因子水平的暴涨和后续器官的损伤等,部分草药还可通过改善环境湿度和释放挥发性成分起到防疫的作用。旨在总结相关防疫经验和机制,为更好理解传统中草药的抗病毒效果提供资料,彰显中医的价值,并为应对疫情后状态和未来可能的呼吸道病毒感染提供经验。

糖皮质激素辅助抗病毒治疗对慢性乙肝患者肝功能及治疗效果的影响研究

目的 分析糖皮质激素辅助抗病毒治疗对慢性乙肝患者肝功能及治疗效果的影响。方法 以我院2021年12月至2022年11月收治的86例慢性乙肝患者为本次研究对象,并以随机数字法分为常规组(43例,常规抗病毒治疗)和观察组(43例,糖皮质激素辅助抗病毒治疗),对比分析两组治疗方案的应用效果。结果 (1)观察组患者的治疗有效率高于常规组(P <0.05);(2)治疗前,两组患者肝功能、血清Th1/Th2型细胞因子相关指标均无对比差异(P> 0.05)。治疗后,观察组患者复查肝功能、血清Th1/Th2型细胞因子相关指标均低于常规组(P <0.05);(3)两组患者的不良反应发生率均无统计学差异(P> 0.05)。结论 以糖皮质激素辅助抗病毒治疗慢性乙肝患者,可取得安全高效的治疗效果。

慢性乙型肝炎患者病毒载量与疾病状态和治疗策略选择

给予慢性乙型肝炎(chronic hepatitis B,CHB)患者及时有效的抗病毒治疗可以阻止或延缓病情进展为肝硬化或肝细胞癌(hepatocellular carcinoma, HCC)等。扩大CHB抗病毒治疗的适应证是为了实现我国消除乙型肝炎公共危害的目标,而高效安全抗病毒药物的可及性和医疗费用的大幅度降低也为扩大治疗提供了保障[1,2]。

Interferon-lambda:New functions on intestinal symptoms in COVID-19

The tremendous public health and economic impact of coronavirus disease 2019(COVID-19), caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2), has become a huge challenge globally. There is increasing evidence that SARS-CoV-2 induces intestinal infections. Type Ⅲ interferon(IFN-λ) has an antiviral role in intestinal infection, with focused, long-lasting, and non-inflammatory characteristics. This review presents a summary of the structure of SARSCoV-2, including its invasion and immune escape mechanisms. Emphasis was placed on the gastrointestinal impact of SARS-CoV-2, including changes to the intestinal microbiome, activation of immune cells, and inflammatory responses.We also describe the comprehensive functions of IFN-λ in anti-enteric SARS-CoV-2 infection, and discuss the potential application of IFN-λ as a therapeutic agent for COVID-19 with intestinal symptoms.

Clinical characteristics,management,and prevention of coronavirus disease 2019

Coronavirus disease 2019(COVID-19)is the third severe acute respiratory disease of the 21st century and the most aggressive global pandemic to date.The whole population has been susceptible to the disease,particularly the emerging variants of the virus.The core pathophysiological mechanism is viral sepsis that can lead to the respiratory tract disorders and even systemic disorders such as cytokine release syndrome,thrombosis,abnormal angiogenesis,and multiple organ dysfunction.Despite only few licensed treatments to date,rapid advances have been made in exploring the effectiveness and safety of pharmacological interventions and vaccines.However,three pillars of preventative and control measures-proactive contact tracing,wearing facial masks,and social distancing-are essential to combat the ongoing pandemic.As the number of patients recovering from COVID-19 rapidly increases,the world has entered the era of caring for patients during the convalescence phase.This phase still represents a largely unmet medical need globally.

Recent advances in the antiviral activity of Forsythiae Fructus

Forsythiae Fructus,a well-known traditional Chinese medicine preparation derived from the dried fruits of Forsythia suspensa(Thunb.)Vahl,has been historically utilized for its heat-clearing and detoxification properties.Forsythiae Fructus has been reported to exhibit antiviral activity such as against SARS-CoV-2 and influenza virus.This review highlights the recent updates on the effects and underlying action mechanisms of compounds in and active fractions from Forsythiae Fructus and Chinese formulae containing Forsythiae Fructus.

朱砂七化学成分及其体外细胞毒性、抗病毒活性研究

目的研究朱砂七Fallopia multiflora var.ciliinervis(Nakai)Yonekura&H.Ohashi化学成分及其体外细胞毒性、抗病毒活性。方法朱砂七75%乙醇提取物采用硅胶柱层析、半制备HPLC进行分离纯化,根据理化性质及波谱数据鉴定所得化合物的结构。采用MTT法测定体外细胞毒活性,CCK-8法测定体外抗病毒活性。结果从中分离得到20个化合物,分别鉴定为3-acetyl-4,5-dimethoxy-benzoic acid(1)、没食子酸甲酯(2)、没食子酸(3)、对羟基苯甲醛(4)、原儿茶酸(5)、3,4-二羟基苯甲醛(6)、丁香酸(7)、4-羟基-3-甲氧基苯甲酸(8)、p-hydroxyphenethyl-O-β-D-glucoside(9)、2-(4-hydroxy-3-methoxyphenyl)-ethyl-O-β-D-glucoside(10)、反式-白藜芦醇(11)、顺式-白藜芦醇(12)、白藜芦醇-3-O-β-D-(2′-O-反式-肉桂酰基)-葡萄糖苷(13)、白藜芦醇-3-O-β-D-(2′-O-顺式-肉桂酰基)-葡萄糖苷(14)、白藜芦醇-3-O-β-D-葡萄糖苷(15)、N-反式阿魏酰-3-甲氧基酪胺(16)、poke-weed cerebroside(17)、何首乌乙素(18)、9,10,13-三羟基十八烷酸(19)、正丁基-β-D-吡喃果糖苷(20)。化合物11对HCT116、SW620细胞的IC 50值分别为(30.87±2.7)、(56.11±0.49)μmol/L,化合物12对EV-A71病毒的抑制率为50.21%。结论化合物1为新天然产物,化合物9~10为首次从蓼科植物中分离得到,化合物8、12、14、17、19为首次从何首乌属植物中分离得到,化合物2、4~7、11、18为首次从该植物中分离得到。化合物11具有细胞毒性,化合物12具有抗病毒活性。