Senolystics from natural products for extending health and lifespan

Senescence,a multifaceted cellular process,intricately regulates organismal aging by imposing irreversible growth arrest on cells.This phenomenon,characterized by altered gene expression and the accumulation of senescent cells,significantly contributes to age-related physiological decline and the onset of various age-associated pathologies[1].Cellular senescence,the irreversible cessation of cell division,is intricately linked to the aging process in individuals[2].As organisms age,the accumulation of senescent cells increases,contributing to tissue dysfunction and the development of age-related pathologies.Understanding the mechanisms underlying cellular senescence holds promise for elucidating the fundamental processes governing aging and may pave the way for targeted interventions to mitigate age-associated decline[3].

Biomimetic fibril-like injectable hydrogels for wound management

Soft tissue repair and regeneration present a significant clinical challenge.Soft hydrogels have emerged as a promising solution for promoting stem cell differentiation and facilitating soft tissue formation[1].Various materials,including synthetic polymers like polydimethyl siloxane and natural polymers like proteins,have been be used as hydrogel matrix for hydrogel preparation[2,3].However,the limited biodegradability,inhomogeneous network structure,and inadequate mechanical properties of these hydrogels hinder their long-term application in complex environments in vivo.Inspired by the nanostructure of collagen fibrils,Li et al.developed a strategy for creating injectable nanofibrillar hydrogels by combining self-assembly and chemical crosslinking of nanoparticles[4].Moreover,injectable hydrogels offer advantages as implantable materials,including better defect filling and reduced risk of infection compared to prefabricated hydrogels[5].

Overcoming the biofilm barrier by cell-like microbubbles for the treatment of biofilm-associated implant infections

Although the advent of antibiotics has significantly improved the quality of life of infected patients,bacterial infections continue to pose a serious threat to public health[1,2].According to a recent report,within the next 30 years,bacterial infections are projected to surpass cancer in terms of lethality rates,resulting in an alarming 10 million deaths annually by 2050 due to the development of bacterial resistance[3].Moreover,the formation of bacterial biofilms hampers the penetration of antibacterial agents and inhibits the host immune response,making biofilm infections extremely challenging to treat[4-7].Hence,the development of innovative antimicrobial biofilm therapeutics is imperative.

Electroluminodynamic therapy for the treatment of drug-resistant pathogen infection

The administration of antibiotics has been the primary strategy for combating bacterial infections[1,2].However,the widespread and excessive use of antibiotics has resulted in the alarming rise of bacterial resistance,posing a significant threat to human health[3–5].Therefore,it is imperative to exploit innovative treatment strategy.

Ultrasound-responsive microbubbles in antibacterial therapy

Microbubbles(MBs)are gas-filled micrometer-scale spheres that are commonly formed by the gas core encapsulated with stabilizing shells,including polymers,surfactants,proteins,or liposomes shells.Clinically,MBs were originally used as contrast agents for enhanced ultrasound(US)imaging and diagnostics.Nowadays,MBs were given expectations that they can be alternative platforms for drug delivery owing to their unique acoustic properties.MBs can respond to the US by cavitation effect which refers to a series of complex dynamic processes,such as oscillation,expansion,contraction,and implosion[1].Drug molecules or therapeutic agents can be associated with the MB shells by means of van-der-Waals forces,electrostatic or hydrophobic interactions,or merely by physical encapsulation[2].Therefore,strategies are emerging which take advantages of US-mediated MBs drug delivery systems,mainly focusing on sonothrombolysis,cancer therapy and central nervous system(CNS)pathologies[3].Nevertheless,several researchers have apperceived the promising potential of US-responsive MBs in antibacterial therapy.Here,we aimed to paint an overview of the latest published papers on MBs for antibacterial therapy,hoping to help understand the perspectives that the field may offer emerging generations of antibacterial agents.

Immunostaining of PD-1/PD-Ls in liver tissues of patients with hepatitis and hepatocellular carcinoma

AIM: To investigate the expression of programmed death (PD)-1,PD ligand 1 (PD-L1) and PD-L2 in liver tissues in the context of chronic hepatitis and hepatocellular carcinoma (HCC).METHODS: Liver biopsies and HCC specimens from patients were collected and histologically examined.The expression of PD-1,PD-L1,and PD-L2 in biopsy specimens of chronic hepatitis and HCC specimens was evaluated by immunohistochemical staining.The association between the expression level of PD-1,PD-L1,and PD-L2 and clinical and pathological variables was analyzed statistically.RESULTS: Expression of PD-1 was found in liverinfiltrating lymphocytes.In contrast,PD-L1 and PD-L2 were expressed in non-parenchyma liver cells and tumor cells.The expression of PD-L1 was significantly correlated with hepatitis B virus infection (1.42 ± 1.165 vs 0.50 ± 0.756,P = 0.047) and with the stage of HCC (7.50 ± 2.121 vs 1.75 ± 1.500 vs 3.00 ± 0.001,P = 0.018).PD-1 and PD-Ls were significantly up-regulated in HCC specimens (1.40 ± 1.536 vs 5.71 ± 4.051,P = 0.000;1.05 ± 1.099 vs 4.29 ± 3.885,P = 0.004;1.80 ± 1.473 vs 3.81 ± 3.400,P = 0.020).CONCLUSION: PD-L1 may contribute to negative regulation of the immune response in chronic hepatitis B.PD-1 and PD-Ls may play a role in immune evasion of tumors.

Models for predicting hepatitis B e antigen seroconversion in response to interferon-α in chronic hepatitis B patients

AIM:To develop models to predict hepatitis B e antigen(HBe Ag)seroconversion in response to interferon(IFN)-αtreatment in chronic hepatitis B patients.METHODS:We enrolled 147 treatment-nave HBe Agpositive chronic hepatitis B patients in China and analyzed variables after initiating IFN-α1b treatment.Patients were tested for serum alanine aminotransferase(ALT),hepatitis B virus-DNA,hepatitis B surface antigen(HBs Ag),antibody to hepatitis B surface antigen,HBe Ag,antibody to hepatitis B e antigen(anti-HBe),and antibody to hepatitis B core antigen(anti-HBc)at baseline and 12 wk,24 wk,and 52 wk after initiating treatment.We performed univariate analysis to identify response predictors among the variables.Multivariate models to predict treatment response were constructed at baseline,12 wk,and 24 wk.RESULTS:At baseline,the 3 factors correlating most with HBe Ag seroconversion were serum ALT level>4×the upper limit of normal(ULN),HBe Ag≤500 S/CO,and anti-HBc>11.4 S/CO.At 12 wk,the 3 factors most associated with HBe Ag seroconversion were HBe Ag level≤250 S/CO,decline in HBe Ag>1 log10 S/CO,and anti-HBc>11.8 S/CO.At 24 wk,the 3 factors most associated with HBe Ag seroconversion were HBe Ag level≤5 S/CO,anti-HBc>11.4 S/CO,and decline in HBe Ag>2 log10 S/CO.Each variable was assigned a score of1,a score of 0 was given if patients did not have any of the 3 variables.The 3 factors most strongly correlating with HBe Ag seroconversion at each time point were used to build models to predict the outcome after IFN-αtreatment.When the score was 3,the response rates at the 3 time points were 57.7%,83.3%,and 84.0%,respectively.When the score was 0,the response rates were 2.9%,0.0%,and 2.1%,respectively.CONCLUSION:Models with good negative and positive predictive values were developed to calculate the probability of response to IFN-αtherapy.

Animal models for the study of hepatitis B virus infection

Even with an effective vaccine, an estimated 240 million people are chronically infected with hepatitis B virus （HBV） worldwide. Current antiviral therapies, including interferon and nucleot（s）ide analogues, rarely cure chronic hepatitis B. Animal models are very crucial for understanding the pathogenesis of chronic hepatitis B and developing new therapeutic drugs or strategies. HBV can only infect humans and chimpanzees, with the use of chimpanzees in HBV research strongly restricted. Thus, most advances in HBV research have been gained using mouse models with HBV replication or infection or models with HBV-related hepadnaviral infection. This review summarizes the animal models currently available for the study of HBV infection.

Development of HBsAg-Binding Aptamers that bind HepG2.2.15 cells via HBV surface antigen

Hepatitis B virus surface antigen （HBsAg）, a specific antigen on the membrane of Hepatitis B virus （HBV）-infected cells, provides a perfect target for therapeutic drugs. The development of reagents with high affinity and specificity to the HBsAg is of great significance to the early-stage diagnosis and treatment of HBV infection. Herein, we report the selection of RNA aptamers that can specifically bind to HBsAg protein and HBsAg-positive hepatocytes. One high affinity aptamer, HBs-A22, was isolated from an initial 115 met library of -1.1 ×10^15 random-sequence RNA molecules using the SELEX procedure. The selected aptamer HBs-A22 bound specifically to hepatoma cell line HepG2.2.15 that expresses HBsAg but did not bind to HBsAg-devoid HepG2 cells. This is the first reported RNA aptamer which could bind to a HBV specific antigen. This newly isolated aptamer could be modified to deliver imaging, diagnostic, and therapeutic agents targeted at HBV-infected cells.

Inhibition of hepatitis B virus replication by APOBEC3G in vitro and in vivo

AIM： To investigate the effect of APOBEC3G mediated antiviral activity against hepatitis B virus （HBV） in cell cultures and replication competent HBV vector-based mouse model. METHODS： The mammalian hepatoma cells Huh7 and HepG2 were cotransfected with various amounts of CMV-driven expression vector encoding APOBEC3G and replication competent 1.3 fold over-length HBV. Levels of HBsAg and HBeAg in the media of the transfected cells were determined by ELISA. The expression of HBcAg in transfected cells was detected by western blot. HBV DNA and RNA from intracellular core particles were examined by Northern and Southern blot analyses. To assess activity of the APOBEC3G in vivo, an HBV vector-based model was used in which APOBEC3G and the HBV vector were co-delivered via high-volume tail vein injection. Levels of HBsAg and HBV DNA in the sera of mice as well as HBV core-associated RNA in the liver of mice were determined by ELISA and quantitative PCR analysis respectively. RESULTS： There was a dose dependent decrease in the levels of intracellular core-associated HBV DNA and extracellular production of HBsAg and HBeAg. The levels of intracellular core-associated viral RNA also decreased, but the expression of HBcAg in transfected cells showed almost no change. Consistent with in vitro results, levels of HBsAg in the sera of mice were dramatically decreased. More than 1.5 log10 decrease in levels of serum HBV DNA and liver HBV RNA were observed in the APOBEC3G-treated groups compared with the control groups.CONCLUSION： These findings indicate that APOBEC3G could suppress HBV replication and antigen expression both in vivo and in vitro, promising an advance in treatment of HBV infection.

Replication of clinical hepatitis B virus isolate and its application for selecting antiviral agents for chronic hepatitis B patients

AIM: To establish a cell model harboring replicative clinical hepatitis B virus (HBV) isolates and evaluate its application in individualized selection of anti-HBV agents for chronic hepatitis B (CHB) patients. METHODS: The full-length HBV genomic DNA from 8 CHB patients was amplified by polymerase chain reaction (PCR). All the patients were treated with lamivudine for at least seven months and finally became resistant to lamivudine. The amplified HBV DNA fragments were inserted into pHY106 vectors by Sap Ⅰ?digestion. The recombinant plasmids containing 1.1 copies of HBV genome were transiently transfected into Huh7 cell line, and the levels of HBsAg, HBeAg and intercellular HBV replicative intermediates were determined by ELISA and Southern blot analysis, respectively, with or without lamivudine and adefovir treatment. The antiviral treatment with adefovir was administered to the patients and analyzed in parallel. RESULTS: A total of 25 independent HBV isolateswere obtained from the sera of 8 patients, each patient had at least two isolates. One isolate from each individual was selected and subcloned into pHY106 vector, including 5 isolates with YVDD mutation and 3 isolates with YIDD mutation. All recombinant plasmids harboring HBV isolates were transfected into Huh7 cells. The results indicated that HBV genome carried in HBV replicons of clinical HBV isolates could effectively replicate and express in Huh7 cells. Adefovir, but not lamivudine, inhibited HBV replication both in vitro and in vivo, and in vitro inhibition was dose-dependent. CONCLUSION: The novel method described herein enables individualized selection of anti-HBV agents in clinic and is useful in future studies of antiviral therapy for CHB.

Expression of PTEN,PPM1A and P-Smad2 in hepatocellular carcinomas and adjacent liver tissues

AIM： To investigate the expressions of PTEN, PPMIA and P-Smad2 in hepatocellular carcinoma （HCC） and their significance.METHODS： The expressions of PTEN, PPMIA and P-Smad2 in 31 HCC tissues, 25 adjacent liver tissues and 13 non-tumor liver tissues were detected by using Envision immunohistochemical technique. RESULTS： The positive expression （64.52%） and staining intensity （4.19 ± 3.31） of PTEN in the cytoplasm of HCC were significantly lower and weaker than those in the adjacent or non-tumor liver tissues （97.37%, 7.88 ± 0.93; 100%, 7.77 ± 0.93, respectively） （P 〈 0.05）, and its staining intensity in the cytoplasm of HCC, which belongs to Edmondson pathologic grades Ⅱ-Ⅲ and above, was also lower than that of grade I and I-Ⅱ. Furthermore, its location in the nucleus or cytoplasm of liver cells was negatively correlated with the progression of liver disease （r = -0.339, P = 0.002）; most of PPMIA might be only expressed in the nucleus of adjacent liver tissues, non-HCC tissues or Edmondson grade I and I - Ⅱ HCC, but it was mainly expressed in the cytoplasm of HCC with Edmondson grade ≥ Ⅱ, weakly or negatively expressed in the nucleus （P 〈 0.05）, and its location was negatively correlated with the progression of liver disease （r = -0.45, P = 0.0000）. P-Smad2, which was mostly located in the nucleus and cytoplasm of grade I and I -Ⅱ HCC, surrounding or non-tumor liver tissues, was only in the nucleus of HCC with Edmondson grade Ⅱ and above （P 〈 0.001）, and its location was positively correlated with the disease progression （r = 0.224, P = 0.016）. Spearman correlation analysis revealed that P-Smad2 was significantly negatively correlated with PTEN and PPMIA （r = -0.748, P = 0.000; r = -0.366, P = 0.001, respectively）; and PTEN and PPMIA were positively correlated with HCC carcinogenesis （r = 0.428, P = 0.000）.CONCLUSION： The aberrant location of expression and staining intensity of PTEN, PPMIA and P-Smad2 in HCC and their relationship might have an impact on the pathogenesis of HCC.

Inhibitory effect of miR-125b on hepatitis C virus core protein-induced TLR2/My D88 signaling in THP-1 cells

AIM: To investigate the role of mi R-125 b in regulating monocyte immune responses induced by hepatitis C virus(HCV) core protein.METHODS: Monocytic THP-1 cells were treated with various concentrations of recombinant HCV core protein, and cytokines and mi R-125 b expression in these cells were analyzed. The requirement of Tolllike receptor 2(TLR2) or My D88 gene for HCV core protein-induced immune responses was determined by the transfection of THP-1 cells with gene knockdown vectors expressing either TLR2 si RNA or My D88 si RNA. The effect of mi R-125 b overexpression on TLR2/My D88 signaling was examined by transfecting THP-1 cells with mi R-125 b mimic RNA oligos.RESULTS: In response to HCV core protein stimulation, cytokine production was up-regulated and mi R-125 b expression was down-regulated in THP-1 cells. The modulatory effect of HCV core protein on cellular events was dose-dependent and required functional TLR2 or My D88 gene. Forced mi R-125 b expression abolished the HCV core protein-induced enhancement of tumor necrosis factor-α, interleukin(IL)-6, and IL-10 expression by 66%, 54%, and 66%, respectively(P < 0.001), by inhibiting My D88-mediated signaling, including phosphorylation of NF-k Bp65, ERK, and P38.CONCLUSION: The inverse correlation between mi R-125 b and cytokine expression after HCV core challenge suggests that mi R-125 b may negatively regulate HCVinduced immune responses by targeting TLR2/My D88 signaling in monocytes.

Phase transitions in bismuth under rapid compression

The structural phase transitions of bismuth under rapid compression has been investigated in a dynamic diamond anvil cell using time-resolved synchrotron x-ray diffraction. As the pressure increases, the transformations from phase I,to phase II, to phase III, and then to phase V have been observed under different compression rates at 300 K. Compared with static compression results, no new phase transition sequence appears under rapid compression at compression rate from 0.20 GPa/s to 183.8 GPa/s. However, during the process across the transition from phase III to phase V, the volume fraction of product phase as a function of pressure can be well fitted by a compression-rate-dependent sigmoidal curve.The resulting parameters indicate that the activation energy related to this phase transition, as well as the onset transition pressure, shows a compression-rate-dependent performance. A strong dependence of over-pressurization on compression rate occurs under rapid compression. A formula for over-pressure has been proposed, which can be used to quantify the over-pressurization.

Use of ^(18)F-FDG PET/CT to locate primary malignancies in patients with hepatic cirrhosis and malignant ascites

Objective：Ascites in patients with hepatic cirrhosis is caused by cirrhosis in most cases.For most malignant ascites,the primary malignancy could be readily identified using conventional imaging methods,e.g.,computer tomography （CT） and magnetic resonance imaging （MRI）.However,in a small fraction of the patients,the primary malignancy remains occult even with these examinations.In this retrospective study,we assessed the usefulness of 18F-FDG PET/CT in patients with hepatic cirrhosis and malignant ascites of otherwise unknown origin.Methods：Twenty-eight patients with malignant ascites of unknown primary sites after CT,MRI and ultrasound during the period of five years between January 2008 and December 2012 had received 18F-FDG PET/CT.Medical records of these patients were reviewed and analyzed.Results：Elevated 18F-FDG absorption was found in 23 of 28 cases in the following sites：gastrointestinal tract （n=10,43.5％）,prostate （n=5,21.7％）,peritoneum （n=4,13.3％）,and ovary （n=4,13.3％）.Cancer was confirmed by pathology in 20 cases after open or laparoscopic surgeries.Five patients were found to have benign ascites,among which,3 were found to be false positive due to tuberculosis.SUV values were significantly higher for tumors than for benign lesions （mean values,6.95 vs.2.94; P=0.005）.Conclusions：The 18F-FDG PET/CT can be as a powerful imaging tool in identifying tissue origin in liver cirrhosis patients suspected of cancers or with cancers of unknown primary sites.

N-terminal and C-terminal cytosine deaminase domain of APOBEC3G inhibit hepatitis B virus replication

AIM: To investigate the effect of human apolipoprotein B mRNA-editing enzyme catalytic-polypeptide 3G (APOBEC3G) and its N-terminal or C-terminal cytosine deaminase domain-mediated antiviral activity against hepatitis B virus (HBV) in vitro and in vivo. METHODS: The mammalian hepatoma cells HepG2 and HuH7 were cotransfected with APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain expression vector and 1.3-fold-overlength HBV DNA as well as the linear monomeric HBV of genotype B and C. For in vivo study, an HBV vector-based mouse model was used in which APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain expression vectors were co-delivered with 1.3-fold-overlength HBV DNA via high-volume tail vein injection. Levels of hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg) in the media of the transfected cells and in the sera of mice were determined by ELISA.The expression of hepatitis B virus core antigen (HBcAg) in the transfected cells was determined by Western blot analysis. Core-associated HBV DNA was examined by Southern blot analysis. Levels of HBV DNA in the sera of mice as well as HBV core-associated RNA in the liver of mice were determined by quantitative PCR and quantitative RT-PCR analysis, respectively. RESULTS: Human APOBEC3G exerted an anti-HBV activity in a dose-dependent manner in HepG2 cells, and comparable suppressive effects were observed on genotype B and C as that of genotype A. Interestingly, the N-terminal or C-terminal cytosine deaminase domain alone could also inhibit HBV replication in HepG2 cells as well as Huh7 cells. Consistent with in vitro results, the levels of HBsAg in the sera of mice were dramatically decreased, with more than 50 times decrease in the levels of serum HBV DNA and core-associated RNA in the liver of mice treated with APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain as compared to the controls. CONCLUSION: Our findings provide probably the first evidence showing that APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain could suppress HBV replication in vitro and in vivo.

Antiviral Effect of Interferon-Induced Guanylate Binding Protein-1 against Coxsackie Virus and Hepatitis B Virus B3 in Vitro

Guanylate binding protein-1(GBP-1)is an interferon-induced protein.To observe its antiviral effect against Hepatitis B virus(HBV)and Coxsackie virus B3(CVB3),we constructed an eukaryotic expression vector of human GBP-1(hGBP-1).Full-length encoding sequence of hGBP-1 was amplified by long chain RT-PCR and inserted into a pCR2.1 vector,then subcloned into a pCDNA3.1(-)vector.Recombinant hGBP-1 plasmids and pHBV1.3 carrying 1.3-fold genome of HBV were contransfected into HepG2 cells,and inhibition effect of hGBP-1 against HBV replication was observed.Hela cells transfected with recombinant hGBP-1 plasmids were challenged with CVB3,and viral yield in cultures were detected.The results indicated that recombinant eukaryotic expression plasmid of hGBP-1 was constructed successfully and the hGBP-1 gene carried in this plasmid could be efficiently expressed in HepG2 cells and Hela cells.hGBP-1 inhibit CVB3 but not HBV replication in vitro.These results demonstrate that hGBP-1 mediates an antiviral effect against CVB3 but not HBV and perhaps plays an important role in the interferon-mediated antiviral response against CVB3.

Construction and Characterization of a Hepatitis B Virus Replicon

建立复制细胞肝炎 B 病毒(HBV ) 当模特儿并且在抗病毒的药评估决定它的应用程序，我们构造了表情包含了 HBV 染色体的 1.3 个拷贝，并且在 Huh7 房间在短暂 transfection 以后测量了病毒的复制的水平的 plasmid。我们然后观察了抗病毒的药管理的效果。HBV (ayw ) 基因碎片的 1.3 褶层被 PCR 和限制 endonuclease 消化克隆进 pCR2.1。recombinant plasmid 是进 Huh7 房间， HBsAg， HBeAg 和 HBV 的短暂 transfected 在 Huh7 房间的上层清液的 DNA 被 ELISA 和即时 PCR 分别地测量；细胞内部的 HBV replicative 中介和细胞内部的 HBV 抄本被南部的污点和北污点分别地检测。adefovir 的抗病毒的效果，新奇 anti-HBV 核苷酸类似物，在这个细胞的模型系统被评估。结果显示 HBV replicon 的 recombinant plasmid 成功地被构造；在 plasmid pHBV1.3 带的 HBV 染色体能高效地复制并且被表示在哈 7 个房间， adefovir 能在这个细胞的模型，和抑制禁止 HBV 复制是剂量依赖者。结论是 HBV replicon，能在 hepatoma 房间高效地开始病毒的复制，可以是在 HBV 复制和抗病毒的药的学习的一个有用工具。关键词肝炎 B 病毒 - 传染 replicon - 表示向量 CLC 数字 R373 基础条款：国家自然科学基础(No.30271170， No.30170889 ) 。

Silencing of UBP43 by shRNA Enhances the Antiviral Activity of Interferon against Hepatitis B Virus

Previous studies have shown that expression of the interferon-sensitive gene （ISG）15 protease UBP43 is increased in the liver biopsy specimens of patients who do not respond to interferon （IFN）-α therapy. We hypothesized that UBP43 might hinder the ability of IFN to inhibit HBV replication. In this study, we investigated whether vector-based siRNA promoted by HI （psiUBP43） could enhance IFN inhibiting HBV replication in cell culture. UBP43 was specifically silenced using shRNA. In HepG2.2.15 cells, the HBeAg and HBV DNA levels were significantly reduced by IFN after transfection of shRNA, imphicated that vector-based siRNA promoted by H1 （psiUBP43） could enhance IFN inhibiting HBV replication in cell culture. These data suggest that UBP43 modulates the anti-HBV type I IFN response, and is a possible therapeutic target for the treatment of HBV infection.

Effect of Hepatitis C Virus Core Protein on Interferon-Induced Antiviral Genes Expression and Its Mechanisms

Emerging data indicated that HCV subverts the antiviral activity of interferon(IFN);however,whether HCV core protein contributes to the process remains controversial.In the present study,we examined the effect of HCV core protein on interferon-induced antiviral gene expression and whether the effect is involved in the activation and negative regulation of the Jak/STAT signaling pathway.Our results showed that,following treatment with IFN-α,the transcription of PKR,MxA and 2'-5'OAS were down-regulated in HepG2 cells expressing the core protein.In the presence of HCV core protein,ISRE-dependent luciferase activity also decreased.Further study indicated that the core protein could inhibit the tyrosine phosphorylation of STAT1,whereas the level of STAT1 expression was unchanged.Accordingly,SOCS3,the negative regulator of the Jak/STAT pathway,was induced by HCV core protein.These results suggests that HCV core protein may interfere with the expression of some interferon-induced antiviral genes by inhibiting STAT1 phosphorylation and induction of SOCS3.