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1.
BMC Vet Res ; 15(1): 134, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064364

RESUMO

BACKGROUND: Duck viral hepatitis (DVH) is an acute disease of young ducklings with no effective veterinary drugs for treatment. Gynostemma pentaphyllum is a well-known traditional Chinese medicine that plays an important role in the treatment of various diseases. Gypenoside (GP), one of the main ingredients of Gynostemma pentaphyllum, was reported with good hepatoprotective effects. However, its low solubility limits its application in the clinics. To improve its solubility and bioactivity, a phosphorylated derivative of gypenoside (pGP) was prepared by the sodium trimetaphosphate-sodium tripolyphosphate (STMP-STPP) method. An infrared spectroscopy method was applied to analyse the structures of GP and pGP. Then, a methyl thiazolyl tetrazolium (MTT) colorimetric assay was applied to study the hepatocyte protective efficacy of these two drugs against duck hepatitis A virus type 1 (DHAV-1) infection, and qPCR, TUNEL labelling and flow cytometry methods were used to study the relevant hepatocyte protective in vitro. RESULTS: The infrared spectroscopy detection results showed that the phosphorylation modification of GP was successful. The MTT colorimetric assay results showed that both GP and pGP possessed good hepatocyte protective efficacy in vitro, and pGP performed better than GP when the drug was added before or after virus inoculation. Furthermore, the qPCR results revealed that both drugs could effectively inhibit the adsorption (when adding GP and pGP pre-virus inoculation), replication and release of DHAV-1, and the viral inhibition rate of pGP was greater than that of GP. The subsequent TUNEL labelling and flow cytometry assays showed that both GP and pGP could significantly inhibit duck embryo hepatocyte apoptosis induced by DHAV-1, and the inhibition effect of pGP was much stronger than that of GP. CONCLUSIONS: GP exerts good hepatocyte protective efficacy not only by inhibiting the proliferation of DHAV-1 but also by inhibiting duck embryonic hepatocyte apoptosis induced by DHAV-1, and phosphorylation modification significantly improves the antiviral and the anti-apoptotic effects of GP. Therefore, pGP has the potential to be developed into a novel drug against DHAV-1 infection.


Assuntos
Vírus da Hepatite do Pato/efeitos dos fármacos , Animais , Antivirais/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Patos , Gynostemma/química , Hepatite Viral Animal/tratamento farmacológico , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Fosforilação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Replicação Viral/efeitos dos fármacos
2.
Nat Commun ; 9(1): 4805, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442932

RESUMO

CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.


Assuntos
Células Endoteliais/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Fígado/efeitos dos fármacos , Proteínas Citotóxicas Formadoras de Poros/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Sulfonamidas/farmacologia , Adenoviridae/genética , Adenoviridae/imunologia , Adenoviridae/patogenicidade , Animais , Anticorpos/administração & dosagem , Antígenos CD40/antagonistas & inibidores , Antígenos CD40/genética , Antígenos CD40/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Capilares/efeitos dos fármacos , Capilares/virologia , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/virologia , Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hepatite Viral Animal/imunologia , Hepatite Viral Animal/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Hepatócitos/virologia , Humanos , Fígado/irrigação sanguínea , Fígado/patologia , Fígado/virologia , Luciferases/genética , Luciferases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/administração & dosagem , Poli I-C/administração & dosagem , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/imunologia
3.
Hepatology ; 67(6): 2127-2140, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29251788

RESUMO

Nucleic acid polymer (NAP) REP 2139 treatment was shown to block the release of viral surface antigen in duck HBV (DHBV)-infected ducks and in patients with chronic HBV or HBV/hepatitis D virus infection. In this preclinical study, a combination therapy consisting of REP 2139 with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was evaluated in vivo in the chronic DHBV infection model. DHBV-infected duck groups were treated as follows: normal saline (control); REP 2139 TDF; REP 2139 + TDF; and REP 2139 + TDF + ETV. After 4 weeks of treatment, all animals were followed for 8 weeks. Serum DHBsAg and anti-DHBsAg antibodies were monitored by enzyme-linked immunosorbent assay and viremia by qPCR. Total viral DNA and covalently closed circular DNA (cccDNA) were quantified in autopsy liver samples by qPCR. Intrahepatic DHBsAg was assessed at the end of follow-up by immunohistochemistry. On-treatment reduction of serum DHBsAg and viremia was more rapid when REP 2139 was combined with TDF or TDF and ETV, and, in contrast to TDF monotherapy, no viral rebound was observed after treatment cessation. Importantly, combination therapy resulted in a significant decrease in intrahepatic viral DNA (>3 log) and cccDNA (>2 log), which were tightly correlated with the clearance of DHBsAg in the liver. CONCLUSION: Synergistic antiviral effects were observed when REP 2139 was combined with TDF or TDF + ETV leading to control of infection in blood and liver, associated with intrahepatic viral surface antigen elimination that persisted after treatment withdrawal. Our findings suggest the potential of developing such combination therapy for treatment of chronically infected patients in the absence of pegylated interferon. (Hepatology 2018;67:2127-2140).


Assuntos
Antivirais/administração & dosagem , Guanina/análogos & derivados , Infecções por Hepadnaviridae/tratamento farmacológico , Vírus da Hepatite B do Pato/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Ácidos Nucleicos/administração & dosagem , Polímeros/administração & dosagem , Tenofovir/administração & dosagem , Animais , Doença Crônica , Sinergismo Farmacológico , Quimioterapia Combinada , Patos , Guanina/administração & dosagem
4.
Artigo em Inglês | MEDLINE | ID: mdl-28638862

RESUMO

BACKGROUND: Duck viral hepatitis (DVH), caused by duck hepatitis A virus (DHAV), is a fatal contagious infectious disease which spreads rapidly with high morbidity and high mortality, and there is no effective clinical drug against DVH. MATERIALS AND METHODS: Raw Rehmannia Radix Polysaccharide (RRRP), Lycii Fructus polysaccharides and Astragalus Radix polysaccharides were experimented in vitro and in vivo. Mortality rate, livers change, liver lesion scoring, peroxidative injury evaluation indexes in vitro and in vivo, and hepatic injury evaluation indexes of optimal one were detected and observed in this experiment. RESULTS: RRRP could reduce mortality with the protection rate about 20.0% compared with that of the viral control (VC) group, finding that RRRP was the most effective against DHAV. The average liver scoring of the VC, blank control (BC), RRRP groups were 3.5, 0, 2.1. Significant difference (P<0.05) appeared between any two groups, demonstrating that it can alleviate liver pathological change. RRRP could make the hepatic injury evaluation indexes similar to BC group while the levels of the VC group were higher than other two groups in general. The levels of SOD, GSH-Px, CAT of RRRP group showed significant higher than that of VC group while the levels of NOS and MDA showed the opposite tendency, thus, RRRP could release peroxidative injury. CONCLUSION: RRRP was the most effective against duck hepatitis A virus (DHAV). RRRP could reduce mortality, alleviate liver pathological change, down-regulate liver lesion score, release peroxidative injury and hepatic injury. The antiviral and peroxidative injury releasing activity of RRRP for DHAV provided a platform to test novel drug strategies for hepatitis A virus in human beings.


Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite do Pato/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Polissacarídeos/administração & dosagem , Doenças das Aves Domésticas/tratamento farmacológico , Rehmannia/química , Animais , Astrágalo (Planta)/química , Patos , Vírus da Hepatite do Pato/fisiologia , Hepatite Viral Animal/diagnóstico por imagem , Hepatite Viral Animal/metabolismo , Hepatite Viral Animal/virologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/virologia , Raízes de Plantas/química , Doenças das Aves Domésticas/metabolismo , Doenças das Aves Domésticas/virologia
5.
PLoS One ; 12(4): e0175495, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28394931

RESUMO

The principal target organ of duck hepatitis A virus type 1 (DHAV-1) is duckling liver, which is an energy-intensive organ and plays important roles in body's energy metabolism and conversion. As the "power house" of the hepatocytes, mitochondria provide more than 90% of the energy. However, mitochondria are much vulnerable to the oxidative stress for their rich in polyunsaturated fatty acids. Although previous researches have demonstrated that DHAV-1 could induce the oxidative stress in the serum of the infected ducklings, no related study on the mitochondria during the pathological process of DVH has been reported by far. To address this issue, we examined the HE stained tissue pathological slices, detected the hepatic SOD, CAT and GPX activities and MDA contents and analyzed the ATP content, mitochondrial ultrastructure and the mitochondrial SOD, GPX activities and MDA content in the liver tissues. The results showed that the hepatic redox status was significantly disturbed so that causing the mitochondrial dysfunction, ATP depletion and mitochondrial oxidative stress during the process of the DHAV-1 infection, and a prescription formulated with Hypericum japonicum flavone, Radix Rehmanniae Recens polysaccharide and Salvia plebeia flavone (HRS), which had been demonstrated with good anti-oxidative activity in serum, could effectively alleviate the hepatic injury and the oxidative stress in liver tissue induced by DHAV-1 thus alleviating the mitochondrial injury and oxidative stress. In a word, this research discovers the oxidative stress induced mitochondrial dysfunction and oxidative stress during the DVH pathological process and demonstrates HRS exerts good anti-oxidative activity in liver tissue to protect mitochondria against reactive oxygen species (ROS).


Assuntos
Antivirais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Vírus da Hepatite do Pato , Hepatite Viral Animal/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Infecções por Picornaviridae/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Patos , Flavonas/farmacologia , Glutationa Peroxidase/metabolismo , Hepatite Viral Animal/metabolismo , Hepatite Viral Animal/mortalidade , Hepatite Viral Animal/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Malondialdeído/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Infecções por Picornaviridae/metabolismo , Infecções por Picornaviridae/mortalidade , Infecções por Picornaviridae/patologia , Polissacarídeos/farmacologia , Distribuição Aleatória , Superóxido Dismutase/metabolismo , Resultado do Tratamento
6.
J Immunol ; 198(9): 3448-3460, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28363907

RESUMO

Although large amounts of vitamin A and its metabolite all-trans retinoic acid (RA) are stored in the liver, how RA regulates liver immune responses during viral infection remains unclear. In this study, we demonstrated that IL-22, mainly produced by hepatic γδ T cells, attenuated liver injury in adenovirus-infected mice. RA can promote γδ T cells to produce mTORC1-dependent IL-22 in the liver, but inhibits IFN-γ and IL-17. RA also affected the aptitude of T cell responses by modulating dendritic cell (DC) migration and costimulatory molecule expression. These results suggested that RA plays an immunomodulatory role in viral infection. Proteomics data revealed that RA downregulated S100 family protein expression in DCs, as well as NF-κB/ERK pathway activation in these cells. Furthermore, adoptive transfer of S100A4-repressed, virus-pulsed DCs into the hind foot of naive mice failed to prime T cell responses in draining lymph nodes. Our study has demonstrated a crucial role for RA in promoting IL-22 production and tempering DC function through downregulating S100 family proteins during viral hepatitis.


Assuntos
Adenoviridae/imunologia , Células Dendríticas/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Interleucinas/metabolismo , Fígado/imunologia , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Tretinoína/uso terapêutico , Animais , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/virologia , Feminino , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/genética , Interleucinas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Linfócitos T/imunologia , Linfócitos T/virologia
7.
Methods Mol Biol ; 1540: 277-294, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27975326

RESUMO

An estimated 350 million people are chronically infected with hepatitis B virus (HBV), and over one million people die each year due to HBV-associated liver diseases, such as cirrhosis and liver cancer. Current therapeutics for chronic HBV infection are limited to nucleos(t)ide analogs and interferon. These anti-HBV drugs in general reduce viral load and improve the long-term outcome of infection but very rarely lead to a cure. Thus, new therapies for chronic HBV infection need to be developed by utilizing liver cell lines and primary cultures and small laboratory animals capable of replicating HBV or surrogate hepadnaviruses for antiviral testing. Natural infection with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to HBV, occurs in woodchucks. Chronic WHV infection has been established over decades as a suitable model for evaluating direct-acting antivirals as well as vaccines, vaccine adjuvants, and immunotherapeutics because animals are fully immunocompetent. Before HBV-specific compounds are applied to woodchucks, they are usually tested in primary woodchuck hepatocytes (PWHs) replicating WHV at high levels for confirming drug specificity against viral or host targets. Here we describe a protocol for the isolation of PWHs from liver of WHV-infected woodchucks, maintenance in culture, and use in assays for determining antiviral efficacy, safety, and associated host innate immune response of new experimental drugs. Exemplary assays were performed with the nucleoside analog, lamivudine, and the immunomodulator, interferon-alpha.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B da Marmota/imunologia , Hepatite Viral Animal/imunologia , Hepatite Viral Animal/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Imunidade Inata , Animais , Separação Celular , Sobrevivência Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Hepatócitos/virologia , Imunidade Inata/genética , Fatores Imunológicos/farmacologia , Interferon-alfa/farmacologia , RNA Viral , Replicação Viral
8.
Int J Biol Macromol ; 94(Pt A): 28-35, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27713010

RESUMO

To screen effective anti-duck hepatitis A virus (DHAV) drugs, we applied STMP-STPP method to prepare phosphorylated Codonopsis pilosula polysaccharide (pCPPS), the phosphorylation-modified product of Codonopsis pilosula polysaccharide (CPPS). The IR spectrum and field emission scanning electron microscope (FE-SEM) were subsequently used to analyze the structure of pCPPS. Several tests were conducted to compare the anti-DHAV activities of CPPS and pCPPS. The MTT method was used to compare the effect of the drugs on DHAV-infected duck embryonic hepatocytes (DEHs), and the Reed-Muench assay was employed to observe changes in the virulence of DHAV. We also applied real-time PCR to examine the relationship between virus replication and the expression of IFN-ß. The results indicated that CPPS could not inhibit the replication of DHAV. In contrast, pCPPS increased the virus TCID50, inhibited viral replication and, accordingly, increased the survival rate of DEHs infected with DHAV. Because DHAV induced the expression of IFN-ß, and the IFN-ß expression level was positively associated with the number of DHAV, the reduction of IFN-ß expression levels after pCPPS treatment demonstrated a decrease in the number of virus particles. These results indicated that pCPPS, which reduces the number of DHAV, was more effective than CPPS in anti-DHAV activity.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite do Pato/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Doenças das Aves Domésticas/tratamento farmacológico , Animais , Proteínas Aviárias/metabolismo , Células Cultivadas , Codonopsis/química , Avaliação Pré-Clínica de Medicamentos , Patos , Vírus da Hepatite do Pato/fisiologia , Hepatite Viral Animal/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Interferon beta/metabolismo , Doenças das Aves Domésticas/virologia , Virulência , Replicação Viral/efeitos dos fármacos
9.
Exp Biol Med (Maywood) ; 242(3): 344-353, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27703041

RESUMO

Duck hepatitis A virus (DHAV) (Picornaviridae) causes an infectious disease in ducks which results in severe losses in duck industry. However, the proper antiviral supportive drugs for this disease have not been discovered. Polysaccharide is the main ingredient of Astragalus that has been demonstrated to directly and indirectly inhibit RNA of viruses replication. In this study, the antiviral activities of Astragalus polysaccharide (APS) and its derivatives against DHAV were evaluated and compared. APS was modified via the sodium trimetaphosphate and sodium tripolyphosphate (STMP-STPP) method and chlorosulfonic acid-pyridine method to obtain its phosphate (pAPS) and sulfate (sAPS), respectively. The infrared structures of APS, pAPS, and sAPS were analyzed with the potassium bromide disc method. Additionally, the antiviral activities were evaluated with the MTT ((4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) method in vitro and the artificial inoculation method in vivo. The clinical therapy effects were evaluated by mortality rate, liver function-related biochemical indicators, and visual changes in pathological anatomy. The anti-DHAV proliferation effects of APS, pAPS, and sAPS on the viral multiplication process in cell and blood were observed with the reverse transcription-polymerase chain reaction method. The results revealed that pAPS inhibited DHAV proliferation more efficiently in the entire process of viral multiplication than APS and sAPS. Moreover, only pAPS significantly improved the survival rate to 33.5% and reduced the DHAV particle titer in the blood as well as liver lesions in clinical trials. The results indicated that pAPS exhibited greater anti-DHAV activity than APS and sAPS both in vitro and in vivo.


Assuntos
Astrágalo (Planta)/química , Vírus da Hepatite do Pato/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Infecções por Picornaviridae/tratamento farmacológico , Polissacarídeos/farmacologia , Doenças das Aves Domésticas/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Animais , Patos/virologia , Medicina Tradicional Chinesa , Fosforilação , Preparações de Plantas/farmacologia , Polissacarídeos/química , Doenças das Aves Domésticas/virologia , Sulfatos/química , Sulfatos/farmacologia
10.
J Pineal Res ; 61(2): 168-76, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27101794

RESUMO

The sphingosine kinase (SphK)1/sphingosine-1-phosphate (S1P) pathway is involved in multiple biological processes, including liver diseases. This study investigate whether modulation of the SphK1/S1P system associates to the beneficial effects of melatonin in an animal model of acute liver failure (ALF) induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2 × 10(4) hemagglutination units of a RHDV isolate and received 20 mg/kg of melatonin at 0, 12, and 24 hr postinfection. Liver mRNA levels, protein concentration, and immunohistochemical labeling for SphK1 increased in RHDV-infected rabbits. S1P production and protein expression of the S1PR1 receptor were significantly elevated following RHDV infection. These effects were significantly reduced by melatonin. Rabbits also exhibited increased expression of toll-like receptor (TLR)4, tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, nuclear factor-kappa B (NF-κB) p50 and p65 subunits, and phosphorylated inhibitor of kappa B (IκB)α. Melatonin administration significantly inhibited those changes and induced a decreased immunoreactivity for RHDV viral VP60 antigen in the liver. Results obtained indicate that the SphK1/S1P system activates in parallel to viral replication and the inflammatory process induced by the virus. Inhibition of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in this animal model of ALF, and supports the potential of melatonin as an antiviral agent.


Assuntos
Infecções por Caliciviridae/metabolismo , Vírus da Doença Hemorrágica de Coelhos , Hepatite Viral Animal/metabolismo , Falência Hepática Aguda/metabolismo , Lisofosfolipídeos/metabolismo , Melatonina/farmacocinética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Animais , Infecções por Caliciviridae/tratamento farmacológico , Hepatite Viral Animal/tratamento farmacológico , Falência Hepática Aguda/tratamento farmacológico , Masculino , Coelhos , Esfingosina/metabolismo
11.
PLoS One ; 11(1): e0146046, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26731101

RESUMO

Because polysaccharide and flavone ingredients display good antiviral activity, we developed a flavone/polysaccharide-containing prescription that would be effective against duck viral hepatitis (DVH) and investigated its hepatoprotective effects. Flavones were derived from Hypericum japonicum (HJF) (entire herb of Hypericum japonicum Thunb) and Salvia plebeia (SPF) (entire herb of Salvia plebeia R. Br.), and polysaccharides were derived from Radix Rehmanniae Recens (RRRP) (dried root of Rehmannia glutinosa Libosch). This prescription combination was based on the theory of syndrome differentiation and treatment in traditional Chinese veterinary medicine. In vitro and in vivo experiments were conducted using the three single ingredients compared to the combined HRS prescription to determine their anti-duck hepatitis A viral (anti-DHAV) activity. The results showed that all experimental conditions displayed anti-DHAV activity, but the HRS prescription presented the best effect. To further investigate the hepatoprotective effect of the HRS prescription on DHAV-induced hepatic injury, we tested the mortality rate, the hepatic pathological severity score, plasma biochemical indexes of hepatic function, blood DHAV gene expression levels and peroxidation damage evaluation indexes and then analyzed correlations among these indexes. The results demonstrated that the HRS prescription significantly decreased the mortality rate, reduced the severity of hepatic injury, decreased the hepatic pathological severity score, depressed blood DHAV gene expression levels, and returned the indexes of hepatic function and peroxidation almost to a normal level. These results indicate that the HRS prescription confers an outstanding hepatoprotective effect, and we expect that it will be developed into a new candidate anti-DHAV drug.


Assuntos
Antivirais/uso terapêutico , Patos/virologia , Flavonas/uso terapêutico , Vírus da Hepatite do Pato/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Infecções por Picornaviridae/veterinária , Polissacarídeos/uso terapêutico , Animais , Antivirais/química , Flavonas/química , Hepatite Viral Animal/patologia , Hypericum/química , Lamiales/química , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/patologia , Polissacarídeos/química , Salvia/química , Drogas Veterinárias/química , Drogas Veterinárias/uso terapêutico
12.
PLoS One ; 10(11): e0140909, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26560490

RESUMO

Previous studies have demonstrated that nucleic acid polymers (NAPs) have both entry and post-entry inhibitory activity against duck hepatitis B virus (DHBV) infection. The inhibitory activity exhibited by NAPs prevented DHBV infection of primary duck hepatocytes in vitro and protected ducks from DHBV infection in vivo and did not result from direct activation of the immune response. In the current study treatment of primary human hepatocytes with NAP REP 2055 did not induce expression of the TNF, IL6, IL10, IFNA4 or IFNB1 genes, confirming the lack of direct immunostimulation by REP 2055. Ducks with persistent DHBV infection were treated with NAP 2055 to determine if the post-entry inhibitory activity exhibited by NAPs could provide a therapeutic effect against established DHBV infection in vivo. In all REP 2055-treated ducks, 28 days of treatment lead to initial rapid reductions in serum DHBsAg and DHBV DNA and increases in anti-DHBs antibodies. After treatment, 6/11 ducks experienced a sustained virologic response: DHBsAg and DHBV DNA remained at low or undetectable levels in the serum and no DHBsAg or DHBV core antigen positive hepatocytes and only trace amounts of DHBV total and covalently closed circular DNA (cccDNA) were detected in the liver at 9 or 16 weeks of follow-up. In the remaining 5/11 REP 2055-treated ducks, all markers of DHBV infection rapidly rebounded after treatment withdrawal: At 9 and 16 weeks of follow-up, levels of DHBsAg and DHBcAg and DHBV total and cccDNA in the liver had rebounded and matched levels observed in the control ducks treated with normal saline which remained persistently infected with DHBV. These data demonstrate that treatment with the NAP REP 2055 can lead to sustained control of persistent DHBV infection. These effects may be related to the unique ability of REP 2055 to block release of DHBsAg from infected hepatocytes.


Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite do Pato/isolamento & purificação , Hepatite Viral Animal/tratamento farmacológico , Oligodesoxirribonucleotídeos/uso terapêutico , Infecções por Picornaviridae/tratamento farmacológico , Animais , Citocinas/biossíntese , Patos , Hepatite Viral Animal/patologia , Hepatite Viral Animal/virologia , Infecções por Picornaviridae/patologia , Infecções por Picornaviridae/virologia
13.
BMC Vet Res ; 11: 205, 2015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-26272639

RESUMO

BACKGROUND: Our previous research showed that icariin (1) and its phosphorylated structural modification (2) improved the survival and attenuated oxidative stress and liver dysfunction induced by duck virus hepatitis. In this paper, we were one step closer to determine the structure of phosphorylation icariin (2) by the FT-IR, HRESIMS and (13)C NMR. Anti-DHAV activities of 1 and 2 were compared in duck embryonic hepatocytes (DEHs) cultured in vitro and by artificial infection method in vivo. Additionally, the antiviral mechanisms of replication/release in vitro and the DHAV gene expression in vivo of 1 and 2 were analyzed. RESULTS: Compound 2's molecular formula was C33H42O18P. The results indicated that 1 and 2 effectively resisted DHAV invading DEHs, that they decreased the mortality of ducklings challenged with DHAV, and that 2 performed more effectively. 1 and 2 performed evenly on DHAV release; however, 2 restrained virus replication far more effectively. Since the anti-DHAV mechanisms of 1 and 2 in vitro probably involve suppression of replication and release, 2's better performance in anti-DHAV may result from its far more effectively inhibiting virus replication. CONCLUSIONS: The compound 2's chemical structure was defined as 8-prenylkaempferol-4'-methylether-3-rhamnosyl-7-(6'''-phosphate)-glycoside. 1 and 2 exhibited anti-virus activity on DHAV. Our results suggest that 1 and 2 might become an anti-virus plant material candidate.


Assuntos
Antivirais/química , Antivirais/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Vírus da Hepatite do Pato/efeitos dos fármacos , Animais , Patos , Hepatite Viral Animal/tratamento farmacológico , Hepatite Viral Animal/virologia , Estrutura Molecular , Fosforilação , Doenças das Aves Domésticas/tratamento farmacológico , Replicação Viral/efeitos dos fármacos
14.
J Gastroenterol ; 50(11): 1145-51, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26208695

RESUMO

BACKGROUND: Resistance-associated variants (RAVs) emerge at multiple positions spanning hepatitis C virus (HCV) NS3/4A and NS5A regions upon failure of asunaprevir/daclatasvir combination therapy. It has not been determined whether the emergence of such RAVs have an impact on re-treatment by a combination of ledipasvir and sofosbuvir, a potent regimen for HCV genotype 1 infection. METHODS: TK-NOG human hepatocyte chimeric mice were inoculated with sera from a patient with treatment failure of asunaprevir/daclatasvir therapy. RESULTS: They developed persistent HCV infection with triple variants of NS3/4A D168V, NS5A L31V plus Y93H. Administration of ledipasvir/GS-558093 (a NS5B nucleotide analog) in these mice failed to achieve end-of-treatment response or sustained virologic response, which was in sharp contrast to the results in mice with wild-type virus infection. The administration of telaprevir/GS-558093 successfully achieved it in those mice. CONCLUSIONS: Treatment failure with asunaprevir/daclatasvir may limit further treatment options. This population may represent a growing unmet medical need.


Assuntos
Farmacorresistência Viral Múltipla/genética , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite Viral Animal/tratamento farmacológico , Animais , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Combinação de Medicamentos , Feminino , Fluorenos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/virologia , Hepatite Viral Animal/virologia , Hepatócitos/virologia , Humanos , Imidazóis/uso terapêutico , Isoquinolinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Quimeras de Transplante , Falha de Tratamento
15.
Int J Biol Macromol ; 80: 217-24, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26118485

RESUMO

Bush Sophora Root polysaccharide (BSRPS) and its sulfate, sulfated Bush Sophora Root polysaccharide (sBSRPS), possess the antiviral activities against duck hepatitis A virus. However their antiviral mechanisms are still not clear. This paper reported their immuno-enhancing roles in the therapeutic effects for duck virus hepatitis (DVH). The effects of BSRPS and sBSRPS on stimulating lymphocyte proliferation were investigated by MTT methods. After that, ducklings were challenged with DHAV and treated with BSRPS and sBSRPS. Meanwhile, the total antibody (Ab), cytokines including interferon gamma (IFN-γ), hepatocyte growth factor (HGF), interleukin (IL)-2, IL-6 and IL-8 were determined by enzyme-linked immuno sorbent assay methods. The results showed that BSRPS owned a fine hepatoprotective effect with stable HGF producing ability. Sulfated modification was able to increase the proliferation rates of B and T lymphocytes and the secretions of total Ab, IFN-γ and IL-2, as comparison with those of BSRPS group. In summary, both of them exhibited immuno-enhancing effects on the therapeutic effects for DVH, and the capacity of sBSRPS was stronger than that of BSRPS.


Assuntos
Hepatite Viral Animal/tratamento farmacológico , Infecções por Picornaviridae/tratamento farmacológico , Raízes de Plantas/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Sophora/química , Sulfatos/química , Animais , Anticorpos Antivirais/sangue , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Patos , Vírus da Hepatite do Pato/efeitos dos fármacos , Vírus da Hepatite do Pato/imunologia , Vírus da Hepatite do Pato/fisiologia , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Polissacarídeos/uso terapêutico , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos
16.
Virus Res ; 204: 58-67, 2015 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-25901935

RESUMO

In our previous study, Bush Sophora Root polysaccharide (BSRPS) and its sulfate (sBSRPS) exhibited anti-duck virus hepatitis (DVH) abilities as well as anti-oxidative and immuno-enhancement effects. The aim of this paper was to ulteriorly investigate the exact anti-DVH mechanisms of BSRPS and sBSRPS by intervention experiments. Hinokitiol and FK506 were used as the pro-oxidant and immunosuppressant, respectively. The dynamic deaths, oxidative and immune evaluation indexes and hepatic pathological change scores were detected. When was intervened by hinokitiol, sBSRPS still possessed therapeutic effect while BSPRS was useless. Under the condition of immunosuppression, BSRPS lost a part role in treating DVH; however such a role of sBSRPS completely exhausted. These results suggested both anti-oxidative and immuno-enhancement effects of BSRPS played roles in healing DVH, and the former was more crucial; unlike BSRPS, only immuno-enhancement ability of sBSRPS was imperative for its curative effect on DVH.


Assuntos
Antioxidantes/farmacologia , Patos/virologia , Vírus da Hepatite do Pato/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Infecções por Picornaviridae/tratamento farmacológico , Polissacarídeos/farmacologia , Doenças das Aves Domésticas/tratamento farmacológico , Sophora/química , Animais , Hepatite Viral Animal/patologia , Hepatite Viral Animal/virologia , Imunossupressores/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Monoterpenos/farmacologia , Infecções por Picornaviridae/patologia , Infecções por Picornaviridae/virologia , Raízes de Plantas/química , Doenças das Aves Domésticas/patologia , Doenças das Aves Domésticas/virologia , Distribuição Aleatória , Sulfatos/farmacologia , Tacrolimo/farmacologia , Tropolona/análogos & derivados , Tropolona/farmacologia
18.
Carbohydr Polym ; 117: 339-45, 2015 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-25498644

RESUMO

This paper studied the anti-duck hepatitis A virus (DHAV) activities of Astragalus polysaccharide (APS) and its sulfate (sAPS) compared with those of Bush Sophora Root polysaccharide (BSRPS) and its sulfate (sBSRPS). The antiviral activities of APS and sAPS were measured by MTT and real-time PCR methods, in vitro. In vivo experiment, the mortality rate and the evaluation indexes of hepatic injury, peroxidative injury and immune level were measured. Just like the condition of BSRPS and sBSRPS, the anti-DHAV activities of sAPS were stronger than those of APS, both in vitro and in vivo. It indicated sulfated modification could enhance the antiviral ability of polysaccharide. But unlike the antiviral effects of BSPRS and sBSRPS in vivo, APS and sAPS did not reduce the mortality rates as their abilities of scavenging free radicals and alleviating the hepatic injuries were weaker than those of BSRPS and sBSRPS. And they even did not enhance the immune levels.


Assuntos
Antivirais/farmacologia , Fabaceae/química , Vírus da Hepatite do Pato/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Antivirais/uso terapêutico , Células Cultivadas , Patos , Extratos Vegetais/uso terapêutico , Polissacarídeos/uso terapêutico , Sulfatos/química
19.
J Ethnopharmacol ; 160: 1-5, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25446633

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Acanthus ilicifolius L. is an important medicinal mangrove plant. It is popularly used for its anti-inflammatory, antioxidant activity and hepatoprotective effects. The present study was conducted to evaluate the effect of treatment with alcohol extract of Acanthus ilicifolius L. on duck hepatitis B. MATERIALS AND METHODS: One-day-old Guangxi shelducks injected intraperitoneally with strong positive duck hepatitis B virus (DHBV) serum were used to establish a duck hepatitis B animal model in the study. The ducks were respectively administered in different groups with low-, middle- and high-dose alcohol extracts of Acanthus ilicifolius L., the positive control drug acyclovir (ACV) and double-distilled water. The levels of serum DHBV DNA were detected by fluorescence quantitative PCR (FQ-PCR). Duck hepatitis B surface antigen (DHBsAg) and duck hepatitis B e antigen (DHBeAg) OD values in the serum were measured by ELISA. The activity of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) in the serum was measured, and the livers were taken for histopathological examination. RESULTS: The levels of serum DHBV DNA and the values of DHBsAg and DHBeAg OD were not significant in any of the dose extract groups. However, the ALT activity was obviously lower in the middle- and high-dose extract groups. It was also found that a high dose of alcohol extract could reduce the activity of AST significantly and significantly improve hepatic pathological effects. CONCLUSIONS: High-dose alcohol extract of Acanthus ilicifolius L. has an obvious protective effect on the liver function and liver tissue. However, the present study finds that Acanthus ilicifolius L. cannot inhibit the replication of duck hepatitis B virus.


Assuntos
Acanthaceae/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Infecções por Hepadnaviridae/tratamento farmacológico , Vírus da Hepatite B do Pato/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Fígado/efeitos dos fármacos , Fitoterapia , Aciclovir/farmacologia , Aciclovir/uso terapêutico , Alanina Transaminase/sangue , Animais , Animais Recém-Nascidos , Antivirais/farmacologia , Antivirais/uso terapêutico , Aspartato Aminotransferases/sangue , DNA Viral/sangue , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Patos , Infecções por Hepadnaviridae/patologia , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite Viral Animal/patologia , Fígado/patologia , Carga Viral/efeitos dos fármacos
20.
J Pharmacol Sci ; 126(3): 208-15, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25409748

RESUMO

A novel codrug, α-DDB-FNCG, was synthesized through coupling of α-biphenyl dimethyl dicarboxylate (α-DDB) and the nucleoside analogue FNCG, via an ester bond. The anti-HBV activity and hepatoprotective effects of this compound were investigated both in vitro and in vivo. In HBV-transfected HepG2.2.15 cell line, the secretion of HBsAg and HBeAg as well as the levels of extracellular and intracellular viral DNA were determined by ELISA and real-time fluorescent quantitative Polymerase Chain Reaction (FQ-PCR), respectively. In DHBV-infected ducks, the viral DNA levels in serum and liver were determined by FQ-PCR. In addition, the levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) in both serum and liver were also examined. The improvement of ducks' livers was evaluated by histopathological analysis. It has been demonstrated that α-DDB-FNCG could suppress the levels of HBV antigens and viral DNA in a time- and dose-dependent manner in the HepG2.2.15 cell line. Furthermore, this codrug could also significantly inhibit the viral DNA replication and reduce the ALT and AST levels in both serum and liver of DHBV-infected ducks, with improved hepatocellular architecture in drug-treated ducks. In short, these results suggest that α-DDB-FNCG could be a promising candidate for further development of new anti-HBV agents with hepatoprotective effects.


Assuntos
Antivirais/farmacologia , Benzodioxóis/farmacologia , Citidina/análogos & derivados , Infecções por Hepadnaviridae/tratamento farmacológico , Vírus da Hepatite B do Pato/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , Fígado/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Citidina/farmacologia , DNA Viral/metabolismo , Relação Dose-Resposta a Droga , Patos , Feminino , Células Hep G2 , Infecções por Hepadnaviridae/sangue , Infecções por Hepadnaviridae/patologia , Infecções por Hepadnaviridae/virologia , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B do Pato/genética , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite Viral Animal/sangue , Hepatite Viral Animal/patologia , Hepatite Viral Animal/virologia , Humanos , Fígado/enzimologia , Fígado/patologia , Fígado/virologia , Masculino , Fatores de Tempo , Transfecção , Carga Viral
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