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1.
J Virol ; 96(4): e0197521, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-34910612

RESUMO

Hepatocellular carcinoma (HCC) is a hypervascular tumor, and accumulating evidence has indicated that stimulation of angiogenesis by hepatitis B virus (HBV) may contribute to HCC malignancy. The small protein of hepatitis B virus surface antigen (HBsAg), SHBs, is the most abundant HBV protein and has a close clinical association with HCC; however, whether SHBs contributes to HCC angiogenesis remains unknown. This study reports that the forced expression of SHBs in HCC cells promoted xenograft tumor growth and increased the microvessel density (MVD) within the tumors. Consistently, HBsAg was also positively correlated with MVD counts in HCC patients' specimens. The conditioned media from the SHBs-transfected HCC cells increased the capillary tube formation and migration of human umbilical vein endothelial cells (HUVECs). Intriguingly, the overexpression of SHBs increased vascular endothelial growth factor A (VEGFA) expression at both the mRNA and protein levels. Higher VEGFA expression levels were also observed in xenograft tumors transplanted with SHBs-expressing HCC cells and in HBsAg-positive HCC tumor tissues than in their negative controls. As expected, in the culture supernatants, the secretion of VEGFA was also significantly enhanced from HCC cells expressing SHBs, which promoted HUVEC migration and vessel formation. Furthermore, all three unfolded protein response (UPR) sensors, inositol-requiring enzyme 1α (IRE1α), protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK), and activating transcription factor 6 (ATF6), associated with ER stress were found to be activated in SHBs-expressing cells and correlated with VEGFA protein expression and secretion. Taken together, these results suggest an important role of SHBs in HCC angiogenesis and may highlight a potential target for preventive and therapeutic intervention for HBV-related HCC and its malignant progression. IMPORTANCE Chronic hepatitis B virus infection is one of the important risk factors for the development and progression of hepatocellular carcinoma (HCC). HCC is characteristic of hypervascularization even at early phases of the disease due to the overexpression of angiogenic factors like vascular endothelial growth factor A (VEGFA). However, a detailed mechanism of HBV-induced angiogenesis remains to be established. In this study, we demonstrate for the first time that the most abundant HBV protein, i.e., small surface antigen (SHBs), can enhance the angiogenic capacity of HCC cells by the upregulation of VEGFA expression both in vitro and in vivo. Mechanistically, SHBs induced endoplasmic reticulum (ER) stress, which consequently activated unfolded protein response (UPR) signaling to increase VEGFA expression and secretion. This study suggests that SHBs plays an important proangiogenic role in HBV-associated HCC and may represent a potential target for antiangiogenic therapy in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Estresse do Retículo Endoplasmático , Antígenos de Superfície da Hepatite B/metabolismo , Neoplasias Hepáticas/patologia , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virologia , Camundongos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/virologia , Transdução de Sinais , Resposta a Proteínas não Dobradas , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Mol Oncol ; 15(1): 228-245, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33128264

RESUMO

Salt-inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial-mesenchymal transition via inhibition of AKT/GSK3ß/ß-catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3ß/ß-catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.


Assuntos
Autofagia , Fosfoproteínas Fosfatases/metabolismo , Proteína Fosfatase 2/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Animais , Linhagem Celular Tumoral , Estudos de Coortes , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Modelos Biológicos , Fenótipo , Fosfoproteínas Fosfatases/genética , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/genética , Regulação para Cima/genética , beta Catenina/metabolismo
3.
BMC Med ; 18(1): 250, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32762696

RESUMO

BACKGROUND: COVID-19 is an extremely severe infectious disease. However, few studies have focused on the epidemiological and clinical characteristics of pediatric COVID-19. This study conducted a retrospective review of the epidemiological and clinical features of COVID-19 in children. METHODS: A retrospective study was conducted on children with a definite diagnosis of COVID-19 in mainland China using the web crawler technique to collect anonymous COVID-19 updates published by local health authorities. RESULTS: Three hundred forty-one children aged 4 days to 14 years with a median age of 7 years were included. Sixty-six percent of pediatric patients were infected via family members with COVID-19. The median incubation period was 9 days (interquartile range, 6 to 13). Asymptomatic cases accounted for 5.9%, of which 30% had abnormal chest radiologic findings. A majority of pediatric COVID-19 cases showed mild to moderate clinical features, and only a few developed severe or critical diseases (0.6% and 0.3%, respectively). Fever (77.9%) and cough (32.4%) were the predominant presenting symptoms of pediatric COVID-19. The pediatric patients had fewer underlying diseases and complications than adults. The treatment modalities for pediatric COVID-19 patients were not as complex as those of adult COVID-19 patients. The overall prognosis of pediatric COVID-19 was benign with a decent recovery. The median time from onset to cure was 16 days (interquartile range, 13 to 21). CONCLUSIONS: Compared to adults, COVID-19 in children has distinct features of epidemiology and clinical manifestations. The findings from this study might help to guide the development of measures to prevent and treat this ongoing global pandemic. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( chictr.org.cn ) identifier: ChiCTR2000030464.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Adolescente , COVID-19 , Criança , Pré-Escolar , China/epidemiologia , Tosse/etiologia , Feminino , Febre/etiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pandemias , Estudos Retrospectivos , SARS-CoV-2
5.
Toxicol Appl Pharmacol ; 381: 114729, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31445927

RESUMO

The PI3K/AKT signaling pathway is one of the most frequently activated signaling networks in human cancers and has become a valuable target in anticancer therapy. However, accumulating reports suggest that adverse effects such as severe liver injury and inflammation may accompany treatment with pan-PI3K and pan-AKT inhibitors. Our prior work has demonstrated that activation of the PI3K/AKT pathway has a protective role in Fas- or TNFα-induced hepatocytic cell death and liver injury. We postulated that PI3K or AKT inhibitors may exacerbate liver damage via the death factor-mediated hepatocyte apoptosis. In this study we found that several drugs targeting PI3K/AKT either clinically used or in clinical trials sensitized hepatocytes to agonistic anti-Fas antibody- or TNFα-induced apoptosis and significantly shortened the survival of mice in in vivo liver damage models. The PI3K or AKT inhibitors promoted Fas aggregation, inhibited the expression of cellular FLICE-inhibitory protein S and L (FLIPL/S), and enhanced procaspase-8 activation. Conversely, cotreatment with the AKT specific activator SC79 reversed these effects. Taken together, these findings suggest that PI3K or AKT inhibitors may render hepatocytes hypersensitive to Fas- or TNFα-induced apoptosis and liver injury.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas , Hepatócitos/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase/toxicidade , Inibidores de Proteínas Quinases/toxicidade , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Aminopiridinas/toxicidade , Animais , Anticorpos/toxicidade , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Imidazóis/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Purinas/toxicidade , Quinazolinonas/toxicidade , Fator de Necrose Tumoral alfa/toxicidade
6.
Toxicol Appl Pharmacol ; 377: 114626, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31201821

RESUMO

Microcystin-LR (MC-LR) is a type of cyclic heptapeptide toxin produced by cyanobacteria during bloom events. MC-LR-induced cell death is critically involved in its potent specific hepatotoxicity. Many studies have demonstrated that prototypical apoptosis as a form of programmed cell death after MC-LR is associated with liver injury. However, whether another form of programmed cell death exists and the underlying mechanism have not been reported. Here, we demonstrate that MC-LR can induce necroptosis via ROS overactivation in primary mouse hepatocytes. Various potential pathways of programmed cell death induced by MC-LR were evaluated by annexin V/PI dual staining for flow cytometric analysis, image-based PI staining analysis and western blot analysis. Cell viability was determined by the CCK8 assay. Rupture of the plasma membrane was indicated by lactate dehydrogenase release. ROS was evaluated with the carboxy-H2DCFDA fluorescent probe. It was found that in MC-LR-treated cells, as the plasma membrane was damaged, annexin V/PI-stained double-positive cells were significantly induced and PI-stained nuclei were more diffuse. Western blot analysis showed that MC-LR treatment significantly upregulated the expression of necroptotic and apoptotic proteins. Mechanistically, MC-LR induced ROS overproduction by dysregulating the expression and activity of the pro-oxidants SOD1, MAOA, and NOX4 and the antioxidant GPX1. These results indicate the presence of a novel mechanism for MC-LR-mediated liver injury and present a novel target in the treatment of MC-LR-exposed patients.


Assuntos
Hepatócitos/efeitos dos fármacos , Microcistinas/toxicidade , Necroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/metabolismo , Proteínas Reguladoras de Apoptose/biossíntese , Membrana Celular/efeitos dos fármacos , Eutrofização , Hepatócitos/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Toxinas Marinhas , Camundongos , Camundongos Endogâmicos C57BL , Oxidantes/metabolismo , Cultura Primária de Células , Regulação para Cima/efeitos dos fármacos
7.
Am J Physiol Gastrointest Liver Physiol ; 316(3): G387-G396, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30629471

RESUMO

Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-α can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-α-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-α-induced apoptosis and protects mice from d-galactosamine (d-Gal)/lipopolysaccharide (LPS)-induced TNF-α-mediated liver injury and damage. SC79 not only enhances the nuclear factor-κB (NF-κB) prosurvival signaling in response to TNF-α stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-α-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury. NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-α-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-α act through both AKT-mediated activation of NF-κB and upregulation of FLIPL/S.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Hepatócitos/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos
8.
Cell Physiol Biochem ; 51(1): 80-96, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30448843

RESUMO

BACKGROUND/AIMS: Chronic hepatitis B virus (HBV) infection markedly increases the risk of development of hepatocellular carcinoma (HCC). Among the seven viral proteins that HBV encodes, HBV X protein (HBx) appears to have the most oncogenic potential. The mitochondria-associated HBx can induce oxidative stress in hepatocytes, leading to the production of abundant reactive oxygen species (ROS). High levels of ROS usually induce oxidative DNA damage and 8-hydroxy-2-deoxyguanosine (8-OHdG), also known as 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG), which is one of the major products of DNA oxidation and an important biomarker for oxidative stress and carcinogenesis. Cells have evolved a mechanism to prevent oxidized nucleotides from their incorporation into DNA through nucleotide pool sanitization enzymes of MTH1 (NUDT1), MTH2 (NUDT15), MTH3 (NUDT18) and NUDT5. However, little is known as to whether HBx can regulate the expression of those enzymes and modulate the formation and accumulation of 8-oxodG in hepatocytes. METHODS: The level of 8-oxodG was assessed by ELISA in stable HBV-producing hepatoma cell lines, an HBV infectious mouse model, HBV and HBx transgenic mice and HBV-infected patients versus their respective controls. Expression of MTH1, MTH2, MTH3 and NUDT5 was determined by a real-time quantitative PCR and western blot analysis. Transcriptional regulation of MTH1 and MTH2 expression by HBx and the effect of HBx on MTH1 and MTH2 promoter hypermethylation were examined using a luciferase reporter assay and bisulfite sequencing analysis. RESULTS: In comparison with controls, significantly higher levels of 8-oxodG were detected in the genome and culture supernatant of stable HBV-producing HepG2.2.15 cells, in the sera and liver tissues of HBV infectious mice and HBV or HBx transgenic mice, and in the sera of HBV-infected patients. Expression of HBx in hepatocytes significantly increased 8-oxodG level and reduced the expression of MTH1 and MTH2 at both mRNA and protein levels. It was also demonstrated that HBx markedly attenuated the MTH1 or MTH2 promoter activities through hypermethylation. Furthermore, enhancement of 8-oxodG production by HBx was reversible by overexpression of MTH1 and MTH2. CONCLUSION: Our data show that HBx expression results in the accumulation of 8-oxodG in hepatocytes through inhibiting the expression of MTH1 and MTH2. This may implicate that HBx may act as a tumor promoter through facilitating the mutational potential of 8-oxodG thus connecting a possible link between HBV infection and liver carcinogenesis.


Assuntos
Enzimas Reparadoras do DNA/metabolismo , Desoxiguanosina/análogos & derivados , Monoéster Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Transativadores/metabolismo , 8-Hidroxi-2'-Desoxiguanosina , Animais , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Metilação de DNA , Enzimas Reparadoras do DNA/genética , Desoxiguanosina/metabolismo , Hepatite B/metabolismo , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/metabolismo , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monoéster Fosfórico Hidrolases/genética , Regiões Promotoras Genéticas , Pirofosfatases/genética , Espécies Reativas de Oxigênio/metabolismo , Transativadores/genética , Proteínas Virais Reguladoras e Acessórias
9.
J Virol ; 92(23)2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30209179

RESUMO

Hepatitis B spliced protein (HBSP) is known to associate with viral persistence and pathogenesis; however, its biological and clinical significance remains poorly defined. Acquired resistance to Fas-mediated apoptosis is thought to be one of the major promotors for hepatitis B virus (HBV) chronicity and malignancy. The purpose of this study was to investigate whether HBSP could protect hepatocytes against Fas-initiated apoptosis. We showed here that HBSP mediated resistance of hepatoma cells or primary human hepatocytes (PHH) to agonistic anti-Fas antibody (CH11)- or FasL-induced apoptosis. Under Fas signaling stimulation, expression of HBSP inhibited Fas aggregation and prevented recruitment of the adaptor molecule Fas-associated death domain (FADD) and procaspase-8 (or FADD-like interleukin-1ß-converting enzyme [FLICE]) into the death-inducing signaling complex (DISC) while increasing recruitment of cellular FLICE-inhibitory protein L (FLIPL) into the DISC. Those effects may be mediated through activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway as evidenced by increased cellular phosphatidylinositol (3,4,5)-trisphosphate (PIP3) content and PI3K activity and enhanced phosphorylation of mTORC2 and PDPK1 as well as Akt itself. Confirmedly, inhibition of PI3K by LY294002 reversed the effect of HBSP on Fas aggregation, FLIPL expression, and cellular apoptosis. These results indicate that HBSP functions to prevent hepatocytes from Fas-induced apoptosis by enhancing PI3K/Akt activity, which may contribute to the survival and persistence of infected hepatocytes during chronic infection.IMPORTANCE Our study revealed a previously unappreciated role of HBSP in Fas-mediated apoptosis. The antiapoptotic activity of HBSP is important for understanding hepatitis B virus pathogenesis. In particular, HBV variants associated with hepatoma carcinoma may downregulate apoptosis of hepatocytes through enhanced HBSP expression. Our study also found that Akt is centrally involved in Fas-induced hepatocyte apoptosis and revealed that interventions directed at inhibiting the activation or functional activity of Akt may be of therapeutic value in this process.


Assuntos
Apoptose , Carcinoma Hepatocelular/patologia , Hepatócitos/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Virais/metabolismo , Receptor fas/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Células Tumorais Cultivadas , Proteínas Virais/genética , Receptor fas/genética
10.
J Immunol ; 201(8): 2303-2314, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30171166

RESUMO

The Fas receptor/ligand system plays a prominent role in hepatic apoptosis and hepatocyte death. Although hepatitis B virus (HBV) surface Ag (HBsAg) is the most abundant HBV protein in the liver and peripheral blood of patients with chronic HBV infection, its role in Fas-mediated hepatocyte apoptosis has not been disclosed. In this study, we report that HBsAg sensitizes HepG2 cells to agonistic anti-Fas Ab CH11-induced apoptosis through increasing the formation of SDS-stable Fas aggregation and procaspase-8 cleavage but decreasing both the expression of cellular FLIPL/S and the recruitment of FLIPL/S at the death-inducing signaling complex (DISC). Notably, HBsAg increased endoplasmic reticulum stress and consequently reduced AKT phosphorylation by deactivation of phosphoinositide-dependent kinase-1 (PDPK1) and mechanistic target of rapamycin complex 2 (mTORC2), leading to enhancement of Fas-mediated apoptosis. In a mouse model, expression of HBsAg in mice injected with recombinant adenovirus-associated virus 8 aggravated Jo2-induced acute liver failure, which could be effectively attenuated by the AKT activator SC79. Based on these results, it is concluded that HBsAg predisposes hepatocytes to Fas-mediated apoptosis and mice to acute liver failure via suppression of AKT prosurviving activity, suggesting that interventions directed at enhancing the activation or functional activity of AKT may be of therapeutic value in Fas-mediated progressive liver cell injury and liver diseases.


Assuntos
Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Hepatite B/metabolismo , Hepatócitos/fisiologia , Falência Hepática Aguda/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor fas/metabolismo , Acetatos/administração & dosagem , Acetatos/farmacologia , Adenoviridae/genética , Animais , Anticorpos Monoclonais/metabolismo , Apoptose , Benzopiranos/administração & dosagem , Benzopiranos/farmacologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Caspase 8/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Células Hep G2 , Hepatite B/patologia , Hepatócitos/virologia , Humanos , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas Proto-Oncogênicas c-akt/agonistas , Receptor fas/imunologia
11.
Am J Pathol ; 188(5): 1171-1182, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29673487

RESUMO

Acute liver failure is a serious clinical problem of which the underlying pathogenesis remains unclear and for which effective therapies are lacking. The Fas receptor/ligand system, which is negatively regulated by AKT, is known to play a prominent role in hepatocytic cell death. We hypothesized that AKT activation may represent a strategy to alleviate Fas-induced fulminant liver failure. We report here that a novel AKT activator, SC79, protects hepatocytes from apoptosis induced by agonistic anti-Fas antibody CH11 (for humans) or Jo2 (for mice) and significantly prolongs the survival of mice given a lethal dose of Jo2. Under Fas-signaling stimulation, SC79 inhibited Fas aggregation, prevented the recruitment of the adaptor molecule Fas-associated death domain (FADD) and procaspase-8 [or FADD-like IL-1ß-converting enzyme (FLICE)] into the death-inducing signaling complex (DISC), but SC79 enhanced the recruitment of the long and short isoforms of cellular FLICE-inhibitory protein at the DISC. All of the SC79-induced hepatoprotective and DISC-interruptive effects were confirmed to have been reversed by the Akt inhibitor LY294002. These results strongly indicate that SC79 protects hepatocytes from Fas-induced fatal hepatic apoptosis. The potent alleviation of Fas-mediated hepatotoxicity by the relatively safe drug SC79 highlights the potential of our findings for immediate hepatoprotective translation.


Assuntos
Acetatos/farmacologia , Apoptose/efeitos dos fármacos , Benzopiranos/farmacologia , Hepatócitos/efeitos dos fármacos , Falência Hepática Aguda/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor fas/metabolismo , Animais , Caspases/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Falência Hepática Aguda/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
12.
Biomed Pharmacother ; 88: 569-573, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28135600

RESUMO

Neuronal apoptosis caused by toxic stimuli such as oxidative stress is believed to be one of the major reasons in the pathologenesis of neurodegenerative diseases. In the current study, the neuroprotective effects of the crude polysaccharide fraction of edible Dictyophora echinovolvata (DEVP) against H2O2-induced cytotoxicity were investigated using PC12 cells. Following exposure of PC12 cells to 750µM H2O2, a significant reduction in cell viability and the number of FDA-stained viable neurons as well as an increase in the number of PI-stained dead cells were observed. Furthermore, H2O2 treatment significantly upregulated the protein expression of Bax, cleaved caspases 3 and cytosolic cytochrome c, and down-regulated Bcl-2 levels. 2h pre-treatment with VP reversed these changes caused by H2O2, including inhibiting neuronal loss and decreasing Bax, cleaved caspases 3 and cytosolic cytochrome c levels, as well as increasing Bcl-2 levels. These results taken together demonstrated that DEVP provided a substantial neuroprotection against H2O2-induced toxicity in PC12 cells, at least partly through inhibiting the mitochondrial apoptotic pathway. These findings suggested that DEVP might be a potential candidate for further preclinical study for preventing neurodegenerative diseases in which oxidative stress and apoptosis are involved.


Assuntos
Apoptose/efeitos dos fármacos , Basidiomycota/química , Peróxido de Hidrogênio/toxicidade , Mitocôndrias/metabolismo , Neuroproteção/efeitos dos fármacos , Polissacarídeos/farmacologia , Animais , Forma Celular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Células PC12 , Ratos
13.
Ying Yong Sheng Tai Xue Bao ; 26(5): 1461-8, 2015 May.
Artigo em Chinês | MEDLINE | ID: mdl-26571666

RESUMO

The yields of cold-waterlogged (CW) paddy fields widely spreading in Jiangnan mountainous areas are moderate or low but have a high potential to be increased. Based on data including 41 soil characteristics of 17 pairs of typical surface soils of cold-waterlogged paddy field and non cold-waterlogged (NCW) paddy field at a neighboring landscape unit in Fujian Province, various index differences of soil properties and causes between CW paddy field and NCW paddy field were systematically studied, and a minimum data set (MDS) of soil quality assessment for CW paddy field was established by principal component analysis. By pair analysis, soil characteristics of CW paddy field showed that the content of organic matter increased by 31.7%, but the microbial biomass C decreased by 37.8%, which belonged to active soil organic matter component. The content of ferrous iron (Fe2+) increased by 177.0%, but the available phosphorus (P) and potassium (K) decreased by 52.3% and 22.8%, respectively. Catalase and invertase activities increased by 58.3% and 22. 1%, but phosphatase, nitrate reductase activities and microflora decreased by 47. 8%, 66.6% and 29.8%-46.0%, respectively. The sand content increased about 8.0%, but the water immersed bulk density decreased by 25.8%. There were significant differences of indices for 28 of all 41 soil characteristics. Five principal components cumulatively exhibiting about 78.5% contribution were concluded from the 28 soil characteristics to reflect characteristics related to soil biochemistry, active organic nitrogen, reducing barriers, physical and chemical nutrients, respectively. Eventually, correlation analysis combined with expert experience method were applied to optimize MDS containing six factors for soil quality assessments, including C/N, bacteria, microbial biomass N, total reducing agents, physical sand and total P.


Assuntos
Oryza , Solo/normas , Bactérias , Biomassa , China , Inundações , Nitrogênio/análise , Fósforo/análise , Potássio/análise , Solo/química , Microbiologia do Solo
14.
Ying Yong Sheng Tai Xue Bao ; 26(5): 1469-76, 2015 May.
Artigo em Chinês | MEDLINE | ID: mdl-26571667

RESUMO

Two consecutive years (4-crop) experiments were conducted to study the influence of different paddy rice-upland crop rotation in cold-waterlogged paddy field on the growth of crops and soil characteristics. The result showed that compared with the rice-winter fallow (CK) pattern, the two-year average yield of paddy rice under four rotation modes, including rape-rice (R-R), spring corn-rice (C-R), Chinese milk vetch-rice (M-R) and bean-rice (B-R), were increased by 5.3%-26.7%, with significant difference observed in C-R and R-R patterns. Except for M-R pattern, the annual average total economic benefits were improved by 79.0%-392.4% in all rotation pattern compared with the CK, and the ration of output/input was enhanced by 0.06-0.72 unit, with the most significant effect found in the C-R pattern. Likewise, compared with the CK, the contents of chlorophyll and carotenoid, and net photosynthetic rate (Pn) of rice plant were all increased during the full-tillering stage of rice in all rotation patterns. The rusty lines and rusty spots of soils were more obvious compared with the CK during the rice harvest, particularly in R-R, C-R and B-R patterns. The ratio of water-stable soil macro aggregates of plough layer of soil (> 2 mm) decreased at different levels in all rotation patterns while the ratios of middle aggregate (0.25-2 mm, expect for M-R) and micro aggregate of soil (< 0.25 mm) were opposite. There was a decreasing trend for soil active reducing agents in all rotation patterns, whereas the available nutrient increased. The amounts of soil bacteria in C-R and B-R patterns, fungi in B-R rotation pattern, cellulose bacteria in R-R, C-R and B-R patterns and N-fixing bacteria in B-R pattern were improved by 285.7%-403.0%, 221.7%, 64.6-92.2% and 162.2%, respectively. Moreover, the differences in all microorganisms were significant. Thus, based on the experimental results of cold-waterlogged paddy field, it was concluded that changing from single cropping rice system to C-R, R-R and B-R rotation patterns had good effect in terms of improving total yield and economic benefits, and soil physical and chemical properties were improved.


Assuntos
Agricultura/métodos , Oryza/crescimento & desenvolvimento , Solo/química , Zea mays/crescimento & desenvolvimento , Temperatura Baixa , Produtos Agrícolas/crescimento & desenvolvimento , Inundações , Microbiologia do Solo , Água
15.
Virus Res ; 195: 236-45, 2015 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-25449573

RESUMO

Hepatitis B virus X protein (HBx) transactivates multiple transcription factors including nuclear factor-kappa B (NF-κB) that regulates inflammatory-related genes. However, the regulatory mechanism of HBx in NF-κB activation remains largely unknown. This study reports that HBx augments the interleukin-1ß (IL-1ß)-induced NF-κB activation via interaction with a Toll-like receptor (TLR) adapter protein, ECSIT (evolutionarily conserved signaling intermediate in Toll pathways). GST pull-down and co-immunoprecipitation analyses showed that HBx interacted with ECSIT. Deletion analysis of HBx in a CytoTrap two-hybrid system revealed that the interaction region of HBx for ECSIT was attributed to aa 51-80. Co-transfection of HBx and ECSIT in IL-1ß-stimulated cells appeared to activate IKK and IκB signaling pathway as phosphorylation of both IKK α/ß and IκBα was increased whereas knockdown of ECSIT or HBxΔ51-80 mutant attenuated the phosphorylation. As a consequence of IκBα degradation, NF-κB was activated as evidenced by increases in NF-κB transcriptional activity and the nuclear translocation of p65 and p50 that resulted in the induction of IL-10. In contrast, knockdown of ECSIT by siRNA or treatment with an NF-κB selective inhibitor (helenalin) abolished the NF-κB activation and IL-10 expression. We conclude that ECSIT appears to be a novel HBx-interacting signal molecule and their interaction is mechanistically important in IL-1ß induction of NF-κB activation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Vírus da Hepatite B/imunologia , Interações Hospedeiro-Patógeno , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Transativadores/metabolismo , Linhagem Celular , Análise Mutacional de DNA , Humanos , Ligação Proteica , Mapeamento de Interação de Proteínas , Técnicas do Sistema de Duplo-Híbrido , Proteínas Virais Reguladoras e Acessórias
16.
Chem Commun (Camb) ; (34): 3995-7, 2008 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-18758604

RESUMO

A metal-organic nanotubular architecture was built from parallel-aligned single-walled nanotubes which interlink by means of micro3-bridged counterions, representing the first example of coordination nanotubes presumably generated from two-dimensional (2D) sheets.

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