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Achievement of a 'clinical cure' in chronic hepatitis B (CHB) implies sustained virological suppression and immunological control over the infection, which is the ideal treatment goal according to domestic and international CHB management guidelines. Clinical practice has shown encouraging results for specific patient cohorts using tailored treatment regimens. These regimens incorporate either nucleos(t)ide analogs, immunomodulatory agents such as pegylated interferon α, or a strategic combination of both, sequentially or concurrently administered. Despite these advancements in the clinical handling of hepatitis B, achieving a clinical cure remains elusive for a considerable subset of patients due to the number of challenges that preclude the realization of optimal treatment outcomes. These include, but are not limited to, the emergence of antiviral resistance, incomplete immune recovery, and the persistence of covalently closed circular DNA. Moreover, the variance in response to interferon therapy and the lack of definitive biomarkers for treatment cessation also contribute to the complexity of achieving a clinical cure. This article briefly overviews the current research progress and existing issues in pursuing a clinical cure for hepatitis B.
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BACKGROUND: Prohibitin 1 (PHB1) has been identified as an antiproliferative protein that is highly conserved and ubiquitously expressed, and it participates in a variety of essential cellular functions, including apoptosis, cell cycle regulation, proliferation, and survival. Emerging evidence indicates that PHB1 may play an important role in the progression of hepatocellular carcinoma (HCC). However, the role of PHB1 in HCC is controversial. AIM: To investigate the effects of PHB1 on the proliferation and apoptosis of human HCC cells and the relevant mechanisms in vitro. METHODS: HCC patients and healthy individuals were enrolled in this study according to the inclusion and exclusion criteria; then, PHB1 levels in the sera and liver tissues of these participates were determined using ELISA, RT-PCR, and immunohistochemistry. Human HepG2 and SMMC-7721 cells were transfected with the pEGFP-PHB1 plasmid and PHB1-specific shRNA (shRNA-PHB1) for 24-72 h. Cell proliferation was analysed with an MTT assay. Cell cycle progression and apoptosis were analysed using flow cytometry (FACS). The mRNA and protein expression levels of the cell cycle-related molecules p21, Cyclin A2, Cyclin E1, and CDK2 and the cell apoptosis-related molecules cytochrome C (Cyt C), p53, Bcl-2, Bax, caspase 3, and caspase 9 were measured by real-time PCR and Western blot, respectively. RESULTS: Decreased levels of PHB1 were found in the sera and liver tissues of HCC patients compared to those of healthy individuals, and decreased PHB1 was positively correlated with low differentiation, TNM stage III-IV, and alpha-fetoprotein ≥ 400 µg/L. Overexpression of PHB1 significantly inhibited human HCC cell proliferation in a time-dependent manner. FACS revealed that the overexpression of PHB1 arrested HCC cells in the G0/G1 phase of the cell cycle and induced apoptosis. The proportion of cells in the G0/G1 phase was significantly increased and the proportion of cells in the S phase was decreased in HepG2 cells that were transfected with pEGFP-PHB1 compared with untreated control and empty vector-transfected cells. The percentage of apoptotic HepG2 cells that were transfected with pEGFP-PHB1 was 15.41% ± 1.06%, which was significantly greater than that of apoptotic control cells (3.65% ± 0.85%, P < 0.01) and empty vector-transfected cells (4.21% ± 0.52%, P < 0.01). Similar results were obtained with SMMC-7721 cells. Furthermore, the mRNA and protein expression levels of p53, p21, Bax, caspase 3, and caspase 9 were increased while the mRNA and protein expression levels of Cyclin A2, Cyclin E1, CDK2, and Bcl-2 were decreased when PHB1 was overexpressed in human HCC cells. However, when PHB1 was upregulated in human HCC cells, Cyt C expression levels were increased in the cytosol and decreased in the mitochondria, which indicated that Cyt C had been released into the cytosol. Conversely, these effects were reversed when PHB1 was knocked down. CONCLUSION: PHB1 inhibits human HCC cell viability by arresting the cell cycle and inducing cell apoptosis via activation of the p53-mediated mitochondrial pathway.
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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality. Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages, but it is often ineffective and suffers from problems such as multidrug resistance, rapid drug clearance, nonspecific targeting, high side effects, and low drug accumulation in tumor cells. In response to these limitations, recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC. This review focuses on recent advances in nanoparticle-based targeted drug delivery systems, with special attention to various receptors overexpressed on HCC cells. These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC. We comprehensively summarize the current understanding of these receptors, their role in nanoparticle targeting, and the impact of such targeted therapies on HCC. By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies, more effective and precise treatment of HCC can be achieved.
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BACKGROUND: As a proteoglycan, VCAN exists in the tumor microenvironment and regulates tumor proliferation, invasion, and metastasis, but its role in hepatocellular carcinoma (HCC) has not yet been elucidated. AIM: To investigate the expression and potential mechanism of action of VCAN in HCC. METHODS: Based on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, we explored the correlation between VCAN expression and clinical features, and analyzed the prognosis of patients with high and low VCAN expression. The potential mechanism of action of VCAN was explored by Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and gene set enrichment analysis. We also explored immune cell infiltration, immune checkpoint gene expression, and sensitivity of immune checkpoint [programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte antigen 4 (CTLA4)] inhibitor therapy in patients with different VCAN expression. VCAN mRNA expression and VCAN methylation in peripheral blood were tested in 100 hepatitis B virus (HBV)-related patients (50 HCC and 50 liver cirrhosis). RESULTS: VCAN was highly expressed in HCC tissues, which was associated with a poor prognosis in HCC patients. No significant difference was found in VCAN mRNA expression in blood between patients with HBV-related cirrhosis and those with HCC, but there was a significant difference in VCAN methylation between the two groups. The correlation between VCAN and infiltrations of several different tumor immune cell types (including B cells, CD8+ T cells, and eosinophils) was significantly different. VCAN was strongly related to immune checkpoint gene expression and tumor mutation burden, and could be a biomarker of sensitivity to immune checkpoint (PD1/CTLA4) inhibitors. In addition, VCAN mRNA expression was associated with hepatitis B e antigen, HBV DNA, white blood cells, platelets, cholesterol, and coagulation function. CONCLUSION: High VCAN level could be a possible biomarker for poor prognosis of HCC, and its immunomodulatory mechanism in HCC warrants investigation.
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BACKGROUND: This research aimed to explore the association between the RIG-I-like receptor (RIG-I and MDA5 encoded by DDX58 and IFIH1, respectively) pathways and the risk or severity of hand, foot, and mouth disease caused by enterovirus 71 (EV71-HFMD). In this context, we explored the influence of gene methylation and polymorphism on EV71-HFMD. METHODOLOGY/PRINCIPAL FINDINGS: 60 healthy controls and 120 EV71-HFMD patients, including 60 mild EV71-HFMD and 60 severe EV71-HFMD patients, were enrolled. First, MiSeq was performed to explore the methylation of CpG islands in the DDX58 and IFIH1 promoter regions. Then, DDX58 and IFIH1 expression were detected in PBMCs using RT-qPCR. Finally, imLDR was used to detect DDX58 and IFIH1 single-nucleotide polymorphism (SNP) genotypes. Severe EV71-HFMD patients exhibited higher DDX58 promoter methylation levels than healthy controls and mild EV71-HFMD patients. DDX58 promoter methylation was significantly associated with severe HFMD, sex, vomiting, high fever, neutrophil abundance, and lymphocyte abundance. DDX58 expression levels were significantly lower in mild patients than in healthy controls and lower in severe patients than in mild patients. Binary logistic regression analysis revealed statistically significant differences in the genotype frequencies of DDX58 rs3739674 between the mild and severe groups. GeneMANIA revealed that 19 proteins displayed correlations with DDX58, including DHX58, HERC5, MAVS, RAI14, WRNIP1 and ISG15, and 19 proteins displayed correlations with IFIH1, including TKFC, IDE, MAVS, DHX58, NLRC5, TSPAN6, USP3 and DDX58. CONCLUSIONS/SIGNIFICANCE: DDX58 expression and promoter methylation were associated with EV71 infection progression, especially in severe EV71-HFMD patients. The effect of DDX58 in EV71-HFMD is worth further attention.
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Proteína DEAD-box 58/genética , Metilação de DNA/genética , Doença de Mão, Pé e Boca/patologia , Helicase IFIH1 Induzida por Interferon/genética , Receptores Imunológicos/genética , Criança , Pré-Escolar , Ilhas de CpG/genética , Proteína DEAD-box 58/metabolismo , Enterovirus Humano A , Feminino , Predisposição Genética para Doença/genética , Doença de Mão, Pé e Boca/virologia , Humanos , Lactente , Helicase IFIH1 Induzida por Interferon/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Receptores Imunológicos/metabolismo , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: To explore the mechanisms of interferon-induced transmembrane protein 3 (IFITM3) in response to enterovirus-71-associated hand, foot and mouth disease (EV71-HFMD), in terms of DNA methylation, single-nucleotide polymorphism (SNP) genotype and gene expression. METHODS: In total, 120 patients with EV71-HFMD (60 with mild EV71-HFMD and 60 with severe EV71-HFMD) and 60 healthy controls were enrolled in this study. SNP genotype, IFITM3 promoter methylation and mRNA expression of peripheral blood mononuclear cells were examined using the improved multi-temperature ligase detection reaction, quantitative reverse transcriptase polymerase chain reaction and MiSeq, respectively. RESULTS: The distribution of methylation in patients with EV71-HFMD was significantly lower compared with healthy controls, and the severe EV71-HFMD group showed the lowest frequency of IFITM3 promoter methylation. The average level of IFITM3 promoter CpG methylation was negatively correlated with IFITM3 mRNA expression, and hypermethylation of several specific CpG units contributed to IFITM3 downregulation. IFITM3 expression and promoter methylation correlated with EV71 infection progression, especially in the severe EV71-HFMD group. Compared with mild cases, genotype GG and the G allele of rs12252 were over-represented in patients with severe EV71-HFMD. CONCLUSIONS: IFITM3 methylation status and SNP genotyping may help clinicians to choose the correct treatment strategy for patients with EV71-HFMD.
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Metilação de DNA , Enterovirus Humano A/fisiologia , Doença de Mão, Pé e Boca/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a RNA/genética , Alelos , Estudos de Casos e Controles , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Leucócitos Mononucleares/metabolismo , Masculino , Regiões Promotoras Genéticas/genéticaRESUMO
Severe hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) infection is associated with high mortality and disability. DC-SIGN, a receptor for EV71, is widely distributed in dendritic cells and may influence the severity of HFMD caused by EV71 infection. This observational study attempts to explore whether single-nucleotide polymorphisms (SNPs) in DC-SIGN are related to the severity of EV71-associated HFMD. Based on linkage disequilibrium and functional predictions, two DC-SIGN SNPs were selected and tested to explore their potential association with the severity of HFMD caused by EV71 infection. Two hundred sixteen Han Chinese children with HFMD caused by EV71 were enrolled to obtain clinical data, including the severity of HFMD, serum DC-SIGN levels, and DC-SIGN SNPs. We found a significant association between the rs7248637 polymorphism (A vs. G: OR = 0.644, 95% CI = 0.515-0.806) and the severity of HFMD caused by EV71 infection, as well as the rs4804800 polymorphism (A vs. G: OR = 1.539, 95% CI =1.229-1.928). These two DC-SIGN SNPs may have an effect on the severity of HFMD caused by EV71 infection.
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Moléculas de Adesão Celular/genética , Infecções por Enterovirus/genética , Predisposição Genética para Doença/genética , Doença de Mão, Pé e Boca/genética , Lectinas Tipo C/genética , Receptores de Superfície Celular/genética , Povo Asiático/genética , Moléculas de Adesão Celular/sangue , Criança , Pré-Escolar , China/epidemiologia , Enterovirus Humano A , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/patologia , Feminino , Estudos de Associação Genética , Genótipo , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/patologia , Humanos , Lactente , Lectinas Tipo C/sangue , Masculino , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/sangue , Índice de Gravidade de DoençaRESUMO
BACKGROUND: New direct-acting antivirals (DAAs)-based anti-hepatitis C virus (HCV) therapies are highly effective in patients with HCV infection. However, safety data are lacking regarding HCV treatment with DAAs and drugs for comorbidities. CASE SUMMARY: Herein, we reported a case of HCV-infection in a 46-year-old man with benign prostatic hypertrophy. The patient received sofosbuvir/velpatasvir as well as methadone maintenance therapy for drug abuse. The viral load became negative at week 1 post treatment. He developed facial and bilateral lower extremity edema 48 h after starting receiving tamsulosin. Edema disappeared 10 d after treatment with oral furosemide and spironolactone. CONCLUSION: In conclusion, this is the first case of an acute edema in the course of treatment with new DAAs, methadone and tamsulosin. These agents are useful in clinical management of patients with HCV infection, particularly in men with benign prostatic hypertrophy. Clinicians should be aware of potential drug-drug interactions in this subset of patients.
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To evaluate the epigenetic regulation of the VDR gene in enterovirus 71 (EV71)-associated severe hand, foot, and mouth disease (HFMD), a total of 116 patients with EV71-HFMD, including 58 with mild EV71-HFMD and 58 with severe EV71-HFMD, as well as 60 healthy controls, were enrolled in this study. Quantitative real-time PCR was used to measure the relative levels of VDR mRNA expression, and the methylation status of the VDR promoter was assessed using a MethylTarget™ assay. The DNA methylation levels of the VDR promoter in children with EV71-associated severe HFMD were lower than those in the healthy controls and in children with mild HFMD (P < 0.05). Hypomethylation at CpG site 133 and hypermethylation at the CpG 42 sites and 68 downregulated VDR expression. Moreover, the methylation level of VDR could be used for differential diagnosis of mild and severe EV71-associated HFMD (AUC56, 0.73; AUC68, 0.699; AUC42, 0.694; AUC66, 0.693). VDR expression and promoter methylation were associated with the progression of EV71 infection. Determining the VDR promoter status might help clinicians initiate the appropriate strategy for treatment of EV71-associated HFMD.
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Enterovirus Humano A/fisiologia , Doença de Mão, Pé e Boca/genética , Receptores de Calcitriol/genética , Criança , Pré-Escolar , China , Enterovirus Humano A/genética , Epigênese Genética , Feminino , Doença de Mão, Pé e Boca/metabolismo , Doença de Mão, Pé e Boca/virologia , Humanos , Lactente , Masculino , Metilação , Regiões Promotoras Genéticas , Receptores de Calcitriol/metabolismoRESUMO
Hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) can lead to high morbidity and mortality, and genetic background plays an important role during the disease process. We investigated the association between the single-nucleotide polymorphism (SNP) rs2564978 of the CD55 gene and susceptibility to and severity of HFMD using the SNPs can multiple SNP typing methods. Soluble CD55 (sCD55) expression was significantly lower in the EV71 HFMD group than in the control group and lower in severe cases than in mild cases (P < .001). Moreover, CD55 rs2564978 (C vs T OR = 1.300, 95% CI, 1.120-1.509) was associated with the risk of EV71 infection, and genotype TC was related to the severity of the infection (TC vs TT OR = 4.523, 95% CI, 2.033-10.066). Our results suggest that sCD55 expression and the CD55 polymorphism rs2564978 may influence the susceptibility to and severity of EV71 infection.
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BACKGROUND: Nucleos(t)ide analog (NA) has shown limited effectiveness against hepatitis B surface antigen (HBsAg) clearance in chronic hepatitis B (CHB) patients. AIM: To evaluate the efficacy and safety of add-on peginterferon α-2a (peg-IFN α-2a) to an ongoing NA regimen in CHB patients. METHODS: In this observational study, 195 CHB patients with HBsAg ≤ 1500 IU/mL, hepatitis B e antigen (HBeAg)-negative (including HBeAg-negative patients or HBeAg-positive patients who achieved HBeAg-negative after antiviral treatment with NA) and hepatitis B virus-deoxyribonucleic acid < 1.0 × 102 IU/mL after over 1 year of NA therapy were enrolled between November 2015 and December 2018 at the Second Affiliated Hospital of Xi'an Jiaotong University, China. Patients were given the choice between receiving either peg-IFN α-2a add-on therapy to an ongoing NA regimen (add-on group, n = 91) or continuous NA monotherapy (monotherapy group, n = 104) after being informed of the benefits and risks of the peg-IFN α-2a therapy. Total therapy duration of peg-IFN α-2a was 48 wk. All patients were followed-up to week 72 (24 wk after discontinuation of peg-IFN α-2a). The primary endpoint was the proportion of patients with HBsAg clearance at week 72. RESULTS: Demographic and baseline characteristics were comparable between the two groups. Intention-to-treatment analysis showed that the HBsAg clearance rate in the add-on group and monotherapy group was 37.4% (34/91) and 1.9% (2/104) at week 72, respectively. The HBsAg seroconversion rate in the add-on group was 29.7% (27/91) at week 72, and no patient in the monotherapy group achieved HBsAg seroconversion at week 72. The HBsAg clearance and seroconversion rates in the add-on group were significantly higher than in the monotherapy group at week 72 (P < 0.001). Younger patients, lower baseline HBsAg concentration, lower HBsAg concentrations at weeks 12 and 24, greater HBsAg decline from baseline to weeks 12 and 24 and the alanine aminotransferase ≥ 2 × upper limit of normal during the first 12 wk of therapy were strong predictors of HBsAg clearance in patients with peg-IFN α-2a add-on treatment. Regarding the safety of the treatment, 4.4% (4/91) of patients in the add-on group discontinued peg-IFN α-2a due to adverse events. No severe adverse events were noted. CONCLUSION: Peg-IFN α-2a as an add-on therapy augments HBsAg clearance in HBeAg-negative CHB patients with HBsAg ≤ 1500 IU/mL after over 1 year of NA therapy.
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Antivirais/administração & dosagem , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Nucleosídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , China , Quimioterapia Combinada , Feminino , Antígenos de Superfície da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Soroconversão , Resultado do TratamentoRESUMO
Coxsackievirus A16 (CA16) remains the most common causative agent of hand, foot, and mouth disease (HFMD), and is related to high incidence and critical complications. Vitamin D receptor (VDR) activity might affect the outcome of CA16 infection. Our case-control research aims to evaluate the relationship between VDR polymorphisms in the gene encoding and susceptibility to and severity of HFMD due to CA16. Three single-nucleotide polymorphisms (SNPs) of VDR gene were selected according to functional prediction and linkage disequilibrium, and were examined utilizing the SNPscan method to identify possible associations with HFMD caused by CA16. A significant relationship was found in the HFMD cases of polymorphism rs11574129 (GA vs GG: odds ratio (OR) = 0.068, 95% confidence interval (CI) = 0.007-0.693, P = .023; GA + AA vs GG: OR = 0.322, 95%CI = 0.106-0.984, P = .047), and vitamin D levels in genotype AA were significantly higher than those in genotype GG (P < .05). These results suggest that VDR rs11574129 may influence genetic susceptibility to CA16-associated HFMD.
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Predisposição Genética para Doença , Doença de Mão, Pé e Boca/genética , Doença de Mão, Pé e Boca/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Vitamina D/sangue , Estudos de Casos e Controles , Pré-Escolar , Enterovirus Humano A , Feminino , Genótipo , Doença de Mão, Pé e Boca/virologia , Humanos , Lactente , MasculinoRESUMO
BACKGROUND: Regimens involving direct-acting antiviral agents (DAAs) are recommended for the treatment of infection with hepatitis C virus (HCV) genotypes 1, 2 and 3. But real-world data is still not enough, especially in Asia. AIM: To investigate the efficacy and safety of DAA-based regimens in a real-life setting in China. METHODS: This study included 366 patients infected with HCV genotypes 1, 2 and 3, with or without cirrhosis, who were observed between May 2015 and December 2018. They were treated with ledipasvir and sofosbuvir (SOF) (genotype 1) with or without ribavirin (RBV), SOF and RBV (genotype 2), or SOF and daclatasvir (genotype 3), with or without RBV, for 12 or more wk. The participants' sustained virological responses (SVR) at post-treatment week 12 (SVR12) was the primary endpoint. The occurrence of adverse events and drug-drug interactions were recorded. RESULTS: In the 366 patients, genotype 1 (59.0%) was the most common genotype, followed by genotypes 2 (34.4%) and 3 (6.6%). Liver cirrhosis was diagnosed in 154 (42.1%) patients. Fifty (13.7%) patients were treatment-experienced. Intention-to-treat analysis revealed that SVR12 was 86.3% (316/366). For modified intention-to-treat analysis, SVR12 was achieved in 96.6% of overall patients (316/327), 96.3% in patients with genotype 1, 97.5% in those with genotype 2, and 95.0% in those with genotype 3. Most of the treatment failures were due to lack of follow-up (3 cases had non-responses, 1 had virological breakthrough, 11 relapsed and 36 did not participate in the follow-up). There was no significant difference in SVR between different genotypes and liver statuses (P < 0.05). Patients with lower alanine aminotransferase levels at baseline who achieved an end of treatment response were more likely to achieve SVR12 (P < 0.05). High SVR was observed regardless of age, gender, liver status, alpha-fetoprotein, HCV RNA levels or history of antiviral therapy (P > 0.05 for all). The cumulative hepatocellular carcinoma occurrence and recurrence rate after using the DAAs was 0.9%. Most of the adverse events were mild. We found two cases of special adverse events. One case involved facial and bilateral lower extremity edema, and the other case showed an interesting change in lipid levels while on medication. No severe adverse events were noted. CONCLUSION: The DAA-based regimens tested in this study have excellent effectiveness and safety in all patients infected with HCV genotypes 1, 2 and 3, including those with cirrhosis.
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Antivirais/administração & dosagem , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , China , Interações Medicamentosas , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resposta Viral SustentadaRESUMO
Severe hand, foot, and mouth disease (HFMD) is sometimes associated with critical complications that can cause substantial child mortality. Activity of the vitamin D receptor (VDR) may influence the outcomes of enterovirus 71 (EV71) infection. This case-control study aimed to assess the association of single-nucleotide polymorphisms (SNPs) in the gene encoding the VDR with the severity of EV71-associated HFMD. We selected four VDR SNPs based on linkage disequilibrium and functional prediction, and we tested them using the SNPscan multiple SNP typing method for potential association with severity of EV71-associated HFMD. We found a significant association in the case of rs11574129 (G vs A: odds ratio (OR), 0.3439; 95% confidence intervals (CI), 0.1778-0.6653) and rs739837 (T vs G: OR, 0.5580; 95%CI, 0.3352-0.9291). Our results suggest that these two SNPs may influence the severity of EV71-associated HFMD.
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Predisposição Genética para Doença , Doença de Mão, Pé e Boca/genética , Doença de Mão, Pé e Boca/patologia , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Enterovirus Humano A/isolamento & purificação , Feminino , Doença de Mão, Pé e Boca/virologia , Humanos , Lactente , MasculinoRESUMO
Hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) presents with a wide variety of clinical manifestations. Host immune response is a factor that influences disease susceptibility and severity. We investigated the potential association of gene polymorphisms in the pattern recognition receptor (PRR) pathway with the risk and severity of EV71 infection. A total of 180 EV71 HFMD cases (108 severe case; 72 mild cases) were enrolled. A group of 201 sex- and age-matched children was included as a control. All subjects were genotyped for the most common single-nucleotide polymorphisms (SNPs) in the PRR and the PRR signaling pathway using the SNPscan multiple SNP typing method. Binary logistic regression analysis revealed statistically significant differences in polymorphism of RIG-1 between patients and controls (rs3739674 G vs C: OR = 1.502, 95%CI: 1.120-2.014; rs9695310 G vs C: OR = 1.782, 95%CI: 1.312-2.419). Polymorphisms of RIG-1 rs3739674 (G vs C: OR = 2.047, 95%CI: 1.307-3.205) and TLR3 rs5743305 (A vs T: OR = 0.346, 95%CI: 0.212-0.566) were found to be associated with disease severity. The results indicated that RIG-1 (rs3739674 and rs9695310) polymorphisms are associated with an increased risk of EV71-induced HFMD in Chinese children, whereas RIG-1 rs3739674 and TLR3 rs5743305 polymorphisms are associated with disease severity. These findings support an important role of innate immune mechanism in EV71 infection.
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Enterovirus Humano A/imunologia , Predisposição Genética para Doença , Doença de Mão, Pé e Boca/genética , Receptores de Reconhecimento de Padrão/genética , Receptores do Ácido Retinoico/genética , Índice de Gravidade de Doença , Transdução de Sinais , Povo Asiático , Criança , Pré-Escolar , China , Feminino , Técnicas de Genotipagem , Doença de Mão, Pé e Boca/patologia , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único , Medição de RiscoRESUMO
AIM: To investigate the antioxidant effect of caffeic acid phenethyl ester (CAPE) in hepatic stellate cell-T6 (HSC-T6) cells cultured in vitro and the potential mechanisms. METHODS: HSC-T6 cells were cultured in vitro and treated with various concentrations of CAPE for 24, 48 and 72 h, respectively. Cell proliferation was investigated using the MTT assay, and cell ultrastructural alterations were observed by transmission electron microscopy. Flow cytometry was employed to investigate the effects of CAPE on apoptosis and the levels of reactive oxygen species in HSC-T6 cells cultured in vitro. An enzyme immunoassay instrument was used to evaluate antioxidant enzyme expression. The effect on α-smooth muscle actin was shown using immunofluorescence. Gene and protein levels of Nrf2, related factors, and mitogen activated protein kinases (MAPKs), in HSC-T6 cells were detected using RT-PCR and Western blot, respectively. RESULTS: CAPE inhibited the proliferation and activation of HSC-T6 cells cultured in vitro. CAPE increased the antioxidant levels and the translocation of Nrf2 from the cytoplasm to the nucleus in HSC-T6 cells. Moreover, the phosphorylation of MAPKs in cells decreased in response to CAPE. Interestingly, CAPE-induced oxidative stress in the cells was significantly attenuated by pretreatment with MAPKs inhibitors. CONCLUSION: CAPE inhibits cell proliferation and up-regulates the antioxidant levels in HSC-T6 cells partly through the Nrf2-MAPKs signaling pathway.
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Antioxidantes/química , Ácidos Cafeicos/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Fator 2 Relacionado a NF-E2/metabolismo , Álcool Feniletílico/análogos & derivados , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Citometria de Fluxo , Células Estreladas do Fígado/metabolismo , Técnicas Imunoenzimáticas , Microscopia de Fluorescência , Estresse Oxidativo , Fenol , Álcool Feniletílico/uso terapêutico , Transporte Proteico , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
OBJECTIVE: To explore the inhibitory effect of estrogen against metastasis of human hepatocellular carcinoma MHCC97H cells and explore the molecular mechanism. METHODS: The inhibitory effect of estrogen on the migration and invasion of MHCC97H cells was evaluated with wound healing assay and Transwell assay. Western blotting was used for investigating the expression of MMP-2, MMP-9, AKT and p-AKT in the cells treated with estrogen. RESULTS: Estrogen treatment significantly inhibited the migration and invasion of MHCC97H cells in a dose-dependent manner. Estrogen significantly down-regulated the protein expressions of MMP-2 and MMP-9 and lowered the phosphorylation level of AKT. CONCLUSION: The anti-metastatic effect of estrogen involves inhibition of MMP-2 and MMP-9 in MHCC97H cells probably by regulating AKT signal pathway.
Assuntos
Carcinoma Hepatocelular , Estrogênios/farmacologia , Neoplasias Hepáticas , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Fosforilação , Transdução de SinaisRESUMO
BACKGROUND: Severe hand, foot, and mouth disease (HFMD) is sometimes associated with serious complications such as acute heart failure that can cause substantial child mortality. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a sensitive and specific biomarker of congestive heart failure. The aim of this study was to use plasma NT-proBNP levels to establish the severity of childhood HFMD. METHODS: A retrospective study was performed in 128 Chinese patients with severe HFMD and 88 patients with mild HFMD treated between January 2014 and October 2015. Univariate and multiple logistic regression analyses were used to analyze the risk factors for severe HFMD. NT-proBNP levels were analyzed in 128 severe HFMD patients, and the predictive value of NT-proBNP was assessed by receiver operating characteristic analyses. RESULTS: Multivariate analysis controlling for several potential confounders showed that enterovirus 71 infection [odds ratio (OR) 19.944, 95 % confidence interval (CI) 6.492-61.271], peripheral WBC count (OR 3.428, 95 % CI 1.186-9.914), fasting glucose (OR 19.428, 95 % CI 2.236-168.784), procalcitonin (OR 9.084, 95 % CI 3.462-23.837, and NT-proBNP (>125 pg/mL) (OR 16.649, 95 % CI 4.731-58.585) were each associated with the severity of HFMD. The 45 dead severe patients had higher pre-procedural levels of NT-proBNP than the 83 cured severe patients (12776 ± 13115 versus 1435 ± 4201 pg/mL, P < 0.001). An NT-proBNP cutoff value of 982 pg/mL predicted mortality with 87 % sensitivity and 86 % specificity. CONCLUSION: Plasma NT-pro-BNP level appears to be a useful biological marker for predicting the severity and mortality of HFMD.
Assuntos
Biomarcadores/sangue , Doença de Mão, Pé e Boca/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Doença de Mão, Pé e Boca/etiologia , Doença de Mão, Pé e Boca/mortalidade , Humanos , Masculino , Análise Multivariada , Razão de Chances , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
AIM: To investigate the effects of guggulsterone on the proliferation and apoptosis of human hepatoma HepG2 cells in vitro and relevant mechanisms. METHODS: Human hepatocellular carcinoma HepG2 cells and normal human liver L-02 cells were treated with different concentrations of guggulsterone (5-100 µmol/L) for 24-72 h. Cell proliferation was tested by MTT assay. Cell cycle and apoptosis were investigated using flow cytometry (FACS). Bcl-2 and Bax mRNA and protein expression was detected by real-time PCR and Western blot, respectively. TGF-ß1, TNF-α, and VEGF contents were determined by ELISA. RESULTS: Guggulsterone significantly inhibited HepG2 cell proliferation in a dose- and time-dependent manner. FACS showed that guggulsterone arrested HepG2 cell cycle at G0/G1 phase. Guggulsterone induced apoptosis was also observed in HepG2 cells, with 24.91% ± 2.41% and 53.03% ± 2.28% of apoptotic cells in response to the treatment with 50 µmol/L and 75 µmol/L guggulsterone, respectively. Bax mRNA and protein expression was significantly increased and Bcl-2 mRNA and protein expression was decreased. ELISA analysis showed that the concentrations of TGF-ß1 and VEGF were significantly decreased and TNF-α concentration was increased. CONCLUSION: Guggulsterone exerts its anticancer effects by inhibiting cell proliferation and inducing apoptosis in HepG2 cells. Guggulsterone induces apoptosis by activation of the intrinsic mitochondrial pathway.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Pregnenodionas/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
AIM: To investigate the hepatoprotective effects and antioxidant activity of caffeic acid phenethyl ester (CAPE) in rats with liver fibrosis. METHODS: A total of 75 male Sprague-Dawley rats were randomly assigned to seven experimental groups: a normal group (n = 10), a vehicle group (n = 10), a model group (n = 15), a vitamin E group (n = 10), and three CAPE groups (CAPE 3, 6 and 12 mg/kg, n = 10, respectively). Liver fibrosis was induced in rats by injecting CCl4 subcutaneously, feeding with high fat forage, and administering 30% alcohol orally for 10 wk. Concurrently, CAPE (3, 6 and 12 mg/kg) was intraperitoneally administered daily for 10 wk. After that, serum total bilirubin (TBil), aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured to assess hepatotoxicity. To investigate antioxidant activity of CAPE, malondialdehyde (MDA), glutathione (GSH) levels, catalase (CAT) and superoxide dismutase (SOD) activities in liver tissue were determined. Moreover, the effect of CAPE on α-smooth muscle actin (α-SMA), a characteristic hallmark of activated hepatic stellate cells (HSCs), and NF-E2-related factor 2 (Nrf2), a key transcription factor for antioxidant systems, was investigated by immunohistochemistry. RESULTS: Compared to the model group, intraperitoneal administration of CAPE decreased TBil, ALT, and AST levels in liver fibrosis rats (P < 0.05), while serum TBil was decreased by CAPE in a dose-dependent manner. In addition, the liver hydroxyproline contents in both the 6 and 12 mg/kg CAPE groups were markedly lower than that in the model group (P < 0.05 and P < 0.001, respectively). CAPE markedly decreased MDA levels and, in turn, increased GSH levels, as well as CAT and SOD activities in liver fibrosis rats compared to the model group (P < 0.05). Moreover, CAPE effectively inhibited α-SMA expression while increasing Nrf2 expression compared to the model group (P < 0.01). CONCLUSION: The protective effects of CAPE against liver fibrosis may be due to its ability to suppress the activation of HSCs by inhibiting oxidative stress.