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Severe acute pancreatitis (SAP) is a highly fatal abdominal emergency, and its association with protein arginine methyltransferase 7 (PRMT7), the sole known type III enzyme responsible for the monomethylation of arginine residue, remains unexplored. In this study, we observe an increase in the PRMT7 levels in the pancreas of SAP mice and Cerulein-LPS-stimulated AR42J cells. Overexpression of Prmt7 exacerbated pancreatic damage in SAP, while the inhibition of PRMT7 improved SAP-induced pancreatic damage. Furthermore, PRMT7 overexpression promoted inflammation, oxidative stress, and ferroptosis during SAP. Mechanically, PRMT7 catalyzed monomethylation at histone H4 arginine 3 (H4R3me1) at the promoter region of high mobility group proteins 2 (HMGB2), thereby enhancing its transcriptional activity. Subsequently, HMGB2 facilitated Acyl CoA synthase long-chain family member 1 (ACSL1) transcription by binding to its promoter region, resulting in the activation of ferroptosis. Inhibition of PRMT7 effectively alleviated ferroptosis in Cerulein-LPS-induced AR42J cells by suppressing the HMGB2-ACSL1 pathway. Overall, our study reveals that PRMT7 plays a crucial role in promoting SAP through its regulation of the HMGB2-ACSL1 pathway to accelerate ferroptosis.
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Ferroptose , Pancreatite , Animais , Camundongos , Doença Aguda , Arginina , Ceruletídeo , Ferroptose/genética , Proteína HMGB2 , Lipopolissacarídeos , Pancreatite/induzido quimicamente , Pancreatite/genética , Proteína-Arginina N-Metiltransferases/genética , Fatores de Transcrição , Ativação TranscricionalRESUMO
BACKGROUND: Granulomatous amoebic encephalitis (GAE) is a rare central nervous system infection caused by the Balamuthia mandrillaris or Acanthamoeba species. Diagnosis is challenging because of the non-specific clinical presentation, cerebrospinal fluid analysis, and radiological features. There is no effective treatment for GAE to date. CASE PRESENTATION: A 54-year-old male was admitted to hospital after experiencing acute onset of numbness and weakness on his left limb. Due to the initial consideration of intracranial tumor, surgical removal of the right parietal lesion was performed. However, the patient had a headache accompanied by diplopia, difficulty walking and a new lesion was found in the left occipital-parietal lobe two weeks after the first operation. High-throughput next-generation sequencing (NGS) detected the presence of high copy reads of the B. mandrillaris genome sequence in the patient's blood, cerebral spinal fluid (CSF), and brain tissue. Pathological investigation of the brain tissue showed granulomatous changes and amoebic trophozoite scattered around blood vessels under high magnification. The patient was re-operated due to developing progressive confusion caused by subfalcine herniation of the left cerebral hemisphere. The lesions of the right parietal lobe were obviously decreasing in size after the first surgery, and the lesions of the left occipital lobe and the sunfalcine herniation didn't ameliorate two months after the second surgery. The patient was transferred to local hospital for continuous treatment with sulfamethoxazole and azithromycin. After five months of the second surgery, the patient showed good recovery with mild headache. CONCLUSIONS: This is the first report of a patient with B. mandrillaris encephalitis initially confirmed by NGS and have experienced two excisions, responding favorably to the combination of surgeries and medications. Early surgical resection of intracranial lesions combined with drug treatment may offer the chance of a cure.
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Amebíase , Balamuthia mandrillaris , Infecções Protozoárias do Sistema Nervoso Central , Encefalite , Encefalite Infecciosa , Amebíase/diagnóstico , Amebíase/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Encefalite/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Fatty liver disease associated with metabolic dysfunction is of increasing concern in mainland China, the world's most populous country. The incidence of fatty liver disease is highest in China, surpassing the incidence in European countries and the USA. An international consensus panel recently published an influential report recommending a novel definition of fatty liver disease associated with metabolic dysfunction. This recommendation includes a switch in name from non-alcoholic fatty liver disease (NAFLD) to metabolic (dysfunction)-associated fatty liver disease (MAFLD) and adoption of a set of positive criteria for disease diagnosis that are independent of alcohol intake or other liver diseases. Given the unique importance of this proposal, the Chinese Society of Hepatology (CSH) invited leading hepatologists and gastroenterologists representing their respective provinces and cities to reach consensus on alternative definitions for fatty liver disease from a national perspective. The CSH endorses the proposed change from NAFLD to MAFLD (supported by 95.45% of participants). We expect that the new definition will result in substantial improvements in health care for patients and advance disease awareness, public health policy, and political, scientific and funding outcomes for MAFLD in China.
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Fígado Gorduroso/fisiopatologia , Gastroenterologia/tendências , China , Fígado Gorduroso/classificação , Gastroenterologia/organização & administração , HumanosRESUMO
BACKGROUND AND AIM: This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of seraprevir, an hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic HCV infection without cirrhosis. METHODS: Treatment-naive or interferon-experienced adult patients without cirrhosis were treated with a universal, combinational regimen of seraprevir 100 mg, twice daily and sofosbuvir 400 mg, once daily, for 12 or 24 weeks. The primary efficacy endpoint was sustained virologic response at week 12 after treatment (SVR12). RESULTS: Overall, 205 patients with genotype 1 HCV infection without cirrhosis were enrolled from 23 sites, 202 of whom completed the full treatment and post-treatment course and 3 discontinued follow-up. In total, 27 patients (13.2%) were interferon experienced. SVR12 was achieved by 201 out of 205 (98.0% [95% CI, 95.1%, 99.5%]) patients, 100.0% of patients with genotype 1a, and 98.0% of genotype 1b. In the other exploratory study, SVR 12 was achieved by 100% patients with genotype 2 (n = 21), genotype 3 (n = 7), and genotype 6 (n = 8). The majority of adverse events were mild to moderate and transient and did not require a specific medical intervention. CONCLUSIONS: The all-oral, ribavirin-free regimen of seraprevir and sofosbuvir is an effective and well-tolerated treatment option for Chinese patients mono-infected with HCV, including those with a history of interferon treatment.
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Hepatite C Crônica , Sofosbuvir , Proteínas não Estruturais Virais , Adulto , Antivirais/efeitos adversos , China/epidemiologia , Quimioterapia Combinada , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Humanos , Cirrose Hepática/epidemiologia , Sofosbuvir/efeitos adversos , Resultado do Tratamento , Proteínas não Estruturais Virais/efeitos adversos , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
BACKGROUND AND AIM: The aim of this study is to investigate the impact of hepatitis B virus (HBV) S gene integration on serum hepatitis B surface antigen (HBsAg) levels in chronic hepatitis B with long-term nucleos(t)ide analogue (NUC) therapy. METHODS: Chronic hepatitis B patients who performed liver biopsy at baseline and treated with long-term NUC therapy were recruited. The integration of HBV S gene in baseline liver biopsy specimen was detected by Alu polymerase chain reaction method. Serum HBsAg levels were measured at baseline and the second year and the fourth year after NUC therapy by Roche reagent, respectively. Serum HBsAg levels between HBV S gene integrated group and nonintegrated group were compared and analyzed. RESULTS: Seventy patients were eligible for this study. Among them, 11 (15.7%) were found to have HBV S gene integration in their baseline liver biopsy specimens. Similar significant decrease of HBsAg levels was found in both integrated and nonintegrated groups (2.63 vs 2.65 log IU/mL, P = 0.478) after the first 2 years of NUC therapy. Thereafter, the decrease of HBsAg level from 2 to 4 years after therapy was largely unchanged in integrated group as compared with that of nonintegrated group (0.1 vs 2.53 log IU/mL, P = 0.002), with statistical difference. CONCLUSIONS: Serum HBsAg could be originated from the expression of the integrated HBV S gene in patients with S gene integration, which implicated the limitations when regarding HBsAg as a surrogate biomarker of covalently closed circular DNA activity and as an indicator of safe NUC discontinuation.
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Antivirais/administração & dosagem , Genes Virais , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Integração Viral/genética , Adulto , Estudos de Coortes , DNA Circular/genética , DNA Viral/genética , Feminino , Hepatite B Crônica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: To investigate the relationship between relapse and the levels of the residual amount of HBV DNA in serum at cessation in chronic hepatitis B patients meeting 2008 Asian Pacific Association for the Study of the Liver (APASL) nucleos(t)ide analogs (NAs) cessation criteria. METHODS: A total of 72 chronic hepatitis B patients who took NAs and had reached 2008 APASL cessation criteria entered the study. Patients were followed up for 6 months or longer after antiviral therapy was stopped. Serum HBV DNA level at cessation was detected by a highly sensitive polymerase chain reaction assay with detection limitation of 2 IU/mL. RESULTS: Of all the 72 patients, 42 patients (65.3%) relapsed after NA cessation. The detectable rate of the trace amount of HBV DNA at cessation was 41.7% by highly sensitive polymerase chain reaction reagents. The detectable rate of patients with consolidation treatment duration of <18 months was higher than that with consolidation duration of ≥18 months (47.5% vs. 15.4%, P=0.034), and the detectable rate of patients with HBeAg seroconversion within 6 months of treatment was lower than that of ≥6 months (25.0% vs. 61.5%, P=0.036). The residual amount of HBV DNA and detectable rate at cessation showed significant differences between relapsed and nonrelapsed patients (130.4±420.90 vs 44.6±155.16 IU/mL, P=0.004; 55.3% vs. 16.0%, P=0.001). The cutoff value predicting relapse was 2.24 IU/mL, with a sensitivity of 0.553 and specificity of 0.840. CONCLUSIONS: Residual amount of HBV DNA in serum at NA cessation is associated with HBV relapse. The cutoff value predicting relapse was 2.24 IU/mL, with a sensitivity of 0.553 and specificity of 0.840.
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DNA Viral/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/sangue , Suspensão de Tratamento/estatística & dados numéricos , Adulto , Antivirais/uso terapêutico , Feminino , Seguimentos , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Nucleotídeos/uso terapêutico , Projetos Piloto , Reação em Cadeia da Polimerase , RecidivaAssuntos
Betacoronavirus , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Mediadores da Inflamação/sangue , Miocárdio/metabolismo , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Biomarcadores/sangue , COVID-19 , Estudos de Casos e Controles , Infecções por Coronavirus/diagnóstico , Hospitalização , Humanos , Mioglobina/sangue , Pandemias , Pneumonia Viral/diagnóstico , Estudos Retrospectivos , SARS-CoV-2 , Troponina I/sangueRESUMO
Through scale-up cultivation of Eriobotrya japonica suspension cells using WAVE bioreactor, the cell growth and ursolic acid (UA) accumulation were studied. The comparison test was carried out in the flask and the reactor with cell dry weight (DW) and UA content as evaluation indexes. The culture medium, DW and UA content were compared in 1 L and 5 L working volumes of bioreactor. The orthogonal test with main actors of inoculation amount, speed and angle of rotation was developed to find the optimal combination, in 1 L working volume of bioreactor. DW of the cell growth and the UA content in bioreactor were higher than those of the shaker by 105.5% and 27.65% respectively. In bioreactor, the dynamic changes of elements in the fluid culture, the dry weight of the cell growth and the UA content in 1 L and 5 L working volumes were similar. Inoculation of 80 g, rotational speed of 26 r · min(-1), and angle of 6 ° was the optimal combination, and the cell biomass of 19.01 g · L(-1) and the UA content of 27.750 mg · g(-1) were achieved after 100 h cultivation in 1 L working volume of bioreactor. WAVE Bioreactor is more suitable than flasks for the E. japonica cell suspension culture, and culture parameters can be achieved from 1 L to 5 L amplification.
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Técnicas de Cultura de Células/métodos , Eriobotrya/química , Eriobotrya/crescimento & desenvolvimento , Triterpenos/análise , Biomassa , Reatores Biológicos , Técnicas de Cultura de Células/instrumentação , Meios de Cultura/química , Meios de Cultura/metabolismo , Eriobotrya/metabolismo , Triterpenos/metabolismo , Ácido UrsólicoRESUMO
Methyltransferase-like 14 (METTL14) is implicated in the regulation of various inflammatory disorders. However, its function and molecular mechanism in severe acute pancreatitis (SAP) remains unrevealed. Here we reported an increase in METTL14 in the pancreas of SAP mice and cerulein-LPS-treated AR42J cells. METTL14 depletion reversed inflammatory response and ferroptosis by reducing the expression of SAT1 (spermidine/spermine N1-acetyltransferase 1) and ACSL4 (acyl-CoA synthetase long chain family member 4) in an m6A-dependent manner. IGF2BP2 (insulin like growth factor 2 mRNA binding protein 2) could recognize m6A-modified SAT1 and ACSL4 mRNA and enhance their stability. Moreover, METTL14 depletion ameliorated pancreatic injury, inflammation, and ferroptosis induced by SAP. METTL14 overexpression aggravated SAP by promoting ferroptosis in vivo. Therefore, these results demonstrated that METTL14-induced ferroptosis promoted the progression of SAP, and targeting METTL14 or ferroptosis could be a potential strategy for the prevention and treatment of SAP.
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Ferroptose , Pancreatite , Animais , Camundongos , Doença Aguda , Adenosina , RNA Mensageiro , Acetiltransferases/metabolismoRESUMO
Purpose: Few studies have reported the integrated characteristics of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after long-term antiviral therapy. This study aimed to investigate the HBV integration features in HBV-HCC patients who had undergone long-term antiviral therapy, evaluate their impact on clinical indicators, and analyze the potential mechanisms involved. Patients and Methods: We utilized genome-wide association study (GWAS) to analyze liver cancer tissues and detect the presence of HBV integration. Seventeen patients with HBV integration were included in the integration (Int) group, while the remaining five patients were included in the non-integration (N-int) group. Clinical indicators were regularly monitored and compared between the two groups. The characteristics of HBV integration patterns were analyzed, and differences between the groups were explored at the chromosome and genomic levels. Results: After long-term antiviral therapy, although the frequency of HBV integration in HBV-HCC was reduced, residual HBV integration still accelerated the development of HCC. It affected the diagnosis, treatment, and prognosis of patients. HBV integration events led to changes in chromosome structure, which were closely related to HCC. Novel fusion genes were detected at a high frequency and had the potential to be specific detection sites for HBV-HCC. Conclusion: HBV integration events are synergistically involved in the human genome and HBV, which can lead to chromosome structural instability, gene rearrangement events closely related to HCC production, and the formation of new specific fusion genes.
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Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, and antineoplastic drugs), and signal of DILI in clinical trials and its assessment.
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Antineoplásicos , Doença Hepática Induzida por Substâncias e Drogas , Falência Hepática Aguda , Humanos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/terapia , China , Fatores de RiscoRESUMO
BACKGROUND: The key endpoint for treatment efficacy in chronic hepatitis C (CHC) is the absence of a detectable virus at 24 weeks after treatment. This study aims to determine the long-term clinical outcomes in patients with CHC after interferon and ribavirin treatment and the factors that influence them. METHODS: A retrospective study was conducted on 259 patients with CHC between 2003 and 2021, and the patients were divided into treated (n = 159) and untreated (n = 100) groups. The median observation duration was four years for the treated group (range: 1-15 years) and four years for untreated groups (range: 1-14 years). RESULTS: The mean ages of the treated and untreated groups were 47.38 ± 9.07 and 51.17 ± 8.38 years, respectively. Regardless of whether antiviral therapy had been administered, patients with undetectable hepatitis C virus (HCV) load had a lower risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) than patients with detectable HCV load (p < 0.05). Furthermore, patients with HCV genotype 1b were more likely to develop cirrhosis and HCC than patients with HCV non-genotype 1b (p < 0.05). Based on the results of multivariate analysis, age of 50 years and above (hazard ratio [HR] = 6.74, 95% confidence interval [CI] = 2.79-16.28) and infection with HCV genotype 1b (HR = 2.43, 95% CI = 1.06-5.56) were significant predictors of liver cirrhosis and HCC development, whereas undetectable HCV RNA load (HR = 0.14, 95% CI = 0.43-0.46) was a protective factor. CONCLUSIONS: During the long-term follow-up, no cases of HCC were discovered in patients with undetectable HCV RNA load. Nevertheless, long-term monitoring is still required in patients with liver cirrhosis, since it increases the risk for developing liver cancer.
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Carcinoma Hepatocelular , Hepatite C Crônica , Neoplasias Hepáticas , Humanos , Adulto , Pessoa de Meia-Idade , Ribavirina/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Carcinoma Hepatocelular/patologia , Estudos Retrospectivos , Antivirais/uso terapêutico , Neoplasias Hepáticas/patologia , Interferon-alfa/uso terapêutico , Hepacivirus/genética , Cirrose Hepática , Resultado do Tratamento , RNA ViralRESUMO
BACKGROUND/AIM: Serum markers to determine the histological grade of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) are still limited. This study aimed to investigate if serum extra spindle pole bodies-like 1 (ESPL1) protein could reflect the histological grade of HBV-related HCC. MATERIALS AND METHODS: A total of 154 patients with HBV-related HCC were enrolled in the experimental group and 41 non-HBV-related patients in the control. Enzyme-linked immunosorbent assay was used to detect serum ESPL1 levels. The differences in serological ESPL1, alpha-fetoprotein (AFP), and des-gamma-carboxy prothrombin (DCP) were compared between the two groups. HCC tumor diameter was measured, and pathological examination was performed to compare the relationship between ESPL1, AFP, and DCP and tumor size and histological grade. RESULTS: Serum AFP and DCP levels showed no significant difference between experimental group and control group, and increased when the tumor diameter increased but were not related to HCC histological grade. Serological ESPL1 levels were higher in the experimental group than those in the control group, and positively correlated with the histological grade. In the experimental group, tumor size and histological grade were almost independent (Kappa=0.000); patients with medium size tumors had the highest serum ESPL1 levels and the highest proportion of poorly differentiated carcinomas, whereas 75.6% of patients with small size tumors had moderately differentiated carcinomas and only 20% well differentiated carcinomas. CONCLUSION: Serum ESPL1 can reflect the malignant degree of HBV-related HCC and is helpful in identifying small size HCC tumors.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Vírus da Hepatite B , alfa-Fetoproteínas , Estudos de Casos e Controles , População do Leste Asiático , Corpos Polares do Fuso , SeparaseRESUMO
INTRODUCTION: A pan-genotypic and effective treatment regimen for patients with chronic hepatitis C virus (HCV) infection remains an unmet medical need in China. Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. We conducted a phase 3 study to evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV infection. METHODS: All patients received 600 mg alfosbuvir tablets plus 60 mg daclatasvir tablets once daily for 12 weeks. The primary endpoint was sustained virological response 12 weeks after the end of treatment (SVR12). A follow-up visit was done at week 4 and 12, and those who achieved SVR12 were followed up at post-treatment week 24. RESULTS: Of the 326 patients who received at least one dose of the study drug, 320 (98.2% [95% confidence interval (CI): 96.5%-99.5%]) achieved sustained virological response at post-treatment week 12 (SVR12), which was superior to the historical SVR12 rate of 88% (p < 0.0001). The SVR12 rates were similar regardless of most baseline characteristics. The most common adverse event (AE) (≥ 10%) was hypercholesterolemia. Serious adverse events (SAEs) were reported in 25 (7.7%) patients, none of which was judged to be related to the study drug. The majority of AEs were mild to moderate in severity. CONCLUSIONS: Alfosbuvir plus daclatasvir for 12 weeks was highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3, or 6, suggesting that this regimen could be a promising option for HCV treatment in China irrespective of genotype. TRIAL REGISTRATION: ClinicalTrial.gov identifier, NCT04070235.
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Anoectochilus roxburghii (Wall.) Lindl, a traditional Chinese medicine, is used for the effective treatment of liver disease in China. Anoectochilus roxburghii polysaccharide (ARPT) is an important constituent of Anoectochilus roxburghii. ARPT exerts a hepatoprotective effect and contributes directly to the therapeutic benefit of Anoectochilus roxburghii. However, the hepatoprotective mechanism of ARPT requires further elucidation. The present study was designed to assess the effects and underlying mechanism of ARPT when used to pretreat carbon tetrachloride (CCl4)-induced liver injury in mice. Mice were randomly divided into three groups: control group (no ARPT treatment or liver injury), model group (liver injury induced with CCl4), and the ARPT group (ARPT pretreatment followed by liver injury). A metabolomic method, based on liquid chromatography combined with mass spectrometry (LC-MS) and pattern recognition analysis, was applied. The data were analyzed with principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), to determine differentiating metabolites in the serum and liver tissue between the experimental groups. The PCA and OPLS-DA scores plots of the serum and liver tissue samples based on the LC-MS data showed a clear separation between the control and liver injury model group, while the ARPT-treated group showed a trend of close with the control. There were eleven metabolites [PS(O-18:0/0:0), phosphocholine, phenylalanine, hippuric acid, α-ketoisovaleric acid, metyrosine, leucinic acid, ketoleucine, Cer(d18:1/19:0), α-kamlolenic acid, and 4-formyl indole] were identified as candidate biomarkers in the serum samples, eight such metabolites (valine, phosphohydroxypyruvic acid, phosphocholine, ornithine, indole, xanthine, uridine, and glucose 6-phosphate) were found in the liver tissue samples, and one metabolite (phosphocholine) was observed in both the serum and liver tissue samples. These endogenous metabolites are considered to be in response to the hepatoprotective effects of ARPT and are involved in amino acid metabolism, lipid metabolism, gut bacteria metabolism, energy metabolism, and the methylation pathway. These findings suggest that ARPT mitigates the metabolic effect of CCl4-induced hepatotoxicity in mice by affecting at least five different pathways. LC-MS-based metabolomics provides a powerful approach for identifying potential biomarkers and for elucidating the protective mechanisms of traditional Chinese medicines against disease.
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Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Metaboloma/efeitos dos fármacos , Orchidaceae/química , Polissacarídeos/farmacologia , Animais , Tetracloreto de Carbono/efeitos adversos , Cromatografia Líquida , Masculino , Espectrometria de Massas , Metabolômica , CamundongosRESUMO
AIMS: To investigate the feasibility of serum extra spindle pole bodies-like 1 (ESPL1) used as a biomarker for patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: 131 chronic HBV-infection patients were recruited and divided into HBV S gene integration, non-HBV S gene integration, chronic hepatitis B (CHB), HBV-related liver cirrhosis (LC) and HBV-related HCC group, 24 non-HBV-related HCC patients were selected as HCC control group, 30 people without HBV-infection as healthy control group. Serum ESPL1 were detected and compared. RESULTS: ESPL1 level of integration group was significantly higher than that of non-integration group (346.7 vs 199.6 ng/ml, P = 0.000) and healthy control group (346.7 vs 41.3 ng/ml, P = 0.000). ESPL1 level of non-integration group was significantly higher than that of healthy control group (199.6 vs 41.3 ng/ml, P = 0.000); ESPL1 levels in chronic HBV-infection related groups were increased in turn according to CHB group (95.8 ng/ml), HBV-related LC group (268.2 ng/ml), HBV-related HCC group (279.9 ng/ml) and integration group (346.7 ng/ml). Except that there was no significant difference in ESPL1 levels between HBV-related LC and HCC group (P = 0.662), pairwise comparisons between other groups showed significant differences (P < 0.05). ESPL1 level of HBV-related HCC group was significantly higher than that of non-HBV-related HCC group (279.9 vs 46.6 ng/ml, P = 0.000), there was no noticeable difference between non-HBV-related HCC and healthy control group (46.6 vs 41.3 ng/ml, P = 0.848). ESPL1 level of HBV-related HCC group after resection was significantly lower than that of before resection (178.4 vs 260.8 ng/ml, P = 0.000). CONCLUSIONS: Chronic HBV-infection patients with high ESPL1 level may indicate HBV S gene integration and is a high-risk population for HBV-related HCC. Serum ESPL1 can be used as a biomarker for screening HBV-related HCC high-risk population and monitoring recurrence.
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Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/etiologia , Hepatite B/complicações , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/etiologia , Separase/sangue , Adulto , Biomarcadores , Biópsia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirurgia , Estudos de Casos e Controles , China , Suscetibilidade a Doenças , Feminino , Seguimentos , Hepatite B/virologia , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirurgia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Prognóstico , Tomografia Computadorizada por Raios XRESUMO
AIM: It has been shown that the integration of hepatitis B virus (HBV) gene into the host genome is a high-risk factor for development of hepatocellular carcinoma (HCC). However, the relationship between HBV S-integrated human extra spindle pole bodies-like 1 (ESPL1) gene and HCC is unknown. This study was designed to detect HBV S-integrated human ESPL1 fusion gene in patients with HCC for potentially using this fusion gene as a biomarker for HCC diagnosis. PATIENTS AND METHODS: Nineteen and 70 patients with chronic hepatitis B (CHB) were recruited to the experimental and control groups, respectively, and both groups underwent an effective nucleoside/nucleotide analog therapy and follow-up for HCC occurrence for up to 11 years. HCC tissues were obtained by surgical resection from the experimental group, while liver tissues were collected by liver biopsy in the control group prior to treatment with nucleoside/nucleotide analogs. Alu polymerase chain reaction was used to assess HBV S gene integration in the liver tissues from both groups. HBV S-integrated human ESPL1 fusion gene was then detected in patients with HBV S gene integration using a gene database. RESULTS: All patients in the experimental group developed HCC, whereas no HCC was diagnosed in the control group. HBV S gene integration was identified in 12 out of 19 HCC tissues in the experimental group, giving a detection rate of 63.2%, which was significantly greater than that of 15.7% (11/70) in the control group (p<0.001). We further showed that HBV S-integrated human ESPL1 fusion gene was detected in eight patients (rate of 66.7%) among the 12 patients with HCC with HBV S gene integration in the experimental group, whereas the fusion gene was not detectable in any of the patients in the control group (p=0.001). CONCLUSION: This research demonstrates a high detection rate of HBV S-integrated human ESPL1 fusion gene in patients with HBV-related HCC and shows that this fusion gene appears to be associated with HCC development in patients with CHB. These findings suggest that HBV S-integrated human ESPL1 fusion gene may potentially serve as a biomarker for early detection of HCC in HBV-infected populations.
Assuntos
Povo Asiático , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Proteínas de Fusão Oncogênica/genética , Separase/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatite B Crônica/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Separase/metabolismo , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismoRESUMO
BACKGROUND: Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1-6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes. METHODS: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov, number NCT02671500, and is completed. FINDINGS: Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94-98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72-98]) of 28 patients without cirrhosis and seven (50% [23-77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir-velpatasvir treatment. INTERPRETATION: Consistent with data from other phase 3 studies, single-tablet sofosbuvir-velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis. FUNDING: Gilead Sciences.
Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Cirrose Hepática/sangue , Sofosbuvir/uso terapêutico , Adulto , China , Combinação de Medicamentos , Feminino , Genótipo , Cefaleia/induzido quimicamente , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Infecções Respiratórias/induzido quimicamente , Singapura , Resposta Viral Sustentada , Tailândia , Resultado do Tratamento , VietnãRESUMO
BACKGROUND: Anoectochilus roxburghii is a widespread herbaceous plant with high medicinal value. Wild A. roxburghii resources face extinction due to their slow growth rate and over exploitation. The growing market demand has led to advances in the field of artificial planting of A. roxburghii. Methods to increase the economic benefits of cultivation and the production of medicinal ingredients are very useful. METHODS: A. roxburghii was exposed to red light, blue light (BL), yellow light (YL), green light, or white light as supplemental lighting at night (18:00-02:00) in a greenhouse or were left in darkness (control, CK) to investigate the effects of various light qualities on growth indices, photosynthetic pigments, chlorophyll fluorescence, root vitality, stomatal density, soluble proteins, sugars, and the accumulation of secondary metabolites. RESULTS: Supplementation of BL had a positive effect on A. roxburghii growth and secondary metabolite accumulation. Leaf number, stem diameter, fresh weight, dry weight, chlorophyll a content, and secondary metabolite (total flavonoids, total polyphenols) content increased significantly. YL treatment showed significantly higher soluble sugar and polysaccharide contents than the control. DISCUSSION: BL treatment was conducive to promoting the growth and accumulation of secondary metabolites (total flavonoids, total polyphenols); YL treatment significantly increased the content of soluble sugar and polysaccharides more than the control. Polysaccharides and total flavonoids are important medicinal ingredients of Anoectochilus, so future research will focus on the combination of blue and YL.
RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Anoectochilus roxburghii (Wall.) Lindl. is traditionally used for the treatment of various types of chronic and acute hepatitis in China. Considering that Anoectochilus roxburghii polysaccharide (ARPT) is the main constituent of Anoectochilus roxburghii, the present study was designed to investigate the hepatoprotective effect of ARPT and its possible mechanism in carbon tetrachloride (CCl4)-induced mice. MATERIAL AND METHODS: The hepatoprotective activity of ARPT (150, 300 and 500mg/kg) were investigated on CCl4-induced acute liver damage in mice. The activities of alanine transaminase (ALT), aspartate transaminase (AST) were determined in serum. The hepatic levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured in liver homogenates. The levels of cytochrome P450 sub family 2E1 (CYP2E1), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), KC (Murine IL-8 ortholog), transforming growth factor-beta1 (TGF-ß1), Bcl-2 and Bax were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expressions of CYP2E1, nuclear factor-kappa B (NF-κB) p65 and caspase-3 were evaluated by western blot assays. The hepatic levels of TNF-α, IL-6, MIP-2 and TGF-ß1 were measured by enzyme-linked immunosorbent assay (ELISA). Furthermore, histopathological observation and terminal-deoxynucleoitidyl transferase mediated nick end labeling assay (TUNEL) were carried out on the separated livers of mice. RESULTS: ARPT significantly decreased serum ALT and AST activities, hepatic MDA level, and markedly enhanced antioxidant enzyme (SOD, CAT and GSH-Px) activities and GSH level in hepatic tissue, in a dose-dependent manner, when compared to the model group. Histopathological observation revealed the hepatoprotective effect of ARPT against the damage. Furthermore, ARPT remarkably inhibited CYP2E1 mRNA expression, decreased NF-κB p65 expression and therefore to prevent the secretion of pro-inflammatory cytokines (TNF-α and IL-6) and chemokines (MCP-1, MIP-2 and KC), suppressed TGF-ß1 expression and hepatocytes apoptosis. Moreover, ARPT could prevent DNA fragmentation based on TUNEL assay results. CONCLUSION: These findings suggested that ARPT possessed hepatoprotective effect against CCl4-induced hepatotoxicity in mice and the action might in part be through reducing oxidative stress, inflammation and apoptosis.