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1.
AIDS ; 36(11): 1591-1595, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35730395

RESUMO

OBJECTIVE: To assess the prevalence of severe transaminitis precluding tuberculosis (TB) preventive therapy (TPT) initiation for people with HIV (PWH) in a high TB/HIV burden setting. DESIGN/METHODS: We conducted a secondary analysis of data from a prospective cohort study of PWH with pre-antiretroviral therapy (ART) CD4 + counts 350 cells/µl or less undergoing systematic TB screening from two HIV clinics in Uganda. For this analysis, we excluded patients with culture-confirmed TB and patients without aspartate transaminase (AST) or alanine transaminase (ALT) levels measured within three months of enrollment. We compared the proportion of patients with any transaminitis (AST or ALT greater than one times the upper limit of normal ULN) and severe transaminitis (AST or ALT >3 times ULN) for patients screening negative for TB by symptoms and for those screening negative by C-reactive protein (CRP). We also assessed the proportion of patients with transaminitis by self-reported alcohol consumption. RESULTS: Among 313 participants [158 (50%) women, median age 34 years (IQR 27-40)], 75 (24%) had any transaminitis and six (2%) had severe transaminitis. Of 32 of 313 (10%) who screened negative for TB by symptoms, none had severe transaminitis. In contrast, six-times more PWH screened negative for TB by CRP (194 of 313; 62%), of whom only four (2.1%) had severe transaminitis. Differences in the proportion with any and severe transaminitis according to alcohol consumption were not statistically significant. CONCLUSION: Prevalence of severe transaminitis was low among PWH without culture-confirmed TB in this setting, and is therefore, unlikely to be a major barrier to scaling-up TPT.


Assuntos
Infecções por HIV , Transaminases , Tuberculose , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/epidemiologia , Humanos , Masculino , Prevalência , Estudos Prospectivos , Transaminases/sangue , Tuberculose/complicações , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , Uganda
2.
Intern Emerg Med ; 17(6): 1777-1784, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35624344

RESUMO

Liver damage worsens the prognosis of coronavirus 19 disease (COVID-19). However, the best strategy to stratify mortality risk according to liver damage has not been established. The aim of this study is to test the predictive value of the validated Fibrosis-4 (FIB-4) Index and compared it to liver transaminases and to the AST-to-Platelet ratio index (APRI). Multicenter cohort study including 992 consecutive COVID-19 patients admitted to the Emergency Department. FIB-4 > 3.25 and APRI > 0.7 were used to define liver damage. Multivariable Cox regression and ROC curve analysis for mortality were performed. Secondary endpoints were (1) need for high-flow oxygen and (2) mechanical ventilation. 240 (24.2%) patients had a FIB-4 > 3.25. FIB-4 > 3.25 associated with an increased mortality (n = 119, log-rank test p < 0.001 and adjusted hazard ratio (HR) 1.72 (95% confidence interval [95%CI] 1.14-2.59, p = 0.010). ROC analysis for mortality showed that FIB-4 (AUC 0.734, 95% CI 0.705-0.761) had a higher predictive value than AST (p = 0.0018) and ALT (p < 0.0001). FIB-4 > 3.25 was also superior to APRI > 0.7 (AUC 0.58, 95% CI 0.553-0.615, p = 0.0008). Using an optimized cut-off > 2.76 (AUC 0.689, 95% CI 0.659-0.718, p < 0.0001), FIB-4 was superior to FIB-4 > 3.25 (p = 0.0302), APRI > 0.7 (p < 0.0001), AST > 51 (p = 0.0119) and ALT > 42 (p < 0.0001). FIB-4 was also associated with high-flow oxygen use (n = 255, HR 1.69, 95% CI 1.25-2.28, p = 0.001) and mechanical ventilation (n = 39, HR 2.07, 95% CI 1.03-4.19, p = 0.043). FIB-4 score predicts mortality better than liver transaminases and APRI score. FIB-4 score may be an easy tool to identify COVID-19 patients at worse prognosis in the emergency department.


Assuntos
COVID-19 , Cirrose Hepática , Índice de Gravidade de Doença , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , COVID-19/sangue , COVID-19/complicações , COVID-19/mortalidade , Estudos de Coortes , Serviço Hospitalar de Emergência , Humanos , Cirrose Hepática/mortalidade , Cirrose Hepática/virologia , Oxigênio/sangue , Contagem de Plaquetas , Curva ROC , Estudos Retrospectivos
3.
Exp Clin Endocrinol Diabetes ; 130(11): 758-764, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35640638

RESUMO

BACKGROUND: Recently, a newly proposed data-driven approach for classifying diabetes has challenged the status quo of the classification of adult-onset patients with diabetes. This study investigated the association between liver injury and diabetes, classified by data-driven cluster analysis, as liver injury is a significant risk factor for diabetes. METHODS: We enrolled 822 adult patients with newly diagnosed diabetes. Two-step cluster analysis was performed using six parameters, including age at diagnosis, body mass index, hemoglobin A1C, homoeostatic assessment model 2 estimates about insulin resistance (HOAM2-IR) and beta-cell function (HOMA2-B), and glutamic acid decarboxylase antibodies (GADA) positivity. Patients were allocated into five clusters. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity were compared as indicators of liver injury among clusters. RESULTS: Serum ALT and AST activities were significantly different among clusters (P=0.002), even among those without GADA positivity (P=0.004). Patients with severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) had a more severe liver injury. Gender dimorphism was also found for serum ALT and AST activities among subgroups. Female patients had better liver function than males with SIRD and MOD. CONCLUSIONS: We verified the feasibility of a newly proposed diabetes classification system and found robust and significant relationship and gender differences between serum ALT and AST activities and diabetes in some specific subgroups. Our findings indicate that more attention should be paid to diabetes subgroups when studying risk factors, indicators, or treatment in diabetic research.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Fígado , Adulto , Feminino , Humanos , Masculino , Alanina Transaminase/sangue , Análise por Conglomerados , Diabetes Mellitus Tipo 2/epidemiologia , Fígado/enzimologia , Fatores Sexuais , Aspartato Aminotransferases/sangue
4.
BMC Cancer ; 22(1): 249, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35255845

RESUMO

BACKGROUND: Inflammation plays a significant role in tumour development, progression, and metastasis. In this study, we focused on comparing the predictive potential of inflammatory markers for overall survival (OS), recurrence-free survival (RFS), and 1- and 2-year RFS in hepatocellular carcinoma (HCC) patients. METHODS: A total of 360 HCC patients were included in this study. A LASSO regression analysis model was used for data dimensionality reduction and element selection. Univariate and multivariate Cox regression analyses were performed to identify the independent risk factors for HCC prognosis. Nomogram prediction models were established and decision curve analysis (DCA) was conducted to determine the clinical utility of the nomogram model. RESULTS: Multivariate Cox regression analysis indicated that the prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) were independent prognostic factors of OS, and aspartate aminotransferase-to-platelet ratio (APRI) was a common independent prognostic factor among RFS, 1-year RFS, and 2-year RFS. The systemic inflammation response index (SIRI) was an independent prognostic factor for 1-year RFS in HCC patients after curative resection. Nomograms established and achieved a better concordance index of 0.772(95% CI: 0.730-0.814), 0.774(95% CI: 0.734-0.815), 0.809(95% CI: 0.766-0.852), and 0.756(95% CI: 0.696-0.816) in predicting OS, RFS, 1-year RFS, and 2-year RFS respectively. The risk scores calculated by nomogram models divided HCC patients into high-, moderate- and low-risk groups (P < 0.05). DCA analysis revealed that the nomogram models could augment net benefits and exhibited a wider range of threshold probabilities in the prediction of HCC prognosis. CONCLUSIONS: The nomograms showed high predictive accuracy for OS, RFS, 1-year RFS, and 2-year RFS in HCC patients after surgical resection. The nomograms could be useful clinical tools to guide a rational and personalized treatment approach and prognosis judgement.


Assuntos
Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Nomogramas , Medição de Risco/métodos , Idoso , Aspartato Aminotransferases/sangue , Biomarcadores/análise , Plaquetas/metabolismo , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/cirurgia , Bases de Dados Factuais , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/cirurgia , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Período Pós-Operatório , Valor Preditivo dos Testes , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
5.
Pak J Pharm Sci ; 35(1(Supplementary)): 281-285, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35228189

RESUMO

In developing countries, myocardial ischemia and the resulting impairments in heart function are the leading cause of illness and mortality. Thymus linearis Benth has been used as an antibiotic, antioxidant, and antihypertensive agent for centuries. The goal of this investigation was to see if Thymus linearis could protect isoproterenol and doxorubicin-induced myocardial ischemia in vivo at doses of 25 mg/kg s.c. and 15 mg/kg i.p., respectively. The level of cardiac enzymes (CK-MB, LDH, and AST) in the serum isolated from the experimental animal's blood was used to determine myocardial ischemia. The anti-ischemic potential was assessed by comparing the levels of the aforementioned cardiac biomarkers in the intoxicated and treated animal groups. The study found substantial increase (p0.0001) in the serum levels of CK-MB, LDH, AST when compared to intoxicated groups, while pretreatment of animals with crude extract of Thymus linearis significantly reduced the rise in serum cardiac indicators. The findings of the study indicated that the aqueous methanolic Thymus linearis crude extract has cardioprotective potential against Isoproterenol and Doxorubicin-induced cardiac necrosis in rats.


Assuntos
Isquemia Miocárdica/induzido quimicamente , Isquemia Miocárdica/prevenção & controle , Extratos Vegetais/farmacologia , Thymus (Planta)/química , Animais , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Feminino , Isoproterenol/toxicidade , L-Lactato Desidrogenase/sangue , Masculino , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley
6.
Asian Pac J Cancer Prev ; 23(2): 703-713, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35225484

RESUMO

BACKGROUND: The sea cucumber, Bohadschia marmorata, is a marine echinoderm consumed and used as a medication. Extract of this species displays a broad spectrum of bioactivity, such as antifungal, antibacterial, immunomodulatory, and cytotoxic properties. This investigation explored sea cucumber extract for hepatorenal protection against the toxicity of methotrexate (MTX). METHODS: Four groups of mice were divided into G1: control, G2: MTX treated, G3: B. marmorata extract-treated daily for 14 days, and G4: B. marmorata extract and MTX treated. RESULTS AND CONCLUSIONS: Biochemical analysis and histopathological examination of liver tissue showed that administration of MTX increased serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), lowered levels of serum albumin, total protein, Superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Administration of B. marmorata extract to MTX- injected mice significantly reversed the increase in serum levels of liver enzymes and induced a significant elevation in serum albumin and total protein levels. SOD, CAT, and GSH levels returned to nearly normal levels. Histopathological examination indicated fewer signs of toxicity in liver and kidney tissues of mice treated with both extract and MTX compared to MTX treatment alone. An extract of B. marmorata will protect mice from hepatorenal toxicity induced by MTX.


Assuntos
Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Metotrexato/efeitos adversos , Substâncias Protetoras/administração & dosagem , Pepinos-do-Mar/química , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Glutationa/sangue , Fígado/metabolismo , Masculino , Camundongos , Albumina Sérica/metabolismo , Superóxido Dismutase/sangue
7.
BMC Endocr Disord ; 22(1): 49, 2022 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-35216556

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has become the most common causes of liver disease in children and adolescents. Although several reports have confirmed the significant correlation between NAFLD and growth hormone (GH)-insulin-like growth factor 1(IGF-1) axis, no study further investigates whether or not recombinant human GH (rhGH) treatment can improve NAFLD in obese children. METHODS: This study was a randomized, open-label study comprising 44 boys with obesity and NAFLD (11.76 ± 1.67 year) to evaluate the effects of 6 months of rhGH administration for boys with obesity and NAFLD. The subjects were randomized divided into treatment group (subjects with recombinant human GH (rhGH)) and control group for 6 months. RESULTS: After 6 months, IGF-1 increased significantly during rhGH treatment, in comparison with the control group (582.45 ± 133.00 vs. 359.64 ± 129.00 ng/ml; p < 0.001). A significant reduction in serum alanine aminotransferase(ALT) (15.00 vs. 28.00 U/L; p = 0.001), aspartate aminotransferase(AST) (20.00 vs. 24.50U/L; p = 0.004), gamma glutamyl transferase(GGT) (14.50 vs. 28.50 U/L; p < 0.001) was observed in the GH-treated boys. In addition, the rhGH group showed a significant decrease in C reactive protein (CRP) (1.17 ± 0.76 vs. 2.26 ± 1.43 mg/L) and body mass index standard deviation scores (BMI SDS) (2.28 ± 0.80 vs. 2.71 ± 0.61) than the control group (p = 0.003, p = 0.049 respectively). GH treatment also reduced low density lipoprotein cholesterol (LDL-C) (2.19 ± 0.42 vs. 2.61 ± 0.66 mmol/L; p = 0.016) and increased high density lipoprotein cholesterol (HDL-C) (1.30 vs. 1.15 mmol/L; p = 0.005), and there were no changes in total cholesterol (TC), triglycerides (TG) and uric acid(UA) between the treatment group and the control group. CONCLUSION: Our findings suggest that 6 months treatment with rhGH may be beneficial for liver enzyme and can improve obesity-related other cardiovascular and metabolic complications in boys with obesity and NAFLD.


Assuntos
Fatores de Risco Cardiometabólico , Hormônio do Crescimento Humano/administração & dosagem , Fígado/enzimologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade Pediátrica/complicações , Adolescente , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Proteína C-Reativa/análise , Criança , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/análise , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade Pediátrica/sangue , Proteínas Recombinantes/administração & dosagem , gama-Glutamiltransferase/sangue
8.
Sci Rep ; 12(1): 2788, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-35181684

RESUMO

Our purpose was to evaluate the biocompatibility and hepatotoxicity of a new bioceramic intracanal medicament, Bio-C Temp (BIO). The biological properties of BIO were compared with calcium hydroxide-based intracanal medicament (Calen; CAL), used as gold pattern. Polyethylene tubes filled with BIO or CAL, and empty tubes (control group, CG) were implanted into subcutaneous tissue of rats. After 7, 15, 30 and 60 days, the samples were embedded in paraffin for morphological, quantitative and immunohistochemistry analyses. At 7 and 60 days, blood samples were collected for analysis of serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels. The data were submitted to two-way ANOVA and Tukey's test (p ≤ 0.05). No significant difference was detected in serum GOT and GPT levels among BIO, CAL and CG specimens. In all periods, BIO specimens exhibited lower number of inflammatory cells and immunoexpression of IL-6, a pro-inflammatory cytokine, than CAL specimens. The reduction of these parameters was accompanied by significant increase in the collagen content and in the immunoexpression of IL-10, a cytokine involved in the tissue repair, over time. Our findings indicate that Bio-C Temp is biocompatible and had no hepatotoxicity effect.


Assuntos
Óxido de Alumínio/farmacologia , Materiais Biocompatíveis/farmacologia , Fígado/enzimologia , Tela Subcutânea/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Hidróxido de Cálcio/farmacologia , Fígado/efeitos dos fármacos , Teste de Materiais , Próteses e Implantes/efeitos adversos , Ratos , Materiais Restauradores do Canal Radicular/farmacologia
10.
Sci Rep ; 12(1): 1711, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110625

RESUMO

Dyslipidemia, a major contributor to cardiovascular diseases, is rapidly increasing in Asian countries including Bangladesh. In addition to the cardiovascular system, abnormal lipid levels are also known to cause complications in renal and hepatic systems. The data regarding dyslipidemia and its relationship with liver enzymes are scarce for the Bangladeshi population. Therefore, this study was conducted to estimate the prevalence of dyslipidemia and determine the relationship between lipid profile and liver enzymes in Bangladeshi adults. A total of 405 participants (318 males and 87 females) were enrolled in the study. Serum levels of TG, TC, LDL, HDL and liver enzymes including ALT, AST, GGT and ALP were analyzed using standard methods. Dyslipidemia and liver function tests abnormalities were defined according to the international standard guidelines. The association between elevated lipid profile markers and liver enzyme abnormalities was assessed by logistic regression analysis. Overall, the prevalence of elevated TG, TC, LDL and low HDL were 30.9%, 23.7%, 26.2% and 78.8%, respectively. On the other hand, the prevalence of elevated liver enzymes ALT, AST, GGT and ALP were 18.8%, 21.6%, 12.9% and 21.9%, respectively. Dyslipidemia and liver enzyme abnormalities were higher in diabetic and hypertensive participants than in the healthy participants. About 61% of participants with dyslipidemia had at least one or more elevated liver enzymes. In regression analysis, an independent association was observed between serum GGT and all lipid components. In conclusion, a high prevalence of dyslipidemia and liver enzyme abnormalities were observed among the study participants. Of the four liver enzymes, the serum levels of GGT showed an independent association with all lipid components. Moreover, this study indicates that subjects with dyslipidemia often have a higher chance of having liver diseases than subjects with no dyslipidemia. However, large-scale prospective studies are needed to understand the underlying mechanisms of lipid-induced hepatic dysfunction in the Bangladeshi population.


Assuntos
Dislipidemias/sangue , Enzimas/sangue , Lipídeos/sangue , Hepatopatias/sangue , Adulto , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Bangladesh/epidemiologia , Biomarcadores/sangue , Ensaios Enzimáticos Clínicos , Estudos Transversais , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Feminino , Humanos , Hepatopatias/diagnóstico , Hepatopatias/epidemiologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Prevalência , Medição de Risco , Fatores de Risco , Regulação para Cima , gama-Glutamiltransferase/sangue
11.
Dis Markers ; 2022: 3533714, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35186165

RESUMO

OBJECTIVE: This study was aimed at exploring the prognostic and clinicopathological roles of aspartate aminotransferase-to-lymphocyte ratio index (ALRI) in patients with hepatocellular carcinoma via a meta-analysis. METHODS: The PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases were comprehensively searched from inception to November 20, 2021. Pooled hazard ratio (HR) and corresponding 95% confidence interval (CI) were used to evaluate the relationship between ALRI and overall survival (OS) as well as progression-free survival (PFS) in patients with hepatocellular carcinoma. Odds ratio (OR) and the corresponding 95% CI were also used to investigate correlations between clinical factors and ALRI in patients with hepatocellular carcinoma. RESULTS: A total of 3914 patients with hepatocellular carcinoma from eleven retrospective cohorts were included in this meta-analysis. The combined results revealed that patients with hepatocellular carcinoma with elevated ALRI tended to have unfavorable OS (HR 1.53 [95% CI 1.25-1.82]; P < 0.001). Pooled HRs revealed that high ALRI was an independent risk factor for inferior PFS in patients with hepatocellular carcinoma (HR 1.36 [95% CI 1.10-1.63]; P < 0.001). In addition, high ALRI was strongly associated with male sex (OR 1.32 [95% CI 1.02-1.70]; P = 0.035), presence of cirrhosis (OR 1.68 [95% CI 1.01-2.81]; P = 0.046), larger tumor size (OR 2.25 [95% CI 1.31-3.88]; P < 0.001), presence of portal vein tumor thrombus (OR 2.50 [95% CI 1.52-4.11]; P < 0.001), and distant metastasis (OR 1.72 [95% CI 1.05-2.82]; P = 0.031). CONCLUSION: Elevated ALRI in patients with hepatocellular carcinoma predicted inferior survival outcomes and was strongly associated with some important features of hepatocellular carcinoma.


Assuntos
Aspartato Aminotransferases/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Linfócitos , Carcinoma Hepatocelular/mortalidade , Humanos , Neoplasias Hepáticas/mortalidade , Contagem de Linfócitos , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
12.
Toxicology ; 466: 153087, 2022 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-34974135

RESUMO

Alcoholic liver injury (ALI) is a major risk factor for alcoholic liver disease, characterized by excessive inflammatory response and abnormal liver dysfunction. Previous studies have indicated that O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1 L) has anti-inflammatory and hepato-protective effects in CCl4-induced liver injury. However, its effect on ALI and underlying mechanism has not been elucidated. This study was designed to evaluate the protective effects of HD-1 L on alcoholic liver injury and reveal the underlying mechanisms. ALI model was established in male C57BL/6 J mice (aged 6-8 weeks) by Gao-Binge protocol. The mice were received different doses of HD-1 L (25 mg/kg, 50 mg/kg, 100 mg/kg) by daily intragastric administration, respectively. Liver function and inflammation were measured. Mechanism underlying the anti-inflammatory and hepato-protective effect of HD-1 L were studied in RAW264.7 cells. In alcoholic liver injury mice, HD-1 L effectively improved the liver pathology, and remarkably reduced the levels of alanine transaminase (ALT), aspartate transaminase (AST), triglyceride (TG) and total cholesterol (T-CHO) in serum. Moreover, HD-1 L markedly suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Our results showed that HD-1 L decreased the activity of Bromodomain-containing Protein 2 (BRD2) and inhibited expression of BRD2 in vivo and in vitro. Furthermore, HD-1 L further alleviated alcohol-induced inflammation after blocking BRD2 with inhibitor (JQ1) or BRD2 small interfering (si)-RNA in RAW264.7 cells. Besides, HD-1 L failed to effectively exert its anti-inflammatory effects after over expression of BRD2. In addition, HD-1 L significantly inhibited the phosphorylation and activation of NF-κB-P65 mediated by BRD2. In conclusion, HD-1 L alleviated liver injury and inflammation mainly by inhibiting BRD2-NF-κB signaling pathway, and HD-1 L may be a potential anti-inflammatory compound in treatment of alcoholic liver disease.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hesperidina/farmacologia , Inflamação/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição/metabolismo , Alanina Transaminase/sangue , Animais , Anti-Inflamatórios/farmacologia , Aspartato Aminotransferases/sangue , Colesterol/sangue , Citocinas/metabolismo , Hesperidina/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Triglicerídeos/sangue
13.
Environ Toxicol Pharmacol ; 90: 103819, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35077907

RESUMO

It is well known that gut microbiota imbalance can promote the development of metabolic disease. Enterobacter cloacae (E. cloacae) is a kind of opportunistic pathogen in the intestine. Therefore, we hypothesized that E. cloacae accelerated the development of metabolic disease. To answer this question, we used E. cloacae to induce disease in guinea pigs. We used H&E staining to detect the pathological changes of liver and aorta and used Oil Red O staining to evaluate the lipid accumulation in the liver. And that we used a kit to detect AST content and used Western blot to detect protein levels in the liver. We found that E. cloacae could induce liver pathological changes and lipid accumulation as well as aortic wall pathological changes in guinea pigs. And E. cloacae increased the liver index to 5.94% and the serum AST level to 41.93 U/L. Importantly, E. cloacae activated liver high mobility group protein (HMGB1)/toll-like receptor 4 (TLR4)/myeloiddifferentiationfactor88 (MYD88)/nuclear factor-kappa B (NF-κB) signal and sterol regulatory element-binding protein 1c (SREBP-1c) and inhibited AMP-activated protein kinase (AMPK). We conclude that E. cloacae promote nonalcoholic fatty liver disease (NAFLD) by inducing inflammation and lipid accumulation, and E. cloacae also promote atherosclerosis. These findings are important for study on the pathogenesis and drug screening of NAFLD and atherosclerosis.


Assuntos
Aterosclerose/etiologia , Infecções por Enterobacteriaceae/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Aorta/patologia , Aspartato Aminotransferases/sangue , Enterobacter cloacae/patogenicidade , Cobaias , Inflamação , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino
14.
ACS Appl Mater Interfaces ; 14(5): 6985-6993, 2022 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-35080175

RESUMO

Monitoring the liver status in a convenient and low-cost way is significant for obtaining a warning about drug-indued liver diseases promptly. Herein, we designed a novel colorimetric point-of-care (POC) platform for the determination of three liver-related biomarkers─aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP). This platform integrated agarose hydrogels into a portable device, where hydrogels were loaded with nanozymes and different reaction substances for triggering specific reactions and generating colorimetric signals. Typically, Au-decorated CoAl-layered double oxide (Au/LDO) was for the first time developed as the nanozyme with peroxidase (POD) mimic activity, which can accelerate the oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue oxTMB with the coexistence of hydrogen peroxide (H2O2). The detection mechanism of AST and ALT is based on the fact that they can cause individual cascade reactions to generate H2O2, and H2O2 further activates the Au/LDO nanozyme to catalyze the chromogenic reaction of TMB. As for ALP, it can catalytically hydrolyze l-ascorbic acid-2-phosphate to ascorbic acid. The latter then discolored the oxTMB that was produced with the assistance of Au/LDO. Teaming up with a smartphone, the color information of hydrogels can be converted to hue values, which allow quantitative analysis of ALT, AST, and ALP with detection limits of 15, 10, and 5 U/L, respectively. Moreover, the simple and cost-effective platform was successfully applied for the simultaneous determination of the three analytes in human plasma. Additionally, since the hydrogel is disposable and can be replaced by new ones loaded with different reaction regents, the platform is expected to serve the POC testing of various chem/bio targets.


Assuntos
Biomarcadores/análise , Colorimetria/métodos , Hidrogéis/química , Fígado/enzimologia , Nanoestruturas/química , Alanina Transaminase/análise , Alanina Transaminase/sangue , Fosfatase Alcalina/análise , Fosfatase Alcalina/sangue , Alumínio/química , Aspartato Aminotransferases/análise , Aspartato Aminotransferases/sangue , Benzidinas/química , Biomarcadores/sangue , Catálise , Ouro/química , Humanos , Peróxido de Hidrogênio/química , Oxirredução , Óxidos/química , Sistemas Automatizados de Assistência Junto ao Leito
15.
Medicine (Baltimore) ; 101(4): e28559, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35089193

RESUMO

ABSTRACT: Although cadmium (Cd) is correlated with elevated levels of hepatic amino transferases, its influence on the degree of liver steatosis and fibrosis are unknown yet. We aimed to investigate the associations between the serum level of Cd and degree of liver steatosis/fibrosis.Clinical data were obtained from Korean National Health and Nutrition Examination Surveys IV-VII. Alanine aminotransferase (ALT) elevation was defined as ≥ 33 IU/L for men and ≥ 25 IU/L for women. Significant steatosis was defined as a hepatic steatosis index ≥ 36, while significant fibrosis was defined as a fibrosis index (FIB-4) ≥ 2.67 and as an aspartate aminotransferase and platelet ratio index ≥ 0.7. Adjusted odds ratios and 95% confidence intervals were calculated after adjustment.The levels of serum Cd were assessable in 15,783 subjects. The serum cadmium concentrations were significantly associated with ALT elevation, significant liver steatosis and fibrosis. Multivariate logistic regression analysis demonstrated serum Cd level in the forth quartile had a positive correlation with ALT elevation, hepatic steatosis index ≥ 36, FIB-4 ≥ 2.67 and aspartate aminotransferase-to-platelet ratio ≥ 0.7 using the first quartile of serum Cd level as the reference, (adjusted odds ratios 1.90, 1.26, 1.73, and 2.53, respectively; P values <.001).The serum level of Cd was associated with liver steatosis and fibrosis. The evaluation of serum Cd may help for assessing an unexplained liver steatosis and fibrosis, and further prospective studies are needed to confirm our findings.


Assuntos
Cádmio/sangue , Cirrose Hepática/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Adulto , Idoso , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Inquéritos Nutricionais , República da Coreia/epidemiologia
16.
Indian J Pathol Microbiol ; 65(1): 55-58, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35074966

RESUMO

BACKGROUND/AIMS: In this study, we investigated the Golgi protein 73 (GP73) level in Hepatitis B and determined the correlation between Hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, and liver histopathology. Materials and. METHODS: GP73 levels were estimated by enzyme-linked immunosorbent assay in serum samples from patients. Liver biopsy specimens were examined by the same pathologist. RESULTS: : This study included a total of 127 patients who underwent liver biopsy. Of patients, 85% were HBeAg negative. HBV DNA level was median 134667 IU/mL (2247-170000000 IU/mL), Liver biopsy results revealed a mean Histological Activity Index (HAI) grade of 7.7 ± 3.4 and a mean fibrosis stage of 2.25 ± 1.06 gr/dL. GP73 was as follows: a mean of 14.8 ± 7.9 ng/mL and a median of 12.9 (4.8-50.1) ng/mL. A weak correlation between GP73 level and AST (r = 0.236, P = 0.11), fibrosis stage (r = 0.287, P = 0.002), and HAI grade (r = 0.218, P = 0.016) was noted. No statistically significant correlation was detected between GP73 and ALT (r = 0.16, P = 0.08), HBV DNA (r = 0.13, P = 0.08). CONCLUSION: Although recent studies revealed a strong correlation and increased GP73 levels in accordance with HAI scores and the fibrosis grade of liver, we detected a weak correlation between serum GP73 levels and HAI scores, fibrosis stage, and AST. This may be due to the insufficient number of patients with higher HAI grading and fibrosis staging in our study. Therefore, we concluded that, in cases of low-moderate fibrosis and HAI grading, GP73 seemed not to be useful and a reliable marker to replace liver biopsy.


Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , DNA Viral/análise , Hepatite B Crônica/sangue , Fígado/patologia , Proteínas de Membrana/sangue , Adulto , Biomarcadores/sangue , Biópsia , Feminino , Hepatite B Crônica/diagnóstico , Humanos , Fígado/virologia , Cirrose Hepática/classificação , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Lancet Gastroenterol Hepatol ; 7(3): 208-218, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35065057

RESUMO

BACKGROUND: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. METHODS: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. FINDINGS: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. INTERPRETATION: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. FUNDING: Bristol Myers Squibb and the US National Institutes of Health.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Ipilimumab/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Nivolumabe/administração & dosagem , Idoso , Alanina Transaminase/sangue , Antineoplásicos Imunológicos/efeitos adversos , Aspartato Aminotransferases/sangue , Carcinoma Hepatocelular/cirurgia , Feminino , Humanos , Ipilimumab/efeitos adversos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Assistência Perioperatória , Intervalo Livre de Progressão
18.
Lancet Gastroenterol Hepatol ; 7(3): 219-229, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35065058

RESUMO

BACKGROUND: Surgical resection of early stage hepatocellular carcinoma is standard clinical practice; however, most tumours recur despite surgery, and no perioperative intervention has shown a survival benefit. Neoadjuvant immunotherapy has induced pathological responses in multiple tumour types and might decrease the risk of postoperative recurrence in hepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma. METHODS: For this single-arm, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Eligible patients were aged 18 years or older, had confirmed resectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate liver function. Patients were excluded if they had metastatic disease, if the surgery was not expected to be curative, if they had a known additional malignancy requiring active treatment, or if they required systemic steroid treatment or any other immunosuppressive therapy. After resection, patients received an additional eight cycles of cemiplimab 350 mg intravenously every 3 weeks in the adjuvant setting. The primary endpoint was significant tumour necrosis on pathological examination (defined as >70% necrosis of the resected tumour). Secondary endpoints included delay of surgery, the proportion of patients with an overall response, change in CD8+ T-cell density, and adverse events. Tumour necrosis and response were analysed in all patients who received at least one dose of cemiplimab and completed surgical resection; safety and other endpoints were analysed in the intention-to-treat population. Patients underwent pre-treatment biopsies and blood collection throughout treatment. This trial is registered with ClinicalTrials.gov (NCT03916627, Cohort B) and is ongoing. FINDINGS: Between Aug 5, 2019, and Nov 25, 2020, 21 patients were enrolled. All patients received neoadjuvant cemiplimab, and 20 patients underwent successful resection. Of the 20 patients with resected tumours, four (20%) had significant tumour necrosis. Three (15%) of 20 patients had a partial response, and all other patients maintained stable disease. 20 (95%) patients had a treatment-emergent adverse event of any grade during the neoadjuvant treatment period. The most common adverse events of any grade were increased aspartate aminotransferase (in four patients), increased blood creatine phosphokinase (in three), constipation (in three), and fatigue (in three). Seven patients had grade 3 adverse events, including increased blood creatine phosphokinase (in two patients) and hypoalbuminaemia (in one). No grade 4 or 5 events were observed. One patient developed pneumonitis, which led to a delay in surgery by 2 weeks. INTERPRETATION: This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti-PD-1 monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identify the optimal treatment duration and definitively establish the clinical benefit of preoperative PD-1 blockade in patients with hepatocellular carcinoma. FUNDING: Regeneron Pharmaceuticals.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Aspartato Aminotransferases/sangue , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Creatina Quinase/sangue , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante
19.
Toxicology ; 468: 153101, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35065160

RESUMO

Monocrotaline (MCT), an unsaturated pyrrolizidine alkaloid (PA) in plants, is mainly toxic to the lung and liver of mammals. As a commonly used tool for liver injury model, the mechanism of MCT hepatoxicity has still not been fully clarified. Kupffer cells (KCs) are the liver-resident macrophages and have various responses to different toxicants and liver damage. However, the role of KCs in MCT-induced liver injury remains controversial. In current work, we investigated the effects of KCs on MCT-induced liver injury, especially on MCT-induced hepatocyte death. KCs were depleted in Balb/c mice by liposome-entrapped clodronate (Lip/Clo) (0.2 mL/mouse, i.p.) or GdCl3 (0.7 mg/kg, i.p.) before MCT administration (300 mg/kg, i.p.), we found that the Lip/Clo group showed higher efficiency in KCs depletion and stronger hepatoprotective effects against MCT. We also found TNF-α was remarkably decreased after KCs depletion, the experiment of administering anti-TNF-α antibody (20 µg/mouse, i.p.) to MCT-treated animals generated the similar results. To further elaborate the function of KCs, we compared the ALT levels released from co-culturing murine hepatic parenchymal cells (HPCs) and RAW264.7 cells with that from HPCs alone. After the treatment of MCT, the released ALT levels in co-culture system were shown to be dependent on the number of RAW264.7 cells, while the anti-TNF-α antibody could suppress it. Finally, we discovered RIPK3/MLKL pathway might be activated by TNF-α released from KCs, and subsequently induced hepatocyte necrosis. Noteworthy, the known mechanisms including ER stress and NF-κB pathways were also found to be involved in the activation of KCs. In conclusion, our study reveals a further mechanism to MCT-induced hepatoxicity mediated directly by KCs via producing TNF-α.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Células de Kupffer/fisiologia , Monocrotalina/toxicidade , Fator de Necrose Tumoral alfa/biossíntese , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hemaglutininas/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C
20.
Int Immunopharmacol ; 104: 108503, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34998036

RESUMO

Type-2 diabetes mellitus and NAFLD are considered as one of the greatest worldwide metabolic disorders with growing incidence. It was found that patients with T2DM have two-fold increase to develop NAFLD. Evidence that some antidiabetic agents improve NAFLD/NASH in patients with T2DM is evolving. However, there are no certain pharmacologic therapies. The current study aimed to investigate the underlying mechanisms for the hepatoprotective effect of dapagliflozin against steatohepatitis in diabetic rats. Type-2 diabetes was induced by HFD followed by a single dose of STZ (30 mg/kg I.P). Fifty rats were randomly divided into 5 groups: Group1; normal control, Group 2; diabetic control, Groups (3-5); diabetic rats received daily dapagliflozin (0.75, 1.5, 3 mg/kg, p.o.) respectively for 6 weeks. At the end of the experiment, blood glucose level and serum insulin were measured. Hepatic tissue homogenization was performed for measuring inflammatory and oxidative stress markers. In addition, histopathological investigation of the hepatic tissue was done. Diabetic rats exhibited remarkable increase in liver weight and liver enzymes, along with histopathological changes, significant elevation in MDA, IL-1 ß, TGFß levels and, NF-κB, alpha-SMA expressions. Dapagliflozin treatment decreased liver weight, liver enzymes, together with marked improvement in histopathological changes. Furthermore, dapagliflozin increased antioxidant enzymes, GSH levels. Interestingly, Dapagliflozin reduced IL-1 ß, TGFß levels and, NF-κB, alpha-SMA expressions. Present data show that dapagliflozin represent a viable approach to protect the liver against diabetes-encouraged steatohepatitis through inhibiting oxidative stress, inflammation and fibrosis progression thus conserving liver function.


Assuntos
Anti-Inflamatórios/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Actinas/metabolismo , Alanina Transaminase/sangue , Animais , Anti-Inflamatórios/farmacologia , Aspartato Aminotransferases/sangue , Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Glucosídeos/farmacologia , Insulina/sangue , Interleucina-1beta/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Fator de Crescimento Transformador beta/metabolismo
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