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BACKGROUND: Fibrosis results from inflammation and healing following injury. The imbalance between extracellular matrix (ECM) secretion and degradation leads to the ECM accumulation and liver fibrosis. This process is regulated by immune cells. T lymphocytes, including alpha beta (αß) T cells, which have adaptive immune functions, and gamma delta (γδ) T cells, which have innate immune functions, are considered regulators of liver fibrosis. This review aimed to present the current understanding of the cross-talk between T lymphocytes and hepatic stellate cells (HSCs), which are the key cells in liver fibrosis. DATA SOURCES: The keywords "liver fibrosis", "immune", and "T cells" were used to retrieve articles published in PubMed database before January 31, 2020. RESULTS: The ratio of CD8+ (suppressor) T cells to CD4+ (helper) T cells is significantly higher in the liver than in the peripheral blood. T cells secrete a series of cytokines and chemokines to regulate the inflammation in the liver and the activation of HSCs to influence the course of liver fibrosis. In addition, HSCs also regulate the differentiation and proliferation of T cells. CONCLUSIONS: The cross-talk between T cells and HSCs regulates liver fibrosis progression. The elucidation of this communication process will help us to understand the pathological process of liver fibrosis.
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Células Estrelladas Hepáticas , Cirrosis Hepática , Linfocitos T , Citocinas , Fibrosis , Células Estrelladas Hepáticas/patología , Humanos , Inflamación , Hígado/patología , Cirrosis Hepática/patologíaAsunto(s)
Hepatitis B/complicaciones , Trasplante de Riñón , Fallo Hepático/cirugía , Trasplante de Hígado/métodos , Receptores de Trasplantes , Uremia/cirugía , Adulto , Anciano , ADN Viral/análisis , Femenino , Supervivencia de Injerto , Virus de la Hepatitis B/genética , Humanos , Fallo Hepático/etiología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The narrow therapeutic window of tacrolimus necessitates daily monitoring and predictive algorithms based on genetic and nongenetic factors. In this study, we constructed predictive algorithms for tacrolimus stable dose in a retrospective cohort of 1045 Chinese renal transplant recipients. All patients were genotyped for CYP3A4 20230T>C (rs2242480), CYP3A4 T>C (rs4646437), CYP3A5*3 6898A>G (rs776746), ABCB1 129T>C (rs3213619); ABCB1 c.1236C>T (rs01128503), ABCB1 c.2677G>T/A (rs2032582) and ABCB1 c.3435C>T (rs1045642) polymorphisms, and the effects of gene-gene and gene-environment interactions on the predictive accuracy of algorithm were evaluated. In wild-type CYP3A4 rs2242480 (TT) carriers, patients who took calcium channel blockers had lower tacrolimus stable doses than those without the concomitant medications (P < 1 × 10-4 ). In contrast, there was no significant difference in mutant type patients. Similarly, the tacrolimus stable doses in wild-type CYP3A5 rs776746 carriers who had hypertension were higher than those without hypertension (P = 4.10 × 10-3 ). More importantly, dose-predictive algorithms with interaction terms showed higher accuracy and better performance than those without interaction terms. Our finding suggested that wild-type CYP3A4 rs2242480 (TT) carriers should be more cautious to take tacrolimus when they are coadministrated with calcium channel blockers, and CYP3A5 rs776746 (AA) carriers may need higher tacrolimus dosage when they are in combination with hypertension.
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Trasplante de Riñón , Tacrolimus/administración & dosificación , Tacrolimus/uso terapéutico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adulto , Algoritmos , Pueblo Asiatico , Bloqueadores de los Canales de Calcio/uso terapéutico , Estudios de Cohortes , Citocromo P-450 CYP3A/genética , Combinación de Medicamentos , Femenino , Interacción Gen-Ambiente , Variación Genética , Humanos , Inmunosupresores/uso terapéutico , Riñón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Receptores de TrasplantesAsunto(s)
Carcinoma Hepatocelular/cirugía , Quimerismo , ADN/análisis , Enfermedad Injerto contra Huésped/diagnóstico , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/efectos adversos , Anciano , Análisis Mutacional de ADN , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Humanos , Mutación INDEL , Masculino , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
This corrects the article DOI: 10.1038/srep42192.
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Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children worldwide, but the mechanisms underlying these disorders are far from well-defined. HCMV infection has been shown to dysregulate the Notch signaling pathway in human neural progenitor cells (NPCs). As an important downstream effector of Notch signaling, the transcriptional regulator Hairy and Enhancer of Split 1 (Hes1) is essential for governing NPC fate and fetal brain development. In the present study, we report that HCMV infection downregulates Hes1 protein levels in infected NPCs. The HCMV 72-kDa immediate-early 1 protein (IE1) is involved in Hes1 degradation by assembling a ubiquitination complex and promoting Hes1 ubiquitination as a potential E3 ubiquitin ligase, followed by proteasomal degradation of Hes1. Sp100A, an important component of PML nuclear bodies, is identified to be another target of IE1-mediated ubiquitination. A C-terminal acidic region in IE1, spanning amino acids 451 to 475, is required for IE1/Hes1 physical interaction and IE1-mediated Hes1 ubiquitination, but is dispensable for IE1/Sp100A interaction and ubiquitination. Our study suggests a novel mechanism linking downregulation of Hes1 protein to neurodevelopmental disorders caused by HCMV infection. Our findings also complement the current knowledge of herpesviruses by identifying IE1 as the first potential HCMV-encoded E3 ubiquitin ligase.
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Infecciones por Citomegalovirus/enzimología , Infecciones por Citomegalovirus/virología , Citomegalovirus/metabolismo , Células-Madre Neurales/metabolismo , Factor de Transcripción HES-1/genética , Ubiquitina-Proteína Ligasas/metabolismo , Citomegalovirus/genética , Infecciones por Citomegalovirus/genética , Regulación hacia Abajo , Interacciones Huésped-Patógeno , Humanos , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/metabolismo , Células-Madre Neurales/enzimología , Células-Madre Neurales/virología , Unión Proteica , Proteolisis , Factor de Transcripción HES-1/metabolismo , Ubiquitina-Proteína Ligasas/genética , UbiquitinaciónRESUMEN
T98G cells have been shown to support long-term human cytomegalovirus (HCMV) genome maintenance without infectious virus release. However, it remains unclear whether these viral genomes could be reactivated. To address this question, a recombinant HCMV (rHCMV) containing a GFP gene was used to infect T98G cells, and the infected cells absent of infectious virus production were designated T98G-LrV. Upon dibutyryl cAMP plus IBMX (cAMP/IBMX) treatment, a serial of phenomena were observed, including GFP signal increase, viral genome replication, lytic genes expression and infectious viruses release, indicating the reactivation of HCMV in T98G-LrV cells from a latent status. Mechanistically, HCMV reactivation in the T98G-LrV cells induced by cAMP/IBMX was associated with the PKA-CREB signaling pathway. These results demonstrate that HCMV was latent in T98G-LrV cells and could be reactivated. The T98G-LrV cells represent an effective model for investigating the mechanisms of HCMV reactivation from latency in the context of neural cells.
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Citomegalovirus/fisiología , Activación Viral , Latencia del Virus , 1-Metil-3-Isobutilxantina/metabolismo , Bucladesina/metabolismo , Línea Celular Tumoral , Genes Reporteros , Proteínas Fluorescentes Verdes/análisis , Proteínas Fluorescentes Verdes/genética , Humanos , Coloración y Etiquetado/métodosRESUMEN
BACKGROUND: CD133 (prominin-1) is widely believed to be a cancer stem cell marker in various solid tumor types, and CD133 has been correlated with tumor-initiating capacity. Recently, the nuclear location of CD133 expression in tumors has been discussed, but hepatocellular carcinoma (HCC) has not been included in these discussions. The goal of this study was to investigate the location of CD133 expression in HCC and this location's potential value as a prognostic indicator of survival in patients with HCC. METHODS: We enrolled 119 cancerous tissues and pair-matched adjacent normal liver tissue from HCC patients. These tissues were obtained immediately after operation, and tissue microarrays were subsequently constructed. The expression of CD133 was measured by immunohistochemistry (IHC), and the correlations between this expression and clinical characteristics and prognosis was estimated using statistical analysis. RESULTS: The results showed that the CD133 protein expression levels of HCC in both the cytoplasm and nucleus were significantly higher than adjacent normal liver tissue. Kaplan-Meier survival and Cox regression analyses revealed that high CD133 expression in the cytoplasm was an independent predictor of poor prognosis for the overall survival (OS) and relapse-free survival (RFS) rates of HCC patients (P = 0.028 and P = 0.046, respectively). Surprisingly, high nuclear CD133 expression of HCC was an independent predictor of the good prognosis of the OS and RFS rates of HCC patients (P = 0.023 and P = 0.012, respectively). CONCLUSIONS: The clinical evidence that revealed cytoplasmic CD133 expression was correlated with poor prognosis, while nuclear CD133 expression was significantly correlated with favorable prognosis.
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Antígeno AC133/metabolismo , Biomarcadores de Tumor , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Células Madre Neoplásicas/metabolismo , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Células Madre Neoplásicas/patología , Pronóstico , Modelos de Riesgos Proporcionales , Transporte de ProteínasAsunto(s)
Selección de Donante , Cirrosis Hepática/cirugía , Trasplante de Hígado/métodos , Hígado/cirugía , Esquistosomiasis Japónica/parasitología , Donantes de Tejidos/provisión & distribución , Adulto , Biopsia , Supervivencia de Injerto , Hepatitis B/complicaciones , Hepatitis B/diagnóstico , Humanos , Hígado/parasitología , Hígado/patología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/virología , Masculino , Esquistosomiasis Japónica/diagnóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Herpes simplex virus type 1 strain 129 (H129) has represented a promising anterograde neuronal circuit tracing tool, which complements the existing retrograde tracers. However, the current H129 derived tracers are multisynaptic, neither bright enough to label the details of neurons nor capable of determining direct projection targets as monosynaptic tracer. METHODS: Based on the bacterial artificial chromosome of H129, we have generated a serial of recombinant viruses for neuronal circuit tracing. Among them, H129-G4 was obtained by inserting binary tandemly connected GFP cassettes into the H129 genome, and H129-ΔTK-tdT was obtained by deleting the thymidine kinase (TK) gene and adding tdTomato coding gene to the H129 genome. Then the obtained viral tracers were tested in vitro and in vivo for the tracing capacity. RESULTS: H129-G4 is capable of transmitting through multiple synapses, labeling the neurons by green florescent protein, and visualizing the morphological details of the labeled neurons. H129-ΔTK-tdT neither replicates nor spreads in neurons alone, but transmits to and labels the postsynaptic neurons with tdTomato in the presence of complementary expressed TK from a helper virus. H129-ΔTK-tdT is also capable to map the direct projectome of the specific neuron type in the given brain regions in Cre transgenic mice. In the tested brain regions where circuits are well known, the H129-ΔTK-tdT tracing patterns are consistent with the previous results. CONCLUSIONS: With the assistance of the helper virus complimentarily expressing TK, H129-ΔTK-tdT replicates in the initially infected neuron, transmits anterogradely through one synapse, and labeled the postsynaptic neurons with tdTomato. The H129-ΔTK-tdT anterograde monosynaptic tracing system offers a useful tool for mapping the direct output in neuronal circuitry. H129-G4 is an anterograde multisynaptic tracer with a labeling signal strong enough to display the details of neuron morphology.
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Colorantes Fluorescentes , Proteínas Fluorescentes Verdes , Vías Nerviosas/citología , Neuronas/citología , Coloración y Etiquetado/métodos , Animales , Herpesvirus Humano 1 , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the "derivation cohort" to develop dose-prediction algorithm, while the remaining 20% constituted the "validation cohort" to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.
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Cálculo de Dosificación de Drogas , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Aprendizaje Automático , Insuficiencia Renal Crónica/inmunología , Tacrolimus/uso terapéutico , Adulto , Teorema de Bayes , Estudios de Cohortes , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Medicina de Precisión , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/cirugía , Receptores de TrasplantesRESUMEN
The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P =0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P =0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.
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Antígeno CTLA-4/genética , Inmunosupresores/administración & dosificación , Interleucina-3/genética , Tacrolimus/administración & dosificación , Adulto , Pueblo Asiatico , Femenino , Rechazo de Injerto/genética , Humanos , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Farmacogenética , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVES: Preservation of renal function is an important issue after living donor liver transplant. We aimed to examine the renal protective efficacy of telbivudine in hepatitis B virus-infected patients after living donor liver transplant. MATERIALS AND METHODS: In this retrospective study, we compared 18 patients who received telbivudine 600 mg once per day and 23 patients who received entecavir 1 mg once per day after living donor liver transplant. Clinical data were obtained through chart review and included Model for End-Stage Liver Disease score and pre- and postoperative aspartate aminotransferase, alanine aminotransferase, and creatinine levels and estimated glomerular filtration rate. RESULTS: Posttransplant estimated glomerular filtration rates and creatinine levels were calculated, and improvement of renal function was found in the group of patients who received telbivudine. Significant improvements were shown in estimated glomerular filtration rates started after 9 months of administration and creatinine levels after 12 months compared with patients who received entecavir. CONCLUSIONS: In our study, long-term telbivudine therapy is associated with a sustained improvement of renal function in patients with hepatitis B virus infection after living donor liver transplant.
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Antivirales/uso terapéutico , Enfermedad Hepática en Estado Terminal/cirugía , Tasa de Filtración Glomerular/efectos de los fármacos , Guanina/análogos & derivados , Hepatitis B/tratamiento farmacológico , Riñón/efectos de los fármacos , Trasplante de Hígado/métodos , Donadores Vivos , Timidina/análogos & derivados , Adulto , Anciano , Antivirales/efectos adversos , Biomarcadores/sangre , Creatinina/sangre , Estudios Transversales , Enfermedad Hepática en Estado Terminal/diagnóstico , Enfermedad Hepática en Estado Terminal/fisiopatología , Enfermedad Hepática en Estado Terminal/virología , Femenino , Estudios de Seguimiento , Guanina/efectos adversos , Guanina/uso terapéutico , Hepatitis B/complicaciones , Hepatitis B/diagnóstico , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Recuperación de la Función , Estudios Retrospectivos , Factores de Riesgo , Taiwán , Telbivudina , Timidina/efectos adversos , Timidina/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Activación Viral/efectos de los fármacosAsunto(s)
Anemia Hemolítica Autoinmune/inmunología , Autoanticuerpos/sangre , Hemólisis , Trasplante de Hígado/efectos adversos , Sistema del Grupo Sanguíneo Rh-Hr/inmunología , Anemia Hemolítica Autoinmune/sangre , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/terapia , Biomarcadores/sangre , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
The AKT pathway serves important roles in tumor cell growth. Its overexpression is associated with poor prognosis in a number of types of cancer; however, the role of AKT in the role of the pathogenesis of hepatocellular carcinoma (HCC) remains unclear. The present study was undertaken to explore the clinical relevance of phosphorylated AKT (p-AKT) in HCC. The level of p-AKT in tumor (TU) and paired adjacent normal liver (AN) tissue from 202 HCC patients was evaluated with immunohistochemistry. The results demonstrated that p-AKT was more highly expressed in TU than in AN tissue. Kaplan-Meier curves and Cox regression revealed that patients with a high expression of p-AKT (AN) exhibited reduced overall and relapse-free survival times; this was not observed at a statistically significant level in p-AKT (TU). Additionally, the high expression of p-AKT (AN) was positively correlated with hepatitis C virus (HCV) infection in HCC patients. These results support the hypothesis that AKT activation is a mechanism of HCV-induced hepatocarcinogenesis, suggesting that AKT can be a therapeutic target for the treatment of recurrent HCC subsequent to surgical resection.
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BACKGROUND: Donor safety and preservation of donor health after living liver donation are of paramount importance. Diarrhea has a significant influence on gastrointestinal quality of life among donors who have undergone living donor hepatectomy. Thus, we aimed to investigate predictors of diarrhea after hepatectomy and its impact on gastrointestinal quality of life in living donors. METHODS: We retrospectively examined the medical records of 204 living liver donors who underwent hepatectomy during the period January 2010 to June 2013 at a single medical center. Diarrhea was defined as the passing of three or more liquid stools per day. The Chinese version of the Gastrointestinal Quality of Life Index (GIQLI) was used to assess the influence of diarrhea on quality of life in donors. RESULTS: During the study period, diarrhea was diagnosed in 62 (30.3%) of the 204 donors and the duration of diarrhea in the majority of them (n = 46, 74%) was <12 months. Risk factors associated with diarrhea included age [risk ratio (RR) = 0.84, 95% confidence interval (CI): 0.79-0.89, risk difference = 16%], and chronic cholecystitis (RR = 0.48, 95% CI: 0.24-0.99, risk difference = 52%). Compared to donors without diarrhea, donors with diarrhea had lower GIQLI scores in the following GIQLI domains: GI symptoms (1.8 vs. 3.6), physical function (2.1 vs. 3.5), emotional function (3.0 vs. 3.6), social function (3.3 vs. 3.7), and treatment reaction (2.6 vs. 3.7). CONCLUSIONS: Our findings show that younger donors and those without chronic cholecystitis are at increased risk for diarrhea after living donor hepatectomy and that diarrhea is associated with lower GIQLI scores after hepatectomy.
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Diarrea/diagnóstico , Diarrea/etiología , Tracto Gastrointestinal/fisiología , Hepatectomía/efectos adversos , Trasplante de Hígado/estadística & datos numéricos , Donadores Vivos , Calidad de Vida , Adulto , Diarrea/epidemiología , Femenino , Tracto Gastrointestinal/fisiopatología , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Encuestas y Cuestionarios , Adulto JovenRESUMEN
New Onset Diabetes after Transplantation (NODAT) is defined as sustained hyperglycemia developing in patients without diabetes history before transplantation. A cohort study was performed to access the effects of tacrolimus on insulin secretion and insulin sensitivity and consequently in the development of NODAT in kidney transplant recipients. Then, we further investigated the association between NODAT and single-nucleotide polymorphisms of IRS-1 and IRS-2 in renal allograft recipients. One hundred and fifty-eight kidney transplant patients, receiving tacrolimus as the base immunosuppressant, were divided into two groups: with or without NODAT. Plasma levels of fasting insulin concentration (FINS) and C-peptide were determined by enhanced chemiluminescence immunoassay and ADVIA Centaur C peptide assay, respectively. The genotypes of Gly1057Asp in IRS-2 and Gly972Arg in IRS-1 were detected through polymerase chain reaction fragment length polymorphism in NODAT and non-NODAT patients. It was found that the concentrations of fasting plasma insulin and C-peptide in NODAT and non-NODAT patients treated with tacrolimus were higher than that in healthy volunteers (p < 0.05). Fasting plasma insulin concentration in NODAT was significantly elevated compared with than that in non-NODAT group (p < 0.05). But there are no statistical differences in fasting plasma C-peptide concentrations between NODAT and non-NODAT groups. The allele and genotype frequencies of IRS-2 Gly1057Asp and IRS-1 Gly972Arg in NODAT patients were not significantly different from non-NODAT patients (p > 0.05). In conclusion, insulin resistance is the primary cause of tacrolimus-induced NODAT. The IRS-2 Gly1057Asp and IRS-1 Gly972Arg genotypes are not related to NODAT.
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Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/epidemiología , Ayuno/sangre , Resistencia a la Insulina , Insulina/sangre , Trasplante de Riñón , Complicaciones Posoperatorias/inducido químicamente , Complicaciones Posoperatorias/epidemiología , Tacrolimus/efectos adversos , Adulto , Estudios de Cohortes , Diabetes Mellitus/genética , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores , Masculino , Complicaciones Posoperatorias/genética , Factores de Riesgo , Factores de TiempoRESUMEN
Aberrant expression of microRNAs (miRNAs) has been shown to be associated with the progression and metastasis of cancer. Dysregulation of miR144 has been observed in numerous types of cancer; however, the exact role of miR144 in hepatocellular carcinoma (HCC) remains unclear. The present study observed that miR144 was downregulated in HCC tissues and cell lines. Forced overexpression of miR144 suppressed proliferation, migration and invasion of HCC cells. AKT3 was identified as a direct target of miR144 in HCC, and this was confirmed by a luciferase activity assay and western blot analysis. Overexpression of AKT3 in miR144 transfected HCC cells effectively reversed the tumor suppressive effects of miR144. Furthermore, AKT3 expression levels were inversely correlated with miR144 expression levels in HCC tissues. In conclusion, the results of the present study suggest that miR144 may act as a tumor suppressor in HCC by targeting AKT3, and miR144 may be a potential therapeutic candidate for HCC.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Regiones no Traducidas 3' , Secuencia de Bases , Carcinogénesis , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación hacia Abajo , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , MicroARNs/genética , Proteínas Proto-Oncogénicas c-akt/genética , Alineación de Secuencia , TransfecciónRESUMEN
Accumulating evidence shows that microRNAs (miRNAs) are involved in the development and progression of multiple tumors, including hepatocellular carcinoma (HCC). Recent studies have found that miR-24 acts as an oncogene in several tumors; however, the function of miR-24 in HCC remains unclear. In this study, we found that miR-24 was increased in HCC tissues and cell lines. Inhibition of miR-24 by inhibitor significantly suppressed HCC cells proliferation, migration, and invasion. Furthermore, the sex-determining region Y (SRY)-box 7 (SOX7), a putative tumor suppressor, was found to be a target of miR-24 in HCC cells. Forced expression of SOX7 substantially attenuated the oncogenic effects of miR-24. Those results strongly suggest that miR-24 plays important role in HCC development partially by targeting SOX7.
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Carcinoma Hepatocelular/patología , Movimiento Celular , Proliferación Celular , Neoplasias Hepáticas/patología , MicroARNs/genética , Factores de Transcripción SOXF/metabolismo , Apoptosis , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Luciferasas/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción SOXF/genética , Células Tumorales CultivadasRESUMEN
OBJECTIVE: Tacrolimus is used clinically for the long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients, although dose optimization is poorly managed. The aim of this study was to examine the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotypes by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplant recipients. MATERIALS AND METHODS: Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients after transplantation. The population pharmacokinetic analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4*1G and CYP3A5*3 genetic polymorphisms from the patients studied were determined by direct sequencing using a validated automated genetic analyzer. RESULTS: A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5*3 and CYP3A4*1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about two-fold higher in kidney transplant patients with higher enzymatic activity of CYP3A5*1 and CYP3A4*1G (with the CYP3A5*1/*1 or *1/*3 and CYP3A4*1/*1G or CYP3A4*1G/*1G) compared with those with lower enzymatic activity (CYP3A5*3/*3 and CYP3A4*1/*1). CONCLUSION: This is the first study to extensively determine the effect of CYP3A4*1G and CYP3A5*3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in Chinese renal transplant recipients. The findings suggest that CYP3A5*3 and CYP3A4*1G polymorphisms and hematocrit are determinant factors in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit. This result may also be useful for maintenance tacrolimus dose optimization and may help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients.