RESUMO
OBJECTIVES: To evaluate the dynamic evolution process of overall brain health in liver transplantation (LT) recipients, we employed a deep learning-based neuroanatomic biomarker to measure longitudinal changes of brain structural patterns before and 1, 3, and 6 months after surgery. METHODS: Because of the ability to capture patterns across all voxels from a brain scan, the brain age prediction method was adopted. We constructed a 3D-CNN model through T1-weighted MRI of 3609 healthy individuals from 8 public datasets and further applied it to a local dataset of 60 LT recipients and 134 controls. The predicted age difference (PAD) was calculated to estimate brain changes before and after LT, and the network occlusion sensitivity analysis was used to determine the importance of each network in age prediction. RESULTS: The PAD of patients with cirrhosis increased markedly at baseline (+ 5.74 years) and continued to increase within one month after LT (+ 9.18 years). After that, the brain age began to decrease gradually, but it was still higher than the chronological age. The PAD values of the OHE subgroup were higher than those of the no-OHE, and the discrepancy was more obvious at 1-month post-LT. High-level cognition-related networks were more important in predicting the brain age of patients with cirrhosis at baseline, while the importance of primary sensory networks increased temporarily within 6-month post-LT. CONCLUSIONS: The brain structural patterns of LT recipients showed inverted U-shaped dynamic change in the early stage after transplantation, and the change in primary sensory networks may be the main contributor. KEY POINTS: ⢠The recipients' brain structural pattern showed an inverted U-shaped dynamic change after LT. ⢠The patients' brain aging aggravated within 1 month after surgery, and the subset of patients with a history of OHE was particularly affected. ⢠The change of primary sensory networks is the main contributor to the change in brain structural patterns.
Assuntos
Encefalopatia Hepática , Transplante de Fígado , Humanos , Estudos Longitudinais , Encefalopatia Hepática/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cirrose Hepática/patologia , FibroseRESUMO
OBJECTIVE: To establish a prediction model of fetal meconium-stained amniotic fluid in re-pregnant women with intrahepatic cholestasis of pregnancy (ICP). METHODS: Clinical data of 180 re-pregnant women with ICP delivering in Women's Hospital, Zhejiang University School of Medicine between January 2009 to August 2014 were collected. An artificial neural network model (ANN) for risk evaluation of fetal meconium-stained fluid was established and assessed. RESULTS: The sensitivity, specificity and accuracy of ANN for predicting fetal meconium-stained fluid were 68.0%, 85.0% and 80.3%, respectively. The risk factors with effect weight >10% were pregnancy complications, serum cholyglycine level,maternal age. CONCLUSION: The established ANN model can be used for predicting fetal meconium-stained amniotic fluid in re-pregnant women with ICP.
Assuntos
Líquido Amniótico/química , Colestase Intra-Hepática/patologia , Mecônio/química , Complicações na Gravidez/patologia , Feminino , Feto , Humanos , Recém-Nascido , Redes Neurais de Computação , Gravidez , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To investigate the effects of fluoride on Fas expression, caspase-3 and caspase-8 activity and apoptosis in rat incisor cells. METHODS: Forty male SD rats were divided into 4 groups randomly and provided with distilled water containing NaF at the doses of 0, 10, 50 and 100 mg/L respectively. Each group had 10 animals. Five animals were sacrificed at 60 and 90 days respectively. Fas expression was measured with immunohistochemistry, and colorimetric assay was used to examine caspase-3 and caspase-8 activity with enzyme-labelled meter. The apoptosis was detected by flow cytometry in mandibular incisor cells. RESULTS: NaF at the doses of 10, 50 and 100 mg/L for 60 d and 90 d caused Fas overexpression, promoted activity of caspase-3 and caspase-8, increased apoptosis rate in mandibular incisor cells. At 60 days, the value of Fas expression was 0.1819 ± 0.0025 for control, 0.2120 ± 0.0084 for 10 mg/L NaF group, 0.2283 ± 0.0183 for 50 mg/L NaF group, 0.2818 ± 0.0233 for 100 mg/L NaF group. At 90 days, the value of Fas expression was 0.2077 ± 0.0289 for control, 0.2216 ± 0.0105 for 10 mg/L NaF group, 0.2377 ± 0.0059 for 50 mg/L NaF group, 0.2775 ± 0.0088 for 100 mg/L NaF group. Statistics analysis yielded close relationship between the dose of NaF in water and the Fas expression, and also between the dose of NaF in water and caspase-3 activities, and the relative coefficient was 0.9728 (60 d, P < 0.01) and 0.9889 (90 d, P < 0.01) for Fas expression, 0.9533 (60 d, P < 0.01) and 0.9849 (90 d, P < 0.01) for caspase-3 activity respectively. Apoptosis rate and caspase-8 activity also had close relationship with the NaF doses, and the relative coefficient was 0.9733 (90 d, P < 0.01) for apoptosis, 0.9928 (90 d, P < 0.01) for caspase-8. At the doses of 10, 50 and 100 mg/L NaF for 60 d and 90 d, obvious relationship was found between Fas expression and caspase-3 activity, and the relative coefficient was 0.9619 (60 d, P < 0.01) and 0.9912 (90 d, P < 0.01). Obvious relationship between Fas expression and apoptosis, between Fas expression and caspase-8 activity was found in groups for 90 d, and the relative coefficient was 0.9841 (P < 0.01) for apoptosis, 0.9767 (P < 0.01) for caspase-8. CONCLUSIONS: Fluoride could induce Fas overexpression and mediate caspase activation and apoptosis at the doses of 10, 50 and 100 mg/L for 60 d and 90 d in rat mandibular incisor cells.
Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Incisivo , Fluoreto de Sódio/farmacologia , Receptor fas/metabolismo , Animais , Cariostáticos/administração & dosagem , Cariostáticos/farmacologia , Relação Dose-Resposta a Droga , Incisivo/citologia , Incisivo/metabolismo , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fluoreto de Sódio/administração & dosagemRESUMO
OBJECTIVE: To investigate the effects of sodium selenite on telomerase activity, apoptosis and expression of TERT, c-myc and p53 in rat hepatocytes. METHODS: Selenium at doses of 2.5, 5.0, and 10 micromol/kg was given to SD rats by gavage. In rat hepatocytes, telomerase activity was measured by the telomeric repeat amplification protocol (TRAP), apoptosis was detected by flow cytometry, and expressions of telomerase reverse transcriptase (TERT), c-myc and p53 were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). c-Myc and P53 proteins were detected by immunochemistry. RESULTS: Selenium at doses of 2.5, 5.0, and 10 micromol/kg significantly increased hepatocellular telomerase activity and induced apoptosis in a dose-dependent manner. Although selenium at doses of 2.5, 5.0, and 10 micromol/kg displayed no obvious enhancing effect on the TERT mRNA expression in rat hepatocytes (P > 0.05), it significantly increased the c-myc mRNA and p53 mRNA expression at the dose of 10 micromol/kg (P < 0.05). Selenium at doses of 5.0 and 10 micromol/kg obviously increased the content of P53 protein in rat hepatocytes, but only at the dose of 10 micromol/kg, it significantly promoted the value of c-Myc protein in them. CONCLUSION: Selenium can slightly increase telomerase activity and TERT expression, and significantly induce apoptosis and over-expression of c-myc and p53 at relatively high doses. The beneficial effects of selenium on senescence and aging may be mediated by telomerase activation and expression of TERT, c-myc, and p53 in rat hepatocytes.
Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Selênio/farmacologia , Telomerase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/citologia , Masculino , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Telomerase/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
OBJECTIVE: To investigate the effects of sodium selenite on telomerase activity and expression of hTERT mRNA in cadmium-transformed 16HBE cells. METHODS: Telomerase activity and expression of genes were measured after cultured cadmium-transformed 16HBE cells were exposed to sodium selenite at different doses (0.625, 1.25, 2.50, 5.00 micromol/L) for 24 hours. RESULTS: Selenium decreased telomerase activity in cadmium-transformed 16HBE cells. There existed an obvious dose-effect relationship between the selenium concentration and these changes. The expression of hTERT and c-myc mRNA also decreased but the expression of mad1 mRNA increased after exposure to selenium for 24 hours. No difference was found in expression of hTRF1 and hTRF2 mRNA after incubated with sodium selenite for 24 hours, compared with control group. CONCLUSION: Selenium inhibits telomerase activity by decreasing hTERT and c-myc mRNA expression and increasing mad1 mRNA expression in cadmium-transformed 16HBE cells and selenium concentration is significantly correlated with these changes.
Assuntos
Cádmio/farmacologia , Selenito de Sódio/farmacologia , Telomerase/antagonistas & inibidores , Sequência de Bases , Linhagem Celular Transformada , Primers do DNA , Humanos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telomerase/genéticaRESUMO
OBJECTIVE: To study the effects of cadmium on hepatocellular DNA damage, expression of proto-oncogenes c-myc, c-fos, and c-jun as well as apoptosis in rats. METHODS: Cadmium chloride at the doses of 5, 10, and 20 micromol/kg was given to rats by i.p. and there were 5 male SD rats in each group. Hepatocellular DNA damage was measured by single cell gel electrophoresis (or comet assay), while expression of proto-oncogenes c-myc, c-fos, and c-jun in rat hepatocytes were measured by Northern dot hybridization. C-Myc, c-Fos, and c-Jun were detected with immuno-histochemical method. Hepatocellular apoptosis was determined by TUNEL (TdT-mediated dUTP Nick End Labelling) and flow cytometry. RESULTS: At the doses of 5, 10, and 20 micromol/kg, cadmium chloride induced DNA damage in rat hepatocytes and the rates of comet cells were 50.20%, 88.40%, and 93.80%, respectively. Results also showed an obvious dose-response relationship between the rates of comet cells and the dose of cadmium chloride (r = 0.9172, P < 0.01). Cadmium chloride at the doses of 5, 10, and 20 micromol/kg induced expression of proto-oncogenes c-myc, c-fos, and c-jun. The positive brown-yellow signal for c-myc, c-fos, and c-jun was mainly located in the cytoplasm of hepatocytes with immunohistochemical method. TUNEL-positive cells were detected in cadmium-treated rat livers. Apoptotic rates (%) of cadmium-treated liver cells at the doses of 5, 10, and 20 micromol/kg were (17.24 +/- 2.98), (20.58 +/- 1.35), and (24.06 +/- 1.77) respectively, being significantly higher than those in the control. The results also displayed an obvious dose-response relationship between apoptotic rates and the dose of cadmium chloride (r = 0.8619, P < 0.05). CONCLUSION: Cadmium at 5-20 micromol/kg can induce hepatocellular DNA damage, expression of proto-oncogenes c-myc, c-fos, and c-jun as well as apoptosis in rats.
Assuntos
Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Dano ao DNA , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas/genética , Animais , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
AIM: To study the effect of fluoride on oxidative stress, DNA damage and apoptosis as well as cell cycle of rat oral mucosal cells and hepatocytes. METHODS: Ten male SD rats weighing 80-120 g were randomly divided into control group and fluoride group, 5 animals each group. The animals in fluoride group had free access to deionized water containing 150 mg/L sodium fluoride (NaF). The animals in control group were given distilled water. Four weeks later, the animals were killed. Reactive oxygen species (ROS) in oral mucosa and liver were measured by Fenton reaction, lipid peroxidation product, malondialdehyde (MDA), was detected by thiobarbituric acid (TBA) reaction, reduced glutathione (GSH) was assayed by dithionitrobenzoic acid (DTNB) reaction. DNA damage in oral mucosal cells and hepatocytes was determined by single cell gel (SCG) electrophoresis or comet assay. Apoptosis and cell cycle in oral mucosal cells and hepatocytes were detected by flow cytometry. RESULTS: The contents of ROS and MDA in oral mucosa and liver tissue of fluoride group were significantly higher than those of control group (P < 0.01), but the level of GSH was markedly decreased (P < 0.01). The contents of ROS, MDA and GSH were (134.73 +/- 12.63) U/mg protein, (1.48 +/- 0.13) mmol/mg protein and (76.38 +/- 6.71) mmol/mg protein in oral mucosa respectively, and (143.45 +/- 11.76) U/mg protein, (1.44 +/- 0.12) mmol/mg protein and (78.83 +/- 7.72) mmol/mg protein in liver tissue respectively. The DNA damage rate in fluoride group was 50.20% in oral mucosal cells and 44.80% in hepatocytes, higher than those in the control group (P < 0.01). The apoptosis rate in oral mucosal cells was (13.63 +/- 1.81) % in fluoride group, and (12.76 +/- 1.67)% in hepatocytes, higher than those in control group. Excess fluoride could differently lower the number of oral mucosal cells and hepatocytes at G0/G1 and S G2/M phases (P < 0.05). CONCLUSION: Excess fluoride can induce oxidative stress and DNA damage and lead to apoptosis and cell cycle change in rat oral mucosal cells and hepatocytes.