RESUMEN
Hypoxia-induced apoptosis and oxidative stress in spermatogenic cells are considered to be important factors leading to male infertility. It was reported that CDX2 expression was downregulated in hypoxia-stimulated spermatogenic cells. However, the effects of CDX2 on hypoxia-induced apoptosis and oxidative stress in spermatogenic cells are still unknown. This study aimed to explore the roles of CDX2 in hypoxia-induced injury of spermatogenic cells, as well as its mechanism of action. Spermatogenic cells were cultured under 1% oxygen for 48 h to established hypoxia damage model. Reactive oxygen species (ROS) generation was determined using 2',7'-dichlorofluorescein diacetate assay. Apoptosis was assessed using flow cytometry. Enzyme-linked immunosorbent assay was used to evaluate oxidative stress markers, including malondialdehyde (MDA) content and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidases (GSH-Px). Protein levels were detected using western blotting. Hypoxia exposure induced increase in ROS generation, apoptosis rate, and oxidative stress in spermatogenic cells. ROS scavenger inhibited hypoxia-induced apoptosis, oxidative stress, and Wnt/ß-catenin pathway activation. Hypoxia exposure induced CDX2 downregulation. CDX2 overexpression suppressed hypoxia-induced ROS generation, apoptosis rate, oxidative stress, and Wnt/ß-catenin pathway activation. Moreover, CDX2 knockdown restores the inhibitory effects of si-ß-catenin or NAC on hypoxia-induced activation of the Wnt/ß-catenin pathway, apoptosis, and oxidative stress. In conclusion, our study suggests that CDX2 overexpression alleviates hypoxia-induced apoptosis and oxidative stress by suppression of ROS-mediated Wnt/ß-catenin pathway in spermatogenic cells.
Asunto(s)
Apoptosis , Factor de Transcripción CDX2 , Hipoxia de la Célula , Estrés Oxidativo , Especies Reactivas de Oxígeno , Vía de Señalización Wnt , Estrés Oxidativo/efectos de los fármacos , Masculino , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Animales , Factor de Transcripción CDX2/metabolismo , Factor de Transcripción CDX2/genética , Ratones , beta Catenina/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/genéticaRESUMEN
AIMS: To investigate the correlation between hypertriglyceridemic waist circumference (HTWC) phenotype and gestational diabetes mellitus (GDM). METHODS: A total of 1083 patients with gestational age ≤8 weeks were divided into four groups: normal triglyceride and waist circumference group (group A, n = 575), simple abdominal obesity group (group B, n = 317), simple high triglyceride group (group C, n = 125), and HTWC group (group D, n = 66). General information and serum biochemical indicators were measured and recorded. Analysis of variance (ANOVA) and logistic regression analysis were used to evaluate the relationship between HTWC with GDM. RESULTS: The prevalence of GDM in the HTWC group was significantly greater than in the other three groups. After adjustment by multivariate logistic regression analysis, the proportion of GDM in the HTWC group was 1.753 times higher than in group A. CONCLUSION: These findings suggest that there is a significant correlation between HTWC phenotype and GDM, indicating that the HTWC phenotype could be applied as a simple marker for identifying GDM risk factors.
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Diabetes Gestacional/epidemiología , Hipertrigliceridemia/epidemiología , Obesidad Abdominal/epidemiología , Circunferencia de la Cintura , Adulto , Femenino , Humanos , Embarazo , Primer Trimestre del Embarazo , Prevalencia , Factores de RiesgoRESUMEN
OBJECTIVES: MicroRNAs have been reported to participate in various important cell biological processes, such as glucose metabolism. The aim of this study was to explore the roles of microRNA-15a (miR-15a) in regulating insulin sensitivity. METHODS: In L6 rat skeletal muscle cells, we observed the effect of miR-15a on glucose metabolism and glucose transporter 4 (GLUT4) translocation by targeting vesicle-associated membrane protein-associated protein A (VAP-A) after insulin treatment. Luciferase reporter assays were performed to demonstrate a direct interaction between miR-15a and the 3'-untranslated region of VAP-A microRNA. RESULTS: We identified miR-15a as an extremely important regulator of GLUT4 translocation via targeting of VAP-A. Additionally, knockdown of endogenous miR-15a or overexpression of VAP-A could increase extracellular glucose by inhibiting the translocation of GLUT4 to the cell membrane after insulin treatment. However, overexpression of miR-15a or knockdown of VAP-A had no significant effect on glucose metabolism. CONCLUSIONS: These findings reveal the following: 1) VAP-A is a marker of skeletal muscle glucose disposal and 2) a novel mechanism for GLUT4 translocation by miR-15a.
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Transportador de Glucosa de Tipo 4/genética , Glucosa/metabolismo , Proteínas de la Membrana/genética , MicroARNs/genética , Músculo Esquelético/metabolismo , Transporte de Proteínas/genética , Regiones no Traducidas 3'/genética , Animales , Diferenciación Celular , Marcación de Gen , Hipoglucemiantes/farmacología , Insulina/farmacología , RatasRESUMEN
BACKGROUND: HbA1c is the standard bio-marker for glycemic control in patients with diabetes. Here, we report a α-globin chain variant and evaluate its effect on HbA1c measurements. METHODS: A 21-year-old female was suspected of harboring a hemoglobin variant following HbA1c measurement during a routine examination using Variant II Turbo 2.0 (Bio-Rad). An oral glucose tolerance test was performed using an AU5800 clinical chemistry system (Beckman Coulter). HbA1c was reanalyzed using D10 (Bio-Rad), Capillarys 2 Flex Piercing (Sebia), and Premier Hb9210 (Trinity Biotech). Hemoglobin analysis was performed using high-performance liquid chromatography (HPLC) on the Bio-Rad Variant II (ß-thalassemia short program) and capillary electrophoresis (CE, Capillarys 2 Flex Piercing, Hb program). Sanger sequencing of α and ß genes was also conducted. RESULTS: HbA1c was initially measured at 24.2% using Variant II Turbo 2.0. For the oral glucose tolerance test, fasting glucose, 1-hour, and 2-hour levels were recorded as 4.25, 7.89, and 5.34 mmol/L, respectively. Subsequently, HbA1c values determined by D10, Capillarys 2 Flex Piercing (HbA1c program), and Premier Hb9210 were 4.5% (26 mmol/mol), no HbA1c value, and 4.8 (29 mmol/mol), respectively. Hemoglobin analyzed using CE and HPLC revealed an abnormal hemoglobin. Sanger sequencing identified a transversion mutation of the α2 gene [CD16(AAG>GAG), Lys>Glu, HBA2: c.49 A>G], corresponding to a Hb I variant. CONCLUSION: An unusually high HbA1c or discordance between blood sugar and HbA1c values should alert about the possibilities of hemoglobin variants.
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Hemoglobina Glucada/química , Hemoglobina Glucada/genética , Hemoglobinas Anormales/química , Hemoglobinas Anormales/genética , Globinas alfa/química , Globinas alfa/genética , Adulto , Glucemia , Análisis Mutacional de ADN , Femenino , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/análisis , Hemoglobinas Anormales/análisis , Humanos , Mutación/genética , Adulto Joven , Globinas alfa/análisisRESUMEN
Gestational Diabetes Mellitus (GDM) has brought great harm to maternal and fetus. Up to now, only a few plasma biomarkers for its early diagnosis have been reported; nevertheless, there is no report about identification of urinary biomarkers for prediction of GDM. Thus, it is necessary to correct this deficiency. In our study, urine samples were collected from 889 healthy young gravidae at the early second trimester (15 to 20 weeks), 69 of whom were subsequently diagnosed with GDM at 24 to 28 weeks. iTRAQ (the isobaric tags for relative and absolute quantification) quantitative proteomics was conducted on sixteen GDM (trial group) and an equal number of matched healthy young gravidae (control group). Validation was performed in 40 cases of each group by ELISA. A total of 1,901 proteins were identified in this study, including 119 significantly differential proteins (fold change â§1.2 or â¦0.83 and p < 0.05). Compared with control group, 83 differential proteins were increased and 36 proteins were decreased in GDM group. The validation for expression of CD59 and IL1RA showed significant difference and the area under the receiver operating characteristic curve was 0.729 and 0.899, respectively (p < 0.05). The two candidate protein biomarkers (CD59 and IL1RA) in urine could be an early, noninvasive diagnostic predictors of young pravidae with GDM, and IL1RA is stronger diagnostic power than CD59.
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Diabetes Gestacional/diagnóstico , Segundo Trimestre del Embarazo/orina , Adulto , Biomarcadores/orina , Diabetes Gestacional/orina , Femenino , Humanos , Espectrometría de Masas , Embarazo , ProteómicaRESUMEN
Febrile seizure is the most common neurologic disorder in infants and children. This study aimed to elaborate safe and effective therapy for preventing FS recurrence by levetiracetam (LEV). A prospective study was performed in two groups of children, the no treatment group (n=51, 24.1±9.0 months) and the LEV treatment group (n=45, 23.3±8.9 months). The findings demonstrated that a significant difference (P<0.01) was observed between the no treatment group 51.0% (26/51) and LEV treatment group 15.5% (7/45) in terms of FS recurrence after 50 weeks. FS recurrence/fever episode was 12.4% (12/97) in the LEV treatment group and 51.8% (57/110) in the no treatment group. Furthermore, LEV administration significantly improved (P<0.001) epileptiform + nonspecific EEG abnormalities (17.8%; 8/45), as compared with the no treatment group (68.6%; 35/51). In conclusion, LEV could function as an effective therapeutic agent for the prevention of FS recurrence and reducing the frequency of fever episodes. Furthermore, LEV administration significantly improved nonspecific EEG abnormalities, which may be used as a clinical monitoring index for LEV treatment in patients with FS.
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Mechanistic target of rapamycin controls cell growth, metabolism, and aging in response to nutrients, cellular energy stage, and growth factors. In cancers including breast cancer, mechanistic target of rapamycin is frequently upregulated. Blocking mechanistic target of rapamycin with rapamycin, first-generation and second-generation mechanistic target of rapamycin inhibitors, called rapalogs, have shown potent reduction of breast cancer tumor growth in preclinical models and clinical trials. In this review, we summarize the fundamental role of the mechanistic target of rapamycin pathway in driving breast tumors. Moreover, we also review key molecules involved with aberrant mechanistic target of rapamycin pathway activation in breast cancer and current efforts to target these components for therapeutic gain. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the mechanistic target of rapamycin pathway.
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Neoplasias de la Mama/genética , Terapia Molecular Dirigida , Serina-Treonina Quinasas TOR/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Proliferación Celular/genética , Femenino , Humanos , Transducción de Señal , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To compare the efficacy and safety of lamivudine or interferon monotherapy and sequential therapy in HBeAg positive chronic hepatitis B patients. METHODS: A total of 225 patients with HBeAg positive chronic hepatitis B were randomized into 3 groups: sequential group (group A, 83 patients), lamivudine group (group B, 89 patients) and interferon group (group C, 53 patients). Group A was administrated with lamivudine 100 mg/d for 32 week, and 5 million units of interferon alpha 2b injected subcutaneously every other day lasting for 24 week were added since week 25. Group B was administrated with lamivudine 100 mg/d for 48 week. Group B was injected with 5 million units of interferon alpha 2b subcutaneously every other day for 24 week. All subjects were followed up for 24 week. Serum HBV DNAs were measured quantitatively by PCR. HBV mutations were analyzed by PCR-RFLP. RESULTS: For groups A, B and C, baseline HBV DNAs were 7.8±1.0, 7.9±1.1 and 8.0±0.9 log10 copies/mL, respectively, P>0.05. Baseline ALTs were 167.5 (99.0, 267.8), 134.0 (101.0,275.0) and 131.0 (99.0, 192.8)U/L, respectively, P>0.05. At the end of the treatment, HBV DNA decrease rates for groups A, B and C were 78.2%, 87.8% and 78.4% (P>0.05), respectively. At the end of the follow-up, HBV DNA decrease rates for groups A, B and C were 54.4%, 63.6% and 66.7% (P>0.05), respectively. At the end of the treatment, group B (83.5%, P<0.05) achieved the highest response rate and group C achieved the lowest (39.6%, P<0.05). At the end of the follow-up, the response rates for groups A, B and C were 36.2%, 54.4% and 42.1% (P>0.05), respectively. YMDD motif mutation rate in group A was lower than that of group B (10.5% vs 26.9%, P<0.05) at the end of the treatment. CONCLUSION: Sequential therapy decreased hepatitis B virus mutation. But no efficacy advantages were found in sequential therapy than in lamivudine or interferon monotherapy.
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Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Lamivudine/uso terapéutico , Adulto , Quimioterapia Combinada , Femenino , Antígenos e de la Hepatitis B/sangre , Humanos , Masculino , Resultado del TratamientoRESUMEN
OBJECTIVE: To observe viral dynamic change in patients with HBeAg positive chronic hepatitis B by lamivudine treatment. METHODS: A multi-center clinical trial. Both outpatients and inpatients with HBeAg positive chronic hepatitis B have been administrated lamivudine 100 mg/d for 24 weeks. To detect the hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels of the baseline, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 4 weeks, 12 weeks, 24 weeks after lamivudine treatment by real time polymerase chain reaction (PCR). To estimate the parameters of viral dynamics through regression analysis. RESULTS: 172 patients were enrolled, 145 male, 30.8 +/- 9.7 (16 - 65) years old. Significant decrease of HBV DNA level occurred 12 hours after administration, the average decrease was 0.45 lg(copies/ml), maximum was 3.86 lg(copies/ml), 4 patients decreased not less than 2 lg(copies/ml). On day 2 and 7, the average decrease was 1.20 lg(copies/ml) and 2.01 lg(copies/ml), maximum was 4.41 lg(copies/ml) and 5.79 lg(copies/ml), respectively. Then HBV DNA level continued decreasing until week 24. 24-week administration of lamivudine cause 4.10 lg(copies/ml) decrease of HBV DNA averagely and 6.68 lg(copies/ml) mostly. Half life of free virion was 2.57 days. Half life of infected hepatocyte was 63.0 days. CONCLUSION: Lamivudine could rapidly decrease the HBV DNA level of patients with HBeAg positive chronic hepatitis B rapidly.
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Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Lamivudine/uso terapéutico , Carga Viral , Adolescente , Adulto , Anciano , ADN Viral/aislamiento & purificación , Femenino , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the effect of antiviral agents on intrahepatic HBV DNA and histology in HBeAg-positive chronic hepatitis B patients. METHODS: Thirty-five patients were treated with lamivudine, 16 with interferon alfa (INF-alpha), 24 with sequential Lamivudine and INF-alpha. The total duration of therapy was 12 months. Intrahepatic HBV DNA was measured quantitatively by real-time polymerase chain reaction. RESULTS: There was significant change in all parameters of the groups of patients at the end of treatment (P < 0.05). The patients treated with sequential treatment had slightly higher HBeAg seroconversion rate (38.1%) than that of the other patients (P=0.1352). The baseline levels of intrahepatic HBV DNA in the patients with HBeAg seroconversion or undetectable serum HBV DNA were significantly lower than that of the other patients (P < 0.05). CONCLUSION: Antiviral agents could effectively inhibit intrahepatic HBV DNA and improve hepatic histology. The patients with low baseline intrahepatic HBV DNA level may achieve better antiviral efficacy. Sequential treatment might produce high HBeAg seroconversion rate.
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Antivirales/farmacología , ADN Viral/metabolismo , Antígenos e de la Hepatitis B/metabolismo , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/patología , Hígado/efectos de los fármacos , Hígado/virología , Adolescente , Adulto , Antivirales/uso terapéutico , ADN Viral/sangre , Quimioterapia Combinada , Femenino , Antígenos e de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Humanos , Interferón-alfa/farmacología , Interferón-alfa/uso terapéutico , Lamivudine/farmacología , Lamivudine/uso terapéutico , Hígado/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
AIM: To evaluate the effects of antiviral agents and HBV genotypes on intrahepatic covalently closed circular DNA (ccc DNA) in HBeAg-positive chronic hepatitis B patients. METHODS: Seventy-one patients received lamivudine (n = 35), or sequential therapy with lamivudine- interferon alpha 2b (IFN-alpha 2b, n = 24) for 48 wk, or IFN-alpha 2b (n = 12) for 24 wk. All subjects were followed up for 24 wk. Intrahepatic ccc DNA was measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. RESULTS: Sequential lamivudine- INF-alpha therapy, lamivudine and INF-alpha monotherapy reduced ccc DNA of 1.7 log, 1.4 log and 0.8 log, respectively (P < 0.05). Seventeen out of the 71 patients developed HBeAg seroconversion, the reduction of ccc DNA in the HBeAg seroconversion patients was more significant than that in the HBeAg positive patients (3.0 log vs 1.6 log, P = 0.0407). Twenty-four weeks after antiviral therapy withdrawal, 16 patients had a sustained virological response, the baseline intrahepatic ccc DNA in the patients with a sustained virological response was significantly lower than that in the patients with virological rebound (4.6 log vs 5.4 log, P = 0.0472). HBV genotype C accounted for 85.9% (n = 61), and genotype B for 14.1% (n = 10), respectively, in the 71 patients. There was no significant difference in the change of ccc DNA level between HBV genotypes C and B (2.1 log vs 1.9 log). CONCLUSION: Forty-eight week sequential lamivudine-INF-alpha therapy and lamivudine monotherapy reduce ccc DNA more significantly than 24-wk INF-alpha monotherapy. Low baseline intrahepatic ccc DNA level may predict the long-term efficacy of antiviral treatment. HBV genotypes C and B have no obvious influence on ccc DNA load.
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Antivirales/farmacología , ADN Circular/metabolismo , Regulación de la Expresión Génica , Genotipo , Antígenos e de la Hepatitis B/biosíntesis , Virus de la Hepatitis B/genética , Hepatitis B/virología , Adulto , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/metabolismo , Lamivudine/farmacología , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Factores de TiempoRESUMEN
OBJECTIVE: To investigate the effect of antepartum injection of hepatitis B immunoglobulin (HBIG) on the maternal serum HBV DNA and the delivery of anti-HBs to the newborns. METHODS: Before and after injection of three doses of HBIG, Serum HBV DNA levels were detected by fluorescence quantitative PCR in 10 non-pregnant and 23 pregnant women of chronic hepatitis B virus (HBV) carrier state. In addition, serum anti-HBs were tested by an enzyme-linked immunoassay in 28 infants born to chronic HBV carrier mothers who received three doses of HBIG during the last trimester pregnancy. RESULTS: Before and after injection of three doses of HBIG the serum HBV DNA levels in 10 non-pregnant and 23 pregnant women of HBV carrier state were not statistically different [(8.18 +/- 0.50) lg copies/ml vs (7.64 +/- 0.41) lg copies/ml and (6.83 +/- 1.51) lg copies/ml vs (6.83 +/- 1.29) lg copies/ml, respectively]. None of the 28 newborns were positive for anti-HBs. CONCLUSION: The administration of three doses of HBIG during the last trimester pregnancy can not reduce the maternal serum HBV DNA levels and the injected HBIG can not be transferred to their newborns. Therefore, there is no sound evidence to support the use of this approach to block mother-to-infant HBV transmission.
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ADN Viral/sangre , Hepatitis B/prevención & control , Inmunoglobulinas/uso terapéutico , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Femenino , Anticuerpos contra la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Humanos , Recién Nacido , Embarazo , Tercer Trimestre del EmbarazoRESUMEN
AIM: To evaluate the effect of antiviral agents on intrahepatic HBV DNA in HBeAg-positive chronic hepatitis B patients. METHODS: Seventy-one patients received treatment with lamivudine, interferon alpha (IFN-alpha 2b) or sequential therapy with lamivudine-IFN-alpha 2b for 48 wk. All subjects were followed up for 24 wk. Serum and intrahepatic HBV DNA were measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. RESULTS: At the end of treatment, the intrahepatic HBV DNA level in 71 patients decreased from a mean of (6.1 +/- 1.0) log10 to (4.9 +/- 1.4) log10. Further, a larger decrease was seen in the intrahepatic HBV DNA level in patients with HBeAg seroconversion. Intrahepatic HBV DNA level (before and after treatment) was not significantly affected by the patients' HBV genotype, or by the probability of virological flare after treatment. CONCLUSION: Intrahepatic HBV DNA can be effectively lowered by antiviral agents and is a significant marker for monitoring antivirus treatment. Low intrahepatic HBV DNA level may achieve better efficacy of antivirus treatment.
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Antivirales/uso terapéutico , ADN Viral/metabolismo , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/metabolismo , Interferón-alfa/uso terapéutico , Lamivudine/uso terapéutico , Adulto , Quimioterapia Combinada , Femenino , Genotipo , Antígenos e de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Humanos , Hígado/metabolismo , Hígado/patología , Hígado/virología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Resultado del Tratamiento , Replicación Viral/efectos de los fármacosRESUMEN
OBJECTIVE: To evaluate the correlation between the efficacy of interferon-alpha-2a and the kinetics of viral load in serum. METHODS: The authors conducted a trial including 58 patients with chronic hepatitis B. Patients were treated with interferon-alpha-2a three times a week for 6 months. Viral kinetics were assessed by serial quantitive measurements of HBV-DNA. RESULTS: A significant decline of serum HBV-DNA was seen after interferon-alpha-2a administration for 1 month, the decreases were (2.50 +/- 0.44) log10, (1.62 +/- 1.12) log10 and (1.05 +/- 1.35) log10 for complete responders, partial responders and no-responders, respectively. After 1 month of treatment, HBV-DNA level was (3.99 +/- 0.91) log10 for complete responders versus (5.63 +/- 1.31) log10 for partial responders, and (6.69 +/- 1.42) log10 for no-responders (P < 0.05). Multivariate analysis suggested that undetectable serum HBV-DNA after 1 month of interferon-alpha-2a treatment was associated with better efficacy; higher baseline ALT or/and no family history were also correlated with better treatment outcomes. CONCLUSION: Kinetics of HBV-DNA level under interferon-alpha-2a treatment are highly predictive of therapeutic response.