Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 111.159
Filtrar
2.
Chem Biol Interact ; 317: 108966, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32004531

RESUMEN

Titanium dioxide nanoparticles (TiO2-NPs) are widely used in the food industry, cosmetics, personal care and paints among others. Through occupational exposure and daily consumption, and because of their small size, TiO2-NPs can enter the body through different routes such as oral, dermal and inhalation, and accumulate in multiple organs including the brain. TiO2-NPs cause severe damage to many cell types, however their effects in the central nervous system remain largely unexplored. Therefore, in the present study we determined the cytotoxic effect of TiO2-NPs on rat astrocytes. We tested the oxidant properties of TiO2-NPs through DTT depletion, and measured oxidative stress-induced damage in mitochondria, through oxidation of 2,7-dichlorodihydrofluorescein diacetate (H2DCFDA) and loss of mitochondrial membrane potential (ΔΨm) with Mitotracker Green FM. We further examined oxidative stress-derived responses such as IκB-α degradation by Western Blot, NF-κB translocation by EMSA, autophagy induction by LC3-II levels, and expression of the inflammasome protein NLRP3. TiO2-NPs showed high oxidant properties and induced strong oxidative stress in astrocytes following their internalization, causing mitochondrial damage detected by ΔΨm loss. Responses against oxidative damage such as NF-κB translocation and autophagy were induced and NLRP3 protein expression was downregulated, indicating lower inflammasome-mediated responses in astrocytes. These results support TiO2-NPs cytotoxicity in astrocytes, cells that play key roles in neuronal homeostasis and their dysfunction can lead to neurological disorders including cognitive impairment and memory loss.


Asunto(s)
Astrocitos/efectos de los fármacos , Autofagia/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Células Cultivadas , Regulación hacia Abajo , Nanopartículas del Metal , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Ratas , Ratas Wistar , Titanio
3.
Life Sci ; 248: 117457, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32092334

RESUMEN

AIMS: Multiple surgical procedures and anesthesia increase the risk of the development in children. However, the influence of such exposures on the developing childhood immunity organs is rarely reported. MATERIALS AND METHODS: High-throughput sequencing of T-cell receptor (TCR) repertoires (TCRseq) from rhesus monkeys' thymus was performed to investigate whether anesthetics could induce de novo antigen recognition via TCR or TCR development impairments. KEY FINDINGS: No significant difference between sevoflurane and control groups regarding VJ gene combinations and diversity of V and J gene was seen, nor was there an obvious change in similar average number of Complementarity Determining Region 3 (CDR3) aa clonotypes. Our analysis of Rank abundance, Gini coefficient, Simpson index, Normalized Shannon Diversity Entropy (NSDE), Morisita-Horn Similarity Index (MHSI) and Bhattacharyya Distance (BD) indicated there is no difference in TCR diversity and similarity. SIGNIFICANCE: These results suggest early events in thymic T cell development and repertoire generation are not abnormality after multiple sevoflurane exposure during childhood. The stabilization of the immune repertoires suggested the safety of sevoflurane in host immune response in children.


Asunto(s)
Anestésicos por Inhalación/farmacología , Regiones Determinantes de Complementariedad/genética , Receptores de Antígenos de Linfocitos T/genética , Sevoflurano/farmacología , Linfocitos T/efectos de los fármacos , Timo/efectos de los fármacos , Animales , Animales Recién Nacidos , Regiones Determinantes de Complementariedad/clasificación , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Macaca mulatta , Masculino , Receptores de Antígenos de Linfocitos T/clasificación , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Timo/citología , Timo/inmunología , Recombinación V(D)J/inmunología
4.
Emerg Microbes Infect ; 9(1): 427-438, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32079505

RESUMEN

Enterovirus 71 (EV71) is a major pathogen that causes hand, foot and mouth disease (HFMD), which is a life threatening disease in certain children. The pathogenesis of EV71-caused HFMD is poorly defined due to the lack of simple and robust animal models with severe phenotypes that recapitulate symptoms observed in humans. Here, we generated the infectious clone of a clinical isolate from a severe HFMD patient. Virus rescued from the cDNA clone was infectious in cell lines. When administrated intraperitoneally to neonatal ICR, BALB/c and C57 immune competent mice at a dosage of1.4 × 104 pfu per mouse, the virus caused weight loss, paralysis and death in the infected mice after 4-5 days of infection. In the infected mice, detectable viral replication was detected in various tissues such as heart, liver, brain, lung, kidney, small intestine, leg skeletal muscle and medulla oblongata. The histology of the infected mice included massive myolysis, glomerular atrophy, villous blunting in small intestine, widened alveolar septum, diminished alveolar spaces and lymphocytes infiltration into the lung. By using the UV-inactivated virus as a control, we elucidated that the virus first amplified in the leg skeletal muscle tissue and the muscle tissue served as a primary viral replication site. In summary, we generated a stable EV71 infectious clone that is capable of infecting neonatal immune competent mice without adaptive mutations and provide a simple, valuable animal model for the studies of EV71pathogenesis and therapy.


Asunto(s)
Enterovirus Humano A/genética , Enterovirus Humano A/patogenicidad , Enfermedad de Boca, Mano y Pie/virología , Animales , Animales Recién Nacidos , Línea Celular Tumoral , ADN Complementario , Modelos Animales de Enfermedad , Humanos , Lactante , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Mutación , ARN Viral , Organismos Libres de Patógenos Específicos , Células Vero , Virulencia , Replicación Viral
5.
Chem Biol Interact ; 319: 108979, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-32045570

RESUMEN

Heart rhythm disturbances have been widely recognized as major triggers of cardiovascular (CV) mortality in chronic kidney disease (CKD) patients. Connexin 43 (Cx43)-composed gap junctions are essential in cardiomyocyte synchronization and may be involved in the pathological response to uremic toxins. Indoxyl sulfate (IS) is one of the most dominant uremic toxins that contribute to CKD-related cardiovascular diseases. In primary cultures of rat neonatal cardiomyocytes, we demonstrated that IS treatment decreased spontaneous contraction without impairing viability. In addition, there was disruption of gap junction intercellular communication (GJIC) between cardiomyocytes after 30 min of IS stimulation. IS caused time- and dose-dependent Cx43 redistribution, and the patterns of Cx43 immunostaining returned to baseline while IS stimulation was removed. Furthermore, IS exposure downregulated Cx43 protein and mRNA levels. Elevated JNK1 and JNK2 phosphorylation was further identified after IS exposure in both rat cardiomyocytes and H9c2 cells. The above changes as well as GJIC and Cx43 suppression were reversed by pretreatment with a JNK inhibitor (SP600125). Inhibition of p-JNK attenuated IS-mediated downward trends in Cx43 transcription and translation. In cardiac muscle from nephrectomy-induced CKD mice, an alteration in Cx43 level was identified at intercalated discs. Our findings disclosed that JNK activation might participate in the remodeling of gap junction and Cx43 expression by uremic toxin-IS both in vitro and in vivo.


Asunto(s)
Conexina 43/metabolismo , Indicán/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Animales , Animales Recién Nacidos , Antracenos/farmacología , Comunicación Celular/efectos de los fármacos , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Uniones Comunicantes/efectos de los fármacos , Uniones Comunicantes/metabolismo , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos
6.
Zhonghua Er Ke Za Zhi ; 58(1): 30-34, 2020 Jan 02.
Artículo en Chino | MEDLINE | ID: mdl-31905473

RESUMEN

Objective: To investigate the impact of hypoxic-ischemic brain injury (HIBI) on brain development in neonatal rats of different sexes. Methods: From January 1 to December 31, 2018, 60 7-day-old SD rats were randomly divided into HIBI-F group (20 rats), HIBI-M group (20 rats), and control group (20 rats, 10 females and 10 males). The animal model of HIBI was established with Rice-Vannucci method, with the rats' left common carotid artery double-ligated and severed. The rats were then placed in an incubator and exposed to a hypoxic gas mixture (8% O(2), 92% N(2)) for 90 minutes. No intervention was given to the control group. Two weeks after HIBI, the motor development was evaluated by footprint analysis, the residual brain volume was measured by brain magnetic resonance imaging (MRI), and the damage of synaptic ultra structure was analyzed by transmission electron microscope. One-way ANOVA or χ(2) test was used for inter-group statistical analysis, and paired sample t test was used to compare the bilateral step length and toe distance of rats in the same group. Results: The mortality rate of HIBI-F was significantly higher than that of HIBI-M (20%(4/20) vs. 10%(2/20), χ(2)=40.000, P=0.001). The right step length and toe distance in HIBI-M group and HIBI-F group were significantly shorter than those in control group ((7.5±0.3) cm and (7.9±0.5) cm vs. (8.2±0.5) cm, F=9.605, P<0.01, (0.9±0.1) cm and (1.0±0.0) cm vs. (1.1±0.1) cm, F=71.437, P<0.01). Besides, according to above data, the right step length and toe distance in HIBI-M group were significantly shorter than those in the HIBI-F group (both P<0.01). Furthermore, the right step length was significantly shorter than the left step length ((8.3±0.4) and (8.3±0.5) cm, t=5.289 and 10.580, P=0.001 and 0.010, respectively) and toe distance ((1.1±0.1) and (1.1±0.1) cm, t=7.953 and 6.435, respectively, both P<0.01) in both HIBI-M group and HIBI-F group. Similarly, the synaptic gap of the left precentral gyrus neurons was longer in HIBI-M group and HIBI-F group than that in control group ((23.4±1.3) and (19.7±1.6) nm vs. (18.9±0.6) nm, F=71.719, P<0.01), and also longer in HIBI-M group than that in HIBI-F group (t=7.645, P<0.01). Likewise, the residual brain volume in HIBI-M group and HIBI-F group was significantly less than that in control group ((67±4)% and (75±5)% vs. 100%, F=406.122, P<0.01), and the residual brain volume in HIBI-M group was significantly less than that in HIBI-F group (t=-5.281, P<0.01). Conclusions: Male neonatal rats are more vulnerable to HIBI and have severer subsequent brain injury and hemiplegia. Different treatment strategies for HIBI patients of different sexes should be developed.


Asunto(s)
Hipoxia-Isquemia Encefálica , Animales , Animales Recién Nacidos , Encéfalo , Modelos Animales de Enfermedad , Femenino , Humanos , Hipoxia-Isquemia Encefálica/mortalidad , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley
7.
Life Sci ; 242: 117211, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31891720

RESUMEN

Ventricular hypertrophy is a risk factors for arrhythmias, ischemia and sudden death. It involves cellular modifications leading to a pathological remodeling and is associated with heart failure. The activation of the G protein-coupled estrogen receptor (GPER) mediates beneficial actions in the cardiovascular system. Our goal was to prevent and regress the hypertrophy by the activation of GPER in neonatal cardiac myocytes (NRCM) and SHR male rats. Aldosterone increased the neonatal cardiomyocytes cell surface area after 48 h of incubation. The aldo-induced hypertrophy was blocked by the mineralocorticoid receptor (MR) inhibitor Eplererone or the reduction of MR expression by siRNA. The activation of GPER by the agonist G-1 totally prevented the increase surface area by Ald. The transfection of neonatal rat cardiac myocytes with a siRNA against GPER or the incubation with GPER blockers G-15 and G-36 inhibited the protection of G-1. The significant increase of cell surface area after 48 h of incubation with Ald was totally regressed in 24 h by the presence of G-1, indicating that the activation of GPER not only prevent the hypertrophy but also regress the hypertrophy when it is already established. In the in vivo model, G-1 or Vehicle was constantly infused via the minipump to SHR. The reduction of the hypertrophy by G-1 was evident by the cross-sectional area, BNP and ANP markers and by echocardiography. In this studied we demonstrated that the activation of GPER prevented and regressed the hypertrophy induced by Ald in NRCM and regressed hypertrophy in SHR rats.


Asunto(s)
Cardiomegalia/prevención & control , Receptores Acoplados a Proteínas G/metabolismo , Animales , Animales Recién Nacidos , Western Blotting , Cardiomegalia/diagnóstico por imagen , Células Cultivadas , Ciclopentanos/farmacología , Ecocardiografía , Eplerenona/farmacología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Quinolinas/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/fisiología
8.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(1): 58-64, 2020 Jan.
Artículo en Chino | MEDLINE | ID: mdl-31948526

RESUMEN

OBJECTIVE: To study the effect and mechanism of action of irisin on hypoxic-ischemic brain damage in neonatal rats. METHODS: A total of 248 7-day-old Sprague-Dawley rats were randomly divided into a sham-operation group, a model group, and low- and high-dose irisin intervention groups (n=62 each). The rats in the model and irisin intervention groups were given hypoxic treatment after right common carotid artery ligation to establish a model of hypoxic-ischemic brain damage. Those in the sham-operation group were given the separation of the right common carotid artery without ligation or hypoxic treatment. The rats in the high- and low-dose irisin intervention groups were given intracerebroventricular injection of recombinant irisin polypeptide at a dose of 0.30 µg and 0.15 µg respectively. Those in the model and sham-operation groups were given the injection of an equal volume of PBS. The water maze test was used to compare neurological behaviors between groups. TTC staining, hematoxylin-eosin staining and TUNEL staining were used to observe histopathological changes of the brain. Western blot was used to measure the expression of the apoptosis-related molecules cleaved-caspase-3 (CC3), BCL-2 and BAX. RESULTS: Compared with the sham-operation group, the model group had a significant increase in latency time and a significant reduction in the number of platform crossings (P<0.05). Compared with the model group, the high-dose irisin intervention group had a significant reduction in latency time and a significant increase in the number of platform crossings (P<0.05). Compared with the sham-operation group, the model group had massive infarction in the right hemisphere, with significant increases in karyopyknosis and karyorrhexis. Compared with the model group, the high-dose irisin intervention group had a smaller infarct area of the right hemisphere, with reductions in karyopyknosis and karyorrhexis. The model group had a significantly higher apoptosis rate of cells in the right cerebral cortex and the hippocampus than the sham-operation group. The high-dose irisin intervention group had a significantly lower apoptosis rate than the model group (P<0.05). At 24 and 48 hours after modeling, the sham-operation group had a significantly lower level of CC3 than the model group (P<0.05). Compared with the model group, the high-dose irisin intervention group had a significantly lower level of CC3 and a significantly higher BCL-2/BAX ratio (P<0.05). The low-dose irisin intervention group had similar laboratory markers and histopathological changes of the brain to the model group. CONCLUSIONS: Irisin can alleviate hypoxic-ischemic brain damage in neonatal rats in a dose-dependent manner, possibly by reducing cell apoptosis in the cerebral cortex and the hippocampus.


Asunto(s)
Hipoxia-Isquemia Encefálica , Animales , Animales Recién Nacidos , Apoptosis , Encéfalo , Ratas , Ratas Sprague-Dawley
9.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(1): 71-76, 2020 Jan.
Artículo en Chino | MEDLINE | ID: mdl-31948528

RESUMEN

OBJECTIVE: To study the protective effect of asiaticoside against hyperoxia-induced bronchopulmonary dysplasia in neonatal rats based on the microRNA-155 (miR-155)/suppressor of cytokine signaling-1 (SOCS1) axis. METHODS: Neonatal rats were randomly divided into a control group, a model group, a low-dose asiaticoside group (10 mg/kg), a middle-dose asiaticoside group (25 mg/kg), a high-dose asiaticoside group (50 mg/kg), and a budesonide group (1.5 mg/kg), with 12 rats in each group. All rats except those in the control group were exposed to a high concentration of oxygen for 14 days to establish a neonatal rat model of bronchopulmonary dysplasia. The low-, middle-, and high-dose asiaticoside groups were given asiaticoside at different doses by gavage, and those in the budesonide group were given budesonide aerosol treatment. Hematoxylin and eosin staining was used to observe lung tissue development and measure radial alveolar count (RAC) and mean linear intercept (MLI). Superoxide dismutase (SOD) and malondialdehyde (MDA) detection kits were used to measure the levels of SOD and MDA in lung tissue. ELISA was used to measure the serum levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Quantitative real-time PCR was used to measure the mRNA expression of miR-155 and SOCS1 in lung tissue. Western blotting was used to measure the protein expression of SOCS1 in lung tissue. RESULTS: Compared with the control group, the model group had the symptoms of bronchopulmonary dysplasia such as a disordered structure of lung tissue, enlargement of alveolar fusion, uneven alveolar septa, enlargement of average alveolar space, and a reduction in alveolar number. The model group also had significant increases in MLI, MDA level in lung tissue, serum levels of IL-6 and TNF-α, and miR-155 level in lung tissue (P<0.05) and significant reductions in RAC, SOD level, and mRNA and protein expression of SOCS1 in lung tissue (P<0.05). Compared with the model group, the low-, middle-, and high-dose asiaticoside groups and the budesonide group had significant improvement in the above symptoms of bronchopulmonary dysplasia, significant reductions in MLI, MDA level in lung tissue, serum levels of IL-6 and TNF-α, and miR-155 level in lung tissue (P<0.05), and significant increases in RAC, SOD level, and mRNA and protein expression of SOCS1 in lung tissue (P<0.05). Asiaticoside improved the above symptoms and indices in a dose-dependent manner. There were no significant differences in the above indices between the high-dose asiaticoside and budesonide groups (P>0.05). CONCLUSIONS: Asiaticoside can alleviate inflammation injury induced by hyperoxia in neonatal rats and improve the symptoms of bronchopulmonary dysplasia in a dose-dependent manner, possibly by down-regulating the expression of miR-155 and up-regulating the expression of SOCS1.


Asunto(s)
Displasia Broncopulmonar , Hiperoxia , Animales , Animales Recién Nacidos , Pulmón , MicroARNs , Ratas , Triterpenos
10.
Adv Exp Med Biol ; 1232: 299-306, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31893424

RESUMEN

Hypoxic ischemic encephalopathy (HIE) is a significant cause of death and neurological disability in newborns. Therapeutic hypothermia at 33.5 °C is one of the most common treatments in HIE and generally improves outcome; however 45-55% of injuries still result in death or severe neurodevelopmental disability. We have developed a systems biology model of cerebral oxygen transport and metabolism to model the impact of hypothermia on the piglet brain (the neonatal preclinical animal model) tissue physiology. This computational model is an extension of the BrainSignals model of the adult brain. The model predicts that during hypothermia there is a 5.1% decrease in cerebral metabolism, 1.1% decrease in blood flow and 2.3% increase in cerebral tissue oxygenation saturation. The model can be used to simulate effects of hypothermia on the brain and to help interpret bedside recordings.


Asunto(s)
Circulación Cerebrovascular , Cerebro , Hipotermia , Modelos Biológicos , Animales , Animales Recién Nacidos , Circulación Cerebrovascular/fisiología , Cerebro/metabolismo , Simulación por Computador , Humanos , Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Porcinos
11.
Cell Host Microbe ; 27(1): 11-13, 2020 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-31951821

RESUMEN

The neonatal gut microbiome undergoes dynamic changes in response to many nutritional and environmental variables. A recent study by Singer et al. in Nature Medicine elucidates several mechanisms to inhibit the expansion of gut-derived pathobionts in a dysbiotic neonatal gut and prevent these pathobionts from disseminating systemically and causing sepsis in neonatal mice.


Asunto(s)
Microbioma Gastrointestinal , Sepsis , Animales , Animales Recién Nacidos , Disbiosis , Ratones
12.
Gene ; 731: 144324, 2020 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-31904498

RESUMEN

BACKGROUND/AIMS: lncRNA NEAT1 is involved in the development of many diseases. However, the function of lncRNA NEAT1 in myocardial infarction is unclear. Therefore, this experimental design based on lncRNA NEAT1 to explore the pathogenesis of myocardial infarction. METHODS: RT-qPCR was used to detect the expression of lncRNA NEAT1 and miR-378a-3p in peripheral blood and mouse cardiomyocytes of patients with myocardial infarction. MTT assay, flow cytometry, Caspase-3 kit and transwell assay were used to detect the effects of lncRNA NEAT1 and miR-378a-3p on cardiomyocyte proliferation, apoptosis and migration. Target gene prediction and screening, luciferase reporter assays were used to verify downstream target genes for lncRNA NEAT1 and miR-378a-3p. Western blotting was used to detect the protein expression of Atg12 and related autophagy genes. RESULTS: lncRNA NEAT1 was highly expressed in peripheral blood and mouse cardiomyocytes of patients with myocardial infarction. Moreover, lncRNA NEAT1 significantly promoted cell proliferation and migration of cardiomyocytes. In addition, lncRNA NEAT1 inhibited miR-378a-3p expression, and miR-378a-3p inhibited Atg12 expression, while lncRNA NEAT1 regulated expression of Atg12 and related autophagic factors via miR-378a-3p. Knockout of microRNA-378-3p reversed the effects of NEAT1 silencing on cell damage. CONCLUSION: lncRNA NEAT1 can regulate the proliferation of cardiomyocytes by regulating miR-378-3p/Atg12 axis, thus accelerating the occurrence and development of cardiomyocytes.


Asunto(s)
MicroARNs/genética , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/metabolismo , ARN Largo no Codificante/genética , Angina Inestable/genética , Angina Inestable/patología , Animales , Animales Recién Nacidos , Estudios de Casos y Controles , Células Cultivadas , Regulación hacia Abajo/genética , Regulación de la Expresión Génica , Silenciador del Gen/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Isquemia Miocárdica/genética , Isquemia Miocárdica/patología , Daño por Reperfusión Miocárdica/genética , Miocitos Cardíacos/patología , Ratas , Estudios Retrospectivos
13.
Endocrinology ; 161(1)2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31742329

RESUMEN

Many neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERα) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown. DNA methylation is important for cell phenotype differentiation throughout the developing organism. We hypothesized that testosterone causes sex differences in neurochemical phenotype via changes in DNA methylation, and tested this by inhibiting DNA methylation neonatally in male and female mice, and in females given a masculinizing dose of testosterone. Neonatal testosterone treatment masculinized calbindin, ERα and kisspeptin cell number of females at weaning. Inhibiting DNA methylation with zebularine increased calbindin cell number only in control females, thus eliminating sex differences in calbindin in the mPOA and BNST. Zebularine also reduced the sex difference in ERα cell number in the VMH, in this case by increasing ERα neuron number in males and testosterone-treated females. In contrast, the neonatal inhibition of DNA methylation had no effect on kisspeptin cell number. We conclude that testosterone normally increases the number of calbindin cells and reduces ERα cells in males through orchestrated changes in DNA methylation, contributing to, or causing, the sex differences in both cell types.


Asunto(s)
Encéfalo/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Diferenciación Sexual/efectos de los fármacos , Testosterona/farmacología , Animales , Animales Recién Nacidos , Encéfalo/citología , Encéfalo/metabolismo , Química Encefálica/efectos de los fármacos , Calbindinas/metabolismo , Citidina/administración & dosificación , Citidina/análogos & derivados , Citidina/farmacología , Receptor alfa de Estrógeno/metabolismo , Femenino , Kisspeptinas/metabolismo , Masculino , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Diferenciación Sexual/fisiología , Factores Sexuales , Testosterona/administración & dosificación
14.
Chemosphere ; 241: 124861, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31605998

RESUMEN

Both arsenic (As) and fluorine (F) are toxic substances widely found in the environment, which threaten to various organs of both human and animals, especially the kidney. In this study, to investigate the individual and combined effects of arsenic (15 mg/L As2O3(III)) and fluoride (100 mg/L NaF), arsenic (15 mg/L As2O3(III)) and fluoride-arsenic (15 mg/L As2O3(III)+100 mg/L NaF) on the renal autophagy during early life, a mouse model of gestationally exposed to As and/or F was established. The results showed that the mRNA expression levels of LC3, LC3I, LC3II, Beclin-1, ULK1, Atg13 and Atg14 were significantly increased with a concomitant decrease in mTOR and Bcl-2 up on individual exposure to As and F rather than in combined (As + F) exposure. In addition, the protein expression levels of LC3-II/LC3-I, Beclin-1, and LAMP1 were significantly increased with a concomitant decrease in mTOR and Bcl-2 in the mice subjected to individual exposure than the combined exposure. Based on the results, it was observed that renal tissue of mice was highly sensitive to F than As. Moreover, the toxicity of the combined (As + F) exposure was significantly lower than that of the individual exposure, which could be attributed due to the antagonism between As and F.


Asunto(s)
Arsénico/toxicidad , Autofagia/efectos de los fármacos , Exposición a Riesgos Ambientales , Fluoruros/toxicidad , Riñón/fisiología , Animales , Animales Recién Nacidos , Interacciones de Drogas , Femenino , Humanos , Masculino , Intercambio Materno-Fetal , Ratones , Embarazo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
15.
Scand J Immunol ; 91(1): e12840, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31630418

RESUMEN

IL-17 participates in the development of many autoimmune diseases by promoting the expression of some chemokines. Chemokine C-C motif ligand 2 (CCL2) is an important factor at the infiltration of mononuclear cells in the myocardial tissue of viral myocarditis (VMC). It was found that IL-17 could aggravate myocardial injury by upregulating CCL2. But the underlying mechanism involved in CCL2 secretion induced by IL-17 in cardiac myocytes remains unclear. This study investigated the role of transcription factor AP-1 in IL-17 induced CCL2 expression. The results showed that IL-17 mediated the activation of Act1, TRAF6, p38MAPK and c-Jun/AP-1 not Wnt or PI3K signalling pathway to upregulate CCL2 expression in cardiac myocytes. After blocking Act1/TRAF6/p38MAPK cascade and interfering AP-1 with Curcumin or c-Jun siRNA, CCL2 expression induced by IL-17 was significantly attenuated at both mRNA and protein levels. Furthermore, the phosphorylation of c-Jun was suppressed when cardiac myocytes were treated with Act1 siRNA, TRAF6 siRNA, SB203580 (p38MAPK inhibitor) or SP600125 (JNK inhibitor) in cardiac myocytes. In conclusion, IL-17 could stimulate the expression of CCL2 in cardiac myocytes via Act1/TRAF6/p38MAPK-dependent AP-1 activation, which may provide a new target for the diagnosis and treatment of VMC.


Asunto(s)
Quimiocina CCL2/genética , Regulación de la Expresión Génica , Interleucina-17/metabolismo , Miocitos Cardíacos/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor de Transcripción AP-1/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Animales Recién Nacidos , Quimiocina CCL2/metabolismo , Interleucina-17/farmacología , Ratones , Miocitos Cardíacos/efectos de los fármacos , Fosforilación , Transducción de Señal/efectos de los fármacos
16.
Life Sci ; 242: 116931, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31618610

RESUMEN

AIMS: With the improvement of the survival rates in children acute lymphoblastic leukemia (ALL), some children ALL survivors show impaired cognitive function. Methotrexate (MTX), an essential component in ALL treatment, has been reported to be related to neurologic sequelae and to increased oxidative stress through its interactions with enzymes in the folate pathway. Asymmetric dimethylarginine (ADMA) is the main endogenous inhibitor of nitric oxide synthase, and increased ADMA may result from increased oxidants. Melatonin is an antioxidant; however, its role in MTX neuropathy is not well studied. We developed a rat model mimicking child ALL treatment to explore peripheral and central homocysteine and ADMA regulation after MTX and found potential treatment choice. MAIN METHODS: Preweaning male Sprague-Dawley rats were used in this study. Experiment 1 evaluated spatial performance in rats with intrathecal (IT) MTX, intraperitoneal (IP) MTX, or combined IT and IP MTX, protocols mimicking ALL treatment in children. Experiment 2 focused on rats with combined IT and IP MTX, evaluating spatial performance and plasma and dorsal hippocampal homocysteine and ADMA levels, their regulation, and the protective effect of melatonin. KEY FINDINGS: Combined IT and IP MTX treatment caused in spatial deficits in developing rats, and melatonin restored the spatial performance. Alterations in peripheral and central homocysteine and ADMA concentrations and their regulation were found and could be alleviated by melatonin treatment. SIGNIFICANCES: Combined IP and IT MTX treatment caused spatial deficits in developing rats. Melatonin could restore spatial performance through alleviating the effects on the imbalance of oxidative stress.


Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Arginina/análogos & derivados , Hipocampo/química , Hiperhomocisteinemia/inducido químicamente , Melatonina/farmacología , Metotrexato/efectos adversos , Conducta Espacial/efectos de los fármacos , Animales , Animales Recién Nacidos , Arginina/análisis , Arginina/sangre , Modelos Animales de Enfermedad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Metotrexato/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley
17.
Arch Dis Child Fetal Neonatal Ed ; 105(1): 18-25, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31123056

RESUMEN

OBJECTIVE: Lung hypoplasia associated with congenital diaphragmatic hernia (CDH) results in respiratory insufficiency and pulmonary hypertension after birth. We have investigated whether aerating the lung before removing placental support (physiologically based cord clamping (PBCC)), improves the cardiopulmonary transition in lambs with a CDH. METHODS: At ≈138 days of gestational age, 17 lambs with surgically induced left-sided diaphragmatic hernia (≈d80) were delivered via caesarean section. The umbilical cord was clamped either immediately prior to ventilation onset (immediate cord clamping (ICC); n=6) or after achieving a target tidal volume of 4 mL/kg, with a maximum delay of 10 min (PBCC; n=11). Lambs were ventilated for 120 min and physiological changes recorded. RESULTS: Pulmonary blood flow (PBF) increased following ventilation onset in both groups, but was 19-fold greater in PBCC compared with ICC lambs at cord clamping (19±6.3 vs 1.0±0.5 mL/min/kg, p<0.001). Cerebral tissue oxygenation was higher in PBCC than ICC lambs during the first 10 min after cord clamping (59%±4% vs 30%±5%, p<0.001). PBF was threefold higher (23±4 vs 8±2 mL/min/kg, p=0.01) and pulmonary vascular resistance (PVR) was threefold lower (0.6±0.1 vs 2.2±0.6 mm Hg/(mL/min), p<0.001) in PBCC lambs compared with ICC lambs at 120 min after ventilation onset. CONCLUSIONS: Compared with ICC, PBCC prevented the severe asphyxia immediately after birth and resulted in a higher PBF due to a lower PVR, which persisted for at least 120 min after birth in CDH lambs.


Asunto(s)
Gasto Cardíaco , Constricción , Hernias Diafragmáticas Congénitas , Respiración con Presión Positiva , Circulación Pulmonar , Cordón Umbilical , Animales , Animales Recién Nacidos , Asfixia Neonatal/prevención & control , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Oxígeno/metabolismo , Ovinos , Volumen de Ventilación Pulmonar , Resistencia Vascular
18.
Food Chem Toxicol ; 135: 110982, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31747621

RESUMEN

With epidemic of obesity, it affects aspects of female reproduction. Genistein could ameliorate obesity in people and animals, but might exert adverse effects on the female reproductive system. To evaluate the effects of fetal and neonatal genistein exposure on the ovarian health of F1 obese female mice with obesity induced by high-fat diet after weaning, we simulated a diet-induced obesity model to observe and determine biological effects of genistein exposure on the ovarian follicle of overfed female mice. Results showed that F1 female mice with obesity induced by high-fat diet significantly prolonged the estrus cycle, disrupted sex hormonal balance and ovarian follicle development after they were exposed to 25 mg/kg b.w./day of genistein during the fetal and neonatal stages. Genistein significantly up-regulated the ovarian mRNA expression of estrogen receptor beta in F1 obese female mice, and high-fat diet influenced the ovarian mRNA expression of estrogen receptor alpha, luteinizing hormone receptor and follicle-stimulating hormone receptor. Hence, genistein exposure from the fetal stage might increase the risk of reproductive diseases in obese females in later life. Thus, the long-term risks of genistein to obese females should be thoroughly assessed.


Asunto(s)
Dieta Alta en Grasa , Genisteína/efectos adversos , Obesidad/tratamiento farmacológico , Folículo Ovárico/efectos de los fármacos , Animales , Animales Recién Nacidos , Estradiol/metabolismo , Receptor beta de Estrógeno/genética , Ciclo Estral/efectos de los fármacos , Femenino , Feto/efectos de los fármacos , Hormona Folículo Estimulante/metabolismo , Expresión Génica/efectos de los fármacos , Hormona Luteinizante/metabolismo , Ratones Endogámicos ICR , Obesidad/metabolismo , Folículo Ovárico/embriología , Folículo Ovárico/patología , Embarazo , ARN Mensajero/metabolismo
19.
Arch Dis Child Fetal Neonatal Ed ; 105(1): 26-32, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31092674

RESUMEN

INTRODUCTION: During delayed umbilical cord clamping, the factors underpinning placental transfusion remain unknown. We hypothesised that reductions in thoracic pressure during inspiration would enhance placental transfusion in spontaneously breathing preterm lambs. OBJECTIVE: Investigate the effect of spontaneous breathing on umbilical venous flow and body weight in preterm lambs. METHODS: Pregnant sheep were instrumented at 132-133 days gestational age to measure fetal common umbilical venous, pulmonary and cerebral blood flows as well as arterial and intrapleural (IP) pressures. At delivery, doxapram and caffeine were administered to promote breathing. Lamb body weights were measured continuously and breathing was assessed by IP pressure changes. RESULTS: In 6 lambs, 491 out of 1117 breaths were analysed for change in body weight. Weight increased in 46.6% and decreased in 47.5% of breaths. An overall mean increase of 0.02±2.5 g per breath was calculated, and no net placental transfusion was observed prior to cord clamping (median difference in body weight 52.3 [-54.9-166.1] g, p=0.418). Umbilical venous (UV) flow transiently decreased with each inspiration, and in some cases ceased, before UV flow normalised during expiration. The reduction in UV flow was positively correlated with the standardised reduction in (IP) pressure, increasing by 109 mL/min for every SD reduction in IP pressure. Thus, the reduction in UV flow was closely related to inspiratory depth. CONCLUSIONS: Spontaneous breathing had no net effect on body weight in preterm lambs at birth. UV blood flow decreased as inspiratory effort increased, possibly due to constriction of the inferior vena cava caused by diaphragmatic contraction, as previously observed in human fetuses.


Asunto(s)
Circulación Placentaria/fisiología , Respiración , Cordón Umbilical , Venas Umbilicales/fisiología , Animales , Animales Recién Nacidos , Velocidad del Flujo Sanguíneo/fisiología , Peso Corporal , Constricción , Modelos Animales de Enfermedad , Femenino , Embarazo , Nacimiento Prematuro , Ovinos , Factores de Tiempo
20.
J Dairy Sci ; 103(1): 1-15, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31677833

RESUMEN

Colostrum is the first milk produced by a cow after she gives birth. Compared with mature milk, it has a high concentration of immunoglobulin G. Calves are born without circulating antibodies, thus ingestion of colostrum is necessary to protect the calf against pathogens in the first challenging weeks of life. In addition to the life-saving supply of antibodies, colostrum contains minerals, vitamins, growth factors, and immune cells. Recently, microRNAs (miRNAs) were added to that list. MicroRNAs are short, non-coding RNA molecules that can regulate gene expression at the post-transcriptional level. They are thought to act as key regulators of diverse biological and developmental processes. Colostrum contains higher amounts of miRNAs than mature milk; immune- and development-related miRNAs are prominent. Their expression pattern in milk is likely to be influenced by maternal nutrition and environment. The fat content of the maternal diet appears to have a major effect on expression of miRNAs in milk and in the neonate. The immunological state of the mammary gland seems to affect miRNA expression as well. In cows diagnosed with subclinical mastitis, alterations in the expression of miRNAs in milk have been observed. It is believed that miRNAs in colostrum and milk are signaling molecules passed from mother to newborn. They are packaged in extracellular vesicles, which makes them resistant to the harsh conditions in the gastrointestinal tract. Therefore, they can reach the small intestine, where they are absorbed and transferred into the bloodstream. MicroRNAs are important for the development of the intestines. For example, miRNAs stimulate cell viability, proliferation, and stem cell activity of the intestinal epithelium. Furthermore, miRNAs seem to act as key players in the development of the complete immune system. They can, among other things, regulate B- and T-cell differentiation and affect interleukin production of macrophages. The abundance of miRNAs in colostrum and milk and the possibility for their absorption in the intestines of the neonate supports the hypothesis that these tiny molecules are important for the development of the newborn. The probable relation of diet to the expression of miRNAs by the mother creates a possible avenue to optimize expression of miRNAs and improve neonatal maturation.


Asunto(s)
Animales Recién Nacidos , Calostro/química , MicroARNs/metabolismo , Leche/química , Animales , Bovinos , Calostro/inmunología , Dieta/veterinaria , Femenino , MicroARNs/química , MicroARNs/genética , Leche/metabolismo , Embarazo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA