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1.
Cancer Sci ; 115(3): 963-973, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38226414

RESUMEN

Ectopic activation of rearranged during transfection (RET) has been reported to facilitate lineage differentiation and cell proliferation in different cytogenetic subtypes of acute myeloid leukemia (AML). Herein, we demonstrate that RET is significantly (p < 0.01) upregulated in AML subtypes containing rearrangements of the lysine methyltransferase 2A gene (KMT2A), commonly referred to as KMT2A-rearranged (KMT2A-r) AML. Integrating multi-epigenomics data, we show that the KMT2A-MLLT3 fusion induces the development of CCCTC-binding (CTCF)-guided de novo extrusion enhancer loop to upregulate RET expression in KMT2A-r AML. Based on the finding that RET expression is tightly correlated with the selective chromatin remodeler and mediator (MED) proteins, we used a small-molecule inhibitor having dual inhibition against RET and MED12-associated cyclin-dependent kinase 8 (CDK8) in KMT2A-r AML cells. Dual inhibition of RET and CDK8 restricted cell proliferation by producing multimodal oxidative stress responses in treated cells. Our data suggest that epigenetically enhanced RET protects KMT2A-r AML cells from oxidative stresses, which could be exploited as a potential therapeutic strategy.


Asunto(s)
Reordenamiento Génico , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proto-Oncogenes , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Estrés Oxidativo/genética , Proteínas Proto-Oncogénicas c-ret/genética
2.
Mol Psychiatry ; 26(5): 1561-1577, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-32963337

RESUMEN

We investigate the role of the mitochondrion, an organelle highly sensitive to environmental agents, in the influence of prenatal air pollution exposure on neurodevelopment and behavior in 96 children with autism spectrum disorder (ASD) [45 with neurodevelopmental regression (NDR); 76% Male; mean (SD) age 10 y 9 m (3 y 9 m)]. Mitochondrial function was assessed using the Seahorse XFe96 in fresh peripheral blood mononuclear cells. Second and third trimester average and maximal daily exposure to fine air particulate matter of diameter ≤2.5 µm (PM2.5) was obtained from the Environmental Protection Agency's Air Quality System. Neurodevelopment was measured using the Vineland Adaptive Behavior Scale 2nd edition and behavior was assessed using the Aberrant Behavior Checklist and Social Responsiveness Scale. Prenatal PM2.5 exposure influenced mitochondrial respiration during childhood, but this relationship was different for those with (r = 0.25-0.40) and without (r = -0.07 to -0.19) NDR. Mediation analysis found that mitochondrial respiration linked to energy production accounted for 25% (SD = 2%) and 10% (SD = 2%) of the effect of average prenatal PM2.5 exposure on neurodevelopment and behavioral symptoms, respectively. Structural equation models estimated that PM2.5 and mitochondrial respiration accounted for 34% (SD = 4%) and 36% (SD = 3%) of the effect on neurodevelopment, respectively, and that behavior was indirectly influenced by mitochondrial respiration through neurodevelopment but directly influenced by prenatal PM2.5. Our results suggest that prenatal exposure to PM2.5 disrupts neurodevelopment and behavior through complex mechanisms, including long-term changes in mitochondrial respiration and that patterns of early development need to be considered when studying the influence of environmental agents on neurodevelopmental outcomes.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Trastorno del Espectro Autista , Efectos Tardíos de la Exposición Prenatal , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Contaminación del Aire/efectos adversos , Niño , Femenino , Humanos , Leucocitos Mononucleares , Masculino , Exposición Materna , Mitocondrias , Embarazo
3.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G439-G450, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31961718

RESUMEN

Methionine is an essential amino acid needed for a variety of processes in living organisms. Ionizing radiation depletes tissue methionine concentrations and leads to the loss of DNA methylation and decreased synthesis of glutathione. In this study, we aimed to investigate the effects of methionine dietary supplementation in CBA/CaJ mice after exposure to doses ranging from 3 to 8.5 Gy of 137Cs of total body irradiation. We report that mice fed a methionine-supplemented diet (MSD; 19.5 vs. 6.5 mg/kg in a methionine-adequate diet, MAD) developed acute radiation toxicity at doses as low as 3 Gy. Partial body irradiation performed with hindlimb shielding resulted in a 50% mortality rate in MSD-fed mice exposed to 8.5 Gy, suggesting prevalence of radiation-induced gastrointestinal syndrome in the development of acute radiation toxicity. Analysis of the intestinal microbiome demonstrated shifts in the gut ecology, observed along with the development of leaky gut syndrome and bacterial translocation into the liver. Normal gut physiology impairment was facilitated by alterations in the one-carbon metabolism pathway and was exhibited as decreases in circulating citrulline levels mirrored by decreased intestinal mucosal surface area and the number of surviving crypts. In conclusion, we demonstrate that a relevant excess of methionine dietary intake exacerbates the detrimental effects of exposure to ionizing radiation in the small intestine.NEW & NOTEWORTHY Methionine supplementation, instead of an anticipated health-promoting effect, sensitizes mice to gastrointestinal radiation syndrome. Mechanistically, excess of methionine negatively affects intestinal ecology, leading to a cascade of physiological, biochemical, and molecular alterations that impair normal gut response to a clinically relevant genotoxic stressor. These findings speak toward increasing the role of registered dietitians during cancer therapy and the necessity of a solid scientific background behind the sales of dietary supplements and claims regarding their benefits.


Asunto(s)
Síndrome de Radiación Aguda/etiología , Suplementos Dietéticos/toxicidad , Intestino Delgado/efectos de los fármacos , Metionina/toxicidad , Traumatismos Experimentales por Radiación/etiología , Síndrome de Radiación Aguda/metabolismo , Síndrome de Radiación Aguda/microbiología , Síndrome de Radiación Aguda/patología , Animales , Metilación de ADN/efectos de los fármacos , Disbiosis , Metabolismo Energético/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/microbiología , Intestino Delgado/patología , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Dosis de Radiación , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/microbiología , Traumatismos Experimentales por Radiación/patología , Factores de Riesgo , Irradiación Corporal Total
4.
BMC Pediatr ; 20(1): 557, 2020 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-33317469

RESUMEN

BACKGROUND: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism. METHODS: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods. RESULTS: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules. Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules. CONCLUSIONS: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.


Asunto(s)
Trastorno del Espectro Autista , Biomarcadores , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Ácido Fólico , Humanos , Madres
5.
FASEB J ; 32(3): 1591-1601, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29127188

RESUMEN

The substantial rise in the prevalence of nonalcoholic steatohepatitis (NASH), an advanced form of nonalcoholic fatty liver disease, and the strong association between NASH and the development of hepatocellular carcinoma indicate the urgent need for a better understanding of the underlying mechanisms. In the present study, by using the Stelic animal model of NASH and NASH-derived liver carcinogenesis, we investigated the role of the folate-dependent 1-carbon metabolism in the pathogenesis of NASH. We demonstrated that advanced NASH and NASH-related liver carcinogenesis are characterized by a significant dysregulation of 1-carbon homeostasis, with diminished expression of key 1-carbon metabolism genes, especially a marked inhibition of the S-adenosylhomocysteine hydrolase ( Ahcy) gene and an increased level of S-adenosyl-l-homocysteine (SAH). The reduction in Ahcy expression was associated with gene-specific cytosine DNA hypermethylation and enrichment of the gene promoter by trimethylated histone H3 lysine 27 and deacetylated histone H4 lysine 16, 2 main transcription-inhibiting markers. These results indicate that epigenetically mediated inhibition of Ahcy expression may be a driving force in causing SAH elevation and subsequent downstream disturbances in transsulfuration and transmethylation pathways during the development and progression of NASH.-Pogribny, I. P., Dreval, K., Kindrat, I., Melnyk, S., Jimenez, L., de Conti, A., Tryndyak, V., Pogribna, M., Ortega, J. F., James, S. J., Rusyn, I., Beland, F. A. Epigenetically mediated inhibition of S-adenosylhomocysteine hydrolase and the associated dysregulation of 1-carbon metabolism in nonalcoholic steatohepatitis and hepatocellular carcinoma.


Asunto(s)
Adenosilhomocisteinasa/biosíntesis , Carcinoma Hepatocelular/enzimología , Epigénesis Genética , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/enzimología , Proteínas de Neoplasias/biosíntesis , Enfermedad del Hígado Graso no Alcohólico/enzimología , Adenosilhomocisteinasa/genética , Animales , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Masculino , Ratones , Proteínas de Neoplasias/genética , Enfermedad del Hígado Graso no Alcohólico/patología , S-Adenosilhomocisteína/metabolismo
6.
Carcinogenesis ; 39(9): 1117-1126, 2018 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-29939201

RESUMEN

Methionine dependency describes the characteristic rapid in vitro death of most tumor cells in the absence of methionine. Combining chemotherapy with dietary methionine deprivation [methionine-deficient diet (MDD)] at tolerable levels has vast potential in tumor treatment; however, it is limited by MDD-induced toxicity during extended deprivation. Recent advances in imaging and irradiation delivery have created the field of stereotactic body radiotherapy (SBRT), where fewer large-dose fractions delivered in less time result in increased local-tumor control, which could be maximally synergistic with an MDD short course. Identification of the lowest effective methionine dietary intake not associated with toxicity will further enhance the cancer therapy potential. In this study, we investigated the effects of MDD and methionine-restricted diet (MRD) in primary and metastatic melanoma models in combination with radiotherapy (RT). In vitro, MDD dose-dependently sensitized mouse and human melanoma cell lines to RT. In vivo in mice, MDD substantially potentiated the effects of RT by a significant delay in tumor growth, in comparison with administering MDD or RT alone. The antitumor effects of an MDD/RT approach were due to effects on one-carbon metabolism, resulting in impaired methionine biotransformation via downregulation of Mat2a, which encodes methionine adenosyltransferase 2A. Furthermore, and probably most importantly, MDD and MRD substantially diminished metastatic potential; the antitumor MRD effects were not associated with toxicity to normal tissue. Our findings suggest that modulation of methionine intake holds substantial promise for use with short-course SBRT for cancer treatment.


Asunto(s)
Antineoplásicos/farmacología , Melanoma/dietoterapia , Melanoma/patología , Metionina Adenosiltransferasa/biosíntesis , Metionina/farmacología , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Humanos , Masculino , Metionina/administración & dosificación , Metionina/metabolismo , Ratones , Ratones Endogámicos C57BL , Metástasis de la Neoplasia/patología
7.
FASEB J ; 31(3): 904-909, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27864377

RESUMEN

Autism spectrum disorder (ASD) is associated with physiological abnormalities, including abnormal redox and mitochondrial metabolism. Lymphoblastoid cell lines (LCLs) from some children with ASD exhibit increased oxidative stress, decreased glutathione redox capacity, and highly active mitochondria with increased vulnerability to reactive oxygen species (ROS). Because unaffected siblings (Sibs) of individuals with ASD share some redox abnormalities, we sought to determine whether LCLs from Sibs share ASD-associated mitochondrial abnormalities. We evaluated mitochondrial bioenergetics in 10 sets of LCLs from children with ASD, Sibs, and unrelated/unaffected controls (Cons) after acute increases in ROS. Additionally, intracellular glutathione and uncoupling protein 2 (UCP2) gene expressions were quantified. Compared to Sib LCLs, ASD LCLs exhibited significantly higher ATP-linked respiration, higher maximal and reserve respiratory capacity, and greater glycolysis and glycolytic reserve. ASD LCLs exhibited a significantly greater change in these parameters, with acute increases in ROS compared to both Sib and Con LCLs. Compared to Con, both ASD and Sib LCLs exhibited significantly higher proton leak respiration. Consistent with this, intracellular glutathione redox capacity was decreased and UCP2 gene expression was increased in both ASD and Sib compared to Con LCLs. These data indicate that mitochondrial respiratory function, not abnormal redox homeostasis, distinguishes ASD from unaffected LCLs.-Rose, S., Bennuri, S. C., Wynne, R., Melnyk, S., James, S. J., Frye, R. E. Mitochondrial and redox abnormalities in autism lymphoblastoid cells: a sibling control study.


Asunto(s)
Trastorno del Espectro Autista/metabolismo , Linfocitos/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Adenosina Trifosfato/metabolismo , Adolescente , Trastorno del Espectro Autista/genética , Estudios de Casos y Controles , Línea Celular , Células Cultivadas , Niño , Preescolar , Glutatión/metabolismo , Humanos , Masculino , Especies Reactivas de Oxígeno/metabolismo , Hermanos , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo
8.
PLoS Comput Biol ; 13(3): e1005385, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28301476

RESUMEN

The number of diagnosed cases of Autism Spectrum Disorders (ASD) has increased dramatically over the last four decades; however, there is still considerable debate regarding the underlying pathophysiology of ASD. This lack of biological knowledge restricts diagnoses to be made based on behavioral observations and psychometric tools. However, physiological measurements should support these behavioral diagnoses in the future in order to enable earlier and more accurate diagnoses. Stepping towards this goal of incorporating biochemical data into ASD diagnosis, this paper analyzes measurements of metabolite concentrations of the folate-dependent one-carbon metabolism and transulfuration pathways taken from blood samples of 83 participants with ASD and 76 age-matched neurotypical peers. Fisher Discriminant Analysis enables multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being correctly identified as such while still correctly identifying 97.6% of the ASD cohort. Furthermore, kernel partial least squares is used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score, where measurement of five metabolites of the pathways was sufficient to predict the Vineland score with an R2 of 0.45 after cross-validation. This level of accuracy for classification as well as severity prediction far exceeds any other approach in this field and is a strong indicator that the metabolites under consideration are strongly correlated with an ASD diagnosis but also that the statistical analysis used here offers tremendous potential for extracting important information from complex biochemical data sets.


Asunto(s)
Trastorno del Espectro Autista/sangre , Trastorno del Espectro Autista/diagnóstico , Metilación de ADN/inmunología , Ácido Fólico/sangre , Análisis Multivariante , Estrés Oxidativo/inmunología , Trastorno del Espectro Autista/inmunología , Biomarcadores/sangre , Niño , Preescolar , Interpretación Estadística de Datos , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y Especificidad
9.
J Theor Biol ; 416: 28-37, 2017 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-28040439

RESUMEN

Previous research has shown a connection between metabolic abnormalities in the methionine cycle and transsulfuration pathway and autism spectrum disorder. Using clinical data from a case-control study investigating measurements of transmethylation and transsulfuration metabolites, a steady-state model of these metabolites in liver cells was developed and participant-specific parameters were identified. Comparison of mean parameter values and parameter distributions between neurotypical study participants and those on the autism spectrum revealed significant differences for four model parameters. Sensitivity analysis identified the parameter describing the rate of glutamylcysteine synthesis, the rate-limiting step in glutathione production, to be particularly important in determining steady-state metabolite concentrations. These results may provide insight into key reactions to target for potential intervention strategies relating to autism spectrum disorder.


Asunto(s)
Trastorno del Espectro Autista/metabolismo , Metionina/metabolismo , Modelos Teóricos , Azufre/metabolismo , Estudios de Casos y Controles , Interpretación Estadística de Datos , Glutamato-Cisteína Ligasa/metabolismo , Glutatión/biosíntesis , Hepatocitos/metabolismo , Humanos , Redes y Vías Metabólicas
11.
FASEB J ; 28(2): 781-90, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24189943

RESUMEN

Cystathionine ß-synthase (CBS) deficiency is a recessive inborn error of metabolism characterized by elevated serum total homocysteine (tHcy). Previously, our laboratory developed a mouse model of CBS deficiency, TgI278T Cbs(-)/(-) (abbreviated as Cbs(-/-)), characterized by low weight, low adiposity, decreased Scd-1 expression, facial alopecia, and osteoporosis. To determine the potential benefit of a methionine-restricted diet (MRD), we fed Cbs(-/-) and Cbs(+/-) control mice either an MRD or a regular diet (RD) from weaning till 240 d of age. Cbs(-/-) mice fed the MRD had a 77% decrease in tHcy, 28% increase in weight, 130% increase in fat mass, 82% increase in Scd-1 expression, and 10.6% increase in bone density and entirely lacked the alopecia phenotype observed in age-matched Cbs(-/-) mice fed the RD. At the end of the study, Cbs(-/-) mice fed the MRD were phenotypically indistinguishable from Cbs(+/-) mice fed the RD. Notably, whereas the MRD diet was highly beneficial to Cbs(-/-) mice, it had nearly opposite effect on Cbs(+/-) mice. These studies show that a low-methionine diet can correct the phenotypic consequences of loss of CBS and provide a striking example of how genotype and diet can interact to influence phenotype in mammals.


Asunto(s)
Cistationina betasintasa/deficiencia , Homocistinuria/dietoterapia , Metionina/uso terapéutico , Absorciometría de Fotón , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Metionina/administración & dosificación , Ratones , Ratones Noqueados
12.
Carcinogenesis ; 35(9): 2102-12, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24832086

RESUMEN

Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein, we evaluated mammary tumor risk in female mouse mammary tumor virus-Wnt-1 transgenic (Tg) offspring exposed to high-fat diet (HFD) or control diet (CD) (45% and 17% kcal from fat, respectively) during gestation and lactation, with CD provided to progeny at weaning. In Tg offspring, maternal HFD exposure increased mammary tumor incidence and decreased tumor latency without affecting tumor volume. Tumor risk was associated with higher tumor necrosis factor-α and insulin and altered oxidative stress biomarkers in sera and with early changes in mammary expression of genes linked to tumor promotion [interleukin 6 (Il6)] or inhibition [phosphatase and tensin homolog deleted on chromosome 10 (Pten), B-cell lymphoma 2 (Bcl2)]. Corresponding wild-type progeny exposed to maternal HFD displayed accelerated mammary development, higher mammary adiposity, increased insulin resistance and early changes in Pten, Bcl2 and Il6, than CD-exposed offspring. Dams-fed HFD showed higher serum glucose and oxidative stress biomarkers but comparable adiposity compared with CD-fed counterparts. In human breast cancer MCF-7 cells, sera from maternal HFD-exposed Tg offspring elicited changes in PTEN, BCL2 and IL6 gene expression, mimicking in vivo exposure; increased cell viability and mammosphere formation and induced measures [insulin receptor substrate-1 (IRS-1), IRS-2] of insulin sensitivity. Serum effects on IRS-1 were recapitulated by exogenous insulin and the PTEN-specific inhibitor SF1670. Hyperinsulinemia and PTEN loss-of-function may thus, couple maternal HFD exposure to enhanced insulin sensitivity via increased mammary IRS-1 expression in progeny, to promote breast cancer risk.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Neoplasias Mamarias Experimentales/etiología , Efectos Tardíos de la Exposición Prenatal/etiología , Proteína Wnt1/fisiología , Animales , Animales Lactantes , Femenino , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Lactancia , Células MCF-7 , Masculino , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Estrés Oxidativo , Fenotipo , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Fenómenos Fisiologicos de la Nutrición Prenatal , Factores de Riesgo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
13.
FASEB J ; 27(6): 2233-43, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23439872

RESUMEN

Dysregulation of one-carbon metabolism-related metabolic processes is a major contributor to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). It is well established that genetic and gender-specific variations in one-carbon metabolism contribute to the vulnerability to NAFLD in humans. To examine the role of one-carbon metabolism dysregulation in the pathogenesis and individual susceptibility to NAFLD, we used a "population-based" mouse model where male mice from 7 inbred were fed a choline- and folate-deficient (CFD) diet for 12 wk. Strain-dependent down-regulation of several key one-carbon metabolism genes, including methionine adenosyltransferase 1α (Mat1a), cystathionine-ß-synthase (Cbs), methylenetetrahydrofolate reductase (Mthfr), adenosyl-homocysteinase (Ahcy), and methylenetetrahydrofolate dehydrogenase 1 (Mthfd1), was observed. These changes were strongly associated with interstrain variability in liver injury (steatosis, necrosis, inflammation, and activation of fibrogenesis) and hyperhomocysteinemia. Mechanistically, the decreased expression of Mat1a, Ahcy, and Mthfd1 was linked to a reduced level and promoter binding of transcription factor CCAAT/enhancer binding protein ß (CEBPß), which directly regulates their transcription. The strain specificity of diet-induced dysregulation of one-carbon metabolism suggests that interstrain variation in the regulation of one-carbon metabolism may contribute to the differential vulnerability to NFLD and that correcting the imbalance may be considered as preventive and treatment strategies for NAFLD.


Asunto(s)
Carbono/metabolismo , Deficiencia de Colina/metabolismo , Colina , Regulación hacia Abajo , Deficiencia de Ácido Fólico/metabolismo , Ácido Fólico , Hígado/lesiones , Hígado/metabolismo , Animales , Deficiencia de Colina/complicaciones , Deficiencia de Colina/genética , Cistationina betasintasa/genética , Modelos Animales de Enfermedad , Hígado Graso/etiología , Hígado Graso/genética , Hígado Graso/metabolismo , Deficiencia de Ácido Fólico/complicaciones , Deficiencia de Ácido Fólico/genética , Humanos , Masculino , Metionina Adenosiltransferasa/genética , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Ratones , Ratones Endogámicos , Enfermedad del Hígado Graso no Alcohólico , Especificidad de la Especie
14.
Brain Behav Immun Health ; 38: 100775, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38706573

RESUMEN

Oxidative stress during pregnancy has been a mechanistic pathway implicated in autism development, yet few studies have examined this association directly. Here, we examined the association of prenatal levels of 8-iso-PGF2α, a widely used measure of oxidative stress, and several neurodevelopmental outcomes related to autism in children. Participants included 169 mother-child pairs from the Early Autism Risk Longitudinal Investigation (EARLI), which enrolled mothers who had an autistic child from a previous pregnancy and followed them through a subsequent pregnancy and until that child reached age 3 years. Maternal urine samples were collected during the second trimester of pregnancy and were later measured for levels of isoprostanes. Child neurodevelopmental assessments included the Mullen Scales of Early Learning (MSEL), the Social Responsiveness Scale (SRS), and the Vineland Adaptive Behavior Scale (VABS), and were conducted around 36 months of age. Primary analyses examined associations between interquartile range (IQR) increases in 8-iso-PGF2α levels, and total composite scores from each assessment using quantile regression. In adjusted analyses, we did not observe statistically significant associations, though estimates suggested modestly lower cognitive scores (ß for MSEL = -3.68, 95% CI: -10.09, 2.70), and minor increases in autism-related trait scores (ß for SRS T score = 1.68, 95% CI: -0.24, 3.60) with increasing 8-iso-PGF2α. These suggestive associations between decreased cognitive scores and increased autism-related traits with increasing prenatal oxidative stress point to the need for continued investigation in larger samples of the role of oxidative stress as a mechanistic pathway in autism and related neurodevelopmental outcomes.

15.
Antimicrob Agents Chemother ; 57(12): 6290-4, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24100498

RESUMEN

Evidence from animal studies suggests that chlamydiae may persist in the gastrointestinal tract (GI) and be a reservoir for reinfection of the genital tract. We hypothesize that there may be a differential susceptibility of organisms in the GI and genital tracts. To determine the effect of azithromycin on persistent chlamydial gut infection, C57BL/6 and BALB/c mice were infected orally and genitally and treated with azithromycin (Az) orally (20, 40, or 80 mg/kg of body weight), and the numbers of chlamydiae were determined from cervix and cecal tissues. The Az concentration in the cecum and cervix was measured by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). Az treatment cleared genital infection in both C57BL/6 and BALB/c mice; however, GI infection was not cleared with the same doses. HPLC data showed the presence of Az at both sites of infection, and significant amounts of Az were measured in treatment groups. However, no significant difference in Az levels between the cecum and the cervix was observed, indicating similar levels of Az reaching both sites of infection. These data indicate that antibiotic levels that are sufficient to cure genital infection are ineffectual against GI infection. The results suggest a reevaluation of antibiotic therapy for chlamydial infection.


Asunto(s)
Antibacterianos/uso terapéutico , Azitromicina/uso terapéutico , Cuello del Útero/microbiología , Infecciones por Chlamydia/tratamiento farmacológico , Animales , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
16.
Mol Carcinog ; 52(4): 318-27, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22213190

RESUMEN

Carcinogenesis is a multistep sequential process of clonal expansion of initiated cells associated with the accumulation of multiple cancer-specific heritable phenotypes. The acquisition of these heritable cancer-specific alterations may be triggered by mutational and/or non-mutational changes in the genome that affect the regulation of gene expression. Currently, cancer-specific epigenetically mediated changes in gene expression are regarded as driving events in tumorigenesis. In the present study, we investigated the role of gene-specific expression changes in the mechanism of rat hepatocarcinogenesis induced by the complete hepatocarcinogen 2-acetylaminofluorene (2-AAF). The results of the present study demonstrate significant alterations in gene expression, especially of Mat1a and Mthfr genes, during early stages of rat 2-AAF-induced liver carcinogenesis. Both of these genes were downregulated in the livers of 2-AAF-treated male rats. Inhibition of Mat1a expression was associated with an increase in histone H3 lysine 27 trimethylation and a decrease in histone H3 lysine 18 acetylation at the gene promoter/first exon region. Additionally, we demonstrate for the first time a critical contribution of miR-22 and miR-29b microRNAs in the inhibition of Mat1a and Mthfr gene expression during 2-AAF-induced rat hepatocarcinogenesis. The downregulation of Mat1a and Mthfr genes was accompanied by marked functional alterations in one-carbon metabolism. The results of the present study suggest that downregulation of the Mat1a and Mthfr genes may be one of the main driver events that promote liver carcinogenesis by causing a profound accumulation of subsequent epigenetic abnormalities during progression of the carcinogenic process.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas Experimentales/genética , Hígado/metabolismo , Metionina Adenosiltransferasa/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , MicroARNs/genética , 2-Acetilaminofluoreno , Acetilación , Animales , Carcinógenos , Línea Celular , Metilación de ADN , Regulación hacia Abajo , Epigénesis Genética , Femenino , Histonas/genética , Histonas/metabolismo , Hígado/efectos de los fármacos , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/metabolismo , Masculino , Regiones Promotoras Genéticas , Ratas , Ratas Sprague-Dawley , S-Adenosilhomocisteína/análisis , S-Adenosilhomocisteína/metabolismo , S-Adenosilmetionina/análisis , S-Adenosilmetionina/metabolismo
17.
Hepatology ; 56(1): 130-9, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22307928

RESUMEN

UNLABELLED: Alcoholic liver injury is a major public health issue worldwide. Even though the major mechanisms of this disease have been established over the past decades, little is known about genetic susceptibility factors that may predispose individuals who abuse alcoholic beverages to liver damage and subsequent pathological conditions. We hypothesized that a panel of genetically diverse mouse strains may be used to examine the role of endoplasmic reticulum (ER) stress and one-carbon metabolism in the mechanism of interindividual variability in alcoholic liver injury. We administered alcohol (up to 27 mg/kg/d) in a high-fat diet using an intragastric intubation model for 28 days to male mice from 14 inbred strains (129S1/SvImJ, AKR/J, BALB/cJ, BALB/cByJ, BTBR T+tf/J, C3H/HeJ, C57BL/10J, DBA/2J, FVB/NJ, KK/HIJ, MOLF/EiJ, NZW/LacJ, PWD/PhJ, and WSB/EiJ). Profound interstrain differences (more than 3-fold) in alcohol-induced steatohepatitis were observed among the strains in spite of consistently high levels of urine alcohol that were monitored throughout the study. We found that ER stress genes were induced only in strains with the most liver injury. Liver glutathione and methyl donor levels were affected in all strains, albeit to a different degree. The most pronounced effects that were closely associated with the degree of liver injury were hyperhomocysteinemia and strain-dependent differences in expression patterns of one-carbon metabolism-related genes. CONCLUSION: Our data demonstrate that strain differences in alcohol-induced liver injury and steatosis are striking and independent of alcohol exposure and the most severely affected strains exhibit major differences in the expression of ER stress markers and genes of one-carbon metabolism.


Asunto(s)
Alcoholes/administración & dosificación , Hígado Graso Alcohólico/metabolismo , Hígado Graso Alcohólico/patología , Ratones Endogámicos/metabolismo , Alcoholes/efectos adversos , Animales , Biopsia con Aguja , Western Blotting , Modelos Animales de Enfermedad , Inmunohistoquímica , Peroxidación de Lípido/fisiología , Masculino , Metionina/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Transferasas del Grupo 1-Carbono/metabolismo , Estrés Oxidativo/fisiología , Distribución Aleatoria , Índice de Severidad de la Enfermedad , Especificidad de la Especie
18.
Toxicol Appl Pharmacol ; 269(3): 263-9, 2013 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-23566951

RESUMEN

Previous studies demonstrated that low-level postnatal and early life exposure to the environmental contaminant, trichloroethylene (TCE), in the drinking water of MRL+/+ mice altered glutathione redox homeostasis and increased biomarkers of oxidative stress indicating a more oxidized state. Plasma metabolites along the interrelated transmethylation pathway were also altered indicating impaired methylation capacity. Here we extend these findings to further characterize the impact of TCE exposure in mice exposed to water only or two doses of TCE in the drinking water (0, 2, and 28mg/kg/day) postnatally from birth until 6weeks of age on redox homeostasis and biomarkers of oxidative stress in the cerebellum. In addition, pathway intermediates involved in methyl metabolism and global DNA methylation patterns were examined in cerebellar tissue. Because the cerebellum is functionally important for coordinating motor activity, including exploratory and social approach behaviors, these parameters were evaluated in the present study. Mice exposed to 28mg/kg/day TCE exhibited increased locomotor activity over time as compared with control mice. In the novel object exploration test, these mice were more likely to enter the zone with the novel object as compared to control mice. Similar results were obtained in a second test when an unfamiliar mouse was introduced into the testing arena. The results show for the first time that postnatal exposure to TCE causes key metabolic changes in the cerebellum that may contribute to global DNA methylation deficits and behavioral alterations in TCE-exposed mice.


Asunto(s)
Conducta Animal/efectos de los fármacos , Cerebelo/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Tricloroetileno/toxicidad , Animales , Animales Recién Nacidos , Cerebelo/química , Cerebelo/metabolismo , Cisteína/análisis , Glutatión/análisis , Glutatión/metabolismo , Masculino , Ratones , Ratones Endogámicos MRL lpr , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Tirosina/análogos & derivados , Tirosina/análisis
19.
Toxicol Appl Pharmacol ; 266(2): 224-32, 2013 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23200774

RESUMEN

The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility.


Asunto(s)
Acetaminofén/toxicidad , Analgésicos no Narcóticos/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hepatitis C/complicaciones , Mitocondrias Hepáticas/efectos de los fármacos , Acetaminofén/administración & dosificación , Enfermedad Aguda , Analgésicos no Narcóticos/administración & dosificación , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Relación Dosis-Respuesta a Droga , Ayuno , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias Hepáticas/patología , Factores de Tiempo
20.
FASEB J ; 26(11): 4592-602, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22872676

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the variability. Feeding mice a choline- and folate-deficient diet for 12 wk caused liver injury similar to NAFLD. The magnitude of liver injury varied among the strains, with the order of sensitivity being A/J ≈ C57BL/6J ≈ C3H/HeJ < 129S1/SvImJ ≈ CAST/EiJ < PWK/PhJ < WSB/EiJ. The interstrain variability in severity of NAFLD liver damage was associated with dysregulation of genes involved in lipid metabolism, primarily with a down-regulation of the peroxisome proliferator receptor α (PPARα)-regulated lipid catabolic pathway genes. Markers of oxidative stress and oxidative stress-induced DNA damage were also elevated in the livers but were not correlated with severity of liver damage. These findings suggest that the PPARα-regulated metabolism network is one of the key mechanisms determining interstrain susceptibility and severity of NAFLD in mice.


Asunto(s)
Deficiencia de Colina/complicaciones , Colina/administración & dosificación , Hígado Graso/etiología , Deficiencia de Ácido Fólico/complicaciones , Ácido Fólico/administración & dosificación , Metabolismo de los Lípidos/genética , Alimentación Animal , Animales , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Daño del ADN , Dieta , Hígado Graso/patología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Variación Genética , Masculino , Ratones , Ratones Endogámicos , Estrés Oxidativo , Análisis por Matrices de Proteínas , Transcriptoma
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