Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 162
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMC Med Res Methodol ; 20(1): 64, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171256

RESUMO

BACKGROUND: Among different investigators studying the same exposures and outcomes, there may be a lack of consensus about potential confounders that should be considered as matching, adjustment, or stratification variables in observational studies. Concerns have been raised that confounding factors may affect the results obtained for the alcohol-ischemic heart disease relationship, as well as their consistency and reproducibility across different studies. Therefore, we assessed how confounders are defined, operationalized, and discussed across individual studies evaluating the impact of alcohol on ischemic heart disease risk. METHODS: For observational studies included in a recent alcohol-ischemic heart disease meta-analysis, we identified all variables adjusted, matched, or stratified for in the largest reported multivariate model (i.e. potential confounders). We recorded how the variables were measured and grouped them into higher-level confounder domains. Abstracts and Discussion sections were then assessed to determine whether authors considered confounding when interpreting their study findings. RESULTS: 85 of 87 (97.7%) studies reported multivariate analyses for an alcohol-ischemic heart disease relationship. The most common higher-level confounder domains included were smoking (79, 92.9%), age (74, 87.1%), and BMI, height, and/or weight (57, 67.1%). However, no two models adjusted, matched, or stratified for the same higher-level confounder domains. Most (74/87, 85.1%) articles mentioned or alluded to "confounding" in their Abstract or Discussion sections, but only one stated that their main findings were likely to be affected by residual confounding. There were five (5/87, 5.7%) authors that explicitly asked for caution when interpreting results. CONCLUSION: There is large variation in the confounders considered across observational studies evaluating the impact of alcohol on ischemic heart disease risk and almost all studies spuriously ignore or eventually dismiss confounding in their conclusions. Given that study results and interpretations may be affected by the mix of potential confounders included within multivariate models, efforts are necessary to standardize approaches for selecting and accounting for confounders in observational studies.

2.
Cell Metab ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32213345

RESUMO

Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine's functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality.

3.
Int J Epidemiol ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31967637

RESUMO

BACKGROUND: Different analytical approaches can influence the associations estimated in observational studies. We assessed the variability of effect estimates reported within and across observational studies evaluating the impact of alcohol on breast cancer. METHODS: We abstracted largest harmful, largest protective and smallest (closest to the null value of 1.0) relative risk estimates in studies included in a recent alcohol-breast cancer meta-analysis, and recorded how they differed based on five model specification characteristics, including exposure definition, exposure contrast levels, study populations, adjustment covariates and/or model approaches. For each study, we approximated vibration of effects by dividing the largest by the smallest effect estimate [i.e. ratio of odds ratio (ROR)]. RESULTS: Among 97 eligible studies, 85 (87.6%) reported both harmful and protective relative effect estimates for an alcohol-breast cancer relationship, which ranged from 1.1 to 17.9 and 0.0 to 1.0, respectively. The RORs comparing the largest and smallest estimates in value ranged from 1.0 to 106.2, with a median of 3.0 [interquartile range (IQR) 2.0-5.2]. One-third (35, 36.1%) of the RORs were based on extreme effect estimates with at least three different model specification characteristics; the vast majority (87, 89.7%) had different exposure definitions or contrast levels. Similar vibrations of effect were observed when only extreme estimates with differences based on study populations and/or adjustment covariates were compared. CONCLUSIONS: Most observational studies evaluating the impact of alcohol on breast cancer report relative effect estimates for the same associations that diverge by >2-fold. Therefore, observational studies should estimate the vibration of effects to provide insight regarding the stability of findings.

4.
Transl Oncol ; 13(1): 42-56, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31760268

RESUMO

Colon cancer is the third most commonly diagnosed cancer in the United States. Recent reports have shown that the location of the primary tumor is of clinical importance. Patients with right-sided colon cancers (RCCs) (tumors arising between the cecum and proximal transverse colon) have poorer clinical outcomes than those with left-sided colon cancers (LCCs) (tumors arising between the distal transverse colon and sigmoid colon, excluding the rectum). Interestingly, women have a lower incidence of colon cancer than men, but have a higher propensity for RCC. The reason for this difference is not known; however, identification of sex-specific differences in gene expression by tumor anatomical location in the colon could provide further insight. Moreover, it could reveal important predictive markers for response to various treatments. This study provides a comprehensive bioinformatic analysis of various genes and molecular pathways that correlated with sex and anatomical location of colon cancers using four publicly available annotated data sets housed in the National Center for Biotechnology Information's Gene Expression Omnibus. We identified differentially expressed genes in tumor tissues from women with RCC, which showed attenuated energy and nutrient metabolism when compared with women with LCC. Specifically, we showed the downregulation of 5' AMP-activated protein kinase alpha subunit (AMPKα) and anti-tumor immune responses in women with RCC. This difference was not seen when comparing tumor tissues from men with RCC to men with LCC. Therefore, women with RCC may have a specific metabolic and immune phenotype which accounts for differences in prognosis and treatment response.

5.
Hum Genomics ; 13(1): 61, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796115

RESUMO

Retinoic acid (RA) is a potent morphogen required for embryonic development. RA is formed in a multistep process from vitamin A (retinol); RA acts in a paracrine fashion to shape the developing eye and is essential for normal optic vesicle and anterior segment formation. Perturbation in RA-signaling can result in severe ocular developmental diseases-including microphthalmia, anophthalmia, and coloboma. RA-signaling is also essential for embryonic development and life, as indicated by the significant consequences of mutations in genes involved in RA-signaling. The requirement of RA-signaling for normal development is further supported by the manifestation of severe pathologies in animal models of RA deficiency-such as ventral lens rotation, failure of optic cup formation, and embryonic and postnatal lethality. In this review, we summarize RA-signaling, recent advances in our understanding of this pathway in eye development, and the requirement of RA-signaling for embryonic development (e.g., organogenesis and limb bud development) and life.

7.
BMC Med ; 17(1): 188, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639007

RESUMO

BACKGROUND: There is growing interest in evaluating differences in healthcare interventions across routinely collected demographic characteristics. However, individual subgroup analyses in randomized controlled trials are often not prespecified, adjusted for multiple testing, or conducted using the appropriate statistical test for interaction, and therefore frequently lack credibility. Meta-analyses can be used to examine the validity of potential subgroup differences by collating evidence across trials. Here, we characterize the conduct and clinical translation of age-treatment subgroup analyses in Cochrane reviews. METHODS: For a random sample of 928 Cochrane intervention reviews of randomized trials, we determined how often subgroup analyses of age are reported, how often these analyses have a P < 0.05 from formal interaction testing, how frequently subgroup differences first observed in an individual trial are later corroborated by other trials in the same meta-analysis, and how often statistically significant results are included in commonly used clinical management resources (BMJ Best Practice, UpToDate, Cochrane Clinical Answers, Google Scholar, and Google search). RESULTS: Among 928 Cochrane intervention reviews, 189 (20.4%) included plans to conduct age-treatment subgroup analyses. The vast majority (162 of 189, 85.7%) of the planned analyses were not conducted, commonly because of insufficient trial data. There were 22 reviews that conducted their planned age-treatment subgroup analyses, and another 3 reviews appeared to perform unplanned age-treatment subgroup analyses. These 25 (25 of 928, 2.7%) reviews conducted a total of 97 age-treatment subgroup analyses, of which 65 analyses (in 20 reviews) had non-overlapping subgroup levels. Among the 65 age-treatment subgroup analyses, 14 (21.5%) did not report any formal interaction testing. Seven (10.8%) reported P < 0.05 from formal age-treatment interaction testing; however, none of these seven analyses were in reviews that discussed the potential biological rationale or clinical significance of the subgroup findings or had results that were included in common clinical practice resources. CONCLUSION: Age-treatment subgroup analyses in Cochrane intervention reviews were frequently planned but rarely conducted, and implications of detected interactions were not discussed in the reviews or mentioned in common clinical resources. When subgroup analyses are performed, authors should report the findings, compare the results to previous studies, and outline any potential impact on clinical care.


Assuntos
Interpretação Estatística de Dados , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Projetos de Pesquisa , Literatura de Revisão como Assunto , Distribuição por Idade , Fatores Etários , Projetos de Pesquisa Epidemiológica , Estudos Epidemiológicos , Feminino , Humanos , Medicina de Precisão/métodos , Medicina de Precisão/estatística & dados numéricos , Projetos de Pesquisa/normas , Projetos de Pesquisa/estatística & dados numéricos
8.
Sci Total Environ ; 690: 853-866, 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31302550

RESUMO

1,4-Dioxane has historically been used to stabilize chlorinated solvents and more recently has been found as a contaminant of numerous consumer and food products. Once discharged into the environment, its physical and chemical characteristics facilitate migration in groundwater, resulting in widespread contamination of drinking water supplies. Over one-fifth of U.S. public drinking water supplies contain detectable levels of 1,4-dioxane. Remediation efforts using common adsorption and membrane filtration techniques have been ineffective, highlighting the need for alternative removal approaches. While the data evaluating human exposure and health effects are limited, animal studies have shown chronic exposure to cause carcinogenic responses in the liver across multiple species and routes of exposure. Based on this experimental evidence, the U.S. Environmental Protection Agency has listed 1,4-dioxane as a high priority chemical and classified it as a probable human carcinogen. Despite these health concerns, there are no federal or state maximum contaminant levels for 1,4-dioxane. Effective public health policy for this emerging contaminant requires additional information about human health effects, chemical interactions, environmental fate, analytical detection, and treatment technologies. This review highlights the current state of knowledge, key uncertainties, and data needs for future research on 1,4-dioxane.

9.
Free Radic Biol Med ; 143: 127-139, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31351176

RESUMO

Depletion of glutathione (GSH) is considered a critical pathogenic event promoting alcohol-induced lipotoxicity. We recently show that systemic GSH deficiency in mice harboring a global disruption of the glutamate-cysteine ligase modifier subunit (Gclm) gene confers protection against alcohol-induced steatosis. While several molecular pathways have been linked to the observed hepatic protection, including nuclear factor erythroid 2-related factor 2 and AMP-activated protein kinase pathways, the precise mechanisms are yet to be defined. In this study, to gain insights into the molecular mechanisms underpinning the protective effects of loss of GCLM, global profiling of hepatic polar metabolites combined with liver microarray analysis was carried out. These inter-omics analyses revealed both low GSH- and alcohol-driven changes in multiple cellular pathways involving the metabolism of amino acids, fatty acid, glucose and nucleic acids. Notably, several metabolic changes were uniquely present in alcohol-treated Gclm-null mouse livers, including acetyl-CoA enrichment and diversion of acetyl-CoA flux from lipogenesis to alterative metabolic pathways, elevation in glutamate concentration, and induction of the glucuronate pathway and nucleotide biosynthesis. These metabolic features reflect low GSH-elicited cellular response to chronic alcohol exposure, which is beneficial for the maintenance of hepatic redox and metabolic homeostasis. The current study indicates that fine-tuning of hepatic GSH pool may evoke metabolic reprogramming to cope with alcohol-induced cellular stress.

10.
Environ Int ; 131: 104969, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31310931

RESUMO

Environmental and occupational exposure to industrial chemicals has been linked to toxic and carcinogenic effects in animal models and human studies. However, current toxicology testing does not thoroughly explore the endocrine disrupting effects of industrial chemicals, which may have low dose effects not predicted when determining the limit of toxicity. The objective of this study was to evaluate the endocrine disrupting potential of a broad range of chemicals used in the petrochemical sector. Therefore, 139 chemicals were classified for reproductive toxicity based on the United Nations Globally Harmonized System for hazard classification. These chemicals were evaluated in PubMed for reported endocrine disrupting activity, and their endocrine disrupting potential was estimated by identifying chemicals with active nuclear receptor endpoints publicly available databases. Evaluation of ToxCast data suggested that these chemicals preferentially alter the activity of the estrogen receptor (ER). Four chemicals were prioritized for in vitro testing using the ER-positive, immortalized human uterine Ishikawa cell line and a range of concentrations below the reported limit of toxicity in humans. We found that 2,6-di-tert-butyl-p-cresol (BHT) and diethanolamine (DEA) repressed the basal expression of estrogen-responsive genes PGR, NPPC, and GREB1 in Ishikawa cells, while tetrachloroethylene (PCE) and 2,2'-methyliminodiethanol (MDEA) induced the expression of these genes. Furthermore, low-dose combinations of PCE and MDEA produced additive effects. All four chemicals interfered with estradiol-mediated induction of PGR, NPPC, and GREB1. Molecular docking demonstrated that these chemicals could bind to the ligand binding site of ERα, suggesting the potential for direct stimulatory or inhibitory effects. We found that these chemicals altered rates of proliferation and regulated the expression of cell proliferation associated genes. These findings demonstrate previously unappreciated endocrine disrupting effects and underscore the importance of testing the endocrine disrupting potential of chemicals in the future to better understand their potential to impact public health.


Assuntos
Bases de Dados Factuais , Disruptores Endócrinos/farmacologia , Poluentes Ambientais/farmacologia , Simulação de Acoplamento Molecular , Animais , Disruptores Endócrinos/química , Poluentes Ambientais/química , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos
11.
J Biol Chem ; 294(18): 7231-7244, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30872403

RESUMO

Ethanol causes dysregulated muscle protein homeostasis while simultaneously causing hepatocyte injury. Because hepatocytes are the primary site for physiological disposal of ammonia, a cytotoxic cellular metabolite generated during a number of metabolic processes, we determined whether hyperammonemia aggravates ethanol-induced muscle loss. Differentiated murine C2C12 myotubes, skeletal muscle from pair-fed or ethanol-treated mice, and human patients with alcoholic cirrhosis and healthy controls were used to quantify protein synthesis, mammalian target of rapamycin complex 1 (mTORC1) signaling, and autophagy markers. Alcohol-metabolizing enzyme expression and activity in mouse muscle and myotubes and ureagenesis in hepatocytes were quantified. Expression and regulation of the ammonia transporters, RhBG and RhCG, were quantified by real-time PCR, immunoblots, reporter assays, biotin-tagged promoter pulldown with proteomics, and loss-of-function studies. Alcohol and aldehyde dehydrogenases were expressed and active in myotubes. Ethanol exposure impaired hepatocyte ureagenesis, induced muscle RhBG expression, and elevated muscle ammonia concentrations. Simultaneous ethanol and ammonia treatment impaired protein synthesis and mTORC1 signaling and increased autophagy with a consequent decreased myotube diameter to a greater extent than either treatment alone. Ethanol treatment and withdrawal followed by ammonia exposure resulted in greater impairment in muscle signaling and protein synthesis than ammonia treatment in ethanol-naive myotubes. Of the three transcription factors that were bound to the RhBG promoter in response to ethanol and ammonia, DR1/NC2 indirectly regulated transcription of RhBG during ethanol and ammonia treatment. Direct effects of ethanol were synergistic with increased ammonia uptake in causing dysregulated skeletal muscle proteostasis and signaling perturbations with a more severe sarcopenic phenotype.


Assuntos
Amônia/metabolismo , Etanol/farmacologia , Músculo Esquelético/efeitos dos fármacos , Animais , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hiperamonemia/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Proteostase/efeitos dos fármacos , Transdução de Sinais , Ureia/metabolismo
12.
Chem Biol Interact ; 304: 168-172, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30894314

RESUMO

ALDH16 is a novel family of the aldehyde dehydrogenase (ALDH) superfamily with unique structural characteristics that distinguish it from the other ALDH superfamily members. In addition to structural characteristics, there is an evolutionary-related grouping within the ALDH 16 genes. The ALDH16 isozymes in frog, lower animals, and bacteria possess a critical Cys residue in their active site, which is absent from ALDH16 in mammals and fish. Genomic analysis and plasma metabolomic studies have associated ALDH16A1 with the pathogenesis of gout in humans, although its actual involvement in this disease is poorly understood. Insight into the structure of ALDH16A1 is an important step in deciphering its function in gout. Herein, we report our efforts towards the structural characterization of Xenopus tropicalis ALDH16B1 (the homolog of human ALDH16A1) that was predicted to be catalytically-active. Recombinant ALDH16B1 was expressed in Sf9 cells and purified using affinity and size exclusion chromatography. Crystallization of ALDH16B1 was achieved by vapor diffusion. A data set was collected at 2.5 Šand preliminary crystallographic analysis showed that the frog ALDH16B1 crystals belong to the P 212 121 space group with unit cell parameters a = 80.48 Å, b = 89.73 Å, c = 190.92 Å, α = ß = γ = 90.00°. Structure determination is currently in progress.


Assuntos
Proteínas de Xenopus , Xenopus , Aldeído Desidrogenase/química , Aldeído Desidrogenase/metabolismo , Animais , Biocatálise , Cromatografia em Gel , Cristalografia por Raios X , Humanos , Modelos Moleculares , Conformação Proteica , Proteínas de Xenopus/química , Proteínas de Xenopus/genética , Proteínas de Xenopus/isolamento & purificação
13.
Psychol Assess ; 31(7): 895-904, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30896210

RESUMO

The success of acceptance and commitment therapy (ACT) in improving life functioning among chronic pain patients is followed by an interest in investigating mechanisms of action via which it unfolds and validating measures to assess its key constructs. The Psychological Inflexibility in Pain Scale (PIPS-II) assesses pain avoidance and fusion. This is the first study to examine the measurement models of this instrument's Greek adaptation (G-PIPS-II) in patients with different pain localizations (i.e., chronic and headache). A community heterogeneous sample of chronic pain sufferers (N = 156) and two clinical samples comprising treatment-seeking chronic pain patients (N = 149) and treatment-seeking headache patients (N = 89) were recruited from nongovernmental chronic pain support organizations and primary care centers. Exploratory and confirmatory factor analyses demonstrated an acceptable model fit of the G-PIPS-II yielding a two-factor model: avoidance (8 items) and cognitive fusion (4 items). Moderate to high correlations with theoretically related measures supported its construct validity; reliability was high for the total scale and the Avoidance subscale and medium for the Cognitive Fusion subscale. Weak measurement invariance was established across the three pain groups, suggesting that regardless of pain localization, chronic pain and headache patients understand the two latent factors in a similar way. G-PIPS-II is a psychometrically sound instrument assessing two constructs targeted for change within ACT and is deemed a conceptually meaningful scale with items having similar meanings for patients with different pain localization. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Dor Crônica/diagnóstico , Dor Crônica/psicologia , Medição da Dor/métodos , Medição da Dor/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Fatorial , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos Testes , Tradução , Adulto Jovem
15.
Chem Biol Interact ; 302: 61-66, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30721697

RESUMO

Alcohol induces various cutaneous changes, such as palmar erythema and jaundice. However, alcohol-induced skin hyperpigmentation due to melanin deposition has not been reported. Aldehyde dehydrogenase 2 (ALDH2), one of 19 human ALDH isozymes, metabolizes endogenous and exogenous aldehydes to their respective carboxylic acids. Reduced ALDH2 greatly affects acetaldehyde metabolism, leading to its accumulation in the body after the consumption of alcohol and the consequent development of a wide range of phenotypes. In the present study, we report a novel phenotype manifesting in a mouse model with the altered expression of ALDH2. Aldh2 knockout (Aldh2+/- and Aldh2-/-) and wild-type (Aldh2+/+) mice were fed a standard solid rodent chow and a bottle of ethanol solution at concentrations of 0%, 3%, 10%, or 20% (v/v) for more than 10 weeks. The intensity of their skin pigmentation was evaluated by macroscopic observation. Ethanol-exposed Aldh2+/- and Aldh2-/- mice exhibited dose-dependent skin pigmentation in areas of hairless skin, including the soles of the paws and tail; no such changes were observed in wild-type mice. The intensity of skin pigmentation correlated with the number of Aldh2 alleles that were altered in the mice (i.e., 0, 1 and 2 for Aldh2+/+, Aldh2+/-, Aldh2-/-, respectively). Interestingly, the skin pigmentation changes reversed upon the discontinuation of ethanol. The histological examination of the pigmented skin demonstrated the presence of melanin-like deposits, mainly in the epidermis. In conclusion, we report a novel finding that the intake of ethanol induces skin hyperpigmentation in an ALDH2 activity-dependent manner.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Hiperpigmentação/patologia , Aldeído-Desidrogenase Mitocondrial/deficiência , Animais , Modelos Animais de Doenças , Etanol/toxicidade , Feminino , Hiperpigmentação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Pele/patologia , Cauda/patologia
16.
Hum Genomics ; 13(1): 11, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782214

RESUMO

Lipocalins (LCNs) are members of a family of evolutionarily conserved genes present in all kingdoms of life. There are 19 LCN-like genes in the human genome, and 45 Lcn-like genes in the mouse genome, which include 22 major urinary protein (Mup) genes. The Mup genes, plus 29 of 30 Mup-ps pseudogenes, are all located together on chromosome (Chr) 4; evidence points to an "evolutionary bloom" that resulted in this Mup cluster in mouse, syntenic to the human Chr 9q32 locus at which a single MUPP pseudogene is located. LCNs play important roles in physiological processes by binding and transporting small hydrophobic molecules -such as steroid hormones, odorants, retinoids, and lipids-in plasma and other body fluids. LCNs are extensively used in clinical practice as biochemical markers. LCN-like proteins (18-40 kDa) have the characteristic eight ß-strands creating a barrel structure that houses the binding-site; LCNs are synthesized in the liver as well as various secretory tissues. In rodents, MUPs are involved in communication of information in urine-derived scent marks, serving as signatures of individual identity, or as kairomones (to elicit fear behavior). MUPs also participate in regulation of glucose and lipid metabolism via a mechanism not well understood. Although much has been learned about LCNs and MUPs in recent years, more research is necessary to allow better understanding of their physiological functions, as well as their involvement in clinical disorders.


Assuntos
Evolução Molecular , Lipocalinas/genética , Animais , Genoma Humano , Humanos , Lipocalinas/metabolismo , Camundongos , Família Multigênica
17.
Chem Biol Interact ; 303: 1-6, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30794799

RESUMO

Glutathione (GSH), the most abundant cellular non-protein thiol, plays a pivotal role in hepatic defense mechanisms against oxidative damage. Despite a strong association between disrupted GSH homeostasis and liver diseases of various etiologies, it was shown that GSH-deficient glutamate-cysteine ligase modifier subunit (Gclm)-null mice are protected against fatty liver development induced by a variety of dietary and environmental insults. The biochemical mechanisms underpinning this protective phenotype have not been clearly defined. The purpose of the current study was to characterize the intrinsic metabolic signature in the livers from GSH deficient Gclm-null mice. Global profiling of hepatic polar metabolites revealed a spectrum of changes in amino acids and metabolites derived from fatty acids, glucose and nucleic acids due to the loss of GCLM. Overall, the observed low GSH-driven metabolic changes represent metabolic adaptations, including elevations in glutamate, aspartate, acetyl-CoA and gluconate, which are beneficial for the maintenance of cellular redox and metabolic homeostasis.


Assuntos
Glutationa/deficiência , Fígado/metabolismo , Animais , Modelos Animais de Doenças , Fígado Gorduroso , Glutamato-Cisteína Ligase/deficiência , Glutamato-Cisteína Ligase/genética , Homeostase , Metabolômica , Camundongos , Camundongos Knockout , Oxirredução
18.
Environ Res ; 169: 163-172, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30458352

RESUMO

Currently, there are >11,000 synthetic turf athletic fields in the United States and >13,000 in Europe. Concerns have been raised about exposure to carcinogenic chemicals resulting from contact with synthetic turf fields, particularly the infill material ("crumb rubber"), which is commonly fabricated from recycled tires. However, exposure data are scant, and the limited existing exposure studies have focused on a small subset of crumb rubber components. Our objective was to evaluate the carcinogenic potential of a broad range of chemical components of crumb rubber infill using computational toxicology and regulatory agency classifications from the United States Environmental Protection Agency (US EPA) and European Chemicals Agency (ECHA) to inform future exposure studies and risk analyses. Through a literature review, we identified 306 chemical constituents of crumb rubber infill from 20 publications. Utilizing ADMET Predictor™, a computational program to predict carcinogenicity and genotoxicity, 197 of the identified 306 chemicals met our a priori carcinogenicity criteria. Of these, 52 chemicals were also classified as known, presumed or suspected carcinogens by the US EPA and ECHA. Of the remaining 109 chemicals which were not predicted to be carcinogenic by our computational toxicology analysis, only 6 chemicals were classified as presumed or suspected human carcinogens by US EPA or ECHA. Importantly, the majority of crumb rubber constituents were not listed in the US EPA (n = 207) and ECHA (n = 262) databases, likely due to an absence of evaluation or insufficient information for a reliable carcinogenicity classification. By employing a cancer hazard scoring system to the chemicals which were predicted and classified by the computational analysis and government databases, several high priority carcinogens were identified, including benzene, benzidine, benzo(a)pyrene, trichloroethylene and vinyl chloride. Our findings demonstrate that computational toxicology assessment in conjunction with government classifications can be used to prioritize hazardous chemicals for future exposure monitoring studies for users of synthetic turf fields. This approach could be extended to other compounds or toxicity endpoints.


Assuntos
Carcinógenos , Exposição Ambiental , Borracha , Elastômeros , Europa (Continente) , Humanos , Compostos Orgânicos , Estados Unidos
19.
Adv Exp Med Biol ; 1032: 37-53, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30362089

RESUMO

Glutathione (GSH) is the most abundant non-protein thiol, attaining cellular concentrations in the millimolar range. GSH functions to protect cells against endogenous and exogenous electrophiles. In addition, GSH serves as a cofactor for the GSH peroxidase family of enzymes which metabolize H2O2 as well as lipid peroxides. Through the action of glutathione S-transferase family of enzymes, GSH is conjugated to a variety of electrophilic endogenous compounds and exogenous chemicals, and thereby facilitates their efficient and safe elimination. Through the transsulfuration pathway, GSH biosynthesis is metabolically linked with cellular methylation, which is pivotal for epigenetic gene regulation. Accumulating evidence suggests that the underlying mechanisms of alcohol-associated tissue injury and carcinogenesis involve: (i) generation of the electrophilic metabolite acetaldehyde, (ii) induction of CYP2E1 leading to the formation of reactive oxygen species and pro-carcinogen activation, and (iii) nutritional deficiencies, such as methyl groups, resulting in enhanced susceptibility to cancer development. In this context, clinical and experimental investigations suggest an intimate involvement of GSH and related enzymes in the development of alcohol-induced pathological conditions. The aim of this review is to provide an overview of the GSH biosynthesis, cellular transsulfuration/transmethylation pathways, and their implications in the pathogenesis and treatment of alcohol-related disease and cancer.


Assuntos
Carcinogênese/induzido quimicamente , Etanol/efeitos adversos , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Metilação , Espécies Reativas de Oxigênio/metabolismo
20.
Adv Exp Med Biol ; 1032: 203-221, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30362100

RESUMO

Excessive consumption of alcohol is a leading cause of lifestyle-induced morbidity and mortality worldwide. Although long-term alcohol abuse has been shown to be detrimental to the liver, brain and many other organs, our understanding of the exact molecular mechanisms by which this occurs is still limited. In tissues, ethanol is metabolized to acetaldehyde (mainly by alcohol dehydrogenase and cytochrome p450 2E1) and subsequently to acetic acid by aldehyde dehydrogenases. Intracellular generation of free radicals and depletion of the antioxidant glutathione (GSH) are believed to be key steps involved in the cellular pathogenic events caused by ethanol. With continued excessive alcohol consumption, further tissue damage can result from the production of cellular protein and DNA adducts caused by accumulating ethanol-derived aldehydes. Much of our understanding about the pathophysiological consequences of ethanol metabolism comes from genetically-engineered mouse models of ethanol-induced tissue injury. In this review, we provide an update on the current understanding of important mouse models in which ethanol-metabolizing and GSH-synthesizing enzymes have been manipulated to investigate alcohol-induced disease.


Assuntos
Modelos Animais de Doenças , Etanol/metabolismo , Neoplasias/induzido quimicamente , Acetaldeído/metabolismo , Álcool Desidrogenase/metabolismo , Animais , Citocromo P-450 CYP2E1/metabolismo , Etanol/toxicidade , Camundongos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA