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1.
Sci Rep ; 9(1): 14675, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604971

RESUMO

Exposure to the environmental toxicant cadmium (Cd) contributes to the development of obesity-associated diseases. Obesity is a risk factor for a spectrum of unhealthy conditions including systemic metabolic dyshomeostasis. In the present study, the effects of whole-life exposure to environmentally-relevant concentrations of Cd on systemic essential metal distribution in adult mice fed a high-fat diet (HFD) were examined. For these studies, male and female mice were exposed to Cd-containing drinking water for >2 weeks before breeding. Pregnant mice and dams with offspring were exposed to Cd-containing drinking water. After weaning, offspring were continuously exposed to the same Cd concentration as their parents, and divided into HFD and normal (low) fat diet (LFD) groups. At 10 and 24 weeks, mice were sacrificed and blood, liver, kidney and heart harvested for metal analyses. There were significant concentration dependent increases in Cd levels in offspring with kidney > liver > heart. Sex significantly affected Cd levels in kidney and liver, with female animals accumulating more metal than males. Mice fed the HFD showed > 2-fold increase in Cd levels in the three organs compared to similarly treated LFD mice. Cadmium significantly affected essential metals levels in blood, kidney and liver. Additionally, HFD affected essential metal levels in these three organs. These findings suggest that Cd interacts with HFD to affect essential metal homeostasis, a phenomenon that may contribute to the underlying mechanism responsible for the development of obesity-associated pathologies.

2.
J Neuroinflammation ; 16(1): 188, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623610

RESUMO

BACKGROUND: The glial response in multiple sclerosis (MS), especially for recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), predicts the success of remyelination of MS plaques and return of function. As a central player in neuroinflammation, activation and polarization of microglia/macrophages (M/M) that modulate the inflammatory niche and cytokine components in demyelination lesions may impact the OPC response and progression of demyelination and remyelination. However, the dynamic behaviors of M/M and OPCs during demyelination and spontaneous remyelination are poorly understood, and the complex role of neuroinflammation in the demyelination-remyelination process is not well known. In this study, we utilized two focal demyelination models with different dynamic patterns of M/M to investigate the correlation between M/M polarization and the demyelination-remyelination process. METHODS: The temporal and spatial features of M/M activation/polarization and OPC response in two focal demyelination models induced by lysolecithin (LPC) and lipopolysaccharide (LPS) were examined in mice. Detailed discrimination of morphology, sensorimotor function, diffusion tensor imaging (DTI), inflammation-relevant cytokines, and glial responses between these two models were analyzed at different phases. RESULTS: The results show that LPC and LPS induced distinctive temporal and spatial lesion patterns. LPS produced diffuse demyelination lesions, with a delayed peak of demyelination and functional decline compared to LPC. Oligodendrocytes, astrocytes, and M/M were scattered throughout the LPS-induced demyelination lesions but were distributed in a layer-like pattern throughout the LPC-induced lesion. The specific M/M polarization was tightly correlated to the lesion pattern associated with balance beam function. CONCLUSIONS: This study elaborated on the spatial and temporal features of neuroinflammation mediators and glial response during the demyelination-remyelination processes in two focal demyelination models. Specific M/M polarization is highly correlated to the demyelination-remyelination process probably via modulations of the inflammatory niche, cytokine components, and OPC response. These findings not only provide a basis for understanding the complex and dynamic glial phenotypes and behaviors but also reveal potential targets to promote/inhibit certain M/M phenotypes at the appropriate time for efficient remyelination.

3.
Stat Med ; 38(15): 2828-2846, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30941812

RESUMO

In observational studies, generalized propensity score (GPS)-based statistical methods, such as inverse probability weighting (IPW) and doubly robust (DR) method, have been proposed to estimate the average treatment effect (ATE) among multiple treatment groups. In this article, we investigate the GPS-based statistical methods to estimate treatment effects from two aspects. The first aspect of our investigation is to obtain an optimal GPS estimation method among four competing GPS estimation methods by using a rank aggregation approach. We further examine whether the optimal GPS-based IPW and DR methods would improve the performance for estimating ATE. It is well known that the DR method is consistent if either the GPS or the outcome models are correctly specified. The second aspect of our investigation is to examine whether the DR method could be improved if we ensemble outcome models. To that end, bootstrap method and rank aggregation method are used to obtain the ensemble optimal outcome model from several competing outcome models, and the resulting outcome model is incorporated into the DR method, resulting in an ensemble DR (enDR) method. Extensive simulation results indicate that the enDR method provides the best performance in estimating the ATE regardless of the method used for estimating GPS. We illustrate our methods using the MarketScan healthcare insurance claims database to examine the treatment effects among three different bones and substitutes used for spinal fusion surgeries. We draw conclusions based on the estimates from the enDR method coupled with the optimal GPS estimation method.

4.
Chem Res Toxicol ; 32(6): 1070-1081, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-30912652

RESUMO

Childhood obesity, which is prevalent in developed countries, is a metabolic risk factor for cardiovascular disease. Cadmium (Cd), a ubiquitous environmental toxic metal, also has deleterious effects on the cardiovascular system. However, the combined effects of a high-fat diet (HFD) and lifelong, low-dose Cd exposure on cardiac remodeling remain unclear. This study aims to determine the effects of combined HFD and Cd exposure on cardiac remodeling, as well as gender-specific differences in the response. C57BL/6J mice were exposed to Cd at a low dose (L-Cd, 0.5 ppm) or high dose (H-Cd, 5 ppm) via drinking water from conception to sacrifice. After being weaned, the offspring mice were fed with a HFD (42% kcal from fat) for an additional 10 weeks. H-Cd exposure significantly increased Cd accumulation in the hearts of both parents and their offspring; a HFD showed no added effects on cardiac Cd content. H-Cd exposure increased cardiac metallothionein protein levels only in female mice, regardless of dietary intake. Histological analysis revealed that H-Cd exposure combined with a HFD induced cardiac hypertrophy and fibrosis only in female mice. This was further supported by elevated expression of ANP and COL1A1 protein levels along with COL1A1, COL1A2, and COL3A1 mRNA levels. Profibrotic markers PAI-1, CTGF, and FN were also elevated in HFD/H-Cd-exposed female mice. Levels of the oxidative stress marker 3-NT significantly increased in the hearts of HFD-fed female mice, whereas Cd exposure showed no additional effects. Of all the antioxidant markers examined, levels of CAT significantly increased in mice fed a HFD, regardless of gender and Cd exposure. In summary, a HFD combined with lifelong, low-dose Cd exposure induces cardiac hypertrophy and fibrosis in female but not male mice, a response that is independent of oxidative stress.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30234998

RESUMO

Alcohol-associated liver disease (ALD) remains a major health concern worldwide. Alcohol consumption gives rise to reactive/toxic acrolein, a pathogenic mediator of liver injury in experimental ALD. Elevated acrolein adducts and metabolites are detectable in blood and urine. This study evaluates the major urinary acrolein metabolite, 3-hydroxypropylmercapturic acid (HPMA), in patients with acute alcoholic hepatitis (AAH), and examines its association with disease severity, and markers of hepatic inflammation and injury. Urine HPMA was significantly higher in severe (MELD≥20) AAH patients compared to non-severe AAH (MELD≤19), or non-alcohol-consuming controls, suggesting that urine HPMA is a novel non-invasive biomarker in severe AAH. The association between HPMA and MELD in AAH patients was nonlinear. In non-severe patients, there was a positive trend, although not significant, while in severe AAH the association was negative, indicative of extensive injury and glutathione depletion. Consistent with the multifactorial etiology of ALD, our data identified strong combined effects of HPMA and proinflammatory cytokines on hepatocyte cell death, thereby supporting the pathogenic role of acrolein in liver injury. HPMA, together with IL-1ß, showed robust associations with CK18-M30 (adjusted R2=0.812, p=0.016) and CK18-M65 (adjusted R2=0.670, p=0.048); similarly HPMA, with IL-8, correlated with CK18-M30 (adjusted R2=0.875, p=0.007) and CK18-M65 (adjusted R2=0.831, p=0.013). The apoptosis index (CK18-M30:CK18-M65 ratio) strongly correlated with HPMA, together with IL-1ß (adjusted R2=0.777, p=0.022) or TNFα (adjusted R2=0.677, p=0.046). In severe AAH patients, IL-1ß, IL-8 and TNFα are the predominant proinflammatory cytokines that interact with HPMA, and play important mediating roles in influencing the extent/pattern of liver cell death.

7.
Cell Metab ; 28(5): 689-705.e5, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30100196

RESUMO

It is clear that obesity increases the risk of many types of cancer, including breast cancer. However, the underlying molecular mechanisms by which obesity is linked to cancer risk remain to be defined. Herein, we report that circulating adipose fatty acid binding protein (A-FABP) promotes obesity-associated breast cancer development. Using clinical samples, we demonstrated that circulating A-FABP levels were significantly increased in obese patients with breast cancer in comparison with those without breast cancer. Circulating A-FABP released by adipose tissue directly targeted mammary tumor cells, enhancing tumor stemness and aggressiveness through activation of the IL-6/STAT3/ALDH1 pathway. Importantly, genetic deletion of A-FABP successfully reduced tumor ALHD1 activation and obesity-associated mammary tumor growth and development in different mouse models. Collectively, these data suggest circulating A-FABP as a new link between obesity and breast cancer risk, thereby revealing A-FABP as a potential new therapeutic target for treatment of obesity-associated cancers.

8.
J Nutr Biochem ; 59: 49-55, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29960116

RESUMO

Zinc deficiency is a frequent complication of alcohol abuse for multiple reasons including poor intake, increased excretion, internal redistribution and altered transporters. Zinc deficiency has been postulated to play a role in the development/progression of alcoholic liver disease (ALD). This study aimed to relate serum zinc levels with alcohol intake, serum albumin concentration and markers of inflammation and liver injury. One hundred and eight male and female very heavy drinking (≥10 drinks/day) individuals without clinical evidence of ALD were grouped by serum zinc concentration: normal-zinc group (zinc level≥71 µg/dl) included 67 patients, and low-zinc group (zinc level<71 µg/dl) included 41 patients. Data were collected on demographics, drinking history in last 90 days (heavy drinking days, HDD90 and total drinks, TD90), lifetime drinking history (LTDH) and clinical/ laboratory assessments. Our data show that in a very well-characterized, chronically heavy-drinking population without clinical evidence of liver disease, about 40% of subjects had low serum zinc levels. Frequency of heavy drinking days (HDD90) was significantly higher in the low-zinc group. Total drinks in past 90 days, LTDH and HDD90 showed significant associations with low zinc levels. The group with the low serum zinc had a higher aspartate aminotransferase/alanine aminotransferase ratio (good marker of alcoholic liver disease). Those in the low-zinc group had the lower albumin levels, a marker of hepatic synthetic function, and the highest C-reactive protein level, a biomarker of inflammation.

9.
Stat Med ; 37(23): 3357-3372, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-29923344

RESUMO

Multisample U-statistics encompass a wide class of test statistics that allow the comparison of 2 or more distributions. U-statistics are especially powerful because they can be applied to both numeric and nonnumeric data, eg, ordinal and categorical data where a pairwise similarity or distance-like measure between categories is available. However, when comparing the distribution of a variable across 2 or more groups, observed differences may be due to confounding covariates. For example, in a case-control study, the distribution of exposure in cases may differ from that in controls entirely because of variables that are related to both exposure and case status and are distributed differently among case and control participants. We propose to use individually reweighted data (ie, using the stratification score for retrospective data or the propensity score for prospective data) to construct adjusted U-statistics that can test the equality of distributions across 2 (or more) groups in the presence of confounding covariates. Asymptotic normality of our adjusted U-statistics is established and a closed form expression of their asymptotic variance is presented. The utility of our approach is demonstrated through simulation studies, as well as in an analysis of data from a case-control study conducted among African-Americans, comparing whether the similarity in haplotypes (ie, sets of adjacent genetic loci inherited from the same parent) occurring in a case and a control participant differs from the similarity in haplotypes occurring in 2 control participants.

10.
J Cardiothorac Vasc Anesth ; 32(3): 1185-1190, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29158058

RESUMO

OBJECTIVE: Left ventricular assist device (LVAD) surgery is complex, high risk, and expensive. The authors' hypothesis is baseline regional cerebral oxygen saturation (rSO2) might be a predictor of postoperative clinical outcomes. DESIGN: Retrospective review of 210 consecutive continuous flow LVAD patients between 2008 and 2014. The primary measure is 30-day mortality rate and secondary measures include modified major adverse cardiocerebral events (MACE), length of stay (LOS), and intensive care unit (ICU) stay. Multiple logistic regression models were applied to examine if a binary outcome variable, such as 30-day mortality and MACE, is associated with rSO2 at baseline. Log-linear model was used to examine whether LOS or ICU stay hours is associated with rSO2 at baseline. SETTING: Single institution, academic hospital. PARTICIPANTS: Patients who received LVAD surgery ​at Jewish Hospital, Louisville, KY. INTERVENTIONS: All patients received LVAD surgery. Cerebral oximetry monitoring was used in both the preoperative and intraoperative periods. MEASUREMENTS AND MAIN RESULTS: The authors found that higher rSO2 at baseline is associated with lower 30-day mortality with an odds ratio of 0.94 and 95% confidence interval (0.888, 0.995) for every 1% increase of rSO2. For secondary outcomes, baseline rSO2 was not significantly associated with MACE, requirement for postoperative renal failure/dialysis, reoperation for bleeding, and LOS or ICU hours. CONCLUSIONS: Regional cerebral oxygen saturation levels at baseline are significantly associated with 30-day mortality after LVAD surgeries.


Assuntos
Circulação Cerebrovascular/fisiologia , Coração Auxiliar/tendências , Consumo de Oxigênio/fisiologia , Complicações Pós-Operatórias/mortalidade , Adulto , Idoso , Feminino , Coração Auxiliar/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/metabolismo , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Tempo
11.
Biometrics ; 74(1): 331-341, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28742267

RESUMO

Phosphorylated proteins provide insight into tumor etiology and are used as diagnostic, prognostic, and therapeutic markers of complex diseases. However, pre-analytic variations, such as freezing delay after biopsy acquisition, often occur in real hospital settings and potentially lead to inaccurate results. The objective of this work is to develop statistical methodology to assess the stability of phosphorylated proteins under short-time cold ischemia. We consider a hierarchical model to determine if phosphorylation abundance of a protein at a particular phosphorylation site remains constant or not during cold ischemia. When phosphorylation levels vary across time, we estimate the direction of the changes in each protein based on the maximum overall posterior probability and on the pairwise posterior probabilities, respectively. We analyze a dataset of ovarian tumor tissues that suffered cold-ischemia shock before the proteomic profiling. Gajadhar et al. (2015) applied independent clusterings for each patient because of the high heterogeneity across patients, while our proposed model shares information allowing conclusions for the entire sample population. Using the proposed model, 15 out of 32 proteins show significant changes during 1-hour cold ischemia. Through simulation studies, we conclude that our proposed methodology has a higher accuracy for detecting changes compared to an order restricted inference method. Our approach provides inference on the stability of these phosphorylated proteins, which is valuable when using these proteins as biomarkers for a disease.

12.
Biom J ; 59(5): 967-985, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28436047

RESUMO

Propensity score based statistical methods, such as matching, regression, stratification, inverse probability weighting (IPW), and doubly robust (DR) estimating equations, have become popular in estimating average treatment effect (ATE) and average treatment effect among treated (ATT) in observational studies. Propensity score is the conditional probability receiving a treatment assignment with given covariates, and propensity score is usually estimated by logistic regression. However, a misspecification of the propensity score model may result in biased estimates for ATT and ATE. As an alternative, the generalized boosting method (GBM) has been proposed to estimate the propensity score. GBM uses regression trees as weak predictors and captures nonlinear and interactive effects of the covariate. For GBM-based propensity score, only IPW methods have been investigated in the literature. In this article, we provide a comparative study of the commonly used propensity score based methods for estimating ATT and ATE, and examine their performances when propensity score is estimated by logistic regression and GBM, respectively. Extensive simulation results indicate that the estimators for ATE and ATT may vary greatly due to different methods. We concluded that (i) regression may not be suitable for estimating ATE and ATT regardless of the estimation method of propensity score; (ii) IPW and stratification usually provide reliable estimates of ATT when propensity score model is correctly specified; (iii) the estimators of ATE based on stratification, IPW, and DR are close to the underlying true value of ATE when propensity score is correctly specified by logistic regression or estimated using GBM.


Assuntos
Biometria/métodos , Modelos Estatísticos , Simulação por Computador , Modelos Logísticos , Pontuação de Propensão
13.
Stat Med ; 36(4): 655-670, 2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-27804146

RESUMO

Although single-index models have been extensively studied, the monotonicity of the link function f in the single-index model is rarely studied. In many situations, it is desirable that f is monotonic, which results in a monotonic single-index model that can be very useful in economics and biometrics. In this article, we propose a monotonic single-index model in which the link function is constructed using penalized I-splines along with constraints on coefficients to achieve monotonicity of the link function f. An algorithm to estimate the single-index parameters and the link function is developed, and the sandwich estimate of the variance of the index parameters is provided. We propose to apply this monotonic single-index model to estimate the dose-response surface and assess drug interactions while considering the variability of the observed data. An extensive simulation study was carried out to evaluate the performance of the proposed monotonic single-index model. A case study is provided to illustrate the application of the proposed model to estimate the dose-response surface and assess drug interactions. Both the simulation and case study show that the proposed monotonic single-index model works very well. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Interações de Medicamentos , Modelos Estatísticos , Algoritmos , Relação Dose-Resposta a Droga , Humanos , Estatística como Assunto
14.
Toxicol Appl Pharmacol ; 324: 61-72, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27592100

RESUMO

Acrolein is a highly toxic, volatile, unsaturated aldehyde generated during incomplete combustion as in tobacco smoke and indoor fires. Because the transient receptor potential ankyrin 1 (TRPA1) channel mediates tobacco smoke-induced lung injury, we assessed its role in high-level acrolein-induced toxicity in mice. Acrolein (100-275ppm, 10-30min) caused upper airway epithelial sloughing, bradypnea and oral gasping, hypothermia, cardiac depression and mortality. Male wild-type mice (WT, C57BL/6; 5-52weeks) were significantly more sensitive to high-level acrolein than age-matched, female WT mice. Both male and female TRPA1-null mice were more sensitive to acrolein-induced mortality than age- and sex-matched WT mice. Acrolein exposure increased lung weight:body weight ratios and lung albumin and decreased plasma albumin to a greater extent in TRPA1-null than in WT mice. Lung and plasma protein-acrolein adducts were not increased in acrolein-exposed TRPA1-null mice compared with WT mice. To assess TRPA1-dependent protective mechanisms, respiratory parameters were monitored by telemetry. TRPA1-null mice had a slower onset of breathing rate suppression ('respiratory braking') than WT mice suggesting TRPA1 mediates this protective response. Surprisingly, WT male mice treated either with a TRPA1 antagonist (HC030031; 200mg/kg) alone or with combined TRPA1 (100mg/kg) and TRPV1 (capsazepine, 10mg/kg) antagonists at 30min post-acrolein exposure (i.e., "real world" delay in treatment) were significantly protected from acrolein-induced mortality. These data show TRPA1 protects against high-level acrolein-induced toxicity in a sex-dependent manner. Post-exposure TRPA1 antagonism also protected against acrolein-induced mortality attesting to a complex role of TRPA1 in cardiopulmonary injury.


Assuntos
Acroleína/toxicidade , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Canais de Receptores Transientes de Potencial/fisiologia , Acroleína/administração & dosagem , Animais , Feminino , Pulmão/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Fatores Sexuais , Canal de Cátion TRPA1
15.
Ann Epidemiol ; 26(10): 710-716.e7, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27623482

RESUMO

PURPOSE: To examine the association between periconceptional self-reported stress levels and fecundability in women. METHODS: Daily stress was reported on a scale from 1 to 4 (lowest to highest) among 400 women who completed daily diaries including data on lifestyle and behavioral factors, menstrual characteristics, contraceptive use, and intercourse for up to 20 cycles or until pregnancy. Discrete survival analysis was used to estimate the associations between self-reported stress during specific windows of the menstrual cycle and fecundability (cycles at risk until pregnancy), adjusting for potential confounders. RESULTS: One hundred thirty-nine women became pregnant. During the follicular phase, there was a 46% reduction in fecundability for a 1-unit increase in self-reported stress during the estimated ovulatory window (fecundability odds ratio [FOR] = 0.54; 95% confidence interval [CI] 0.35-0.84) and an attenuated trend for the preovulatory window (FOR = 0.73; 95% CI 0.48-1.10). During the luteal phase, higher stress was associated with increased probability of conception (FOR = 1.63, 95% CI 1.07-2.50), possibly due to reverse causality. CONCLUSIONS: Higher stress during the ovulatory window may reduce probability of conception; however, once conception occurs, changes in the hormonal milieu and/or knowledge of the pregnancy may result in increased stress. These findings reinforce the need for encouraging stress management techniques in the aspiring and expecting mother.


Assuntos
Resultado da Gravidez , Taxa de Gravidez , Autorrelato , Estresse Psicológico/epidemiologia , Adulto , Estudos de Coortes , Intervalos de Confiança , Feminino , Fertilidade , Humanos , Razão de Chances , Cuidado Pré-Concepcional , Gravidez , Estudos Prospectivos , Índice de Gravidade de Doença , Estresse Psicológico/fisiopatologia , Estados Unidos , Adulto Jovem
16.
Toxicol Sci ; 153(1): 124-36, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27370414

RESUMO

Obesity has become a common public health problem in the world and raises the risk of various cardiovascular diseases. Zinc is essential for multiple organs in terms of normal structure and function. The present study investigated the effects of high fat diet (HFD) induced obesity on the aorta in mice, and evaluated whether it can be affected by zinc deficiency or supplementation. Four-week-old male C57BL/6J mice were fed HFD with varied amounts of zinc (deficiency, adequate and supplementation) for 3 and 6 months. Results showed that HFD feeding induced a time-dependent aortic remodeling, demonstrated by increased vessel wall thickness, tunica cell proliferation and fibrotic responses, and inflammatory response, reflected by increased expression of inflammatory cytokines (tumor necrosis factor-α and vascular cell adhesion molecule 1). HFD feeding also caused aortic oxidative damage, reflected by 3-nitrotyrosine and 4-hydroxy-2-nonenal accumulation, and down-regulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression and function, shown by down-regulation of its downstream antioxidants, catalase, NAD(P)H dehydrogenase (quinone 1), and metallothionein expression. The vascular effects of obesity-induced by HFD was exacerbated by zinc deficiency but significantly improved by zinc supplementation. In addition, down-regulation of Nrf2 function and associated antioxidants expression were also worsened by zinc deficiency but improved by zinc supplementation. These results suggest that HFD induces aortic remodeling, which can be exacerbated by zinc deficiency and improved by zinc supplementation.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Vasculite/prevenção & controle , Zinco/deficiência , Animais , Western Blotting , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Zinco/administração & dosagem
17.
Diabetologia ; 59(7): 1558-1568, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27115417

RESUMO

AIMS/HYPOTHESIS: Diabetic nephropathy is the leading cause of end-stage renal disease. Previously we reported that C66, a novel analogue of curcumin with a very high bioavailability, ameliorated diabetic nephropathy in mice, with little known about the mechanism. The present study aimed to define the mechanism by which C66 ameliorates diabetic nephropathy. METHODS: Our aim was to discover whether C66 acts through the activation of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2), which governs the antioxidant response. Streptozotocin-induced Nrf2 (also known as Nfe2l2)-knockout and wild-type (WT) diabetic mice were treated with C66. To determine whether the actions of C66 on NRF2 are mediated by microRNA (miR)-200a, WT diabetic mice were treated with C66 in the presence or absence of an in vivo miR-200a inhibitor (locked nucleic acid-modified anti-miR-200a [LNA-200a]) for 6 months. To determine whether miR-21 downregulation provided an NRF2-independent basis for C66 protection, Nrf2-knockout diabetic mice were treated with either C66 or an inhibitor of miR-21 (locked nucleic acid-modified anti-miR-21 [LNA-21]). RESULTS: Deletion of Nrf2 partially abolished diabetic nephropathy protection by C66, confirming the requirement of NRF2 for this protection. Diabetic mice, but not C66-treated diabetic mice, developed significant albuminuria, renal oxidative damage and fibrosis. C66 upregulated renal miR-200a, inhibited kelch-like ECH-associated protein 1 and induced NRF2 function, effects that were prevented by LNA-200a. However, LNA-200a only partially reduced the protection afforded by C66, suggesting the existence of miR-200a/NRF2-independent mechanisms for C66 protection. C66 was also found to inhibit diabetes induction of miR-21. Both C66 and LNA-21 produced similar reductions in miR-21, albuminuria and renal fibrosis. CONCLUSIONS/INTERPRETATION: The present study indicates that in addition to upregulating NRF2 by increasing miR-200a, C66 also protects against diabetic nephropathy by inhibiting miR-21.


Assuntos
Curcumina/uso terapêutico , Nefropatias Diabéticas/metabolismo , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Western Blotting , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Heterozigoto , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/genética
18.
Exp Neurol ; 279: 261-273, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26875994

RESUMO

Most in vivo spinal cord injury (SCI) experimental models use rodents. Due to the anatomical and functional differences between rodents and humans, reliable large animal models, such as non-human primates, of SCI are critically needed to facilitate translation of laboratory discoveries to clinical applications. Here we report the establishment of a controlled spinal contusion model that produces severity-dependent functional and histological deficits in non-human primates. Six adult male rhesus macaque monkeys underwent mild to moderate contusive SCI using 1.0 and 1.5mm tissue displacement injuries at T9 or sham laminectomy (n=2/group). Multiple assessments including motor-evoked potential (MEP), somatosensory-evoked potential (SSEP), MR imaging, and monkey hindlimb score (MHS) were performed. Monkeys were sacrificed at 6 months post-injury, and the lesion area was examined for cavitation, axons, myelin, and astrocytic responses. The MHS demonstrated that both the 1.0 and 1.5mm displacement injuries created discriminative neurological deficits which were severity-dependent. The MEP response rate was depressed after a 1.0mm injury and was abolished after a 1.5mm injury. The SSEP response rate was slightly decreased following both the 1.0 and 1.5mm SCI. MRI imaging demonstrated an increase in T2 signal at the lesion site at 3 and 6months, and diffusion tensor imaging (DTI) tractography showed interrupted fiber tracts at the lesion site at 4h and at 6 months post-SCI. Histologically, severity-dependent spinal cord atrophy, axonal degeneration, and myelin loss were found after both injury severities. Notably, strong astrocytic gliosis was not observed at the lesion penumbra in the monkey. In summary, we describe the development of a clinically-relevant contusive SCI model that produces severity-dependent anatomical and functional deficits in non-human primates. Such a model may advance the translation of novel SCI repair strategies to the clinic.


Assuntos
Contusões/patologia , Traumatismos da Medula Espinal/patologia , Animais , Astrócitos/patologia , Atrofia , Axônios/patologia , Comportamento Animal , Contusões/psicologia , Modelos Animais de Doenças , Potencial Evocado Motor , Potenciais Somatossensoriais Evocados , Gliose/patologia , Membro Posterior , Locomoção , Macaca mulatta , Masculino , Bainha de Mielina/patologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/psicologia
19.
Res Rep Health Eff Inst ; (184): 111-39; discussion 141-71, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25842618

RESUMO

Although epidemiologic and experimental studies suggest that chronic exposure to diesel exhaust (DE*) emissions causes adverse cardiovascular effects, neither the specific components of DE nor the mechanisms by which DE exposure could induce cardiovascular dysfunction and exacerbate cardiovascular disease (CVD) are known. Because advances in new technologies have resulted in cleaner fuels and decreased engine emissions, uncertainty about the relationship between DE exposure and human cardiovascular health effects has increased. To address this ever-changing baseline of DE emissions, as part of the larger Advanced Collaborative Emissions Study (ACES) bioassay studying the health effects of 2007-compliant diesel engine emissions (new-technology diesel exhaust), we examined whether plasma markers of vascular inflammation, thrombosis, cardiovascular aging, cardiac fibrosis, and aorta morphometry were changed over 24 months in an exposure-level-, sex-, or exposure-duration-dependent manner. Many plasma markers--several recognized as human CVD risk factors--were measured in the plasma of rats exposed for up to 24 months to filtered air (the control) or DE. Few changes in plasma markers resulted from 12 months of DE exposure, but significant exposure-level-dependent increases in soluble intercellular adhesion molecule 1 (sICAM-1) and interleukin-6 (IL-6) levels, as well as decreases in total and non-high-density-lipoprotein cholesterol (non-HDL) levels in plasma, were observed in female rats after 24 months of DE exposure. These effects were not observed in male rats, and no changes in cardiac fibrosis or aorta morphometry resulting from DE exposure were observed in either sex. Collectively, the significant changes may reflect an enhanced sensitivity of the female cardiovascular system to chronic DE exposure; however, this conclusion should be interpreted within both the context and limitations of the current study.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/fisiopatologia , Emissões de Veículos/toxicidade , Envelhecimento/metabolismo , Animais , Biomarcadores , Citocinas/metabolismo , Feminino , Mediadores da Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interleucinas/metabolismo , Lipídeos/sangue , Masculino , Proteínas/metabolismo , Ratos , Fatores Sexuais , Fatores de Tempo
20.
Comput Stat Data Anal ; 85: 54-66, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25620827

RESUMO

Use of zero-inflated count data models is common in applications where the number of zero counts exceeds that predicted from a traditional count data model such as Poisson or negative binomial. When count data exhibiting inflated zero counts are correlated among subjects, a natural approach will be to fit a marginal model with the help of generalized estimating equations (GEE) that can incorporate subject-to-subject correlations. A GEE based zero-inflated negative binomial (ZINB) model is proposed to fit clustered counts with excessive zeros. However, the corresponding sandwich variance estimator appears to underestimate the true variance. The theoretical reasons for its failure are explained and a correction under additional modeling assumptions is offered. In addition, a clustered resampling (bootstrap) procedure is proposed to estimate the variance and it is shown that the bootstrap procedure captures the correct variance under no additional model assumptions. Utility of this marginal GEE based ZINB model over two other competing models has been assessed using a thorough simulation study. The resulting inference procedure is applied to study the association between the dental caries and fluoride exposures using a dataset extracted from the Iowa Fluoride Study. A number of risk factors of clinical significance are reliably identified using the proposed model.

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