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1.
Front Immunol ; 10: 2449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824476

RESUMO

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by mucosa damage associated with an uncontrolled inflammatory response. This immunological impairment leads to altered inflammatory mediators such as IL-33, which is shown to increase in the mucosa of active UC (aUC) patients. MicroRNAs present a distorted feature in inflamed colonic mucosa and are potential IL-33 regulating candidates in UC. Therefore, we studied the microRNA and mRNA profiles in inflamed colonic samples of UC patients, evaluating the effect of a microRNA (selected by in silico analysis and its expression in UC patients), on IL-33 under inflammatory conditions. We found that inflamed mucosa (n = 8) showed increased expression of 40 microRNAs and 2,120 mRNAs, while 49 microRNAs and 1,734 mRNAs were decreased, as determined by microarrays. In particular, IL-33 mRNA showed a 3.8-fold increase and eight members of a microRNA family (miR-378), which targets IL-33 mRNA in the 3'UTR, were decreased (-3.9 to -3.0 times). We selected three members of the miR-378 family (miR-378a-3p, miR-422a, and miR-378c) according to background information and interaction energy analysis, for further correlation analyses with IL-33 expression through qPCR and ELISA, respectively. We determined that aUC (n = 24) showed high IL-33 levels, and decreased expression of miR-378a-3p and miR-422a compared to inactive UC (n = 10) and controls (n = 6). Moreover, both microRNAs were inversely correlated with IL-33 expression, while miR-378c does not show a significant difference. To evaluate the effect of TNFα on the studied microRNAs, aUC patients with anti-TNF therapy were compared to aUC receiving other treatments. The levels of miR-378a-3p and miR-378c were higher in aUC patients with anti-TNF. Based on these findings, we selected miR-378a-3p to exploring the molecular mechanism involved by in vitro assays, showing that over-expression of miR-378a-3p decreased the levels of an IL-33 target sequence ß-gal-reporter gene in HEK293 cells. Stable miR-378a-3p over-expression/inhibition inversely modulated IL-33 content and altered viability of HT-29 cells. Additionally, in an inflammatory context, TNFα decreased miR-378a-3p levels in HT-29 cells enhancing IL-33 expression. Together, our results propose a regulatory mechanism of IL-33 expression exerted by miR-378a-3p in an inflammatory environment, contributing to the understanding of UC pathogenesis.

2.
J Therm Biol ; 86: 102435, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31789231

RESUMO

An ongoing challenge in material science has been to reduce heat strain experienced by individuals wearing chemical protective ensembles. The objective of this study is to analyze the relationship between the thermal properties of eight chemical protective fabrics and heat strain in ten chemical protective ensembles constructed with those fabrics. The fabric samples were tested on a sweating guarded hot plate to measure fabric thermal and evaporative resistance. The ensembles were then tested on thermal manikins to measure ensemble thermal and evaporative resistance. An empirical thermoregulatory model, the Heat Strain Decision Aid (HSDA), was used to predict thermal responses of core temperature and endurance times. Model inputs included ensemble thermal and evaporative resistances, four environmental conditions and a metabolic rate of 400 W. The fabric intrinsic thermal and evaporative resistances ranged from 0.01 to 0.05 m2 °C·W-1 and from 5.9 to 12.82 m2 Pa·W-1, respectively. Ensemble intrinsic thermal and evaporative resistances ranged from 0.23 to 0.31 m2 °C·W-1 and 51.7-67.8 m2 Pa·W-1, respectively. Predicted endurance times varied from 170 to 300 min at 20 °C/50% RH/2 m s-1 and 26 °C/55% RH/9 m s-1 conditions, and varied from 91 to 98 min at 30 °C/75% RH/2 m s-1 and 40 °C/20% RH/2 m s-1 conditions. Improved fabric thermal properties reduced heat strain and extended endurance times, but the magnitude of the extended times is dependent on the environmental conditions. Consequently, the benefits of improved fabric thermal properties may only be observed under certain environmental conditions.

3.
Nat Commun ; 10(1): 5196, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729367

RESUMO

Spermatogonial stem cells (SSCs) have the dual capacity to self-renew and differentiate into progenitor spermatogonia that develop into mature spermatozoa. Here, we document that preferentially expressed antigen of melanoma family member 12 (PRAMEF12) plays a key role in maintenance of the spermatogenic lineage. In male mice, genetic ablation of Pramef12 arrests spermatogenesis and results in sterility which can be rescued by transgenic expression of Pramef12. Pramef12 deficiency globally decreases expression of spermatogenic-related genes, and single-cell transcriptional analysis of post-natal male germline cells identifies four spermatogonial states. In the absence of Pramef12 expression, there are fewer spermatogonial stem cells which exhibit lower expression of SSC maintenance-related genes and are defective in their ability to differentiate. The disruption of the first wave of spermatogenesis in juvenile mice results in agametic seminiferous tubules. These observations mimic a Sertoli cell-only syndrome in humans and may have translational implications for reproductive medicine.

4.
Sci Rep ; 9(1): 13618, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541158

RESUMO

Spermatogenesis is a differentiation process that requires dramatic changes to DNA architecture, a process governed in part by Transition Nuclear Proteins 1 and 2 (TNP1 and TNP2). Translation of Tnp1 and Tnp2 mRNAs is temporally disengaged from their transcription. We hypothesized that RNA regulatory proteins associate specifically with Tnp mRNAs to control the delayed timing of their translation. To identify potential regulatory proteins, we isolated endogenous mRNA/protein complexes from testis extract and identified by mass spectrometry proteins that associated with one or both Tnp transcripts. Five proteins showed strong association with Tnp transcripts but had low signal when Actin mRNA was isolated. We visualized the expression patterns in testis sections of the five proteins and found that each of the proteins was detected in germ cells at the appropriate stages to regulate Tnp RNA expression.

5.
Temperature (Austin) ; 6(2): 150-157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312674

RESUMO

Physiological responses to work in cold water have been well studied but little is known about the effects of exercise in warm water; an overlooked but critical issue for certain military, scientific, recreational, and professional diving operations. This investigation examined core temperature responses to fatiguing, fully-immersed exercise in extremely warm waters. Twenty-one male U.S. Navy divers (body mass, 87.3 ± 12.3 kg) were monitored during rest and fatiguing exercise while fully-immersed in four different water temperatures (Tw): 34.4, 35.8, 37.2, and 38.6°C (Tw34.4, Tw35.8, Tw37.2, and Tw38.6 respectively). Participants exercised on an underwater cycle ergometer until volitional fatigue or core temperature limits were reached. Core body temperature and heart rate were monitored continuously. Trial performance time decreased significantly as water temperature increased (Tw34.4, 174 ± 12 min; Tw35.8, 115 ± 13 min; Tw37.2, 50 ± 13 min; Tw38.6, 34 ± 14 min). Peak core body temperature during work was significantly lower in Tw34.4 water (38.31 ± 0.49°C) than in warmer temperatures (Tw35.8, 38.60 ± 0.55°C; Tw37.2, 38.82 ± 0.76°C; Tw38.6, 38.97 ± 0.65°C). Core body temperature rate of change increased significantly with warmer water temperature (Tw34.4, 0.39 ± 0.28°C·h-1; Tw35.8, 0.80 ± 0.19°C·h-1; Tw37.2, 2.02 ± 0.31°C·h-1; Tw38.6, 3.54 ± 0.41°C·h-1). Physically active divers risk severe hyperthermia in warmer waters. Increases in water temperature drastically increase the rate of core body temperature rise during work in warm water. New predictive models for core temperature based on workload and duration of warm water exposure are needed to ensure warm water diving safety.

6.
J Am Heart Assoc ; 8(15): e011012, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31311395

RESUMO

Background The contribution of glucocorticoids to sexual dimorphism in the heart is essentially unknown. Therefore, we sought to determine the sexually dimorphic actions of glucocorticoid signaling in cardiac function and gene expression. To accomplish this goal, we conducted studies on mice lacking glucocorticoid receptors (GR) in cardiomyocytes (cardioGRKO mouse model). Methods and Results Deletion of cardiomyocyte GR leads to an increase in mortality because of the development of spontaneous cardiac pathology in both male and female mice; however, females are more resistant to GR signaling inactivation in the heart. Male cardioGRKO mice had a median survival age of 6 months. In contrast, females had a median survival age of 10 months. Transthoracic echocardiography data showed phenotypic differences between male and female cardioGRKO hearts. By 3 months of age, male cardioGRKO mice exhibited left ventricular systolic dysfunction. Conversely, no significant functional deficits were observed in female cardioGRKO mice at the same time point. Functional sensitivity of male hearts to the loss of cardiomyocyte GR was reversed following gonadectomy. RNA-Seq analysis showed that deleting GR in the male hearts leads to a more profound dysregulation in the expression of genes implicated in heart rate regulation (calcium handling). In agreement with these gene expression data, cardiomyocytes isolated from male cardioGRKO hearts displayed altered intracellular calcium responses. In contrast, female GR-deficient cardiomyocytes presented a response comparable with controls. Conclusions These data suggest that GR regulates calcium responses in a sex-biased manner, leading to sexually distinct responses to stress in male and female mice hearts, which may contribute to sex differences in heart disease, including the development of ventricular arrhythmias that contribute to heart failure and sudden death.

7.
Chem Commun (Camb) ; 55(68): 10068-10071, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31355392

RESUMO

Herein, we first report a tunable organic magnetoresistance (OMAR) effect in polyaniline (PANI) coated acid treated poly(p-phenylene-2,6-benzobisoxazole) (t-PBO) short fibers. This unique OMAR is interpreted using the paramagnetic nature of PBO molecules combined with the localization length a0 calculated from the wave-function shrinkage model and forward interference model.

8.
Sci Signal ; 12(577)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992401

RESUMO

Stress is increasingly associated with heart dysfunction and is linked to higher mortality rates in patients with cardiometabolic disease. Glucocorticoids are primary stress hormones that regulate homeostasis through two nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), both of which are present in cardiomyocytes. To examine the specific and coordinated roles that these receptors play in mediating the direct effects of stress on the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction and died prematurely from heart failure. In contrast, the cardioMRKO mice exhibited normal heart morphology and function. Despite the presence of myocardial stress, the cardioGRMRdKO mice were resistant to the cardiac remodeling, left ventricular dysfunction, and early death observed in the cardioGRKO mice. Gene expression analysis revealed the loss of gene changes associated with impaired Ca2+ handling, increased oxidative stress, and enhanced cell death and the presence of gene changes that limited the hypertrophic response and promoted cardiomyocyte survival in the double knockout hearts. Reexpression of MR in cardioGRMRdKO hearts reversed many of the cardioprotective gene changes and resulted in cardiac failure. These findings reveal a critical role for balanced cardiomyocyte GR and MR stress signaling in cardiovascular health. Therapies that shift stress signaling in the heart to favor more GR and less MR activity may provide an improved approach for treating heart disease.

9.
Commun Biol ; 2: 104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911679

RESUMO

Excessive or chronic stress can lead to a variety of diseases due to aberrant activation of the glucocorticoid receptor (GR), a ligand activated transcription factor. Pregnancy represents a particular window of sensitivity in which excessive stress can have adverse outcomes, particularly on the developing fetus. Here we show maternal hepatic stress hormone responsiveness is diminished via epigenetic silencing of the glucocorticoid receptor during pregnancy. Provocatively, reinstallation of GR to hepatocytes during pregnancy by adeno-associated viral transduction dysregulates genes involved in proliferation, resulting in impaired pregnancy-induced hepatomegaly. Disruption of the maternal hepatic adaptation to pregnancy results in in utero growth restriction (IUGR). These data demonstrate pregnancy antagonizes the liver-specific effects of stress hormone signaling in the maternal compartment to ultimately support the healthy development of embryos.

10.
Nat Commun ; 10(1): 305, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659182

RESUMO

DNA methylation is an essential epigenetic process in mammals, intimately involved in gene regulation. Here we address the extent to which genetics, sex, and pregnancy influence genomic DNA methylation by intercrossing 2 inbred mouse strains, C57BL/6N and C3H/HeN, and analyzing DNA methylation in parents and offspring using whole-genome bisulfite sequencing. Differential methylation across genotype is detected at thousands of loci and is preserved on parental alleles in offspring. In comparison of autosomal DNA methylation patterns across sex, hundreds of differentially methylated regions are detected. Comparison of animals with different histories of pregnancy within our study reveals a CpG methylation pattern that is restricted to female animals that had borne offspring. Collectively, our results demonstrate the stability of CpG methylation across generations, clarify the interplay of epigenetics with genetics and sex, and suggest that CpG methylation may serve as an epigenetic record of life events in somatic tissues at loci whose expression is linked to the relevant biology.


Assuntos
Metilação de DNA/genética , Epigênese Genética , Prenhez/genética , Animais , Ilhas de CpG , Metilação de DNA/fisiologia , Feminino , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Gravidez , Prenhez/fisiologia , Fatores Sexuais , Especificidade da Espécie , Sequenciamento Completo do Genoma
11.
J Clin Invest ; 129(3): 1345-1358, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30652972

RESUMO

In the stomach, chronic inflammation causes metaplasia and creates a favorable environment for the evolution of gastric cancer. Glucocorticoids are steroid hormones that repress proinflammatory stimuli, but their role in the stomach is unknown. In this study, we show that endogenous glucocorticoids are required to maintain gastric homeostasis. Removal of circulating glucocorticoids in mice by adrenalectomy resulted in the rapid onset of spontaneous gastric inflammation, oxyntic atrophy, and spasmolytic polypeptide-expressing metaplasia (SPEM), a putative precursor of gastric cancer. SPEM and oxyntic atrophy occurred independently of lymphocytes. However, depletion of monocytes and macrophages by clodronate treatment or inhibition of gastric monocyte infiltration using the Cx3cr1 knockout mouse model prevented SPEM development. Our results highlight the requirement for endogenous glucocorticoid signaling within the stomach to prevent spontaneous gastric inflammation and metaplasia, and suggest that glucocorticoid deficiency may lead to gastric cancer development.

12.
Exp Ther Med ; 16(6): 4664-4668, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30542418

RESUMO

This study retrospectively analyzed the clinical and pathological data of 1,231 patients affected by anemia after surgical treatment of hyperthyroidism to explore the influencing factors of anemia after surgical treatment of hyperthyroidism. The clinical data of 1,231 patients affected by anemia after surgical treatment of hyperthyroidism from 1987 to 2017 were analyzed. Clinical data included the surgery methods, sex, age and pathological types. SPSS 22.0 statistical software was used for all statistical analyses. Correlation analyses were performed by using logistic regression analysis, and other enumeration data were subjected to χ2 test. p<0.05 was considered to be statistically significant. The occurrence of anemia after surgical treatment of hyperthyroidism was significantly correlated with age and pathological types (p<0.05). Correlation analysis also showed that age and pathological types were significantly correlated with the occurrence of anemia after surgical treatment of hyperthyroidism. Age and pathological types may be the risk factors for anemia in patients with surgical treatment of hyperthyroidism. Age and pathological type were significantly correlated with the occurrence of anemia after surgical treatment of hyperthyroidism, and may be risk factors for this disease.

13.
J Therm Biol ; 78: 100-105, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30509625

RESUMO

This paper presents an expanded dataset for survival times during cold water immersion. In 1946, the first set of human data for cold water survival was derived from the US Navy medical reports during WWII. Although this is the largest and most widely used data source, it has only 23 data points and immersion times are less than 5.5 h for water temperature below 20 °C. For the new dataset, data (i.e., immersion times, water temperatures, clothing worn, and in some cases, body masses, heights, and survival times for the deaths witnessed by survivors) was retrieved from 12 well-documented incidents of accidental immersions which involved 22 survivors and 21 deaths. These data were combined with the 1946 dataset to create the expanded dataset which included 122 data points. Analysis of the dataset revealed critical details pertinent to cold water survival: 1) immersion times, up to 75 h, at water temperatures below 20 °C, were longer than most immersion times documented in the 1946 dataset; 2) thermal protection (wetsuit or drysuit), high body mass, and partial immersion may significantly impact survival during immersion in cold water; 3) twenty-one actual survival times until witnessed death are added. A maximal survival time curve was derived to represent the survival limit which many victims are unlikely to approach and few can exceed except under unique circumstances.


Assuntos
Afogamento/fisiopatologia , Hipotermia/fisiopatologia , Resposta ao Choque Frio , Conjuntos de Dados como Assunto , Afogamento/epidemiologia , Humanos , Hipotermia/etiologia , Hipotermia/prevenção & controle , Roupa de Proteção/estatística & dados numéricos , Sobreviventes/estatística & dados numéricos
14.
J Appl Physiol (1985) ; 125(5): 1498-1510, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30138077

RESUMO

Reduced dexterity is a major problem in cold weather, with a need for a countermeasure that increases hand (Thand) and finger (Tfing) temperatures and improves dexterity. The purpose of this study was to determine whether electric heat (set point, 42°C) applied to the forearm (ARM, 82 W), face (FACE, 9.2 W), or combination of both (COMB, 91.2 W), either at the beginning of cold exposure (COLD; 0.5°C, 120 min; 2 clo insulation, seated, bare-handed) or after Tfing fell to 10.5°C [delayed trials (D)], improves Thand, Tfing, dexterity, and finger key pinch strength (Sfing). Volunteers ( n = 8; 26 ± 9 yr) completed 7 experimental trials in COLD: ARM, ARM-D, FACE, FACE-D, COMB, COMB-D, and no heating (CON). Temperatures were measured before (BASE) and throughout COLD. Tests of dexterity [Purdue Pegboard assembly (PP) and magazine loading (MAGLOAD)] and Sfing were measured at BASE and after 45 and 90 min of COLD. Data presented are at minute 90. Thand was warmer ( P < 0.001) during ARM (18.0 ± 2.6°C) and COMB (18.9 ± 2.0°C) versus CON (15.3 ± 1.5°C) and FACE (15.8 ± 1.5°C) for heating that was initiated at the beginning of COLD. Tfing was higher ( P < 0.04) during COMB (12.7 ± 5.1°C) versus CON (9.7 ± 2.1°C) and FACE (8.9 ± 2.2°C). The change from BASE for PP (no. of pieces) was less ( P < 0.005) in COMB (-4.5 ± 3.3) and ARM (-5.0 ± 6.0) versus CON (-13.0 ± 7.3) and FACE (-10.0 ± 8.3), and for MAGLOAD, it tended ( P = 0.06) to be less in COMB (-8.9 ± 6.2 cartridges) versus CON (-14.8 ± 3.7 cartridges). There was no change in Sfing from BASE (10.5 kg) to minute 90 in ARM or COMB (0.7 ± 1.4 and -0.2 ± 1.7 kg, respectively) but a decrease ( P < 0.01) in CON and FACE (-2.1 ± 2.0 and -1.6 ± 1.9 kg, respectively). There were no differences in Thand, Tfing, dexterity, and Sfing at minute 90 when comparing heating that was initiated at the beginning of COLD versus delayed heating. In conclusion, heating using either COMB or ARM, compared with CON and FACE, improved Thand and Tfing and reduced the decline in dexterity by 20%-50% and Sfing by 90%. Furthermore, delayed heating had no deleterious effect on Thand, Tfing, dexterity, and Sfing compared with heating that started at the beginning of cold exposure. NEW & NOTEWORTHY The present study demonstrated that, during sedentary cold air exposure, localized heating that was applied from the beginning of cold exposure on the forearm increases hand and finger temperatures and finger strength, leading to subsequent improvements in manual dexterity. In addition, localized heating that was delayed until finger temperatures cooled significantly also caused higher peripheral temperatures, leading to better strength and manual dexterity, compared with no heating.


Assuntos
Temperatura Baixa/efeitos adversos , Calefação , Microclima , Destreza Motora , Temperatura Cutânea , Adolescente , Adulto , Pressão Arterial , Face , Feminino , Antebraço , Voluntários Saudáveis , Humanos , Masculino , Força de Pinça , Termogênese , Sensação Térmica , Adulto Jovem
15.
Front Mol Neurosci ; 11: 251, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30127715

RESUMO

Studies conducted in rodents subjected to chronic stress and some observations in humans after psychosocial stress, have allowed to establish a link between stress and the susceptibility to many complex diseases, including mood disorders. The studies in rodents have revealed that chronic exposure to stress negatively affects synaptic plasticity by triggering changes in the production of trophic factors, subunit levels of glutamate ionotropic receptors, neuron morphology, and neurogenesis in the adult hippocampus. These modifications may account for the impairment in learning and memory processes observed in chronically stressed animals. It is plausible then, that stress modifies the interplay between signal transduction cascades and gene expression regulation in the hippocampus, therefore leading to altered neuroplasticity and functioning of neural circuits. Considering that miRNAs play an important role in post-transcriptional-regulation of gene expression and participate in several hippocampus-dependent functions; we evaluated the consequences of chronic stress on the expression of miRNAs in dorsal (anterior) portion of the hippocampus, which participates in memory formation in rodents. Here, we show that male rats exposed to daily restraint stress (2.5 h/day) during 7 and 14 days display a differential profile of miRNA levels in dorsal hippocampus and remarkably, we found that some of these miRNAs belong to the miR-379-410 cluster. We confirmed a rise in miR-92a and miR-485 levels after 14 days of stress by qPCR, an effect that was not mimicked by chronic administration of corticosterone (14 days). Our in silico study identified the top-10 biological functions influenced by miR-92a, nine of which were shared with miR-485: Nervous system development and function, Tissue development, Behavior, Embryonic development, Organ development, Organismal development, Organismal survival, Tissue morphology, and Organ morphology. Furthermore, our in silico study provided a landscape of potential miRNA-92a and miR-485 targets, along with relevant canonical pathways related to axonal guidance signaling and cAMP signaling, which may influence the functioning of several neuroplastic substrates in dorsal hippocampus. Additionally, the combined effect of miR-92a and miR-485 on transcription factors, along with histone-modifying enzymes, may have a functional relevance by producing changes in gene regulatory networks that modify the neuroplastic capacity of the adult dorsal hippocampus under stress.

16.
Front Immunol ; 9: 1026, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867993

RESUMO

Crohn's disease (CD) is a chronic inflammatory bowel disorder characterized by deregulated inflammation triggered by environmental factors. Notably, adherent-invasive Escherichia coli (AIEC), a bacterium with the ability to survive within macrophages is believed to be one of such factors. Glucocorticoids are the first line treatment for CD and to date, it is unknown how they affect bactericidal and inflammatory properties of macrophages against AIEC. The aim of this study was to evaluate the impact of glucocorticoid treatment on AIEC infected macrophages. First, THP-1 cell-derived macrophages were infected with a CD2-a AIEC strain, in the presence or absence of the glucocorticoid dexamethasone (Dex) and mRNA microarray analysis was performed. Differentially expressed mRNAs were confirmed by TaqMan-qPCR. In addition, an amikacin protection assay was used to evaluate the phagocytic and bactericidal activity of Dex-treated macrophages infected with E. coli strains (CD2-a, HM605, NRG857c, and HB101). Finally, cytokine secretion and the inflammatory phenotype of macrophages were evaluated by ELISA and flow cytometry, respectively. The microarray analysis showed that CD2-a, Dex, and CD2-a + Dex-treated macrophages have differential inflammatory gene profiles. Also, canonical pathway analysis revealed decreased phagocytosis signaling by Dex and anti-inflammatory polarization on CD2-a + Dex macrophages. Moreover, amikacin protection assay showed reduced phagocytosis upon Dex treatment and TaqMan-qPCR confirmed Dex inhibition of three phagocytosis-associated genes. All bacteria strains induced TNF-α, IL-6, IL-23, CD40, and CD80, which was inhibited by Dex. Thus, our data demonstrate that glucocorticoids impair phagocytosis and induce anti-inflammatory polarization after AIEC infection, possibly contributing to the survival of AIEC in infected CD patients.


Assuntos
Doença de Crohn/microbiologia , Dexametasona/farmacologia , Infecções por Escherichia coli/imunologia , Glucocorticoides/farmacologia , Macrófagos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Animais , Aderência Bacteriana , Doença de Crohn/imunologia , Citocinas/imunologia , Escherichia coli/patogenicidade , Humanos , Inflamação , Macrófagos/microbiologia , Camundongos , Camundongos Knockout , Análise em Microsséries , Proteína Adaptadora de Sinalização NOD2/genética , Reação em Cadeia da Polimerase em Tempo Real , Células THP-1 , Fator de Necrose Tumoral alfa/imunologia
17.
Comput Biol Med ; 99: 1-6, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29803944

RESUMO

Core body temperature (TC) is a key physiological metric of thermal heat-strain yet it remains difficult to measure non-invasively in the field. This work used combinations of observations of skin temperature (TS), heat flux (HF), and heart rate (HR) to accurately estimate TC using a Kalman Filter (KF). Data were collected from eight volunteers (age 22 ±â€¯4 yr, height 1.75 ±â€¯0.10 m, body mass 76.4 ±â€¯10.7 kg, and body fat 23.4 ±â€¯5.8%, mean ±â€¯standard deviation) while walking at two different metabolic rates (∼350 and ∼550 W) under three conditions (warm: 25 °C, 50% relative humidity (RH); hot-humid: 35 °C, 70% RH; and hot-dry: 40 °C, 20% RH). Skin temperature and HF data were collected from six locations: pectoralis, inner thigh, scapula, sternum, rib cage, and forehead. Kalman filter variables were learned via linear regression and covariance calculations between TC and TS, HF, and HR. Root mean square error (RMSE) and bias were calculated to identify the best performing models. The pectoralis (RMSE 0.18 ±â€¯0.04 °C; bias -0.01 ±â€¯0.09 °C), rib (RMSE 0.18 ±â€¯0.09 °C; bias -0.03 ±â€¯0.09 °C), and sternum (RMSE 0.20 ±â€¯0.10 °C; bias -0.04 ±â€¯0.13 °C) were found to have the lowest error values when using TS, HF, and HR but, using only two of these measures provided similar accuracy.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Frequência Cardíaca/fisiologia , Modelos Biológicos , Temperatura Cutânea/fisiologia , Adulto , Humanos , Masculino
18.
J Hazard Mater ; 353: 166-172, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29674091

RESUMO

In this work, a nanocarbon bridged nanomagnetite network (NC-NMN) is developed through the electrospinning of epichlorohydrin functionalized polystyrene (f-PS), followed by the direct calcination of f-PS and ferric nitrate, which is capable of superfast removing hexavalent chromium (Cr(VI)) from polluted water within only 15 s benefiting from its gridding framework, with an adsorption rate constant of 1.64 g mg-1 min-1 according to the pseudo-second-order kinetics. The well-fitted Langmuir isotherm model indicates a monolayer adsorption for Cr(VI) on NC-NMN. The thermodynamic parameters including negative ΔG° and positive ΔH° demonstrate that the Cr(VI) adsorption on NC-NMN is spontaneous and endothermic. The Cr(VI) adsorption retention, which is only 3.8%, is achieved for NC-NMN after five cycles, exhibiting a prominent stability and an excellent recyclability. X-ray photoelectron spectroscopy (XPS), zeta potential and energy-filter transmission electron spectroscopy (EFTEM) results illustrate that both the electrostatic attraction and the network structure of NC-NMN are responsible for the superior Cr(VI) adsorption performance. This work intends to provide a new method for designing the novel structure materials for polluted water treatment.

19.
Cell Rep ; 22(10): 2690-2701, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29514097

RESUMO

Glucocorticoids (GCs) are master regulators of systemic metabolism. Intriguingly, Cushing's syndrome, a disorder of excessive GCs, phenocopies several menopause-induced metabolic pathologies. Here, we show that the glucocorticoid receptor (GR) drives steatosis in hypogonadal female mice because hepatocyte-specific GR knockout mice are refractory to developing ovariectomy-induced steatosis. Intriguingly, transcriptional profiling revealed that ovariectomy elicits hepatic GC hypersensitivity globally. Hypogonadism-induced GC hypersensitivity results from a loss of systemic but not hepatic estrogen (E2) signaling, given that hepatocyte-specific E2 receptor deletion does not confer GC hypersensitivity. Mechanistically, enhanced chromatin recruitment and ligand-dependent hyperphosphorylation of GR underlie ovariectomy-induced glucocorticoid hypersensitivity. The dysregulated glucocorticoid-mediated signaling present in hypogonadal females is a product of increased follicle-stimulating hormone (FSH) production because FSH treatment in ovary-intact mice recapitulates glucocorticoid hypersensitivity similar to hypogonadal female mice. Our findings uncover a regulatory axis between estradiol, FSH, and hepatic glucocorticoid receptor signaling that, when disrupted, as in menopause, promotes hepatic steatosis.


Assuntos
Estrogênios/deficiência , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Receptores de Glucocorticoides/metabolismo , Animais , Cromatina/metabolismo , Síndrome de Cushing/metabolismo , Estradiol/deficiência , Estradiol/metabolismo , Feminino , Hormônio Foliculoestimulante/farmacologia , Ligantes , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Ovariectomia , Ovário/metabolismo , Ovário/patologia , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
20.
Chemistry ; 24(7): 1694-1700, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29131431

RESUMO

Fucosylated chondroitin sulfate (FuCS) is a structurally distinct glycosaminoglycan with excellent anticoagulant activity. Studies show that FuCS and its depolymerized fragments exhibit a different anticoagulant mechanism from that of heparin derivatives, with decreased risks of adverse effects and bleeding. However, further exploitation has been hindered by the scarcity of structurally defined oligosaccharides. Herein, facile method is reported for the synthesis of the repeating trisaccharide unit of FuCS based on the degradation of chondroitin sulfate polymers. A series of simplified FuCS glycomimetics that have highly tunable structures, controllable branches, and defined sulfation motifs were generated by copper-catalyzed alkyne-azide cycloaddition. Remarkable improvement in activated partial thromboplastin time (APTT) assay activities was observed as the branches increased, but no significant influences were observed for prothrombin time (PT) and thrombin time (TT) assay activities. Further FXase inhibition tests suggested that glycoclusters 33 b-40 b selectively inhibited intrinsic anticoagulant activities, but had little effect on the extrinsic and common coagulation pathways. Notably, glycoclusters with the 2,4-di-O-sulfated fucosyl residue displayed the most potency, which was in consistent with that of natural polysaccharides. These FuCS clusters demonstrated potency to mimic linear glycosaminoglycans and offer a new framework for the development of novel anticoagulant agents.


Assuntos
Anticoagulantes/síntese química , Sulfatos de Condroitina/síntese química , Alquinos/química , Anticoagulantes/farmacologia , Azidas/química , Coagulação Sanguínea/efeitos dos fármacos , Catálise , Sulfatos de Condroitina/farmacologia , Cobre/química , Reação de Cicloadição , Cisteína Endopeptidases , Glicosilação , Humanos , Estrutura Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Tempo de Tromboplastina Parcial , Relação Estrutura-Atividade , Trissacarídeos/síntese química , Trissacarídeos/farmacologia
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