Search

Epidemiological studies in humans and experimental work in rodents suggest that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental toxicant, is associated with incidence of heart disease. Although TCDD toxicity depends by and large on the aryl hydrocarbon receptor (AHR), the role of the cardiac AHR in TCDD induced cardiovascular disease is not well defined. To determine whether the Ahr gene mediates disruption of heart function by TCDD, we generated a cardiomyocyte-specific Ahr knockout mouse by crossing Ahr(fx/fx) mice with βMhc:cre/+ mice, in which expression of Cre recombinase is driven by the promoter of the βMhc (myosin heavy chain-beta) gene. Starting at three months of age, mice with cardiomyocyte-specific Ahr ablation were exposed to 1μg/kg/week of TCDD or control vehicle by oral gavage for an additional three months. Relative to unexposed controls, TCDD-exposure induced cardiomyocyte Ahr-independent changes in males but not females, including a significant increase in body weight, blood pressure, and cardiac hypertrophy and a decrease in cardiac ejection fraction. TCDD exposure also induced cardiomyocyte Ahr-dependent changes in fibrosis and calcium signaling gene expression in both males and females. TCDD exposure appears to cause sexually dimorphic effects on heart function and induce fibrosis and changes in calcium signaling in both males and females through activation of the cardiomyocyte-specific Ahr.

Few studies have examined the association between perioperative blood transfusion and postoperative delirium (POD) in aged patients undergoing total hip replacement surgery. In this prospective study, 186 patients older than 65 years undergoing elective unilateral total hip replacement surgery were enrolled. Of those, 94 patients were randomly assigned to the restrictive strategy transfusion strategy group, in which red blood cells were transfused in order to maintain 10.0 g/dL>hemoglobin≧8.0 g/dL. Ninety-two patients were randomly assigned to the liberal transfusion strategy group, in which red blood cells were transfused in order to maintain hemoglobin≧10.0 g/dL. POD was diagnosed by confusion assessment method. The baseline characteristics of patients, the length of hospital stay, the incidence of POD, myocardial infarction, stroke, wound infection, pulmonary embolism, and the transfusion volume were recorded. No difference was observed in the baseline characteristics, the length of hospital stay, and the incidence of POD, myocardial infarction, stroke, wound infection, and pulmonary embolism between the two groups (P>0.05). The proportion of patients transfused with red blood cell and frozen plasma was decreased in the restrictive transfusion group compared with the liberal transfusion group (P

The aryl hydrocarbon receptor (AHR) is a transcription factor and environmental sensor that regulates expression of genes involved in drug-metabolism and cell cycle regulation. Chromatin immunoprecipitation analyses, Ahr ablation in mice and studies with orthologous genes in invertebrates suggest that AHR may also play a significant role in embryonic development. To address this hypothesis, we studied the regulation of Ahr expression in mouse embryonic stem cells and their differentiated progeny. In ES cells, interactions between OCT3/4, NANOG, SOX2 and Polycomb Group proteins at the Ahr promoter repress AHR expression, which can also be repressed by ectopic expression of reprogramming factors in hepatoma cells. In ES cells, unproductive RNA polymerase II binds at the Ahr transcription start site and drives the synthesis of short abortive transcripts. Activation of Ahr expression during differentiation follows from reversal of repressive marks in Ahr promoter chromatin, release of pluripotency factors and PcG proteins, binding of Sp factors, establishment of histone marks of open chromatin, and engagement of active RNAPII to drive full-length RNA transcript elongation. Our results suggest that reversible Ahr repression in ES cells holds the gene poised for expression and allows for a quick switch to activation during embryonic development.

Hydrogen has been reported to selectively reduce hydroxyl radicals and peroxynitrite anion in many pathologic processes. This study aimed to test the hypothesis that hydrogen-rich saline (HRS) may ameliorate organ dysfunction in a rat model of polymicrobial sepsis.Sepsis was induced in male Sprague-Dawley rats by cecal ligation and puncture (CLP). Twenty-four rats were equally assigned to Sham group, CLP group, and CLP + HRS group (n = 8). At 0, 6, and 18 h after CLP or sham operation, rats received an intraperitoneal injection of HRS (5 mL/kg) or the same volume of normal saline. Malondialdehyde, superoxide dismutase activities, inflammatory mediators, pulmonary nitric oxide, myeloperoxidase activities, wet-to-dry weight ratio, histologic scores, apoptotic analysis, alanine aminotransferase, creatinine, and blood urea nitrogen were assessed at 24 h after operation. The 7-d survival rate was also recorded.HRS administration significantly reduced the serum high-mobility group box, alanine aminotransferase, creatinine, and blood urea nitrogen levels; the pulmonary interleukin 6, high-mobility group box, nitric oxide, and malondialdehyde levels; and the wet-to-dry weight ratio, total histologic scores, and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, whereas it increased the superoxide dismutase activities 24 h after CLP when compared with the CLP group. However, there was no significant difference in survival rate between the CLP + HRS and CLP groups.HRS has potential protective effects against sepsis by decreasing proinflammatory responses, oxidative stress, and apoptosis in a rat model of polymicrobial sepsis.

Purpose To investigate the effects of α2A-adrenoreceptor blockade on acute lung injury (ALI) and high mobility group box-1 protein (HMGB1) expression in a rat model of sepsis. Methods Sepsis was induced in male rats by cecal ligation and puncture (CLP). Thirty adult male Sprague-Dawley rats were equally randomized to the Sham group, the CLP group, and the CLP + maleate group. Five hours after CLP, rats received an intraperitoneal injection of BRL-44408 maleate or the same volume of vehicle. Serum levels of TNF-α, IL-6, IL-10, HMGB1, and norepinephrine were measured at baseline, 6, 18, and 24 h after CLP. Lung TNF-α, IL-6, IL-10, immunohistochemical and western blotting analysis of HMGB1, nuclear factor (NF)-κB activation, myeloperoxidase (MPO) activity, histological scores, and wet-to-dry weight ratio were determined 24 h after CLP. In additional CLP and CLP + maleate groups, the 7 day survival rate was evaluated. Results Compared with the CLP group, serum TNF-α at 6 h, HMGB1 at 18 and 24 h, and norepinephrine at 6 and 18 h after CLP decreased in the CLP + maleate group. Lung TNF-α, IL-6, and HMGB1 expressions decreased at 24 h after CLP. NF-κB activation, MPO activity, histological scores, and wet-to-dry weight ratio were lower in the CLP + maleate group than the CLP group. There was no significant difference in 7 day survival rate between the CLP and CLP + maleate groups. Conclusions The α2A-adrenoreceptor blockade by a specific antagonist maleate improves sepsis-induced acute lung injury accompanied with depressed HMGB1 expression in rats. The mechanism seemed to be mediated partly through downregulation of the signal transductions of the NF-κB pathway.

Arsenic is a widespread environmental toxic agent that has been shown to cause diverse tissue and cell damage and at the same time to be an effective anti-cancer therapeutic agent. The objective of this study is to explore the signaling mechanisms involved in arsenic toxicity. We show that the IkappaB kinase beta (IKKbeta) plays a crucial role in protecting cells from arsenic toxicity. Ikkbeta(-)(/)(-) mouse 3T3 fibroblasts have decreased expression of antioxidant genes, such as metallothionein 1 (Mt1). In contrast to wild type and IKKbeta-reconstituted Ikkbeta(-)(/)(-) cells, IKKbeta-null cells display a marked increase in arsenic-induced reactive oxygen species (ROS) accumulation, which leads to activation of the MKK4-c-Jun NH(2)-terminal kinase (JNK) pathway, c-Jun phosphorylation, and apoptosis. Pretreatment with the antioxidant N-acetylcysteine (NAC) and expression of MT1 in the Ikkbeta(-)(/)(-) cells prevented JNK activation; moreover, NAC pretreatment, MT1 expression, MKK4 ablation, and JNK inhibition all protected cells from death induced by arsenic. Our data show that two signaling pathways appear to be important for modulating arsenic toxicity. First, the IKK-NF-kappaB pathway is crucial for maintaining cellular metallothionein-1 levels to counteract ROS accumulation, and second, when this pathway fails, excessive ROS leads to activation of the MKK4-JNK pathway, resulting in apoptosis.

Excess neuronal excitation by glutamate induces neuron cell death, which may contribute to the pathogenesis of acute brain injuries and neurodegenerative diseases. Our previous studies using a mouse with hippocampal c-fos gene deletion showed that c-fos regulates neuronal excitability and excitotoxicity. Moreover, a delayed induction of brain-derived neurotrophic factor (BDNF) protein expression in response to kainic acid (KA) treatment was found in c-fos mutant mice compared to wildtype controls, suggesting that c-fos is important in the temporal control of BDNF induction. To further investigate mechanisms of in vivo regulation of c-fos on BDNF expression, we studied the expression of BDNF mRNA and its colocalization with c-Fos protein in the hippocampal formation in the presence and absence of KA. By in situ hybridization, we observed that the c-fos mutant and wildtype mice exhibited similar basal expression of BDNF in the absence of KA. In contrast, the KA-induced BDNF mRNA levels were significantly different in wildtype and c-fos mutant mice in CA3 and dentate gyrus regions. Our findings indicate that c-fos regulates expression of BDNF in distinct neuron populations of the hippocampal formation in vivo.

Excitotoxicity by which excitatory amino acid induces neuronal cell death may underlie mechanisms of neurodegenerative diseases. We previously found that c-fos is critically involved in neuronal excitability and survival. Mice that carry hippocampal mutations of c-fos exhibited hyper-excitability, hyper-excitotoxicity and higher mortality in kainic acid (KA)-induced seizures compared to wild-type mice. To further understand the neuroprotective signal transduction pathways regulated by c-fos in the hippocampal formation, we identified 172 genes that are either regulated by KA or are differentially expressed in wild-type and hippocampal-specific c-fos mutant mice using cDNA microarrays. One gene encodes the neuropeptide Y (NPY). We confirmed that c-fos regulates the expression of NPY by using immunohistochemistry. We found that c-fos is critical in up-regulation of NPY expression in the granule cell layer of dentate gyrus in response to KA administration. As NPY is an important endogenous anti-epileptic agent, our result is consistent with a hypothesis that the neuroprotective function of c-fos is mediated in part by regulation of NPY expression.