Stress-sensitive Genes Research Articles

Identification and Analysis of PPO Gene Family Members in Paulownia fortunei.

Polyphenol oxidase (PPO) is a common metalloproteinase in plants with important roles in plant responses to abiotic and biotic stresses. There is evidence that PPOs contribute to stress responses in Paulownia fortunei. In this study, PPO gene family members in P. fortunei were comprehensively identified and characterized using bioinformatics methods as well as analyses of phylogenetic relationships, gene and protein structure, codon usage bias, and gene expression in response to stress. The genome contained 10 PPO gene family members encoding 406-593 amino acids, with a G/C bias. Most were localized in chloroplasts. The motif structure was conserved among family members, and α-helices and random coils were the dominant elements in the secondary structure. The promoters contained many cis-acting elements, such as auxin, gibberellin, salicylic acid, abscisic acid, and photoresponsive elements. The formation of genes in this family was linked to evolutionary events, such as fragment replication. Real-time quantitative PCR results showed that PfPPO7, PfPPO10, PfPPO1, PfPPO2, PfPPO3, PfPPO4, PfPPO5, and PfPPO8 may be key genes in drought stress resistance. PfPPO1, PfPPO3, PfPPO4, and PfPPO10 were resistant stress-sensitive genes. These results provide a reliable basis for fully understanding the potential functions of these genes and the selection of resistance breeding.

Maternal immune activation alters placental histone-3 lysine-9 tri-methylation, offspring sensorimotor processing, and hypothalamic transposable element expression in a sex-specific manner

Animal models of maternal immune activation (MIA) are central to identifying the biological mechanisms that underly the association between prenatal infection and neuropsychiatric disorder susceptibility. Many studies, however, have limited their scope to protein coding genes and their role in mediating this inherent risk, while much less attention has been directed towards exploring the roles of the epigenome and transposable elements (TEs). In Experiment 1, we demonstrate the ability of MIA to alter the chromatin landscape of the placenta. We induced MIA by injecting 200 μg/kg (i.p.) of lipopolysaccharide (LPS) on gestational day 15 in Sprague-Dawley rats. We found a sex-specific rearrangement of heterochromatin 24-h after exposure to MIA, as evidenced by an increase in histone-3 lysine-9 trimethylation (H3K9me3). In Experiment 2, MIA was associated with long-term sensorimotor processing deficits as indicated by reduced prepulse inhibition (PPI) of the acoustic startle reflex in adult male and female offspring and an increased mechanical allodynia threshold in males. Analyses of gene expression within the hypothalamus-chosen for its involvement in the sex-specific pathogenesis of schizophrenia and the stress response-revealed significantly higher levels of the stress-sensitive genes Gr and Fkbp5. Deleterious TE expression is often a hallmark of neuropsychiatric disease and we found sex-specific increases in the expression of several TEs including IAP, B2 SINE, and LINE-1 ORF1. The data from this study warrant the future consideration of chromatin stability and TEs as part of the mechanism that drives MIA-associated changes in the brain and behavior.

Insights into the expression of DNA (de)methylation genes responsive to nitric oxide signaling in potato resistance to late blight disease.

Our previous study concerning the pathogen-induced biphasic pattern of nitric oxide (NO) burst revealed that the decline phase and a low level of NO, due to S-nitrosoglutathione reductase (GSNOR) activity, might be decisive in the upregulation of stress-sensitive genes via histone H3/H4 methylation in potato leaves inoculated with avr P. infestans. The present study refers to the NO-related impact on genes regulating DNA (de)methylation, being in dialog with histone methylation. The excessive amounts of NO after the pathogen or GSNO treatment forced the transient upregulation of histone SUVH4 methylation and DNA hypermethylation. Then the diminished NO bioavailability reduced the SUVH4-mediated suppressive H3K9me2 mark on the R3a gene promoter and enhanced its transcription. However, we found that the R3a gene is likely to be controlled by the RdDM methylation pathway. The data revealed the time-dependent downregulation of the DCL3, AGO4, and miR482e genes, exerting upregulation of the targeted R3a gene correlated with ROS1 overexpression. Based on these results, we postulate that the biphasic waves of NO burst in response to the pathogen appear crucial in establishing potato resistance to late blight through the RdDM pathway controlling R gene expression.

Identification of a 5-Nutrient Stress-Sensitive Gene Signature to Predict Survival for Colorectal Cancer.

Background The high heterogeneity and the complexity of the tumor microenvironment of colorectal cancer (CRC) have enhanced the difficulty of prognosis prediction based on conventional clinical indicators. Recent studies revealed that tumor cells could overcome various nutritional deficiencies by gene regulation and metabolic remodeling. However, whether differentially expressed genes (DEGs) in CRC cells under kinds of nutrient deficiency could be used to predict prognosis remained unveiled. Methods Three datasets (GSE70976, GSE13548, and GSE116087), in which colon cancer cells were, respectively, cultured in serum-free, glucose-free, or glutamine-free medium, were included to delineate the profiles of gene expression by nutrient stress. DEGs were figured out in three datasets, and gene functional analysis was performed. Survival analyses and Cox proportional hazards model were then used to identify nutrient stress sensitive genes in CRC datasets (GSE39582 and TCGA COAD). Then, a 5-gene signature was constructed and the risk scores were also calculated. Survival analyses, cox analyses, and nomogram were applied to predict the prognosis of patients with colorectal cancer. The effectiveness of the risk model was also tested. Results A total of 48 genes were found to be dysregulated in serum, glucose, or glutamine-deprived CRC cells, which were mainly enriched in cell cycle and endoplasmic reticulum stress pathways. After further analyses, 5 genes, MCM5, MCM6, CDCA2, GINS2, and SPC25, were identified to be differentially expressed in CRC and be related to prognosis of in CRC datasets. We used the above nutrient stress-sensitive genes to construct a risk scoring model. CRC samples in the datasets were divided into low-risk and high-risk groups. Data showed that higher risk scores were associated with better outcomes and risk scores decreased significantly with tumor procession. Moreover, the risk score could be used to predict the probability of survival based on nomogram. Conclusions The 5-nutrient stress-sensitive gene signature could act as an independent biomarker for survival prediction of CRC patients.

Resveratrol Alleviates the Inhibitory Effect of Tunicamycin-Induced Endoplasmic Reticulum Stress on Expression of Genes Involved in Thyroid Hormone Synthesis in FRTL-5 Thyrocytes.

Recently, ER stress induced by tunicamycin (TM) was reported to inhibit the expression of key genes involved in thyroid hormone synthesis, such as sodium/iodide symporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG), and their regulators such as thyrotropin receptor (TSHR), thyroid transcription factor-1 (TTF-1), thyroid transcription factor-2 (TTF-2) and paired box gene 8 (PAX-8), in FRTL-5 thyrocytes. The present study tested the hypothesis that resveratrol (RSV) alleviates this effect of TM in FRTL-5 cells. While treatment of FRTL-5 cells with TM alone (0.1 µg/mL) for 48 h strongly induced the ER stress-sensitive genes heat shock protein family A member 5 (HSPA5) and DNA damage inducible transcript 3 (DDIT3) and repressed NIS, TPO, TG, TSHR, TTF-1, TTF-2 and PAX-8, combined treatment with TM (0.1 µg/mL) and RSV (10 µM) for 48 h attenuated this effect of TM. In conclusion, RSV alleviates TM-induced ER stress and attenuates the strong impairment of expression of genes involved in thyroid hormone synthesis and their regulators in FRTL-5 thyrocytes exposed to TM-induced ER stress. Thus, RSV may be useful for the treatment of specific thyroid disorders, provided that strategies with improved oral bioavailability of RSV are applied.

The transcriptomic responses of Atlantic salmon (Salmo salar) to high temperature stress alone, and in combination with moderate hypoxia

BackgroundIncreases in ocean temperatures and in the frequency and severity of hypoxic events are expected with climate change, and may become a challenge for cultured Atlantic salmon and negatively affect their growth, immunology and welfare. Thus, we examined how an incremental temperature increase alone (Warm & Normoxic-WN: 12 → 20 °C; 1 °C week− 1), and in combination with moderate hypoxia (Warm & Hypoxic-WH: ~ 70% air saturation), impacted the salmon’s hepatic transcriptome expr\\ession compared to control fish (CT: 12 °C, normoxic) using 44 K microarrays and qPCR.ResultsOverall, we identified 2894 differentially expressed probes (DEPs, FDR < 5%), that included 1111 shared DEPs, while 789 and 994 DEPs were specific to WN and WH fish, respectively. Pathway analysis indicated that the cellular mechanisms affected by the two experimental conditions were quite similar, with up-regulated genes functionally associated with the heat shock response, ER-stress, apoptosis and immune defence, while genes connected with general metabolic processes, proteolysis and oxidation-reduction were largely suppressed. The qPCR assessment of 41 microarray-identified genes validated that the heat shock response (hsp90aa1, serpinh1), apoptosis (casp8, jund, jak2) and immune responses (apod, c1ql2, epx) were up-regulated in WN and WH fish, while oxidative stress and hypoxia sensitive genes were down-regulated (cirbp, cyp1a1, egln2, gstt1, hif1α, prdx6, rraga, ucp2). However, the additional challenge of hypoxia resulted in more pronounced effects on heat shock and immune-related processes, including a stronger influence on the expression of 14 immune-related genes. Finally, robust correlations between the transcription of 19 genes and several phenotypic traits in WH fish suggest that changes in gene expression were related to impaired physiological and growth performance.ConclusionIncreasing temperature to 20 °C alone, and in combination with hypoxia, resulted in the differential expression of genes involved in similar pathways in Atlantic salmon. However, the expression responses of heat shock and immune-relevant genes in fish exposed to 20 °C and hypoxia were more affected, and strongly related to phenotypic characteristics (e.g., growth). This study provides valuable information on how these two environmental challenges affect the expression of stress-, metabolic- and immune-related genes and pathways, and identifies potential biomarker genes for improving our understanding of fish health and welfare.

Cold priming uncouples light- and cold-regulation of gene expression in Arabidopsis thaliana

BackgroundThe majority of stress-sensitive genes responds to cold and high light in the same direction, if plants face the stresses for the first time. As shown recently for a small selection of genes of the core environmental stress response cluster, pre-treatment of Arabidopsis thaliana with a 24 h long 4 °C cold stimulus modifies cold regulation of gene expression for up to a week at 20 °C, although the primary cold effects are reverted within the first 24 h. Such memory-based regulation is called priming. Here, we analyse the effect of 24 h cold priming on cold regulation of gene expression on a transcriptome-wide scale and investigate if and how cold priming affects light regulation of gene expression.ResultsCold-priming affected cold and excess light regulation of a small subset of genes. In contrast to the strong gene co-regulation observed upon cold and light stress in non-primed plants, most priming-sensitive genes were regulated in a stressor-specific manner in cold-primed plant. Furthermore, almost as much genes were inversely regulated as co-regulated by a 24 h long 4 °C cold treatment and exposure to heat-filtered high light (800 μmol quanta m− 2 s− 1). Gene ontology enrichment analysis revealed that cold priming preferentially supports expression of genes involved in the defence against plant pathogens upon cold triggering. The regulation took place on the cost of the expression of genes involved in growth regulation and transport. On the contrary, cold priming resulted in stronger expression of genes regulating metabolism and development and weaker expression of defence genes in response to high light triggering. qPCR with independently cultivated and treated replicates confirmed the trends observed in the RNASeq guide experiment.ConclusionA 24 h long priming cold stimulus activates a several days lasting stress memory that controls cold and light regulation of gene expression and adjusts growth and defence regulation in a stressor-specific manner.

Δ9-Tetrahydrocannabinol leads to endoplasmic reticulum stress and mitochondrial dysfunction in human BeWo trophoblasts

While studies have demonstrated that the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC) alone induces placental insufficiency and fetal growth restriction, the underlying mechanisms remain elusive. Given that both (i) endoplasmic reticulum (ER) stress in pregnancy and (ii) gestational exposure to Δ9-THC leads to placental deficiency, we hypothesized that Δ9-THC may directly induce placental ER stress, influencing trophoblast gene expression and mitochondrial function. BeWo human trophoblast cells treated with Δ9-THC (3–30 μM) led to a dose-dependent increase in all ER stress markers and CHOP; these effects could be blocked with CB1R/CB2R antagonists. Moreover, expression of ER stress-sensitive genes ERRγ, VEGFA, and FLT-1 were increased by Δ9-THC, and abrogated with the ER stress inhibitor TUDCA. Δ9-THC also diminished mitochondrial respiration and ATP-coupling due to decreased abundance of mitochondrial chain complex proteins. Collectively, these findings indicate that Δ9-THC can directly augment ER stress resulting in aberrant placental gene expression and impaired mitochondrial function.

The effect on early renal function of various dynamic preservation strategies in a preclinical pig ischemia-reperfusion autotransplant model.

The aims of this study were to determine the most optimal timing to start machine perfusion during kidney preservation to improve early graft function and to evaluate the impact of temperature and oxygen supply during machine perfusion in a porcine ischemia-reperfusion autotransplant model. The left kidney of an approximately 40-kg female Belgian Landrace pig was exposed to 30 minutes of warm ischemia via vascular clamping and randomized to 1 of 6 study groups: (1) 22-hour static cold storage (SCS) (n = 6), (2) 22-hour hypothermic machine perfusion (HMP) (n = 6), (3) 22-hour oxygenated HMP (n = 7), (4) 20-hour HMP plus 2-hour normothermic perfusion (NP) (n = 6), (5) 20-hour SCS plus 2-hour oxygenated HMP (n = 7), and (6) 20-hour SCS plus 2-hour NP (n = 6). Graft recovery measured by serum creatinine level was significantly faster for continuous HMP preservation strategies compared with SCS alone and for all end-ischemic strategies. The active oxygenated 22-hour HMP group demonstrated a significantly faster recovery from early graft function compared with the 22-hour nonactive oxygenated HMP group. Active oxygenation was also found to be an important modulator of a faster increase in renal flow during HMP preservation. Continuous oxygenated HMP applied from the time of kidney procurement until transplant might be the best preservation strategy to improve early graft function.

Common and differential transcriptional responses to different models of traumatic stress exposure in rats

The effect of six different traumatic stress protocols on the transcriptome of the rat adrenal gland was examined using RNA sequencing. These protocols included chronic variable stress, chronic shock, social defeat and social isolation. The response of the transcriptome to stress suggested that there are genes that respond in a universal or stress modality-independent manner, as well as genes that respond in a stress modality-specific manner. Using a small number of the genes selected from the modality-independent set of stress-sensitive genes, a sensitive and robust measure of chronic stress exposure was developed. This stress-sensitive gene expression (SSGE) index could detect chronic traumatic stress exposure in a wide range of different stress models in a manner that was relatively independent of the modality of stress exposure and that paralleled the intensity of stress exposure in a dose-dependent manner. This measure could reliably distinguish control and stressed individuals in the case of animals exposed to the most intense stress protocols. The response of a subset of the modality-specific genes could also distinguish some types of stress exposure, based solely on changes in the pattern of gene expression. The results suggest that it is possible to develop diagnostic measures of traumatic stress exposure based solely on changes in the level of expression of a relatively small number of genes.

The ameliorative effect ofAspergillus awamori on aflatoxin B1-induced hepatic damage in rabbits

This study was conducted to investigate the effect of dietary supplementation ofAspergillus awamorion aflatoxin B1(AFB1)-induced liver damage in rabbits. Administration of AFB1(0.3 mg/kg diet) led to a significant reduction in body weight, body weight gain, total feed intake, total serum proteins, albumin, high density lipoprotein-cholesterol, phagocytic activity, phagocytic index, and the antioxidant enzyme, glutathione peroxidase (GPx). Moreover, AFB1administration was associated with a significant increase in feed conversion ratio, lipid peroxidation and serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase and total bilirubin. In addition, livers of AFB1-supplemented animals showed fatty degeneration with vacuolisation, focal areas of necrosis, mononuclear cells infiltration hyperplasia of bile ducts and sinusoids. A significant increase in the hepatic expression of the biotransformation gene (Cyp3A6), stress-sensitive genes (HO1andSOD1), and inflammation-related genes (IL6, TNFa, NF-kB,andCox2) was also observed. Supplementation of the diets with 0.05, 0.1 or 0.15%A. awamoriameliorated all AFB1deleterious effects with the best improvement observed at the lowest concentration. This is the first investigation to report that supplementation of rabbit diets withA. awamorihas an ameliorative effect against AFB1-induced liver damage possibly through preventing hepatic oxidative stress, promoting the antioxidant defence systems, and inhibiting expression ofCyp3A6,HO1,SOD1,IL6, TNFa, NF-kB,andCox2. Therefore,A. awamoricould be used as a potential preventive or therapeutic agent for aflatoxicosis.

Impact of Terahertz Radiation on Stress-Sensitive Genes of E.Coli Cell

Terahertz (THz) radiation is increasingly used in scientific studies, as well in practical applications, primarily in medicine and safety systems, therefore, exposure of living cells to THz-waves present significant interest. We studied the impact of THz radiation on E. coli biosensor cells containing plasmids with promoters of stress-sensitive genes controlling the expression of GFP. The impact of THz radiation was nonthermal, i.e., special care was taken to keep specimen temperature in the ${\hbox{35}}\pm 2^{\circ}{\hbox{C}}$ range during irradiation so that heat shock genes would not be induced. GFP level was measured by fluorometry. We found that THz radiation activates genes associated with oxidative stress response. Lower activation levels were found for copper homeostasis genes, while antibiotics resistance genes showed no response. Thus, THz radiation impact varies for different E. coli stress systems. We conclude that THz radiation significantly affects oxidative homeostasis, which is vital for E. coli cells.

Preexposure to Olive Oil Polyphenols Extract Increases Oxidative Load and Improves Liver Mass Restoration after Hepatectomy in Mice via Stress-Sensitive Genes.

Polyphenols can act as oxidants in some conditions, inducing redox-sensitive genes. We investigated the effect of preexposure to the olive oil polyphenols extract (PFE) on time-dependent changes in the hepatic oxidative state in a model of liver regeneration—a process in which oxidative stress associated with the metabolic overload accounts for the early events that contribute to the onset of liver self-repair. Liver regeneration was induced by one-third hepatectomy in mice. Prior to hepatectomy, mice were intraperitoneally given either PFE (50 mg/kg body weight) or saline for seven consecutive days, while respective controls received vehicle alone. Redox state-regulating enzymes and thiol proteins along with the mRNA levels of Nrf2 gene and its targets γ-glutamylcysteine synthetase and heme oxygenase-1 were determined at different time intervals after hepatectomy. The liver mass restoration was calculated to assess hepatic regeneration. The resulting data demonstrate the effectiveness of preexposure to PFE in stimulating liver regeneration in a model of a small tissue loss which may be ascribed to the transient increase in oxidant load during the first hours after hepatectomy and associated induction of stress response gene-profiles under the control of Nrf2.

Effect of Low Doses (5-40 cGy) of Gamma-irradiation on Lifespan and Stress-related Genes Expression Profile in Drosophila melanogaster.

Studying of the effects of low doses of γ-irradiation is a crucial issue in different areas of interest, from environmental safety and industrial monitoring to aerospace and medicine. The goal of this work is to identify changes of lifespan and expression stress-sensitive genes in Drosophila melanogaster, exposed to low doses of γ-irradiation (5 – 40 cGy) on the imaginal stage of development. Although some changes in life extensity in males were identified (the effect of hormesis after the exposure to 5, 10 and 40 cGy) as well as in females (the effect of hormesis after the exposure to 5 and 40 cGy), they were not caused by the organism “physiological” changes. This means that the observed changes in life expectancy are not related to the changes of organism physiological functions after the exposure to low doses of ionizing radiation. The identified changes in gene expression are not dose-dependent, there is not any proportionality between dose and its impact on expression. These results reflect nonlinear effects of low dose radiation and sex-specific radio-resistance of the postmitotic cell state of Drosophila melanogaster imago.

Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

SummaryDepression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain.Video

Tickling Rats to Screen for Depressive-like Behavior in Preclinical Research

Introduction Rats produce high-frequency sounds (USVs) inaudible to the human ear. When rats are tickled their sound production increases – this is said to reflect positive emotions. The Flinders Sensitive Line (FSL) rat is a genetic rodent model of depression; hence, its altered emotional state may result in a distinct USV profile. Objectives To investigate whether USV profiles differ between rat strains and whether tickling has an antidepressant effect. To examine the effect of ketamine, a presumed rapid-acting antidepressant, on the USV profile. Lastly, to study tickling's effect on genes involved in feeding-regulation in hypothalamus and stress-sensitive genes in the submandibular glands. Aims To explore the utility of USV production during tickling stimulation as a screening method for depressive-like behavior in preclinical research. Methods We investigated the FSL rats’ USVs during six weeks of tickling. Flinders Resistant Line rats, Sprague Dawley rats and a light-touch group were used as controls. Depressive-like behavior was evaluated with the forced swim test. Ketamine or a vehicle was administered acutely after five weeks of tickling. Results Preliminary results show a significant difference between strains in their USV production during tickling. However, data analysis is still in progress and further results will be presented at the congress. Conclusions The study will elucidate the differential development of USVs following tickling stimulation in the FSL, FRL and SD rats, and furthermore shed light on the effect of tickling on the behavioral phenotype and gene expression.

The inhibitory effect of ethanol on Sestrin3 in the pathogenesis of ethanol-induced liver injury.

Sestrins (Sesns) are a family of stress-sensitive genes that have been suggested to regulate lipid metabolism. Chronic ethanol feeding is known to cause lipid accumulation in hepatocytes. This study was designed to investigate the role of Sesn3 in the pathogenesis of alcohol-induced hepatic steatosis. We demonstrated that ethanol inhibited the expression of Sesn3 in VL-17A cells. Overexpression of Sesn3 ameliorated triglyceride accumulation; downregulation using short hairpin RNA significantly deteriorated triglyceride accumulation in these cells. The expression of Sesn3 was also reduced in mice fed with ethanol for 4 wk. Overexpression of Sesn3 prevented hepatic steatosis, whereas knockdown of Sesn3 worsened hepatic steatosis in ethanol-fed mice. Overexpression of Sesn3 significantly reduced the expression of genes encoding for lipid synthesis through AMPK pathway. Overexpression of Sesn3 augmented the effect of ethanol on phospho-p70 S6 kinase. The levels of hepatic light chain 3, a marker for autophagy, expression were significantly decreased in ethanol-fed mice after Sesn3 gene was knocked down. Our findings suggest that inhibitory effect of ethanol on Sesn3 may play an important role in the development of ethanol-induced fatty liver.

Salubrinal promotes healing of surgical wounds in rat femurs

Phosphorylation of eukaryotic initiation factor 2α (eIF2α), transiently activated by various cellular stresses, is known to alleviate stress-induced cellular damage. Here, we addressed a question: does elevation of eIF2α phosphorylation by salubrinal (a pharmacological inhibitor of eIF2α dephosphorylation) enhance healing of bone wounds? We hypothesized that salubrinal would accelerate a closure of surgically generated bone holes by modifying expression of stress-sensitive genes. To examine this hypothesis, we employed a rat wound model. Surgical wounds were generated on anterior and posterior femoral cortexes, and salubrinal was locally administered on the anterior side. The results showed that, compared to a contralateral control, the size of surgical wounds was reduced by 10.8% (day 10) and 18.0% (day 20) on the anterior side (both p<0.001), and 4.1% (day 10; p<0.05) and 11.1% (day 20; p<0.001) on the posterior side. In addition, salubrinal locally elevated cortical thickness and increased BMD and BMC. Pharmacokinetic analysis revealed that subcutaneous injection of salubrinal transiently increased its concentration in plasma followed by a rapid decrease within 24h, and its half-life in plasma was 1.2h. Salubrinal altered the phosphorylation level of eIF2α as well as the mRNA levels of ATF3, ATF4, and CHOP, and suppressed cell death induced by stress to the endoplasmic reticulum. In summary, the results herein demonstrate that subcutaneous administration of salubrinal accelerates healing of surgically generated bone holes through the modulation of eIF2α phosphorylation.

Challenges for Engineers in Biomedical and Clinical Sciences

Challenges for Engineers in Biomedical and Clinical Sciences

HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells

An important aspect of vascular biology is the identification of regulators of stress-sensitive genes that play critical roles in mediating inflammatory response. Here, we show that expression of HuR in human umbilical vein endothelial cells is regulated by shear stress and statin treatment; HuR, in turn, regulates other stress-sensitive genes such as Kruppel-like factor 2 (Klf2), endothelial nitric oxide synthase (eNOS), and bone morphogenic protein 4 (BMP-4). We found that siRNA knockdown of HuR-inhibited inflammatory responses in endothelial cells, including ICAM-1 and VCAM-1 up-regulation, NFkappaB phosphorylation, and adhesion of monocytes. Tissue staining of the mouse aorta revealed increased HuR expression in the lesser curvature region of the arch that is exposed to disturbed flow, consistent with our in vitro data. Taken together, these results suggest that HuR plays a critical role in inducing inflammatory response of endothelial cells under mechanical and biochemical stresses.