Endothelin-3 Suppresses Luteinizing Hormone Receptor Expression by Regulating the cAMP-PKA Pathway in Hen Granulosa Cells.

Previous research identified the expression of EDN3 in granulosa cells of preovulatory follicles in chickens. Notably, the expression level of EDN3 in Silky Fowl with low egg-laying performance was significantly higher than that in high-yield laying breed White Leghorn. Given the crucial role of granulosa cells in follicular development and maturation, it is very important to study the effect of EDN3 on the biological function of granular cells. In this study, an EDN3 overexpression plasmid was constructed and transfected into granular cells. The viability of these cells was detected using quantiative (qPCR), Cell Counting Kit-8 (CCK8), and 5-Ethynyl-2'-deoxyuridine (EdU) assays. Gonadal hormone synthesis was detected using enzyme-linked immunosorbent assay (ELISA) techniques. Finally, transcriptome sequencing was employed to identify differentially expressed genes. Result showed thatoverexpression of EDN3 was observed to promote cell viability. In addition, it significantly inhibits the expressions of LHR and cAMP-PKA signaling pathways. Cell transcriptome sequencing data displayed that EDN3 can upregulate energy metabolism and immune-related signaling pathways, whereas follicle maturation and the GnRH signaling pathway were downregulated. In conclusion, this study demonstrates that EDN3 can enhance granulosa cell viability and inhibit the expression of LHCGR, a process likely mediated through the cAMP-PKA signaling pathway. However, further evidence is required to substantiate the regulatory relationship between EDN3 and the cAMP-PKA signaling pathway.

Auriculocondylar syndrome: Pathogenesis, clinical manifestations and surgical therapies.

Auriculocondylar syndrome (ARCND) is a genetic and rare craniofacial condition caused by abnormal development of the first and second pharyngeal arches during the embryonic stage and is characterized by peculiar auricular malformations (question mark ears), mandibular condyle hypoplasia, micrognathia and other less-frequent features. GNAI3, PLCB4 and EDN1 have been identified as pathogenic genes in this syndrome so far, all of which are implicated in the EDN1-EDNRA signal pathway. Therefore, ARCND is genetically classified as ARCND1, ARCND2 and ARCND3 based on the mutations in GNAI3, PLCB4 and EDN1, respectively. ARCND is inherited in an autosomal dominant or recessive mode with significant intra- and interfamilial phenotypic variation and incomplete penetrance, rendering its diagnosis difficult and therapies individualized. To raise clinicians' awareness of the rare syndrome, we focused on the currently known pathogenesis, pathogenic genes, clinical manifestations and surgical therapies in this review.

Further delineation of auriculocondylar syndrome based on 14 novel cases and reassessment of 25 published cases.

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.

Genetic variant in the 5' untranslated region of endothelin1 (EDN1) gene in children with primary nephrotic syndrome.

Endothelin-1 plays a crucial role in the pathophysiology of nephrotic syndrome (NS) in children. The primary purpose of this study is to evaluate the contribution of the EDN1 (3A/4A; rs1800997) variant to the risk of nephrotic syndrome. This study involves 200 participants (100 healthy controls, 50 steroid-sensitive nephrotic syndromes [SSNS] patients, and 50 steroid-resistant nephrotic syndromes [SRNS] patients]. Genomic DNA has been characterized using the PCR-RFLP technique. The predominant genotype that is common in this study population was the EDN1 3A/3A genotype (NS [75%] and healthy controls [88%]). The prevalence of EDN1 3A/4A genotype and EDN1 4A allele was significantly increased among NS patients compared with healthy subjects (p-value < 0.05). Furthermore, the frequency of the EDN1 (3A/4A; rs1800997) variant was statistically significant among SRNS patients (p-value < 0.05). The EDN1 3A/4A genotype and the EDN1 4A allele were identified as independent risk factors of the nephrotic syndrome among children.

Asthma and Allergy: Unravelling a Tangled Relationship with a Focus on New Biomarkers and Treatment.

Asthma is a major driver of health care costs across ages. Despite widely disseminated asthma-treatment guidelines and a growing variety of effective therapeutic options, most patients still experience symptoms and/or refractoriness to standard of care treatments. As a result, most patients undergo a further intensification of therapy to optimize symptom control with a subsequent increased risk of side effects. Raising awareness about the relevance of evaluating aeroallergen sensitizations in asthmatic patients is a key step in better informing clinical practice while new molecular tools, such as the component resolved diagnosis, may be of help in refining the relationship between sensitization and therapeutic recommendations. In addition, patient care should benefit from reliable, easy-to-measure and clinically accessible biomarkers that are able to predict outcome and disease monitoring. To attain a personalized asthma management and to guide adequate treatment decisions, it is of paramount importance to expand clinicians' knowledge about the tangled relationship between asthma and allergy from a molecular perspective. Our review explores the relevance of allergen testing along the asthma patient's journey, with a special focus on recurrent wheezing children. Here, we also discuss the unresolved issues regarding currently available biomarkers and summarize the evidence supporting the eosinophil-derived neurotoxin as promising biomarker.

Sirtuin-1 inhibits endothelin-2 expression in human granulosa-lutein cells via hypoxia inducible factor 1 alpha and epigenetic modifications†.

Endothelin-2 (EDN2) expression in granulosa cells was previously shown to be highly dependent on the hypoxic mediator, hypoxia inducible factor 1 alpha (HIF1A). Here, we investigated whether sirtuin-1 (SIRT1), by deacetylating HIF1A and class III histones, modulates EDN2 in human granulosa-lutein cells (hGLCs). We found that HIF1A was markedly suppressed in the presence of resveratrol or a specific SIRT1 activator, SRT2104. In turn, hypoxia reduced SIRT1 levels, implying a mutually inhibitory interaction between hypoxia (HIF1A) and SIRT1. Consistent with reduced HIF1A transcriptional activity, SIRT1 activators, resveratrol, SRT2104, and metformin, each acting via different mechanisms, significantly inhibited EDN2. In support, knockdown of SIRT1 with siRNA markedly elevated EDN2, whereas adding SRT2104 to SIRT1-silenced cells abolished the stimulatory effect of siSIRT1 on EDN2 levels further demonstrating that EDN2 is negatively correlated with SIRT1. Next, we investigated whether SIRT1 can also mediate the repression of the EDN2 promoter via histone modification. Chromatin immunoprecipitation (ChIP) analysis revealed that SIRT1 is indeed bound to the EDN2 promoter and that elevated SIRT1 induced a 40% decrease in the acetylation of histone H3, suggesting that SIRT1 inhibits EDN2 promoter activity by inducing a repressive histone configuration. Importantly, SIRT1 activation, using SRT2104 or resveratrol, decreased the viable numbers of hGLC, and silencing SIRT1 enhanced hGLC viability. This effect may be mediated by reducing HIF1A and EDN2 levels, shown to promote cell survival. Taken together, these findings propose novel, physiologically relevant roles for SIRT1 in downregulating EDN2 and survival of hGLCs.

ERN1 knockdown modifies the impact of glucose and glutamine deprivations on the expression of EDN1 and its receptors in glioma cells.

Objective. The aim of the present investigation was to study the impact of glucose and gluta-mine deprivations on the expression of genes encoding EDN1 (endothelin-1), its cognate receptors (EDNRA and EDNRB), and ECE1 (endothelin converting enzyme 1) in U87 glioma cells in response to knockdown of ERN1 (endoplasmic reticulum to nucleus signaling 1), a major signaling pathway of endoplasmic reticulum stress, for evaluation of their possible implication in the control of glioma growth through ERN1 and nutrient limitations. Methods. The expression level of EDN1, its receptors and converting enzyme 1 in control U87 glioma cells and cells with knockdown of ERN1 treated by glucose or glutamine deprivation by quantitative polymerase chain reaction was studied. Results. We showed that the expression level of EDN1 and ECE1 genes was significantly up-regulated in control U87 glioma cells exposure under glucose deprivation condition in comparison with the glioma cells, growing in regular glucose containing medium. We also observed up-regulation of ECE1 gene expression in U87 glioma cells exposure under glutamine deprivation as well as down-regulation of the expression of EDN1 and EDNRA mRNA, being more significant for EDN1. Furthermore, the knockdown of ERN1 signaling enzyme function significantly modified the response of most studied gene expressions to glucose and glutamine deprivation conditions. Thus, the ERN1 knockdown led to a strong suppression of EDN1 gene expression under glucose deprivation, but did not change the effect of glutamine deprivation on its expression. At the same time, the knockdown of ERN1 signaling introduced the sensitivity of EDNRB gene to both glucose and glutamine deprivations as well as completely removed the impact of glucose deprivation on the expression of ECE1 gene. Conclusions. The results of this study demonstrated that the expression of endothelin-1, its receptors, and ECE1 genes is preferentially sensitive to glucose and glutamine deprivations in gene specific manner and that knockdown of ERN1 significantly modified the expression of EDN1, EDNRB, and ECE1 genes in U87 glioma cells. It is possible that the observed changes in the expression of studied genes under nutrient deprivation may contribute to the suppressive effect of ERN1 knockdown on glioma cell proliferation and invasiveness.

Charcot-Leyden crystal protein/galectin-10 interacts with cationic ribonucleases and is required for eosinophil granulogenesis.

BACKGROUND: The human eosinophil Charcot-Leyden crystal (CLC) protein is a member of the Galectin superfamily and is also known as galectin-10 (Gal-10). CLC/Gal-10 forms the distinctive hexagonal bipyramidal crystals that are considered hallmarks of eosinophil participation in allergic responses and related inflammatory reactions; however, the glycan-containing ligands of CLC/Gal-10, its cellular function(s), and its role(s) in allergic diseases are unknown. OBJECTIVE: We sought to determine the binding partners of CLC/Gal-10 and elucidate its role in eosinophil biology. METHODS: Intracellular binding partners were determined by ligand blotting with CLC/Gal-10, followed by coimmunoprecipitation and coaffinity purifications. The role of CLC/Gal-10 in eosinophil function was determined by using enzyme activity assays, confocal microscopy, and short hairpin RNA knockout of CLC/Gal-10 expression in human CD34+ cord blood hematopoietic progenitors differentiated to eosinophils. RESULTS: CLC/Gal-10 interacts with both human eosinophil granule cationic ribonucleases (RNases), namely, eosinophil-derived neurotoxin (RNS2) and eosinophil cationic protein (RNS3), and with murine eosinophil-associated RNases. The interaction is independent of glycosylation and is not inhibitory toward endoRNase activity. Activation of eosinophils with INF-γ induces the rapid colocalization of CLC/Gal-10 with eosinophil-derived neurotoxin/RNS2 and CD63. Short hairpin RNA knockdown of CLC/Gal-10 in human cord blood-derived CD34+ progenitor cells impairs eosinophil granulogenesis. CONCLUSIONS: CLC/Gal-10 functions as a carrier for the sequestration and vesicular transport of the potent eosinophil granule cationic RNases during both differentiation and degranulation, enabling their intracellular packaging and extracellular functions in allergic inflammation.

Genome-wide analysis of facial skeletal regionalization in zebrafish.

Patterning of the facial skeleton involves the precise deployment of thousands of genes in distinct regions of the pharyngeal arches. Despite the significance for craniofacial development, how genetic programs drive this regionalization remains incompletely understood. Here we use combinatorial labeling of zebrafish cranial neural crest-derived cells (CNCCs) to define global gene expression along the dorsoventral axis of the developing arches. Intersection of region-specific transcriptomes with expression changes in response to signaling perturbations demonstrates complex roles for Endothelin 1 (Edn1) signaling in the intermediate joint-forming region, yet a surprisingly minor role in ventralmost regions. Analysis of co-variance across multiple sequencing experiments further reveals clusters of co-regulated genes, with in situ hybridization confirming the domain-specific expression of novel genes. We then created loss-of-function alleles for 12 genes and uncovered antagonistic functions of two new Edn1 targets, follistatin a (fsta) and emx2, in regulating cartilaginous joints in the hyoid arch. Our unbiased discovery and functional analysis of genes with regional expression in zebrafish arch CNCCs reveals complex regulation by Edn1 and points to novel candidates for craniofacial disorders.

Growth factor and receptor malfunctions associated with human genetic deafness.

A variety of different signaling pathways are necessary for development and maintenance of the human auditory system. Normal hearing allows for the detection of soft sounds within the frequency range of 20 to 20 000 Hz, but more importantly to perceive the human voice frequency band of 250 to 6000 Hz. Loss of hearing is common, and is a clinically heterogeneous disorder that can be caused by environmental factors such as exposure to loud noise, infections and ototoxic drugs. In addition, variants of hundreds of genes have been reported to disrupt processes required for hearing. Noncoding regulatory variants and variants of additional genes necessary for hearing remain to be discovered as many individuals with inherited deafness are without a genetic diagnosis, despite the advent of whole exome sequencing. Here, we discuss in detail some of these deafness-causing variants of genes encoding a ligand or its receptor. Spotlighted in this review are three growth factor-receptor-pairs EDN3/EDNRB, HGF/MET and JAG/NOTCH, which individually are necessary for normal hearing. We also offer our perspective on unanswered questions, future challenges and potential opportunities for treatments emerging from molecular genetic and mechanistic studies of deafness due to these causes.

Endothelin-1 rs9296344 associates with the susceptibility of childhood primary nephrotic syndrome.

BACKGROUND: Recently, the rs5370 single nucleotide polymorphisms (SNPs) of Endothelin-1 (EDN1) showed association with the susceptibility of childhood primary nephrotic syndrome (CPNS). This study aims to investigate potential relationships between other EDN1 SNPs and CPNS. METHODS: Seven SNPs (rs5370, rs10478723, rs1476046, rs1800541, rs2070698, rs2071942, and rs9296344) of the EDN1 gene were genotyped in 579 CPNS patients and 586 age-matched healthy children. Then, we analyzed potential associations of the six SNPs with susceptibility of CPNS by using rs5370 as a conditional variant in a logistic regression model. SNP-SNP interaction analysis was performed to investigate the joint effects of the seven SNPs in the pathogenesis of CPNS. RESULTS: Independent with rs5370, only rs9296344 significantly associated (T vs C, odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.57-0.88, P = .001) with the susceptibility of CPNS. Meanwhile, no joint effect among the analyzed seven SNPs was discovered in this study. CONCLUSIONS: This study discovered that C allele of rs9296344 on EDN1 is a novel independent risk factor for CPNS.

Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells.

Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-ß receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondrial reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis.

Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data.

BACKGROUND: The alpha-adrenergic agonist phenylephrine is often used to treat hypotension during anesthesia. In clinical situations, low blood pressure may require prompt intervention by intravenous bolus or infusion. Differences in responsiveness to phenylephrine treatment are commonly observed in clinical practice. Candidate gene studies indicate genetic variants may contribute to this variable response. METHODS: Pharmacological and physiological data were retrospectively extracted from routine clinical anesthetic records. Response to phenylephrine boluses could not be reliably assessed, so infusion rates were used for analysis. Unsupervised k-means clustering was conducted on clean data containing 4130 patients based on phenylephrine infusion rate and blood pressure parameters, to identify potential phenotypic subtypes. Genome-wide association studies (GWAS) were performed against average infusion rates in two cohorts: phase I (n = 1205) and phase II (n = 329). Top genetic variants identified from the meta-analysis were further examined to see if they could differentiate subgroups identified by k-means clustering. RESULTS: Three subgroups of patients with different response to phenylephrine were clustered and characterized: resistant (high infusion rate yet low mean systolic blood pressure (SBP)), intermediate (low infusion rate and low SBP), and sensitive (low infusion rate with high SBP). Differences among clusters were tabulated to assess for possible confounding influences. Comorbidity hierarchical clustering showed the resistant group had a higher prevalence of confounding factors than the intermediate and sensitive groups although overall prevalence is below 6%. Three loci with P < 1 × 10-6 were associated with phenylephrine infusion rate. Only rs11572377 with P = 6.09 × 10-7, a 3'UTR variant of EDN2, encoding a secretory vasoconstricting peptide, could significantly differentiate resistant from sensitive groups (P = 0.015 and 0.018 for phase I and phase II) or resistant from pooled sensitive and intermediate groups (P = 0.047 and 0.018). CONCLUSIONS: Retrospective analysis of electronic anesthetic records data coupled with the genetic data identified genetic variants contributing to variable sensitivity to phenylephrine infusion during anesthesia. Although the identified top gene, EDN2, has robust biological relevance to vasoconstriction by binding to endothelin type A (ETA) receptors on arterial smooth muscle cells, further functional as well as replication studies are necessary to confirm this association.

Rho and Rac, but not ROCK, are required for secretion of human and mouse eosinophil-associated RNases.

BACKGROUND: Eosinophil-associated RNases (EARs) are stored preformed in eosinophil cytoplasmic secretory granules and have a key role in eosinophil effector functions in host defence and inflammatory disorders. However, the secretion mechanisms of EARs are poorly understood. OBJECTIVE: Our study aimed to understand the involvement of cytoskeleton machinery in EAR secretion. METHODS: Fresh human and mouse eosinophils were stimulated with CCL11, and the secretion of enzymatically active EARs was detected using an RNase activity assay. The involvement of cytoskeletal elements or microtubules was probed using specific inhibitors. RESULTS: We found that dynamic polymerization of microtubules and cytoskeletal elements, such as Rho and Rac, is required for chemokine-mediated EAR secretion from human and mouse eosinophils. However, inhibition of ROCK (Rho-associated protein kinase) increased EAR secretion in human and mouse eosinophils even in the absence of chemokine stimulation, suggesting ROCK negatively regulates EAR secretion. CONCLUSIONS: Collectively, these data suggest a cytoskeleton-dependent mechanism of EAR secretion from eosinophils, findings that are pertinent to host defence, allergy and other eosinophil-associated diseases.

Ultrastable and Biofunctionalizable Conjugated Polymer Nanoparticles with Encapsulated Iron for Ferroptosis Assisted Chemodynamic Therapy.

We report the development of novel tumor-targeted conjugated polymer nanoparticles (CPNPs) carrying iron for chemodynamic therapy (CDT). Tumor cell killing proceeds through ferroptosis, a reactive oxygen species (ROS) mechanism that is not dependent on external activation by, for example, light, as is the case in photodynamic therapy (PDT). The ferroptosis mechanism is also not heavily reliant on oxygen availability and is, therefore, promising for the treatment of hypoxic tumors. In this work, we apply this development to the case study of melanoma, a difficult to treat cancer in advanced stages due to resistance to chemotherapy. The iron-carrying CPNPs reported here are targeted to endothelin-B receptors (EDNRB) through endothelin-3 surface moieties (EDN3-CPNPs). Our results show excellent targeting to tumor cells that overexpress EDNRB, specifically for melanoma and bladder tumor cells. In these cases, efficient cell killing, over 80% at higher doses, was found. Conversely, tumor cells not targeted by the EDN3-CPNPs show little effects of CDT, with tumor cell death under 20% in most cases. The outcomes of our work demonstrate that EDN3-CPNPs enable ferroptosis-assisted CDT and present a new therapeutic avenue for tumor treatment.

MicroRNA-124 Enhances Dopamine Receptor Expression and Neuronal Proliferation in Mouse Models of Parkinson's Disease via the Hedgehog Signaling Pathway by Targeting EDN2.

Recent studies have elaborated on the concept that a number of microRNAs (miRNAs) have a potential effect on the pathogenesis and development of Parkinson's disease (PD). PD is recognized as a common progressive bradykinetic disorder that results from the death of dopaminergic neurons in the substantia nigra. The purpose of this study was to explore whether microRNA-124 (miR-124) affected dopamine receptor (DAR) expression and neuronal proliferation and apoptosis in the 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse models of PD. The targeting relationship of miR-124 and EDN2 was confirmed through bioinformatic predictions and dual-luciferase reporter assay. The expression of miR-124 and EDN2 was altered to assess their effect on the expression of DAR in the substantia nigra and isolated neurons, as well as the neuronal proliferation and apoptosis rate. The obtained results implied that the treatments of miR-124 mimic and si-EDN2 resulted in elevated expressions of Glil, SHH, PTCH1, DAT, DRD1, and DRD2. However, these treatments facilitated neuronal proliferation and suppressed neuronal apoptosis, corresponding to reduced expression of caspase-3 and Bax, as well as increased levels of Bcl-2 expression. These results were discovered to be achieved through the activation of the Hedgehog signaling pathway. With this taken into account, our study demonstrated that miR-124 overexpression promoted DAR expression and neuronal proliferation and suppressed neuronal apoptosis by downregulating EDN2 via activating the Hedgehog signaling pathway.

Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells.

OBJECTIVE: The aim of the present investigation was to study the effect of hypoxia on the expression of genes encoding endothelin-1 (EDN1) and its cognate receptors (EDNRA and EDNRB) as well as endothelin converting enzyme 1 (ECE1) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of glioma growth through ERN1 and hypoxia. METHODS: The expression level of EDN1, EDNRA, EDNRB, and ECE1 genes as well as micro-RNA miR-19, miR-96, and miR-206 was studied in control and ERN1 knockdown U87 glioma cells under hypoxia by quantitative polymerase chain reaction. RESULTS: It was shown that the expression level of EDN1, EDNRA, EDNRB, and ECE1 genes was up-regulated in ERN1 knockdown glioma cells in comparison with the control glioma cells, being more significant for endothelin-1. We also observed down-regulation of microRNA miR-206, miR-96, and miR-19a, which have specific binding sites in mRNA EDN1, EDNRA, and EDNRB, correspondingly, and can participate in posttranscriptional regulation of these mRNA expressions. Furthermore, inhibition of ERN1 endoribonuclease lead to up-regulation of EDNRA and ECE1 gene expressions and down-regulation of the expression level of EDN1 and EDNRB genes in glioma cells. Thus, the expression of EDNRA and ECE1 genes is regulated by ERN1 endoribonuclease, but EDN1 and EDNRB genes preferentially by ERN1 protein kinase. We have also shown that hypoxia enhanced the expression of EDN1, EDNRA, and ECE1 genes and that knockdown of ERN1 signaling enzyme function significantly modified the response of all studied gene expressions to hypoxia. Thus, effect of hypoxia on the expression level of EDN1 and ECE1 genes was significantly or completely reduced in ERN1 knockdown glioma cells since the expression of EDNRA gene was down-regulated under hypoxia. Moreover, hypoxia is induced the expression of EDNRB gene in ERN1 knockdown glioma cells. CONCLUSIONS: Results of this investigation demonstrate that ERN1 knockdown significantly increased the expression of endothelin-1 and its receptors as well as ECE1 genes by different mechanisms and that all studied gene expressions were sensitive to hypoxia. It is possible that hypoxic regulation of the expression of these genes is a result of complex interaction of variable ERN1 related transcription and regulatory factors with HIF1A and possibly contributed to the control of glioma growth.

Gene Expression Profiles of Tumor Necrosis Factor-α and Endothelin-1 in Obstructive Sleep Apnea.

BACKGROUND/AIMS: The aim of this study was to observe the relationship between the gene expression profiles of tumor necrosis factor (TNF)-α and endothelin (EDN)-1 and obstructive sleep apnea (OSA). METHODS: A prospective, cross-sectional study performed at a tertiary-care academic center; 108 patients with snoring and day-time sleeplessness were included in this study carried out in the Otolaryngology Department. All patients were evaluated with 1-night polysomnography (PSG). There were 63 patients with OSA and 45 patients without OSA. In the OSA group, the median apnea hypopnea index (AHI) was 29.1; in the non-OSA group, the median AHI was 2.1. Blood samples were obtained from all 108 patients for the genetic analysis of the expression of TNF-α and EDN-1. PSG findings and gene expression levels were evaluated in both groups. RESULTS: The median (range) age was 46 (20-81) years, BMI 24.9 (15-49), EDN-1 gene expression 0.45 (0.02-67.88) pg/µL, and TNF-α gene expression 1.71 (0.08-59.52) pg/µL. We found that EDN-1 and TNF-α gene expression levels were significantly higher in the OSA group than in the control group (p = 0.009 vs. p < 0.001). CONCLUSION: EDN-1 and TNF-α gene expression levels were associated with the occurrence of OSA.

Facial whisker pattern is not sufficient to instruct a whisker-related topographic map in the mouse somatosensory brainstem.

Facial somatosensory input is relayed by trigeminal ganglion (TG) neurons and serially wired to brainstem, thalamus and cortex. Spatially ordered sets of target neurons generate central topographic maps reproducing the spatial arrangement of peripheral facial receptors. Facial pattern provides a necessary template for map formation, but may be insufficient to impose a brain somatotopic pattern. In mice, lower jaw sensory information is relayed by the trigeminal nerve mandibular branch, whose axons target the brainstem dorsal principal sensory trigeminal nucleus (dPrV). Input from mystacial whiskers is relayed by the maxillary branch and forms a topographic representation of rows and whiskers in the ventral PrV (vPrV). To investigate peripheral organisation in imposing a brain topographic pattern, we analysed Edn1(-/-) mice, which present ectopic whisker rows on the lower jaw. We found that these whiskers were innervated by mandibular TG neurons which initially targeted dPrV. Unlike maxillary TG neurons, the ectopic whisker-innervating mandibular neuron cell bodies and pre-target central axons did not segregate into a row-specific pattern nor target the dPrV with a topographic pattern. Following periphery-driven molecular repatterning to a maxillary-like identity, mandibular neurons partially redirected their central projections from dPrV to vPrV. Thus, while able to induce maxillary-like molecular features resulting in vPrV final targeting, a spatially ordered lower jaw ectopic whisker pattern is insufficient to impose row-specific pre-target organisation of the central mandibular tract or a whisker-related matching pattern of afferents in dPrV. These results provide novel insights into periphery-dependent versus periphery-independent mechanisms of trigeminal ganglion and brainstem patterning in matching whisker topography.