ABSTRACT
@#Objective To investigate the mechanism of insulin alleviating pulmonary edema in mice with acute lung injury(ALI) by serine/threonine protein kinase-1(SGK1).Methods 32 male adult C3H/HeN mice were randomly divided into control group(only pumped with the same amount of normal saline as the treatment group),ALI group(continuously pumped with the same amount of normal saline as the treatment group after modeling),treatment group [continuously pumped with 0.1 U/(kg·h) of insulin through jugular vein after establishing ALI model] and SGK1 siRNA group[continuously pumped with 0.1 U/(kg·h) of insulin and given SGK1 siRNA(75 μg SGK1 siRNA diluted in 100 μL saline) simultaneously after establishing ALI model] with 8 mice in each group.After 8 h,the mice were killed for arterial blood gas analysis(1 h after establishment of the model) and the changes of plasma glucose levels were detected(0,1,4and 8 h);The bronchoalveolar lavage fluid(BALF) was collected to detect the content of total protein,and the alveolar epithelial permeability and lung water content were measured;The pathological changes of lung tissue and apoptosis of lung epithelial cells were observed;The protein expressions of alveolar epithelial sodium channel(ENaC) and α_1-Na~+,K~+-ATPase and the phosphorylation level of SGK1 were determined by Western blot.Results There was no significant difference in plasma glucose level of ALI and treatment group at 0,1,4 and 8 h after insulin infusion(t=1.330 0,0.986 0,0.565 7 and 0.724 3,P=0.204 7,0.340 7,0.580 6 and 0.480 8,respectively).Compared with ALI group,the partial pressure of oxygen in arterial blood in treatment group increased significantly(t=6.026,P <0.000 1),while the BALF protein content,alveolar epithelial permeability,lung water content and lung epithelial cells apoptosis decreased significantly(t=7.39,5.286,5.651 and 3.312,P <0.000 1,=0.000 4,=0.000 2 and=0.007 8,respectively),and the expression of α-ENaC and α_1-Na~+,K~+-ATPase and the phosphorylation level of SGK1 in lung tissue significantly increased(t=26,18.67 and 8.547,P <0.000 1,<0.000 1 and=0.000 1,respectively);Compared with the treatment group,the BALF protein content,alveolar epithelial permeability,lung water content and lung epithelial cells apoptosis increased significantly in SGK1 siRNA group(t=5.964,3.449,3.148 and 3.520,P=0.000 2,0.006 2,0.010 4 and0.016 9,respectively),while α-ENaC and α_1-Na~+,K~+-ATPase protein expression and SGK1 phosphorylation level decreased significantly(t=13,9.874 and 7.741,P <0.000 1,<0.000 1 and=0.001 5,respectively).Conclusion Exogenous insulin can alleviate the pulmonary edema in ALI mice,which might be mediated via up-regulation of the expressions of α-ENaC and α_1-Na~+,K~+-ATPase by SGK1.
ABSTRACT
Aim To analyze the genotype-phenotype characteristics of voltage-gated potassium channels (Kv) associated genetic epilepsy and evaluate the efficacy of anti-seizure medications(ASMs). Methods PubMed database was searched and patients meeting the inclusion criteria were included for analysis. We divided the patients into “benign”, “encephalopathic” and other phenotypes according to the clinical characteristics. We performed descriptive statistical analysis of patients' mutated genes, clinical phenotype and drug efficacy, and used logistic regression to explore the influencing factors of treatment outcome. Results Data of 474 children were included for analysis. There were significant differences among different phenotypes in mutated genes, source of mutations and so on. In terms of clinical characteristics, there were also significant differences between patients with different phenotypes in age of onset, combined developmental delay and so on. In terms of monotherapy, phenobarbital was the most common treatment choice for children with “benign” phenotype, and sodium channel blockers (SCBs) were the most common treatment choice for children with “encephalopathy” phenotype, and the efficacy of SCBs monotherapy was superior to that of other ASMs. Multivariate Logistic analysis of the children receiving monotherapy showed that whether the children were combined with developmental delay and whether SCBs were used were significant factors influencing the efficacy of drug therapy. Conclusions Patients with the “benign” and “encephalopathic” phenotypes differ in several aspects of genetic variation, clinical characteristics, and drug selection. These results suggest that SCBs may be one of the recommended options for monotherapy.
ABSTRACT
Aim To investigate the effects of IL-33/ST2 signal regulation by osteomortin on immune function and sodium channel in otitis media rats. Methods Fifty SD rats were randomly divided into NO group (normal rats with gavage of normal saline), MO group (model rats with gavage of normal saline), OS group (model rats with gavage of 40 mg • kg-
ABSTRACT
OBJECTIVE@#To investigate the variations in the expression of voltage-gated sodium (Nav) channel subunits during development of rat cerebellar Purkinje neurons and their correlation with maturation of electrophysiological characteristics of the neurons.@*METHODS@#We observed the changes in the expression levels of NaV1.1, 1.2, 1.3 and 1.6 during the development of Purkinje neurons using immunohistochemistry in neonatal (5-7 days after birth), juvenile (12-14 days), adolescent (21-24 days), and adult (42-60 days) SD rats. Using whole-cell patch-clamp technique, we recorded the spontaneous electrical activity of the neurons in ex vivo brain slices of rats of different ages to analyze the changes of electrophysiological characteristics of these neurons during development.@*RESULTS@#The expression of NaV subunits in rat cerebellar Purkinje neurons showed significant variations during development. NaV1.1 subunit was highly expressed throughout the developmental stages and increased progressively with age (P < 0.05). NaV1.2 expression was not detected in the neurons in any of the developmental stages (P > 0.05). The expression level of NaV1.3 decreased with development and became undetectable after adolescence (P < 0.05). NaV1.6 expression was not detected during infancy, but increased with further development (P < 0.05). NaV1.1 and NaV1.3 were mainly expressed in the early stages of development. With the maturation of the rats, NaV1.3 expression disappeared and NaV1.6 expression increased in the neurons. NaV1.1 and NaV1.6 were mainly expressed after adolescence. The total NaV protein level increased gradually with development (P < 0.05) and tended to stabilize after adolescence. The spontaneous frequency and excitability of the Purkinje neurons increased gradually with development and reached the mature levels in adolescence. The developmental expression of NaV subunits was positively correlated with discharge frequency (r=0.9942, P < 0.05) and negatively correlated with the excitatory threshold of the neurons (r=0.9891, P < 0.05).@*CONCLUSION@#The changes in the expression levels of NaV subunits are correlated with the maturation of high frequency electrophysiological properties of the neurons, suggesting thatmature NaV subunit expressions is the basis of maturation of electrophysiological characteristics of the neurons.
Subject(s)
Rats , Animals , Purkinje Cells/physiology , Rats, Sprague-Dawley , Neurons , Brain , Sodium/metabolismABSTRACT
A diagnosis of congenital long QT interval syndrome based on history and electrocardiogram was made in a child in the absence of readily available genetic testing. A genotype 3 (LQT3) was suspected after exclusion of other variants as the child was non?responsive to beta?blocker and sodium channel blocker medication. As the child continues to show episodic bradycardia, polymorphic ventricular ectopy, and T?wave alternans, a single?chamber automated implantable cardioverter?defibrillator implantation was done successfully. This report highlights how the diagnosis of LQT3 was arrived at as well as the anesthetic challenges in the management of patients with LQTS.
ABSTRACT
@#Abstract: Objective To understand the kdr (knockdown resistance, kdr) gene mutation of the voltage-gated sodium channel (VGSC) of Anopheles sinensis in Yunnan Province. Methods From 2018 to 2019, mosquitoes were collected in Luoping County, Suijiang County, Tengchong City, Yingjiang County, Yuanjiang County and Mengla County in Yunnan Province. The collected mosquitoes were morphologically identified as Anopheles sinensis and genomic DNA was extracted by kits. The DNA templates were sequenced after PCR amplification and the sequencing results were identify as Anopheles sinensis by homology alignment in NCBI. After the ⅡS5 and ⅡS6 fragments of the sodium channels in Anopheles sinensis were amplified and sequenced, the sequencing results were multiple aligned by DNAMAN software, and the mutations were analyzed one by one with BioEdit software to determine the kdr allele types and genotypes, and the frequencies were calculated. Results This survey amplified 287 sequences, and the sequence maps showed that 1014 loci had three alleles, including wild type TTG/L (89.20%), mutant type TTT/F (9.76%) and TCG/S (1.04%). Five genotypes: homozygous wildtype L/L (85.02%), homozygous mutant F/F (6.27%) and S/S (0.35%), heterozygous mutant L/F (6.97%) and L/S (1.39%). The wild type allele TTG/L was the main allele in six sampling sites except Suijiang County. The frequency of wild type allele in Tengchong City was the highest (100.00%). That is, no mutation was detected, while the rest of counties occurred different degrees of mutation at 1014 loci. The frequency of mutant allele in Suijiang County was the highest, reaching 55.68%. Luoping County, Mengla County and Suijiang County had two mutant types. Yingjiang County and Yuanjiang County had one heterozygous mutant L/F. Conclusion Wild type L1014 (TTG/L) is still dominant in most areas of Yunnan Province. The kdr mutation type is mainly L1014F, followed by L1014S, and the mutation frequency is lower than that in central provinces of China.
ABSTRACT
Objective:To explore the clinical phenotype characteristics of early-onset epileptic encephalopathy (EOEE) caused by sodium channel mutations.Methods:A retrospective study was used.A total of 52 EOEE patients treated in the Department of Neurology, Children′s Hospital of Fudan University and Department of Neurology, Wuhan Children′s Hospital, Tongji Medical College, Huazhong University of Science & Technology from June 2016 to June 2019 were recruited.Peripheral blood samples of 52 patients and their parents were collected for analyzing pathogenic mutations by the next generation sequencing and copy number variations of whole exons in family. Chi- square test was used to compare seizure control data among different voltage-gated sodium channel α1 subunit ( SCN1A) mutation types. Results:A total of 35/52 cases (67.3%) were diagnosed as Dravet syndrome, 3/52 cases (5.8%) were West syndrome, and 14/52 cases (26.9%) were non-symptomatic EOEE.The electroencephalogram (EEG) findings showed a large number of multifocal spikes, spike-slow waves, sharp waves, and sharp-slow waves.A total of 45/52 cases (86.5%) showed normal brain magnetic resonance imaging(MRI), 1 case had slightly widened bilateral frontal sulcus, 1 case had widened bilateral temporal pole and frontal top subarachnoid space, and the remaining 5 cases had widened extracerebral space and slightly larger ventricles.Thirteen cases were re-examined with brain MRI, and 3 cases had mild brain atrophy.A total of 43/52 cases (82.7%) were examined with SCN1A gene mutations, of which 28/52 cases (53.8%) were missense mutations, 5/52 cases (9.6%) were nonsense mutations, 7/52 cases (13.5%) were frameshift mutations and 3/52 cases (5.8%) were splice site mutations.A total of 3/52 cases (5.8%) had SCN2A mutations, of which 2/52 cases (3.8%) were missense mutations, and 1/52 case (1.9%) was a frameshift mutation, 1/52 cases (1.9%) carrying the missense mutation of the SCN3A gene.A total of 5/52 cases (9.6%) had missense mutations of the SCN8A gene.After an average of 1-year follow-up, a total of 13/52 cases (25.0%) had more than 1-year control of seizure, of which 6/52 cases (11.5%) with seizure control for more than 2 years, and 4/52 cases (7.7%) with more than 3-year control.Children carrying SCN1A missense mutations were relatively easier to be controlled for seizures than those carrying SCN1A truncation mutations (nonsense mutations+ frameshift mutations) ( P<0.05). In 5 children carrying SCN8A mutations, 2 cases of them had seizures control for more than 1 year after adding Oxcarbazepine, but the improvement of mental motor function was not obvious. Conclusions:In children with EOEE associated with sodium channel gene mutations, SCN1A, SCN2A, SCN3A, and SCN8A mutations were pathogenic factors.Among them, SCN1A was the most common pathogenic gene for EOEE, with the mutation rate of 82.7%.Dravet syndrome was the most common clinical phenotype of EOEE associated with sodium channel gene mutations.Epileptic seizures in children carrying SCN1A missense mutations were easier to be controlled than those with truncated mutation (nonsense mutations + frameshift mutations), suggesting that the gene mutation type was related to the degree of seizures control.Oxcarbazepine was effective in the treatment of EOEE with SCN8A gene mutations, indicating that the combination therapy using anti-epilepsy drugs can be applied to EOEE patients according to the type of gene function.
ABSTRACT
ObjectiveTo observe the regulatory effect of Xiao Qinglongtang and its ingredients on lung water transport-related proteins， and to explain the biological connotation of lung governing water movement， based on which the regulatory mechanism of Xiao Qinglongtang will be explored. MethodAccording to the composition rules of classical formula， Xiao Qinglongtang （11.22 g·kg-1）， Guizhi Gancao （2.70 g·kg-1）， Shaoyao Gancao （2.70 g·kg-1）， Jiangxinwei （3.90 g·kg-1）and Banxia Muahuang （0.032 7 g·kg-1） were prepared. The pathological model of syndrome of cold fluid accumulated in lung of rats was established by the "coldness of body + drinking cold + cold bath" method， and Xiao Qinglongtang and its ingredients were administrated to intervene with the model rats. Lung function parameters of forced vital capacity （FVC）， functional residual capacity （FRC）， mean mid-expiratory flow （MMEF）， inspiratory time （tI）， and inspiratory time （tE） were determined by lung function analyzer. Hematoxylin and eosin （HE） staining was used to observe the changes in pathological morphology. The expression of aquaporin （AQP）1， AQP5， epithelial sodium channel α subunit（α-ENaC） and Na+-K+-ATPase in lung tissues of rats， the content of tumor necrosis factor -α（TNF-α）， the mRNA expression of cyclic adenosine monophosphate （cAMP）， protein kinase A （PKA） and cAMP-response element binding protein （CREB）， and the protein expression of cAMP， PKA， CREB， and phosphorylated-CREB （p-CREB） were detected by immunohistochemistry （IHC）， enzyme-linked immunosorbent assay （ELISA）， Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）， and Western blot， respectively. ResultCompared with normal group， functions of FVC， FRC and MMEF in model group were significantly decreased (P<0.01)， and the time of tI and tE was significantly prolonged （P<0.05，P<0.01）. The content of TNF-α in lung tissue was significantly increased （P<0.01）. The mRNA and protein expressions of cAMP， PKA and CREB in lung tissue were significantly decreased （P<0.01）. The expression of AQP5 and α-ENAC in lung tissue decreased significantly. The alveolar cavity of rats was filled with edema fluid， surrounding tissue hyperemia， inflammatory cell infiltration, bronchial mucosa epithelial adhesion. Compared with model group， Xiao Qinglongtang and its fangyuan group could significantly enhance the FVC, FRC and MMEF functions of model rats （P<0.05，P<0.01）， and tI and tE time were shortened （P<0.05，P<0.01）. The content of TNF-α in lung tissues of Xiao Qinglongtang group， Guizhi Gancao group and Banxia Mahuang group was significantly decreased （P<0.01）. The mRNA expressions of cAMP， PKA and CREB in Xiao Qinglongtang group were significantly up-regulated （P<0.01）， and the mRNA expressions of cAMP and PKA in Guizhi Gancao， Jiangxinwei and Banxia Mahuang groups were significantly up-regulated （P<0.01）. The protein expressions of cAMP， PKA and CREB in Xiao Qinglongtang group， Guizhi Gancao group， Jiangxinwei group and Banxia Mahuang group were significantly up-regulated （P<0.01）， and the protein expression of CREB in Shaoyao Gancao group was significantly up-regulated（P<0.05）. Xiao Qinglongtang could up-regulate the positive expression of AQP5 and α-ENAC， and Guizhi Gancao group could up-regulate the positive expression of α-ENAC. Xiao Qinglongtang and its fangyuan can reduce the lung edema， inflammatory cell infiltration and bronchial mucosal adhesion of model rats. ConclusionXiao Qinglongtang and its ingredients can reduce lung edema and inhibit inflammation by improving the expression of lung water transport-related proteins AQP1， AQP5， and α-ENaC through cAMP/PKA pathway， thereby restoring the lung functions in rats with syndrome of cold fluid accumulated in lung. Na+-K+-ATPase may play an auxiliary role in the regulation of lung water transport. This provides a certain objective basis for preliminarily elucidating the connotation of lung governing water movement from the perspective of lung water transport-related proteins.
ABSTRACT
Objective:To report 2 young infants of sodium channel related epilepsy with SCN2A gene mutation, and to discuss the clinical characteristics of the disease and the efficacy and safety of lacosamide combined with the literature.Methods:Corresponding information of 2 children hospitalized in the Department of Neurology of Hunan Children′s Hospital in July 2021 and October 2021 was collected, including the symptoms, comprehensive physical examination, blood, cerebrospinal fluid, imaging, electrophysiological examination, diagnosis and treatment process, response to treatment and other clinical data, as well as the sequencing results of the whole exome of the children. The efficacy and safety of lacosamide were analyzed, and the related literatures of the Biomedical Literature Database, Wanfang Data Knowledge Service Platform and Chinese Knowledge Infrastructure Database were searched and reviewed.Results:Both of the 2 cases were girl. Their onset age was within 3 months. The initial symptoms were frequent convulsions and backward development. There was no structural abnormality in the head image. The convulsions could not be controlled according to conventional multidrug treatment. The seizures were quickly controlled with lacosamide. Now they have been followed up for 6 months. No obvious adverse reactions were found. Case 1 gene test results showed the SCN2A gene (chr2:166152333-166246334) heterozygous deletion, SCN1A gene (chr2:166847754-16693013) heterozygous deletion, the deletion size being about 5.72 Mb. Case 2 gene test results showed new missense mutation of SCN2A (c.1285G>A, p.Glu429Lys). There were dozens of seizures every day. They were treated with valproic acid, oxcarbazepine and levetiracetam successively. The seizures could not be controlled. Three focal seizures originated in the left temporal region were detected by electroencephalogram. There was no recurrence on the third day after adding lacosamide, and there was no attack after 5 months of follow-up. No obvious adverse reactions were found during follow-up.Conclusions:Sodium channel related epileptic encephalopathy often starts early, has frequent seizures, and can be accompanied by backward psychomotor development at the same time. The slow sodium channel blocker lacosamide has good efficacy and safety in the treatment of sodium channel-related epilepsy with SCN2A gene mutation or combined SCN1A gene mutation.
ABSTRACT
Sodium channel Nav1. 7 is one of the subtypes of voltage-gated sodium channel. Most of it is expressed on the nociceptors of small C fibers in dorsal root ganglion (DRG). It has the characteristics of slow opening and slow closing of inactivation. It can produce a large amount of ramp current, reduce the threshold of action potential in sensory neurons, and amplify the external small and slow depolarization ramp current. Thus, it can increase the excitability of neurons and play a key role in the generation, transmission and regulation of pain. With the deepening of genetic research, Nav1. 7 channel has become a particularly attractive drug target in new analgesic therapy due to its function acquired mutation and function deletion mutation. However, the study found that Nav1. 7 channel improves neuronal excitability and participates in neuropathic pain through different ways in neuropathic pain caused by different factors, which has brought great obstacles to the research and development of Nav1. 7 selective inhibitors. Although the existing Nav1. 7 selective inhibitors have effective analgesic effects without obvious side effects or addiction problems, it is extremely difficult to find Nav1. 7 selective ligands. In addition, the existing Nav1. 7 selective inhibitors also differ in inhibitory efficacy, targeting, safety and feasibility due to different types of neuropathic pain. It is suggested that finding the general mechanism of Nav1. 7 channel acting on different neuropathic pain or the specific receptor binding site of Nav1. 7 channel may be the main direction of the research and development of Nav1. 7 selective inhibitors in the future. This paper briefly reviews the main role of Nav1. 7 channel in neuropathic pain caused by different factors.
ABSTRACT
Abstract Londrina is the fourth most populous city in southern Brazil. Its subtropical weather with rain in all seasons, as well as its high population density, make the city perfect for the Aedes aegypti (Linnaeus, 1762) life cycle. Over the last few years, Londrina presented high infestation indexes and was one of the cities with the most reported cases of dengue. Uncontrolled use of synthetic insecticides may influence the mosquito's genetic composition. In this paper, we studied mitochondrial DNA and kdr mutations in Aedes aegypti. The analysis of the ND4 gene in 330 specimens showed the presence of 27 haplotypes. The pyrethroid resistance alleles (kdr) evaluated are present in the collected populations, with a 50% frequency of the Val1016Ile and 48% of the Phe1534Cys mutations. Such analysis of the mutations in the populations collected at the State University of Londrina's campus - a microenvironment that differs from the rest of the city - showed frequencies of 57% and 62%, respectively. The low gene flow observed, Nm = 0.11 and Nm = 0.10, along with the elevated differentiation, Fst = 0.19 and Fst = 0.18, among populations suggest an influence of genetic drift. The strong presence of resistance alleles kdr in the city is evident, which demonstrates that even with the interruption of the use of pyrethroids by the National Dengue Control Program, resistance may be maintained due to domestic use. Thus, the results have shown the need for genetic monitoring, alongside other entomological surveillance monitoring tools, to create strategies of mosquito control.
ABSTRACT
Severe neonatal episodic laryngospasm (SNEL) is an ion channel disease characterized by recurrent life-threatening myotonia of respiratory muscle due to mutations in the voltage-gated sodium channel genes. Here we reported a newborn manifested as paroxysmal cyanosis and limb myotonia after birth. The neonate also developed muscle hypertrophy and stunted growth during the follow-up. Whole exome sequencing confirmed c.2395G>A, p. Ala799Thr heterozygous mutation of SCN4A. Carbamazepine was found to be effective on treating the disease. This case expands our understanding of the phenotype resulting from SCN4A mutations. By summarizing the characteristics of reported 16 cases in SNEL, we found they were mainly in the p.G1306E mutation. The common symptoms were upper airway muscle stiffness and feeding difficulties during neonates. When grow up, most patients have different degrees of recurrent attacks of myotonia and progressed muscle hypertrophy. Some of them have athlete-like special faces but all showed myotonic discharge in eletromyogram.
ABSTRACT
Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and small-diameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.
Subject(s)
Animals , Rats , Analgesia , Ganglia, Spinal , Growth Differentiation Factor 15 , Sensory Receptor Cells , Sodium Channels , Tetrodotoxin/pharmacologyABSTRACT
Sensory modalities are important for survival but the molecular mechanisms remain challenging due to the polymodal functionality of sensory neurons. Here, we report the C. elegans outer labial lateral (OLL) sensilla sensory neurons respond to touch and cold. Mechanosensation of OLL neurons resulted in cell-autonomous mechanically-evoked Ca
ABSTRACT
Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and small-diameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.
ABSTRACT
Objective:To explore the potential role of amyloid precursor protein (APP) in the sodium-channel-voltage-beta 2B (SCN2B)-mediated improvement of memory and cognitive function in Alzheimer's Disease (AD).Methods:The SCN2B gene knockout mice (SCN2B -/-) were hybridized with APP gene knockout mice (APP -/-), APP gene heterozygous mice (APP +/-) and APP gene transgenic mice (APP +/+), and the tail tissue of the same mouse was genotyped by PCR gene detection.The mice were divided into SCN2B -/-APP -/- group, SCN2B -/-APP +/- group and SCN2B -/-APP +/+ group.The C57BL/6 wild-type mice were Wild type (WT) group, with 9 mice in each group.SCN2B -/-APP -/-, SCN2B -/-APP +/-, SCN2B -/-APP +/+ transgenic mice and the wild-type mice at the age of 6 months, 12 months, and 18 months were tested by Morris water Maze and Y maze test to detect the cognitive function between each group.Meanwhile, SCN2B -/-APP -/-, SCN2B -/-APP +/-, SCN2B -/-APP +/+ transgenic mice aged 6, 12, 18 months and age-match wild-type were selected to detect neuronal processes in hippocampal CA1 region, and the number of neuronal processes in basal and distal regions of hippocampal CA1 region was quantitatively analyzed.SPSS 21.0 statistical software was used for data statistics and analysis.The differences between the two groups were compared and analyzed by independent-sample t test, the comparison between multiple groups was analyzed by one way analysis of variance (ANOVA), and repeated measurement ANOVA was used to analyze behavioral deta. Results:Repeated measurement ANOVA was used to analyze the data of water maze test. The data showed that the interaction effect of escape latency group and time was significant in 18 month old mice ( Ftime×group=3.63, P<0.01). Simple effect analysis showed that compared with SCN2B -/-APP +/- group and SCN2B -/-APP -/-group, the escape latency of mice in SCN2B -/-APP +/+ group was significantly prolonged from day 4 to 6 (4th day: (47.00±2.00)s, (43.11±1.96) s, (41.89±3.06)s, t=-4.16, 1.00, both P<0.05; 5th day: (45.22±2.54) s, (36.33±2.78) s, (37.00±2.45)s, t=-7.08, -0.54, both P<0.05; 6th day: (38.11±2.03)s, (34.11±2.32)s, (33.00±2.91)s, t=-3.90, 0.90, both P<0.05). The residence time in the target quadrant was shortened((18.00±1.73)s, (25.56±1.33)s, (24.33 ±1.94)s; t=10.37, 1.56, both P<0.05). (2) Y-maze results showed that compared with SCN2B -/-APP +/- group and SCN2B -/-APP -/-group, the number of novel arm entry in 18 month old mice in SCN2B -/-APP +/+ group was decreased((50.22±3.68), (57.22±3.74), (58. 44±5.14) ; t=3.40, -0.48, both P<0.05), and the residence time of stay in the new arm was reduced((10.89±0.62)min, (14.33±0.59)min, (13.89±0.74)min; t= 8.16, 0.44, both P<0.05), and the distance of movement in the new arm was significantly reduced ((37.26±2.01)m , (45.67±2.45)m , (46.11±3.27)m ; t=7.81, 0.91, both P<0.05). (3) Golgi staining showed that SCN2B -/-APP +/- group and SCN2B -/-APP -/-group, the number of apical dendrites in hippocampal neurons of 18 month old mice in SCN2b -/-App +/+ group(number of apical dendrites: (1.78±0.37), (3.67±0.81), (3.00±1.21); t=3.36, 1.41, both P<0.05) and the number of basal dendrites (the number of basal dendrites: (1.11±0.50), (3.11±0.50), (2.56±0.69); t=4.06, 1.21, both P<0.05). Conclusion:SCN2B knockdown can improve the ability of spatial learning and memory in aged mice.Overexpression of APP can partially offset the improvement of cognitive function caused by SCN2B knockdown, and may be affected by the number of basal and distal processes of neurons in the hippocampal CA1 region of the mice.
ABSTRACT
Las mutaciones KDR en el gen del canal del sodio (VGSC) han sido ya detectadas en al menos 13 especies de mosquitos Anopheles en su mayoría especies de África, pero aún resta por determinar los cebadores específicos para la detección en especies de Latinoamérica. En nuestro país la especie Anopheles darlingi es el vector principal de la malaria, y el A. albitarsis, el vector secundario. Se emplearon muestras de mosquitos Anoheles de las especies A. strodei, A. albitarsis, A. fluminensis, A. evansae, A. nuneztovari, A. nyssorhynchela lutzi y A. oswaldoi capturadas en los departamentos de Caaguazú y Alto Paraná en Paraguay. Para la amplificación y secuenciación se usaron cebadores reportados para el gen VGSC de A. albimanus en Guatemala, que resultaron ser específicos solo para la especie A. strodei. La secuencia revela el codón TTA que codifica para una Leucina como la secuencia TTG, reportada para la versión susceptible en la posición L1014. El fragmento amplificado es de aproximadamente 225 pares de bases. A nuestro entender, esta es la primera caracterización del gen VGSC en mosquitos Anopheles del Paraguay y para la especie A. strodei
KDR mutations in the sodium channel gene (VGSC) have already been detected in at least 13 species of Anopheles mosquitoes, mostly African species, but the molecular techniques for detection in Latin American species have yet to be determined. In our country, Anopheles darlingi species is the main vector of Malaria, and A. albitarsis, the secondary vector. We used samples of Anoheles from the species A. strodei, A. albitarsis, A. fluminensis, A. evansae, A. nuneztovari, A. nyssorhynchela lutzi and A. oswaldoi collected at the departments of Caaguazú and Alto Paraná in Paraguay. For the amplification and sequentiation, primers reported for the VGSC gen of A. strodei in Guatemala were used and were specific only for A. strode in this case. The sequence revealed the TTA codon that codifies for a leucine as the TTG sequence, reported for the susceptible version at position L1014. The amplified fragment is approximately 225 base pairs. To our knowledge, this is the first characterization of the VGSC gene in Anopheles mosquitoes in Paraguay and for the species A. strodei
Subject(s)
Animals , Polymerase Chain Reaction , Anopheles , Sodium Channels , Mosquito VectorsABSTRACT
RESUMEN Se presenta caso de una niña de 10 años con cuadro de epilepsia mioclónica juvenil severa en la infancia, que a los 6 meses de edad debutó con crisis tónico-clónicas generalizadas (TCG) luego de la administración de una dosis de vacuna DPT, con posteriores crisis TCG, mioclónicas y múltiples episodios de estado epiléptico refractarios a fármacos antiepilépticos (FAE) de primera y segunda línea durante los primeros 5 años. Las crisis se asociaron a retraso global en el desarrollo luego del primer episodio. Durante la evolución se realizaron estudios que incluyen resonancia magnética cerebral que fue normal y tomografía por emisión de positrones (PET-CT) que evidenció alteraciones en el metabolismo en región temporal izquierda, además de estudios para inmunodeficiencias y trombofilias sin alteraciones. Los electroencefalogramas iniciales fueron normales, pero video electroencefalograma de 12 horas mostró actividad irritativa en la región central con diseminación bilateral. Los estudios genéticos identificaron una mutación en el marco de lectura de tipo "frameshift" del gen SCN1A mediante secuenciación de la región codificante. Luego de los primeros años de vida, la paciente presenta, atípicamente, remisión progresiva de las crisis con posterior desmonte de FAE y mejoría del neuro-desarrollo en el proceso interdisciplinario de rehabilitación.
SUMMARY We report the case of a 10-year-old female with a history of severe myoclonic epilepsy of infancy who presents with generalized tonic-clonic (GTC) seizures at 6 months of age after administration of a DPT vaccine, who then begins to present frequent and severe GTC seizures, myoclonic seizures and multiple refractory status epilepticus poorly controlled with first and second line anti-epileptic drugs (AEDs). This was accompanied by development delay. Studies performed on the patient included brain MRI which was normal, immunodeficiency and trombophilic studies which were normal and electroencephalographs: studies (EEG) that were at first mostly normal. The most significant findings were seen during a 12-hour video-EEG which reported epileptogenic activity in central region with bilateral dissemination and a PET-CT that showed metabolism alterations in the left temporal region. Due to this presentation a channelopathy was suspected and a coding region sequentiation study was performed which identified a frameshift mutation of the SCN1A gene confirming the diagnosis. Atipically, after 5 years the patient begins to present a favorable evolution with significant seizure remission even allowing the progressive weaning of AEDs and a remarkable stalemate of developmental delay after interdisciplinary rehabilitation process was started.
Subject(s)
Transit-Oriented DevelopmentABSTRACT
Systemic toxicity by local anesthetics (LAs) is a severe and feared complication in anesthetic practice that generally results from the administration of an inappropriately high dose of LAs or an injection at an inappropriate place, either intravascular or a site with high absorption[1]. However, it is known that the susceptibility to these drugs may vary within the population, which may occur due to genetic changes in the LA binding site, located in the potential-dependent Na+ channels (Nav), thus increasing or decreasing its affinity and, therefore, its clinical consequences. We present a case of a 61 years-old female patient with a medical history of increased sensitivity to LAs. In this scenario, a genetic study was performed to exclude a Nav channel dysfunction.
La toxicidad sistémica por anestésicos locales (ALs) es una grave y temida complicación en la práctica anestésica que generalmente resulta de la administración de una dosis inapropiadamente alta de ALs o a una inyección en un lugar inadecuado, llámese intravascular o un sitio al alta absorción[1]. A pesar de lo anterior, es conocido que la susceptibilidad al efecto de estos fármacos puede variar dentro de la población, lo cual puede ocurrir debido a cambios genéticos en el sitio de unión de los AL, localizado en los canales de Na+ dependientes de potencial (Nav), incrementando o disminuyendo así su afinidad y, por ende, sus consecuencias clínicas. Presentamos el caso de una paciente de 61 años con historia de sensibilidad aumentada a Als. En este escenario, se le ofreció un estudio genético para excluir una disfunción específica a nivel de canal Nav
Subject(s)
Humans , Female , Middle Aged , Sodium Channels/drug effects , Drug Hypersensitivity/etiology , Drug Hypersensitivity/genetics , Anesthetics, Local/adverse effects , Lidocaine/adverse effects , Sodium Channels/genetics , Anesthetics, Local/pharmacology , Lidocaine/pharmacologyABSTRACT
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction, which causes most CF morbidity and mortality. This article reviews the pathophysiology of CF, recent animal models, and current treatment of CF.