Search Results (210)

Artemisia indica Willd. is widely used in traditional medicine and dietary practices. Phytochemical analysis of Artemisia indica Willd. aqueous extract (AAE) by HPLC–ESI–MS/MS identified isochlorogenic acid C (ICAC) as a major constituent. Angiotensin II (Ang II) disrupts renal tubular epithelial cell homeostasis and contributes to renal injury. In this study, we evaluated the protective effects of AAE and ICAC in Ang II-stimulated NRK52E cells. Both AAE and ICAC significantly reduced reactive oxygen species (ROS) production, mitochondrial dysfunction, and proinflammatory cytokine release. Mechanistic analyses showed that AAE inhibited Ang II type 1 receptor (AT1R)-mediated NF-κB activation and suppressed NLRP3 inflammasome signaling, thereby alleviating inflammatory responses and pyroptosis. In addition, AAE and ICAC restored sodium homeostasis by reactivating neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2), promoting epithelial sodium channel (ENaC) ubiquitination and reducing its apical membrane accumulation. Molecular docking suggested that ICAC interacts with the extracellular domain of α-ENaC, supporting its regulatory role. Overall, AAE and ICAC protect renal tubular epithelial cells against Ang II-induced injury by reducing oxidative stress, inflammation, and dysregulated sodium transport, highlighting their potential as plant-derived therapeutic agents for hypertension-associated renal dysfunction. Full article

Dravet syndrome (DS) is a severe, catastrophic childhood epilepsy predominantly caused by loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Na_v1.1. In this study, we evaluated the therapeutic potential of 5-(Benzofuran-2-yl)-3-(2-chloro-4-fluorobenzyl)-1,3,4-oxadiazol-2(3H)-one (GM-90663), a novel small molecule designed to address the complex pathophysiology of DS. Using scn1lab knockout (KO) zebrafish larvae—a robust vertebrate model for DS—we demonstrated that GM-90663 significantly alleviates seizure-like behavioral movements and rescues deficit in cognitive-like functions. Whole-cell patch-clamp recordings in hippocampal slices revealed that GM-90663 modulates voltage-gated Na⁺ channel kinetics; specifically, it suppresses slow ramp-induced currents, thereby effectively attenuating neuronal hyperexcitability. Furthermore, neurochemical profiling indicated that GM-90663 treatment leads to a marked increase in endogenous serotonin (5-HT) levels in both wild-type and KO larvae. Molecular docking simulations and subsequent in vitro enzymatic assays confirmed that this elevation in serotonin is mediated through the potent inhibition of monoamine oxidase (MAO) activity. Collectively, our findings suggest that GM-90663 exerts its anti-seizure effects through a synergistic dual mechanism—stabilizing sodium channel conductance and elevating serotonergic activity—positioning it as a promising multi-target candidate for the treatment of DS. Full article

Objective: Gastric cancer (GC) is characterized by molecular heterogeneity, yet current classifications are largely based on cross-sectional molecular profiles and do not account for the temporal order of mutation accumulation. This study aimed to reconstruct somatic mutation trajectories to identify prognostically distinct subtypes and to examine transcriptomic and microenvironmental features associated with these inferred trajectories. Methods: We applied the Subtype and Stage Inference (SuStaIn) algorithm to TCGA-STAD somatic mutation data to infer the temporal sequence of mutation accumulation. Stage-correlated gene expression analysis was performed to identify genes whose expression levels changed with evolutionary stage. The tumor microenvironment (TME) was characterized using EcoTyper and single-cell RNA sequencing deconvolution, while drug sensitivity was estimated through transcriptome-based IC₅₀ prediction. The clinical relevance of the inferred trajectories was further evaluated in three independent external transcriptomic cohorts. Results: We identified two distinct evolutionary trajectories: the Accelerated Path (AP, 65%) and the Gradual Path (GP, 35%). In the AP, TP53 mutations were positioned at an earlier evolutionary stage (Stage 3) compared to the GP (Stage 8). AP patients had significantly worse overall survival (Hazard Ratio = 1.437, p = 0.044, adjusted for clinical stage and molecular subtypes). The AP was associated with stage-correlated downregulation of the sodium channel gene SCN4A (ρ = −0.36, p < 0.001) and an increase in a squamous-associated gene expression score, while the GP showed stage-correlated expression changes in the mitochondrial gene SDHD (ρ = −0.35, p < 0.001). The AP was further characterized by higher inferred abundance of extracellular matrix CAFs (eCAFs) and lower inferred immune cell scores, whereas the GP was associated with higher inferred signatures of activated B cells and effector memory T cells. Computational drug sensitivity modeling predicted a negative correlation between AP stage and IC₅₀ values for 5-Fluorouracil and Docetaxel. Conclusions: Two distinct mutational ordering patterns identified by SuStaIn are associated with divergent transcriptomic features, TME compositions, and clinical outcomes in gastric cancer. The AP subtype is characterized by early TP53 mutations, SCN4A downregulation, and a stromal-enriched microenvironment, while the GP subtype is associated with later TP53 mutations, SDHD-correlated expression, and higher inferred immune cell scores. The reproducibility of these associations was confirmed in independent cohorts. The computational drug sensitivity predictions and the proposed mechanistic links between gene expression patterns and clinical outcomes should be viewed as hypothesis-generating findings that require prospective and functional validation. Full article

Brugada syndrome (BrS) is a rare but potentially life-threatening condition that may lead to sudden cardiac death. Among the causes, dysfunctions of ion channels involved in the cardiac action potential (specifically in SCN5A and SCN10A genes) are particularly significant. Among diagnosed Brugada patients, fever-induced episodes occur in 20–30% of cases. Fever worsens sodium channel dysfunction, as elevated temperature further reduces their conductance. First clinical manifestation of BrS occurs usually during a febrile episode, especially in young people. We performed a multiparametric examination in addition to genetic analysis. We treated a 19-year-old man presenting with subfebrility. During the patient’s subfebrile episodes, 12-lead ECG recordings revealed ST-segment elevations in leads V1–V3. Notably, the patient remained asymptomatic. Targeted genetic testing of SCN5A did not reveal any disease-causing variants as an underlying cause of the syndrome, but the temperature-inducing effect was demonstrated. The occurrence of the Brugada type 1 pattern has also been observed at subfebrile episodes, although significantly rarely. This case demonstrates that in susceptible patients, even a relatively mild elevation in body temperature can trigger ion channel dysfunctions. Timely diagnosis and follow-up are important in preserving quality of life and preventing fatal outcomes. Full article

Salt stress inhibits plant growth, requiring salt-tolerant genes for the development of resilient plants. A key tolerance mechanism is potassium/sodium homeostasis, governed by Shaker K⁺ channels. Given that Shaker K⁺ channels from salt-sensitive species have been extensively studied while their counterparts in salt-tolerant plants remain largely unexplored, this study investigates the evolution and function of these channels in salt-tolerant bermudagrass to address this knowledge gap. Genomic analysis identified 25 Shaker K⁺ channel genes, an expanded family relative to other species. Phylogenetics placed them into five groups (I–V), with groups I, II, III, and V expanded via segmental duplication. Salt stress response screening revealed that only CdKAT1.1 was rapidly upregulated. Functional assays in yeast demonstrated that both CdKAT1.1 and its closest homolog CdKAT1.2 improve potassium uptake and salt tolerance, but the enhancement from CdKAT1.1 was significantly greater. This work elucidates the expansion and functional divergence of Shaker K⁺ channels in bermudagrass. CdKAT1.1 emerges as a superior regulator of potassium efficiency and salt tolerance, making it a prime candidate for molecular breeding to improve plant resilience in saline-alkaline soils. Full article

Background: Brugada syndrome (BrS) is a genetic cardiac arrhythmia disorder inherited in an autosomal dominant manner, characterized by ST-segment elevation in the right precordial leads (V1–V3) on electrocardiograms (ECGs). This syndrome predominantly affects young individuals with structurally normal hearts and significantly increases the risk of ventricular arrhythmias and sudden cardiac death (SCD). The most common genotype found among BrS patients is caused by variants in the SCN5A gene, which lead to a loss of function of the cardiac sodium channel Nav1.5 by different mechanisms. Methods: Plasmids containing SCN5A were constructed using PCR and site-directed mutagenesis to create the D372H variant. HEK293 cells were cultured and transfected with the WT, D372H, or a combination of both plasmids. Patch-clamp recordings assessed sodium current characteristics. Confocal microscopy visualized channel localization. Quantitative RT-PCR was used to analyze mRNA expression levels, while Western blot evaluated protein expression using specific antibodies. Results: In HEK293 cells expressing the D372H mutant, functional assays revealed a near-complete loss of sodium currents. Co-transfection of WT and D372H plasmids resulted in a significant reduction in current density compared with WT alone, while activation, inactivation, and recovery kinetics were unaffected. In addition, both the mutant protein and protein expressed in co-transfected cells exhibited reduced fluorescence intensity, indicating decreased expression levels. These findings were further supported by Western blot and RT-qPCR analyses. Conclusions: In summary, our findings indicate that the D372H variant produces a marked reduction in Nav1.5 function through reduced sodium current density and decreased channel expression. Given its critical position within the DI-pore loop, this defect is expected to markedly diminish the inward sodium current necessary for normal depolarization. Such impaired excitability—particularly relevant in the right ventricular outflow tract—may accentuate regional differences in repolarization and create conditions that favor reentrant activity. These findings provide mechanistic insights into how the p.D372H variant alters Nav1.5 channel function in vitro and offer functional evidence that may assist in interpreting its potential relevance to Brugada syndrome. Full article

Gitelman syndrome (GS) is a rare, autosomal recessive salt-losing tubulopathy caused by mutations in the SLC12A3 gene. It involves dysfunction of the sodium-chloride cotransporter positioned on the apical membranes of the distal convoluted tubule cells, causing sodium shortage and mimicking the use of thiazide diuretics. Hyperaldosteronism secondary to sodium depletion and hypovolemia causes hypokalaemia and metabolic alkalosis. This is associated with inhibition of the Transient Receptor Potential Cation Channel, Subfamily M, Member 6 –TRPM6 channel, which leads to urinary magnesium leakage and hypomagnesemia, subsequently stopping PTH secretion and resulting in hypocalcemia and hypocalciuria. Gitelman syndrome frequently presents later in life, as the symptoms are usually not very threatening. However, early identification, diagnosis, and urgent intervention are essential to improve patient prognosis and quality of life. Importantly, both hypomagnesemia and hypokalaemia can impair insulin secretion and sensitivity. Furthermore, hyperaldosteronism caused by the secondary activation of the R-A-A system can also lead to these disorders. Glucose metabolism problems have been shown to prevail amongst GS patients and manifest more frequently in comparison to the general population. When it comes to the treatment used to reduce hyperglycemia in GS-related T2DM, we consider which of the available drugs are the best for those patients. The article analyses the association of Gitelman syndrome with diabetes mellitus based on the available medical literature—as there are no clinical trials or meta-analyses available for this group, it is presented as a narrative review. Full article

GNE myopathy is a rare genetic neuromuscular disorder caused by mutations in the GNE gene. The respective gene product, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), is a bifunctional enzyme that initiates endogenous sialic acid biosynthesis. Sialic acids are important building blocks for the glycosylation machinery of cells and are typically found at the terminal ends of glycoprotein N- and O-glycans. The exact pathomechanism of GNE myopathy remains elusive, and a better understanding of the disease is urgently needed for the development of therapeutic strategies. The purpose of this study was to examine the effects of hyposialylation on glycan structures and subsequent downstream effects in the C2C12 Gne knockout cell model. No overall remodeling of N-glycans was observed in the absence of Gne, but differences in glycosaminoglycan expression and O-GlcNAcylation were detected. Expression analysis of myopathogenes revealed concomitant down-regulation of muscle-specific genes. Among the top candidates were the sodium channel protein type 4 subunit α (Scn4a), voltage-dependent L-type calcium channel subunit α-1s (Cacna1s), ryanodine receptor 1 (Ryr1), and glycogen phosphorylase (Pygm), which are associated with excitation-contraction coupling and energy metabolism. The results suggest that remodeling of the glycome could have detrimental effects on intracellular signaling, excitability of skeletal muscle tissue, and glucose metabolism. Full article

Dravet Syndrome (DS) is a severe genetic epileptic encephalopathy caused by mutations in the SCN1A gene that encodes the voltage-gated sodium channel (Na_V1.1) subunit alpha. DS is characterized by intractable seizures, progressive developmental delay, cognitive impairment, and high mortality due to sudden unexpected death in epilepsy (SUDEP). SUDEP is mediated by respiratory dysfunction, but the exact molecular underpinnings are unclear. Though hippocampal metabolic alterations have been reported in DS mice, such changes in brain regions controlling breathing have not been studied. We used Scn1a^A1783V/WT DS mice to study temporal alterations in the brain metabolome, including analysis of brainstem and forebrain regions. Glycolytic and pentose phosphate pathway intermediates were significantly elevated in the brainstem of DS mice during the period of enhanced susceptibility to mortality (post-natal days P20–30). In older P40–P50 mice, mitochondrial aconitate and the antioxidant glutathione were significantly elevated in the brainstem. Single-nuclei RNA sequencing (snRNA seq) and proteomic analyses revealed alterations in genes associated with neurotransmission, cellular respiration, and protein translation, as well as reorganization of protein kinase-mediated pathways that are specific to the brainstem. These findings suggest that there are widespread metabolic changes in the brainstem of DS mice. Full article

Chinese wolfberry (Lycium barbarum L.), a specialty crop with ecological, medical, and economic value in Ningxia province of China, is subject to severe damage from Aphis gossypii Glover. Currently, A. gossypii populations show extremely high-level resistance to beta-cypermethrin in the major wolfberry planting areas in Ningxia. The specific resistance mechanisms, however, are still not known. In this work, we collected a field A. gossypii strain (HSP) from a wolfberry orchard in Ningxia in 2021 using a single-time sampling method, and its resistance to beta-cypermethrin was determined to be extremely high (994.74-fold) as compared with that of a susceptible strain (SS). Then we explored the potential resistance mechanisms from two aspects, namely, metabolic detoxification and target-site alterations. Bioassays of beta-cypermethrin with or without a synergist showed that piperonyl butoxide (PBO) significantly increased the toxicity of beta-cypermethrin (4.72-fold) to the HSP strain, while triphenyl phosphate (TPP) and diethyl maleate (DEM) exhibited no significant synergistic effects. Correspondingly, the O-demethylase activity of cytochrome P450s in the HSP strain was 1.68-fold higher than that in the susceptive strain (SS), whereas changes in carboxylesterases and glutathione S-transferases activities were unremarkable. Also, fifteen upregulated P450 genes were identified by both RNA-Seq and qRT-PCR technologies, containing eleven CYP6 genes, three CYP4 genes, and one CYP380 gene. Especially, five CYP6 genes with high relative expression levels (>3.00-fold) were intensively expressed by beta-cypermethrin induction in the HSP aphids. These metabolism-related results indicate the key role of P450-mediated metabolic detoxification in HSP resistance to beta-cypermethrin. Sequencing of voltage-gated sodium channel (VGSC) genes identified a prevalent M918L mutation and a new G1012D mutation in HSP A. gossypii. Moreover, heterozygous 918 M/L and 918 M/L + G1012D mutations were the dominant genotypes with frequencies of 60.00% and 36.67% in the HSP population, respectively. Overall, VGSC mutations along with P450-mediated metabolic resistance contributed to the extremely high resistance of the HSP wolfberry aphids to beta-cypermethrin, providing support for A. gossypii control and resistance management in the wolfberry planting areas of Ningxia using insecticides with different modes of action. Full article

Introduction: Cardiomyopathies (DCM, HCM, and ACM) and primary arrhythmogenic disorders (BrS, LQTS, and CPVT) represent the most common causes of sudden cardiac death (SCD) in young individuals. Systematic genome-wide single-nucleotide polymorphism (SNP) analyses and genome-wide association studies (GWASs) have enabled the identification of numerous genetic variants associated with cardiovascular diseases. Body: Genetic testing for cardiomyopathies and inherited channelopathies primarily involves panel testing of genes with definitive and strong evidence of disease association; genes supported by moderate evidence may also be considered. Cardiomyocytes express a variety of proteins implicated in the pathogenesis of genetic cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal, and nuclear envelope proteins. Inherited cardiac channelopathies result from mutations in genes encoding cellular components that influence calcium ion availability or affect membrane ion channels, including sodium, potassium, and calcium channels. Common variants associated with SCD are found in genes encoding cardiac ion channels (e.g., SCN5A, KCNQ1, and KCNH2), calmodulin (CALM2), sarcomeric proteins (MYH7, MYBPC3, TTN, and TNNI3), and desmosomal proteins (RyR2 and DES). Conclusions: This review demonstrates that specific genetic variants are significantly associated with an increased risk of SCD. The evidence underscores the importance of genetic screening and early intervention in individuals with a family history of SCD or other risk factors for inherited cardiac disorders predisposing to SCD. Future research should focus on gene-specific management strategies for familial cardiomyopathies and inherited channelopathies, with the goal of improving targeted genetic therapies and reducing the burden of sudden cardiac death. Full article

Variants in neuronal sodium channel genes are responsible for a spectrum of neurological disorders, including developmental and epileptic encephalopathies (DEEs), with considerable genetic and phenotypic heterogeneity and drug resistance. Gene variants can produce loss-, gain-, or mixed-function effects, resulting in complex genotype-phenotype correlations. Current treatments rely mainly on symptomatic polytherapy with antiseizure medications, with sodium channel blockers contraindicated in loss-of-function cases but beneficial in gain-of-function forms. Existing therapies often provide limited benefit or even no seizure control at all and fail to address developmental impairments, highlighting the need for novel approaches. Emerging strategies include antisense oligonucleotides, gene therapy, and selective small-molecule modulators, which have shown antiseizure potential in preclinical models and in initial clinical studies by modulating SCN gene expression and function. Additionally, pharmacological agents such as fenfluramine, stiripentol, and cannabidiol, although not acting directly on sodium channels, represent recognized therapeutic options for SCN1A-related Dravet syndrome. This review summarizes recent advances in approved and investigational treatments for sodium channel-related neurological disorders, highlighting the transition from symptomatic to precision therapies. Full article

Pediculosis produced by the presence of the human head louse (Pediculus humanus capitis DeGeer, 1767) and the body louse (Pediculus humanus humanus L., 1758) remains a neglected tropical disease in Nigeria, where permethrin-based pediculicides are widely used. However, the resistance status of lice populations has not been previously assessed. Knockdown resistance (kdr) to pyrethroids is primarily driven by two mutations—T917I and L920F—in the voltage-sensitive sodium channel (VSSC) gene. This study investigated the presence of these mutations in 85 head and body lice collected from school-age children in two settlements in Nigeria. The T917I mutation was detected in head lice at frequencies ranging from 21% to 76%, and in body lice from 10% to 95%, with significant variation between sites and louse types. Remarkably, all lice examined carried the L920F mutation, regardless of T917I genotype, a pattern not previously reported in body lice. These findings suggest that pyrethroid resistance is well established or under active selection in the study populations. This is the first report of kdr mutations in human lice from Nigeria and highlights the urgent need for resistance monitoring programs. Early genetic surveillance of these mutations can inform treatment strategies and help prevent widespread resistance in lice populations, preserving the efficacy of available pediculicides. Full article

Pine wilt disease, which is induced by pine wood nematode (PWN, Bursaphelenchus xylophilus), has caused huge economic and ecological losses. To overcome the drawbacks of chemical control against PWN, twenty compounds were screened, and a synergistic botanical–chemical combination was identified. A proportion of abamectin to rotenone of 7:3 (5.73 and 1.78 mg/L, respectively) achieved the highest co-toxicity coefficient of 231.09 with a median lethal concentration of 3.18 mg/L. It revealed 0% mortality in Pinus massoniana seedlings at 60 days post-treatment when applied at 400 times the synergistic concentration (2.29 g/L abamectin + 0.71 g/L rotenone) at 7 days after PWN inoculation. Furthermore, the synergistic combination significantly affected the physiological activity and population dynamics of PWN. Female oviposition was reduced by 71.92%, the egg hatching rates declined to 13.09 ± 0.02%, and head thrashing frequency was inhibited by 99.23 ± 0.01%. The enzymatic activities of peroxidase, acetylcholinesterase, succinate dehydrogenase, and glutathione S-transferase were significantly increased, while the population size declined by 96.17%. Transcriptomic and gene expression analyses suggested a potential “Na⁺/Ca²⁺/Cl⁻ ionic storm,” since the synergistic combination significantly activated genes associated with voltage-gated calcium channels, glutamate-gated chloride channels, and amiloride-sensitive sodium channels. These findings provide an eco-friendly strategy for PWN management via chemical control. Full article

Nannochloropsis oceanica (Suda & Miyashita) R. E. Lee holds considerable potential for the production of high-value compounds, including pigments, lipids, and polyunsaturated fatty acids. Sodium acetate, a widely used carbon source in microbial cultivation, is both cost-effective and efficient. Although it has been reported to enhance biomass production in various microalgae, its effects on metabolic pathways differ substantially across species. In this study, we investigated the transcriptional responses of N. oceanica to sodium acetate supplementation using high-throughput mRNA sequencing. Sodium acetate significantly promoted growth but elicited a distinct metabolic reprogramming in contrast to patterns commonly observed in other microalgae. We identified 747 differentially expressed genes (399 upregulated and 348 downregulated), reflecting a substantial transcriptomic shift. Pathways related to lipid metabolism, carbon fixation, and photosynthesis were markedly suppressed. Notably, genes associated with photosynthesis were downregulated by 34–43 fold, suggesting a strategic reallocation of resources away from energy-intensive photosynthetic processes in the presence of an external organic carbon source. In sharp contrast to Chlamydomonas reinhardtii P. A. Dangear and Haematococcus pluvialis (Flotow) Wille, lipid metabolism in N. oceanica was not enhanced under sodium acetate supplementation. Instead, expression of lipid metabolism genes decreased by 5–14 fold, with most fatty acid- and lipase-related genes also downregulated (4–30 fold). Together, these findings reveal that N. oceanica adopts a unique adaptive strategy, channeling acetate-derived carbon primarily into rapid biomass accumulation rather than energy storage or high-value metabolite synthesis. This work provides new insights into the species-specific responses of microalgae to organic carbon sources. Full article