Search Results (76,405)

Kansui Radix, the root of Euphorbia kansui, was first described in Shen Nong Ben Cao Jing as a traditional Chinese medicine, known for its effects of expelling water, reducing edema, and dissipating masses. It is traditionally indicated for conditions such as “watery accumulation” and “abdominal masses (zheng-jia)”, which share certain similarities with the clinical manifestations of renal cell carcinoma (RCC), including renal masses, edema, and body cavity effusion. Despite the recognized antitumor effects of Kansui Radix, the pharmacological basis and specific molecular mechanisms underlying its inhibition of RCC progression remain unclear. The goal of this study was therefore to evaluate the antitumor efficacy of Kansui-DCM in RCC and to explore its potential mechanism. To this end, the chemical composition of the dichloromethane fraction of Kansui Radix (Kansui-DCM) was characterized by UPLC-MS. The antiproliferative effects of Kansui-DCM on 786-O and RENCA cells were evaluated using the CCK-8 assay. Apoptotic morphology, apoptosis rate, cell migration and invasion abilities were assessed. An RCC mouse model was established, and tumor growth and histopathological staining were evaluated after drug administration. Immunohistochemistry, transcriptomic analysis, WGCNA (weighted gene co-expression network analysis), network pharmacology, and immunofluorescence were employed to investigate the molecular pathway. Protein and gene expression were analyzed by Western blot and qRT-PCR, respectively. Finally, the interactions between the active components and key targets were substantiated through molecular docking and molecular dynamics simulations. A total of 1397 compounds were detected in Kansui-DCM by UPLC-MS. In vitro experiments demonstrated that Kansui-DCM inhibited the proliferation of 786-O and RENCA cells in a dose-dependent manner, induced apoptosis, and suppressed cell invasion and migration in RENCA cells. Treatment with Kansui-DCM markedly suppressed tumor growth in vivo, as reflected by a reduction in tumor volume. Immunohistochemical analysis indicated that the expression levels of CD31, COX-2, and Ki67 were markedly decreased, while the expression level of CD8 was significantly increased. Integrated analysis using WGCNA and network pharmacology predicted that Kansui-DCM may exert its effects through the regulation of the HIF/VEGF signaling pathway, which was further validated by immunofluorescence, Western blot, and qRT-PCR assays. Molecular docking and molecular dynamics simulations demonstrated stable interactions between multiple active components of Kansui-DCM and key targets such as VEGFR2 and HIF-2α. In conclusion, these findings suggested that Kansui-DCM exerts anti-RCC effects associated with regulation of the HIF/VEGF pathway. Full article

Background/Objectives: Epoxide hydrolase 2 (EPHX2), which encodes soluble epoxide hydrolase (sEH), is involved in arachidonic acid metabolism and has been associated with inflammation, lipid metabolism, and tumor biology. However, its prognostic significance and biological associations in lung adenocarcinoma (LUAD) remain unclear. This study aimed to investigate the expression profile, prognostic value, and molecular pathways of EPHX2 in LUAD using bioinformatics analyses. Methods: EPHX2 expression was evaluated using TNMplot, GEPIA2, and GEO datasets, while protein expression was assessed using the Human Protein Atlas and CPTAC/UALCAN platforms. Prognostic analyses were performed using Kaplan–Meier Plotter, GEPIA2, and Human Protein Atlas datasets. Co-expression and gene set enrichment analyses were conducted using LinkedOmics, and functional enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome databases. Correlation and protein–protein interaction (PPI) analyses were evaluated using GEPIA2 and STRING. Results: EPHX2 expression was significantly reduced in LUAD tissues compared with normal lung tissues across datasets, and these findings were supported at the protein level. High EPHX2 expression was associated with better overall survival and retained independent prognostic significance in multivariate Cox analysis. Functional enrichment analyses demonstrated associations with lipid metabolism, arachidonic acid metabolism, cytochrome P450-related pathways, and oxidative processes. Correlation analyses suggested potential associations between EPHX2 and angiogenesis, extracellular matrix remodeling, and hypoxia-related pathways. Conclusions: Bioinformatics analyses suggest that EPHX2 may participate in metabolic and tumor progression-related regulatory networks and may serve as a prognostic biomarker in LUAD. Full article

Populus hopeiensis is an important native poplar species in northern China, but herbivorous insect damage seriously affects its growth and ecological function. WRKY transcription factors play important roles in plant stress responses; however, the function of WRKY23 homologs in woody plant resistance to chewing herbivores remains unclear. In this study, a herbivore-responsive WRKY transcription factor gene, PhWRKY23, was identified from P. hopeiensis. PhWRKY23 expression was significantly induced by Spodoptera litura feeding, with a maximum increase of approximately 69.71-fold the control level at the highest damage level, and the encoded protein was predominantly localized in the nucleus. To investigate its function, PhWRKY23-overexpressing and RNA interference transgenic lines were generated. In the choice feeding assay, the consumed leaf area of PhWRKY23-overexpressing plants was approximately 85.5% lower than that of WT plants after 8 h. In the no-choice feeding assay, the total larval mass after 6 d was approximately 38.8% lower in larvae fed on overexpression plants and 51.0% higher in larvae fed on RNAi plants than in those fed on WT plants. Physiological analysis showed that RNAi plants accumulated significantly more MDA than WT and overexpression plants, whereas overexpression plants had higher chlorophyll a, chlorophyll b, and carotenoid contents than the other genotypes. Phytohormone analysis further showed that PhWRKY23-overexpressing plants accumulated higher levels of jasmonic acid, jasmonoyl-L-isoleucine, and salicylic acid, whereas abscisic acid showed no significant difference among genotypes. Yeast two-hybrid screening identified several candidate PhWRKY23-interacting proteins, and pairwise validation confirmed that PhWRKY23 interacted with PhDOX1 in yeast. These results indicate that PhWRKY23 positively contributes to herbivore resistance in P. hopeiensis and that this resistance phenotype is associated with changes in JA, JA-Ile, and SA accumulation and defense-related physiological traits. Full article

The twin-tail phenotype of goldfish represents a striking domestication-associated remodeling of the vertebrate caudal axial system and is classically linked to disruption of Chordin/BMP-mediated dorsal–ventral patterning. Although previous knockdown studies implicated sizzled (szl) in this process, genetic evidence from targeted disruption of endogenous szl loci remains limited. Here, we used CRISPR/Cas9 to mutate conserved coding regions shared by the duplicated goldfish paralogues szlA and szlB in single-tail embryos. Sanger sequencing and ICE analysis showed that szl-sgRNA2 and szl-sgRNA3 efficiently induced indels at both loci, whereas szl-sgRNA1 was ineffective. Across three independent biological replicates, twin-tail-like caudal bifurcation was observed in 44.63–48.19% of szl-sgRNA2-injected larvae, 69.47–79.61% of szl-sgRNA3-injected larvae, and 64.29–76.19% of larvae injected with the sgRNA mixture; szl-sgRNA1-injected larvae remained single-tailed. Calcein staining further revealed separation of distal caudal fin rays and partial splitting of the caudal skeletal complex in szl-edited larvae. qRT-PCR showed selective remodeling of dorsal–ventral patterning genes, including reduced chdA and eve1 expression and increased bmp2 and nog1 expression. These findings provide direct functional evidence that szl regulates median caudal patterning in goldfish and suggest that szl-dependent modulation of the Chordin/BMP network can generate twin-tail-like caudal morphology. Full article

Major depressive disorder (MDD) is a heterogeneous psychiatric disorder characterized by impaired mood, neuroplasticity, neuroinflammation, and dysregulated stress response systems. Chronic stress can induce epigenetic changes leading to depression. Evidence suggests that histone acetylation and deacetylation are epigenetic processes involved in changes in gene expression. Histone deacetylases (HDACs) modulate chromatin structure and transcription, and their dysregulation is associated with stress susceptibility, decreased brain-derived neurotrophic factor (BDNF) signaling, impaired synaptic plasticity, and inflammatory activation. HDAC isoforms HDAC3 and HDAC6 have emerged as epigenetic regulators in stress-induced depression. HDAC3 is a transcriptional regulator involved in neuroplasticity-related gene expression, inflammatory signaling, and glucocorticoid receptor-mediated stress responses. In contrast, HDAC6 is cytoplasmic and regulates non-histone substrates involved in microtubule dynamics, synaptic function, protein trafficking, and the regulation of the hypothalamic–pituitary–adrenal axis (HPA axis). Preclinical studies show that HDAC3 or HDAC6 inhibition can exert antidepressant-like effects by promoting neuroplasticity, reducing neuroinflammation, and restoring stress-related signaling. Dual targeting is an interesting therapeutic approach because both regulate complementary mechanisms. However, clinical translation is limited by poor blood–brain barrier penetration, systemic toxicity, insufficient isoform selectivity, and a lack of clinical evidence. This review summarizes the roles and mechanisms of HDAC3 and HDAC6, the rationale for dual targeting, translational limitations, and future therapeutic perspectives. Full article

Abdominal aortic aneurysm (AAA) is a progressive and often asymptomatic vascular disease associated with high mortality after rupture, but reliable circulating biomarkers for noninvasive detection remain limited. We aimed to identify and validate plasma protein biomarkers for AAA using an integrated proteomics-based approach. Plasma samples from 22 patients with AAA and 22 healthy controls were analyzed through data-independent acquisition (DIA) mass spectrometry. Differentially expressed proteins were subjected to bioinformatic analyses, including Gene Ontology enrichment, Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein–protein interaction, and weighted gene coexpression network analyses. Candidate biomarkers were selected on the basis of differential abundance, diagnostic performance, and biological relevance and subsequently validated by enzyme-linked immunosorbent assay in an independent cohort comprising 93 patients with AAA and 83 non-AAA controls. DIA proteomics identified 111 differentially abundant proteins, revealing enrichment of pathways related to mitochondrial respiration, oxidative stress, inflammation, extracellular matrix remodeling, and proteostasis. Among the candidates, plasma CHRDL1 levels were significantly reduced, whereas OGN and CCL18 levels were significantly elevated in patients with AAA; these findings were consistently confirmed in the validation cohort. A combined three-protein model demonstrated strong diagnostic performance, with an area under the receiver operating characteristic curve of 0.890. These findings identify CHRDL1, OGN, and CCL18 as promising plasma biomarkers for AAA detection and further highlight mitochondrial dysfunction, chronic inflammation, ECM remodeling, and dysregulated proteostasis as key molecular features of AAA. Full article

Osteosarcoma is the third most common malignancy among children and adolescents, necessitating the development of effective therapeutic strategies. This study investigated the anticancer activity of green-synthesized zinc oxide nanoparticles (ZnO-NPs) fabricated using bark extract of Ficus benghalensis against the human osteosarcoma Saos-2 cell line. The synthesized ZnO-NPs were characterized using UV–Vis spectroscopy, Fourier Transform Infrared (FTIR), and X-ray Diffraction (XRD), confirming nanoparticle formation and a hexagonal wurtzite crystalline structure. Cytotoxicity evaluation revealed significant dosage-dependent inhibition of Saos-2 cell proliferation, with an IC₅₀ value of 75 μg mL⁻¹. Morphological alterations and 4′,6-diamidino-2-phenylindole (DAPI) staining confirmed apoptotic cell death following ZnO-NPs treatment. Furthermore, ZnO-NPs induced oxidative stress by increasing nitric oxide (NO) and lipid peroxidation (LPO) levels while significantly reducing antioxidant markers, including catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH). Flow cytometry analysis demonstrated G0/G1cell cycle arrest, accompanied by elevated caspase-8 activity. Gene expression analysis showed upregulation of Bax and p53 and downregulation of Bcl-2, indicating activation of the mitochondrial apoptotic pathway. Collectively, these findings demonstrate that phytochemical-mediated ZnO-NPs exert potent anticancer effects against Saos-2 cells through oxidative stress-induced apoptosis and cell-cycle arrest, highlighting their potential for osteosarcoma therapy. Full article

The characteristic red walnut germplasm ‘RW-1′ (Juglans regia L.) exhibits a stable red seed coat phenotype due to the abundant accumulation of anthocyanins and proanthocyanidins (PAs). The regulatory mechanisms underlying PA biosynthesis in red walnut remain poorly studied, which hinders the improvement of walnut color quality. Leucoanthocyanidin reductase (LAR) is a key enzyme in the PA metabolic pathway, while its function in red walnut remains unclear. Here, the leucoanthocyanidin reductase gene JrLAR1, whose expression pattern is consistent with the accumulation trend of PAs, was cloned from the seed coats of red walnut ‘RW-1′, and its function in PA biosynthesis was verified via heterologous overexpression in Arabidopsis thaliana, a well-recognized cross-species LAR functional validation system free of endogenous LAR interference due to absent native homologs. The results showed that the full-length coding sequence (CDS) of JrLAR1 gene is 1104 bp, encoding a 367-amino-acid protein belonging to the NADB_Rossmann superfamily, and the protein shares an extremely high sequence similarity with grape VvLAR2. Heterologous overexpression of JrLAR1 significantly increased total PA content in the leaves and seeds of A. thaliana. Integrated transcriptomic and metabolomic analyses further revealed that JrLAR1 overexpression markedly upregulated the core genes involved in PA metabolism and the transcription factor GL3 in A. thaliana, specifically induced (+)-catechin synthesis, and ultimately promoted the significant accumulation of procyanidin B3. In addition, a set of antioxidant enzyme-encoding genes were substantially upregulated in JrLAR1-overexpressing A. thaliana lines. Yeast one-hybrid and dual-luciferase reporter assays demonstrated that JrEGL1b, a homolog of A. thaliana GL3, can bind to the promoter region of JrLAR1 gene and significantly enhance its transcriptional activity. Transient overexpression of JrLAR1 or JrEGL1b in red walnut leaves significantly promoted PA accumulation, and JrEGL1b overexpression notably upregulated JrLAR1 expression. In conclusion, JrLAR1 plays a crucial role in PA biosynthesis in red walnut and is positively regulated by the transcription factor JrEGL1b. These findings improve the molecular regulatory network of pigment metabolism in red walnut and provide valuable molecular targets for the quality improvement and directional breeding of walnuts. Full article

A systematic evaluation of salt tolerance at the seedling stage was conducted using 143 maize inbred lines under a 150 mM mixed-salt solution (NaCl:Na₂SO₄ = 9:1, EC = 16.78 dS/m) that mirrors the ionic composition of saline groundwater in the Yellow River Delta. The comprehensive salt tolerance index (D value) ranged from 0.15 to 0.85 across the population, with the elite line B114 exhibiting the highest D value (0.835) and the sensitive line PHT55 ranking near the bottom. Under salt stress, B114 displayed remarkable growth stability, with plant height decreasing by only 25.9%, fresh weight by 13.3%, and dry weight remaining unchanged, whereas PHT55 suffered severe growth inhibition (plant height: 61.5% decrease; fresh weight: 63.2% decrease; dry weight: 33.3% decrease). Time-series RNA-seq of root tissues across four time points (5, 8, 11, and 14 days) revealed markedly distinct transcriptional dynamics: B114 exhibited relatively stable temporal regulation (2261–9124 DEGs), whereas PHT55 showed a pronounced early transcriptional burst that progressively intensified (3728–10,108 DEGs). Using random forest-based machine learning, 50 core salt tolerance-related genes were unbiasedly identified from 16,194 significantly differentially expressed genes. Functional enrichment analysis revealed that these genes were primarily involved in redox regulation, ion homeostasis maintenance, and stress signal transduction pathways. qRT-PCR validation confirmed biphasic expression patterns, with Zm00001d024160 showing the strongest early induction (48-fold at 5 h). This study established a maize salt tolerance evaluation system closely aligned with field conditions and demonstrated that coordinated temporal transcriptional regulation represents a core molecular mechanism underlying high salt tolerance in maize. The elite salt-tolerant germplasm and key candidate genes identified here provide valuable genetic resources and a theoretical foundation for molecular breeding of salt-tolerant maize adapted to saline-alkaline soils. Full article

Neurons of the arcuate nucleus (AN) produce dopamine, which inhibits prolactin secretion. Tyrosine hydroxylase (TH), the key enzyme of dopamine synthesis, is expressed in AN in dopaminergic neurons and in neurons expressing only TH or both enzymes but lacking the dopamine transporter. These neurons are distributed differently between the ventrolateral and dorsomedial regions of the AN (further—ventrolateral or dorsomedial AN). We hypothesized that noradrenaline released by noradrenergic afferents inhibits TH synthesis in AN neurons postnatally. To test this hypothesis, we assessed: (i) adrenoreceptors gene expression in the ventrolateral and dorsomedial AN of intact rats at postnatal days (P) 5 and 60 and (ii) TH levels in sections of each AN region from rats at P5 and P60 after 6 h incubation in the absence or presence of noradrenaline, as well as noradrenaline with adrenoreceptor antagonists. It was shown that (i) AN neurons express genes for all types of adrenoreceptors in each region of AN on P5 and P60; (ii) neurons in both regions of AN synthesize TH, but to a greater extent at P60 than at P5; and (iii) noradrenaline inhibits TH synthesis, but only in the ventrolateral AN at P60—this action is mediated via α1-adrenoreceptors. Full article

The powdery mildew pathogen Erysiphe necator poses a major threat to global viticulture, yet the earliest hours of colonization remain transcriptionally uncharacterized at the single-cell resolution. Here, we constructed a single-cell leaf transcriptomic atlas of Vitis vinifera during early E. necator infection by profiling 113,346 cells across five leaf cell types at 0-, 3-, 6-, and 12 h post-inoculation. This revealed cell-type-specific temporal dynamics of defense-related gene expression, with epidermal cells showing delayed transcriptional activation relative to other cell types. Pseudotime trajectory analysis identified four sequential transcriptional states in epidermal cells, and co-expression network analysis uncovered defense-associated gene modules. We identified 230 NLR immune receptor genes exhibiting distinct cell-type-specific expression patterns and 20 small secreted peptide (SSP)-encoding genes differentially expressed in epidermal cells, including four candidates upregulated at 3 or 6 hpi. These findings provide a transcriptomic framework for understanding cell-type-specific defense dynamics and prioritizing candidate genes for functional studies, thereby offering a molecular resource for breeding powdery mildew-resistant grapevine cultivars. Full article

Soybean root rot caused by Fusarium graminearum is an important soil-borne disease. It hinders seedling establishment and ultimately reduces soybean yield. Resistant germplasm and reliable molecular markers are therefore needed for resistance breeding. In this study, 336 soybean accessions were evaluated for resistance to F. graminearum root rot using the disease severity index (DSI), which ranged from 5.71 to 100.00 across the association panel. Genome-wide association analysis was performed using resequencing-based single nucleotide polymorphism (SNP) data with mixed linear model (MLM) and Fixed and random model Circulating Probability Unification (FarmCPU) models, which detected 117 and 113 candidate resistance-associated SNPs, respectively. Among these, 105 shared SNPs were used to define candidate genomic intervals containing 247 annotated genes. Based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, functional annotation, and allelic-effect analysis, six candidate genes and their associated exonic SNPs were prioritized. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis showed infection-responsive expression patterns for all six candidate genes, with Glyma.17g202500 and Glyma.18g266700 showing stronger induction in the resistant accession. Two SNPs in these genes were converted into Kompetitive allele-specific PCR (KASP) assays. KASP-S17_32244510 and KASP-S18_55105706 were successfully developed for genotype screening, with screening efficiencies of 73.08% and 74.29%, respectively. These findings identify useful genetic targets and molecular markers for improving soybean resistance to root rot caused by F. graminearum. Full article

Plants have evolved sophisticated immune systems to defend against diverse pathogens, whereas pathogens deploy effectors to manipulate host cellular processes for successful infection. Recent studies have revealed that pathogen effectors can target host RNA processing, particularly pre-mRNA alternative splicing (AS), to reshape transcript isoform profiles and modulate plant immunity. However, the common principles and specific differences among pathogen effector-mediated regulation of host AS and their impacts on plant immunity have not been systematically summarized. In this review, we summarize recent advances in pathogen effector-mediated regulation of plant AS, focusing on three major mechanisms: targeting host splicing factors, altering RNA regulatory elements, and interfering with RNA-processing pathways. We discuss how effector-induced AS reprogramming affects immune-related gene expression and contributes to pathogen virulence. Furthermore, we highlight the emerging potential of AS regulation in disease resistance and disease-resistant crop breeding, and propose future directions for dissecting effector-specific splicing targets and translating AS-based regulatory mechanisms into crop improvement strategies. This review emphasizes host RNA splicing as an important regulatory layer in plant-pathogen interactions and provides new perspectives for understanding pathogen manipulation of plant immunity. Full article

Lysophosphatidic acid receptor 5 (LPA₅, formerly designated GPR92) is a G protein-coupled receptor that recognizes lysophosphatidic acid. Previous studies have indicated that the absence of LPA₅ confers protection against the development of neuropathic pain. Although LPA₅ expression has been identified in mast cells, macrophages, and microglia, its specific contribution to allergic responses remains insufficiently characterized. In this study, we evaluated the therapeutic potential of LPA₅ inhibition in allergic asthma. To this end, the effects of the selective LPA₅ antagonist 6,7-dimethoxy-2-(5-methyl-1,2-benzisoxazol-3-yl)-4-(1-piperidinylcarbonyl)-1(2H)-isoquinolinone (AS2717638) were examined using both an in vitro mast cell degranulation model and an in vivo ovalbumin-induced asthma model in BALB/c mice. In RBL-2H3 cells expressing the lpar5 gene, AS2717638 treatment attenuated antigen-induced degranulation. In vivo, administration of AS2717638 reduced airway resistance triggered by ovalbumin exposure. Furthermore, treatment with AS2717638 led to a decrease in eosinophil and lymphocyte infiltration, as well as reduced levels of inflammatory cytokines in bronchoalveolar lavage fluid. Histopathological analysis additionally demonstrated diminished pulmonary inflammation following AS2717638 administration, accompanied by significant reductions in cytokine expression within lung tissue. Collectively, these findings suggest that pharmacological inhibition of LPA₅ using AS2717638 mitigates key features of allergic asthma, supporting LPA₅ as a potential therapeutic target for this condition. Full article

Atrial cardiomyopathy (ACM) is defined as any complex of structural, architectural, functional, electrophysiological, and molecular changes affecting the atria that may result in clinically significant health consequences. ACM can be caused by a variety of factors, including age-related changes, valvular or vascular disease, genetic diseases, congestive heart failure, metabolic diseases, cardiovascular disease (CVD) risk factors such as arterial hypertension (AH) or obesity, obstructive sleep apnea, and other infectious or noninfectious diseases predisposing to chronic inflammation. The diagnosis of ACM relies on several modalities, including electrocardiography, echocardiography, cardiac magnetic resonance imaging (MRI), computed tomography (CT), electroanatomical mapping (EAM), genetic studies, and biomarkers, which can detect and characterize structural, mechanical, and electrical atrial dysfunction. These changes often include structural atrial remodeling (fibrosis), abnormal structure of the atrial wall and its components, and contractile and electrical dysfunctions. When assessing aspects of ACM, structural changes in the atria such as left atrium (LA) size and fibrosis; LA architectural changes such as the expression of remodeling; changes in LA mechanics such as echocardiographic stress indices; changes in reservoir function and changes in contraction; biological factors determining changes in biomarkers; possible genetic predispositions and higher expression of certain genes encoding certain proteins; and arrhythmogenic factors associated with a higher risk of atrial fibrillation (AF) and stroke and a worse short- and long-term prognosis are very important. When considering the challenges of diagnosing ACM, it should be noted that without standardized diagnostics, most ACM diagnostic situations remain primarily research tools rather than practical clinical diagnostic methods. This review critically evaluates the evidence and translational gaps in the diagnosis of ACM, synthesizing the emerging role of advanced diagnostics and their clinical and prognostic implications as a key future tool for individual risk stratification. Full article