Search Results (449)

γ-aminobutyric acid (GABA) is crucial in neural inhibition and sleep regulation. This study screened lactic acid bacteria isolated from breast milk and infant fecal samples for their GABA-producing ability; their acid tolerance, bile salt resistance, and growth performance were evaluated. Based on TLC-HPLC analysis, Lactobacillus gasseri F002, Lactiplantibacillus plantarum R7, and Lacticaseibacillus rhamnosus B2-1 were identified as promising GABA-producing strains. L. gasseri F002 was selected for liquid-state fermentation of the Baihe Dihuang decoction. During fermentation, L. gasseri F002 utilized carbohydrates in the decoction matrix, increased GABA accumulation, with a peak of 0.063 mg/mL at 24 h, and reduced total saponin content, suggesting that lactic acid bacterial fermentation induced compositional shifts of major functional constituents in the Baihe Dihuang decoction. The sleep-promoting effect of the fermented decoction was assessed using a caffeine-induced zebrafish insomnia model. The fermented Baihe Dihuang decoction significantly prolonged sleep bout duration, while reducing wakefulness and total locomotor activity. Moreover, correlative changes altered sleep-related molecular and biochemical indicators in the zebrafish model. Correlative changes in the expression of gabra1, htr1aa, drd2a, dbh, and th, as well as in GABA, melatonin (MT), and monoamine oxidase (MAO) levels, suggest a potential association with the observed sleep-improving phenotypes. Therefore, fermentation with GABA-producing lactic acid bacteria may enhance the sleep-promoting potential of the Baihe Dihuang decoction and provide preliminary experimental support for the development of fermented medicinal–food homologous products aimed at improving sleep. Full article

Recent evidence reveals that several psychotropic compounds exert significant biological effects on the skin through neurochemical and immunomodulatory pathways. Cannabinoids such as tetrahydrocannabinol (THC) show potent anti-inflammatory, antipruritic, and anti-aging properties when applied topically, and may hold therapeutic potential. Antidepressants, particularly fluoxetine (Prozac), have been shown to regulate the expression of pro-inflammatory cytokines in keratinocytes, suggesting benefits applied in allergic pathologies. Additionally, fluoxetine promotes wound healing and cell regeneration, indicating broader dermatological applications. Psychedelics, acting as serotonin receptor agonists (5-HTR), may influence cellular aging and immune modulation via the serotonergic system. Studies report that 5-HT receptor agonists can prevent UV-induced photocarcinogenesis, while psilocybin has been observed to reduce aging markers in human fibroblasts. Furthermore, recent data suggests that psilocin may alleviate acute itch involving the kynurenine pathway. These findings highlight the emerging relevance of psychoactive compounds in cutaneous biology, bridging neuropharmacology and dermatology toward novel therapeutic strategies. Full article

Adequate placental development and function, prerequisites for the development of a healthy fetus, rely on controlled trophoblast invasion into the decidua and remodeling of the spiral arteries. These tightly regulated processes involve epithelial–mesenchymal transition (EMT) and endovascular differentiation of trophoblast cells. Taxifolin (dihydroquercetin), a natural flavonoid with various pharmacological effects, previously showed cytoprotective, antioxidant, and anti-inflammatory activity on trophoblast cells. Given that the literature indicates that this flavonoid suppresses EMT and can affect angiogenesis across different cell types, we investigated the potential of taxifolin (10 and 100 µM) to modulate invasion and endothelial-like differentiation in human extravillous trophoblast HTR-8/SVneo cells by functional tests. Expression of different molecular markers relevant to these processes was evaluated at the mRNA and protein levels. Our results showed that taxifolin inhibited invasion of HTR-8/SVneo cells, involving downregulation of integrin α5 subunit and modulation of MMP-2 and MMP-9 mRNA expression and secretion. No changes in the concentrations of secreted TIMP-1 and TIMP-2 were observed following taxifolin treatment. Furthermore, downregulation of N-cadherin and vimentin in treated trophoblast cells indicated suppression of EMT. Taxifolin inhibited endothelial-like differentiation of HTR-8/SVneo cells, as evidenced by reduced tube formation and downregulation of VE-cadherin in treated cells. Moreover, expression of TGFB1 was upregulated in treated cells, as were levels of phosphorylated SMAD2/3, indicating involvement of TGF-β signaling in TF-induced effects on trophoblast cells. The in vitro effects of taxifolin on suppression of trophoblast invasion, EMT, and endothelial-like differentiation highlight its potential impact on placental development processes. Full article

Rice (Oryza sativa L.) production is constantly threatened by devastating diseases such as rice blast, bacterial blight, and brown planthopper infestation. The AP2-type transcription factor OsHTR (also known as SMOS1/SHB/RAL1/NGR5/GR5) has been previously implicated in hormonal signaling networks and nitrogen use efficiency; however, its role in disease resistance remains largely unexplored. In this study, we functionally characterized OsHTR in disease resistance using knockout (KO) and overexpression (OE) transgenic lines in the ZH11 background. Transcriptome analysis revealed that differentially expressed genes in the htr mutant were significantly enriched in plant–pathogen interaction pathways, with multiple NBS-LRR and NB-ARC resistance-related genes upregulated. Real-time PCR validation confirmed the upregulation of 15 candidate resistance genes in the htr mutant. Comprehensive resistance evaluations suggested that HTR-KO lines exhibited enhanced resistance to rice blast and bacterial blight compared to wild-type ZH11 and HTR-OE lines, which displayed moderate susceptibility. In contrast, all lines remained highly susceptible to brown planthopper, indicating a disease-specific regulatory function of OsHTR. Furthermore, targeted knockout of individual upregulated resistance-related genes (LOC_Os10g04090, LOC_Os12g29690, LOC_Os02g11980, and LOC_Os11g11770) and OsHTR-interacting gene LOC_Os06g03710 confirmed their distinct contributions to blast and bacterial blight resistance but did not establish them as direct targets of OsHTR. Collectively, our results indicate that OsHTR functions as a negative regulator of disease resistance in rice, likely acting through transcriptional repression of defense-related genes, although direct binding remains to be demonstrated. This study uncovers a novel regulatory module connecting AP2-type transcription factors to disease resistance and provides valuable genetic resources for molecular breeding of broad-spectrum-resistant rice cultivars. Full article

Sea cucumbers (Apostichopus japonicus) show fleeing, adhesion, and thanatosis patterns upon exposure to various stressors. However, the molecular mechanisms underlying these contrasting stress response patterns remain largely unknown. In the present study, we performed a transcriptomic analysis of coelomocytes on stressed sea cucumbers to elucidate the potential molecular mechanisms. The RNA-seq results revealed that several matrix metalloproteinase (MMP) family genes, along with HTR4, HRH2, and ADRA1D (which are involved in neuroactive ligand–receptor interactions), were significantly upregulated in the fleeing pattern. These genes may facilitate rapid movement. In the adhesion pattern, PHKA and PGK were significantly downregulated, and the differentially expressed genes (DEGs) were significantly enriched in the longevity regulating pathway, accompanied by downregulation of KRAS and HSPA1. These genes and the pathway may be involved in the reallocation of energy resources during the adhesion pattern. In the thanatosis pattern, DEGs were significantly enriched in the MAPK signaling pathway (including upregulation of ANGPT1 and FGFR1) and in the Rap1 and Ras signaling pathways (with downregulation of key genes: RAPGEF4, RRAS2, and RaLA). These genes potentially contribute to sustaining the thanatosis pattern. These transcriptomic profiles provide novel insights into the distinct molecular signatures underlying each stress response pattern in A. japonicus. Full article

Background: This study was conducted to identify genetic risk variants associated with nicotine addiction in the CHRNA5, HTR2A, DRD4, and CYP2A6 genes among electronic cigarette users who also smoke combustible cigarettes (dual users), and to assess potential genotoxic and cytotoxic damage in the oral mucosal cells of the study population. Methods: We included dual e-cig users (ECIG, n = 70), combustible cigarette smokers (CCU, n = 24), and non-smokers and non-e-cig users (NS, n = 110). Genetic variants in CHRNA5, HTR2A, DRD4, and CYP2A6 were genotyped. Micronucleus analysis was performed on oral mucosal cells to detect cellular abnormalities. Results: The ECIG group demonstrated greater nicotine addiction on the Fagerström Test for Nicotine Dependence (FTND, 5.5 vs. 1, p = 0.023). Salivary cotinine levels were significantly higher in the ECIG group compared to the CCU group (39 vs. 12 ng/mL, p < 0.001). The carriers of the A allele (rs16969968/CHRNA5) had higher FTND scores, carriers of the C allele (rs1800955/DRD4) used electronic cigarettes more frequently each day, and carriers of the T allele (rs4105144/CYP2A6) started using nicotine products at a younger age. The number of micronuclei and cellular abnormalities in the oral mucosa was higher in the ECIG and CCU groups compared to the NS group. Conclusions: Salivary cotinine levels and FTND are higher in dual e-cigarette users than in combustible cigarette users. Dual users exhibit risk alleles in the CHRNA5, DRD4, and CYP2A6 genes, which are associated with traits linked to increased nicotine addiction. Dual e-cigarette use poses comparable genotoxic risks to combustible smoking. Full article

Background/Objectives: Early-life environment may influence long-term neurodevelopment through epigenetic regulation. Serotonergic and glutamatergic pathways are central to brain development and have been implicated in DNA methylation changes following prenatal adversity. In this study, we examined whether preterm birth (PTB) in birthweight-discordant twins is associated with differential DNA methylation in the serotonin receptor signaling pathway and the glutamatergic synapse pathway in adult twins. Methods: Genome-wide DNA methylation data were obtained from whole blood samples of 288 individuals (144 monozygotic birthweight-discordant twin pairs), including a younger cohort (140 individuals; mean age 33 years) and an older cohort (148 individuals; mean age 63 years). DNA methylation was measured using the Illumina HumanMethylation450 BeadChip. Linear models were fitted for association testing, adjusting for leukocyte composition and twin pair correlation. Pathway-level differential methylation was assessed using Rotation Gene Set Testing. Results: In the glutamatergic synapse pathway, no consistent directional enrichment of hypo- or hypermethylation was observed. However, gene-level analyses identified consistent hypomethylation of GRIA2 and GRIA4 across cohorts. In the serotonin receptor signaling pathway, the young cohort exhibited a mixed methylation pattern, whereas the old cohort showed significant enrichment of hypermethylation. At the gene level, HTR1A was hypomethylated in the young cohort but hypermethylated in the old cohort, indicating a cohort-dependent effect in the methylation patterns. Conclusions: These findings suggest that PTB is associated with long-term epigenetic variation in neurodevelopmentally relevant pathways, as reflected in blood cells. The results further indicate distinct methylation architectures across pathways, with more consistent pathway-level signals in the serotonergic system and more localized gene-level effects in the glutamatergic pathway. Full article

Spontaneous abortion (SA) is intimately associated with ferroptosis in placental trophoblasts. Asperosaponin VI (AVI), a major active triterpene saponin extracted from Dipsacus asperoides, has emerged as a promising therapeutic candidate for SA; however, its precise molecular mechanisms remain poorly elucidated. This study aimed to investigate the protective efficacy of AVI against SA and clarify its underlying pathways. In vivo, an SA model was established via the subcutaneous administration of bromocriptine. AVI intervention significantly reduced the embryo resorption rate and ameliorated placental injury. Biochemically, AVI attenuated the accumulation of MDA and Fe²⁺, downregulated pro-ferroptotic markers (TFR-1 and ACSL4), and systematically modulated the expression of SLC7A11 alongside the ferroptosis-related KEAP1/NRF2/GPX4 signaling axis. In silico analyses, including molecular docking and molecular dynamics simulations, confirmed a robust binding affinity between AVI and NRF2. In vitro, AVI dose-dependently reversed erastin-induced trophoblast dysfunction and mitochondrial impairment, while effectively abrogating the ferroptosis-associated overproduction of ROS, Fe²⁺, and MDA. Crucially, pharmacological inhibition of NRF2 by ML385 partially negated these cytoprotective effects. Comprehensive molecular analyses (RT-qPCR, IF and Western blotting) revealed that AVI suppressed KEAP1 while concomitantly upregulating NRF2, GPX4, and SLC7A11. In conclusion, AVI prevents SA by suppressing trophoblast ferroptosis through KEAP1/NRF2/GPX4 signaling, offering a novel therapeutic approach. Full article

Background: Impulse control disorders (ICDs) are a common non-motor complication in Parkinson’s disease (PD) patients with multiple negative consequences for the individual and caregivers. Although ICDs are strongly linked to dopaminergic therapy, particularly dopamine agonists, only a percentage of patients develop these behaviors, suggesting the involvement of additional susceptibility factors, including genetic variability. This review aims to analyze current knowledge on the genetic background of ICDs. Methods: A literature search was conducted in the PubMed and Scopus databases for peer-reviewed research regarding the role of genetics in ICDs, published in the English language from 1996 to 2026. References of the selected articles for possible additional articles were also screened in order to include most of the key recent evidence. Genes that are involved in the dopaminergic system play a central role in ICD susceptibility, although the findings in studies are often inconsistent and not replicated. Moreover, variants in genes related to the glutamatergic (e.g., GRIN2B), serotonergic (e.g., HTR2A and TPH2), and opioid systems (e.g., OPRK1 and OPRM1) have been implicated, supporting a multi-system contribution to ICD pathophysiology. Conclusions: Early recognition of genetic factors that increase susceptibility to ICDs in PD patients is awaited to increase diagnostic accuracy and expedite individualized treatment. Full article

Background: Emerging evidence has established ferroptosis as a vital factor in the pathogenesis of cardiovascular diseases, especially in septic cardiomyopathy (SCM). Meanwhile, ondansetron (OND), a well-established 5-HT3 receptor antagonist, has gained increasing attention for its pleiotropic effects. However, its potential to modulate ferroptosis in the cardiovascular field remains unexplored. This study aims to fill this gap by exploring the potential of OND as an innovative therapeutic intervention for SCM. Methods: This study utilized both in vitro and in vivo models of septic cardiomyopathy (SCM), which was induced by lipopolysaccharide (LPS) stimulation in neonatal rat cardiomyocytes (NRCMs) and C57BL/6 mice. Through RNA sequencing, as well as molecular and functional assessments—including echocardiography and ferroptosis-related measurements—we revealed the anti-ferroptotic effect of ondansetron (OND). Mechanistically, ATF3 was identified as a pivotal regulator, with its overexpression via AAV9 in vivo and ADV in vitro confirming its role in OND-induced cardioprotection. Results: Ondansetron (OND) showed potent anti-ferroptotic effects in both cellular and murine models of septic cardiomyopathy (SCM). Treatment with OND not only improved cardiac performance but also reduced ferroptotic markers, mitigated lipid peroxidation and iron overload, and bolstered antioxidant defense. Notably, OND administration attenuated oxidative and endoplasmic reticulum (ER) stress while restoring mitochondrial integrity. Mechanistically, the anti-ferroptotic activity of OND was mediated through the HTR3A/ATF3 axis: ATF3 overexpression negated OND’s protective effects, while HTR3A antagonism with VUF10166 recapitulated its benefits. Conversely, HTR3A agonism with PBG attenuated ferroptosis resistance, further implicating this pathway as central to OND’s mechanism. Conclusions: This study demonstrated a novel pharmacological role for ondansetron (OND) in attenuating ferroptosis in septic cardiomyopathy (SCM) via the HTR3A/ATF3 signaling pathway. This finding delineates a novel therapeutic avenue and supports the repurposing of OND beyond its traditional antiemetic use to cardiovascular applications. Full article

Background/Objectives: This study aimed to describe cumulative reproductive outcomes across three embryo transfer (ET) cycles after hysteroscopic endometrial polypectomy using a hysteroscopic tissue removal system (HTRS) and to identify determinants of cumulative and per-cycle pregnancy. Methods: In this single-center retrospective cohort study, we included infertile women who underwent HTRS-based endometrial polypectomy between January 2023 and December 2024 and subsequently initiated at least one ET cycle. Patients were followed from ET1 through ET3. The primary endpoint was the cumulative clinical pregnancy rate (CCPR) within three ET cycles. In the observed cumulative analysis, treatment discontinuation was considered as non-pregnancy. Kaplan–Meier (KM) analysis was used to estimate the cumulative pregnancy probability, with treatment discontinuation considered as censoring. Multivariate logistic regression and generalized estimating equations were used to identify patient-level and cycle-level predictors. Results: Among 100 patients, 79 achieved clinical pregnancy within three ET cycles (CCPR 79.0%). The KM estimate at ET3 was 87.4%, and the cumulative live birth rate was 65.0%. Pregnancy rates declined with advancing maternal age (≤34 years, 91.9%; 35–39 years, 78.3%; ≥40 years, 52.9%). Maternal age independently predicted lower cumulative pregnancy and lower per-cycle pregnancy probability, whereas blastocyst transfer was associated with a higher probability of pregnancy per cycle. Conclusions: In women who underwent ET after HTRS polypectomy, cumulative pregnancy across three ET cycles was relatively high; however progression to live birth declined with advancing maternal age. As no non-surgical comparison group was included, these findings should be interpreted as descriptive rather than causal. Full article

Objectives: Attention-deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder diagnosed during childhood, primarily characterized by continuous symptoms of inattention, hyperactivity, and impulsivity. The present study aimed to investigate the genetic association between polymorphisms in the serotonergic system-related genes, HTR1B and HTR2A, and the susceptibility to ADHD in a Korean sample. Methods: The study cohort consisted of 234 children diagnosed with ADHD and 1686 healthy controls. Clinical diagnosis was established based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria. Genetic analysis focused on single nucleotide polymorphisms (SNPs) within the serotonergic pathway: rs6296 in HTR1B, and three SNPs (rs6311, rs6313, and rs9534495) in HTR2A. Genotype and allele frequencies were analyzed using Chi-square tests. Risk estimates were calculated as odds ratios (OR) with 95% confidence intervals (CI) across dominant, recessive, and additive inheritance models. Results: A statistically significant association was observed between the HTR2A rs9534495 polymorphism and ADHD. Specifically, significant associations were identified under the dominant (OR 0.67, 95% CI 0.48–0.93, p = 0.017), recessive (OR 0.67, 95% CI 0.48–0.93, p = 0.016), and additive (OR 0.80, 95% CI 0.65–1.00, p = 0.046) models. However, these significant findings did not persist after applying the Bonferroni correction for multiple comparisons. Conversely, no significant associations were detected for the HTR1B (rs6296) and the other HTR2A (rs6311, rs6313) polymorphisms. Conclusions: These findings suggest that genetic variations in the serotonergic system, particularly within the HTR2A gene, may contribute to the genetic susceptibility to ADHD. This study confirmed gene SNIPs associated with the serotonergic system in the pathophysiology of ADHD. Future research involving large-scale multi-ethnic cohorts, functional assays, and gene–environment interaction analyses is warranted to further elucidate the underlying mechanisms of serotonergic genes. Full article

Triptolide (TPL), the core active component of the traditional Chinese medicinal herb Tripterygium wilfordii Hook F (TwHF), possesses a wide spectrum of pharmacological activities, including anti-inflammatory, neuroprotective, immunosuppressive, and anti-tumor activities. However, its clinical application is severely limited by significant reproductive toxicity, the mechanism of which remains poorly understood. Using an integrated analysis of MeRIP-seq and mRNA-seq data, coupled with experimental validation in HTR-8/SVneo cells, we systematically elucidated the molecular mechanism by which TPL induces trophoblast cell injury. Our findings revealed that TPL significantly altered intracellular N⁶-methyladenosine (m⁶A) modification and gene expression profiles, with 1774 genes displaying hypomethylation concurrent with mRNA upregulation. According to the functional enrichment analysis, these genes showed significant enrichment in several key pathways associated with reproduction, including autophagy, DNA damage response, mitochondrial outer membrane, and positive regulation of apoptotic process. Molecular docking further demonstrated direct and stable binding of TPL to key m⁶A regulators, leading to specific demethylation of targets including E2F1 and PPP1CC. This study uncovers a novel post-transcriptional mechanism where TPL disrupts m⁶A modification, thereby perturbing essential trophoblast functions and driving reproductive toxicity. Full article

Objectives: To overcome the limitations of invasive diagnostic approaches for ulcerative colitis (UC) diagnosis, this study integrates liquid chromatography–mass spectrometry (LC–MS)-based serum metabolomics with mucosal transcriptomics to elucidate the interplay between systemic metabolic perturbations and neuroendocrine signaling in UC pathogenesis. Methods: Serum metabolites and mucosal differentially expressed genes (DEGs) were identified through multi-omics profiling. Key neurotransmitter receptor-related genes (NRRGs) were prioritized using three machine learning algorithms: LASSO, Random Forest, and SVM-RFE. A three-gene diagnostic nomogram was developed and rigorously validated across multiple independent cohorts (GSE48958, GSE73661) using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA). Results: The integrated analysis revealed 334 dysregulated metabolites and 3093 DEGs, both converging on the serotonergic synapse pathway. Specific molecular alterations were uncovered, including tryptophan depletion linked to the downregulation of SLC6A4, concomitant with abnormal serotonin accumulation and PTGS2-mediated inflammatory responses. The three-gene signature, HTR3C, RPS6KA6, and NETO2, formed a highly robust diagnostic model, achieving an area under the ROC curve (AUC) exceeding 0.96 in both the training cohort and external validation sets. Conclusions: This multi-omics study delineates a neuroimmune mechanism in UC centered on dysregulation of the serotonergic synapse. The resulting three-gene nomogram identifies a candidate biomarker signature that demonstrates strong discriminative potential; however, given the exceptionally high performance metrics, these findings should be interpreted as a preliminary diagnostic framework rather than a clinically validated tool, and its efficacy relative to standard markers like CRP or fecal calprotectin requires further investigation in prospective real-world cohorts. Nonetheless, this study provides critical mechanistic insights into gut–brain axis dysfunction in UC. Full article

SUMOylation may be involved in preeclampsia (PE) progression. We aimed to investigate the roles of SUMOylation in PE and its underlying mechanism using animal and cell models. A rat PE model was established by dexamethasone (DEX) treatment from pregnancy day 7.5–17.5. HTR8 and BeWo trophoblasts were used as cell models. Placental RNA-seq analysis coupled with Western blotting showed upregulated SUMOylation in placentas of DEX-treated rats. SUMOylation inhibitor TAK-981 treatment robustly alleviated PE-like features including reduced blood pressure and improved renal injury, fetal weight, spiral artery remodeling and placental blood flow in DEX-treated rats. DEX increased SUMOylation in HTR8 and BeWo cells. TAK-981 reversed DEX-induced dysfunction in HTR8 and BeWo cells, such as migration, invasion and syncytialization. Mass spectrum analysis of SUMO1 immunoprecipitation coupled with functional validation showed that SUMOylated proteins related to oxidative stress caused by DEX were reversed by TAK-981 in cultured trophoblasts. TAK-981 mitigated placental oxidative stress in DEX-treated rats. GEO database combined with Western blotting showed upregulated SUMOylation in human placentas with PE. Our findings indicate that protein SUMOylation is one of the key events in PE, particularly in that associated with high glucocorticoid exposure. Targeting placental SUMOylation might be a promising therapeutic strategy for PE. Full article