Search Results (249)

Background/Objectives: Coupled with the already-problematic background rates of traditional cigarette consumption during pregnancy, the surging epidemic of electronic cigarette usage among pregnant women redoubles the importance of understanding the impacts of nicotine exposure during critical periods of development. To date, a burgeoning body of human epidemiological and animal model research indicates that not only the children but also the grandchildren of maternal smokers are at higher risk for neurodevelopmental disorders such as ADHD, autism, and schizophrenia and are predisposed to neurodevelopmental abnormalities which transcend these diagnoses. However, the roles of discrete cellular sub-populations in these and other intergenerational consequences of smoking during pregnancy remain indeterminate. Methods: Toward the resolution of this void in the literature, the present study characterized alterations in the gene expression profiles of dopamine receptor D1-expressing striatal cells from the first- and second-generation male progeny of female mice that were continuously exposed to nicotine beginning prior to conception, continuing throughout pregnancy, and concluding upon weaning of offspring. Results: Dopamine receptor D1-expressing striatal cells from our mouse models of the children and grandchildren of maternal smokers exhibit differential expression patterns for a multitude of genes that are (1) individually associated with neurodevelopmental disorders, (2) collectively overrepresented in gene set annotations related to brain, behavioral, neurobiological, and epigenomic phenotypes shared among neurodevelopmental disorders, and (3) orthologous to human genes that exhibit differential DNA methylation signatures in the newborns of maternal smokers. Conclusions: Together with our and others’ previous findings, the results of this study support the emerging theory that, by inducing extensive alterations in gene expression that in turn elicit cascading neurobiological changes which ultimately confer widespread neurobehavioral abnormalities, nicotine-induced epigenomic dysregulation may be a primary driver of neurodevelopmental deficits and disorders in the children and grandchildren of maternal smokers. Full article

The gut microbiome produces thousands of metabolites with potential to modulate central nervous system function through peripheral or direct neural mechanisms. Tourette syndrome, attention-deficit/hyperactivity disorder, and autism spectrum disorder exhibit shared neurotransmitter dysregulation and microbiome alterations, yet mechanistic links between microbial metabolites and receptor-mediated neuromodulation remain unclear. We screened 27,642 microbiome SMILES metabolites for blood–brain barrier permeability using rule-based SwissADME classification and a PyTorch 2.0 neural network trained on 7807 experimental compounds (test accuracy 86.2%, AUC 0.912). SwissADME identified 1696 BBB-crossing metabolites following Lipinski’s criteria, while PyTorch classified 2484 metabolites with expanded physicochemical diversity. Following 3D conformational optimization (from SMILES) and curation based on ≤32 rotatable bonds, molecular docking was performed against five neurotransmitter receptors representing ionotropic (GABRA2, GRIA2, GRIN2B) and metabotropic (DRD4, HTR1A) receptor classes. The top 50 ligands across five receptors demonstrated method-specific BBB classification (44% SwissADME-only, 44% PyTorch-only, 12% overlap), validating complementary prediction approaches. Fungal metabolites from Ascomycota dominated high-affinity top ligands (66%) and menaquinone MK-7 showed broad phylogenetic conservation (71.4% of phylum). Our results establish detailed receptor–metabolite interaction maps, with fungal metabolites dominating high-affinity ligands, challenging the prevailing bacterial focus of the microbiome and providing a foundation for precision medicine and a framework for developing microbiome-targeted therapeutics to address clinical needs in neurodevelopmental disorders. Full article

The integration of omics technologies, including genomics, proteomics, metabolomics, and microbiomics, has transformed sports science, particularly soccer, by providing new opportunities to optimize player performance, reduce injury risk, and enhance recovery. This systematic literature review was conducted in accordance with PRISMA 2020 guidelines and structured using the PICOS/PECOS framework. Comprehensive searches were performed in PubMed, Scopus, and Web of Science up to August 2025. Eligible studies were peer-reviewed original research involving professional or elite soccer players that applied at least one omics approach to outcomes related to performance, health, recovery, or injury prevention. Reviews, conference abstracts, editorials, and studies not involving soccer or omics technologies were excluded. A total of 139 studies met the inclusion criteria. Across the included studies, a total of 19,449 participants were analyzed. Genomic investigations identified numerous single-nucleotide polymorphisms (SNPs) spanning key biological pathways. Cardiovascular and vascular genes (e.g., ACE, AGT, NOS3, VEGF, ADRA2A, ADRB1–3) were associated with endurance, cardiovascular regulation, and recovery. Genes related to muscle structure, metabolism, and hypertrophy (e.g., ACTN3, CKM, MLCK, TRIM63, TTN-AS1, HIF1A, MSTN, MCT1, AMPD1) were linked to sprint performance, metabolic efficiency, and muscle injury susceptibility. Neurotransmission-related genes (BDNF, COMT, DRD1–3, DBH, SLC6A4, HTR2A, APOE) influenced motivation, fatigue, cognitive performance, and brain injury recovery. Connective tissue and extracellular matrix genes (COL1A1, COL1A2, COL2A1, COL5A1, COL12A1, COL22A1, ELN, EMILIN1, TNC, MMP3, GEFT, LIF, HGF) were implicated in ligament, tendon, and muscle injury risk. Energy metabolism and mitochondrial function genes (PPARA, PPARG, PPARD, PPARGC1A, UCP1–3, FTO, TFAM) shaped endurance capacity, substrate utilization, and body composition. Oxidative stress and detoxification pathways (GSTM1, GSTP1, GSTT1, NRF2) influenced recovery and resilience, while bone-related variants (VDR, P2RX7, RANK/RANKL/OPG) were associated with bone density and remodeling. Beyond genomics, proteomics identified markers of muscle damage and repair, metabolomics characterized fatigue- and energy-related signatures, and microbiomics revealed links between gut microbial diversity, recovery, and physiological resilience. Evidence from omics research in soccer supports the potential for individualized approaches to training, nutrition, recovery, and injury prevention. By integrating genomics, proteomics, metabolomics, and microbiomics data, clubs and sports practitioners may design precision strategies tailored to each player’s biological profile. Future research should expand on multi-omics integration, explore gene–environment interactions, and improve representation across sexes, age groups, and competitive levels to advance precision sports medicine in soccer. Full article

Since there is currently no cure for Parkinson’s disease, pharmacobiotic approaches based on gut microbiota—capable of producing pharmacologically active compounds—are under development. In this study, we propose LfU21, derived from the strain Limosilactobacillus fermentum U-21, as a candidate pharmacobiotic. To evaluate its efficacy, a combined LPS- and lactacystin (LAC)-induced Parkinson’s disease model was established in Wistar rats. Effects were assessed using behavioral, biochemical, immunomodulatory, and transcriptomic biomarkers. LfU21 administration reduced α-synuclein levels, altered motor performance in the “Rung ladder” test, and modulated bdnf gene expression in the right and left striata. Under LPS exposure, LfU21 prevented alterations in immune response markers, GSH levels, drd2 and bdnf gene expression, and intestinal goblet cell counts. In LAC and LAC + LPS groups, LfU21 mitigated the rise in α-synuclein, the decline in bdnf expression, and behavioral deficits in the “Open Field” and “Rung ladder” tests, respectively. The multifunctional activity of LfU21 in a combined Parkinson’s disease model underscores its therapeutic potential and helps identify a target patient cohort for future clinical trials. Full article

Background/Objectives: Despite therapeutic advances, managing relapsed/refractory multiple myeloma (RRMM) remains challenging. For patients with frailty, comorbidities, mobility limitations, or when treatment preference and drug accessibility are key considerations, the all-oral ixazomib–lenalidomide–dexamethasone (IRd) regimen offers a practical alternative. Methods: We performed a multicenter retrospective study of RRMM patients treated with IRd in Hungary between 1 January 2020 and 30 June 2025. Results: The median age at treatment initiation was 73.7 years. Treatment was initiated for clinical progression in 38.2%, biochemical progression in 53.3%, and for intolerance or toxicity of prior therapy in 8.6%. Median progression-free survival (PFS) was 18.7 months, and median overall survival (OS) was 34.7 months. Patients treated at biochemical progression had significantly longer PFS than those treated at clinical progression (24.3 vs. 15.6 months; p = 0.004), with additional benefit when IRd was initiated owing to intolerance or toxicity of previous therapy (p = 0.04). In the second-line setting, median PFS was 24.5 months, and median OS was not reached. Adverse events occurred in 68.3% of patients; dose reductions were required in 18.4%, and 21.6% discontinued treatment because of intolerance or toxicity. Most common toxicities were neutropenia (32.9%), thrombocytopenia (27.6%), diarrhoea (25%), peripheral neuropathy (25.3%), and infections (22.4%). Conclusions: IRd initiation at biochemical progression was associated with superior PFS compared with treatment at clinical progression. When compared with a recent Hungarian multicenter cohort treated with second-line daratumumab, lenalidomide, and dexamethasone, outcomes with IRd are not significantly inferior (36-month OS calculated from 2nd line treatment initiation: 65.5% for DRd vs. 60% in our cohort; p = 0.56). These real-world data support IRd as an effective, convenient, all-oral option for appropriately selected RRMM patients. Full article

A novel, label-free chemiluminescence sensing platform for CpG methylation was developed, leveraging the G-quadruplex (G4) structural sensitivity of G4–protein interactions to eliminate bisulfite conversion. This sensing system is based on the enhancement of luminol chemiluminescence generated from myoglobin upon binding to the G4-forming DNA. At the core of this biosensor is the G4-structure-dependent modulation of the peroxidase-like activity generating luminol chemiluminescence of myoglobin. The structural change by CpG methylation within the G4-forming sequence of the B cell lymphoma 2 (BCL2) gene promoter altered its binding to myoglobin, transducing the methylation state into a measurable signal catalyzed by myoglobin. This principle was validated in a practical assay using immobilized probes to capture the target DNA for methylation analysis. This system demonstrated the capability to distinguish methylation differences of 50% when the target DNA concentration was over 25 nM. Versatility was further confirmed using the sequence from the dopamine receptor D2 (DRD2) gene promoter, where the methylation similarly induced distinct topological and functional changes. This is the first study to directly link the epigenetic state of a G4-forming DNA sequence to a protein-mediated enzymatic output, offering a framework for simple, rapid, and highly adaptable biosensors for research and clinical applications. Full article

This study investigated how prolonged aggression in male CD1 mice alters responses to chronic LPS (lipopolysaccharide)-induced inflammation. Experience of aggression induced pathological aggression in 36% of mice. Following LPS, aggressors resolved systemic inflammation within five days—evidenced by normalized locomotor activity, WBC (white blood cells), and lymphocyte counts—while controls remained inflamed. LPS did not alter established aggression or anxiety. Furthermore, aggressors demonstrated accelerated inflammation resolution in the brain, showing a higher proportion of resting microglia and a lower percentage of activated microglia following LPS-induced inflammation compared to control animals. Gene expression analysis revealed a more pronounced inflammatory response in the hypothalamus than in the nucleus accumbens. Aggressive mice exhibited a profile associated with inflammation resolution, indicated by increased expression of the Trem2 gene. These differential immune responses may be modulated by the dopaminergic system. Elevated Drd1 gene expression in the hypothalamus could possibly contribute to the anti-inflammatory signaling, while changes in nucleus accumbens dopaminergic activity, involving D2 receptor activation, appear linked to the development of pathological aggression. Thus, this study demonstrates that prolonged aggression induces persistent changes in behavioral, neuroimmune, and neuroendocrine systems in male CD1 mice. Aggressive animals develop a distinct neuroimmune phenotype characterized by accelerated resolution of both systemic and brain inflammation following LPS challenge. Full article

With the increasing global burden of major depressive disorder (MDD), identifying modifiable environmental risk factors has become a critical priority. Per- and polyfluoroalkyl substances (PFASs), characterized by environmental persistence and bioaccumulation, have been linked to elevated mental health risks. However, the potential neurotoxicity of GenX—a novel PFAS developed to replace perfluorooctanoic acid (PFOA)—and its molecular association with MDD remain unclear. In this study, peripheral blood serum transcriptomic data from the Gene Expression Omnibus (GEO) were integrated with multidimensional bioinformatics analyses to elucidate molecular mechanisms connecting GenX exposure with MDD. Four hub genes (UCP2, AKR1B1, TP53, and F5) were identified, showing strong combined diagnostic performance (AUC = 0.925). Functional enrichment and immune infiltration analyses revealed their involvement in energy metabolism, oxidative stress, and immune-coagulation regulation. Molecular docking and dynamics simulations further confirmed stable interactions between GenX and these proteins, providing structural support for their mechanistic roles. Although classical dopaminergic markers (TH, SLC6A3, DRD1–5) were not detected in the serum-derived transcriptomes, the identified hub genes may still affect dopaminergic function indirectly by modulating metabolic, oxidative stress, and inflammatory/coagulation pathways, thereby influencing MDD susceptibility. This study provides the first integrated transcriptomic and structural evidence linking GenX to psychiatric risk, proposing a novel “GenX-dopamine-MDD” framework for understanding pollutant-mediated neuropsychiatric mechanisms. Full article

Background/Objectives: Borderline personality disorder (BPD) is a serious psychiatric condition characterized by affective instability, impulsivity, and self-harming behaviors. Increasing evidence suggests that epigenetic mechanisms, especially DNA methylation, may mediate the interaction between genetic susceptibility and adverse environmental factors. This systematic review aimed to synthesize available findings on DNA methylation in BPD, including candidate gene studies and epigenome-wide association studies (EWAS). Methods: We conducted a systematic search of PubMed, Embase, and Scopus databases following PRISMA guidelines. Eligible studies (N = 19) included original research examining DNA methylation in individuals with BPD, assessed either through candidate gene approaches or genome-wide platforms. Data were extracted regarding study design, sample characteristics, psychometric instruments, genes, CpG sites analyzed, and main findings. Results: Inconsistent associations were found between BPD and altered methylation of several candidate genes, such as NR3C1, FKBP5, BDNF, DRD2, HTR2A, and COMT. Differential methylation was often linked to early-life adversities and symptom severity. EWAS also identified new loci, including APBA3, MCF2, PXDN, and OPRK1. Across studies, methodological heterogeneity and small sample sizes limited definitive conclusions. Conclusions: Evidence for DNA methylation alterations in BPD is mixed, and current findings do not allow firm conclusions about their mechanisms or clinical relevance. Larger and longitudinal studies are required to clarify whether these epigenetic changes contribute meaningfully to BPD. Full article

Background: Chronic gastritis (CG) involves gastric mucosal imbalance, with H. pylori (>90% cases), acid-pepsin imbalance, and bile reflux as druggable mechanisms. FDA-approved drugs show limited efficacy against antibiotic-resistant strains and fail to target undruggable pathways (e.g., inflammation, autoimmune atrophy). Traditional Chinese Medicine (TCM), particularly Qing-Wei-Zhi-Tong micro-pills (QWZT), offers multi-target advantages, though its mechanisms remain poorly understood. Methods: The dual-algorithm integration framework predicts QWZT’s pharmacological effects to treat gastritis. For druggable processes (pathways targeted by existing drugs), the structure–target–pathway similarity algorithm quantifies QWZT similar activities to FDA drugs, validated by gastrointestinal smooth muscle experiments. For undruggable processes (novel biological mechanisms not addressed by current therapies), the multi-target perturbation algorithm predicts QWZT’s unique capacity to undruggable processes and is validated via LPS-induced inflammation in RAW264.7 and GES-1 cells. Results: Structure–target–pathway similarity algorithm identified QWZT compounds sharing prokinetic mechanisms with FDA drugs, validated by dopamine-induced relaxations and acetylcholine-induced contractions in gastrointestinal smooth muscle. Multi-target perturbation algorithm quantified QWZT’s superior disruption of undruggable immune/inflammation networks, confirmed by restored cell viability in LPS-injured GES-1 cells and significantly reduced the expression of NO, IL-6, and TNF-α in RAW264.7 cells via key compounds (paeoniflorin and berberine). Conclusions: QWZT may exert its regulatory effects on gastrointestinal smooth muscle by mediating muscarinic and dopamine receptor D2 (DRD2), and reduce the expression of NO, IL-6, and TNF-α to achieve anti-inflammatory effects, thereby effectively treating CG. The integration strategy that integrates algorithms and experiments to reveal the common and distinct mechanisms of QWZT compared to FDA-approved drugs, offering a novel approach for studying Traditional Chinese Medicine mechanisms. Full article

Background and Objectives: The dopamine D2 receptor (DRD2) plays a central role in fronto-striatal circuits regulating cognitive control and reward processing. The rs1076560 polymorphism alters receptor isoform expression, potentially modifying impulsivity and vulnerability to stimulant use disorders. We examined gene–environment interactions between rs1076560 and stimulant dependence in relation to impulsivity, ADHD traits, and hedonic capacity. Methods: A total of 517 men (235 stimulant-dependent, 282 controls) completed the Barratt Impulsiveness Scale (BIS-11), Adult ADHD Self-Report Scale (ASRS v1.1), and Snaith–Hamilton Pleasure Scale (SHAPS). Genotyping for rs1076560 was performed using real-time PCR, and two-way ANOVAs tested genotype-by-group effects. Results: Significant genotype-by-group interactions were observed across all BIS-11 subscales and ASRS scores. In the stimulant-dependent group, C/C homozygotes showed the highest levels of attentional impulsivity and attentional dysregulation compared to both A/C and C/C controls. In contrast, within the control group, A/A homozygotes demonstrated higher motor impulsivity, non-planning impulsivity, and BIS-11 total scores than C/C controls. No significant main effects or interactions were found for SHAPS scores. Conclusions: DRD2 rs1076560 moderates impulsivity-related traits through dopaminergic pathways relevant to executive dysfunction in stimulant use disorders. These findings highlight a neurobiological mechanism of addiction vulnerability and may inform precision approaches in neurology and psychiatry. Full article

Objectives: This in silico study sought to identify specific biomarkers for mild traumatic brain injury (mTBI) through the analysis of publicly available gene and miRNA databases, hypothesizing their influence on neuronal structure, axonal integrity, and regeneration. Methods: This study implemented a three-step process: (1) data searching for mTBI-related genes in Gene and MalaCard databases and literature review, (2) data analysis involved performing functional annotation through GO and KEGG, identifying hub genes using Cytoscape, mapping protein–protein interactions via DAVID and STRING, and predicting miRNA targets using miRSystem, miRWalk2.0, and mirDIP, and (3) RNA-sequencing analysis applied to the mTBI dataset GSE123336. Results: Eleven candidate hub genes associated with mTBI outcome were identified: APOE, S100B, GFAP, BDNF, AQP4, COMT, MBP, UCHL1, DRD2, ASIC1, and CACNA1A. Enrichment analysis linked these genes to neuron projection regeneration and synaptic plasticity. miRNAs linked to the mTBI candidate genes were hsa-miR-9-5p, hsa-miR-204-5p, hsa-miR-1908-5p, hsa-miR-16-5p, hsa-miR-10a-5p, has-miR-218-5p, has-miR-34a-5p, and has-miR-199b-5p. The RNA sequencing revealed 2664 differentially expressed miRNAs post-mTBI, with 17 showing significant changes at the time of injury and 48 h post-injury. Two miRNAs were positively correlated with direct head hits. Conclusions: Our bioinformatic analysis suggests that specific genes and miRNAs, particularly hsa-miR-10a-5p, may be involved in molecular pathways influencing mTBI outcomes. Our research may guide future mTBI diagnostics, emphasizing the need to measure and track these specific genes and miRNAs in diverse cohorts. Full article

Background/Objectives: The role of daratumumab, lenalidomide, and dexamethasone (DRd) in autologous stem cell transplantation (ASCT)-eligible patients with multiple myeloma (MM) after first-line bortezomib, cyclophosphamide, and dexamethasone (VCd) treatment is not yet established. Methods: We retrospectively evaluated ASCT-eligible patients with MM who received second-line therapy with DRd after initial induction therapy with VCd between 2017 and 2023 (salvage group). For comparison, patients who successfully underwent per-protocol treatment with VCd induction, followed by ASCT during the same period, were selected (control group). Results: Eight patients with a median age of 61 years (range, 36–68 years) were included in the salvage group. After a median of 5 DRd cycles, the best response was partial response (PR) in two patients (25%) and a very good partial response (VGPR) in six (75%). All patients underwent ASCT, resulting in PR in one (13%), VGPR in four (50%), and stringent complete response in three (38%). Measurable residual disease (MRD) assessed using multicolor flow cytometry was negative in four patients (50%). The controls included thirteen patients with a median age of 60 years (range, 44–64 years). While most patients in both groups received various post-ASCT therapies, the post-ASCT 2-year time to the next treatment rate was slightly better in the salvage group than in the control group (88% vs. 49%, p = 0.089). However, hypogammaglobulinemia was more common in the salvage group (75% vs. 15%, p = 0.018). Conclusions: This small case series suggests that DRd is promising for ASCT-eligible patients with MM after VCd failure. Full article

Since colonic dopamine levels are markedly reduced during inflammatory bowel disease (IBD), we investigated how dopamine affects regulatory T-cells (Treg), which critically limit gut inflammation. Previously, we showed that the stimulation of the high-affinity dopamine receptor D₃ (Drd3) impairs suppressive Treg activity and limits their recruitment into the colon upon gut inflammation. Here we study the role of the low-affinity dopamine receptor Drd2 in Treg. We find that mice harbouring Drd2-deficient T-cells developed more severe colitis induced by dextran sodium sulphate. The stimulation of Drd2 potentiated the suppressive Treg activity and increased their ability to reach the colonic tissue. A transcriptomic analysis of intestinal mucosa from IBD patients revealed an association with increased DRD3 and reduced DRD2 expression. Bioluminescence resonance energy transfer assays revealed that Drd2 and Drd3 form a heteromer. An in situ proximity ligation assay indicated that the Drd2:Drd3 heteromer was expressed on colonic Treg, and its expression was increased upon inflammation. Using peptides analogous to the transmembrane (TM) segments from Drd2 and Drd3 in bimolecular fluorescence complementation assays, we found TM peptides able to disassemble this heteromer. The heteromer disassembly dampened the suppressive Treg activity and impaired the recruitment of Treg into the colon upon inflammation. Our findings indicate that the Drd2:Drd3 heteromer constitutes a dopamine sensor that regulates suppressive Treg activity and their colonic recruitment. Full article

Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neurons (DNs) and movement disorders. Low efficiency of pharmacotherapy requires improvement, e.g., using receptor agonists or antagonists as drugs. Our work aims to initiate these developments by studying the expression levels of genes encoding neurotransmitters, neuropeptides and hormone receptors in substantia nigra pars compacta (SNpc) cells and in isolated DNs in intact mice, and changes in expression of these genes in MPTP mouse models of PD at preclinical and clinical stages. Expression of all 12 studied genes was detected in the SNpc and only 10 in DNs—Cckar and Glp1r were undetectable. In intact mice, the expression of Drd2, Grin2b, Grm1 and Ntsr2 predominates in SNpc tissue, whereas that of Gria2, Chrnb2, Gper1, Igf1r is higher in DNs. In PD models, change in receptor gene expression was detected in DNs but not in SNpc tissue. In the preclinical PD, Drd2 expression increased and Gria2 decreased, whereas in a clinical model, Drd2, Grm1, Ntsr2 expression decreased. Thus, the above genes are expressed in DNs and other cells of SNpc; expression of some genes changes in PD models, which opens up prospects for development of therapy using receptor agonists and antagonists. Full article