Search Results (763)

Background/Objectives: Alzheimer’s disease (AD) is characterized by amyloid-beta accumulation and neuroinflammation, yet the molecular target of Ginsenoside Rg1 remains elusive. This study aimed to elucidate the neuroprotective mechanism of Ginsenoside Rg1, specifically investigating its interaction with C-C motif chemokine receptor 3 (CCR3). Methods: We utilized 5xFAD transgenic mice and CCR3-overexpressing BV2 microglial cells. Behavioral assessments, enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, molecular docking, and surface plasmon resonance were employed to evaluate cognitive function and molecular pathways. Results: Ginsenoside Rg1 treatment significantly ameliorated spatial learning and memory deficits. Quantitatively, Rg1 reduced cortical amyloid-beta 1–40 levels (p < 0.05) and bound directly to CCR3 with a dissociation constant of 3.599 × 10⁻⁵ mol/L. This inhibition suppressed neuroinflammation and restored neurotrophic factors, including Brain-derived neurotrophic factor. Conclusions: CCR3 is a novel pharmacological target for Ginsenoside Rg1, providing a precise molecular basis for its neuroprotective effects. Future research should focus on clarifying the pharmacokinetic profile and brain bioavailability of Ginsenoside Rg1 to facilitate clinical translation. Full article

The bone marrow tumor microenvironment (TME) is critical for acute myeloid leukemia (AML) progression, immune evasion, and treatment resistance. SRC, a non-receptor tyrosine kinase involved in multiple oncogenic pathways, has not been systematically characterized in AML in relation to prognosis and immune regulation. We integrated bulk transcriptomic and single-cell RNA-sequencing datasets from TCGA, BeatAML, and GEO. Immune-related targets were identified using xCell-based immune scoring and weighted gene co-expression network analysis (WGCNA), followed by protein–protein interaction analysis and multi-algorithm machine-learning screening. We then evaluated SRC expression patterns, prognostic associations, immune microenvironment features, predicted drug sensitivity, single-cell differentiation dynamics, intercellular communication, and in silico virtual knockout perturbation (scTenifoldKnk). SRC emerged as the most robust hub gene after integration of WGCNA, PPI analysis, machine-learning feature selection, and survival screening. SRC was significantly upregulated in AML compared with normal controls and was independently associated with poor overall survival (HR = 1.231, p = 0.037). High SRC expression was linked to adverse ELN/FAB features, increased immune checkpoint expression, enrichment of inflammatory and immunoregulatory pathways, and a higher proportion of primitive leukemia-associated cell states. Single-cell analyses further suggested that SRC was enriched in CD34⁺ progenitor compartments, associated with altered cell–cell communication, and accompanied by distinct mutation and pathway profiles. Drug-response prediction and in silico network perturbation analysis further supported the potential biological and translational relevance of SRC-centered programs. SRC is a prognostically relevant and immune-associated hub linked to AML microenvironment remodeling, and may serve as a candidate biomarker and potential therapeutic target that warrants further experimental validation. Full article

(1) Objective. To conduct a comparative bioinformatics analysis of the transcriptomic profiles of peri-implantitis and periodontitis to identify common and specific molecular signatures underlying their pathogenesis, as well as molecular parallels with atherosclerosis. (2) Methods: We used datasets from the Gene Expression Omnibus (GEO) database: dataset GSE223924 (30 gingival tissue samples from patients with peri-implantitis, periodontitis, and healthy subjects) and GSE100927 (atherosclerotic and control tissue; n = 104). Differentially expressed genes (DEGs) were identified based on the criteria: |logFC| > 1 and FDR < 0.05. To quantitatively assess the relative abundance of immune cells, we used the xCell deconvolution algorithm. (3) Results: In the peri-implantitis group, 3669 DEGs with upregulated expression and 3106 with downregulated expression were identified; in the periodontitis group, 1968 and 1250 DEGs, respectively. Functional analysis of the upregulated DEGs revealed activation of inflammatory processes, cell adhesion, and angiogenesis in both diseases. Key differences lay in the activation of adaptive immune mechanisms in peri-implantitis (enrichment of the “graft rejection” and “T-cell receptor signaling”) and innate immunity in periodontitis (enrichment of the “lipopolysaccharide response” and “Toll-like receptors (TLR) signaling” pathways). Analysis of downregulated DEGs revealed more profound disruptions in cytoskeletal organization and epithelial differentiation in periodontitis, as well as suppression of xenobiotic and lipid metabolism in both diseases. xCell deconvolution confirmed a significant increase in B cells, neutrophils, monocytes, M1 macrophages, and dendritic cells in peri-implantitis, and also revealed a trend toward an increase in these cells in periodontitis (p > 0.05), which is consistent with the activation of TLR signaling. In periodontitis, a significant increase in M2 macrophages and a decrease in Th1 cells were observed. Comparison with atherosclerosis revealed 272 common DEGs with peri-implantitis and 173 common DEGs with periodontitis. Functional analysis of the common genes confirmed their role in leukocyte transendothelial migration, cytokine production, and the “Lipids and Atherosclerosis” pathway. (4) Conclusions: Functional analysis and immune deconvolution consistently demonstrate that peri-implantitis is characterized by statistically significant activation of both adaptive and innate immunity, whereas in periodontitis, the activation of innate immunity manifests primarily at the level of signaling pathways. The significant overlap found between the transcriptional profiles of both diseases and atherosclerosis may indicate the presence of common pathogenetic links. Full article

Conventional treatments for androgenetic alopecia (AGA) are often limited by suboptimal efficacy and potential adverse effects, highlighting the need for alternative approaches. We aimed to evaluate the efficacy and safety of a multi-targeted cosmetic formulation containing TrinogeniX™, composed of synthetic small-molecule inhibitors of glycogen phosphorylase, the prostaglandin D₂ receptor, and 15-hydroxyprostaglandin dehydrogenase, developed using the artificial intelligence-driven platform DeepZema^®, in individuals with AGA. This 24-week, randomized, double-blind, placebo-controlled trial involved 56 participants, of whom 49 completed the study. Efficacy was assessed using phototrichogram analysis, visual evaluation by dermatologists, and subjective questionnaires. Safety was evaluated based on adverse event reports and dermatological examinations. The test group demonstrated a significant increase in hair density and thickness over 24 weeks (p < 0.05), whereas no significant changes were observed in the placebo group. Expert visual assessments confirmed greater improvements in the test group. Subjective evaluations revealed consistently greater perceived improvements in hair loss symptoms, hair richness, and front hairline conditions in the test group. No adverse events or clinically significant abnormalities were observed. The multi-targeted cosmetic formulation (Motifull hair tonic) significantly improved hair density, thickness, and overall hair condition without adverse effects, suggesting its potential as a safe and effective option for AGA. Clinical trial registration: CRIS No. KCT0010804: A double-blind, randomized, placebo-controlled clinical trial evaluating the efficacy and safety of “Motifull Hair Tonic” (tentative name) for the alleviation of hair loss symptoms. Full article

Biosensors based on electrolyte-gated organic field-effect transistors (EGOFETs) have attracted considerable attention due to their advantages, including low cost, inherent signal amplification, and low-voltage operation. A critical step influencing sensing performance is the integration of specific receptors onto the device surface. Among various strategies, the covalent immobilization of biorecognition elements onto gold surfaces via thiol chemistry is one of the most widely used approaches. In this study, we report the optimization of a mixed self-assembled monolayer (SAM) composed of 11-mercaptoundecanoic acid (11-MUA) and 3-mercaptopropionic acid (3-MPA) for label-free detection of human IgG using EGOFETs. The quality of the SAM was systematically modulated by varying the total concentration from 10 to 400 mM and characterized using X-ray Photoelectron Spectroscopy (XPS), Electrochemical Impedance Spectroscopy (EIS), Cyclic Voltammetry (CV), and Atomic Force Microscopy (AFM). The results revealed that a concentration of 50 mM yielded a densely packed and well-ordered monolayer. After covalent immobilization of anti-IgG antibodies via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) chemistry and subsequent blocking with ethanolamine and bovine serum albumin (BSA), the functionalized gate electrodes were integrated into poly(3-hexylthiophene) (P3HT)-based EGOFETs. Electrical measurements demonstrated that EGOFET biosensors functionalized with the 50 mM SAM achieved optimal sensing performance. The devices exhibited a highly linear response (R² = 0.998) over a wide concentration range from 1 fM to 10 nM, with a LOD of 2.82 fM, and showed excellent selectivity against non-target immunoglobulins A and M (IgA and IgM). This SAM concentration optimization strategy provides a versatile approach for engineering high-performance EGOFET biosensors, with potential applicability to a broad range of disease biomarkers. Full article

Fibromyalgia (FM) is a chronic pain syndrome characterized by central sensitization, in which glutamatergic and purinergic signaling pathways are thought to play critical roles. This study aimed to evaluate the diagnostic potential of serum glutamate ionotropic receptor N-methyl-D-aspartate type subunit 1 (GRIN1), purinergic receptor P2X 1 (P2RX1), and purinergic receptor P2Y 2 (P2RY2) levels in patients with FM. A total of 93 newly diagnosed FM patients and 93 age- and sex-matched healthy controls were included in the study. Serum levels of GRIN1, P2RX1, and P2RY2 were measured using enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic performance of these biomarkers. ROC analysis demonstrated good diagnostic accuracy for all three biomarkers. The area under the curve (AUC) values were 0.817 for GRIN1, 0.778 for P2RX1, and 0.842 for P2RY2 (p < 0.001 for all). At optimal cut-off values, GRIN1, P2RX1, and P2RY2 showed sensitivities of 91.4%, 78.5%, and 92.5%, and specificities of 72.00%, 75.3%, and 80.6%, respectively. Serum GRIN1, P2RX1, and P2RY2 levels exhibit strong diagnostic performance in FM and may serve as promising biomarkers reflecting altered glutamatergic and purinergic signaling in disease pathophysiology. Full article

Background: The introduction of targeted therapy in oncology has led to several challenges. These medicines are relatively new in clinical practice and are not well known to specialists with regard to adverse drug reactions (ADRs) and potential drug–drug interactions (pDDIs). In addition, cancer affects multiple body systems, including weight loss, anemia, liver and kidney function, depression, and pain. Patients frequently have comorbidities, leading to polypharmacy and the use of special foods, nutritional supplements, and herbal products for self-medication. Identification of pDDIs is essential, as concomitant use of multiple medicinal products increases the risk of ADRs and may compromise treatment. Objective: This study aims to retrospectively review and analyze data on ADRs and pDDIs in the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors and to evaluate the relationship between them. Method: EudraVigilance and UpToDate^® Lexidrug™ application were used to screen suspected ADRs and pDDIs, respectively. Descriptive statistical analysis was performed. Results: After reviewing Line Listing Reports (LLRs) from 2021 to 2023 in EudraVigilance, the number of suspected adverse drug reactions (ADRs) reported was higher when drug interactions classified as risk categories D and X were identified, compared with cases involving EGFR inhibitor monotherapy or other drug combinations. Of the 144 cases involving category D and/or X interactions, 63 demonstrated a possible association with the reported ADRs of EGFR inhibitors. The most common pDDIs detected were erlotinib–ranitidine (14 cases, category D) and osimertinib–amiodarone (13 cases, category D). Conclusions: Although EGFR inhibitors improve overall and progression-free survival in NSCLC, screening for pDDIs before treatment is essential to improve safety and quality of life. Full article

Introduction: Diabetic gastroparesis increases the risk of aspiration, pneumonia, and sepsis, yet the impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on these outcomes is uncertain because of their gastric-emptying effects. Methods: We performed a retrospective cohort study using the TriNetX Global Research Network. Adults (≥18 years) with diabetes mellitus and gastroparesis were identified and divided into two cohorts based on GLP-1 RA exposure. Propensity score matching (1:1) balanced demographics, comorbidities, and antidiabetic medications, yielding 23,371 patients per cohort. Outcomes, assessed from 180 days after index, included pneumonia, pneumonitis, mechanical ventilation, ventilator-associated pneumonia, sepsis, bacteremia, empyema, lung abscess, acute respiratory distress syndrome (ARDS), and need for enteral feeding. Risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated. Results: Compared with GLP-1 users, non-GLP-1 patients had higher incidences of pneumonitis (3.6% vs. 2.5%; HR 1.76, 95% CI 1.58–1.95), pneumonia (13.2% vs. 12.2%; HR 1.34, 95% CI 1.27–1.41), mechanical ventilation (4.4% vs. 3.3%; HR 1.63, 95% CI 1.49–1.79), sepsis (12.8% vs. 11.1%; HR 1.44, 95% CI 1.37–1.52), and bacteremia (5.2% vs. 4.4%; HR 1.46, 95% CI 1.35–1.59) (all p < 0.001). Empyema and ARDS were also numerically lower among GLP-1 users, while ventilator-associated pneumonia and lung abscess were rare and similar between groups. No patients required percutaneous endoscopic gastrostomy or nasal enteral feeding. Conclusions: In patients with diabetes and gastroparesis, GLP-1 RA therapy was associated with significantly fewer pulmonary and systemic infectious complications. These data suggest that the systemic benefits of GLP-1 RAs may outweigh concerns regarding delayed gastric emptying in this high-risk population. Full article

Dry eye disease (DED) is an ocular surface disorder characterized by tear film instability, inflammation, epithelial damage, and neurosensory abnormalities. Due to its multifactorial etiology and pathophysiology, conventional therapies that focus on lubrication and immunosuppression often fall short in addressing the neuropathic component of ocular pain experienced by a growing subset of patients. Recent developments in sensory neuroscience have highlighted the pivotal role of ion channels in mediating ocular surface homeostasis, pain signaling, and inflammation. This review examines the role of the following major ion channel families in the pathophysiology of DED and neuropathic ocular pain: transient receptor potential (TRP) channels, voltage-gated sodium (Nav) channels, and purinergic P2X receptors. The review details their anatomical distribution, molecular function, and responses to environmental stimuli such as heat, cold, osmolarity, and injury. Current treatments, such as artificial tears, anti-inflammatory drops, and systemic neuromodulators, are also reviewed in relation to their effects on ion channel modulation. Additionally, emerging therapies that directly target sensory transduction pathways are introduced. This review highlights the therapeutic potential of ion channel modulation in personalizing treatment for patients with ocular surface pain, particularly those with neuropathic features unresponsive to standard care. Full article

Chronic alcohol exposure disrupts blood–brain barrier (BBB) integrity and promotes neuroinflammation, with P2X7 receptor (P2X7R) signaling playing a critical role. Our prior work in male mice linked P2X7R inhibition to reduced extracellular adenosine triphosphate (eATP) release, modulated extracellular vesicle (EV) cargo, and attenuated neuroinflammation in chronic intermittent ethanol (CIE)-exposed mice. However, sex-specific roles of P2X7R signaling and EV-mediated mechanisms in alcohol-induced neuroinflammation remain unclear. Male and female mice were exposed to ethanol vapor for three weeks and treated with Brilliant Blue G (BBG), a P2X7R inhibitor. Compared to their respective CIE-unexposed controls, brain gene expression of tumor necrosis factor–α (Tnf-α), interleukin-1 beta (Il-1b), interleukin-6 (Il-6), monocyte chemoattractant protein-1 (Mcp-1), and Fas ligand (Fasl) significantly increased in CIE-exposed males, while only Il-1b increased in females. P2X7R inhibition significantly reduced these cytokines. Pericyte immunostaining was decreased by CIE (indicating BBB injury) in male mice only and was restored by P2X7R inhibition with no difference between groups in females. Occludin staining (another BBB marker) did not differ between the treatment groups in male and female animals. Circulating cytokines (Macrophage inflammatory protein-1 alpha (MIP-1α), tumor necrosis factor–α (TNF-α), interleukin-1 beta (IL-1β), and interleukin-27 subunit p28/interleukin-30 (IL-27p28/IL-30) were significantly elevated in CIE-exposed males but not in females, with BBG treatment reducing cytokines in males. Circulating eATP, P2X7Rs, P-glycoprotein (P-gp), EVs, and EV-mtDNA, which we identified in our previous study, were increased in both sexes and partially decreased by P2X7R blockade. Spatial memory was impaired by CIE exposure in males but not females, and this deficit was reversed by BBG treatment. Our findings reveal sex differences in CIE-induced circulating cytokines, neuroinflammation, and memory impairment, with a stronger response in males. However, other markers of cell injury associated with CIE exposure were upregulated in both sexes; P2X7R inhibition effectively mitigated these effects, highlighting the functional relevance of targeting the P2X7R in alcohol-induced injury. Full article

Inflammation is a key feature in breast cancer progression, with neutrophil extracellular traps (NETs) playing an important role. NETs are DNA-based structures released by neutrophils that can promote tumor adhesion, invasion, and immune evasion. Another crucial mechanism is the inflammasome, a multiprotein complex that drives inflammation through cytokine release. Both mechanisms are present in tumors and may act synergistically. In this study, we evaluated how isolated NETs modulate the NLRP3 inflammasome in a human breast cancer model. Exposure of MDA-MB-231 cells to NETs increased the expression of NLRP3, CASP1, and IL1B. Blocking IL-1R with Anakinra reduced IL1B expression, while inhibition of the P2X7 receptor with A740003 decreased NLRP3 and IL1B. ELISA confirmed that NETs stimulate IL-1β release, which was reduced by MCC950, Anakinra, and A740003. Functionally, NETs accelerated tumor cell migration, and this effect was inhibited by MCC950 and Anakinra. Bioinformatics analysis of TCGA breast cancer samples showed differential inflammasome gene expression among subtypes and a positive correlation between inflammasome components and NET-related genes. These findings highlight the interplay between inflammatory and immune mechanisms in breast cancer progression and may support the development of new therapeutic strategies. Full article

The purinergic ionotropic receptor P2X7 stands out from other members of the P2X family due to its ability to form a macropore, activate multiple intracellular signaling pathways, and, as more recently reported, to mediate scavenger activity toward apoptotic cells. In addition, P2X7 exhibits a high number of single nucleotide polymorphisms (SNPs) and splice variants, several of which have been shown to impair ATP-mediated macropore formation. The aim of this study was to determine whether specific SNPs or deletion variants that have lost channel conductance or macropore activity retain other reported P2X7 functions. To address this, we analyzed the following variants: P2X7A (wild-type), P2X7B (unable to activate the macropore), P2X7 T283M (lacking conductance and macropore formation), P2X7 with N-terminal deletion (∆N; deficient in signal transduction), and P2X7 DN (dominant-negative double mutant W167A/C168A, lacking all known activities). We evaluated calcium influx, macropore formation, ERK and p38 signaling, and scavenger activity. Our results indicate that macropore formation depends on channel conductance, in contrast to what has been previously reported for P2X7B. Moreover, all modifications tested impaired signaling pathway activation. Strikingly, none of the mutations affected receptor-mediated phagocytic activity. These findings suggest that loss of conductance or macropore formation does not necessarily entail loss of other P2X7 functions, and our data reveals a functional independence between scavenger activity and the canonical roles of P2X7 (channel/macropore, MAPKs). This modular view provides a framework to reconcile the apparently discordant phenotypes of P2X7 variants observed across diverse pathophysiological settings. Full article

Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor (GPCR) expressed in both the peripheral and central nervous systems. It plays a pivotal role in mediating neuroimmune interactions, particularly in the context of inflammation and pain. Upon activation by proteases, PAR2 modulates nociception through signaling cascades that influence key ion channels, including transient receptor potential (TRP) ion channels vanilloid 1 and 4 (TRPV1 and TRPV4), ankyrin 1 (TRPA1), acid-sensing ion channel 3 (ASIC3), P2X purinoceptor 3 (P2X3), Cav3.2 (T-type Ca²⁺ channel), and potassium Kv7 (M-current) channels, altering their expression and function. Through this crosstalk, PAR2 contributes to heightened neuronal excitability and pain hypersensitivity in various inflammatory conditions. In this narrative review, we highlight and discuss the mechanistic and functional interplay between PAR2 and nociceptive ion channels, which might be contributing to the pathogenesis of inflammatory pain. Targeting these specific molecular interactions between PAR2 and nociceptive ion channels may offer a promising therapeutic strategy for treating inflammatory pain. Full article

Background/Objectives: Nature has evolved millions of venom-derived peptides with diverse biological functions, a substantial fraction of which target complex membrane proteins such as G-protein-coupled receptors and ion channels. Many of these peptides are stabilized by multiple disulfide bonds, endowing them with exceptional structural stability and favorable pharmacological properties. Methods: Leveraging this natural diversity, we developed a robust venom peptide therapeutics discovery system built on phage display technology and constructed a library using approximately 482 venom-derived scaffolds. The library design was guided by a machine learning (ML) model capable of predicting mutation-tolerant residues that preserve peptide foldability, maximizing structural integrity and sequence diversity. Results: The resulting VCX library was evaluated through screening against four diverse targets (CD47, DLL3, IL33, and P2X7R), yielding strong binders for all four, a success rate of 100%. Furthermore, by integrating high-throughput recombinant expression of thioredoxin–venom fusion proteins along with ML-assisted affinity maturation, we rapidly identified potential leads for DLL3 binders. Conclusions: This venom-based discovery platform offers significant advantages in both functionality and developability compared with conventional peptide discovery approaches. By combining natural structural diversity, ML-guided design, and recombinant expression, it enables efficient identification of “antibody-like” binders with molecular weights much smaller than those of antibodies. Consequently, it provides a powerful strategy for developing next-generation peptide therapeutics targeting challenging protein–protein interactions and complex membrane proteins. Full article

The Middle Meningeal Artery (MMA) occupies a pivotal role in the pathophysiology of migraine, functioning as a vascular and neuroimmune interface that precipitates the characteristic pulsatile pain. The inhibition of this pathophysiological cascade has been investigated as a therapeutic strategy. However, fewer than a dozen centers globally have disseminated procedural or mechanistic data. Given the nascency of this field and the imperative for standardization, the present review synthesizes mechanistic and clinical evidence underpinning intra-arterial pharmacological modulation of the MMA for migraine management. Methods: A focused narrative review was undertaken, drawing upon select but influential studies from pioneering research groups investigating intra-arterial interventions targeting the MMA. The extant literature was thematically categorized and organized according to the loci of cascade interruption and their corresponding clinical outcomes. Results: Since 2009, intra-arterial therapies for severe headache syndromes have evolved, initially utilizing nimodipine for vasospasm-related headaches, progressing to verapamil for reversible cerebral vasoconstriction, and more recently, lidocaine for refractory or status migrainosus, occasionally in conjunction with MMA embolization. Contemporary research uses language that conceptualizes migraine as an immunologically mediated neurovascular disorder, as opposed to a purely vascular or neuronal entity. Recent investigations have identified interleukins such as Interleukin-1β, Tumor Necrosis Factor-α, and Interleukin-6 as critical amplifiers of trigeminovascular activation. Purinergic signaling through the P2X3 receptor and the P2Y13 receptor, in conjunction with pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide pathways, has been implicated in the modulation of MMA excitability and neuropeptide release. The development of novel calcitonin gene-related peptide receptor antagonists, such as zavegepant, further substantiates the artery’s significance as a pharmacological target. Conclusions: These findings support a shift toward immune-modulating intra-arterial therapeutic strategies, with migraine interventions targeting cytokine and neuroimmune signaling within the MMA, rather than relying exclusively on vasodilatory mechanisms. Full article