Search Results (580)

Gamma-aminobutyric acid type A receptors (GABA_ARs) are pentameric ligand-gated ion channels essential for inhibitory neurotransmission in the central nervous system. Subtype-specific expression patterns of GABA_AR subunits underlie their diverse roles in regulating anxiety, motor function, and sedation. While non-selective GABA_AR positive allosteric modulators (PAMs), such as benzodiazepines, are clinically effective anxiolytic drugs, their non-selective activity across α1/2/3/5 subunit-containing GABA_ARs leads to sedation, cognitive impairment, and risk of dependence. To address this, we evaluated ENX-102, a novel GABA_AR PAM, which exhibits selectivity for α2/3/5 subunits. In rodents, ENX-102 demonstrated dose-dependent anxiolytic-like activity following acute and sub-chronic administration, without sedation. ENX-102 exhibited a dose-dependent quantitative electroencephalography (qEEG) spectral signature in rodents that was distinct from that of benzodiazepines. In a double-blind, placebo-controlled, multiple-ascending dose study in healthy human volunteers, ENX-102 was evaluated using the NeuroCart, a CNS test battery including saccadic peak velocity (SPV), adaptive tracking, pupillometry, body sway, the Bond and Lader Visual Analog Scale (VAS), the Visual Verbal Learning Task (VVLT), and qEEG. ENX-102 produced reductions in SPV that were indicative of central target engagement, with minimal effects on alertness and motor coordination, which is consistent with subtype-selective GABA_AR targeting. Notably, qEEG revealed increased β-band power and decreased δ- and θ-band activity, which were distinct from the spectral profile of non-selective PAMs, supporting translational alignment with preclinical findings. Across dose levels, ENX-102 was well tolerated and exhibited favorable pharmacokinetics. These results support further clinical development of ENX-102 as a next-generation GABA_AR subtype-selective anxiolytic drug. Full article

Background: Tumor-associated macrophages (TAMs) are essential regulators of the glioblastoma (GBM) microenvironment; their functional heterogeneity and interaction networks are not fully elucidated. We identify RNF135 as a novel TAM-enriched gene associated with immune activation and adverse prognosis in GBM. Methods: To evaluate RNF135’s expression profile, prognostic significance, and functional pathways, extensive transcriptome analyses from TCGA and CGGA cohorts were conducted. The immunological landscape and cellular origin of RNF135 were outlined using single-cell RNA-seq analyses and bulk RNA-seq immune deconvolution (MCP-counter, xCell and ssGSEA). Cell–cell communication networks between tumor cells and RNF135-positive and -negative tumor-associated macrophage subsets were mapped using CellChat. Results: RNF135 predicted a poor overall survival and was markedly upregulated in GBM tissues. Functional enrichment analyses showed that increased cytokine signaling, interferon response, and innate immune activation were characteristics of RNF135-high samples. Immune infiltration profiling showed a strong correlation between the abundance of T cells and macrophages and RNF135 expression. According to the single-cell analyses, RNF135 was primarily expressed in TAMs, specifically in proliferation, phagocytic, and transitional subtypes. RNF135-positive TAMs demonstrated significantly improved intercellular communication with aggressive tumor subtypes in comparison to RNF135-negative TAMs. This was facilitated by upregulated signaling pathways such as MHC-II, CD39, ApoE, and most notably, the CCL signaling axis. The CCL3/CCL3L3–CCR1 ligand–receptor pair was identified as a major mechanistic driver of TAM–TAM crosstalk. High RNF135 expression was also linked to greater sensitivity to Selumetinib, a selective MEK1/2 inhibitor that targets the MAPK/ERK pathway, according to drug sensitivity analysis. Conclusions: RNF135 defines a TAM phenotype in GBM that is both immunologically active and immunosuppressive. This phenotype promotes inflammatory signaling and communication between cells in the tumor microenvironment. Targeting the CCL–CCR1 axis or combining RNF135-guided immunomodulation with certain inhibitors could be a promising therapeutic strategies for GBM. Full article

Background: Cancer remains a leading cause of morbidity and mortality worldwide, and current therapies are limited by toxicity, cost, and resistance. Inhibition of the MDM2–p53 interaction is a promising anticancer strategy, as this pathway is frequently dysregulated across tumors. Spiro-isatin-thiazolidinone derivatives have shown diverse biological activities, including anticancer effects, but require optimization to improve potency and selectivity. The aims were to design, synthesize, and evaluate novel spiro-isatin-thiazolidinone hybrids with enhanced cytotoxicity against cancer cells and reduced toxicity toward normal cells. Methods: Derivatives were designed using molecular docking against MDM2, followed by structural optimization. Cytotoxic activity was evaluated in vitro by MTT assays on human and murine cancer cell lines and pseudo-normal cells. Docking and 100 ns molecular dynamics simulations assessed binding stability, while ADMET properties were predicted in silico. Results: Several derivatives exhibited micromolar cytotoxicity, with compound 18 emerging as the most potent and selective candidate (IC₅₀ 6.67–8.37 µM across most cancer lines; >100 µM in HaCaT). Docking showed a strong affinity for MDM2 (−10.16 kcal/mol), comparable to the reference ligand, and stable interactions in simulations. ADMET predictions confirmed good oral bioavailability and moderate acute toxicity, fully compliant with Lipinski’s Rule of Five. Overall, the newly synthesized spiro-isatin-thiazolidinone hybrids, particularly compound 18, demonstrated potent and selective anticancer activity, favorable pharmacokinetic properties and a good toxicity profile. Full article

Introduction: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor alpha), but resistance to tyrosine kinase inhibitors (TKIs) such as imatinib remains a major clinical challenge. Alterations in fibroblast growth factor receptor 2 (FGFR2), although rare, are emerging as important contributors to tumor progression and drug resistance. This review evaluates the molecular mechanisms, expression profiles, detection methods, and therapeutic implications of FGFR2 in GIST. Methods: We searched PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published between January 2010 and June 2025, using combinations of keywords related to FGFR2, gastrointestinal stromal tumor, resistance mechanisms, gene fusion, amplification, polymorphisms, and targeted therapy. Eligible studies were critically assessed to distinguish GIST-specific data from evidence extrapolated from other cancers. Results:FGFR2 is expressed in multiple normal tissues and at variable levels in mesenchymal-derived tumors, including GIST. Its alterations occur in approximately 1–2% of GIST cases, most commonly as gene fusions (e.g., FGFR2::TACC2, <1%) or amplifications (1–2%); point mutations and clinically significant polymorphisms are extremely rare. These alterations activate the MAPK/ERK and PI3K/AKT pathways, contribute to bypass signaling, and enhance DNA damage repair, thereby promoting TKI resistance. Beyond mutations, mechanisms such as amplification, ligand overexpression, and microenvironmental interactions also play roles. FGFR2 alterations appear mutually exclusive with KIT/PDGFRA mutations but occasional co-occurrence has been reported. Current clinical evidence is largely limited to small cohorts, basket trials, or case reports. Conclusions:FGFR2 is an emerging oncogenic driver and biomarker of resistance in a rare subset of GISTs. Although direct evidence remains limited, particularly regarding DNA repair and polymorphisms, FGFR2-targeted therapies (e.g., erdafitinib, pemigatinib) show potential, especially in combination with TKIs or DNA-damaging agents. Future research should prioritize GIST-specific clinical trials, the development of FGFR2-driven models, and standardized molecular diagnostics to validate FGFR2 as a therapeutic target. Full article

Alopecia areata (AA) is a chronic autoimmune disorder characterized by non-scarring hair loss, with subtypes ranging from patchy alopecia (AAP) to alopecia totalis and universalis (AT/AU). The aim of this research is to investigate molecular features across AA severity by performing an integrated analysis of scalp transcriptomic datasets (GSE148346, GSE68801, GSE45512, GSE111061) and matched serum proteomic data from GSE148346. Differential expression analysis indicated that, relative to normal scalp, non-lesional AA tissue shows early immune activation—including Type 1 (C-X-C motif chemokine ligand 9 (CXCL9), CXCL10, CD8a molecule (CD8A), C-C motif chemokine ligand 5 (CCL5)) and Type 2 (CCL13, CCL18) signatures—together with reduced expression of hair-follicle structural genes (keratin 32(KRT32)–35, homeobox C13 (HOXC13)) (FDR < 0.05, |fold change| > 1.5). Lesional AAP and AT/AU scalp showed stronger pro-inflammatory upregulation and greater loss of keratins and keratin-associated proteins (KRT81, KRT83, desmoglein 4 (DSG4), KRTAP12/15) compared with non-lesional scalp (FDR < 0.05, |fold change| > 1.5). Ferroptosis-associated genes (cAMP responsive element binding protein 5 (CREB5), solute carrier family 40 member 1 (SLC40A1), (lipocalin 2) LCN2, SLC7A11) and IRS (inner root sheath) differentiation genes (KRT25, KRT27, KRT28, KRT71–KRT75, KRT81, KRT83, KRT85–86, trichohyalin (TCHH)) were consistently repressed across subtypes, with the strongest reductions in AT/AU lesions versus AAP lesions, suggesting that oxidative-stress pathways and follicular structural integrity may contribute to subtype-specific pathology. Pathway analysis of lesional versus non-lesional scalp highlighted enrichment of IFN-α/γ, cytotoxic, and IL-15 signaling. Serum proteomic profiling, contrasting AA vs. healthy controls, corroborated scalp findings, revealing parallel alterations in immune-related proteins (CXCL9–CXCL10, CD163, interleukin-16 (IL16)) and structural markers (angiopoietin 1 (ANGPT1), decorin (DCN), chitinase-3-like protein 1 (CHI3L1)) across AA subtypes. Together, these data offer an integrated view of immune, oxidative, and structural changes in AA and found ferroptosis-related and IRS genes, along with immune signatures, as potential molecular indicators to support future studies on disease subtypes and therapeutic strategies. Full article

This study investigates the corrosion inhibition efficiency of [2-(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole] and its Zn and Cu complexes for mild steel in 1.0 M HCl. The ligand was selected for its non-toxic profile and high electron density, favoring strong adsorption onto the metal surface. Electrochemical methods, including EIS, PDP, LPR, and CASP, were employed to evaluate the inhibitors’ performance. The results showed a significant decrease in corrosion current density and increased polarization resistance, with the Zn complex achieving the highest inhibition efficiency (93.8%). EIS fitting confirmed the formation of a protective film with high charge transfer and film resistance. Surface analyses by SEM and EDS revealed smoother steel morphology and inhibitor adsorption. XPS confirmed the presence of Fe³⁺, Zn²⁺and Cu²⁺ oxides, as well as all active inhibitor elements on the surface, supporting a mixed inhibition mechanism. The enhanced performance of the metal complexes is attributed to synergistic effects between the metal ions and the heterocyclic ligand, offering a promising strategy for the design of effective and environmentally friendly corrosion inhibitors. Full article

A novel heterobimetallic ruthenium(II)–gold(I) complex featuring a bridging bis(diphenylphosphino)butane (dppb) ligand was prepared and fully characterized. Single-crystal X-ray diffraction revealed a piano-stool geometry around Ru(II) with η⁶-cymene, two chlorido ligands, and one phosphorus atom from dppb, while the Au(I) center adopts a linear P–Au–Cl coordination. Structural integrity in the solution was confirmed by 1D and 2D NMR spectroscopy, while solution behavior was further monitored by variable solvent ³¹P NMR and UV/Vis spectroscopy, indicating that the organometallic Ru–arene core remains intact, whereas the chlorido ligands coordinated to Ru exhibit partial lability. Complementary characterization included elemental analysis, FTIR, and UV/Vis spectroscopy. Spectrofluorimetric and FRET analyses showed that Au(dppb), Ru(dppb), and the heterobimetallic AuRu complex bind to BSA with apparent constants of 1.41 × 10⁵, 5.12 × 10², and 2.66 × 10⁴ M⁻¹, respectively, following a static quenching mechanism. In vivo biological evaluation in Wistar rats revealed no significant hepatotoxicity or nephrotoxicity, with only mild and reversible histological alterations and preserved hepatocyte nuclear morphology. Hematological analysis indicated a statistically significant reduction in leukocyte populations, suggesting immunomodulatory potential, while elevated serum glucose levels point to possible endocrine or metabolic activity. These findings highlight compound structural stability and intriguing bioactivity profile, making it a promising platform for further organometallic drug development and testing. Full article

Background/Objectives: Whilst adoptive cell therapy (ACT) using chimeric antigen receptor-engineered T (CAR-T) cells represents an efficient approach for the treatment of patients suffering from several hematological malignancies, solid tumors have been shown to be far more challenging to tackle, mainly due to the hostile tumor microenvironment that inhibits optimal T cell functionality. As proven by the broad clinical success of immune checkpoint inhibitors, blocking the interaction of programmed cell death ligand 1 (PD-L1) expressed on tumor cells and the checkpoint receptor programmed cell death 1 (PD-1) expressed on activated T cells allows an intrinsic T cell-mediated anti-tumor response to be unleashed. We developed a cellular product (MDG1015) consisting of New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/L antigen family member 1a (LAGE-1a)-specific CD8+ T cell receptor-transduced (TCR-)T cells co-expressing the costimulatory switch protein (CSP) PD1-41BB, which turns an inhibitory signal mediated by the PD-1:PD-L1 axis into positive T cell costimulation. Methods: In vitro co-cultures of MDG1015 and PD-L1-positive or -negative target cells were used to analyze TCR-T cell functionality, such as TCR-T (poly-)cytokine release, the killing of target cells, and TCR-T proliferation. The safety of MDG1015 was evaluated via different panels of antigen-negative cell lines or primary cells expressing or lacking PD-L1. Results: Preclinical analyses demonstrated TCR-gated activation of the CSP, leading to enhanced functionality of MDG1015 against antigen-expressing, PD-L1-positive tumor cells without any impact on antigen-negative target cells. Conclusions: The favorable, preclinical functionality and safety profile qualifies MDG1015 as a promising cellular therapy for explorative clinical testing in hard-to-treat solid tumor indications. Full article

Oxidative stress, caused by excessive free radicals, leads to cellular damage and various diseases. Antioxidant peptides from natural proteins offer potential in alleviating this stress. In this study, antioxidant peptides were identified from deer antler proteins using in silico enzymatic hydrolysis and machine learning. Peptides with high prediction scores and non-toxic profiles were selected for evaluation. The antioxidant activities of top candidates, PHPAPTL and VPHGL, were confirmed by radical scavenging assays and their protective effects in HepG2 cells. Molecular dynamics simulations revealed stable binding of these peptides to Keap1, enhancing system stability and reducing residue fluctuations at the ligand-binding interface. Key interactions involved Arg415, Arg483, Arg380, and Ser555. Secondary structure analysis showed peptide binding induced local conformational transitions, notably increasing parallel β-sheet formation near active sites. These findings provide mechanistic insight into their antioxidant effects and support their potential application in functional food development. Full article

This review of thiazolidinedione or glitazone, which have a five-membered heterocyclic ring C₃NS, shows their versatile properties in terms of pharmacological actions such as antimicrobial, antifungal, insecticidal, pesticidal, antidiabetic, anti-inflammatory, anti-proliferative, anti-neurotoxicity, anticonvulsant, anti-thyroidal, and anti-tubercular uses. While having a wide range of biological activities, the TZDs mainly act via binding to the peroxisome proliferator-activated receptor (PPAR) members. PPAR-γ are ligand-activated transcription factors, which are members of the nuclear hormone receptors group. Activations of PPAR-γ regulate cell proliferation and differentiation, glucose homeostasis, apoptosis, lipid metabolism, and inflammatory responses. This review explores the synthesis of a thiazolidinedione and its derivatives, focusing on their pharmacological profiles and antidiabetic activity. It highlights the benefits of synthesis, reaction profiles, and catalyst recovery, which may encourage further investigation into these scaffolds by researchers. Based on synthesized derivatives, some glimpses of the structure–activity relationships of some compounds have been compiled. All the synthesized derivatives have been reviewed concerning their standard drugs already available and concluded with the highly or moderately active synthesized derivatives of thiazolidinedione. The data for this review was collected by an extensive review of current scientific literature, including on the synthesis, biological evaluation, SAR, and patents (2015–25). Full article

Introduction: Tumor necrosis factor-α (TNF-α) is a key regulator of inflammatory responses, and its biological activity is dependent on proteolytic processing by the tumor necrosis factor-α-converting enzyme (TACE), also known as ADAM17. Aberrant TACE activity has been associated with various inflammatory and immune-mediated diseases, positioning it as a compelling target for therapeutic intervention. Methods: While our previous study explored TACE inhibition via repositioned FDA-approved drugs, the present study aims to examine previously untested chemical scaffolds from the Enamine compound library, seeking first-in-class TACE inhibitors. We employed an integrated in silico workflow that combined ligand-based virtual screening using a graph convolutional network (GCN) model trained on known TACE inhibitors with structure-based methodologies, including molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. Results: Several enamine-derived compounds demonstrated strong predicted inhibitory potential, favorable docking scores, and stable interactions with the TACE active site. Among them, Z1459964184, Z2242870510, and Z1450394746 emerged as lead candidates based on their highly stable 300 ns RMSD and robust hydrogen bonding profile as compared to the reference compound BMS-561392. Conclusions: This study highlights the utilization of deep learning-driven screening combined with extended 300 ns molecular simulations to identify novel small-molecule scaffolds for TACE inhibition and supports further exploration of these hits as potential anti-inflammatory therapeutics. Full article

Parkinson’s disease is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons, resulting in multiple motor and cognitive impairments. Among the hypotheses proposed for its etiology, oxidative stress mediated by the enzyme monoamine oxidase B (MAO-B) stands out, as it is directly associated with dopamine metabolism. In this context, the search for molecules with potential antiparkinsonian activity and low toxicity, particularly those of natural origin, has been extensively investigated using computational approaches. In the present study, a pharmacophore-based virtual screening was carried out on molecules belonging to the alkaloid and flavonoid groups, followed by the evaluation of their pharmacokinetic, toxicological, and biological activity profiles, as well as ligand–receptor interaction analysis through molecular docking. The results indicated that palmatine, genistein, ZINC00597214, and ZINC72342127 exhibited superior performance compared to the other analyzed structures, considering all evaluated criteria. Therefore, this study, through in silico methodologies, demonstrated the antiparkinsonian potential of several chemical structures, attributable to their inhibitory activity on the MAO-B enzyme. Further experimental investigations, both in vitro and in vivo, are necessary to more comprehensively characterize the properties of these molecules, with the ultimate goal of developing new therapeutic strategies for the treatment of Parkinson’s disease. Full article

Nucleotide diphosphate hydrolase type 5 (NUDT5) plays a significant role in the estrogen-signaling pathway and is overexpressed in breast cancer. This study aimed to explore the anti-breast cancer potential of quercetin and its 52 structural analogs by targeting the NUDT5 enzyme using the in silico molecular docking method. Moreover, Molecular Mechanics/General Born Surface Area (MM/GBSA) calculations were performed for compounds with superior binding affinity scores than quercetin. Their drug-likeness, according to Lipinski’s rule of five, water solubility, and Caco-2 permeability were predicted. In addition, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile was determined for the top-scoring compounds from the docking studies and MM/GBSA calculations, as well as for those that complied with the rules of Lipinski and exhibited high permeability. The obtained results showed that all the tested ligands interact with the active site of NUDT5. Their binding energies ranged from −11.24 to −7.36 kcal/mol. The MM/GBSA calculations further supported the binding affinity predictions. ADMET analysis enabled the selection of compounds with favorable pharmacokinetic profiles in comparison to quercetin. Quercetin analogs L1 and L28 were identified as promising anti-breast cancer drug candidates worthy of further experimental evaluation. Full article

Metal–organic compounds, and especially those containing well-known antioxidant natural flavonoids (Chrysin, Chr) and metal ions (Ti(IV)), attract keen interest for their potential biological activity nutritionally and pharmacologically. To that end, chemical reactivity profiling in binary/ternary systems was investigated synthetically, revealing unique structural correlations between mononuclear (Ti(IV)-Chr) and tetranuclear assemblies (Ti(IV)-Chr-phen). Chemical profiling involved physicochemical characterization through elemental analysis, FT-IR, UV–Visible, 1D-2D NMR, ESI-MS spectrometry, solid-state luminescence, and X-ray crystallography, with theoretical work on intra(inter)molecular interactions of 3D assemblies pursued through Hirshfeld analysis and BVS calculations. An in-depth study of their chemical reactivity shed light onto specific structural properties in the solid-state and in solution, while concurrently exemplifying quenching behavior due to their distinct flavonoid pattern. In the framework of biological activity, the materials were investigated for their antibacterial properties toward Gram(−)-E. coli and Gram(+)-S. aureus, exhibiting an enhanced effect compared to the free ligand and metal ion. Further investigation of BSA denaturation revealed strong anti-inflammatory properties compared to Chr and Diclofenac, an anti-inflammatory agent. Finally, in vitro studies using physiological and cancer cell lines, including breast (MCF10A, MCF7) and lung tissues (MRC-5, A549), formulated a structure–tissue relation reactivity profile, thus justifying their potential as future metallodrugs. Full article

Background: Epilepsy is a chronic, non-communicable brain disorder characterized by recurrent seizures. Some derivatives of 1,2,3,4-tetrahydroisoquinolines have demonstrated anticonvulsant effects. This study aims to investigate the effects of 33 derivatives of 1-aryl-1,2,3,4-tetrahydroisoquinoline on seizures induced by nicotine and strychnine. Methods: The anticonvulsant effects of 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives were evaluated in white male mice. Convulsant agents were administered subcutaneously at doses of 10.0 mg/kg for nicotine and 1.5 mg/kg for strychnine, 60 min after the oral administration of the test compounds at doses ranging from 0.1 to 10 mg/kg. The onset time, duration of tremors and seizures, and survival rate of the animals were recorded. The docking studies were conducted for 32 tested compounds targeting the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (PDB ID: 1FTL). Furthermore, a predictive ADMET study was conducted to evaluate the pharmacokinetic and toxicity profiles of the compounds. Results: Compounds 20 and 25 exhibited the highest activity against strychnine-induced seizures. When evaluating the effects of 1-aryl-1,2,3,4-tetrahydroisoquinolines and reference drugs on the tremorogenic and convulsive actions of nicotine at doses of 0.1–5 mg/kg, compounds 3, 6, 8, 14, 16, 25, 27, 29, 30, 31, and 34 demonstrated comparable activity to the reference drugs. The docking results targeting AMPA (PDB ID: 1FTL) revealed comparable binding interactions for most of the compounds, with a (−)C-Docker interaction energy range of 33.82–45.41 Kcal/mol, compared to that of the ligand (41.60 Kcal/mol). The structural requirements of the studied scaffold were analyzed to identify the essential pharmacophoric features for anticonvulsant activity. Furthermore, a predictive ADMET study was conducted to evaluate the pharmacokinetic and toxicity profiles of the compounds. Conclusions: Certain derivatives of 1,2,3,4-tetrahydroisoquinolines may serve as potential anticonvulsant agents for epilepsy. Full article