Search Results (14,733)

G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in gene regulation and genome stability. Among them, the telomeric repeat-containing RNA (TERRA) forms biologically relevant RNA G4s (rG4s) that participate in telomere maintenance and genome stability. Although many ligands targeting DNA G4s have been reported, the recognition and modulation of RNA G4 topologies remain less explored. In this work, we investigated the interaction between TERRA and the spermine-functionalized Zn(II) porphyrin, ZnTCPPSpm4, using UV–vis absorption, fluorescence, resonance light scattering (RLS), and circular dichroism (CD) spectroscopy. In K⁺, where TERRA adopts a parallel G4 conformation, ZnTCPPSpm4 binds through a stepwise mechanism involving external end-stacking, forming discrete supramolecular complexes without altering the native topology. In contrast, under Na⁺ conditions, ZnTCPPSpm4 induces a gradual conformational rearrangement of TERRA from the antiparallel to a parallel-like G4 topology. A CD melting study showed that ZnTCPPSpm4 stabilizes the parallel RNA G4, while slightly destabilizing the antiparallel topology. Overall, our results demonstrate that ZnTCPPSpm4 is not a simple G4 binder, but a topology-selective ligand capable of remodeling TERRA G4 structures, highlighting the potential of metalloporphyrins as RNA G4-targeting scaffolds. Full article

Oxidative stress is characterised by the production of free radicals in higher amounts than the antioxidant scavenging capacity. This may cause damage to several organs especially the main site of detoxification, the liver. In this study, the antioxidant activity of five novel lipophilic fluoroquinolones (FQs) derivatives was evaluated against oxidative stress induced by acetaminophen (APAP) and carbon tetrachloride (CCl₄). Sixty-four male Wistar rats were divided into two oxidative-stress models. FQ compounds (25 mg/kg) were administered six hours after CCl₄ or APAP administration. Serum liver enzymes including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Changes in antioxidant parameters were determined in the serum including measurement of total antioxidant status and reduced-glutathione levels as well as catalase, glutathione peroxidase and superoxide dismutase activities. Additionally, molecular docking analyses were performed against catalase, CYP3A4, and Keap-1 to elucidate the potential molecular interactions underlying the observed biological activities. A significant decrease in ALT and AST levels was seen following FQ compound administration in both models. In addition, FQ compounds exhibited excellent antioxidant activity, leading to increased antioxidant enzyme activity, high total antioxidant status, and elevated reduced-glutathione levels. The docking results revealed that compound 4A exhibited the highest binding affinities toward catalase, CYP3A4, and Keap-1. These interactions suggest a possible enhancement of catalase activity, modulation of CYP3A4, and activation of the Keap-1/Nrf2 signalling pathway. Overall, these findings demonstrate the promising therapeutic potential on hepatic injury and oxidative stress of the novel FQ derivatives. Full article

K-Rev Interaction Trapped protein-1 (KRIT1) is a scaffold protein that forms functional protein complexes involved in physiologically important signaling networks. While it is primarily recognized for its association with Cerebral Cavernous Malformations (CCMs), KRIT1 may also play critical roles in tumor formation and the acquisition of malignant phenotypes, regulating cell adhesion, cytoskeletal dynamics, and angiogenesis. In this study, we investigated the role of KRIT1 in cancer cell migration and metastasis, with a focus on identifying novel interacting proteins and characterizing the intracellular signaling pathways activated upon its loss. By using a yeast two-hybrid screening, we identified Kinesin Family Member 1C (KIF1C), a protein involved in regulating podosome and invadopodium elongation, as a novel binding partner of KRIT1, and the interaction was confirmed in melanoma and epithelial cancer cells. In silico docking and interaction interface analyses supported the KRIT1–KIF1C interaction, providing structural insight into the binding mode as shown experimentally. We also found that SRC and focal adhesion kinase (FAK) phosphorylation, as well as Ras homolog family member A (RhoA) expression, represent additional pathways affected by the loss of KRIT1. This study confirms our earlier hypothesis that KRIT1 functions as a tumor suppressor and uncovers a compelling link between its loss and enhanced cancer aggressiveness. Full article

Volatile amphiphiles and surfactant mixtures have gained wide applications in diverse areas of industry, cosmetics, and medicine. The surface tension isotherms, measured at different solute ratios, and data processing, using appropriate theoretical models, provide quantitative information on their bulk and interfacial properties. Here, this approach is applied for mixtures of volatile amphiphile (benzyl acetate, linalool, geraniol, menthol, citronellol) and sodium dodecyl sulfate (SDS). All surface tension isotherms are described by the van der Waals model for a two-component adsorption layer, taking into account the counterion binding in the Stern layer, by varying only one adjustable parameter (interfacial pair interaction energy between adsorbed molecules). Knowing the parameters of the model, we computed various properties of the adsorption layers (adsorptions of different components, occupancy of the Stern layer, and interfacial electrostatic potential). The experimental aqueous solubilities of mixtures are fitted using the regular solution theory to obtain the pair bulk interaction parameter. The mixing of SDS and: (i) benzyl acetate and citronellol is antagonistic; (ii) linalool and geraniol is synergistic; and (iii) menthol is ideal. The reported properties of the volatile amphiphiles and SDS mixtures could be of interest for increasing the range of their applicability in practice. Full article

This study evaluated the iron-chelating capacity (ICC) of Lupinus mutabilis protein hydrolysate (LMPH) and its peptide fractions obtained through ultrafiltration and purification by immobilized metal ion affinity chromatography (IMAC) and gel filtration chromatography (GFC). Peptides were identified by LC-MS/MS, and their interactions with Fe²⁺ were analysed using molecular docking. LMPH was produced by enzymatic hydrolysis with Alcalase and subsequently subjected to ultrafiltration to concentrate peptides smaller than 2 kDa. This fraction exhibited higher ICC (35.1 mg Fe²⁺·g⁻¹) than the hydrolysate (22.75 mg Fe²⁺·g⁻¹). Sequential purification by IMAC and GFC yielded peptide fractions with enhanced ICC values (45.20 and 13.51 mg Fe²⁺·g⁻¹). A total of 176 peptides were identified by de novo LC-MS/MS sequencing, from which nine were selected based on favourable structure–ICC relationships and absence of predicted toxicity. Molecular docking analysis suggested spatial proximity between Fe²⁺ and the selected peptides. Although stable multi-site binding was not predicted under the applied computational model, the results support the potential of these sequences to interact with Fe²⁺. These findings provide molecular and chemical insights supporting the iron-binding potential of LMPH-derived peptides and highlight their future potential as functional ingredients for preventing and managing iron deficiency. Full article

Glycation of superoxide dismutase 1 (SOD1) has been shown to modulate the cytosolic levels of phosphorylated TAR DNA-binding protein 43 (TDP-43), a hallmark of amyotrophic lateral sclerosis (ALS) pathology. In this study, we investigated the interaction between TDP-43 and SOD1 and assessed how methylglyoxal (MGO)-induced glycation and the ALS-associated G93A SOD1 mutation affect this interplay in H4 cells. MGO exposure reduced SOD1 activity and TDP-43 phosphorylation in cells expressing WT SOD1, but not in those expressing G93A SOD1. Both WT and mutant SOD1 interacted with TDP-43 in the nucleus and cytosol; however, cytosolic interactions were more prevalent in G93A-expressing cells. Although MGO did not significantly alter the overall interaction between TDP-43 and WT SOD1, it induced cytosolic inclusion formation at 0.4 mM, a concentration associated with reduced cell viability. These inclusions did not colocalize with stress granules, indicating alternative aggregation pathways. Treatment with cyclosporin A, which inhibits the phosphatase calcineurin, decreased both TDP-43–WT SOD1 inclusions and cytosolic interactions between TDP-43 and G93A SOD1. Together, these findings suggest that SOD1 damage, induced by glycation or ALS-linked mutation, may affect TDP-43 phosphorylation status and promote its cytosolic mislocalization and aggregation, providing new insights into ALS-associated proteinopathy. Full article

Background: Magnesium sulfate (MgSO₄) has been investigated as an adjuvant in perioperative analgesia because of its antagonistic effects on the N-methyl-D-aspartate receptor (NMDA receptor) and its potential to attenuate central sensitization. However, clinical findings regarding its analgesic efficacy remain inconsistent across surgical procedures. Lumbar microdiscectomy is a common spinal procedure in which effective early postoperative pain control is important for patient comfort and early mobilization. This study aimed to evaluate the effect of intraoperative MgSO₄ administration on early postoperative analgesia and perioperative outcomes in patients undergoing lumbar microdiscectomy. Methods: This retrospective single-center cohort study included thirty-eight patients with American Society of Anesthesiologists (ASA) physical status I–II who underwent elective single-level lumbar microdiscectomy under general anesthesia. Patients were divided into two groups according to intraoperative magnesium administration: a control group receiving standard anesthesia without MgSO₄ (n = 19) and an MgSO₄ group receiving an intravenous MgSO₄ bolus of 30 mg/kg followed by a continuous infusion of 10 mg/kg/h until skin closure (n = 19). Postoperative pain intensity was assessed using the Numeric Rating Scale (NRS) at 0, 5, 10, 15, and 30 min after admission to the post-anesthesia care unit. Secondary outcomes included intraoperative remifentanil consumption, extubation time, and time to first mobilization. Complementary in silico analyses included molecular docking and protein–protein interaction (PPI) network analysis. Results: Postoperative NRS scores were numerically lower in the MgSO₄ group; however, between-group differences were not statistically significant. Mean intraoperative remifentanil consumption was numerically lower in the MgSO₄ group (236 ± 166 µg) compared with the control group (319 ± 298 µg), without statistical significance (p = 0.27). Repeated-measures analysis demonstrated the significant effect of time on postoperative NRS scores, whereas the overall group effect was not significant. Molecular analyses indicated stable morphine binding to opioid receptors and highlighted glutamatergic signaling components as central nodes within the interaction network. Conclusions: Intraoperative MgSO₄ administration was not associated with significant improvements in early postoperative pain scores or perioperative recovery parameters following lumbar microdiscectomy. Molecular analyses provide exploratory in silico insights and should be interpreted cautiously given the retrospective design and the in silico nature of these findings. Full article

Objective: ZhiZhu Kuanzhong (ZZKZ) capsule, a Chinese herbal extract, is extensively employed for the clinical management of functional dyspepsia (FD) in China. This study aimed to elucidate the therapeutic efficacy and underlying mechanisms of ZZKZ on the co-morbidity of anxiety and depression of FD. Methods: The FD model was established in Sprague–Dawley rats via neonatal gastric irritation with 0.1% iodoacetamide. Subsequently, FD rats were gavaged with ZZKZ or fluoxetine. Depression-like behaviors were evaluated using the sucrose preference test (SPT) and forced swimming test (FST), while anxiety-like behaviors were assessed via light-dark box (LDB) and open field tests (OFTs). Network pharmacology and molecular docking were conducted to explore the mechanisms of ZZKZ’s action. Hippocampal levels of monoamine neurotransmitters and monoaminergic system components were evaluated by HPLC and RT-qPCR, respectively. Serum concentrations of HPA axis hormones were determined by ELISA. Results: ZZKZ administration reversed the deficits in body weight gain and food intake in FD rats. Behaviorally, ZZKZ increased sucrose consumption in SPT and prolonged swimming duration in FST, and it increased duration and entries into the central zone in OFT. According to the prediction of network pharmacology, ZZKZ treatment elevated hippocampal levels of 5-HT/NE/DA, increased expression of TPH2/TH, and decreased expression of MAO_A/SERT in FD rats. Molecular docking further confirmed high-affinity binding between core ingredients of ZZKZ and TPH2/TH/MAO_A/SERT. Moreover, ZZKZ administration attenuated the stress-induced elevation of serum CRH/ACTH/CORT. Conclusions: ZZKZ effectively ameliorates the disordered gut–brain interaction and mitigates anxiety-like and depression-like behaviors, which might be modulated by the hippocampal monoaminergic system and hypothalamic–pituitary–adrenal axis response. Full article

Periodontitis represents a primary etiological factor in tooth mobility, with oxidative stress contributing critically to periodontal tissue destruction. Evodiamine (EVO), a quinazolinocarboline alkaloid, exhibits multiple biological activities; however, its antioxidant effects and mechanism in periodontitis have not been elucidated. The aim of this study was to investigate the regulatory effect of EVO on oxidative stress in periodontitis and to explore the associated molecular mechanism. The results indicate that EVO exhibits potent antimicrobial activity against key periodontal pathogens and suppresses pathogen-induced ROS generation as well as the release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) under periodontitis conditions. EVO binds specifically to the Kelch domain of KEAP1 with a strong binding energy (−11.67 kcal/mol), inhibits KEAP1–NRF2 interaction, and consequently upregulates the expression of antioxidant enzymes (HO-1, NQO1, GCLC, and SOD2), while downregulating the expression of iNOS, COX2, and NOX2. Furthermore, EVO inhibits the pro-apoptotic effect of the JAK2/STAT3 signaling axis and mitigates inflammation, alleviates cell cycle arrest, and promotes the migration and repair of periodontal ligament cells. Collectively, these findings suggest that EVO acts as a potential binder of KEAP1 that alleviates periodontal inflammation through modulation of oxidative stress and regulation of the JAK2/STAT3 pathway. Full article

Background: Patients with type 2 diabetes mellitus (T2DM) undergoing cardiac surgery represent a high-risk population characterized by substantial cardiometabolic stress and increased susceptibility to postoperative heart failure, renal dysfunction, and unplanned rehospitalization. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors provide established cardiorenal protection in ambulatory populations, their perioperative impact in cardiac surgery cohorts remains insufficiently defined. Methods: In a single-center retrospective cohort of 620 T2DM patients, inverse probability of treatment weighting and time-dependent Cox regression were applied to account for perioperative treatment interruption and delayed postoperative reinitiation when evaluating the association between chronic SGLT2 inhibitor therapy and 12-month rehospitalization risk. To provide biological context for the observed clinical associations, target-driven systems pharmacology, molecular docking against SGLT2, NHE1, AMPK, and NLRP3, and protein–protein interaction (PPI) network analysis were performed. Hub proteins were identified using Maximal Clique Centrality, followed by functional enrichment (GO/KEGG) analysis. Results: Chronic SGLT2 inhibitor therapy was associated with reduced first rehospitalization (HR 0.64; 95% CI 0.48–0.85; p = 0.002) and a lower cumulative rehospitalization burden (IRR 0.61; 95% CI 0.46–0.82; p = 0.001), primarily driven by heart failure-related and metabolic phenotypes. Molecular docking analyses identified favorable binding with SGLT2 and additional cardiometabolic and inflammatory targets, including NHE1, AMPK, NLRP3, IKKβ, IL-6Rα, and PPAR isoforms, suggesting modulation of myocardial ion homeostasis, metabolic resilience, and inflammatory signaling. PPI analysis identified eight hub proteins (AKT1, MTOR, STAT3, EGFR, PIK3CA, SRC, MAPK1, and MAPK3) significantly enriched in PI3K/AKT, MAPK/ERK, and ErbB signaling pathways. Conclusions: Chronic SGLT2 inhibitor therapy was independently associated with reduced postoperative rehospitalization and cumulative event burden in T2DM patients undergoing cardiac surgery. Integrated in silico analyses offer mechanistic hypotheses consistent with the observed clinical associations. These findings suggest that structured perioperative SGLT2 inhibitor management may contribute to improved postoperative outcomes, while prospective validation in future studies would strengthen these findings. However, given the retrospective observational design, these findings should be interpreted as associative rather than causal. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells when the spike receptor-binding domain (RBD) engages angiotensin-converting enzyme 2 (ACE2). Cannabinoid scaffolds have recently been reported to bind S1/RBD, block spike-mediated membrane fusion, and modulate host inflammatory pathways, making them attractive candidates for entry inhibition. Here, we applied an integrated computational pipeline to prioritize cannabis-derived compounds as interfacial blockers of the RBD–ACE2 complex across variants. Eleven phytocannabinoids were docked into the wild-type (WT) RBD–ACE2 interface, identifying three cavities, with ligands preferentially occupying pocket 1. Complexes were subjected to triplicate 200 ns all-atom molecular dynamics (MD) simulations for WT, Delta, and Omicron BA.1 RBD–ACE2. Binding energetics were quantified using molecular mechanics/generalized Born surface area (MM/GBSA) and solvated interaction energy (SIE), and per-residue contributions were analyzed together with solvent-accessible surface area (SASA) and residue interaction networks. Among all compounds, cannabidiol (CBD) and cannabinol (CBN) were the only ligands that remained stably bound in pocket 1 for all variants. CBN showed the most favorable ligand–complex binding in WT, whereas CBD preserved favorable binding in Omicron BA.1 despite reduced interface burial, indicating that van der Waals/electrostatic complementarity and solvation, rather than surface coverage alone, govern affinity. Both ligands weakened modeled RBD–ACE2 binding by perturbing hot-spot residues centered on Y505 or N501Y in RBD and E37, A387, and R393 in ACE2. Overall, our results highlight CBD and CBN as tractable, variant-spanning interface disruptors and illustrate how MD-based free-energy calculations can support computational drug discovery against evolving viral protein–protein interfaces. Full article

Six 1,4-disubstituted pyrazoles linked to a benzenesulfonamide and a benzodioxane unit have been synthesized through a copper(I)-catalyzed formal [3+2] cycloaddition (32CA) reaction of alkynes with 3-arylsydnones. The Cu-catalyzed sydnone–alkyne cycloaddition (CuSAC) procedure has been optimized to promote the formation of the pyrazole ring and to deliver in three steps the six target compounds 5a–f, fully characterized by ¹H/¹³C-NMR and mass spectrometry (EIMS). Ten solvent conditions were evaluated. The reaction proceeded most efficiently in the presence of copper(II) sulfate pentahydrate in aqueous t-butanol in the presence sodium acetate, to reach a yield of 96%. The mechanism of the Cu(I)-catalyzed reaction has been studied within the Molecular Electron Density Theory (MEDT). This rection is a domino process that consists in a Cu(I)-catalyzed formal [3+2] cycloaddition followed of an extrusion of CO₂ yielding the final pyrazole. The capacity of heterocyclic compounds 5a–f to interact with human cyclophilin A (Cyp A), which is a host cofactor for hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1), and with the HIV-1 protein gp120-CD4 was evaluated using molecular docking. Compounds 5a,b,d,f showed a satisfactory protein binding capacity. The physicochemical and metabolic properties of the compounds were also evaluated in silico. These predictions provide important information to guide future design in this series of potential antiviral agents. Full article

Picnomon acarna (L.) Cass. is a Mediterranean medicinal plant with limited phytochemical and bioactivity characterisation. In this study, methanolic extracts obtained by maceration (MAC), Soxhlet (SOE), and ultrasound-assisted extraction (UAE) were comparatively investigated to determine their phytochemical composition and biological potential. Liquid chromatography–electrospray ionisation–tandem mass spectrometry (LC–ESI–MS/MS) analysis identified and quantified 24 phenolic compounds, with hesperidin, chlorogenic acid, and hyperoside as the dominant constituents. The maceration extract exhibited the highest total phenolic content (29.06 mg GAE/g extract) and showed superior antioxidant performance across six complementary assays [2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), phosphomolybdenum, and ferrous-ion chelation), reflected by the highest relative antioxidant capacity index (RACI = 0.93). Enzyme inhibition assays revealed extraction-dependent activity patterns: Soxhlet and ultrasound extracts demonstrated stronger acetylcholinesterase inhibition (IC₅₀ ≈ 1.23 mg/mL), while Soxhlet extract showed the most potent tyrosinase (AChE) inhibition (IC₅₀ = 1.48 mg/mL). α-Amylase inhibition was comparable among extracts (IC₅₀ = 1.90–2.03 mg/mL). Pearson correlation analysis indicated strong relationships between major phenolics and antioxidant activity. Molecular docking further supported these findings, showing favourable binding affinities of hesperidin, hyperoside, and chlorogenic acid toward α-amylase and acetylcholinesterase, while only chlorogenic acid and hyperoside demonstrated favourable interactions with tyrosinase-related protein-1 (TYRP1), whereas hesperidin did not exhibit a meaningful binding affinity. Overall, the results demonstrate that the extraction strategy significantly influences the phenolic composition and multi-target bioactivity of P. acarna, highlighting its potential as a source of natural antioxidant and enzyme-modulating compounds. Full article

To investigate the potential of halogen-containing building blocks in the development of artificial carbohydrate receptors, the 1,3,5-trisubstituted 2,4,6-triethylbenzene scaffold with halogenated subunits and classical hydrogen bonding sites was used as a model system. In the first studies, the influence of the presence of halogens on the binding properties of compounds bearing benzamidomethyl units was investigated, whereby the type of halogen and its ring position were varied. The question was whether the presence of halogens could lead to an increase in binding effectivity and whether this increase can be attributed to the formation of halogen bonds (especially for X = Br and I in ortho position) with the sugar substrate or to other effects. The binding studies revealed some interesting relationships between structure and binding affinity for the tested compounds 1–9. For those bearing the halogen substituent in the ortho position to the amide functionality, the binding affinity increases in the expected order 4 (o-F) < 3 (o-Cl) < 2 (o-Br) < 1 (o-I). In the presence of small amounts of water in CDCl₃, an increase in binding strength was observed in comparison to experiments conducted in dry CDCl₃. The present studies aim to provide impulses for the use of halogenated building blocks in the design of artificial carbohydrate receptors. Optimizing the type of halogenated units and the receptor architecture should result in more effective carbohydrate receptors capable of functioning effectively in aqueous media through a combination of different noncovalent interactions. Full article

Background: Cysteinyl leukotrienes are components of slow-reacting substances of anaphylactic shock (SRS-A) and play a key role in asthma and inflammatory responses. Although chromone-2-carboxylic acids and substituted (aryloxy)alkanoic acids have the potential to be SRS-A antagonists, their comprehensive structure–activity relationships and pharmacokinetic characteristics remain understudied. Objective: This study integrated computational and experimental approaches, including QSAR modeling, molecular docking, ADMET analysis, molecular dynamics (MD) simulations, and antioxidant evaluation to identify and prioritize bifunctional compounds with anti-inflammatory and free radical-scavenging properties. Methods: A set of 68 compounds was analyzed using 2D and 3D quantitative structure–activity relationships (QSAR) (MLR, MNLR, SVR, ANN, and atom-based partial least squares). Molecular docking and 100 ns MD simulations were performed against the CysLT₁ receptor (PDB ID: 6RZ5). ADMET and drug-like properties of the compounds were predicted using ADMETlab 2.0 and SwissADME, and the in vitro antioxidant activity of the top-ranked compounds was evaluated using the DPPH method. Results: The atom-based 3D-QSAR model showed strong predictive power (R² = 0.9524, Q² = 0.5382). Compounds 25, 41, and 47 stood out with the most significant binding energies: −9.5 kcal/mol for 25, −10.0 kcal/mol for 41, and −9.4 kcal/mol for 47. MD simulations confirmed the structural stability and consistent interactions of the protein-compound 47 complex. ADMET analysis showed that compounds 25 and 41 had good pharmacokinetic properties, and in vitro antioxidant assays verified their free radical-scavenging efficacy. Conclusion: Our results highlight the utility of an integrated computational–experimental strategy for the discovery of dual-acting SRS-A antagonists. Compound 25 is highlighted as a promising lead compound for further preclinical development, which effectively combines leukotriene receptor antagonism and antioxidant activity. This framework provides an effective strategy for prioritizing lead compounds in anti-inflammatory drug development. Full article