European journal of pharmacology最新文献

Ischemic stroke (IS) remains a major cause of global mortality and disability, with neuroinflammation driven by microglial pyroptosis representing a key pathological mechanism. This study examined the neuroprotective efficacy of morroniside-an iridoid glycoside from Cornus officinalis-in experimental model of IS, focusing on its regulation of microglial inflammasome activation, pyroptosis and associated signaling cascades. Using a transient middle cerebral artery occlusion/reperfusion (tMCAO/R) model in Sprague-Dawley rats and an oxygen-glucose deprivation/reperfusion (OGD/R) model in BV2 microglia, morroniside was administered at 270 mg/kg intragastrically in vivo and at concentrations of 1-100 μmol/L in vitro. Protein expression was assessed by Western blotting, cellular markers by immunofluorescence, cytokine levels by enzyme-linked immunosorbent assay (ELISA), and pathway alterations by transcriptomic profiling. Morroniside treatment significantly attenuated microglial activation, as evidenced by reduced ionized calcium-binding adapter molecule 1 (IBA-1) expression, and suppressed pyroptosis through downregulation of gasdermin D (GSDMD), NOD-like receptor family pyrin domain containing 3 (NLRP3), caspase-1, interleukin-1β (IL-1β), and interleukin-18 (IL-18) in both models. Transcriptomic analysis revealed marked enrichment in inflammatory and immune response pathways, with notable suppression of interleukin-17 (IL-17) signaling. Mechanistic analyses showed that morroniside concurrently suppressed IL-17 expression, nuclear factor-κB (NF-κB) phosphorylation, and NLRP3 inflammasome assembly, implicating coordinated inhibition of the IL-17/NF-κB/NLRP3 cascade. Functional in vitro assays confirmed the pathway's essential role: recombinant IL-17 partially reversed, whereas selective IL-17 blockade enhanced, morroniside-mediated suppression of pyroptosis, demonstrating that IL-17 signaling is both necessary and targetable in this cascade. Collectively, these findings identify morroniside as a regulator of IS-associated neuroinflammation that mitigates microglial pyroptosis by interrupting the IL-17/NF-κB/NLRP3 axis, underscoring its potential as a therapeutic candidate for stroke.

Background: Multidrug resistance (MDR) is a major obstacle in cancer therapy, largely driven by efflux transporters such as P-glycoprotein (P-gp). Current strategies remain limited, highlighting the need for novel agents. Natural chalcones are promising modulators, and 2',6'-dihydroxy-4'-methoxydihydrochalcone (DHMC), isolated from Fissistigma cupreonitens, represents a unique candidate with dual, dose-dependent effects.

Purpose: To define the biphasic actions of DHMC in MDR cancer and elucidate the molecular mechanisms underlying its pro-apoptotic and chemosensitizing activities.

Methods: Drug-sensitive (HeLa S3, KB, MDA-MB-231) and resistant (KB/VIN, MDA-MB-231/DOC) cell lines were tested. Assays included cytotoxicity, apoptosis, cell cycle, ROS, mitochondrial potential, and transporter efflux. Mechanistic studies involved STAT3 phosphorylation, Western blotting, docking, ATPase activity, and efflux kinetics. Apoptosis antibody arrays with GO/KEGG analyses identified signaling pathways. Zebrafish xenografts assessed in vivo efficacy.

Results: DHMC displayed concentration-dependent dual actions. High doses promoted apoptosis and cell cycle arrest, with bioinformatics implicating CD40LG, TNF, and MAPK pathways in immune-related apoptosis. Low doses enhanced chemosensitivity by inhibiting P-gp, MRP1, and BCRP, increasing intracellular drug accumulation. Mechanistically, DHMC suppressed P-gp expression and non-competitively blocked efflux, leading to >130-fold reversal of paclitaxel resistance in KB/VIN cells. Zebrafish models confirmed tumor suppression and synergy with paclitaxel without toxicity.

Conclusion: DHMC acts as a novel natural chalcone that overcomes MDR via dual mechanisms, apoptosis induction and transporter inhibition, underscoring its importance as a potential adjuvant in cancer therapy.

Electroconvulsive therapy (ECT), an effective augmentation for treatment-resistant schizophrenia, is associated with clinically significant, unpredictable elevations in serum clozapine concentrations, posing a substantial toxicity risk. Delirium, urinary retention, constipation, hypersalivation etc. have been frequently noticed. This study aimed to develop a quantitative systems pharmacology (QSP) model that provides a quantitative explanation for the observed clinical interaction. An integrated QSP model was constructed, incorporating a two-compartment pharmacokinetic model for clozapine, dynamic models for key inflammatory biomarkers (interleukin-6, C-reactive protein, tumour necrosis factor-alpha), and a mechanistic link representing their inhibitory effect on CYP1A2 enzyme activity. The model was parameterized using literature-derived data and retrospective clinical concordance was done against clinical findings at our centre. The model accurately simulates a progressive, multi-fold increase in clozapine concentrations over a course of six ECT sessions. This accumulation is mechanistically driven by a transient, pulsatile inflammatory response initiated by each ECT treatment. This response causes a cumulative, stepwise reduction in CYP1A2 activity, which reaches a nadir of approximately 30% of its baseline function. Consequently, simulated dopamine D₂ receptor occupancy surpasses the 80% threshold associated with an elevated risk of extrapyramidal symptoms following the fourth ECT session. The QSP model provides a robust, mechanistically plausible explanation for the observed ECT-clozapine interaction, identifying the inflammatory cascade as the critical driver of impaired clozapine metabolism. The model serves as a powerful tool for simulating patient risk and provides a quantitative foundation for developing personalized, model-informed dosing strategies to enhance the safety of this crucial concomitant therapy.

Chronic pain often acts as a trigger of depression. Mitochondrial dysfunction is increasingly recognized as a key player in the pathogenesis of depression and pain. Sirtuin 3 (SIRT3), a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, has been found to ameliorate mitochondrial function. However, the role of SIRT3 in the development of chronic pain-induced depression remains unclear. In this study, it was observed that the expression of SIRT3 in the central amygdala (CeA) was downregulated in spared nerve injury (SNI) male mice with comorbid pain and depression. However, the overexpression of SIRT3 in CeA γ-aminobutyric acid-ergic (GABAergic) neurons mitigated the sensory pain and depressive-like behaviors induced by SNI. Further study demonstrated that the overexpression of SIRT3 in CeA GABAergic neurons decreased the acetylation level of lysine 166 (K166) on cyclophilin D (CypD), inhibited the opening of mitochondrial permeability transition pore (mPTP) and the production of reactive oxygen species (ROS), and increased mitochondrial membrane potential (MMP) and manganese superoxide dismutase (MnSOD) levels in SNI mice. Nevertheless, CypD-K166R mutant mice that mimic deacetylation were protected from mitochondrial dysfunction and depressive-like behaviors caused by SNI. Furthermore, blocking mPTP opening using cyclosporin A (CsA) improved mitochondrial function and alleviated neuropathic pain and its comorbid depression in SNI mice. Taken together, our findings suggest that SIRT3 in CeA GABAergic neurons attenuates chronic pain and its comorbid depression by deacetylating CypD-K166 and subsequently ameliorating mitochondrial dysfunction. This study provides a potential therapeutic target for both the sensory and emotional dimensions of chronic pain.

Estrogen mediates diverse physiological and pathological processes through estrogen receptors (ERα and ERβ). Andrographolide analogues have broad pharmacological effects including anti-inflammation and antimicrobial, antiviral, and hepatoprotective activity. However, the direct targets of these andrographolide analogues are not clear yet. To evaluate whether andrographolide analogues deoxyandrographolide (DAGP), 14-deoxyandrographolide (14-DAGP) and 14-deoxy-11, 12-didehydroandrographolide (DDHA) could activate ERs, computational molecular docking, surface plasmon resonance (SPR) using purified ERα and ERβ ligand binding domain (LBD) proteins, luciferase reporter assay, and in vivo animal experiments were conducted. Molecular docking and SPR confirmed direct interaction of these analogues with ERα/β LBD. 14-DAGP and DDHA activated ERα (not ERβ) transcriptional activity in reporter assays, and stimulated endometrial cell proliferation in ovariectomized female mice and rats, indicating ERα agonism in vivo. 14-DAGP decreased total white adipose tissue (WAT) mass in ovariectomized rodents by activating ERα. In male mice, DDHA reduced UV-induced skin damage via ERα activation. This study identifies andrographolide analogues 14-DAGP and DDHA as a class of phytoestrogens in vitro and in vivo. They could reduce WAT mass and alleviate UV-induced skin damage in vivo through activation of ERα. Further studies are merited to reveal whether ERα mediated other pharmacological activities of andrographolide analogues.

Autophagy has emerged as a central regulator of cellular homeostasis, integrating metabolic state, stress responses, and cell fate decisions. Once regarded primarily as a cytoprotective housekeeping process, autophagy is now understood as a context-dependent pathway whose dysregulation can actively contribute to the initiation and progression of major civilization diseases, including cancer, neurodegeneration, metabolic disorders, and organ-specific complications. In parallel, advances in metabolic biology have revealed highly dynamic and adaptable networks that closely intersect with autophagic regulation. This Special Issue of The European Journal of Pharmacology provides a unified conceptual framework for understanding how the autophagy-metabolism axis shapes disease pathophysiology and therapeutic response. Bringing together integrative reviews and original research articles, the collection highlights how autophagy can be both protective and pathogenic, depending on disease stage, tissue context, and environmental stress. Contributions span neurodegenerative disorders, cancer signalling and chemoresistance, metabolic complications, and emerging therapeutic strategies, including pathway-targeted drugs, metabolic modulators, natural compounds, and advanced delivery platforms. Collectively, this volume positions autophagy not as an isolated pathway but as a central, actionable interface between metabolism and pharmacological intervention, underscoring the need for precise, context-aware modulation in future therapeutic designs.

Background: Gastric cancer (GC) requires novel therapies. This study employed artificial neural networks (ANNs) to repurpose existing drugs against GC.

Methods: ANN models predicted candidates from DrugBank using pharmacogenomic descriptors. Top compounds, selected by favorable IC₅₀ and Z-scores, were screened in vitro (cytotoxicity in AGS/MKN-45 cells; toxicity in HDFs). Leads were validated in vivo in MKN-45 xenograft mice, assessing tumor markers (Ki67, CD44) and target genes.

Results: Two leads, amitriptylinoxide (20313) and phytonadione (5284607), exhibited high in vitro potency and selectivity. In vivo, both significantly inhibited tumor growth, achieving final volumes of 2.0 ± 1.9 mm³ and 0.05 ± 0.02 mm³, respectively. This efficacy was comparable (0.08 ± 0.03 mm³) or superior to cisplatin. Critically, both compounds induced significant body weight gain, indicating markedly lower systemic toxicity than the weight loss observed with cisplatin. They also suppressed Ki67/CD44 expression (>50%) and stemness genes.

Conclusion: This ANN-driven approach successfully identified amitriptylinoxide and phytonadione as potent GC drug candidates with in vivo efficacy rivaling cisplatin and a significantly improved toxicity profile.

Hypertension remains a significant global health issue. Low-density neutrophils (LDNs), a subset of neutrophils, contribute to vascular injury through immune activation. This study aimed to explore the effects of valsartan on LDNs in hypertension and to elucidate the molecular mechanisms underlying their role in therapeutic response. Newly diagnosed hypertensive patients received 80 mg/day valsartan for one month. Single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) collected before and after treatment. Mendelian randomization (MR) analysis was used to identify genes associated with valsartan response among the differentially expressed genes. Eleven cell subpopulations were identified, including four distinct LDN subtypes: CAMK1D, PI3, ISG15, and S100A12. Valsartan treatment reduced immune activation-related transcripts in LDNs, with decreased CAMK1D and increased PI3 expression. Lower MMP9 transcript levels in the PI3 subtype were linked to limited differentiation of LDNs into the CAMK1D subtype, with a preference for retention in the PI3 subtype, potentially contributing to valsartan's ehanced efficacy. Theses findings highlight CAMK1D and PI3 as LDN-related genes influencing valsartan response in hypertension, offering a foundation for future functional studies.

In vitro patient-derived models, predicting the benefit of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, have the potential to find effective drugs for cystic fibrosis patients (pwCF) through a personalized CFTR pharmacotherapeutic approach. To date, human nasal epithelial (HNE) cells and human intestinal organoids (HIOs) represent the most utilized in vitro system in Cystic Fibrosis (CF) research, carrying a patient-specific genomic background. The first one is expected to represent key processes occurring in the airways, and the second to mimic the features of the gastrointestinal tract. Both are important target tissues and are utilized as sensitive and robust tools for the diagnosis of CF. In this review, we evaluated the efficacy of nasal and intestinal models in predicting similar therapeutic responses of CFTR variants to CFTR modulators and other treatments by conducting an analysis of the published data reporting responses in both cellular models derived from the same individuals. The data confirm a high concordance in CFTR rescue across the two models, supporting their use as equally reliable and complementary theranostic tools for assessing in vitro drug efficacy of highly efficient CFTR modulator therapies (HEMT).