European journal of pharmacology最新文献

Introduction: Cannabis use is increasing among pregnant women, although such use associates with fetal growth restriction and preeclampsia. While most research focuses on Δ9-tetrahydrocannabinol (THC), many pregnant women use cannabidiol (CBD)-containing products like CBD-oils. It is unknown whether CBD is transferred across the placenta.

Methods: CBD transfer was studied using an ex vivo placental perfusion model, making use of healthy term placentas. CBD was added to the maternal side. Placentas were perfused for 180 minutes. Using liquid chromatography-tandem mass spectrometry, CBD was quantified in perfusates and post-perfusion biopsies. Vascular reactivity of CBD and THC was determined in chorionic plate arteries using wire-myography with and without antagonists for the 2 types of CB receptors (CB1 and CB2).

Results: CBD concentrations in the maternal buffer dropped by >80% within 30 minutes due to rapid oxidation and remained undetectable in fetal samples. Albumin in combination with the anti-oxidant sodium ascorbate prevented this rapid drop. With albumin and sodium ascorbate being present, CBD transfer to the fetal side could be observed, reaching a fetal/maternal ratio of 0.32±0.23, while 11±4% was recovered in tissue. Furthermore, CBD dilated healthy placental arteries by 36±4%. This was attenuated by AM251 (CB1 receptor antagonist) and AM630 (CB2 receptor antagonist). THC induced vasoconstriction in the presence of AM251.

Discussion: Rapid oxidation of CBD can be prevented by adding an antioxidant. Under those conditions, CBD transfers to the fetus. CBD dilates fetoplacental vessels, while THC induces constriction. These data may help to understand potential risks of cannabis use in pregnancy.

Androgenetic alopecia (AGA) is a prevalent form of hair loss primarily driven by androgen receptor (AR) signaling. Currently, therapeutic options for AGA are limited. In this study, we conducted structure-based virtual screening of 3,014 known compounds and identified teicoplanin, a glycopeptide antibiotic, as having potent binding affinity for the AR ligand-binding domain along with inhibition of protein expression. To investigate the potential therapeutic effects of teicoplanin on AGA, we performed both in vitro and in vivo experiments. In vitro, treatment with teicoplanin resulted in dose-dependent enhancement of human dermal papilla cell proliferation, while AR protein levels decreased. Additionally, dihydrotestosterone (DHT) induced AGA mice were treated with teicoplanin (5 mg/kg low dose and 10 mg/kg high dose) or vehicle as a control for 17 days. Results showed that subcutaneous administration of teicoplanin significantly improved hair regrowth in high dose group (average coverage: 52.3% ± 8.8% in the teicoplanin high dose group vs. 10.5% ± 3.6% in AGA group). Furthermore, hair follicles in the teicoplanin-treated group were notably larger than those in the AGA group. Immunofluorescent analysis revealed that teicoplanin treatment significantly increased Ki-67 staining, a marker of cellular proliferation, while reducing AR staining intensity. Real-time quantitative reverse transcription polymerase chain reaction and Western blotting analyses demonstrated that teicoplanin downregulated AR and its downstream target gene, transmembrane protease serine 2, by 66% and 35%, while promoting AR ubiquitination and proteasomal degradation. Concurrently, teicoplanin enhanced β-catenin expression and upregulated vascular endothelial growth factor-A mRNA. Our findings suggest that teicoplanin may serve as a promising candidate for the treatment of AGA.

Objectives: This study investigated the antimetastatic potential of eupatolitin, a naturally occurring flavonoid, against oral squamous cell carcinoma.

Methods: MTT assays suggested that eupatolitin exerted no cytotoxic effects. However, Transwell and wound healing assays revealed that eupatolitin suppressed the migration and invasion of oral cancer cells in a dose- and time-dependent manner.

Results: Mechanistic investigations indicated that eupatolitin modulated mitogen-activated protein kinase signaling in SCC-9 and SAS cells by activating p38 phosphorylation. In addition, eupatolitin upregulated E-cadherin and downregulated mesenchymal markers such as Slug, Snail, and N-cadherin. Pretreatment with SB203580, a mitogen-activated protein kinase inhibitor, partially reversed the inhibitory effects of eupatolitin on the migration and invasion of both SCC-9 and SAS cells. Furthermore, overexpression of the proteases cathepsin S and cathepsin B blocked the inhibitory effects of eupatolitin. Molecular docking experiments revealed that eupatolitin stably bound to the active sites of cathepsin S and cathepsin B.

Conclusion: This study suggests that eupatolitin suppresses, at least partially, the migration and invasion of oral cancer cells by promoting p38 phosphorylation and downregulating cathepsin S and cathepsin B expression. The findings provide experimental evidence supporting the antimetastatic potential of eupatolitin. Nonetheless, further studies are required to confirm its translational relevance.

Knee arthrofibrosis is a serious complication most commonly arising after anterior cruciate ligament reconstruction or total knee arthroplasty, as well as a part of knee osteoarthritis pathology. It is characterized by excessive extracellular matrix deposition, joint stiffness and loss of joint mobility. Fibrosis has been extensively studied in organs such as the liver, lung, and heart, but knee joint fibrosis remains largely neglected, with no approved therapies or ongoing clinical trials targeting its underlying mechanisms. This review presents a comprehensive overview of the cellular and molecular pathways driving pathological fibrosis. We detail the activation and phenotypic diversity of macrophages and fibroblasts, highlighting how dysregulated interactions between these cell types establish self-perpetuating fibrotic loops. The most important mediators and signalling pathways are discussed, as well as the role of enzymes lysyl oxidase, transglutaminase-2 and matrix metalloproteinases in the formation of the fibrotic tissue. An overview of the latest drug candidates under clinical investigation in the last 5 years for other fibrotic conditions was provided, while potential directions for druggable targets specifically related to the knee joint arthrofibrosis were proposes such as hypoxia inducible factor 1-alpha, nuclear protein 1, Hippo pathway signalling, and Wnt signalling. Particular emphasis is given to some innovative local (intra-articular) drug delivery systems based on micro- and nanoparticles, hydrogels, and extracellular vesicles. Advancing our understanding of knee-specific fibrotic mechanisms is critical to developing effective, mechanism-driven treatments for knee arthrofibrosis.

Postoperative neurocognitive disorder (PND) is a significant complication in elderly surgical patients, primarily driven by hippocampal neuroinflammation and oxidative stress. This study investigated the role of Insulin-like Growth Factor-1 Receptor (IGF1R) signaling in the pathogenesis of PND and evaluated the therapeutic potential of isoliensinine (ISL). Using a tibial surgery model in aged mice, we assessed cognitive function, hippocampal IGF-1/IGF1R pathway activity, and the effects of daily intraperitoneal ISL administration (5 or 10 mg/kg). Surgery induced significant cognitive deficits and anxiety-like behaviors, accompanied by a marked reduction in hippocampal IGF-1 protein levels and IGF1R phosphorylation, which were predominantly localized in neurons. Daily high-dose ISL administration effectively reversed these behavioral impairments and restored hippocampal IGF-1 expression and IGF1R phosphorylation. These neuroprotective effects were causally linked to IGF1R activation, as co-administration of the selective IGF1R inhibitor picropodophyllin (PPP) completely abolished ISL's therapeutic benefits. Mechanistically, ISL's effects were mediated by robust antioxidant and anti-inflammatory actions. ISL treatment reversed surgery-induced oxidative stress by promoting the nuclear translocation of NRF2 and restoring antioxidant defenses. Furthermore, ISL suppressed neuroinflammation by reducing hippocampal microglial activation and inhibiting the phosphorylation of p38 MAPK. Critically, these antioxidant and anti-inflammatory effects were also blocked by PPP. In conclusion, our findings demonstrate that ISL ameliorates PND by reactivating the neuronal IGF-1/IGF1R signaling pathway, which in turn suppresses downstream oxidative stress and microglial-driven neuroinflammation. This highlights ISL as a promising therapeutic candidate for the prevention and treatment of PND.

Chronic kidney disease is largely driven by renal fibrosis (RF), where dendritic cells (DCs) play a key role in renal immunity, exacerbate RF through metabolic reprogramming and interactions with renal tubular epithelial cells (RTECs). Hydroxychloroquine (HCQ), has shown anti-fibrotic potential, but its mechanisms in RF remain unclear. Here, we investigated HCQ's therapeutic effects and underlying immunological pathways in adenine-induced RF mice and lipopolysaccharide -stimulated bone marrow-derived DCs. In vivo, HCQ administration (10/20 mg/kg) significantly attenuated renal histopathological damage, reduced collagen deposition, improved renal function indices (serum creatinine, blood urea nitrogen), and regulated oxidative stress markers (superoxide dismutase /malondialdehyde) levels. HCQ inhibited DCs maturation, enhanced immunosuppressive markers [(programmed death-ligand1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), immunoglobulin-like transcript (ILT)-3], suppressed pro-inflammatory cytokines while elevating anti-inflammatory cytokines both in vivo and in vitro. Ex vivo, HCQ disrupted DCs-RTECs crosstalk, reversing RTECs apoptosis and fibrotic markers [α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β₁, collagen type I (Col-I)] expression. Metabolically, HCQ suppressed DCs glycolipid metabolism by downregulating glucose uptake, non-esterified fatty acid secretion, and mitochondrial membrane potential, concomitant with altered expression of glycolysis/lipid utilization-related genes. Notably, HCQ reduced phosphorylation of phosphatidylinositol 3-kinase [PI3K (Tyr458)], protein kinase B [AKT (Ser473)], thereby retaining forkhead box O1 (FoxO1) in nucleus and elevated expression of PD-L1 mediated by disturbing the interaction between FoxO1 and PD-L1 to enhance DCs immunosuppressive activity. Rescue experiments with PI3K agonist 740Y-P confirmed the involvement of downstream signaling. Collectively, HCQ alleviates RF by modulating DCs metabolism and impairing DCs-RTECs crosstalk, underscoring its therapeutic promise for RF.

Chemotherapeutic agent-induced organ toxicities, including cardiotoxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity, remain significant challenges in cancer treatment, often limiting therapeutic utility, effectiveness and patient quality of life (QOL). These toxicities arise from numerous mechanisms such as oxidative stress, inflammation, and apoptosis, driven by chemotherapeutic agents like doxorubicin, cisplatin, cyclophosphamide, and methotrexate. Various strategies are being explored to mitigate these toxicities without compromising the effectiveness of the treatment. Polypharmacological or dual-targeting agents that combat cancer cells, sensitize resistant cancer types, and minimize organ damage show enormous promise in therapeutics. Among emerging therapeutic targets, the endocannabinoid system, comprising cannabinoid receptors and metabolizing enzymes, offers potential in both cancer chemotherapy and reducing organ toxicities. The therapeutic potential of cannabinoids is attributed to their role in modulating inflammation, oxidative stress, and cell survival which are the common components of cancer pathogenesis and organ toxicities. Preclinical studies demonstrate that cannabinoid receptor-agonists, such as JWH-133 and beta-caryophyllene, mitigate organ damage by suppressing pro-inflammatory cytokines, reducing reactive oxygen species (ROS) production, and inhibiting apoptotic pathways. For instance, cannabinoid receptor 2 (CB2) activation has been shown to attenuate doxorubicin-induced cardiotoxicity by enhancing antioxidant defenses and reducing myocardial inflammation. Similarly, in cisplatin-induced nephrotoxicity, cannabinoids alleviate renal injury by decreasing tubular cell apoptosis and inflammatory infiltrates. Despite these promising findings, challenges remain, including the development of highly selective cannabinoid receptor agonists, understanding tissue-specific responses, and addressing translational gaps between animal models and human pathophysiology. This review highlights the mechanistic overview of cannabinoid receptor agonists in mitigating chemotherapy-induced organ toxicities and adverse effects, summarizes preclinical evidence, and discusses the potential for clinical application. By elucidating the therapeutic potential of the activation of cannabinoid receptors, this work underscores its viability as a novel strategy to enhance the effectiveness of chemotherapeutic regimens and improve patient outcomes, however, further research is the need of the hour to advance cannabinoid-mediated therapies into clinical practice.

Opioid addiction persists as a critical public health crisis, where drug-seeking behaviors frequently re-emerge despite extended periods of abstinence. Current therapeutic approaches often fail to effectively address the substantial risk of relapse triggered by drug-related cues. Existing pharmacotherapies primarily focus on alleviating withdrawal symptoms or cravings, but they do not directly intervene in the memory processes that underlie relapse. Here, we assessed the promise of JMV2959, a specific GHSR1A antagonist, in disrupting the reconsolidation of heroin-associated memories by a rat assay. After retrieval of heroin-associated conditioned stimuli, JMV2959 administration led to a significant reduction in cue-induced and drug-primed reinstatement of heroin-seeking behaviors. This effect was observed only during the reconsolidation window-administration outside this critical period, or without prior retrieval, did not produce any noticeable effect. Importantly, the reduction in cue-induced heroin-seeking behavior persisted following a 4-week withdrawal phase, suggesting a lasting disruption of the memory trace. These findings suggest that JMV2959, by targeting GHSR1A, offers a promising pharmacological strategy to weaken drug-seeking behavior and prevent relapse in opioid addiction.