European journal of pharmacology最新文献

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.

Background: The increasing prevalence of diabetes mellitus with depression (DD) has emerged as a significant global public health concern. Nootkatone (NKT), as a natural sesquiterpenoid compound, exhibits anti-inflammatory, anti-diabetic, and neuroprotective effects. This study aimed to investigate the underlying mechanisms of NKT in treating DD through network pharmacology, molecular docking, and experimental validation.

Methods: Network pharmacology was utilized to screen the potential targets and mechanisms related to the effects of NKT on DD. Molecular docking was conducted to confirm the interactions between NKT and core targets. The DD model was established through a high-fat diet in conjunction with streptozotocin (STZ) administration and chronic unpredictable mild stress (CUMS). The therapeutic effects of NKT on DD were assessed by indices of glucose metabolism, behavioral tests, H&E staining, enzyme-linked immunosorbent assay (ELISA) and Western blot.

Results: Based on network pharmacology and molecular docking analyses, this study proposes the potential mechanisms of NKT on DD, with AKT1 identified as a key target. In vivo experiments demonstrated that NKT improved body weight and glucose metabolism, and alleviated depression-like behaviors in DD mice (P < 0.05). In addition, NKT attenuated neuronal injury and increased monoamine neurotransmitters in the hippocampus (P < 0.05). NKT also decreased inflammatory response induced by STZ-CUMS and upregulated proteins associated with PI3K/AKT pathway (P < 0.05).

Conclusion: NKT alleviated depression-like behaviors, attenuated hippocampal injury, and increased monoamine neurotransmitters in DD mice. The protective effect of NKT on DD might be associated with the activation of the PI3K/AKT pathway.

Piperine is a common anti-ischemic compound and an active ingredient of herbal medicine for various ailments. It is widely sourced and affordable. However, its bioactivity and anti-ischemic effects on retinal ischemic injury are unknown. The chemical-gene interactions of piperine were analyzed using data from "SwissTargetPrediction," "Binding DB", and "TargetNet" databases. Gene expression data from GSE43671 dataset and the Kyoto encyclopedia of genes and genomes (KEGG) were used for differential gene and ontology analyses. To evaluate the activation of disease pathways, by analyzing gene sets and applying weighted gene co-expression networks to differential gene interaction data. Additionally, molecular complex detection analyses of retinal ischemia and control samples were performed to determine which genes are affected by piperine, to compare gene expression differences, and to map receiver operator characteristic data. Utilizing network pharmacology and transcriptome sequencing, this study elucidates the targets and pathways affected by pharmacological interventions involving piperine in retinal ischemia injury. 176 target genes connected to piperine were identified and retrieved. Screening of 8 hub genes using machine learning. Through screening, we detected disease-associated genes, differential genes, and drug targets, and pinpointed two biomarker genes, Aoc3 and Gabra3. We found that piperine may have a protective effect on retinal ischemic injury. Consequently, piperine may modulate retinal ischemic injury through specifically targeting Aoc3 and Gabra3 for retinal protection.