European journal of pharmacology最新文献

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.

Colorectal cancer (CRC) continues to be a leading cause of cancer-related mortality globally, with metastasis representing a critical determinant to poor prognosis. Vasculogenic mimicry (VM), a non-endothelial tumor microcirculation pattern, promotes tumor aggression and resistance to conventional anti-angiogenic therapies. Epithelial-mesenchymal transition (EMT) and cytoskeletal remodeling are critical for VM formation and metastasis. Koumine (KM), a primary alkaloid from Gelsemium elegans Benth, exhibits anti-tumor properties. This study employed a multidimensional experimental approach to systematically evaluate the inhibitory effects of KM on colorectal cancer metastasis. Our findings demonstrate that KM effectively inhibits multiple metastatic processes in CRC, including cell migration, invasion, and VM formation in vitro and in vivo. Proteomics analysis revealed downregulation of EphA2, a key VM regulator, and enrichment of cytoskeleton-related pathways. KM disrupted actin reorganization, stabilized Vinculin-rich focal adhesions, and suppressed EMT, as evidenced by E-cadherin upregulation couple with downregulation of N-cadherin, Vimentin, Snail. In xenografts models, KM reduced tumor growth, VM and lung metastasis. These effects were accompanied by the downregulation of the EphA2 and FAK. These results suggest that KM may have potential as an adjunctive therapeutic agent for CRC metastasis.

Psoriasis is a chronic, immune-mediated inflammatory skin disease induced by genetic and environmental factors, with dysfunctional contact inhibition of keratinocytes being a core pathological feature leading to hyperproliferation. Our previous gene chip screening identified a significant downregulation of PTCHD1 following treatment with recombinant human parathyroid hormone (1-34) (rhPTH(1-34)), which inhibited keratinocyte proliferation. PTCHD1 (Patched domain-containing protein 1) is a transmembrane protein that regulates intercellular communication and proliferative signaling. This study aimed to investigate whether rhPTH(1-34) restores contact inhibition and controls keratinocyte proliferation by downregulating PTCHD1 to modulate the Hippo signaling pathway. In vitro experiments showed that rhPTH(1-34) treatment significantly suppressed HaCaT cell viability, downregulated PTCHD1 mRNA and protein expression, and reduced the cell adhesion index. In a PTCHD1-overexpressing HaCaT model, enhanced cell adhesion, proliferation, and elevated IL-1β expression were observed, all of which were reversed by rhPTH(1-34). Inhibition of the Hippo pathway with Verteporfin recapitulated the contact inhibition phenotype. Mechanistically, rhPTH(1-34) downregulated PTCHD1, activated the key MST1/2-LATS1 kinase cascade, promoted phosphorylation of YAP at Ser127, and facilitated its cytoplasmic retention. In vivo, intraperitoneal injection of rhPTH(1-34) ameliorated psoriatic lesions in a mouse model, evidenced by reduced erythema, scaling, epidermal thickening, and lower inflammatory cytokine levels, without inducing fluctuations in serum calcium. In conclusion, rhPTH(1-34) restores contact inhibition and suppresses keratinocyte proliferation and inflammation by downregulating PTCHD1 to regulate the Hippo signaling pathway, demonstrating its potential as a treatment for psoriasis.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have transformed the management of type 2 diabetes by effectively lowering glucose levels through the promotion of glucosuria and natriuresis. Beyond these primary actions, a growing body of experimental and clinical evidence suggests that this drug class exerts a wide range of pleiotropic effects independent of glycemic control. Laboratory studies have shown that SGLT2 inhibitors influence fundamental aspects of cellular metabolism and survival, including the promotion of ketogenesis as an efficient energy source, upregulation of sirtuin 1 that modulates stress resistance and longevity, and attenuation of inflammation and oxidative stress through adenosine monophosphate-activated protein kinase - mechanistic target of rapamycin complex 1 (AMPK - mTORC1) signaling. Collectively, these pathways suggest cytoprotective properties that may underlie the emerging benefits of SGLT2 inhibitors in cardiovascular, renal, and other systemic diseases. This review provides an updated and comprehensive overview of the molecular and cellular mechanisms underlying the extraglycemic actions of SGLT2 inhibitors, links these mechanistic insights to ongoing clinical trials, and underscores their expanding potential for therapeutic repurposing beyond diabetes management.

Obesity is a chronic metabolic disorder characterized by systemic and hypothalamic inflammation that impairs neuronal signaling and disrupts the fine-tuning of energy balance regulation. Leptin resistance, a hallmark of obesity, arises from this inflammatory state and contributes to increased food intake and reduced energy expenditure (EE). Fibroblast growth factor 19 (FGF19), a gut-derived hormone with beneficial metabolic effects in peripheral tissues, also acts centrally to reduce body weight. However, the mechanisms underlying its hypothalamic action remain unclear. In this study, we investigated whether central administration of FGF19 attenuates hypothalamic inflammation and restores leptin signaling in diet-induced obese (DIO) mice, thereby improving energy homeostasis. DIO mice received FGF19 via intracerebroventricular delivery using a cerebral infusion kit connected to an osmotic pump for 10 days. FGF19 treatment increased EE and reduced food intake in DIO mice, resulting in improved energy balance without changes in locomotor activity. These effects were accompanied by a marked reduction in hypothalamic inflammatory markers and glial activation, including reactive astrocytes. Notably, FGF19 restored hypothalamic leptin-induced Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) phosphorylation and normalized expression of anorexigenic neuropeptides. Our findings position FGF19 as a central regulator of leptin sensitivity and hypothalamic inflammation, highlighting its therapeutic potential for obesity through modulation of appetite and EE.

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.