European journal of pharmacology最新文献

Context: The morbidity of bone cancer pain (BCP) is on the rise, yet current treatments have limited analgesic efficacy. Sodium Danshensu (SDSS), or sodium 3-(3,4-dihydroxyphenyl)-DL-lactate, exhibits anti-inflammatory, anti-osteoporotic properties. Current research shows that bone cancer pain is closely related to the development of osteoclasts.

Objective: To investigate the analgesic effects of SDSS on BCP in mice and explore the underlying mechanisms.

Materials & methods: Nociceptive behaviors in BCP mice were evaluated by paw withdrawal threshold (PWT) and limb using score (LUS). Network pharmacology, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, and molecular docking identified potential targets. Histological analyses, Western blot, RT-qPCR, ELISA, and immunofluorescence staining were performed on mice femurs.

Results: SDSS significantly increased PWT and LUS in BCP mice. Forty-three common targets were identified, with the estrogen signaling pathway showing the highest enrichment. Molecular docking analysis suggested a potential binding affinity between SDSS and ESRα. SDSS administration up-regulated ESRα expression and down-regulated RANKL, RANK, NFATc1, c-fos, TRAP, and Cathepsin K (CTSK). In addition, SDSS suppressed the abnormal increase of calcitonin gene-related peptide-positive (CGRP⁺) neural budding and expression in nerve endings, effects which were reversed by ESRa inhibitor ICI-182780.

Conclusions: SDSS relieves bone cancer pain by inhibiting osteoclast activity, providing a potential new drug option for cancer pain patients.

Background: Pathological cardiac hypertrophy is a hallmark of various cardiovascular diseases, unfortunately, effective targeted therapies are still lacking. This study aims to verify the role of plant-homeodomain finger protein21b (PHF21B) in pathological cardiac hypertrophy.

Methods: Angiotensin-II (Ang II) induced cardiomyocyte hypertrophy in vitro, and short hairpin (sh) RNA-mediated PHF21B silencing was used to assess its role in hypertrophic growth. Transverse aortic constriction (TAC) was performed to induce cardiac hypertrophy in mice. To assess the effect of PHF21B on pathological cardiac hypertrophy in vivo, the myocardium was transduced with adeno-associated virus 9 (AAV9) encoding a PHF21B-targeting shRNA for gene ablation. Chromatin immunoprecipitation-polymerase chain reaction (PCR), western blotting, and quantitative reverse transcription-PCR were performed to elucidate the mechanisms through which PHF21B regulates pathological cardiac hypertrophy.

Results: This investigation revealed that PHF21B levels were elevated in patients with pathological cardiac hypertrophy. PHF21B inhibition alleviated pressure overload-induced cardiac dysfunction and hypertrophy in vivo, and Ang-II-induced cardiomyocyte hypertrophy in vitro. Genome-wide transcriptome analysis and biological experiments revealed that PHF21B silencing inhibited the Wnt signalling pathway, include the protein expression of β-catenin, and the phosphorylation of glycogen synthase kinase (GSK)-3β. Mechanistically, PHF21B influenced the translation of bone morphogenetic protein (BMP)-4 and facilitated the activation of the GSK3β/β-catenin pathway. The anti-hypertrophic effects of PHF21B knockdown were blocked by BMP4 supplementation.

Conclusions: Collectively, our results demonstrated that PHF21B is contributes to pathological cardiac hypertrophy by regulating BMP4 expression and the GSK3β/β-catenin pathway. The inhibition of PHF21B is a potential new therapeutic strategy to mitigate pathological cardiiac hypertrophy.

Background: Tryptanthrin (Couroupitine A) is isolated from indigo-bearing traditional Chinese herbal medicines. It has a broad spectrum of pharmacological and biological activities. However, the potential effects of tryptanthrin on platelet function and thrombus formation remain elusive.

Methods: Platelets were harvested from C57BL/6 mice and healthy individuals. Following incubation with tryptanthrin, various platelet functions were assessed. Thrombus formation in the presence of tryptanthrin was evaluated both in vitro, using a BioFlux 200 microfluidic system, and in vivo, through FeCl₃-induced thrombosis and mouse deep venous thrombosis experiments. The closure times of the tryptanthrin-treated whole blood samples were determined using the PFA-200 system. Platelet proteomics sequencing was conducted to elucidate the underlying mechanisms by which tryptanthrin influences platelet function.

Results: Tryptanthrin inhibited mouse platelet function and impaired carotid artery and deep venous thrombus formation. Tryptanthrin also inhibited human platelet spreading, aggregation and clot retraction. The signaling pathways related to platelet activation, aggregation, hemostasis, and the fibrin clotting cascade were significantly suppressed in platelets treated with tryptanthrin. Notably, the expression of Gp1bα in platelets was diminished by tryptanthrin.

Conclusions: Tryptanthrin impairs platelet function and thrombus formation.

Triple-negative breast cancer (TNBC) presents an unmet medical challenge due to poor outcomes and limited treatment options. Metabolic signals are coupled to oncogenesis. Fatty acid oxidation (FAO) plays a crucial role in cancer initiation, progression, metastasis, and therapy resistance, but its precise functions and underlying molecular mechanisms in TNBC remain unclear. Here, we conducted a comprehensive study to investigate the biological roles and drug modulation of FAO in TNBC using data from The Cancer Genome Atlas (TCGA), Genomics of Drug Sensitivity in Cancer (GDSC), and Connectivity Map (CMap) databases. We found that altered FAO activity was not related to patient age, clinical stage, tumor mutational burden, microsatellite instability, or homologous recombination deficiency. Nevertheless, upregulated FAO activity correlated with poor prognosis, increased stemness, accelerated cell cycle progression, altered mutation rates of several top 20 most frequently mutated genes, as well as higher activity of pathways involving oncogenic signaling, cellular metabolism, protein turnover, and so forth. Elevated FAO activity also appeared to foster an immunosuppressive microenvironment, influence microbial composition, and confer resistance to chemotherapies. What's more, we identified several compounds that may regulate FAO activity, including the HDAC inhibitor chidamide, which induced FAO activation in TNBC cells. Co-treatment with an FAO inhibitor etomoxir enhanced the combined effects of chidamide with established chemotherapy drugs, as well as their efficacy as single agents in TNBC cells. In conclusion, FAO likely exerts pleiotropic biological effects in TNBC and modulating FAO may offer a promising strategy to improve therapeutic outcomes in TNBC.

Glioblastoma multiforme (GBM) is a deadly type of brain tumor with low patient survival rates. Previous studies have shown that inhibiting the intracellular bile acid transport protein can suppress brain tumor growth, migration, and angiogenesis. This study aims to investigate the effects of the bile acid nuclear receptor (farnesoid X receptor, FXR) agonist GW4064 on the migration, and invasion in GBM cells. GW4064 treatment inhibited the migration and invasion of GBM cells. The protein expression of phosphorylated focal adhesion kinase and protein kinase C alpha (PKCα) and activity of matrix metalloproteinase-2 (MMP2) were decreased by GW4064. The PKC activator phorbol 12-myristate 13-acetate (PMA) reversed the GW4064-reduced invasion ability in LN229 cells. Moreover, GW4064 combined with temozolomide (TMZ) treatment inhibited tumor progression in null mice. According to the hematoxylin and eosin stain (HE) and immunostaining, the tumor area and p-PKCα were reduced in the GW4064 combined with TMZ group. These results suggested that GW4064 declined the progression of GBM cells, with the inhibition of invasion mediated through PKC signaling. Targeting FXR may contribute to future therapeutic strategies for GBM.

Benign prostatic hyperplasia (BPH) is a widespread age-related health issue. Every year, new pathological cues are revealed in the pathogenesis of BPH, however, the role of serotonin, Janus tyrosine kinase (JAK)-2/ signal transducer and activator of the transcription (STAT)-3 and non-canonical nuclear factor-kappa B (NF-κB p52) pathways and their interaction with the androgen receptor (AR) in BPH are still not fully investigated. Accordingly, the aim of the current study was to unveil the possible modulatory effect of ondansetron alone and in combination with tamsulosin on these pathways and their utilization as therapeutic targets. Five groups of rats were utilized; group 1 received corn oil to serve as normal control, while the other groups administered testosterone (3 mg/kg, subcutaneously) dissolved in corn oil for 2 weeks followed by the co-administration of either tamsulosin (0.2 mg/kg, orally), ondansetron (2 mg/kg, intraperitoneally) or their combination for another 15 days along with testosterone injections. All treatments improved kidney function (creatinine and blood urea nitrogen), decreased oxidative stress (reduced glutathione and malondialdehyde), attenuated inflammation (NF-κB, cyclooxygenase-2), decreased AR expression, NF-κB p52, P-STAT3, transforming growth factor beta-1 in addition to markers of epithelial-mesenchymal transition (alpha smooth muscle actin and vimentin) this was associated with an increase in the prostatic content of serotonin, improvement in the histopathological picture and overall shrinkage in relative prostate weight. These results show that ondansetron is a very promising treatment for BPH especially in combination with tamsulosin and unveiled NF-κB p52 and serotonin as novel therapeutic targets in the management of BPH.

Dentin, a complex, living, and porous mineral substance, is produced by the mineralization of predentin, which is secreted by odontoblasts. This substance is crucial for maintaining the health of teeth. However, the specific function of the vitamin D receptor (Vdr) in the mineralization of odontoblasts, dentin homeostasis, and its interaction with Wnt signaling pathway during dentin apposition is not well understood. In this study, we employed Vdr transgenic knockout mice to study the dental effects and observed enlarged pulp cavities, diminished dentin, and increased predentin thickness in Vdr^-/- mice. We further reduced Vdr expression in odontoblasts and analyzed the changes in mineralization and Wnt signaling pathway. Our results showed decreased levels of mineralization and its markers Dspp, Alpl, Opn, Col-1, and Bsp in Vdr-knockdown odontoblasts. Additionally, the Wnt signaling pathway was downregulated, as indicated by lower levels of β-catenin, Lef1, and Axin2, and higher levels of Dkk1. We then attempted to rescue these effects by treating them with lithium chloride (LiCl) which activated the Wnt signaling pathway and appeared to restore the mineralization capacity of odontoblasts. Overall, our findings suggest that Vdr can mediate the Wnt signaling pathway to regulate odontoblasts differentiation during dentin apposition, presenting new potential approaches for improving dental health.

Cannabidiol (CBD) is one of the principal constituents of Cannabis Sativa with no psychoactive properties. CBD is a promising neuroprotective compound bearing anti-inflammatory and antioxidant properties. However, considering its low solubility, CBD delivery to the retina represents an unresolved issue. The first aim was to investigate the potential neuroprotective effects of CBD in an in vivo model of retinal excitotoxicity induced by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Rats underwent intravitreal co-injection of AMPA (42 nmol) and CBD (10^-4 M). The neuroprotective effect of CBD was investigated with histology and immunohistochemical evaluation of inflammatory and oxidative stress biomarkers. CBD reversed the AMPA-induced total retinal, inner nuclear layer and inner plexiform layer shrinkage and loss of amacrine cells. Moreover, CBD decreased the AMPA induced number of cleaved caspase-3, Iba-1 and nitrotyrosine (NT) positive cells. Based on this evidence, we developed a nanotechnological formulation of CBD to overcome critical issues related to its eye delivery. Particularly, nanostructured lipid carriers (NLC) loaded with CBD were prepared, optimized and characterized. Due to the optimal physicochemical characteristics, CBD-NLC3 has been selected and the in vitro release profile has been investigated. Additionally, CBD-NLC3 was topically administered to rats, and retinal CBD levels were determined. CBD-NLC3 formulation, after a single topical administration, efficiently delivered CBD in the retina (C_max= 98 ± 25.9 ng/mg; T_max = 60 minutes), showing a high translational value. In conclusion, these findings showed a good PD/PK profile of CBD warranting further pre-clinical and clinical evaluation of the new formulation for the treatment of retinal degenerative diseases.

Psoriasis, a chronic inflammatory skin disorder, is characterized by a complex interplay among immune cells. Although the specific mechanisms of platelet involvement in psoriasis are not fully elucidated, platelet activation is considered a major pathogenic factor. In this study, we investigated the role of Cathelicidin-HG (Cath-HG), a peptide derived from Hylarana guentheri skin that exhibits potent inhibitory activity against platelet glycoprotein VI (GPVI), in an imiquimod-induced psoriasis mouse model. Our experimental findings demonstrated that Cath-HG significantly alleviates psoriasis symptoms, reduces platelet-neutrophil complexes (PNCs) formation, and attenuates neutrophil activation at lesion sites. In vitro studies confirmed that Cath-HG inhibits collagen-induced platelet activation via GPVI, thereby disrupting PNCs formation and suppressing subsequent inflammatory responses. These findings not only establish GPVI as a key regulator of PNC-mediated inflammation in psoriasis but also identify Cath-HG as a promising therapeutic candidate. This study provides a novel mechanistic insight into platelet-neutrophil interactions in psoriasis and highlights the potential of GPVI as a therapeutic target for innovative psoriasis treatments.