European journal of pharmacology最新文献

Several studies have associated the epitranscriptomic RNA modification of N6-methyladenosine (m⁶A) with cardiovascular diseases; however, how m⁶A modification affects cardiomyocyte pyroptosis after myocardial infarction (MI) remains unknown. Here, we showed that AlkB homolog 5 (ALKBH5), an m⁶A demethylase, is crucial in cardiomyocyte pyroptosis after MI. We used MI rat and mouse models, a cell hypoxia model of rat primary cardiomyocytes (RCMs), and rat embryonic ventricle cell line (H9c2) to explore the functional role of m⁶A modification and ALKBH5 in the heart and cardiomyocytes. Using plasmids and small interfering RNAs, the expressions of ALKBH5 and NOD-like receptor family pyrin domain-containing 3 (NLRP3) were determined to study their functions in regulating cardiomyocyte m⁶A and pyroptosis, respectively. We characterized the role of ALKBH5, which exhibited elevated expression in the ischemic heart tissue of rats and mice and hypoxic cardiomyocytes (RCMs and H9c2 cells). ALKBH5 knockdown alleviated hypoxia-induced H9c2 cell pyroptosis by inhibiting NLRP3 inflammasome activation, whereas ALKBH5 overexpression had the opposite effect. NLRP3 knockdown alleviated hypoxia-induced H9c2 cardiomyocyte pyroptosis by inhibiting ALKBH5 expression, whereas NLRP3 overexpression had the opposite effect. Mechanistically, ALKBH5 mediated m⁶A modification of NLRP3 mRNA in an IGF2BP2-dependent manner, and NLRP3, as a nuclear transcription factor, regulated the ALKBH5 transcription process. Targeting the ALKBH5-NLRP3 loop with the small-molecule inhibitors alleviated cardiomyocyte pyroptosis. Our results highlight that ALKBH5-NLRP3 forms a positive feedback loop that promotes cardiomyocyte pyroptosis after MI. Therefore, inhibiting the ALKBH5-NLRP3 loop is a potential strategy for treating cardiovascular diseases.

Acne is a prevalent and chronic inflammatory skin disease, and its treatment remains a huge clinical challenge. In the present study, we evaluated the therapeutic potential of combining the peptides RL-QN15 and OH-CATH30 for the treatment of acne in mice. Results indicated that the topical application of RL-QN15 and OH-CATH30 significantly inhibited the proliferation of Propionibacterium acnes (P. acnes) and alleviated acne-induced edema. Furthermore, the combined treatment suppressed the overexpression of proinflammatory cytokines induced by P. acnes, including interleukin -1 beta (IL-1β), interleukin -6 (IL-6), interleukin -8 (IL-8), tumor necrosis factor-alpha (TNF-α) induced by P. acnes and facilitated collagen deposition, thereby effectively mitigating skin damage associated with acne. Mechanistically, the combination of RL-QN15 and OH-CATH30 inhibited the expression of toll-like receptor 2 (TLR2) and activation nuclear factor kappa-B (NF-κB) signaling pathway (phosphorylation of P65 and IκB) in both mice and RAW 264.7 cells. These results suggested that this combination may inhibit the excretion of inflammatory factors and facilitate the collagen deposition by TLR2/NF-κB signaling. Overall, our study demonstrates the potent therapeutic effects of the combined application of RL-QN15 and OH-CATH30, highlights the TLR2/NF-κB pathway as a key target in acne treatment, and provides a novel strategy for developing innovative acne therapeutics.

Oral squamous cell carcinoma (OSCC) remains a major cause of morbidity and mortality worldwide with high recurrence rates and resistance to conventional therapies. Recent studies have highlighted the pivotal role of oral cancer stem cells (OCSCs) in driving treatment resistance and tumor recurrence. OCSCs possess unique properties, including self-renewal, differentiation potential, and resistance to chemotherapy and radiotherapy, which contribute to their ability to survive treatment and initiate tumor relapse. Several signaling pathways, such as Wnt/β-catenin, Hedgehog, Notch, and PI3K/Akt/mTOR, have been implicated in maintaining OCSC properties, promoting survival, and conferring resistance. Additionally, mechanisms such as drug efflux, enhanced DNA repair, epithelial-mesenchymal transition (EMT), and resistance to apoptosis further contribute to resilience. Targeting these pathways offers promising therapeutic strategies for eliminating OCSCs and improving treatment outcomes. Approaches such as immunotherapy, nanotechnology-based drug delivery, and targeting of the tumor microenvironment are emerging as potential solutions to overcome OCSC-mediated resistance. However, further research is needed to fully understand the molecular mechanisms governing OCSCs and develop effective therapies to prevent tumor recurrence. This review discusses the role of OCSCs in treatment resistance and recurrence and highlights the current and future directions for targeting these cells in OSCC.

The study investigated the anxiolytic, antidepressant, sedative/hypnotic and in silico molecular docking properties of the synthetic ephedrine-based derivative of thiourea, 3-benzothioyl-1-(3-hydroxy-3-phenyl-3-propyl)-1-methylthiourea. Safety profile of the compound at various doses was determined in an acute toxicity test. Results showed significant anti-anxiety effects of the compound in all mice studies. In the elevated plus maze (EPM), the time spent and entries into open arms were significantly increased upon treatment with the test compound. In the light-dark (LD) box test the drug increased the time spent in the light compartment. In hole board (HB) assay, exploration of hole and rearing significantly increased. For anxiolytic activity, 20 mg/kg was determined to represent the optimal dose, while at a higher dose (i.e., 40 mg/kg), it caused significant sedation and increased sleep duration in thiopental-induced sleep test. Escape latency in the tail suspension test (TST) and in the forced swim test (FST) increased and immobility was significantly reduced upon 3-benzothioyl-1-(3-hydroxy-3-phenyl-3-propyl)-1-methylthiourea administration. The molecular docking analysis was performed against the various protein target involved in the pathogenesis of anxiety. The molecular docking, molecular dynamic (MD) simulation and free energy calculation showed high binding affinity and stability of ligand with the 7VOD and 2C65 protein. Taken together, it is concluded from both the in vivo assays and molecular modeling studies that 3-benzothioyl-1-(3-hydroxy-3-phenyl-3-propyl)-1-methylthiourea possesses significant anxiolytic and antidepressant activity in concomitant with a high safety profile.

Purpose: Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly individuals. Retinal pigment epithelium (RPE) ferroptosis is a significant pathogenetic component in AMD. This study aims to elucidate the role and mechanisms of fatty acid desaturase 1 (FADS1) in ferroptosis as well as AMD progression.

Methods: An integrated bioinformatics analysis based on the array of data from the GEO database was conducted to identify candidates involved in ferroptosis during AMD. Subsequently, cellular and mouse models of AMD were developed using sodium iodate (NaIO₃) to confirm the altered expression of FADS1. After treatment with a FADS1 inhibitor, cell survival, lipid peroxidation, and indicators of AMD were assessed in vitro and in vivo models. Further, immunofluorescence, immunohistochemistry, and swept-source OCT imaging were performed to assess the impacts of pharmacological inhibition of transcription factor specificity protein 1 (Sp1) on FADS1 and ferroptosis.

Results: FADS1 expression was upregulated in AMD patients and in vitro and in vivo models of AMD. Its pharmacological inhibition had decreased mitochondrial ROS formation, lipid peroxidation, and ferroptosis as well as increased RPE cell function in ARPE-19 cells and C57BL/6J mouse models of AMD. Mechanistically, Sp1 was identified as a key transcription factor of FADS1. Moreover, Sp1 inhibition downregulated FADS1 expression consequently attenuating FADS1-mediated ferroptosis as well as AMD phenotypes.

Conclusion: For the first time, we demonstrated that Sp1 regulates FADS1-mediated ferroptosis in RPE cells. Our findings provide novel insights into the progression and treatment of AMD.

Exosomes, cell-derived vesicles produced by cells, are fascinating and drawing growing interest in biomedical exploration due to their exceptional properties. There is intriguing evidence that exosomes are involved in major biological processes, including diseases and regeneration. Exosomes from mesenchymal stem cells (MSCs) have shown promising outcomes in regenerative medicine. Numerous studies suggest that exosomes have several advantages over conventional synthetic nanocarriers, opening novel frontiers for innovative drug delivery. Regenerative medicine has demonstrated the profound therapeutic outcomes of engineered or loaded exosomes from MSCs. Different methods are being used to modify or/load exosomes. These exosomes can improve cell signaling pathways for bone and cartilage diseases, liver diseases, nerve tissues, kidney diseases, skin tissue, and cardiovascular diseases. Despite extensive research, clinical translation of these exosomes remains a challenge. The optimization of cargo loading methods, efficiency, physiological stability, and the isolation and characterization of exosomes present some challenges. The upcoming examination should include the development of large-scale, quality-controllable production approaches, the modification of drug loading approaches, and numerous in vivo investigations and clinical trials. Here, we provided an informative overview of the extracellular vesicles and modification/loading methods of exosomes. We discuss the last exosome research on regeneration disorders, highlighting the therapeutic applications of MSCs-derived exosomes. We also highlight future directions and challenges, underscoring the significance of addressing the main questions in the field.

Obesity due to excessive body fat accumulation remains a global problem. Patients with obesity have high cortisol levels, and its dysregulation is caused by increased 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) levels. The effects and mechanism of J2H-1702, an 11β-HSD1 inhibitor, on nonalcoholic steatohepatitis (NASH) were explored. This study compared the antiadipogenic effects of J2H-1702, elafibranor (PPARα/δ agonist), and BVT14225 (selective 11β-HSD1 inhibitor) using mouse 3T3-L1 pre-adipocytes. J2H-1702, elafibranor, and BVT14225 inhibited adipocyte differentiation and intracellular lipid accumulation in 3T3-L1 cells by downregulating phospho-extracellular signal-regulated kinase, extracellular signal-regulated kinase, phospho-c-Jun-N-terminal Kinase, c-Jun-N-terminal Kinase, phospho-P38 (P-P38), P38, CCAAT/enhancer-binding proteins alpha and β, peroxisome proliferator-activated receptor γ, and glucocorticoid receptor. Additionally, J2H-1702, elafibranor, and BVT14225 treatments effectively inhibited 11β-HSD1 activity, as revealed by cortisol concentrations, and inhibited cortisone-induced adipocyte differentiation and intracellular lipid accumulation in 3T3-L1 cells. These effects were associated with 11β-HSD1 protein inhibition. Furthermore, J2H-1702 and BVT14225 increased the expression of Akt and phosphoinositide 3-kinase involved in insulin resistance in 3T3L-1 adipocytes. In the LX-2 human hepatic stellate cell line, the relative expression of N-cadherin, 11β-HSD1, collagen1α (COLA1), α-actin of smooth muscle (α-SMA) genes in LX-2 activated with TGF-β increased significantly, and after treatment with J2H-1702, it was significantly reduced. The expression of E-cadherin is decreased in TGF-β-treated LX-2 cells and increased after treatment with J2H-1702. We tested the potential of J2H-1702 as a therapeutic agent for NASH using a high-fat diet-induced NASH model, with obeticholic acid, an FXR agonist, and elafibranor as reference drugs. All drugs significantly decreased the elevated triglyceride levels in the livers of high-fat, high-carbohydrate (HFHC-fed mice. The results may add to the benefits of targeting 11β-HSD1 inhibitors with antiadipogenic activity in developing a therapeutic agent for obesity treatment.

Background: The Dutch National Pharmacotherapy Assessment (DNPA), which focuses on assessing medication safety and essential drug knowledge, was introduced to improve clinical pharmacology and therapeutics education in the Netherlands. This study investigated how the performance of final-year medical students on the DPNA was affected by the assessment programme (traditional with summative or formative assessment, and programmatic assessment).

Methods: This multicentre retrospective longitudinal observation study (2019-2023) involved final-year medical students from four medical schools in the Netherlands. The DNPA was used in different ways - either as a summative or formative assessment in a traditional assessment programme or as a non-high-stakes assessment in a programmatic assessment programme. Three medical schools changed from assessment programme over time.

Results: This study involved 1894 students. Summative assessment resulted in significantly higher scores and pass rates than formative assessment in a traditional assessment programme (mean score of 84.3% vs. 67.5%, and pass rate of 60.4% vs. 5.9%). In contrast, slightly lower scores were obtained when the assessment was non-high-stakes as part of a programmatic assessment programme rather than a summative assessment in a traditional assessment programme (mean score of 81.% vs. 84.3%, pass rate of 51.8% vs. 60.4%). In curricula where the assessment became summative instead of formative, scores and pass rates significantly improved (mean increase of +14.4% and 42.3%, respectively), when the assessment programme changed from traditional with summative assessment to programmatic with non-high-stakes assessment, scores and pass rates modestly decreased (decrease of 3.3% and 14.2%, respectively).

Conclusion: Integrating the DNPA within a traditional assessment programme is most effective when assessed summatively, as it results in significantly higher scores compared to formative assessment. In the context of a programmatic assessment programme, the scores may be slightly lower. Changing assessment programmes within a medical school influences DNPA scores. Scores increase when the assessment is summative rather than formative within a traditional assessment programme. Conversely, scores mildly decrease when the assessment programme shifts from traditional with summative assessment to non-high-stakes programmatic assessment.

Background: Despite increasing studies underscoring the effectiveness of new media teaching strategies in pharmacology education, the influence of different educational backgrounds is still unclear. We aimed to evaluate the efficacy of new media teaching under various educational backgrounds in pharmacology education using network meta-analysis.

Methods: Literature databases were searched from their inception to February 28, 2024 for eligible trials. Educational backgrounds included 3 majors (pharmacy, medicine, and nursing) and 3 degrees (junior college, undergraduate, and graduate). Academic performance, comprehensive competency, and satisfaction were analyzed using Stata (version 17), Review Manager 5.3 software (RevMan 5.3), and R software (version 4.3.1).

Results: A total of 46 studies involving 6447 students were included. The surface under the cumulative ranking curve (SUCRA) indicated that compared to other majors, new media teaching among nursing students was the most effective in improving theoretical scores (88.63%), experimental scores (93.28%), learning interest (88.27%), self-learning ability (91.17%), mastery of knowledge (96.81%), and the proportion of satisfaction (97.30%) in pharmacology education. As for degrees, new media teaching among junior college students had the best effect on enhancing theoretical scores (75.60%), experimental scores (86.23%), pass rates (88.33%), self-learning ability (90.36%), mastery of knowledge (97.73%), and the proportion of satisfaction (85.28%) in pharmacology learning.

Conclusion: Overall, new media teaching among nursing students or junior college students appears to be more effective in pharmacology education. Thus pedagogues can better implement new media teaching strategies among these students and incorporate more web-based tools.