European journal of pharmacology最新文献

Background: The treatment of ulcerative colitis (UC) remains a huge challenge worldwide. Dictamnine is a natural product derived from Dictamnus dasycarpus Turcz. root bark and possesses multi-pharmacological properties, including anti-inflammation effects. However, its protective effect on UC and its underlying mechanisms are unknown.

Purpose: Here we explored the protective effect and underlying mechanism of dictamnine against dextran sulfate sodium (DSS)-induced colitis in mice.

Methods: The experimental colitis was established by adding 3% DSS on drinking water of mice and the effects of dictamnine (10, 20, 40 mg/kg, p.o, once a day by 10 days) in colon tissues was analyzed. NCM460 cell was induced by RSL3 to detect the effect of dictamnine on ferroptosis and the underlying mechanism. Pathological damage was determined by H&E. Indicators related to intestinal permeability were detected by FITC and immunofluorescence. Cytokines levels (TNF-α、IL-1β and IL-6) , antioxidant enzymes activities (MDA and GSH), the level of Fe²⁺ Cytokines levels and Gpx4 activity were detected by ELISA. Finally, the activation of nuclear factor erythroid 2-like 2 (Nrf2) was detected to explore the mechanism.

Results: The results indicated that dictamnine significantly attenuated DSS-induced colon pathological damage, intestinal barrier, cytokines levels, and increased the antioxidant enzymes activities. Moreover, dictamnine attenuated ferroptosis in DSS-induced colon injury and upregulated Gpx4 expression in DSS-induced mice. Mechanistic experiments revealed that dictamnine activated Nrf2 in mice.

Conclusion: Taken together, this study evaluates that dictamnine alleviates DSS-induced colitis mice by inhibiting ferroptosis of enterocytes and its protective effects are associated with activating the Nrf2-Gpx4 signaling pathway.

In previous studies, polymyxin MRX-8 demonstrated potent in vitro antibacterial activity with a reduced nephrotoxicity risk and an improved PK/PD profile compared with polymyxin B. In this study, the in vivo antibacterial efficacy of intravenously administered MRX-8 was evaluated in murine models of systemic infection (induced by intraperitoneal injection), lung infection (induced by intratracheal route inoculation), and ascending urinary tract infection (induced by intraurethral inoculation) with P. aeruginosa, K. pneumoniae, E. coli, and A. baumannii as the challenging pathogens. MRX-8 demonstrated superiority to polymyxin B against carbapenem-resistant K. pneumoniae, P. aeruginosa and E. coli infections; however, the efficacy of MRX-8 was less than or comparable with that of polymyxin B against carbapenem-resistant A. baumannii infections. The results suggest MRX-8 could be an efficacious treatment alternative versus Gram-negative, treatment-resistant pathogens that can confound current antimicrobial agents.

Introduction: & Aim: Novel treatments for idiopathic pulmonary fibrosis (IPF) are needed urgently. A better understanding of the molecular pathways activated by TGFβ1 in human lung tissue may facilitate the development of more effective anti-fibrotic medications. This study utilized proteomic analysis to test the hypothesis that TGFβ1 induces pro-fibrotic effects on human lung parenchyma proteome, and to evaluate the viability of this model for testing novel therapeutic targets.

Methods: Non-fibrotic human lung parenchymal tissue from 11 patients was cultured for 7 days in serum-free (SF) media supplemented with TGFβ1 (10 ng/mL) or vehicle control, and the putative antifibrotic K_Ca3.1 ion channel blocker senicapoc or vehicle control. The tissue was homogenized, digested for bottom-up proteomics, and analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Principal component analysis, differential expression analysis, pathway analysis, and drug repurposing analysis were performed.

Results: TGFβ1 stimulation for 7 days induced a strong fibrotic protein response relevant to IPF pathology. A total of 2,391 proteins were quantified, 306 upregulated and 285 downregulated (FDR-adjusted p-value<0.05). Of these, 118 were upregulated and 28 downregulated at log₂(FC)>0.58. These changes were attenuated by senicapoc (100 nM). Drug repurposing analysis identified 265 drugs predicted to inhibit the effects of TGFβ1 in this model. These included clotrimazole, a K_Ca3.1 blocker, and nintedanib, a drug licenced for the treatment of IPF, providing validation of this approach.

Conclusion: A pro-fibrotic proteome is induced in human lung parenchyma exposed to TGFβ1, sensitive to pharmacological intervention. This approach has the potential to enhance therapeutic drug screening for IPF treatment.

N-methyl-D-aspartate receptors (NMDARs) are involved in the pathophysiology of depression and are inhibited by many antidepressants. In this work, we studied the action of the vortioxetine, a relatively new multitarget antidepressant, on native NMDARs in rat hippocampal CA1 pyramidal neurons and compared it to the action of structurally similar antidepressant fluoxetine. Vortioxetine inhibited these receptors with IC₅₀ value of 11±1 μM at -80 mV holding voltage, being about three-fold more potent than fluoxetine in these conditions. The inhibition by both compounds was not competitive. Both vortioxetine and fluoxetine demonstrated complex voltage dependence with voltage-dependent and voltage-independent components. The voltage-dependent component corresponded to trapping channel block, while the voltage-independent component - to allosteric inhibition. Vortioxetine and fluoxetine were able to inhibit both open and closed NMDAR channels. Thus, NMDARs can be among important targets for vortioxetine or structurally related drugs. In addition, structural similarity of vortioxetine and fluoxetine allows to assume that these compounds may share other molecular targets besides serotonin transporter and NMDARs.

Senescence, defined by the cessation of cell proliferation, plays a critical and multifaceted role in breast cancer progression and treatment. Senescent cells produce senescence-associated secretory phenotypes (SASP) comprising inflammatory cytokines, chemokines, and small molecules, which actively shape the tumor microenvironment, influencing cancer development, progression, and metastasis. This review provides a comprehensive analysis of the types and origins of senescent cells in breast cancer, alongside their markers and detection methods. Special focus is placed on pharmacological strategies targeting senescence, including drugs that induce or inhibit senescence, their molecular mechanisms, and their roles in therapeutic outcomes when combined with chemotherapy and radiotherapy. By exploring these pharmacological interventions and their impact on breast cancer treatment, this review underscores the potential of senescence-targeting therapies to revolutionize breast cancer management.

Objective: To compare the effects of deinorgestrel and Guizhi Fuling Capsules on ovarian function, inflammatory variables, and the rate of conception in clients receiving endometriosis treatment.

Methods: Ninety endometriosis patients were divided into the control and test groups. Patients in the control group received oral treatment with Guizhi Fuling Capsules, and those in the test group received oral treatment with Deinorgestrel Tablets.

Results: Compared with the control group, the overall effective therapy rate in the test group was significantly increased. Following the intervention, the test group experienced a considerably larger decrease in interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels than the control group. The visual analog scale (VAS ) values for dysmenorrhea, dyspareunia, and non-menstrual lower abdomen discomfort were all considerably lower after therapy than those before therapy. In comparison to the control group, the VAS grades for dysmenorrhea, non-menstrual lower abdomen pain, and sexual intercourse discomfort showed a substantial increase in the test group. Compared with the control group, the 1-year cumulative pregnancy rate in the test group was significant increase in the test group (42.22% (19/45) vs. 64.44% (29/45)).

Conclusion: Denogestone significantly alleviates clinical symptoms and body's inflammatory state of Endometriosis patients, without ovarian function damage.

Objective: PRIS has been documented in epilepsy patients treated with propofol. But the clinical features associated with the occurrence of PRIS in patients with epilepsy remain incompletely elucidated. This study aimed to investigate the relationship between epilepsy, antiepileptic drugs, and PRIS and draw conclusions about its clinical features.

Methods: Extracted PRIS reports documented in the FAERS (January 2013 to December 2023). Epilepsy patients and non-epilepsy patients were distinguished based on the indication information. We performed multivariate analyses for demography, epilepsy status, and the use of antiepileptic drugs between these two populations. Additionally, we collected all published reports on propofol usage that resulted in PRIS. We focused on the differences in clinical manifestations of PRIS between epilepsy patients and non-epilepsy patients and analyzed them retrospectively.

Results: For 349 PRIS cases in the FAERS database, 94 cases involved epilepsy. Epilepsy was a significant risk factor for PRIS development (ROR = 3.89) and death outcomes (ROR = 1.997). Further analysis of antiepileptic drug regimens revealed that valproic acid was associated with an increased risk of PRIS (ROR = 3.264) and adverse outcomes (ROR = 2.518). For 185 PRIS cases in this review, 49 demonstrated a history of epilepsy. Patients with epilepsy displayed a lower median infusion rate of propofol than those without but a higher median cumulative dose.

Conclusion: When using propofol, epilepsy patients are at high risk of PRIS and are vulnerable to death. Therefore, patients with epilepsy must be closely monitored for safety during treatment, especially when they using valproic acid.