Eur. J. Pharmacol. [JOURNAL]
Sun
200 papers
Novel gastroprotective role of Alogliptin: Modulating the GDNF/PI3K/Akt/GSK3β, SDF-1/CXCR4, and CREB/COX-2/PGE2 signalling pathways to ameliorate diclofenac-induced peptic ulcer in rats.
Ghoneim ME, Noureldin MH, El Sayed I … +2 more , El Banna YY, El Sayed NF
Eur J Pharmacol · 2026 Jul · PMID 42217721 · Publisher ↗
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain and inflammation, yet their clinical utility is limited by their propensity to induce gastric injury. Alogliptin, a dipeptidyl peptidase-4 inhibitor,...
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain and inflammation, yet their clinical utility is limited by their propensity to induce gastric injury. Alogliptin, a dipeptidyl peptidase-4 inhibitor, exerts pleiotropic effects beyond glucagon-like peptide-1 enhancement, including preservation of stromal cell-derived factor-1 (SDF-1) from degradation, and modulation of glial cell-derived neurotrophic factor (GDNF), a key mediator of gastrointestinal barrier integrity. However, its protective role against NSAID-induced gastric injury has not yet been investigated. Therefore, this study aimed to evaluate the gastroprotective effect of alogliptin against diclofenac-induced gastric ulcer, with emphasis on mucosal repair pathways, oxidative stress, inflammation, and apoptosis. Rats were randomly allocated into four groups: a control group receiving saline for 14 days; Diclofenac group administered diclofenac (50 mg/kg/day, i.p., days 8-14) to induce gastric ulceration; and two pretreatment groups receiving either omeprazole (20 mg/kg/day, p.o.) or alogliptin (40 mg/kg/day, p.o.) for 14 days, concomitantly with diclofenac administration during days 8-14. Alogliptin significantly reduced the ulcer index and preserved gastric mucosal architecture, surpassing omeprazole across most evaluated parameters. Mechanistically, alogliptin restored GDNF/PI3K/Akt signaling, enhanced p-GSK3β/p-CREB, increased COX-2/PGE2 expression, and reestablished SDF-1/CXCR4, collectively supporting mucosal regeneration. Furthermore, Alogliptin suppressed NF-κB/TNF-α-driven inflammation, mitigated oxidative stress, as evidenced by decreased MDA and increased SOD activity, and shifted the apoptotic balance toward cell survival by reducing Bax and elevating Bcl-2 levels. Ultimately, alogliptin exerts multifaceted gastroprotective effects against diclofenac-induced gastric ulcer by enhancing mucosal defense and orchestrating anti-inflammatory, antioxidant, and anti-apoptotic mechanisms through interplay between GDNF/PI3K/Akt, CREB/COX-2/PGE2, and SDF-1/CXCR4 trajectories.
P-glycoprotein-mediated efflux of rapaprotin-L dictates sensitivity of cancer cells to the inducer of 26S proteasome disassembly.
Zhang Q, Asbell T, Rao AVS … +8 more , Pasunooti KK, Zhang J, Shi M, Domae AF, Rees MG, Roth JA, Mao Y, Liu JO
Eur J Pharmacol · 2026 May · PMID 42217720 · Publisher ↗
The 26S proteasome is an essential regulator of protein homeostasis and a clinically validated therapeutic target in multiple myeloma (MM). Rapaprotin, a novel macrocycle identified from a rapamycin-inspired rapafucin li...
The 26S proteasome is an essential regulator of protein homeostasis and a clinically validated therapeutic target in multiple myeloma (MM). Rapaprotin, a novel macrocycle identified from a rapamycin-inspired rapafucin library, disrupts 26S proteasome function by inducing disassembly of the 19S regulatory particle in the 26S proteasome, leading to apoptosis in MM cells. Its bioactivation requires prolyl endopeptidase (PREP)-mediated cleavage to generate Rapaprotin-L, a negatively charged, linear metabolite with potent proteasome-disassembly activity. Using the PRISM cancer cell line profiling platform, we identified high P-glycoprotein (P-gp/ABCB1) expression as a major determinant of Rapaprotin resistance in solid tumor cell lines. Efflux assays confirmed Rapaprotin-L, but not its parent Rapaprotin, as a high-efficiency P-gp substrate. Co-treatment with the third-generation P-gp inhibitor tariquidar restored the intracellular accumulation of Rapaprotin-L, reinstating proteasome inhibition and consequent apoptosis in Rapaprotin-resistant colorectal cancer cell lines. Strong synergy between Rapaprotin and tariquidar was observed in a 3D spheroid model. These results establish P-gp as a key mediator of resistance to Rapaprotin and identify a rare example of a negatively charged Rapaprotin-L as a P-gp substrate. Together, these findings expand the potential therapeutic scope of Rapaprotin beyond hematologic malignancies to a broader range of solid tumors.
Deoxyelephantopin, a natural sesquiterpene lactone, suppresses IL-2 production of ConA-activated T lymphocytes through inhibiting NF-κB and calcineurin/NFAT signaling.
Cai M, Qi R, Wang M … +7 more , Wu C, Chen Q, Guo Y, Liu Y, Huang X, Gao Y, Qi Y
Eur J Pharmacol · 2026 Jul · PMID 42217719 · Publisher ↗
Deoxyelephantopin (DET) is a sesquiterpene lactone isolated from Elephantopus scaber, a traditional medicinal plant valued for its heat-clearing and detoxifying properties. As one of the major bioactive components, DET e...
Deoxyelephantopin (DET) is a sesquiterpene lactone isolated from Elephantopus scaber, a traditional medicinal plant valued for its heat-clearing and detoxifying properties. As one of the major bioactive components, DET exhibits a variety of pharmacological activities, such as antitumor, antimicrobial, and anti-inflammatory effects. Nevertheless, its effect on T cell activation remains underexplored. Our study indicated that DET suppressed the proliferation and interleukin-2 (IL-2) production in T cells activated by various stimuli for T cell receptor (TCR)/CD3 signaling (i.e., concanavalin A (ConA), anti-CD3 antibody, and allogeneic major histocompatibility complex (MHC)). Mechanistically, DET lowered IL-2 mRNA level without affecting its stability in ConA-activated Jurkat T cells. Among three nuclear transcriptional pathways (mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), nuclear factor of activated T cells (NFAT)) triggered by ConA, DET did not suppress MAPK signaling, but significantly inhibited NF-κB activation by hindering inhibitor of kappa-B alpha (IκBα) phosphorylation and degradation, thereby preventing p65 nuclear translocation. Concurrently, DET could dampen the activation of NFAT signaling through inhibiting the activity of calcineurin (CaN) to impede NFAT nuclear translocation independent of decreasing cytoplasmic Ca (Ca). Unlike classical CaN inhibitors (CNIs), DET inhibits CaN activity without involving immunophilins. In vivo, DET could also reduce serum IL-2 level in acute T-cell activation mouse model induced by intravenous injection of anti-CD3 antibody. In conclusion, our findings reveal DET's dual mechanisms (NF-κB and NFAT inhibition) responsible for repressing IL-2 expression in the activated T cells, which may provide a promising candidate for the development of a novel IL-2 suppressive agent.
Relationship between β-arrestin1-GAPDH interaction and the DADLE-mediated protection of brain microvascular endothelial cells from hypoxia-ischemic/reperfusion injury.
Zhang R, Deng Z, Chen X … +5 more , Gao J, Zhu Y, Kong L, Shen B, Zhang L
Eur J Pharmacol · 2026 Jul · PMID 42217718 · Publisher ↗
Cerebral stroke has a high mortality rate primarily driven by the pathophysiological processes of ischemia-reperfusion (I/R) injury. [D-Ala, D-Leu]-enkephalin (DADLE), the agonist of δ receptor, has raised interest as a...
Cerebral stroke has a high mortality rate primarily driven by the pathophysiological processes of ischemia-reperfusion (I/R) injury. [D-Ala, D-Leu]-enkephalin (DADLE), the agonist of δ receptor, has raised interest as a tissue-protective agent for its ability to improve I/R injury, although its specific mechanism remains unclear. In this study, middle cerebral artery occlusion/reperfusion (MCAO/R) was induced in rats, while oxygen-glucose deprivation/reoxygenation (OGD/R) was applied to brain microvascular endothelial cells (BMECs). The effect of DADLE effect on autophagy regulation was assessed, and the interaction between β-arrestin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified. DADLE elevated autophagy levels in both in vivo and in vitro I/R models and improve BMEC viability under I/R conditions. After I/R injury, β-arrestin-GAPDH interaction tended to increase; however, DADLE treatment released GAPDH that was bound to β-arrestins. Simultaneously, DADLE reversed GAPDH activity caused by I/R injury. Quantitative real-time PCR detection revealed that, BMECs dominantly express a subtype of β-arrestin, β-arrestin1, which is necessary for DADLE-dependent cellular autophagy level and GAPDH activity enhancement. Therefore, this study provides evidence that DADLE may serve as a potential anti-ischemic stroke therapeutic agent.
SGLT2 inhibitors ameliorate myocardial hypertrophy in rats via AMPK/Nrf2-mediated ferroptosis suppression and antioxidant response.
Wang J, Zhang WQ, Zhang LL … +1 more , Shi HT
Eur J Pharmacol · 2026 Jul · PMID 42214780 · Publisher ↗
This study investigated whether dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, alleviates myocardial hypertrophy by modulating the AMP-activated protein kinase (AMPK)/nuclear factor E2-related factor 2 (Nrf2)...
This study investigated whether dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, alleviates myocardial hypertrophy by modulating the AMP-activated protein kinase (AMPK)/nuclear factor E2-related factor 2 (Nrf2) signaling pathway, thereby reducing oxidative stress and ferroptosis. A rat model of myocardial hypertrophy was created using abdominal aortic stenosis. Rats were divided into blank, sham, surgery (Abdominal Aortic Coarctation, AAC), and dapagliflozin-treated groups (n = 4), with evaluations at 2, 4, 8, and 12 weeks post-surgery. In vitro, an isoproterenol-induced hypertrophic model in H9C2 cardiomyocytes was used, involving control, ISO, dapagliflozin intervention, and separate or combined intervention groups with AMPK and Nrf2 inhibitors. Dapagliflozin treatment significantly improved cardiac function in pressure-overloaded rats, reduced myocardial hypertrophy and fibrosis, and lowered myocardial hypertrophy marker expression. It also enhanced superoxide dismutase activity, decreased malondialdehyde levels and myocardial iron deposition, and improved mitochondrial ultrastructural integrity, indicative of reduced ferroptosis. Mechanistic studies showed that dapagliflozin activates AMPK phosphorylation, promotes Nrf2 nuclear translocation, and upregulates downstream proteins. This protective effect was nullified when either AMPK or Nrf2 was specifically inhibited. Further, changes in expression levels following separate inhibition of AMPK and Nrf2 confirmed AMPK's regulatory role over Nrf2. In conclusion, dapagliflozin mitigates stress-induced myocardial hypertrophy by activating the AMPK/Nrf2 signaling pathway at least in the early stages, boosting myocardial antioxidant defence, and inhibiting ferroptosis. This study identifies the AMPK/Nrf2 pathway as a crucial mechanism in dapagliflozin's cardiovascular protective effects.
Targeting antioxidant mechanisms in myocardial ischemia-reperfusion injury: A review of therapeutic strategies and clinical progress.
Wang J, Li H, Shao Q … +7 more , Zhao Y, Yang X, Fan M, Gan H, Tang Q, Jiang S, Xie J
Eur J Pharmacol · 2026 Jul · PMID 42214779 · Publisher ↗
Myocardial ischemia-reperfusion injury (MIRI) is a secondary injury that occurs upon the restoration of blood flow to ischemic myocardium, significantly diminishing the clinical benefits of reperfusion therapy. Excessive...
Myocardial ischemia-reperfusion injury (MIRI) is a secondary injury that occurs upon the restoration of blood flow to ischemic myocardium, significantly diminishing the clinical benefits of reperfusion therapy. Excessive production of reactive oxygen species (ROS) and subsequent oxidative stress are recognized as central pathological mechanisms underlying MIRI, making antioxidant intervention a key therapeutic strategy. In recent years, significant progress has been made in the development of antioxidant agents targeting ROS scavenging and the modulation of oxidative stress. This review systematically summarizes recent advancements in MIRI interventions based on antioxidant mechanisms, including strategies for direct ROS elimination and the activation of endogenous antioxidant pathways. Through integrated target prediction and network analysis, the molecular basis and interactions of various antioxidant strategies are elucidated, highlighting compounds such as Honokiol as critical nodes within the intervention network. Additionally, utilizing the National Center for Biotechnology Information (NCBI) database, this work compiles and discusses the clinical progress of related antioxidant drugs in myocardial protection, offering a comprehensive overview and future perspectives. Ultimately, this review provides valuable insights for the future development of effective and low-toxicity antioxidant-based therapies for MIRI.
Effects of obacunone against myocardial fibrosis: Mechanistic insights from network pharmacology and experimental validation.
Liang G, Lin Y, Li L … +2 more , Cai J, Liu X
Eur J Pharmacol · 2026 Jul · PMID 42214778 · Publisher ↗
Myocardial fibrosis (MF), a common pathological consequence of cardiovascular diseases, compromises cardiac function and elevates the risk of heart failure and arrhythmias. Considering the limited therapeutic options, th...
Myocardial fibrosis (MF), a common pathological consequence of cardiovascular diseases, compromises cardiac function and elevates the risk of heart failure and arrhythmias. Considering the limited therapeutic options, this study explored the antifibrotic potential of Obacunone (OB), focusing on its links to lipid metabolism pathways. Potential OB targets, MF-associated genes, and lipid metabolism-related genes were curated from databases and literature. Transcriptomic datasets were analyzed to identify differentially expressed genes (DEGs) in MF, and lipid metabolism-related DEGs (LMDEGs) were subsequently intersected with these target sets to identify OB-associated targets. These core targets were further investigated via protein-protein interaction (PPI) network, consensus clustering, functional enrichment, and molecular docking analysis. Key findings were validated via western blotting. Intersection analysis identified ten LMDEGs associated with OB. Moreover, PPI network analysis highlighted a subnetwork of seven strongly interacting targets-CYP19A1, STAT3, LGALS3, PDGFRA, SCN5A, SLC9A1, and SERPINE1. Functional enrichment indicated OB's involvement in the epidermal growth factor receptor (EGFR), advanced glycation end-product-receptor for advanced lycation end-products (AGE-RAGE), and hypoxia-inducible factor-1 (HIF-1) signaling pathways. Furthermore, consensus clustering revealed distinct subtypes of MF. Molecular docking confirmed strong binding affinities between OB and core targets. In vivo, OB attenuated fibrosis, downregulated SLC9A1 and SERPINE1 expression, and upregulated CYP19A1, LGALS3, PDGFRA, and SCN5A. This integrated study demonstrates that OB exerts antifibrotic effects by regulating lipid metabolism-related genes and pathways. The identification of MF subtypes supports personalized therapy, positioning OB as a promising candidate for MF treatment.
Antidepressant effect of psychedelic compounds and mechanisms underlying the G protein-coupled receptors activation psychedelics: Antidepressant action and GPCR signaling.
Gollo Bertollo A, Alexandre Wippel V, Eduarda Dama Mingoti M … +2 more , Daniel Prediger R, Maria Ignácio Z
Eur J Pharmacol · 2026 Jul · PMID 42208645 · Publisher ↗
Major Depressive Disorder (MDD) is a debilitating mental health condition that significantly impacts quality of life. Despite available pharmacological treatments, response rates remain suboptimal, with a considerable nu...
Major Depressive Disorder (MDD) is a debilitating mental health condition that significantly impacts quality of life. Despite available pharmacological treatments, response rates remain suboptimal, with a considerable number of patients experiencing treatment-resistant depression (TRD). Indeed, classical antidepressants, primarily targeting monoaminergic systems, exhibit a therapeutic delay due to complex neuroadaptive changes. On the other hand, psychedelic compounds have recently emerged as promising, rapid-acting antidepressant agents, demonstrating efficacy particularly in TRD. This review explores the antidepressant effects of psychedelics, focusing on the underlying mechanisms involving G protein-coupled receptors (GPCRs). It is discussed how psychedelics, predominantly through 5-HT receptor activation, trigger distinct intracellular signaling cascades (e.g., Gq/11 and β-arrestin pathways) leading to neuroplasticity, synaptogenesis, and functional remodeling of neural circuits, such as the default mode network (DMN). The review also examines their modulatory effects on glutamatergic transmission and anti-inflammatory properties, highlighting how these mechanisms contribute to their rapid and sustained therapeutic effects. Furthermore, the review examines the impact of psychedelics on key transcription factors (e.g., EGR1, CREB, NF-κB) and epigenetic modifications, which underpin enduring changes in gene expression and neuronal function. Finally, the central and predominant role of GPCRs, especially 5-HT receptors, in mediating the antidepressant effects of psychedelics is discussed, acknowledging the complementary involvement of other receptors and neurotransmitter systems. This review aims to highlight existing knowledge gaps, particularly concerning the intricate interactions between different mechanistic pathways, and to propose future research directions to fully elucidate the therapeutic potential and safety of psychedelics in depression treatment.
Inhibitory mechanism of fluoxetine in collagen-induced platelet aggregation.
Da XW, Fang P, Li G … +10 more , Du MY, Xu M, He AD, Xie W, Liu G, Liang ML, Song W, Xu Y, Zhou F, Ming ZY
Eur J Pharmacol · 2026 Jul · PMID 42208644 · Publisher ↗
BACKGROUND: Fluoxetine, a selective serotonin reuptake inhibitor, is commonly prescribed as an antidepressant; however, studies have demonstrated that it increases bleeding risk. This study examined the potential mechani...
BACKGROUND: Fluoxetine, a selective serotonin reuptake inhibitor, is commonly prescribed as an antidepressant; however, studies have demonstrated that it increases bleeding risk. This study examined the potential mechanisms underlying the effects of fluoxetine on platelet activation. METHODS: Washed platelets and platelet-rich plasma were used to investigate the effects of fluoxetine on collagen- and collagen-related peptide-induced platelet aggregation and secretion. Flow cytometry was used to measure its effects on P-selectin expression in washed human platelets stimulated with collagen. Western blotting was used to detect protein phosphorylation. RESULTS: Fluoxetine significantly reduced collagen-induced platelet aggregation in a dose-dependent manner. Fluoxetine decreased the levels of phospholipase C gamma 2 (PLCγ2), spleen tyrosine kinase (Syk), protein kinase B (Akt), and glycogen synthase kinase 3 beta (GSK3β) phosphorylation in the glycoprotein Ⅵ (GPⅥ) signaling pathway, as well as the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the mitogen-activated protein kinase (MAPK) family. However, fluoxetine did not affect p38 MAPK or c-Jun N-terminal kinase (JNK) phosphorylation. 5-HT analogs block the effects of fluoxetine on platelets and downstream signaling pathways of GPⅥ. Administration of an additional 5-HT2 receptor antagonist, ketanserin, resulted in a reduction of platelet aggregation levels; however, the values remained statistically distinct from those observed in the fluoxetine-alone group. CONCLUSIONS: Fluoxetine attenuates collagen-induced platelet activation and interferes with the Syk-PLCγ2-Akt-GSK3β and ERK1/2 signaling pathways; this effect may be attributed to its dual inhibition of 5-HT receptors and Serotonin transporters (SERTs).
Targeting the untargeted: Molecular insights and emerging therapeutic strategies for primary aldosteronism.
Lu H, Zhang Y, Qiu D … +4 more , Xie Z, Wang Z, Liu J, Zhang Y
Eur J Pharmacol · 2026 Jul · PMID 42208643 · Publisher ↗
Primary aldosteronism (PA), the most common form of endocrine hypertension, is evolving from a simple hormonal disorder to a complex molecular syndrome. While somatic mutations in genes like KCNJ5 and CACNA1D illuminate...
Primary aldosteronism (PA), the most common form of endocrine hypertension, is evolving from a simple hormonal disorder to a complex molecular syndrome. While somatic mutations in genes like KCNJ5 and CACNA1D illuminate part of the pathogenesis, the integrated role of epigenetic dysregulation remains a critical frontier. This review argues that the traditional "one-size-fits-all" approach, reliant on conventional mineralocorticoid receptor antagonists (MCRAs), is inadequate due to its off-target effects and failure to address residual cardiovascular risk. We comprehensively synthesize emerging evidence that the future of PA management lies in molecular subtyping. This paradigm shift is already being catalyzed by next-generation agents-including non-steroidal MCRAs and aldosterone synthase inhibitors(ASIs), which promise targeted intervention. By critically appraising the path from molecular mechanisms to precision therapeutic strategies, this review delineates a roadmap for overcoming the current dissociation between hypertension control and long-term organ protection, ultimately paving the way for a personalized medicine era in PA.
Combination of Deferoxamine and Deferiprone demonstrates superior efficiency compared to monotherapies in management of cardiac iron overload: Evidence from meta-analysis.
Basu S, Pal S, Sarkar D … +4 more , Mukherjee A, Chakrabarti N, Shukla PC, Chakravorty N
Eur J Pharmacol · 2026 Jul · PMID 42208642 · Publisher ↗
OBJECTIVE: Cardiac iron overload is a significant but treatable complication linked to various diseases. Iron chelators, such as Deferasirox (DFX), Deferiprone (DFP), and Deferoxamine (DFO), are commonly prescribed eithe...
OBJECTIVE: Cardiac iron overload is a significant but treatable complication linked to various diseases. Iron chelators, such as Deferasirox (DFX), Deferiprone (DFP), and Deferoxamine (DFO), are commonly prescribed either as monotherapy or in combination for the treatment of systemic iron overload. However, the management of cardiac iron overload remains challenging owing to the absence of a standardized chelation regimen exclusively for the management of the condition in patients. This meta-analysis intends to evaluate the comparative efficacy of different iron chelation regimens for the treatment of cardiac iron overload. METHODS: The meta-analysis included twenty-nine studies (2000-2025) and applied a random-effects model to calculate Hedges' g summary effect and assess heterogeneity to assess the efficacy of the chelation regimens in increasing cardiac T2∗ values. Pooled analysis of cardiac T2∗ change between chelation regimens for patients with significant cardiac iron overload was also performed to establish the most effective chelation regimen for the treatment of this condition. RESULTS: Among the iron chelation therapies, DFO-DFP combination produced the largest and significant improvement (Hedges' g = 1.11), followed by DFX-DFO combination (Hedges' g = 0.53). In patients with baseline cardiac T2∗ <20 ms, DFO-DFP combination achieved the greatest mean increase of cardiac T2∗ values (7.51 ms), followed by DFO monotherapy and DFX-DFO combination. CONCLUSION: The combination of Deferoxamine and Deferiprone demonstrated comparatively greater efficacy than the other evaluated regimens in decreasing cardiac iron overload. However, this finding should be interpreted with caution in consideration of the study limitations when applied to clinical decision-making.
Novel mechanisms and emerging therapeutic strategies in vascular calcification.
Li H, Zhang K, Chen N … +2 more , Feng K, Zhang B
Eur J Pharmacol · 2026 Jul · PMID 42203066 · Publisher ↗
Vascular calcification, a multifactorial condition associated with aging, chronic kidney disease, and diabetes, is a major cause of cardiovascular mortality. The process is driven by the osteogenic conversion of vascular...
Vascular calcification, a multifactorial condition associated with aging, chronic kidney disease, and diabetes, is a major cause of cardiovascular mortality. The process is driven by the osteogenic conversion of vascular smooth muscle cells (VSMCs). This review summarizes recent advances in the interconnected mechanisms that govern this process. The focal points of this review include metabolic reprogramming (with an emphasis on polyamine metabolism and metabolite signaling), the synergistic interplay between mitochondrial dysfunction and ferroptosis, and the epigenetic stabilization of the osteogenic phenotype (comprising histone modifications, DNA methylation, and non-coding RNAs). These cell-autonomous changes are amplified by pathological intercellular communication, particularly via extracellular vesicles and bidirectional endothelial-VSMC crosstalk, forming a self-perpetuating pathological network. In accordance with this framework, we hereby present several emerging therapeutic paradigms, including molecular glues for biased G protein-coupled receptor (GPCR) signaling, targeted protein degradation (TPD), ferroptosis inhibition, repurposed drugs, and gene editing. A further aspect of our research encompasses the evaluation of investigational agents that are currently undergoing clinical trials. Examples of such agents include SNF472 and ataciguat. Finally, we address key translational challenges and propose future directions for developing effective, multi-targeted interventions.
Miltefosine attenuates silicosis involving inhibiting the Akt/mTOR signaling pathway.
Zhang F, Dou X, Dong R … +12 more , Zhang S, Yue H, He J, Li X, Li H, Zhang H, Liu H, Zhou L, Li T, Zhou Y, Zuo P, Liu K
Eur J Pharmacol · 2026 Jul · PMID 42203065 · Publisher ↗
Silicosis is an irreversible respiratory condition resulting from exposure to respirable crystalline silica. Presently, the prevalence of silicosis remains significant, with treatment options being notably limited. Milte...
Silicosis is an irreversible respiratory condition resulting from exposure to respirable crystalline silica. Presently, the prevalence of silicosis remains significant, with treatment options being notably limited. Miltefosine, an inhibitor of phosphatidylcholine synthesis, has been found to possess both anti-inflammatory properties and inhibitory effects on immune cell infiltration in the airways. The present study evaluated the therapeutic potential of miltefosine in silica-associated pulmonary fibrosis. We established mouse models via airway administration of silicon dioxide (SiO) (200 mg/kg). Different type of pulmonary fibrosis (PF) model including bleomycin (BLM) and Fluorescein Isothiocyanate (FITC) were then utilized to examine the therapeutic effect of Miltefosine. Oral miltefosine exhibits significant therapeutic efficacy against pulmonary fibrosis induced by SiO, as well as other etiologies such as BLM and FITC. This efficacy is evidenced by significant reductions in fibrotic markers and pathological staining characteristics post-treatment, paralleling the antifibrotic effects observed with pirfenidone. In cellular experiments, primary fibroblasts from idiopathic pulmonary fibrosis (IPF) patients and healthy controls were utilized for in vitro therapeutic evaluation and mechanistic exploration. Miltefosine was found to attenuate fibrosis progression by inhibiting fibroblast activation, proliferation, and migration capabilities, while promoting apoptosis. Mechanistically, miltefosine exerts its effects by inhibiting Akt activation, which in turn prevents mTOR phosphorylation. Additionally, human precision-cut lung slices (hPCLS) was employed to evaluate the efficacy of miltefosine in treating pulmonary fibrosis induced by a cocktail of agents, and miltefosine significantly reduced its collagen deposition. Our results imply that miltefosine can alleviate SiO-induced pulmonary fibrosis in murine models and attenuate fibrosis progression in hPCLS by inhibiting fibroblast activation through the suppression of Akt activation and mTOR phosphorylation.
Distinguishing psychomimetic from antidepressant-like effects in mice using molecular and electrophysiological biomarkers.
Merino E, Cervera-Ferri A, Lanuza E … +5 more , Cabanu S, Pilar-Cuéllar F, Adell A, Teruel-Martí V, Martínez-Ricós J
Eur J Pharmacol · 2026 Jul · PMID 42203064 · Publisher ↗
Ketamine exerts rapid, long-lasting antidepressant effects after a single administration and thus overcomes the limitations of classic drugs, but also induces psychomimetic effects. It is, therefore, essential to delve d...
Ketamine exerts rapid, long-lasting antidepressant effects after a single administration and thus overcomes the limitations of classic drugs, but also induces psychomimetic effects. It is, therefore, essential to delve deeper into its mechanisms of action to optimize its use as an antidepressant. With this aim, we examined, in male mice, the temporal evolution of the antidepressant-like and psychomimetic effects of 5 and 30 mg/kg of ketamine. In addition, the electrical activity and the expression of the plasticity-related molecules in both the ventromedial prefrontal cortex and the dorsal hippocampus were measured. Ketamine induced immediate psychomimetic behaviors. These were milder and shorter at the 5 mg/kg dose, with both doses showing equivalent antidepressant-like effects at 2 and 24 h. Both doses evoked a short-lasting electrical pattern that was dose-dependent, characterized mainly by increased synchronized gamma, excitatory/inhibitory balance, synchronized theta, phase-amplitude coupling, and decreased mutual information in slow (SW), beta, and theta waves. The higher dose led to longer-lasting changes. The most significant were decreased SW and beta, and increased gamma and communication in theta and beta. Both doses altered sleep architecture at 24 h and the expression of AKT, pAKT, pAKT/AKT, pERK/ERK, and p-mTOR/mTOR at 2 and 24 h. Given their temporal association, decreased SW and beta mutual information, changes in hyperexcitability, and gamma and theta activity may be biomarkers of ketamine's psychomimetic effects. However, changes in sleep architecture and the expression of plasticity proteins, along with delayed increased raw information, gamma, and excitability, are likely associated with its antidepressant potential.
Clozapine-Induced parotid inflammation and the effect of N-Acetyl cysteine on it: An experimental study.
Aksoy ZK, Aydın A, Kılınç İ … +4 more , Oltulu P, Özkürkçüler A, İyisoy MS, Kozak HH
Eur J Pharmacol · 2026 Jul · PMID 42203063 · Publisher ↗
OBJECTIVE: Clozapine is associated with systemic and salivary gland inflammation, but the mechanisms underlying parotid toxicity remain unclear. This study evaluated oxidative stress, inflammatory responses, and histopat...
OBJECTIVE: Clozapine is associated with systemic and salivary gland inflammation, but the mechanisms underlying parotid toxicity remain unclear. This study evaluated oxidative stress, inflammatory responses, and histopathological changes in the parotid glands of rats treated with clozapine and investigated the protective effects of N-acetylcysteine (NAC). METHODS: Thirty-six male Wistar Albino rats were randomly allocated to Control, Clozapine (40 mg/kg/day), or Clozapine + NAC (240 mg/kg/day) groups for 23 days. Serum and parotid tissues were analyzed for total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), TNF alpha, IL-10, and C-reactive protein (CRP). Histopathological assessments included inflammation, nuclear degeneration, ductal dilatation, and mucinous metaplasia. RESULTS: Clozapine significantly increased TOS, OSI, TNF alpha, and CRP, while decreasing TAS and IL-10 in both serum and parotid tissue compared to controls (p < 0.05). NAC co-administration reversed these changes, indicating reduced oxidative stress and inflammation. Histologically, clozapine induced periductal, lobular, and periglandular inflammation, nuclear degeneration, and ductal dilatation; these alterations were markedly attenuated by NAC (p < 0.001). Mild mucinous metaplasia was observed in the serous component of the parotid in clozapine-treated rats, independent of NAC treatment. CONCLUSION: Clozapine disrupts antioxidant and inflammatory balance in rat serum and parotid glands, inducing structural and biochemical alterations. NAC co-administration significantly attenuates these effects, suggesting a potential therapeutic role in preventing clozapine-induced parotid toxicity. Further studies are warranted to explore clinical implications for sialorrhea and salivary gland protection.
Pharmacological inhibition of TRPM4 channel stabilizes atherosclerotic plaque via inhibiting AMPK-Beclin1-mediated autophagy.
Ding X, Zhao R, Wu W … +6 more , Huang D, Wang M, Wu Y, Zhou P, Wang L, Zhao D
Eur J Pharmacol · 2026 Jul · PMID 42203062 · Publisher ↗
Transient receptor potential melastatin 4 (TRPM4) channel plays an important role in regulation of endothelial dysfunction. However, whether TRPM4 contributes to the developing of atherogenesis remains unexplored. In thi...
Transient receptor potential melastatin 4 (TRPM4) channel plays an important role in regulation of endothelial dysfunction. However, whether TRPM4 contributes to the developing of atherogenesis remains unexplored. In this study, ApoE mice feeding with a high-fat diet (HFD) for 16 weeks to establish atherosclerosis model, were administered with or without 9-phenanthrol (9-Phe), a specific inhibitor of TRPM4. Our data showed that TRPM4 expression levels in aortas, particularly on endothelium, were significantly increased in HFD-induced atherosclerotic mice. While pharmacological inhibition with 9-Phe failed to reduce the HFD-induced atherosclerotic plaque area, it significantly stabilized vulnerable plaques in HFD-fed ApoE mice. Upon exposed to oxidized low-density lipoprotein (ox-LDL), TRPM4 expression level was notably upregulated in primary cultured endothelial cells (ECs). Both 9-Phe and knockdown of TRPM4 protected ox-LDL-induced impairment of cell viability. Furthermore, ox-LDL-treated ECs showed impaired migration ability and enhanced release of adhesion molecules, including ICAM-1, VCAM-1 and E-selectin, which was also alleviated by 9-Phe. Notably, 9-Phe also inhibited the ox-LDL-triggered autophagy and apoptosis in ECs. Mechanistically, ox-LDL upregulated TRPM4 expression and induced activation of AMPK and autophagy signaling pathway; AMPK agonist acadesine (AICAR) was able to abolish the protective effect of 9-Phe against excessive autophagy and apoptosis in ECs. Taken together, our study reveals that atherosclerotic stress-induced increase in TRPM4 expression may contribute to HFD-induced progression of atherosclerosis and 9-Phe prevents these pathological processes by blunting AMPK-Beclin1-mediated excessive autophagy and apoptosis in ECs. We suggest that TRPM4 may be a potential therapeutic target for preventing HFD-induced atherosclerosis.
Ergostatrien-3β-ol suppresses breast cancer anoikis resistance and metastasis by targeting the miR-93-5p/leupaxin axis.
Rengamanar H, Chen WC, Kuo YH … +7 more , Tsai HC, Fong YC, Guo JH, Liu CL, Huang TM, Wu CY, Tang CH
Eur J Pharmacol · 2026 Jul · PMID 42191085 · Publisher ↗
Breast cancer is the malignancy most frequently diagnosed among women and ranks as a top cause of cancer-related deaths globally, with distant metastasis being the main factor behind these fatalities. Current systemic an...
Breast cancer is the malignancy most frequently diagnosed among women and ranks as a top cause of cancer-related deaths globally, with distant metastasis being the main factor behind these fatalities. Current systemic and locoregional therapies are hampered by severe side effects and limited survival benefits, highlighting the urgent need for novel therapeutic strategies. Ergostatrien-3β-ol (EK100), a natural sterol isolated from Antrodia camphorata, is known for its anti-inflammatory properties; however, its role in breast cancer metastasis remains unexplored. Here, we demonstrate that EK100 potently inhibits migration and anoikis resistance in breast cancer cells. RNA sequencing revealed significant downregulation of focal adhesion pathway genes, with leupaxin identified as a key target. Clinical correlation analyses showed that elevated leupaxin expression is linked with advanced disease, metastasis, and poor overall survival in breast cancer patients. Mechanistically, EK100 induces miR-93-5p upregulation, which suppresses leupaxin expression, thereby attenuating leupaxin-dependent migration and anoikis resistance. Molecular docking further predicts direct binding of EK100 to leupaxin, supporting a potential direct inhibitory mechanism. Importantly, EK100 suppresses leupaxin expression and significantly reduces breast cancer metastasis in vivo. Collectively, these findings position EK100 as a promising therapeutic candidate for metastatic breast cancer.
PANoptosis in atherosclerotic plaques: Molecular mechanisms, clinical significance, and therapeutic potential.
Qin R, Li C, Xu H … +2 more , Lai X, Chen L
Eur J Pharmacol · 2026 Jul · PMID 42191084 · Publisher ↗
Atherosclerosis (AS) is a leading cause of cardiovascular disease and occurs in the setting of chronic inflammation and lipid accumulation in the artery walls. A major driver of cardiovascular events is plaque vulnerabil...
Atherosclerosis (AS) is a leading cause of cardiovascular disease and occurs in the setting of chronic inflammation and lipid accumulation in the artery walls. A major driver of cardiovascular events is plaque vulnerability, characterized by large lipid-rich necrotic cores and thin fibrous caps. PANoptosis is a hybrid form of apoptosis, pyroptosis and necroptosis and has recently been identified as a critical regulator of plaque instability. This process is executed by the multi-protein PANoptosome complex, with key molecules such as Z-DNA binding protein 1 (ZBP1), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), absent in melanoma 2 (AIM2), and caspases driving inflammation and cell death in macrophages and vascular smooth muscle cells. PANoptosis-related molecules regulating inflammation and necrosis, such as AIM2 and dynamin-related protein 1 (DRP1), also modulate the stability of plaque. For example, targeting PANoptosis pathways, by inhibiting AIM2 or modulating mitochondrial fission, could be a therapeutic intervention. However, the dynamic crosstalk between PANoptosis and other regulated cell death pathways has not been fully clarified. Here, we review molecular mechanisms and clinical significance of PANoptosis in atherosclerosis, as well as the potential of PANoptosis-related molecules as biomarkers and therapeutic targets. Future studies should elucidate the spatiotemporal dynamics of PANoptosis and design targeted therapies to modulate this pathway, which will provide new strategies for the treatment of atherosclerosis.
Design, synthesis, and inhibition of oxidative, amyloidogenic, and cholinergic dysfunction of saxagliptin-derived schiff bases against STZ-induced sporadic AD-like pathology.
Pattanaik S, Sahu PK, Paidesetty SK … +4 more , Prusty SK, Pakeeraiah K, Panda PK, Lopamudra
Eur J Pharmacol · 2026 Jun · PMID 42178013 · Publisher ↗
Alzheimer's disease (AD) shares significant pathological convergence with diabetes, primarily through insulin resistance. This leads to oxidative stress, neuronal inflammation, plaque formation, cholinergic dysfunction,...
Alzheimer's disease (AD) shares significant pathological convergence with diabetes, primarily through insulin resistance. This leads to oxidative stress, neuronal inflammation, plaque formation, cholinergic dysfunction, and impaired neuronal survival. Herein, we report 10 Saxagliptin (SXG, a potent DPP-IV inhibitor)-derived Schiff base derivatives that were virtually designed and screened. Five leads were prioritized using ADMET profiling and molecular docking, then synthesized via Schiff base condensation with selected aryl aldehydes to target AD progression associated with diabetes. Structural integrity, redox activity, and stability were confirmed by comprehensive characterization, including chromatographic and spectroscopic analyses, DFT calculations, and in vitro antioxidant assays. Neuroprotective potential was thus assessed in vivo by inducing AD-like pathology in rats with a single i.p. dose of STZ at 45 mg/kg, thereby reproducing brain insulin resistance, oxidative-nitrosative stress, and cholinergic dysfunction. Significant neurodegeneration in STZ-treated rats was evidenced by behavioral analyses, biochemical markers (AChE, Aβ42), oxidative stress indices (SOD, CAT, GSH, GPx, MDA, NO, MPO), and hippocampal histology. Treatment with SXG and derivatives at 0.5 mg/kg, orally, resulted in significant restoration of antioxidant defenses, inhibition of lipid peroxidation and NO overproduction, reduction of inflammatory oxidative bursts, and improved cognition in treated groups. Remarkably, derivatives 3c and 3e showed superior free-radical scavenging and greater regulation of redox biomarkers, which were associated with healthy, defined hippocampal cytoarchitecture and reduced neuronal pyknosis and necrosis compared with SXG. Additionally, 3e showed strong therapeutic efficacy by targeting oxidative stress, cholinergic, and amyloidogenic pathways synchronously.
Trifluoperazine induces ferroptosis in acute myeloid leukemia by suppressing the Nrf2/SLC7A11/GPX4 axis.
Xu J, Yang W, Zhang Y … +5 more , Liu J, Cui X, Hao J, Ren F, Wang H
Eur J Pharmacol · 2026 Jul · PMID 42178012 · Publisher ↗
Acute myeloid leukemia (AML) remains a therapeutic challenge due to high relapse rates and limited treatment options. Drug repurposing offers a promising strategy to accelerate clinical translation. In this study, we inv...
Acute myeloid leukemia (AML) remains a therapeutic challenge due to high relapse rates and limited treatment options. Drug repurposing offers a promising strategy to accelerate clinical translation. In this study, we investigated the anti-AML potential of the FDA-approved antipsychotic drug trifluoperazine (TFP) and explored its underlying mechanisms. We found that TFP markedly inhibits AML cell proliferation by inducing cell cycle arrest and apoptosis, while exhibiting minimal toxicity to normal human umbilical vein endothelial cells and bone marrow stromal cells. Mechanistically, TFP triggers impairments in mitochondrial activity and promotes the accumulation of reactive oxygen species (ROS), and induces ferroptosis, a form of iron-dependent cell death characterized by iron overload, glutathione depletion, and lipid peroxidation. The ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively rescued TFP-induced cell death. Moreover, TFP synergized with the ferroptosis inducer erastin to enhance ferroptotic cell death. At the molecular level, TFP suppressed the Nrf2/SLC7A11/GPX4 antioxidant axis, an effect that was reversible by the Nrf2 activator ML334. In an AML xenograft model, TFP monotherapy significantly inhibited tumor growth and alleviated hepatosplenomegaly. Importantly, TFP synergized with venetoclax, a standard AML therapy, to enhance antileukemic efficacy both in vitro and in vivo. Collectively, our findings identify TFP as a potent ferroptosis inducer in AML and suggest its potential as a repurposed therapeutic agent, either as monotherapy or in combination with venetoclax.
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