European Journal Of Pharmacology[JOURNAL]
Sun
200 papers
CDT1 and E2F1 synergistically promote the glycolysis and progression of non-small cell lung cancer through the TPX2/AKT pathway.
Tan J, Zhu L, Hu B … +9 more , Wang Z, Zhang J, Guo Q, Kuang J, Yan J, Mo Y, Zheng Q, Wu Y, Yang Y
Eur J Pharmacol · 2026 May · PMID 42035943 · Publisher ↗
Emerging data indicate that chromatin licencing and DNA replication factor 1 (CDT1) plays an important role in several cancers. However, it remains unclear whether CDT1 is functionally indispensable in lung cancer. Here,...
Emerging data indicate that chromatin licencing and DNA replication factor 1 (CDT1) plays an important role in several cancers. However, it remains unclear whether CDT1 is functionally indispensable in lung cancer. Here, constructing tissue microarrays and performing in vitro and vivo experiments, we showed that CDT1 was significantly overexpressed in lung adenocarcinoma tissues, and its expression level significantly correlated with pathological stage, tumour invasiveness, and overall patient survival. Mechanistic investigations revealed that CDT1 possibly interacted with the transcription factor adenovirus early region 2 binding factor 1 (E2F1), thereby cooperatively enhancing the transcriptional activity of the targeting protein for Xenopus kinesin-like protein 2 (TPX2) gene. This phenomenon subsequently increased the expression of glycolysis-related molecules aldolase C and pyruvate kinase M2 via the PI3K/AKT signalling pathway, which promoted the proliferation and migration of non-small cell lung cancer (NSCLC) cells. Critically, knockdown of TPX2 or treatment with either the AKT pathway inhibitor MK-2206 2HCl or the glycolysis inhibitor AZ33 effectively reversed the promoting effects of CDT1 on AKT pathway activity, glycolytic metabolism, and tumour progression in CDT1-overexpressing NSCLC cells. Collectively, this study elucidates that CDT1 and E2F1 mutually promote the glycolysis and progression of NSCLC cells by activating the TPX2/AKT pathway. These findings provide novel therapeutic targets for refractory NSCLC treatment.
Nintedanib is a potent FLT3 inhibitor with activity against FLT3-ITD and overcomes the gatekeeper F691L resistance mutation in acute myeloid leukemia.
Gu C, He J, Fan J … +6 more , Wang C, Zhou W, Xu Y, Deng T, Wang S, Wang P
Eur J Pharmacol · 2026 May · PMID 42035942 · Publisher ↗
Acute myeloid leukemia (AML) is a molecularly heterogeneous malignancy in which FMS-like tyrosine kinase 3 (FLT3) mutations, particularly internal tandem duplications (FLT3-ITD), occur in approximately 30% of cases and a...
Acute myeloid leukemia (AML) is a molecularly heterogeneous malignancy in which FMS-like tyrosine kinase 3 (FLT3) mutations, particularly internal tandem duplications (FLT3-ITD), occur in approximately 30% of cases and are associated with poor prognosis and high relapse risk. While FLT3 inhibitors have improved clinical outcomes, acquired resistance, often mediated by secondary tyrosine kinase domain (TKD) mutations or other mechanisms, remains a major therapeutic challenge. Nintedanib is an oral multi-kinase inhibitor approved for the treatment of fibrotic lung diseases; however, its potential activity against FLT3-ITD-positive AML has not been explored. Here, we identified nintedanib as a putative FLT3 inhibitor by analyzing drug-sensitivity data from the BeatAML database. Direct target engagement was validated by computational docking, cellular thermal shift assay (CETSA), and in vitro kinase inhibition assays. In FLT3-ITD-mutant human cell lines (MV4-11, MOLM13), primary AML blasts, and engineered Ba/F3 cells expressing FLT3-ITD with or without secondary TKD mutations, nintedanib suppressed FLT3 autophosphorylation and downstream STAT5, ERK, and AKT signaling, leading to cell cycle arrest and apoptosis. Notably, nintedanib retained efficacy against common resistance mutations, including the gatekeeper F691L mutation, both in vitro and in vivo. In a Ba/F3 FLT3-ITD-F691L mouse model, nintedanib demonstrated superior anti-leukemic efficacy compared with gilteritinib and quizartinib. Furthermore, nintedanib potently inhibited primary AML blasts harboring FLT3-ITD while normal bone marrow remained intact. These findings identify nintedanib as a promising FLT3 inhibitor and support its further therapeutic investigation in FLT3-ITD-positive AML.
Bradykinin modulates endothelin-1-enhanced and monocrotaline-induced pulmonary arterial hypertension-associated arrhythmogenesis in rabbit right ventricular outflow tract via a nitric oxide-dependent pathway.
Lu YY, Lin FJ, Chen YC … +4 more , Chin CG, Chan CS, Higa S, Chen YJ
Eur J Pharmacol · 2026 May · PMID 42035941 · Publisher ↗
Bradykinin, a vasoactive substance, lowers ventricular tachycardia inducibility in ischemic animal models. The right ventricular outflow tract (RVOT) has distinctive electrophysiological characteristics and calcium homeo...
Bradykinin, a vasoactive substance, lowers ventricular tachycardia inducibility in ischemic animal models. The right ventricular outflow tract (RVOT) has distinctive electrophysiological characteristics and calcium homeostasis, leading to its high arrhythmogenesis. Endothelin-1 (ET-1), a vasoconstrictor, plays a key role in the pathophysiology of pulmonary arterial hypertension (PAH) and increases the risk of ventricular arrhythmia. This study investigated whether bradykinin modulates the impact of ET-1 or PAH-induced RVOT arrhythmogenesis in a rabbit model. Using conventional microelectrodes and whole-cell patch clamp techniques, action potentials and ionic currents were recorded in control, ET-1-treated or monocrotaline-induced PAH isolated rabbit RVOT tissues and isolated cardiomyocytes before and after bradykinin treatment. Fluorescence imaging was performed in RVOT myocytes with and without bradykinin to evaluate calcium transient and sarcoplasmic reticulum (SR) calcium content, and nitric oxide (NO) production. In rabbit RVOTs, bradykinin decreased contractility, shortened action potential duration, reduced I, NCX, and I currents, increased I, and lowered calcium transients and SR calcium content, with prolonged time to peak and delay τ, as well as increased NO production. Bradykinin also ameliorated the pro-arrhythmia effects of ET-1 in the RVOTs under rapid ventricular pacing. The anti-arrhythmic effect of bradykinin on ET-1-induced RVOT arrhythmogenesis was blocked by treatment with L-NAME (a non-selective NOS inhibitor) or L-NIO (an eNOS inhibitor). In addition, bradykinin mitigated rapid pacing-induced arrhythmias in PAH RVOTs. In conclusion, bradykinin modulates RVOT electrophysiology and ET-1-induced arrhythmogenesis via NO synthesis, suggesting a novel therapeutic target for RVOT arrhythmias in patients with PAH.
Mitochondrial dysfunction and senescence accompany glioblastoma cell death triggered by a putative metabolic inhibitor.
Yadav A, Bhutkar S, Barot S … +4 more , Aher AA, Patel K, Muth A, Dukhande V
Eur J Pharmacol · 2026 May · PMID 42035940 · Full text
Glioblastoma (GBM) is a fatal cancer with a dismal prognosis and a dire need for novel chemotherapeutics. Metabolic reprogramming is an established hallmark of cancer. In our previous study on GBM, we aimed at targeting...
Glioblastoma (GBM) is a fatal cancer with a dismal prognosis and a dire need for novel chemotherapeutics. Metabolic reprogramming is an established hallmark of cancer. In our previous study on GBM, we aimed at targeting the metabolic reprogramming of cancer by using stiripentol (STP), a putative lactate dehydrogenase (LDH) inhibitor and an FDA-approved anti-epileptic drug. However, the precise mechanism of STP's anti-cancer activity remains unclear. We aimed to elucidate the mechanism of action of STP in GBM to further develop STP as a therapeutic. We employed a multiomic approach followed by metabolic and cellular assays. STP treatment induced genetic and metabolic alterations in GBM cells. Inhibition of LDH by STP was moderate but not potent. The cellular changes were accompanied by an increase in reactive oxygen species, a decrease in mitochondrial membrane potential, and induction of senescence in GBM cells. Our research indicates that further research in senescence-inducing agents and novel LDH inhibitors can provide novel therapeutics for GBM.
Safety and efficacy of remimazolam sedation for ICU patients on invasive mechanical ventilation: A meta-analysis of randomized controlled trials.
Xu Z, Lu J, Saeed S … +1 more , Lian C
Eur J Pharmacol · 2026 May · PMID 42031055 · Publisher ↗
BACKGROUND AND AIM: The management of sedation in mechanically ventilated intensive care unit (ICU) patients is very challenging in critical care medicine. Remimazolam and propofol are used as sedative agents for ICU pat...
BACKGROUND AND AIM: The management of sedation in mechanically ventilated intensive care unit (ICU) patients is very challenging in critical care medicine. Remimazolam and propofol are used as sedative agents for ICU patients undergoing mechanical ventilation. This meta-analysis evaluates the efficacy and safety of remimazolam compared to propofol in mechanically ventilated ICU patients. METHODS: We conducted a comprehensive database search up to April 2025, included the studies that met our inclusion criteria. We evaluated mortality rates and other secondary outcomes to compare the efficacy of remimazolam and propofol. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated using RevMan software. RESULTS: Three RCTs were selected from a total of 745 retrieved articles, including 220 patients undergoing IMV in an ICU setting. The findings revealed no statistically significant difference in mortality rates (OR 0.54; 95% CI: 0.26 to 1.12; p = 0.10) or 28-day survival rates (OR 1.59; 95% CI: 0.81 to 3.12; p = 0.18), and the mean difference in ICU duration of stay was -1.50 days (95% CI: -5.01 to 2.02; p = 0.40) between the two sedatives. Remimazolam demonstrated a significant reduction in total adverse events (OR 0.38; 95% CI: 0.20 to 0.72; p = 0.00) and the occurrence of delirium (OR 0.36; 95% CI: 0.16 to 0.83; p = 0.02), with no observed heterogeneity (I = 0%). CONCLUSION: This meta-analysis shows that remimazolam provides comparable efficacy to propofol regarding mortality and survival, with significant advantages in reducing adverse events and delirium.
The silymarin and quercetin-loaded pH-sensitive chitosan-tripolyphosphate/Eudragit® S100 nanoparticles improve acetic acid-induced colonic inflammation in rats by modulating Th1 cells, inflammatory cytokines, and oxidative stress.
Bagheri N, Badihi M, Mirzaei Y … +3 more , Taheri F, Khosravian-Dehkordi P, Azadegan-Dehkordi F
Eur J Pharmacol · 2026 May · PMID 42025668 · Publisher ↗
Silymarin (SM) and quercetin (Que) are flavonoids with antioxidant and anti-inflammatory effects. Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation. This study aimed to...
Silymarin (SM) and quercetin (Que) are flavonoids with antioxidant and anti-inflammatory effects. Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation. This study aimed to develop pH-sensitive cross-linked chitosan-tripolyphosphate/Eudragit® S100 nanoparticles (EU S100/CS-TPP NPs) as delivery systems for SM and Que, and to evaluate their anti-inflammatory and antioxidant effects in an acetic acid-induced rat model of colonic inflammation. A total of 80 rats were randomly divided into ten groups. Colonic inflammation was induced with 4% acetic acid and followed by oral treatment with SM, Que, or EU S100/CS-TPP NPs. Colon tissues were collected for macroscopic and histopathological evaluation. Th1 (CD4 IFN-γ) cell frequency and inflammatory cytokine expression were assessed using immunofluorescence and real-time PCR. Antioxidant parameters, catalase (CAT), malondialdehyde (MDA), nitric oxide (NO), and superoxide dismutase (SOD), were measured spectrophotometrically. Treatment with mesalazine, SM, SM/CS-TPP/EU S100 NPs, Que, Que/CS-TPP/EU S100 NPs, SM/Que, and SM/Que/CS-TPP/EU S100 NPs significantly increased colon length and reduced macroscopic damage, DAI score, colon weight, and histological damage score. Th1 cell frequency, expression of inflammatory cytokines and apoptotic genes, and oxidative stress were significantly downregulated by treatment with mesalazine, SM, SM/CS-TPP/EU S100 NPs, Que, Que/CS-TPP/EU S100 NPs, SM/Que, and SM/Que/CS-TPP/EU S100 NPs compared with the colonic inflammation group. SM/Que/EU S100/CS-TPP NPs showed the strongest therapeutic effects against UC, with potent anti-inflammatory and antioxidant activities and a reduced frequency of CD4IFN-γ cells, suggesting possible involvement of Th1-related pathways. These findings support the potential of this nanoformulation for future UC therapy.
Corrigendum to "Cinnamaldehyde ameliorates diabetic kidney disease via anti-inflammatory effects: Bridging traditional use and molecular mechanisms" [Eur. J. Pharmacol. (2026) doi: 10.1016/j.ejphar.2026.178783].
Yang D
Eur J Pharmacol · 2026 May · PMID 42025547 · Publisher ↗
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Amygdalin attenuates post-ischemic neuroinflammation by targeting TLR4/NF-κB signaling and NLRP3 inflammasome in cerebral ischemia-reperfusion injury.
Wang YC, Wang HY, Yuan YF … +7 more , Zhang ZJ, Wang YH, Liu JJ, Peng L, Zhang G, Gao J, Yan YG
Eur J Pharmacol · 2026 May · PMID 42013993 · Publisher ↗
Cerebral ischemia-reperfusion injury (CIRI) is a major contributor to neuronal damage after ischemic stroke, and current therapies remain limited by a narrow therapeutic window and reperfusion-associated injury. Amygdali...
Cerebral ischemia-reperfusion injury (CIRI) is a major contributor to neuronal damage after ischemic stroke, and current therapies remain limited by a narrow therapeutic window and reperfusion-associated injury. Amygdalin (Amg) has anti-inflammatory and antioxidant activities, but its role in regulating microglial polarization, pyroptosis, and the TLR4/NF-κB/NLRP3 axis in CIRI remains unclear. In this study, rat MCAO/R and BV-2 cell OGD/R models were used to evaluate the protective effects of Amg in vivo and in vitro. Transcriptomics, untargeted metabolomics, integrated pathway analysis, and molecular docking were combined with qPCR, Western blotting, LPS/ATP stimulation, and inhibitor interventions using TAK-242 and MCC950. Amg enhanced BV-2 cell viability, reduced OGD/R-induced pro-inflammatory cytokine release, and restored antioxidant enzyme activities. In MCAO/R rats, Amg significantly improved neurological function and alleviated brain tissue damage. In addition, Amg attenuated inflammation and oxidative stress, suppressed microglial M1 polarization while promoting M2-related phenotypes, and reduced pyroptosis-related marker expression in vivo and in vitro. Integrated multi-omics analysis further narrowed the candidate mechanisms to core pathways including NF-κB, Toll-like receptor, and NOD-like receptor signaling, and identified Tlr4, Myd88, Nlrp3, and Caspase-1 as key candidate molecules; pharmacological dissection experiments showed that combined treatment with Amg and either a TLR4 inhibitor or an NLRP3 inhibitor did not produce a significant additional synergistic effect, suggesting that its protective action depends on regulation of the TLR4/NF-κB/NLRP3-signaling axis. These findings provide mechanistic evidence for the neuroprotective effects of Amg in CIRI and support its potential as a therapeutic candidate for ischemic stroke.
Lysosomal accumulation of masitinib alters autophagy via pH-dependent trapping.
El Sayed A, Kluzek M, Serwa R … +1 more , Azzi A
Eur J Pharmacol · 2026 May · PMID 42009094 · Publisher ↗
Small-molecule kinase inhibitors often exhibit complex cellular behaviors that cannot be explained solely by target inhibition. Masitinib is a clinically investigated tyrosine kinase inhibitor with reported anti-inflamma...
Small-molecule kinase inhibitors often exhibit complex cellular behaviors that cannot be explained solely by target inhibition. Masitinib is a clinically investigated tyrosine kinase inhibitor with reported anti-inflammatory and neuroprotective effects, yet its intracellular mechanism of action remains poorly defined. Here, we show that masitinib undergoes pH-dependent lysosomal sequestration that dominates its cellular activity. Across multiple cell lines, masitinib suppresses mTORC1 signaling while paradoxically inducing AKT phosphorylation through a VPS34 and rapamycin-sensitive pathway independent of class I PI3K. Thermal proteome profiling identifies lysosomal proteins as the primary off-target signature of masitinib. Using defined membrane model systems that recapitulate lysosomal lipid composition and acidity, we demonstrate that masitinib preferentially accumulates and intercalates into acidic, negatively charged membranes. This lysosomal accumulation impairs lysosomal acidification and disrupts autophagic flux, providing a mechanistic link between the physicochemical properties of masitinib and its downstream signaling effects. Together, our findings highlight lysosomal sequestration as a key determinant of kinase inhibitor behavior and underlie the importance of subcellular drug distribution in modulating cellular responses.
Functional β1-selectivity of novel pyrazoloquinolinones at GABA receptors revealed by electrophysiology, mutagenesis and docking.
Schnalzer D, Haller C, Doppler AM … +9 more , Gashi L, Asai M, Bampali K, Koniuszewski F, Schaar B, Schnürch M, Mihovilovic MD, Khom S, Ernst M
Eur J Pharmacol · 2026 May · PMID 42009093 · Publisher ↗
Gamma-aminobutyric acid type A (GABA) receptors are ligand-gated anion channels, encoded by nineteen subunit genes in mammals. Recent cryo-electron microscopy studies of native human receptors from brain cortex revealed...
Gamma-aminobutyric acid type A (GABA) receptors are ligand-gated anion channels, encoded by nineteen subunit genes in mammals. Recent cryo-electron microscopy studies of native human receptors from brain cortex revealed that β1 subunits contribute to diverse assemblies, including non-canonical arrangements of subunits. β subunits contribute to both GABA binding sites and allosteric sites targeted by general anesthetics. However, studying β1-containing receptors remains hampered by the absence of selective ligands. Here, we present novel pyrazoloquinolinone (PQ) ligands that act as functionally selective allosteric modulators and propose a structural hypothesis for their binding site. Two-microelectrode voltage clamp recordings in Xenopus laevis oocytes expressing recombinant GABA receptors were used to generate concentration-response curves, asses functional β1-selectivity and probe the impact of a mutation in the putative binding site. Four PQ derivatives significantly enhanced GABA-induced currents at α1β1 receptors but showed markedly reduced efficacy at α1β3 receptors, demonstrating functional β1-selectivity. Incorporation of the γ2 subunit reduced or abolished this modulation, and mutational analysis identified β1R41 as key determinant of activity. The emerging structure-activity relationships define a distinct interaction profile and provide quantitative evidence for β1-selectivity. Together, our results pave the way for further design of binding selective ligands. Future applications of β1-selective compounds include their use as research tools for example in autoradiography or functional mapping of receptor populations, and perspectives as diagnostic and therapeutic agents in a variety of neuropsychiatric conditions, as the subunit encoding GABRB1 gene has been implicated in epileptic encephalopathy and is under investigation for a potential role in addictive disorders.
Pleiotropic mechanisms and translational trajectory of SGLT2 inhibitors in sepsis-induced cardiomyopathy: Navigating the evidence hierarchy.
Zhang X, Ren L, Li M … +5 more , Li X, Feng B, Wang S, Yang X, Huang Y
Eur J Pharmacol · 2026 May · PMID 42002093 · Publisher ↗
Sepsis-induced cardiomyopathy (SICM) is a common but heterogeneous syndrome of acute myocardial dysfunction characterized by inflammatory dysregulation, endothelial and microcirculatory injury, mitochondrial bioenergetic...
Sepsis-induced cardiomyopathy (SICM) is a common but heterogeneous syndrome of acute myocardial dysfunction characterized by inflammatory dysregulation, endothelial and microcirculatory injury, mitochondrial bioenergetic failure, ionic instability, and regulated cell injury. Although recognition of SICM is increasing, management remains largely supportive, and no therapy has yet been established to directly modify myocardial vulnerability. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed as glucose-lowering agents, exert pleiotropic cardiovascular effects that intersect with several dominant injury axes of SICM. This interface appears most compelling at the metabolic-mitochondrial level, with additional anti-inflammatory, redox-modulating, and endothelial-protective effects. This review examines the mechanistic rationale for SGLT2 inhibition in SICM, the strength and limits of the current evidence, and the principal barriers to translation. Available evidence most strongly supports an AMPK-centered mitochondrial protective network as the leading mechanistic interface between SGLT2 inhibition and SICM. Anti-inflammatory, redox-modulating, and cell-protective effects are biologically coherent but are supported more by cross-model consistency than by direct validation in septic myocardium. Human evidence remains even more limited, deriving mainly from observational data on antecedent outpatient exposure rather than from prospective ICU initiation, while randomized evidence in broader acute-care populations has not demonstrated automatic clinical benefit. Current data therefore support biologic plausibility, but not routine clinical use, for SGLT2 inhibition in SICM. The immediate implication is not bedside adoption, but disciplined prospective testing after initial hemodynamic stabilization in phenotype-defined SICM, rather than de novo initiation during early septic shock.
Sodium houttuyfonate alleviates monocrotaline-induced pulmonary hypertension by regulating canonical transient receptor potential channel proteins via CHIP.
Zhang S, Ju G, Zhang J … +1 more , Dong F
Eur J Pharmacol · 2026 Jun · PMID 42002092 · Publisher ↗
The influx of extracellular Ca through store-operated Ca channels (SOCCs), known as store-operated calcium entry (SOCE), significantly contributes to the elevation of intracellular Ca concentration ([Ca]) in pulmonary ar...
The influx of extracellular Ca through store-operated Ca channels (SOCCs), known as store-operated calcium entry (SOCE), significantly contributes to the elevation of intracellular Ca concentration ([Ca]) in pulmonary arterial smooth muscle cells (PASMCs), which plays a crucial role in pulmonary hypertension (PH). Canonical transient receptor potential channel (TRPC) proteins are the crucial constituents of SOCCs. Sodium houttuyfonate (SH) is a compound derived from the combination of sodium bisulfite and houttuynin. Our recent study demonstrates that SH alleviates monocrotaline (MCT)-induced PH (MCT-PH) by suppressing pulmonary arterial smooth muscle cell (PASMC) proliferation via TRPC1,4,6-SOCE-[Ca] signaling pathway. In this study, we investigated the contributions of Carboxyl terminus of Hsc70-interacting protein (CHIP) to TRPC1,4,6-SOCE-[Ca] signaling pathway and PASMC proliferation. Furthermore, based on the actions of CHIP, we explored the mechanism by which SH regulates TRPC1,4,6-SOCE-[Ca] signaling pathway. The results revealed that: 1) CHIP promotes MCT-induced PASMC proliferation by enhancing TRPC1,4,6-SOCE-[Ca] signaling pathway; 2) SH significantly downregulates CHIP expression in distal pulmonary arteries (PAs) and cultured PASMCs from MCT-PH rats. 3) Overexpression of CHIP attenuated the inhibitory effect of SH on MCT-elevated TRPC1,4,6-SOCE-[Ca] signaling pathway and PASMC proliferation. Collectively, these findings provide compelling evidence that SH effectively mitigates MCT-PH by inhibiting PASMC proliferation through the TRPC1,4,6-SOCE-[Ca] pathway, likely mediated by CHIP.
Chrysin attenuates tramadol-driven renal dysfunction via regulation of RNA networks, antioxidant pathways, and ketogenic metabolism.
Öz MA, Kandemir Ö, Özdemir S … +5 more , Şimşek H, Küçükler S, Yazıcı R, Mutlu H, Kandemir FM
Eur J Pharmacol · 2026 May · PMID 42002091 · Publisher ↗
This study aimed to evaluate the nephrotoxic effects of tramadol (TR) on renal function and the possible protective role of chrysin (CH) based on multiple biochemical, molecular, and metabolic parameters. The administrat...
This study aimed to evaluate the nephrotoxic effects of tramadol (TR) on renal function and the possible protective role of chrysin (CH) based on multiple biochemical, molecular, and metabolic parameters. The administration of TR resulted in substantial elevations in serum creatinine and BUN levels, concurrently increasing renal damage biomarkers including KIM-1, NGAL, FABP, IL-18, MCP-1, and YKL-40. Furthermore, elevated mRNA levels of Cst3, Timp2, Igfbp7, Hgf, IL-9, and Dkk3 were noted, along with a significant increase in inflammation-related proteins IL-1β, IL-3, IL-4, IL-5, IL-6, and IL-21. TR interrupted LINC01187 and additional regulatory RNA networks, reduced the concentrations of β-hydroxybutyrate, NAD, and acetyl-CoA, essential for ketogenesis, and inhibited HMGCS2 expression. Furthermore, reduced levels of Nrf2, PPARγ, XCT, GPX4, and FPN proteins elevated oxidative stress, diminished SOD, CAT, and GPX levels, and heightened MDA concentrations. The CH administration resulted in partial or substantial enhancement in all these parameters, mitigating the molecular, metabolic, and functional decline induced by TR. PCA analysis indicated that CH aligned the biomarker profile more closely with normal physiological levels. These findings indicate that CH may serve as a potential nephroprotective agent in TR-induced renal injury.
Mangiferin improves learning and memory deficits in prenatal stress offspring through ER stress and BDNF pathway.
Deng L, He W, Gao Y … +7 more , Shang B, Wang J, He J, Hu J, Fang M, Guan F, Cao YJ
Eur J Pharmacol · 2026 May · PMID 42000022 · Publisher ↗
Prenatal stress (PS) significantly influences the neurodevelopment of offsprings, potentially resulting in deficits in learning and memory. Mangiferin (MGF) is a naturally occurring flavonoid compound found in many plant...
Prenatal stress (PS) significantly influences the neurodevelopment of offsprings, potentially resulting in deficits in learning and memory. Mangiferin (MGF) is a naturally occurring flavonoid compound found in many plants, exhibits various pharmacological effects. The study investigates the potential molecular mechanisms of MGF in improving learning and memory deficits in offspring exposed to PS. Animal model of PS offspring and ACR-induced PC12 cell model were used to investigate the effects of MGF. Synaptic plasticity-related proteins and the BDNF signaling pathway were studied, as well as MGF's potential to alleviate endoplasmic reticulum stress (ERS). MGF can mitigate learning and memory impairments and enhance the density of hippocampal neurons, as well as increase the expression of neuronal markers Neurogranin (Ng), DLG4 and activity marker c-fos in the offspring of PS mice. Meanwhile, MGF significantly increased BDNF signaling pathway and synaptic plasticity-related proteins in PS offspring. MGF also efficiently alleviated ERS. Additionally, MGF significantly up-regulated the reduced viability, DLG4 protein expression and synaptic plasticity-related proteins in ACR-induced PC12 cells. MGF can improve endoplasmic reticulum morphology and down regulated the expression of key molecular proteins in the endoplasmic reticulum signaling pathway. MGF could improve the cognitive and memory impairments in the PS offspring mice. The underlying mechanisms involved the alleviation of ERS and improvement of synaptic plasticity-related proteins. The study indicated that MGF holds promise as an effective intervention for ameliorating learning and memory deficits associated with PS, and it offers potential therapeutic effect for neurological disorders linked to ACR dysfunction.
EGR1 regulates PDE12 mediated mitochondrial dysfunction to induce oral mucosal epithelial barrier damage in oral submucous fibrosis.
Peng J, Chen L, Xie J … +5 more , Wang X, Wang X, Chen C, Wang R, Xie X
Eur J Pharmacol · 2026 May · PMID 42000021 · Publisher ↗
The treatment of oral submucosal fibrosis (OSF) is challenging owing to the complex pathogenesis. It is characterized by excessive collagen deposition in the subepithelium along with epithelial damage. Betel nut chewing...
The treatment of oral submucosal fibrosis (OSF) is challenging owing to the complex pathogenesis. It is characterized by excessive collagen deposition in the subepithelium along with epithelial damage. Betel nut chewing is considered a major cause of OSF. We previously found that phosphodiesterase 12 (PDE12) was involved in the oral mucosal epithelial barrier damage, promoting the occurrence of OSF. Early growth response 1 (EGR1), a well-characterized transcription factor, has been implicated in the development of fibrotic diseases, including oral fibrosis. This study aimed to explore the effects and underlying mechanisms of PDE12 overexpression on oral epithelial cells in OSF. Overexpression of PDE12 was employed to verify its critical role in mitochondrial dysfunction and oral mucosal epithelial barrier disruption in HOKs. Subsequently, electrophoretic mobility shift assay and chromatin immunoprecipitation analysis were performed to demonstrate that EGR1 interacted with the promoter of the PDE12 gene, thereby upregulating its expression in HOKs. By combining EGR1 silencing and PDE12 overexpressing strategies, our study confirmed that PDE12-induced impairment of mitochondrial function and oral mucosal epithelial barrier was dependent on EGR1. These findings suggest that regulating the expression of PDE12 through EGR1 could alleviate arecoline-induced epithelial injury, thereby inhibiting the development of OSF and offering a potential therapeutic strategy to combat OSF.
Sinomenine modulates autoantigen-specific immune responses by inhibiting dendritic cell activation in experimental arthritis.
Zhang D, Wu L, Chen F … +4 more , Chen X, Zheng S, Li J, Chen S
Eur J Pharmacol · 2026 May · PMID 42000020 · Publisher ↗
BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic joint inflammation. Although sinomenine (SIN) is clinically effective against RA, its potential to modulate autoantigen-specific im...
BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic joint inflammation. Although sinomenine (SIN) is clinically effective against RA, its potential to modulate autoantigen-specific immune responses and the underlying mechanisms remain incompletely understood. METHODS: Spleen and lymph node cells from collagen-induced arthritis (CIA) mice were cultured to investigate the effects of SIN on type II collagen (CII)-induced T cell activation both in vivo and in vitro. Antibody levels and T cell subsets proportions were also assessed. Bone marrow-derived dendritic cells (BMDCs) were generated and activated with TNF-α, and the effects of SIN on dendritic cell (DC) maturation and activation were examined. RESULTS: SIN markedly suppressed CII-induced T cell activation in vitro, but did not affect T cell activation induced by TCR mimetics anti-CD3 and anti-CD28 antibodies. SIN also lowered CD80 and CD86 expression on TNF-α-activated BMDCs, reduced IL-6 and IL-12 secretion, and downregulated Il-6, Il-12, and Tnf-α mRNA expression. In vivo SIN intervention prior to arthritis onset suppressed CII-induced T cell activation in lymph node cells upon ex vivo stimulation, decreased serum anti-CII antibodies, lowered Th1 and Th17 cell proportions, and increased the frequency of Treg cells. Moreover, administration of SIN reduced MHC-II expression on cDC1 in draining lymph nodes after CII/CFA immunization. CONCLUSION: SIN inhibits the activation of DCs, leading to suppressed T cell activation induced by autoantigen CII. SIN also shifts the T cell subset balance toward immunotolerance. Together, these effects alleviate the inflammatory response in CIA mice.
Dendrobine alleviates the T2D/AD comorbidity in 3xTg-AD mice feeding high-fat diet via the Cav-1/PERK/CHOP pathways.
Xu F, Yi Y, Chi L … +4 more , Liu B, Zhang W, Wu Q, Li Z
Eur J Pharmacol · 2026 May · PMID 41997409 · Publisher ↗
BACKGROUND AND PURPOSE: Type 2 diabetes mellitus (T2D) exacerbates Alzheimer's disease (AD). Dendrobium nobile Lindl. alkaloids exhibited beneficial effects against T2D and/or AD. Dendrobine, a main alkaloid of Dendrobiu...
BACKGROUND AND PURPOSE: Type 2 diabetes mellitus (T2D) exacerbates Alzheimer's disease (AD). Dendrobium nobile Lindl. alkaloids exhibited beneficial effects against T2D and/or AD. Dendrobine, a main alkaloid of Dendrobium nobile, against T2D/AD comorbidity was further examined in this study. EXPERIMENTAL APPROACH: The T2D/AD comorbidity model was established by feeding 4-month-old 3 × Tg-AD mice with high-fat diet (HFD) for 8 months. Dendrobine was administered for 6 months after 2 months of high-fat diet feeding Blood glucose was monitored monthly and behavioral tests were conducted after 8-month of HFD. At the end of experiment, blood was collected for lipid profiling; pancreas and brain for histopathology, immunohistochemistry, and immunofluorescence. Hippocampal tissues were frozen for oxidative stress assays (ELISA) and protein analysis (Western blot). KEY RESULTS: Dendrobine ameliorated metabolic changes and pancreas damage, improved cognitive function and brain pathology in T2D/AD mice. It reduced oxidative damage in the pancreas and brain, as evidenced by Dihydroethidium staining and reduced ROS and reactive nitrogen species levels with increased antioxidant superoxide dismutase and glutathione S-transferase levels. Dendrobine increased insulin while decreased glucagon in pancreatic islet cells, but also increased insulin receptor expression in the brain, thus alleviating insulin resistance. T2D/AD comorbidity decreased Cav-1 in the pancreas and brain, accompanied by increased PERK and CHOP proteins to induce ER stress, which were ameliorated by Dendrobine in a dose-dependent manner. CONCLUSION AND IMPLICATIONS: Dendrobine was effective in the protection against T2D/AD comorbidity. The mechanisms of protection could be attributed to reversed insulin resistance, reduced oxidative damage and ER stress through the Cav-1/PERK/CHOP pathways.
Nitrate treatment decreases circulating matrix metalloproteinases concentrations in overweight women.
Cássia-Barros A, Sanches-Lopes JM, Conde-Tella SO … +6 more , Louzada-Junior P, Coelho EB, Kemp R, Salgado Júnior W, Moreno Junior H, Tanus-Santos JE
Eur J Pharmacol · 2026 May · PMID 41997408 · Publisher ↗
Nitrate is bioactivated to nitrite and nitric oxide (NO) and has been used to treat cardiovascular and metabolic diseases. Patients with obesity or overweight are exposed to increased cardiovascular risk, which is in par...
Nitrate is bioactivated to nitrite and nitric oxide (NO) and has been used to treat cardiovascular and metabolic diseases. Patients with obesity or overweight are exposed to increased cardiovascular risk, which is in part attributable to increased matrix metalloproteinase (MMP) activity and cardiovascular remodeling. Here, we examined the effects of NO supplementation with oral nitrate treatment on the circulating concentrations of MMP-2, MMP-9, and their endogenous inhibitors, the tissue inhibitors of MMPs (TIMP-1,-2,-3 and -4) in overweight women who had previously undergone Roux-en-Y gastric bypass (RYGB) surgery (n = 15), and those with no history of bariatric procedures (control, n = 13). Patients received 5g of beetroot extract enriched with sodium nitrate to daily intake of 0.1 mmol/kg body weight of nitrate for 14 days. Ambulatory blood pressure monitoring, carotid-femoral pulse wave velocity (PWV), and the Augmentation Index (AIx) were assessed at baseline and after nitrate treatment. Venous blood samples were collected for biochemical analysis at baseline and after nitrate treatment. MMP-2, MMP-9, and TIMP-1,-2,-3 and -4 were assessed using two Human Luminex® Discovery Assays. Nitrite and nitrate concentrations were assessed using ozone-based reductive chemiluminescence methods. Nitrate treatment decreased net MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios (which reflect net MMP activity) in overweight control women, but not in those with previous bariatric surgery (All P < 0.05). Nitrite and nitrate concentrations were negatively associated with net MMP-2 and MMP-9 activity. While VOP showed no significant differences, MMP-2 concentrations or MMP-2/TIMP-2 ratio associated positively with AIx. Our results provide evidence that nitrate treatment reduces net MMP-2 and MMP-9 activity in overweight women, highlighting its therapeutic potential to prevent cardiovascular remodeling. However, this effect appears to be attenuated in women with prior RYGB surgery.
Quizartinib-induced resistance drives clonal emergence of MV4-11 cells with molecular alterations enabling multidrug antileukemic escape.
de Miranda LBL, Lima K, Pereira-Martins DA … +11 more , Coelho-Silva JL, Tomaz V, Cortez LGF, Silva MFB, Guedes RLM, Campregher PV, Sternadt D, Rego EM, Traina F, Schuringa JJ, Machado-Neto JA
Eur J Pharmacol · 2026 May · PMID 41997407 · Publisher ↗
FLT3 inhibitors have become a cornerstone in the treatment of FLT3-mutated acute myeloid leukemia (AML), however, durable clinical responses are frequently limited by the emergence of acquired resistance. In this study,...
FLT3 inhibitors have become a cornerstone in the treatment of FLT3-mutated acute myeloid leukemia (AML), however, durable clinical responses are frequently limited by the emergence of acquired resistance. In this study, we established and comprehensively characterized a quizartinib-resistant FLT3-ITD AML model to elucidate the molecular and functional mechanisms underlying therapeutic failure. Prolonged exposure of MV4-11 cells to escalating concentrations of quizartinib resulted in the selection of quizartinib resistant clones (MV4-11QR), displaying an increase in IC and a shift from cytotoxic to predominantly cytostatic responses. Resistant cells maintained MAPK signaling despite FLT3 inhibition. Global proteomic profiling revealed extensive reprogramming, with enrichment of pathways related to energy metabolism, RNA processing, and translational regulation, accompanied by enhanced mitochondrial respiration and glycolytic capacity. Whole-genome sequencing identified acquisition of the FLT3 mutation and clonal expansion of TP53 with loss of the wild-type TP53 allele, indicating strong treatment-driven clonal selection. Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 inhibitor resistance in AML.
The history of β-aminoisobutyric acid: from a waste metabolite to a druggable compound for metabolic disease. A narrative review.
Begriche K, Massart J, Fromenty B
Eur J Pharmacol · 2026 May · PMID 41997406 · Publisher ↗
β-Αminoisobutyric acid (BAIBA) is a β-amino acid discovered in the 1950's as a waste product of valine and thymine biotransformation. In the early 2000s, we discovered that BAIBA could promote hepatic fatty acid oxidatio...
β-Αminoisobutyric acid (BAIBA) is a β-amino acid discovered in the 1950's as a waste product of valine and thymine biotransformation. In the early 2000s, we discovered that BAIBA could promote hepatic fatty acid oxidation (FAO) and ketogenesis, reduce fatty liver and body fatness, and improve glucose intolerance in obese mice, in a leptin-dependent manner. A few years later, another team reported that BAIBA was a myokine acting on white adipocytes to induce browning and confirmed that it could promote hepatic FAO. Since then, other researchers have borne out that BAIBA is a bona fide myokine whose circulating levels could serve as a biomarker in certain metabolic states and diseases. Moreover, further investigations showed that BAIBA could act on cells other than hepatocytes and adipocytes, including osteocytes, endothelial and neuronal cells, myocytes, and cardiomyocytes. In these cells, BAIBA exerts its metabolic and cytoprotective effects via different signaling pathways involving, for instance, AMP-activated protein kinase, protein kinase A, peroxisome proliferator-activated receptor γ coactivator 1, and peroxisome proliferator-activated receptors α and δ. Overall, these studies provide strong evidence that BAIBA presents favorable effects on different conditions associated with obesity and diabetes. This could make BAIBA a potential druggable compound since it presents an apparent good safety profile, while derivatives are currently being developed to enhance BAIBA biodistribution. This narrative review aims to tell the fascinating history of BAIBA, which spans 75 years.
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