European Journal Of Pharmacology[JOURNAL]
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200 papers
Betulinic acid ameliorates cavernous nerve injury-induced erectile dysfunction through Nrf2/HO-1 pathway activation and inhibition of mitochondrial damage-dependent corpus cavernosum smooth muscle cells apoptosis.
Xi Y, Zhang S, Li X … +4 more , Zhang X, Xue X, Hou G, Zhu F
Eur J Pharmacol · 2026 Jun · PMID 42114731 · Publisher ↗
The most prevalent complication of radical prostatectomy is erectile dysfunction (ED) resulting from cavernous nerve injury (CNI), which is primarily characterized by corporal apoptosis. Betulinic acid (BA) is an active...
The most prevalent complication of radical prostatectomy is erectile dysfunction (ED) resulting from cavernous nerve injury (CNI), which is primarily characterized by corporal apoptosis. Betulinic acid (BA) is an active pentacyclic triterpenoid with significant anti-apoptosis properties. Nevertheless, whether BA can improve CNI-induced ED remains unclear. A total of 20 male Sprague-Dawley rats randomized into Sham, bilateral CNI (BCNI), BCNI + low-dose BA, and BCNI + high-dose BA groups. Four weeks after daily intragastric administration of phosphate-buffered saline (PBS) or BA, electrical stimulation of the cavernous nerves was performed for erectile function assessment, followed by collection of penile tissues for histological analysis. An apoptotic model of corpus cavernosum smooth muscle cells (CCSMCs) was established using HO. Both low- and high-dose BA treatment improved ED and alleviated cavernous tissue damage in BCNI rats, accompanied by upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Additionally, BA alleviated HO-induced oxidative stress, mitochondrial damage, and apoptosis in CCSMCs. This protection was associated with coordinated decreases in reactive oxygen species, mitochondrial superoxide, mitochondrial permeability transition pore opening, and caspase3 levels, along with increased mitochondrial membrane potential, activated Nrf2/HO-1 signaling pathway, and improved mitochondrial morphology. However, this protective effect was partially attenuated by the Nrf2 inhibitor ML385. Overall, BA ameliorated ED and alleviated cavernosal damage in BCNI rats, primarily through Nrf2/HO-1-mediated protection against mitochondrial damage-dependent apoptosis in CCSMCs.
Inhibition of the serotonin transporter and risk of heart valve disease: A systematic review and meta-analysis.
Campbell A, Adamo A, Bektik E … +7 more , Kosuri Y, Karcher C, Levine D, Ramakrishnan R, Grau JB, Levy RJ, Ferrari G
Eur J Pharmacol · 2026 Jun · PMID 42107747 · Publisher ↗
BACKGROUND: The serotonin transporter (SERT) plays an essential role in regulating a wide range of physiological and psychological processes, including neurotransmitter homeostasis, circadian rhythm, sleep regulation, pl...
BACKGROUND: The serotonin transporter (SERT) plays an essential role in regulating a wide range of physiological and psychological processes, including neurotransmitter homeostasis, circadian rhythm, sleep regulation, platelet function, immune modulation, mood and emotions. Although SERT was initially studied in the context of neurological and psychiatric disorders, growing evidence highlights how its off-target exogenous inhibition, and the resulting dysregulation of serotonin signaling, can promote valvular interstitial cell proliferation, extracellular matrix remodeling, and fibrosis, thereby contributing to the pathophysiology of heart valve disease (HVD). Despite the increasing interest in the role of SERT in valve biology, mechanistic studies remain limited, and a deeper understanding of the implications of commonly used SERT-targeting drugs in the progression of HVD is still needed. METHODS: In this review, we examine the impact of drug-induced SERT inhibition on HVD, integrating findings from cellular studies, animal models, and clinical data to better understand the risks associated with chronic use of SERT inhibitors. To strengthen the clinical relevance of our review, we also performed a meta-analysis of published clinical studies on SERT-modulating drugs, which revealed a significant association between the use of these medications and increased HVD risk (OR = 2.76). CONCLUSIONS: Our analysis supports the implementation of clinical screening for high-risk patients, such as those with diabetes, hypertension, or pre-existing valvular abnormalities, prior to serotonergic drug recommendations. Ultimately, a deeper understanding of the role of serotonin and SERT in valvular pathophysiology may guide safer prescribing practices and facilitate the development of novel therapeutics for managing or preventing the progression of HVD.
SAHA induces immunogenic cell death in triple negative breast cancer cells and its efficacy is enhanced by SOCS3 functional replacement.
Castellano G, Bucciero C, Cugudda A … +4 more , La Manna S, Marasco D, Portella G, Malfitano AM
Eur J Pharmacol · 2026 Jun · PMID 42107746 · Publisher ↗
Triple negative breast cancer (TNBC) is an aggressive subtype associated with poor prognosis and limited therapeutic options. Epigenetic changes contribute to TNBC tumorigenesis, and histone deacetylase inhibitors (HDACi...
Triple negative breast cancer (TNBC) is an aggressive subtype associated with poor prognosis and limited therapeutic options. Epigenetic changes contribute to TNBC tumorigenesis, and histone deacetylase inhibitors (HDACi) have emerged as promising therapeutic agents. However, their efficacy as monotherapy in solid tumors remains limited. Recent evidence highlights their immunomodulatory potential, supporting the development of combination strategies. We investigated the effect of the HDACi suberoylanilide hydroxamic acid (SAHA) on cell viability and immunogenic cell death (ICD), as well as its combinatory potential with a SOCS3 peptidomimetic (KIRCONG chim PEG), designed to inhibit STAT3 phosphorylation (pSTAT3), in TNBC cell lines. SAHA reduced TNBC cell viability and, at its IC, induced ICD hallmarks in MDA-MB-231 cells, including ATP release, calreticulin surface exposure, and increased HMGB1 levels, accompanied by enhanced IL-6 secretion. In contrast, MDA-MB-468 cells showed limited ICD features under the same conditions. The higher IL-6 secretion observed in untreated MDA-MB-231 cells was associated with lower basal SOCS3 expression compared to MDA-MB-468 cells. Given the potential role of IL-6/JAK/STAT3 signaling in limiting HDACi efficacy, SAHA was combined with the SOCS3 peptidomimetic KIRCONG chim PEG. In MDA-MB-231 cells, co-treatment reduced pSTAT3 levels and increased BAK expression. Moreover, the combination shifted the IC of SAHA, indicating enhanced sensitivity to sub-toxic concentrations. Conditioned media from co-treated MDA-MB-231 cells promoted CD4T cell activation, as shown by increased HLA-DR and CD69 expression. Overall, these findings indicate that SOCS3 functional replacement enhances SAHA anti-cancer and immunogenic effects in IL-6 high TNBC cells, supporting a context-dependent combinatory strategy targeting the IL-6/STAT3 axis.
Heart-brain axis dysregulation in PTSD mice: Vagal-mediated insular cortex hyperactivity and its reversal by propranolol.
Niu J, Xia W, Li H … +6 more , Xia R, Wang J, Zhang J, Yang S, Zhu G, Chen L
Eur J Pharmacol · 2026 May · PMID 42107745 · Publisher ↗
BACKGROUND: While abnormal brain connectivity is central to PTSD, sympathetically-driven cardiac dysfunction also occurs. Given the established role of cardiac modulation of brain function and its implication in psychiat...
BACKGROUND: While abnormal brain connectivity is central to PTSD, sympathetically-driven cardiac dysfunction also occurs. Given the established role of cardiac modulation of brain function and its implication in psychiatric disorders, this study aims to delineate the role of the heart-brain connection in the mechanisms underlying PTSD. METHODS: A single prolonged stress (SPS)-induced male C57BL/6J mouse model of PTSD was employed. Anxiety- and fear-like behaviors were assessed using behavioral tests. Cardiac function and insular cortex excitability were measured via ECG, in vivo electrophysiology, and immunofluorescence. Chronic isoproterenol (ISO) mimicked sympathetic cardiac overactivation. Left cervical vagotomy tested the cardiac-to-insular pathway. Propranolol's therapeutic effect was evaluated. RESULTS: Both SPS and chronic ISO treatment significantly increased heart rate and induced prominent PTSD-like behaviors in mice. Electrophysiological and immunofluorescence analyses revealed markedly enhanced neuronal excitability in the insular cortex following SPS and ISO, as evidenced by increased c-Fos-positive neurons, elevated local field potential power spectral density, and altered frequency band distribution. Vagotomy blocked ISO-induced tachycardia and behavioral effects, identifying the vagus nerve as the critical signaling conduit. Furthermore, propranolol effectively reduced heart rate, suppressed excessive neuronal activation and abnormal oscillatory activity in the insular cortex, and significantly alleviated PTSD-like behaviors in SPS mice. CONCLUSION: This study highlights the critical role of heart-insular cortex functional interaction in PTSD pathogenesis, mediated by vagal transmission of sympathetically driven cardiac signals leading to insular cortex hyperactivity and behavioral abnormalities. Propranolol targets this pathway, showing therapeutic potential and providing novel insights into PTSD heart-brain mechanisms.
Cold-induced liver dysfunction drives cardiac damage through a liver-heart axis.
Feng J, Zhao T, Yao L … +10 more , Tang H, Zhang C, Hao Y, Sun X, Kachanov D, Dinislam K, Liu X, Fan Y, Zhang Y, Jiang W
Eur J Pharmacol · 2026 Jun · PMID 42107744 · Publisher ↗
A cold environment is a significant risk factor for cardiovascular diseases (CVDs), and its pathophysiological mechanisms involve complex interactions across multiple organ systems. However, the role of the liver as a ce...
A cold environment is a significant risk factor for cardiovascular diseases (CVDs), and its pathophysiological mechanisms involve complex interactions across multiple organ systems. However, the role of the liver as a central organ for metabolism and energy homeostasis in cold-related CVDs remains unclear. In this study, we systematically investigated the role of the liver in the pathogenesis of cardiac damage in cold regions by integrating clinical cohort studies, bioinformatic analysis, and animal experiments. The results demonstrated that in a cold-exposed population, serum alanine aminotransferase levels remained an independent risk factor for heart failure after adjusting for traditional cardiovascular risk factors. Transcriptomic analysis of liver tissues from chronically cold-exposed mice in a public database revealed that differentially expressed genes were significantly enriched in pathways related to lipid metabolism and cell cycle regulation. Animal experiments further confirmed that long-term cold exposure induced liver injury and dyslipidemia, accompanied by cardiac structural remodeling and myocardial injury. We identified and validated an activated hepatic cell cycle program through protein-protein interaction network analysis and Ki67 immunohistochemistry staining in cold-exposed mice. In vitro co-culture experiments further demonstrated that hepatocytes overexpressing cell cycle regulators induce cardiomyocyte injury through paracrine secretion of multiple factors. In summary, we identified liver injury as an independent risk factor for CVDs in cold regions and demonstrated that chronic cold stress induces liver metabolic dysregulation and aberrant activation of cell cycle signaling, which together contribute to cardiac injury through liver-heart crosstalk.
DL-norvaline attenuated HFD-induced metabolic inflammation and dysfunction with integrated pharmacokinetic, biodistribution, and safety evaluation.
Li X, Wang X, Lü X
Eur J Pharmacol · 2026 Jun · PMID 42105997 · Publisher ↗
Metabolic inflammation is a major contributor to obesity-related metabolic disturbances, yet safe and bioavailable dietary candidates with multi-organ activity remain limited. DL-norvaline, a nonproteinogenic amino acid,...
Metabolic inflammation is a major contributor to obesity-related metabolic disturbances, yet safe and bioavailable dietary candidates with multi-organ activity remain limited. DL-norvaline, a nonproteinogenic amino acid, was examined for its safety, pharmacokinetic characteristics, tissue distribution, and anti-inflammatory effects in models of high-fat diet (HFD)-induced obesity. Acute and subchronic oral toxicity studies showed no mortality or observable adverse effects, indicating a favorable safety margin. Pharmacokinetic analysis revealed rapid absorption, broad tissue distribution-particularly in liver, intestine, adipose tissue, and kidney-and approximately 20% cumulative excretion, suggesting systemic exposure without excessive accumulation. In vitro experiments using RAW264.7 macrophages demonstrated that DL-norvaline reduced LPS-induced expression of pro-inflammatory cytokines. In HFD-fed mice, DL-norvaline lowered LPS and inflammatory mediators, attenuated hepatic activation of multiple toll-like receptors and downstream MyD88/NF-κB signaling, and restored Nrf2-associated antioxidant genes. Improvements in oxidative stress, lipid-related gene expression, and liver injury further supported a protective role. Similar anti-inflammatory effects were observed in acute LPS-challenged and combined HFD-LPS models. Together, these findings indicate that DL-norvaline is a safe and systemically bioavailable amino acid that alleviates HFD-induced metabolic inflammation and dysfunction. The integrated toxicological, pharmacokinetic, and mechanistic results support its potential as a candidate for further development in the context of obesity-associated inflammatory disorders.
Multitarget pharmacological effects of Lawsone in mitigating Alzheimer's disease.
Bashir MA, Ullah I, Batool GA … +2 more , Khan AU, Shah SUA
Eur J Pharmacol · 2026 Jun · PMID 42105996 · Publisher ↗
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive neuronal loss, cognitive impairment, oxidative stress, neuroinflammation, and aggregation of abnormal proteins, includi...
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive neuronal loss, cognitive impairment, oxidative stress, neuroinflammation, and aggregation of abnormal proteins, including amyloid precursor protein (APP), amyloid-beta (Aβ), and hyper phosphorylated Tau (p-Tau). Developing therapies that simultaneously target multiple pathogenic pathways remains a major therapeutic challenge. Lawsone (LW), a naturally occurring naphthoquinone derived from the leaf of henna plant (Lawsonia inermis), was investigated for its therapeutic potential in AD. Computational studies were performed to evaluate binding affinities and stability of the compound against key AD-related molecular targets. Sprague-Dawley rats were randomly assigned to five groups: vehicle control, Scopolamine (SCP), donepezil (DNZ), and two groups treated with LW at doses of 2.5 and 5 mg/kg. Morris water Maze and Y Maze tests were employed to validate the behavioral performance. Oxidative stress markers were measured biochemically, tissue histopathology was evaluated using hematoxylin-eosin and Congo red staining. Expression of the proinflamatory markers, nuclear factor kappa β (NF-κβ), c-Jun N terminal kinase (c-JNK), Tumor necrosis factor-α (TNF-α) and Alzheimer's associated proteins APP, Aβ, and p-Tau were assessed through real time polymerase chain reaction (qPCR), enzyme linked immunosorbent assay (ELISA). Computational evaluation showed strong binding to NF-κβ, c-JNK, acetylcholinestrase (AChE), butyrylcholinestrase (BuChE) and TNF-α, supporting its multi-target potential. LW demonstrated neuropharmacological efficacy through preservation of neuronal structure, suppression of Aβ pathology, enhancement of cognitive function, restoration of antioxidant defenses, downregulation of proinflamatory, amyloidogenic, and tauopathic markers. These findings featured its potential as a multi target therapeutic agent for the management of AD.
Glycin-proline-hydroxyproline modified N-terminal 20 peptide from CEMP1 blocks calcium ion influx to alleviate inflammatory response in gingival fibroblasts.
Sun Y, Zhao Y, Xu L … +1 more , Sun W
Eur J Pharmacol · 2026 Jun · PMID 42105995 · Publisher ↗
Gingival fibroblasts play a pivotal role in the progression of periodontitis, and targeted inhibition of calcium ion influx in gingival fibroblasts represents a potential therapeutic strategy for ameliorating periodontal...
Gingival fibroblasts play a pivotal role in the progression of periodontitis, and targeted inhibition of calcium ion influx in gingival fibroblasts represents a potential therapeutic strategy for ameliorating periodontal inflammation. The N-terminal 20-amino-acid peptide derived from cementum protein 1 (N20) possesses calcium-chelating capacity, whereas the glycine-proline-hydroxyproline (GPH) tripeptide confers collagen-targeting binding ability. In this study, we engineered a GPH-modified N20 peptide (GPH-N20) and systematically investigated its anti-inflammatory effects in vitro. Our results demonstrated that GPH-N20 achieved high-efficiency targeted binding to both normal gingival fibroblasts and lipopolysaccharide (LPS)-stimulated inflammatory macrophages. This specific binding significantly blocked intracellular calcium influx and aberrant calcium signaling activation, and effectively abrogated LPS-induced pro-inflammatory responses in these cells. Mechanistic analyses further revealed that the dual functions of GPH-N20, its collagen-targeting capacity and calcium-chelating activity, synergistically suppressed the activation of the LPS-triggered Ca/calmodulin-dependent protein kinase II/nuclear factor-κB (CaMKII/NF-κB) signaling pathway, thereby attenuating the downstream pro-inflammatory cascades. Collectively, these findings validate that GPH-N20 is a promising anti-inflammatory agent with specific efficacy in alleviating gingival tissue inflammation, and thus provides a novel therapeutic candidate for the clinical management of periodontal inflammatory diseases.
Brimonidine attenuates choroidal thinning and hypoperfusion in guinea pigs with form-deprivation myopia: Involvement of NOS and TGF-β1.
Zeng F, He H, Luo Y … +4 more , Yang J, Li A, Zeng T, Huang G
Eur J Pharmacol · 2026 May · PMID 42105994 · Publisher ↗
Myopia is a major public health concern that poses a serious threat to vision. The combination of precise monitoring of changes in the choroidal structure and blood flow, along with early prevention and control through p...
Myopia is a major public health concern that poses a serious threat to vision. The combination of precise monitoring of changes in the choroidal structure and blood flow, along with early prevention and control through pharmacological intervention, represents a key direction in myopia research. In the present study, swept-source optical coherence tomography angiography was used to obtain dynamic assessments of wide-field choroidal thickness and blood flow in guinea pigs before and after form-deprivation (FD). The effects of brimonidine on refraction, axial length, choroidal thickness, and perfusion in guinea pigs with form-deprivation myopia (FDM) were assessed. In addition, the choroidal expression of nitric oxide synthase (NOS), neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), transforming growth factor-beta1 (TGF-β1), and α-smooth muscle actin (α-SMA) was quantified. The choroidal changes observed in the guinea pigs with FDM showed spatial heterogeneity, with areas of lower baseline choroidal thickness and blood flow showing greater susceptibility to FD stimulation and exhibiting more significant reductions. Brimonidine significantly slowed refraction and axial elongation in the FDM guinea pigs and broadly alleviated choroidal thinning and hypoperfusion. At the molecular level, brimonidine markedly reduced the FD-induced elevated choroidal expression of NOS, nNOS, eNOS, TGF-β1, and α-SMA. Brimonidine showed anti-myopic effects by preserving choroidal thickness and perfusion in FDM guinea pigs, potentially through suppression of the abnormally elevated expression of NOS, TGF-β1, and α-SMA in the choroid. These findings offer new insights and therapeutic targets for pharmacological prevention and control of myopia.
Multifaceted mechanisms of 4-hydroxybenzaldehyde in reducing hemorrhagic transformation in ischemic stroke ameliorating based on transcriptomics and metabolomics.
Chen M, Tan X, Hu D … +6 more , Sun H, Feng J, Li Y, Song X, Lin Q, He F
Eur J Pharmacol · 2026 Jun · PMID 42105993 · Publisher ↗
AIM OF THE STUDY: The PI3K-AKT signaling pathway has emerged as a central modulator in the pathophysiology of hemorrhagic transformation (HT). Gastrodia elata Blume, a classic neuroprotective herb used in Traditional Chi...
AIM OF THE STUDY: The PI3K-AKT signaling pathway has emerged as a central modulator in the pathophysiology of hemorrhagic transformation (HT). Gastrodia elata Blume, a classic neuroprotective herb used in Traditional Chinese Medicine, traditionally believed to "calm endogenous wind" and "unblock meridians". Although phenolic compounds are recognized as key neuroprotective constituents, their anti-hemorrhagic mechanisms remain. This study aimed to validate 4-hydroxybenzaldehyde (4-HBd), a major phenolic component of G. elata, as a therapeutic candidate against ischemic stroke (IS)-associated HT, with a focus on its modulation of PI3K-AKT signaling. MATERIALS AND METHODS: A rat model of transient middle cerebral artery occlusion with induced HT (tMCAO-HT) was established and treated with 4-HBd (20 mg/kg) for assessment of intracerebral hemorrhage and neurological function. Integrated transcriptomic and metabolomic profiling identified 214 differentially expressed genes and 38 differential metabolites. Molecular docking simulations evaluated 4-HBd binding to PI3K and AKT, and in vitro validation was performed in hypoxia-exposed PC12 cells using viability assays and western blot analysis. RESULTS: 4-HBd administration significantly attenuated cerebral hemorrhage (P < 0.01) and improved neurological function (P < 0.01). Multi-omics analysis revealed convergent enrichment of the PI3K-AKT pathway (KEGG: hsa04151), supported by high-affinity docking to both PI3K (ΔG = -5.7 kcal/mol) and AKT (ΔG = -5.3 kcal/mol). Treatment enhanced p-PI3K and p-AKT expression (P < 0.01), rescuing PC12 cells viability under hypoxic conditions (P < 0.05). CONCLUSIONS: 4-HBd exerts protective effects against HT by restoring PI3K-AKT signaling.
N-(3-((3-(trifluoromethyl)phenyl)selanyl)prop-2-yn-1-yl) benzamide ameliorates lipopolysaccharide-induced depression-like behavior in mice targeting inflammatory, apoptotic, and oxidative pathways.
Pires CS, da Rocha MJ, Zuge NP … +11 more , Besckow EM, Gonçalves AS, Birmann PT, Pinton S, Sousa FSS, Collares TV, Seixas FK, Fabrin MMI, Godoi B, Bortolatto CF, Brüning CA
Eur J Pharmacol · 2026 Jun · PMID 42105992 · Publisher ↗
The organoselenium compound CFSePB has previously shown promise as an antidepressant due to its modulation of the serotonergic system. This study aimed to investigate the potential of CFSePB to ameliorate depressive-like...
The organoselenium compound CFSePB has previously shown promise as an antidepressant due to its modulation of the serotonergic system. This study aimed to investigate the potential of CFSePB to ameliorate depressive-like behaviors induced by lipopolysaccharide (LPS) in mice. Male Swiss mice were pretreated with CFSePB (10 mg/kg, i. g.), vehicle (10 mL/kg, i. g.), or fluoxetine (20 mg/kg, i. p.), and 30 min later, they were treated with LPS (0.83 mg/kg, i. p.) or vehicle (10 mL/kg, i. p.). Twenty-four hours after LPS treatment, the forced swim test, tail suspension test, and splash test were conducted to assess depressive-like behaviors and open-field test was conducted to evaluate the locomotor activity. Mice were euthanized, and the hippocampal tissue was removed for biochemical parameters and gene expression analysis. Blood was also collected for corticosterone analysis. CFSePB effectively reversed LPS-induced depressive-like behaviors without affecting locomotion. Furthermore, CFSePB prevented the increase in the expression of the pro-inflammatory genes nuclear factor kappa B (NF-κB), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, and cyclooxygenase-2 (COX-2) and the apoptotic genes caspase-1, caspase-8, and BCL-2-Associated X Protein (BAX) induced by LPS in hippocampus, indicating its potential to target inflammation and neuronal death pathways. Furthermore, CFSePB increased BCL-2 and BDNF, targets associated with neuronal survival. It also reduced reactive species (RS) and lipid peroxidation levels in hippocampus induced by LPS. Additionally, the treatment with the compound reduced the LPS-induced plasma corticosterone levels. These findings highlight the potential of CFSePB as a novel therapeutic agent for depression, particularly in models involving inflammation-mediated mechanisms.
Micropeptide PEP1695 mitigates lung injury in COPD mice by inhibiting epithelial-mesenchymal transition of type II alveolar epithelial cells.
Zhang M, Zhang X, Zhou Y … +5 more , Zhang Y, Huang Y, Xie G, Bao W, Tian X
Eur J Pharmacol · 2026 Jun · PMID 42105991 · Publisher ↗
Micropeptides encoded by small open reading frames (smORFs) within long noncoding RNAs (lncRNAs) have emerged as important regulators of various biological processes. However, whether micropeptides mitigate lung tissue d...
Micropeptides encoded by small open reading frames (smORFs) within long noncoding RNAs (lncRNAs) have emerged as important regulators of various biological processes. However, whether micropeptides mitigate lung tissue damage in chronic obstructive pulmonary disease (COPD) remains poorly understood. In COPD, the epithelial-mesenchymal transition (EMT) of type II alveolar epithelial (ATII) cells plays a crucial role in lung injury, contributing to fibrosis and airway remodeling. Modulating EMT could offer a promising therapeutic strategy for COPD. In this study, we identified a micropeptide, PEP1695, encoded by lncRNA-MSTRG.1695.1, as a key regulator of EMT in mouse ATII cells. Mechanistic investigations revealed that PEP1695 inhibits EMT in ATII cells by binding to p38-MAPK. Using a COPD mouse model, we observed a significant reduction in PEP1695 expression in ATII cells, administration of PEP1695 effectively improved lung function and reduced inflammation, highlighting its potential as a novel targeted biologic therapy for COPD. Moreover, preliminarily serum analysis from COPD patients revealed a positive correlation between PEP1695 homolog levels and lung function. PEP1695 represents a promising therapeutic target for lung injury in COPD and has preliminarily shown potential as a serum marker for the evaluation of early fibrosis in COPD patients.
Troxerutin attenuates paclitaxel-induced cardiotoxicity through modulation of ferroptosis and GRP78/ATF6/CHOP signaling in rats.
El-Naggar YM, El Wakeel S, George MY … +1 more , Elsherbiny DA
Eur J Pharmacol · 2026 Jun · PMID 42103053 · Publisher ↗
Paclitaxel (PXT) is an effective chemotherapeutic agent whose clinical use is limited by serious cardiotoxic effects, including arrhythmias, myocardial infarction, and heart failure. Troxerutin (TXR) is a bioflavonoid wi...
Paclitaxel (PXT) is an effective chemotherapeutic agent whose clinical use is limited by serious cardiotoxic effects, including arrhythmias, myocardial infarction, and heart failure. Troxerutin (TXR) is a bioflavonoid with demonstrated cardioprotective properties in various cardiac injury models, including cardioprotective effects in doxorubicin-induced myocardial injury, as well as diabetic myocardiopathy. This study, therefore, investigates whether TXR can mitigate PXT-induced cardiotoxicity and explores the underlying protective mechanisms. Male Wistar rats were treated with either PXT (7.5 mg/kg/week, i.p.) and/or TXR (150 mg/kg/day, oral) for 28 days. TXR restored the histological structure of the myocardial tissues, as well as heart weight and heart index, which were disrupted following PXT treatment. In addition, TXR alleviated PXT-induced elevation of cardiac damage indicators such as Troponin I and CK-MB. Furthermore, TXR counteracted the PXT effect on cardiac iron deposits and mitigated PXT-induced imbalance of redox homeostasis as evidenced by the abridged reactive oxygen species level, raised levels of the antioxidant enzymes glutathione peroxidase-4, catalase and superoxide dismutase, attenuating ferroptosis induced by PXT. Besides, TXR ameliorated PXT-induced endoplasmic reticulum (ER) stress as indicated by reduced ER stress markers C/EBP homologous protein, activating transcription factor-6, and glucose regulatory protein-78. Moreover, TXR hindered apoptosis induced by PXT, as evidenced by its effect on the BAX and BCL-2 expressions. Importantly, TXR did not abrogate the anticancer activity of PXT in cultured human MDA-MB cells. In conclusion, TXR hindered the cardiotoxicity of PXT and showed cardioprotective effects via its inhibitory actions on ER stress, ferroptosis, oxidative stress, and apoptosis.
Therapeutic effect of rutin on Henoch-Schönlein purpura by attenuating inflammation and protection of the intestinal barrier function in rats.
Zhao W, Ouyang M, Mu J … +5 more , You L, Li X, Yu J, Hu Y, Guo P
Eur J Pharmacol · 2026 May · PMID 42103052 · Publisher ↗
Henoch-Schönlein purpura (HSP) or immunoglobulin A vasculitis (IgAV) is the most common systemic vasculitis in children. Rutin is a flavonoid with anti-inflammatory and antioxidant effects. This study aimed to investigat...
Henoch-Schönlein purpura (HSP) or immunoglobulin A vasculitis (IgAV) is the most common systemic vasculitis in children. Rutin is a flavonoid with anti-inflammatory and antioxidant effects. This study aimed to investigate the protective effects of rutin in a rat model of HSP induced by ovalbumin. Results showed that 12.05 mg/kg of rutin significantly alleviated skin purpura, renal injury and systemic inflammation. It ameliorated vascular endothelial injury by reducing IgA deposition, modulating vasoactive substances including nitric oxide and endothelin-1, as well as vascular endothelial growth factor, and inhibiting the transforming growth factor-β1/SMAD family member 3 signaling pathway. These therapeutic effects were mediated through multiple mechanisms, including increasing the expression of zonula occludens-1 and occludin to maintain intestinal barrier integrity, modulating gut microbiota composition, and regulating the metabolism of short-chain fatty acids and amino acids. This study provides novel mechanistic insights and evidence supporting the clinical application of rutin in HSP.
Astilbin directly targets trimethylguanosine synthase 1 to enhance telomerase activity thus alleviating pulmonary fibrosis.
Zhao J, Xia B, Hu X … +6 more , Chang C, Zhou X, Li X, Zhu B, Liu X, Wang Y
Eur J Pharmacol · 2026 May · PMID 42097201 · Publisher ↗
Pulmonary fibrosis (PF) is an intractable chronic interstitial lung disease with limited effective therapeutic options. Accumulating evidence suggests that astilbin (AST), a natural flavonoid isolated from traditional Ch...
Pulmonary fibrosis (PF) is an intractable chronic interstitial lung disease with limited effective therapeutic options. Accumulating evidence suggests that astilbin (AST), a natural flavonoid isolated from traditional Chinese herbs, possesses anti-inflammatory and anti-fibrotic properties. However, its therapeutic potential and underlying mechanisms in PF remain incompletely understood. In this study, a bleomycin (BLM)-induced mouse model was established to evaluate the in vivo anti-fibrotic efficacy of AST. HE staining and Masson's Trichrome staining were employed to assess the severity of PF. Western blot, RT-qPCR, ELISA, and immunofluorescence assays were used to investigate the mechanism of AST. Molecular docking, molecular dynamics simulations, and microscale thermophoresis (MST) were performed to evaluate whether TGS1 may serve as a direct binding target of AST. Finally, trimethylguanosine synthase 1 (TGS1) knockdown was performed to validate whether AST exerts its anti-fibrotic effects in a TGS1-dependent manner. The results supported a direct interaction between AST and TGS1, increased telomerase-related components, and alleviated the DNA damage response (DDR). These changes were associated with suppression of the STING-IRF3-NF-κB cascade, leading to reduced release of senescence-associated secretory phenotype (SASP) factors. This further inhibited the TGF-β1/SMAD pathway and reduced the expression of fibrotic markers in lung tissues. Collectively, these findings indicate that AST exerts anti-fibrotic effects, at least in part, through interaction with TGS1, thereby providing a basis for the development of AST-based anti-fibrotic drugs.
Neuropeptide S alleviates neuropathic pain through lateral hypothalamic orexinergic circuit in rats.
Patil UP, Kawade HM, Pandhare DM … +4 more , Bothikar SA, Dhinakaran S, Subhedar NK, Kokare DM
Eur J Pharmacol · 2026 Jun · PMID 42097200 · Publisher ↗
Neuropathic pain poses a significant clinical challenge due to limited treatment options. Neuropeptide S (NPS) system is known to modulate pain and related affective states; however, the underlying mechanisms remain unex...
Neuropathic pain poses a significant clinical challenge due to limited treatment options. Neuropeptide S (NPS) system is known to modulate pain and related affective states; however, the underlying mechanisms remain unexplained. NPS activates lateral hypothalamic (LH) orexinergic neurons involved in feeding, drug seeking, and stress-induced analgesia. Herein, we test the hypothesis that pain modulatory action of NPS is mediated by the LH-orexinergic system. Neuropathic pain was induced in rats via chronic constriction injury (CCI) of the sciatic nerve and the response was investigated using paw withdrawal latency (PWL) and paw withdrawal threshold (PWT). Decreased expression of NPS protein and NPS receptor mRNA was observed in the LH of CCI rats. Intra-LH injection of NPS to CCI rats significantly increased the PWL and PWT, while NPSR antagonist SHA-68 exacerbated the responses. Orexin-1/2 receptor antagonist (intra-ventrolateral periaqueductal gray (vlPAG) blocked the antinociceptive effect of NPS. However, infusion of SB-334867 into the nucleus accumbens and ventral tegmental area, the primary targets of orexinergic fibres, resulted in partial blockade. To test whether NPS in the LH activates the orexinergic projection to the vlPAG, Fast Blue was injected into the vlPAG and the fibers were retrogradely traced to orexin neurons in the LH. Intra-LH administration of NPS to CCI rats resulted in increased expression of cFos in the orexin neurons. The vlPAG in CCI rats showed elevated GABA and reduced glutamate; the changes were reversed following intra-LH NPS administration. We suggest that the NPS system, acting via LH-vlPAG orexinergic circuit, may alleviate neuropathic pain.
Neuroprotective effects of cinnamaldehyde and naltrexone on morphine-induced hippocampal neurotoxicity: Behavioral, biochemical, ultrastructural evaluations.
Mahmoudi SS, Farshid AA, Tamaddonfard E … +2 more , Erfanparast A, Imani M
Eur J Pharmacol · 2026 Jun · PMID 42097199 · Publisher ↗
Chronic consumption of opiates such as morphine can exert serious adverse effects such as cognitive disturbances. Cinnamaldehyde has a potent neuroprotective property. The current study was targeted to explore the effect...
Chronic consumption of opiates such as morphine can exert serious adverse effects such as cognitive disturbances. Cinnamaldehyde has a potent neuroprotective property. The current study was targeted to explore the effect of cinnamaldehyde on morphine-induced behavioral and hippocampal biochemistry, histopathology and ultrastructure outcomes and molecular changes. Thirty rats were divided into five groups of six rats in each for receiving normal saline + normal saline, normal saline + morphine 40 mg/kg, cinnamaldehyde 10 mg/kg + morphine 40 mg/kg, cinnamaldehyde 20 mg/kg + morphine 40 mg/kg and naltrexone (an opioid receptor antagonist) 5 mg/kg + morphine 40 mg/kg. Another 24 rats were divided into four groups of six for treating with the above-mentioned treatments in the absence of morphine. Weekly body weight, behavioral tests and hippocampal tissue biochemical, histopathological, ultrastructural alterations were determined. Morphine-induced body weight loss and cognitive deficits, as measured with the Morris water maze (MWM) and elevated plus maze-transfer latency (EPM-TL) tests, were improved by cinnamaldehyde and naltrexone. Hippocampal malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant (TAC), tumor necrosis factor-α (TNF-α), caspase-3, and acetylcholinesterase (AChE) content alterations were restored by cinnamaldehyde and naltrexone. Neuronal shrinkage, vacuolation and loss and mitochondrial vacuolation and myelin sheath lamellar spacing in the hippocampus were improved. No significant differences were observed in normal saline, cinnamaldehyde and naltrexone treatments in the absence of morphine. These results indicated that cinnamaldehyde and naltrexone exert neuroprotective effects against morphine-induced cognitive deficits through antioxidant, anti-inflammatory, anti-apoptotic and anti-AChE mechanisms in the hippocampus.
A ferulic acid derivative FAD012 protects brain microvascular endothelial cells from HO-induced ferroptosis via NRF2 activation.
Aoyama T, Xuan M, Kitaoka S … +6 more , Takayama J, Yuan B, Matsuzaki H, Egawa Y, Sakamoto T, Okazaki M
Eur J Pharmacol · 2026 May · PMID 42097198 · Publisher ↗
Ferroptosis, a regulated form of necrotic cell death characterized by iron-dependent lipid peroxidation, has been implicated in blood-brain barrier (BBB) disruption during ischemia-reperfusion injury, particularly in bra...
Ferroptosis, a regulated form of necrotic cell death characterized by iron-dependent lipid peroxidation, has been implicated in blood-brain barrier (BBB) disruption during ischemia-reperfusion injury, particularly in brain microvascular endothelial cells. We previously developed a novel derivative of ferulic acid (FA), FAD012, and demonstrated its neurovascular protective effects in multiple rat models of cerebral ischemia. In this study, we investigated whether FAD012 protects rat brain microvascular endothelial cells (RBMVECs) from hydrogen peroxide (HO)-induced ferroptosis and further elucidated its underlying mechanisms. HO-induced cell death was attenuated by ferroptosis inhibitors (ferrostatin-1 and deferoxamine) and was accompanied by downregulation of glutathione peroxidase 4 and 4-hydroxynonenal accumulation, collectively indicating the induction of ferroptosis. Pretreatment with FAD012 restored cell viability, mitigated lipid peroxidation, and prevented ferroptosis more effectively than its parent compound, FA. Mechanistically, FAD012 scavenged reactive oxygen species and promoted nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation and downstream antioxidant signaling. Inhibition of NRF2 by ML385 abolished the cytoprotective effects of FAD012, confirming the critical role of NRF2 activation. These findings suggest that FAD012 suppresses HO-induced ferroptosis in RBMVECs through both direct antioxidant activity and NRF2 activation, providing a mechanistic basis for its potential to preserve BBB integrity under oxidative stress in vivo.
Citral exerts a more pronounced antinociceptive effect in obese adult male C57BL/6J mice mediated through the CB2 receptor.
Dario FL, Aquino MLA, Emílio-Silva MT … +9 more , Fagundes FL, de Oliveira LVF, Guidolin IG, Fioravanti MM, Assunção R, Rodrigues VP, Bueno G, Nishijima CM, Hiruma-Lima CA
Eur J Pharmacol · 2026 Jun · PMID 42092487 · Publisher ↗
BACKGROUND: Obesity is a prevalent chronic disease strongly associated with pain, primarily due to low-grade systemic inflammation that sensitizes nociceptive neurons. OBJECTIVE: To evaluate the effects of citral, an acy...
BACKGROUND: Obesity is a prevalent chronic disease strongly associated with pain, primarily due to low-grade systemic inflammation that sensitizes nociceptive neurons. OBJECTIVE: To evaluate the effects of citral, an acyclic monoterpene, present in essential oils such as Cymbopogon citratus (lemongrass), on nociception in obese mice and identify the mechanisms involved. METHODS: Adult male C57BL/6J mice (n = 270) were fed a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. Metabolic alterations were confirmed using an oral glucose tolerance test. Nociception was assessed using the formalin test to evaluate both neurogenic (phase I) and inflammatory (phase II) pain. Citral (100 or 300 mg/kg) was orally administered. Carrageenan-induced paw edema was utilized to investigate anti-inflammatory properties. Antagonists for 5-HT2A (ketanserin, 1 mg/kg, i.p.) and CB2 (AM630, 1 mg/kg, i.p.) receptors were used. The vehicle group received 1% Tween 80 (10 mL/kg, orally). Statistical significance was set at p < 0.05. RESULTS: HFD-fed mice developed obesity, hyperglycemia, and increased thermal sensitivity. Citral (300 mg/kg) significantly reduced nociception in both phases of the formalin test in SD and HFD mice, with a greater effect in the HFD group. CB2 receptor antagonism reversed the antinociceptive effects of citral in both phases of the formalin test, whereas 5-HT2A antagonism produced no change. LPS did not influence citral-induced antinociception only in obese mice, and citral showed no effect in the hot-plate test. CONCLUSION: Citral exerts antinociceptive effects in both eutrophic and obese mice, with enhanced efficacy in obese mice. Its action is mediated, at least in part, by CB2 receptor modulation, which reduces both neurogenic and inflammatory pain. These findings suggest that citral is a potential therapeutic candidate for pain management in obesity-related conditions.
The pulmonary circadian rhythms (diurnal rhythms) role of the Bmal1/Per2 axis in mitigating ventilator-induced lung injury and fibrosis through Nrf2 antioxidant pathway activation.
Li DC, Wu MH, Ruan HY
Eur J Pharmacol · 2026 Jun · PMID 42092486 · Publisher ↗
BACKGROUNDS: While lung-protective ventilation strategies are standard care, effective adjunctive pharmacotherapies for ventilator-induced lung injury (VILI) remain lacking. Disruption of circadian (diurnal) rhythms is i...
BACKGROUNDS: While lung-protective ventilation strategies are standard care, effective adjunctive pharmacotherapies for ventilator-induced lung injury (VILI) remain lacking. Disruption of circadian (diurnal) rhythms is implicated in various lung pathologies, and the exploration of circadian regulation in VILI has emerged as a clinically relevant research direction for optimizing mechanical ventilation strategies. We hypothesized that the pulmonary Bmal1/Per2 axis confers protection against VILI by activating the Nrf2 antioxidant pathway. METHODS: A murine model of VILI was established via high-tidal volume ventilation. Lung epithelial cell-specific Bmal1 knockout mice (Bmal1; ∗SPC-CreERT2∗) and wild-type littermates were used to define the role of the Bmal1/Per2 axis. Lung injury was assessed histologically, by bronchoalveolar lavage fluid protein, and wet/dry weight ratio. Fibrosis was evaluated after a recovery period using hydroxyproline assay and Masson's trichrome staining. Molecular mechanisms were analyzed by qPCR, western blot, and immunohistochemistry. The specific Nrf2 inhibitor ML385 was employed to validate pathway involvement. RESULTS: VILI significantly disrupted pulmonary circadian rhythms, suppressing rhythmic Bmal1 and Per2 expression. Bmal1 deficiency markedly exacerbated VILI, increasing lung injury scores by approximately 2-fold, alveolar permeability by 1.8-fold, and edema. These mice subsequently developed more severe pulmonary fibrosis. This aggravated phenotype was associated with a blunted activation of the Nrf2-mediated antioxidant response, demonstrated by reduced expression of Nrf2 and its downstream targets HO-1 and NQO1. Pharmacological inhibition of Nrf2 with ML385 in wild-type mice abolished the protective effect, resulting in injury and fibrosis severity comparable to Bmal1-deficient animals. CONCLUSION: This study establishes a crucial functional link between the circadian clock and oxidative stress in mechanical lung injury, identifying the Bmal1/Per2-Nrf2 axis as a potential target for chronotherapeutic intervention. Notably, this work is the first to define the specific Bmal1/Per2 regulatory module and its direct causal connection with the Nrf2 pathway in mediating VILI-induced pulmonary fibrosis, extending prior observations of general circadian rhythm disruption in lung injury to a mechanistically actionable signaling axis.
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