Eur. J. Pharmacol. [JOURNAL]
Sun
200 papers
Nitric oxide signaling in Alzheimer's disease: A double-edged sword.
Wasim R
Eur J Pharmacol · 2026 Jul · PMID 42140516 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral changes, primarily affecting the elderly population. Despite extensive research,...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral changes, primarily affecting the elderly population. Despite extensive research, the exact pathogenesis of AD remains elusive, with proposed mechanisms involving amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, neuroinflammation, and neuronal apoptosis. Nitric oxide (NO), a gaseous signaling molecule synthesized by nitric oxide synthases (NOS), plays dual roles in AD pathophysiology-acting as both a neuroprotective and neurotoxic agent depending on its concentration and cellular context. The NO-cGMP signaling pathway is integral to synaptic plasticity, long-term potentiation, and neurogenesis, processes essential for memory and learning. Conversely, excessive NO generation via inducible NOS contributes to neuroinflammation, oxidative and nitrosative stress, and neuronal damage. NO also modulates cerebral blood flow, neuroplasticity, and myelination, influencing AD progression. Current pharmacological management focuses on symptomatic relief through cholinesterase inhibitors and NMDA receptor antagonists, while emerging NO-based therapies and PDE-5 inhibitors show potential neuroprotective benefits. Additionally, anti-inflammatory agents and herbal compounds targeting NO-mediated pathways, exhibit promising neuroprotective properties. A deeper understanding of NO's dualistic role may provide novel therapeutic strategies for mitigating AD progression and enhancing cognitive resilience.
Transcriptomics-driven drug screening identifies BRD-K78062244 in promoting white adipose tissue browning.
Xiong N, Mi L, Wang X … +8 more , Zhang T, Zhang G, Chen Y, Mo D, Peng J, Yao H, Li S, Shi G
Eur J Pharmacol · 2026 Jun · PMID 42140515 · Publisher ↗
Obesity and its related comorbidities have become increasingly challenging in public health globally, and white adipose tissue (WAT) browning enhances energy expenditure and provides a promising therapeutic strategy for...
Obesity and its related comorbidities have become increasingly challenging in public health globally, and white adipose tissue (WAT) browning enhances energy expenditure and provides a promising therapeutic strategy for treating obesity. However, few drugs have been clinically approved for promoting WAT browning largely due to the involvement of complex signaling pathways, which limits the application of traditional drug screening approaches. Thus, a cross-species gene set that marks the adipose browning process was constructed, and a systematic strategy for compound screening was developed. By integrating single-nucleus and bulk RNA sequencing data from both humans and mice, we established a signature gene set named "white adipose tissue browning-associated gene" (WAT-BAG) through differential gene expression analysis. Candidate compounds were identified by integrating the WAT-BAG gene set with the Connectivity Map (CMap) database, followed by functional validation both in vitro and in vivo. Among the candidates, BRD-K78062244 was ranked as a top compound that induced transcriptional changes resembling the WAT-to-BAT transition. Further analysis revealed that BRD-K78062244 activated the PPAR signaling pathway and inhibited lipid droplet accumulation in adipocytes in vitro. Moreover, intra-inguinal injection of BRD-K78062244 enhanced glucose handling capacity in lean adult mice, accompanied by transcriptomic evidence of enhanced thermogenesis and suppression of lipogenic programs in adipose tissue. This study introduces a transcriptome-guided drug screening strategy that overcomes the limitations of conventional single-target approaches and highlights the potential of BRD-K78062244 in metabolic remodeling. Our findings offer a new framework for identifying compounds that promotes WAT browning via multi-omics-derived gene signatures.
Multi-target mechanisms of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone from Syzygium nervosum DC. flower buds in alleviating obesity and metabolic complications: An integrated study combining network pharmacology and experimental validation.
Fei R, Xu L, Yuanyuan L … +6 more , Feng W, Zhentao M, Wenjun W, Yiqi L, Lu X, Wenna L
Eur J Pharmacol · 2026 Jun · PMID 42140514 · Publisher ↗
The flower buds of Syzygium nervosum DC., a traditional herbal tea in southern China, contain the principal chalcone 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC). DMC exhibits multiple pharmacological activiti...
The flower buds of Syzygium nervosum DC., a traditional herbal tea in southern China, contain the principal chalcone 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC). DMC exhibits multiple pharmacological activities, yet its impact on obesity and related metabolic diseases (ORD) remains to be fully explored. To systematically characterise the therapeutic targets and mechanisms of DMC against ORD, network pharmacology was applied to predict DMC targets, followed by protein-protein interaction (PPI) network construction and GO/KEGG enrichment analysis. Molecular docking was performed using MOE software. For in vivo validation, high-fat diet (HFD)-induced obese rats were administered DMC for 8 weeks, and metabolic phenotyping, histopathology, ELISA, qRT-PCR, and western blotting were evaluated. Analysis identified 92 common targets, with IL-6, IL1B, TNF, MMP9, and PTGS2 confirmed as core targets. KEGG analysis revealed significant enrichment of pathways in cancer, lipid and atherosclerosis, and endocrine resistance pathways. DMC intervention effectively alleviated metabolic profiles, reduced adiposity and hepatic steatosis, promoted mitochondrial β-oxidation, and maintained intestinal barrier integrity through anti-inflammatory and antioxidant mechanisms. Molecular docking confirmed stable binding between DMC and 12 key proteins involved in inflammation, oxidative stress, and energy homeostasis. Collectively, these findings indicate that DMC ameliorates ORD through multi-target mechanisms involving metabolic regulation, intestinal barrier protection, and anti-inflammatory actions, supporting its potential as a natural therapeutic agent.
Carboplatin alleviates astrocytic TDP-43 neurotoxicity by inhibiting NF-κB activation.
Song J, Lee S, Lee J … +6 more , Gil Y, Kim T, Kim SY, Cha SJ, Kim HJ, Kim K
Eur J Pharmacol · 2026 Jun · PMID 42134762 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) is a rare and progressive motor neuron disease; however, its exact pathogenic mechanisms remain unclear. Currently, no effective treatments are available for this disease. Therefore, i...
Amyotrophic lateral sclerosis (ALS) is a rare and progressive motor neuron disease; however, its exact pathogenic mechanisms remain unclear. Currently, no effective treatments are available for this disease. Therefore, in this study, we investigated the anti-inflammatory effects of the anti-cancer agent, carboplatin, on neuronal cells and its potential therapeutic effects against ALS. Carboplatin inhibited NF-κB phosphorylation in the transactive response DNA-binding protein (TDP)-43-transfected astrocytes, reducing pro-inflammatory cytokine levels, without affecting the TDP-43 protein levels. In neuron-astrocyte co-culture models, carboplatin effectively alleviated TDP-43-induced toxicity by restoring mitochondrial integrity, specifically rescuing basal respiration, ATP production, and maximal respiratory capacity. In vivo, carboplatin rescued the locomotor deficits in glial-specific TDP-43-expressing Drosophila, without altering TDP-43 protein levels and subcellular localization. These findings suggest that TDP-43-induced astrocytic damage compromises mitochondrial functions in adjacent neurons, and that carboplatin-mediated restoration of TDP-43-mediated astrocyte damage is critical for neuronal survival and functions. Therefore, carboplatin, a chemotherapeutic agent, represents as a potential therapeutic candidate for TDP-43-associated proteinopathies.
Poliumoside alleviates oxidative stress and improves mitochondrial function to alleviate ischemic stroke injury.
Qin R, Han BW, Tao JY … +6 more , Jin XZ, Zhang WF, Zhao WL, Feng WD, Du GH, Wang YH
Eur J Pharmacol · 2026 Jun · PMID 42134761 · Publisher ↗
This study investigated the neuroprotective effects and mechanisms of poliumoside (POL) against ischemic stroke, focusing on oxidative stress and mitochondrial dysfunction. Using an Oxygen-Glucose Deprivation/Reperfusion...
This study investigated the neuroprotective effects and mechanisms of poliumoside (POL) against ischemic stroke, focusing on oxidative stress and mitochondrial dysfunction. Using an Oxygen-Glucose Deprivation/Reperfusion (OGD/R) model in Neuro-2a cells and a photothrombotic stroke model in C57BL/6J mice, we demonstrated that POL treatment significantly improved post-injury outcomes. In mice, POL enhanced motor coordination and grip strength, reduced cerebral infarct volume, and alleviated neuronal damage and apoptosis. Crucially, it suppressed brain oxidative stress, as shown by decreased reactive oxygen species (ROS) levels. In OGD/R-injured Neuro-2a cells, POL dose-dependently increased cell viability, reduced ROS and apoptosis, and improved mitochondrial function by stabilizing membrane potential and attenuating calcium overload. Mechanistically, POL activated the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway antioxidant pathway, promoting Nrf2 nuclear translocation and upregulating downstream proteins Heme oxygenase 1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). It also modulated autophagy by affecting Microtubule-associated proteins 1A/1B light chain 3B (LC3B) and Sequestosome 1 (SQSTM1), and exerted anti-apoptotic effects by regulating B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax). In conclusion, POL confers protection against ischemic injury primarily by mitigating oxidative stress and preserving mitochondrial integrity via activation of the Nrf2 pathway and regulation of associated cellular processes.
Inhibition of mPTP and GSDME-mediated pyroptosis alleviates lung injury in septic mice.
Lu N, Yu MJ, Zhang R … +5 more , Meng ZF, Ye HW, Yu Y, Gao Q, Hu JF
Eur J Pharmacol · 2026 Jun · PMID 42134760 · Publisher ↗
OBJECTIVE: To explore the role of mitochondrial permeability transition pore (mPTP) and gasdermin E (GSDME) - mediated pyroptosis in septic lung injury in mice model. METHODS: Adult male c57BL/6J mice were randomly assig...
OBJECTIVE: To explore the role of mitochondrial permeability transition pore (mPTP) and gasdermin E (GSDME) - mediated pyroptosis in septic lung injury in mice model. METHODS: Adult male c57BL/6J mice were randomly assigned with 10 mice in each group. Sepsis model was established by cecal ligation and puncture (CLP) operation. Alisporivir (AL) was used to inhibit the opening of mPTP, plumbagin (PL) was used to open mPTP. Knockdown or overexpression of GSDME were done by Adeno associated virus 6 (AAV 6). The changes of lung tissue, ultrastructure, reactive oxygen species (ROS), GSDME-mediated pyroptosis related proteins, inflammatory factors and mitochondrial function were detected. RESULTS: Compared with Sham group, the aggravating of lung injury, mitochondrial dysfunction, oxidative stress and inflammatory reaction were shown in CLP and GSDME high-expression groups, and the opening of mPTP, the mRNA levels of pyroptosis related genes were increased, the expressions of pyroptosis related proteins were increased. After inhibiting mPTP opening by AL or knockdown GSDME respectively, septic lung injury was alleviated, mitochondrial function was improved, oxidative stress and inflammatory response were reduced, the mRNA levels of GSDME and Caspase-3 were decreased, the protein expressions of GSDME, Caspase-3, IL-1β and IL-18 were reduced. In knockdown GSDME group, the application of PL to open mPTP still played the protective role. CONCLUSION: Inhibiting mPTP opening or GSDME-mediated pyroptosis both alleviated septic lung injury. The mPTP is the upstream of GSDME, GSDME-N can also positively promote mPTP opening, mPTP and GSDME regulates each other in the GSDME-mediated pyroptosis pathway.
Characterization of mitochondrial dysfunction induced by BAX trigger site activator 1 in the ARPE-19 retinal pigment epithelial cell model.
Kashihara T, Akiyama Y, Morita A … +3 more , Deguchi S, Odaka R, Nakahara T
Eur J Pharmacol · 2026 Jun · PMID 42134759 · Publisher ↗
Mitochondrial dysfunction in the retinal pigment epithelium (RPE) is a key pathological feature of age-related macular degeneration (AMD). However, mechanistically defined experimental models that recapitulate stress-med...
Mitochondrial dysfunction in the retinal pigment epithelium (RPE) is a key pathological feature of age-related macular degeneration (AMD). However, mechanistically defined experimental models that recapitulate stress-mediated mitochondrial injury remain limited. Bcl-2-associated X (BAX), a key pro-apoptotic effector, serves as a critical upstream regulator of mitochondrial outer membrane permeabilization. In this study, we systematically characterized mitochondrial dysfunction induced by BAX trigger site activator 1 (BTSA1), a selective small-molecule BAX activator, in ARPE-19 cells. Treatment with BTSA1 (3-60 μM) for 24 and 48 h induced a concentration- and time-dependent reduction in cell viability, accompanied by caspase-3 activation. Mitochondrial membrane potential, assessed via tetramethylrhodamine ethyl ester staining, was markedly reduced in a BAX-dependent manner and associated with increased reactive oxygen species production following prolonged exposure or at high concentrations. BTSA1 profoundly altered mitochondrial dynamics by promoting DRP1-mediated fission while suppressing fusion through MFN2 downregulation and stress-associated OPA1 processing, resulting in pronounced mitochondrial fragmentation. Furthermore, BAX activation elicited a biphasic response in mitochondrial quality control pathways: mild stress induced impaired autophagic flux and compensatory mitochondrial biogenesis, whereas severe stress triggered mitophagy accompanied by failure of biogenic compensation. These coordinated alterations closely mirror mitochondrial pathologies observed in the degenerating RPE in AMD. Collectively, our findings demonstrate that BAX activation by BTSA1 is sufficient to induce a comprehensive cascade of mitochondrial dysfunction. This system represents a mechanistically defined experimental model for dissecting BAX-mediated mitochondrial pathology and evaluating therapeutic strategies to preserve mitochondrial integrity in AMD.
Neuroinflammatory diseases triggered by cerebral hemorrhage: microglial iron accumulation and ferroptosis.
Gao X, Li H, Liang J … +1 more , Liu S
Eur J Pharmacol · 2026 Jun · PMID 42134758 · Publisher ↗
After a cerebral hemorrhage (CH), heme oxygenase-1 (HO-1) catalyzes the conversion of heme to release Fe. Microglia are the primary cells responsible for immune function in the brain. Upon the uptake of heme and iron ion...
After a cerebral hemorrhage (CH), heme oxygenase-1 (HO-1) catalyzes the conversion of heme to release Fe. Microglia are the primary cells responsible for immune function in the brain. Upon the uptake of heme and iron ions, microglia are activated, leading to the subsequent release of inflammatory mediators and reactive oxygen species. Neuroinflammation and oxidative stress are common features of various brain diseases. Cerebral hemorrhage can trigger microglial iron accumulation and ferroptosis, which in turn leads to neuroinflammation and oxidative stress imbalance in the brain. Therefore, inhibiting microglial iron accumulation and ferroptosis alleviates cerebral hemorrhage-mediated neural damage and counteracts various brain diseases induced by it. We propose that the occurrence of many brain diseases is influenced by the location of cerebral microbleeds, suggesting that cerebral microbleeds may be a high-risk factor for inducing these diseases.
In silico and in vitro evaluation of risedronate as a DKK1 antagonist: Implications for neuroprotection through DKK1-LRP6 modulation.
Manandhar S, Govindula A, Atchou K … +3 more , Nassar A, Kabekkodu SP, Pai KSR
Eur J Pharmacol · 2026 Jun · PMID 42134757 · Publisher ↗
Dickkopf-1 (DKK1) mediated dysregulation of the Wnt/β-catenin signaling pathway contributes to synaptic loss in Alzheimer's disease (AD). Risedronate, a third-generation bisphosphonate, shows promise in pathologies relat...
Dickkopf-1 (DKK1) mediated dysregulation of the Wnt/β-catenin signaling pathway contributes to synaptic loss in Alzheimer's disease (AD). Risedronate, a third-generation bisphosphonate, shows promise in pathologies related to the Wnt pathway, although its direct interaction with the DKK1-LRP6 complex has yet to be investigated. This study aimed to characterize risedronate as a novel small-molecule DKK1 antagonist and evaluate its capacity to restore canonical Wnt signaling and provide neuroprotection. In silico studies were performed using the Schrödinger Maestro (v2018-3) platform, utilizing molecular docking, molecular simualtion, SiteMap and WaterMap analysis to define the thermodynamic hydration energetics of the DKK1-LRP6 interface. In vitro validation was conducted using LRP6-overexpressing HEK-293T cells, with Wnt modulation quantified via immunofluorescence of membrane-associated DKK1 and β-catenin stabilization assays and neuroprotective assay in presence of glutamate in SHSY5Y cells. In silico analysis identified a high-affinity binding site on the DKK1 C-terminal domain (Dscore: 0.998). WaterMap analysis and simulation study revealed that risedronate binding is driven by the displacement of high-energy "unfavorable" water molecules (ΔG > 0) at the Arg203/Lys222 residue cluster. In HEK-293LRP6 cells, risedronate (IC: 65.94 μM) significantly attenuated DKK1-mediated LRP6 sequestration (p < 0.0001), acting as a molecular "plug" to restore β-catenin signaling. This restoration successfully suggests a potential modulation of downstream of Wnt pathway restoration. Risedronate demonstrates potential inhibitory effects on DKK1 in in vitro and in silico models. By bridging bone pharmacology and neurobiology, this study provides a mechanistically grounded repurposing strategy to counteract Wnt signaling failure in neurodegenerative disorders.
Alpinetin alleviates sepsis-induced cardiomyopathy by suppressing serine/threonine protein phosphatase 1γ-mediated ROS accumulation.
Gu AQ, Shu H, Zhang Y … +7 more , Yang B, Li S, Ma J, Liang ST, Wang KY, Guo HH, Huang S
Eur J Pharmacol · 2026 Jun · PMID 42128194 · Publisher ↗
Sepsis-induced cardiomyopathy (SICM) affects over half of sepsis patients admitted to intensive care units and is a major contributor to mortality and circulatory shock. Despite incomplete understanding of its underlying...
Sepsis-induced cardiomyopathy (SICM) affects over half of sepsis patients admitted to intensive care units and is a major contributor to mortality and circulatory shock. Despite incomplete understanding of its underlying mechanisms, effective pharmacological treatments for SICM are urgently needed. This study investigates the cardioprotective effects and underlying mechanism of the natural compound alpinetin in septic cardiomyopathy. We evaluated the impact of alpinetin on the overall survival of mice subjected to cecal ligation and puncture (CLP). Alpinetin significantly improved survival and reduced mortality in CLP-induced polymicrobial sepsis. It markedly attenuated intracellular reactive oxygen species (ROS) accumulation and calcium influx in cardiomyocytes and prevented apoptosis induced by lipopolysaccharide (LPS) combined with interferon-γ (IFN-γ) stimulation. Elevated expression of serine/threonine protein phosphatase 1γ (PP1γ) was found to contribute to cardiomyocyte hypertrophy during sepsis. The role of PP1γ in septic cardiac injury was assessed through recombinant lentivirus-mediated overexpression and small interfering RNA knockdown in cardiomyocytes. PP1γ was upregulated in septic cardiomyocytes and positively correlated with the expression of the early hypertrophy marker atrial natriuretic peptide (ANP). Suppression of PP1γ effectively attenuated cardiomyocyte hypertrophy. Further investigation revealed an interaction between PP1γ and peroxiredoxin 1 (PRDX1). Alpinetin treatment significantly attenuated PP1γ upregulation and disrupted the PP1γ-PRDX1 interaction, which was associated with reduced ROS production and improved cardiac function, suggesting restoration of PRDX1-mediated antioxidant function. Molecular docking simulations further suggested a potential direct interaction between alpinetin and PP1γ, providing basis for future mechanistic studies. These findings suggest that alpinetin may represent a promising therapeutic strategy for septic cardiomyopathy.
Ursocholic acid ameliorates hepatic steatosis via direct AMPK activation in preclinical models of MASLD.
Li Y, Zeng ZJ, Ye A … +6 more , Wang W, Huang D, Hu L, Li S, Li J, Zhang L
Eur J Pharmacol · 2026 Jun · PMID 42128193 · Publisher ↗
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health challenge lacking effective therapeutic agents. Ursocholic acid (UCA), a natural bile acid with established cholestero...
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health challenge lacking effective therapeutic agents. Ursocholic acid (UCA), a natural bile acid with established cholesterol-lowering properties, has not been evaluated for MASLD treatment. OBJECTIVE: To investigate the therapeutic efficacy, mechanism of action, and pharmacokinetic profile of UCA in MASLD. METHODS: Hepatoprotective effects were assessed in free fatty acid (FFA)-induced Huh7 cells and high-fat diet (HFD)-fed mice. RNA sequencing identified target pathways. Direct AMPK interaction was validated by molecular docking, molecular dynamics simulation, and cellular thermal shift assay. Pharmacokinetics was compared with ursodeoxycholic acid (UDCA). RESULTS: UCA dose-dependently reduced hepatic lipid accumulation in vitro and in vivo. Transcriptomic analysis revealed AMPK signaling as the primary modulated pathway. Mechanistically, UCA directly bound to AMPK, promoted Thr172 phosphorylation, and downregulated lipogenic genes (SREBF1, LPIN1, FASN, SCD1), and these effects were abrogated by Compound C (AMPK inhibitor). Pharmacokinetically, UCA exhibited dose-proportional oral exposure (AUC 1120-13,700 h ng/mL across 30-300 mg/kg) with a terminal half-life of 3.7-5.9 h, comparable to UDCA. CONCLUSION: UCA is a direct AMPK agonist that ameliorates MASLD by suppressing the SREBF1/LPIN1 lipogenic axis, representing a promising natural therapeutic candidate.
Therapeutic potential of nicorandil vs nebivolol in attenuating PKC/P38MAPK signaling via PPARγ/KLOTHO/CREB pathway signaling: molecular docking and experimental validation in rat model of unilateral ureteric obstruction.
Khalifa AK, Galal AM, Saber S … +8 more , El-Sayed AF, Alsibaee AM, Saeedi T, Alsubhi S, Miski SF, Aboulhoda BE, Mohamed EEE, Wanas H
Eur J Pharmacol · 2026 Jun · PMID 42128192 · Publisher ↗
UNLABELLED: This study is designed to highlight the comparative efficacy of nicorandil (NO donor/K opener) vs nebivolol (β1blocker with NO-induced vasodilatory and antioxidant actions) in a rat model of unilateral ureter...
UNLABELLED: This study is designed to highlight the comparative efficacy of nicorandil (NO donor/K opener) vs nebivolol (β1blocker with NO-induced vasodilatory and antioxidant actions) in a rat model of unilateral ureteric obstruction (UUO) to assess whether mitigating oxidative stress, inflammatory drive, and apoptosis could modulate UUO -driven fibrogenic remolding.Moreover, their therapeutic potential was further assessed by docking analysis. METHODOLOGY: Sham control group (1); UUO Group (2); Group (3): The nicorandil-treated group, in which rats received 15 mg/kg/day following ureteric obstruction for 21 days, and Group (4): the nebivolol-treated group, in which rats received 2 mg/kg/day orally following ureteric obstruction for 21 days. RESULTS: bioinformatically, Notable findings include nebivolol's superior binding affinity to Catalase, TGFβ1R and LOX-1 and nicorandil's higher affinity to TP53and Smad-3. These interactions suggest that both compounds may mitigate oxidative stress, inflammation, and fibrosis. Nebivolol potentially offers greater renal protection through enhanced suppression of pro-inflammatory signaling. Mechanistically, nebivolol demonstrates superior efficacy through coordinated modulation of key molecular pathways. Nebivolol disrupts the self-amplifying cycle of oxidative stress and inflammation by upregulating SIRT-1, miRNA200a expression restoring Nrf2 activity, and downregulating Keap1 re-establishing redox homeostasis. It further attenuates NF-κB-driven proinflammatory signaling and suppresses downstream PKC/p38 MAPK activation, reducing fibrotic and apoptotic responses. Concurrently, nebivolol enhances protective signaling via PPARγ, Klotho, and CREB, promoting cellular resilience and structural preservation. These multifaceted actions converge to normalize renal function, mitigate tissue injury, and maintain glomerular-tubular integrity. CONCLUSION: By targeting interconnected redox, inflammatory, and apoptotic pathways, nebivolol could emerge as a mechanistically therapeutic candidate, offering promise for repurposing in obstructive nephropathy and potentially in broader contexts of chronic kidney disease characterized by complex molecular dysregulation.
Phenethylamines in pre-workout supplements alter arterial pressure, heart rate, and body temperature in rats.
Pinckaers NET, Blankesteijn WM, Peeters R … +5 more , Dijkstra P, Tinnemans R, Opperhuizen A, van Schooten FJ, Vrolijk M
Eur J Pharmacol · 2026 Jun · PMID 42128191 · Publisher ↗
Phenethylamine (PEA) and its analogues are frequently present in pre-workout and weight loss food supplements and share structural similarity with amphetamine and the endogenous catecholamines (nor)adrenaline and dopamin...
Phenethylamine (PEA) and its analogues are frequently present in pre-workout and weight loss food supplements and share structural similarity with amphetamine and the endogenous catecholamines (nor)adrenaline and dopamine, suggesting potential sympathomimetic activity. Multiple adverse cardiovascular events have been associated with the use of food supplements containing these ingredients, while knowledge of the underlying pharmacology and toxicology of such food supplements and their ingredients remains limited. Therefore, the aim of the current study was to investigate the acute cardiovascular effects of a selection of PEAs in conscious rats. Heart rate (HR), arterial pressure (AP) and body temperature were continuously, and wirelessly, monitored using pressure telemetry in Wistar-Kyoto rats that were intravenously exposed to cumulative doses of PEA and seven commonly used analogues: BMPEA, halostachine, higenamine, isopropyloctopamine, p-octopamine, p-synephrine and p-tyramine. All PEAs, except PEA itself and BMPEA, significantly altered AP with maximal absolute increases between 65 and 103 mmHg. Maximal absolute increases in HR induced by higenamine and isopropyloctopamine were found to be 110 and 123 beats per minute, respectively. The PEA analogues BMPEA, p-octopamine, halostachine and p-synephrine, instantly lead to reduced body temperatures, ranging from minus 0.5 to minus 1.5 °C. This study demonstrates that several PEAs, exert pronounced and rapid effects on AP, HR and body temperature in rats. The magnitudes of these effects were similar to or even higher than the cardiovascular changes induced by adrenaline, suggesting that combining these substances with physical exercise may amplify sympathetic load and pose a serious health risk, particularly for individuals with underlying cardiovascular vulnerabilities.
BIX-01294, a pharmacological inhibitor of EHMT2, suppresses retinoblastoma tumorigenesis through MAPK pathway inhibition.
Chen Y, Liu J, Chen T … +4 more , Zhang Y, Yao C, Chen S, Huang G
Eur J Pharmacol · 2026 Jun · PMID 42119769 · Publisher ↗
This study investigated the antitumor effects of BIX01294, a pharmacological inhibitor of euchromatic histone-lysine N-methyltransferase 2 (EHMT2), in retinoblastoma and explored the underlying mechanisms. EHMT2 expressi...
This study investigated the antitumor effects of BIX01294, a pharmacological inhibitor of euchromatic histone-lysine N-methyltransferase 2 (EHMT2), in retinoblastoma and explored the underlying mechanisms. EHMT2 expression was evaluated using Gene Expression Profiling Interactive Analysis (GEPIA), human retinoblastoma specimens, publicly available Gene Expression Omnibus (GEO) datasets, and cultured cell lines. Cell proliferation was assessed using Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays. Cell cycle distribution and apoptosis were analysed by flow cytometry. RNA sequencing (RNA-seq), quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting were performed to investigate downstream molecular changes. An orthotopic xenograft model was established to assess the in vivo pharmacological effects of BIX01294. EHMT2 was upregulated in retinoblastoma tissues and in retinoblastoma cell lines. BIX01294 reduced EHMT2 expression, inhibited proliferation, induced apoptosis, and caused cell cycle arrest, accompanied by downregulation of cyclin A, cyclin-dependent kinase 2 (CDK2), cyclin B, and phosphorylated cell division cycle 2 (p-CDC2). Under the same 48 h treatment conditions, ARPE-19 cells showed minimal changes in viability and no obvious alterations in apoptosis or cell-cycle distribution, supporting a degree of pharmacological selectivity. Transcriptomic profiling and protein analysis indicated that BIX01294 treatment was associated with attenuation of mitogen-activated protein kinase (MAPK) signalling. In the orthotopic xenograft model, BIX01294 reduced tumour burden and Ki-67 staining. These findings support EHMT2 as a potential pharmacological target in retinoblastoma; however, additional mechanistic studies are required to define the causal link between EHMT2 inhibition and MAPK pathway modulation.
Interleukin-4 alleviate polycystic ovary syndrome through promoting the polarization of M2 type macrophages via targeting NF-κB/IκB pathway.
Shi M, Sun Q, Guo S … +1 more , Sun X
Eur J Pharmacol · 2026 Jun · PMID 42119768 · Publisher ↗
Polycystic ovary syndrome (PCOS) represents a prevalent endocrine disorder that constitutes a significant threat to female reproductive health. Immune dysregulation and chronic low-grade inflammation are increasingly rec...
Polycystic ovary syndrome (PCOS) represents a prevalent endocrine disorder that constitutes a significant threat to female reproductive health. Immune dysregulation and chronic low-grade inflammation are increasingly recognized as pivotal contributors to ovarian dysfunction in this condition. In the present study, we enrolled PCOS patients clinically and established a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Our findings revealed elevated levels of pro-inflammatory M1 macrophages, diminished anti-inflammatory M2 macrophages, and aberrant distribution of associated inflammatory cytokines in both PCOS patients and animal models, implicating the macrophage phenotypic plasticity in the pathogenesis of PCOS. Interleukin-4 (IL-4), a potent immunomodulatory cytokine, effectively ameliorated ovarian histopathological alterations and restored ovulatory function in the DHEA-induced PCOS mice through the promotion of M2 macrophage polarization. Specifically, IL-4 administration attenuated serum concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), concomitantly enhancing interleukin-10 (IL-10) and interferon-γ (IFN-γ) expression, whilst suppressing M1 macrophage infiltration. Furthermore, IL-4 treatment mitigated ovarian cellular apoptosis, upregulated ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1) expression, and reinstated ovulatory capacity. Mechanistically, IL-4 facilitated M2 macrophage polarization via the modulation of the nuclear factor-κB (NF-κB) signaling pathway; these polarized M2 macrophages subsequently attenuated apoptosis in co-cultured KGN granulosa cells and enhanced ADAMTS1 expression. This investigation preliminarily elucidates novel insights into the inflammatory and immune microenvironment underlying PCOS pathophysiology, demonstrating that IL-4 could ameliorate ovarian apoptosis and promote ovulatory function through NF-κB/IκB-mediated M2 macrophage polarization, thereby alleviating PCOS-associated manifestations and furnishing a theoretical foundation for innovative therapeutic strategies.
Antifibrotic efficacy of adipose-derived mesenchymal stem cell-based therapeutic strategies in pre-clinical models of pulmonary fibrosis: A systematic review and meta-analysis.
Jabeen H, Ali M, Anum F … +4 more , Najam S, Ali S, Saeed N, Ishaque A
Eur J Pharmacol · 2026 Jun · PMID 42119767 · Publisher ↗
BACKGROUND: Pulmonary fibrosis (PF) represents a heterogeneous group of chronic fibrotic lung diseases, characterized by excessive extracellular matrix (ECM) deposition and irreversible scarring, lacking curative therapi...
BACKGROUND: Pulmonary fibrosis (PF) represents a heterogeneous group of chronic fibrotic lung diseases, characterized by excessive extracellular matrix (ECM) deposition and irreversible scarring, lacking curative therapies. This review highlights the antifibrotic efficacy of adipose-derived mesenchymal stem cells (AD-MSCs) in pre-clinical PF models. METHODS: The review was prospectively registered in the PROSPERO database (registration number: CRD420251119193). Peer-reviewed experimental investigations/original articles were searched from Google Scholar, PubMed, and ScienceDirect up to April 2025. Risk of bias in in-vivo studies was assessed using SYRCLE's tool and for in-vitro studies, quality was evaluated with the QUIN tool. Results were synthesized narratively and quantitatively, using a random-effects model to pool mean differences (MD) with 95% confidence intervals for antifibrotic outcomes based on Ashcroft scores. Heterogeneity was assessed using Cochran's Q test and I statistic. RESULTS: A comprehensive literature search yielded 397 studies, out of which 19 studies selected after title-based, abstract-based, and full text-based screening. Forest plot showed overall mean difference as -1.35 [95% CI: -3.19, 0.49]. Ashcroft scores were lower in treated groups compared with control group, but overall mean difference was not statistically significant (z = 1.44, p = 0.15), likely due to small number of studies included and high heterogeneity. However, individual studies demonstrated reduced fibrosis in treated groups. CONCLUSION: AD-MSCs consistently reduced fibrosis in pre-clinical PF models while modulating pathways relevant to IPF pathogenesis i.e., Smad, NF-κB, ERK, and key miRNA networks. Collectively, current evidences position AD-MSCs and their derivatives as promising antifibrotic candidates with strong clinical translation potential.
Corrigendum to: "SUMO2-mediated SUMOylation of SH3GLB1 promotes ionizing radiation-induced hypertrophic cardiomyopathy through mitophagy activation'' [Europ. J. Pharmacol. 5 (2022) 174980 59897].
Gao A, Zou J, Mao Z … +2 more , Zhou H, Zeng G
Eur J Pharmacol · 2026 May · PMID 42115010 · Publisher ↗
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The effect of dehydroepiandrosterone on the vascular system: role of HS/NO pathways.
Turnaturi C, Indolfi C, Correale M … +6 more , Esposito E, Schettino A, Vellecco V, Sorrentino R, Mitidieri E, d'Emmanuele di Villa Bianca R
Eur J Pharmacol · 2026 Jun · PMID 42114734 · Publisher ↗
Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone that serves as a precursor to androgens and estrogens and participates in several physiological processes. Its levels naturally decline with age, and reduced DH...
Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone that serves as a precursor to androgens and estrogens and participates in several physiological processes. Its levels naturally decline with age, and reduced DHEA concentrations have been associated with an increased risk of cardiovascular disease. However, this relationship is complex, and further research is required to clarify whether DHEA supplementation may help to prevent age-related vascular dysfunction. Here, we investigated the vascular effects of DHEA using mouse aorta and bovine aortic endothelial cells (BAEC), focusing on the potential involvement of hydrogen sulfide (HS). DHEA exhibited a more pronounced vasorelaxant effect in endothelium intact aortas, mediated not only by nitric oxide (NO) but also by HS. A significant increase in HS production was observed following incubation of the aorta with DHEA compared to the vehicle. In addition to HS, the involvement of L-type calcium channels in DHEA-induced vasorelaxation was found. Nifedipine, an inhibitor of L-type calcium channels, significantly reduced DHEA-induced vasorelaxation, and vice versa, suggesting a shared target. Consistent with the aortic findings, an increase in NO formation was observed in BAEC exposed to DHEA. Using two complementary approaches, we further demonstrate that DHEA enhanced HS production in BAEC, with effects persisting for up to 2 h. Collectively, these findings suggest that DHEA promotes vasodilation through dual NO- and HS-dependent pathways, along with modulation of L-type calcium channels. Our data provide new insights into the mechanisms of action of DHEA, supporting its protective role in the vasculature.
Resveratrol modulates the sFRP4/Wnt signaling Pathway and preserves blood-brain barrier integrity in rats with ischemic stroke.
Zhang H, Xu Z, Wang Y … +4 more , Zhou X, Yun Q, Deng L, He B
Eur J Pharmacol · 2026 May · PMID 42114733 · Publisher ↗
Resveratrol is a polyphenolic natural product. It has been demonstrated that resveratrol has protective effects on various neurological diseases. However, the mechanism by which resveratrol protects the neurological func...
Resveratrol is a polyphenolic natural product. It has been demonstrated that resveratrol has protective effects on various neurological diseases. However, the mechanism by which resveratrol protects the neurological function in stroke remains unclear. In this study, we established a stroke rat via middle cerebral artery occlusion (MCAO). The MCAO rats were intraperitoneally administered with resveratrol (30 mg/kg) for 7 consecutive days. Neurological function scoring, cerebral infarct area assessment, tissue collection for subsequent assays, and pathological, neuroinflammatory, and oxidative stress analyses were performed at 24 h post-stroke, while the Morris water maze test for poststroke cognitive impairment (PSCI) was conducted from day 8 to day 14 post-stroke. The differentially expressed proteins (DEPs) were identified through proteomic analysis. The key regulatory pathways were verified through western blotting. Resveratrol significantly reduced the neurological function score, decreased the infarct area, and alleviated PSCI. Resveratrol significantly reduced the levels of inflammatory factors, lowered the malondialdehyde (MDA) level, and increased the levels of glutathione (GSH) and total antioxidant capacity (T-AOC). Proteomic analysis identified 263 DEPs. Protein‒protein interaction analysis suggested that secreted frizzled-related protein 4 (sFRP4)/Wnt pathway might be a potential target of resveratrol. Western blotting confirmed that resveratrol effectively reversed the stroke-induced upregulation of sFRP4, and also abrogated the stroke-induced downregulation of Wnt3a, Wnt4, Wnt5, Wnt11, and β-catenin levels. Additionally, resveratrol reversed the stroke-induced reduction in the levels of ZO-1, Occludin, and Claudin 5. It is concluded that resveratrol maintains the integrity of the blood-brain barrier and modulates the sFRP4/Wnt signaling pathway.
Identification of small-molecule autophagy activators via GFP-LC3 high-throughput screening and a cargo-based autophagy flux and processing assay.
Mertens F, Takhsha FS, Lallier M … +12 more , Engedal N, Goossens V, Audenaert D, Guns PJ, Roth L, Vandenabeele P, Fransen E, Vindis C, Van der Veken P, Timmerman V, De Meyer GRY, Martinet W
Eur J Pharmacol · 2026 Jun · PMID 42114732 · Publisher ↗
BACKGROUND AND AIM: Autophagy maintains cellular homeostasis by recycling macromolecules and nutrients. It involves the sequestration of superfluous or damaged cellular components into autophagosomes, which fuse with lys...
BACKGROUND AND AIM: Autophagy maintains cellular homeostasis by recycling macromolecules and nutrients. It involves the sequestration of superfluous or damaged cellular components into autophagosomes, which fuse with lysosomes for degradation. Reduced autophagy is implicated in numerous diseases, which may be treatable with autophagy-inducing drugs. However, most clinically available inducers act through mTORC1 inhibition, causing off-target effects that limit their therapeutic use. This study aimed to identify novel autophagy-inducing compounds that act independently of mTORC1, thereby offering greater translational potential. METHODS: A high-throughput imaging assay was optimised to quantify autophagosome-like structures in L929 fibroblasts expressing GFP-LC3, a fluorescent autophagosome membrane marker. Hits were validated alongside several reference autophagy modulators in retinal epithelial hTERT RPE-1 cells expressing the LDHB-mKeima autophagy cargo reporter. This assay distinguishes functional autophagy flux inducers from compounds that merely increase autophagosome accumulation by blocking late-stage autophagy. Western blotting was used to investigate the mechanism of autophagy initiation. RESULTS: High-throughput screening identified 30 hits that increased autophagosome-like structures more than fourfold. Ten compounds were confirmed to induce autophagic flux of bulk cargo. Nine of these acted independently of mTORC1, while elevating autophagic flux to a similar extent as the mTORC1 inhibitor rapamycin. CONCLUSION: While GFP-LC3-based assays enabled efficient high-throughput screening, incorporation of the LDHB-mKeima cargo-based assay was essential for identifying functional autophagy flux activators. Nine compounds were identified that promoted autophagic cargo flux via mTORC1-independent mechanisms, providing promising leads for discovering new molecular targets and developing safer, more effective autophagy-based interventions to treat human disease.
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