Eur. J. Pharmacol. [JOURNAL]
Sun
200 papers
Fenchone and cinnamyl acetate attenuate L-NAME-induced hypertension via modulation of vascular dysfunction, oxidative stress, and renal injury: An integrated network pharmacology, molecular docking, and ADMET study.
Zeeshan A, Malik A, Ali M … +5 more , Qaisar MN, Ahmad I, Wajid M, Khalid A, Muhammad G
Eur J Pharmacol · 2026 Jun · PMID 42250790 · Publisher ↗
Hypertension is a major cardiovascular disorder associated with oxidative stress, endothelial dysfunction, and renal damage, necessitating safer therapeutic alternatives. The antihypertensive potential of cinnamyl acetat...
Hypertension is a major cardiovascular disorder associated with oxidative stress, endothelial dysfunction, and renal damage, necessitating safer therapeutic alternatives. The antihypertensive potential of cinnamyl acetate (Cmyl) and fenchone (Fcon) was assessed using integrated network pharmacology, molecular docking, ADMET, and in vivo validation. Targets and pathways were identified via network pharmacology and KEGG analysis, followed by molecular docking and ADMET profiling. Antihypertensive activity was assessed in an L-NAME-induced hypertensive rat model through blood pressure (BP), oxidative stress markers, renal biomarkers, gene expression, and histopathology. Cmyl (31 targets) and Fcon (17 targets) were linked to PI3K-Akt signaling, lipid metabolism, and inflammatory pathways. Docking showed strong binding of Cmyl with 5-HTR2A (-4.686 kcal/mol) and Fcon with NPC1L1 (-5.541 kcal/mol). ADMET confirmed drug-likeness and safety. L-NAME elevated systolic blood pressure/diastolic blood pressure (SBP/DBP: 145.78/98.88 mmHg; p < 0.0001), which was reduced by Fcon (121.69/81.61 mmHg, 400 mg/kg) and Cmyl (122.63/83.72 mmHg, 50 mg/kg). Antioxidants enzymes (CAT: up to 9.17-10.23 pg/mL; SOD: 3.53-3.84 U/mL; GSH: 700.83-738.82 pg/mL) were improved significantly, and malondialdehyde (MDA) was decreased (2.63-2.40 nmol/L) with the restoration of urea (21.0-22.4 mg/dL) and creatinine (1.30-1.34 mg/dL). Both compounds downregulated iNOS, AGT, renin, 5-HTR2A, and NPC1L1, and restored Agtr2 expression. Kidney histopathological analysis showed superior renoprotection with Fcon, whereas Cmyl showed mild interstitial fibrosis. Cmyl and Fcon exert potent antihypertensive effects via multi-target mechanisms involving antioxidant, metabolic, and renoprotective pathways. Fcon showed superior efficacy, supporting their potential as natural antihypertensive agents.
In situ perfusion with MCC950 modulates the pyroptosis-related axis and DAMP-TLR4 signaling in kidneys from brain-dead donor.
Marzochi LL, do Nascimento Gonçalves N, Luz MAM … +3 more , Mendes GEF, Abbud-Filho M, Caldas HC
Eur J Pharmacol · 2026 Jun · PMID 42248502 · Publisher ↗
Brain death (BD), followed by static cold storage (SCS), induces sterile inflammation in donor kidneys, leading to molecular injury that compromises graft quality. This response is associated with activation of the NLRP3...
Brain death (BD), followed by static cold storage (SCS), induces sterile inflammation in donor kidneys, leading to molecular injury that compromises graft quality. This response is associated with activation of the NLRP3 inflammasome and pyroptosis related pathways. We investigated whether pharmacological inhibition of NLRP3 with MCC950, administered during in situ renal perfusion, during SCS, or through a combined strategy, could attenuate BD-induced inflammation exacerbated by SCS. Male Wistar rats (n = 36) were subjected to BD followed by 6 h of donor maintenance and subsequent 16 h of SCS. MCC950 was delivered during in situ perfusion, added to the preservation solution, or administered using both approaches. Renal inflammation and injury were evaluated by gene expression analysis and histopathology. BD increased the expression of inflammasome and pyroptosis related genes (NLRP3, CASP1, GSDMD), mediators of DAMP-TLR4 signaling (HMGB1, TLR4, NF-κB) and apoptotic regulation (BCL2), with further amplification after SCS. In situ MCC950 administration markedly reduced the expression of inflammasome-related genes and downstream inflammatory signaling, whereas supplementation during SCS alone showed limited effects. Combined treatment enhanced suppression of selected mediators, including IL-18 and HMGB1. IL-1β expression and macrophage infiltration were not significantly altered. Overall, in situ renal perfusion with MCC950 attenuated BD and preservation-induced inflammation more effectively than inhibition restricted to SCS. These findings support targeted NLRP3 inhibition during donor management as a molecular preconditioning strategy that attenuates preservation-associated activation of inflammasome and pyroptosis related inflammatory signaling, with potential relevance for marginal kidneys.
Edaravone-dexborneol improves neurological function after cerebral ischemia-reperfusion injury by activating NRF2/p62 and suppressing NF-κB/NLRP3 signaling.
Xu Z, Wang Y, Chen H … +5 more , Liu J, Hao R, Zhou X, Xiong X, Zhang H
Eur J Pharmacol · 2026 Jun · PMID 42248501 · Publisher ↗
Edaravone-dexborneol (EDB) is a prospective neuroprotective agent for ischemic stroke. However, its integrated mechanisms of action remain to be elucidated. Here, we investigated the multiple effects of EDB in a rat mode...
Edaravone-dexborneol (EDB) is a prospective neuroprotective agent for ischemic stroke. However, its integrated mechanisms of action remain to be elucidated. Here, we investigated the multiple effects of EDB in a rat model of cerebral ischemia-reperfusion injury induced by transient middle cerebral artery occlusion (MCAO). Rats received intraperitoneal EDB (4 mL/kg, once daily). Acute infarct volume and biochemical parameters were assessed 24 h after reperfusion. Longitudinal behavioral and histological outcomes were evaluated after a 7-day treatment course. EDB significantly reduced neurological deficit scores and infarct size. EDB ameliorated deficits in affective-like behaviors, social cognition, learning and memory, and motor coordination. EDB markedly attenuated neuroinflammation by decreasing interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels, concomitant with reduced nuclear factor-κB (NF-κB) signaling and NLR family pyrin domain-containing 3 (NLRP3) abundance. In addition, EDB mitigated oxidative stress, as demonstrated by decreased malondialdehyde (MDA) and restoration of glutathione (GSH) and total antioxidant capacity(T-AOC). At the molecular level, EDB increased nuclear factor erythroid 2-related factor 2 (NRF2) and sequestosome-1 (p62/SQSTM1) protein expression and modulated autophagy-associated markers, including Beclin-1 and microtubule-associated protein 1 light chain 3B (LC3B). Histological analyses demonstrated that EDB alleviated tissue injury and reduced glial activation, including attenuation of reactive astrocyte hypertrophy and microglial amoeboid transformation. To summarize, EDB promotes functional recovery, mediated by enhanced NRF2/p62-dependent cytoprotection and NF-κB/NLRP3-driven suppression of neuroinflammation.
Survival benefit analysis of beta-blockers in patients with sepsis-induced TnT-positive myocardial injury across different clinical subtypes of sepsis: A retrospective study based on the MIMIC-IV database.
Guo W, Ma L, Wang Y … +6 more , Gao X, Zhang L, Qin Q, Li X, Nuermaimaiti M, Yu X
Eur J Pharmacol · 2026 Jun · PMID 42248500 · Publisher ↗
OBJECTIVE: To explore the survival benefits of beta-blockers in patients with sepsis-induced TnT-positive myocardial injury across different clinical subtypes and to analyze their potential mechanisms of action. METHODS:...
OBJECTIVE: To explore the survival benefits of beta-blockers in patients with sepsis-induced TnT-positive myocardial injury across different clinical subtypes and to analyze their potential mechanisms of action. METHODS: Based on the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, 1102 patients meeting sepsis-induced TnT-positive myocardial injury criteria were included. Unsupervised machine learning methods were used for clinical subtype clustering analysis, and multivariate Cox regression was employed to evaluate the impact of beta-blockers on 28-day and 90-day mortality. The mediating role of inflammatory cytokine interleukin-6 (IL-6) and procalcitonin (PCT) was also analyzed. RESULTS: Patients were classified into three subtypes: moderate organ dysfunction sepsis-induced TnT-positive myocardial injury, severe inflammatory high-injury sepsis-induced TnT-positive myocardial injury, mild compensatory stable sepsis-induced TnT-positive myocardial injury. Beta-blocker use was significantly associated with reduced all-cause mortality: in all subtypes, 28-day mortality risk was reduced by 81.3% [hazard ratio (HR) = 0.187], 76.6% (HR = 0.234), and 65.9% (HR = 0.341), respectively, and 90-day mortality risk was reduced by 74.2% (HR = 0.258), 65.1% (HR = 0.349), and 63.6% (HR = 0.364), respectively. Selective beta-1 receptor blockers demonstrated the most optimal effects. The mediating role of IL-6 and PCT was not significant on the 28-day mortality rate in patients receiving beta-blocker. CONCLUSION: Beta-blockers can significantly improve short-term and medium-term survival rates in patients with sepsis-induced TnT-positive myocardial injury across all subtypes, particularly selective beta-1 blockers.
Ribosome impairment, tau alternative splicing, and stress granules: a convergent axis of neuronal vulnerability driving Alzheimer's disease.
Masi M, Oliviero C, Govoni S … +3 more , Wolozin B, Racchi M, Buoso E
Eur J Pharmacol · 2026 Jun · PMID 42248499 · Publisher ↗
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by the pathological aggregation and deposition of amyloid-β (Aβ) plaques and tau neurofibrillary tangles. However, accumulating eviden...
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by the pathological aggregation and deposition of amyloid-β (Aβ) plaques and tau neurofibrillary tangles. However, accumulating evidence points at the disruption of RNA metabolism and translational control as central players in the disease progression. Emerging studies suggest that pathogenic mechanisms previously considered separately-namely ribosome biogenesis impairment, dysregulation of tau alternative splicing, and persistent stress granule (SG) formation-could be components of an integrated axis of neuronal vulnerability contributing to early AD pathogenesis. In AD, ribosomal loss and rDNA transcriptional silencing correlate with tau hyperphosphorylation and tau-ribosome interaction, while SG-mediated sequestration of splicing factors may exacerbate 3R/4R tau imbalance, promoting aggregation-prone isoforms. These processes appear to mutually reinforce through neuroinflammation and chronic translational stress, driving progressive proteostatic failure and cognitive decline. Converging evidence across systems (histopathological, in vivo and in vitro models) strongly suggest the existence of a ribosome-tau splicing-SG axis that operates at a pre-aggregative phase of the disease. In this context, this early disruption of translational homeostasis may trigger neuronal vulnerability decades before Aβ and tau aggregation as well as symptomatic disease. In this review, we synthesize current evidence supporting a stepwise, feed-forward model that links ribosome dysfunction, splicing alterations, and chronic SG persistence in AD. Our hypothesized integrated framework highlights potential pharmacological routes each capable of targeting distinct pathogenic nodes of the axis to restore translational homeostasis and reduce neuronal vulnerability, thus outlining potential upstream intervention strategies beyond the traditional Aβ- and tau-centric therapeutic approaches.
Norisoboldine inhibits endoplasmic reticulum stress and alleviates depressive behaviors in CUMS mice by activating growth hormone secretagogue receptor type 1a in the hippocampus.
Wang X, Zang S, Ban Z … +9 more , Zhang Y, Hou L, Zhang X, Wang Y, Li D, An F, Liu Y, Jia Y, Gao Y
Eur J Pharmacol · 2026 Jun · PMID 42242493 · Publisher ↗
Depression is a common mental and mood disorder. Norisoboldine (NIB) has been shown to provide neuroprotective benefits. However, its potential antidepressant effects and underlying mechanisms remain to be elucidated. Ou...
Depression is a common mental and mood disorder. Norisoboldine (NIB) has been shown to provide neuroprotective benefits. However, its potential antidepressant effects and underlying mechanisms remain to be elucidated. Our findings indicated that NIB ameliorates depressive behaviors and mitigates hippocampal neuronal damage induced by chronic unpredictable mild stress (CUMS). Numerous studies have corroborated the neuroprotective effects of gastrointestinal hormones such as ghrelin and its endogenous receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a). Notably, NIB demonstrated minimal impact on the expression levels of ghrelin and GHSR-1a. We furtherly investigated whether NIB could directly activate GHSR-1a in vitro. Treatment with NIB increased cell viability and inhibited CORT-induced apoptosis in HT-22 cells in a dose-dependent manner. The use of a GHSR-1a antagonist and GHSR-1a knockdown weakened the inhibitory effect of NIB on cell apoptosis. NIB attenuated endoplasmic reticulum (ER) stress via GHSR-1a in HT-22 cells, thereby protecting against cell apoptosis and loss. Molecular docking results showed an interaction between NIB and GHSR-1a, and CESTA results showed that NIB increased the thermal stability of GHSR-1a. In conclusion, NIB can reduce ER stress-induced injury to hippocampal neurons through GHSR-1a and improve depressive behavior in mice induced by CUMS.
Capsaicin attenuates DSS-induced IBD by suppressing macrophage M1 polarization via inhibition of the TRAF1/NF-κB pathway.
Chen L, Zhang Q, Liu D … +4 more , Li J, Wang N, Wu XY, Wu XD
Eur J Pharmacol · 2026 Jun · PMID 42242492 · Publisher ↗
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestine caused by multiple factors, with a global incidence that is increasing year by year, severely affecting patients' quality of life. Caps...
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestine caused by multiple factors, with a global incidence that is increasing year by year, severely affecting patients' quality of life. Capsaicin (CAP), the main active component in chili peppers, has anti-inflammatory and antioxidant effects. As a key part of the immune system, macrophages play a critical role in maintaining intestinal homeostasis. Growing evidence suggests that M1 macrophage polarization is closely associated with the onset and progression of IBD. This study used a dextran sulfate sodium (DSS)-induced IBD model, lipopolysaccharide (LPS)-induced macrophage M1 polarization and bone marrow-derived macrophages (BMDMs), and found that CAP can significantly alleviate macrophage M1 polarization by reducing the expression of CD86 and iNOS, inhibiting the release of inflammatory factors tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), and improving intestinal pathological damage. RNA sequencing (RNA-seq) analysis suggested that CAP may act through the TNF receptor-associated factor 1 (TRAF1)/nuclear factor kappa B (NF-κB) pathway, further, silencing TRAF1 with siRNA and AAV confirmed that this pathway plays a key role in CAP regulation of macrophage polarization and alleviation of IBD. This study reveals the molecular pathway by which CAP alleviates IBD through regulating M1 macrophage polarization, providing an important theoretical basis for a deeper understanding of the pathogenesis of IBD and the development of new therapeutic strategies.
D-Amino acid oxidase inhibitor ameliorates cerebral ischemia-reperfusion injury in rats via D-Serine/GluN2A/BDNF signaling pathway.
Huang J, Zhu J, Zheng H … +5 more , Zhu E, Yang C, Ying L, Zhou Y, Liu H
Eur J Pharmacol · 2026 Jun · PMID 42242491 · Publisher ↗
To investigate the mechanisms of D-Amino acid oxidase inhibitor (DAAOi) in ameliorating cerebral ischemia-reperfusion (I/R) injury and the underlying neuroprotective effect of substrate D-Serine. A middle cerebral artery...
To investigate the mechanisms of D-Amino acid oxidase inhibitor (DAAOi) in ameliorating cerebral ischemia-reperfusion (I/R) injury and the underlying neuroprotective effect of substrate D-Serine. A middle cerebral artery occlusion (MCAO) rat model and an oxygen-glucose deprivation (OGD)-induced HT22 cell model were used to mimic ischemic stroke. The modified Neurological Severity Scores (mNSS) and 2, 3, 5-triphenyltetrazolium chloride staining were applied to assess neurological behavioral scores and cerebral infarct area, respectively. The effects of DAAOi 4H-Furo[3,2-b]pyrrole-5- carboxylic acid (SUN) and D-Serine intervention on cognitive and behavioral functions in MCAO rats were evaluated by using the Y-maze and Novel Object Recognition Test (NORT). Intracerebral stereotaxic injection of Compound SUN and D-Serine (0.21 mg, 1.05 mg, 2.1 mg) significantly reduced cerebral infarct area, indicating that DAAOi might improve cerebral I/R injury by elevating D-Serine levels. Similarly, D-Serine significantly enhanced cognitive and behavioral performance in MCAO rats (mNSS: improved by 2.3 scores; Y-maze: spontaneous alternation rate increased by 14.76%; NORT: recognition index improved by 12.28%). D-Serine pretreatment (10 μM-10 mM) dose-dependently increased the viability of HT22 cells subjected to OGD. In both in vitro and in vivo models, D-Serine significantly increased the protein level of N-methyl-D-aspartate receptor subunit 2A (GluN2A). Additionally, D-Serine promoted the expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein-95 but inhibited the apoptosis-related p38 MAPK phosphorylation. This study demonstrated that the neuroprotective effect of DAAOi was at least partly mediated by elevating cerebral D-Serine levels, which regulated the GluN2A/BDNF axis to enhance synaptic plasticity and cognitive function.
Long non-coding RNA TTN-AS1 promotes acute liver injury in sepsis: A novel potential monitoring and therapeutic target.
Wang J, Yan Y, Wang C … +6 more , Tao X, Cheng P, Liu B, Gong J, Qin J, Niu B
Eur J Pharmacol · 2026 Jul · PMID 42235876 · Publisher ↗
Sepsis-associated liver injury (SALI) is a severe complication of sepsis that markedly worsens clinical outcomes. Currently, specific early diagnostic biomarkers and effective therapeutic strategies remain limited. In th...
Sepsis-associated liver injury (SALI) is a severe complication of sepsis that markedly worsens clinical outcomes. Currently, specific early diagnostic biomarkers and effective therapeutic strategies remain limited. In this study, we integrated whole-blood transcriptomic sequencing data from patients with SALI with gene expression data obtained from the publicly available dataset to identify key regulatory factors involved in disease pathogenesis. By combining weighted gene co-expression network analysis (WGCNA), differential expression analysis, and construction of a competing endogenous RNA (ceRNA) network, we identified the long non-coding RNA (lncRNA) TTN-AS1 as a potential regulatory molecule. The upregulation of TTN-AS1 in SALI was further validated using an independent public dataset. Functional validation was performed using a cecal ligation and puncture (CLP) mouse model. Overexpression of TTN-AS1 markedly aggravated liver injury, as demonstrated by significantly increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (P < 0.001), elevated concentrations of the inflammatory cytokines, disrupted hepatic architecture and enhanced inflammatory cell infiltration, increased expression of the apoptosis-related proteins Caspase-3 (P < 0.001) and BCL2-associated X (BAX) (P < 0.01), and a higher number of apoptotic hepatocyte as determined (P < 0.001). Mechanistically, the results suggest that TTN-AS1 may contribute to SALI by modulating inflammatory signaling through a microRNA-mediated post-transcriptional regulatory network. In summary, this study provides evidence that lncRNA TTN-AS1 promotes the progression of SALI, highlighting its potential value as a diagnostic biomarker and a therapeutic target. Nevertheless, the tissue-specific expression patterns of TTN-AS1 and the mechanisms underlying its functional heterogeneity require further investigation.
Corrigendum to Hypoxia-induced upregulation of Orai1 drives colon cancer invasiveness and angiogenesis [Eur. J. Pharmacol. (2018) 832 1-10].
Liu X, Wan X, Kan H … +6 more , Wang Y, Yu F, Feng L, Jin J, Zhang P, Ma X
Eur J Pharmacol · 2026 Jul · PMID 42230189 · Publisher ↗
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Reinforcing and discriminative stimulus effects of 4-fluorobutyrfentanyl, 4-fluoroisobutyrfentanyl, and isobutyrfentanyl in male rats.
Lai M, Wen L, Li H … +7 more , Fu D, Xu Z, Jin Q, Shi B, Zhou W, Liu L, Xu P
Eur J Pharmacol · 2026 Jun · PMID 42229741 · Publisher ↗
RATIONALE: 4-fluorobutyrfentanyl (4F-BF), 4-fluoroisobutyrfentanyl (4F-iBF), and isobutyrfentanyl (iBF) are isomers of butyrfentanyl. Despite these fentanyl analogs being directly involved in numerous fatal overdoses, th...
RATIONALE: 4-fluorobutyrfentanyl (4F-BF), 4-fluoroisobutyrfentanyl (4F-iBF), and isobutyrfentanyl (iBF) are isomers of butyrfentanyl. Despite these fentanyl analogs being directly involved in numerous fatal overdoses, their abuse liability profiles have yet to be fully elucidated. OBJECTIVES: This study evaluated the reinforcing effects of 4F-BF, 4F-iBF, and iBF on drug self-administration and their relationship to the interoceptive effects of heroin via drug discrimination. METHODS: Rats were trained to self-administer heroin (50 μg/kg/inf) under a fixed ratio (FR) 1 schedule. After 10 days of acquisition, dose response curves were generated for heroin, fentanyl, 4F-BF, 4F-iBF, and iBF. Separate cohorts of rats were trained to self-administer heroin (50 μg/kg/inf), fentanyl (2.5 μg/kg/inf), 4F-BF (25 μg/kg/inf), 4F-iBF (25 μg/kg/inf), or iBF (25 μg/kg/inf) under the FR1 schedule, followed by behavioral economic analysis to assess their reinforcing efficacy. In drug discrimination tests, rats trained to discriminate heroin (400 μg/kg) from saline underwent substitution tests for fentanyl, and fentanyl analogs. RESULTS: 4F-BF, 4F-iBF, and iBF showed inverted U-shaped dose-response curves; the reinforcing potency of three analogs was comparable and intermediate between that of fentanyl and heroin. Rats acquired self-administration of three analogs, and behavioral economic analysis ranked their reinforcing efficacy as follows: iBF > 4F-iBF ≈ 4F-BF > fentanyl ≈ heroin. Each compound elicited full discriminative stimulus effects of heroin, with a potency order of fentanyl > 4F-iBF ≈ 4F-BF ≈ iBF > heroin. CONCLUSIONS: These findings highlight the significant abuse liability of 4F-iBF, 4F-BF, and iBF, suggesting that these compounds pose a unique threat to public health.
Perinatal LC-ω-3-PUFA supplementation offsets prenatal THC-induced cognitive deficit via sex-specific modulation of hippocampal neuroplasticity.
Lavanco G, Castelli V, D'Amico C … +5 more , Feo S, Kuchar M, Palivec P, Brancato A, Cannizzaro C
Eur J Pharmacol · 2026 Jun · PMID 42229740 · Publisher ↗
Long-chain polyunsaturated fatty acids (LC-PUFAs) are crucial for brain development, with ω-3 species supporting neuronal membrane architecture, synaptogenesis and cognitive maturation, and ω-6 species linking lipid meta...
Long-chain polyunsaturated fatty acids (LC-PUFAs) are crucial for brain development, with ω-3 species supporting neuronal membrane architecture, synaptogenesis and cognitive maturation, and ω-6 species linking lipid metabolism to neuronal signalling via the endocannabinoid system (ECS), the network of receptors, lipid mediators, and enzymatic pathways that orchestrate neurodevelopmental processes. Prenatal exposure to Δ-tetrahydrocannabinol (THC), the psychoactive component of cannabis, impairs memory and disrupts hippocampal plasticity markers affecting the excitatory/inhibitory (E/I) balance, in a sex-dependent manner. This dysregulation is closely associated with a lipid shift favouring ω-6-derived mediators, leading to ECS imbalance. We investigated whether perinatal LC-ω-3-PUFA supplementation could prevent prenatal THC-induced neurodevelopmental deficits. Pregnant rats received THC (2 mg/kg, gestational days 5-20) and either a standard or LC-ω-3-PUFA-enriched diet (ω-3/ω-6 ratio = 1.4) from gestation through lactation. Adolescent offspring were evaluated for hippocampus-dependent memory (Novel object recognition) and gene expression of hippocampal plasticity markers (NR1, mGluR5, CB1R, Nlgn-1/2/3) and endocannabinoid metabolising enzymes (DAGLα, NAPE-PLD, MAGL, FAAH). LC-ω-3-PUFAs prevented prenatal THC-induced memory impairment in both sexes. Molecular analyses revealed sex-specific recovery mechanisms. In males, LC-ω-3-PUFAs counteracted prenatal THC-induced synaptic hyperexcitability by restoring NR1, mGluR5, and CB1R expression, reducing Nlgn-1 and enhancing the Nlgn-3 levels, together with increased NAPE-PLD expression. In females, LC-ω-3-PUFAs rebalanced the prenatal THC-induced predominant inhibitory shift by reducing Nlgn-2/-3- and NAPE-PLD expression levels. These findings identify perinatal LC-ω-3-PUFA supplementation as a safe, effective nutritional strategy to counteract THC-induced neurodevelopmental vulnerability by restoring ECS balance and supporting sex-specific neuronal plasticity and cognitive integrity.
Investigating the efficacy of propranolol in treating chronic stress combined with colorectal cancer in mice and its antitumor potential.
Zhou S, Xia L, Zhao L … +12 more , Song J, Lv H, Wan Q, Wang S, Yuan H, Zhang J, Lv M, Gui H, Jing Q, Li L, Zhang Y, Nie Y
Eur J Pharmacol · 2026 Jul · PMID 42229739 · Publisher ↗
PURPOSE: This study aimed to investigate the anti-tumor effects and mechanisms of propranolol (Prop) in mice with colorectal cancer (CRC) combined with chronic stress, as well as its potential impact when used in combina...
PURPOSE: This study aimed to investigate the anti-tumor effects and mechanisms of propranolol (Prop) in mice with colorectal cancer (CRC) combined with chronic stress, as well as its potential impact when used in combination with high-mobility group nucleosome-binding domain 1(HMGN1). The findings are intended to provide a novel therapeutic strategy and theoretical basis for cancer patients with comorbid psychological stress or depression. RESULTS: Chronic stress facilitated colorectal cancer progression in both in vivo and in vitro models. Propranolol inhibited cell proliferation and colony formation while inducing apoptosis. A single intratumoral injection of propranolol achieved a 100% complete tumor regression rate (9 of 9 mice) in both the CT26 murine colorectal cancer model subjected to chronic stress and the control model, without affecting body weight or physiological status, while inducing durable tumor-specific immune memory up to 80 days post-treatment. Recurrent inoculation of CT26 cells on the same or contralateral side failed to establish tumors in completely responded, whereas allogeneic 4T1 cells grew normally. Cross-model supplementary data demonstrated the tumor-suppressive effects of propranolol in other neoplasms. In combination therapy, intraperitoneal administration of propranolol enhanced HMGN1's anti-tumor efficacy, inhibiting tumor growth with significantly greater effects under chronic stress compared to controls. Epinephrine suppressed immune cell activation and triggered stress-related neuroendocrine changes, which were partially reversed by propranolol. CONCLUSION: We demonstrated the anti-tumor potential of β-adrenergic receptor (β-AR) blockade and elucidated the antitumor effects and underlying mechanisms of its antagonist propranolol. Combination immunotherapy broadly enhanced immune function under chronic stress conditions and exhibited strong potential for clinical translation.
Dimethyl fumarate attenuates post-infarct myocardial injury and is associated with modulation of the NRG-1/ErbB2/Akt pathway and reduction of oxidative stress.
Tekin I, Gundogdu G, Kilic-Erkek O … +2 more , Anber T, Abban-Mete G
Eur J Pharmacol · 2026 Jul · PMID 42229738 · Publisher ↗
BACKGROUND: Dimethyl fumarate (DMF) is a clinically approved antioxidant and anti-inflammatory agent. This study investigated whether DMF treatment is associated with enhanced myocardial repair after isoproterenol (ISO)-...
BACKGROUND: Dimethyl fumarate (DMF) is a clinically approved antioxidant and anti-inflammatory agent. This study investigated whether DMF treatment is associated with enhanced myocardial repair after isoproterenol (ISO)-induced myocardial infarction (MI) with a focus on the neuregulin-1 (NRG-1)/ErbB2/protein kinase B (Akt) pathway. METHODS: MI was induced in male Sprague-Dawley rats via subcutaneous ISO administration (85 mg/kg, two doses 24 h apart). Rats were assigned to Control, MI, Tween-80, and DMF groups. DMF (25 mg/kg/day, oral) was administered for 21 days, and rats were sacrificed on days 7 and 21 to evaluate early and subacute responses. Serum cardiac injury markers, oxidative stress parameters [total antioxidant-oxidant status (TAS-TOS), and oxidative stress index (OSI)], and cardiac tissue levels of NRG-1, ErbB2, PI3K, and Akt-1 were measured. Histological and immunohistochemical analyses assessed myocardial structure, fibrosis, apoptosis (TUNEL), proliferation (BrdU), and progenitor cell activation (c-Kit). RESULTS: DMF significantly reduced serum troponin-I, creatine kinase-MB, and lactate dehydrogenase levels in the early phase. It improved oxidative balance by increasing TAS and reducing TOS and OSI, while increasing myocardial NRG-1, ErbB2, and Akt-1 levels compared to the MI group. Histological analyses showed preserved fiber integrity, reduced fibrosis, and fewer apoptotic nuclei. Increased BrdU- and c-Kit-positive cells indicated enhanced cardiomyocyte proliferation and progenitor cell activation through the subacute phase. CONCLUSION: DMF attenuated myocardial injury and was associated with modulation of the NRG-1/ErbB2/Akt signaling pathway, improved redox balance, and enhanced indices of cellular repair across early and subacute post-infarction periods. These findings suggest that DMF may represent a promising candidate for pharmacological repurposing in post-infarction recovery; however, further mechanistic studies are required to confirm causality.
1,2,4-trimethoxybenzene exerts multi-target effects against ulcerative colitis by inhibiting the NLRP3 inflammasome and remodeling the gut microbiota-metabolism axis.
Yang T, Feng M, Yin H … +7 more , Wan JH, Liang YH, Zhang X, Peng C, Yang T, Yang M, Zhang HY
Eur J Pharmacol · 2026 Jul · PMID 42225164 · Publisher ↗
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) with limited treatment options. The natural compound 1,2,4-Trimethoxybenzene (ZY12) is a known NLRP3 inflammasome inhibitor, but its potential in UC r...
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) with limited treatment options. The natural compound 1,2,4-Trimethoxybenzene (ZY12) is a known NLRP3 inflammasome inhibitor, but its potential in UC remains unclear. This study evaluated the efficacy of ZY12 using a dextran sulfate sodium (DSS)-induced mouse model and integrated molecular, histological, 16S ribosomal RNA (16S rRNA) sequencing, short-chain fatty acids (SCFAs) and metabolomics analyses. Results showed that ZY12 significantly alleviated DSS-induced UC in mice, as evidenced by reduced weight loss, less colon shortening, and lower DAI scores. Mechanistically, ZY12 effectively inhibited NLRP3 inflammasome activation and downregulated the expression of pro-inflammatory cytokines, specifically interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and also reduced the level of calprotectin (S100A8/A9), a clinical marker of intestinal inflammation. Furthermore, ZY12 ameliorated colonic oxidative stress by enhancing the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), while reducing the levels of the oxidative damage markers malondialdehyde (MDA) and myeloperoxidase (MPO). Concurrently, ZY12 upregulated the key intestinal barrier-related proteins, namely Claudin-1, Occludin, zonula occludens-1 (ZO-1), and mucin 2 (MUC2). Comprehensive analyses revealed that ZY12 reshapes the gut microbiota composition by enriching beneficial bacterial taxa, increases levels of SCFAs (i.e., acetic acid, propionic acid, and butyric acid), and restores dysregulated host-microbiota co-metabolism, particularly through targeted modulation of the primary bile acid biosynthesis pathway. In conclusion, ZY12 alleviates UC via a synergistic regulatory network involving "immune modulation-microbiota reshaping-metabolic restoration". These findings highlight ZY12's potential as a promising multi-target therapeutic candidate for UC.
Pharmacological inhibition of fatty acid-binding protein 4 alleviates sepsis-associated acute kidney injury in mice via suppressing ferroptosis.
Ye J, Wang Y, Xie L … +6 more , He S, Shi X, Gao Y, Chen Q, Gao Y, Huang J
Eur J Pharmacol · 2026 May · PMID 42219054 · Publisher ↗
Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening clinical condition with limited therapeutic options, where ferroptosis serves as a key pathogenic driver. In this study, we conducted clinical sample a...
Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening clinical condition with limited therapeutic options, where ferroptosis serves as a key pathogenic driver. In this study, we conducted clinical sample analyses and proteomic profiling, and identified that fatty acid-binding protein 4 (FABP4) was significantly upregulated in the plasma of patients with SA-AKI, as well as in the renal tissues of SA-AKI model mice. To explore the functional role of FABP4, we administered BMS-309403 (BMS), a selective FABP4 inhibitor, in both a lipopolysaccharide (LPS)-induced murine SA-AKI model and an in vitro model of RAS-selective lethal 3 (RSL3)-treated human renal tubular epithelial (HK-2) cells. Our results demonstrated that BMS treatment markedly improved renal function, reduced tubular injury, and alleviated renal inflammation in mice. These protective effects were tightly associated with the inhibition of ferroptosis, as evidenced by reduced lipid peroxidation, decreased iron deposition, improved mitochondrial function, and the reversal of abnormal expression of key ferroptosis-related proteins, glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long chain family member 4 (ACSL4). Furthermore, in vitro experiments confirmed that BMS effectively mitigated RSL3-induced ferroptosis in HK-2 cells. To our knowledge, this study is the first to demonstrate that FABP4 exacerbates SA-AKI by promoting ferroptosis, suggesting that targeted inhibition of FABP4 may represent a promising novel therapeutic strategy for SA-AKI.
Effectiveness and Safety of Susvimo (Ranibizumab Port Delivery System) in Diabetic Retinopathy and Diabetic Macular Edema: A Systematic Review and Meta-analysis.
Chen KY, Chan HC, Chan CM
Eur J Pharmacol · 2026 May · PMID 42219053 · Publisher ↗
INTRODUCTION: Diabetic retinopathy (DR) and diabetic macular edema (DME) are major causes of vision impairment. The ranibizumab port delivery system (PDS; Susvimo) enables sustained intraocular anti-vascular endothelial...
INTRODUCTION: Diabetic retinopathy (DR) and diabetic macular edema (DME) are major causes of vision impairment. The ranibizumab port delivery system (PDS; Susvimo) enables sustained intraocular anti-vascular endothelial growth factor delivery and may reduce treatment burden compared with frequent intravitreal injections. METHODS: PubMed, Scopus, the Cochrane Library, ScienceDirect, and Google Scholar were searched from inception to December 2, 2025, for studies evaluating ranibizumab PDS in DR and/or DME. Study selection followed modified PICOS criteria and distinguished independent peer-reviewed randomized therapeutic trials from supportive derivative reports, conference abstracts, and device-engineering evidence. Risk of bias was assessed using RoB 2 and visualized with robvis for eligible randomized therapeutic trials. Random-effects proportion meta-analyses were performed only when clinically appropriate and when non-overlapping data were available. RESULTS: In center-involved DME, PDS every 24 weeks (Q24W) achieved noninferior best-corrected visual acuity (BCVA) gains compared with monthly ranibizumab through weeks 60 and 64 (+9.6 vs +9.4 Early Treatment Diabetic Retinopathy Study (ETDRS) letters; difference, 0.2 letters; 95% CI, -1.2 to 1.6). In nonproliferative diabetic retinopathy (NPDR) without center-involved DME, PDS every 36 weeks (Q36W) achieved at least 2-step Diabetic Retinopathy Severity Scale (DRSS) improvement in 80.1% of participants at week 52. Across the included therapeutic trial evidence, 39.0% to 80.1% of participants achieved at least 2-step DRSS improvement. In exploratory proportion meta-analyses based on available non-overlapping data, adverse events occurred in 22.3% of participants (95% CI, 18.8% to 26.4%), and supplemental treatment was required in 3.3% of participants (95% CI, 2.2% to 4.8%). No endophthalmitis was reported within the available DR/DME trial follow-up windows. CONCLUSION: Ranibizumab PDS demonstrates sustained functional and DR-severity benefits, low supplemental-treatment requirements, and largely manageable procedure-related adverse events over the reported follow-up periods; however, longer-term and real-world safety data remain necessary.
2-guanidine-4-methylquinazoline inhibits platelet activation and thrombosis by targeting the acid-sensing ion channel 3.
Zhang P, Liu P, Yu H … +8 more , Liu D, Wei M, Zhang K, Huang J, Li Y, Su Y, Zhang T, Zhang J
Eur J Pharmacol · 2026 May · PMID 42219052 · Publisher ↗
Platelets are key mediators of hemostasis and thrombosis. Acid-sensing ion channel 3 (ASIC3), a proton-gated cation channel, can be directly activated at pH 7.4 by the synthetic compound 2-guanidine-4-methylquinazoline (...
Platelets are key mediators of hemostasis and thrombosis. Acid-sensing ion channel 3 (ASIC3), a proton-gated cation channel, can be directly activated at pH 7.4 by the synthetic compound 2-guanidine-4-methylquinazoline (GMQ). However, the role of GMQ in platelet activation and its potential dependence on ASIC3 remain unclear. This study investigated whether GMQ modulates platelet function at physiological pH (7.4), whether this regulation is mediated by ASIC3, and what the underlying molecular mechanisms are. We found that GMQ significantly suppressed platelet activation in both human and murine platelets at pH 7.4 and attenuated thrombus formation and hemostatic function in mice. ASIC3 was confirmed to be functionally expressed in human and murine platelets. Although ASIC3 deficiency did not affect basal platelet characteristics or platelet activation at pH 7.4, it markedly diminished GMQ-mediated suppression of platelet activation, thrombosis, and hemostasis. Mechanistically, GMQ enhanced cyclic adenosine monophosphate (cAMP) production and promoted protein kinase A (PKA) Thr197 phosphorylation through interaction with ASIC3-cyclase-associated protein 1 (CAP1), thereby suppressing platelet function. Overall, this study demonstrates, for the first time, that GMQ inhibits platelet activation and thrombosis under physiological pH by targeting ASIC3 and activating the CAP1/cAMP/PKA signaling pathway. These findings suggest that targeting the non-proton domain of ASIC3 at physiological pH may represent a novel and promising antiplatelet therapeutic strategy.
Updated review on modern context of drug resistance in visceral leishmaniasis.
Pramanik M, Datta N, Dasmahapatra S … +3 more , Guchhait S, Khas SK, Mahapatra SK
Eur J Pharmacol · 2026 Jul · PMID 42219051 · Publisher ↗
Visceral leishmaniasis, a multifactorial disease, is life-threatening infectious neglected tropical disease caused by Leishmania donovani in the Indian subcontinent causing immune suppression to the host. There are annua...
Visceral leishmaniasis, a multifactorial disease, is life-threatening infectious neglected tropical disease caused by Leishmania donovani in the Indian subcontinent causing immune suppression to the host. There are annually 50 thousand to 90 thousand new cases of VL occur worldwide, while, only 25-45% reported to WHO and unfortunately 95% cases of these are still left untreated. In addition, higher cytotoxicity, severe side effects, and lower therapeutic indexes of the current anti-leishmanial drugs have created a necessity to develop new therapeutics. Furthermore, in poor endemic countries their extensive use was condensed immensely due to the emergence of their resistance. Several resistance cases were reported from the different regions of the world leading to treatment failure with the non-responsiveness of drugs. So, it is an intense issue to combat the arrival of resistance to new drugs. To overcome this condition, new treatment options or combination therapy, monitoring of therapy and enhanced diagnostics could play a vital role. The list of standard drugs presently available are the pentavalent antimonial, amphotericin B, and miltefosine (oral) which are most effective, while, paromomycin and very few compounds proposed by DNDi are still under clinical trial. There are some accepted mechanisms of drug resistance of leishmaniasis in field isolates. In this review, we have described the mechanism of drug resistance, the possible treatment options, and strategies to overcome the challenges of present treatments.
Srsf7 stabilization by the PIWI-interacting RNA AB352916 enhances Pkm alternative splicing to orchestrate cardiac fibrosis.
Wang X, Zhang Q, Zhang Z … +11 more , Zheng G, Yin D, Li H, Liu X, Yan H, Liu Y, Gao X, Ji H, Cai B, Zhao L, Liu Y
Eur J Pharmacol · 2026 May · PMID 42217722 · Publisher ↗
Cardiac fibrosis is a key pathological process following in myocardial infarction (MI), involves excessive extracellular matrix deposition and scar formation, leading to increased ventricular stiffness and reduced compli...
Cardiac fibrosis is a key pathological process following in myocardial infarction (MI), involves excessive extracellular matrix deposition and scar formation, leading to increased ventricular stiffness and reduced compliance. Our team recently identified a highly conserved PIWI-interacting RNA, AB352916 (termed CRAPIR), critical for cardiac regeneration. However, its role in post-MI cardiac fibrosis remains unclear. In this study, we demonstrated that myofibroblast-specific overexpression of AB352916 significantly exacerbated post-MI cardiac function and fibrosis. Conversely, adeno-associated virus (AAV)-mediated knockdown of AB352916 in myofibroblasts notably improved cardiac function and ameliorated pathological cardiac fibrosis. Furthermore, AB352916 overexpression promoted fibroblast activation, whereas its inhibition significantly attenuates TGF-β1-regulated fibrotic response. Mechanistically, AB352916 specifically bound to the RNA recognition motif (RRM) domin of serine and arginine-rich splicing factor 7 (Srsf7) and inhibited Srsf7 ubiquitination, thereby facilitating Srsf7-mediated alternative splicing of pyruvate kinase (Pkm), leading to a pro-fibrotic metabolic shift characterized by enhanced glycolysis and mitochondrial respiration that drives the progression of cardiac fibrosis. Importantly, myofibroblast-specific overexpression of Srsf7 abrogates the rescue effect of AB352916 knockdown on post-MI cardiac fibrosis. Moreover, overexpression of PkmΔE2 could attenuate the protective effects of the AB352916 antagomir or Srsf7 siRNA on TGF-β1-induced fibroblast activation and metabolic dysregulation. Collectively, our findings indicate that AB352916 drives post-MI cardiac fibrosis through Srsf7-dependent alternative splicing of Pkm, inducing a metabolic switch towards enhanced glycolysis and mitochondrial respiration, highlighting the AB352916/Srsf7/PkmΔE2 axis as a potential therapeutic target for fibrotic remodeling.
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