European Journal Of Pharmacology[JOURNAL]
Sun
200 papers
Multi-omics reveals rutin directly targets RUNX1 to disrupt the RUNX1/TET2 complex and alleviate NAFLD via TLR4/NF-κB inhibition.
He P, Luo Z, Liu X … +6 more , Fang F, Yan Q, Liu B, Chen Z, Yu Z, Hou T
Eur J Pharmacol · 2026 May · PMID 41997405 · Publisher ↗
Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder driven by metabolic dysregulation and chronic inflammation, for which targeted pharmacotherapies remain limited. Rutin, a bioactive flavonoid from S...
Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder driven by metabolic dysregulation and chronic inflammation, for which targeted pharmacotherapies remain limited. Rutin, a bioactive flavonoid from Sophora japonica and Fagopyrum esculentum, possesses notable anti-inflammatory and antioxidant properties. This study explored its pharmacological effects and underlying mechanism in NAFLD using a combination of in vivo and in vitro approaches. We found that rutin administration markedly attenuated hepatic steatosis, reduced oxidative stress, restored mitochondrial function, and improved liver injury markers, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), in both high-fat diet (HFD)-fed ApoE mice and free fatty acid (FFA)-exposed HepG2 cells. Furthermore, rutin significantly suppressed the production of pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Mechanistic studies integrating multi-omics and molecular biology approaches demonstrated that rutin directly binds to Runt-related transcription factor 1 (RUNX1), disrupts its interaction with ten-eleven translocation 2 (TET2), and thereby inhibits the downstream Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. Our results illuminate a novel pharmacological axis for rutin, positioning it as a promising multi-target candidate for NAFLD treatment by synchronously ameliorating lipid metabolism, oxidative injury, and inflammatory response.
The precision revolution: Machine learning and the future of personalized therapy in hematologic malignancies.
Xu L, Li Y, Marczyk M … +1 more , Łos MJ
Eur J Pharmacol · 2026 May · PMID 41997404 · Publisher ↗
Abstract loading — click title to view on PubMed.
Glycyl-L-histidyl-L-lysine-Cu2 (GHK-Cu) Attenuates CuSO or LPS induced-inflammation in Zebrafish larvae model.
Hu J, Zhang C, Wang F
Eur J Pharmacol · 2026 May · PMID 41997403 · Publisher ↗
Inflammation serves as a basic defense mechanism against both internal and external threats, while the unresolved or excessive inflammation can lead to irreversible tissue damage. Glycyl-L-histidyl-L-lysine-Cu (GHK-Cu),...
Inflammation serves as a basic defense mechanism against both internal and external threats, while the unresolved or excessive inflammation can lead to irreversible tissue damage. Glycyl-L-histidyl-L-lysine-Cu (GHK-Cu), a bioactive tripeptide complex known for its anti-aging and tissue repair properties, is extensively utilized in dermatological and hair care formulations. However, the role of GHK-Cu in regulating inflammation is less known. In this study, we explored the anti-inflammatory effects of GHK-Cu against the acute inflammation induced by copper sulfate (CuSO) and lipopolysaccharide (LPS) in zebrafish larvae. GHK-Cu notably decreased the migration of neutrophils and macrophages, suppressed the expression of pro-inflammatory cytokines (tnf-a, il-1β, il6) and increased the expression of the anti-inflammatory cytokine il-10. Moreover, GHK-Cu mitigated oxidative stress by reducing levels of nitric oxide (NO) and reactive oxygen species (ROS), and improved superoxide dismutase (SOD) activity. Furthermore, pathway analysis revealed that GHK-Cu administration downregulated the JAK1 pathway. In summary, this study highlights the dual role of GHK-Cu in both anti-inflammatory and anti-oxidant properties, which provides the theoretical evidences supporting its addition as a functional cosmetic ingredient.
Friedelin and 6-methoxyflavone from Imperata cylindrica ameliorate APAP-induced liver injury by activating AKT1 to suppress Caspase-3/GSDME-mediated pyroptosis.
Wu P, Chen W, Li J … +7 more , Xing J, Wu H, Tong J, Chen P, Tong H, Chen Y, Pan C
Eur J Pharmacol · 2026 May · PMID 41997402 · Publisher ↗
Acetaminophen (APAP) overdose causes acute liver injury (ALI) by triggering regulated hepatocyte death. While Imperata cylindrica (Imperatae Rhizoma) (IR) is used in traditional medicine for its hepatoprotective effects,...
Acetaminophen (APAP) overdose causes acute liver injury (ALI) by triggering regulated hepatocyte death. While Imperata cylindrica (Imperatae Rhizoma) (IR) is used in traditional medicine for its hepatoprotective effects, its active compounds and their capacity to modulate this pyroptotic switch remain unknown. In the present study, friedelin (FRI) and 6-methoxyflavone (6-METH) were identified as the principal active compounds of IR, and their protective effects against APAP-induced ALI were evaluated in vivo and in vitro. The results showed that both FRI and 6-METH significantly ameliorated APAP-induced liver injury and reduced hepatocyte death. Mechanistically, their hepatoprotective effects were associated with AKT1-dependent activation of the PI3K/AKT pathway, accompanied by suppression of Caspase-3/Gasdermin E (GSDME) signaling and attenuation of apoptosis and pyroptosis. Moreover, pharmacological inhibition or genetic silencing of AKT1 markedly weakened these protective effects. Taken together, these findings suggest that FRI and 6-METH are major hepatoprotective constituents of IR and that modulation of the AKT1-mediated Caspase-3/GSDME pathway may contribute to their protective actions against APAP-induced ALI. These findings validate its active compounds as promising therapeutic leads for ALI.
From mechanisms to therapeutics: The expanding role of cell-based strategies in Alzheimer's disease.
Sun X, Deng W, Yu J … +1 more , Xu X
Eur J Pharmacol · 2026 May · PMID 41997401 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Its core pathologies include the deposition of amyloid-β plaques, the formation of neurofibrillary tangles composed...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Its core pathologies include the deposition of amyloid-β plaques, the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, and neuronal loss. With the rapidly aging global population, the prevalence of AD continues to rise. Current pharmacological treatments offer only limited symptomatic relief and cannot modify the underlying disease trajectory, leaving a significant unmet clinical need. In this context, cell-based therapy has emerged as a promising therapeutic strategy, leveraging its unique multi-targeted and regenerative capacities. This review systematically examines the therapeutic potential of various cell types, including mesenchymal stem cells, neural stem cells, immune cells, and engineered cells. We elaborate on their mechanisms of action, which encompass neurotrophic support, immunomodulation, and clearance of pathological proteins. These concerted actions contribute to remodeling the hostile brain microenvironment and promoting neuroregeneration in AD. Although preclinical evidence is robust, the clinical translation of cellular therapies faces considerable challenges. These hurdles include selecting the optimal cell source, developing efficient delivery strategies, determining the ideal intervention timing, and establishing standardized manufacturing protocols. Looking forward, we discuss how the development of precise disease models, the integration of gene editing and engineering strategies, advances in combination therapies, and the establishment of personalized treatment regimens are poised to position cell therapy at the forefront of comprehensive AD management. These innovations hold new promise for achieving true disease modification.
Acute hyperglycemia induces NETosis and futile recanalization after ischemic stroke via RAGE/DIAPH1 pathway.
Li Q, Wu B, Chen Z … +9 more , Gong Q, Liu Y, Li Y, Ru X, Li W, Wu N, Chen Z, Chen Y, Yang Z
Eur J Pharmacol · 2026 May · PMID 41990906 · Publisher ↗
Acute hyperglycemia significantly exacerbates cerebral ischemia‒reperfusion injury and worsens clinical outcomes. Notably, insulin-based hypoglycemic therapy during the perioperative period of recanalization does not hav...
Acute hyperglycemia significantly exacerbates cerebral ischemia‒reperfusion injury and worsens clinical outcomes. Notably, insulin-based hypoglycemic therapy during the perioperative period of recanalization does not have a clear protective effect, suggesting that the underlying mechanisms are complex and require further investigation. In this study, we established a middle cerebral artery occlusion/reperfusion (MCAO/r) mouse model and induced acute hyperglycemia via intraperitoneal injection of 50% glucose solution before surgery. Blood glucose levels in acute hyperglycemic MCAO/r mice spontaneously returned to normal within 3 h. Nevertheless, 24 h after reperfusion, acute hyperglycemia significantly promoted the formation of neutrophil extracellular traps (NETs) via the receptor for advanced glycation end products (RAGE)/diaphanous-1 (DIAPH1) signaling axis, thereby exacerbating microvascular obstruction and brain injury following ischemic stroke. Intervention with FPS-ZM1 (N-benzyl-4-chloro-N-cyclohexylbenzamide) or deoxyribonuclease I (DNase I) significantly alleviated these pathological features. These data provide novel mechanistic insights into this pathological process and suggest a potential therapeutic strategy for improving outcomes in stroke patients at risk of futile recanalization.
IGF-1 attenuates high fat diet-elicited cardiomyopathy via arachidylcarnitine-dependent suppression of ferroptosis and mitochondrial dysfunction.
Wang L, Shen M, Abudureyimu M … +11 more , Ye H, Lin J, Abdulkhaliq AA, Reiter RJ, Dong F, Li G, Dong M, Zou R, Yuan M, Lin L, Ren J
Eur J Pharmacol · 2026 May · PMID 41990905 · Publisher ↗
Obesity is associated with low circulating IGF-1 levels, mitochondrial injury, and myocardial anomalies, however, the precise interplay between IGF-1 and obesity cardiomyopathy remains unclear. Our work evaluated the imp...
Obesity is associated with low circulating IGF-1 levels, mitochondrial injury, and myocardial anomalies, however, the precise interplay between IGF-1 and obesity cardiomyopathy remains unclear. Our work evaluated the impact of IGF-1 on high fat (HF) diet-evoked alterations in cardiac geometry, function, and mitochondrial integrity. WT and cardiac-specific IGF-1 transgenic mice were offered a low fat (LF, 10% fat calorie) or HF (60% fat calorie) diet for 20 weeks before assessing glucose sensitivity, plasma profiles, myocardial remodeling and function, ROS, mitochondrial integrity, and cell death. Transcriptomic analyses of obese human and murine hearts revealed that obesity cardiomyopathy was characterized by significant metabolic reprogramming, marked by a shift from TCA cycle to glycolysis and disrupted fatty acid homeostasis, alongside identification of ferroptosis as a key regulatory node in myocardial injury. HF led to hyperleptinemia, hypertriglyceridemia, reduced plasma IGF-1, and glucose intolerance, cardiac hypertrophy (higher LV dimensions, wall thickness), interstitial fibrosis, contractile dysfunction (lower fractional shortening, ejection fraction, cell contractile and intracellular Ca derangement), oxidative stress, apoptosis, ferroptosis, and mitochondrial injury (declined PGC1α and UCP-2). Notably, cardiac-specific IGF-1 overexpression mitigated HF-induced myocardial remodeling, dysfunction, mitochondrial injury, and ferroptosis, without affecting systemic glucose metabolism or plasma profiles. Importantly, targeted metabolomics revealed a distinct plasma acylcarnitine signature in obese patients, with C20:0 (arachidylcarnitine) identified as a top discriminative metabolite. Furthermore, reduced myocardial L-carnitine level was observed in HF-fed mice, and L-carnitine supplementation rescued HF-induced cardiac geometric, functional, and mitochondrial anomalies. These data indicate that IGF-1 confers beneficial effect for chronic HF intake-induced damage possibly via preserved mitochondrial integrity, suppressed ferroptosis, and restored arachidylcarnitine levels, highlighting a metabolomic-metabolic axis in obesity-related cardiac dysfunction.
Inhibition of PKM2 lactylation by geniposide ameliorates synovial hyperplasia in experimental arthritis.
Li B, Gan PR, Pang J … +2 more , Li JJ, Wu H
Eur J Pharmacol · 2026 May · PMID 41990904 · Publisher ↗
Glycolytic reprogramming-driven aberrant proliferation of FLSs is a major cause of synovial hyperplasia in rheumatoid arthritis (RA). Geniposide (GE), an iridoid glycoside extracted from the plant Gardenia jasminoides J....
Glycolytic reprogramming-driven aberrant proliferation of FLSs is a major cause of synovial hyperplasia in rheumatoid arthritis (RA). Geniposide (GE), an iridoid glycoside extracted from the plant Gardenia jasminoides J. Ellis, has been confirmed to inhibit the proliferative activity of RA-FLSs. However, whether this effect involves the regulation of glycolytic metabolism remains unclear. In this study, collagen-induced arthritis (CIA) rat models and TNF-α-induced MH7A cell models were established to investigate the specific mechanism by which GE regulates glycolytic reprogramming. The results showed that GE not only ameliorated synovial hyperplasia and suppressed glycolysis in CIA rats, but reduced the abnormal proliferation and glycolytic levels of TNF-α-induced MH7A cells. Increased lactylation of PKM2 was observed in the synovium of CIA rats and in TNF-α-induced MH7A cells, accompanied by the transition of PKM2 from tetramer to dimer and enhanced nuclear translocation. GE was found to inhibit the lactylation of PKM2. The SphK1/p300 signaling axis was activated both in vivo and in vitro. Investigations revealed that PF543, an inhibitor of SphK1, and A-485, an inhibitor of p300, inhibited the lactylation of PKM2. Moreover, GE suppressed the SphK1/p300 axis and prevented the interaction between PKM2 and p300. The inhibitory effect of GE on glycolysis was attenuated by lactate and the p300 agonist Cholera Toxin B (CTB). It was also found the suppression of glycolysis by GE was counteracted by both lactate and CTB. These results suggested GE suppressed the abnormal proliferation of FLSs by inhibiting the SphK1/p300-mediated lactylation of PKM2, highlighting a novel treatment strategy for RA.
Time-dependent neuroprotective effects of YL-IPA08 in repetitive mild traumatic brain injury associated with changes in Caprin1/SHH signaling.
Yu C, Ye Q, Song Z … +7 more , Li J, Li Z, Wang Z, Wang J, Li H, Li Y, Ouyang W
Eur J Pharmacol · 2026 May · PMID 41990903 · Publisher ↗
Repetitive mild traumatic brain injury (rmTBI) triggers chronic neuroinflammation, oxidative stress, and synaptic dysfunction, resulting in long-term cognitive and emotional impairments. Effective pharmacological interve...
Repetitive mild traumatic brain injury (rmTBI) triggers chronic neuroinflammation, oxidative stress, and synaptic dysfunction, resulting in long-term cognitive and emotional impairments. Effective pharmacological interventions remain scarce. Caprin1, a stress-responsive RNA-binding protein, regulates stress granules (SGs) dynamics and mRNA translation, while Sonic Hedgehog (SHH) signaling mediates neurogenesis and glial reactivity. YL-IPA08, a potent translocator protein (TSPO) ligand, exhibits neuroprotective efficacy in several neurological models, yet its temporal effects in rmTBI are unknown. Using a murine thinned-skull rmTBI model, we compared acute (YL-AcT, 0-3 days post-injury) and intermediate-phase (YL-IntT, 8-42 days) YL-IPA08 treatment paradigms. YL-AcT enhanced Caprin1/SHH co-expression, increased Caprin1-associated cytoplasmic granules consistent with SGs-like structures, and elevated DCX immature neuronal signals in the hippocampal DG without behavioral improvement, suggesting persistent cellular stress responses. In contrast, YL-IntT significantly improved motor, affective, and cognitive performance, reduced Caprin1 and SHH immunoreactivity, decreased the abundance of Caprin1-associated cytoplasmic granules, and partially restored hippocampal cytoarchitecture. YL-IntT also suppressed SHH/C3 co-expression, suggesting attenuation of neurotoxic astrocytic activation. TSPO expression showed dynamic, cell type-specific modulation across astrocytes and other cell populations, supporting a phase-dependent neuroprotective mechanism. Collectively, these findings suggest that YL-IPA08 exerts timing (treatment-window)-dependent neuroprotective effects that are temporally associated with alterations in Caprin1 and SHH signaling proteins, Caprin1-associated stress-responsive granule dynamics, and changes in TSPO expression patterns, potentially contributing to neuron-glia homeostasis under conditions of TSPO modulation. However, the present findings reflect associative relationships, and further studies will be required to determine the causal mechanisms linking TSPO modulation, Caprin1/SHH signaling, and functional recovery following rmTBI.
Trace amine associated receptors in neuronal circuits: Mechanistic insights for therapeutic interventions.
Jahangir M, Gowtham L, Nath M … +2 more , Halder N, Velpandian T
Eur J Pharmacol · 2026 May · PMID 41990902 · Publisher ↗
Trace amines (TAs) are typical biogenic amines which are found in the human body in pico-to-femto grams in the body fluids and tissues. TAs play crucial role in various physiological processes. Initially TAs were not con...
Trace amines (TAs) are typical biogenic amines which are found in the human body in pico-to-femto grams in the body fluids and tissues. TAs play crucial role in various physiological processes. Initially TAs were not considered significant due to their low levels in the body and no known receptor. After Trace amine-associated receptors (TAARs) discovery, TAs gained importance. TAs and TAARs are key regulators of neurotransmitter release thereby exerting their effects on dopaminergic, serotonergic, and noradrenergic pathways. This review delves into TAAR1, which is a G-protein coupled receptor which modulates neurotransmitter reuptake by regulating dopamine, serotonin, and noradrenaline transporters while also influencing vesicular monoamine transporter 2 function to ensure balanced neurotransmitter storage and release. Multiple studies have demonstrated that dysregulation of this system is closely linked to several neurodegenerative disorders, most notably Parkinson's disease and Alzheimer's disease. In addition, TAAR1 signaling has been strongly implicated in psychiatric conditions such as schizophrenia, mood disorders, and cognitive decline. These disorders share convergent pathological mechanisms, including oxidative stress, excitotoxicity, and neuroinflammation, all of which are influenced by TAAR1 activity. Growing preclinical and clinical evidence highlights TAARs, particularly TAAR1, as promising therapeutic targets for substance use disorders, due to their modulatory roles in dopaminergic and monoaminergic neurotransmission. Consequently, TAAR1 targeted pharmacological interventions present a promising approach for mitigating neurotransmitter imbalances and slowing neurodegenerative progression. This review seeks to provide a comprehensive understanding of the mechanistic and therapeutic implications of TAs and their receptors in various neurodegenerative conditions.
Proanthocyanidins alleviate ovarian ischemia reperfusion injury by inhibiting ferroptosis through the SIRT1/Nrf2/GPX4 pathway.
Liu X, Hou M, Lv X … +8 more , Lan W, Li X, Han X, Su Q, Hu J, Zhang Y, Liu Y, Leng Y
Eur J Pharmacol · 2026 May · PMID 41990901 · Publisher ↗
Ovarian ischemia reperfusion injury (IRI) is a dangerous gynecological disorder caused by ovarian torsion from the ovarian mass and surgical manipulation. To improve patient outcomes, it is necessary to explore more effe...
Ovarian ischemia reperfusion injury (IRI) is a dangerous gynecological disorder caused by ovarian torsion from the ovarian mass and surgical manipulation. To improve patient outcomes, it is necessary to explore more effective therapeutic approaches as well as their underlying mechanisms. Proanthocyanidins (PA) are polyphenolic compounds commonly present in fruits, seeds, peels of plants, and leaves. Several studies have demonstrated that PA can alleviate IRI in the liver, intestines, heart, brain, and kidneys. In the ovarian IRI, PA's exact molecular mechanisms have not yet been identified. For the purpose of elucidating PA's role and its mechanisms in the ovarian IRI, rat models of the ovarian IRI were used. Ovarian pathological changes and ferroptosis-related parameters were analyzed. Further mechanistic insights were obtained through glutathione peroxidase 4 (GPX4) inhibitor, ferroptosis inhibitor, nuclear factor E2 related factor 2 (Nrf2) agonist, Nrf2 inhibitor, sirtuin-1 (SIRT1) agonist, SIRT1 inhibitor, network pharmacology, and Western blot. Our results revealed that ferroptosis was involved in the ovarian IRI. PA pretreatment effectively alleviated IRI-induced ovarian damage, improved ovarian reserve, reduced oxidative stress, and recovered ferroptosis-related proteins in rats. Network pharmacology analysis suggested that PA may target SIRT1 and Nrf2 in ovarian IRI. SIRT1/Nrf2 signaling protected against GPX4-dependent ferroptosis in ovarian IRI. Inhibition of SIRT1/Nrf2 signaling negated PA's anti-ferroptosis effects on ovarian IRI. Overall, these findings validate that PA alleviates ovarian IRI and preserves ovarian reserve by inhibiting ferroptosis through the SIRT1/Nrf2/GPX4 pathway. These findings offer new insight into PA's protective mechanisms against ovarian IRI, supporting its potential as a therapeutic agent.
Normalization of magnesium deficiency with magnesium-L-Threonate alleviates bladder overactivity in cyclophosphamide-induced cystitis: Mechanisms of inflammatory modulation and barrier restoration.
Chen J, Luo R, Huang J … +7 more , Xie M, Liu C, Huang Y, Ding H, Zhang C, Li W, Xu B
Eur J Pharmacol · 2026 May · PMID 41985648 · Publisher ↗
Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) is a chronic urological syndrome predominantly affecting women, with an incidence of 2.7-6.5%. It is characterized by bladder-related pain and lower urinary tract symp...
Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) is a chronic urological syndrome predominantly affecting women, with an incidence of 2.7-6.5%. It is characterized by bladder-related pain and lower urinary tract symptoms, with inflammation and urothelial barrier disruption as primary mechanisms. Our previous research demonstrated that normalization of magnesium deficiency with Magnesium-L-Threonate (L-TAMS) alleviates mechanical allodynia, depressive-like behaviors, and memory deficits in cyclophosphamide (CYP)-induced cystitis by suppressing neuroinflammatory responses. In the present study, we established a rat BPS/IC model through intraperitoneal CYP injections (50 mg/kg every 3 days for three doses) and administered L-TAMS via drinking water at 604 mg/kg/day. Micturition frequency was assessed using cystometry, and bladder tissue was evaluated through hematoxylin and eosin staining, TUNEL assay, toluidine blue staining, and Western blotting. L-TAMS restored magnesium homeostasis and ameliorated bladder overactivity by prolonging intercontractile intervals. Histopathological alterations including epithelial defects, edema, and vascular congestion were alleviated. Increased apoptosis and mast cell infiltration were reversed. Additionally, TNF-α/NF-κB signaling and IL-1β expression were suppressed, and the integrity of bladder tight junction proteins was restored. These findings suggest that oral L-TAMS effectively reduces bladder overactivity in CYP-induced cystitis by inhibiting inflammatory signaling pathways and restoring bladder barrier integrity, supporting its therapeutic potential for BPS/IC management.
Impaired autophagic flux processing in cardiovascular diseases: the restorative role of ω-3 polyunsaturated fatty acids.
Wang S, Li J, Song C … +3 more , Li Q, Yang H, Chen M
Eur J Pharmacol · 2026 May · PMID 41985647 · Publisher ↗
Polyunsaturated fatty acids (PUFAs) have attracted increasing attention as dietary compounds with potential cardiovascular benefits. Owing to their favourable safety profile and comparatively low incidence of adverse eff...
Polyunsaturated fatty acids (PUFAs) have attracted increasing attention as dietary compounds with potential cardiovascular benefits. Owing to their favourable safety profile and comparatively low incidence of adverse effects, PUFAs have garnered increasing interest as potential adjunctive therapeutic agents in cardiovascular disease (CVD). Nevertheless, the molecular and cellular basis for their beneficial effects has not yet been fully elucidated. Growing evidence indicates that autophagic flux impairment is a common pathological feature in multiple forms of CVD, and that PUFAs partially restore autophagic homeostasis in patients under these conditions. These observations suggest that autophagy regulation may be essential for the cardioprotective mechanisms of PUFAs. This review systematically summarises the principal members, dietary sources, and metabolic pathways of the ω-3 and ω-6 PUFA families, emphasising the signalling pathways and molecular mechanisms through which PUFAs modulate autophagic flux, thereby influencing the progression of CVD. Additionally, this review aims to provide mechanistic insight to support the rational use of PUFAs in the clinical practice.
Studying synergistic anticancer effects of repurposed ATB losartan with antidiabetics metformin, rosiglitazone in triple-negative breast cancer cells.
Al-Mashhadani Z, Al Mulla Hummadi YMK, Al-Khfajy WS … +1 more , Numan NAM
Eur J Pharmacol · 2026 Apr · PMID 41967625 · Publisher ↗
This article investigates the effects of losartan, metformin, and rosiglitazone on triple-negative breast cancer (TNBC) with an intent to repurpose these drugs for cancer therapy. The cytotoxicity of the compounds was ev...
This article investigates the effects of losartan, metformin, and rosiglitazone on triple-negative breast cancer (TNBC) with an intent to repurpose these drugs for cancer therapy. The cytotoxicity of the compounds was evaluated through the MTT assay, where cells were exposed to each drug, both singularly and in combinations, over 48 h. The median inhibitory concentration (IC50) for each drug was calculated using nonlinear regression via GraphPad Prism, yielding IC50 values of 1231 μM for losartan, 30.37 μM for metformin, and 267.1 μM for rosiglitazone. The study highlights a synergistic effect particularly between losartan and metformin in TNBC, revealing a 1.6-fold increase in potency at a fixed 1:1 combination ratio. This combination facilitated enhanced cell growth inhibition over individual drug treatments, particularly at concentrations below 1280 μM. Furthermore, when losartan was combined with rosiglitazone, there was a notable augmentation in synergistic effects, underscoring improved efficacy, as seen by right-shifted dose-response curves and increased maximal responses at concentrations of 320 μM or higher. In assays with MDA-MB-231 cells, strong synergy was detected at minimal doses when losartan and metformin were combined, leading to significant dose reduction indices (DRIs) of 21.92 for losartan and 17.247 for metformin. In contrast, findings indicated that while losartan moderately inhibited growth within 48 h, the combination treatment did not yield any additional synergism with rosiglitazone at lower doses. The study concludes that although losartan and rosiglitazone exhibit strong synergy in inhibiting TNBC growth, the concurrent administration of these drugs at lower dosages presents limitations in achieving further synergistic or additive effects.
Artesunate reverses gefitinib resistance in lung adenocarcinoma by inducing ferroptosis and suppressing the Wnt/β-catenin pathway.
Zhang B, Lv X, Liu M … +6 more , Huang H, Huang X, Su H, Zhang R, Yu C, Huang Y
Eur J Pharmacol · 2026 Apr · PMID 41967624 · Publisher ↗
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve survival outcomes in lung adenocarcinoma (LUAD) patients, resistance inevitably remains a critical therapeutic challe...
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve survival outcomes in lung adenocarcinoma (LUAD) patients, resistance inevitably remains a critical therapeutic challenge. Artesunate (ART) has demonstrated antitumor potential in various malignancies, but whether ART increases the efficacy of EGFR-TKIs and reverses drug resistance in LUAD remains unexplored. In this research, the reversal effects and potential mechanisms of ART in gefitinib-resistant LUAD were investigated both in vitro and in vivo. ART effectively suppressed the viability, migration, invasion and colony formation of gefitinib-resistant cells. ART induced ferroptosis in LUAD by promoting Fe accumulation, ROS formation, and MDA production and suppressing the GSH/GSSG ratio as well as the ferroptosis-related proteins SLC7A11 and GPX4. Mechanistically, ART was found to inhibit the Wnt/β-catenin pathway by upregulating GSK3β and p-β-catenin expression while downregulating β-catenin, TCF4, Cyclin D1 and c-Myc expression, thereby promoting ferroptosis. These finding revealed that ART is an effective anticancer drug that enhances the therapeutic efficacy of gefitinib in LUAD cells by inducing ferroptosis and suppressing the Wnt/β-catenin pathway, which provides a promising foundation for the combined application of ART and EGFR-TKIs in the treatment of LUAD.
Corrigendum to "CT2-3 induces cell cycle arrest and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes through regulating PI3K/AKT pathway" [Eur. J. Pharmacol. 956 (2023) 175871].
Chen J, Lin X, Liu K … +7 more , He J, Li X, Zhang C, Deng Y, Luo L, Tao C, Wang Q
Eur J Pharmacol · 2026 Apr · PMID 41966959 · Publisher ↗
Abstract loading — click title to view on PubMed.
5-Bromocytidine protects against hyperuricemia-induced renal injury by suppressing TLR4/NF-κB-mediated inflammation.
Wang M, Han L, Tian D … +9 more , Meng X, Guan Z, Hu Z, Kang J, Gao X, Zhang Y, Gu Y, Liu X, Chen X
Eur J Pharmacol · 2026 Apr · PMID 41966318 · Publisher ↗
Hyperuricemia (HUA), a prevalent metabolic disorder, is an independent risk factor for chronic kidney disease (CKD). Elevated serum uric acid (UA) level leads to renal UA deposition, causing kidney inflammation, impairin...
Hyperuricemia (HUA), a prevalent metabolic disorder, is an independent risk factor for chronic kidney disease (CKD). Elevated serum uric acid (UA) level leads to renal UA deposition, causing kidney inflammation, impairing renal function, and accelerating HUA progression. In this study, an inflammation model in RAW264.7 cells induced by monosodium urate (MSU) was established to screen for compounds resistant to MSU-induced inflammation. Fortunately, 5-bromocytidine, a nucleic acid analogue, demonstrated potent anti-inflammatory activity in MSU-treated RAW264.7 cells and exhibited excellent therapeutic effects in HUA rats by reducing serum UA, creatinine (CRE) and blood urea nitrogen (BUN) amounts. Furthermore, we found that 5-bromocytidine blocked the activation of TLR4/NF-κB signaling pathway which mediated inflammation, and downregulated the expression of IL-1β and NLRP3. In summary, 5-bromocytidine may ameliorate HUA by suppressing the renal TLR4/NF-κB signaling pathway, suggesting a new candidate compound for HUA therapy.
Essential roles of IL-4 signaling in the prophylactic effect of gardiquimod on chronic stress-induced depression-like behaviors and neuroinflammatory responses.
Liu N, Yan L, Ye M … +7 more , Huang C, Li Q, Lu X, Yang R, Gu J, Wang H, Tong L
Eur J Pharmacol · 2026 Apr · PMID 41962890 · Publisher ↗
Neuroinflammation is a key pathological feature of depression, and strategies to mitigate neuroinflammatory response hold therapeutic potential. Innate immune priming is a physiological process in which prior immune acti...
Neuroinflammation is a key pathological feature of depression, and strategies to mitigate neuroinflammatory response hold therapeutic potential. Innate immune priming is a physiological process in which prior immune activation enhances defense against subsequent insults. Evidence indicates that pre-stimulation of innate immune response can confer resilience to stress-induced depression. This study examined the prophylactic effect of gardiquimod (GDQ), a selective Toll-like receptor 7 (TLR7) agonist, in a mouse model of chronic unpredictable stress (CUS). Administration of GDQ (0.5-1.5 mg/kg) one day before stress prevented the development of depression-like behaviors in a dose-dependent manner, whereas a lower dose (0.1 mg/kg) was ineffective. The protective window was temporally limited: a single 1.5 mg/kg dose was effective when given one day before stress onset, but its efficacy was lost with a ten-day pretreatment interval. This loss could be overcome by administering a second GDQ injection ten days after the first, or by using a multi-dose regimen ten days prior to stress. At the molecular level, GDQ pretreatment prevented CUS-induced up-regulation of pro-inflammatory cytokine mRNA in the hippocampus and medial prefrontal cortex. The preventive effects of GDQ on CUS-induced depression-like behaviors and neuroinflammatory responses were abolished by pre-treatment with the innate immune inhibitor minocycline, or by central infusion of an interleukin-4 (IL-4) neutralizing antibody before stress onset. In summary, these findings demonstrate that GDQ, via a mechanism dependent on innate immune priming and subsequent IL-4 signaling, can confer resistance to chronic stress-induced neuroinflammation and depression-like behaviors, supporting its investigation as a prophylactic immunomodulatory agent.
Klotho-derived peptide preserves erectile function by limiting fibrosis, oxidative stress, and apoptosis of penile smooth muscle cells in cavernous nerve injured-rats through suppression of the TGF-β1/TGF-β type II receptor signaling.
Xi Y, Han G, Li X … +4 more , Zhang X, Zhang S, Ma K, Zhu F
Eur J Pharmacol · 2026 Apr · PMID 41962889 · Publisher ↗
Patients with prostate cancer frequently complain of erectile dysfunction (ED) after radical prostatectomy (RP). Corporal fibrosis and apoptosis following cavernous nerve injury (CNI) significantly contribute to RP-induc...
Patients with prostate cancer frequently complain of erectile dysfunction (ED) after radical prostatectomy (RP). Corporal fibrosis and apoptosis following cavernous nerve injury (CNI) significantly contribute to RP-induced ED. Klotho is an anti-aging protein, and Klotho-derived peptide (KP) has been introduced as an antagonist of tissue fibrosis and apoptosis. However, it is unknown whether CNI-induced functional and morphological changes in the penis. This study was designed to explore the impact of KP on CNI-induced ED. The rats were randomly divided into three groups: Sham operation, bilateral CNI with saline injection, and bilateral CNI with KP injection. Assessments of erectile function were conducted three weeks post-treatment. Penile tissues were obtained for histopathological examination. Corpus cavernosum smooth muscle cells (CCSMCs) treated with transforming growth factor-beta 1 (TGF-β1) served as an in vitro model to assess the impact of KP. Rats subjected to bilateral CNI developed severe ED. Penile tissues exhibited reduced smooth muscle abundance and nitric oxide synthase expression, alongside increased fibrosis, oxidative stress, apoptosis, and TGF-β1 signaling activation. However, KP ameliorated these functional and morphological damage. Moreover, KP exerted anti-fibrotic and anti-apoptotic effects on TGF-β1-stimulated CCSMCs by downregulating TGF-β type II receptor, which intercepted the Smad2/JNK signaling and activated the AKT pathway. Overall, KP improved CNI-induced ED and corporal remodeling. These beneficial effects were mediated by TGF-β type II receptor downregulation, which rebalanced the TGF-β1-driven Smad2/JNK activation and PI3K/AKT suppression, thereby ameliorating CCSMC dysfunction. Our results establish the potential of KP as a therapy for neurogenic ED.
Regulation of OATP1B1 and OATP1B3 by HNF3α and/or c-Jun mediates rosuvastatin hepatic uptake.
Ren L, Wang D, He Y … +7 more , Wu X, Zhu W, Yin Y, Lin Y, Yu X, Su Z, Wu Y
Eur J Pharmacol · 2026 Apr · PMID 41962420 · Publisher ↗
Organic anion transporting polypeptides 1B1 (OATP1B1, gene: SLCO1B1) and 1B3 (OATP1B3, gene: SLCO1B3), primarily expressed in the liver, mediate the hepatocellular uptake of various endogenous and exogenous compounds. Wh...
Organic anion transporting polypeptides 1B1 (OATP1B1, gene: SLCO1B1) and 1B3 (OATP1B3, gene: SLCO1B3), primarily expressed in the liver, mediate the hepatocellular uptake of various endogenous and exogenous compounds. While polymorphisms in their coding regions influence drug pharmacokinetics, the mechanisms regulating their transcription remain unclear. This study investigates the transcriptional regulation of SLCO1B1 and SLCO1B3 by identifying critical promoter regions and transcription factor binding sites. Luciferase reporter assays revealed key promoter regions: -52 to -208 nt for SLCO1B1 and -69 to -198 nt for SLCO1B3. Bioinformatics analysis predicted binding sites for HNF3α and c-Jun in the SLCO1B1 promoter, and a c-Jun binding site in the SLCO1B3 promoter. Mutagenesis and EMSA confirmed these sites' functional significance. Overexpression of HNF3α and c-Jun enhanced SLCO1B1 promoter activity and expression, while their knockdown had the opposite effect. Similarly, c-Jun overexpression upregulated SLCO1B3, and its knockdown reduced SLCO1B3 activity. Using rosuvastatin as a substrate, we found that overexpression of c-Jun and HNF3α, or increased phosphorylation of c-Jun, significantly increased hepatic uptake of rosuvastatin, while knockdown of HNF3α and c-Jun or inhibition of c-Jun phosphorylation decreased it. In conclusion, SLCO1B1 is co-regulated by HNF3α and c-Jun, while SLCO1B3 is primarily regulated by c-Jun. These findings highlight the role of HNF3α and/or c-Jun in regulating OATP1B1 and OATP1B3 expression and their impact on drug disposition.
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