Eur. J. Pharmacol. [JOURNAL]
Sun
200 papers
Eupalinolide A attenuates bleomycin-induced pulmonary fibrosis by inhibiting lung fibroblast transition.
Gu J, Chen T, Dai J … +4 more , Huang Y, Chen X, Sun X, Jiang X
Eur J Pharmacol · 2026 Jun · PMID 42178011 · Publisher ↗
This work aimed to investigate the effects of eupalinolide A on bleomycin-induced pulmonary fibrosis and the possible underlying mechanism. We found that in vitro, the antifibrotic activity of eupalinolide A was better t...
This work aimed to investigate the effects of eupalinolide A on bleomycin-induced pulmonary fibrosis and the possible underlying mechanism. We found that in vitro, the antifibrotic activity of eupalinolide A was better than that of eupalinolide G and eupalinolide I and that it was also superior to that of ginkgolide A, ginkgolide B, ginkgolide C, and bilobalide. Eupalinolide A significantly suppressed lung fibroblast transition and decreased the production of extracellular matrix (ECM). Mechanistically, eupalinolide A reduced serum response factor (SRF) levels. Knockdown of SRF inhibited lung fibroblast transition, confirming the effect of eupalinolide A. Moreover, eupalinolide A significantly reduced the level of phosphorylated extracellular regulated protein kinase (ERK), and knockdown of ERK significantly suppressed the transforming growth factor β1 (TGF-β1)-induced increase in SRF levels and lung fibroblast transition. Eupalinolide A significantly reduced the level of phosphorylated mitogen-activated protein kinase kinase (MEK), and genetic and pharmacological inhibition of MEK significantly decreased the levels of phosphorylated ERK, the levels of SRF and the transition of lung fibroblasts. In vivo, eupalinolide A reduced ECM deposition, and inhibited lung fibroblast transition. Additionally, eupalinolide A decreased the levels of phosphorylated MEK/ERK and the level of SRF in mouse lung tissues. Together, this study was the first evidence to demonstrate that eupalinolide A attenuates lung fibrosis by inhibiting the abnormal transition of lung fibroblasts and that the underlying mechanism is related to MEK/ERK/SRF signaling pathway inhibition. These findings provide evidence for the discovery of lead compounds with novel structures for use in treating chemical therapy-induced pulmonary fibrosis.
Metformin-associated lactic acidosis: Bridging pharmacokinetic determinants, metabolic pathways, and clinical outcomes.
Anwar KR, Khan MM, Badruddeen … +3 more , Nisha A, Siddiqui EM, Ahmad U
Eur J Pharmacol · 2026 Jul · PMID 42178010 · Publisher ↗
Metformin is the first-line oral anti-hyperglycemic agent for the treatment of type 2 diabetes mellitus due to its effectiveness, cost-efficiency, and acceptable safety profile. Although metformin possesses a favorable s...
Metformin is the first-line oral anti-hyperglycemic agent for the treatment of type 2 diabetes mellitus due to its effectiveness, cost-efficiency, and acceptable safety profile. Although metformin possesses a favorable safety profile, a rare but serious adverse event known as metformin-associated lactic acidosis (MALA) may occur, particularly in patients with impaired renal clearance or predisposing comorbidities that favor drug retention. High anion-gap metabolic acidosis, increased concentrations of lactate (>5 mmol/L), and arterial pH of less than 7.35 are the hallmarks of MALA. MALA has a multifactorial pathophysiology, driven primarily by mitochondrial complex I inhibition, leading to an altered intracellular redox state and decreased hepatic lactate clearance. Crucially, MALA is fundamentally an accumulation disorder precipitated by an acute decline in kidney function rather than an intrinsic toxicity of metformin at therapeutic concentrations. Many precipitating factors, including acute kidney injury (AKI), chronic kidney disease (CKD), hepatic impairment, sepsis, hypoxia, and dehydration, substantially predispose individuals to this complication. Early identification of clinical signs, such as metabolic acidosis, tachypnea, hypotension, and altered mental status, is essential to a better patient outcome. Diagnostic assessment is based on arterial blood gas values, serum lactate, and renal function tests. Management aims at stopping metformin immediately, providing supportive care, and eliminating the medication through renal replacement therapy (RRT) in severe instances. Prevention measures focus on appropriate patient selection, renal monitoring, dose adjustment, and proactive temporary drug withdrawal during acute intercurrent illnesses ("sick-day rules"). MALA is not highly prevalent, and contemporary evidence demonstrates that mortality is highly context-dependent, with prompt extracorporeal interventions yielding robust survival rates.
Isoliquiritigenin ameliorates Pseudomonas aeruginosa-induced acute lung injury through inhibiting lung epithelial cell ferroptosis via PPARγ/Nrf2/GPX4 axis.
Cao H, Yu M, Tang S … +3 more , He Y, Wu M, Pang Z
Eur J Pharmacol · 2026 Jul · PMID 42178009 · Publisher ↗
Pseudomonas aeruginosa, an opportunistic pathogen, is a primary cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in immunocompromised individuals. Isoliquiritigenin (ISL), a natural flavono...
Pseudomonas aeruginosa, an opportunistic pathogen, is a primary cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in immunocompromised individuals. Isoliquiritigenin (ISL), a natural flavonoid primarily found in liquorice (Glycyrrhiza glabra), has demonstrated protective effects against infection-induced ALI. However, the therapeutic potential and molecular mechanisms of ISL against P. aeruginosa-induced ALI remain unclear. In this study, we established a mouse model of acute bacterial pneumonia and an in vitro lung epithelial cell infection model to assess the therapeutic efficacy and underlying mechanisms of ISL. Results showed that ISL improved the survival and alleviated the P. aeruginosa-induced ALI in mice by reducing neutrophil recruitment, pulmonary cell death and bacterial load. Transcriptomic and enrichment analyses revealed that ISL reversed infection-induced inflammation and oxidative stress, while also providing supporting evidence for ferroptosis-related alterations. Moreover, ISL treatment significantly preserved the structural and functional integrity of the pulmonary epithelial barrier by attenuating pulmonary edema, reducing pulmonary epithelial permeability, and restoring tight junction protein expression. Network pharmacology identified AKT1, EGFR, PPARG and COX-2 as candidate targets of ISL. SPR, molecular docking and molecular dynamics simulation further verified the interaction between ISL and PPARγ. Subsequent mechanistic investigations demonstrated that ISL activated the PPARγ/Nrf2/GPX4 signaling axis and inhibited lung epithelial cell ferroptosis both in vivo and in vitro. Altogether, ISL protects against P. aeruginosa-induced ALI by activating PPARγ/Nrf2/GPX4 axis and suppressing lung epithelial cell ferroptosis, thereby preserving lung epithelial barrier integrity and reducing inflammatory responses.
CCN5 overexpression suppresses trophoblast HTR-8/SVneo cell proliferation, migration, invasion, and epithelial-mesenchymal transition.
Gong Y, Li J, Wang C … +6 more , Bai J, Huang J, Wang Z, Yin Q, Liao S, Liu M
Eur J Pharmacol · 2026 Jul · PMID 42178008 · Publisher ↗
BACKGROUND: Preeclampsia (PE) is a highly prevalent, significant obstetric condition associated with aberrant placental trophoblast cell proliferation and infiltration. Cellular communication network factor 5 (CCN5), als...
BACKGROUND: Preeclampsia (PE) is a highly prevalent, significant obstetric condition associated with aberrant placental trophoblast cell proliferation and infiltration. Cellular communication network factor 5 (CCN5), also referred to as WISP-2, is involved in essential cellular functions, including growth, adhesion, and migration. Nevertheless, the specific roles of CCN5 in trophoblast-related functions remain unexplored. METHODS: CCN5 expression levels in placental samples from 30 individuals diagnosed with PE and healthy pregnant controls were initially assessed via quantitative reverse transcription PCR (qRT-PCR). Next, cultured human trophoblast cells (HTR-8/SVneo) were transfected with CCN5 short hairpin RNA (shRNA) or CCN5-overexpression plasmids. The efficacy of CCN5 transfection was validated by qRT-PCR and western blotting. Cell proliferation was assessed using colony formation and CCK-8 assays, whereas cell migration and invasion were measured using wound-healing and Transwell assays. Western blotting was performed to analyze the expression levels of extracellular signal-regulated kinase (ERK), phosphorylated-ERK (p-ERK), Twist1, E-cadherin, N-cadherin, and ZO-1 proteins. RESULTS: Our study initially demonstrated that placental tissues from PE patients had significantly higher CCN5 levels than those from the control group. Functionally, silencing CCN5 in HTR-8/SVneo cells markedly enhanced proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), whereas overexpression significantly inhibited these processes. Notably, CCN5 has been identified as a regulator of EMT, thereby influencing the functional behavior of trophoblast cells. Mechanistically, CCN5 reduced p-ERK levels in HTR-8/SVneo cells, leading to a reduction in Twist1 expression, thereby suppressing EMT. CONCLUSION: CCN5 overexpression may reduce proliferation and EMT in humans trophoblast cells via the ERK/Twist1 pathway. This finding suggests that CCN5 could serves as a viable target in PE treatment.
Identification and validation of glycosylation-related biomarkers in the hippocampus for Alzheimer's disease diagnosis and drug repurposing.
Mu Y, Yu S, Yang Z … +2 more , Chen S, Sun J
Eur J Pharmacol · 2026 Jul · PMID 42178007 · Publisher ↗
As a crucial type of post-translational modification, glycosylation plays a fundamental role in maintaining cellular homeostasis and is closely associated with the progression of Alzheimer's Disease (AD). Given the centr...
As a crucial type of post-translational modification, glycosylation plays a fundamental role in maintaining cellular homeostasis and is closely associated with the progression of Alzheimer's Disease (AD). Given the central involvement of the hippocampus in AD pathogenesis, elucidating the mechanisms of glycosylation in this brain region may provide critical insights and facilitate the development of precision medicine strategies for AD. We employed an integrated bioinformatics framework to identify glycosylation-related diagnostic biomarkers for AD. Limma and WGCNA were conducted on a hippocampal gene expression microarray dataset to detect glycosylation-associated DEGs, which were intersected with a glycosylation gene set obtained from GeneCards. Key diagnostic genes were selected using three machine learning algorithms in an independent cohort. The diagnostic model was subsequently validated in two additional independent microarrays datasets. Functional exploration and hippocampal heterogeneity were assessed at both bulk-tissue and single-cell levels. PPI analysis and NMF clustering further stratified AD patients into two subtypes. Finally, qRT-PCR validated the expression of biomarkers, and molecular docking based on the CTD suggested potential therapeutic candidates. Our analysis identified CKMT1B and AP1S1 as key downregulated glycosylation-related genes in AD. These genes were predominantly and highly enriched in hippocampal microglia at both bulk and single-cell levels and demonstrated strong diagnostic potential. PPI network analysis and NMF revealed that these hub genes could stratify AD patients into two distinct molecular subgroups. Furthermore, quercetin was identified as a potential multi-target therapeutic agent through database screening and CTD molecular docking studies. Collectively, this study bridges fundamental discovery with clinical translation by providing a diagnostic model, patient stratification subtypes, and a repositioned therapeutic candidate, outlining a promising path toward personalized AD management.
Sulfonated peptide alleviates hypertensive renal injury via antioxidant, anti-inflammatory, and renal metabolomics.
Li Y, Song S, Lin Q … +1 more , Jin H
Eur J Pharmacol · 2026 Jun · PMID 42176725 · Publisher ↗
Excessive dietary salt intake is a well-established risk factor for hypertension, with numerous underscoring its significant role in the pathogenesis of cardiovascular diseases. Dietary management is widely recognized as...
Excessive dietary salt intake is a well-established risk factor for hypertension, with numerous underscoring its significant role in the pathogenesis of cardiovascular diseases. Dietary management is widely recognized as essential for both the prevention and treatment of hypertension. This study aimed to evaluate the preventive efficacy of a sulfonated peptide, Leucyl-glycyl-asparaginyl-glycyl-cysteinylsulfonic acid-proline (Leu-Gly-Asn-Gly-Cya-Pro, SLP), against high-salt-induced hypertension and renal injury, thereby providing new insights into hypertension prevention strategies. Compared with the unsulfonated peptide, Leucyl-glycyl- asparaginyl-glycyl-cysteinyl-proline (Leu-Gly-Asn-Gly-Cys-Pro, LP), SLP was more effective in attenuating the elevation of blood pressure, inhibiting renal fibrosis, improving markers of renal injury (alpha-1-microglobulin and uric acid), and reducing levels of inflammatory factors and adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukin-1β). Additionally, SLP upregulated endothelial nitric oxide synthase while downregulating inducible nitric oxide synthase in the kidney. Similarly, high levels of nuclear factor-kappa B and phosphorylated nuclear factor-kappa B induced by high-salt in the kidney were effectively prevented by SLP treatment. Furthermore, SLP exerted antihypertensive effects through the regulation of tryptophan, purine, glycerophospholipid, and cysteine metabolism, as well as the citrate cycle. Overall, sulfonation modification enhances the anti-inflammatory and metabolic regulatory activities of peptides, with the sulfonated peptides SLP significantly preventing high-salt-induced hypertension and its associated renal complications.
14-3-3η protein ameliorates glomerular endothelial cell injury in lupus nephritis by regulating mTOR pathway-mediated autophagy.
Song X, Tang K, Gao J … +3 more , Liu X, Jiang Q, Ma L
Eur J Pharmacol · 2026 Jul · PMID 42176724 · Publisher ↗
BACKGROUND: Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), is characterized by glomerular endothelial cell injury, inflammation, and immune complex deposition. The 14-3-3η protein, a m...
BACKGROUND: Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), is characterized by glomerular endothelial cell injury, inflammation, and immune complex deposition. The 14-3-3η protein, a multifunctional regulator, plays roles in various cellular processes, however, its specific role in LN and the underlying mechanisms remain unclear. This study investigates the role of 14-3-3η in LN by modulating mTOR pathway-mediated autophagy. METHODS: Human renal glomerular endothelial cells (HRGECs) overexpressing 14-3-3η were treated with plasma from healthy donors and LN patients. Cell viability, nitric oxide (NO) levels, and the expression of syndecan-1, VCAM-1, 14-3-3η, and autophagy markers (LC3, PINK1, Parkin) were analyzed. In vivo, an LN mouse model was established, and treated with 14-3-3η-overexpressing adenovirus or rapamycin (RAP) was administered. Renal histopathology, serum syndecan-1, VCAM-1, and autophagy markers were evaluated. RESULTS: In vitro, 14-3-3η overexpression attenuated LN plasma-induced endothelial injury, enhanced cell viability, reduced NO levels, and downregulated syndecan-1 and VCAM-1 expression. It also suppressed autophagy by promoting mTORC1 complex formation and downstream signaling via mTOR S1276 phosphorylation. In vivo, 14-3-3η overexpression ameliorated glomerular pathology and inhibited autophagy by regulating mTOR, LC3, PINK1, and Parkin. CONCLUSION: 14-3-3η alleviates LN-induced glomerular endothelial injury and renal dysfunction by modulating mTOR-mediated autophagy. This study identifies 14-3-3η as a potential therapeutic target for LN and advances the understanding of its role in kidney diseases.
Connexin32 inhibits renal tubulointerstitial fibrosis in diabetic kidney disease by regulating NOX4/MRTF-A positive feedback loop.
Tang D, Liu Z, He Y … +9 more , Liang S, Feng T, Ou G, Chen Y, Nong Q, Chen G, Zhang Q, Jiao Y, Chen Z
Eur J Pharmacol · 2026 Jul · PMID 42173394 · Publisher ↗
Diabetic kidney disease (DKD) is typified by the epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells (TECs). EMT gives rise to renal tubulointerstitial fibrosis (TIF). Our previous study has shown t...
Diabetic kidney disease (DKD) is typified by the epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells (TECs). EMT gives rise to renal tubulointerstitial fibrosis (TIF). Our previous study has shown that Connexin32 (Cx32) can improve renal TIF in DKD by inhibiting EMT. However, the specific mechanism of Cx32 in regulating EMT remains to be further elucidated. In the present study, we found that Cx32 protein expression was decreased in renal tubules of patients with DKD compared with controls. However, specific overexpression of Cx32 (tail vein injection of AAV9-Cx32) in renal tubular epithelial cells can effectively alleviate tubular mitochondrial damage, reduce reactive oxygen species (ROS) levels, inhibit EMT, and improve renal function and TIF in db/db mice. At the same time, overexpression of Cx32 inhibited HG-induced ROS overproduction and EMT in NRK-52E cells, and inhibited renal tubular epithelial cell fibrosis. Interestingly, there was a positive feedback regulation between NADPH oxidase 4 (NOX4) and Myocardin-related transcription factor A (MRTF-A) in NRK-52E cells induced by high glucose (HG). In addition, the treatment of AAV9-Cx32 inhibited the abnormal protein expression of NOX4 and MRTF-A, reduced the nuclear accumulation of MRTF-A in the kidney of db/db mice. Moreover, Cx32 overexpression reduced the colocalization of NOX4 and MRTF-A in HG-induced NRK-52E cells, thereby inhibiting the NOX4/MRTF-A positive feedback loop. Mechanistically, Cx32 regulates the NOX4/MRTF-A positive feedback loop through its C-terminal domain. Consequently, this study offers a more substantial experimental foundation for the utilization of Cx32 as a potential therapeutic target for DKD.
DTMB attenuates hepatic inflammation and lipid dysregulation via PPAR-γ modulation in diet-induced steatohepatitis.
Lee J, Oh E, Cho S … +7 more , Kang JH, Gwak SH, Shin WS, Yoon S, Han YH, Kim J, Kim KT
Eur J Pharmacol · 2026 Jul · PMID 42173393 · Publisher ↗
Steatohepatitis is a progressive liver disease characterized by hepatic steatosis, chronic inflammation, and fibrotic remodeling, ultimately leading to cirrhosis and hepatocellular carcinoma. Despite recent therapeutic a...
Steatohepatitis is a progressive liver disease characterized by hepatic steatosis, chronic inflammation, and fibrotic remodeling, ultimately leading to cirrhosis and hepatocellular carcinoma. Despite recent therapeutic advances, strategies that effectively target both inflammatory and metabolic dysfunction without exacerbating metabolic liabilities remain limited. Here, we investigated the effects of [4-(4-methoxyphenyl)-8-methyl-2-oxochromen-7-yl] (2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate (DTMB), a selective modulator of peroxisome proliferator-activated receptor gamma (PPAR-γ), in multiple diet-induced models of steatohepatitis. DTMB treatment reduced hepatic inflammation by suppressing NF-κB-driven inflammatory signaling. Concurrently, DTMB attenuated hepatic steatosis in association with increased adipose triglyceride lipase (ATGL) expression. Notably, these effects were observed without the weight gain and lipid storage typically associated with full PPAR-γ agonists. Together, these findings suggest that DTMB functions as a selective PPAR-γ modulator that uncouples anti-inflammatory and lipid-regulatory benefits from adverse metabolic effects, highlighting its therapeutic potential for steatohepatitis.
Therapeutic effects of zanamivir against L-NAME-induced preeclampsia in mice and network pharmacology analysis.
Hu T, Yang L, Tang C … +2 more , Yang Y, Du T
Eur J Pharmacol · 2026 Jun · PMID 42167670 · Publisher ↗
Since structural and functional damage of endothelial glycocalyx was observed in preeclampsia patients, maintaining the glycocalyx integrity appears to be a potential strategy to treat preeclampsia. Neuraminidase, which...
Since structural and functional damage of endothelial glycocalyx was observed in preeclampsia patients, maintaining the glycocalyx integrity appears to be a potential strategy to treat preeclampsia. Neuraminidase, which degrades the endothelial glycocalyx by stripping sialic acid residues, represents a novel target to restore the integrity of glycocalyx and the normal function of endothelium. Therefore, this work studied the potential effects of zanamivir, a neuraminidase inhibitor, against preeclampsia using a mouse disease model and network pharmacology analysis. Preeclampsia model was established in pregnant CD-1 mice after daily administration of L-NAME from gestational day (GD)8 to GD17. The preeclampsia mice showed hallmarks of disease, including elevated blood pressure, increased urine total protein, and reduced litter size and pup weight. More importantly, zanamivir treatment led to reduction of hypertension, mitigation of proteinuria, and protection of fetus, suggesting its therapeutical effects against preeclampsia. The major mechanisms of zanamivir involved the preservation of glycocalyx integrity and improvement of systemic endothelial function by inhibiting neuraminidase. Further network pharmacology analysis identified 74 potential targets by which zanamivir exerts regulation of preeclampsia pathogenesis. PPI network and clustering, GO annotation, pathway and organ system & cell-type enrichment analysis also supported that regulation of blood pressure was the core biological action of zanamivir in treating preeclampsia. Taken together, the in vivo and in silico findings demonstrated the therapeutic effects of zanamivir against preeclampsia, particularly the regulation of hypertension, the importance of restoring glycocalyx integrity and endothelial function, and the potential of targeting neuraminidase when seeking novel therapies for preeclampsia.
Establishment of a novel model of depression caused by olfactory dysfunction through intranasal administration of 3-methylindole.
Song XJ, Bai L, Dong XR … +3 more , Zhang H, Chen YB, Cui YL
Eur J Pharmacol · 2026 Jul · PMID 42167669 · Publisher ↗
Olfactory dysfunction has been closely linked to depression. However, the olfactory bulbectomy (OBX) model, a commonly employed animal model of depression, presents significant limitations, including poor alignment with...
Olfactory dysfunction has been closely linked to depression. However, the olfactory bulbectomy (OBX) model, a commonly employed animal model of depression, presents significant limitations, including poor alignment with clinical etiology and an elevated risk of mortality. In this study, we introduced an innovative, non-invasive model of depression by inducing olfactory dysfunction via the intranasal administration of a thermosensitive poloxamer gel containing 3-methylindole (3-MI) loaded in hydroxypropyl-β-cyclodextrin (HP-β-CD). This method specifically targets the olfactory pathway, thereby enhancing the model's safety and reliability. Through behavioral assessments, histopathological examination, transmission electron microscopy (TEM), immunohistochemistry, and neurotransmitter analyses, we found that the intranasal administration of the 3-MI gel significantly impaired olfactory sensitivity, damaged the olfactory epithelium, and induced inflammation and oxidative stress within the olfactory bulb. These alterations resulted in depressive-like behaviors, mitochondrial dysfunction, and apoptosis in the hippocampus, as well as reduced neurotransmitter release and metabolism in brain tissues. Treatment with mecobalamin or fluoxetine effectively alleviated olfactory dysfunction and depressive symptoms, respectively. Mecobalamin restored olfactory function and ameliorated depressive pathologies. Importantly, fluoxetine substantiated the model's predictive validity by reversing depressive and neurochemical deficits, although its efficacy in improving olfactory function was limited. Compared with the OBX and chronic unpredictable mild stress (CUMS) models, the intranasal 3-MI gel administration approach avoids both invasive surgery and prolonged stress exposure, aligning with animal welfare principles through minimized distress. These findings affirm the dual utility of this approach as both an effective and ethically optimized method for modeling depression.
Isoastragaloside II modulates PPAR-α/FXR signaling and bile acid metabolism to ameliorate cholestatic liver diseases (CLD).
Luo L, Liu W, Qi S … +7 more , Chen J, Zhang H, Mu Y, Chen G, Yuan W, Liu P, Zhang L
Eur J Pharmacol · 2026 Jul · PMID 42167668 · Publisher ↗
Cholestatic liver disease (CLD) is a severe hepatobiliary disorder with limited treatment options. Although the natural compound Isoastragaloside II (IAS II) has been suggested to possess general hepatoprotective propert...
Cholestatic liver disease (CLD) is a severe hepatobiliary disorder with limited treatment options. Although the natural compound Isoastragaloside II (IAS II) has been suggested to possess general hepatoprotective properties, its therapeutic efficacy against CLD has not been reported. In this study, the therapeutic potential and underlying mechanisms of IAS II for CLD were investigated using a murine model established by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding. It was demonstrated that DDC-induced cholestatic liver injury was significantly alleviated by IAS II treatment, as indicated by the normalization of key serum biochemical parameters. An integrated analysis of histopathological, protein, and gene expression data demonstrated that IAS II treatment effectively suppressed the ductular reaction, inhibited hepatic fibrosis, and attenuated inflammation. Analysis of 16S rRNA sequencing data revealed that IAS II treatment was accompanied by alterations in gut microbiota composition, including an enrichment of Bacteroides and a reduction in Lachnospiraceae_NK4A136_group. Antibiotic depletion experiments demonstrated that the hepatoprotective effects of IAS II were abrogated by gut microbiota depletion, confirming the essential role of the gut microbiota in its pharmacological action. At the molecular level, IAS II activated both the PPAR-α pathway (as indicated by transcriptomic analysis) and the FXR pathway (as confirmed by subsequent validation), which collectively resulted in a significant reduction in the hepatic accumulation of toxic bile acids (BAs). In vitro studies in LCA-induced HepG2 cells further revealed that the restoration of PPAR-α, ACOX2, FXR, and BSEP protein expression by IAS II required receptor activation, as these effects were blocked by specific inhibitors. In summary, to our knowledge, this study provides the first demonstration that a protective effect against DDC-induced cholestatic liver injury is conferred by IAS II through coordinated regulation of PPAR-α and FXR signaling, restoration of BA homeostasis, and in a gut microbiota-dependent manner, with these effects requiring the activation of both PPAR-α and FXR pathways, thereby identifying IAS II as a novel and promising therapeutic candidate for CLD.
Paris polyphylla saponin Ⅱ induces autophagy-associated ferroptosis by regulating the BECLIN1/SLC7A11 axis in cervical cancer.
Ma Y, Chu J, Li Y … +6 more , Long J, Wang M, Wang M, Wang Z, Li Q, Cheng H
Eur J Pharmacol · 2026 Jun · PMID 42162690 · Publisher ↗
Cervical cancer remains a lethal gynecologic malignancy requiring novel therapies. Here, we investigated the antitumor mechanism of Paris polyphylla saponin Ⅱ (PPSⅡ) in vitro and in vivo. PPSⅡ suppressed proliferation an...
Cervical cancer remains a lethal gynecologic malignancy requiring novel therapies. Here, we investigated the antitumor mechanism of Paris polyphylla saponin Ⅱ (PPSⅡ) in vitro and in vivo. PPSⅡ suppressed proliferation and induced cell death in SiHa, U14, and HeLa cells. The ferroptosis inhibitor ferrostatin-1 (Fer-1) and the autophagy inhibitor chloroquine (CQ) both partially reversed PPSⅡ-induced cell death, indicating involvement of both pathways. Mechanistically, SLC7A11 overexpression reversed the effects of PPSⅡ on GPX4 and ACSL4 expression, whereas BECLIN1 knockdown altered SLC7A11 expression, suggesting that PPSⅡ acts via the BECLIN1/SLC7A11 axis to induce autophagy-dependent ferroptosis. In a HeLa xenograft mouse model, PPSⅡ (1 or 2 mg/kg) significantly reduced tumor volume and weight. Immunohistochemistry showed decreased Ki-67 positivity, and H&E staining revealed tumor necrosis comparable to cisplatin. Notably, PPSⅡ caused no significant pathological changes in heart, liver, spleen, lungs, or kidneys, whereas cisplatin induced renal tubular vacuolation and hepatic inflammation, indicating a better safety profile. In conclusion, PPSⅡ induces autophagy-dependent ferroptosis in cervical cancer cells by modulating the BECLIN1/SLC7A11 pathway and shows potent in vivo antitumor efficacy with low toxicity. These results support PPSⅡ as a promising candidate for cervical cancer therapy.
Hyperbaric oxygen therapy alleviates acute carbon monoxide poisoning-induced transition of cardiac fibroblast to myofibroblast and ameliorates cardiac fibrosis via the NRF2/ROS/TGFβ1/Smad pathway.
Wang J, Shi B, Hao Y … +3 more , Chai L, Chen M, Zhang J
Eur J Pharmacol · 2026 Jun · PMID 42162689 · Publisher ↗
BACKGROUND: Acute carbon monoxide poisoning (ACOP) is one of the leading causes of poisoning-related deaths worldwide, inducing severe complications such as myocardial fibrosis and cardiac dysfunction. Hyperbaric oxygen...
BACKGROUND: Acute carbon monoxide poisoning (ACOP) is one of the leading causes of poisoning-related deaths worldwide, inducing severe complications such as myocardial fibrosis and cardiac dysfunction. Hyperbaric oxygen (HBO) therapy is an effective clinical treatment for carbon monoxide (CO) poisoning, but its underlying mechanisms require further investigation. METHODS: An ACOP mouse model was established and treated with HBO. Carboxyhemoglobin (COHb) levels were measured, and myocardial histopathological changes and collagen deposition were determined via hematoxylin-eosin staining, Masson's trichrome staining, and immunohistochemical staining. An ACOP cell model was constructed in the human cardiac fibroblast line HCF. Cell proliferation and migration were tested in CCK-8 and Transwell assays. The DHE fluorescent probe was applied in the determination of intracellular reactive oxygen species (ROS) levels. Alpha-Smooth Muscle Actin (α-SMA) expression was examined by immunofluorescence. Finally, qRT-PCR and Western blot were used to measure the expression of fibrosis markers and proteins related to the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/Transforming Growth Factor Beta 1 (TGF-β1)/Mothers Against Decapentaplegic Homolog (Smad) pathway. RESULTS: HBO therapy significantly reduced COHb levels, improved myocardial histopathological changes and collagen deposition, repressed cell proliferation and migration, and alleviated oxidative stress. Mechanistically, HBO therapy activated the NRF2 signaling pathway, reduced ROS levels, and suppressed the TGF-β1/Smad signaling pathway, thus mitigating the transition of cardiac fibroblasts to myofibroblasts. CONCLUSION: HBO therapy effectively represses ACOP-induced cardiac fibroblast-to-myofibroblast transition and ameliorates cardiac fibrosis by modulating the NRF2/ROS/TGF-β1/Smad signaling pathway.
Beyond motor symptoms: efficacy of pharmacotherapies on motor, functional, and cognitive domains in Huntington's disease - a systematic review.
Wiprich MT, Pereira WD, Colonetti T … +8 more , Pacagnan LO, Teixeira AG, Redivo H, Lodetti G, Endler AT, Bonan CD, Rosa MID, Rico EP
Eur J Pharmacol · 2026 Jun · PMID 42162688 · Publisher ↗
INTRODUCTION: Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, neuropsychiatric, cognitive, and peripheral alterations impairing functional capacity and quality of life (QoL)....
INTRODUCTION: Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, neuropsychiatric, cognitive, and peripheral alterations impairing functional capacity and quality of life (QoL). Pharmacotherapies, including dopaminergic and glutamatergic drugs, primarily target motor symptoms, while cholinergic modulators address cognitive decline. However, the literature lacks comprehensive reviews evaluating the combination of these three drug classes across a broad spectrum of clinical outcomes, extending beyond the total motor score (TMS). OBJECTIVE: This systematic review aimed to assess the efficacy of dopaminergic, glutamatergic, and cholinergic drugs on motor, functional, cognitive decline, and QoL in HD patients. METHODOLOGY: Following PRISMA guidelines, searches were performed in MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library until October 2025. Randomized clinical trials evaluating these three classes of drugs in adults with genetically confirmed HD were included. Primary outcomes were Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS), Total Functional Capacity (TFC), and cognitive performance. Secondary outcomes included the Independence Scale (IS) and QoL. Risk of bias was assessed using the Cochrane RoB 2 tool. Due to substantial heterogeneity, results were synthesized descriptively. RESULTS: From 32,746 studies, 15 were included in the final analysis. Findings showed that UHDRS TMS was improved with dopaminergics (tetrabenazine, deutetrabenazine, and pridopidine) and glutamatergic (riluzole) drugs. Only pridopidine treatment exhibited efficacy on UHDRS TFC, subsequently improving UHDRS IS. For QoL, deutetrabenazine treatment proved effective. In the UHDRS cognitive domain, tetrabenazine improved performance in the Stroop Color and Word test, while rivastigmine (cholinergic) improved verbal fluency. CONCLUSION: Dopaminergic, glutamatergic, and cholinergic drugs exhibit distinct efficacy profiles across various motor and non-motor UHDRS components. This positions them as therapeutic options for attenuating both the motor and non-motor symptoms in HD.
Corrigendum to "Spinal NGF induces anti-intrathecal opioid-initiated cardioprotective effect via regulation of TRPV1 expression" [Eur. J. Pharmacol. 844 (2019) 145-155].
Cheng XY, Chen C, He SF … +4 more , Huang CX, Zhang L, Chen ZW, Zhang Y
Eur J Pharmacol · 2026 Jun · PMID 42161726 · Publisher ↗
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Maraviroc ameliorates doxorubicin-induced atrioventricular block through blocking CCL5-CCR5 interaction in macrophage-cardiomyocyte axis.
Wang H, Zhang Y, Shen L … +5 more , Wu G, Yu H, Zhang L, Sun Y, Xue S
Eur J Pharmacol · 2026 Jun · PMID 42155834 · Publisher ↗
Doxorubicin (Dox)-induced cardiotoxicity (DIC) remains a challenge in tumor chemotherapy. Targeting macrophage-secreted molecules is a potential strategy to mitigate DIC. Transcriptome analysis of RAW264.7 cells treated...
Doxorubicin (Dox)-induced cardiotoxicity (DIC) remains a challenge in tumor chemotherapy. Targeting macrophage-secreted molecules is a potential strategy to mitigate DIC. Transcriptome analysis of RAW264.7 cells treated with 100 nM Dox revealed increases in 33 proteins located in the extracellular space, including CCL5. An animal model of DIC characterized by degree I atrioventricular block was established in 9-12 weeks old male C57BL/6 mice through three doses of 5 mg/kg Dox intraperitoneally (i.p.) administered every third day. The plasma CCL5 level in these mice consistently increased, which could be attenuated by macrophage depletion using clodronate liposome (15 mg/kg, i. p.). In pharmacological experiments with these animals, administration of maraviroc (MVC) (50 mg/kg, i. p., daily) prevented PR interval elongation caused by Dox. Both in vitro and in vivo experiments showed that MVC attenuated Ca overload induced by CCL5 in H9C2 cells and by Dox in cardiomyocytes from DIC models. Further in vitro experiments confirmed that CCL5 decreases the SERCA2a level and PKA-C, PLB phosphorylation in H9C2 cells, exacerbating Ca overload and CaMKII phosphorylation, which can be attenuated by MVC administration. In conclusion, Dox can induce an increase in macrophage-derived CCL5 in plasma, and MVC targeting the CCL5's receptor CCR5 can ameliorate atrioventricular block caused by Dox toxicity, suggesting that it may be a candidate for DIC treatment in chemotherapy.
Elafibranor inhibits neointima formation by downregulating CDK1 expression in carotid artery injury mice model.
Wang X, Chen J, Huo B … +5 more , Lin W, Jiang DS, Cheng W, Zhao F, Gong FH
Eur J Pharmacol · 2026 Jun · PMID 42150712 · Publisher ↗
In-stent restenosis remains a major challenge in coronary artery disease management. The proliferation, migration, and phenotypic switching of vascular smooth muscle cells (VSMCs) are key drivers of neointimal hyperplasi...
In-stent restenosis remains a major challenge in coronary artery disease management. The proliferation, migration, and phenotypic switching of vascular smooth muscle cells (VSMCs) are key drivers of neointimal hyperplasia and restenosis. Pharmacological agents targeting these processes may therefore offer a strategy to prevent or treat neointima formation. Here, we demonstrate that elafibranor (also known as GFT505), a dual agonist of peroxisome proliferator-activated receptor alpha (PPARα) and peroxisome proliferator-activated receptor delta (PPARδ), significantly reduced neointima formation in a mouse model of carotid artery injury. In vitro, PDGF-BB stimulation induced VSMC proliferation, migration, and a phenotypic switch towards a synthetic state-all of which were markedly suppressed by elafibranor. Cell Counting Kit-8 assays, 5-Ethynyl-2'-deoxyuridine (EdU) incorporation, and proliferation markers (phosphorylated histone H3 (Ser10) and Proliferating Cell Nuclear Antigen (PCNA)) indicated that elafibranor inhibited VSMC proliferation primarily by inducing cell cycle arrest at the G2/M phase. Transwell assays and reduced expression of matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9) pointed to a significant inhibition of VSMC migration. In addition, elafibranor suppressed the transition of VSMCs from a contractile to a synthetic phenotype, as shown by changes in marker expression. Mechanistically, transcriptome sequencing with Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) analyses revealed that elafibranor modulated pathways linked to cell proliferation and cycle control. In particular, it downregulated cyclin-dependent kinase 1 (CDK1), a key regulator of the G2/M checkpoint. Overexpression of CDK1 reversed the inhibitory effects of elafibranor on VSMC proliferation, migration, and phenotypic switching. Together, these findings identify elafibranor as a potential therapeutic agent capable of suppressing neointimal hyperplasia, pointing to a new approach for preventing and treating in-stent restenosis.
IKK-β inhibition as a precision therapeutic approach to disrupt the NF-κB neuroinflammatory cascade in Parkinson's disease.
Das S, Roy A, Bhattacharya P … +1 more , Borah A
Eur J Pharmacol · 2026 Jun · PMID 42144052 · Publisher ↗
Parkinson's disease (PD) is a progressive neurodegenerative disorder hallmarked by dopaminergic neuronal loss and pathological α-synuclein accumulation. Increasing evidence positions neuroinflammation as a central driver...
Parkinson's disease (PD) is a progressive neurodegenerative disorder hallmarked by dopaminergic neuronal loss and pathological α-synuclein accumulation. Increasing evidence positions neuroinflammation as a central driver of disease initiation and progression, orchestrating maladaptive glial responses that amplify neuronal vulnerability. At the heart of these inflammatory cascades lies the NF-κB signaling pathway, a master regulator of immune and stress responses in neurons and glia. While basal NF-κB activity supports neuronal homeostasis, chronic dysregulation in PD perpetuates microglial activation, oxidative stress, and α-synuclein-induced neurotoxicity. IκB kinase-β (IKK-β), a critical upstream regulator of NF-κB, has emerged as a promising therapeutic target, with preclinical studies demonstrating that its modulation attenuates neuroinflammatory signaling and preserves neuronal integrity. This review consolidates current mechanistic insights into NF-κB dysregulation in PD, highlighting the interplay between glial activation, mitochondrial dysfunction, and progressive neurodegeneration. We discuss emerging strategies to target IKK-β, encompassing pharmacological inhibitors and genetic approaches, alongside considerations for central nervous system specificity and translational feasibility. By integrating molecular, cellular, and preclinical perspectives, we propose a framework in which precise modulation of NF-κB signaling through IKK-β offers a mechanistically informed avenue to counteract neuroinflammation and potentially modify PD pathology.
The antiplatelet activity of 6-piperazinyl-purine analogues bearing nitrate esters is determined by the length of the carbon side chain.
Haug M, Fransén K, Pournara DT … +11 more , Fotopoulou T, Kritsi E, Ifanti E, Ansari S, Lindström EG, Jakobsson J, Lindkvist M, Ramström S, Zervou M, Koufaki M, Grenegård M
Eur J Pharmacol · 2026 Jun · PMID 42142574 · Publisher ↗
BACKGROUND: The nitrate ester-bearing 6-piperazinyl-purine analogue MK128 is a Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor with cardioprotective, anti-inflammatory, and antiplatelet properties....
BACKGROUND: The nitrate ester-bearing 6-piperazinyl-purine analogue MK128 is a Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor with cardioprotective, anti-inflammatory, and antiplatelet properties. However, structure-activity relationships of this compound class have not been systematically explored. This study aimed to elucidate the impact of spacer length on the antiplatelet activity of closely related piperazinyl-purine analogues and to identify the most active candidate for further evaluation. METHODS: Antiplatelet activity of piperazinyl-purine analogues bearing short (MK128), intermediate (MK176), and long (MK118) spacers was evaluated by lumi-aggregometry and flow cytometry in isolated platelets and whole blood. Platelets were activated by proteinase-activated receptor-1 agonist SFLLRN-OH or collagen. Binding interactions with ROCK1/ROCK2 were examined using SelectScreen™ Kinase Profiling, in silico docking, and molecular dynamics simulations. RESULTS: MK128 exhibited the strongest inhibition of platelet aggregation and secretion in isolated platelets and whole blood, and rapidly promoted disaggregation of preformed aggregates. The rank order of potency in whole blood was MK128>MK176>MK118. All analogues inhibited ROCK1 and ROCK2 in cell-free assays, while broader kinase profiling demonstrated high selectivity. Docking studies suggested stable bidentate interactions between the purine core and hinge region, whereas molecular dynamics simulations identified spacer length-dependent differences in nitrate ester tail interactions. Reduced spacer flexibility in MK128 enabled productive interactions with catalytically relevant residues, providing a mechanistic explanation for its superior functional activity. CONCLUSION: Spacer length critically determines the antiplatelet effect of piperazinyl-purine analogues. The one-carbon spacer analogue MK128 demonstrated superior platelet and ROCK inhibition, making it a promising lead candidate for further evaluation in ischemic disease models.
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