European Journal Of Pharmacology[JOURNAL]
Sun
200 papers
Ibogalogs and their pyridoindole homologs activate or inhibit the 5-HT receptor by modulating the distance between transmembrane segments TM3 and TM6 in the orthosteric site.
Arias HR, Rudin D, Ren X … +2 more , Liechti ME, Huang N
Eur J Pharmacol · 2026 Jun · PMID 42092485 · Publisher ↗
Previous behavioral studies showed that ibogalogs induce beneficial effects in various neurological animal paradigms (see Introduction). Thus, the binding, functional, and mechanistic characterization of ibogalogs and th...
Previous behavioral studies showed that ibogalogs induce beneficial effects in various neurological animal paradigms (see Introduction). Thus, the binding, functional, and mechanistic characterization of ibogalogs and their pyridoindole homologs at the serotonin subtype 2B receptor (5-HTR) is essential to determine the relevance of this receptor subtype in future behavioral studies as well as to discriminate molecular mechanisms underlying the stimulatory vs competitive antagonistic properties of these compounds. The radioligand binding results showed that DM506 (ibogaminalog) has higher affinity than its structural pyridoindole homolog 2MePI. The functional assays showed that DM506 and PNU-22394 act as potent and efficient agonists, whereas the rest of the compounds behave as weaker partial agonists. Functional competition results indicated that IBG (ibogainalog), CAG (catharanthine), and TBG (tabernanthalog) potently inhibited the stimulatory activity of 5-HT, indicating that they functionally behave as competitive antagonists. Molecular docking and molecular dynamics results showed that agonists such as DM506 and PNU-22394 open the ionic lock, increasing the TM6-TM3 distance to ∼12.7-10.4 Å (approaching the active-state conformation of 13.6 Å), whereas inhibitors such as IBG and TBG close the ionic lock, reducing the distance to 6.5-9.6 Å, consistent with the inactive state. Additional structural components led to a decrease in compound activity: substituting methoxy with hydroxyl group in nor-IBG and introducing steric hindrance in CAG resulted in unfavorable interactions, while replacing hexahydroazepine with tetrahydropyridine in pyridoindole derivatives induced conformational changes. The per-residue binding energy decomposition analysis identified key residues involved in the interaction of each compound with the docking site. The structure-activity relationship for inhibitors showed positive correlations with molecular volume and solvent-accessible surface area of the compound, suggesting that larger molecules might be less buried within the orthosteric site.
Dihydromyricetin: A potential candidate for the treatment of cholestatic liver injury via inhibition of the NLRP3 inflammasome.
Zhang H, Dang Y, Guo Y … +8 more , Fisher D, Hien NTT, Musabaev E, Shmanai VV, Zhu Z, Luo M, Ge C, Zhao L
Eur J Pharmacol · 2026 May · PMID 42092484 · Publisher ↗
OBJECTIVE: Cholestatic liver injury is a hepatic disorder caused by abnormal bile acid metabolism and biliary obstruction, with limited clinical treatment options. Activation of the NLRP3 inflammasome is recognized as a...
OBJECTIVE: Cholestatic liver injury is a hepatic disorder caused by abnormal bile acid metabolism and biliary obstruction, with limited clinical treatment options. Activation of the NLRP3 inflammasome is recognized as a key pathogenic mechanism. This study aims to investigate whether DHM, a natural flavonoid, alleviates cholestatic liver injury by modulating the NLRP3 inflammasome and to elucidate its underlying mechanism. METHODS: The protective effects of DHM were evaluated both in vivo (using an ANIT-induced mouse cholestasis model) and in vitro (using an LPS plus nigericin-induced ANA-1 macrophage model). Assessments included liver function, histopathology, inflammatory cytokine levels, and the expression of key molecules in the NLRP3 inflammasome pathway (NLRP3, ASC, Caspase-1, GSDMD, IL-1β, IL-18). Cell viability was measured by CCK-8 assay, while molecular expression was analyzed via Western blot, qPCR, ELISA, and immunofluorescence. The specific role of NLRP3 was confirmed using siRNA knockdown. RESULTS: DHM demonstrated good safety profiles in both experimental settings. In the ANIT-induced cholestatic model, DHM significantly improved liver function markers (ALT, AST, ALP, TBIL), reduced histopathological damage, and suppressed the expression and activation of key components in the NLRP3 inflammasome pathway. In vitro studies further confirmed that DHM exerts its anti-inflammatory effects by inhibiting ROS burst, preventing NLRP3 inflammasome assembly, and blocking the subsequent pyroptosis process. NLRP3 knockdown experiments indicated that the anti-inflammatory effect of DHM is highly dependent on the presence of NLRP3. CONCLUSION: DHM alleviates cholestatic liver injury by inhibiting the activation of the NLRP3 inflammasome in macrophages, a mechanism involving multi-level anti-inflammatory and antioxidant pathways. This study provides a theoretical foundation for DHM as a potential therapeutic agent against cholestatic liver injury and identifies the NLRP3 inflammasome as its critical molecular target.
Downregulation of claudin-2 expression and chemoresistance by saquinavir in human lung adenocarcinoma cells.
Komoto S, Kimura R, Yoshino Y … +7 more , Morimoto K, Shinoda T, Shirouzu M, Ishikawa Y, Matsunaga T, Endo S, Ikari A
Eur J Pharmacol · 2026 May · PMID 42081994 · Publisher ↗
Claudin-2 (CLDN2) is a tight junction-associated transmembrane protein that is highly expressed in lung adenocarcinoma and contributes to chemoresistance. Here, we screened Food and Drug Administration-approved small-mol...
Claudin-2 (CLDN2) is a tight junction-associated transmembrane protein that is highly expressed in lung adenocarcinoma and contributes to chemoresistance. Here, we screened Food and Drug Administration-approved small-molecule drugs to identify compounds capable of reducing CLDN2 expression and enhancing anticancer drug-induced cytotoxicity in cancer cells. A structure based virtual screening targeting CLDN2 predicted that saquinavir (SQV), a human immunodeficiency virus (HIV) protease inhibitor, binds to the second extracellular loop of CLDN2 protein. Consistent with the prediction, SQV markedly decreased CLDN2 protein levels without affecting its mRNA expression in human lung adenocarcinoma A549 cells. In contrast, ritonavir, another HIV protease inhibitor, or raltegravir, an HIV integrase inhibitor, has no significant effect, indicating that inhibition of viral enzymes is not directly involved in the regulation of CLDN2 expression. A cycloheximide-chase assay revealed that SQV reduces the stability of CLDN2 protein. Pharmacological inhibition experiments further revealed that SQV-induced CLDN2 downregulation is mediated by enhanced clathrin-dependent endocytosis and subsequent lysosomal degradation. In three-dimensional spheroid models, SQV reduced oxidative stress and expression of nuclear factor erythroid 2-related factor 2 protein expression without altering spheroid size, cell viability, or hypoxic stress. Notably, SQV enhanced the cytotoxic effects of multiple anticancer agents, including doxorubicin, cisplatin, and SN-38, in lung adenocarcinoma cell line-derived spheroids and patient-derived organoids. We suggest that SQV improves chemoresistance by reducing CLDN2 expression and oxidative stress in lung adenocarcinoma.
Icariside II suppresses bladder cancer progression via endoplasmic reticulum stress-mediated autophagy and lysosomal dysfunction.
Wang J, He K, Qi H … +9 more , Xu J, Yin Y, Hu H, Chen Z, Li Y, Dai Y, Lian W, Chu X, Tang Y
Eur J Pharmacol · 2026 May · PMID 42081993 · Publisher ↗
BACKGROUND: Icariside II is an active compound extracted from Herba Epimedii, a traditional Chinese medicine known for its remarkable effects in treating erectile dysfunction and arthritis. However, the specific mechanis...
BACKGROUND: Icariside II is an active compound extracted from Herba Epimedii, a traditional Chinese medicine known for its remarkable effects in treating erectile dysfunction and arthritis. However, the specific mechanism underlying its anticancer activity in bladder cancer remains unclear. This study aims to explore the effects and mechanisms of Icariside II in bladder cancer. METHODS: We validated the role of Icariside II in bladder cancer through various in vitro experiments. Additionally, transcriptome sequencing was performed to explore the potential mechanism of Icariside II in suppressing bladder cancer. The results of the transcriptome sequencing were further confirmed by Western Blot, immunofluorescence, and Transmission Electron Microscope. In vivo validation was conducted using tumor xenograft models. RESULTS: Our findings demonstrated that Icariside II effectively inhibited the proliferation and migration of bladder cancer. Transcriptome sequencing revealed significant alterations in autophagy and Endoplasmic Reticulum stress related genes in bladder cancer cells after treatment with Icariside II. This result was supported by the observations made through Transmission Electron Microscope and Western Blot. Further investigations indicated that Icariside II induced autophagy through the IRE1α and PERK pathway and inhibited autophagic flow by reducing the number of lysosomes and suppressing their activity. In tumor xenograft models, Icariside II significantly inhibited bladder cancer proliferation. CONCLUSIONS: Our data suggest that Icariside II holds promise as a natural medicine for the significant inhibition of bladder cancer, achieved through the induction of endoplasmic reticulum stress-induced autophagy and inhibition of lysosomal activity.
Therapeutic opportunities for ferroptosis in lipopolysaccharides- induced acute kidney injury; Liproxstatin-1 versus N- acetyl cysteine.
Ibrahim HF, Thabet EH, Assem S … +4 more , Abd El Mottelib LMMA, Abd El-Kader SB, Khan MS, Rostom D
Eur J Pharmacol · 2026 May · PMID 42081992 · Publisher ↗
Acute kidney injury (AKI) is a fatal condition with high morbidity and mortality rates. Recent studies indicated that ferroptosis is implicated in the pathogenesis of AKI. This suggests that ferroptosis inhibitors deserv...
Acute kidney injury (AKI) is a fatal condition with high morbidity and mortality rates. Recent studies indicated that ferroptosis is implicated in the pathogenesis of AKI. This suggests that ferroptosis inhibitors deserve more attention as AKI therapeutic options. We explored the comparative effectiveness of liproxstatin-1 (Lip-1) and N- acetyl cysteine (NAC) in mitigating ferroptosis in lipopolysaccharides (LPS)- induced AKI. Herein, mice were exposed to a single intraperitoneal (IP) injection of 10 mg/kg LPS. They were treated either by 10 mg/kg Lip-1 or NAC (total 3 doses of each drug over 6 days). Serum urea, creatinine and malondialdehyde, along with tissue EGR-1, GPX-4 and iron, were assessed. Histological, immuno-fluorescence and ultrastructural studies were conducted as well. Our results elucidated that; Lip-1 possesses significant antiferroptotic effects that modulated the three cornerstones of ferroptosis; MDA, GPX-4 and iron. Additionally, it downregulated EGR-1 and PERK, and upregulated GB3P1, affecting the cellular pathways that relate ferroptosis to endoplasmic reticulum stress (ER stress), stress granules (SGs) formation and lysophagy. The antiferroptotic actions of NAC were less remarkable. In conclusion, our study presents a foundation for therapeutic options directed against ferroptosis in AKI, advocating application of Lip-1 or NAC, with a specific focus on Lip-1.
Phloretin inhibits osteoclast differentiation and alleviates disuse osteoporosis through the PI3K/AKT/NF-κB pathway.
Wei F, Yang B, Ruan B … +6 more , Zhang L, Wang C, Cai J, Wang J, Wang H, Wang Y
Eur J Pharmacol · 2026 May · PMID 42081991 · Publisher ↗
Mechanical unloading that results from aging, prolonged bed rest, or spaceflight leads to disuse osteoporosis (DOP), a significant public health concern. However, the mechanisms underlying this condition, as well as effe...
Mechanical unloading that results from aging, prolonged bed rest, or spaceflight leads to disuse osteoporosis (DOP), a significant public health concern. However, the mechanisms underlying this condition, as well as effective therapeutic strategies, remain incompletely defined. In this study, significant bone deterioration, increased osteoclast activation, and upregulation of the PI3K/AKT/NF-κB signaling cascade were observed in femoral specimens from hindlimb suspension (HLS) mice, a well-established DOP model. Phloretin, a naturally occurring flavonoid with notable antioxidant and anti-inflammatory activities, has shown anti-osteoclastogenic effects in chemically induced models. Nevertheless, its therapeutic efficacy and direct molecular targets in mechanical unloading-induced bone loss, a condition characterized by a distinct pathophysiology, remain largely undefined. Herein, we demonstrated that phloretin markedly suppressed osteoclastogenesis, attenuated excessive bone resorption and effectively counteracted bone loss in the hindlimb-unloading murine model. Complementing these in vivo findings, primary osteoclast cultures revealed that phloretin reduced osteoclast formation and activity by inhibiting the PI3K/AKT/NF-κB signaling axis. Importantly, pharmacological activation of the PI3K pathway with 740 Y-P significantly reduced Phloretin's inhibitory effects on osteoclast differentiation and bone protection, confirming that this pathway is the primary regulatory target. Unlike general anti-resorptive agents, phloretin specifically addresses the PI3K-mediated signaling activation triggered by mechanical unloading. Our findings provide robust evidence for the application of phloretin as a targeted therapy for disuse-related skeletal disorders.
Elotuzumab enhances the anti-tumor activity of Vγ9Vδ2 T cells against primary effusion lymphoma.
Maeda K, Kariya R, Panaampon J … +2 more , Matsuda K, Okada S
Eur J Pharmacol · 2026 May · PMID 42081990 · Publisher ↗
Primary Effusion Lymphoma (PEL) is an aggressive B-cell lymphoma with no standard treatment. Vγ9Vδ2 T cells contribute to tumor eradication but have limited cytotoxicity on their own. Elotuzumab (Elo), an anti-SLAMF7 mon...
Primary Effusion Lymphoma (PEL) is an aggressive B-cell lymphoma with no standard treatment. Vγ9Vδ2 T cells contribute to tumor eradication but have limited cytotoxicity on their own. Elotuzumab (Elo), an anti-SLAMF7 monoclonal antibody approved for multiple myeloma, primarily acts through NK cells; however, its direct effect on γδ T cells has not been reported. In this study, we examined whether Elo enhances γδ T cell cytotoxicity against PEL. We found that SLAMF7 is expressed on both PEL cells and γδ T cells. Elo treatment significantly increased γδ T cell cytotoxicity and degranulation, and these effects were prevented by Fc receptor blockade or by Fc-deficient Elo, indicating an antibody-dependent cellular cytotoxicity (ADCC) mechanism. Our findings demonstrate for the first time that Elo directly boosts γδ T cell anti-tumor activity against PEL, offering novel preclinical evidence for combining Elo with γδ T cell therapy as a potential treatment strategy for this intractable lymphoma.
Insights into semaglutide cardiovascular research: Mechanisms, trials, and frontiers.
Zhang J, Gao G, He M … +1 more , Sun T
Eur J Pharmacol · 2026 May · PMID 42070764 · Publisher ↗
Cardiovascular disease (CVD) remains the leading cause of global mortality, with pathophysiological alterations such as heart failure with preserved ejection fraction, diabetic cardiomyopathy, and atherosclerotic cardiom...
Cardiovascular disease (CVD) remains the leading cause of global mortality, with pathophysiological alterations such as heart failure with preserved ejection fraction, diabetic cardiomyopathy, and atherosclerotic cardiomyopathy representing major risk factors. Semaglutide, a novel long-acting glucagon-like peptide-1 receptor agonist, has demonstrated substantial efficacy in glycemic control and weight reduction. Since 2016, accumulating evidence has highlighted its promising cardiovascular benefits, establishing semaglutide as a strong therapeutic candidate for CVD. This review synthesizes evidence since 2016 to elucidate semaglutide's cardiovascular outcomes, underlying mechanisms, and emerging frontiers, employing bibliometric analytical approaches such as burst detection mapping and cluster timeline analysis of references and keywords. Research on semaglutide in CVD has advanced rapidly, with mechanistic insights including improvements in insulin resistance, anti-inflammatory activity, and anti-atherosclerotic effects, as well as novel associations with ferroptosis inhibition. Clinical evidence across diverse patient subgroups indicates that future implementation will require precision-based regimen design. Moreover, although oral semaglutide alleviates injection-related discomfort, its gastrointestinal tolerability remains a concern. Furthermore, the potential reduction in lean mass requires further validation. Overall, this review aims to broaden the clinical application of semaglutide and highlight novel therapeutic avenues for patients with cardiovascular disease.
Targeted knockdown of hepatic XDH via GalNAc-siRNA alleviates hyperuricaemia and renal injury in UOX mice.
Li R, Li Y, Zhang C … +4 more , Liu H, Jiang J, Yao D, Wei X
Eur J Pharmacol · 2026 May · PMID 42070763 · Publisher ↗
Hyperuricaemia is a metabolic disorder characterized by elevated serum urate levels. Uric acid production primarily results from purine metabolism, with xanthine dehydrogenase (XDH) serving as a key enzyme determining ur...
Hyperuricaemia is a metabolic disorder characterized by elevated serum urate levels. Uric acid production primarily results from purine metabolism, with xanthine dehydrogenase (XDH) serving as a key enzyme determining uric acid synthesis. RNA interference technology has emerged as a powerful tool for gene regulation in recent years. Specifically, N-acetylgalactosamine (GalNAc)-modified small interfering RNA (siRNA), hereafter referred to as GalNAc-siRNA, can selectively deliver siRNAs to hepatocytes, achieving highly efficient knockdown of liver target genes. This study employed GalNAc-siRNA to specifically knock down hepatic XDH expression of hyperuricaemia mice, offering a promising therapeutic strategy. Initially, AML12 cells were used to identify siRNAs that knocked down XDH expression. A hyperuricaemia cell model, established by supplementing culture medium of AML12 cells with xanthine, was used to validate the effects of an XDH-targeting siRNA on uric acid synthesis. Moreover, following the subcutaneous injection of XDH-targeting GalNAc-siRNA (GalNAc-siXDH) in mice, XDH expression levels across various organs were measured to verify liver-specific knockdown. Additionally, the safety of GalNAc-siXDH was evaluated through serum biochemistry and histopathological analysis of major organs. Finally, the therapeutic effects of GalNAc-siXDH were evaluated in the urate oxidase knockout (UOX) hyperuricaemia mouse model. Our results demonstrated that GalNAc-siXDH can reduce serum urate levels, and alleviate renal damage including inflammation and fibrosis, indicating that GalNAc-siXDH is a potential therapeutic candidate for the treatment of hyperuricaemia.
Agmatine interaction with imidazoline receptor inhibits manifestation of depression-like behavior in 3-Nitropropionic acid-induced Huntington's disease-like phenotype in rats.
Katariya R, Jari S, Dhaigude P … +4 more , Pable A, Kotagale N, Umekar M, Taksande B
Eur J Pharmacol · 2026 May · PMID 42070762 · Publisher ↗
Huntington's disease (HD)-associated depression is a prevalent psychiatric symptom affecting between one-third and over two-thirds of patients, significantly impacting their quality of life. Agmatine, a biogenic amine pr...
Huntington's disease (HD)-associated depression is a prevalent psychiatric symptom affecting between one-third and over two-thirds of patients, significantly impacting their quality of life. Agmatine, a biogenic amine produced by the decarboxylation of L-arginine, has recently garnered attention for its antidepressant-like effects by modulating imidazoline receptors in neurodegenerative and mood disorders. This study aimed to investigate the effect of agmatine in attenuating depression-like behavior through its interaction with imidazoline receptors in a 3-Nitropropionic acid (3-NP) rat model of HD. 3-NP is a selective mitochondrial toxin known to induce bilateral striatal lesions by inhibiting succinate dehydrogenase enzyme, thereby contributing to psychiatric symptoms observed in HD. Rats received 3-NP (10 mg/kg, i.p.) on days 1, 3, 5, 7, and 9, followed by agmatine treatment on days 18-20. Systemic administration of 3-NP produced significant depressive-like behaviors, neurochemical imbalance, and neuroinflammation. However, treatment with imidazoline I1/I2 receptor agonist agmatine (10-20 mg/kg; i.p.), imidazoline I1 receptor agonist moxonidine (0.25 mg/kg; i.p.), and imidazoline I2 receptor agonist 2-(2-Benzofuranyl)-2-imidazoline hydrochloride (3 mg/kg; i.p.) with agmatine (5 mg/kg, i.p.) resulted in marked improvement in behavioral abnormalities exhibited by reduced immobility time in forced swim test, normalization of GABA/glutamate levels, decreased proinflammatory cytokines, and restored BDNF expression. Conversely, anti-depressant effects of agmatine were blocked by I1 receptor antagonist efaroxan (1 mg/kg; i.p.) and I2 receptor antagonist idazoxan (1 mg/kg; i.p.), signifying the involvement of imidazoline receptors in the beneficial effects of agmatine. In conclusion, these findings highlight the therapeutic potential of agmatine in mitigating psychiatric complications associated with HD through receptor-mediated mechanisms.
Spleen-brain axis regulates myelin integrity via TGF-β1 signaling in cuprizone-induced demyelination and remyelination model.
Cai Y, Zhu T, Zhao M … +7 more , Xu D, Murayama R, Liu G, Yue Y, Yang JJ, Nakamura H, Hashimoto K
Eur J Pharmacol · 2026 May · PMID 42069173 · Publisher ↗
Demyelination and impaired remyelination are hallmark features of many neurodegenerative and psychiatric disorders. Although central mechanisms have been widely investigated, the contribution of peripheral immune organs...
Demyelination and impaired remyelination are hallmark features of many neurodegenerative and psychiatric disorders. Although central mechanisms have been widely investigated, the contribution of peripheral immune organs such as the spleen remains poorly understood. In this study, we examined the role of the spleen and transforming growth factor-β1 (TGF-β1) in cuprizone (CPZ)-induced demyelination and remyelination in mice. Splenectomy performed before CPZ exposure significantly worsened demyelination in the corpus callosum, as indicated by reduced myelinated area and myelin basic protein (MBP) intensity. Likewise, splenectomy immediately after CPZ withdrawal markedly impaired remyelination during the recovery phase. Immunohistochemical analysis showed that splenectomy reduced TGF-β1 expression in the corpus callosum at both 2 and 7 weeks after surgery. Moreover, systemic administration of a neutralizing anti-TGF-β1 antibody during either the demyelination or remyelination phase reproduced the effects of splenectomy, resulting in greater myelin loss or reduced myelin repair, respectively. Antibody treatment significantly decreased TGF-β1 levels in both brain and plasma, which were positively correlated with the degree of myelination. Together, these findings reveal a previously unrecognized role of the spleen in preserving myelin integrity and facilitating repair through TGF-β1 signaling. They further suggest that the spleen-brain axis contributes to myelin homeostasis and that peripheral TGF-β1 may represent a potential biomarker and therapeutic target for demyelinating disorders.
Transcriptomic alterations upon nuclear XIAP overexpression reveal IGFBP6/Wnt as a regulatory axis in breast cancer cell survival and chemoresistance.
Mendonça BDS, Binato R, Abdelhay E … +5 more , Lima NS, de Araujo WM, Maia RC, Carvalho RS, Nestal de Moraes G
Eur J Pharmacol · 2026 Jun · PMID 42069172 · Publisher ↗
X-linked inhibitor of apoptosis protein (XIAP) is an antiapoptotic protein which plays canonical functions in the cytoplasm. However, we have previously demonstrated that nuclear XIAP is associated with increased cell gr...
X-linked inhibitor of apoptosis protein (XIAP) is an antiapoptotic protein which plays canonical functions in the cytoplasm. However, we have previously demonstrated that nuclear XIAP is associated with increased cell growth and drug resistance as well as unfavorable outcomes in breast cancer. Therefore, this work aimed to investigate the non-canonical molecular functions associated with abnormal XIAP nuclear localization in breast cancer. To address this, we have performed both transcriptomic and proteomic large-scale approaches with breast cancer cell line models overexpressing HA-tagged ectopic XIAP (WT, H467A, ΔRING and NLS mutants) in distinct subcellular locations. Nuclear XIAP overexpressing cells (XIAP) have been shown enriched for genes implicated in cellular processes other than apoptosis inhibition, such as proliferation, transport, locomotion, migration, cell motility, and protein phosphorylation. Interestingly, the validation analysis has shown differential expression of genes associated with the Wingless-related integration site (Wnt)/β-catenin pathway, as well as the insulin-like growth factor-binding protein 6 (IGFBP6) tumor suppressor gene. IGFBP6 transcript levels have been found reduced in XIAP-overexpressing cells, as well as invasive breast cancer patients. Notably, IGFBP6 knockdown modulated long-term cell proliferation and doxorubicin sensitivity in cells overexpressing nuclear XIAP, further suggesting that nuclear XIAP might indirectly target the IGFBP6 pathway to promote chemoresistance. Finally, Wnt signaling effectors were identified in nuclear XIAP interactomes, closely linked to activation of β-catenin transcriptional activity in XIAP-overexpressing cells. Our data establishes a non-canonical role for XIAP in the regulation of pathways related to cell growth in the nucleus, with Wnt/IGFBP6 emerging as a potential regulatory node associated with nuclear XIAP effects in breast cancer.
Ginsenoside Rb1 alleviates cerebral ischaemia/reperfusion injury by suppressing oxidative stress and excessive autophagy via ATM-CHK2-Beclin 1 pathway.
Yuan Y, Shan X, Li Y … +4 more , Wei L, Lei Y, Cai B, Wang G
Eur J Pharmacol · 2026 May · PMID 42069171 · Publisher ↗
Recent studies have demonstrated that ginsenoside Rb1 (GRb1) exhibits neuroprotective effects against cerebral ischaemia/reperfusion (I/R) injury. However, whether GRb1 modulates autophagy and oxidative stress induced by...
Recent studies have demonstrated that ginsenoside Rb1 (GRb1) exhibits neuroprotective effects against cerebral ischaemia/reperfusion (I/R) injury. However, whether GRb1 modulates autophagy and oxidative stress induced by cerebral I/R remains unclear. This study aims to determine whether GRb1 attenuates cerebral I/R injury by suppressing autophagy and oxidative stress via regulation of the ATM-CHK2-Beclin 1 pathway. Middle cerebral artery occlusion/reperfusion (MCAO/R) in 60 SPF C57BL/6 mice and oxygen-glucose deprivation/reperfusion (OGD/R) in rat pheochromocytoma (PC12) cells were employed to evaluate the protective effects of GRb1 on neurological injury, autophagy, and oxidative stress. Molecular mechanisms were validated using Western blot, immunofluorescence, and pharmacological inhibitors. The results showed that GRb1 alleviated neurological impairments, decreased cerebral infarct volume, and reduced histological damage in MCAO/R mice. Besides, GRb1 alleviated cell injury and reduced intracellular ROS production in PC12 cells induced by OGD/R. Furthermore, during MCAO/R and OGD/R, GRb1 suppressed autophagy and oxidative stress. Moreover, GRb1 treatment also decreased p-ATM/ATM and p-CHK2/CHK2 ratio and increased Beclin 1-Bcl-2 interaction both in vivo and in vitro. Molecular docking further elucidated that the mechanism by which GRb1 improves cerebral ischaemia maybe related to its direct binding to ATM, which in turn inhibited the phosphorylation of ATM. Additionally, the drug affinity response target stability (DARTS) and cellular thermal shift assay (CETSA) were also performed to suggest that GRb1 directly interacts with ATM. Collectively, these findings demonstrated that GRb1 reduced ischemic stroke-induced oxidative stress and autophagy through ATM-CHK2-Beclin 1 pathway, and GRb1 may be a protective medication for the treatment of cerebral ischaemia.
From pathology to precision therapy: Contemporary and emerging strategies in Alzheimer's disease treatment.
Belavadi S, Kadiri SK
Eur J Pharmacol · 2026 May · PMID 42067018 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by dementia, confusion, irritability, a lack of cognition, and mood swings. Since its discovery in 1906, many small molecules have been de...
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by dementia, confusion, irritability, a lack of cognition, and mood swings. Since its discovery in 1906, many small molecules have been designed to block disease progression by targeting the primary targets β-amyloid and tau proteins. Subsequent research focused on small-molecule inhibitors targeting secondary targets, such as β-secretases and γ-secretases. However, the clinically approved conventional therapies include acetylcholinesterase inhibitors and N-methyl-D-aspartate inhibitors that relieve only disease symptoms, and their efficacy remains limited. Recently, approved novel approaches, such as monoclonal antibodies and vaccines, aim to slow disease progression by targeting the molecular mechanisms underlying amyloid and tau proteins. In addition, these drugs have controversial side effects, which call into question their therapeutic efficacy. A newer strategy involving small peptides is gaining traction because of their lower toxicity, improved permeability, and target specificity. Various homogenous and heterogeneous peptidomimetic inhibitors have been designed to target traditional protein targets. Although various peptidomimetic inhibitors have demonstrated therapeutic efficacy, none have entered clinical trials. Upon conducting an extensive literature survey, we identified several regions, targets, and technologies that could be leveraged to ameliorate Alzheimer's disease progression. In this review, we address the progression of AD, its historical context, and the development of therapeutic approaches that target this disease. We focus on the evolution of subsequent therapies aimed at alleviating the disease and highlight recent developments in drug delivery and formulation techniques that enhance therapeutic efficacy and address the shortcomings of traditional treatments.
Apilimod in oncology: From non-malignant origins to emerging anti-cancer potential.
Evrard C, Gündel B, Löhr M … +2 more , Heffinger L, Heuchel R
Eur J Pharmacol · 2026 May · PMID 42067017 · Publisher ↗
Apilimod is an emerging therapeutic compound whose clinical potential has renewed interest in the PIKfyve signaling pathway, a central regulator of endolysosomal trafficking and cellular homeostasis. This review provides...
Apilimod is an emerging therapeutic compound whose clinical potential has renewed interest in the PIKfyve signaling pathway, a central regulator of endolysosomal trafficking and cellular homeostasis. This review provides a critical overview of the current state of knowledge on Apilimod, spanning early mechanistic studies, preclinical models, and ongoing phase II clinical trials. Apilimod primarily inhibits PIKfyve, leading to profound alterations in vesicular trafficking and vacuolization. Beyond its canonical role in endosomal dynamics, accumulating evidence implicates PIKfyve in broader biological processes, including immune regulation and metabolic control, thereby expanding the potential therapeutic relevance of its pharmacological targeting. Preclinical and clinical studies have suggested possible applications of Apilimod in inflammatory diseases, hematological malignancies, and solid tumors. However, despite encouraging initial findings, important uncertainties remain regarding its precise mechanisms of action, context-dependent efficacy, and safety profile. In particular, the translatability of preclinical observations to clinical benefit, the identification of predictive biomarkers, and the management of potential adverse effects require further investigation. Finally, we discuss emerging therapeutic strategies, including combination approaches with RAS pathway inhibitors, while highlighting the key challenges that must be addressed to fully exploit the therapeutic potential of Apilimod.
Piperlonguminine attenuates atherosclerosis in mice via phenotype switching inhibition of vascular smooth muscle cells.
Sun Y, Zhu D, Luo X … +10 more , Ren Z, Yang X, Du W, Wang M, Hu Y, Rao G, Wu X, Zhuang X, Huang F, Tong X
Eur J Pharmacol · 2026 May · PMID 42067016 · Publisher ↗
Phenotypic switching of vascular smooth muscle cells (VSMCs) plays diverse roles in the development of atherosclerosis. These cells are a primary contributor to plaque formation and can transition between contractile and...
Phenotypic switching of vascular smooth muscle cells (VSMCs) plays diverse roles in the development of atherosclerosis. These cells are a primary contributor to plaque formation and can transition between contractile and synthetic states in response to inflammation or oxidized low-density lipoproteins, exacerbating atherosclerosis. Piperlonguminine (PLG), a bioactive compound obtained from Piper longum L., is commonly used as traditional Mongolian medicine. To elucidate the effects and mechanisms of PLG on atherosclerosis via inhibition of the phenotype switch of VSMCs, we investigated the effects of PLG in the phenotypic transformation, proliferation, and migration of VSMCs. From the view of the symptoms of atherosclerosis, PLG alleviated the pathological changes of atherosclerosis; downregulated total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels; and decreased the levels of inflammatory cytokines. PLG regulated VSMC phenotypic switch proteins and also inhibited the proliferation and migration of VSMCs. Matrix metalloproteinases (MMPs) play a fundamental role in the phenotypic switch of VSMCs. The expression of MMP-2 and MMP-9 was assessed to elucidate the effects of PLG. PLG reduced the expression of MMP-2 and MMP-9 to inhibit the proliferation and migration of VSMCs. The findings collectively illustrate that PLG inhibited the phenotypic transformation, proliferation, and migration of VSMCs, thereby impeding the advancement of atherosclerosis. This inhibition was, in part, linked to reduced MMP-2 and MMP-9 expression.
Intestinal-restricted farnesoid X receptor agonist Fex3 alleviates cholestatic liver injury via FGF15-CYP7A1 axis.
Song J, Wang Y, Guo R … +7 more , Wang K, Hu Y, Cui M, Wang G, Hao H, Wang H, Xu X
Eur J Pharmacol · 2026 May · PMID 42067015 · Publisher ↗
Maintaining bile acids (BAs) homeostasis is a recognized key strategy for treating primary biliary cholangitis (PBC), with the farnesoid X receptor (FXR) playing a significant regulatory role in this process. Compared to...
Maintaining bile acids (BAs) homeostasis is a recognized key strategy for treating primary biliary cholangitis (PBC), with the farnesoid X receptor (FXR) playing a significant regulatory role in this process. Compared to systemic FXR agonists, activation of intestinal FXR also benefit to BAs homeostasis, which have limited target genes, intestinal FXR activation may cause milder side effects. In this study, we evaluated the therapeutic efficacy, mechanism of action, and pharmacokinetic properties of Fex3 (fexaramine-3, an intestinal-restricted FXR agonist previously synthesized by our team) for cholestasis therapy. Results showed that Fex3 effectively alleviated cholestatic liver injury by activating the intestinal FXR-fibroblast growth factor 15 (FGF15) signaling pathway, which subsequently suppressed hepatic cholesterol 7α-hydroxylase (CYP7A1) expression. In mouse models, Fex3 demonstrated good tolerability and an excellent safety profile. These findings indicate that the intestinal-restricted FXR agonist Fex3 represents a promising novel therapeutic agent for PBC, providing a new insight into intervention for PBC targeting FXR.
Glucose transporter 9 inhibition as a potential novel approach for lowering uric acid.
Deai K, Fukui K, Naruoka S … +4 more , Shinozaki Y, Sasase T, Urashima T, Nishiu J
Eur J Pharmacol · 2026 May · PMID 42067014 · Publisher ↗
Glucose transporter 9 (GLUT9) is a uric acid transporter that plays a key role in maintaining uric acid homeostasis. JTT-763 is a novel GLUT9 inhibitor identified based on its uric acid transport inhibitory activity agai...
Glucose transporter 9 (GLUT9) is a uric acid transporter that plays a key role in maintaining uric acid homeostasis. JTT-763 is a novel GLUT9 inhibitor identified based on its uric acid transport inhibitory activity against human GLUT9 (hGLUT9). Using JTT-763 as a pharmacological tool, we aimed to evaluate the concept of GLUT9 inhibition for urate lowering. In vitro, JTT-763 inhibited uric acid transport by hGLUT9 short form (hGLUT9S) and hGLUT9 long form (hGLUT9L) in a concentration-dependent manner and showed high selectivity for hGLUT9 over other uric acid-related molecules. JTT-763 also inhibited uric acid transport through hGLUT9S/L co-expressing cells, a model that mimics renal uric acid reabsorption in vivo. In mice, JTT-763 increased uric acid excretion in urine but did not significantly affect blood uric acid levels. Therefore, we evaluated JTT-763 in tufted capuchin monkeys, whose uric acid metabolism is relatively similar to humans. JTT-763 showed a significant dose-dependent decrease in blood uric acid levels, and this effect was stronger than that of benzbromarone, an existing uricosuric drug, on a dose basis. Unexpectedly, benzbromarone significantly increased urinary uric acid excretion in monkeys, whereas JTT-763 did not. These results suggest that GLUT9 inhibition increases uric acid excretion not only in the kidney but also from extrarenal tissues and may represent a novel urate-lowering approach for hyperuricemia.
LS21013A-06, a PDE4 inhibitor, preserves blood-brain barrier integrity in experimental ischemic stroke models through PKA-dependent modulation of LECT2.
Wang J, Zeng C, Ye F … +2 more , Wang H, Xu J
Eur J Pharmacol · 2026 May · PMID 42044766 · Publisher ↗
Ischemic stroke (IS) disrupts the blood-brain barrier (BBB), thereby aggravating neurological deterioration. Loss of tight junction (TJ) and adherens junction (AJ) proteins is a key event in BBB breakdown, but the upstre...
Ischemic stroke (IS) disrupts the blood-brain barrier (BBB), thereby aggravating neurological deterioration. Loss of tight junction (TJ) and adherens junction (AJ) proteins is a key event in BBB breakdown, but the upstream mechanisms remain incompletely understood. Here, we investigated whether LS21013A-06 (A06), a phosphodiesterase-4 inhibitor, protects brain microvascular endothelial cells and preserves BBB integrity after ischemia/reperfusion, with particular focus on whether its protective effects are PKA-dependent and accompanied by changes in leukocyte cell-derived chemotaxin-2 (LECT2). In human brain microvascular endothelial cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R), LECT2 knockdown preserved TJ and AJ proteins, reduced Bax upregulation, restored Bcl-2 expression, and diminished reactive oxygen species accumulation. A06 pretreatment (3 μM) recapitulated these effects and markedly reduced OGD/R-induced LECT2 expression. The PKA inhibitor H89 (5 μM) abolished A06-mediated LECT2 suppression, junctional preservation, and reductions in apoptosis and reactive oxygen species, whereas LECT2 overexpression similarly abrogated the protective effects of A06. In a rat middle cerebral artery occlusion/reperfusion (MCAO/R) model, post-ischemic A06 administration (1 or 3 mg/kg, intraperitoneally) improved neurological scores and motor performance, reduced infarct volume and Evans blue extravasation, and increased ZO-1, VE-cadherin, and Occludin levels in peri-infarct cortex, together with reduced LECT2 expression and attenuated apoptosis-related changes in Bcl-2 and Bax. These findings indicate that A06 preserves BBB integrity after experimental ischemia. Mechanistically, its protective effects were PKA-dependent and accompanied by reduced LECT2 levels, preserved junctional proteins, and attenuated apoptosis-related changes. A06 enhanced PKA signaling, whereas PKA silencing blunted both its protective effects and the associated reduction in LECT2 expression.
Inhibition of ferroptosis exerts renal protective effects in membranous nephropathy rats via the Nrf2/HO-1 pathway.
Shi X, Shi Y, Chang M … +6 more , Duan H, Chen H, Tuerxun X, Zhao M, Shi Z, Zhang Y
Eur J Pharmacol · 2026 May · PMID 42044765 · Publisher ↗
The incidence of membranous nephropathy (MN) is gradually increasing; however, safe and effective targeted therapies are still lacking. Ferroptosis may be involved in the disease progression of MN; however, the specific...
The incidence of membranous nephropathy (MN) is gradually increasing; however, safe and effective targeted therapies are still lacking. Ferroptosis may be involved in the disease progression of MN; however, the specific pathways involved remain unknown. This study investigated whether the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway mediates MN progression via ferroptosis. A passive Heymann nephritis rat model was established by tail vein injection of anti-Fx1A. The rats were treated with ferrostatin-1 (Fer-1), the ferroptosis inhibitor, and the Nrf2 inhibitor ML385 for 2 weeks. After treatment, 24-h urine protein samples were collected along with blood and renal tissue samples. Renal tissue pathological damage, lipid peroxidation, iron deposition, ferroptosis-related proteins, and expression of the Nrf2/HO-1 pathway were assessed. The passive Heymann nephritis rat model exhibited massive proteinuria, hypoalbuminemia, and hyperlipidemia. Fer-1 reduced proteinuria, alleviated pathological damage to renal tissues, inhibited lipid peroxidation and iron deposition, suppressed ferroptosis in renal tissues, and restored the expression of Nrf2 and HO-1. Furthermore, when the Nrf2 inhibitor ML385 was combined with Fer-1, the inhibition of Nrf2 exacerbated proteinuria, worsened renal tissue pathological damage, increased lipid peroxidation and iron deposition, and aggravated ferroptosis. These findings demonstrated that ferroptosis inhibition alleviates renal injury in MN by activating the Nrf2/HO-1 pathway, suggesting a potential therapeutic target for this disease.
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