Eur. J. Pharmacol. [JOURNAL]
Sun
200 papers
Astaxanthin inhibits platelet-mediated thrombosis via suppression of bidirectional αIIbβ3 signaling.
Choi H, Kim YJ, Shin HW … +2 more , Jung SM, Kim K
Eur J Pharmacol · 2026 Jul · PMID 42392252 · Publisher ↗
Platelets are central mediators of hemostasis and thrombosis, and dysregulated platelet activation substantially contributes to the pathogenesis of cardiovascular diseases. Astaxanthin (AZ), a xanthophyll carotenoid and...
Platelets are central mediators of hemostasis and thrombosis, and dysregulated platelet activation substantially contributes to the pathogenesis of cardiovascular diseases. Astaxanthin (AZ), a xanthophyll carotenoid and a bioactive compound derived from Haematococcus lacustris, possesses potent antioxidant and anti-inflammatory properties. Nevertheless, its regulatory effects on platelet function remain insufficiently elucidated. This study investigated the impact of AZ on platelet function and thrombosis. In vitro experiments demonstrated that AZ significantly inhibited agonist-induced platelet aggregation, secretion of dense and α-granules, intracellular calcium mobilization, αIIbβ3 integrin activation, platelet spreading, and clot retraction. In addition, AZ reduced intracellular reactive oxygen species (ROS) generation under collagen-related peptide (CRP)-stimulated platelet activation in a concentration-dependent manner. Mechanistic analyses revealed that AZ suppressed the phosphorylation of key kinases involved in the bidirectional signaling of αIIbβ3 integrin, including spleen tyrosine kinase (Syk), phospholipase C (PLC), phosphoinositide 3-kinase (PI3K), Akt, proline-rich tyrosine kinase 2 (Pyk2), and focal adhesion kinase (FAK). In vivo, oral administration of AZ significantly prolonged FeCl-induced carotid artery occlusion time and tail bleeding time. Collectively, these findings suggest that AZ modulates platelet activation and thrombosis through coordinated effects on integrin-associated signaling, intracellular kinase phosphorylation, and redox-related regulatory mechanisms.
Repurposing of alogliptin to mitigate experimentally-induced ulcerative colitis and its associated pulmonary injury in rats through regulating inflammatory, necroptotic, and ER stress pathways.
Didamoony MA, Shokr MM, Eladawy RM … +1 more , Ahmed LA
Eur J Pharmacol · 2026 Jul · PMID 42392251 · Publisher ↗
Lung injury is one of the clinically reported conditions associated with inflammatory bowel diseases. The purpose of this study was to assess, for the first time, alogliptin's possible therapeutic effect in acetic acid (...
Lung injury is one of the clinically reported conditions associated with inflammatory bowel diseases. The purpose of this study was to assess, for the first time, alogliptin's possible therapeutic effect in acetic acid (AA)-induced UC and its associated lung injury in rats, with investigation of the probable molecular mechanisms of protection. To induce UC, rats were given a single intrarectal injection of 1 ml of 4% AA. Following 24 h of induction, rats were treated orally with ALO for 2 weeks at doses of 15 or 30 mg/kg/day. Higher-dose of ALO provided an ancillary improvement towards the treatment of AA-induced UC and its associated lung injury compared to lower-dose of ALO. Notably, ALO improved the rats' overall health, body weights and mitigated the pathological changes induced by AA in the colon and lungs. Besides, ALO enhanced tight junction integrity by modulating the gut DPP-4/GLPs axis, which in turn led to inhibition of systemic inflammation induced by TNF-α/claudin-1 axis. These outcomes subsequently prevented the pulmonary injury associated with TLR4/NF-κB p65/TNF-α, RIPK1/MLKL/HMGB1, IRE-1α/p-JNK, oxidative stress, and TGF-β1/COL1A1/COL3A1 cascades with notable anti-fibrotic effects. In this context, ALO could be a promising nominee for the treatment of UC and its associated pulmonary injury through attenuating colonic inflammation, preserving gut integrity, and preventing systemic inflammation and its associated lung-induced injury.
Erianin ameliorates liver fibrosis through the PRDX3/NLRX1 axis.
Zhu M, Yang X, Xie J … +8 more , Shi X, Li J, Shi Y, Zhang L, Tian X, Li Y, Yao J, Sun R
Eur J Pharmacol · 2026 Jul · PMID 42392250 · Publisher ↗
Liver fibrosis constitutes a central pathological hallmark of advanced chronic liver diseases. However, effective therapeutic targets and pharmacological interventions remain insufficiently defined. Mitochondrial oxidati...
Liver fibrosis constitutes a central pathological hallmark of advanced chronic liver diseases. However, effective therapeutic targets and pharmacological interventions remain insufficiently defined. Mitochondrial oxidative stress plays a pivotal role in the pathogenesis of hepatic stellate cells (HSCs) activation during liver fibrosis. While erianin, a natural bibenzyl compound extracted from the stems of Dendrobium chrysotoxum Lindl., exerts antioxidant effects in various diseases, its protective effect against liver fibrosis remains elusive. Thus, this study aimed to evaluate the therapeutic potential of erianin against liver fibrosis and to explore the underlying molecular mechanisms. The results revealed that erianin markedly attenuated CCl-and TGF-β1-induced HSCs activation and liver fibrosis. Molecular docking analyses identified PRDX3 as a specific binding target of erianin, with a subsequent increase in PRDX3 expression. However, PRDX3 knockdown abolished the protective effects of erianin on liver fibrosis. Mechanistically, RNA-seq and molecular assays demonstrated that PRDX3 alleviated liver fibrosis by activating NLRX1 and that erianin mediated its protection through the PRDX3/NLRX1 pathway. Collectively, these findings demonstrate that erianin alleviates liver fibrosis via the PRDX3/NLRX1 axis.
4-Octyl itaconate attenuates renal calculi formation by inhibiting ferroptosis and oxidative stress via the Nrf2-HO-1/SLC7A11 axis.
Zhou X, Cheng W, Zeng G … +8 more , Zhang Y, Wang Y, Wang J, Hu X, Lan Y, Zheng F, Hu J, Chen H
Eur J Pharmacol · 2026 Jul · PMID 42392249 · Publisher ↗
BACKGROUND: Calcium oxalate (CaOx) kidney stones are the most common form of urolithiasis and are characterized by high incidence and recurrence rates. 4-Octyl itaconate (4-OI), an itaconate derivative, has been shown to...
BACKGROUND: Calcium oxalate (CaOx) kidney stones are the most common form of urolithiasis and are characterized by high incidence and recurrence rates. 4-Octyl itaconate (4-OI), an itaconate derivative, has been shown to exert broad protective effects in various disease models owing to its anti-inflammatory and antioxidant properties. However, its role in CaOx kidney stone formation remains largely unknown. METHODS AND RESULTS: A CaOx kidney stone model was established in 6-week-old male C57BL/6 mice by glyoxylic acid induction, followed by treatment with 4-OI at 50 mg/kg. Renal tissues were subjected to HE, TUNEL, DHE, Prussian blue, and von Kossa staining to evaluate renal tissue injury, apoptosis, reactive oxygen species (ROS) production, iron deposition, and CaOx crystal deposition. Mechanistically, we observed that 4-OI exerts its effects through the NRF2-HO-1/SLC7A11 pathway in HK-2 cells. Our results suggest that 4-OI prevents CaOx crystal formation, attenuates oxidative stress, and mitigates ferroptosis both in vitro and in vivo via the NRF2-HO-1/SLC7A11 pathway. CONCLUSION: 4-OI attenuates renal CaOx formation, reduces oxidative stress, and alleviates ferroptosis through the NRF2-HO-1/SLC7A11 pathway. These findings suggest that 4-OI has significant therapeutic potential for the treatment of CaOx kidney stones.
VER155008 rescues cognitive impairment in P301S tauopathy mice by promoting HSPA8-mediated lipophagy.
Guo H, Zheng S, Shi X … +3 more , Wang X, Ma R, Li G
Eur J Pharmacol · 2026 Jul · PMID 42391923 · Publisher ↗
Alzheimer's disease (AD) features tau accumulation and pathogenic lipid droplet (LD) buildup, driving neurodegeneration through oxidative stress and neuroinflammation. The chaperone heat shock protein family A member 8 (...
Alzheimer's disease (AD) features tau accumulation and pathogenic lipid droplet (LD) buildup, driving neurodegeneration through oxidative stress and neuroinflammation. The chaperone heat shock protein family A member 8 (HSPA8) is upregulated in AD, which may have implications for impaired LD clearance via lipophagy. We investigated whether targeting HSPA8 with the small-molecule antagonist VER155008 alleviates tau pathology and cognitive deficits by activating lipophagy in P301S tauopathy models. P301S tau transgenic mice and HEK293T-P301S cells were utilized. Western blotting, immunohistochemistry, and immunofluorescence were performed to assess HSPA8 levels, lipophagy, tau proteins, and inflammatory markers. VER155008 or vehicle control was administered to P301S mice for four weeks, starting at seven months of age. Cognitive function was evaluated using the Morris water maze and novel object recognition tests. Synaptic density was assessed through Golgi staining and electron microscopy. HSPA8 was elevated in P301S mice, correlating with impaired lipophagy and suppressed AMP-activated protein kinase (AMPK) activity. VER155008 treatment restored cognitive function and synaptic density. Critically, it activated lipophagy and reduced hippocampal LDs and tau pathology. Moreover, HSPA8 overexpression suppressed lipophagy and increased both LD accumulation and tau pathology. Inhibition of HSPA8 by VER155008 activates AMPK-mediated lipophagy, concurrently reducing tau pathology, oxidative stress, and neuroinflammation in AD models. These beneficial effects were eliminated by treatment with the AMPK inhibitor Compound C. This identifies the HSPA8-lipophagy axis as a promising therapeutic target for tauopathies.
Okanin alleviates osteoarthritis by suppressing oxidative stress and pyroptosis via Nrf2/HO-1 activation.
Guo D, Xia T, Han D … +2 more , He S, Xi H
Eur J Pharmacol · 2026 Jul · PMID 42391922 · Publisher ↗
Osteoarthritis (OA) is a chronic joint disorder characterized by degenerative cartilage and chondrocyte dysfunction. Oxidative stress and NLRP3 inflammasome-mediated pyroptosis play pivotal roles in OA progression. This...
Osteoarthritis (OA) is a chronic joint disorder characterized by degenerative cartilage and chondrocyte dysfunction. Oxidative stress and NLRP3 inflammasome-mediated pyroptosis play pivotal roles in OA progression. This study investigated the protective effects and mechanisms of Okanin, a natural flavonoid, in a mouse model of knee osteoarthritis. We found that Okanin effectively activated the Nrf2/HO-1 signaling pathway, significantly enhanced the antioxidant capacity of chondrocytes and scavenged excess ROS. Concurrently, Okanin inhibited the assembly and activation of the NLRP3 inflammasome, thereby suppressing the caspase-1/GSDMD-dependent pyroptosis pathway. In vivo experiments demonstrated that Okanin treatment improved articular cartilage morphology, reduced proteoglycan loss, and decreased OARSI scores in a destabilization of the medial meniscus (DMM) murine model. Mechanistically, Nrf2 was identified as a key target of Okanin through siRNA knockdown. This study is the first to reveal that Okanin exerts dual chondroprotective effects against oxidative stress and pyroptosis via the Nrf2/HO-1 axis, suggesting a novel strategy for OA treatment.
Baicalin downregulates Thromboxane A receptor via SIRT1/NRF2 and NLRP3 pathways to attenuate Cyclosporine A-induced hypertension.
Gao T, Li Q, Chen J … +6 more , Li Q, Fan X, Yang L, Liu J, Wang B, Wang C
Eur J Pharmacol · 2026 Jul · PMID 42385976 · Publisher ↗
Cyclosporine A, an immunosuppressant, is clinically limited by its hypertensive and nephrotoxic effects. Baicalin, a bioactive flavonoid derived from Scutellaria baicalensis, effectively alleviates CsA-induced hypertensi...
Cyclosporine A, an immunosuppressant, is clinically limited by its hypertensive and nephrotoxic effects. Baicalin, a bioactive flavonoid derived from Scutellaria baicalensis, effectively alleviates CsA-induced hypertension by downregulating the thromboxane A (TP) receptor via the SIRT1/NRF2 and NLRP3 pathways. Ex vivo, in vivo, and in vascular smooth muscle cells (VSMCs), baicalin markedly reversed CsA-induced vasoconstriction, elevated blood pressure, upregulation of TP receptor, KEAP-1, NLRP3, Caspase-1, IL-1β, and ASC, as well as downregulation of SIRT1, NRF2, HO-1, and NQO-1. Importantly, siRNA-mediated knockdown of SIRT1 or NLRP3 abolished baicalin's protective effects. CETSA and ITDRF-CETSA demonstrated that baicalin directly binds to and stabilizes SIRT1 and NLRP3. Molecular docking further confirmed strong binding affinity of baicalin to both TP receptor and SIRT1. Immunofluorescence revealed that baicalin significantly inhibited CsA-induced NLRP3/ASC speck formation. Collectively, baicalin may improve CsA-induced hypertension by downregulating the TP receptor through the SIRT1/NRF2 and NLRP3 pathways.
Arbutin as a therapeutic candidate for autism: Current evidence and mechanistic insights into PI3K/Akt/mTOR and Nrf2 pathways.
Abhishek, Singh S
Eur J Pharmacol · 2026 Jul · PMID 42385975 · Publisher ↗
Arbutin is a natural glycoside that protects neurons and is useful in a variety of neurological conditions. There is a need to further explore its scientific properties as arbutin regulates mitochondrial function, contro...
Arbutin is a natural glycoside that protects neurons and is useful in a variety of neurological conditions. There is a need to further explore its scientific properties as arbutin regulates mitochondrial function, control apoptotic proteins, lowers oxidative stress, enhance behavioral and cognitive outcomes and thus may be considered a potential target for Parkinson's, Alzheimer's, neuroinflammation, epilepsy and Huntington's disease. Arbutin via PI3K/Akt/mTOR and Nrf2 signaling pathways, helps to balance redox equilibrium, mitochondrial integrity and neuronal survival, plays a major role in mediating these effects. Autism Spectrum Disorder (ASD) is closely associated with dysfunction of these pathways, which cause oxidative 2 stress, synaptic deficits and neuroinflammation. While reducing NF-κB mediated pro-inflammatory cytokines including TNF-α, IL-1β and IL-6, arbutin increases Akt phosphorylation and Nrf2 nuclear translocation, activating antioxidant enzymes like SOD, GSH, HO-1 and NQO1. These coordinated molecular processes may help preserve neuronal homeostasis, inhibit apoptosis and decrease ROS induced neuronal damage. Arbutin may enhance synaptic plasticity and potentially modulate the pathogenic pathways underlying ASD and other neurodevelopmental disorders by concurrently regulating oxidative stress, mitochondrial dysfunction and neuroinflammation. Taken together these finding suggest arbutin may act as a promising therapeutic candidate capable of restoring neuronal homeostasis and translating mechanistic understanding into potential therapeutic applications. Arbutin is a promising phytochemical with potential relevance for autism and associated neurological diseases due to its combined molecular actions. However, direct experiment and clinical evidence supporting the role of arbutin in ASD remains limited.
Repeated ethanol exposure in female rats impairs cerebral endothelial function and increases cerebrovascular stiffness.
Baumoel EJ, Heitkamp MC, Thaqi A … +4 more , Luchetta J, DeMarco GM, Karkhanis AN, Chapman AC
Eur J Pharmacol · 2026 Jul · PMID 42385974 · Publisher ↗
There are several lifestyle factors known to increase the risk for age-related cognitive decline and dementia, including chronic alcohol consumption and alcohol use disorder. Chronic alcohol use in adulthood causes decre...
There are several lifestyle factors known to increase the risk for age-related cognitive decline and dementia, including chronic alcohol consumption and alcohol use disorder. Chronic alcohol use in adulthood causes decreased gray matter and atrophy in brain regions central to learning and memory, including the hippocampus. Further, people with alcohol use disorder have a high incidence of cerebral white matter hyperintensities, the hallmark of cerebral small vessel disease, suggesting a link between alcohol consumption and cerebrovascular disease. However, how ethanol exposure impacts the cerebral circulation remains unclear. Here, we investigated the effects of a single ethanol vapor exposure (12 h), repeated ethanol exposures (12 h/day for 10 days) or air exposure (controls; n = 8/group) on cerebrovascular function and structure in adult female Wistar rats, as women are more sensitive to alcohol-related brain injury. Endothelial function and myogenic reactivity of isolated and pressurized posterior cerebral arteries (PCAs), the pial artery responsible for perfusing the hippocampus, were assessed ex-vivo using pressure myography. Both single and repeated ethanol exposure impaired PCA endothelial function, however, had a differential effect on myogenic tone. Repeated ethanol exposure caused oxidative stress, vascular inflammation and reduced myogenic tone of PCAs compared to a single exposure. Further, PCAs from rats repeatedly exposed to ethanol were stiffer than arteries from controls and a single ethanol exposure, which commonly occurs with aging. These findings demonstrate that ethanol exposure rapidly impairs endothelial function in the cerebrovasculature of females and suggest that repeated exposures may result in disrupted hemodynamics and accelerated vascular aging.
Valerenic acid attenuates chronic stress-exacerbated metabolic dysfunction-associated steatotic liver disease via the estrogen receptor α-GDF15 axis.
Wu X, Jiang Y, Wang J … +7 more , Gu S, Wang Y, Li N, Qian C, Nie H, Zheng Y, Li Y
Eur J Pharmacol · 2026 Jul · PMID 42385973 · Publisher ↗
The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been rising annually. Meanwhile, with intensifying societal pressure, there has been a parallel surge in the prevalence of psychologic...
The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been rising annually. Meanwhile, with intensifying societal pressure, there has been a parallel surge in the prevalence of psychological disorders. The coexistence of these conditions creates a complex comorbidity, leading to heightened metabolic and cardiovascular risks, and posing challenges to traditional therapeutic approaches. Valerenic acid, a natural compound derived from the roots of Valeriana officinalis, exhibits sedative, anxiolytic, anti-inflammatory, and antioxidant effects, which may offer a promising therapeutic intervention for MASLD complicated by stress. The present study aims to experimentally evaluate the therapeutic effects of valerenic acid as well as to explore its pharmacological mechanisms, thereby providing evidence for its clinical application. Both male and female C57BL/6J mice were utilized in this study. A Western diet was employed to induce MASLD, while moderate, intermittent, and prolonged restraint stress was applied to simulate chronic stress, whereas valerenic acid was orally gavaged to assess its therapeutic efficacy. The outcomes revealed that, in both sexes, the initial phase of restraint stress induced concurrent reductions in food intake and body weight; however, following an adaptation period, persistent chronic stress paradoxically resulted in escalation of both food consumption and weight gain. Intervention with valerenic acid effectively attenuated stress-induced fluctuations in feeding behavior and body weight. Furthermore, estrogen receptor α was identified as a key target of valerenic acid, which regulated the pivotal immunometabolic mediator growth differentiation factor 15, thereby suppressing appetite while ameliorating hepatic inflammatory pathology.
Theranekron prevents endotoxin-induced acute kidney injury by modulating inflammatory and mitochondrial apoptotic pathways.
Altuntas A, Asci H, Ilhan I … +5 more , Ozturk SA, Sirazi E, Ozmen O, Akpınar Z, Yurt DS
Eur J Pharmacol · 2026 Jun · PMID 42379491 · Publisher ↗
BACKGROUND: Lipopolysaccharide (LPS)-induced acute kidney injury (AKI) is characterized by oxidative stress, inflammation, and apoptotic injury. Theranekron (THERA) has been suggested to exert immunomodulatory effects; h...
BACKGROUND: Lipopolysaccharide (LPS)-induced acute kidney injury (AKI) is characterized by oxidative stress, inflammation, and apoptotic injury. Theranekron (THERA) has been suggested to exert immunomodulatory effects; however, its impact on renal oxidative status and related molecular pathways remains unclear. METHODS: Thirty-two male Wistar albino rats were allocated into four groups: Control, LPS, LPS + THERA, and THERA. Renal oxidative stress was assessed by measuring total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI). Serum creatinine and urea levels, histopathological alterations, and immunohistochemical expression of endothelial nitric oxide synthase (eNOS), interferon-gamma (IFN-γ), and interleukin-8 (IL-8) were evaluated. Sirtuin-1 (SIRT1), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), B-cell lymphoma-2 (BCL2), BCL2-associated X protein (BAX), aquaporin-2 (AQP2), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10) gene expression were measured. RESULTS: LPS significantly increased urea and creatinine levels and induced marked renal histopathological injury. Renal TAS was significantly decreased, and OSI was significantly increased. THERA treatment significantly increased TAS and reduced OSI compared with the LPS group. LPS significantly reduced SIRT1, NRF2, and HO-1 mRNA expression, and prophylactic THERA treatment significantly increased only HO-1 expression. LPS induced a pro-apoptotic shift and reduced AQP2 expression, all of which were significantly prevented by THERA. In parallel, THERA significantly reduced TNF-α expression and IL-10 levels, decreased IFN-γ and IL-8 immunoreactivity, and reduced eNOS immunoreactivity. CONCLUSION: Prophylactic THERA administration partially protected against early renal injury by improving renal antioxidant capacity, upregulating HO-1, and suppressing inflammatory and apoptotic responses, with preservation of AQP2 expression.
Icariside Ⅱ alleviates heart failure based on Wnt/β-catenin-mitochondrial apoptotic pathway.
Zhu J, Tang W, Huang D … +3 more , Sun L, Wang Y, Yang D
Eur J Pharmacol · 2026 Jun · PMID 42378990 · Publisher ↗
Heart failure (HF) represents a major global health challenge. This condition is closely linked to the dysregulation of a key signaling mechanism known as the Wnt/β-catenin pathway. Using an isoproterenol (ISO)-induced m...
Heart failure (HF) represents a major global health challenge. This condition is closely linked to the dysregulation of a key signaling mechanism known as the Wnt/β-catenin pathway. Using an isoproterenol (ISO)-induced mice model of HF and H9c2 cells injury, we examined the effects of Icariside II (ICS II) on ventricular remodeling and apoptosis, focusing on the Wnt/β-catenin and mitochondrial apoptotic pathways. ICS II significantly improved cardiac function, reduced left ventricular hypertrophy, and decreased expression of the HF markers atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). In HF mice treated with ICS II, Western blot analysis revealed reduced levels of both Wnt/β-catenin pathway proteins and apoptotic markers in cardiac tissue. Consistent with these in vivo findings, ICS II also protected H9c2 cells from ISO-induced injury in vitro. This protection was accompanied by a decrease in cell area and apoptosis, as well as a similar suppression of Wnt/β-catenin pathway proteins. GSK-3β inhibitor SB216763 reversed ICS II's protective effects, increasing H9c2 cells apoptosis and restoring Wnt/β-catenin pathway activity (except Wnt3A). These findings demonstrate that ICS II alleviates HF by modulating the Wnt/β-catenin-mitochondrial apoptotic pathway. Given that this compound improves cardiac function while simultaneously addressing pathological remodeling and apoptosis, it holds promise as a new therapeutic approach for HF.
Tetrandrine improves obesity-induced adipose metabolic disorders through suppressing macrophage NF-κB activation.
Quan Z, Xin Q, Hao H … +3 more , Wu H, Hu J, Pan Y
Eur J Pharmacol · 2026 Jun · PMID 42372935 · Publisher ↗
Obesity is closely associated with chronic low-grade inflammation in adipose tissue, which drives systemic metabolic dysfunction. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid from Stephania tetrandra, exhibits pot...
Obesity is closely associated with chronic low-grade inflammation in adipose tissue, which drives systemic metabolic dysfunction. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid from Stephania tetrandra, exhibits potent anti-inflammatory and immunomodulatory effects, yet its impact on obesity-associated metabolic disorders remains unclear. Administration of TET significantly attenuated body weight gain, adipose tissue mass, glucose intolerance, and hyperinsulinemia in diet-induced and genetic obese mouse models. Histological analyses of adipose tissues revealed that TET treatment decreased adipocyte hypertrophy, macrophage infiltration, and fibrosis, which were corroborated by transcriptomic and protein-level assessments showing downregulation of pro-inflammatory cytokines and inhibition of NF-κB signaling. In vitro, TET suppressed NF-κB activation in macrophages without affecting adipocyte differentiation, indicating macrophages as one of potential cellular targets. Collectively, these findings support TET as a promising immunometabolic regulator capable of restoring adipose tissue homeostasis and improving systemic metabolic health, providing evidence for the therapeutic potential of natural bioactive compounds in obesity-related metabolic disorders.
HSP70: From molecular chaperone to integrative hub in castration-resistant prostate cancer therapeutic resistance.
Liu Q, Huang T, Li L … +4 more , Liang Z, Liu Y, Xiao J, Wang X
Eur J Pharmacol · 2026 Jun · PMID 42372934 · Publisher ↗
The emergence of castration-resistant prostate cancer (CRPC), driven by 'undruggable' targets such as androgen receptor splice variant 7 (AR-V7), represents a fundamental barrier to curative therapeutic outcomes. This re...
The emergence of castration-resistant prostate cancer (CRPC), driven by 'undruggable' targets such as androgen receptor splice variant 7 (AR-V7), represents a fundamental barrier to curative therapeutic outcomes. This review proposes a conceptual framework reconceptualizing heat shock protein 70 (HSP70) as a potential integrative hub that may coordinate multiple resistance mechanisms. We synthesize available evidence to explore the hypothesis that HSP70 lies at the nexus of these pathways. We delineate how HSP70 has been reported to be associated with a multidimensional network: stabilizing oncoproteins (AR/AR-V7), potentially contributing to lineage plasticity via Plexin D1 (PLXND1), modulating ferroptosis through the AR-membrane-associated O-acyltransferase domain protein 2 (MBOAT2) axis, and engaging in synthetic vulnerability with heat shock protein 60 (HSP60). Consequently, therapeutic strategies are undergoing a paradigm shift from broad-spectrum inhibition to precision modalities targeting specific HSP70 interactions and functions. We provide a framework for leveraging this hub to overcome CRPC resistance.
Network pharmacology and in vivo validation reveal the protective mechanism of 6-gingerol against diabetic encephalopathy.
Liu RX, Cheng FC, Zhang TS … +7 more , Li ZY, Ge JH, Wang HM, Wang F, Wang H, Zhang JG, Zhang F
Eur J Pharmacol · 2026 Jun · PMID 42372933 · Publisher ↗
Diabetic encephalopathy (DE) is a prevalent and severe neurological complication associated with the advanced stages of type 2 diabetes mellitus (T2DM). Its pathogenesis is multifactorial and not yet fully understood, an...
Diabetic encephalopathy (DE) is a prevalent and severe neurological complication associated with the advanced stages of type 2 diabetes mellitus (T2DM). Its pathogenesis is multifactorial and not yet fully understood, and currently, there are no effective therapeutic interventions available. 6-Gingerol, a natural phenolic compound derived from ginger, exhibits favorable brain-targeting properties and diverse pharmacological activities, making it a promising candidate for the treatment of DE. In this study, the multi-target mechanism of 6-gingerol in DE was systematically investigated by integrating network pharmacological analysis with in vivo experimental validation. Network pharmacology results identified PPARG (namely PPARγ), mTOR, and ESR1 as key core targets of 6-gingerol, which were primarily enriched in pathways related to inflammatory regulation, amyloid-β metabolism, and neuroprotection. Animal experiments demonstrated that four weeks of 6-gingerol treatment significantly reduced fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG) and body weight, while improving cognitive function in 13-week-old db/db mice. Additionally, 6-gingerol markedly attenuated neuroinflammatory responses and decreased soluble amyloid-β levels in the hippocampus. Notably, partial beneficial effects of 6-gingerol were significantly attenuated by GW9662 (a selective PPARγ antagonist), while pioglitazone (a well-known PPARγ agonist) replicated the neuroprotective effects of 6-gingerol in multiple pathological endpoints. Collectively, these findings imply that 6 - gingerol may exert its protective effect against DE via a multi-target synergistic mechanism in which PPARγ plays a key regulatory role.
Corrigendum to "Piezo1 activation mediates stiffness-induced aortic medial calcification: Pharmacological evidence from agonist and antagonist studies" [Eur. J. Pharmacol. 1011 (2026) 178465].
Liu Y, Guo J, Gu X … +11 more , Xu J, Duan B, Miao Y, Xiao L, Xue H, Guo Q, Tian D, Jin S, Zhang Y, Wu Y, Teng X
Eur J Pharmacol · 2026 Jun · PMID 42364932 · Publisher ↗
Abstract loading — click title to view on PubMed.
Early prediabetes aggravates neuroinflammatory and cognitive dysfunctional responses to chlorpyrifos exposure: Possible amelioration by arachidonic acid.
Arida RE, Abd Elkader HAE, Abuiessa SA … +5 more , Agami M, Abdallah SM, Helmy MM, El-Mallah AI, El-Yazbi AF
Eur J Pharmacol · 2026 Jun · PMID 42364895 · Publisher ↗
Chronic exposure to organophosphorus pesticides (OPs) is increasingly implicated in neuroinflammatory and cognitive disorders, yet susceptibility factors and pharmacological modulators remain poorly defined. Given the gl...
Chronic exposure to organophosphorus pesticides (OPs) is increasingly implicated in neuroinflammatory and cognitive disorders, yet susceptibility factors and pharmacological modulators remain poorly defined. Given the global rise in metabolic dysfunction, this study investigated whether prediabetes amplifies the neurotoxic impact of chronic chlorpyrifos (CPF) exposure and examined arachidonic acid (AA) as a potential modulator of the associated detrimental phenotype, with emphasis on endocannabinoid system (ECS) perturbation. Male Sprague-Dawley rats were rendered prediabetic and dermally exposed to CPF for 35 days, in the absence or presence of oral AA supplementation (3 mg/kg/day). Chronic CPF exposure induced systemic metabolic dysfunction, cerebrovascular hypoperfusion, adipose inflammation, and marked neuroinflammation accompanied by cognitive and motor impairment, as assessed by behavioral testing, laser speckle imaging, biochemical assays, histopathology, immunohistochemistry, and LC-MS/MS. These effects were exacerbated in prediabetic rats. CPF accumulated preferentially in adipose depots and brain tissue and was associated with elevated IL-1β and oxidative stress. Molecularly, CPF disrupted ECS homeostasis, with increased hippocampal 2-arachidonoylglycerol levels, downregulation of CB1 receptors, and upregulation of CB2 receptors, consistent with a stress-induced but functionally impaired endocannabinoid response. AA supplementation significantly mitigated CPF- and prediabetes-induced dysfunctional phenotype, and rebalanced ECS signaling. Collectively, these findings identify early prediabetes as a critical vulnerability state that aggravates OP neurotoxicity and demonstrate that AA exerts broad neuroprotective and metabolic benefits, in part through modulation of endocannabinoid and inflammatory signaling. This work highlights the ECS-adipose-brain axis as a pharmacologically relevant interface linking environmental toxicant exposure to metabolic and neurocognitive decline.
Diammonium glycyrrhizinate attenuates neuroinflammation after intracerebral hemorrhage by suppressing VCAM-1 expression via the PI3K-Akt pathway.
Feng M, Zhang K, Wang F … +2 more , Wu H, Qin Q
Eur J Pharmacol · 2026 Jun · PMID 42364894 · Publisher ↗
Intracerebral hemorrhage (ICH) is a devastating stroke subtype with limited therapeutic options, and excessive neuroinflammation plays a critical role in secondary brain injury following ICH. Here, we investigated whethe...
Intracerebral hemorrhage (ICH) is a devastating stroke subtype with limited therapeutic options, and excessive neuroinflammation plays a critical role in secondary brain injury following ICH. Here, we investigated whether diammonium glycyrrhizinate (DG), a clinically approved anti-inflammatory agent, confers neuroprotection in a mouse model of ICH and explored the underlying mechanisms. Adult male C57BL/6J mice subjected to collagenase-induced ICH were treated with DG or vehicle, and we assessed neurological function, brain water content, hematoma volume, and blood-brain barrier (BBB) integrity at 3 days post-ICH. DG treatment significantly reduced brain edema, hematoma volume, and BBB leakage while improving neurological outcomes. RNA sequencing revealed that DG downregulated 94 genes, with enrichment in cell surface receptor activity pathways, and identified Vascular cell adhesion molecule-1 (VCAM-1) as a key downstream target. VCAM-1 upregulation in brain microvascular endothelial cells after ICH was markedly suppressed by DG, accompanied by reduced neutrophil infiltration, attenuated microglial M1 polarization, and decreased production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), matrix metalloproteinase-9, oxidative stress markers, and apoptotic factors. Mechanistically, DG activated the PI3K-Akt signaling pathway, and this activation was associated with suppression of VCAM-1 expression and subsequent attenuation of neuroinflammation. These findings demonstrate that DG attenuates neuroinflammation and secondary brain injury after ICH by activating the PI3K-Akt pathway to suppress VCAM-1 expression, thereby limiting peripheral immune cell infiltration and modulating microglial polarization. The PI3K-Akt/VCAM-1 axis represents a promising therapeutic target, and DG may serve as a potential candidate for ICH management.
Maresin-1 protects against lipopolysaccharide (LPS)-induced depressive-like behavior in adolescent mice and promotes M2 microglial polarization via ERK/NF-κB signaling.
Guo J, Cao X, Liu C … +3 more , Chen F, Ye Z, Qiu T
Eur J Pharmacol · 2026 Jun · PMID 42364893 · Publisher ↗
Adolescence is a critical developmental stage characterized by heightened vulnerability to psychiatric symptoms associated with neuroimmune challenges. Maresin-1 (MaR1), a specialized pro-resolving mediator, exerts poten...
Adolescence is a critical developmental stage characterized by heightened vulnerability to psychiatric symptoms associated with neuroimmune challenges. Maresin-1 (MaR1), a specialized pro-resolving mediator, exerts potent anti-inflammatory actions; however, its effects on inflammation-associated mood-related behavioral alterations during adolescence remain unclear. This study investigated the prophylactic effects of MaR1 in a lipopolysaccharide (LPS)-induced acute inflammatory challenge model using male adolescent C57BL/6J mice. MaR1 (5 μg/kg, i.p.) was administered 1 h before LPS challenge, and behavioral assessments were conducted 24 h later, a time point selected to reduce, but not eliminate, potential confounding by acute sickness-like responses. MaR1 pretreatment attenuated LPS-induced reductions in sucrose preference and increases in tail suspension immobility. MaR1 also reduced hippocampal inflammatory responses, as indicated by decreased TNF-α and IL-1β levels and changes in M1/M2-associated microglial marker profiles. Whole hippocampal tissue analyses showed that MaR1 dampened LPS-induced hippocampal ERK/NF-κB activation in vivo, while BV-2 cell experiments showed that MaR1 suppressed LPS-induced ERK and NF-κB phosphorylation in vitro. The MEK inhibitor U0126 partially mimicked the behavioral and inflammatory effects of MaR1, and co-administration did not produce additive behavioral benefits, consistent with the involvement of an ERK-related component. Collectively, these findings suggest that MaR1 pretreatment mitigates LPS-induced inflammation-associated depressive-like behavioral alterations in male adolescent mice, accompanied by reduced hippocampal inflammatory signaling and modulation of microglia-associated inflammatory marker profiles. These results support further investigation of MaR1 and related pro-resolving mediators as candidate modulators of inflammation-associated mood-related disturbances during development.
In silico prediction of gallic acid binding to Zika virus NS3/RdRp proteins and in vitro confirmation of its antiviral activity.
Heo JH, Kang N, Lee YJ … +2 more , Kim EA, Heo SJ
Eur J Pharmacol · 2026 Jun · PMID 42364892 · Publisher ↗
The global health threat posed by the Zika virus (ZIKV), characterized by its association with severe neurological sequelae and congenital malformations, is exacerbated by the current lack of clinically approved antivira...
The global health threat posed by the Zika virus (ZIKV), characterized by its association with severe neurological sequelae and congenital malformations, is exacerbated by the current lack of clinically approved antiviral interventions. This study aimed to identify a benzoic acid-derived anti-ZIKV candidate through in silico-in vitro screening of derivatives and to characterize the selected lead compound. Gallic acid (GA), a naturally occurring phenolic compound, emerged as the most suitable candidate and was selected for further analyses. Molecular docking and 100 ns molecular dynamics (MD) simulations demonstrated that GA formed stable interactions with the catalytic domains of ZIKV NS3 and RdRp, with conformational perturbations in RdRp. This suggests that GA inhibits protein activation through active-site occlusion and/or structural destabilization. Treatment with non-cytotoxic concentrations of GA significantly suppressed viral replication in ZIKV-infected Vero E6 cells, with >98% inhibition of plaque formation and NS1 mRNA expression at concentrations of 100-200 μM, and modulated the expression of innate immune response genes including TNF-α, IFIT, IFITM, OAS, and PKR. Collectively, these findings indicate that GA exerts potent antiviral activity through the direct inhibition of viral non-structural proteins, underscoring its potential as a promising lead compound for the development of anti-ZIKV therapeutics.
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