European journal of pharmacology最新文献_第8页

Cognitive enhancing effect of Canagliflozin in aluminum-induced rat model of Alzheimer's-like disease: Cross-talk between Amyloid-Β and BDNF/GSK-3β signaling 卡格列净在铝诱导的阿尔茨海默病大鼠模型中的认知增强作用：淀粉样蛋白-Β与BDNF/GSK-3β信号的串导

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-20 DOI: 10.1016/j.ejphar.2026.178581

Raafat A. Abdel-Aal , Fatma Y. Meligy , Gehad Kamel , Israa El-Sayed Mohamed Ashry

The strong relationship between Alzheimer's Disease (AD) and diabetes mellitus (DM) is described by the term “type 3 diabetes”. Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), is an antidiabetic agent under investigation as a potential new treatment for AD due to its acetylcholinesterase (AChE) inhibitory properties. We aimed to examine the effect of CAN on the efficacy of the anti-acetylcholinesterase, rivastigmine (RIV), against aluminum chloride (AlCl₃)-induced AD rat model. The efficacy of CAN, RIV, and CAN plus RIV against abnormal behavioral, biochemical, and histological changes in AlCl₃-induced AD in rats was examined. Three weeks of treatment with CAN partially reversed the AlCl₃-induced behavioral dysfunction, along with significantly elevated levels of brain-derived neurotrophic factor (BDNF) and decreased levels of AChE, glycogen synthase kinase-3β (GSK3β), amyloid beta (Aβ) deposits, and inducible nitric oxide synthase (iNOS) expression. Histological examination revealed that CAN administration significantly increased RIV's efficacy by protecting neurons in rats' hippocampal tissues from AlCl₃-induced damage. Interestingly, the RIV + CAN combination exhibited a more pronounced inhibitory effect on Aβ plaque formation, iNOS activity, and neurodegeneration compared to either RIV or CAN alone. However, this combination did not show any additive benefits for behavior, AChE activity, BDNF, or GSK3β concentrations compared with RIV alone. Our research indicates that CAN has potential benefits for AD, as evidenced by improvements in cognitive abilities, cholinergic activity, and neurogenesis in rats with AD. This is attributed to the upregulation of BDNF/GSK3β signaling, reduced neuroinflammation, and Aβ deposition.

阿尔茨海默病（AD）和糖尿病（DM）之间的密切关系被称为“3型糖尿病”。坎格列净（Canagliflozin， CAN）是一种钠-葡萄糖共转运蛋白2抑制剂（SGLT2i），由于其抑制乙酰胆碱酯酶（AChE）的特性，作为一种潜在的治疗AD的新药物正在研究中。我们的目的是研究CAN对抗乙酰胆碱酯酶利瓦斯汀（RIV）对氯化铝（AlCl3）诱导的AD大鼠模型的影响。观察CAN、RIV及CAN + RIV对alcl3诱导的AD大鼠异常行为、生化和组织学变化的影响。三周的CAN治疗部分逆转了alcl3诱导的行为功能障碍，脑源性神经营养因子（BDNF）水平显著升高，AChE、糖原合成酶激酶3β (GSK3β)、β淀粉样蛋白（Aβ）沉积和诱导型一氧化氮合酶（iNOS）表达水平降低。组织学检查显示，CAN通过保护大鼠海马组织神经元免受alcl3诱导的损伤，显著提高了RIV的疗效。有趣的是，与单独使用RIV或CAN相比，RIV+CAN联合使用在a β斑块形成、iNOS活性和神经退行性方面表现出更明显的抑制作用。然而，与单独使用RIV相比，该组合在行为、AChE活性、BDNF或GSK3β浓度方面没有显示出任何附加益处。我们的研究表明，CAN对阿尔茨海默病有潜在的益处，正如在阿尔茨海默病大鼠的认知能力、胆碱能活性和神经发生的改善所证明的那样。这是由于BDNF/GSK3β信号的上调，神经炎症和Aβ沉积的减少。

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引用次数: 0

Peptide FK2 attenuates inflammation and pro-fibrotic cellular transitions via targeting the IKKβ/NF-κB/TGF-β1 axis in renal fibrosis 肽FK2通过靶向IKKβ/NF-κB/TGF-β1轴在肾纤维化中减轻炎症和促纤维化细胞转变。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-19 DOI: 10.1016/j.ejphar.2026.178567

Runling Yang, Xiaocui Feng, Jianfeng Zhang, Tianyi Chen, Wenqian Wang, Yangrui Liu, Wanru Chen, Jingya Bai, Bangzhi Zhang

Chronic kidney disease (CKD) refers to a pathological change characterized by the progressive and irreversible loss of renal function. Renal fibrosis is the final pathological outcome of CKD without effective treatment. Persistent inflammation is one of the most important factors in the occurrence and development of fibrosis. FK2, a 9-amino-acid-residue peptide originating from the silk of Zea mays L., was reported to have anti-inflammatory effects on mice. In this study, we verified for the first time that FK2 has an inhibitory effect on the process of renal fibrosis both in vivo and in vitro. Mechanistically, we identified IKKβ as a direct target of FK2. By binding to IKKβ, FK2 concurrently suppresses the IKKβ/NF-κB and TGF-β1/Smad2/3 signaling axes, thereby effectively mitigating the associated inflammatory response and key cellular processes including macrophage-to-myofibroblast transition (MMT) and epithelial-mesenchymal transition (EMT). Our research provides a promising candidate molecule for the development of anti-renal fibrosis drugs, and targeting IKKβ presents a viable strategy for treating kidney fibrosis.

慢性肾脏疾病（Chronic kidney disease， CKD）是指以进行性、不可逆的肾功能丧失为特征的一种病理变化。肾纤维化是CKD无有效治疗的最终病理结果。持续性炎症是纤维化发生发展的重要因素之一。FK2是一种源自玉米蚕丝的9个氨基酸残基肽，据报道对小鼠具有抗炎作用。在本研究中，我们首次在体内和体外验证了FK2对肾纤维化过程具有抑制作用。在机制上，我们确定IKKβ是FK2的直接靶点。通过与IKKβ结合，FK2同时抑制IKKβ/NF-κB和TGF-β1/Smad2/3信号轴，从而有效减轻相关的炎症反应和关键的细胞过程，包括巨噬细胞到肌成纤维细胞转化（MMT）和上皮-间质转化（EMT）。我们的研究为开发抗肾纤维化药物提供了一个有希望的候选分子，并且靶向IKKβ为治疗肾纤维化提供了一个可行的策略。

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引用次数: 0

Neurochemical and behavioral evidence of high abuse liability of 3F-NEB, a novel synthetic cathinone 新型合成卡西酮3F-NEB高滥用倾向的神经化学和行为证据。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-17 DOI: 10.1016/j.ejphar.2026.178570

Stephanie Pain , Núria Nadal-Gratacós , Morgane De Macedo , Virginie Lardeux , Sandra Mata , Pol Puigseslloses , Fu-Hua Wang , Liselott Källsten , David Pubill , Xavier Berzosa , Jan Kehr , Jorge Camarasa , Elena Escubedo , Raul López-Arnau , Nathalie Thiriet , Marcello Solinas

Synthetic cathinones constitute a major class of New Psychoactive Substances (NPS) with significant abuse potential. Within this class, 3F-N-ethylbuphedrone (3F-NEB or 2-(ethylamino)-1-(3-fluorophenyl)butan-1-one), a novel N-ethyl buphedrone derivative, has recently emerged in recreational drug markets. However, its pharmacological properties and abuse liability remain uncharacterized.

The present study aimed to evaluate the neurochemical mechanisms and behavioral effects of 3F-NEB to assess its potential for abuse and addiction. To this end, we conducted in vitro monoamine uptake inhibition assays and in mice we performed locomotor activity and conditioned place preference tests. In rats, we conducted in vivo microdialysis in the nucleus accumbens, intravenous self-administration, and assessed neuroadaptive changes by ΔFosB immunohistochemistry following chronic self-administration.

Our results demonstrate that 3F-NEB acts as a potent dopamine transporter (DAT) inhibitor, with more than 100-fold selectivity over the serotonin transporter (SERT). Acute administration (3 mg/kg) rapidly increased extracellular dopamine levels in the nucleus accumbens of rats. At the behavioral level, 3F-NEB induced dose-dependent locomotor increases (10–30 mg/kg), with anxiety-like effects at the highest doses, and conditioned place preference at all tested doses (3–30 mg/kg) in mice. 3F-NEB was readily self-administered by rats under both fixed-ratio and progressive-ratio schedules. Furthermore, chronic self-administration significantly increased ΔFosB expression in dorsomedial and dorsolateral striatum, mirroring patterns observed with methamphetamine.

Taken together, these results demonstrate that 3F-NEB exhibits potent dopaminergic activity and high abuse liability through selective dopamine transporter inhibition. The compound's robust reinforcing properties and induction of addiction-related molecular adaptations suggest significant public health risks warranting immediate regulatory control.

合成卡西酮是一类具有严重滥用潜力的新型精神活性物质。在这类药物中，3f - n-乙基buphe酮（3F-NEB或2-（乙胺）-1-（3-氟苯基）丁烷-1- 1）是一种新型n-乙基buphe酮衍生物，最近出现在娱乐性药物市场上。然而，其药理特性和滥用倾向仍不明确。本研究旨在评估3F-NEB的神经化学机制和行为效应，以评估其滥用和成瘾的可能性。为此，我们进行了体外单胺摄取抑制试验，并在小鼠中进行了运动活动和条件位置偏好测试。在大鼠中，我们在伏隔核进行体内微透析，静脉给药，并通过ΔFosB免疫组织化学评估慢性自我给药后的神经适应性变化。我们的研究结果表明，3F-NEB作为一种有效的多巴胺转运蛋白（DAT）抑制剂，其选择性比血清素转运蛋白（SERT）高100倍以上。急性给药（3mg /kg）迅速增加大鼠伏隔核细胞外多巴胺水平。在行为水平上，3F-NEB诱导小鼠的剂量依赖性运动增加（10-30 mg/kg），在最高剂量下具有焦虑样效应，在所有测试剂量（3-30 mg/kg）下具有条件性位置偏好。3F-NEB在固定比例和递进比例两种情况下均易于大鼠自我给药。此外，慢性自我给药显著增加ΔFosB在背内侧纹状体和背外侧纹状体的表达，与甲基苯丙胺观察到的模式相似。综上所述，这些结果表明3F-NEB通过选择性抑制多巴胺转运体表现出强大的多巴胺能活性和高滥用倾向。该化合物强大的增强特性和诱导成瘾相关的分子适应表明，存在重大的公共卫生风险，需要立即进行监管控制。

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引用次数: 0

Sevoflurane postconditioning mitigates cognitive impairment induced by hemorrhagic shock resuscitation through inhibition of METTL3-mediated m6A modification of Sirt1 mRNA 七氟醚后处理通过抑制mettl3介导的Sirt1 mRNA的m6A修饰，减轻失血性休克复苏诱导的认知障碍。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-17 DOI: 10.1016/j.ejphar.2026.178578

Yujie Wu , Zhilun Niu , Shoufeng Zhu , Wenli Huang , Jianan Wang , Wenhui Tao , Bingqian Fan , Li Zhang , Xianwen Hu

Hemorrhagic shock resuscitation (HSR) induces cognitive impairment. Sevoflurane postconditioning (SPC) exerts neuroprotection, partially via Sirt1 activation. N6-methyladenosine (m6A), a crucial eukaryotic mRNA modification regulated by methyltransferase METTL3, influences brain function. However, METTL3's role in SPC-mediated neuroprotection against HSR remains unclear. Using HSR mouse models and HT22 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), we administered SPC. Mice received METTL3-overexpressing adeno-associated virus injection into the CA1 region prior to HSR induction. Cognitive function was assessed via novel object recognition and Morris water maze tests, and cerebral infarction was evaluated by TTC staining. SPC alleviated HSR-induced cognitive deficits and cerebral infarction, concurrently reduced elevated m6A levels and METTL3 expression. Crucially, METTL3 overexpression reversed SPC's beneficial effects, reinstating cognitive impairment and infarction. In vitro, METTL3 overexpression in SPC-treated OGD/R cells exacerbated oxidative stress, inflammation, and apoptosis. Mechanistically, SPC downregulated METTL3, reducing m6A modification and degradation of Sirt1 mRNA, thereby enhancing Sirt1 expression. Furthermore, SPC inhibited HSR-triggered microglial inflammation, an effect also negated by METTL3 overexpression. These results demonstrate that SPC protects against HSR-induced cognitive impairment by suppressing METTL3-mediated m6A modification of Sirt1 mRNA, revealing a novel epigenetic mechanism for SPC and identifying METTL3/m6A/Sirt1 as a potential diagnostic and therapeutic target for HSR.

失血性休克复苏（HSR）引起认知障碍。七氟醚后处理（SPC）部分通过Sirt1激活发挥神经保护作用。n6 -甲基腺苷（m6A）是一种重要的真核mRNA修饰，由甲基转移酶METTL3调节，影响脑功能。然而，METTL3在spc介导的高铁神经保护中的作用尚不清楚。我们使用HSR小鼠模型和缺氧-葡萄糖剥夺/再氧化（OGD/R）的HT22细胞给予SPC。小鼠在HSR诱导前在CA1区注射过表达mettl3的腺相关病毒。通过新物体识别和Morris水迷宫测试评估认知功能，通过TTC染色评估脑梗死。SPC减轻hsr诱导的认知缺陷和脑梗死，同时降低升高的m6A水平和METTL3表达。至关重要的是，METTL3过表达逆转了SPC的有益作用，恢复了认知障碍和梗死。在体外，spc处理的OGD/R细胞中，METTL3过表达加重了氧化应激、炎症和凋亡。在机制上，SPC下调了METTL3，减少了m6A修饰和Sirt1 mRNA的降解，从而增强了Sirt1的表达。此外，SPC抑制hsr引发的小胶质细胞炎症，这种作用也被METTL3过表达否定。这些结果表明，SPC通过抑制METTL3介导的m6A对Sirt1 mRNA的修饰来保护HSR诱导的认知障碍，揭示了SPC的一种新的表观遗传机制，并确定了METTL3/m6A/Sirt1是HSR的潜在诊断和治疗靶点。

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引用次数: 0

Metformin use and reduced dementia risk in older adults with type 2 diabetes and delirium 老年2型糖尿病和谵妄患者使用二甲双胍可降低痴呆风险。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-17 DOI: 10.1016/j.ejphar.2026.178534

Mingyang Sun , Xiaoling Wang , Zhongyuan Lu , Yitian Yang , Shuang Lv , Mengrong Miao , Wan-Ming Chen , Szu-Yuan Wu , Jiaqiang Zhang

Background

Diabetes-related delirium markedly impairs cognitive function in older adults with type 2 diabetes mellitus (T2DM) and may precede dementia. Metformin, a first-line antidiabetic drug, has shown potential neuroprotective effects, but its impact on dementia risk among patients with T2DM and delirium remains unclear.

Research design and methods

We conducted a nationwide cohort study of individuals aged ≥65 years with T2DM and a history of hospitalization for delirium. Participants were categorized as metformin users or active comparators based on medication patterns. Propensity score matching balanced key variables, and Cox regression models assessed dementia and all-cause mortality risks. Metformin exposure was quantified by cumulative defined daily doses (cDDDs).

Results

Among 66,050 patients, metformin use was associated with a 27 % lower dementia risk (adjusted HR, 0.72; 95 % CI, 0.68–0.76; P < 0.0001) and a 52 % lower all-cause mortality risk (adjusted HR, 0.48; 95 % CI, 0.46–0.51; P < 0.0001). A clear dose-response relationship was observed, with higher cDDDs corresponding to greater dementia risk reduction.

Conclusion

Metformin use in older adults with T2DM and delirium is linked to significantly lower risks of dementia and mortality, supporting its potential neuroprotective role in this high-risk population.

背景：糖尿病相关性谵妄显著损害老年2型糖尿病（T2DM）患者的认知功能，并可能是痴呆的前兆。二甲双胍是一种一线降糖药，已显示出潜在的神经保护作用，但其对T2DM和谵妄患者痴呆风险的影响尚不清楚。研究设计和方法：我们对年龄≥65岁且有谵妄住院史的2型糖尿病患者进行了一项全国性队列研究。参与者根据用药模式被分类为二甲双胍使用者或活跃比较者。倾向评分匹配平衡关键变量，Cox回归模型评估痴呆和全因死亡率风险。二甲双胍暴露量通过累积限定日剂量（cDDDs）进行量化。结果：在66,050例患者中，二甲双胍的使用与痴呆风险降低27%（校正HR， 0.72; 95% CI, 0.68-0.76; P < 0.0001）和全因死亡风险降低52%（校正HR， 0.48; 95% CI, 0.46-0.51; P < 0.0001）相关。观察到明显的剂量-反应关系，较高的cDDDs对应较大的痴呆风险降低。结论：二甲双胍用于老年T2DM合并谵妄患者可显著降低痴呆和死亡风险，支持其在这一高危人群中潜在的神经保护作用。

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引用次数: 0

Cathepsin B mediates HDAC inhibitor-induced epithelial-mesenchymal transition in lung cancer cells 组织蛋白酶B介导HDAC抑制剂诱导的肺癌细胞上皮-间质转化。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-17 DOI: 10.1016/j.ejphar.2026.178565

Xiaorui Wan , Huanchen Wu , Jie Xue, Haidong Xu, Jing Wang, Jiani Huang, Weilong Wu, Ruihan Zhang, Zhongqin Liang, Zhenyu Xuan, Yan Wang

This study investigates the mechanisms by which histone deacetylase (HDAC) inhibitors induce epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC), focusing on the role of Cathepsin B. Lung cancer cell lines A549 and H1975 were treated with HDAC inhibitors SAHA and SB939, and various assays were conducted to assess cell viability, apoptosis, migration, invasion, and cytoskeletal changes. The expression of EMT-related proteins and Cathepsin B was analyzed using Western blotting, immunofluorescence, and quantitative PCR. The results demonstrated that HDAC inhibitors reduced cell viability and increased apoptosis while promoting EMT phenotypes, enhancing migration and invasion. Cathepsin B was identified as a key mediator of the HDAC inhibitor-induced EMT, which it promotes by interacting with and upregulating the transcription factor Slug. These findings suggest that Cathepsin B is a crucial factor in HDAC inhibitor-induced EMT in NSCLC, indicating that targeting this enzyme may provide a novel therapeutic strategy to counteract invasiveness in lung cancer.

本研究探讨了组蛋白去乙酰化酶（HDAC）抑制剂在非小细胞肺癌（NSCLC）中诱导上皮-间质转化（EMT）的机制，重点研究了组织蛋白酶b的作用。用HDAC抑制剂SAHA和SB939处理肺癌细胞系A549和H1975，并进行了各种检测，以评估细胞活力、凋亡、迁移、侵袭和细胞骨架变化。采用western blotting、免疫荧光和定量PCR分析emt相关蛋白和组织蛋白酶B的表达。结果表明，HDAC抑制剂降低细胞活力，增加细胞凋亡，同时促进EMT表型，增强迁移和侵袭。组织蛋白酶B被认为是HDAC抑制剂诱导的EMT的关键介质，它通过与转录因子Slug相互作用并上调转录因子来促进EMT。这些发现表明，组织蛋白酶B是HDAC抑制剂诱导的非小细胞肺癌EMT的关键因素，表明靶向这种酶可能提供一种新的治疗策略来对抗肺癌的侵袭性。

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引用次数: 0

Unraveling sex-related cardiovascular toxicity of immune checkpoint inhibitors by pharmacovigilance and single-cell transcriptomic analysis 通过药物警戒和单细胞转录组分析揭示免疫检查点抑制剂与性别相关的心血管毒性。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-16 DOI: 10.1016/j.ejphar.2026.178569

Shaocong Sang , Huiming Han , Mingyue Liu , Nan Zhang , Yanrui Cui , Kaidong Liu , Kai Xiong , Haihai Liang , Lifang Lv , Yunyan Gu

Background

Immune checkpoint inhibitor (ICI) has revolutionized cancer treatment but can trigger severe immune-related adverse events (irAEs). Among these, cardiovascular irAEs (CV-irAEs) are rare yet associated with particularly high morbidity and mortality. This study aims to characterize the clinical features and underlying molecular mechanisms of CV-irAEs using pharmacovigilance and single-cell RNA sequencing data.

Methods

CV-irAEs are identified in the FDA Adverse Event Reporting System (FAERS) database through disproportionality analysis using reporting odds ratios. Onset times are compared across clinical variables using non-parametric tests. Factors associated with fatal outcomes are evaluated by Fisher's exact test, whereas logistic regression is employed to identify predictors of CV-irAEs occurrence. Finally, single-cell RNA sequencing explores sex differences in myocarditis irAEs.

Results

Twenty-six cardiovascular toxicity events are identified as CV-irAEs. Over 55 % of patients with CV-irAEs are diagnoses with lung or skin cancer. Additionally, CV-irAEs have a 43.91% fatality rate, and 51.82% of patients experience CV-irAEs within one month of ICI therapy initiation. Notably, patients over 75 years of age and those receiving anti-PD-1 monotherapy or combination therapy with anti-CTLA-4 are more susceptible to developing CV-irAEs. Furthermore, males experience more severe CV-irAEs. Accordingly, single-cell analysis reveals enhanced MIF and CD99 signaling between dendritic cells and effector memory T cells in male myocarditis irAEs patients, potentially explaining their greater susceptibility to severe CV-irAEs compared to females.

Conclusions

We identify key clinical risk factors and a male-specific immune signature in CV-irAEs, providing a foundation for personalized risk assessment and further mechanistic studies.

背景：免疫检查点抑制剂（ICI）已经彻底改变了癌症治疗，但可能引发严重的免疫相关不良事件（irAEs）。其中，心血管irAEs （CV-irAEs）罕见，但发病率和死亡率特别高。本研究旨在利用药物警戒和单细胞RNA测序数据来表征CV-irAEs的临床特征和潜在的分子机制。方法：在FDA不良事件报告系统（FAERS）数据库中，使用报告优势比进行歧化分析，确定cv - irae。发病时间采用非参数测试比较不同临床变量。采用Fisher精确检验评估与致命结果相关的因素，而采用逻辑回归来确定CV-irAEs发生的预测因素。最后，单细胞RNA测序探索心肌炎irae的性别差异。结果：26例心血管毒性事件被鉴定为CV-irAEs。超过55%的cv - irae患者有肺癌或皮肤癌的迹象。此外，CV-irAEs的死亡率为43.91%，51.82%的患者在ICI治疗开始一个月内发生CV-irAEs。值得注意的是，75岁以上的患者和接受抗pd -1单药治疗或与抗ctla -4联合治疗的患者更容易发生CV-irAEs。此外，男性经历更严重的cv - irae。因此，单细胞分析显示，男性心肌炎irAE患者树突状细胞和效应记忆T细胞之间的MIF和CD99信号传导增强，这可能解释了与女性相比，男性对严重cv -irAE的易感性更高。结论：我们确定了CV-irAEs的关键临床危险因素和男性特异性免疫特征，为个性化风险评估和进一步的机制研究提供了基础。

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引用次数: 0

PEGylated cerium oxide nanoparticles alleviate osteoarthritis progression by inhibiting chondrocyte ferroptosis and maintaining cartilage homeostasis 聚乙二醇化氧化铈纳米颗粒通过抑制软骨细胞铁下垂和维持软骨稳态来缓解骨关节炎的进展

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-16 DOI: 10.1016/j.ejphar.2026.178563

Huajie Li , Huangming Zhuang , Panghu Zhou

Background

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by disruption of articular cartilage homeostasis, with ferroptosis of chondrocytes playing a crucial role. Cerium oxide nanoparticles (CeONPs), a class of inorganic nanozymes, exhibit potent antioxidant and anti-inflammatory properties. However, their effects on OA chondrocytes remain poorly understood.

Methods: mPEG_2k-DSPE was employed to facilitate the transfer of CeONPs into the aqueous phase, resulting in PEG-CeONPs. Primary chondrocytes were isolated and subjected to erastin treatment to induce ferroptosis. The impact of PEG-CeONPs on oxidative stress, Fe²⁺ concentrations, mitochondrial dysfunction, ferroptosis-associated proteins, and OA-related catabolic phenotypes was evaluated. Additionally, the involvement of NRF2 in ferroptosis and its chondroprotective effects were investigated using NRF2-siRNA. An experimental OA model was established in rats through anterior cruciate ligament transection.

Results

Our study demonstrated that PEG-CeONPs attenuated erastin-induced cytotoxicity and reduced oxidative stress in chondrocytes. Moreover, PEG-CeONPs inhibited erastin-induced ferroptosis and promoted collagen matrix synthesis and secretion. The protective effects of PEG-CeONPs were mediated by the NRF2 pathway, as NRF2 silencing via siRNA significantly diminished the anti-ferroptosis and chondroprotective effects of PEG-CeONPs in vitro. These findings were further validated in OA rat models, where PEG-CeONPs treatment led to a reduction in ferroptosis-related gene expression and significantly alleviated cartilage degradation.

Conclusions

This study elucidates the previously unexplored relationship between PEG-CeONPs and ferroptosis in OA chondrocytes. PEG-CeONPs demonstrate anti-ferroptosis and chondroprotective effects by activating the NRF2 pathway, suggesting their potential as therapeutic agents for OA.

骨关节炎（OA）是一种常见的退行性关节疾病，其特征是关节软骨内稳态的破坏，软骨细胞的铁上吊起着至关重要的作用。氧化铈纳米颗粒（CeONPs）是一类无机纳米酶，具有强大的抗氧化和抗炎特性。然而，它们对OA软骨细胞的影响仍然知之甚少。方法：采用mPEG2k-DSPE促进CeONPs向水相转移，得到PEG-CeONPs。分离原代软骨细胞，经erastin处理诱导铁凋亡。研究人员评估了PEG-CeONPs对氧化应激、Fe2+浓度、线粒体功能障碍、死铁相关蛋白和oa相关分解代谢表型的影响。此外，利用NRF2- sirna研究了NRF2参与铁下垂及其软骨保护作用。采用前交叉韧带横断法建立大鼠实验性骨关节炎模型。结果我们的研究表明，PEG-CeONPs可以减轻骨石膏蛋白诱导的细胞毒性，并降低软骨细胞的氧化应激。此外，PEG-CeONPs还能抑制erastin诱导的铁下垂，促进胶原基质的合成和分泌。PEG-CeONPs的保护作用是通过NRF2途径介导的，通过siRNA沉默NRF2可显著降低PEG-CeONPs在体外的抗铁凋亡和软骨保护作用。这些发现在OA大鼠模型中得到进一步验证，PEG-CeONPs治疗导致铁中毒相关基因表达降低，并显著缓解软骨降解。结论本研究阐明了PEG-CeONPs与OA软骨细胞铁下垂之间先前未被探索的关系。PEG-CeONPs通过激活NRF2通路显示出抗铁下垂和软骨保护作用，表明其作为OA治疗剂的潜力。

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引用次数: 0

Vericiguat inhibits the progress of cardiac hypertrophy and prevents hypertrophy-induced heart failure by multiple mechanisms Vericiguat通过多种机制抑制心脏肥厚的进展并预防肥厚引起的心力衰竭。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-16 DOI: 10.1016/j.ejphar.2026.178561

Ying-Qi Liu , Yi Zhang , Yu Song , Qin Yang , Guo-Wei He

Heart failure (HF) is often a result of cardiac hypertrophy, and it is still the main public health challenge. Although vericiguat has been proved to be effective in treating heart failure through soluble guanylate cyclase (sGC), its potential preventive effects on myocardial hypertrophy and the exact related mechanisms are still unclear. We aimed to investigate the mechanism of the effectiveness of vericiguat in treating HF, focusing on its multi-targets of therapeutic effect. Echocardiographic assessments performed after treatment of vericiguat revealed significant improvements in cardiac function compared to untreated controls (TAC + SS). Biochemically, vericiguat effectively reversed the decrease of cGMP levels observed in hypertrophic mice hearts. Histological analysis showed that hypertrophy and fibrosis were reduced, myofibril arrangement, mitochondrial function and autophagy were improved, and the swelling of the sarcoplasmic reticulum was reduced. This study for the first time demonstrates that in addition to the direct effect of cGMP signaling, vericiguat may target and regulate HDAC1 expression and may repair sarcoplasmic reticulum swelling and enhance autophagy in hypertrophic hearts. We conclude that the preventive effect of vericiguat on the HF through multiple mechanisms and the results emphasize the potential clinical usefulness of vericiguat in the prevention of the progress of HF.

心力衰竭（HF）通常是由心脏肥厚引起的，它仍然是主要的公共卫生挑战。虽然vericiguat已被证明可通过可溶性鸟苷酸环化酶（sGC）治疗心力衰竭，但其对心肌肥厚的潜在预防作用及其确切的相关机制尚不清楚。我们旨在探讨vericiguat治疗心衰的作用机制，重点探讨其多靶点的治疗效果。在vericiguat治疗后进行的超声心动图评估显示，与未治疗的对照组（TAC+SS）相比，心功能有显著改善。从生物化学角度来看，vericiguat有效地逆转了肥厚小鼠心脏中cGMP水平的下降。组织学分析显示，肥大和纤维化减轻，肌原纤维排列、线粒体功能和自噬改善，肌浆网肿胀减轻。本研究首次证明，除了cGMP信号的直接作用外，vericiguat还可能靶向和调节HDAC1的表达，并可能在肥厚性心脏中修复肌浆网肿胀，增强自噬。我们得出结论，vericiguat对HF的预防作用是通过多种机制实现的，结果强调了vericiguat在预防HF进展方面的潜在临床应用价值。

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引用次数: 0

Sodium channel Nav1.6 involved in modulating isoflurane-induced perioperative cognitive disorder of mice 钠通道Nav1.6参与调节异氟醚诱导的小鼠围手术期认知障碍

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-16 DOI: 10.1016/j.ejphar.2026.178545

Min Xia , Bin Wang , Jincheng Lu , Yuan Liu , Tianyu Wang , Jinnian Duan , Zuodong Wang , Lingchao Li , Shao Li , Dongbai Li

Perioperative neurocognitive disorder (PND), a major contributor to poor postoperative outcomes and excessive healthcare costs, has been associated with isoflurane inhalation, although the underlying mechanisms remain poorly defined. Voltage-gated sodium channels (VGSCs or Na_v) have been implicated in mediating the anesthetic effects of isoflurane. We previously reported that the Na_v1.6 subtype modulates neural network activity and cognitive function. Here we investigated whether Na_v1.6-mediated network disturbances contribute to isoflurane-induced PND. In the present study, we observed an increase in hippocampal Na_v1.6 expression, accompanied by abnormal neural network excitability characterized by decreased β- and γ-band power on electroencephalogram (EEG) recordings. This dysfunction led to excessive glutamate release and subsequent cognitive impairment. Correspondingly, downregulation of Na_v1.6 by lidocaine abolished both the abnormal network excitability and excessive glutamate release in isoflurane-exposed mice. In parallel, changes in excitatory synaptic proteins and excitatory amino acid transporters contributed to improved cognitive performance in isoflurane-inhaled mice. Taken together, isoflurane-induced increase in Na_v1.6 evokes the abnormal network excitability, leading to excessive glutamate release and eventually cognitive decline. Our study offers a novel potential mechanism linking Na_v1.6 to isoflurane-induced PND and suggests lidocaine as a potential therapeutic candidate.

围手术期神经认知障碍（PND）是术后预后不良和医疗费用过高的主要因素，与异氟烷吸入有关，但其潜在机制尚不明确。电压门控钠通道（VGSCs或Nav）参与介导异氟烷的麻醉作用。我们之前报道过Nav1.6亚型调节神经网络活动和认知功能。在这里，我们研究了nav1.6介导的网络干扰是否有助于异氟醚诱导的PND。在本研究中，我们观察到海马Nav1.6表达增加，伴有神经网络兴奋性异常，其特征是脑电图（EEG）记录的β和γ波段功率下降。这种功能障碍导致谷氨酸过度释放和随后的认知障碍。相应的，利多卡因下调Nav1.6可消除异氟醚暴露小鼠异常的神经网络兴奋性和过量的谷氨酸释放。同时，兴奋性突触蛋白和兴奋性氨基酸转运蛋白的变化有助于改善异氟醚吸入小鼠的认知能力。综上所述，异氟醚诱导的Nav1.6升高引起神经网络异常兴奋性，导致谷氨酸过度释放，最终导致认知能力下降。我们的研究提供了一种将Nav1.6与异氟醚诱导的PND联系起来的新的潜在机制，并建议利多卡因作为潜在的治疗候选药物。

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引用次数: 0