European journal of pharmacology最新文献_第7页

Modulation of mineralocorticoid and peroxisome proliferator activated receptors in attenuating hyperlipidemia induced endothelial dysfunction and vascular dementia. 调节矿化皮质激素和过氧化物酶体增殖物激活受体在减轻高脂血症诱导的内皮功能障碍和血管性痴呆中的作用。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-22 DOI: 10.1016/j.ejphar.2026.178588

Baldev Raj, Pankaj Bhatia, Amit Kumar, Nirmal Singh, Amteshwar Singh Jaggi

Vascular dementia (VaD) is closely associated with metabolic disturbances and endothelial dysfunction. The present study evaluated the effects of eplerenone, a mineralocorticoid receptor antagonist, pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, and fenofibrate, a PPARα agonist, administered alone and in combination, in a high-fat diet (HFD)-induced rat model of endothelial dysfunction and VaD. Rats were fed an HFD for 90 days to induce metabolic and vascular alterations. Cognitive performance was assessed using the Morris Water Maze test. Endothelial function was evaluated by measuring endothelium-dependent vasorelaxation in isolated aortic rings and serum nitrite levels. Biochemical markers of oxidative stress, inflammation, and cholinergic function, along with histopathological changes in brain tissue, were also analysed. HFD feeding resulted in marked endothelial dysfunction, evidenced by impaired vasorelaxation and reduced serum nitrite levels, along with significant cognitive deficits. These changes were accompanied by increased oxidative stress, indicated by elevated thiobarbituric acid reactive substances and reduced glutathione levels, as well as increased acetylcholinesterase and myeloperoxidase activities and neutrophil infiltration in the brain. Treatment with eplerenone, pioglitazone, and fenofibrate, individually and in combination, attenuated endothelial dysfunction, improved cognitive performance, and normalized biochemical and histopathological alterations, with combination therapy showing greater overall efficacy. The novelty of this study lies in its systematic comparison and rational combination of mineralocorticoid receptors (MR) antagonism with PPARα and PPARγ activation in a high-fat diet-induced model of vascular dementia, demonstrating enhanced neurovascular protection with low-dose combination therapy.

血管性痴呆（VaD）与代谢紊乱和内皮功能障碍密切相关。本研究评估了矿皮质激素受体拮抗剂eplerenone、过氧化物酶体增殖物激活受体(PPAR) γ激动剂吡格列酮和PPARα激动剂非诺贝特在高脂肪饮食（HFD）诱导的内皮功能障碍和VaD大鼠模型中单独或联合使用的效果。大鼠连续90天饲喂HFD，以诱导代谢和血管改变。认知能力评估采用莫里斯水迷宫测试。通过测量离体主动脉环内皮依赖性血管松弛和血清亚硝酸盐水平来评估内皮功能。我们还分析了氧化应激、炎症和胆碱能功能的生化指标，以及脑组织的组织病理学变化。HFD喂养导致明显的内皮功能障碍，表现为血管松弛受损和血清亚硝酸盐水平降低，以及显著的认知障碍。这些变化伴随着氧化应激的增加，表现为硫代巴比妥酸活性物质升高和谷胱甘肽水平降低，以及乙酰胆碱酯酶和髓过氧化物酶活性增加和脑中性粒细胞浸润。依普利酮、吡格列酮和非诺贝特单独或联合治疗可减轻内皮功能障碍，改善认知能力，并使生化和组织病理学改变正常化，联合治疗显示出更大的总体疗效。本研究的新颖之处在于，在高脂饮食诱导的血管性痴呆模型中，系统比较并合理结合矿化皮质激素受体（MR）拮抗剂与PPARα和PPARγ激活，证明低剂量联合治疗可增强神经血管保护。

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引用次数: 0

Triple drug co-delivery within nanosystems for synergistic anti-infective, anti-inflammatory, antinociceptive and neuroregenerative therapeutic effects: a focus on pharmacological and nanotechnological aspects 纳米系统内三联药共递送的协同抗感染、抗炎、抗伤害和神经再生治疗效果：药理学和纳米技术方面的重点。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.ejphar.2026.178585

Maria Sofia Anastácio , Francisco Veiga , Ana Cláudia Paiva-Santos , Patrícia C. Pires

Nanotechnology has emerged as an innovative tool capable of overcoming the limitations of traditional drug delivery systems, by enabling enhanced drug solubility and stability, controlled drug release, and improved drug targeting. Additionally, nanosystems can allow the co-encapsulation of multiple drugs simultaneously, harnessing their synergistic pharmacological effects, leading to increased therapeutic efficacy and safety. The purpose of this review is to critically analyze studies that have developed triple drug-loaded nanosystems, exploring various different nanoplatforms, such as polymeric nanoparticles, lipid nanoparticles, microcapsules, nanoemulsions, nanoemulgels, thermosensitive hydrogels, and nanocomposite hydrogels. Triple drug co-encapsulation has been achieved for non-steroidal anti-inflammatory drugs such as indomethacin, analgesic and antipyretic drugs such as paracetamol, immunosuppressant drugs such as methotrexate, antiretroviral drugs such as efavirenz, lopinavir, ritonavir, and tenofovir, antibacterial drugs such as amoxicillin and clarithromycin, antiulcer drugs such as omeprazole and famotidine, ion channel antagonists such as lomerizine hydrochloride, oxidized adenosine triphosphate, and zonampanel monohydrate, photosensitive molecules such as indocyanine green, genetic material such as MMP-9 siRNA, enzymes such as catalase, and/or plant-derived bioactive compounds such as curcumin, resveratrol, sinomenine, and thymoquinone. These molecules’ triple co-encapsulation into nanometric formulations has led to controlled and sustained drug release, extended circulation time, enhanced bioavailability, and reduced systemic toxicity, with an overall improvement in drug targeting and therapeutic outcomes in rheumatoid arthritis, psoriasis and other inflammation-based conditions, HIV and Helicobacter pylori infection, and trauma-induced central nervous system secondary degeneration, ultimately opening a door for improved patient compliance due to simplified dosing regimens.

纳米技术已经成为一种创新的工具，能够克服传统药物传递系统的局限性，通过增强药物的溶解度和稳定性，控制药物释放，改善药物靶向性。此外，纳米系统可以允许多种药物同时共包封，利用它们的协同药理作用，从而提高治疗效果和安全性。本综述的目的是批判性地分析已经开发的三重药物负载纳米系统的研究，探索各种不同的纳米平台，如聚合纳米颗粒、脂质纳米颗粒、微胶囊、纳米乳液、纳米凝胶、热敏水凝胶和纳米复合水凝胶。非甾体抗炎药如吲哚美辛，镇痛解热药如扑热息痛，免疫抑制剂如甲氨喋呤，抗逆转录病毒药物如依非韦伦、洛匹那韦、利托那韦、替诺福韦，抗菌药物如阿莫西林、克拉霉素，抗溃疡药物如奥美拉唑、法莫替丁，离子通道拮抗剂如盐酸洛美嗪、氧化三磷酸腺苷，光敏分子如吲哚菁绿，遗传物质如MMP-9 siRNA，酶如过氧化氢酶，和/或植物源性生物活性化合物如姜黄素、白藜芦醇、青藤碱和百里醌。这些分子的三重共包被纳米制剂，导致了药物的可控和持续释放，延长了循环时间，提高了生物利用度，降低了全身毒性，在类风湿关节炎、牛皮癣和其他炎症性疾病、HIV和幽门螺杆菌感染以及创伤性中枢神经系统继发性变性方面的药物靶向性和治疗效果得到了全面改善。由于简化了给药方案，最终为提高患者依从性打开了大门。

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引用次数: 0

CRISPR/Cas9-based genome-wide screen reveals a synergistic effect of Irinotecan and USP1 inhibitor in colorectal cancer 基于CRISPR/ cas9的全基因组筛选揭示了伊立替康和USP1抑制剂在结直肠癌中的协同作用。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.ejphar.2026.178558

Lei Wang , Min Miao , Lijing Bao , Junfeng Chu , Juan Zhou , Wenbo Song , Peipei Cai , Chen Cheng , Hongye Xu , Tao Wang , Rongrong Zhao , Hang Wang , Feng Liu , Ming Xu , Guangyu Tian

Irinotecan resistance remains a significant challenge in metastatic colorectal cancer (mCRC) therapy. To address this, we identified USP1 as a synthetic lethal partner of Irinotecan through genome-wide CRISPR/Cas9 screening in HCT-116 cells. Combining the USP1 inhibitor I-138 with Irinotecan in HCT-116, HT-29, and SW620 cell lines significantly reduced IC₅₀, suppressed proliferation, and diminished colony formation compared to monotherapy, demonstrating a synergistic effect (combination index CI < 1). The synergistic therapeutic efficacy was further validated in the xenograft mouse model. Mechanistic studies revealed that I-138 significantly upregulated pCREB (Ser133), concurrently dynamically regulating the activity of USP1, FANCD2/FANCI, and PCNA upon DNA damage response and repair. RNA sequencing further highlighted the enrichment of cAMP, PI3K-AKT, and Wnt pathways, which are all linked to CREB activity in the combination group. These findings establish USP1 inhibition as a promising strategy to overcome Irinotecan resistance through the combination strategy, providing a novel therapeutic avenue for CRC.

在转移性结直肠癌（mCRC）治疗中，伊立替康耐药性仍然是一个重大挑战。为了解决这个问题，我们通过在HCT-116细胞中进行全基因组CRISPR/Cas9筛选，确定了USP1是伊立替康的合成致死伴侣。与单药治疗相比，USP1抑制剂I-138与伊立替康联合治疗HCT-116、HT-29和SW620细胞系可显著降低IC50，抑制增殖，减少菌落形成，显示出协同效应（联合指数CI）

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引用次数: 0

Transglutaminase 2 activation is involved in thoracic aortic dissection through disruption of endothelial adherens junctions 转谷氨酰胺酶2激活通过破坏内皮粘附连接参与胸主动脉夹层

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.ejphar.2026.178548

Xinyao Li , Weixin Zhang , Jie Gao , Lin Zhang , Yuqing Liao , Qin Liu , Qinghua Zhang , Chaoyun Wang , Lin Zhong , Xinkang Wang , Yumei Li

Thoracic aortic dissection (TAD) is a life-threatening condition. While medial degeneration is a hallmark of TAD, emerging evidence underscores endothelial dysfunction as a critical initiating event. However, the specific molecular mediators orchestrating endothelial damage in TAD remain poorly defined. Transglutaminase 2 (TGM2), a multifunctional enzyme upregulated in TAD tissues, has been implicated in vascular pathology but its cell-specific roles, particularly in endothelium, are unknown. Here, we hypothesize that endothelial TGM2 is a key instigator of TAD pathogenesis. Using transmission electron microscopy in a β-aminopropionitrile (BAPN)-induced rat TAD model, we further identified profound ultrastructural damage in the aortic intima, including disrupted endothelial junctions and cell loss, etc. We found that TGM2 expression was significantly elevated specifically within the damaged aortic intima of patients and rats with TAD. In vitro, TGM2 knockdown in human aortic endothelial cells (HAECs) preserved intercellular junction integrity, whereas its overexpression exacerbated endothelial dysfunction. Mechanistically, TGM2 activation triggered the nuclear factor kappa-B (NF-κB) signaling pathway, leading to downregulation of VE-cadherin and upregulation of matrix metalloproteinase 2 (MMP2), thereby disrupting adherens junctions and promoting extracellular matrix degradation. In vivo, the TGM2 inhibitor cystamine dihydrochloride (Cys-D) attenuated aortic intima thickening, restored junctional integrity, reduced plasma TGM2 levels, and decreased TAD-related morbidity and mortality in rats. Our findings unveil a previously unrecognized endothelium-intrinsic role for TGM2 in driving TAD, positioning it as a promising therapeutic target directed at the endothelial origin of this devastating disease.

胸主动脉夹层（TAD）是危及生命的疾病。虽然内侧退变是TAD的标志，但新出现的证据强调内皮功能障碍是一个关键的起始事件。然而，在TAD中协调内皮损伤的特定分子介质仍然不明确。转谷氨酰胺酶2 （TGM2）是一种在TAD组织中上调的多功能酶，与血管病理有关，但其细胞特异性作用，特别是在内皮细胞中的作用尚不清楚。在这里，我们假设内皮细胞TGM2是TAD发病的一个关键促动因子。在β-氨基丙腈（BAPN）诱导的大鼠TAD模型中，我们进一步发现了主动脉内膜的严重超微结构损伤，包括内皮连接破坏和细胞丢失等。我们发现，在TAD患者和大鼠受损的主动脉内膜中，TGM2的表达显著升高。在体外，TGM2在人主动脉内皮细胞（HAECs）中下调可保持细胞间连接的完整性，而其过表达则会加剧内皮功能障碍。机制上，TGM2激活触发核因子κ b （NF-κB）信号通路，导致VE-cadherin下调，基质金属蛋白酶2 （MMP2）上调，从而破坏粘附体连接，促进细胞外基质降解。在体内，TGM2抑制剂盐酸半胺（cyys - d）可减轻大鼠主动脉内膜增厚，恢复连接完整性，降低血浆TGM2水平，降低tad相关的发病率和死亡率。我们的研究结果揭示了TGM2在驱动TAD中以前未被认识到的内皮内在作用，将其定位为针对这种毁灭性疾病的内皮起源的有希望的治疗靶点。

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引用次数: 0

Modulatory effect of dopamine receptors on long-term potentiation in dorsal and ventral hippocampus in anesthetized kindled rats. 多巴胺受体对麻醉点燃大鼠海马背侧和腹侧长期增强的调节作用。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.ejphar.2026.178590

Maryam Sharifi, Shahrbanoo Oryan, Alireza Komaki, Abdolrahman Sarihi, Javad Mirnajafi-Zadeh

The dopaminergic system acts as a crucial regulator of synaptic plasticity. Nonetheless, the exact role of dopamine receptors in modulating this process following seizure remains unclear. We investigated the role of dopamine receptors on synaptic plasticity in the dorsal and ventral hippocampal CA1 regions of PTZ-kindled rats. Following kindling induction with repeated PTZ (37.5 mg/kg), evoked field potentials were obtained from the CA1 region in response to Schaffer collateral stimulation in urethane-anesthetized (1.5 g/kg) rats. Quinpirole hydrochloride (D2-like receptor agonist, 2.5, 5, 10, and 20μg/2.5 μL) or SKF38393 hydrochloride (D1-like receptor agonist, 5 and 10 μg/μL) were microinjected into the lateral ventricle 30 or 25 min before long-term potentiation (LTP) induction, respectively. Haloperidol (D2-like receptor antagonist, 2 μg/μL) was administered 15 min prior to quinpirole hydrochloride. D2-like receptors activation had a dual effect on synaptic potentiation in control and kindled animals across both hippocampal regions. Quinpirole hydrochloride affected on synaptic plasticity in a U-shaped manner in control rats, while restored impaired LTP in kindled animals. Haloperidol inhibited theses effects in both groups, while SKF38393 had no impact on synaptic plasticity. These findings underscore the function of dopaminergic receptors in synaptic plasticity and their potential therapeutic implications for alleviating seizure-induced dysfunction.

多巴胺能系统是突触可塑性的关键调节器。尽管如此，多巴胺受体在癫痫发作后调节这一过程中的确切作用仍不清楚。我们研究了多巴胺受体在ptz点燃大鼠海马CA1区背侧和腹侧突触可塑性中的作用。经反复PTZ （37.5 mg/kg）点燃后，对麻醉大鼠（1.5 g/kg）的CA1区进行Schaffer侧枝刺激的诱发场电位测定。将盐酸喹匹罗（d2样受体激动剂，2.5、5、10和20μg/2.5μL）或盐酸SKF38393 （d1样受体激动剂，5和10μg/μL）分别在长时程增强（LTP）诱导前30和25 min微注射到侧脑室。氟哌啶醇（d2样受体拮抗剂，2μg/μL）在盐酸喹匹罗治疗前15 min给药。d2样受体的激活对对照组和点燃动物的两个海马区域的突触增强有双重影响。盐酸喹匹罗对对照组大鼠突触可塑性的影响呈u型，对点燃大鼠LTP损伤有恢复作用。氟哌啶醇抑制了两组的这些作用，而SKF38393对突触可塑性没有影响。这些发现强调了多巴胺能受体在突触可塑性中的作用及其在缓解癫痫诱发功能障碍方面的潜在治疗意义。

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引用次数: 0

YAP inhibition by gloriosine unlocks autophagic cell death as an anticancer strategy in lung malignancies glosine抑制YAP开启自噬细胞死亡作为肺恶性肿瘤的抗癌策略。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.ejphar.2026.178582

Biswajit Dey , Bharat Goel , Essha Chatterjee , Hoshiyar Singh , Hari Chander Reddy , Anjali Cholkar , Santanu Basak , Anamika Sharma , Rahul Kumar , Swathi Lakshmi S. , Shreyans Kumar Jain , Pankaj Kumar Singh , Nandkumar Doijad , Santosh Kumar Guru

Historically, lung cancer has been considered the leading cause of cancer-related death worldwide. Though some of the chemotherapeutic agents show promising outcomes in the ongoing battle against cancer, the overall survival rate for advanced-stage disease remains poor due to drug resistance, toxicity, and limited efficacy. Therefore, new chemotherapeutic agents are required to enhance efficacy, reduce side effects, and combat drug resistance. In the present study, we isolated a compound, gloriosine, and investigated its anticancer potential against different cancer cells, with a special focus on A549 lung adenocarcinoma cells. Treatment with gloriosine resulted in a significant reduction in cell viability in a dose- and time-dependent manner and reduced tumor size in the tumor xenograft model. Interestingly, gloriosine exhibited minimal cytotoxicity on normal cells, indicating its selective activity on cancer cells. Mechanistically, gloriosine induced G2/M cell cycle arrest in A549 cells within an hour of treatment and was found to affect the Hippo signaling pathway, leading to the retention and phosphorylation of the Yes-associated protein (YAP) in the cytoplasm, thereby inhibiting the activation of downstream target genes. This, in turn, led to the suppression of the AKT/mTOR pathway and the activation of autophagy-dependent cell death. These findings suggest that gloriosine could be a promising candidate for the development of new lung cancer therapies.

从历史上看，肺癌一直被认为是全球癌症相关死亡的主要原因。尽管一些化疗药物在与癌症的持续斗争中显示出有希望的结果，但由于耐药性、毒性和有限的疗效，晚期疾病的总体生存率仍然很低。因此，需要新的化疗药物来提高疗效，减少副作用，并对抗耐药性。在本研究中，我们分离了一种化合物，光荣苷，并研究了它对不同癌细胞的抗癌潜力，特别关注A549肺腺癌细胞。在异种肿瘤移植模型中，用光荣苷治疗导致细胞活力以剂量和时间依赖的方式显著降低，肿瘤大小减小。有趣的是，光荣苷对正常细胞表现出最小的细胞毒性，表明它对癌细胞有选择性活性。在机制上，在A549细胞中，荣光苷在1小时内诱导G2/M细胞周期阻滞，并发现影响Hippo信号通路，导致细胞质中yes相关蛋白（YAP）的保留和磷酸化，从而抑制下游靶基因的激活。这进而导致AKT/mTOR通路的抑制和自噬依赖性细胞死亡的激活。这些发现表明，荣耀氨酸可能是开发新的肺癌治疗方法的有希望的候选者。

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引用次数: 0

4-Phenylbutyrate attenuates doxorubicin-induced cardiorenal comorbidity by suppressing ER stress-mediated epithelial-mesenchymal transition and endothelial-mesenchymal transition 4-苯基丁酸通过抑制内质电应激介导的上皮-间质转化和内皮-间质转化，减轻阿霉素诱导的心肾合并症

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-20 DOI: 10.1016/j.ejphar.2026.178580

Wenyu Hui , Weiwei Cui , Jie Li , Mengyuan Cheng , Yangyang Liu , Yunru Peng , Yongfang Ding

Objective

Cardiorenal syndrome (CRS), a spectrum of disorders involving intertwined cardiac and renal dysfunction, poses a significant challenge to mechanistic research due to a lack of accurate in vivo models. This study investigated the role of endoplasmic reticulum (ER) stress in mediating endothelial-to-mesenchymal transition (EndMT) and epithelial-to-mesenchymal transition (EMT) in a mouse model of cardiorenal comorbidity. Moreover, we investigated the therapeutic potential of 4-phenylbutyrate (4-PBA), an ER stress inhibitor, in attenuating cardiorenal comorbidity.

Methods

We employed a doxorubicin (Dox)-induced mouse model of cardiorenal comorbidity to investigate the role of ER stress in mediating EndMT and EMT. Six weeks post-Dox treatment, echocardiography, urinalysis, and blood tests were performed, complemented by immunofluorescence and Western blot analyses of cardiac and renal tissues. 4-PBA was intraperitoneally administered to evaluate the effect of ER stress inhibition on cardiorenal comorbidity.

Results

Dox administration significantly impaired cardiac and renal function, accompanied by pronounced fibrosis and upregulation of EndMT, EMT and ER stress markers. 4-PBA treatment attenuated cardiac injury, restored function, and ameliorated renal lesions. Consistent with in vivo results, Dox activated ER stress in HUVEC and HK-2 cells, promoting mesenchymal transformation. Critically, 4-PBA suppressed EndMT and EMT in vitro, supporting ER stress involvement in these processes.

Conclusions

Our findings demonstrate that Dox induces concurrent cardiorenal dysfunction, primarily through ER stress-mediated EndMT and EMT transitions. Importantly, pharmacological inhibition of ER stress with 4-PBA attenuated these pathological changes, suggesting its potential as a therapeutic strategy for cardiorenal syndrome.

心肾综合征（CRS）是一系列涉及心脏和肾脏功能紊乱的疾病，由于缺乏准确的体内模型，对其机制研究构成了重大挑战。本研究探讨了内质网应激在心肾合并症小鼠模型中介导内皮-间质转化（EndMT）和上皮-间质转化（EMT）中的作用。此外，我们还研究了内质网应激抑制剂4-苯基丁酸酯（4-PBA）在减轻心肾合并症方面的治疗潜力。方法采用多柔比星（Dox）诱导的心肾合并症小鼠模型，探讨内质网应激在EndMT和EMT中的作用。dox治疗6周后，进行超声心动图、尿液分析和血液检查，并辅以心脏和肾脏组织的免疫荧光和Western blot分析。腹腔注射4-PBA以评估内质网应激抑制对心肾合并症的影响。结果dox给药显著损害了心脏和肾脏功能，伴有明显的纤维化和EndMT、EMT和ER应激标志物的上调。4-PBA治疗可减轻心脏损伤，恢复功能，改善肾脏病变。与体内实验结果一致，Dox激活HUVEC和HK-2细胞的内质网应激，促进间质转化。关键的是，4-PBA在体外抑制了EndMT和EMT，支持内质网应激参与这些过程。结论研究结果表明，Dox主要通过内质网应激介导的EndMT和EMT转换诱导并发心肾功能障碍。重要的是，4-PBA对内质网应激的药理学抑制减轻了这些病理变化，表明其作为心肾综合征治疗策略的潜力。

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引用次数: 0

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