European journal of pharmacology最新文献_第9页

N-(4-methoxyphenyl) quinoline-8-sulfonamide reduces the inflammatory response of fibroblast-like synoviocytes by targeting receptor (calcitonin) activity modifying protein 1 in rheumatoid arthritis N-（4-甲氧基苯基）喹啉-8-磺酰胺通过靶向受体（降钙素）活性修饰蛋白 1 减轻类风湿性关节炎成纤维细胞样滑膜细胞的炎症反应。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-19 DOI: 10.1016/j.ejphar.2024.177064

Ying-Li Yang , Ning Yao , Shang-Qing Ge , Biao Song , Han Xu , Zeng Li , Xiao-Feng Li , Jun Li

Background

Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium of joints. Fibroblast-like synoviocytes (FLS) play an important role in RA pathogenesis. We aimed to investigate the effect of N-(4-methoxyphenyl) quinoline-8-sulfonamide (QS-3g) on the inflammatory response of FLS and explore the potential underlying mechanisms.

Methods

We screened and found that QS-3g exhibits the best anti-inflammatory response against FLS using the CCK8 assay. To investigate the therapeutic effects of QS-3g on K/BxN STA mice, we used H&E staining, immunofluorescence, immunohistochemistry, micro-CT, and other techniques. Additional investigations, including RNA-seq, molecular docking, and CETSA, revealed that QS-3g binds to RAMP1.

Results

Among a series of 8-quinoline sulfonyl amide derivatives, QS-3g reduced the inflammatory response in TNF-α stimulated FLS, such as the release of interleukin (IL)-1β and IL-6. H&E staining and micro-CT showed that QS-3g inhibited synovial hypertrophy, inflammatory cell infiltration, and bone destruction. RNA-seq and CETSA analyses revealed the targeted inhibition of RAMP1 by QS-3g. Inhibition of RAMP1 expression could reduce IL-6 and IL-1β levels. Compared with RAMP1-si, combined administration of QS-3g and RAMP1-si reduced the TNF-α-induced inflammation in TNF-α stimulated FLS without statistically significant differences. Finally, the results of in vitro experiments showed that QS-3g could restore the balance of Gαi/Gαs by inhibiting Gαi and activating Gαs and up-regulate the expression of cAMP protein, thus inhibiting the RAMP1-mediated inflammatory response in FLS.

Conclusion

QS-3g could inhibit RAMP1 activity and mediate the Gαs/Gαi–cAMP pathway to reduce FLS inflammatory response. Therefore, QS-3g may serve as a novel anti-inflammatory compound for treating RA.

背景：类风湿性关节炎（RA类风湿性关节炎（RA）的特征是关节滑膜的慢性炎症。成纤维细胞样滑膜细胞（FLS）在 RA 的发病机制中发挥着重要作用。我们旨在研究N-（4-甲氧基苯基）喹啉-8-磺酰胺（QS-3g）对FLS炎症反应的影响，并探索其潜在的内在机制：我们利用 CCK8 试验筛选并发现 QS-3g 对 FLS 的抗炎反应最佳。为了研究 QS-3g 对 K/BxN STA 小鼠的治疗效果，我们使用了 H&E 染色、免疫荧光、免疫组化、显微 CT 等技术。包括RNA-seq、分子对接和CETSA在内的其他研究发现，QS-3g与RAMP1结合：结果：在一系列 8-喹啉磺酰胺衍生物中，QS-3g 可降低 TNF-α 刺激的 FLS 的炎症反应，如白细胞介素（IL）-1β 和 IL-6 的释放。H&E 染色和显微 CT 显示，QS-3g 可抑制滑膜肥厚、炎症细胞浸润和骨质破坏。RNA-seq 和 CETSA 分析显示，QS-3g 对 RAMP1 有靶向抑制作用。抑制 RAMP1 的表达可降低 IL-6 和 IL-1β 的水平。与RAMP1-si相比，联合使用QS-3g和RAMP1-si可减少TNF-α刺激FLS诱发的炎症，但差异无统计学意义。最后，体外实验结果表明，QS-3g可通过抑制Gαi和激活Gαs来恢复Gαi/Gαs的平衡，并上调cAMP蛋白的表达，从而抑制RAMP1介导的FLS炎症反应：结论：QS-3g 可抑制 RAMP1 的活性，介导 Gαs/Gαi-cAMP 通路，从而减轻 FLS 的炎症反应。因此，QS-3g 可作为治疗 RA 的新型抗炎化合物。

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引用次数: 0

Escin ameliorates CUMS-induced depressive-like behavior via BDNF/TrkB/CREB and TLR4/MyD88/NF-κB signaling pathways in rats Escin可通过BDNF/TrkB/CREB和TLR4/MyD88/NF-κB信号通路改善CUMS诱导的大鼠抑郁样行为。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-18 DOI: 10.1016/j.ejphar.2024.177063

Fengjiao Liu , Yaxin Jia , Liwei Zhao , Li-na Xiao , Xizhen Cheng , Yingying Xiao , Ying Zhang , Yuling Zhang , Huimin Yu , Qiao-en Deng , Yuanyuan Zhang , Yimeng Feng , junfang Wang , Yonggang Gao , Xuan Zhang , Yunyun Geng

Major depressive disorder (MDD) is a prevalent psychiatric disorder associated with brain inflammation and neuronal damage. Derived from the Aesculus chinensis Bunge fruit, escin has shown anti-inflammatory and neuroprotective effects. However, its potential as a treatment for MDD is unclear. This study investigates the antidepressant properties of escin using in vivo experimentation. The chronic unpredictable mild stress (CUMS) model was used to analyze the potential antidepressant effects and underlying mechanisms of escin. Wistar rats were exposed to CUMS for 35 consecutive days to induce MDD. The rats were then given either escin (1, 3, and 10 mg/kg) or fluoxetine (2 mg/kg) on a daily basis. Notably, escin significantly alleviated the depressive behaviors induced by CUMS, as evaluated through a series of behavioral assessments. Moreover, escin administration reduced TNF-α, IL-1β, and IL-6 levels in the hippocampus. It also decreased serum adrenal cortical hormone (ACTH) and corticosterone (CORT) levels while increasing 5-HT and Brain-derived neurotrophic factor (BDNF) levels in the CUMS rats, as measured by the enzyme-linked immunosorbent assay (ELISA). Pathological changes in the hippocampal regions were identified through Nissl staining, and Western blotting was used to quantify the protein levels of BDNF, TrkB, CREB, TLR4, MyD88, and NF-κB. Escin mitigated neuronal injury, elevated TrkB, BDNF, and CREB, and reduced TLR4, MyD88, and NF-κB protein levels in CUMS rats. The data from this study suggest that escin holds the potential for alleviating depression-like symptoms induced by CUMS. This effect may be mediated through the modulation of two signaling pathways, BDNF/TrkB/CREB and TLR4/MyD88/NF-κB.

重度抑郁症（MDD）是一种常见的精神疾病，与脑部炎症和神经元损伤有关。从 Aesculus chinensis Bunge 果实中提取的 escin 具有抗炎和保护神经的作用。然而，它作为 MDD 治疗药物的潜力尚不明确。本研究通过体内实验研究了埃斯京的抗抑郁特性。研究采用了慢性不可预知轻度应激（CUMS）模型来分析埃斯京的潜在抗抑郁作用及其内在机制。将 Wistar 大鼠连续暴露于 CUMS 35 天，以诱发 MDD。然后每天给大鼠服用埃辛（1、3 和 10 毫克/千克）或氟西汀（2 毫克/千克）。值得注意的是，通过一系列行为评估，埃斯京明显减轻了CUMS诱导的抑郁行为。此外，服用埃斯京能降低海马中 TNF-α、IL-1β 和 IL-6 的水平。通过酶联免疫吸附试验（ELISA）测定，它还降低了CUMS大鼠血清肾上腺皮质激素（ACTH）和皮质酮（CORT）的水平，同时提高了5-羟色胺和脑源性神经营养因子（BDNF）的水平。通过 Nissl 染色确定了海马区的病理变化，并用 Western 印迹法量化了 BDNF、TrkB、CREB、TLR4、MyD88 和 NF-κB 的蛋白水平。埃辛减轻了 CUMS 大鼠的神经元损伤，提高了 TrkB、BDNF 和 CREB 的水平，降低了 TLR4、MyD88 和 NF-κB 蛋白水平。这项研究的数据表明，埃斯京有可能减轻 CUMS 诱发的抑郁症状。这种作用可能是通过调节两种信号通路（BDNF/TrkB/CREB 和 TLR4/MyD88/NF-κB）来实现的。

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引用次数: 0

Longikaurin A induces ferroptosis and inhibits glioblastoma progression through DNA methylation - Mediated GPX4 suppression 龙葵素 A 通过 DNA 甲基化介导的 GPX4 抑制作用诱导铁变态反应并抑制胶质母细胞瘤的进展。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-18 DOI: 10.1016/j.ejphar.2024.177061

Xiangrui Meng , Qingqing Yang , Yisu Gao , Yawei Liu , Fang Chen , Wangsen Cao , Guan Sun

Glioblastoma (GBM) is the most common primary intracranial tumor highly resistant to conventional clinical chemotherapy. Recently, the induction of ferroptosis is emerging as a putative strategy to treat various tumors. However, the identification of the effective and applicable tumor ferroptosis-inducing agents remains challenging. In this study, we showed that longikaurin A (LK-A), a natural diterpenoid isolated from the medicinal plant Isodon ternifolius with strong anti-GBM capacities, induced remarkable GBM cell ferroptosis along with suppressing the key anti-ferroptosis factor glutathione peroxidase 4 (GPX4). GPX4 promoter contains conserved CpG islands. The LK-A-induced GPX4 suppression coincided with the inhibition of ten-eleven translocation 2 (TET2), a key DNA demethylation enzyme and an increase in the hypermethylation of the GPX4 promoter. Further, LK-A promoted the GBM ferroptotic alterations and inhibited GBM progression in both subcutaneous and orthotopic xenograft mouse models, whereas GPX4 overexpression largely abrogated its anti-GBM effects both in vitro and in vivo, suggesting that LK-A inductions of the DNA methylation-incurred GPX4 suppression and ferroptosis are crucial for its anti-GBM functions. Together, our study has elaborated an important epigenetic pathway of GBM ferroptosis and uncovered a critical pharmacological property of LK-A for treating GBM patients.

胶质母细胞瘤（GBM）是最常见的原发性颅内肿瘤，对传统的临床化疗高度耐药。最近，诱导铁变态反应正在成为治疗各种肿瘤的一种可能策略。然而，确定有效且适用的肿瘤铁诱导剂仍具有挑战性。在这项研究中，我们发现从药用植物 Isodon ternifolius 中分离出来的天然二萜类化合物 Longikaurin A（LK-A）具有很强的抗 GBM 能力，它能诱导 GBM 细胞显著的铁变态反应，同时抑制关键的抗铁变态反应因子谷胱甘肽过氧化物酶 4（GPX4）。GPX4 启动子含有保守的 CpG 岛。LK-A 诱导的 GPX4 抑制作用与十-十一转位 2（TET2）（一种关键的 DNA 去甲基化酶）的抑制作用和 GPX4 启动子高甲基化的增加相吻合。此外，在皮下和正位异种移植小鼠模型中，LK-A促进了GBM的铁变态改变并抑制了GBM的进展，而GPX4的过表达在很大程度上削弱了其体外和体内的抗GBM作用，这表明LK-A诱导DNA甲基化引起的GPX4抑制和铁变态是其抗GBM功能的关键。总之，我们的研究阐述了 GBM 铁凋亡的一个重要表观遗传学途径，并发现了 LK-A 治疗 GBM 患者的一个关键药理学特性。

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引用次数: 0

Sodium nitrite induces tolerance in the mouse aorta: Involvement of the renin-angiotensin system, nitric oxide synthase, and reactive oxygen species 亚硝酸钠诱导小鼠主动脉的耐受性：肾素-血管紧张素系统、一氧化氮合酶和活性氧的参与。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-18 DOI: 10.1016/j.ejphar.2024.177056

Natalia Ferreira de Araujo , Natalia Ribeiro Cabacinha Nobrega , Daniela Esteves Ferreira dos Reis Costa , Janaina Aparecida Simplicio , Naiara de Assis Rabelo Ribeiro , Carlos Renato Tirapelli , Daniella Bonaventura

Nitrites have emerged as promising therapeutic agents for cardiovascular diseases, alongside nitrates. While chronic use of organic nitrates is well recognized to lead to vascular tolerance, the tolerance associated with nitrite therapy remains incompletely understood. The aim of the present study was to investigate vascular tolerance to sodium nitrite and the underlying molecular mechanisms. Endothelium-denuded aortic rings isolated from male Balb/C mice were incubated with either the EC₅₀ (10⁻⁴ mol/L) or EC₁₀₀ (10⁻² mol/L) concentration of sodium nitrite for 15 min to induce tolerance. The EC₁₀₀ concentration of sodium nitrite induced vascular tolerance. Pre-incubation with captopril and losartan effectively reversed sodium nitrite-induced tolerance. Similarly, pre-incubation with L-NAME and L-arginine prevented sodium nitrite-induced tolerance. Increased levels of reactive oxidative species (ROS) and reduced bioavailability of nitric oxide (NO) were observed in tolerant aortas. Increased superoxide dismutase (SOD) activity and decreased catalase activity were also verified in tolerant aortas. Both captopril and L-NAME prevented the increased levels of ROS observed in tolerant aortas. Furthermore, pre-incubation with catalase effectively prevented sodium nitrite-induced tolerance. Our findings suggest that sodium nitrite induces vascular tolerance through a signaling pathway involving the renin-angiotensin system, nitric oxide synthase, and ROS. This study contributes to the understanding of the interaction between nitrites and vascular tolerance and highlights potential targets to overcome or prevent this phenomenon.

亚硝酸盐与硝酸盐一样，已成为治疗心血管疾病的有前途的药物。虽然长期使用有机硝酸盐会导致血管耐受性，但人们对亚硝酸盐疗法的耐受性仍不甚了解。本研究旨在探讨血管对亚硝酸钠的耐受性及其分子机制。用 EC50（10-4 mol/L）或 EC100（10-2 mol/L）浓度的亚硝酸钠孵育雄性 Balb/C 小鼠 15 分钟，诱导其产生耐受性。EC100 浓度的亚硝酸钠可诱导血管耐受。预孵育卡托普利和洛沙坦能有效逆转亚硝酸钠诱导的耐受性。同样，预孵育 L-NAME 和 L-精氨酸可防止亚硝酸钠诱导的耐受性。在耐受性主动脉中观察到活性氧化物（ROS）水平升高，一氧化氮（NO）的生物利用率降低。耐受性主动脉中的超氧化物歧化酶（SOD）活性增加，过氧化氢酶活性降低。卡托普利和 L-NAME 都能阻止耐受性主动脉中观察到的 ROS 水平升高。此外，预孵育过氧化氢酶可有效防止亚硝酸钠诱导的耐受性。我们的研究结果表明，亚硝酸钠通过涉及肾素-血管紧张素系统、一氧化氮合酶和 ROS 的信号途径诱导血管耐受性。这项研究有助于人们了解亚硝酸盐与血管耐受性之间的相互作用，并突出了克服或预防这种现象的潜在靶点。

{"title":"Sodium nitrite induces tolerance in the mouse aorta: Involvement of the renin-angiotensin system, nitric oxide synthase, and reactive oxygen species","authors":"Natalia Ferreira de Araujo , Natalia Ribeiro Cabacinha Nobrega , Daniela Esteves Ferreira dos Reis Costa , Janaina Aparecida Simplicio , Naiara de Assis Rabelo Ribeiro , Carlos Renato Tirapelli , Daniella Bonaventura","doi":"10.1016/j.ejphar.2024.177056","DOIUrl":"10.1016/j.ejphar.2024.177056","url":null,"abstract":"<div><div>Nitrites have emerged as promising therapeutic agents for cardiovascular diseases, alongside nitrates. While chronic use of organic nitrates is well recognized to lead to vascular tolerance, the tolerance associated with nitrite therapy remains incompletely understood. The aim of the present study was to investigate vascular tolerance to sodium nitrite and the underlying molecular mechanisms. Endothelium-denuded aortic rings isolated from male Balb/C mice were incubated with either the EC<sub>50</sub> (10<sup>−4</sup> mol/L) or EC<sub>100</sub> (10<sup>−2</sup> mol/L) concentration of sodium nitrite for 15 min to induce tolerance. The EC<sub>100</sub> concentration of sodium nitrite induced vascular tolerance. Pre-incubation with captopril and losartan effectively reversed sodium nitrite-induced tolerance. Similarly, pre-incubation with L-NAME and L-arginine prevented sodium nitrite-induced tolerance. Increased levels of reactive oxidative species (ROS) and reduced bioavailability of nitric oxide (NO) were observed in tolerant aortas. Increased superoxide dismutase (SOD) activity and decreased catalase activity were also verified in tolerant aortas. Both captopril and L-NAME prevented the increased levels of ROS observed in tolerant aortas. Furthermore, pre-incubation with catalase effectively prevented sodium nitrite-induced tolerance. Our findings suggest that sodium nitrite induces vascular tolerance through a signaling pathway involving the renin-angiotensin system, nitric oxide synthase, and ROS. This study contributes to the understanding of the interaction between nitrites and vascular tolerance and highlights potential targets to overcome or prevent this phenomenon.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177056"},"PeriodicalIF":4.2,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel prospects in targeting neurodegenerative disorders via autophagy 通过自噬靶向治疗神经退行性疾病的新前景。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-18 DOI: 10.1016/j.ejphar.2024.177060

Shumayila Khan , Saurabh Upadhyay , Md. Imtaiyaz Hassan

Protein aggregation occurs as a consequence of dysfunction in the normal cellular proteostasis, which leads to the accumulation of toxic fibrillar aggregates of certain proteins in the cell. Enhancing the activity of proteolytic pathways may serve as a way of clearing these aggregates in a cell, and consequently, autophagy has surfaced as a promising target for the treatment of neurodegenerative disorders. Several strategies involving small molecule compounds that stimulate autophagic pathway of cell have been discovered. However, despite many compounds having demonstrated favorable outcomes in experimental disease models, the translation of these findings into clinical benefits for patient's remains limited. Consequently, alternative strategies are actively being explored to effectively target neurodegeneration via autophagy modulation. Recently, newer approaches such as modulation of expression of autophagic genes have emerged as novel and interesting areas of research in this field, which hold promising potential in neuroprotection. Similarly, as discussed for the first time in this review, the use of autophagy-inducing nanoparticles by utilizing their physicochemical properties to stimulate the autophagic process, rather than relying on their role as drug carriers, offers a completely fresh avenue for targeting neurodegeneration without the risk of drug-associated adverse effects. This review provides fresh perspectives on developing autophagy-targeted therapies for neurodegenerative disorders. Additionally, it discusses the challenges and impediments of implementing these strategies to alleviate the pathogenesis of neurodegenerative disorders in clinical settings and highlights the prospects and directions of future research in this context.

蛋白质聚集是正常细胞蛋白稳态功能失调的结果，它导致细胞中某些蛋白质有毒的纤维状聚集体的积累。因此，自噬已成为治疗神经退行性疾病的一个很有前景的靶点。目前已经发现了几种涉及小分子化合物的策略，可以刺激细胞的自噬途径。然而，尽管许多化合物在实验性疾病模型中表现出了良好的效果，但将这些研究成果转化为对患者的临床益处仍然有限。因此，人们正在积极探索其他策略，以通过自噬调节来有效治疗神经退行性变。最近，自噬基因表达调控等新方法已成为该领域新颖而有趣的研究领域，在神经保护方面具有广阔的前景。同样，正如本综述首次讨论的那样，利用自噬诱导纳米粒子的理化特性来刺激自噬过程，而不是依赖其作为药物载体的作用，为靶向神经退行性病变提供了一条全新的途径，而且没有药物相关不良反应的风险。本综述为开发针对神经退行性疾病的自噬疗法提供了新的视角。此外，它还讨论了在临床环境中实施这些策略以缓解神经退行性疾病发病机制所面临的挑战和障碍，并强调了在此背景下未来研究的前景和方向。

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引用次数: 0

Polarized macrophage functions are affected differentially after CSF-1R inhibition with PLX5622 使用 PLX5622 抑制 CSF-1R 后，极化巨噬细胞的功能会受到不同程度的影响。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-16 DOI: 10.1016/j.ejphar.2024.177059

Julia Barilo, Nasry Zane Bouzeineddine, Alecco Philippi, Sam Basta

PLX5622 is a colony stimulating factor 1 receptor (CSF-1R) inhibitor that is known to deplete microglial cells in vivo. Recently its effects on macrophages (Mφ) were also observed in vivo. Therefore, we performed this study to assess its in vitro effects on the differentiation and functions of polarized Mφ derived from different tissues. Our findings show that addition of PLX5622 early on after ex vivo isolation hinders Mφ differentiation and survival. However, its addition post Mφ differentiation did not significantly affect the viability. Furthermore, PLX5622 affects certain functions and degree of polarization of IL-4 (M2a) Mφ but not polarization of M1-like Mφ. Our study provides novel aspects on the application of PLX5622 to study Mφ functions in vitro, where polarization is affected by CSF-1R signalling and provides distinctive evidence to its ability to affect certain populations of Mφ during in vitro differentiation and maturation.

PLX5622 是一种集落刺激因子 1 受体（CSF-1R）抑制剂，已知可在体内消耗小胶质细胞。最近在体内也观察到了它对巨噬细胞（Mφ）的影响。因此，我们进行了这项研究，以评估它在体外对来自不同组织的极化 Mφ 的分化和功能的影响。我们的研究结果表明，在体内外分离后早期加入 PLX5622 会阻碍 Mφ 的分化和存活。然而，在 Mφ 分化后添加 PLX5622 对其存活率并无明显影响。此外，PLX5622 会影响 IL-4（M2a）Mφ 的某些功能和极化程度，但不会影响 M1 样 Mφ 的极化。我们的研究为应用 PLX5622 研究 Mφ 在体外的功能（极化受 CSF-1R 信号的影响）提供了新的视角，并为 PLX5622 在体外分化和成熟过程中影响特定 Mφ 群体的能力提供了独特的证据。

引用次数: 0

Low-dose treatment with Epirubicin, a novel histone deacetylase 1 inhibitor, exerts anti-leukemic effects by inducing ferroptosis 新型组蛋白去乙酰化酶 1 抑制剂表柔比星的低剂量治疗可通过诱导铁变态反应发挥抗白血病作用

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-14 DOI: 10.1016/j.ejphar.2024.177058

Guancui Yang , Shijie Yang , Jiarun Li , Peijie Jiang , Xiaolong Tian , Xiaoqi Wang , Jin Wei , Xi Zhang , Jinyi Liu

Aims

Leukemia is hematopoietic stem cell malignant tumor with poor outcomes. Histone deacetylase 1 (HDAC1) is highly expressed in leukemia and current HDAC1 inhibitors have clinical limitations in leukemia therapy. Therefore, novel HDAC1 inhibitor is imperative to being found and its mechanism needs to be further explored.

Materials and methods

Novel HDAC1 inhibitors were discovered through drug virtual screening. CCK-8, EdU and soft agar assay were used to assess the anti-leukemic effect of the candidate HDAC1 inhibitor. ROS, lipid peroxidation, intracellular Fe²⁺ and LIP assay were employed to verify cell ferroptosis. Additionally, a xenograft model was performed to explore the efficacy and safety of the candidate HDAC1 inhibitor in vivo.

Results

HDAC1 might be a promising therapeutic target for leukemia and Epirubicin (Epi) could be used as a potential HDAC1 inhibitor. Low-dose Epi exhibited good anti-leukemic effects by inhibiting cell proliferation, DNA synthesis and colony formation. Low-dose Epi could induce ferroptosis by triggering lipid peroxidation, which was better than that treated with current HDAC1 inhibitors Chidamide or Vorinostat, ROS generation and Fe²⁺ overload in leukemia cells. Mechanistically, low-dose Epi induced ferroptosis by targeting amino acid metabolism and iron metabolism. Similar results were found in a xenograft model in NOG mice with a good safety profile.

Conclusion

Our study demonstrated that Epi might be used as a HDAC1 inhibitor. Low-dose Epi could inhibit tumor progression by inducing cell ferroptosis in vitro and in vivo. Thus, Epi administration with lower concentration may be much more favorable and safer in the treatment with leukemia.

目的：白血病是一种预后不良的造血干细胞恶性肿瘤。组蛋白去乙酰化酶 1（HDAC1）在白血病中高度表达，目前的 HDAC1 抑制剂在白血病治疗中存在临床局限性。因此，寻找新型 HDAC1 抑制剂势在必行，其作用机制也有待进一步探索：通过药物虚拟筛选发现新型 HDAC1 抑制剂。采用 CCK-8、EdU 和软琼脂试验评估候选 HDAC1 抑制剂的抗白血病效果。ROS、脂质过氧化反应、细胞内 Fe2+ 和 LIP 检测被用来验证细胞的铁变态反应。此外，还通过异种移植模型探讨候选 HDAC1 抑制剂在体内的有效性和安全性：结果：HDAC1可能是白血病的治疗靶点，表柔比星（Epi）可作为潜在的HDAC1抑制剂。小剂量 Epi 通过抑制细胞增殖、DNA 合成和集落形成，表现出良好的抗白血病作用。小剂量Epi能通过引发脂质过氧化诱导铁变态反应，其效果优于目前的HDAC1抑制剂奇达姆或伏立诺他，并能抑制白血病细胞ROS生成和Fe2+过载。从机理上讲，低剂量 Epi 通过靶向氨基酸代谢和铁代谢诱导铁变态反应。在NOG小鼠的异种移植模型中也发现了类似的结果，而且安全性良好：我们的研究表明，Epi可用作HDAC1抑制剂。结论：我们的研究表明，Epi可作为一种HDAC1抑制剂，低剂量Epi可通过诱导体外和体内的细胞铁变态反应抑制肿瘤进展。因此，低浓度 Epi 对白血病的治疗更为有利和安全。

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引用次数: 0

Captopril inhibits the overproduction of proopiomelanocortin and adrenocorticotropic hormone in the pituitary gland of male diabetic mice in close relationship with an increase in glucocorticoid receptor expression 卡托普利可抑制雄性糖尿病小鼠垂体中原绒毛膜促皮质素和促肾上腺皮质激素的过度分泌，这与糖皮质激素受体表达的增加密切相关。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-11 DOI: 10.1016/j.ejphar.2024.177057

Amanda da Silva Chaves , Nathalia Santos Magalhães , Daniella Bianchi Reis Insuela , Patrícia Machado Rodrigues e Silva , Marco Aurélio Martins , Vinicius Frias Carvalho

Prior investigation shows that diabetic patients present hypothalamus-pituitary-adrenal (HPA) axis hyperactivity related to impaired negative feedback. This study investigates the effect of Captopril on the overproduction of adrenocorticotropic hormone (ACTH) and its precursor proopiomelanocortin (POMC) in the pituitary gland of male diabetic mice. Diabetes was induced by intravenous injection of alloxan into fasted Swiss-webster mice, and the animals were treated with Captopril for 14 consecutive days, starting 7 days post-diabetes induction. Plasma corticosterone levels were evaluated by ELISA, while pituitary gland expressions of angiotensin-II type 1 receptor (AT₁), angiotensin-II type 2 receptor (AT₂), ACTH, Bax, Bcl-2, KI-67, POMC, and glucocorticoid receptor (GR) were evaluated using immunohistochemistry or Western blot. Diabetic mice showed pituitary gland overexpression of AT₁, without altering AT₂ levels, which were sensitive to Captopril treatment. Furthermore, diabetic mice presented hypercortisolism, along with an increase in the number of corticotroph cells, POMC and ACTH expression, and number of proliferative cells, and a decrease of GR expression in the pituitary gland. In addition, treatment with Captopril reduced systemic corticosterone levels, corticotroph and proliferative cell numbers, and Bcl-2, POMC, and ACTH expression in the pituitary gland of diabetic mice, besides increasing the expression of Bax and GR. In conclusion, these findings show that Captopril is a promising therapy for treating complications associated with HPA axis hyperactivity in diabetic patients, in a mechanism probably related to the downregulation of POMC production in the pituitary gland and subsequent reduction of systemic corticosterone levels.

先前的调查显示，糖尿病患者的下丘脑-垂体-肾上腺（HPA）轴活动亢进与负反馈受损有关。本研究探讨了卡托普利对雄性糖尿病小鼠垂体促肾上腺皮质激素（ACTH）及其前体促绒毛膜促皮质素（POMC）过度分泌的影响。通过向禁食的瑞士鼬鼠静脉注射阿脲诱导糖尿病，并从糖尿病诱导后 7 天开始连续 14 天使用卡托普利治疗动物。血浆皮质酮水平通过酶联免疫吸附进行评估，垂体血管紧张素-II 1型受体（AT1）、血管紧张素-II 2型受体（AT2）、促肾上腺皮质激素（ACTH）、Bax、Bcl-2、KI-67、POMC和糖皮质激素受体（GR）的表达则通过免疫组化或Western印迹进行评估。糖尿病小鼠垂体AT1过度表达，而AT2水平没有改变，对卡托普利治疗敏感。此外，糖尿病小鼠出现皮质醇过多症，同时垂体中的皮质营养细胞数量、POMC 和 ACTH 表达、增殖细胞数量增加，GR 表达减少。此外，使用卡托普利治疗可降低全身皮质酮水平、促肾上腺皮质激素细胞和增殖细胞数量，以及糖尿病小鼠垂体中 Bcl-2、POMC 和 ACTH 的表达，此外还可增加 Bax 和 GR 的表达。总之，这些研究结果表明，卡托普利是一种治疗糖尿病患者 HPA 轴亢进相关并发症的有效疗法，其机制可能与下调垂体中 POMC 的分泌以及随后降低全身皮质酮水平有关。

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引用次数: 0

Impact of neonatal hyperoxia on adult cardiac autonomic function in rats: Role of angiotensin II type 1 receptor activation 新生儿高氧对大鼠成年心脏自主神经功能的影响：血管紧张素 II 1 型受体激活的作用

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-11 DOI: 10.1016/j.ejphar.2024.177026

Jéssica Hellen Poletto Bonetto , Alyson Deprez , Daniele Wolf , Rafael Oliveira Fernandes , Karina Casali , Aurélie Sonea , Adrien Flahault , Marina Siqueira Flores , Ying He , Adriane Belló-Klein , Daniela Ravizzoni Dartora , Anne Monique Nuyt

Individuals born preterm present altered cardiac autonomic function, a risk factor to heart diseases. Neonatal renin-angiotensin-system activation contributes to adult cardiomyopathy in rats exposed to neonatal hyperoxia, a well-established model of preterm birth-related conditions. Central angiotensin II receptor activation is a key modulator of the autonomic drive to the heart. Whether neonatal hyperoxia leads to alteration of the cardiac autonomic function through activation of the angiotensin II receptor type 1 (AT1) is unknown and was examined in the present study.

Sprague-Dawley pups were exposed to hyperoxia or room air from postnatal days 3–10. AT1 antagonist losartan or water was given orally postnatal days 8–10. Blood pressure, autonomic function, left ventricular sympathetic innervation, β-adrenergic-receptors expression, and AT1 expression in the solitary-tract-nucleus were examined in adult rats.

Neonatal hyperoxia led to loss of day-night blood pressure variation, decreased heart rate variability, increased sympathovagal balance, increased AT1 expression in the solitary-tract, decreased left ventricle sympathetic innervation, and increased β1-adrenergic-receptor protein expression. Losartan prevented the autonomic changes and AT1 expression in the solitary-tract but did not impact the loss of circadian blood pressure variation nor the changes in sympathetic innervation and in β1-adrenergic-receptor expression.

In conclusion, neonatal hyperoxia leads to both central autonomic and cardiac sympathetic changes, partly programmed by neonatal activation of the renin-angiotensin system.

早产儿的心脏自主神经功能会发生改变，这是导致心脏病的一个危险因素。新生儿肾素-血管紧张素系统活化是导致大鼠患上成人心肌病的原因。中枢血管紧张素 II 受体激活是心脏自律神经驱动的一个关键调节器。新生儿高氧是否会通过激活血管紧张素 II 受体 1 型（AT1）而导致心脏自主神经功能的改变尚不清楚，本研究对此进行了研究。出生后第 8-10 天口服 AT1 拮抗剂洛沙坦或水。对成年大鼠的血压、自律神经功能、左心室交感神经支配、β肾上腺素能受体表达以及孤束核中AT1的表达进行了检测。新生儿高氧导致昼夜血压变化消失、心率变异性降低、交感-迷走平衡增加、孤束核中AT1表达增加、左心室交感神经支配减少以及β1肾上腺素能受体蛋白表达增加。总之，新生儿高氧会导致中枢自律神经和心脏交感神经的变化，其中部分原因是新生儿肾素-血管紧张素系统的激活。

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引用次数: 0

Anti-nociceptive effects of non-antibiotic derivatives of demeclocycline and doxycycline against formalin-induced pain stimulation 去甲环素和强力霉素的非抗生素衍生物对福尔马林引起的疼痛刺激的抗痛觉作用。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-10 DOI: 10.1016/j.ejphar.2024.177054

Glauce Crivelaro Nascimento , Airam Nicole Vivanco-Estela , Laurent Ferrié , Bruno Figadere , Rita Raisman-Vozari , Patrick Pierre Michel , Elaine Del Bel

In previous studies, some tetracycline (TC) antibiotics showed potential as analgesic. We investigated here the analgesic activity of new non-antibiotic TC derivatives using the formalin-induced nociceptive pain model in adult C57BL/6 mice. Specifically, we tested the effects of i.p. injections of DDMC (5, 10, 20 mg kg⁻¹) and DDOX (10, 20, 40 mg kg⁻¹), which are non-antibiotic derivatives of demeclocycline and doxycycline, respectively. Repeated treatments with DDMC remarkably reduced nociceptive pain in both phases of the test, at 10 mg kg⁻¹ its efficacy was comparable to that of 10 mg kg⁻¹ of morphine. DDOX was also effective in this paradigm but intrinsically less potent than DDMC, exerting analgesic effects between 20 and 40 mg kg⁻¹. Interestingly, a single injection of DDMC (10 mg kg⁻¹) was sufficient to produce a robust anti-nociceptive effect similar to that of morphine. A single injection of DDOX (40 mg kg⁻¹) also produced anti-nociceptive effects but only in the second phase of the test. Noticeably, male mice exhibited a better analgesic response to DDMC (10 mg kg⁻¹) than females. A single injection of DDMC (10 mg kg⁻¹) and morphine but not of DDOX (40 mg kg⁻¹), powerfully inhibited formalin-induced spinal cord c-Fos expression whereas both TC derivatives restrained the activation of Iba-1-immunoreactive cells, indicating a potential indirect effect on inflamed microglial cells. In summary, the non-antibiotic TCs, DDMC and DDOX, demonstrated notable analgesic efficacy against formalin-induced pain, suggesting their potential as alternatives for analgesic treatment.

在以前的研究中，一些四环素（TC）抗生素显示出镇痛潜力。在此，我们利用福尔马林诱导的成年 C57BL/6 小鼠痛觉模型，研究了新型非抗生素 TC 衍生物的镇痛活性。具体来说，我们测试了静注 DDMC（5、10、20 mg.kg-1）和 DDOX（10、20、40 mg.kg-1）的效果，它们分别是去甲环素和多西环素的非抗生素衍生物。在两个阶段的试验中，重复使用 DDMC 都能显著减轻痛觉疼痛，10 毫克/千克的疗效与 10 毫克/千克吗啡相当。DDOX 在这一范例中也有效，但内在效力低于 DDMC，其镇痛效果介于 20 至 40 毫克/千克-1 之间。有趣的是，单次注射 DDMC（10 毫克/千克）足以产生与吗啡相似的强效抗痛觉效应。单次注射 DDOX（40 毫克/千克-1）也能产生抗痛觉作用，但只在试验的第二阶段。值得注意的是，雄性小鼠对 DDMC（10 毫克/千克）的镇痛反应优于雌性小鼠。单次注射 DDMC（10 毫克/千克-1）和吗啡（而不是 DDOX（40 毫克/千克-1））可有效抑制福尔马林诱导的脊髓 c-Fos 表达，而这两种 TC 衍生物都能抑制 Iba-1 免疫反应细胞的活化，这表明它们对发炎的小胶质细胞有潜在的间接影响。总之，DDMC 和 DDOX 这两种非抗生素类三氯乙酸对福尔马林引起的疼痛具有显著的镇痛效果，表明它们有可能成为镇痛治疗的替代品。

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引用次数: 0