European journal of pharmacology最新文献_第10页

Pre-treated mesenchymal stem cell-derived exosomes: A new perspective for accelerating spinal cord injury repair

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.ejphar.2025.177349

Zhiqiang Liao , Junjian Zeng , Aiqing Lin , Yu Zou , Zhidong Zhou

Spinal cord injury (SCI) is a devastating event for the central nervous system (CNS), often resulting in the loss of sensory and motor functions. It profoundly affects both the physiological and psychological well-being of patients, reducing their quality of life while also imposing significant economic pressure on families and the healthcare system. Due to the complex pathophysiology of SCI, effective treatments for promoting recovery remain scarce. Mesenchymal stem cell-derived exosomes (MSC-Exos) offer advantages such as low immunogenicity, good biocompatibility, and the ability to cross the blood-spinal cord barrier (BSCB). In preclinical studies, they have progressively shown efficacy in promoting SCI repair and functional recovery. However, the low yield and insufficient targeting of MSC-Exos limit their therapeutic efficacy. Currently, genetic engineering and other preprocessing techniques are being employed to optimize both the yield and functional properties of exosomes, thereby enhancing their therapeutic potential. Therefore, this paper provides an overview of the pathophysiology of SCI and the biogenesis of exosomes. It also summarizes current approaches to optimizing exosome performance. Additionally, it details the mechanisms through which optimized exosomes provide neuroprotection and explores the potential of combined treatments involving MSC-Exos and hydrogels.

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引用次数: 0

Experimental study on the inhibitory effect of Halofuginone on NSCLC Halofuginone对NSCLC抑制作用的实验研究。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.ejphar.2024.177221

Yuehua Han , Shiyao Liu , Juan Zhu , Peipei Liu , Zixuan Meng , Yongping Li , Shanshan Li , Fangtian Fan , Mengxiao Zhang , Hao Liu

In recent decades, significant advancements have been achieved in non-small cell lung cancer (NSCLC) treatment. However, drug resistance, postoperative recurrence, distant metastasis, and other critical issues arise during NSCLC treatment. Natural products play a crucial role in the development of anti-tumor drugs. Halofuginone (HF) is a derivative of Febrifugine, an extract of Dichroa febrifuga Lour, a traditional Chinese medicine. Recent studies on HF have demonstrated its antitumor activity and great potential for clinical applications. However, its antitumor effects and mechanisms in NSCLC remain unknown. This study aimed to elucidate the antitumor effect of HF on NSCLC and preliminarily explore its mechanism of action. The proliferation-related assay revealed that HF could inhibit the proliferation of lung adenocarcinoma cells HCC827 and H1975. Network pharmacology of HF and NSCLC indicated that HF could induce cellular oxidative stress, and the antitumor effect was related to autophagy, apoptosis, and cell cycle arrest. Experimental analysis using flow cytometry and western blotting confirmed that HF indeed induced autophagy, enhanced apoptosis, and caused cell cycle arrest. The addition of N-acetyl-cysteamine acid inhibits the HF-induced increase in reactive oxygen species levels, inhibits autophagy and apoptosis, and alters cell cycle distribution. The HCC827 transplantation tumor animal model established that HF substantially inhibited the growth of transplanted tumors. These findings suggest that HF exerts a significant inhibitory effect on NSCLC in vivo and in vitro. The inhibitory effect of HF on NSCLC was associated with the increase of ROS in tumor cells, induction of autophagy and apoptosis, and cell cycle arrest.

近几十年来，非小细胞肺癌（NSCLC）的治疗取得了重大进展。然而，在非小细胞肺癌治疗过程中出现了耐药性、术后复发、远处转移和其他关键问题。天然产物在抗肿瘤药物的开发中起着至关重要的作用。Halofuginone （HF）是一种衍生品，它是一种中药白桦（dicroa febrifuga Lour）的提取物。近年来的研究表明，心衰具有良好的抗肿瘤活性和巨大的临床应用潜力。然而，其在非小细胞肺癌中的抗肿瘤作用和机制尚不清楚。本研究旨在阐明HF对NSCLC的抗肿瘤作用，并初步探讨其作用机制。增殖相关实验显示HF能抑制肺腺癌细胞HCC827和H1975的增殖。HF和NSCLC的网络药理学研究表明，HF可诱导细胞氧化应激，其抗肿瘤作用与自噬、凋亡和细胞周期阻滞有关。流式细胞术和western blotting实验分析证实，HF确实诱导细胞自噬，增强细胞凋亡，导致细胞周期阻滞。添加n -乙酰半胱胺可抑制hf诱导的活性氧水平升高，抑制自噬和凋亡，改变细胞周期分布。HCC827移植肿瘤动物模型的建立表明，HF能明显抑制移植肿瘤的生长。这些结果表明，HF在体内和体外均对NSCLC有明显的抑制作用。HF对NSCLC的抑制作用与肿瘤细胞中ROS的增加、诱导自噬和凋亡、细胞周期阻滞有关。

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引用次数: 0

Deciphering TGF-β1's role in drug resistance and leveraging plant bioactives for cancer therapy 解读TGF-β1在耐药中的作用并利用植物生物活性物治疗癌症。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.ejphar.2024.177218

Vishal Kumar Deb, Nidhi Chauhan, Utkarsh Jain

The intricate regulatory mechanisms governing TGF-β1 expression play pivotal roles in tumor progression. Key proteins such as FKBP1A, SMAD6, and SMAD7 trigger this process, modulating cell growth inhibition via p15INK4b and p21CIP1 induction. Despite TGF-β′s tumor-suppressive functions, cancer cells adeptly evade its effects, fueling disease advancement. Tumor microenvironmental TGF-β1 prompts epithelial-mesenchymal transition (EMT), facilitated by transcription factors like slug, twist-1, and snail. Notably, cancer-associated fibroblasts (CAFs) amplify this effect by secreting TGF-β1, fostering drug resistance. Of particular concern is the resistance observed with BRAF/MEK inhibitors (BRAFi/MEKi), highlighting the clinical significance of TGF-β signaling in cancer therapeutics. However, emerging interest in natural anti-cancer agents, with their distinct pharmacological actions on signaling proteins offers promising avenues for therapeutic intervention. This review emphasizes the multifaceted interplay between TGF-β signaling, tumor microenvironment dynamics, and therapeutic resistance mechanisms, illuminating potential targets for combating cancer progression by plant-derived-natural-bioactive compounds. However, this review additionally explores the currently available advanced methods for detecting various types of cancer. Not only that, but it also discussed the function of plant-derived compounds in clinical aspects, as well as its limitations.

TGF-β1表达的复杂调控机制在肿瘤进展中起关键作用。FKBP1A、SMAD6和SMAD7等关键蛋白触发这一过程，通过p15INK4b和p21CIP1诱导调节细胞生长抑制。尽管TGF-β具有肿瘤抑制功能，但癌细胞熟练地逃避其作用，加速疾病进展。肿瘤微环境TGF-β1促进上皮-间质转化（EMT），由slug、twist-1和snail等转录因子促进。值得注意的是，癌症相关成纤维细胞（CAFs）通过分泌TGF-β1增强这种作用，促进耐药性。特别值得关注的是BRAF/MEK抑制剂（BRAFi/MEKi）的耐药性，这突出了TGF-β信号在癌症治疗中的临床意义。然而，人们对天然抗癌药物的兴趣日益浓厚，它们对信号蛋白具有独特的药理作用，为治疗干预提供了有希望的途径。本综述强调了TGF-β信号、肿瘤微环境动力学和治疗耐药机制之间的多方面相互作用，阐明了天然生物活性化合物对抗癌症进展的潜在靶点。然而，这篇综述还探讨了目前可用的检测各种类型癌症的先进方法。不仅如此，还讨论了植物源性化合物在临床方面的功能，以及其局限性。

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引用次数: 0

Harmine-induced disruption of the blood-brain barrier via excessive mitophagy in zebrafish 大麻碱通过斑马鱼过度自噬诱导血脑屏障的破坏。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.ejphar.2024.177223

Yi Wu , Menghui He , Ying He, Tingting Jin, Siju Li, Feng He

Stroke is a serious condition with sudden onset, high severity, and significant rates of mortality and disability, ranking as the second leading cause of death globally at 11.6%. Hemorrhagic stroke, characterized by non-traumatic rupture of cerebral vessels, can cause secondary brain injury such as neurotoxicity, inflammation, reactive oxygen species, and blood-brain barrier (BBB) damage. The integrity of the BBB plays a crucial role in stroke outcomes, as its disruption can exacerbate injury. Harmine, a natural β-carboline alkaloid, has been studied for various pharmacological effects, including its potential benefits in protecting cardiac and cognitive functions. However, its impact on cerebrovascular conditions, particularly in the context of stroke, remains underexplored. This study investigates harmine’s effects on BBB integrity and its role in inducing cerebral hemorrhage in zebrafish. We found that harmine disrupts BBB permeability, leading to cerebral hemorrhage through modulation of tight junction protein Claudin-5 and cytoskeletal protein F-actin expression. Furthermore, harmine altered mitochondrial morphology, causing structural imbalance, excessive mitophagy, and cell death. Together, these data indicate that harmine can induce BBB damage and intracerebral hemorrhage in zebrafish, and provide a possible mechanism and explanation for this effect.

中风是一种突发、严重程度高、死亡率和致残率高的严重疾病，是全球第二大死亡原因，占11.6%。出血性中风以非创伤性脑血管破裂为特征，可引起继发性脑损伤，如神经毒性、炎症、活性氧和血脑屏障（BBB）损伤。血脑屏障的完整性在卒中预后中起着至关重要的作用，因为血脑屏障的破坏会加剧损伤。鼠碱是一种天然的β-碳碱生物碱，其药理作用已被研究，包括其在保护心脏和认知功能方面的潜在益处。然而，它对脑血管疾病的影响，特别是在中风的情况下，仍未得到充分探讨。本研究探讨了伤害碱对斑马鱼血脑屏障完整性的影响及其在诱导脑出血中的作用。我们发现，毒芹碱破坏血脑屏障的通透性，通过调节紧密连接蛋白cludin -5和细胞骨架蛋白F-actin的表达导致脑出血。此外，有害生物碱改变线粒体形态，导致结构失衡、线粒体过度自噬和细胞死亡。综上所述，这些数据表明，害人碱可诱导斑马鱼血脑屏障损伤和脑出血，并提供了可能的机制和解释。

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引用次数: 0

Andrographolide mitigates neurotoxicity induced by lipopolysaccharide or amyloid-β through modulation of miR-222-mediated p62 and NF-κBp65 expression 穿心莲内酯通过调节mir -222介导的p62和NF-κBp65的表达，减轻脂多糖或淀粉样蛋白诱导的神经毒性。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.ejphar.2024.177224

Can Wang, Jiayi Liu, Miao Zheng, Min Hu, Qin Li, Xinyue Zhang, Lili Gu

MicroRNA-222 (miR-222) plays a crucial role in neurodegeneration and is up-regulated in Alzheimer's disease (AD) patients. Andrographolide (Andro) has been reported to have anti-inflammatory and neuroprotective effects, showing potential for treating AD. The relationship between Andro's anti-AD mechanism and the regulation of miR-222 was discussed in this study. Andro protected against cytotoxicity induced by lipopolysaccharide (LPS) or amyloid-β, accompanied by upregulating p62 and Nrf2 mRNA and protein, downregulating TLR4 and NF-κBp65 mRNA and protein, and increasing LC3Ⅱ protein in vitro. miRNA and mRNA sequencing results showed that Andro downregulated miR-222 and upregulated sqstm1/p62. Andro was observed to inhibit the expression of miR-222 and the phosphorylation of NF-κBp65, while simultaneously enhancing the levels of p62 and LC3Ⅱ proteins, decreasing Aβ levels, and attenuating the release of inflammatory factors in the 3xTg-AD mice. MiR-222 mimic increased NF-κBp65 mRNA and protein levels in LPS-induced cells, while miR-222 inhibitors increased p62 mRNA and protein levels as well as Nrf2 and LC3Ⅱ protein, and decreased p-NF-κBp65 protein level in LPS-induced cells. Furthermore, miR-222 mimic reversed the increase in p62 and LC3Ⅱ protein and the decrease in NF-κBp65 mRNA and protein, as well as the decrease in Tau protein levels induced by Andro in LPS-induced cells. These findings suggest that Andro plays a neuroprotective role through downregulation of miR-222 to promote p62 expression while inhibiting NF-kB p65 expression, providing new insights into the mechanism of action of Andro for treating AD.

MicroRNA-222 （miR-222）在阿尔茨海默病（AD）患者的神经退行性变中起着至关重要的作用。据报道穿心术内酯（Andrographolide, Andro）具有抗炎和神经保护作用，显示出治疗AD的潜力。本研究探讨了Andro抗ad机制与miR-222调控之间的关系。对脂多糖（LPS）或淀粉样蛋白诱导的细胞毒性有保护作用，同时上调p62和Nrf2 mRNA和蛋白，下调TLR4和NF-κBp65 mRNA和蛋白，上调LC3Ⅱ蛋白。miRNA和mRNA测序结果显示，Andro下调miR-222，上调sqstm1/p62。在3XTg-AD小鼠中，观察到Andro可以抑制miR-222的表达和NF-κBp65的磷酸化，同时提高P62和LC3II/I蛋白水平，降低Aβ水平，减轻炎症因子的释放。MiR-222模拟物增加了lps诱导细胞中NF-κBp65 mRNA和蛋白水平，MiR-222抑制剂增加了lps诱导细胞中p62 mRNA和蛋白水平以及Nrf2和LC3Ⅱ蛋白水平，降低了p-NF-κBp65蛋白水平。此外，miR-222模拟物逆转了lps诱导的细胞中p62和LC3Ⅱ蛋白的升高，NF-κBp65 mRNA和蛋白的降低，以及Andro诱导的Tau蛋白水平的降低。这些发现提示，Andro通过下调miR-222促进p62表达，抑制NF-kB p65表达，发挥神经保护作用，为Andro治疗AD的作用机制提供了新的认识。

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引用次数: 0

Pyr3 inhibits cell viability and PKCα activity to suppress migration in human bladder cancer cells Pyr3通过抑制细胞活力和PKCα活性抑制人膀胱癌细胞的迁移。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.ejphar.2024.177235

Hui-Kung Ting , Yi-Chien Dou , Yi-Hsuan Lin , Tzu-Min Chen , Yu-Ling Tsai , Wen-Chiuan Tsai , Sheng-Tang Wu , Ying Chen

Bladder cancer, more prevalent in men, has high recurrence rates in non-muscle-invasive forms and is highly lethal upon metastasis in muscle-invasive cases. Transient receptor potential canonical channels (TRPCs), specifically TRPC3, play a role in calcium signaling, influencing cancer cell behavior. This study examines the effects of Pyr3, a TRPC3 inhibitor, and TRPC3 knockdown on both muscle-invasive (T24) and non-muscle-invasive (RT4) bladder cancer cells. Pyr3 treatment reduced cell viability, migration, adhesion, and calcium influx in these cells. Additionally, Pyr3 treatment and siTRPC3 downregulated protein kinase C alpha (PKCα), phospho-PKCα, and protein phosphatase 2A (PP2A) levels. While PKC activator phorbol 12-myristate 13-acetate (PMA) could not restore Pyr3-induced viability loss, it reversed the migration inhibition. In a xenograft model, Pyr3 suppressed T24 cell viability, Ki67, phospho-PKCα, PP2A and TRPC3 expression. These findings suggest that Pyr3 inhibits bladder cancer cell migration through PKC signaling and holds potential as a therapeutic agent for bladder cancer.

膀胱癌多见于男性，非肌肉侵袭性膀胱癌有很高的复发率，而肌肉侵袭性膀胱癌的转移是高度致命的。瞬时受体电位规范通道（Transient receptor potential canonical channels, trpc），特别是TRPC3，在钙信号传导中发挥作用，影响癌细胞行为。本研究探讨了Pyr3（一种TRPC3抑制剂）和TRPC3敲低对肌肉侵袭性（T24）和非肌肉侵袭性（RT4）膀胱癌细胞的影响。Pyr3处理降低了这些细胞的活力、迁移、粘附和钙内流。此外，Pyr3处理和siTRPC3下调蛋白激酶Cα (PKCα)、磷酸化PKCα和蛋白磷酸酶2A （PP2A）水平。PKC激活剂phorbol 12-肉豆蔻酸酯13-乙酸酯（PMA）不能恢复pyr3诱导的活力丧失，但可以逆转迁移抑制。在异种移植模型中，Pyr3抑制T24细胞活力、Ki67、磷酸化pkc α、PP2A和TRPC3的表达。这些发现表明Pyr3通过PKC信号抑制膀胱癌细胞的迁移，并具有作为膀胱癌治疗剂的潜力。

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引用次数: 0

Vodobatinib overcomes cancer multidrug resistance by attenuating the drug efflux function of ABCB1 and ABCG2 Vodobatinib通过减弱ABCB1和ABCG2的药物外排功能来克服癌症多药耐药。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.ejphar.2024.177231

Yen-Ching Li , Bing-Huan Lin , Megumi Murakami , Yu-Shan Wu , Tai-Ho Hung , Chin-Chuan Chen , Suresh V. Ambudkar , Chung-Pu Wu

Multidrug resistance (MDR) remains a significant obstacle in cancer treatment, primarily attributable to the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2 within cancer cells. These transporters actively diminish the effectiveness of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux, thereby reducing intracellular drug accumulation. Given the absence of approved treatments for multidrug-resistant cancers and the established benefits of combining tyrosine kinase inhibitors (TKIs) with conventional anticancer drugs, we investigate the potential of vodobatinib, a potent c-Abl TKI presently in clinical trials, to restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells overexpressing ABCB1 and ABCG2. Results indicate that vodobatinib, administered at sub-toxic concentrations, effectively restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. Moreover, vodobatinib enhances drug-induced apoptosis in these cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, while maintaining their expression levels. Moreover, we found that while vodobatinib enhances the ATPase activity of ABCB1 and ABCG2, the overexpression of these transporters does not induce resistance to vodobatinib. These results strongly suggest that increased levels of ABCB1 or ABCG2 are unlikely to play a significant role in the development of resistance to vodobatinib in cancer patients. Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach.

多药耐药（MDR）仍然是癌症治疗的一个重要障碍，主要是由于癌细胞内atp结合盒（ABC）转运体如ABCB1和ABCG2的过度表达。这些转运体通过促进ATP水解依赖的药物外排，从而减少细胞内药物积累，从而主动降低细胞毒性药物的有效性。鉴于缺乏针对多药耐药癌症的批准治疗方法，以及酪氨酸激酶抑制剂（TKIs）与常规抗癌药物联合使用的既定益处，我们研究了vodobatinib（一种目前处于临床试验中的强效c-Abl TKI）在过度表达ABCB1和ABCG2的多药耐药癌细胞中恢复对化疗药物敏感性的潜力。结果表明，以亚毒性浓度给药的伏多巴替尼可以有效地恢复多药耐药癌细胞对细胞毒性药物的敏感性，并呈浓度依赖性。此外，vodobatinib通过抑制ABCB1和ABCG2的药物外排功能，在维持其表达水平的同时，增强了这些细胞中药物诱导的凋亡。此外，我们发现虽然vodobatinib增强了ABCB1和ABCG2的atp酶活性，但这些转运体的过表达不会诱导对vodobatinib的抗性。这些结果强烈表明，ABCB1或ABCG2水平的升高不太可能在癌症患者对沃多巴替尼的耐药发展中发挥重要作用。总的来说，我们的研究结果揭示了vodobatinib对ABCB1和ABCG2活性的额外药理学方面，表明它可能结合到以高ABCB1或ABCG2水平为特征的肿瘤患者的特定亚群的联合治疗中。需要进一步的研究来充分阐明这种治疗方法的临床意义。

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引用次数: 0

Klotho supplementation decreases blood pressure and albuminuria in mice with lupus nephritis Klotho补充剂降低狼疮肾炎小鼠的血压和蛋白尿。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.ejphar.2024.177229

Tsuneo Takenaka , Hiroyuki Kobori , Yoshifumi Kurosaki , Naohito Ishii , Tsutomu Inoue , Toshiaki Miyazaki , Hiromichi Suzuki , Arif Hasan , Akira Nishiyama , Matsuhiko Hayashi

Klotho deficiency is prevalent in various chronic kidney diseases. Although klotho is known to bind transforming growth factor β (TGFβ) receptor 1 to antagonize renal fibrosis, TGFβ also maintains regulatory T cells with inducing forkhead box protein P3 (FOXP3). Female New Zealand Black/White F₁ (NZBWF1) mice were divided into two groups (n = 10 for each): one group was treated with daily subcutaneous injection of klotho protein (30 μg/kg/day) for 8 weeks, and the other only received vehicle. Klotho supplementation suppressed blood pressure, 8-epi-prostaglandin F2α excretion, albuminuria, and renal angiotensin II levels (p < 0.05 for all) without affecting the glomerular filtration rate (GFR) in NZBWF1 mice. Klotho protein supplementation reduced the number of cluster of differentiation (CD)4+FOXP3+ T cells (p < 0.05) without altering the anti-DNA antibody levels. Klotho supplementation augmented glomerular cellularity, but decreased glomerular crescent formation and interstitial fibrosis in NZBWF1 mice (p < 0.05). Klotho protein supplementation inactivated renal renin-angiotensin system, ameliorating blood pressure and albuminuria in NZBWF1 mice. Klotho supplementation hampered regulatory T cells without altering autoantibodies, exerting dual effects on glomerular pathology in NZBWF1 mice without changes in GFR.

Klotho缺乏症在各种慢性肾脏疾病中普遍存在。虽然已知klotho结合转化生长因子β (TGFβ)受体1拮抗肾纤维化，但TGFβ也通过诱导叉头盒蛋白P3 （FOXP3）维持调节性T细胞。将雌性新西兰黑/白F1 （NZBWF1）小鼠分为两组，每组10只，一组每日皮下注射klotho蛋白（30 μg/kg/d），连续8周，另一组只注射载药。Klotho补充剂可抑制血压、8-肾上腺前列腺素F2α排泄、蛋白尿和肾血管紧张素II水平

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引用次数: 0

Dimethyl fumarate is repurposed to ameliorate aortic aneurysm and dissection in mice 富马酸二甲酯用于改善小鼠主动脉瘤和夹层。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.ejphar.2024.177215

Xuan Wang , Jin Kuang , Xiao-Tian Li , Xi Hu , Yu-Hang Liu , Chang-Ping Hu , Mi Wang , Qing Wang , Zheng Zhang

Aortic aneurysm and dissection pose fatal threats but no effective drug therapies are available. Previous work has been directed to reduce risk factors or target key pathological events, but none of the translational efforts succeeds. Here, we attempt to repurpose dimethyl fumarate (DMF), an FDA-approved immunomodulatory drug for multiple sclerosis, for the treatment of aortic aneurysm and dissection. In three preclinical mouse models of abdominal aortic aneurysm (porcine pancreatic elastase perfusion or CaCl₂ incubation) and thoracic aortic aneurysm and dissection (β-Aminopropionitrile feeding), DMF invariably protected mice from aneurysm growth, aortic dissection, rupture and death. Histological H&E and EVG staining demonstrated aortic architecture-preserving effects of DMF. Through transcriptome profiling and the connectivity map (CMap), we showed that DMF restored SRC-FAK signaling in aortic smooth muscle cells and increased collagen I turnover in the tunica media. Our work suggests the potential of DMF being repurposed for aortic aneurysm and dissection, and highlights the importance of SRC-FAK signaling in aortic homeostasis.

主动脉瘤和夹层构成致命威胁，但没有有效的药物治疗。以前的工作是针对降低风险因素或针对关键病理事件，但没有一个转化努力成功。在这里，我们试图重新利用富马酸二甲酯（DMF），一种fda批准的多发性硬化免疫调节药物，用于治疗主动脉瘤和夹层。在三个临床前小鼠腹主动脉瘤模型（猪胰腺弹性蛋白酶灌注或CaCl2孵育）和胸主动脉瘤和夹层模型（β-氨基丙腈喂养）中，DMF始终保护小鼠免于动脉瘤生长、主动脉夹层、破裂和死亡。组织学H&E和EVG染色显示DMF对主动脉结构的保护作用。通过转录组分析和连接图（CMap），我们发现DMF恢复了主动脉平滑肌细胞中的SRC-FAK信号，并增加了中膜中胶原I的周转。我们的研究表明，DMF可能被重新用于主动脉瘤和夹层，并强调了SRC-FAK信号在主动脉稳态中的重要性。

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引用次数: 0

Effects of canagliflozin preconditioning on post-resuscitation myocardial function in a diabetic rat model of cardiac arrest and cardiopulmonary resuscitation 加格列净预处理对糖尿病大鼠心脏骤停和心肺复苏模型复苏后心肌功能的影响。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.ejphar.2024.177212

Minjie Wang , Tianfeng Hua , Yijun Zhang , Qihui Huang , Wei Shi , Yuqian Chu , Yan Hu , Sinong Pan , Bingrui Ling , Wanchun Tang , Min Yang

Background

Canagliflozin can reduce the risk of cardiovascular disease in patients except for its targeted antidiabetic effects. However, it remains unknown whether canagliflozin alleviates the post-resuscitation myocardial dysfunction (PRMD) in type 2 diabetes mellitus.

Objective

To explore the effects and potential mechanisms of canagliflozin on myocardial function after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in a type 2 diabetic rat model.

Methods

Twenty-four type 2 diabetic rats were randomized into four groups: (1) sham + canagliflozin, (2) sham + placebo, (3) CPR + placebo, and (4) CPR + canagliflozin. Except for the sham + canagliflozin and placebo groups, both the CPR + placebo and canagliflozin groups underwent 8 min of CPR after the induction of ventricular fibrillation for 6 min. Myocardial function and hemodynamics were assessed at baseline and within 6 h after autonomous circulation (ROSC) return. Left ventricular tissues were sampled to determine the expressions of relevant proteins in the NLRP3 inflammasome pathway.

Results

The results demonstrated that the mean arterial pressure (MAP) was significantly improved in the CPR + canagliflozin group after ROSC compared with the CPR + placebo group (p < 0.05). Meanwhile, both ejection fraction (EF) and fraction shortening (FS) were dramatically increased in the CPR + canagliflozin group when compared with the CPR + placebo group at 2h, 4h, and 6h after ROSC (p < 0.05). In addition, the levels of NT-proBNP, cTn-I, and NLRP3 inflammatory inflammasome-associated proteins were significantly decreased in the CPR + canagliflozin group compared with the CPR + placebo group.

Conclusions

In type 2 diabetic rats, pretreatment of canagliflozin alleviates PRMD. The potential mechanisms may include inhibition of the NLRP3/caspase-1 signaling pathway.

背景：卡格列净除了具有靶向降糖作用外，还能降低患者心血管疾病的风险。然而，卡格列净是否能缓解2型糖尿病患者复苏后心肌功能障碍（PRMD）尚不清楚。目的：探讨卡格列净对2型糖尿病大鼠心脏骤停（CA）及心肺复苏（CPR）后心肌功能的影响及其可能机制。方法：24只2型糖尿病大鼠随机分为4组：(1)假手术+卡格列净，(2)假手术+安慰剂，(3)心肺复苏术+安慰剂，(4)心肺复苏术+卡格列净。除假手术+卡格列净组和安慰剂组外，心肺复苏术+安慰剂组和卡格列净组均在心室颤动诱导6分钟后进行8分钟心肺复苏术。在基线和自主循环（ROSC）恢复后6小时内评估心肌功能和血流动力学。取左心室组织标本，测定NLRP3炎性体通路相关蛋白的表达。结果：与CPR+安慰剂组相比，ROSC后CPR+卡格列净组的平均动脉压（MAP）明显改善(p)。结论：2型糖尿病大鼠预处理卡格列净可减轻PRMD。潜在的机制可能包括抑制NLRP3/caspase-1信号通路。

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引用次数: 0