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Heparan sulfate proteoglycan affinity of adeno-associated virus vectors: Implications for retinal gene delivery 腺相关病毒载体的硫酸肝素蛋白聚糖亲和力:对视网膜基因传递的影响。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-11 DOI: 10.1016/j.ejps.2025.107012
Dimitri Romanovsky , Hanna Scherk , Bastian Föhr, Sabrina Babutzka, Jacqueline Bogedein, Yi Lu, Alice Reschigna, Stylianos Michalakis
Adeno-associated virus (AAV)-based vectors have emerged as an effective and widely used technology for somatic gene therapy approaches, including those targeting the retina. A major advantage of the AAV technology is the availability of a large number of serotypes that have either been isolated from nature or produced in the laboratory. These serotypes have different properties in terms of sensitivity to neutralizing antibodies, cellular transduction profile and efficiency. The infectivity of AAV vectors depends on the affinity to certain molecules on the cell surface, in particular to cellular glycosaminoglycans (GAGs) such as heparan sulfate proteoglycans (HSPGs). Here, we tested how altering HSPG affinity in AAV vectors affects cellular tropism and transduction efficiency. The previously developed AAV2.GL variant was used as a starting variant to alter or disrupt HSPG affinity. The HSPG-independent AAV9 serotype was used to introduce different HSPG-binding sites. As an indicator of HSPG affinity, we measured the binding strength of the vector variant on a heparin chromatography column. We show that modification of capsid-exposed residues has a strong impact on HSPG affinity, cellular tropism and transduction efficiency in HeLa cells and in vivo in mouse retina. Our study shows that key properties of AAV vectors can be tailored in different directions and used to improve tropism and efficiency.
基于腺相关病毒(AAV)的载体已成为体细胞基因治疗(包括针对视网膜的基因治疗)的一种有效且广泛应用的技术。AAV 技术的一大优势是可提供大量从自然界分离或在实验室生产的血清型。这些血清型在对中和抗体的敏感性、细胞转导特征和效率方面具有不同的特性。AAV 载体的感染性取决于与细胞表面某些分子的亲和力,特别是与细胞糖胺聚糖(GAGs),如硫酸肝素蛋白聚糖(HSPGs)的亲和力。在这里,我们测试了改变 AAV 载体的 HSPG 亲和力如何影响细胞趋向性和转导效率。以前开发的 AAV2.GL 变体被用作改变或破坏 HSPG 亲和力的起始变体。不依赖 HSPG 的 AAV9 血清型被用来引入不同的 HSPG 结合位点。作为 HSPG 亲和力的指标,我们测量了载体变体在肝素层析柱上的结合强度。我们的研究表明,在 HeLa 细胞和小鼠视网膜中,对囊膜暴露残基的修饰对 HSPG 亲和力、细胞滋养性和转导效率有很大影响。我们的研究表明,AAV载体的关键特性可以从不同方向进行定制,并用于提高其趋向性和效率。
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引用次数: 0
In vitro study of the pro-apoptotic mechanism of amino acid Schiff base copper complexes on anaplastic thyroid cancer 氨基酸席夫碱铜配合物对间变性甲状腺癌促凋亡机制的体外研究。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-11 DOI: 10.1016/j.ejps.2025.107005
Peiran Zhao , Xinyan Zhang , Jianfang Dong , Lianzhi Li , Xiao Meng , Lei Gao
In the endocrine system, anaplastic thyroid cancer (ATC) is extremely aggressive since it inhibits the majority of medications and treatments. Therefore, there is an immediate demand to identify new treatment approaches or drugs to deal with ATC. Recently, amino acid Schiff base copper complexes have received great attention due to their excellent anti-tumor activity. In this research, three copper(II) complexes, [Cu(o-van-D-Trp)(phen)](1), [Cu(o-van-D-Trp)(bipy)](2), [Cu(naph-D-Trp)(bipy)](3), [D-Trp = D-tryptophan; o-van = o-vanillin; naph = 2‑hydroxy-1- naphthaldehyde; phen = 1,10-phenanthroline; bipy = 2,2-biprydine], have been synthesized and investigated as potential anticancer agents. The crystal structure data of the complexes demonstrate that the central copper (II) atom forms a twisted polyhedral environment with nitrogen and oxygen atoms. The MTT results demonstrated that three complexes exhibited superior cytotoxicity against five cell lines of thyroid cancer (Cal-62 cells, ARO cells, KHM-5 m cells, BHP10–3 cells and K1 cells), especially complex 1 with the IC50 values of 0.59±0.05 μM, 2.36±0.47 μM, 1.10±0.87 μM, 0.75±0.09 μM, 1.72±0.06 μM, when cisplatin was used as a control. Research on antitumor mechanisms has demonstrated that complex 1 can significantly reduce the mitochondrial membrane potential, raise autophagy, and produce reactive oxygen species (ROS) in ARO cells in a dose-dependent manner. RNA sequencing study reveals that complex 1 may cause apoptosis in ARO cells and exhibit anticancer efficacy in vitro through ROS-mediated downregulation of Akt and p38 MAPK activation.
在内分泌系统中,间变性甲状腺癌(ATC)具有极强的侵袭性,因为它抑制了大多数药物和治疗。因此,迫切需要找到新的治疗方法或药物来治疗ATC。近年来,氨基酸席夫碱铜配合物因其良好的抗肿瘤活性而受到广泛关注。在本研究中,三种铜(II)配合物,[Cu(o-van-D-Trp)(phen)](1), [Cu(o-van-D-Trp)(bipy)](2), [Cu(naph-D-Trp)(bipy)](3), [D-Trp = d -色氨酸;O-van = o-香兰素;Naph = 2‑羟基-1-萘醛;Phen = 1,10-菲罗啉;Bipy = 2,2-biprydine],作为潜在的抗癌药物已被合成和研究。配合物的晶体结构数据表明,中心的铜(II)原子与氮、氧原子形成一个扭曲多面体环境。MTT结果表明,3种复合物对5种甲状腺癌细胞系(Cal-62细胞、ARO细胞、khm - 5m细胞、BHP10-3细胞和K1细胞)均表现出较强的细胞毒性,其中复合物1的IC50值以顺铂为对照分别为0.59±0.05 μM、2.36±0.47 μM、1.10±0.87 μM、0.75±0.09 μM、1.72±0.06 μM。抗肿瘤机制研究表明,复合物1可以显著降低线粒体膜电位,提高自噬,并在ARO细胞中产生活性氧(ROS),并呈剂量依赖性。RNA测序研究表明复合物1可能通过ros介导的下调Akt和p38 MAPK的激活而导致ARO细胞凋亡,并在体外表现出抗癌作用。
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引用次数: 0
Drug interaction evaluation of the novel phosphodiesterase type 5 inhibitor tunodafil (youkenafil): Effects of tunodafil on omeprazole pharmacokinetics based on CYP2C19 gene polymorphism, and effects of ritonavir on tunodafil pharmacokinetics 新型磷酸二酯酶5型抑制剂妥诺他非(尤肯那非)的药物相互作用评价:基于CYP2C19基因多态性的妥诺他非对奥美拉唑药代动力学的影响,利托那韦对妥诺他非药代动力学的影响。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-09 DOI: 10.1016/j.ejps.2025.107010
Keli Wang , Juefang Ding , Minlu Cheng , Xianjing Li , Huan Zhou , Qinxin Song , Yuanxun Yang , Juan Li , Li Ding

Purpose

To evaluate the drug-drug interactions (DDI) of tunodafil (youkenafil), a novel phosphodiesterase type 5 inhibitor, its inhibitory effects on CYP450 enzymes in vitro and its clinical trials in combination with ritonavir or omeprazole were conducted.

Methods

The inhibitory effect of tunodafil on seven major CYP450 enzymes in human liver microsomes was investigated by probe substrate method. The effect of tunodafil on the pharmacokinetics of omeprazole (CYP2C19 substrate) in 40 healthy subjects, who received a single dose of 40 mg omeprazole in combination with tunodafil on the day 8 after taking 100 mg tunodafil daily for 7 days, was assessed based on CYP2C19 genotypes. The clinical DDI of ritonavir (potent CYP3A4 inhibitor) on tunodafil was studied in 28 healthy subjects who received a single dose of 50 mg tunodafil in combination with ritonavir on the day 6 after taking ritonavir twice a day for 5 days.

Results

Tunodafil showed moderate inhibition on CYP2C19 and CYP3A4/5 in vitro. When co-administration omeprazole with tunodafil, the AUC of omeprazole in the Extensive, Intermediate and Poor Metabolizers increased by 26 %, 37 % and 21 %, respectively. After co-administration tunodafil with ritonavir, ritonavir increased the AUC and Cmax of tunodafil in human by about 78- fold and 13-fold respectively.

Conclusions

Tunodafil slightly increased omeprazole exposure in the Extensive and Intermediate Metabolizers of CYP2C19, but had no significant effect on omeprazole exposure in the Poor Metabolizers. Ritonavir could strongly inhibit the metabolism of tunodafil, and the combination of tunodafil with ritonavir should be prohibited.
目的:评价新型磷酸二酯酶5型抑制剂妥诺非(youkenafil)的药物相互作用(DDI)、体外对CYP450酶的抑制作用及与利托那韦或奥美拉唑联合应用的临床试验。方法:采用探针底物法研究妥诺非对人肝微粒体中7种主要CYP450酶的抑制作用。以CYP2C19基因型为基础,观察40例健康受试者在连续7天每日服用100 mg妥诺非后,于第8天给予单剂量40 mg奥美拉唑联合妥诺非对奥美拉唑(CYP2C19底物)药代动力学的影响。研究了利托那韦(强效CYP3A4抑制剂)对妥那非的临床DDI。28名健康受试者在每日两次服用利托那韦5天后,于第6天接受单剂量50 mg妥那非与利托那韦联用。结果:妥诺非对体外培养的CYP2C19、CYP3A4/5有中等抑制作用。当奥美拉唑与妥诺非合用时,奥美拉唑在广泛代谢组、中等代谢组和不良代谢组的AUC分别增加26%、37%和21%。妥诺他非与利托那韦合用后,利托那韦使妥诺他非在人体内的AUC和Cmax分别提高约78倍和13倍。结论:妥诺非可轻微增加CYP2C19广泛代谢和中等代谢者的奥美拉唑暴露,但对低代谢者的奥美拉唑暴露无显著影响。利托那韦对妥诺非的代谢有强烈抑制作用,应禁止妥诺非与利托那韦合用。
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引用次数: 0
Study on the impact of β-CD inclusion complex on the in vivo metabolism of ginsenoside Re: A pharmacokinetic, metabolite analysis, and tissue distribution investigation in a rat model β-CD包合物对人参皂苷Re体内代谢影响的研究:大鼠模型药代动力学、代谢物分析及组织分布研究
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-08 DOI: 10.1016/j.ejps.2025.107004
Hui Li , Rui Liu , Yuxin Guo , Anqi Wang , Ting Zhou , Shuhang Wang , Wei Wu
Triol-type ginsenoside Re (GS-Re) exhibits potent anti-myocardial ischemia-reperfusion effects, but its clinical use is hindered by poor bioavailability. This study evaluates the impact of β-cyclodextrin (β-CD) inclusion on GS-Re bioavailability and tissue dynamics in rat models. The GS-Re-β-CD complex was prepared using aqueous stirring and characterized. Male Wistar rats (200 ± 20 g) were administered GS-Re at a dose of 500 mg/kg. Plasma concentrations were quantified using UHPLC-MS/MS to evaluate pharmacokinetics and analyze metabolites in tissues and feces. Compared to the group receiving GS-Re alone, the GS-Re-β-CD inclusion complex exhibited significantly improved pharmacokinetic characteristics in rats: Maximum concentration (Cmax) increased by 1.86-fold. Area under the curve (AUC0–24 h) increased by 2.09-fold. Time to reach peak concentration (Tmax) was reduced, while the half-life (t1/2) was extended, suggesting a faster and prolonged absorption of GS-Re. Metabolite analysis showed higher concentrations of Rg1, Rg2, Rh1, F1, PPT, and Re in tissues with GS-Re-β-CD, while metabolite types remained unchanged. The inclusion of β-CD significantly enhanced the bioavailability and tissue concentration of GS-Re, as demonstrated by increased Cmax and AUC, along with a shorter Tmax and longer t1/2. These findings suggest that β-CD inclusion could be an effective strategy to improve the clinical applicability of GS-Re, providing valuable pharmacokinetic and tissue concentration insights for further development.
三醇型人参皂苷Re (GS-Re)具有较强的抗心肌缺血再灌注作用,但其生物利用度较差,阻碍了其临床应用。本研究评估了β-环糊精(β-CD)包合物对大鼠GS-Re生物利用度和组织动力学的影响。采用水搅拌法制备了GS-Re-β-CD配合物,并对其进行了表征。雄性Wistar大鼠(200±20 g)按500 mg/kg剂量给予GS-Re。采用高效液相色谱-质谱联用技术(UHPLC-MS/MS)定量测定血药浓度,评估药代动力学并分析组织和粪便中的代谢物。与单独给药组相比,GS-Re-β-CD包合物在大鼠体内的药动学特征明显改善,最大浓度(Cmax)提高了1.86倍。曲线下面积(AUC0-24h)增加2.09倍。达到峰值浓度的时间(Tmax)减少,半衰期(t1/2)延长,表明GS-Re的吸收速度更快,时间更长。代谢物分析显示,GS-Re-β-CD组组织中Rg1、Rg2、Rh1、F1、PPT和Re浓度较高,代谢物类型保持不变。β-CD的加入显著提高了GS-Re的生物利用度和组织浓度,增加了Cmax和AUC,缩短了Tmax,延长了t1/2。这些发现表明,β-CD包埋可能是提高GS-Re临床适用性的有效策略,为进一步开发提供了有价值的药代动力学和组织浓度信息。
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引用次数: 0
Physiologically-based pharmacokinetic modeling to predict the exposure and provide dosage regimens of tacrolimus in pregnant women with infection disease 基于生理的药代动力学模型预测感染孕妇的他克莫司暴露并提供剂量方案。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-07 DOI: 10.1016/j.ejps.2025.107003
Jianwen Xu , Guimu Guo , Shuifang Zhou , Han Wang , Yuewen Chen , Rongfang Lin , Pinfang Huang , Cuihong Lin
Tacrolimus is extensively used for the prevention of graft rejection following solid organ transplantation in pregnant women. However, knowledge gaps in the dosage of tacrolimus for pregnant patients with different CYP3A5 genotypes and infection conditions have been identified. This study aimed to develop a pregnant physiologically based pharmacokinetic (PBPK) model to characterize the maternal and fetal pharmacokinetics of tacrolimus during pregnancy and explore and provide dosage adjustments. We developed PBPK models for nonpregnant patients and validated them via data from previous clinical studies using PK-Sim and Mobi software. To extrapolate to pregnancy, we considered anatomical, physiological, and metabolic alterations and simulated tacrolimus by adding six groups of IL-6 concentrations (0, 5, 25, 50, 500, and 5000 pg/mL). Models were verified by assessing goodness-of-fit plots and ratios of predicted-to-observed pharmacokinetic parameters.
The developed PBPK models adequately describe the available clinical data; the fold errors of the predicted and observed values of the area under the curve and peak plasma concentration were between 0.59 and 1.64, and the average folding error and the absolute average folding error values for all concentration–time data points were 1.15 and 1.36, respectively. The simulation results indicated that the area under the steady-state concentration‒time curve and trough concentrations decreased from the first to the third trimester of pregnancy. The trough concentrations were not within the therapeutic range (4–11 ng/mL) in pregnant patients with the CYP3A5 genotype for most of the infection conditions and exceeded its effective concentration in all the CYP3A5 nonexpressers. Based on the model-derived dosing regimen, the tacrolimus trough concentration in pregnant patients with different CYP3A5 genotypes could fall into the therapeutic window, which provided a clinical practice reference for dosage adjustments during pregnancy.
他克莫司被广泛用于预防孕妇实体器官移植后的移植排斥反应。然而,对于不同CYP3A5基因型和感染情况的孕妇,他克莫司的剂量存在知识空白。本研究旨在建立基于妊娠生理的药代动力学(PBPK)模型,以表征妊娠期间他克莫司的母胎药代动力学,探索并提供剂量调整。我们为未怀孕的患者建立了PBPK模型,并使用PK-Sim和Mobi软件通过先前临床研究的数据对其进行了验证。为了推断妊娠,我们考虑了解剖、生理和代谢的变化,并通过添加六组IL-6浓度(0、5、25、50、500和5000 pg/mL)来模拟他克莫司。通过评估拟合优度图和预测与观察的药代动力学参数的比率来验证模型。开发的PBPK模型充分描述了现有的临床数据;曲线下面积和峰值血药浓度预测值和观测值的折叠误差在0.59 ~ 1.64之间,各浓度-时间数据点的平均折叠误差和绝对平均折叠误差分别为1.15和1.36。模拟结果表明,从妊娠早期到妊娠晚期,稳态浓度-时间曲线下的面积和谷浓度呈下降趋势。在大多数感染情况下,CYP3A5基因型孕妇的谷浓度不在治疗范围(4-11 ng/mL)内,而在所有CYP3A5非表达者中,谷浓度均超过其有效浓度。基于模型衍生的给药方案,不同CYP3A5基因型妊娠患者他克莫司谷浓度可落入治疗窗口,为妊娠期剂量调整提供临床实践参考。
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引用次数: 0
Activation of SIRT1 by SRT1720 alleviates dyslipidemia, improves insulin sensitivity and exhibits liver-protective effects in diabetic rats on a high-fat diet: New insights into the SIRT1/Nrf2/NFκB signaling pathway SRT1720激活SIRT1可缓解高脂饮食下糖尿病大鼠的血脂异常、改善胰岛素敏感性并显示肝脏保护作用:SIRT1/Nrf2/NFκB信号通路的新见解
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-06 DOI: 10.1016/j.ejps.2025.107002
Elsayed A. Elmorsy , Hossam A. Elsisi , Abdullah S. Alkhamiss , Norah Suliman Alsoqih , Mostafa M. Khodeir , Abdulaziz A. Alsalloom , Ahmad A. Almeman , Sahar R. Elghandour , Eman Hassan Nadwa , Amira Karam khalifa , Bahaa Eldin Ali Khaled , Asmaa Ramadan , Manal M. Kamal , Thamir Saad Alsaeed , Mariam S. Alharbi , Abdel-Moneim Hafez Abdel-Moneim , Abousree T. Ellethy , Sameh Saber
Insulin resistance and diabetes are associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) conditions, which are distinguished by metabolic dysfunction, oxidative stress and inflammation. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, is fundamental in regulating metabolic pathways, reducing inflammation, and improving antioxidant defenses. This is the first study to investigate the effects of SRT1720, a SIRT1 activator, in diabetic rats on a high-fat diet. SRT1720 significantly lowered fasting blood glucose and insulin levels and enhanced glucose tolerance and HOMA-IR and QUICKI scores, indicating increased insulin sensitivity. The treatment also reduced total cholesterol, triglycerides, and LDL levels, showing amelioration of dyslipidemia. Moreover, SRT1720 lowered markers of liver fibrosis, including TGF-β, TIMP-1, Col1a1, and hydroxyproline, and decreased inflammation by reducing NFκB activity and pro-inflammatory cytokines (TNF-α and IL-6). Furthermore, SRT1720 augmented Nrf2 activity and HO-1 levels. Consequently, the SRT1720’s protective role improved liver function and histology and prolonged rats’ survival. These functions were suppressed by the co-administration of the SIRT1 inhibitor EX527, confirming that the beneficial effects of SRT1720 are SIRT1-dependent. Correlation analyses uncovered that increased SIRT1 activity was strongly associated with decreased oxidative stress, inflammation, insulin resistance, and fibrosis markers. To conclude, our results find that SRT1720 represents a promising therapeutic strategy for managing Type 2 diabetes in NAFLD or NASH patients possibly through the modulation of the SIRT1/Nrf2/NFκB signaling pathwa. SRT1720 could potentially halt or reverse the progression of these conditions and associated complications and merits further investigations.
胰岛素抵抗和糖尿病与非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)有关,这两种疾病的特征是代谢功能障碍、氧化应激和炎症。SIRT1是一种依赖NAD+的去乙酰化酶,在调节代谢途径、减少炎症和提高抗氧化防御能力方面发挥着重要作用。这是第一个研究SRT1720(一种SIRT1激活剂)对高脂肪饮食的糖尿病大鼠的影响的研究。SRT1720显著降低空腹血糖和胰岛素水平,提高葡萄糖耐量和HOMA-IR和QUICKI评分,表明胰岛素敏感性增加。治疗还降低了总胆固醇、甘油三酯和低密度脂蛋白水平,显示了血脂异常的改善。此外,SRT1720降低肝纤维化标志物TGF-β、TIMP-1、Col1a1、羟脯氨酸,并通过降低nf - κ b活性和促炎细胞因子(TNF-α、IL-6)来减轻炎症。此外,SRT1720增强了Nrf2活性和HO-1水平。因此,SRT1720的保护作用改善了肝功能和组织学,延长了大鼠的生存期。这些功能被SIRT1抑制剂EX527抑制,证实SRT1720的有益作用依赖于SIRT1。相关分析发现,SIRT1活性的增加与氧化应激、炎症、胰岛素抵抗和纤维化标志物的降低密切相关。总之,我们的研究结果发现,SRT1720可能通过调节SIRT1/Nrf2/NFκB信号通路,为NAFLD或NASH患者治疗2型糖尿病提供了一种有希望的治疗策略。SRT1720有可能阻止或逆转这些疾病和相关并发症的进展,值得进一步研究。
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引用次数: 0
Corrigendum to “Comparison of ionizable lipids for lipid nanoparticle mediated DNA delivery” [European Journal of Pharmaceutical Sciences 203 (2024), 106898] “脂质纳米颗粒介导DNA递送的可电离脂质比较”的更正[欧洲药物科学杂志203(2024),106898]。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.ejps.2024.106965
Claudia Lotter , Evrim Ümit Kuzucu , Jens Casper , Claudio Luca Alter , Ramya Deepthi Puligilla , Pascal Detampel , Juana Serrano Lopez , Alexander Sebastian Ham , Jörg Huwyler
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引用次数: 0
Corrigendum to “Evaluation of rivaroxaban amorphous solid dispersions physical stability via molecular mobility studies and molecular simulations” [European Journal of Pharmaceutical Sciences 157 (2021) 105642] 通过分子迁移率研究和分子模拟评估利伐沙班无定形固体分散体的物理稳定性》[《欧洲药学杂志》157 (2021) 105642]更正。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.ejps.2024.106932
Afroditi Kapourani , Kalliopi Eleftheriadou , Konstantinos N. Kontogiannopoulos , Panagiotis Barmpalexis
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引用次数: 0
Editorial: Biologically inspired engineering of the lungs: Advances in preclinical pulmonary pathobiology models for translational and therapeutic applications 社论:肺的生物启发工程:临床前肺部病理生物学模型在转化和治疗应用方面的进展。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.ejps.2024.106972
Kambez H. Benam , Carsten Ehrhardt , Josué Sznitman
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引用次数: 0
Epigenetic therapeutics attenuate kidney injury and fibrosis by restoring the expression of epigenetically reprogrammed fibrogenic genes and signaling pathways 表观遗传疗法通过恢复表观遗传重编程的纤维化基因和信号通路的表达来减轻肾损伤和纤维化。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.ejps.2024.106977
Narayan Acharya , Ramji Kandel , Priti Roy , Irfan Warraich , Kamaleshwar P Singh
Kidney fibrosis is a commonly observed pathological condition during development of chronic kidney disease. Therapeutic options currently available are effective only in slowing the progression of kidney fibrosis and there is no cure for this disease. Aberrant expression and excessive accumulation of extracellular matrix (ECM) proteins in the peritubular space is a characteristic pathological feature of fibrotic kidney. However, the molecular basis of aberrant regulation of fibrotic genes in kidneys is not clear. In this context, this study aimed to evaluate the role of epigenetic reprogramming in kidney fibrosis. Folic acid (FA)-induced acute kidney injury (AKI) and kidney fibrosis in mice as an in vivo model and long-term arsenic or FA-exposed fibrogenic HK-2 cells as an in vitro model were used to evaluate the role of DNA methylation and histone modifications in fibrosis. DNA demethylating agent 5aza2 deoxycytidine (5-aza-2-dC) and histone deacetylase inhibitor Trichostatin A (TSA) were used to treat FA-injected mice. Results of histopathological and immunofluorescence staining of kidney tissue, serum albumin- creatinine levels, body weight, and gene expression analysis revealed significant protective effects of 5-aza-2-dC and TSA in FA-induced AKI and fibrosis. Insignificant change in the expression of N-cadherin whereas a significant decrease in E-cadherin as well as an increase in the expression of Vimentin and α-SMA suggest partial EMT associated with fibrosis. Aberrant expression of epithelial-mesenchymal-transition (EMT) and ECM-regulators (MMP2, Smad7, and TIMP3) as well as fibrogenic signaling pathways (Notch, TGF-beta, and Wnt signaling), and their restoration by 5-aza-2-dC and TSA treatments suggest epigenetic reprogramming of these genes and signaling pathways during FA-induced fibrosis. In summary, this study provides new information on the role of epigenetic reprogramming of fibrogenic genes and signaling pathways during the development of kidney fibrosis. Attenuation of fibrosis after 5-aza-2-dC and TSA treatments suggest the promise of these epigenetic-based therapeutics in the clinical management of this disease.
肾纤维化是慢性肾脏疾病发展过程中常见的病理状态。目前可用的治疗方案仅在减缓肾纤维化的进展方面有效,而且这种疾病无法治愈。小管周围细胞外基质(ECM)蛋白的异常表达和过度积累是纤维化肾的一个特征性病理特征。然而,肾脏纤维化基因异常调控的分子基础尚不清楚。在此背景下,本研究旨在评估表观遗传重编程在肾纤维化中的作用。采用叶酸(FA)诱导的小鼠急性肾损伤(AKI)和肾纤维化作为体内模型,并采用长期砷或FA暴露的纤维化性HK-2细胞作为体外模型来评估DNA甲基化和组蛋白修饰在纤维化中的作用。用DNA去甲基化剂5aza2脱氧胞苷(5-aza-2-dC)和组蛋白去乙酰化酶抑制剂Trichostatin A (TSA)治疗fa注射小鼠。肾组织病理和免疫荧光染色、血清白蛋白-肌酐水平、体重和基因表达分析结果显示,5-aza-2-dC和TSA对fa诱导的AKI和纤维化具有显著的保护作用。N-cadherin的表达变化不显著,而E-cadherin的表达显著降低,Vimentin和α-SMA的表达增加,提示部分EMT与纤维化有关。上皮-间质转化(EMT)和ecm调节因子(MMP2、Smad7和TIMP3)以及纤维化信号通路(Notch、tgf - β和Wnt信号通路)的异常表达,以及5-aza-2-dC和TSA治疗对它们的恢复表明,在fa诱导的纤维化过程中,这些基因和信号通路发生了表观遗传重编程。总之,本研究为纤维化基因的表观遗传重编程和信号通路在肾纤维化发展过程中的作用提供了新的信息。5-aza-2-dC和TSA治疗后纤维化的衰减表明这些基于表观遗传学的治疗方法在该疾病的临床管理中有希望。
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引用次数: 0
期刊
European Journal of Pharmaceutical Sciences
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