曲美他嗪通过靶向长非编码 RNA CBR3-AS1 介导的 miRNA-29 和 Resistin-Like Molecule alpha 1 缓解博莱霉素诱导的肺纤维化：解密 LncRNA CBR3-AS1/miRNA-29/FIZZ1 轴在肺纤维化中的新型三重作用

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2024-09-05 DOI:10.2147/dddt.s463626

Abdullah R Alzahrani, Doaa I Mohamed, Hebatallah H Abo Nahas, Dalia Alaa El-Din Aly El-Waseef, Abdulmalik S Altamimi, Ibrahim H Youssef, Ibrahim Abdel Aziz Ibrahim, Soha MY Mohamed, Yasmine Gamal Sabry, Alaa H Falemban, Nasser Attia Elhawary, Ghazi A Bamagous, Mariusz Jaremko, Essa M Saied

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引用次数: 0

摘要

简介：肺纤维化（PF）和组织重塑会极大地损害肺功能，并常常导致致命后果：在本研究中，我们探索了长非编码（Lnc）RNA CBR3-AS1/ miRNA-29/ FIZZ1轴在博莱霉素（BLM）诱导的肺纤维化中调节炎症过程、免疫反应和氧化应激途径的新型分子相互作用。此外，我们还研究了三甲脒（TMZ）在改善肺纤维化方面的药理潜力：结果发现，与对照组相比，BLM 治疗组表观遗传调控因子 lncRNA CBR3-AS1 和 FIZZ1 的表达显著上调（P< 0.0001），同时 miRNA-29 的表达下调。此外，相关分析表明，lnc CBR3-AS1与FIZZ1之间存在显著的正相关（R=0.7723，P< 0.05），而miRNA-29与FIZZ1之间存在显著的负相关（R=- 0.7535，P< 0.05），表明lnc CBR3-AS1是肺纤维化中FIZZ1的表观遗传调控因子。BLM治疗可明显增加Notch、Jagged1、Smad3、TGFB1和羟脯氨酸的表达。有趣的是，生化和组织学分析表明，服用 TMZ 能够减轻 BLM 治疗引起的恶化效应。我们的研究发现，TMZ作为抗纤维化药物的治疗潜力可归因于它能直接靶向表观遗传调节因子lncRNA CBR3-AS1/ miRNA-29/ FIZZ1，进而减轻肺纤维化。组织学和免疫组化分析进一步验证了TMZ通过减轻与纤维化相关的结构损伤而具有潜在的抗纤维化作用：综上所述，我们的研究首次显示了表观遗传lncRNA CBR3-AS1和miRNA-29在肺纤维化中的相互作用，并证明FIZZ1可能是lncRNA CBR3-AS1和miRNA-29的下调基因。我们的主要研究结果表明，TMZ能显著降低肺纤维化相关的纤维化、氧化应激、免疫调节和炎症标志物以及表观遗传调节因子的表达。这验证了TMZ通过靶向CBR3-AS1/miRNA-29/FIZZ1轴作为有效抗纤维化药物的潜力。关键词：肺纤维化；长非编码 RNA CBR3-AS1；miRNA-29；FIZZ1；曲美他嗪；组织病理学

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Trimetazidine Alleviates Bleomycin-Induced Pulmonary Fibrosis by Targeting the Long Noncoding RNA CBR3-AS1-Mediated miRNA-29 and Resistin-Like Molecule alpha 1: Deciphering a Novel Trifecta Role of LncRNA CBR3-AS1/miRNA-29/FIZZ1 Axis in Lung Fibrosis

Introduction: Pulmonary fibrosis (PF) and tissue remodeling can greatly impair pulmonary function and often lead to fatal outcomes.
Methodology: In the present study, we explored a novel molecular interplay of long noncoding (Lnc) RNA CBR3-AS1/ miRNA-29/ FIZZ1 axis in moderating the inflammatory processes, immunological responses, and oxidative stress pathways in bleomycin (BLM)-induced lung fibrosis. Furthermore, we investigated the pharmacological potential of Trimetazidine (TMZ) in ameliorating lung fibrosis.
Results: Our results revealed that the BLM-treated group exhibited a significant upregulation in the expression of epigenetic regulators, lncRNA CBR3-AS1 and FIZZ1, compared to the control group (P< 0.0001), along with the downregulation of miRNA-29 expression. Furthermore, Correlation analysis showed a significant positive association between lnc CBR3-AS1 and FIZZ1 (R=0.7723, p< 0.05) and a significant negative association between miRNA-29 and FIZZ1 (R=− 0.7535, p< 0.05), suggesting lnc CBR3-AS1 as an epigenetic regulator of FIZZ1 in lung fibrosis. BLM treatment significantly increased the expression of Notch, Jagged1, Smad3, TGFB1, and hydroxyproline. Interestingly, the administration of TMZ demonstrated the ability to attenuate the deterioration effects caused by BLM treatment, as indicated by biochemical and histological analyses. Our investigations revealed that the therapeutic potential of TMZ as an antifibrotic drug could be ascribed to its ability to directly target the epigenetic regulators lncRNA CBR3-AS1/ miRNA-29/ FIZZ1, which in turn resulted in the mitigation of lung fibrosis. Histological and immunohistochemical analyses further validated the potential antifibrotic effects of TMZ by mitigating the structural damage associated with fibrosis.
Discussion: Taken together, our study showed for the first time the interplay between epigenetic lncRNAs CBR3-AS1 and miRNA-29 in lung fibrosis and demonstrated that FIZZ1 could be a downregulatory gene for lncRNA CBR3-AS1 and miRNA-29. Our key findings demonstrate that TMZ significantly reduces the expression of fibrotic, oxidative stress, immunomodulatory, and inflammatory markers, along with epigenetic regulators associated with lung fibrosis. This validates its potential as an effective antifibrotic agent by targeting the CBR3-AS1/miRNA-29/FIZZ1 axis.

Keywords: lung fibrosis, long noncoding RNA CBR3-AS1, miRNA-29, FIZZ1, trimetazidine, histopathology

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.