Exogenous GABA as a natural epigenetic modifier for managing glycemic memory and diabetic nephropathy by modifying the epigenetic axis.

IF 3.9 4区医学 Q1 PHARMACOLOGY & PHARMACY

Journal of Drug Targeting Pub Date : 2025-07-02 DOI:10.1080/1061186X.2025.2523990

Kriti Kushwaha, Debojyoti Mandal, Sourbh Suren Garg, Rupal Dubey, Navneet Khurana, Jeena Gupta

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Abstract

Background: Glycemic memory contributes to the progression of diabetic nephropathy (DN) despite glycemic control. This study investigates γ-aminobutyric acid (GABA), a natural compound with 82.5% structural similarity to metformin, for its potential in mitigating glycemic memory and DN.

Methods: Structural similarity and molecular docking identified GABA as a SIRT1-targeting metformin analog (binding affinity: 5.8 kcal/mol), supported by ADME profiling. In vitro assays assessed antioxidant activity (DPPH IC₅₀: 141.09 µg/mL), cytotoxicity (MTT assay), oxidative stress markers, and histone H3 acetylation. In vivo, high-fat diet-fed Sprague-Dawley rats underwent dietary reversal and GABA treatment (100/200 mg/kg) to evaluate metabolic, renal, hepatic, oxidative, and epigenetic effects.

Results: GABA maintained >90% cell viability at 5 µM, with no cytotoxicity up to 150 µM. It reduced oxidative markers and restored histone acetylation in vitro. In vivo, 200 mg/kg GABA treatment significantly reduced cholesterol (44.44%), triglycerides (28.64%), and LDL (40.80%), while increasing HDL by 103.65%. At 100 mg/kg, GABA lowered blood urea (30.43%), creatinine (4.65%), uric acid (75.00%), bilirubin (53.57%), SGOT (54.24%), SGPT (39.52%), and ALP (60.58%), with histopathological improvements in renal tissues.

Conclusion: GABA exhibits antioxidant, hepatoprotective, and renoprotective properties, highlighting its potential as a therapeutic agent for glycemic memory-associated DN.

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外源性GABA作为一种天然表观遗传修饰因子，通过修饰表观遗传轴来管理血糖记忆和糖尿病肾病。

背景：血糖记忆在糖尿病肾病（DN）的进展中起着至关重要的作用，即使在血糖得到控制后也是如此。γ-氨基丁酸（GABA）是一种天然化合物，其结构与二甲双胍相似度为82.5%，本研究旨在评估GABA在缓解血糖记忆和DN方面的潜力。方法：通过结构相似性搜索确定GABA为二甲双胍的潜在类似物。与SIRT1蛋白进行分子对接，并进行ADME分析。体外实验评估了抗氧化活性（DPPH法）、细胞毒性（MTT法）、氧化应激生物标志物和组蛋白乙酰化。在体内实验中，采用高脂肪饮食喂养的Sprague-Dawley大鼠进行饮食逆转和GABA治疗，以评估其对血糖控制、脂质代谢、肾功能和肝功能、氧化应激和表观遗传调节的影响。结果：GABA与SIRT1具有较强的结合亲和力（-5.8 kcal/mol）和良好的ADME特性。其抗氧化活性高（DPPH IC50: 141.09µg/mL），细胞活力高（5µM时为90.82%），150µM时无细胞毒性。在体外，GABA减少氧化标记物，恢复组蛋白H3乙酰化。在体内，DR GABA （200mg/kg）显著改善了脂质特征：胆固醇降低44.44%，甘油三酯降低28.64%，LDL降低40.80%。相反，HDL增加了103.65%。肾功能（100mg/kg DR GABA）使血尿素降低30.43%，肌酐降低4.65%，尿酸降低75.00%。与对照组相比，肝功能测试（100mg/kg DR GABA）显著降低胆红素53.57%,SGOT/AST 54.24%, SGPT/ALT 39.52%，碱性磷酸酶60.58%，组织病理学特征显示炎症减轻，肾小球结构改善。结论：GABA是二甲双胍类似物，具有抗氧化、保护肾脏和保护肝脏的特性。通过改善代谢谱和恢复表观遗传调节，GABA有望成为解决血糖记忆和预防糖尿病肾病进展的新型治疗药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Drug Targeting 医学-药学

CiteScore

9.10

自引率

0.00%

发文量

165

审稿时长

2 months

期刊介绍： Journal of Drug Targeting publishes papers and reviews on all aspects of drug delivery and targeting for molecular and macromolecular drugs including the design and characterization of carrier systems (whether colloidal, protein or polymeric) for both vitro and/or in vivo applications of these drugs. Papers are not restricted to drugs delivered by way of a carrier, but also include studies on molecular and macromolecular drugs that are designed to target specific cellular or extra-cellular molecules. As such the journal publishes results on the activity, delivery and targeting of therapeutic peptides/proteins and nucleic acids including genes/plasmid DNA, gene silencing nucleic acids (e.g. small interfering (si)RNA, antisense oligonucleotides, ribozymes, DNAzymes), as well as aptamers, mononucleotides and monoclonal antibodies and their conjugates. The diagnostic application of targeting technologies as well as targeted delivery of diagnostic and imaging agents also fall within the scope of the journal. In addition, papers are sought on self-regulating systems, systems responsive to their environment and to external stimuli and those that can produce programmed, pulsed and otherwise complex delivery patterns.