Archive > Volume 17 Issue 2 > 2025,17(2):352-367. DOI:ttps://doi.org/10.1016/j.chmed.2025.02.007 Prev Next

以LDL-R和LXR介导的胆固醇逆向转运为靶点，富含毛蕊花苷的腺叶茉莉叶提取物改善动脉粥样硬化并发症和血脂异常

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Amelioration of atherosclerotic complications and dyslipidemia by verbascoside-enriched fraction of Clerodendrum glandulosum leaves targeting LDL-R and LXR-mediated reverse cholesterol transport

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    摘要:
    目的：腺叶茉莉（Clerodendrum glandulosum）广泛用于中医和印度传统医学中，用于治疗高血压和糖尿病等疾病。尽管已有许多研究报告其药理效益，但针对其抗动脉粥样硬化（AS）特性的研究较少。AS 是一种与脂质代谢紊乱（DLD）和炎症相关的慢性心血管疾病。本研究旨在鉴定腺叶茉莉提取物中的活性分级，评估其对 AS 和 DLD 的潜在治疗效果，并探讨其在胆固醇代谢中的分子机制。 方法：本研究采用生物活性引导的分级方法，通过筛选生化酶的抑制潜力来评估腺叶茉莉的活性。将活性分级用于体外试验，以评估其抗炎和抗细胞粘附性能。在高胆固醇-胆酸-硫脲饮食（CCT）诱导的动脉粥样硬化大鼠中，每天经口给予 50 mg/kg 和 100 mg/kg 的活性分级，评估其对脂质、抗氧化指标、炎症标志物及胆固醇代谢通路的影响，并通过 Western blotting 分析其分子机制。同时，对主动脉、肝脏、心脏和肾脏的组织进行组织病理学分析。此外，采用分子对接技术分析了毛蕊花苷（VER）与标准他汀类药物阿托伐他汀（ATS）在本研究分子靶点上的结合能力。 结果：通过生物活性引导的分级和筛选发现，乙酸乙酯分级（EAF）中富含主要植物活性成分毛蕊花苷（VER）。EAF 显示出显著的酶抑制活性，其对胰脂肪酶的 IC50 值为 1.059 mg/mL，对 α-葡萄糖苷酶的 IC50 值为 22.48 μg/mL。体外实验结果表明，EAF 能显著降低细胞间粘附，从病变对照组的 2.5 倍降至 0.57 倍，并恢复炎症细胞因子水平。在 CCT 饮食诱导的大鼠中，升高的血清胆固醇（92.1 mg/dL）和低密度脂蛋白（LDL）（78.49 mg/dL）分别降至 63.52 mg/dL 和 58.51 mg/dL（EAF 100 mg/kg）。同时，EAF 100 mg/kg 将氧化 LDL 水平从 CCT 饮食组的 157.1 ng/mL 降至 53.63 ng/mL。EAF 通过将超氧化物歧化酶（SOD）和过氧化氢酶（CAT）的活性分别提高到 73.78 和 17.72 U/mg 蛋白（CCT 饮食组分别为 42.22 和 9.62 U/mg 蛋白），恢复抗氧化活性。EAF 还使炎症因子恢复至正常水平。组织学分析表明，EAF 的补充对主动脉、肝脏、心脏和肾脏组织结构的完整性具有保护作用。Western blotting 显示，EAF 可通过上调过氧化物酶体增殖物激活受体γ（PPARγ）、肝 X 受体α（LXRα）和 ATP 结合盒转运体 G1 亚家族成员（ABCG1）以及 LDL 受体（LDL-R）的表达，调节肝组织的胆固醇代谢通路。分子对接分析表明，与 ATS 不同，毛蕊花苷在靶分子上表现出较强的相互作用。 结论：EAF 通过 PPARγ/LXRα/ABCG1 通路的反向胆固醇转运机制，有效预防了 DLD 和 AS，展现了其在心血管健康领域的潜在治疗价值。

    Abstract:
    Objective: Clerodendrum glandulosum is widely used in traditional Chinese and Indian systems of medicine for conditions like hypertension and diabetes. While various pharmacological benefits have been reported, research on its anti-atherosclerotic properties remains limited. Atherosclerosis (AS) is a chronic cardiovascular disease linked to dyslipidemia (DLD) and inflammation. This study aims to identify the bioactive fraction from C. glandulosum extract, evaluate its potential against AS and DLD, and explore the molecular mechanisms of cholesterol metabolism. Methods: Bioactivity-guided fractionation was employed to investigate the bioactivity of C. glandulosum by screening biochemical enzyme inhibitory potential. The active fraction was subjected to in vitro testing to assess the anti-inflammatory and anti-adhesion properties. The fraction was administered at 50 and 100 mg/kg per os (p.o.) to cholesterol-cholic acid-thiouracil (CCT) diet-induced atherosclerotic Wistar rats. Changes in lipid and antioxidant profiles, inflammatory markers, and cholesterol metabolism pathways were assessed using Western blotting. Histopathological analyses of the aorta, liver, heart, and kidneys were also conducted. Molecular docking was conducted for the verbascoside (VER) and the standard statin, atorvastatin (ATS), for their binding capabilities with the molecular targets considered in this study. Results: Bioactivity-guided fractionation and screening revealed that ethyl acetate fraction (EAF) contained VER as the principal phytoconstituent. EAF exhibited potent enzyme inhibitory activity, with IC50 values of 1.059 mg/mL for pancreatic lipase and 22.48 lg/mL for a-glucosidase. In vitro analysis revealed that EAF significantly lowered cell-to-cell adhesion to 0.57 folds from 2.5 folds in the disease control and normalized the inflammatory cytokines. In CCT-diet-induced rats, elevated serum cholesterol and low-density lipoproteins (LDL) levels (92.1 mg/dL and 78.49 mg/dL, respectively) were reduced to 63.52 mg/dL and 58.51 mg/dL with EAF at 100 mg/kg. EAF at 100 mg/kg reduced oxidized LDL to 53.63 ng/mL compared to 157.1 ng/mL in CCT-diet-fed rats. EAF also restored antioxidant activity by increasing superoxide dismutase and catalase levels to 73.78 and 17.72 U/mg protein, respectively, compared to 42.22 and 9.62 U/mg protein in CCT-diet-fed rats. EAF restored inflammatory cytokines to normal levels. Histological analyses validated the protective benefits of EAF supplementation for the structural integrity of the aorta, liver, heart, and kidney tissues. Western blotting analysis of liver tissues revealed changes in the cholesterol metabolic pathway by upregulating peroxisome proliferatoractivated receptor gamma (PPARc)/liver X receptor alpha (LXRa)/adenosine triphosphate-binding cassette sub-family G member 1 (ABCG1) and low-density lipoprotein receptor (LDL-R) expression. Unlike ATS, molecular docking analyses indicated strong interactions between VER and molecular targets. Conclusion: EAF prevented DLD and AS by reverse cholesterol transport via the PPARc/LXRa/ABCG1 pathway, offering potential therapeutic benefits for cardiovascular health.

    关键词:
    动脉粥样硬化;胆固醇;脂质代谢紊乱;腺叶茉莉;LDL-R;LXRα;毛蕊花苷

    Keywords:


    Project Supported:
    This work has been supported by the In-house core-funded research project (No. IASST/R&D/ICP/IHP-19/2023-24/1301-1310) of the Institute of Advanced Study in Science and Technology. We sincerely acknowledge the Indian Council of Medical Research for the ICMR-SRF Fellowship granted to Ms. Puspanjali Khound (No. 45/04/2022/TRM/BMS), Sophisticated Analytical Instrument Centre, Institute of Advanced Study in Science and Technology, and the Department of Science and Technology, Government of India, for providing the necessary support. We would also like to acknowledge the Sophisticated Analytical Instrument Facility, the Indian Institute of Technology, Bombay (IIT Bombay) (SAIF), for conducting the HR-LCMS analysis.

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