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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介導(dǎo)的膽固醇逆向轉(zhuǎn)運為靶點，富含毛蕊花苷的腺葉茉莉葉提取物改善動脈粥樣硬化并發(fā)癥和血脂異常

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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：腺葉茉莉（Clerodendrum glandulosum）廣泛用于中醫(yī)和印度傳統(tǒng)醫(yī)學(xué)中，用于治療高血壓和糖尿病等疾病。盡管已有許多研究報告其藥理效益，但針對其抗動脈粥樣硬化（AS）特性的研究較少。AS 是一種與脂質(zhì)代謝紊亂（DLD）和炎癥相關(guān)的慢性心血管疾病。本研究旨在鑒定腺葉茉莉提取物中的活性分級，評估其對 AS 和 DLD 的潛在治療效果，并探討其在膽固醇代謝中的分子機制。 方法：本研究采用生物活性引導(dǎo)的分級方法，通過篩選生化酶的抑制潛力來評估腺葉茉莉的活性。將活性分級用于體外試驗，以評估其抗炎和抗細胞粘附性能。在高膽固醇-膽酸-硫脲飲食（CCT）誘導(dǎo)的動脈粥樣硬化大鼠中，每天經(jīng)口給予 50 mg/kg 和 100 mg/kg 的活性分級，評估其對脂質(zhì)、抗氧化指標、炎癥標志物及膽固醇代謝通路的影響，并通過 Western blotting 分析其分子機制。同時，對主動脈、肝臟、心臟和腎臟的組織進行組織病理學(xué)分析。此外，采用分子對接技術(shù)分析了毛蕊花苷（VER）與標準他汀類藥物阿托伐他?。ˋTS）在本研究分子靶點上的結(jié)合能力。 結(jié)果：通過生物活性引導(dǎo)的分級和篩選發(fā)現(xiàn)，乙酸乙酯分級（EAF）中富含主要植物活性成分毛蕊花苷（VER）。EAF 顯示出顯著的酶抑制活性，其對胰脂肪酶的 IC50 值為 1.059 mg/mL，對 α-葡萄糖苷酶的 IC50 值為 22.48 μg/mL。體外實驗結(jié)果表明，EAF 能顯著降低細胞間粘附，從病變對照組的 2.5 倍降至 0.57 倍，并恢復(fù)炎癥細胞因子水平。在 CCT 飲食誘導(dǎo)的大鼠中，升高的血清膽固醇（92.1 mg/dL）和低密度脂蛋白（LDL）（78.49 mg/dL）分別降至 63.52 mg/dL 和 58.51 mg/dL（EAF 100 mg/kg）。同時，EAF 100 mg/kg 將氧化 LDL 水平從 CCT 飲食組的 157.1 ng/mL 降至 53.63 ng/mL。EAF 通過將超氧化物歧化酶（SOD）和過氧化氫酶（CAT）的活性分別提高到 73.78 和 17.72 U/mg 蛋白（CCT 飲食組分別為 42.22 和 9.62 U/mg 蛋白），恢復(fù)抗氧化活性。EAF 還使炎癥因子恢復(fù)至正常水平。組織學(xué)分析表明，EAF 的補充對主動脈、肝臟、心臟和腎臟組織結(jié)構(gòu)的完整性具有保護作用。Western blotting 顯示，EAF 可通過上調(diào)過氧化物酶體增殖物激活受體γ（PPARγ）、肝 X 受體α（LXRα）和 ATP 結(jié)合盒轉(zhuǎn)運體 G1 亞家族成員（ABCG1）以及 LDL 受體（LDL-R）的表達，調(diào)節(jié)肝組織的膽固醇代謝通路。分子對接分析表明，與 ATS 不同，毛蕊花苷在靶分子上表現(xiàn)出較強的相互作用。 結(jié)論：EAF 通過 PPARγ/LXRα/ABCG1 通路的反向膽固醇轉(zhuǎn)運機制，有效預(yù)防了 DLD 和 AS，展現(xiàn)了其在心血管健康領(lǐng)域的潛在治療價值。

    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.

    關(guān)鍵詞:
    動脈粥樣硬化;膽固醇;脂質(zhì)代謝紊亂;腺葉茉莉;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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