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对香豆酸调控TLR4/NF-κB炎症途径抗急性心肌缺血的作用机制

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中草药 | 药理与临床 2026,57(9): 3384-3398

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中草药 |药理与临床 2026 , 57 (9) : 3384 -3398

对香豆酸调控TLR4/NF-κB炎症途径抗急性心肌缺血的作用机制

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蔺虎琴¹, 林珀吏¹, 任萍¹, 陈家黎², 曹博雅¹, 何平³, 毛伯³, 曹俊岭^1,4, 张建³

作者信息

通讯作者:

曹俊岭

作者简介:

蔺虎琴: 蔺虎琴,硕士研究生,研究方向为心血管药理学。E-mail:linhq107@163.com

Mechanisms of p-coumaric acid in attenuating acute myocardial ischemia through regulation of TLR4/NF-κB inflammatory pathway

LIN Huqin, LIN Poli, REN Ping, CHEN Jiali, CAO Boya, HE Ping, MAO Boyan, CAO Junling, ZHANG Jian

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doi: 10.7501/j.issn.0253-2670.2026.09.012

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目的探究对香豆酸抑制炎症途径改善急性心肌缺血（acute myocardial ischemia，AMI）的保护作用和分子机制。方法应用PubChem等数据库预测筛选对香豆酸与AMI的共同靶点，将获得的共同靶点导入STRING数据库构建蛋白相互作用网络（protein-protein interaction，PPI），并对PPI结果进行拓扑分析；利用DAVID数据库和微生信平台进行基因本体（gene ontology，GO）功能和京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）通路富集分析；运用分子对接技术和分子动力学模拟分析对香豆酸与Toll样受体4（Toll-like receptor 4，TLR4）共受体髓样分化因子2（myeloid differentiation 2，MD2）的结合能力和稳定性。采用冠状动脉左前降支结扎法建立AMI小鼠模型，设置假手术组、模型组、对香豆酸（100 mg/kg）组、卡维地洛（7.6 mg/kg）组及TAK-242（3 mg/kg）组，连续给药7 d，末次给药后采用超声心动评价对香豆酸对心功能的保护作用；采用苏木素-伊红（hematoxylin-eosin，HE）及Masson染色观察心肌组织病理学损伤；检测血清中肌酸激酶同工酶（creatine kinase-MB，CK-MB）活性、心肌肌钙蛋白I（cardiac troponin I，cTnI）水平和心肌组织炎症因子水平；采用Western blotting检测心肌组织TLR4/核因子-κB（nuclear factor-κB，NF-κB）炎症通路相关蛋白的表达。构建H9c2心肌细胞缺氧炎症复合损伤模型，进一步探究对香豆酸对TLR4/NF-κB炎症途径的调控机制。结果网络药理学分析显示对香豆酸可作用于TLR4等核心靶点并调控TLR及NF-κB通路治疗AMI，分子对接结果显示对香豆酸与TLR4共受体MD2具有较好的亲和力，分子动力学模拟表明对香豆酸-MD2具有良好的稳定性。动物实验结果显示，对香豆酸能显著改善AMI小鼠心功能（P＜0.01、0.001），减轻心肌组织炎症细胞浸润，抑制胶原蛋白沉积及心肌纤维化，降低血清中CK-MB活性及cTnI水平（P＜0.01、0.001），下调心肌组织中TLR4、p-NF-κB/NF-κB、NOD样受体热蛋白结构域相关蛋白3（NOD-like receptor thermal protein domain associated protein 3，NLRP3）、gasdermin D蛋白（gasdermin D，GSDMD）和白细胞介素-1β（interleukin-1β，IL-1β）蛋白表达以及IL-6水平（P＜0.05、0.01、0.001）。细胞实验结果显示，对香豆酸可显著抑制TLR4、p-NF-κB/NF-κB、NLRP3蛋白表达水平（P＜0.05、0.01）。结论对香豆酸可显著改善AMI小鼠心功能、抑制心肌组织炎症反应及心肌纤维化，其作用机制与调控TLR4/NF-κB炎症途径有关。

关键词

对香豆酸 / 心肌缺血 / 网络药理学 / 分子对接 / 分子动力学模拟 / TLR4 / NF-κB

Abstract

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Objective To investigate the protective effects and underlying molecular mechanisms of p-coumaric acid (p-CA) against acute myocardial ischemia (AMI) through inhibition of inflammatory signaling. Methods Common targets of p-CA and AMI were predicted and screened using databases such as PubChem. These common targets were imported into the STRING database to construct a protein-protein interaction (PPI) network, followed by topological analysis. Gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed using DAVID database and bioinformatics platform. The binding affinity and stability between p-CA and myeloid differentiation 2 (MD2), a co-receptor of Toll-like receptor 4 (TLR4), were analyzed using molecular docking and molecular dynamics simulations. An AMI mouse model was established by ligating the left anterior descending coronary artery. The mice were randomly assigned into sham group, model group, p-CA (100 mg/kg) group, carvedilol (7.6 mg/kg) group and TAK-242 (3 mg/kg) group. After seven consecutive days of treatment, echocardiography was performed to evaluate cardiac function. Myocardial histopathological damage was observed using hematoxylin-eosin (HE) and Masson staining. Activity of creatine kinase-MB, level of cardiac troponin I (cTnI) in serum and levels of inflammatory factors in myocardial tissue were detected. The expressions of proteins related to TLR4/nuclear factor-κB (NF-κB) inflammatory pathway in myocardial tissue were measured by Western blotting. A hypoxia-inflammatory complex injury model in H9c2 cardiomyocytes was constructed to further evaluate the regulatory mechanism of p-CA on TLR4/NF-κB inflammatory signaling pathway. Results Network pharmacology analysis indicated that p-CA could act on core targets such as TLR4 and regulate TLR and NF-κB pathways to treat AMI. Molecular docking results demonstrated that p-CA exhibited favorable binding affinity with MD2, a co-receptor of TLR4. Molecular dynamics simulations further verified that the p-CA-MD2 complex possessed good structural stability. The results of animal experiments showed that p-CA significantly improved cardiac function in AMI mice (P < 0.01, 0.001), alleviated inflammatory cell infiltration in myocardial tissue, inhibited collagen deposition and myocardial fibrosis, and reduced activity of CK-MB and level of cTnI in serum (P < 0.01, 0.001). Furthermore, p-CA downregulated TLR4, p-NF-κB/NF-κB, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), gasdermin D (GSDMD), interleukin-1β (IL-1β) protein expressions and IL-6 level in myocardial tissue (P < 0.05, 0.01, 0.001). The results of cell experiments confirmed that p-CA significantly suppressed the protein expression levels of TLR4, p-NF-κB/NF-κB and NLRP3 (P < 0.05, 0.01). Conclusion p-CA could improve cardiac function in AMI, inhibit myocardial inflammatory response and fibrosis, and its mechanism is associated with the regulation of TLR4/NF-κB inflammatory pathway.

Key words

p-coumaric acid / myocardial ischemia / network pharmacology / molecular docking / molecular dynamics simulation / TLR4 / NF-κB

引用本文

蔺虎琴, 林珀吏, 任萍, 陈家黎, 曹博雅, 何平, 毛伯, 曹俊岭, 张建. 对香豆酸调控TLR4/NF-κB炎症途径抗急性心肌缺血的作用机制. 中草药, 2026 , 57 (9) : 3384 -3398 . DOI: 10.7501/j.issn.0253-2670.2026.09.012

LIN Huqin, LIN Poli, REN Ping, CHEN Jiali, CAO Boya, HE Ping, MAO Boyan, CAO Junling, ZHANG Jian. Mechanisms of p-coumaric acid in attenuating acute myocardial ischemia through regulation of TLR4/NF-κB inflammatory pathway[J]. Chinese Traditional and Herbal Drugs, 2026 , 57 (9) : 3384 -3398 . DOI: 10.7501/j.issn.0253-2670.2026.09.012

基金

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江苏省基础研究计划——青年基金项目(BK20250552);江苏省卓越博士后计划(2024ZB119);中药制药过程控制与智能制造技术全国重点实验室定向课题(SKL2023D02002)

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Vaduganathan M, Mensah G A, Turco J V, et al. The global burden of cardiovascular diseases and risk a compass for future health[J]. J Am Coll Cardiol, 2022, 80(25):2361-2371.
Pagliaro B R, Cannata F, Stefanini G G, et al. Myocardial ischemia and coronary disease in heart failure[J]. Heart Fail Rev, 2020, 25(1):53-65.
Lian Y J, Zhang H Y, Liu H X, et al. Shen Yuan Yi Qi Huo Xue Capsules inhibit neutrophil NETosis by regulating the PAD4/NLRP3 signaling pathway to prevent heart failure after myocardial infarction[J]. Phytomedicine, 2025, 148:157462.
Liu J Q, Wang H J, Li J. Inflammation and inflammatory cells in myocardial infarction and reperfusion injury:A double-edged sword[J]. Clin Med Insights Cardiol, 2016,10:CMC.S33164.
Imbesi A, Greco A, Spagnolo M, et al. Targeting inflammation after acute myocardial infarction[J]. JACC,2025, 86(15):1146-1169.
周成如,姚志刚,杨维维.对香豆酸通过Akt/TSC/m TOR通路对食管癌细胞增殖、凋亡及内质网应激分子信号表达的影响[J].现代中西医结合杂志, 2025,34(3):318-324.
Chen F X, Zhang X X, Wang J X, et al. p-Coumaric acid:Advances in pharmacological research based on oxidative stress[J]. Curr Top Med Chem, 2024, 24(5):416-436.
管西芹,毛近隆,唐迎雪,等.对香豆酸的药理作用研究进展[J].中草药, 2018, 49(17):4162-4170.
Shiromwar S, Chidrawar V. Combined effects of pcoumaric acid and naringenin against doxorubicin-induced cardiotoxicity in rats[J]. Phcog Res, 2011, 3(3):214.
Li N, Guo X Y, Li R, et al. p-Coumaric acid regulates macrophage polarization in myocardial ischemia/reperfusion by promoting the expression of indoleamine2,3-dioxygenase[J]. Bioengineered, 2021, 12(2):10971-10981.
廖韵诺,赵凯丽,郭宏伟.中药网络药理学的研究应用与挑战[J].中草药, 2024, 55(12):4204-4213.
Zhao W B, Wang B Y, Li S. Network pharmacology for traditional Chinese medicine in era of artificial intelligence artificial intelligence[J]. Chin Herb Med, 2024, 16(4):558-560.
Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human Toll-like receptors and related genes[J].Biol Pharm Bull, 2005, 28(5):886-892.
Chong A J, Shimamoto A, Hampton C R, et al. Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart[J]. J Thorac Cardiovasc Surg, 2004, 128(2):170-179.
Bachar O, Adner M, Uddman R, et al. Toll-like receptor stimulation induces airway hyper-responsiveness to bradykinin, an effect mediated by JNK and NF-κB signaling pathways[J]. Eur J Immunol, 2004, 34(4):1196-1207.
Zhang C L, Teng X D, Cao Q H, et al. Gut microbiota dysbiosis exacerbates heart failure by the LPS-TLR4/NF-κB signalling axis:Mechanistic insights and therapeutic potential of TLR4 inhibition[J]. J Transl Med, 2025,23(1):762.
Kawaguchi M, Takahashi M, Hata T, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury[J]. Circulation, 2011, 123(6):594-604.
Roychoudhury S, Sinha B, Choudhury B P, et al.Scavenging properties of plant-derived natural biomolecule para-coumaric acid in the prevention of oxidative stress-induced diseases[J]. Antioxidants, 2021,10(8):1205.
Chen L F, Fu W T, Zheng L L, et al. Recent progress in the discovery of myeloid differentiation 2(MD2)modulators for inflammatory diseases[J]. Drug Discov Today, 2018,23(6):1187-1202.
Pinzi L, Rastelli G. Molecular docking:Shifting paradigms in drug discovery[J]. Int J Mol Sci, 2019, 20(18):4331.
Liu X W, Shi D F, Zhou S Y, et al. Molecular dynamics simulations and novel drug discovery[J]. Expert Opin Drug Discov, 2018, 13(1):23-37.
Sherman B T, Hao M, Qiu J, et al. DAVID a web server for functional enrichment analysis and functional annotation of gene lists(2021 update)[J]. Nucleic Acids Res, 2022,50(W1):W216-W221.
Zhang Y L, Sha R, Wang K G, et al. Protective effects of tetrahydropalmatine against ketamine-induced learning and memory injury via antioxidative, anti-inflammatory and anti-apoptotic mechanisms in mice[J]. Mol Med Rep,2018, 17(5):6873-6880.
Ono Y, Maejima Y, Saito M, et al. TAK-242, a specific inhibitor of Toll-like receptor 4 signalling, prevents endotoxemia-induced skeletal muscle wasting in mice[J].Sci Rep, 2020, 10:694.
Gao J, Yan J, Zu X W, et al. Ferulic acid ameliorates TLR4-mediated macrophage activation by irreversibly binding to peroxiredoxin 1 to inhibit its dimerization and secretion[J]. Phytomedicine, 2025, 148:157254.
Rehman S U, Ali T, Alam S I, et al. Ferulic acid rescues LPS-induced neurotoxicity via modulation of the TLR4receptor in the mouse hippocampus[J]. Mol Neurobiol,2019, 56(4):2774-2790.
Shu C, Li C, Liu H M, et al. 10-Hydroxy-2-decenoic acid ameliorates LPS-induced acute lung injury through targeting MD2-mediated inflammatory signaling pathways[J]. Toxicol Appl Pharmacol, 2025, 505:117589.
Zhang H, Thai P N, Shivnaraine R V, et al. Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target[J]. Cell, 2024, 187(25):7143-7163.
Hansson G K. Inflammation, atherosclerosis, and coronary artery disease[J]. N Engl J Med, 2005, 352(16):1685-1695.
Feng M, Chen X X, Huang F, et al. Alpinetin alleviates cardiac inflammation and remodeling via TLR4/MyD88/NF-κB signaling pathway in rats with acute myocardial infarction[J]. Int J Mol Sci, 2025, 26(20):10073.
Nguyen T U, Kwon S J, Hurh S, et al. LMT2368(1-(4-chlorophenyl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)urea)negatively regulates inflammation by inhibiting NLRP3 inflammasome activation[J]. Pharmaceutics,2025, 17(10):1241.
Liu X, Zhang Z B, Ruan J B, et al. Inflammasomeactivated gasdermin D causes pyroptosis by forming membrane pores[J]. Nature, 2016, 535(7610):153-158.
Xu H, Yang J L, Gao W Q, et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome[J]. Nature, 2014, 513(7517):237-241.
Avlas O, Fallach R, Shainberg A, et al. Toll-like receptor 4stimulation initiates an inflammatory response that decreases cardiomyocyte contractility[J]. Antioxid Redox Signal, 2011, 15(7):1895-1909.
Wang Z, Chu R, Ge H, et al. GRK2-facilitated TLR4signaling promotes cardiac fibrosis in rheumatic mice[J].Int Immunopharmacol, 2025, 157:114709.
Yang R H, Song Z X, Wu S Q, et al. Toll-like receptor 4contributes to a myofibroblast phenotype in cardiac fibroblasts and is associated with autophagy after myocardial infarction in a mouse model[J].Atherosclerosis, 2018, 279:23-31.
Ryu J K, Kim S J, Rah S H, et al. Reconstruction of LPS transfer cascade reveals structural determinants within LBP, CD14, and TLR4-MD2 for efficient LPS recognition and transfer[J]. Immunity, 2017, 46(1):38-50.

2026年第57卷第9期

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doi: 10.7501/j.issn.0253-2670.2026.09.012

接收时间：2025-11-19
首发时间：2026-09-09

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收稿日期：2025-11-19

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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