Therapeutic potential of Ziziphora clinopodioides in cardiovascular diseases: areview

Abstract

Cardiovascular diseases (CVDs) are driven by intricate and multifactorial pathophysiological mechanisms, presenting substantial challenges for the development of effective therapeutic strategies. Recent studies have highlighted the therapeutic potential of various traditional Chinese medicines (TCMs), which exert vasodilatory, anti-inflammatory, and antioxidant effects that may alleviate clinical symptoms and slow CVD progression. Ziziphora clinopodioides, a traditional herbal medicine, contains primarily flavonoids, phenolic acids, and essential oils. These compounds contribute to its pharmacological activities, including inhibition of apoptosis inhibition, inflammation reduction, oxidative stress mitigation, mitochondrial function improvement, and vasodilation promotion, all of which are relevant to CVD treatment. This review comprehensively examines the pathophysiological basis of CVDs, elucidates the molecular mechanisms and signaling pathways involved in the cardioprotective actions of Ziziphora clinopodioides, and summarizes its emerging clinical applications in cardiovascular therapy. The findings aim to inform future research and promote the rational development of this medicinal plant as a complementary or adjunctive treatment for CVDs.

Keywords

Ziziphora clinopodioides / Cardiovascular diseases / Chemical constituents / Pharmacological effects / Herbal combinations / Clinical applications

References

[1] Roth GA, Mensah GA, Johnson CO, et al.Global burden of cardiovascular diseases and risk factors, 199-2019: update from the GBD 2019 study. J Am Coll Cardiol. 2020; 76(25):2982-3021. https://doi.org/10.1016/j.jacc.2020.11.010.

[2] Jebari-Benslaiman S, Galicia-García U, Larrea-Sebal A, et al.Pathophysiology of atherosclerosis. Int J Mol Sci. 2022; 23(6):3346. https://doi.org/10.3390/ijms23063346.

[3] Hao P, Jiang F, Cheng J, et al. Traditional Chinese medicine for cardiovascular disease: evidence and potential mechanisms. J Am Coll Cardiol. 2017; 69(24):2952-2966. https://doi.org/10.1016/j.jacc.2017.04.041.

[4] Man AWC, Li H, Xia N. Circadian rhythm: potential therapeutic target for atherosclerosis and thrombosis. Int J Mol Sci. 2021; 22(2):676. https://doi.org/10.3390/ijms22020676.

[5] Tsao CW, Aday AW, Almarzooq ZI, et al.Heart disease and stroke statistics— 2023 update: a report from the American Heart Association. Circulation. 2023; 147(8):e93-e621. https://doi.org/10.1161/cir.0000000000001123.

[6] Wu S, Xu W, Guan C, et al.Global burden of cardiovascular disease attributable to metabolic risk factors,1990-2019: an analysis of observational data from a 2019 Global Burden of Disease Study. BMJ Open. 2023; 13(5):e069397. https://doi.org/10.1136/bmjopen-2022-069397.

[7] Goldsborough E, Osuji N, Blaha MJ.Assessment of cardiovascular disease risk: a 2022 Update. Endocrinol Metab Clin North Am. 2022; 51(3):483-509. https://doi.org/10.1016/j.ecl.2022.02.005.

[8] Soppert J, Lehrke M, Marx N, et al. Lipoproteins and lipids in cardiovascular disease: from mechanistic insights to therapeutic targeting. Adv Drug Deliv Rev. 2020; 159:4-33. https://doi.org/10.1016/j.addr.2020.07.019.

[9] Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022; 80(14):1366-1418. https://doi.org/10.1016/j.jacc.2022.07.006.

[10] Gao J, Hou T. Cardiovascular disease treatment using traditional Chinese medicine: mitochondria as the Achilles’ heel. Biomed Pharmacother. 2023;164:114999. https://doi.org/10.1016/j.biopha.2023.114999.

[11] Whaley AO, Ivkin DY, Zhaparkulova KA, et al. Chemical composition and cardiotropic activity of Ziziphora clinopodioides subsp. bungeana (Juz.) Rech.f. J Ethnopharmacol. 2023;315:116660. https://doi.org/10.1016/j.jep.2023.116660.

[12] Ahmadi A, Gandomi H, Derakhshandeh A, et al. Phytochemical composition and in vitro safety evaluation of Ziziphora clinopodioides Lam. ethanolic extract: cytotoxicity, genotoxicity and mutagenicity assessment. J Ethnopharmacol. 2021;266:113428. https://doi.org/10.1016/j.jep.2020.113428.

[13] Zhou X, Yu Q, Gong H, et al. GC-MS analysis of Ziziphora clinopodioides essential oil from North Xinjiang, China. Nat Prod Commun. 2012; 7:(1):81-82. https://doi.org/10.1177/1934578x1200700128.

[14] Nemzer BV, Al-Taher F, Yashin A, et al. Cranberry: chemical composition, antioxidant activity and impact on human health: overview. Molecules. 2022; 27(5):1503. https://doi.org/10.3390/molecules27051503.

[15] Ciumărnean L, Milaciu MV, Runcan O, et al. The effects of flavonoids in cardiovascular diseases. Molecules. 2020; 25(18):4320. https://doi.org/10.3390/molecules25184320.

[16] Zhang W, Zheng Y, Yan F, et al. Research progress of quercetin in cardiovascular disease. Front Cardiovasc Med. 2023;10:1203713. https://doi.org/10.3389/fcvm.2023.1203713.

[17] Maleki SJ, Crespo JF, Cabanillas B.Anti-inflammatory effects of flavonoids. Food Chem. 2019;299:125124. https://doi.org/10.1016/j.foodchem.2019.125124.

[18] Joyner PM. Protein adducts and protein oxidation as molecular mechanisms of flavonoid bioactivity. Molecules. 2021; 26(16):5102. https://doi.org/10.3390/molecules26165102.

[19] Yang WJ, Liu C, Gu ZY, et al. Protective effects of acacetin isolated from Ziziphora clinopodioides Lam. (Xintahua) on neonatal rat cardiomyocytes. Chin Med. 2014; 9(1):28. https://doi.org/10.1186/s13020-014-0028-3.

[20] He J, Yang W, Cheng B, et al. Integrated metabolomic and transcriptomic profiling reveals the tissue-specific flavonoid compositions and their biosynthesis pathways in Ziziphora bungeana. Chin Med. 2020; 15(1):73. https://doi.org/10.1186/s13020-020-00354-6.

[21] Zhang XM, An DQ, Guo LL, et al. Identification and screening of active components from Ziziphora clinopodioides Lam. in regulating autophagy. Nat Prod Res. 2019; 33(17):2549-2553. https://doi.org/10.1080/14786419.2018.1452002.

[22] Gursoy N, Sihoglu-Tepe A, Tepe B. Determination of in vitro antioxidative and antimicrobial properties and total phenolic contents of Ziziphora clinopodioides, Cyclotrichium niveum, and Mentha longifolia ssp. typhoides var.typhoides. J Med Food. 2009; 12(3):684-689. https://doi.org/10.1089/jmf.2008.0102.

[23] Sun W, Shahrajabian MH. Therapeutic potential of phenolic compounds in medicinal plants—natural health products for human health. Molecules. 2023; 28(4):1845. https://doi.org/10.3390/molecules28041845.

[24] Afnan, Saleem A, Akhtar MF, et al. Anticancer, cardio-protective and anti-inflammatory potential of natural-sources-derived phenolic acids. Molecules. 2022; 27(21):7286. https://doi.org/10.3390/molecules27217286.

[25] Ali SS, Ahmad WANW, Budin SB, et al. Implication of dietary phenolic acids on inflammation in cardiovascular disease. Rev Cardiovasc Med. 2020; 21(2):225-240. https://doi.org/10.31083/j.rcm.2020.02.49.

[26] Pacifici F, Rovella V, Pastore D, et al. Polyphenols and ischemic stroke: insight into one of the best strategies for prevention and treatment. Nutrients. 2021; 13(6):1967. https://doi.org/10.3390/nu13061967.

[27] Abdelsalam SA, Renu K, Abu ZH, et al. Polyphenols mediate neuroprotection in cerebral ischemic stroke—an update. Nutrients. 2023; 15(5):1107. https://doi.org/10.3390/nu15051107.

[28] Mukherjee S, Chopra H, Goyal R, et al. Therapeutic effect of targeted antioxidant natural products. Discov Nano. 2024; 19(1):144. https://doi.org/10.1186/s11671-024-04100-x.

[29] Li G, Meng Q, Luo B, et al. Isolation of chemical constituents from Ziziphora clinopodioides Lam. with recycling preparative high performance liquid chromatography. Chin J Chromatogr. 2015; 33(1):84-89. https://doi.org/10.3724/sp.j.1123.2014.09033.

[30] Ju YX, Ning L, Li MD, et al. Isolation and identification of constituents from Ziziphora clinopodioides Lam. J Shenyang Pharm Univ. 2008; 25(6):456-458. https://doi.org/10.1631/jzus.B0820047.

[31] Xue L, Fang ZZ, Jun T. Analysis of volatile constituents from Ziziphora clinopodioides Lam. by GC/MS. J Chin Mass Spectr Soc. 2008; 29(2):105-109. https://doi.org/10.3724/SP.J.1011.2008.00529.

[32] Tian S, Shi Y, Yu Q, et al. Determination of oleanolic acid and ursolic acid contents in Ziziphora clinopodioides Lam. by HPLC method. Pharmacogn Mag. 2010; 6(22):116-119. https://doi.org/10.4103/0973-1296.62898.

[33] Nan X, Yang Z, Su S, et al. The mechanism of volatile oil of Rhodiola tangutica against hypoxia-induced pulmonary hypertension in rats based on RAS pathway. BioMed Res Int. 2022;2022:9650650. https://doi.org/10.1155/2022/9650650.

[34] Quintero WL, Moreno EM, Pinto SML, et al. Immunomodulatory, trypanocide, and antioxidant properties of essential oil fractions of Lippia alba (Verbenaceae). BMC Complement Med Ther. 2021; 21(1):187. https://doi.org/10.1186/s12906-021-03347-6.

[35] Holanda TM, Rocha DG, Silveira JAM, et al. Effect of essential oil of Alpinia zerumbet on cardiovascular and autonomic function in rats with isoproterenol induced acute myocardial infarction. An Acad Bras Ciênc. 2023; 95(suppl 1):e20201878. https://doi.org/10.1590/0001-3765202320201878.

[36] Thitinarongwate W, Nimlamool W, Khonsung P, et al. Anti-inflammatory activity of essential oil from Zingiber ottensii Valeton in animal models. Molecules. 2022; 27(13):4260. https://doi.org/10.3390/molecules27134260.

[37] Lai M, Su D, Ai Z, et al. Inhalation of Curcumae Rhizoma volatile oil attenuates depression-like behaviours via activating the Nrf2 pathway to alleviate oxidative stress and improve mitochondrial dysfunction. J Pharm Pharmacol. 2024; 76(11):1449-1462. https://doi.org/10.1093/jpp/rgae082.

[38] Shahbazi Y. Chemical compositions, antioxidant and antimicrobial properties of Ziziphora clinopodioides Lam. essential oils collected from different parts of Iran. J Food Sci Technol. 2017; 54(11):3491-3503. https://doi.org/10.1007/s13197-017-2806-2.

[39] Aljaafari MN, AlAli AO, Baqais L, et al. An overview of the potential therapeutic applications of essential oils. Molecules. 2021; 26(3):628. https://doi.org/10.3390/molecules26030628.

[40] Alves-Silva JM, Zuzarte M, Girão H, et al. The role of essential oils and their main compounds in the management of cardiovascular disease risk factors. Molecules. 2021; 26(12):3506. https://doi.org/10.3390/molecules26123506.

[41] Althurwi HN, Abdel-Kader MS, Alharthy KM, et al. Cymbopogon proximus essential oil protects rats against isoproterenol-induced cardiac hypertrophy and fibrosis. Molecules. 2020; 25(8):1786. https://doi.org/10.3390/molecules25081786.

[42] Gu C, Yang Z, Su S, et al. 4-Terpineol attenuates pulmonary vascular remodeling via suppressing PI3K/Akt signaling pathway in hypoxia-induced pulmonary hypertension rats. Toxicol Appl Pharmacol. 2023;473:116596. https://doi.org/10.1016/j.taap.2023.116596.

[43] Safaeian L, Asghari-Varzaneh M, Alavi SS, et al. Cardiovascular protective effects of cinnamic acid as a natural phenolic acid: a review. Arch Physiol Biochem. 2025; 131(1):52-62. https://doi.org/10.1080/13813455.2024.2387694.

[44] Ding W, Yang T, Liu F, et al. Effect of different growth stages of Ziziphora clinopodioides Lam. on its chemical composition. Pharmacogn Mag. 2014; 10(Suppl 1):S1-S5. https://doi.org/10.4103/0973-1296.127329.

[45] Lei LZ, Rong LJ, Heng W, et al. Composition analysis for the essential oil of Ziziphora clinopodioides Lam. J Shihezi Univ Natl Sci. 2008; 4:483-486. https://doi.org/10.13880/j.cnki.65-1174/n.2008.04.028.

[46] Omer QK, et al.Malik Al-Saadi SAA, Hiwa AH, Antibacterial and antioxidant activity of Ziziphora clinopodioid Lam. (Lamiaceae) essential oil. Arch Razi Inst. 2023; 78(1):205-211. https://doi.org/10.22092/ARI.2022.358487.2228.

[47] Ajourloo M, Khanjari A, Misaghi A, et al. Combined effects of Ziziphora clinopodioides essential oil and lysozyme to extend shelf life and control Listeria monocytogenes in Balkan-style fresh sausage. Food Sci Nutr. 2021; 9(3):1665-1675. https://doi.org/10.1002/fsn3.2141.

[48] Sharopov FS, Setzer WN. Chemical diversity of Ziziphora clinopodioides: composition of the essential oil of Z.clinopodioides from Tajikistan. Nat Prod Commun. 2011; 6(5):695-698. https://doi.org/10.1177/1934578x1100600524.

[49] Keefe P, Puthanveetil P. Compare and contrast of the cellular actions of related flavonoids, apigenin and chrysin. Nutrients. 2024; 16(23):4195. https://doi.org/10.3390/nu16234195.

[50] Ren K, Jiang T, Zhou HF, et al. Apigenin retards atherogenesis by promoting ABCA1-mediated cholesterol efflux and suppressing inflammation. Cell Physiol Biochem. 2018; 47(5):2170-2184. https://doi.org/10.1159/000491528.

[51] Mou A, Sun F, Tong D, et al. Dietary apigenin ameliorates obesity-related hypertension through TRPV4-dependent vasorelaxation and TRPV4-independent adiponectin secretion. Biochim Biophys Acta Mol Basis Dis. 2024; 1870(8): 167488. https://doi.org/10.1016/j.bbadis.2024.167488.

[52] Chen WJ, Cheng Y, Li W, et al. Quercetin attenuates cardiac hypertrophy by inhibiting mitochondrial dysfunction through SIRT3/PARP-1 pathway. Front Pharmacol. 2021;12:739615. https://doi.org/10.3389/fphar.2021.739615.

[53] Kim SG, Kim JR, Choi HC. Quercetin-induced AMP-activated protein kinase activation attenuates vasoconstriction through LKB1-AMPK signaling pathway. J Med Food. 2018; 21(2):146-153. https://doi.org/10.1089/jmf.2017.4052.

[54] Zhang XL, Li JP, Wu MZ, et al. Quercetin protects against hypertensive renal injury by attenuating apoptosis: an integrated approach using network pharmacology and RNA sequencing. J Cardiovasc Pharmacol. 2024; 84(3):370-382. https://doi.org/10.1097/fjc.0000000000001598.

[55] Chekalina N, Burmak Y, Petrov Y, et al. Quercetin reduces the transcriptional activity of NF-κB in stable coronary artery disease. Indian Heart J. 2018; 70(5):593-597. https://doi.org/10.1016/j.ihj.2018.04.006.

[56] Si L, Lai Y. Pharmacological mechanisms by which baicalin ameliorates cardiovascular disease. Front Pharmacol. 2024;15:1415971. https://doi.org/10.3389/fphar.2024.1415971.

[57] Cai Y, Jiang S, Huang C, et al. Baicalin inhibits pressure overload-induced cardiac hypertrophy by regulating the SIRT3-dependent signaling pathway. Phytomedicine. 2023;114:154747. https://doi.org/10.1016/j.phymed.2023.154747.

[58] Zheng L, Zhang C, Li L, et al. Baicalin ameliorates renal fibrosis via inhibition of transforming growth factor β1 production and downstream signal transduction. Mol Med Rep. 2017; 15(4):1702-1712. https://doi.org/10.3892/mmr.2017.6208.

[59] Wu X, Shen A, Bao L, et al. Qingda Granules attenuate hypertensive cardiac remodeling and inflammation in spontaneously hypertensive rats. Biomed Pharmacother. 2020;129:110367. https://doi.org/10.1016/j.biopha.2020.110367.

[60] Zhang T, Deng W, Deng Y, et al. Mechanisms of ferroptosis regulating oxidative stress and energy metabolism in myocardial ischemia-reperfusion injury and a novel perspective of natural plant active ingredients for its treatment. Biomed Pharmacother. 2023;165:114706. https://doi.org/10.1016/j.biopha.2023.114706.

[61] Bréhat J, Leick S, Musman J, et al. Identification of a mechanism promoting mitochondrial sterol accumulation during myocardial ischemia-reperfusion: role of TSPO and STAR. Basic Res Cardiol. 2024; 119(3):481-503. https://doi.org/10.1007/s00395-024-01043-3.

[62] Chang X, Feng X, Li S, et al. Taoren Honghua Decoction alleviates atherosclerosis by inducing autophagy and inhibiting the PI3K-AKT signaling pathway to regulate cholesterol efflux and inflammatory responses. Int Immunopharmacol. 2025;144:113629. https://doi.org/10.1016/j.intimp.2024.113629.

[63] Wu YT, Chen L, Tan ZB, et al. Luteolin inhibits vascular smooth muscle cell proliferation and migration by inhibiting TGFBR1 signaling. Front Pharmacol. 2018;9:1059. https://doi.org/10.3389/fphar.2018.01059.

[64] Jing L, Zhang Y, Fan S, et al. Preventive and ameliorating effects of citrus D-limonene on dyslipidemia and hyperglycemia in mice with high-fat diet-induced obesity. Eur J Pharmacol. 2013; 715(1-3):46-55. https://doi.org/10.1016/j.ejphar.2013.06.022.

[65] Younis NS, Abduldaium MS, Mohamed ME. Protective effect of geraniol on oxidative, inflammatory and apoptotic alterations in isoproterenol-induced cardiotoxicity: role of the Keap1/Nrf2/HO-1 and PI3K/Akt/mTOR pathways. Antioxidants (Basel). 2020; 9(10):977. https://doi.org/10.3390/antiox9100977.

[66] Lin JF, Liu YS, Huang YC, et al. Borneol and tetrandrine modulate the blood-brain barrier and blood-tumor barrier to improve the therapeutic efficacy of 5-fluorouracil in brain metastasis. Integr Cancer Ther. 2022;21:15347354221077682. https://doi.org/10.1177/15347354221077682.

[67] Jin JS, Chou JM, Tsai WC, et al. Effectively α-terpineol suppresses glioblastoma aggressive behavior and downregulates KDELC2 expression. Phytomedicine. 2024;127:155471. https://doi.org/10.1016/j.phymed.2024.155471.

[68] Demirel S. Geraniol and β-citronellol participate in the vasorelaxant effects of Rosa damascena Miller essential oil on the rat thoracic aorta. Fitoterapia. 2022;161:105243. https://doi.org/10.1016/j.fitote.2022.105243.

[69] Cardeal dos SAN, da Cruz FJE, Rodrigues BF, et al. Translational perspectives on the therapeutic potential of Hyptis crenata essential oil terpenes in smooth muscle function. Planta Med. 2024; 90(13):1005-1014. https://doi.org/10.1055/a-2409-3735.

[70] Younis NS, Elsewedy HS, Soliman WE, et al. Geraniol isolated from lemon grass to mitigate doxorubicin-induced cardiotoxicity through Nrf2 and NF-κB signaling. Chem Biol Interact. 2021;347:109599. https://doi.org/10.1016/j.cbi.2021.109599.

[71] Tavakoli PA, Sadeghnezhad G, Azmoun Z, et al. The effect of geraniol on nickel-induced embryotoxicity and cardiotoxicity in rats. Int J Immunopathol Pharmacol. 2024;38:3946320241272693. https://doi.org/10.1177/03946320241272693.

[72] Durço AO, Santos SD, Rhana P, et al. D-Limonene complexed with cyclodextrin attenuates cardiac arrhythmias in an experimental model of doxorubicin-induced cardiotoxicity: possible involvement of calcium/calmodulin-dependent protein kinase type II. Toxicol Appl Pharmacol. 2023;474:116609. https://doi.org/10.1016/j.taap.2023.116609.

[73] Baroutidou A, Dimitroulas T, Arvanitaki A, et al. Endothelial dysfunction in adults with congenital heart disease: a systematic review and meta-analysis. Eur J Clin Invest. 2025; 55(5):e14376. https://doi.org/10.1111/eci.14376.

[74] Wang Y, Bai M, Peng Q, et al. Angiogenesis, a key point in the association of gut microbiota and its metabolites with disease. Eur J Med Res. 2024; 29(1):614. https://doi.org/10.1186/s40001-024-02224-5.

[75] Centner AM, Cullen AE, Khalili L, et al. The role of sex in the effects of smoking and nicotine on cardiovascular function, atherosclerosis, and inflammation. Nicotine Tob Res. 2025; 27(6):1116-1126. https://doi.org/10.1093/ntr/ntae274.

[76] Wendt TS, Ansar S, Gonzales RJ. OxLDL/LOX-1 mediated sex, age, stiffness, and endothelial dependent alterations in mouse thoracic aortic vascular reactivity. Front Physiol. 2024;15:1471272. https://doi.org/10.3389/fphys.2024.1471272.

[77] Laksono S, Kusharsamita H. Unravelling the role of carotid atherosclerosis in predicting cardiovascular disease risk: a review. ARYA Atheroscler. 2024; 20(5):52-59. https://doi.org/10.48305/arya.2024.41271.2862.

[78] Bielikova YO, Khranovskyi AM, Motsak TM, et al. The connection of systemic inflammation and atherosclerosis: what do we know nowadays? Wiad Lek. 2024; 77(11):2332-2339. https://doi.org/10.36740/WLek/197122.

[79] Wang X, Geng S, Dai L, et al. Unc5b prevents macrophage-derived foam cell migration and promotes atherosclerotic development via the P53-cuproptosis signaling pathway. Life Sci. 2025;361:123334. https://doi.org/10.1016/j.lfs.2024.123334.

[80] Mazmanyan D, Zhu R, Gao J, et al. Post-operative venous thromboembolism in patients after extracranial otologic surgery: a case series. J Otol. 2024; 19(2):59-62. https://doi.org/10.1016/j.joto.2024.01.001.

[81] Papazoglou N, Sfikakis PP, Tektonidou MG. Atherosclerotic plaque progression and incident cardiovascular events in a 10-year prospective study of patients with systemic lupus erythematosus: the impact of persistent cardiovascular risk factor target attainment and sustained DORIS remission. Arthritis Rheumatol. 2025; 77(6):716-726. https://doi.org/10.1002/art.43097.

[82] Wu W, Tanweer S, Tapia-Orihuela RKA, et al. Hemodynamic microenvironment of coronary stent strut malapposition. Comput Biol Med. 2025;184:109378. https://doi.org/10.1016/j.compbiomed.2024.109378.

[83] Niu H, Liu Z, Guan Y, et al. Harnessing synergistic effects of MMP-2 inhibition and bFGF to simultaneously preserve and vascularize cardiac extracellular matrix after myocardial infarction. Acta Biomater. 2025; 191:189-204. https://doi.org/10.1016/j.actbio.2024.10.050.

[84] Fleisher TA. Apoptosis. Ann Allergy Asthma Immunol. 1997; 78(3):245-250. https://doi.org/10.1016/s1081-1206(10)63176-6.

[85] Zhu D, Wang H, Wu W, et al. Circulating cell-free DNA fragmentation is a stepwise and conserved process linked to apoptosis. BMC Biol. 2023; 21(1):253. https://doi.org/10.1186/s12915-023-01752-6.

[86] González A, Fortuño MA, Querejeta R, et al.Cardiomyocyte apoptosis in hypertensive cardiomyopathy. Cardiovasc Res. 2003; 59(3):549-562. https://doi.org/10.1016/s0008-6363(03)00498-x.

[87] Azimi M, Mehrzad J, Ahmadi A, et al. Apoptosis induced by Ziziphora tenuior essential oil in human colorectal cancer cells. Biomed Res Int. 2021;2021:5522964. https://doi.org/10.1155/2021/5522964.

[88] Wu Y, Wang Y, Nabi X. Protective effect of Ziziphora clinopodioides flavonoids against H₂O₂-induced oxidative stress in HUVEC cells. Biomed Pharmacother. 2019;117:109156. https://doi.org/10.1016/j.biopha.2019.109156.

[89] Wang X, Bove AM, Simone G, et al. Molecular bases of VEGFR-2-mediated physiological function and pathological role. Front Cell Dev Biol. 2020;8:599281. https://doi.org/10.3389/fcell.2020.599281.

[90] Liu Z, Wang M, Ding X, et al. Exploration the effective components of Gastrodia elata in improving cerebral ischemia reperfusion injury based on “spectrum-effect” correlation and zebrafish verification experiment. Phytomedicine. 2024;135:156211. https://doi.org/10.1016/j.phymed.2024.156211.

[91] Stojanović NM, Ranđelović PJ, Simonović M, et al. Essential oil constituents as anti-inflammatory and neuroprotective agents: an insight through microglia modulation. Int J Mol Sci. 2024; 25(10):5168. https://doi.org/10.3390/ijms25105168.

[92] Kianpour F, Mohseni M, Beigmohamadi M, et al. The protective effects of Ziziphora tenuior L. against chlorpyrifos induced toxicity: involvement of inflammatory and cell death signaling pathway. J Ethnopharmacol. 2021;272:113959. https://doi.org/10.1016/j.jep.2021.113959.

[93] Zhao S, Cheng CK, Zhang CL, et al. Interplay between oxidative stress, cyclooxygenases, and prostanoids in cardiovascular diseases. Antioxid Redox Signal. 2021; 34(10):784-799. https://doi.org/10.1089/ars.2020.8105.

[94] Liu H, Zhang J, Yan X, et al. The anti-atherosclerosis mechanism of Ziziphora clinopodioides Lam. based on network pharmacology. Cell Biochem Biophys. 2023; 81(3):515-532. https://doi.org/10.1007/s12013-023-01151-2.

[95] Jing S, Chong L, Wen C. Protective effect and mechanism of Ziziphora clinopodioides flavonoids against myocardial ischemia-reperfusion injury in Rats. Chin J Exp Tradit Med Form. 2018; 24(14):115-121. https://doi.org/10.13422/j.cnki.syfjx.20181424.

[96] Blanco S, Hernández R, Franchelli G, et al. Melatonin influences NO/NOS pathway and reduces oxidative and nitrosative stress in a model of hypoxic-ischemic brain damage. Nitric Oxide. 2017; 62:32-43. https://doi.org/10.1016/j.niox.2016.12.001.

[97] Ma HX, Wu K, Dong FH, et al. Effects of empagliflozin and dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reduction. Sci Rep. 2024;14:30764. https://doi.org/10.1038/s41598-024-80829-w.

[98] Zhao R, Liang H, Clarke E, et al.Inflammation in chronic wounds. Int J Mol Sci. 2016; 17(12):2085. https://doi.org/10.3390/ijms17122085.

[99] Kozarov E, Huber K, Wojta J. Infection-associated biomarkers of inflammation in atherosclerosis. Curr Pharm Des. 2015; 21(13):1776-1782. https://doi.org/10.2174/1381612821666141129173343.

[100] Wu Y, Wang Y, Liu X, et al. Ziziphora clinopodioides flavonoids based on network pharmacology attenuates atherosclerosis in rats induced by high-fat emulsion combined with vitamin D by down-regulating VEGF/AKT/NF-κB signaling pathway. Biomed Pharmacother. 2020;129:110399. https://doi.org/10.1016/j.biopha.2020.110399.

[101] Ma XY, Zhao HR, Qiao HL, et al. Mechanism of total flavonoids of Ziziphora clinopodioides in improving atherosclerosis by regulating PI3K/Akt/mTOR pathway. Chin J Chin Mater Med. 2023; 48(2):465-471. https://doi.org/10.19540/j.cnki.cjcmm.20220726.403.

[102] Boyman L, Karbowski M, Lederer WJ. Regulation of mitochondrial ATP production: Ca²⁺ signaling and quality control. Trends Mol Med. 2020; 26(1):21-39. https://doi.org/10.1016/j.molmed.2019.10.007.

[103] Adebayo M, Singh S, Singh AP, et al. Mitochondrial fusion and fission: the fine-tune balance for cellular homeostasis. FASEB J. 2021; 35(6):e21620. https://doi.org/10.1096/fj.202100067R.

[104] Xu M, Wang W, Cheng J, et al. Effects of mitochondrial dysfunction on cellular function: role in atherosclerosis. Biomed Pharmacother. 2024;174:116587. https://doi.org/10.1016/j.biopha.2024.116587.

[105] Feng X, Cai W, Li Q, et al. Activation of lysosomal Ca²⁺ channels mitigates mitochondrial damage and oxidative stress. J Cell Biol. 2025;224:e202403104. https://doi.org/10.1083/jcb.202403104.

[106] Cao P, Wang Y, Zhang C, et al. Quercetin ameliorates nonalcoholic fatty liver disease (NAFLD) via the promotion of AMPK-mediated hepatic mitophagy. J Nutr Biochem. 2023;120:109414. https://doi.org/10.1016/j.jnutbio.2023.109414.

[107] Ghafari H, Yasa N, Mohammadirad A, et al. Protection by Ziziphora clinopoides of acetic acid-induced toxic bowel inflammation through reduction of cellular lipid peroxidation and myeloperoxidase activity. Hum Exp Toxicol. 2006; 25(6):325-332. https://doi.org/10.1191/0960327105ht626oa.

[108] Lin ZH, Liu Y, Xue NJ, et al. Quercetin protects against MPP⁺/MPTP-induced dopaminergic neuron death in Parkinson’s disease by inhibiting ferroptosis. Oxid Med Cell Longev. 2022;2022:7769355. https://doi.org/10.1155/2022/7769355.

[109] Gutierrez-Huerta CA, Quiroz-Delfi G, Faleel FDM, et al. Impaired endothelial function contributes to cardiac dysfunction: role of mitochondrial dynamics. Am J Physiol Heart Circ Physiol. 2025; 328(1):H29-H36. https://doi.org/10.1152/ajpheart.00531.2024.

[110] Sawuer GLGN, Wei L kuan MX, et al. Effects of Tianxiangdan on microvascular endothelial structure and functionin rats with coronary microcirculation disorders. Chin J Integr Med Cardio Cerebrovasc Dis. 2022; 20(19):3554-3559. https://doi.org/10.12102/j.issn.1672-1349.2022.19.018.

[111] Sun LF, An DQ, Niyazi GL, et al. Effects of Tianxiangdan Granule treatment on atherosclerosis via NF-κB and p38 MAPK signaling pathways. Mol Med Rep. 2018; 17(1):1642-1650. https://doi.org/10.3892/mmr.2017.8067.

[112] Smith R, Tran K, Smith C, et al. The role of the Nrf2/ARE antioxidant system in preventing cardiovascular diseases. Diseases. 2016; 4(4):34. https://doi.org/10.3390/diseases4040034.

[113] Zhao MF, Sun LF, Xie XL, et al. Proteomic study of Tianxiangdan intervention in rats with myocardial ischemia. J Physiol Pharmacol. 2022; 73(2):13. https://doi.org/10.26402/jpp.2022.2.13.

[114] Shuang Y, Qian W, Yue C, et al. Experimental study on Compound Ziziphora clinopodioides Lam. Granule intervening as plaque inflammation signaling pathways. J Xinjiang Med Univ. 2014; 37(10):1269-1271. https://doi.org/10.3969/j.issn.1009-5551.2014.10.006.

[115] Zhang Y, Zhang XY, Shi SR, et al. Natural products in atherosclerosis therapy by targeting PPARs: a review focusing on lipid metabolism and inflammation. Front Cardiovasc Med. 2024;11:1372055. https://doi.org/10.3389/fcvm.2024.1372055.

[116] Hong CJ, Zhi H, Jun RY, et al. Assessment of using the Ningxintongbi Capsule helpling rehabilitation therapy in chronic heart failure of Tanyuhuzu type. Modern Med J Chin. 2010; 12(5):9-11. https://doi.org/10.3969/j.issn.1672-9463.2010.05.003.

[117] Xin QQ, Chen X, Yuan R, et al. Correlation of platelet and coagulation function with blood stasis syndrome in coronary heart disease: a systematic review and meta-analysis. Chin J Integr Med. 2021; 27(11):858-866. https://doi.org/10.1007/s11655-021-2871-2.

[118] Hong NJ, Ying ZH. Effects of Ningxin Tongbi Capsule on myocardial ischemia and contraction of thoracic aorta in rats. Chin Dispen. 2013; 24(27):2504-2506. https://doi.org/10.6039/j.issn.1001-0408.2013.27.03.

[119] Hong NJ, Ying ZH. Effects of Ningxin Tongbi Capsule on acute myocardial ischemia of Dogs. Chin J Modern Appl Pharm. 2013; 30(8):832-836 https://doi.org/10.13748/j.cnki.issn1007-7693.2013.08.009.

[120] Jiemusi AMGL, Che WY, Sailike JLHSBK, et al. Protective effect of Compound Xinta Flower on myocardial ischemia. Cent South Pharm. 2021; 19(3):418-425. https://doi.org/10.7539/j.issn.1672-2981.2021.03.009.

[121] Wu Y, Wang Y, Xinhua N. Network pharmacology based method for mechanistic investigation of the Compound Xintahua in the treatment of atherosclerosis. TMR Mod Herb Med. 2019; 2(4):225. https://doi.org/10.53388/tmrmhm2017b57.

[122] Zhao H, Ren S, Yang H, et al. Peppermint essential oil: its phytochemistry, biological activity, pharmacological effect and application. Biomed Pharmacother. 2022;154:113559. https://doi.org/10.1016/j.biopha.2022.113559.

[123] Sánchez M, Romero M, Gómez-Guzmán M, et al.Cardiovascular effects of flavonoids. Curr Med Chem. 2019; 26(39):6991-7034. https://doi.org/10.2174/0929867326666181220094721.

[124] de Andrade T, Brasil G, Endringer D, et al. Cardiovascular activity of the chemical constituents of essential oils. Molecules. 2017; 22(9):1539. https://doi.org/10.3390/molecules22091539.

[125] Toma L, Sanda G, Niculescu L, et al. Phenolic compounds exerting lipid-regulatory, anti-inflammatory and epigenetic effects as complementary treatments in cardiovascular diseases. Biomolecules. 2020; 10(4):641. https://doi.org/10.3390/biom10040641.

[126] Torres-Fuentes C, Suárez M, Aragonès G, et al. Cardioprotective properties of phenolic compounds: a role for biological rhythms. Mol Nutr Food Res. 2022; 66(21):2100990. https://doi.org/10.1002/mnfr.202100990.

[127] Nguyen TN, Ahmad F, Lindley RI. Frailty in clinical drug trials: frailty assessments, subgroup analyses and outcomes. Br J Clin Pharmacol. 2025; 91(1):8-22. https://doi.org/10.1111/bcp.16034.

[128] Wojtunik-Kulesza KA. Toxicity of selected monoterpenes and essential oils rich in these compounds. Molecules. 2022; 27(5):1716. https://doi.org/10.3390/molecules27051716.

[129] Taheri A, Ganjeali A, Arefi-Oskouie A, et al. The variability of phenolic constituents and antioxidant properties among wild populations of Ziziphora clinopodioides Lam. Physiol Mol Biol Plants. 2023; 29(2):221-237. https://doi.org/10.1007/s12298-023-01283-y.