{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:48:11Z","timestamp":1785422891817,"version":"3.56.0"},"reference-count":118,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2024-0033978861382116530101"],"award-info":[{"award-number":["RS-2024-0033978861382116530101"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"award":["RS-2024-0033978861382116530101"],"award-info":[{"award-number":["RS-2024-0033978861382116530101"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Cardiovascular disease (CVDs) and atherosclerosis remain a major causes of morbidity and mortality worldwide. Endothelial dysfunction is a central driver of atherosclerosis, which is significantly accelerated in diabetes mellitus through hyperglycemia-induced oxidative stress, oxidized low-density lipoprotein (oxLDL) accumulation, and NLRP3 inflammasome activation. Phenolic acids, a class of plant-derived polyphenols, have gained attention as vasoprotective agents due to their antioxidant and anti-inflammatory properties. Among them, rosmarinic acid and salvianolic acid have gained attention, yet no previous review has systematically compared their distinct molecular mechanisms. This review addresses the gap by summarizing the pathophysiological mechanisms linking endothelial dysfunction to atherosclerotic progression and comparing how rosmarinic acid and salvianolic acid modulate oxidative stress, nitric oxide signaling, inflammatory responses, and NLRP3 inflammasome activation. Rosmarinic acid primarily exerts its effects through the p38 MAPK-FOXO1-TXNIP and AMPK\/eNOS pathways, while salvianolic acid mainly acts via the PKM2\/PKR and NF-\u0138B\/NLRP3 signaling pathways. Despite these findings, clinical evidence remains limited, primarily limited to Phase 1 pharmacokinetic studies and mixed-extract trials, leaving compound-specific efficacy in humans unverified. This review highlights these translational gaps and suggests prioritizing clinical trials of purified compounds, bioavailability optimization, and dose-standardization studies to advance rosmarinic acid and salvianolic acid toward clinical application in diabetic atherosclerosis.<\/jats:p>","DOI":"10.3390\/ijms27156625","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"6625","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protective Effect of Natural Phenolic Acids, Rosmarinic Acid and Salvianolic Acid, Against Diabetic Atherosclerosis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3389-8100","authenticated-orcid":false,"given":"Yaeram","family":"Won","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea"},{"name":"Department of Convergence Medical Science (BK21 Four), Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7067-6810","authenticated-orcid":false,"given":"Hye Jung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea"},{"name":"Department of Convergence Medical Science (BK21 Four), Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.5334\/gh.1288","article-title":"The heart of the world","volume":"19","author":"Perel","year":"2024","journal-title":"Glob. Heart"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S0140-6736(19)32008-2","article-title":"Modifiable risk factors, cardiovascular disease, and mortality in 155,722 individuals from 21 high-income, middle-income, and low-income countries (PURE): A prospective cohort study","volume":"395","author":"Yusuf","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","article-title":"Global burden of cardiovascular diseases and risk factors, 1990\u20132019: Update from the GBD 2019 study","volume":"76","author":"Roth","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1093\/eurjpc\/zwae281","article-title":"Global burden of cardiovascular diseases: Projections from 2025 to 2050","volume":"32","author":"Chong","year":"2024","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.arcmed.2015.06.006","article-title":"Global overview of the epidemiology of atherosclerotic cardiovascular disease","volume":"46","author":"Barquera","year":"2015","journal-title":"Arch. Med. Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Cho, J.G., Lee, A., Chang, W., Lee, M.-S., and Kim, J. (2018). Endothelial to mesenchymal transition represents a key link in the interaction between inflammation and endothelial dysfunction. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00294"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Poznyak, A., Grechko, A.V., Poggio, P., Myasoedova, V.A., Alfieri, V., and Orekhov, A.N. (2020). The diabetes mellitus\u2013atherosclerosis connection: The role of lipid and glucose metabolism and chronic inflammation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051835"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Karakasis, P., Theofilis, P., Patoulias, D., Vlachakis, P.K., Antoniadis, A.P., and Fragakis, N. (2025). Diabetes-driven atherosclerosis: Updated mechanistic insights and novel therapeutic strategies. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26052196"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.redox.2018.09.025","article-title":"New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis","volume":"20","author":"Yuan","year":"2019","journal-title":"Redox Biol."},{"key":"ref_10","first-page":"7","article-title":"The role of phytomedicine: Bridging the gap between the past, present, and future","volume":"7","author":"Coopoosamy","year":"2025","journal-title":"J. Med. Plants Econ. Dev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dini, I., and Grumetto, L. (2022). Recent advances in natural polyphenol research. Molecules, 27.","DOI":"10.3390\/molecules27248777"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Be\u0161lo, D., Golubi\u0107, N., Rastija, V., Agi\u0107, D., Karna\u0161, M., \u0160ubari\u0107, D., and Lu\u010di\u0107, B. (2023). Antioxidant activity, metabolism, and bioavailability of polyphenols in the diet of animals. Antioxidants, 12.","DOI":"10.3390\/antiox12061141"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"225","DOI":"10.31083\/j.rcm.2020.02.49","article-title":"Implication of dietary phenolic acids on inflammation in cardiovascular disease","volume":"21","author":"Ali","year":"2020","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sun, H.-J., Wu, Z.-Y., Nie, X.-W., and Bian, J.-S. (2020). Role of endothelial dysfunction in cardiovascular diseases: The link between inflammation and hydrogen sulfide. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01568"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Rahimi, N. (2017). Defenders and challengers of endothelial barrier function. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01847"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Katoh, K. (2023). Effects of mechanical stress on endothelial cells in situ and in vitro. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216518"},{"key":"ref_17","first-page":"455","article-title":"Vascular endothelial growth factor (VEGF)-key factor in normal and pathological angiogenesis","volume":"59","author":"Melincovici","year":"2018","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Theofilis, P., Sagris, M., Oikonomou, E., Antonopoulos, A.S., Siasos, G., Tsioufis, C., and Tousoulis, D. (2021). Inflammatory mechanisms contributing to endothelial dysfunction. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070781"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.yjmcc.2015.01.021","article-title":"Cellular and molecular biology of aging endothelial cells","volume":"89","author":"Donato","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.mvr.2018.03.012","article-title":"Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy?","volume":"119","author":"Yuyun","year":"2018","journal-title":"Microvasc. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2853","DOI":"10.1016\/j.cell.2022.06.010","article-title":"Nitric oxide signaling in health and disease","volume":"185","author":"Lundberg","year":"2022","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Tran, J., Magenau, A., Rodriguez, M., Rentero, C., Royo, T., Enrich, C., Thomas, S.R., Grewal, T., and Gaus, K. (2016). Activation of endothelial nitric oxide (eNOS) occurs through different membrane domains in endothelial cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151556"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s11658-023-00423-2","article-title":"Endothelial dysfunction due to eNOS uncoupling: Molecular mechanisms as potential therapeutic targets","volume":"28","author":"Dobrucki","year":"2023","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Chen, W., Xiao, H., Rizzo, A.N., Zhang, W., Mai, Y., and Ye, M. (2014). Endothelial nitric oxide synthase dimerization is regulated by heat shock protein 90 rather than by phosphorylation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105479"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.niox.2015.01.006","article-title":"Endothelium microenvironment sensing leading to nitric oxide mediated vasodilation: A review of nervous and biomechanical signals","volume":"45","author":"Quillon","year":"2015","journal-title":"Nitric Oxide"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.jphs.2015.09.002","article-title":"Vascular nitric oxide: Beyond eNOS","volume":"129","author":"Zhao","year":"2015","journal-title":"J. Pharmacol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1111\/bph.13828","article-title":"Reactive oxygen species: Key regulators in vascular health and diseases","volume":"175","author":"Chen","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.freeradbiomed.2020.11.021","article-title":"The homeostatic role of hydrogen peroxide, superoxide anion and nitric oxide in the vasculature","volume":"162","author":"Costa","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.jacc.2017.05.043","article-title":"Oxidative stress and cardiovascular risk: Obesity, diabetes, smoking, and pollution: Part 3 of a 3-part series","volume":"70","author":"Niemann","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_30","first-page":"1417981","article-title":"Role of the eNOS uncoupling and the nitric oxide metabolic pathway in the pathogenesis of autoimmune rheumatic diseases","volume":"2020","author":"Madej","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Shaito, A., Aramouni, K., Assaf, R., Parenti, A., Orekhov, A., El Yazbi, A., Pintus, G., and Eid, A.H. (2022). Oxidative stress-induced endothelial dysfunction in cardiovascular diseases. Front. Biosci., 27.","DOI":"10.31083\/j.fbl2703105"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Poznyak, A.V., Nikiforov, N.G., Starodubova, A.V., Popkova, T.V., and Orekhov, A.N. (2021). Macrophages and foam cells: Brief overview of their role, linkage, and targeting potential in atherosclerosis. Biomedicines, 9.","DOI":"10.3390\/biomedicines9091221"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11324","DOI":"10.3390\/ijms150711324","article-title":"Endothelial dysfunction in chronic inflammatory diseases","volume":"15","author":"Steyers","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e233","DOI":"10.1161\/ATVBAHA.119.312580","article-title":"Endothelial response to pathophysiological stress","volume":"39","author":"Peng","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e419","DOI":"10.1016\/j.crvasa.2015.08.002","article-title":"Monocyte adhesion to the endothelium is an initial stage of atherosclerosis development","volume":"58","author":"Poledne","year":"2016","journal-title":"Cor Vasa"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.tcm.2008.11.004","article-title":"Monocyte-endothelial cell interactions in the development of atherosclerosis","volume":"18","author":"Mestas","year":"2008","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1194\/jlr.R500008-JLR200","article-title":"Thematic review series: The immune system and atherogenesis. Molecular mechanisms regulating monocyte recruitment in atherosclerosis","volume":"46","author":"Quehenberger","year":"2005","journal-title":"J. Lipid Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Wittchen, E.S. (2009). Endothelial signaling in paracellular and transcellular leukocyte transmigration. Front. Biosci. A J. Virtual Libr., 14.","DOI":"10.2741\/3395"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Medrano-Bosch, M., Sim\u00f3n-Codina, B., Jim\u00e9nez, W., Edelman, E.R., and Melgar-Lesmes, P. (2023). Monocyte-endothelial cell interactions in vascular and tissue remodeling. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1196033"},{"key":"ref_40","first-page":"189","article-title":"Structure of low density lipoprotein (LDL) particles: Basis for understanding molecular changes in modified LDL","volume":"1488","author":"Hevonoja","year":"2000","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Biol. Lipids"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1016\/j.cca.2010.08.038","article-title":"Mechanisms of LDL oxidation","volume":"411","author":"Yoshida","year":"2010","journal-title":"Clin. Chim. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"714653","DOI":"10.1155\/2013\/714653","article-title":"The role of oxidized low-density lipoproteins in atherosclerosis: The myths and the facts","volume":"2013","author":"Maiolino","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/jcmm.12689","article-title":"Macrophage-mediated cholesterol handling in atherosclerosis","volume":"20","author":"Chistiakov","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"41","DOI":"10.3803\/EnM.2017.32.1.41","article-title":"The role of macrophage lipophagy in reverse cholesterol transport","volume":"32","author":"Jeong","year":"2017","journal-title":"Endocrinol. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1093\/cvr\/cvs094","article-title":"Contribution of monocyte-derived macrophages and smooth muscle cells to arterial foam cell formation","volume":"95","author":"Allahverdian","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.tibs.2016.09.002","article-title":"Mechanism and regulation of NLRP3 inflammasome activation","volume":"41","author":"He","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/s41419-020-02985-x","article-title":"NLRP3 inflammasome in endothelial dysfunction","volume":"11","author":"Bai","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.tibs.2022.10.002","article-title":"The NLRP3 inflammasome: Activation and regulation","volume":"48","author":"Xu","year":"2023","journal-title":"Trends Biochem. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1038\/s41423-021-00740-6","article-title":"NLRP3 inflammasome activation and cell death","volume":"18","author":"Huang","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1007\/s10753-021-01439-6","article-title":"The signaling pathways regulating NLRP3 inflammasome activation","volume":"44","author":"Chen","year":"2021","journal-title":"Inflammation"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Chen, P., and Li, X. (2024). NLRP3 inflammasome in atherosclerosis: Mechanisms and targeted therapies. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1430236"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"443","DOI":"10.5551\/jat.RV17001","article-title":"Role of NLRP3 Inflammasomes in Atherosclerosis","volume":"24","author":"Karasawa","year":"2017","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Jubaidi, F.F., Zainalabidin, S., Mariappan, V., and Budin, S.B. (2020). Mitochondrial dysfunction in diabetic cardiomyopathy: The possible therapeutic roles of phenolic acids. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176043"},{"key":"ref_54","first-page":"823539","article-title":"Therapeutic potential of dietary phenolic acids","volume":"2015","author":"Saibabu","year":"2015","journal-title":"Adv. Pharmacol. Pharm. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"114246","DOI":"10.1016\/j.bcp.2020.114246","article-title":"Rosmarinic acid inhibits oxLDL-induced inflammasome activation under high-glucose conditions through downregulating the p38-FOXO1-TXNIP pathway","volume":"182","author":"Nyandwi","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Herrador, S., Corral-Sarasa, J., Gonz\u00e1lez-Garc\u00eda, P., Morillas-Morota, Y., Olivieri, E., Jim\u00e9nez-S\u00e1nchez, L., and D\u00edaz-Casado, M.E. (2025). Natural hydroxybenzoic and hydroxycinnamic acids derivatives: Mechanisms of action and therapeutic applications. Antioxidants, 14.","DOI":"10.3390\/antiox14060711"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1038\/s41598-020-59451-z","article-title":"Structure-antioxidant activity relationship of methoxy, phenolic hydroxyl, and carboxylic acid groups of phenolic acids","volume":"10","author":"Chen","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Kiokias, S., and Oreopoulou, V. (2021). A review of the health protective effects of phenolic acids against a range of severe pathologic conditions (including coronavirus-based infections). Molecules, 26.","DOI":"10.3390\/molecules26175405"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Nadeem, M., Imran, M., Aslam Gondal, T., Imran, A., Shahbaz, M., Muhammad Amir, R., Wasim Sajid, M., Batool Qaisrani, T., Atif, M., and Hussain, G. (2019). Therapeutic potential of rosmarinic acid: A comprehensive review. Appl. Sci., 9.","DOI":"10.3390\/app9153139"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Guan, H., Luo, W., Bao, B., Cao, Y., Cheng, F., Yu, S., Fan, Q., Zhang, L., Wu, Q., and Shan, M. (2022). A comprehensive review of rosmarinic acid: From phytochemistry to pharmacology and its new insight. Molecules, 27.","DOI":"10.3390\/molecules27103292"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"44053","DOI":"10.1039\/C5RA04605J","article-title":"RA abrogates hepatic gluconeogenesis and insulin resistance by enhancing IRS-1 and AMPK signalling in experimental type 2 diabetes","volume":"5","author":"Jayanthy","year":"2015","journal-title":"RSC Adv."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Kowalczyk, A., Tuberoso, C.I.G., and Jerkovi\u0107, I. (2024). The role of Rosmarinic acid in cancer prevention and therapy: Mechanisms of antioxidant and anticancer activity. Antioxidants, 13.","DOI":"10.3390\/antiox13111313"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.bbrc.2009.02.132","article-title":"Up-regulation of thioredoxin interacting protein (Txnip) by p38 MAPK and FOXO1 contributes to the impaired thioredoxin activity and increased ROS in glucose-treated endothelial cells","volume":"381","author":"Li","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Nyandwi, J.-B., Ko, Y.S., Jin, H., Yun, S.P., Park, S.W., and Kim, H.J. (2021). Rosmarinic acid increases macrophage cholesterol efflux through regulation of ABCA1 and ABCG1 in different mechanisms. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168791"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7091904","DOI":"10.1155\/2017\/7091904","article-title":"Rosmarinic acid alleviates the endothelial dysfunction induced by hydrogen peroxide in rat aortic rings via activation of AMPK","volume":"2017","author":"Zhou","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3892\/ijmm.2022.5125","article-title":"Rosmarinic acid downregulates the oxLDL-induced interaction between monocytes and endothelial cells, in addition to monocyte diapedesis, under high glucose conditions","volume":"49","author":"Nyandwi","year":"2022","journal-title":"Int. J. Mol. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"7420","DOI":"10.1021\/acs.jafc.2c01176","article-title":"Rosmarinic acid inhibits platelet aggregation and neointimal hyperplasia in vivo and vascular smooth muscle cell dedifferentiation, proliferation, and migration in vitro via activation of the keap1-Nrf2-ARE antioxidant system","volume":"70","author":"Chen","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"115576","DOI":"10.1016\/j.fct.2025.115576","article-title":"Protective Effects of Rosmarinic Acid Against Oxidative Damage and Atherosclerosis via the PI3K\/AKT Pathway","volume":"203","author":"Tang","year":"2025","journal-title":"Food Chem. Toxicol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Nyandwi, J.B., Ko, Y.S., Jin, H., Yun, S.P., Park, S.W., and Kim, H.J. (2021). Rosmarinic acid exhibits a lipid-lowering effect by modulating the expression of reverse cholesterol transporters and lipid metabolism in high-fat diet-fed mice. Biomolecules, 11.","DOI":"10.3390\/biom11101470"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Ma, L., Tang, L., and Yi, Q. (2019). Salvianolic acids: Potential source of natural drugs for the treatment of fibrosis disease and cancer. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00097"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.7150\/ijbs.37467","article-title":"Salvianolic acid A & B: Potential cytotoxic polyphenols in battle against cancer via targeting multiple signaling pathways","volume":"15","author":"Qin","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1080\/13102818.2018.1532318","article-title":"Biosynthesis of bioactive ingredients of Salvia miltiorrhiza and advanced biotechnologies for their production","volume":"32","author":"Xu","year":"2018","journal-title":"Biotechnol. Biotechnol. Equip."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Liang, Q., Liu, X., Xu, X., Chen, Z., Luo, T., Su, Y., Xie, H., Gao, H., and Xie, C. (2025). Anti-atherosclerotic effects and molecular targets of salvianolic acids from Salvia miltiorrhiza Bunge. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1574086"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Zhu, J., Chen, H., Le, Y., Guo, J., Liu, Z., Dou, X., and Lu, D. (2022). Salvianolic acid A regulates pyroptosis of endothelial cells via directly targeting PKM2 and ameliorates diabetic atherosclerosis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1009229"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"155002","DOI":"10.1016\/j.phymed.2023.155002","article-title":"Salvianolic acid B inhibits atherosclerosis and TNF-\u03b1-induced inflammation by regulating NF-\u03baB\/NLRP3 signaling pathway","volume":"119","author":"Zhao","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"8332825","DOI":"10.1155\/2022\/8332825","article-title":"Salvianolic Acid B Suppresses ER Stress-Induced NLRP3 Inflammasome and Pyroptosis via the AMPK\/FoxO4 and Syndecan-4\/Rac1 Signaling Pathways in Human Endothelial Progenitor Cells","volume":"2022","author":"Tang","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"154694","DOI":"10.1016\/j.phymed.2023.154694","article-title":"Salvianolic acid A alleviates atherosclerosis by inhibiting inflammation through Trc8-mediated 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation","volume":"112","author":"Xie","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Ma, Q., Yang, Q., Chen, J., Yu, C., Zhang, L., Zhou, W., and Chen, M. (2020). Salvianolic acid A ameliorates early-stage atherosclerosis development by inhibiting NLRP3 inflammasome activation in zucker diabetic fatty rats. Molecules, 25.","DOI":"10.3390\/molecules25051089"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"120039","DOI":"10.1016\/j.lfs.2021.120039","article-title":"Salvianolic acid B ameliorates vascular endothelial dysfunction through influencing a bone morphogenetic protein 4-ROS cycle in diabetic mice","volume":"286","author":"Liu","year":"2021","journal-title":"Life Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"112240","DOI":"10.1016\/j.postharvbio.2023.112240","article-title":"Bio-source substances against postharvest diseases of fruits: Mechanisms, applications and perspectives","volume":"198","author":"Chen","year":"2023","journal-title":"Postharvest Biol. Technol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"774","DOI":"10.4162\/nrp.2024.18.6.774","article-title":"p-Coumaric acid modulates cholesterol efflux and lipid accumulation and inflammation in foam cells","volume":"18","author":"Moon","year":"2024","journal-title":"Nutr. Res. Pract."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"109204","DOI":"10.1016\/j.jnutbio.2022.109204","article-title":"Attenuation of hepatic fibrosis by p-Coumaric acid via modulation of NLRP3 inflammasome activation in C57BL\/6 mice","volume":"112","author":"Truong","year":"2023","journal-title":"J. Nutr. Biochem."},{"key":"ref_83","first-page":"74","article-title":"Caffeic acid: A brief overview of its presence, metabolism, and bioactivity","volume":"3","year":"2020","journal-title":"Bioact. Compd. Health Dis."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Migliori, M., Cantaluppi, V., Mannari, C., Bertelli, A.A., Medica, D., Quercia, A.D., Navarro, V., Scatena, A., Giovannini, L., and Biancone, L. (2015). Caffeic acid, a phenol found in white wine, modulates endothelial nitric oxide production and protects from oxidative stress-associated endothelial cell injury. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117530"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"559","DOI":"10.3892\/etm.2023.12257","article-title":"Caffeic acid methyl ester inhibits LPS-induced inflammatory response through Nrf2 activation and NF-\u03baB inhibition in human umbilical vein endothelial cells","volume":"26","author":"Park","year":"2023","journal-title":"Exp. Ther. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jphs.2022.12.006","article-title":"Caffeic acid protects against atherosclerotic lesions and cognitive decline in ApoE\u2212\/\u2212 mice","volume":"151","author":"Sun","year":"2023","journal-title":"J. Pharmacol. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Elseweidy, M.M., Elawady, A.S., Sobh, M.S., Alqhtani, A.H., Al-Gabri, N.A., and Elnagar, G.M. (2023). Potential of caffeic acid and 10-dehydrogingerdione as lipid regulators relevant to their inhibitory effect on miR-122 and ATP citrate lyase activity in diabetic hyperlipidemic rats. Biomedicines, 11.","DOI":"10.3390\/biomedicines11030726"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Alam, M.A. (2019). Anti-hypertensive effect of cereal antioxidant ferulic acid and its mechanism of action. Front. Nutr., 6.","DOI":"10.3389\/fnut.2019.00121"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.fct.2013.12.024","article-title":"Ferulic acid: Pharmacological and toxicological aspects","volume":"65","author":"Mancuso","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.lfs.2015.12.044","article-title":"Ferulic acid enhances nitric oxide production through up-regulation of argininosuccinate synthase in inflammatory human endothelial cells","volume":"145","author":"Zhao","year":"2016","journal-title":"Life Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jff.2018.06.024","article-title":"Ferulic acid inhibits advanced glycation end products (AGEs) formation and mitigates the AGEs-induced inflammatory response in HUVEC cells","volume":"48","author":"Liu","year":"2018","journal-title":"J. Funct. Foods"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1007\/s12265-021-10196-8","article-title":"Ferulic acid alleviates atherosclerotic plaques by inhibiting VSMC proliferation through the NO\/p21 signaling pathway","volume":"15","author":"Wu","year":"2022","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Gu, Y., Zhang, Y., Li, M., Huang, Z., Jiang, J., Chen, Y., Chen, J., Jia, Y., Zhang, L., and Zhou, F. (2021). Ferulic acid ameliorates atherosclerotic injury by modulating gut microbiota and lipid metabolism. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.621339"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1080\/10408347.2015.1095064","article-title":"Gallic acid: Review of the methods of determination and quantification","volume":"46","author":"Fernandes","year":"2016","journal-title":"Crit. Rev. Anal. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Lin, Y., Luo, T., Weng, A., Huang, X., Yao, Y., Fu, Z., Li, Y., Liu, A., Li, X., and Chen, D. (2020). Gallic acid alleviates gouty arthritis by inhibiting NLRP3 inflammasome activation and pyroptosis through enhancing Nrf2 signaling. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.580593"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Yan, X., Zhang, Q.-Y., Zhang, Y.-L., Han, X., Guo, S.-B., and Li, H.-H. (2020). Gallic acid attenuates angiotensin II-induced hypertension and vascular dysfunction by inhibiting the degradation of endothelial nitric oxide synthase. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.01121"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"109132","DOI":"10.1016\/j.jnutbio.2022.109132","article-title":"Gallic acid ameliorates atherosclerosis and vascular senescence and remodels the microbiome in a sex-dependent manner in ApoE\u2212\/\u2212 mice","volume":"110","author":"Clark","year":"2022","journal-title":"J. Nutr. Biochem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"7909971","DOI":"10.1155\/2022\/7909971","article-title":"Low-Dose Gallic Acid Administration Does Not Improve Diet-Induced Metabolic Disorders and Atherosclerosis in Apoe Knockout Mice","volume":"2022","author":"Bai","year":"2022","journal-title":"J. Immunol. Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.tifs.2022.02.023","article-title":"Discovering multifaceted role of vanillic acid beyond flavours: Nutraceutical and therapeutic potential","volume":"122","author":"Kaur","year":"2022","journal-title":"Trends Food Sci. Technol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Festa, J., Hussain, A., Al-Hareth, Z., Bailey, S.J., Singh, H., and Da Boit, M. (2024). Phenolic Metabolites Protocatechuic Acid and Vanillic Acid Improve Nitric Oxide Bioavailability via the Akt-eNOS Pathway in Response to TNF-\u03b1 Induced Oxidative Stress and Inflammation in Endothelial Cells. Metabolites, 14.","DOI":"10.3390\/metabo14110613"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.ejphar.2014.09.010","article-title":"Vanillic acid prevents the deregulation of lipid metabolism, endothelin 1 and up regulation of endothelial nitric oxide synthase in nitric oxide deficient hypertensive rats","volume":"743","author":"Kumar","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Mantzourani, C., Tarantilis, P.A., and Kokotou, M.G. (2023). Carnosic acid and carnosol: Analytical methods for their determination in plants, foods and biological samples. Separations, 10.","DOI":"10.3390\/separations10090481"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.phytochem.2014.12.026","article-title":"Carnosic acid","volume":"115","author":"Dussort","year":"2015","journal-title":"Phytochemistry"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.62347\/FKNZ9461","article-title":"Carnosic acid attenuates diabetic retinopathy via the SIRT1 signaling pathway: Neuroprotection and endothelial cell preservation","volume":"17","author":"Mai","year":"2025","journal-title":"Am. J. Transl. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/ptr.3276","article-title":"Rosemary extracts improve flow-mediated dilatation of the brachial artery and plasma PAI-1 activity in healthy young volunteers","volume":"25","author":"Sinkovic","year":"2011","journal-title":"Phytother. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1007\/s10068-026-02113-z","article-title":"Protective effects of rosemary and ginger extracts on DNA integrity, oxidative stress, and vascular endothelial function: A pilot randomized, double-blind, placebo-controlled trial","volume":"35","author":"Park","year":"2026","journal-title":"Food Sci. Biotechnol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Zhou, A.-m., Xiang, Y.-j., Liu, E.-q., Cai, C.-h., Wu, Y.-h., Yang, L.-b., and Zeng, C.-l. (2020). Salvianolic acid a inhibits platelet activation and aggregation in patients with type 2 diabetes mellitus. BMC Cardiovasc. Disord., 20.","DOI":"10.1186\/s12872-019-01316-z"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e43305","DOI":"10.1097\/MD.0000000000043305","article-title":"Salvianolic acid A inhibits the activation and aggregation of platelets in patients with acute coronary syndrome","volume":"104","author":"Wang","year":"2025","journal-title":"Medicine"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Chen, P., Zhang, H., Gao, Z., Shi, D., and Zhang, J. (2024). Efficacy and safety of salvianolate injection in treating acute myocardial infarction: A meta-analysis and systematic literature review. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1478558"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"100726","DOI":"10.1016\/j.phyplu.2024.100726","article-title":"Unlocking the potential of Rosmarinic acid: A review on extraction, isolation, quantification, pharmacokinetics and pharmacology","volume":"5","author":"Harindranath","year":"2025","journal-title":"Phytomed. Plus"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e4561","DOI":"10.1002\/bmc.4561","article-title":"Pharmacokinetics of salvianolic acid B, rosmarinic acid and Danshensu in rat after pulmonary administration of Salvia miltiorrhiza polyphenolic acid solution","volume":"33","author":"Lu","year":"2019","journal-title":"Biomed. Chromatogr."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"9057","DOI":"10.1039\/C6RA28237G","article-title":"Pharmacokinetics of rosmarinic acid in rats by LC-MS\/MS: Absolute bioavailability and dose proportionality","volume":"7","author":"Wang","year":"2017","journal-title":"RSC Adv."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Melero, J., L\u00f3pez-Mitjavila, J.-J., Garc\u00eda-Celma, M.J., Rodriguez-Abreu, C., and Grijalvo, S. (2022). Rosmarinic acid-loaded polymeric nanoparticles prepared by low-energy nano-emulsion templating: Formulation, biophysical characterization, and in vitro studies. Materials, 15.","DOI":"10.3390\/ma15134572"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"6147315","DOI":"10.1155\/2018\/6147315","article-title":"Liposomal incorporation to improve dissolution and stability of rosmarinic acid and carvacrol extracted from oregano (O. onites L.)","volume":"2018","author":"Baranauskaite","year":"2018","journal-title":"BioMed Res. Int."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"He, G., Chen, G., Liu, W., Ye, D., Liu, X., Liang, X., and Song, J. (2023). Salvianolic acid B: A review of pharmacological effects, safety, combination therapy, new dosage forms, and novel drug delivery routes. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15092235"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Bumrungpert, A., Lilitchan, S., Tuntipopipat, S., Tirawanchai, N., and Komindr, S. (2018). Ferulic acid supplementation improves lipid profiles, oxidative stress, and inflammatory status in hyperlipidemic subjects: A randomized, double-blind, placebo-controlled clinical trial. Nutrients, 10.","DOI":"10.3390\/nu10060713"},{"key":"ref_117","unstructured":"Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (2016). Botanical Drug Development: Guidance for Industry, U.S. Food and Drug Administration."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Ji, X., Huang, K., Lu, A., Hu, X., and Wu, H. (2025). Protective effect of Salvianolic acid B against atherosclerosis: A preclinical systematic review and meta-analysis. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1548811"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6625\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:11:40Z","timestamp":1785211900000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":118,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156625"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156625","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]}}}