Mechanism Repositioning Based on Integrative Pharmacology: Anti-Inflammatory Effect of Safflower in Myocardial Ischemia-Reperfusion Injury

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Mar 29

PMID 36982389

Authors

Feng Zhao

Hong Jiang

Tong Zhang

Hong Chen

Weijie Li

Xin Li

Ping Wang

Haiyu Xu

Affiliations

Soon will be listed here.

Abstract

Safflower (. L) possesses anti-tumor, anti-thrombotic, anti-oxidative, immunoregulatory, and cardio-cerebral protective effects. It is used clinically for the treatment of cardio-cerebrovascular disease in China. This study aimed to investigate the effects and mechanisms of action of safflower extract on myocardial ischemia-reperfusion (MIR) injury in a left anterior descending (LAD)-ligated model based on integrative pharmacology study and ultra-performance liquid chromatography-quadrupole time-of-flight-tandem mass spectrometer (UPLC-QTOF-MS/MS). Safflower (62.5, 125, 250 mg/kg) was administered immediately before reperfusion. Triphenyl tetrazolium chloride (TTC)/Evans blue, echocardiography, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, lactate dehydrogenase (LDH) ability, and superoxide dismutase (SOD) levels were determined after 24 h of reperfusion. Chemical components were obtained using UPLC-QTOF-MS/MS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to analyze mRNA and protein levels, respectively. Safflower dose-dependently reduced myocardial infarct size, improved cardiac function, decreased LDH levels, and increased SOD levels in C57/BL6 mice. A total of 11 key components and 31 hub targets were filtered based on the network analysis. Comprehensive analysis indicated that safflower alleviated inflammatory effects by downregulating the expression of NFκB1, IL-6, IL-1β, IL-18, TNFα, and MCP-1 and upregulating NFκBia, and markedly increased the expression of phosphorylated PI3K, AKT, PKC, and ERK/2, HIF1α, VEGFA, and BCL2, and decreased the level of BAX and phosphorylated p65. Safflower shows a significant cardioprotective effect by activating multiple inflammation-related signaling pathways, including the NFκB, HIF-1α, MAPK, TNF, and PI3K/AKT signaling pathways. These findings provide valuable insights into the clinical applications of safflower.

Citing Articles

Investigation on the Effect of Three Different Nonthermal Sterilization Methods on Volatile Organic Compounds in Safflower Using HS-GC-IMS.

Zou Y, Zhang X, Xiao W, Du Y, Li Y, Ai W ACS Omega. 2025; 10(4):3838-3850.

PMID: 39926510 PMC: 11799980. DOI: 10.1021/acsomega.4c09389.

References

Gonzalez R, Ballester I, Lopez-Posadas R, Suarez M, Zarzuelo A, Martinez-Augustin O . Effects of flavonoids and other polyphenols on inflammation. Crit Rev Food Sci Nutr. 2011; 51(4):331-62. DOI: 10.1080/10408390903584094. View

Islam A, Islam M, Rahman M, Uddin M, Akanda M . The pharmacological and biological roles of eriodictyol. Arch Pharm Res. 2020; 43(6):582-592. DOI: 10.1007/s12272-020-01243-0. View

Zhou M, Ren H, Han J, Wang W, Zheng Q, Wang D . Protective Effects of Kaempferol against Myocardial Ischemia/Reperfusion Injury in Isolated Rat Heart via Antioxidant Activity and Inhibition of Glycogen Synthase Kinase-3β. Oxid Med Cell Longev. 2015; 2015:481405. PMC: 4525766. DOI: 10.1155/2015/481405. View

Reed G, Rossi J, Cannon C . Acute myocardial infarction. Lancet. 2016; 389(10065):197-210. DOI: 10.1016/S0140-6736(16)30677-8. View

Dinda B, Dinda S, DasSharma S, Banik R, Chakraborty A, Dinda M . Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders. Eur J Med Chem. 2017; 131:68-80. DOI: 10.1016/j.ejmech.2017.03.004. View

Fang F, Li D, Pan H, Chen D, Qi L, Zhang R . Luteolin inhibits apoptosis and improves cardiomyocyte contractile function through the PI3K/Akt pathway in simulated ischemia/reperfusion. Pharmacology. 2011; 88(3-4):149-58. DOI: 10.1159/000330068. View

Lu Q, Xu J, Li Q, Wu W, Wu Y, Xie J . Therapeutic Efficacy and Safety of Safflower Injection in the Treatment of Acute Coronary Syndrome. Evid Based Complement Alternat Med. 2021; 2021:6617772. PMC: 7994092. DOI: 10.1155/2021/6617772. View

Serafini M, Peluso I, Raguzzini A . Flavonoids as anti-inflammatory agents. Proc Nutr Soc. 2010; 69(3):273-8. DOI: 10.1017/S002966511000162X. View

Li J, Yan R, Ma P, Fu P, Tian H, Wang L . Effects of luteolin in different doses on the cardiomyocyte apoptosis in rats with myocardial ischemia reperfusion. J Biol Regul Homeost Agents. 2020; 34(6):2311-2315. DOI: 10.23812/20-560-L. View

10.

Challa S, Akula A, Metla S, Gopal P . Partial role of nitric oxide in infarct size limiting effect of quercetin and rutin against ischemia-reperfusion injury in normal and diabetic rats. Indian J Exp Biol. 2011; 49(3):207-10. View

11.

Aziz N, Kim M, Cho J . Anti-inflammatory effects of luteolin: A review of in vitro, in vivo, and in silico studies. J Ethnopharmacol. 2018; 225:342-358. DOI: 10.1016/j.jep.2018.05.019. View

12.

Kolchin I, MAKSIUTINA N, Balanda P, Luik A, Bulakh V, Moibenko A . [The cardioprotective action of quercetin in experimental occlusion and reperfusion of the coronary artery in dogs]. Farmakol Toksikol. 1991; 54(6):20-3. View

13.

Bai Y, Lu P, Han C, Yu C, Chen M, He F . Hydroxysafflor yellow A (HSYA) from flowers of Carthamus tinctorius L. and its vasodilatation effects on pulmonary artery. Molecules. 2013; 17(12):14918-27. PMC: 6268686. DOI: 10.3390/molecules171214918. View

14.

Xiao C, Xia M, Wang J, Zhou X, Lou Y, Tang L . Luteolin Attenuates Cardiac Ischemia/Reperfusion Injury in Diabetic Rats by Modulating Nrf2 Antioxidative Function. Oxid Med Cell Longev. 2019; 2019:2719252. PMC: 6476158. DOI: 10.1155/2019/2719252. View

15.

Hausenloy D, Chilian W, Crea F, Davidson S, Ferdinandy P, Garcia-Dorado D . The coronary circulation in acute myocardial ischaemia/reperfusion injury: a target for cardioprotection. Cardiovasc Res. 2018; 115(7):1143-1155. PMC: 6529918. DOI: 10.1093/cvr/cvy286. View

16.

Song G, Jin M, Du Y, Cao L, Xu H . UPLC-QTOF-MS/MS based screening and identification of the metabolites in rat bile after oral administration of imperatorin. J Chromatogr B Analyt Technol Biomed Life Sci. 2016; 1022:21-29. DOI: 10.1016/j.jchromb.2016.04.007. View

17.

Kim D, Ha K, Kwon D, Kim M, Kim H, Chae S . Kaempferol protects ischemia/reperfusion-induced cardiac damage through the regulation of endoplasmic reticulum stress. Immunopharmacol Immunotoxicol. 2008; 30(2):257-70. DOI: 10.1080/08923970701812530. View

18.

Suchal K, Malik S, Gamad N, Malhotra R, Goyal S, Chaudhary U . Kaempferol Attenuates Myocardial Ischemic Injury via Inhibition of MAPK Signaling Pathway in Experimental Model of Myocardial Ischemia-Reperfusion Injury. Oxid Med Cell Longev. 2016; 2016:7580731. PMC: 4819110. DOI: 10.1155/2016/7580731. View

19.

Ibanez B, Heusch G, Ovize M, Van de Werf F . Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015; 65(14):1454-71. DOI: 10.1016/j.jacc.2015.02.032. View

20.

Yan H, Zou Y, Zou C . [Mechanism of decoction for treatment of COVID-19: analysis based on network pharmacology and molecular docking technology]. Nan Fang Yi Ke Da Xue Xue Bao. 2020; 40(5):616-623. PMC: 7277311. DOI: 10.12122/j.issn.1673-4254.2020.05.02. View