Bio-Actives from Natural Products with Potential Cardioprotective Properties: Isolation, Identification, and Pharmacological Actions of Apigenin, Quercetin, and Silibinin
Abstract
1. Introduction
2. Literature Search Strategy
3. Results and Discussion
3.1. Chemical Structure, Plant Origin (Family), Methods of Isolation, and Identification
3.1.1. Apigenin
Methods for Isolation: Column Chromatography and Preparative HPLC
Methods for Identification: HPLC and LC-MS Analysis
3.1.2. Quercetin
Methods for Isolation: Column Chromatography and Preparative HPLC
Methods for Identification: HPLC and LC-MS Analysis
3.1.3. Silymarin Extract and Constituents
Methods for Isolation and Identification
Botanical Name (Family) | Extract/Residue-Fraction | Plant Parts | Method/Solvents | References |
---|---|---|---|---|
Apigenin | ||||
Ailanthus excelsa Roxb. [A. excelsus Roxb.] (Simaroubaceae) | 70% Methanol/Ethyl acetate (isolation) | L. | CC (Sephadex LH-20) | [22] |
Chrysanthemum morifolium Ramat. (Asteraceae) | Aqueous, Ethanol (identification) | Fl. | LC-MS | [36] |
Cynara cardunculus L. (Asteraceae) | Aqueous (identification) | L. | HPLC analysis | [35] |
Gentiana veitchiorum Hemsl. (Gentianaceae) | 70% Methanol (identification) | Fl. | HPLC-MS/MS 0.1% formic acid/water and methanol | [31] |
70% Methanol (isolation) | CC (silica gel)/CHCl3-MeOH (100:1 to 1:1), Semi-prep HPLC/MeCN-H2O | |||
Matricaria recutita L. (Asteraceae) | 70% Methanol (isolation) | L. | CC (Sephadex LH-20)/acetone | [30] |
Merremia tridentata (L.) Hallier f. (Convolvulaceae) | Aqueous, 50% Ethanol (isolation; identification) | Stem; R. | CC (silica gel)/MeOH, CHCl3 | [34] |
HPLC-DAD | ||||
Petroselinum crispum (Mill.) Nym. ex A.W. Hill (Apiaceae) | Aqueous/Ethyl acetate (isolation) | L. | CC (Sephadex LH-20)/EtOH | [26] |
Premna foetida Renw. ex Blume (Lamiaceae) | Methanol (identification) | L. | RP-HPLC/0.1% H3PO4: ACN (gradient system) | [27] |
Chloroform (isolation) | CC | |||
Platycodon grandiflorum (Jacq.) A. DC. [P. grandiflorum A. DC.] (Campanulaceae) | Ethanol/Ethyl acetate (isolation) | Fl. | CC (silica gel)/CH2Cl2: MeOH (19:1 to 9:1) | [25] |
Morus indica L. (Moraceae) | 80% Methanol (isolation) | L. | prep-HPLC | [32] |
Sophora alopecuroides L. (Leguminosae) | 75% Ethanol/Ethyl acetate (isolation) | A.p.; R.; S. | CC (Sephadex LH-20)/MeOH | [33] |
Teucrium polium L. (Lamiaceae) | Methanol (isolation) | A.p. | CC (silica gel)/different solvent systems | [23,24] |
CC (Sephadex LH-20)/MeOH | ||||
Ziziphora clinopodioides Lam. (Lamiaceae) | Hydroalcoholic (80% Ethanol:20% Water)/Dichloromethane (isolation) | Whole plant | CC (Sephadex LH-20) Flash CC (silica gel) | [28] |
Quercetin | ||||
Acacia arabica (Lam.) Willd. (Leguminosae) | Hot water (isolation) | B. | RP-HPLC | [59] |
Allium victorialis L. (Alliaceae; Liliaceae p) | 50% Ethanol/Ethyl acetate (isolation) | L. | CC | [44] |
Anacardium humile A.St.-Hil. (Anacardiaceae) | 98% Ethanol (identification) | L. | HPLC-ESI-MS/MS)/water acidified with formic acid (0.1% v/v) and MeOH | [66] |
Artemisia capillaris Thunb. (Asteraceae) | Methanol (isolation) | Whole plant | CC | [43] |
Bauhinia megalandra Griseb. (Leguminosae) | Methanol/Ethyl acetate-acetone (8:2) (isolation) | L. | CC (Sephadex LH-20) | [74] |
Bauhinia strychnifolia Craib. (Leguminosae) | Ethanol/Ethyl acetate (isolation; identification) | Stem | CC (Sephadex LH-20) | [61] |
LC-QTOF/MS | ||||
Bryophyllum pinnatum (Lam.) Oken (Crassulaceae) | Methanol/Ethyl acetate (isolation) | L. | CC (silica gel)/ MeOH:EtOAc:H2O (5:3:2) | [53] |
Carya illinoinensis (Wangenh.) K. Koch (Juglandaceae) | 70% Ethanol (isolation) | B. | CC | [40] |
Cordia boissieri A.DC. (Boraginaceae) | Hydroalcoholic/Ethyl acetate (isolation) | L. | CC (polyamide, Sephadex LH-20) | [51] |
Coreopsis lanceolata L. (Asteraceae) | Methanol/Ethyl acetate (isolation) | Fl. | RP-CC/MeOH:H2O; CH3CN:H2O, CC (Sephadex LH-20)/MeOH | [57] |
Coreopsis tinctoria Nutt. (Asteraceae) | Ethanol (isolation) | Flower buds | ODS-RP-18 column/MeOH: H2O, CC (Sephadex LH-20)/MeOH | [46] |
Crataegus pinnatifida Bge. var. major N.E.Br. [C. pinnatifida f. major (N.E.Br.) W.Lee] (Rosaceae) | 70% Ethanol | L. | CC | [60] |
Cuscuta pedicellata Ledeb. (Convolvulaceae) | Ethanol (isolation) | Whole plant | CC | [48] |
Cyclocarya paliurus (Batal.) Iljinsk. (Juglandaceae; Cyclocaryaceae p) | 75% Ethanol/Chloroform (isolation) | B. | CC (silica gel, Sephadex LH-20) | [41] |
Cynanchum acutum L. (Asclepiadaceae; Apocynaceae p) | Methanol/Ethyl acetate (isolation) | Whole plant | CC (Sephadex LH-20) | [58] |
Dillenia indica Blanco (Dilleniaceae) | Methanol/Ethyl acetate (isolation) | L. | CC | [45] |
Geigeria alata (DC), Oliv. and Hiern. [G. alata Benth. and Hook.f. ex Oliv.] (Asteraceae) | 80% Ethanol/Chloroform, Ethyl acetate (isolation) | n.d. | CC (silica gel)/DCM:MeOH | [56] |
Lactuca serriola L. (Asteraceae) | Methanol (isolation) | A.p. | n.d. | [55] |
Leonurus cardiaca L. (Lamiaceae) | 70% Ethanol (identification) | A.p. | HPLC | [63] |
Mandevilla moricandiana Woodson (Apocynaceae) | Hydroalcoholic (70% Ethanol: 30% Water)/Ethyl acetate (identification) | L. | UHPLC-DAD-ESI-MSn | [65] |
Phyllanthus emblica L. (Euphorbiaceae) | Methanol (isolation) | Fr. | CC (silica gel)/CHCl3: MeOH | [54] |
Polygonum hyrcanicum Rech.f. (Polygonaceae) | Methanol/Ethyl acetate (isolation) | A.p. | CC (silica gel, Sephadex LH-20) | [42] |
Pueraria thomsonii Benth (Fabaceae) | 75% Ethanol/Ethyl acetate (isolation; identification) | L. | CC (silica gel, SHP-20P) | [62] |
HPLC-DAD | ||||
Sarcopyramis nepalensis Wall. (Melastomataceae) | 70% Ethanol/Ethyl acetate (isolation) | Whole plant | CC (Sephadex LH-20/MeOH) | [47] |
Sophora alopecuroides L. (Leguminosae) | 75% Ethanol/Ethyl acetate (isolation) | A.p.; R.; S. | CC (Sephadex LH-20)/MeOH | [33] |
Tetracera indica Merr. [T. indica (Christm. and Panz.) Merr.] (Dilleniaceae) | Ethanol/Ethyl acetate (isolation) | Stems | CC (Silica gel, Sephadex LH-20) | [50] |
Toona sinensis (A.Juss.) M.Roem. (Meliaceae) | 80% Ethanol/Chloroform, Ethyl acetate (isolation) | L. | CC (silica gel)/n-hexane:EtOAc:MeOH, capillary electrophoresis using silica gel CC | [49] |
Ugni molinae Turcz. (Myrtaceae) | Aqueous (identification) | Fr. | HPLC/1% HCOOH: ACN | [64] |
Xenophyllum poposum (Phil.) V.A.Funk (Asteraceae) | Hydroalcoholic (Ethanol:Water, 1:1)/Ethyl acetate (isolation; identification) | A.p. | CC | [52] |
HPLC-DAD-MS/MS | ||||
Flavonolignans and extracts of Silybum marianum (L.) Gaertn. (Asteraceae) | ||||
Silymarin constituents | n.d. (identification) | n.d. | HPLC-DAD/H2O + 0.1% HCOOH; MeOH + 0.1% HCOOH | [69] |
Silychristin | n.d. (isolation) | prep-HPLC | [69] | |
S. marianum | Ethyl acetate (identification) | S. | HPLC/H3PO4: MeOH: H2O (0.5:35:65–0.5:50:50 v/v/v) | [72] |
S. marianum | Ethanol:Water (1:1) (identification) | S. | HPLC-DAD/ water with 0.1% formic acid; MeOH (1:1) | [73] |
3.2. Physicochemical and Biopharmaceutical Properties
3.2.1. Apigenin
3.2.2. Quercetin
3.2.3. Silymarin Extract and Constituents
3.3. Bio-Actives’ Cardiovascular Prevention Activity Based on Preclinical and Clinical Studies
3.3.1. Hypertension
3.3.2. Diabetes
3.3.3. Dyslipidemia
3.3.4. Atherosclerosis
3.3.5. Obesity
3.3.6. Cardiac Injury
3.3.7. Metabolic Syndrome
Cardiovascular Disease | Mechanism | Bio-Active | References |
---|---|---|---|
Hypertension | ↓SBP and DBP | quercetin | [96,109,110] |
↓ADMA | silibinin | [18] | |
↓CXCR4 and SDF-1 | |||
↓PAH | |||
↓ROS, ↓oxidative stress, and ↓MCP-1 | apigenin, quercetin | [11,93,94,95,96] | |
↓overproduction of eNOS and cNOS | [21,103,104,105] | ||
↓lipid peroxides | [97] | ||
Activation of AMPK/SIRT1 | [98,99] | ||
ACE inhibition | [22,102] | ||
Inhibition of calcium exchange | [46,64] | ||
↑NO production/bioavailability and vasorelaxation | quercetin, silibinin | [29,35,41,94,95,96] | |
↓inflammatory cytokines (IL-1β, IL-6, IL-10, TNF-α, and MCP-1) | apigenin, quercetin, silibinin | [11,18,95] | |
Diabetes | Restoration of Bcl-2/Bax levels | apigenin | [126] |
↓ TNF-α and IL-6 | [125] | ||
↓ CK-MB and LDH | [124] | ||
↑insulin release and sensitivity | [24] | ||
Inhibition of PKCβII activation | [104] | ||
↓ICAM-1 and E-selectin | [36] | ||
↓ROS oxidative stress | quercetin | [118] | |
↑glucose uptake via GLUT4 stimulation | [115,116,117,119] | ||
DPP-IV inhibition | [57] | ||
↓ TNF-α, IL-1β, and IFNγ | silibinin/silymarin | [122,123,133] | |
↓pancreatic protein damage and creatinine levels | [135] | ||
↓blood glucose levels | apigenin, quercetin | [32,54] | |
Inhibition of myocardial fibrosis and cardiac remodeling | apigenin, silymarin | [122,126,128,129,130] | |
Inhibition of lipid peroxidation, ↓MDA, and ↑GSH/GSSG ratio | quercetin, silymarin | [72,118,131,132] | |
↓NF-κB/p65 and Akt phosphorylation | apigenin, quercetin, silibinin | [36,49,58,95,123,126] | |
Dyslipidemia | Restoration of HDL, LOX-1, and Bcl-2/Bax levels | quercetin | [139,142,143] |
↓ICAM-1, ↓IL-6, and ↓VCAM-1 | [144,145,146] | ||
↓lipid accumulation | apigenin, quercetin | [139,146] | |
↓BW | [140,141] | ||
↓levels of TC, TG, and LDL | apigenin, quercetin, silymarin | [140,141] | |
Atherosclerosis | ↓proinflammatory cytokines | apigenin | [11,155,159,190] |
↓ICAM-1 and MCP-1 | quercetin | [156,158] | |
↓elastin degradation, ↓macrophage infiltration, and ↓MMP-9 and VCAM-1 expression | [168,169,170] | ||
↓LDL oxidation | silymarin | [165] | |
Induction of autophagy and foam cell formation | apigenin, quercetin | [154,155,156,157] | |
↓atherosclerotic plaque formation | quercetin, silymarin | [17,166] | |
↑ABCA1 and ABCA1-mediated cholesterol efflux | apigenin, quercetin, silymarin | [159,160,161,162,163,164] | |
↓inflammation via TLR-4/NF-κB signaling pathway | |||
Obesity | ↓BW | apigenin, quercetin | [140,176,177] |
↑AMPK phosphorylation | apigenin | [173] | |
↓fatty acid-binding protein 4 and stearoyl-CoA desaturase | |||
Downregulation of MAPK, ERK, and JNK | quercetin | [177] | |
↑glucose uptake | quercetin, silymarin | [59,69,160,178] | |
↓fasting blood glucose levels | quercetin | [42,43,45,61,62] | |
↓activity of pancreatic lipase and fatty acid synthase | apigenin | [174] | |
Cardiac injury | Inhibition of cardiomyocyte apoptosis via the PI3K/Akt and SIRT1/TMBIM6 pathways | quercetin | [12,182,183] |
Stimulation of mitophagy events | [184] | ||
Impedes Ca2+ influx via L-type Ca2+ channels | [186] | ||
Inhibition of MAPK phosphorylation and MDA, LDH, and CK release | [187] | ||
↓MAPK | [194] | ||
Anti-platelet activity | apigenin, quercetin | [26] | |
↓LDL oxidation | [27] | ||
↓myocardial infract size | apigenin, quercetin, silibinin | [189,191,192] | |
↑SOD activity | |||
↓ER and oxidative stress, reverse of inflammation via the NF-kB pathway | silibinin | [193] | |
Metabolic syndrome | ↑insulin secretion and sensitization | quercetin | [120,121] |
↓plasma lipid content | silymarin | [200] | |
↑NAD+ levels in liver | apigenin, silymarin | [75,195] | |
↓inflammatory cytokines | [75,196,197] | ||
↓ROS production and oxidative stress in β pancreatic cells |
Cardiovascular Disease | Study Design | Main Outcomes | Bio-Active | Ref. |
---|---|---|---|---|
Hypertension | Meta-analysis: Seven RCTs, 587 pts, HTN, healthy individuals | ↓SBP | quercetin | [112] |
Meta-analysis: Ten RCTs, 841 pts, HTN, healthy individuals | ↓SBP and DBP | [113] | ||
Cohort study, 15,662 pts, healthy individuals | No effect on hypertension incidence | [114] | ||
Diabetes | Non-controlled pilot study, 15 pts, T2DM | ↓glycosylated hemoglobin, ↓basal insulin, ↓TSH, ↓usCRP, ↓both SBP, ↓DBP | quercetin | [137] |
Meta-analysis: Ten clinical trials, 700 pts, healthy, T2DM, NAFLD | ↓FBG, ↓HbA1c, ↓insulin, ↓TC, ↓TG, ↓LDL, ↑HDL | silymarin | [15] | |
Meta-analysis: Five RCTs, 270 pts, healthy, T2DM | ↓FBG, ↓HbA1c | [138] | ||
Dyslipidemia | Meta-analysis: Five RCTs, 442 pts, healthy, T2DM, HTN, hyperlipidemia | ↓TG | quercetin | [147] |
Meta-analysis: Sixteen RCTs, 1575 pts, healthy, HTN, T2DM, hypercholesterolemic | ↓TC, ↔TG, ↓LDL | [148] | ||
Double-blinded, placebo-controlled cross-over study, 175 pts, overweight with high-CVD risk | ↓LDL | [149] | ||
Randomized, double-blinded, placebo-controlled cross-over trial, 70 pts, overweight-to-obese patients with pre-hypertension | ↔FBG, ↔LDL | [150] | ||
Meta-analysis: Five RCTs, 270 pts, healthy, T2DM | ↔lipid levels | silymarin | [138] | |
Meta-analysis: Eight RCTs, 195 pts, T2DM | ↓FBG, ↓HbA1c, ↓LDL, ↓MDA, ↑HDL | [139] | ||
Meta-analysis: Ten RCTs, 620 pts, hyperlipidemic | ↓TC, ↓TG, ↓LDL, ↑HDL | [152] | ||
Obesity | Randomized, placebo-controlled, double-blind trial, 110 pts, MS | ↓BW, ↓SBP, ↓DBP, ↓TC, ↓LDL, ↓fasting plasma insulin | quercetin | [179] |
Double-blind crossover study, 49 pts, healthy with different APOE isoforms | ↓waist circumference, ↓TG, ↑HDL | [180] | ||
Meta-analysis: Seven RCTs, 896 pts, healthy, obese, HTN | ↓SBP, ↓DBP, ↔BW, ↔BMI, ↔waist circumference, ↔waist-to-hip ratio | [181] | ||
Double-blinded, placebo-controlled cross-over study, 172 pts, overweight, high-CVD risk phenotype | ↓SBP, ↓ox-LDL, ↔TNF-a, ↔C-reactive protein | [149] | ||
Metabolic syndrome | Meta-analysis: Eighteen RCTs, 987 pts, HTN, overweight, MS, T2DM, NAFLD | ↓SBP, ↓DBP, ↓TC, ↓TG, ↓LDL, ↑HDL, ↓glucose levels | quercetin | [202] |
Meta-analysis: Nine RCTs, 781 pts, HTN, T2DM, obesity, PCOS | ↔FBG, ↔HbA1c, ↓insulin, | [203] |
4. Limitations of the Study
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
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Tomou, E.-M.; Papakyriakopoulou, P.; Skaltsa, H.; Valsami, G.; Kadoglou, N.P.E. Bio-Actives from Natural Products with Potential Cardioprotective Properties: Isolation, Identification, and Pharmacological Actions of Apigenin, Quercetin, and Silibinin. Molecules 2023, 28, 2387. https://doi.org/10.3390/molecules28052387
Tomou E-M, Papakyriakopoulou P, Skaltsa H, Valsami G, Kadoglou NPE. Bio-Actives from Natural Products with Potential Cardioprotective Properties: Isolation, Identification, and Pharmacological Actions of Apigenin, Quercetin, and Silibinin. Molecules. 2023; 28(5):2387. https://doi.org/10.3390/molecules28052387
Chicago/Turabian StyleTomou, Ekaterina-Michaela, Paraskevi Papakyriakopoulou, Helen Skaltsa, Georgia Valsami, and Nikolaos P. E. Kadoglou. 2023. "Bio-Actives from Natural Products with Potential Cardioprotective Properties: Isolation, Identification, and Pharmacological Actions of Apigenin, Quercetin, and Silibinin" Molecules 28, no. 5: 2387. https://doi.org/10.3390/molecules28052387
APA StyleTomou, E.-M., Papakyriakopoulou, P., Skaltsa, H., Valsami, G., & Kadoglou, N. P. E. (2023). Bio-Actives from Natural Products with Potential Cardioprotective Properties: Isolation, Identification, and Pharmacological Actions of Apigenin, Quercetin, and Silibinin. Molecules, 28(5), 2387. https://doi.org/10.3390/molecules28052387