New Insight into the Mechanisms of Ginkgo Biloba Extract in Vascular Aging Prevention

Author(s): Xiaoxue Li, Liuyi Lu, Jie Chen, Chao Zhang, Hong Chen, Hui Huang*

Journal Name: Current Vascular Pharmacology

Volume 18 , Issue 4 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Aging-associated vascular dysfunction promotes cardiovascular diseases. Recently, Ginkgo biloba extract (GBE) has attracted considerable attention in the prevention of aged vasculature.

Methods: This review discusses the pathophysiological alterations in aged vasculature and the underlying mechanisms of GBE in vascular aging suppression.

Results: Both arterial stiffening and endothelial dysfunction are critical aging-related vascular phenotypes that result in the progression of cardiovascular diseases in the general population. Consistent oxidative stress and inflammatory reaction lead to vascular dysfunction. GBE ameliorates aging-related vascular dysfunction, due to its antioxidant and anti-inflammatory properties. The main effects of GBE in aged vasculature might be associated with the longevity signaling pathways. GBE also attenuates the progression of vascular aging in diabetes mellitus via regulation of glucose and lipid metabolism.

Conclusion: GBE plays an important role in the prevention of vascular aging process. It is a promising therapeutic approach to ameliorate aging-related vascular dysfunction and cardiovascular diseases.

Keywords: Ginkgo biloba extract (GBE), aging, vascular dysfunction, oxidative stress, inflammation, longevity pathways.

Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation 2003; 107(1): 139-46.
[] [PMID: 12515756]
Najjar SS, Scuteri A, Lakatta EG. Arterial aging: is it an immutable cardiovascular risk factor? Hypertension 2005; 46(3): 454-62.
[] [PMID: 16103272]
Alfaras I, Di Germanio C, Bernier M, et al. Pharmacological strategies to retard cardiovascular aging. Circ Res 2016; 118(10): 1626-42.
[] [PMID: 27174954]
Nowak KL, Rossman MJ, Chonchol M, Seals DR. Strategies for achieving healthy vascular aging. Hypertension 2018; 71(3): 389-402.
[] [PMID: 29311256]
Bjørklund G, Dadar M, Martins N, et al. Brief challenges on medicinal plants: an eye-opening look at ageing-related disorders. Basic Clin Pharmacol Toxicol 2018; 122(6): 539-58.
[] [PMID: 29369521]
Zuo W, Yan F, Zhang B, Li J, Mei D. Advances in the studies of Ginkgo biloba leaves extract on aging-related diseases. Aging Dis 2017; 8(6): 812-26.
[] [PMID: 29344418]
Chan PC, Xia Q, Fu PP. Ginkgo biloba leave extract: biological, medicinal, and toxicological effects. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2007; 25(3): 211-44.
[] [PMID: 17763047]
Cicero AFG, Fogacci F, Banach M. Botanicals and phytochemicals active on cognitive decline: The clinical evidence. Pharmacol Res 2018; 130: 204-12.
[] [PMID: 29289576]
Ong Lai Teik D, Lee XS, Lim CJ, Low CM, Muslima M, Aquili L. Ginseng and Ginkgo biloba effects on cognition as modulated by cardiovascular reactivity: a randomised trial. PLoS One 2016; 11(3) e0150447
[] [PMID: 26938637]
Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med 2000; 108(4): 276-81.
[] [PMID: 11014719]
Fan Y, Jin X, Man C, Gong D. Does adjuvant treatment with Ginkgo biloba to statins have additional benefits in patients with dyslipidemia? Front Pharmacol 2018; 9: 659.
[] [PMID: 29988404]
Wu Y, Li S, Cui W, Zu X, Du J, Wang F. Ginkgo biloba extract improves coronary blood flow in healthy elderly adults: role of endothelium-dependent vasodilation. Phytomedicine 2008; 15(3): 164-9.
[] [PMID: 18258419]
Tian J, Liu Y, Chen K. Ginkgo biloba extract in vascular protection: molecular mechanisms and clinical applications. Curr Vasc Pharmacol 2017; 15(6): 532-48.
[] [PMID: 28707602]
Diamond BJ, Shiflett SC, Feiwel N, et al. Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil 2000; 81(5): 668-78.
[] [PMID: 10807109]
North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res 2012; 110(8): 1097-108.
[] [PMID: 22499900]
Niiranen TJ, Lyass A, Larson MG, et al. Prevalence, correlates, and prognosis of healthy vascular aging in a western community-dwelling cohort: the framingham heart study. Hypertension 2017; 70(2): 267-74.
[] [PMID: 28559398]
Currie G, Delles C. Healthy vascular aging. Hypertension 2017; 70(2): 229-31.
[] [PMID: 28559393]
Kucharska-Newton AM, Stoner L, Meyer ML. Determinants of vascular age: an epidemiological perspective. Clin Chem 2019; 65(1): 108-18.
[] [PMID: 30459170]
Zachariah JP, Rong J, Larson MG, et al. Metabolic predictors of change in vascular function: prospective associations from a community-based cohort. Hypertension 2018; 71(2): 237-42.
[] [PMID: 29279312]
Terentes-Printzios D, Vlachopoulos C, Xaplanteris P, et al. Cardiovascular risk factors accelerate progression of vascular aging in the general population: results from the CRAVE Study (cardiovascular risk factors affecting vascular age). Hypertension 2017; 70(5): 1057-64.
[] [PMID: 28923899]
Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010; 55(13): 1318-27.
[] [PMID: 20338492]
Lu Y, Zhu M, Bai B, et al. Comparison of carotid-femoral and brachial-ankle pulse-wave velocity in association with target organ damage in the community-dwelling elderly chinese: the northern shanghai study. J Am Heart Assoc 2017; 6(2) e004168
[] [PMID: 28219916]
van Sloten TT, Schram MT, van den Hurk K, et al. Local stiffness of the carotid and femoral artery is associated with incident cardiovascular events and all-cause mortality: the Hoorn study. J Am Coll Cardiol 2014; 63(17): 1739-47.
[] [PMID: 24583306]
Paneni F, Diaz Cañestro C, Libby P, Lüscher TF, Camici GG. The aging cardiovascular system: understanding it at the cellular and clinical levels. J Am Coll Cardiol 2017; 69(15): 1952-67.
[] [PMID: 28408026]
Durham AL, Speer MY, Scatena M, Giachelli CM, Shanahan CM. Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc Res 2018; 114(4): 590-600.
[] [PMID: 29514202]
Lacolley P, Regnault V, Avolio AP. Smooth muscle cell and arterial aging: basic and clinical aspects. Cardiovasc Res 2018; 114(4): 513-28.
[] [PMID: 29514201]
Sehgel NL, Vatner SF, Meininger GA. Smooth muscle cell stiffness syndrome-revisiting the structural basis of arterial stiffness. Front Physiol 2015; 6: 335.
[] [PMID: 26635621]
Qiu H, Zhu Y, Sun Z, et al. Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging. Circ Res 2010; 107(5): 615-9.
[] [PMID: 20634486]
Sehgel NL, Sun Z, Hong Z, et al. Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging. Hypertension 2015; 65(2): 370-7.
[] [PMID: 25452471]
Tesauro M, Mauriello A, Rovella V, et al. Arterial ageing: from endothelial dysfunction to vascular calcification. J Intern Med 2017; 281(5): 471-82.
[] [PMID: 28345303]
Ungvari Z, Tarantini S, Kiss T, et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat Rev Cardiol 2018; 15(9): 555-65.
[] [PMID: 29795441]
Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation 2005; 111(3): 363-8.
[] [PMID: 15668353]
Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003; 42(7): 1149-60.
[] [PMID: 14522472]
Walker AE, Henson GD, Reihl KD, et al. Greater impairments in cerebral artery compared with skeletal muscle feed artery endothelial function in a mouse model of increased large artery stiffness. J Physiol 2015; 593(8): 1931-43.
[] [PMID: 25627876]
Bellien J, Favre J, Iacob M, et al. Arterial stiffness is regulated by nitric oxide and endothelium-derived hyperpolarizing factor during changes in blood flow in humans. Hypertension 2010; 55(3): 674-80.
[] [PMID: 20083732]
Della Corte V, Tuttolomondo A, Pecoraro R, Di Raimondo D, Vassallo V, Pinto A. Inflammation, endothelial dysfunction and arterial stiffness as therapeutic targets in cardiovascular medicine. Curr Pharm Des 2016; 22(30): 4658-68.
[] [PMID: 27160758]
Winter JC. The effects of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat. Physiol Behav 1998; 63(3): 425-33.
[] [PMID: 9469738]
Wu Z, Smith JV, Paramasivam V, et al. Ginkgo biloba extract EGb 761 increases stress resistance and extends life span of Caenorhabditis elegans. Cell Mol Biol 2002; 48(6): 725-31.
[PMID: 12396085]
Kampkötter A, Pielarski T, Rohrig R, et al. The Ginkgo biloba extract EGb761 reduces stress sensitivity, ROS accumulation and expression of catalase and glutathione S-transferase 4 in Caenorhabditis elegans. Pharmacol Res 2007; 55(2): 139-47.
[] [PMID: 17207635]
Liu J, Wang J, Chen X, Guo C, Guo Y, Wang H. Ginkgo biloba extract EGB761 protects against aging-associated diastolic dysfunction in cardiomyocytes of D-galactose-induced aging rat. Oxid Med Cell Longev 2012; 2012 418748
[] [PMID: 22693651]
Dong XX, Hui ZJ, Xiang WX, Rong ZF, Jian S, Zhu CJ. Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity. J Cardiovasc Pharmacol 2007; 49(2): 111-5.
[] [PMID: 17312453]
Nishida S, Satoh H. Mechanisms for the vasodilations induced by Ginkgo biloba extract and its main constituent, bilobalide, in rat aorta. Life Sci 2003; 72(23): 2659-67.
[] [PMID: 12672511]
Nishida S, Satoh H. Age-related changes in the vasodilating actions of Ginkgo biloba extract and its main constituent, bilobalide, in rat aorta. Clin Chim Acta 2005; 354(1-2): 141-6.
[] [PMID: 15748610]
Nishida S, Satoh H. Comparative vasodilating actions among terpenoids and flavonoids contained in Ginkgo biloba extract. Clin Chim Acta 2004; 339(1-2): 129-33.
[] [PMID: 14687903]
Cui L, Li Z, Chang X, Cong G, Hao L. Quercetin attenuates vascular calcification by inhibiting oxidative stress and mitochondrial fission. Vascul Pharmacol 2017; 88: 21-9.
[] [PMID: 27932069]
Beazley KE, Eghtesad S, Nurminskaya MV. Quercetin attenuates warfarin-induced vascular calcification in vitro independently from matrix Gla protein. J Biol Chem 2013; 288(4): 2632-40.
[] [PMID: 23223575]
Schöttker B, Brenner H, Jansen EH, et al. Evidence for the free radical/oxidative stress theory of ageing from the CHANCES consortium: a meta-analysis of individual participant data. BMC Med 2015; 13: 300.
[] [PMID: 26666526]
Jayedi A, Rashidy-Pour A, Parohan M, Zargar MS, Shab-Bidar S. Dietary antioxidants, circulating antioxidant concentrations, total antioxidant capacity, and risk of all-cause mortality: a systematic review and dose-response meta-analysis of prospective observational studies. Adv Nutr 2018; 9(6): 701-16.
[] [PMID: 30239557]
Donato AJ, Eskurza I, Silver AE, et al. Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB. Circ Res 2007; 100(11): 1659-66.
[] [PMID: 17478731]
Kim M, Kim M, Yoo HJ, Lee SY, Lee SH, Lee JH. Age-specific determinants of pulse wave velocity among metabolic syndrome components, inflammatory markers, and oxidative stress. J Atheroscler Thromb 2018; 25(2): 178-85.
[] [PMID: 28740031]
Nagaoka T, Kuo L, Ren Y, Yoshida A, Hein TW. C-reactive protein inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production. Invest Ophthalmol Vis Sci 2008; 49(5): 2053-60.
[] [PMID: 18436840]
Li H, Förstermann U. Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr Opin Pharmacol 2013; 13(2): 161-7.
[] [PMID: 23395155]
Durrant JR, Seals DR, Connell ML, et al. Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase. J Physiol 2009; 587(Pt 13): 3271-85.
[] [PMID: 19417091]
Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med 2013; 60: 1-4.
[] [PMID: 23434764]
Jung IH, Lee YH, Yoo JY, et al. Ginkgo biloba extract (GbE) enhances the anti-atherogenic effect of cilostazol by inhibiting ROS generation. Exp Mol Med 2012; 44(5): 311-8.
[] [PMID: 22282402]
Chen JW, Chen YH, Lin FY, Chen YL, Lin SJ. Ginkgo biloba extract inhibits tumor necrosis factor-alpha-induced reactive oxygen species generation, transcription factor activation, and cell adhesion molecule expression in human aortic endothelial cells. Arterioscler Thromb Vasc Biol 2003; 23(9): 1559-66.
[] [PMID: 12893683]
Koltermann A, Hartkorn A, Koch E, Fürst R, Vollmar AM, Zahler S. Ginkgo biloba extract EGb 761 increases endothelial nitric oxide production in vitro and in vivo. Cell Mol Life Sci 2007; 64(13): 1715-22.
[] [PMID: 17497242]
Tsai HY, Huang PH, Lin FY, Chen JS, Lin SJ, Chen JW. Ginkgo biloba extract reduces high-glucose-induced endothelial reactive oxygen species generation and cell adhesion molecule expression by enhancing HO-1 expression via Akt/eNOS and p38 MAP kinase pathways. Eur J Pharm Sci 2013; 48(4-5): 803-11.
[] [PMID: 23357604]
Guimarães DA, Rizzi E, Ceron CS, et al. Atorvastatin and sildenafil decrease vascular TGF-β levels and MMP-2 activity and ameliorate arterial remodeling in a model of renovascular hypertension. Redox Biol 2015; 6: 386-95.
[] [PMID: 26343345]
Tsai KL, Chang YL, Huang PH, et al. Ginkgo biloba extract inhibits oxidized low-density lipoprotein (oxLDL)-induced matrix metalloproteinase activation by the modulation of the lectin-like oxLDL receptor 1-regulated signaling pathway in human umbilical vein endothelial cells. J Vasc Surg 2016; 63(1): 204-15.
[] [PMID: 25080882]
Li D, Liu L, Chen H, Sawamura T, Ranganathan S, Mehta JL. LOX-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells. Circulation 2003; 107(4): 612-7.
[] [PMID: 12566375]
Förstermann U, Xia N, Li H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res 2017; 120(4): 713-35.
[] [PMID: 28209797]
Collins AR, Lyon CJ, Xia X, et al. Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes. Circ Res 2009; 104(6): e42-54.
[] [PMID: 19265038]
Donato AJ, Walker AE, Magerko KA, et al. Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice. Aging Cell 2013; 12(5): 772-83.
[] [PMID: 23714110]
Fukai T, Ushio-Fukai M. Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 2011; 15(6): 1583-606.
[] [PMID: 21473702]
Zhou RH, Vendrov AE, Tchivilev I, et al. Mitochondrial oxidative stress in aortic stiffening with age: the role of smooth muscle cell function. Arterioscler Thromb Vasc Biol 2012; 32(3): 745-55.
[] [PMID: 22199367]
Wenzel P, Schuhmacher S, Kienhöfer J, et al. Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction. Cardiovasc Res 2008; 80(2): 280-9.
[] [PMID: 18596060]
Satoh K, Godo S, Saito H, Enkhjargal B, Shimokawa H. Dual roles of vascular-derived reactive oxygen species--with a special reference to hydrogen peroxide and cyclophilin A. J Mol Cell Cardiol 2014; 73: 50-6.
[] [PMID: 24406688]
Oelze M, Kröller-Schön S, Steven S, et al. Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging. Hypertension 2014; 63(2): 390-6.
[] [PMID: 24296279]
Choi S, Kim JA, Li HY, et al. KCa 3.1 upregulation preserves endothelium-dependent vasorelaxation during aging and oxidative stress. Aging Cell 2016; 15(5): 801-10.
[] [PMID: 27363720]
Rodríguez-Martínez MA, Alonso MJ, Redondo J, Salaíces M, Marín J. Role of lipid peroxidation and the glutathione-dependent antioxidant system in the impairment of endothelium-dependent relaxations with age. Br J Pharmacol 1998; 123(1): 113-21.
[] [PMID: 9484861]
Sadowska-Krępa E, Kłapcińska B, Pokora I, Domaszewski P, Kempa K, Podgórski T. Effects of six-week ginkgo biloba supplementation on aerobic performance, blood pro/antioxidant balance, and serum brain-derived neurotrophic factor in physically active men. Nutrients 2017; 9(8): 803.
[] [PMID: 28933745]
Ran K, Yang DL, Chang YT, et al. Ginkgo biloba extract postconditioning reduces myocardial ischemia reperfusion injury. Genet Mol Res 2014; 13(2): 2703-8.
[] [PMID: 24782084]
Mozet C, Martin R, Welt K, Fitzl G. Cardioprotective effect of EGb 761 on myocardial ultrastructure of young and old rat heart and antioxidant status during acute hypoxia. Aging Clin Exp Res 2009; 21(1): 14-21.
[] [PMID: 19225264]
Ou HC, Lee WJ, Lee IT, et al. Ginkgo biloba extract attenuates oxLDL-induced oxidative functional damages in endothelial cells. J Appl Physiol 2009; 106(5): 1674-85.
Chen JX, Zeng H, Chen X, Su CY, Lai CC. Induction of heme oxygenase-1 by Ginkgo biloba extract but not its terpenoids partially mediated its protective effect against lysophosphatidylcholine-induced damage. Pharmacol Res 2001; 43(1): 63-9.
[] [PMID: 11207067]
Cheng D, Liang B, Li Y. Antihyperglycemic effect of Ginkgo biloba extract in streptozotocin-induced diabetes in rats. BioMed Res Int 2013; 2013 162724
[] [PMID: 23509685]
Lian N, Tong J, Li W, Wu J, Li Y. Ginkgetin ameliorates experimental atherosclerosis in rats. Biomed Pharmacother 2018; 102: 510-6.
[] [PMID: 29579712]
Zheng Y, Wu Z, Yi F, et al. By activating Akt/eNOS bilobalide b inhibits autophagy and promotes angiogenesis following focal cerebral ischemia reperfusion. Cell Physiol Biochem 2018; 47(2): 604-16.
[] [PMID: 29794436]
Cheung F, Siow YL. Inhibition by ginkgolides and bilobalide of the production of nitric oxide in macrophages (THP-1) but not in endothelial cells (HUVEC). Biochem Pharmacol 2001; 61(4): 503-10.
[] [PMID: 11226385]
Ma L, Liu X, Zhao Y, Chen B, Li X, Qi R. Ginkgolide B reduces LOX-1 expression by inhibiting Akt phosphorylation and increasing Sirt1 expression in oxidized LDL-stimulated human umbilical vein endothelial cells. PLoS One 2013; 8(9) e74769
[] [PMID: 24069345]
Jimenez R, Lopez-Sepulveda R, Romero M, et al. Quercetin and its metabolites inhibit the membrane NADPH oxidase activity in vascular smooth muscle cells from normotensive and spontaneously hypertensive rats. Food Funct 2015; 6(2): 409-14.
[] [PMID: 25562607]
Singh T, Newman AB. Inflammatory markers in population studies of aging. Ageing Res Rev 2011; 10(3): 319-29.
[] [PMID: 21145432]
Miles EA, Rees D, Banerjee T, et al. Age-related increases in circulating inflammatory markers in men are independent of BMI, blood pressure and blood lipid concentrations. Atherosclerosis 2008; 196(1): 298-305.
[] [PMID: 17118371]
Donato AJ, Black AD, Jablonski KL, Gano LB, Seals DR. Aging is associated with greater nuclear NF kappa B, reduced I kappa B alpha, and increased expression of proinflammatory cytokines in vascular endothelial cells of healthy humans. Aging Cell 2008; 7(6): 805-12.
[] [PMID: 18782346]
Scuteri A, Orru M, Morrell C, et al. Independent and additive effects of cytokine patterns and the metabolic syndrome on arterial aging in the SardiNIA Study. Atherosclerosis 2011; 215(2): 459-64.
[] [PMID: 21241986]
Heringa SM, van den Berg E, Reijmer YD, et al. Markers of low-grade inflammation and endothelial dysfunction are related to reduced information processing speed and executive functioning in an older population - the Hoorn Study. Psychoneuroendocrinology 2014; 40: 108-18.
[] [PMID: 24485482]
Chung HY, Cesari M, Anton S, et al. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev 2009; 8(1): 18-30.
[] [PMID: 18692159]
Mozos I, Malainer C, Horbańczuk J, et al. Inflammatory markers for arterial stiffness in cardiovascular diseases. Front Immunol 2017; 8: 1058.
[] [PMID: 28912780]
Angel K, Provan SA, Gulseth HL, Mowinckel P, Kvien TK, Atar D. Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: a controlled study. Hypertension 2010; 55(2): 333-8.
[] [PMID: 20038753]
Csiszar A, Labinskyy N, Smith K, Rivera A, Orosz Z, Ungvari Z. Vasculoprotective effects of anti-tumor necrosis factor-alpha treatment in aging. Am J Pathol 2007; 170(1): 388-98.
[] [PMID: 17200210]
Arenas IA, Xu Y, Davidge ST. Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-alpha antagonism. Am J Physiol Heart Circ Physiol 2006; 290(3): H1259-63.
[] [PMID: 16284227]
Wang M, Zhang J, Telljohann R, et al. Chronic matrix metalloproteinase inhibition retards age-associated arterial proinflammation and increase in blood pressure. Hypertension 2012; 60(2): 459-66.
[] [PMID: 22689745]
Siegel G, Ermilov E, Knes O, Rodríguez M. Combined lowering of low grade systemic inflammation and insulin resistance in metabolic syndrome patients treated with Ginkgo biloba. Atherosclerosis 2014; 237(2): 584-8.
[] [PMID: 25463092]
Jiao YB, Rui YC, Li TJ, Yang PY, Qiu Y. Expression of pro-inflammatory and anti-inflammatory cytokines in brain of atherosclerotic rats and effects of Ginkgo biloba extract. Acta Pharmacol Sin 2005; 26(7): 835-9.
[] [PMID: 15960890]
Li EG, Tian J, Xu ZH. Effects of Gingko biloba extract (EGb 761) on vascular smooth muscle cell calcification induced by β-glycerophosphate. Ren Fail 2016; 38(4): 552-7.
[] [PMID: 26908182]
Chen JS, Chen YH, Huang PH, et al. Ginkgo biloba extract reduces high-glucose-induced endothelial adhesion by inhibiting the redox-dependent interleukin-6 pathways. Cardiovasc Diabetol 2012; 11: 49.
[] [PMID: 22553973]
Li Y, Wu Y, Yao X, et al. Ginkgolide A ameliorates LPS-induced inflammatory responses in vitro and in vivo. Int J Mol Sci 2017; 18(4) E794
[] [PMID: 28394269]
Feng Z, Yang X, Zhang L, et al. Ginkgolide B ameliorates oxidized low-density lipoprotein-induced endothelial dysfunction via modulating Lectin-like ox-LDL-receptor-1 and NADPH oxidase 4 expression and inflammatory cascades. Phytother Res 2018; 32(12): 2417-27.
[] [PMID: 30136446]
Zhao Q, Gao C, Cui Z. Ginkgolide A reduces inflammatory response in high-glucose-stimulated human umbilical vein endothelial cells through STAT3-mediated pathway. Int Immunopharmacol 2015; 25(2): 242-8.
[] [PMID: 25681539]
Chen K, Sun W, Jiang Y, et al. Ginkgolide B suppresses TLR4-mediated inflammatory response by inhibiting the phosphorylation of JAK2/STAT3 and p38 mapk in high glucose-treated HUVECs. Oxid Med Cell Longev 2017; 2017 9371602
[] [PMID: 28785380]
de Almeida AJPO, Ribeiro TP, de Medeiros IA. Aging: molecular pathways and implications on the cardiovascular system. Oxid Med Cell Longev 2017; 2017 7941563
[] [PMID: 28874954]
Donato AJ, Machin DR, Lesniewski LA. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ Res 2018; 123(7): 825-48.
[] [PMID: 30355078]
Watanabe R, Wei L, Huang J. mTOR signaling, function, novel inhibitors, and therapeutic targets. J Nucl Med 2011; 52(4): 497-500.
[] [PMID: 21421716]
Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009; 460(7253): 392-5.
[] [PMID: 19587680]
Lesniewski LA, Seals DR, Walker AE, et al. Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways. Aging Cell 2017; 16(1): 17-26.
[] [PMID: 27660040]
De Meyer GR, Grootaert MO, Michiels CF, Kurdi A, Schrijvers DM, Martinet W. Autophagy in vascular disease. Circ Res 2015; 116(3): 468-79.
[] [PMID: 25634970]
Nussenzweig SC, Verma S, Finkel T. The role of autophagy in vascular biology. Circ Res 2015; 116(3): 480-8.
[] [PMID: 25634971]
LaRocca TJ, Gioscia-Ryan RA, Hearon CM Jr, Seals DR. The autophagy enhancer spermidine reverses arterial aging. Mech Ageing Dev 2013; 134(7-8): 314-20.
[] [PMID: 23612189]
Lu Q, Zuo WZ, Ji XJ, et al. Ethanolic Ginkgo biloba leaf extract prevents renal fibrosis through Akt/mTOR signaling in diabetic nephropathy. Phytomedicine 2015; 22(12): 1071-8.
[] [PMID: 26547529]
Koh PO. Gingko biloba extract (EGb 761) prevents cerebral ischemia-induced p70S6 kinase and S6 phosphorylation. Am J Chin Med 2010; 38(4): 727-34.
[] [PMID: 20626058]
Mazumder AG, Sharma P, Patial V, Singh D. Ginkgo biloba L. attenuates spontaneous recurrent seizures and associated neurological conditions in lithium-pilocarpine rat model of temporal lobe epilepsy through inhibition of mammalian target of rapamycin pathway hyperactivation. J Ethnopharmacol 2017; 204: 8-17.
[] [PMID: 28390940]
Lee YJ, Choi HS, Seo MJ, Jeon HJ, Kim KJ, Lee BY. Kaempferol suppresses lipid accumulation by inhibiting early adipogenesis in 3T3-L1 cells and zebrafish. Food Funct 2015; 6(8): 2824-33.
[] [PMID: 26174858]
Che J, Liang B, Zhang Y, Wang Y, Tang J, Shi G. Kaempferol alleviates ox-LDL-induced apoptosis by up-regulation of autophagy via inhibiting PI3K/Akt/mTOR pathway in human endothelial cells. Cardiovasc Pathol 2017; 31: 57-62.
[] [PMID: 28985493]
He Y, Cao X, Guo P, et al. Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia. Free Radic Biol Med 2017; 103: 165-76.
[] [PMID: 27979659]
Garcia D, Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 2017; 66(6): 789-800.
[] [PMID: 28622524]
Lesniewski LA, Zigler MC, Durrant JR, Donato AJ, Seals DR. Sustained activation of AMPK ameliorates age-associated vascular endothelial dysfunction via a nitric oxide-independent mechanism. Mech Ageing Dev 2012; 133(5): 368-71.
[] [PMID: 22484146]
Bradley EA, Eringa EC, Stehouwer CD, et al. Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside in the muscle microcirculation increases nitric oxide synthesis and microvascular perfusion. Arterioscler Thromb Vasc Biol 2010; 30(6): 1137-42.
[] [PMID: 20224051]
Wang S, Zhang M, Liang B, et al. AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. Circ Res 2010; 106(6): 1117-28.
[] [PMID: 20167927]
Cheang WS, Tian XY, Wong WT, et al. Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5′ adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor δ pathway. Arterioscler Thromb Vasc Biol 2014; 34(4): 830-6.
[] [PMID: 24482374]
Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun 2013; 4: 2192.
[] [PMID: 23900241]
Ou HC, Hsieh YL, Yang NC, et al. Ginkgo biloba extract attenuates oxLDL-induced endothelial dysfunction via an AMPK-dependent mechanism. J Appl Physiol J Appl Physiol 2013; 114(2): 2192-85.
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): 146-53.
[] [PMID: 29035613]
Shen Y, Croft KD, Hodgson JM, et al. Quercetin and its metabolites improve vessel function by inducing eNOS activity via phosphorylation of AMPK. Biochem Pharmacol 2012; 84(8): 1036-44.
[] [PMID: 22846602]
Wu J, Xu X, Li Y, et al. Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3-mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. Eur J Pharmacol 2014; 745: 59-68.
[] [PMID: 25446924]
Cao C, Han D, Su Y, Ge Y, Chen H, Xu A. Ginkgo biloba exocarp extracts induces autophagy in Lewis lung cancer cells involving AMPK / mTOR / p70S6k signaling pathway. Biomed Pharmacother 2017; 93: 1128-35.
[] [PMID: 28738521]
Chen BL, Wang LT, Huang KH, Wang CC, Chiang CK, Liu SH. Quercetin attenuates renal ischemia/reperfusion injury via an activation of AMP-activated protein kinase-regulated autophagy pathway. J Nutr Biochem 2014; 25(11): 1226-34.
[] [PMID: 25087994]
Zhang Y, Miao JM. Ginkgolide K promotes astrocyte proliferation and migration after oxygen-glucose deprivation via inducing protective autophagy through the AMPK/mTOR/ULK1 signaling pathway. Eur J Pharmacol 2018; 832: 96-103.
[] [PMID: 29787772]
Ueda T, Inden M, Shirai K, et al. The effects of Brazilian green propolis that contains flavonols against mutant copper-zinc superoxide dismutase-mediated toxicity. Sci Rep 2017; 7(1): 2882.
[] [PMID: 28588226]
Kitada M, Ogura Y, Koya D. The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis. Aging (Albany NY) 2016; 8(10): 2290-307.
[] [PMID: 27744418]
Donato AJ, Magerko KA, Lawson BR, Durrant JR, Lesniewski LA, Seals DR. SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. J Physiol 2011; 589(Pt 18): 4545-54.
[] [PMID: 21746786]
Gano LB, Donato AJ, Pasha HM, Hearon CM Jr, Sindler AL, Seals DR. The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice. Am J Physiol Heart Circ Physiol 2014; 307(12): H1754-63.
[] [PMID: 25326534]
Gao D, Zuo Z, Tian J, et al. activation of sirt1 attenuates klotho deficiency-induced arterial stiffness and hypertension by enhancing amp-activated protein kinase activity. Hypertension 2016; 68(5): 1191-9.
[] [PMID: 27620389]
Mitchell SJ, Martin-Montalvo A, Mercken EM, et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep 2014; 6(5): 836-43.
[] [PMID: 24582957]
Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 2013; 25(10): 1939-48.
[] [PMID: 23770291]
Longpré F, Garneau P, Christen Y, Ramassamy C. Protection by EGb 761 against beta-amyloid-induced neurotoxicity: involvement of NF-kappaB, SIRT1, and MAPKs pathways and inhibition of amyloid fibril formation. Free Radic Biol Med 2006; 41(12): 1781-94.
[] [PMID: 17157181]
Zhang J, Yang S, Chen F, Li H, Chen B. Ginkgetin aglycone ameliorates LPS-induced acute kidney injury by activating SIRT1 via inhibiting the NF-κB signaling pathway. Cell Biosci 2017; 7: 44.
[] [PMID: 28852469]
Hung CH, Chan SH, Chu PM, Tsai KL. Quercetin is a potent anti-atherosclerotic compound by activation of SIRT1 signaling under oxLDL stimulation. Mol Nutr Food Res 2015; 59(10): 1905-17.
[] [PMID: 26202455]
Ganesan S, Faris AN, Comstock AT, et al. Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression. Respir Res 2010; 11: 131.
[] [PMID: 20920189]
Huang WC, Chen YL, Liu HC, Wu SJ, Liou CJ. Ginkgolide C reduced oleic acid-induced lipid accumulation in HepG2 cells. Saudi Pharm J 2018; 26(8): 1178-84.
[] [PMID: 30532639]
Peng J, Li Q, Li K, et al. quercetin improves glucose and lipid metabolism of diabetic rats: involvement of Akt signaling and SIRT1. J Diabetes Res 2017; 2017 3417306
[] [PMID: 29379801]
Laakso M, Kuusisto J. Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat Rev Endocrinol 2014; 10(5): 293-302.
[] [PMID: 24663222]
Cameron JD, Bulpitt CJ, Pinto ES, Rajkumar C. The aging of elastic and muscular arteries: a comparison of diabetic and nondiabetic subjects. Diabetes Care 2003; 26(7): 2133-8.
[] [PMID: 12832325]
Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J 2013; 34(31): 2436-43.
[] [PMID: 23641007]
Chia CW, Egan JM, Ferrucci L. Age-related changes in glucose metabolism, hyperglycemia, and cardiovascular risk. Circ Res 2018; 123(7): 886-904.
[] [PMID: 30355075]
Li XS, Zheng WY, Lou SX, Lu XW, Ye SH. Effect of Ginkgo leaf extract on vascular endothelial function in patients with early stage diabetic nephropathy. Chin J Integr Med 2009; 15(1): 26-9.
[] [PMID: 19271166]
Rhee KJ, Lee CG, Kim SW, Gim DH, Kim HC, Jung BD. Extract of ginkgo biloba ameliorates streptozotocin-induced type 1 diabetes mellitus and high-fat diet-induced type 2 diabetes mellitus in mice. Int J Med Sci 2015; 12(12): 987-94.
[] [PMID: 26664261]
Banin RM, Hirata BK, Andrade IS, et al. Beneficial effects of Ginkgo biloba extract on insulin signaling cascade, dyslipidemia, and body adiposity of diet-induced obese rats. Braz J Med Biol Res 2014; 47(9): 780-8.
[] [PMID: 25075573]
Natalicchio A, Tortosa F, Labarbuta R, et al. The p66(Shc) redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells. Diabetologia 2015; 58(6): 1260-71.
[] [PMID: 25810038]
Varshney R, Varshney R, Mishra R, Gupta S, Sircar D, Roy P. Kaempferol alleviates palmitic acid-induced lipid stores, endoplasmic reticulum stress and pancreatic β-cell dysfunction through AMPK/mTOR-mediated lipophagy. J Nutr Biochem 2018; 57: 212-27.
[] [PMID: 29758481]
Liu G, Grifman M, Macdonald J, Moller P, Wong-Staal F, Li QX. Isoginkgetin enhances adiponectin secretion from differentiated adiposarcoma cells via a novel pathway involving AMP-activated protein kinase. J Endocrinol 2007; 194(3): 569-78.
[] [PMID: 17761896]
Tian J, Liu Y, Liu Y, Chen K, Lyu S. Ginkgo biloba leaf extract protects against myocardial injury via attenuation of endoplasmic reticulum stress in streptozotocin-induced diabetic ApoE-/- mice. Oxid Med Cell Longev 2018; 2018 2370617
[] [PMID: 29682154]
von Gunten A, Schlaefke S, Überla K. Efficacy of Ginkgo biloba extract EGb 761® in dementia with behavioural and psychological symptoms: A systematic review. World J Biol Psychiatry 2016; 17(8): 622-33.
[] [PMID: 26223956]
Savaskan E, Mueller H, Hoerr R, von Gunten A, Gauthier S. Treatment effects of Ginkgo biloba extract EGb 761® on the spectrum of behavioral and psychological symptoms of dementia: meta-analysis of randomized controlled trials. Int Psychogeriatr 2018; 30(3): 285-93.
[] [PMID: 28931444]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 21 June, 2019
Page: [334 - 345]
Pages: 12
DOI: 10.2174/1570161117666190621150725
Price: $65

Article Metrics

PDF: 44
PRC: 1