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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Mini-Review Article

Natural Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Review

Author(s): Sonia Singh*, Himanshu Sharma, Raghavan Ramankutty, Sarada Ramaswamy and Nitin Agrawal

Volume 26, Issue 15, 2023

Published on: 14 July, 2023

Page: [2668 - 2678] Pages: 11

DOI: 10.2174/1386207326666230627122630

Price: $65

Abstract

PCSK9 (proprotein convertase subtilisin/kexin type 9) is an enzyme that helps to reduce cardiovascular events. This clinical result is attributable primarily to the crucial involvement of PCSK9 in regulating the low-density lipoprotein cholesterol level. Because oral anti-PCSK9 medications have yet to be available, the benefits of this unique treatment approach have been diminished. Identifying naturally occurring PCSK9 inhibitors may lead to considerable progress in this regard. These inhibitors serve as a starting point for producing oral and effective components that could be used with statins to boost the proportion of patients who achieve their LDL-cholesterol goals. In this review, we have briefly summarised the recent information regarding natural components or extracts that have been shown to inhibit PCSK9 activity.

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[1]
Ferri, N.; Ruscica, M. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and metabolic syndrome: insights on insulin resistance, inflammation, and atherogenic dyslipidemia. Endocrine, 2016, 54(3), 588-601.
[http://dx.doi.org/10.1007/s12020-016-0939-0] [PMID: 27038318]
[2]
Seidah, N.G.; Benjannet, S.; Wickham, L.; Marcinkiewicz, J.; Jasmin, S.B.; Stifani, S.; Basak, A.; Prat, A.; Chrétien, M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA, 2003, 100(3), 928-933.
[http://dx.doi.org/10.1073/pnas.0335507100] [PMID: 12552133]
[3]
Tavori, H.; Christian, D.; Minnier, J.; Plubell, D.; Shapiro, M.D.; Yeang, C.; Giunzioni, I.; Croyal, M.; Duell, P.B.; Lambert, G.; Tsimikas, S.; Fazio, S. PCSK9 association with lipoprotein (a). Circ. Res., 2016, 119(1), 29-35.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.308811] [PMID: 27121620]
[4]
Ruscica, M.; Simonelli, S.; Botta, M.; Ossoli, A.; Lupo, M.G.; Magni, P.; Corsini, A.; Arca, M.; Pisciotta, L.; Veglia, F.; Franceschini, G.; Ferri, N.; Calabresi, L. Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders. Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 2018, 1863(9), 991-997.
[http://dx.doi.org/10.1016/j.bbalip.2018.05.015] [PMID: 29852278]
[5]
Macchi, C.; Banach, M.; Corsini, A.; Sirtori, C.R.; Ferri, N.; Ruscica, M. Changes in circulating pro-protein convertase subtilisin/kexin type 9 levels – experimental and clinical approaches with lipid-lowering agents. Eur. J. Prev. Cardiol., 2019, 26(9), 930-949.
[http://dx.doi.org/10.1177/2047487319831500] [PMID: 30776916]
[6]
Horton, J.D.; Shah, N.A.; Warrington, J.A.; Anderson, N.N.; Park, S.W.; Brown, M.S.; Goldstein, J.L. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl. Acad. Sci. USA, 2003, 100(21), 12027-12032.
[http://dx.doi.org/10.1073/pnas.1534923100] [PMID: 14512514]
[7]
Dubuc, G.; Chamberland, A.; Wassef, H.; Davignon, J.; Seidah, N.G.; Bernier, L.; Prat, A. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol., 2004, 24(8), 1454-1459.
[http://dx.doi.org/10.1161/01.ATV.0000134621.14315.43] [PMID: 15178557]
[8]
Ruscica, M.; Ricci, C.; Macchi, C.; Magni, P.; Cristofani, R.; Liu, J.; Corsini, A.; Ferri, N. Suppressor of cytokine signaling-3 (SOCS-3) induces proprotein convertase subtilisin kexin type 9 (PCSK9) expression in hepatic HepG2 cell line. J. Biol. Chem., 2016, 291(7), 3508-3519.
[http://dx.doi.org/10.1074/jbc.M115.664706] [PMID: 26668321]
[9]
Li, H.; Dong, B.; Park, S.W.; Lee, H.S.; Chen, W.; Liu, J. Hepatocyte nuclear factor 1α plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J. Biol. Chem., 2009, 284(42), 28885-28895.
[http://dx.doi.org/10.1074/jbc.M109.052407] [PMID: 19687008]
[10]
Cohen, J.; Pertsemlidis, A.; Kotowski, I.K.; Graham, R.; Garcia, C.K.; Hobbs, H.H. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet., 2005, 37(2), 161-165.
[http://dx.doi.org/10.1038/ng1509] [PMID: 15654334]
[11]
Abifadel, M.; Varret, M.; Rabès, J.P.; Allard, D.; Ouguerram, K.; Devillers, M.; Cruaud, C.; Benjannet, S.; Wickham, L.; Erlich, D.; Derré, A.; Villéger, L.; Farnier, M.; Beucler, I.; Bruckert, E.; Chambaz, J.; Chanu, B.; Lecerf, J.M.; Luc, G.; Moulin, P.; Weissenbach, J.; Prat, A.; Krempf, M.; Junien, C.; Seidah, N.G.; Boileau, C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet., 2003, 34(2), 154-156.
[http://dx.doi.org/10.1038/ng1161] [PMID: 12730697]
[12]
Ferri, N.; Corsini, A.; Macchi, C.; Magni, P.; Ruscica, M. Proprotein convertase subtilisin kexin type 9 and high-density lipoprotein metabolism: experimental animal models and clinical evidence. Transl. Res., 2016, 173, 19-29.
[http://dx.doi.org/10.1016/j.trsl.2015.10.004] [PMID: 26548330]
[13]
Dong, H.; Wang, N.; Zhao, L.; Lu, F. Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis. Evid. Based Complement. Alternat. Med., 2012, 2012, 591654.
[http://dx.doi.org/10.1155/2012/591654] [PMID: 23118793]
[14]
Lan, J.; Zhao, Y.; Dong, F.; Yan, Z.; Zheng, W.; Fan, J.; Sun, G. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J. Ethnopharmacol., 2015, 161, 69-81.
[http://dx.doi.org/10.1016/j.jep.2014.09.049] [PMID: 25498346]
[15]
Wang, L.; Ye, X.; Hua, Y.; Song, Y. Berberine alleviates adipose tissue fibrosis by inducing AMP-activated kinase signaling in high-fat diet-induced obese mice. Biomed. Pharmacother., 2018, 105, 121-129.
[http://dx.doi.org/10.1016/j.biopha.2018.05.110] [PMID: 29852389]
[16]
Andola, H.C.; Gaira, K.S.; Rawal, R.S.; Rawat, M.S.M.; Bhatt, I.D. Habitat-dependent variations in berberine content of Berberis asiatica Roxb. ex. DC. in Kumaon, Western Himalaya. Chem. Biodivers., 2010, 7(2), 415-420.
[http://dx.doi.org/10.1002/cbdv.200900041] [PMID: 20151388]
[17]
Kong, W.; Wei, J.; Abidi, P.; Lin, M.; Inaba, S.; Li, C.; Wang, Y.; Wang, Z.; Si, S.; Pan, H.; Wang, S.; Wu, J.; Wang, Y.; Li, Z.; Liu, J.; Jiang, J.D. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat. Med., 2004, 10(12), 1344-1351.
[http://dx.doi.org/10.1038/nm1135] [PMID: 15531889]
[18]
Horton, J.D.; Goldstein, J.L.; Brown, M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest., 2002, 109(9), 1125-1131.
[http://dx.doi.org/10.1172/JCI0215593] [PMID: 11994399]
[19]
Cameron, J.; Ranheim, T.; Kulseth, M.A.; Leren, T.P.; Berge, K.E. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis, 2008, 201(2), 266-273.
[http://dx.doi.org/10.1016/j.atherosclerosis.2008.02.004] [PMID: 18355829]
[20]
Abidi, P.; Chen, W.; Kraemer, F.B.; Li, H.; Liu, J. The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms. J. Lipid Res., 2006, 47(10), 2134-2147.
[http://dx.doi.org/10.1194/jlr.M600195-JLR200] [PMID: 16885565]
[21]
Kong, W.J.; Zhang, H.; Song, D.Q.; Xue, R.; Zhao, W.; Wei, J.; Wang, Y.M.; Shan, N.; Zhou, Z.X.; Yang, P.; You, X.F.; Li, Z.R.; Si, S.Y.; Zhao, L.X.; Pan, H.N.; Jiang, J.D. Berberine reduces insulin resistance through protein kinase C–dependent up-regulation of insulin receptor expression. Metabolism, 2009, 58(1), 109-119.
[http://dx.doi.org/10.1016/j.metabol.2008.08.013] [PMID: 19059538]
[22]
Dong, B.; Li, H.; Singh, A.B.; Cao, A.; Liu, J. Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin-proteasome degradation pathway. J. Biol. Chem., 2015, 290(7), 4047-4058.
[http://dx.doi.org/10.1074/jbc.M114.597229] [PMID: 25540198]
[23]
Liu, Y.T.; Hao, H.P.; Xie, H.G.; Lai, L.; Wang, Q.; Liu, C.X.; Wang, G.J. Extensive intestinal first-pass elimination and predominant hepatic distribution of berberine explain its low plasma levels in rats. Drug Metab. Dispos., 2010, 38(10), 1779-1784.
[http://dx.doi.org/10.1124/dmd.110.033936] [PMID: 20634337]
[24]
Hua, W.; Ding, L.; Chen, Y.; Gong, B.; He, J.; Xu, G. Determination of berberine in human plasma by liquid chromatography–electrospray ionization–mass spectrometry. J. Pharm. Biomed. Anal., 2007, 44(4), 931-937.
[http://dx.doi.org/10.1016/j.jpba.2007.03.022] [PMID: 17531424]
[25]
Shitan, N.; Tanaka, M.; Terai, K.; Ueda, K.; Yazaki, K. Human MDR1 and MRP1 recognize berberine as their transport substrate. Biosci. Biotechnol. Biochem., 2007, 71(1), 242-245.
[http://dx.doi.org/10.1271/bbb.60441] [PMID: 17213652]
[26]
Ras, R.T.; Geleijnse, J.M.; Trautwein, E.A. LDL-cholesterol-lowering effect of plant sterols and stanols across different dose ranges: a meta-analysis of randomised controlled studies. Br. J. Nutr., 2014, 112(2), 214-219.
[http://dx.doi.org/10.1017/S0007114514000750] [PMID: 24780090]
[27]
Momtazi, A.A.; Banach, M.; Pirro, M.; Katsiki, N.; Sahebkar, A. Regulation of PCSK9 by nutraceuticals. Pharmacol. Res., 2017, 120, 157-169.
[http://dx.doi.org/10.1016/j.phrs.2017.03.023] [PMID: 28363723]
[28]
Simonen, P.; Stenman, U.H.; Gylling, H. Serum proprotein convertase subtilisin/kexin type 9 concentration is not increased by plant stanol ester consumption in normo- to moderately hypercholesterolaemic non-obese subjects. The BLOOD FLOW intervention study. Clin. Sci. (Lond.), 2015, 129(5), 439-446.
[http://dx.doi.org/10.1042/CS20150193] [PMID: 25857271]
[29]
De Smet, E.; Mensink, R.P.; Konings, M.; Brufau, G.; Groen, A.K.; Havinga, R.; Schonewille, M.; Kerksiek, A.; Lütjohann, D.; Plat, J. Acute intake of plant stanol esters induces changes in lipid and lipoprotein metabolism-related gene expression in the liver and intestines of mice. Lipids, 2015, 50(6), 529-541.
[http://dx.doi.org/10.1007/s11745-015-4020-1] [PMID: 25931382]
[30]
Sirtori, C.R.; Lovati, M.R.; Manzoni, C.; Castiglioni, S.; Duranti, M.; Magni, C.; Morandi, S.; D’Agostina, A.; Arnoldi, A. Proteins of white lupin seed, a naturally isoflavone-poor legume, reduce cholesterolemia in rats and increase LDL receptor activity in HepG2 cells. J. Nutr., 2004, 134(1), 18-23.
[http://dx.doi.org/10.1093/jn/134.1.18] [PMID: 14704287]
[31]
Marchesi, M.; Parolini, C.; Diani, E.; Rigamonti, E.; Cornelli, L.; Arnoldi, A.; Sirtori, C.R.; Chiesa, G. Hypolipidaemic and anti-atherosclerotic effects of lupin proteins in a rabbit model. Br. J. Nutr., 2008, 100(4), 707-710.
[http://dx.doi.org/10.1017/S000711450894215X] [PMID: 18315889]
[32]
Bähr, M.; Fechner, A.; Krämer, J.; Kiehntopf, M.; Jahreis, G. Lupin protein positively affects plasma LDL cholesterol and LDL:HDL cholesterol ratio in hypercholesterolemic adults after four weeks of supplementation: a randomized, controlled crossover study. Nutr. J., 2013, 12(1), 107.
[http://dx.doi.org/10.1186/1475-2891-12-107] [PMID: 23902673]
[33]
Bähr, M.; Fechner, A.; Kiehntopf, M.; Jahreis, G. Consuming a mixed diet enriched with lupin protein beneficially affects plasma lipids in hypercholesterolemic subjects: A randomized controlled trial. Clin. Nutr., 2015, 34(1), 7-14.
[http://dx.doi.org/10.1016/j.clnu.2014.03.008] [PMID: 24746974]
[34]
Sirtori, C.R.; Triolo, M.; Bosisio, R.; Bondioli, A.; Calabresi, L.; De Vergori, V.; Gomaraschi, M.; Mombelli, G.; Pazzucconi, F.; Zacherl, C.; Arnoldi, A. Hypocholesterolaemic effects of lupin protein and pea protein/fibre combinations in moderately hypercholesterolaemic individuals. Br. J. Nutr., 2012, 107(8), 1176-1183.
[http://dx.doi.org/10.1017/S0007114511004120] [PMID: 22032303]
[35]
Lammi, C.; Zanoni, C.; Calabresi, L.; Arnoldi, A. Lupin protein exerts cholesterol-lowering effects targeting PCSK9: From clinical evidences to elucidation of the in vitro molecular mechanism using HepG2 cells. J. Funct. Foods, 2016, 23, 230-240.
[http://dx.doi.org/10.1016/j.jff.2016.02.042]
[36]
Pavanello, C.; Lammi, C.; Ruscica, M.; Bosisio, R.; Mombelli, G.; Zanoni, C.; Calabresi, L.; Sirtori, C.R.; Magni, P.; Arnoldi, A. Effects of a lupin protein concentrate on lipids, blood pressure and insulin resistance in moderately dyslipidaemic patients: A randomised controlled trial. J. Funct. Foods, 2017, 37, 8-15.
[http://dx.doi.org/10.1016/j.jff.2017.07.039]
[37]
Lammi, C.; Bollati, C.; Lecca, D.; Abbracchio, M.P.; Arnoldi, A. Lupin peptide T9 (GQEQSHQDEGVIVR) modulates the mutant PCSK9D374Y Pathway: in vitro characterization of its dual hypocholesterolemic behavior. Nutrients, 2019, 11(7), 1665.
[http://dx.doi.org/10.3390/nu11071665] [PMID: 31330826]
[38]
Lammi, C.; Zanoni, C.; Aiello, G.; Arnoldi, A.; Grazioso, G. Lupin peptides modulate the protein-protein interaction of PCSK9 with the low density lipoprotein receptor in HepG2 cells. Sci. Rep., 2016, 6(1), 29931.
[http://dx.doi.org/10.1038/srep29931] [PMID: 27424515]
[39]
Banach, M.; Patti, A.M.; Giglio, R.V.; Cicero, A.F.G.; Atanasov, A.G.; Bajraktari, G.; Bruckert, E.; Descamps, O.; Djuric, D.M.; Ezhov, M.; Fras, Z.; von Haehling, S.; Katsiki, N.; Langlois, M.; Latkovskis, G.; Mancini, G.B.J.; Mikhailidis, D.P.; Mitchenko, O.; Moriarty, P.M.; Muntner, P.; Nikolic, D.; Panagiotakos, D.B.; Paragh, G.; Paulweber, B.; Pella, D.; Pitsavos, C.; Reiner, Ž.; Rosano, G.M.C.; Rosenson, R.S.; Rysz, J.; Sahebkar, A.; Serban, M.C.; Vinereanu, D.; Vrablík, M.; Watts, G.F.; Wong, N.D.; Rizzo, M. The role of nutraceuticals in statin intolerant patients. J. Am. Coll. Cardiol., 2018, 72(1), 96-118.
[http://dx.doi.org/10.1016/j.jacc.2018.04.040] [PMID: 29957236]
[40]
Sirtori, C.R.; Pavanello, C.; Calabresi, L.; Ruscica, M. Nutraceutical approaches to metabolic syndrome. Ann. Med., 2017, 49(8), 678-697.
[http://dx.doi.org/10.1080/07853890.2017.1366042] [PMID: 28786719]
[41]
Ruscica, M.; Pavanello, C.; Gandini, S.; Gomaraschi, M.; Vitali, C.; Macchi, C.; Morlotti, B.; Aiello, G.; Bosisio, R.; Calabresi, L.; Arnoldi, A.; Sirtori, C.R.; Magni, P. Effect of soy on metabolic syndrome and cardiovascular risk factors: a randomized controlled trial. Eur. J. Nutr., 2018, 57(2), 499-511.
[http://dx.doi.org/10.1007/s00394-016-1333-7] [PMID: 27757595]
[42]
Durazzo, A.; Lucarini, M.; Souto, E.B.; Cicala, C.; Caiazzo, E.; Izzo, A.A.; Novellino, E.; Santini, A. Polyphenols: A concise overview on the chemistry, occurrence, and human health. Phytother. Res., 2019, 33(9), 2221-2243.
[http://dx.doi.org/10.1002/ptr.6419] [PMID: 31359516]
[43]
Potì, F.; Santi, D.; Spaggiari, G.; Zimetti, F.; Zanotti, I. Polyphenol health effects on cardiovascular and neurodegenerative disorders: a review and meta-analysis. Int. J. Mol. Sci., 2019, 20(2), 351.
[http://dx.doi.org/10.3390/ijms20020351] [PMID: 30654461]
[44]
Cicero, A.F.G.; Colletti, A. Polyphenols effect on circulating lipids and lipoproteins: From biochemistry to clinical evidence. Curr. Pharm. Des., 2018, 24(2), 178-190.
[http://dx.doi.org/10.2174/1381612824666171128110408] [PMID: 29189140]
[45]
Chambers, K.F.; Day, P.E.; Aboufarrag, H.T.; Kroon, P.A. Polyphenol effects on cholesterol metabolism via bile acid biosynthesis, CYP7A1: a review. Nutrients, 2019, 11(11), 2588.
[http://dx.doi.org/10.3390/nu11112588] [PMID: 31661763]
[46]
Fraga, C.G.; Croft, K.D.; Kennedy, D.O.; Tomás-Barberán, F.A. The effects of polyphenols and other bioactives on human health. Food Funct., 2019, 10(2), 514-528.
[http://dx.doi.org/10.1039/C8FO01997E] [PMID: 30746536]
[47]
Del Rio, D.; Rodriguez-Mateos, A.; Spencer, J.P.E.; Tognolini, M.; Borges, G.; Crozier, A. Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid. Redox Signal., 2013, 18(14), 1818-1892.
[http://dx.doi.org/10.1089/ars.2012.4581] [PMID: 22794138]
[48]
Moon, J.; Lee, S.M.; Do, H.J.; Cho, Y.; Chung, J.H.; Shin, M.J. Quercetin up-regulates LDL receptor expression in HepG2 cells. Phytother. Res., 2012, 26(11), 1688-1694.
[http://dx.doi.org/10.1002/ptr.4646] [PMID: 22388943]
[49]
Mbikay, M.; Sirois, F.; Simoes, S.; Mayne, J.; Chrétien, M. Quercetin-3-glucoside increases low-density lipoprotein receptor (LDLR) expression, attenuates proprotein convertase subtilisin/kexin 9 (PCSK9) secretion, and stimulates LDL uptake by Huh7 human hepatocytes in culture. FEBS Open Bio, 2014, 4(1), 755-762.
[http://dx.doi.org/10.1016/j.fob.2014.08.003] [PMID: 25349780]
[50]
Nishikido, T.; Ray, K.K. Non-antibody approaches to proprotein convertase subtilisin kexin 9 inhibition: siRNA, antisense oligonucleotides, adnectins, vaccination, and new attempts at small-molecule inhibitors based on new discoveries. Front. Cardiovasc. Med., 2019, 5, 199.
[http://dx.doi.org/10.3389/fcvm.2018.00199] [PMID: 30761308]
[51]
Li, S.; Cao, H.; Shen, D.; Jia, Q.; Chen, C.; Xing, S. Quercetin protects against ox LDL induced injury via regulation of ABCAl, LXR α and PCSK9 in RAW264.7 macrophages. Mol. Med. Rep., 2018, 18(1), 799-806.
[http://dx.doi.org/10.3892/mmr.2018.9048] [PMID: 29845234]
[52]
Adorni, M.P.; Cipollari, E.; Favari, E.; Zanotti, I.; Zimetti, F.; Corsini, A.; Ricci, C.; Bernini, F.; Ferri, N. Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages. Atherosclerosis, 2017, 256, 1-6.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.11.019] [PMID: 27940374]
[53]
Ricci, C.; Ruscica, M.; Camera, M.; Rossetti, L.; Macchi, C.; Colciago, A.; Zanotti, I.; Lupo, M.G.; Adorni, M.P.; Cicero, A.F.G.; Fogacci, F.; Corsini, A.; Ferri, N. PCSK9 induces a pro-inflammatory response in macrophages. Sci. Rep., 2018, 8(1), 2267.
[http://dx.doi.org/10.1038/s41598-018-20425-x] [PMID: 29396513]
[54]
Mbikay, M.; Mayne, J.; Sirois, F.; Fedoryak, O.; Raymond, A.; Noad, J.; Chrétien, M. Mice fed a high-cholesterol diet supplemented with quercetin-3-glucoside show attenuated hyperlipidemia and hyperinsulinemia associated with differential regulation of PCSK9 and LDLR in their liver and pancreas. Mol. Nutr. Food Res., 2018, 62(9), 1700729.
[http://dx.doi.org/10.1002/mnfr.201700729] [PMID: 29396908]
[55]
Jia, Q.; Cao, H.; Shen, D.; Li, S.; Yan, L.; Chen, C.; Xing, S.; Dou, F. Quercetin protects against atherosclerosis by regulating the expression of PCSK9, CD36, PPARγ, LXRα and ABCA1. Int. J. Mol. Med., 2019, 44(3), 893-902.
[http://dx.doi.org/10.3892/ijmm.2019.4263] [PMID: 31524223]
[56]
Tabrizi, R.; Tamtaji, O.R.; Mirhosseini, N.; Lankarani, K.B.; Akbari, M.; Heydari, S.T.; Dadgostar, E.; Asemi, Z. The effects of quercetin supplementation on lipid profiles and inflammatory markers among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials. Crit. Rev. Food Sci. Nutr., 2020, 60(11), 1855-1868.
[http://dx.doi.org/10.1080/10408398.2019.1604491] [PMID: 31017459]
[57]
Terao, J. Factors modulating bioavailability of quercetin-related flavonoids and the consequences of their vascular function. Biochem. Pharmacol., 2017, 139, 15-23.
[http://dx.doi.org/10.1016/j.bcp.2017.03.021] [PMID: 28377278]
[58]
Moon, Y.J.; Wang, L.; DiCenzo, R.; Morris, M.E. Quercetin pharmacokinetics in humans. Biopharm. Drug Dispos., 2008, 29(4), 205-217.
[http://dx.doi.org/10.1002/bdd.605] [PMID: 18241083]
[59]
Cooray, H.C.; Janvilisri, T.; van Veen, H.W.; Hladky, S.B.; Barrand, M.A. Interaction of the breast cancer resistance protein with plant polyphenols. Biochem. Biophys. Res. Commun., 2004, 317(1), 269-275.
[http://dx.doi.org/10.1016/j.bbrc.2004.03.040] [PMID: 15047179]
[60]
Hsiu, S.L.; Hou, Y.C.; Wang, Y.H.; Tsao, C.W.; Su, S.F.; Chao, P.D.L. Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats. Life Sci., 2002, 72(3), 227-235.
[http://dx.doi.org/10.1016/S0024-3205(02)02235-X] [PMID: 12427482]
[61]
Scambia, G.; Ranelletti, F.O.; Panici, P.B.; De Vincenzo, R.; Bonanno, G.; Ferrandina, G.; Piantelli, M.; Bussa, S.; Rumi, C.; Cianfriglia, M.; Mancuso, S. Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target. Cancer Chemother. Pharmacol., 1994, 34(6), 459-464.
[http://dx.doi.org/10.1007/BF00685655] [PMID: 7923555]
[62]
Santangelo, R.; Silvestrini, A.; Mancuso, C. Ginsenosides, catechins, quercetin and gut microbiota: Current evidence of challenging interactions. Food Chem. Toxicol., 2019, 123, 42-49.
[http://dx.doi.org/10.1016/j.fct.2018.10.042] [PMID: 30336256]
[63]
Dabeek, W.M.; Marra, M.V. Dietary quercetin and kaempferol: Bioavailability and potential cardiovascular-related bioactivity in humans. Nutrients, 2019, 11(10), 2288.
[http://dx.doi.org/10.3390/nu11102288] [PMID: 31557798]
[64]
Zhao, J.; Yang, J.; Xie, Y. Improvement strategies for the oral bioavailability of poorly water-soluble flavonoids: An overview. Int. J. Pharm., 2019, 570, 118642.
[http://dx.doi.org/10.1016/j.ijpharm.2019.118642] [PMID: 31446024]
[65]
Riva, A.; Ronchi, M.; Petrangolini, G.; Bosisio, S.; Allegrini, P. Improved oral absorption of quercetin from quercetin phytosome®, a new delivery system based on food grade lecithin. Eur. J. Drug Metab. Pharmacokinet., 2019, 44(2), 169-177.
[http://dx.doi.org/10.1007/s13318-018-0517-3] [PMID: 30328058]
[66]
Li, L.; Stillemark-Billton, P.; Beck, C.; Boström, P.; Andersson, L.; Rutberg, M.; Ericsson, J.; Magnusson, B.; Marchesan, D.; Ljungberg, A.; Borén, J.; Olofsson, S.O. Epigallocatechin gallate increases the formation of cytosolic lipid droplets and decreases the secretion of apoB-100 VLDL. J. Lipid Res., 2006, 47(1), 67-77.
[http://dx.doi.org/10.1194/jlr.M500424-JLR200] [PMID: 16227197]
[67]
Zanka, K.; Kawaguchi, Y.; Okada, Y.; Nagaoka, S. Epigallocatechin gallate induces upregulation of LDL Receptor via the 67 kDa Laminin receptor-independent pathway in HepG2 Cells. Mol. Nutr. Food Res., 2020, 64(7), 1901036.
[http://dx.doi.org/10.1002/mnfr.201901036] [PMID: 31978263]
[68]
Li, Y.; Wu, S. Epigallocatechin gallate suppresses hepatic cholesterol synthesis by targeting SREBP-2 through SIRT1/FOXO1 signaling pathway. Mol. Cell. Biochem., 2018, 448(1-2), 175-185.
[http://dx.doi.org/10.1007/s11010-018-3324-x] [PMID: 29446047]
[69]
Kitamura, K.; Okada, Y.; Okada, K.; Kawaguchi, Y.; Nagaoka, S. Epigallocatechin gallate induces an up-regulation of LDL receptor accompanied by a reduction of PCSK9 via the annexin A2-independent pathway in HepG2 cells. Mol. Nutr. Food Res., 2017, 61(8), 1600836.
[http://dx.doi.org/10.1002/mnfr.201600836] [PMID: 28181408]
[70]
Momose, Y.; Maeda-Yamamoto, M.; Nabetani, H. Systematic review of green tea epigallocatechin gallate in reducing low-density lipoprotein cholesterol levels of humans. Int. J. Food Sci. Nutr., 2016, 67(6), 606-613.
[http://dx.doi.org/10.1080/09637486.2016.1196655] [PMID: 27324590]
[71]
Huang, L.H.; Liu, C.Y.; Wang, L.Y.; Huang, C.J.; Hsu, C.H. Effects of green tea extract on overweight and obese women with high levels of low density-lipoprotein-cholesterol (LDL-C): A randomised, double-blind, and cross-over placebo-controlled clinical trial. BMC Complement. Altern. Med., 2018, 18(1), 294.
[http://dx.doi.org/10.1186/s12906-018-2355-x] [PMID: 30400924]
[72]
Lee, M.J.; Maliakal, P.; Chen, L.; Meng, X.; Bondoc, F.Y.; Prabhu, S.; Lambert, G.; Mohr, S.; Yang, C.S. Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans: Formation of different metabolites and individual variability. Cancer Epidemiol. Biomarkers Prev., 2002, 11(10 Pt 1), 1025-1032.
[PMID: 12376503]
[73]
Del Rio, D.; Calani, L.; Cordero, C.; Salvatore, S.; Pellegrini, N.; Brighenti, F. Bioavailability and catabolism of green tea flavan-3-ols in humans. Nutrition, 2010, 26(11-12), 1110-1116.
[http://dx.doi.org/10.1016/j.nut.2009.09.021] [PMID: 20080030]
[74]
Sang, S.; Lambert, J.D.; Ho, C.T.; Yang, C.S. The chemistry and biotransformation of tea constituents. Pharmacol. Res., 2011, 64(2), 87-99.
[http://dx.doi.org/10.1016/j.phrs.2011.02.007] [PMID: 21371557]
[75]
Scholl, C.; Lepper, A.; Lehr, T.; Hanke, N.; Schneider, K.L.; Brockmöller, J.; Seufferlein, T.; Stingl, J.C. Population nutrikinetics of green tea extract. PLoS One, 2018, 13(2), e0193074.
[http://dx.doi.org/10.1371/journal.pone.0193074] [PMID: 29466429]
[76]
Yashiro, T.; Nanmoku, M.; Shimizu, M.; Inoue, J.; Sato, R. Resveratrol increases the expression and activity of the low density lipoprotein receptor in hepatocytes by the proteolytic activation of the sterol regulatory element-binding proteins. Atherosclerosis, 2012, 220(2), 369-374.
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.11.006] [PMID: 22153697]
[77]
Jing, Y.; Hu, T.; Lin, C.; Xiong, Q.; Liu, F.; Yuan, J.; Zhao, X.; Wang, R. Resveratrol downregulates PCSK9 expression and attenuates steatosis through estrogen receptor α-mediated pathway in L02 cells. Eur. J. Pharmacol., 2019, 855, 216-226.
[http://dx.doi.org/10.1016/j.ejphar.2019.05.019] [PMID: 31085239]
[78]
Wang, Y.; Ye, J.; Li, J.; Chen, C.; Huang, J.; Liu, P.; Huang, H. Polydatin ameliorates lipid and glucose metabolism in type 2 diabetes mellitus by downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9). Cardiovasc. Diabetol., 2016, 15(1), 19.
[http://dx.doi.org/10.1186/s12933-015-0325-x] [PMID: 26833058]
[79]
Li, L.; Shen, C.; Huang, Y.X.; Li, Y.N.; Liu, X.F.; Liu, X.M.; Liu, J.H. A new strategy for rapidly screening natural inhibitors targeting the PCSK9/LDLR interaction in vitro. Molecules, 2018, 23(9), 2397.
[http://dx.doi.org/10.3390/molecules23092397] [PMID: 30235833]
[80]
Haghighatdoost, F.; Hariri, M. Effect of resveratrol on lipid profile: An updated systematic review and meta-analysis on randomized clinical trials. Pharmacol. Res., 2018, 129, 141-150.
[http://dx.doi.org/10.1016/j.phrs.2017.12.033] [PMID: 29305228]
[81]
Guo, X.F.; Li, J.M.; Tang, J.; Li, D. Effects of resveratrol supplementation on risk factors of non-communicable diseases: A meta-analysis of randomized controlled trials. Crit. Rev. Food Sci. Nutr., 2018, 58(17), 3016-3029.
[http://dx.doi.org/10.1080/10408398.2017.1349076] [PMID: 28933578]
[82]
Wang, P.; Sang, S. Metabolism and pharmacokinetics of resveratrol and pterostilbene. Biofactors, 2018, 44(1), 16-25.
[http://dx.doi.org/10.1002/biof.1410] [PMID: 29315886]
[83]
Singh, A.P.; Singh, R.; Verma, S.S.; Rai, V.; Kaschula, C.H.; Maiti, P.; Gupta, S.C. Health benefits of resveratrol: Evidence from clinical studies. Med. Res. Rev., 2019, 39(5), 1851-1891.
[http://dx.doi.org/10.1002/med.21565] [PMID: 30741437]
[84]
Springer, M.; Moco, S. Resveratrol and its human metabolites—Effects on metabolic health and obesity. Nutrients, 2019, 11(1), 143.
[http://dx.doi.org/10.3390/nu11010143] [PMID: 30641865]
[85]
Dong, Z.; Zhang, W.; Chen, S.; Liu, C. Silibinin A decreases statin induced PCSK9 expression in human hepatoblastoma HepG2 cells. Mol. Med. Rep., 2019, 20(2), 1383-1392.
[http://dx.doi.org/10.3892/mmr.2019.10344] [PMID: 31173243]
[86]
Barzaghi, N.; Crema, F.; Gatti, G.; Pifferi, G.; Perucca, E. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Eur. J. Drug Metab. Pharmacokinet., 1990, 15(4), 333-338.
[http://dx.doi.org/10.1007/BF03190223] [PMID: 2088770]
[87]
Valentová, K.; Havlík, J.; Kosina, P.; Papoušková, B.; Jaimes, J.D. Káňová, K.; Petrásková, L.; Ulrichová, J.; Křen, V. Biotransformation of silymarin flavonolignans by human fecal microbiota. Metabolites, 2020, 10(1), 29.
[http://dx.doi.org/10.3390/metabo10010029] [PMID: 31936497]
[88]
Sui, G.G.; Xiao, H.B.; Lu, X.Y.; Sun, Z.L. Naringin activates AMPK resulting in altered expression of SREBPs, PCSK9, and LDLR to reduce body weight in obese C57BL/6J mice. J. Agric. Food Chem., 2018, 66(34), 8983-8990.
[http://dx.doi.org/10.1021/acs.jafc.8b02696] [PMID: 30092639]
[89]
Zeng, X.; Su, W.; Zheng, Y.; He, Y.; He, Y.; Rao, H.; Peng, W.; Yao, H. Pharmacokinetics, tissue distribution, metabolism, and excretion of naringin in aged rats. Front. Pharmacol., 2019, 10, 34.
[http://dx.doi.org/10.3389/fphar.2019.00034] [PMID: 30761003]
[90]
Gao, W.Y.; Chen, P.Y.; Chen, S.F.; Wu, M.J.; Chang, H.Y.; Yen, J.H. Pinostrobin inhibits proprotein convertase subtilisin/kexin-type 9 (PCSK9) gene expression through the modulation of FoxO3a protein in HepG2 cells. J. Agric. Food Chem., 2018, 66(24), 6083-6093.
[http://dx.doi.org/10.1021/acs.jafc.8b02559] [PMID: 29862818]
[91]
Sayre, C.L.; Alrushaid, S.; Martinez, S.E.; Anderson, H.D.; Davies, N.M. Pre-clinical pharmacokinetic and pharmacodynamic characterization of selected chiral flavonoids: Pinocembrin and pinostrobin. J. Pharm. Pharm. Sci., 2015, 18(4), 368-395.
[http://dx.doi.org/10.18433/J3BK5T] [PMID: 26626242]
[92]
Jo, H.K.; Kim, G.W.; Jeong, K.J.; Kim, D.Y.; Chung, S.H. Eugenol ameliorates hepatic steatosis and fibrosis by down-regulating SREBP1 gene expression via AMPK-mTOR-p70S6K signaling pathway. Biol. Pharm. Bull., 2014, 37(8), 1341-1351.
[http://dx.doi.org/10.1248/bpb.b14-00281] [PMID: 25087956]
[93]
Elbahy, D.A.; Madkour, H.I.; Abdel-Raheem, M.H. Evaluation of antihyperlipidemic activity of eugenol in triton induced hyperlipidemia in rats. Int. J. Res. Stud. Biosci., 2015, 3(10), 19-26.
[94]
Zia, S.; Batool, S.; Shahid, R. Could PCSK9 be a new therapeutic target of Eugenol? In vitro and in silico evaluation of hypothesis. Med. Hypotheses, 2020, 136, 109513.
[http://dx.doi.org/10.1016/j.mehy.2019.109513] [PMID: 31812013]
[95]
Guénette, S.A.; Ross, A.; Marier, J.F.; Beaudry, F.; Vachon, P. Pharmacokinetics of eugenol and its effects on thermal hypersensitivity in rats. Eur. J. Pharmacol., 2007, 562(1-2), 60-67.
[http://dx.doi.org/10.1016/j.ejphar.2007.01.044] [PMID: 17321520]
[96]
Macchi, C.; Sirtori, C.R.; Corsini, A.; Santos, R.D.; Watts, G.F.; Ruscica, M. A new dawn for managing dyslipidemias: The era of rna-based therapies. Pharmacol. Res., 2019, 150, 104413.
[http://dx.doi.org/10.1016/j.phrs.2019.104413] [PMID: 31449975]
[97]
Shahane, K.; Kshirsagar, M.; Tambe, S.; Jain, D.; Rout, S.; Ferreira, M.K.M.; Mali, S.; Amin, P.; Srivastav, P.P.; Cruz, J.; Lima, R.R. An updated review on the multifaceted therapeutic potential of Calendula officinalis L. Pharmaceuticals (Basel), 2023, 16(4), 611.
[http://dx.doi.org/10.3390/ph16040611] [PMID: 37111369]
[98]
de Almeida, R.B.M.; Barbosa, D.B.; do Bomfim, M.R.; Amparo, J.A.O.; Andrade, B.S.; Costa, S.L.; Campos, J.M.; Cruz, J.N.; Santos, C.B.R.; Leite, F.H.A.; Botura, M.B. Identification of a novel dual inhibitor of acetylcholinesterase and butyrylcholinesterase: In vitro and in silico studies. Pharmaceuticals (Basel), 2023, 16(1), 95.
[http://dx.doi.org/10.3390/ph16010095] [PMID: 36678592]
[99]
Muzammil, S.; Neves Cruz, J.; Mumtaz, R.; Rasul, I.; Hayat, S.; Khan, M.A.; Khan, A.M.; Ijaz, M.U.; Lima, R.R.; Zubair, M. Effects of drying temperature and solvents on in vitro diabetic wound healing potential of Moringa oleifera leaf extracts. Molecules, 2023, 28(2), 710.
[http://dx.doi.org/10.3390/molecules28020710] [PMID: 36677768]
[100]
Alves, F.S.; Cruz, J.N.; de Farias Ramos, I.N.; do Nascimento Brandão, D.L.; Queiroz, R.N.; da Silva, G.V.; da Silva, G.V.; Dolabela, M.F.; da Costa, M.L.; Khayat, A.S.; de Arimatéia Rodrigues do Rego, J.; do Socorro Barros Brasil, D. Evaluation of antimicrobial activity and cytotoxicity effects of extracts of Piper nigrum L. and Piperine. Separations, 2022, 10(1), 21.
[http://dx.doi.org/10.3390/separations10010021]
[101]
Murti, Y.; Semwal, B.C.; Goyal, A.; Mishra, P. Naringenin scaffold as a template for drug designing. Curr. Tradit. Med., 2021, 7(1), 28-44.
[http://dx.doi.org/10.2174/2215083805666190617144652]
[102]
Gupta, J.; Ahuja, A.; Gupta, R. Green approaches for cancers management: An effective tool for health care. Anticancer. Agents Med. Chem., 2021, 22(1), 101-114.
[http://dx.doi.org/10.2174/1871520621666210119091826] [PMID: 33463475]
[103]
Harwansh, R.K.; Bahadur, S. Herbal medicines to fight against COVID-19: New battle with an old weapon. Curr. Pharm. Biotechnol., 2022, 23(2), 235-260.
[http://dx.doi.org/10.2174/1389201022666210322124348] [PMID: 33749558]
[104]
Verma, T.; Sinha, M.; Bansal, N.; Yadav, S.R.; Shah, K.; Chauhan, N.S. Plants used as antihypertensive. Nat. Prod. Bioprospect., 2021, 11(2), 155-184.
[http://dx.doi.org/10.1007/s13659-020-00281-x] [PMID: 33174095]
[105]
Poli, A.; Barbagallo, C.M.; Cicero, A.F.G.; Corsini, A.; Manzato, E.; Trimarco, B.; Bernini, F.; Visioli, F.; Bianchi, A.; Canzone, G.; Crescini, C.; de Kreutzenberg, S.; Ferrara, N.; Gambacciani, M.; Ghiselli, A.; Lubrano, C.; Marelli, G.; Marrocco, W.; Montemurro, V.; Parretti, D.; Pedretti, R.; Perticone, F.; Stella, R.; Marangoni, F. Nutraceuticals and functional foods for the control of plasma cholesterol levels. An intersociety position paper. Pharmacol. Res., 2018, 134, 51-60.
[http://dx.doi.org/10.1016/j.phrs.2018.05.015] [PMID: 29859248]
[106]
Fogacci, F.; Banach, M.; Mikhailidis, D.P.; Bruckert, E.; Toth, P.P.; Watts, G.F.; Reiner, Ž.; Mancini, J.; Rizzo, M.; Mitchenko, O.; Pella, D.; Fras, Z.; Sahebkar, A.; Vrablik, M.; Cicero, A.F.G. Safety of red yeast rice supplementation: A systematic review and meta-analysis of randomized controlled trials. Pharmacol. Res., 2019, 143, 1-16.
[http://dx.doi.org/10.1016/j.phrs.2019.02.028] [PMID: 30844537]
[107]
Ruscica, M.; Gomaraschi, M.; Mombelli, G.; Macchi, C.; Bosisio, R.; Pazzucconi, F.; Pavanello, C.; Calabresi, L.; Arnoldi, A.; Sirtori, C.R.; Magni, P. Nutraceutical approach to moderate cardiometabolic risk: Results of a randomized, double-blind and crossover study with Armolipid Plus. J. Clin. Lipidol., 2014, 8(1), 61-68.
[http://dx.doi.org/10.1016/j.jacl.2013.11.003] [PMID: 24528686]

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