Abstract
This chapter will cover one group of flavonoids, flavonolignans, found in Silybum marianum (L.) Gaertn. A mixture of several different flavonolignans, silybin A and B, isosilybin A and B, silychristin, and silydianin, is isolated from S. marianum (milk thistle) fruit and represents a well-known natural product called silymarin. Among these silymarin flavonolignans, silybin, a mixture of silybin A and B diastereomers in equimolar concentration, represents its main compound, the first discovered flavonolignan in nature, and the most studied flavonolignan. Silymarin is a well-known natural product since ancient times because of its medicinal properties, particularly for liver disorders. Nowadays, silymarin and silybin are important resources for the pharmaceutical industry as constituents of dietary supplements for improving liver functions. This chapter will describe the most relevant scientific data about the potential use and new perspectives for application, as well as scientific evidence about the natural origin, biosynthesis pathways, and physicochemical properties of silybin and silymarin flavonolignans. The latest scientific knowledge about the application of different modern technologies for improvement of their application in drug formulations, metabolism in the human body, and potential as therapeutics will be discussed.
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References
Abdelazim SAA (2017) Effect of silymarin as natural antioxidants and antimicrobial activity. J Agric Res 95(2):2017
Abenavoli L, Capasso R, Milic N, Capasso F (2010) Milk thistle in liver diseases: past, present, future. Phytother Res 24(10):1423–1432. https://doi.org/10.1002/ptr.3207
Abenavoli L, Greco M, Nazionale I, Peta V, Milic N, Accattato F, Foti D, Gulletta E, Luzza F (2015) Effects of Mediterranean diet supplemented with silybin-vitamin E-phospholipid complex in overweight patients with non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 9(4):519–527. https://doi.org/10.1586/17474124.2015.1004312
Abenavoli L, Greco M, Milic N, Accattato F, Foti D, Gulletta E, Luzza F (2017) Effect of Mediterranean diet and antioxidant formulation in non-alcoholic fatty liver disease: a randomized study. Nutrients 9(8):870. https://doi.org/10.3390/nu9080870
Abenavoli L, Izzo AA, Milić N, Cicala C, Santini A, Capasso R (2018) Milk thistle (Silybum marianum): a concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res 32(11):2202–2213. Wiley. https://doi.org/10.1002/ptr.6171
Abhilash PA, Harikrishnan R, Indira M (2013) Ascorbic acid is superior to silymarin in the recovery of ethanol-induced inflammatory reactions in hepatocytes of Guinea pigs. J Physiol Biochem 69:785–798. https://doi.org/10.1007/s13105-013-0255-6P
AbouZid SF, Ahmed HS, Moawad AS, Owis AI, Chen SN, Nachtergael A, McAlpine JB, Brent Friesen J, Pauli GF (2017) Chemotaxonomic and biosynthetic relationships between flavonolignans produced by Silybum marianum populations. Fitoterapia 119:175–184. https://doi.org/10.1016/J.FITOTE.2017.04.002
Ahmadi-Ashtiani H, Allameh A, Rastegar H, Soleimani M, Barkhordari E (2012) Inhibition of cyclooxygenase-2 and inducible nitric oxide synthase by silymarin in proliferating mesenchymal stem cells: comparison with glutathione modifiers. J Nat Med 66(1):85–94. https://doi.org/10.1007/S11418-011-0554-6
Alzoubi KH, Khabour OF, Alkofahi AS, Mhaidat NM, Abu-Siniyeh AA (2021) Anticancer and antimutagenic activity of Silybum marianum L. and Eucalyptus camaldulensis Dehnh. against skin cancer induced by DMBA: in vitro and in vivo models. Pak J Pharm Sci 34(3):987–993. https://doi.org/10.36721/PJPS.2021.34.3.REG.987-993.1
Andrzejewska J, Sadowska K, Mielcarek S (2011) Effect of sowing date and rate on the yield and flavonolignan content of the fruits of milk thistle (Silybum marianum L. Gaertn.) grown on light soil in a moderate climate. Ind Crop Prod 33(2):462–468. https://doi.org/10.1016/J.INDCROP.2010.10.027
Aziz M, Saeed F, Ahmad N, Ahmad A, Afzaal M, Hussain S, Mohamed AA, Alamri MS, Anjum FM (2021) Biochemical profile of milk thistle (Silybum marianum L.) with special reference to silymarin content. Food Sci Nutr 9(1):244–250. https://doi.org/10.1002/fsn3.1990
Bai TC, Zhu JJ, Hu J, Zhang HL, Huang CG (2007) Solubility of silybin in aqueous hydrochloric acid solution. Fluid Phase Equilib 254(1–2):204–210. https://doi.org/10.1016/j.fluid.2007.03.009
Baradaran A, Samadi F, Ramezanpour SS, Yousefdoust S (2019) Hepatoprotective effects of silymarin on CCl4-induced hepatic damage in broiler chickens model. Toxicol Rep 6:788–794. https://doi.org/10.1016/J.TOXREP.2019.07.011
Biedermann D, Vavříková E, Cvak L, Křen V (2014) Chemistry of silybin. Nat Prod Rep 31(9):1138–1157. Royal Society of Chemistry. https://doi.org/10.1039/c3np70122k
Bijak M (2017) Silybin, a major bioactive component of milk thistle (Silybum marianum L. Gaernt.) – chemistry, bioavailability, and metabolism. Molecules 22(11):1942. MDPI AG. https://doi.org/10.3390/molecules22111942
Boroja T, Katanić J, Rosić G, Selaković D, Joksimović J, Mišić D, Stanković V, Jovičić N, Mihailović V (2018) Summer savory (Satureja hortensis L.) extract: phytochemical profile and modulation of cisplatin-induced liver, renal and testicular toxicity. Food Chem Toxicol 118:252–263. https://doi.org/10.1016/J.FCT.2018.05.001
Calani L, Brighenti F, Bruni R, del Rio D (2012) Absorption and metabolism of milk thistle flavanolignans in humans. Phytomedicine 20(1):40–46. https://doi.org/10.1016/j.phymed.2012.09.004
Campos R, Garrido A, Guerra R, Valenzuela A (1989) Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 55(5):417–419. https://doi.org/10.1055/S-2006-962055
Can V, Abouelnour A, Locke I, Bligh A, Getting S (2017) P35 the anti-inflammatory effect of silymarin in chondrocytes. Biochem Pharmacol 139:137. https://doi.org/10.1016/J.BCP.2017.06.036
Chambers C, Valentova K, Kren V (2015) “Non-Taxifolin” derived flavonolignans: phytochemistry and biology. Curr Pharm Des 21(38):5489–5500. https://doi.org/10.2174/1381612821666151002112720
Cristofalo R, Bannwart-Castro CF, Magalhães CG, Borges VT, Peraçoli JC, Witkin SS, Peraçoli MT (2013) Silibinin attenuates oxidative metabolism and cytokine production by monocytes from preeclamptic women. Free Radic Res 47(4):268–275. https://doi.org/10.3109/10715762.2013.765951
Das S, Roy P, Pal R, Auddy RG, Chakraborti AS (2014) Engineered Silybin nanoparticles educe efficient control in experimental diabetes. PLoS One 9(7):101818. https://doi.org/10.1371/journal.pone.0101818
Davis-Searles PR, Nakanishi Y, Kim NC, Graf TN, Oberlies NH, Wani MC, Wall ME, Agarwal R, Kroll DJ (2005) Milk thistle and prostate cancer: differential effects of pure flavonolignans from Silybum marianum on antiproliferative end points in human prostate carcinoma cells. Cancer Res 65(10):4448–4457. https://doi.org/10.1158/0008-5472.CAN-04-4662
de Oliveira DR, Tintino SR, Braga MFBM, Boligon AA, Athayde ML, Coutinho HDM, de Menezes IRA, Fachinetto R (2015) In vitro antimicrobial and modulatory activity of the natural products silymarin and silibinin. Biomed Res Int 2015:292797. https://doi.org/10.1155/2015/292797
Deep G, Agarwal R (2007) Chemopreventive efficacy of silymarin in skin and prostate cancer. Integr Cancer Ther 6(2):130–145. https://doi.org/10.1177/1534735407301441
Delmas D (2020) Silymarin and derivatives: from biosynthesis to health benefits. Molecules 25(10):2415. https://doi.org/10.3390/MOLECULES25102415
Detaille D, Sanchez C, Sanz N, Lopez-Novoa JM, Leverve X, El-Mir M-Y (2008) Interrelation between the inhibition of glycolytic flux by silibinin and the lowering of mitochondrial ROS production in perifused rat hepatocytes. Life Sci 82:1070–1076. https://doi.org/10.1016/j.lfs.2008.03.007
Dewick PM (2001) Medicinal natural products a biosynthetic approach second edition. Retrieved July 21, 2022, from http://www.wiley.co.uk
di Costanzo A, Angelico R (2019) Formulation strategies for enhancing the bioavailability of silymarin: the state of the art. Molecules 24(11):2155. MDPI AG. https://doi.org/10.3390/molecules24112155
Dong GL, Hyung KK, Park Y, Park SC, Woo ER, Hye GJ, Hahm KS (2003) Gram-positive bacteria specific properties of silybin derived from Silybum marianum. Arch Pharm Res 26(8):597–600. https://doi.org/10.1007/BF02976707
Drouet S, Tungmunnithum D, Lainé É, Hano C (2020) Gene expression analysis and metabolite profiling of silymarin biosynthesis during milk thistle (Silybum marianum (L.) gaertn.) fruit ripening. Int J Mol Sci 21(13):1–18. https://doi.org/10.3390/ijms21134730
Dunnick JK, Singh B, Nyska A, Peckham J, Kissling GE, Sanders JM (2011) Investigating the potential for toxicity from long-term use of the herbal products, goldenseal and milk thistle. Toxicol Pathol 39(2):398–409. https://doi.org/10.1177/0192623310394211
Dvořák Z, Kosina P, Walterová D, Šimánek V, Bachleda P, Ulrichová J (2003) Primary cultures of human hepatocytes as a tool in cytotoxicity studies: cell protection against model toxins by flavonolignans obtained from Silybum marianum. Toxicol Lett 137(3):201–212. https://doi.org/10.1016/S0378-4274(02)00406-X
Ebrahimpour Koujan S, Gargari BP, Mobasseri M, Valizadeh H, Asghari-Jafarabadi M (2015) Effects of Silybum marianum (L.) Gaertn. (silymarin) extract supplementation on antioxidant status and hs-CRP in patients with type 2 diabetes mellitus: a randomized, triple-blind, placebo-controlled clinical trial. Phytomed Int J Phytother Phytopharmacol 22(2):290–296. https://doi.org/10.1016/J.PHYMED.2014.12.010
Eita AAB (2022) Milk thistle (Silybum marianum (L.)Gaertn.): an overview about its pharmacology and medicinal uses with an emphasis on oral diseases. J Oral Biosci 64(1):71–76. https://doi.org/10.1016/j.job.2021.12.005
Elateeq AA, Sun Y, Nxumalo W, Gabr AMM (2020) Biotechnological production of silymarin in Silybum marianum L.: a review. Biocatal Agric Biotechnol 29:101775. https://doi.org/10.1016/J.BCAB.2020.101775
El-Lakkany NM, Hammam OA, El-Maadawy WH, Badawy AA, Ain-Shoka AA, Ebeid FA (2012) Anti-inflammatory/anti-fibrotic effects of the hepatoprotective silymarin and the schistosomicide praziquantel against Schistosoma mansoni-induced liver fibrosis. Parasit Vectors 5(1):1–14. https://doi.org/10.1186/1756-3305-5-9/FIGURES/5
El-Shitany NA, El-Haggar S, El-desoky K (2008) Silymarin prevents adriamycin-induced cardiotoxicity and nephrotoxicity in rats. Food Chem Toxicol 46(7):2422–2428. https://doi.org/10.1016/J.FCT.2008.03.033
European Medicines Agency, Committee on Herbal Medicinal Products (2018) Assessment report on Silybum marianum (L.) Gaertn., fructus. www.ema.europa.eu/contact
Evren E, Yurtcu E (2015) In vitro effects on biofilm viability and antibacterial and antiadherent activities of silymarin. Folia Microbiol 60(4):351–356. https://doi.org/10.1007/S12223-015-0399-6/FIGURES/2
Fathalah WF, Abdel Aziz MA, Abou EL, Soud NH, El Raziky MES (2017) High dose of silymarin in patients with decompensated liver disease: a randomized controlled trial. J Interf Cytokine Res 37:480–487. https://doi.org/10.1089/jir.2017.0051
Federico A, Dallio M, Loguercio C (2017) Silymarin/Silybin and chronic liver disease: a marriage of many years. Molecules 22(2):191. MDPI AG. https://doi.org/10.3390/molecules22020191
Ferenci P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, Meryn S, Base W, Schneider B (1989) Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 9:105–113
Fu H, Lin M, Muroya Y, Hata K, Katsumura Y, Yokoya A, Shikazono N, Hatano Y (2009) Free radical scavenging reactions and antioxidant activities of silybin: mechanistic aspects and pulse radiolytic studies. Free Radic Res 43(9):887–897. https://doi.org/10.1080/10715760903136996
Garrido A, Fairlie J, Guerra R, Campos R, Valenzuela A (1989) The flavonoid silybin ameliorates the protective effect of ethanol on acetaminophen hepatotoxicity. Res Commun Subst Abuse 10:193–196
Gholami M, Moallem SA, Afshar M, Amoueian S, Etemad L, Karimi G (2016) Teratogenic effects of silymarin on mouse fetuses. Avicenna J Phytomed 6(5):542
Gillessen A, Schmidt HHJ (2020) Silymarin as supportive treatment in liver diseases: a narrative review. Adv Ther 37(4):1279. https://doi.org/10.1007/S12325-020-01251-Y
Golestaneh E, Aslani A, Aghaei M, Hashemnia M, Aarabi MH (2021) Preparation and characterisation of a new form of silymarin as a potential antidiabetic agent in the adult male rat. Arch Physiol Biochem:1–11. https://doi.org/10.1080/13813455.2021.1874018
Gresta F, Avola G, Guarnaccia P (2007) Agronomic characterization of some spontaneous genotypes of milk thistle (Silybum marianum L Gaertn.) in Mediterranean environment. J Herbs Spices Med Plants 12:51–60
Gu M, Zhao P, Huang J, Zhao Y, Wang Y, Li Y, Li Y, Fan S, Ma YM, Tong Q, Yang L, Ji G, Huang C (2016) Silymarin ameliorates metabolic dysfunction associated with diet-induced obesity via activation of Farnesyl X receptor. Front Pharmacol 7(SEP):345. https://doi.org/10.3389/FPHAR.2016.00345/BIBTEX
Gugliandolo E, Crupi R, Biondi V, Licata P, Cuzzocrea S, Passantino A (2022) Protective effect of silibinin of lipopolysaccharide induced inflammatory responses in equine peripheral blood mononuclear cells, an in vitro study. Animals 10(11). https://doi.org/10.3390/ani10112022
Guigas B, Naboulsi R, Villanueva GR, Taleux N, Lopez-Novoa JM, Leverve XM, El-Mir M-Y (2007) The flavonoid silibinin decreases glucose-6-phosphate hydrolysis in perfused rat hepatocytes by an inhibitory effect on glucose-6-phosphatase. Cell Physiol Biochem 20(6):925–934. https://doi.org/10.1159/000110453
Guo Y, Wang S, Wang Y, Zhu T (2016) Silymarin improved diet-induced liver damage and insulin resistance by decreasing inflammation in mice. Pharm Biol 54(12):2995–3000. https://doi.org/10.1080/13880209.2016.1199042
Hajaghamohammadi AA, Ziaee A, Raflei R (2008) The efficacy of silymarin in decreasing transaminase activities in nonalcoholic fatty liver disease. A randomized controlled clinical trial. Hepat Mon 8:191–195
Hashemi SJ, Hajiani E, Sardabi EH (2009) A placebo-controlled trial of silymarin in patients with nonalcoholic fatty liver disease. Hepat Mon 9(4):265–270
Hollis A, Ahmed Z (2013) Preserving antibiotics, rationally. N Engl J Med 369(26):2474–2476. https://doi.org/10.1056/NEJMP1311479
Hosseini S, Rezaei S, Reza M, Moghaddam N, Elyasi S, Karimi G (2021) Evaluation of oral nano-silymarin formulation efficacy on prevention of radiotherapy induced mucositis: a randomized, double-blinded, placebo-controlled clinical trial. Pharma Nutr 15:100253. https://doi.org/10.1016/j.phanu.2021.100253
Hsu WC, Ng LT, Wu TH, Lin LT, Yen FL, Lin CC (2012) Characteristics and antioxidant activities of silymarin nanoparticles. J Nanosci Nanotechnol 12(3):2022–2027. https://doi.org/10.1166/JNN.2012.5173
Huseini HF, Asghari B, Asgarpanah J, Zarch TE, Zach AB (2012) Investigation of α-amylase and α-glucosidases inhibitory effects of Silybum marianum (L. Gaertn) seed extracts in vitro. J Med Plants 11:239–247
IARC (n.d.) Publications website – World Cancer Report: Cancer Research for Cancer Prevention. Retrieved June 20, 2022, from https://publications.iarc.fr/586
Jančová P, Šiller M, Anzenbacherová E, Křen V, Anzenbacher P, Šimánek V (2011) Evidence for differences in regioselective and stereoselective glucuronidation of silybin diastereomers from milk thistle (Silybum marianum) by human UDP-glucuronosyltransferases. 41(9):743–751. https://doi.org/10.3109/00498254.2011.573017
Jung HJ, Lee DG (2008) Synergistic antibacterial effect between silybin and N,N′-dicyclohexylcarbodiimide in clinical Pseudomonas aeruginosa isolates. J Microbiol (Seoul, Korea) 46(4):462–467. https://doi.org/10.1007/S12275-008-0138-7
Kang HK, Kim HY, Cha JD (2011) Synergistic effects between silibinin and antibiotics on methicillin-resistant Staphylococcus aureus isolated from clinical specimens. Biotechnol J 6(11):1397–1408. https://doi.org/10.1002/BIOT.201000422
Karkanis A, Bilalis D, Efthimiadou A (2011) Cultivation of milk thistle (Silybum marianum L. Gaertn.), a medicinal weed. Ind Crop Prod 34(1):825–830. https://doi.org/10.1016/j.indcrop.2011.03.027
Katanić Stanković JS, Srećković N, Mišić D, Gašić U, Imbimbo P, Monti DM, Mihailović V (2020) Bioactivity, biocompatibility and phytochemical assessment of lilac sage, Salvia verticillata L. (Lamiaceae) – a plant rich in rosmarinic acid. Ind Crops Prod 143:111932. https://doi.org/10.1016/j.indcrop.2019.111932
Katiyar SK (2005) Silymarin and skin cancer prevention: anti-inflammatory, antioxidant and immunomodulatory effects (review). Int J Oncol 26(1):169–176. https://doi.org/10.3892/ijo.26.1.169
Katiyar SK, Mukhtar H, Leukoc Biol J (2001) Green tea polyphenol(−)-epigallocatechin-3-gallate treatment to mouse skin prevents UVB-induced infiltration of leukocytes, depletion of antigen-presenting cells, and oxidative stress. J Leukoc Biol 69(5):719–726. https://doi.org/10.1189/JLB.69.5.719
Kawaguchi-Suzuki M, Frye RF, Zhu HJ, Brinda BJ, Chavin KD, Bernstein HJ, Markowitz JS (2014) The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. Drug Metab Dispos 42(10):1611–1616. https://doi.org/10.1124/dmd.114.057232
Kayedpoor P, Mohamadi S, Karimzadeh-Bardei L, Nabiuni M (2017) Anti-inflammatory effect of silymarin on ovarian immunohistochemical localization of TNF-α associated with systemic inflammation in polycystic ovarian syndrome. Int J Morphol 35(2):723–732
Kim M, Yang S-G, Kim J-M, Lee J-W, Kim Y-S, Lee J-I (2012) Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells. Int J Mol Med 30(3):473–479. https://doi.org/10.3892/ijmm.2012.1029
Kim SH, Choo GS, Yoo ES, Woo JS, Han SH, Lee JH, Jung JY (2019) Silymarin induces inhibition of growth and apoptosis through modulation of the MAPK signaling pathway in AGS human gastric cancer cells. Oncol Rep 42(5):1904–1914. https://doi.org/10.3892/OR.2019.7295
Köksal E, Gülçin I, Beyza S, Sarikaya Ö, Bursal E (2009) In vitro antioxidant activity of silymarin. J Enzyme Inhib Med Chem 24(2):395–405. https://doi.org/10.1080/14756360802188081
Koo C-H, Choi D-Y, Song I-Y (2002) Compositions and preparations of silymarin complex with the improved bioavailability. WO2002069962A1. Application filed by Bukwang Pharmaceutical Company Ltd.PCT/KR2002/000291. WIPO – World Intellectual Property Organization
Křen V, Gažák R, Purchartová K, Marhol P, Biedermann D, Sedmera P (2009) Chemoenzymatic preparative separation of silybins A and B. J Mol Catal B Enzym 61(3–4):247–251. https://doi.org/10.1016/j.molcatb.2009.07.013
Kumburovic I, Selakovic D, Juric T, Jovicic N, Mihailovic V, Stankovic JK, Sreckovic N, Kumburovic D, Jakovljevic V, Rosic G (2020) Antioxidant effects of Satureja hortensis L attenuate the anxiogenic effect of cisplatin in rats. Oxid Med Cell Longev:2019. https://doi.org/10.1155/2019/8307196
Lee DYW, Liu Y (2003) Molecular structure and stereochemistry of silybin A, silybin B, isosilybin A, and isosilybin B, isolated from Silybum marianum (milk thistle). J Nat Prod 66(9):1171–1174. https://doi.org/10.1021/np030163b
Lee MH, Huang Z, Kim DJ, Kim SH, Kim MO, Lee SY, Xie H, Park SJ, Kim JY, Kundu JK, Bode AM, Surh YJ, Dong Z (2013) Direct targeting of MEK1/2 and RSK2 by silybin induces cell-cycle arrest and inhibits melanoma cell growth. Cancer Prev Res (Philadelphia, PA) 6(5):455–465. https://doi.org/10.1158/1940-6207.CAPR-12-0425
Lee JS, Hong DY, Kim ES, Lee HG (2017) Improving the water solubility and antimicrobial activity of silymarin by nanoencapsulation. Colloids Surf B: Biointerfaces 154:171–177. https://doi.org/10.1016/J.COLSURFB.2017.03.004
Li LH, Wu LJ, Jiang YY, Tashiro SI, Onodera S, Uchiumi F, Ikejima T (2007) Silymarin enhanced cytotoxic effect of anti-Fas agonistic antibody CH11 on A375-S2 cells. J Asian Nat Prod Res 9(7):593–602. https://doi.org/10.1080/10286020600882502
Loguercio C, Andreone P, Brisc C, Brisc MC, Bugianesi E, Chiaramonte M, Cursaro C, Danila M, de Sio I, Floreani A, Freni MA, Grieco A, Groppo M, Lazzari R, Lobello S, Lorefice E, Margotti M, Miele L, Milani S, Okolicsanyi L, Palasciano G, Portincasa P, Saltarelli P, Smedile A, Somalvico F, Spadaro A, Sporea I, Sorrentino P, Vecchione R, Tuccillo C, Del Vecchio Blanco C, Federico A (2012) Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic Biol Med 52(9):1658–1665. https://doi.org/10.1016/j.freeradbiomed.2012.02.008
Lorenz D, Lucker PW, Mennicke WH, Wetzelsberger N (1984) Pharmacokinetic studies with silymarin in human serum and bile. J Clin Pharmacol 6:655
Lovelace ES, Wagoner J, MacDonald J, Bammler T, Bruckner J, Brownell J, Beyer RP, Zink EM, Kim YM, Kyle JE, Webb-Robertson BJM, Waters KM, Metz TO, Farin F, Oberlies NH, Polyak SJ (2015) Silymarin suppresses cellular inflammation by inducing reparative stress signaling. J Nat Prod 78(8):1990. https://doi.org/10.1021/ACS.JNATPROD.5B00288
Lv Y, Gao S, Xu S, Du G, Zhou J, Chen J (2017) Spatial organization of silybin biosynthesis in milk thistle [Silybum marianum (L.) Gaertn]. Plant J 92(6):995–1004. https://doi.org/10.1111/tpj.13736
Madaus R, Gorler K, Molls W (1983) Method for the extraction of silymarin from plants. US4368195A United States. Application filed by Dr Madaus GmbH and Co
Maghrani M, Zeggwagh NA, Lemhadri A, el Amraoui M, Michel JB, Eddouks M (2004) Study of the hypoglycaemic activity of Fraxinus excelsior and Silybum marianum in an animal model of type 1 diabetes mellitus. J Ethnopharmacol 91(2–3):309–316. https://doi.org/10.1016/J.JEP.2004.01.008
Mahli A, Koch A, Czech B, Peterburs P, Lechner A, Haunschild J, Müller M, Hellerbrand C (2015) Hepatoprotective effect of oral application of a silymarin extract in carbon tetrachloride-induced hepatotoxicity in rats. Clin Phytosci 1(1):1–8. https://doi.org/10.1186/S40816-015-0006-Z
Mahmood Juma’a K, Ahmed ZA, Numan IT, Abdul S, Hussain R (2009) Dose-dependent anti-inflammatory effect of silymarin in experimental animal model of chronic inflammation. Afr J Pharm Pharmacol 3(5):242–247. http://www.academicjournals.org/ajpp
Marceddu R, Dinolfo L, Carrubba A, Sarno M, di Miceli G (2022) Milk thistle (Silybum Marianum L.) as a novel multipurpose crop for agriculture in marginal environments: a review. Agronomy 12(3):729. MDPI. https://doi.org/10.3390/agronomy12030729
Martinelli T, Whittaker A, Benedettelli S, Carboni A, Andrzejewska J (2017) The study of flavonolignan association patterns in fruits of diverging Silybum marianum (L.) Gaertn. chemotypes provides new insights into the silymarin biosynthetic pathway. Phytochemistry 144:9–18. https://doi.org/10.1016/j.phytochem.2017.08.013
Mihailović V, Mihailović M, Uskoković A, Arambašić J, Mišić D, Stanković V, Katanić J, Mladenović M, Solujić S, Matić S (2013) Hepatoprotective effects of Gentiana asclepiadea L. extracts against carbon tetrachloride induced liver injury in rats. Food Chem Toxicol 52:83–90. https://doi.org/10.1016/j.fct.2012.10.034
Mihailović V, Katanić J, Mišić D, Stanković V, Mihailović M, Uskoković A, Arambašić J, Solujić S, Mladenović M, Stanković N (2014) Hepatoprotective effects of secoiridoid-rich extracts from Gentiana cruciata L. against carbon tetrachloride induced liver damage in rats. Food Funct 5(8):1795–1803. https://doi.org/10.1039/c4fo00088a
Mihailović V, Katanić Stanković JS, Jurić T, Srećković N, Mišić D, Šiler B, Monti DM, Imbimbo P, Nikles S, Pan SP, Bauer R (2020) Blackstonia perfoliata (L.) Huds. (Gentianaceae): a promising source of useful bioactive compounds. Ind Crop Prod 145:111974. https://doi.org/10.1016/j.indcrop.2019.111974
Milk Thistle Supplements Market, Milk Thistle Supplements Market Analysis by Form (Softgel, Capsules, Liquid, Tablets, Milk Thistle Supplement Powder & Granules), by Sales Channel, by Region – Global Forecast 2022–2032, January 2022. FACT662MR). https://www.factmr.com/report/662/milk-thistle-supplements-market
Mirzaei E, Sabetian G, Masjedi M, Heidari R, Mirjalili M, Dehghanian A, Vazin A (2021) The effect of silymarin on liver enzymes and antioxidant status in trauma patients in the intensive care unit: a randomized double blinded placebo-controlled clinical trial. Clin Exp Hepatol 7(2):149–155. https://doi.org/10.5114/ceh.2021.107067
Montemurro P, Fracchiolla M, Lonigro A (2007) Effects of some environmental factors on seed germination and spreading potentials of Silybum marianum Gaertner. Ital J Agron 2(3):315–320. https://doi.org/10.4081/IJA.2007.315
Nencini C, Giorgi G, Micheli L (2007) Protective effect of silymarin on oxidative stress in rat brain. Phytomed Int J Phytother Phytopharmacol 14(2–3):129–135. https://doi.org/10.1016/J.PHYMED.2006.02.005
Nyiredy S, Samu Z, Szücs Z, Gulácsi K, Kurtán T, Antus S (2008) New insight into the biosynthesis of flavanolignans in the white-flowered variant of Silybum marianum. J Chromatogr Sci 46(2):93–96. https://doi.org/10.1093/chromsci/46.2.93
Pferschy-Wenzig E-M, Atanasov AG, Malainer C, Noha SM, Kunert O, Schuster D, Heiss EH, Oberlies NH, Wagner H, Bauer R, Dirsch VM (2007) Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma. Cell Physiol Biochem 20(6):925–934. https://doi.org/10.1159/000110453
Popović-Djordjević BJ, Klaus AS, Žižak ŽS, Matić IZ, Drakulić BJ (2016) Antiproliferative and аntibacterial аctivity of some glutarimide derivatives. J Enzyme Inhib Med Chem 31:915–923. https://doi.org/10.3109/14756366.2015.1070844
Popović-Djordjević BJ, Katanić Stanković SJ, Mihailović V, Pereira AG, Garcia-Oliveira P, Prieto MA, Simal-Gandara J (2021) Algae as a source of bioactive compounds to prevent the development of type 2 diabetes mellitus. Curr Med Chem 28:1–24. https://doi.org/10.2174/0929867328666210325100654
Pourjabar A, Azimi MR, Mostafaie A, Kahrizi D, Cheghamirza K (2019) Proteome analysis of milk thistle (Silybum marianum L.) cell suspension cultures in response to methyl jasmonate and yeast extract elicitors. Appl Ecol Environ Res 17(1):547–560. https://doi.org/10.15666/aeer/1701_547560
Pradeep K, Mohan CVR, Gobianand K, Karthikeyan S (2007) Silymarin modulates the oxidant-antioxidant imbalance during diethylnitrosamine induced oxidative stress in rats. Eur J Pharmacol 560(2–3):110–116. https://doi.org/10.1016/J.EJPHAR.2006.12.023
Pradeep K, Mohan CVR, Gobianand K, Karthikeyan S (2008) Silymarin: an effective hepatoprotective agent against diethylnitrosamine-induced hepatotoxicity in rats. Pharm Biol 45(9):707–714. https://doi.org/10.1080/13880200701575254
Qavami N, Badi HN, Labbafi MR, Mehrafarin A (2013) A review on pharmacological, cultivation and biotechnology aspects of milk thistle (Silybum marianum (L.) Gaertn.). J Med Plants 12(47):19–37. https://www.researchgate.net/publication/273205291
Radhika MI, Ezhilarasan D, Gopinath P (2017) Antimicrobial efficacy of Silymarin and Silibinin against oral microorganisms. J Microbiol Infect Dis 7(3):139–143. https://doi.org/10.5799/jmid.367545
Ramasamy K, Agarwal R (2008) Multitargeted therapy of cancer by silymarin. Cancer Lett 269(2):352–362. https://doi.org/10.1016/j.canlet.2008.03.053
Rao PR, Viswanath RK (2007) Cardioprotective activity of silymarin in ischemia-reperfusion-induced myocardial infarction in albino rats. Exp Clin Cardiol 12(4):179
Rastegarpanah M, Malekzadeh R, Vahedi H, Mohammadi M, Elahi E, Chaharmahali M, Safarnavadeh T, Abdollahi M (2015) A randomized, double blinded, placebo-controlled clinical trial of silymarin in ulcerative colitis. Chin J Integr Med 21(12):902–906. https://doi.org/10.1007/s11655-012-1026-x
Rolo AP, Oliveira PJ, Moreno AJM, Pameira CM (2003) Protection against post-ischemic mitochondrial injury in rat liver by silymarin or TUDC. Hepatol Res Off J Jpn Soc Hepatol 26(3):217–224. https://doi.org/10.1016/S1386-6346(03)00108-6
Romanucci V, di Fabio G, Zarrelli A (2019) A new class of synthetic flavonolignan-like dimers: still few molecules, but with attractive properties. Molecules, MDPI AG 24(1). https://doi.org/10.3390/molecules24010108
Roy J, Blervacq AS, Créach A, Huss B, Hawkins S, Neutelings G (2017) Spatial regulation of monolignol biosynthesis and laccase genes control developmental and stress-related lignin in flax. BMC Plant Biol 17(1). https://doi.org/10.1186/s12870-017-1072-9
Salmi HA, Sarna S (1982) Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 17(4):517–521. https://doi.org/10.3109/00365528209182242
Sekar P, Ravitchandirane R, Khanam S, Muniraj N, Cassinadane AV (2022) Novel molecules as the emerging trends in cancer treatment: an update. Med Oncol 39(2). https://doi.org/10.1007/s12032-021-01615-6
Singh RP, Tyagi AK, Zhao J, Agarwal R (2002) Silymarin inhibits growth and causes regression of established skin tumors in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis. Carcinogenesis 23(3):499–510. https://doi.org/10.1093/CARCIN/23.3.499
Srećković N, Katanić Stanković JS, Matić S, Mihailović NR, Imbimbo P, Monti DM, Mihailović V (2020) Lythrum salicaria L. (Lythraceae) as a promising source of phenolic compounds in the modulation of oxidative stress: comparison between aerial parts and root extracts. Ind Crop Prod 155. https://doi.org/10.1016/j.indcrop.2020.112781
Stanković V, Mihailović V, Mitrović S, Jurišić V (2017) Protective and therapeutic possibility of medical herbs for liver cirrhosis. Romanian J Morphol Embryol 2017(3):723–729. http://www.rjme.ro/
Su CH, Chen LJ, Liao JF, Cheng JT (2013) Dual effects of silymarin on nasopharyngeal carcinoma cells (NPC-TW01). Forschende Komplementarmedizin (2006) 20(4):261–266. https://doi.org/10.1159/000354594
Surai PF (2015) Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants 4(1):204. https://doi.org/10.3390/ANTIOX4010204
Tewari D, Mocan A, Parvanov ED, Sah AN, Nabavi SM, Huminiecki L, Ma ZF, Lee YY, Horbańczuk JO, Atanasov AG (2017) Ethnopharmacological approaches for therapy of jaundice: Part II. Highly used plant species from Acanthaceae, Euphorbiaceae, Asteraceae, Combretaceae, and Fabaceae families. Front Pharmacol 8(8) Frontiers Media S.A. https://doi.org/10.3389/fphar.2017.00519
Theodosiou E, Purchartová K, Stamatis H, Kolisis F, Křen V (2014) Bioavailability of silymarin flavonolignans: drug formulations and biotransformation. Phytochem Rev 13(1):1–18. https://doi.org/10.1007/s11101-013-9285-5
Toyoda-Hokaiwado N, Yasui Y, Muramatsu M, Masumura K, Takamune M, Yamada M, Ohta T, Tanaka T, Nohmi T (2011) Chemopreventive effects of silymarin against 1,2-dimethylhydrazine plus dextran sodium sulfate-induced inflammation-associated carcinogenicity and genotoxicity in the colon of gpt delta rats. Carcinogenesis 32(10):1512–1517. https://doi.org/10.1093/carcin/bgr130
Trappoliere M, Caligiuri A, Schmid M, Bertolani C, Failli P, Vizzutti F, Novo E, di Manzano C, Marra F, Loguercio C, Pinzani M (2009) Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. J Hepatol 50(6):1102–1111. https://doi.org/10.1016/J.JHEP.2009.02.023
Tvrdý V, Pourová J, Jirkovský E, Křen V, Valentová K, Mladěnka P (2021) Systematic review of pharmacokinetics and potential pharmacokinetic interactions of flavonolignans from silymarin. Med Res Rev 41(4):2195–2246. Wiley. https://doi.org/10.1002/med.21791
Vaid M, Katiyar SK (2010) Molecular mechanisms of inhibition of photocarcinogenesis by silymarin, a phytochemical from milk thistle (Silybum marianum L. Gaertn.) (review). Int J Oncol 36(5). https://doi.org/10.3892/IJO_00000586
Vailati A, Aristia L, Sozzé E, Milani F, Inglese V, Galenda P, Bossolo PA, Ascari E, Lampertico M, Comis S, Marena C (1993) Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 64:219–228
Valcavi U, Monterosso V, Caponi R, Bosone E, Wachter WP, Szejtli J (1990) Inclusion complexes with silybinin, their preparation and pharmaceutical compositions containing them. EP0422497A2 European Patent Office. Application filed by Madaus AG, Istituto Biochimico Italiano Giovanni Lorenzini SpA
Valentová K, Vidlář A, Zatloukalová M, Stuchlík M, Vacek J, Šimánek V, Ulrichová J (2013) Biosafety and antioxidant effects of a beverage containing silymarin and arginine. A pilot, human intervention cross-over trial. Food Chem Toxicol 56:178–183. https://doi.org/10.1016/j.fct.2013.02.023
Varga Z, Seres I, Nagy E, Ujhelyi L, Balla G, Balla J, Antus S (2006) Structure prerequisite for antioxidant activity of silybin in different biochemical systems in vitro. Phytomed Int J Phytother Phytopharmacol 13(1–2):85–93. https://doi.org/10.1016/J.PHYMED.2004.06.019
Vargas-Mendoza N, Madrigal-Santillán E, Morales-González Á, Esquivel-Soto J, Esquivel-Chirino C, García-Luna y González-Rubio MG, Gayosso-de-Lucio JA, Morales-González JA (2014) Hepatoprotective effect of silymarin. World J Hepatol 6(3):144–149. https://doi.org/10.4254/WJH.V6.I3.144
Veisi S, Johari SA, Tyler CR, Mansouri B, Esmaeilbeigi M (2021) Antioxidant properties of dietary supplements of free and nanoencapsulated silymarin and their ameliorative effects on silver nanoparticles induced oxidative stress in Nile tilapia (Oreochromis niloticus). Environ Sci Pollut Res 28(20):26055–26063. https://doi.org/10.1007/S11356-021-12568-8/TABLES/3
Vengerovskii AI, Khazanov VA, Eskina KA, Vasilyev KY (2007) Effects of silymarin (hepatoprotector) and succinic acid (bioenergy regulator) on metabolic disorders in experimental diabetes mellitus. Bull Exp Biol Med 144(1):53–56. https://doi.org/10.1007/S10517-007-0252-2
Vilahur G, Casaní L, Peña E, Crespo J, Juan-Babot O, Ben-Aicha S, Mendieta G, Béjar MT, Borrell M, Badimon L (2018) Silybum marianum provides cardioprotection and limits adverse remodeling post-myocardial infarction by mitigating oxidative stress and reactive fibrosis. Int J Cardiol 270:28–35. https://doi.org/10.1016/J.IJCARD.2018.06.030
Vrba J, Papoušková B, Roubalová L, Zatloukalová M, Biedermann D, Křen V, Valentová K, Ulrichová J, Vacek J (2018) Metabolism of flavonolignans in human hepatocytes. J Pharm Biomed Anal 152:94–101. https://doi.org/10.1016/J.JPBA.2018.01.048
Wah Kheong C, Nik Mustapha NR, Mahadeva S (2017) A randomized trial of silymarin for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 15(12):1940–1949.e8. https://doi.org/10.1016/J.CGH.2017.04.016
Wellington K, Adis BJ (2001) Silymarin: a review of its clinical properties in the management of hepatic disorders. BioDrugs 15(7):465–489. https://doi.org/10.2165/00063030-200115070-00005
Weyhenmeyer R, Mascher H, Birkmayer J (1992) Study on dose-linearity of the pharmacokinetics of silibinin diastereomers using a new stereospecific assay. Int J Clin Pharmacol Ther 30:134–138
Wianowska D, Wiśniewski M (2015) Simplified procedure of silymarin extraction from Silybum marianum L. Gaertner. J Chromatogr Sci 53(2):366–372. https://doi.org/10.1093/chromsci/bmu049
Won DH, Kim LH, Jang B, Yang IH, Kwon HJ, Jin B, Oh SH, Kang JH, Hong SD, Shin JA, Cho SD (2018) In vitro and in vivo anti-cancer activity of silymarin on oral cancer. Tumor Biol 40(5). https://doi.org/10.1177/1010428318776170
Wu CG, Chamuleau RAFM, Bosch KS, Frederiks WM (1993) Protective effect of silymarin on rat liver injury induced by ischemia. Virchows Archiv B Cell Pathol Incl Mol Pathol 64(5):259–263. https://doi.org/10.1007/BF02915120
Wu JW, Lin LC, Hung SC, Chi CW, Tsai TH (2007) Analysis of silibinin in rat plasma and bile for hepatobiliary excretion and oral bioavailability application. J Pharm Biomed Anal 45(4):635–641. https://doi.org/10.1016/j.jpba.2007.06.026
Xie Y, Zhang D, Zhang J, Yuan J (2019) Metabolism, transport and drug–drug interactions of silymarin. Molecules 24(20) MDPI AG. https://doi.org/10.3390/molecules24203693
Yongtao J, Jiyong C, Xinxin F, Xiuyu F (2004) Legalon soft capsule and its preparing method. CN1572293A. Application filed by Shangdong Luye Natural Drug Research and Development Co Ltd. China
Zalat ZA, Kohaf NA, El-Din A, Elewa MA, Abdel-Latif HM (2021) Silymarin: a promising cardioprotective agent. Azhar Int J Pharmaceut Med Sci 1(1):13–21. https://doi.org/10.21608/aijpms.2021.52962.1014
Zarban A, Ziaee M (2008) Evaluation of antioxidant properties of silymarin and its potential to inhibit peroxyl radical in vitro. Pak J Pharm Sci 21(3):249–254
Zhao YSA (1999) Significant inhibition by the flavonoid antioxidant silymarin against 12-O-tetradecanoylphorbol 13-acetate-caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interleukin-1alpha expression in SENCAR mouse epidermis: implications in the prevention of stage I tumor promotion. Mol Carcinog 26(4):321–333. https://pubmed.ncbi.nlm.nih.gov/10569809/
Zhao J, Lahiri-Chatterjee M, Sharma Y, Agarwal R (2000) Inhibitory effect of a flavonoid antioxidant silymarin on benzoyl peroxide-induced tumor promotion, oxidative stress and inflammatory responses in SENCAR mouse skin. Carcinogenesis 21(4):811–816. https://doi.org/10.1093/CARCIN/21.4.811
Zhong S, Fan Y, Yan Q, Fan X, Wu B, Han Y, Zhang Y, Chen Y, Zhang H, Niu J (2017) The therapeutic effect of silymarin in the treatment of nonalcoholic fatty disease: a meta-analysis (PRISMA) of randomized control trials. Medicine 96(49). https://doi.org/10.1097/MD.0000000000009061
Zhu QY, Hackman RM, Ensunsa JL, Holt RR, Keen CL (2002) Antioxidative activities of oolong tea. J Agric Food Chem 50(23):6929–6934. https://doi.org/10.1021/JF0206163
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This work was supported by the Serbian Ministry of Education, Science and Technological Development (Agreements Nos. 451-03-68/2022-14/200122 and 451-03-68/2022-14/200026).
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Mihailović, V., Srećković, N., Popović-Djordjević, J.B. (2023). Silybin and Silymarin: Phytochemistry, Bioactivity, and Pharmacology. In: Xiao, J. (eds) Handbook of Dietary Flavonoids. Springer, Cham. https://doi.org/10.1007/978-3-030-94753-8_20-1
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