556
Views
73
CrossRef citations to date
0
Altmetric
Review

The Osteoprotective Effects Of Kaempferol: The Evidence From In Vivo And In Vitro Studies

ORCID Icon, ORCID Icon & ORCID Icon
Pages 3497-3514 | Published online: 07 Oct 2019

References

  • Duque G, Rivas D, Li W, et al. Age-related bone loss in the LOU/c rat model of healthy ageing. Exp Gerontol. 2009;44:183–189. doi:10.1016/j.exger.2008.10.00418992316
  • Chin KY, Ima-Nirwana S. The effects of orchidectomy and supraphysiological testosterone administration on trabecular bone structure and gene expression in rats. Aging Male. 2015;18:60–66. doi:10.3109/13685538.2014.95499525166624
  • Chen Z, Xue J, Shen T, Mu S, Fu Q. Curcumin alleviates glucocorticoid-induced osteoporosis through the regulation of the Wnt signaling pathway. Int J Mol Med. 2016;37:329–338. doi:10.3892/ijmm.2015.243226677102
  • Mohamad N-V, Che Zulkepli MAA, May Theseira K, et al. Establishing an animal model of secondary osteoporosis by using a gonadotropin-releasing hormone agonist. Int J Med Sci. 2018;15:300–308. doi:10.7150/ijms.2273229511366
  • Broulik PD, Vondrova J, Ruzicka P, et al. The effect of chronic alcohol administration on bone mineral content and bone strength in male rats. Physiol Res. 2010;59:599–604.19929136
  • Hapidin H, Othman F, Soelaiman IN, Shuid AN, Mohamed N. Effects of nicotine administration and nicotine cessation on bone histomorphometry and bone biomarkers in Sprague-Dawley male rats. Calcif Tissue Int. 2011;88:41–47. doi:10.1007/s00223-010-9426-420953592
  • Wong SK, Chin KY, Suhaimi FH, et al. The relationship between metabolic syndrome and osteoporosis: a review. Nutrients. 2016;8:347. doi:10.3390/nu8060347
  • Tu KN, Lie JD, Wan CKV, et al. Osteoporosis: a review of treatment options. P & T. 2018;43:92–104.29386866
  • Kling JM, Clarke BL, Sandhu NP. Osteoporosis prevention, screening, and treatment: a review. J Womens Health. 2014;23:563–572. doi:10.1089/jwh.2013.4611
  • Wong SK, Mohamad NV, Ibrahim N, et al. The molecular mechanism of vitamin E as a bone-protecting agent: a review on current evidence. Int J Mol Sci. 2019;20. doi:10.3390/ijms20061453
  • Wong SK, Chin KY, Ima-Nirwana S. Berberine and musculoskeletal disorders: the therapeutic potential and underlying molecular mechanisms. Phytomedicine. 2019;152892. doi:10.1016/j.phymed.2019.15289230902523
  • Chin KY, Ima-Nirwana S. Olives and bone: a green osteoporosis prevention option. Int J Environ Res Public Health. 2016;13. doi:10.3390/ijerph13121252
  • Chin K-Y, Ima-Nirwana S. The biological effects of tocotrienol on bone: a review on evidence from rodent models. Drug Des Devel Ther. 2015;9:2049–2061. doi:10.2147/DDDT.S79660
  • Wong SK, Chin KY, Suhaimi FH, Ahmad F, Ima-Nirwana S. Exploring the potential of tocotrienol from Bixa orellana as a single agent targeting metabolic syndrome and bone loss. Bone. 2018;116:8–21. doi:10.1016/j.bone.2018.07.00329990585
  • Wong SK, Chin KY, Suhaimi FH, et al. The effects of vitamin E from elaeis guineensis (oil palm) in a rat model of bone loss due to metabolic syndrome. Int J Environ Res Public Health. 2018;15:1828.
  • Wong SK, Chin KY, Suhaimi FH, Ahmad F, Ima-Nirwana S. The effects of palm tocotrienol on metabolic syndrome and bone loss in male rats induced by high-carbohydrate high-fat diet. J Funct Foods. 2018;44:246–254. doi:10.1016/j.jff.2018.03.022
  • Wong SK, Chin K-Y, Ima-Nirwana S. The effects of tocotrienol on bone peptides in a rat model of osteoporosis induced by metabolic syndrome: the possible communication between bone cells. Int J Environ Res Public Health. 2019;16:3313. doi:10.3390/ijerph16183313
  • Calderon-Montano JM, Burgos-Moron E, Perez-Guerrero C, et al. A review on the dietary flavonoid kaempferol. Mini Rev Med Chem. 2011;11:298–344.21428901
  • Imran M, Rauf A, Shah ZA, et al. Chemo-preventive and therapeutic effect of the dietary flavonoid kaempferol: A comprehensive review. Phytother Res. 2019;33:263–275. doi:10.1002/ptr.622730402931
  • Yang L, Takai H, Utsunomiya T, et al. Kaempferol stimulates bone sialoprotein gene transcription and new bone formation. J Cell Biochem. 2010;110:1342–1355. doi:10.1002/jcb.2264920564228
  • Trivedi R, Kumar S, Kumar A, et al. Kaempferol has osteogenic effect in ovariectomized adult Sprague-Dawley rats. Mol Cell Endocrinol. 2008;289:85–93. doi:10.1016/j.mce.2008.02.02718400372
  • Nowak B, Matuszewska A, Nikodem A, et al. Oral administration of kaempferol inhibits bone loss in rat model of ovariectomy-induced osteopenia. Pharmacol Rep. 2017;69:1113–1119. doi:10.1016/j.pharep.2017.05.00229031689
  • Ma X-Q, Han T, Zhang X, et al. Kaempferitrin prevents bone lost in ovariectomized rats. Phytomedicine. 2015;22:1159–1162. doi:10.1016/j.phymed.2015.09.00326598914
  • Adhikary S, Choudhary D, Ahmad N, et al. Dietary flavonoid kaempferol inhibits glucocorticoid-induced bone loss by promoting osteoblast survival. Nutrition. 2018;53:64–76. doi:10.1016/j.nut.2017.12.00329655780
  • Nguyen LT, Maidar O, Sharma AR, et al. Enhanced healing process of fracture by treatment of Kaempferol. Biomed Res. 2016;27.
  • Kim H, Han C, Maidar O, et al. Biomechanical effects of kaempferol treatments on the bone healing process of murine tibia. Paper presented at the ASME 2014 International Mechanical Engineering Congress and Exposition, Montreal, QC; 2014.
  • Gupta G, Kumar A, Khedgikar V, et al. Osteogenic efficacy enhancement of kaempferol through an engineered layer-by-layer matrix: a study in ovariectomized rats. Nanomedicine. 2013;8:757–771. doi:10.2217/nnm.12.17123311987
  • Kumar A, Gupta G, Khedgikar V, et al. In vivo efficacy studies of layer-by-layer nano-matrix bearing kaempferol for the conditions of osteoporosis: a study in ovariectomized rat model. Eur J Pharm Biopharm. 2012;82:508–517. doi:10.1016/j.ejpb.2012.08.00122926146
  • Tsuchiya S, Sugimoto K, Kamio H, et al. Kaempferol-immobilized titanium dioxide promotes formation of new bone: effects of loading methods on bone marrow stromal cell differentiation in vivo and in vitro. Int J Nanomedicine. 2018;13:1665–1676. doi:10.2147/IJN.S15078629593412
  • Zhu J, Tang H, Zhang Z, et al. Kaempferol slows intervertebral disc degeneration by modifying LPS-induced osteogenesis/adipogenesis imbalance and inflammation response in BMSCs. Int Immunopharmacol. 2017;43:236–242. doi:10.1016/j.intimp.2016.12.02028043032
  • Miyake M, Arai N, Ushio S, Iwaki K, Ikeda M, Kurimoto M. Promoting effect of kaempferol on the differentiation and mineralization of murine pre-osteoblastic cell line MC3T3-E1. Biosci Biotechnol Biochem. 2003;67:1199–1205. doi:10.1271/bbb.67.119912843643
  • Yamaguchi M, Hamamoto R, Uchiyama S, Ishiyama K. Effects of flavonoid on calcium content in femoral tissue culture and parathyroid hormone-stimulated osteoclastogenesis in bone marrow culture in vitro. Mol Cell Biochem. 2007;303:83–88. doi:10.1007/s11010-007-9458-x17541507
  • Marino S, Logan JG, Mellis D, Capulli M. Generation and culture of osteoclasts. Bonekey Rep. 2014;3:570. doi:10.1038/bonekey.2014.6525228983
  • Pang J, Ricupero D, Huang S, et al. Differential activity of kaempferol and quercetin in attenuating tumor necrosis factor receptor family signaling in bone cells. Biochem Pharmacol. 2006;71:818–826. doi:10.1016/j.bcp.2005.12.02316434028
  • Kim CJ, Shin SH, Kim BJ, et al. The effects of kaempferol-inhibited autophagy on osteoclast formation. Int J Mol Sci. 2018;19:125.
  • Shahi M, Peymani A, Sahmani M. Regulation of bone metabolism. Rep Biochem Mol Biol. 2017;5:73–82.28367467
  • Krane SM, Inada M. Matrix metalloproteinases and bone. Bone. 2008;43:7–18. doi:10.1016/j.bone.2008.03.02018486584
  • Paiva KB, Granjeiro JM. Bone tissue remodeling and development: focus on matrix metalloproteinase functions. Arch Biochem Biophys. 2014;561:74–87. doi:10.1016/j.abb.2014.07.03425157440
  • Almalki SG, Agrawal DK. Effects of matrix metalloproteinases on the fate of mesenchymal stem cells. Stem Cell Res Ther. 2016;7:129. doi:10.1186/s13287-016-0393-127612636
  • Kelwick R, Desanlis I, Wheeler GN, et al. The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family. Genome Biol. 2015;16:113. doi:10.1186/s13059-015-0667-426025392
  • Wong SK, Chin KY, Suhaimi FH, Ahmad F, Jamil NA, Ima-Nirwana S. Osteoporosis is associated with metabolic syndrome induced by high-carbohydrate high-fat diet in a rat model. Biomed Pharmacother. 2018;98:191–200. doi:10.1016/j.biopha.2017.12.04229257979
  • Wong SK, Chin KY, Suhaimi FH, Ahmad F, Ima-Nirwana S, Bader M. Effects of metabolic syndrome on bone mineral density, histomorphometry and remodelling markers in male rats. PLoS One. 2018;13:e0192416. doi:10.1371/journal.pone.019241629420594
  • Valenzuela R, Videla LA. The importance of the long-chain polyunsaturated fatty acid n-6/n-3 ratio in development of non-alcoholic fatty liver associated with obesity. Food Funct. 2011;2:644–648. doi:10.1039/c1fo10133a22008843
  • Byun MR, Jeong H, Bae SJ, Kim AR, Hwang ES, Hong J-H. TAZ is required for the osteogenic and anti-adipogenic activities of kaempferol. Bone. 2012;50:364–372. doi:10.1016/j.bone.2011.10.03522108137
  • Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest. 2006;116:1186–1194. doi:10.1172/JCI2855016670759
  • Lee H-R, Kim T-H, Choi K-C. Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse. Lab Anim Res. 2012;28:71–76. doi:10.5625/lar.2012.28.2.7122787479
  • Gupte AA, Pownall HJ, Hamilton DJ. Estrogen: an emerging regulator of insulin action and mitochondrial function. J Diabetes Res. 2015;2015:9. doi:10.1155/2015/815839
  • Khalid AB, Krum SA. Estrogen receptors alpha and beta in bone. Bone. 2016;87:130–135. doi:10.1016/j.bone.2016.03.01627072516
  • Prouillet C, Maziere JC, Maziere C, et al. Stimulatory effect of naturally occurring flavonols quercetin and kaempferol on alkaline phosphatase activity in MG-63 human osteoblasts through ERK and estrogen receptor pathway. Biochem Pharmacol. 2004;67:1307–1313. doi:10.1016/j.bcp.2003.11.00915013846
  • Guo AJ, Choi RC, Zheng KY, et al. Kaempferol as a flavonoid induces osteoblastic differentiation via estrogen receptor signaling. Chin Med. 2012;7:10. doi:10.1186/1749-8546-7-1022546174
  • Tang X, Zhu X, Liu S, Nicholson RC, Ni X. Phytoestrogens induce differential estrogen receptor beta-mediated responses in transfected MG-63 cells. Endocrine. 2008;34:29–35. doi:10.1007/s12020-008-9099-118937077
  • Yang L, Chen Q, Wang F, Zhang G. Antiosteoporotic compounds from seeds of Cuscuta chinensis. J Ethnopharmacol. 2011;135:553–560. doi:10.1016/j.jep.2011.03.05621463675
  • Wu M, Chen G, Li YP. TGF-beta and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009. doi:10.1038/boneres.2016.927563484
  • Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov. 2012;11:234. doi:10.1038/nrd366922378270
  • Kim IR, Kim SE, Baek HS, et al. The role of kaempferol-induced autophagy on differentiation and mineralization of osteoblastic MC3T3-E1 cells. BMC Complement Altern Med. 2016;16:333. doi:10.1186/s12906-016-1320-927581091
  • Chiou W-F, Lee C-H, Liao J-F, Chen CC. 8-Prenylkaempferol accelerates osteoblast maturation through bone morphogenetic protein-2/p38 pathway to activate Runx2 transcription. Life Sci. 2011;88:335–342. doi:10.1016/j.lfs.2010.12.00921163272
  • Long M, Li SX, Xiao JF, et al. Kidney tubular-cell secretion of osteoblast growth factor is increased by kaempferol: a scientific basis for “the kidney controlling the bone” theory of Chinese medicine. Chin J Integr Med. 2014;20:675–681. doi:10.1007/s11655-014-1336-z25012631
  • Lacey DC, Simmons PJ, Graves SE, Hamilton JA. Proinflammatory cytokines inhibit osteogenic differentiation from stem cells: implications for bone repair during inflammation. Osteoarthritis Cartilage. 2009;17:735–742. doi:10.1016/j.joca.2008.11.01119136283
  • Seong S, Kim JH, Kim N. Pro-inflammatory cytokines modulating osteoclast differentiation and function. J Rheum Dis. 2016;23:148–153. doi:10.4078/jrd.2016.23.3.148
  • Confalone E, D’Alessio G, Furia A. IL-6 induction by TNFα and IL-1β in an osteoblast-like cell line. Int J Biomed Sci. 2010;6:135–140.23675187
  • Zhu JF, Valente AJ, Lorenzo JA, Carnes D, Graves DT. Expression of monocyte chemoattractant protein 1 in human osteoblastic cells stimulated by proinflammatory mediators. J Bone Miner Res. 1994;9:1123–1130. doi:10.1002/jbmr.56500907217942160
  • Pietschmann P, Mechtcheriakova D, Meshcheryakova A, Föger-Samwald U, Ellinger I. Immunology of osteoporosis: a mini-review. Gerontology. 2016;62:128–137. doi:10.1159/00043109126088283
  • Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001;142:5050–5055. doi:10.1210/endo.142.12.853611713196
  • Hardy R, Cooper MS. Bone loss in inflammatory disorders. J Endocrinol. 2009;201:309–320. doi:10.1677/JOE-08-056819443863
  • Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther. 2007;9:S1. doi:10.1186/ar217217634140
  • Boyce BF, Xing L. The RANKL/RANK/OPG pathway. Curr Osteoporos Rep. 2007;5:98–104.17925190
  • Wimalawansa SJ. Nitric oxide and bone. Ann N Y Acad Sci. 2010;1192:391–403. doi:10.1111/j.1749-6632.2009.05230.x20392265
  • Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33:829d–837d. doi:10.1093/eurheartj/ehr30421890489
  • Zheng H, Yu X, Collin-Osdoby P, et al. RANKL stimulates inducible nitric-oxide synthase expression and nitric oxide production in developing osteoclasts. An autocrine negative feedback mechanism triggered by RANKL-induced interferon-beta via NF-kappaB that restrains osteoclastogenesis and bone resorption. J Biol Chem. 2006;281:15809–15820. doi:10.1074/jbc.M51322520016613848
  • Cuzzocrea S, Mazzon E, Dugo L, et al. Inducible nitric oxide synthase mediates bone loss in ovariectomized mice. Endocrinology. 2003;144:1098–1107. doi:10.1210/en.2002-22059712586786
  • Lee WS, Lee EG, Sung MS, et al. Kaempferol inhibits IL-1beta-stimulated, RANKL-mediated osteoclastogenesis via downregulation of MAPKs, c-Fos, and NFATc1. Inflammation. 2014;37:1221–1230. doi:10.1007/s10753-014-9849-624696323
  • Yu Q, Zeng K, Ma X, et al. Resokaempferol-mediated anti-inflammatory effects on activated macrophages via the inhibition of JAK2/STAT3, NF-kappaB and JNK/p38 MAPK signaling pathways. Int Immunopharmacol. 2016;38:104–114. doi:10.1016/j.intimp.2016.05.01027261558
  • Lee SB, Shin JS, Han HS, et al. Kaempferol 7-O-beta-D-glucoside isolated from the leaves of Cudrania tricuspidata inhibits LPS-induced expression of pro-inflammatory mediators through inactivation of NF-kappaB, AP-1, and JAK-STAT in RAW 264.7 macrophages. Chem Biol Interact. 2018;284:101–111. doi:10.1016/j.cbi.2018.02.02229470957
  • Domazetovic V, Marcucci G, Iantomasi T, Brandi ML, Vincenzini MT. Oxidative stress in bone remodeling: role of antioxidants. Clin Cases Miner Bone Metab. 2017;14:209–216. doi:10.11138/ccmbm/2017.14.1.20929263736
  • Liu AL, Zhang ZM, Zhu BF, Liao Z-H, Liu Z. Metallothionein protects bone marrow stromal cells against hydrogen peroxide-induced inhibition of osteoblastic differentiation. Cell Biol Int. 2004;28:905–911. doi:10.1016/j.cellbi.2004.09.00415566960
  • Arai M, Shibata Y, Pugdee K, Abiko Y, Ogata Y. Effects of reactive oxygen species (ROS) on antioxidant system and osteoblastic differentiation in MC3T3-E1 cells. IUBMB Life. 2007;59:27–33. doi:10.1080/1521654060115618817365177
  • Wauquier F, Leotoing L, Coxam V, Guicheux J, Wittrant Y. Oxidative stress in bone remodelling and disease. Trends Mol Med. 2009;15:468–477. doi:10.1016/j.molmed.2009.08.00419811952
  • Deng S, Dai G, Chen S, et al. Dexamethasone induces osteoblast apoptosis through ROS-PI3K/AKT/GSK3β signaling pathway. Biomed Pharmacother. 2019;110:602–608. doi:10.1016/j.biopha.2018.11.10330537677
  • Suh KS, Choi EM, Kwon M, et al. Kaempferol attenuates 2-deoxy-d-ribose-induced oxidative cell damage in MC3T3-E1 osteoblastic cells. Biol Pharm Bull. 2009;32:746–749. doi:10.1248/bpb.32.74619336918
  • Almeida M, Han L, Martin-Millan M, et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007;282:27285–27297. doi:10.1074/jbc.M70281020017623659
  • Wattel A, Kamel S, Mentaverri R, et al. Potent inhibitory effect of naturally occurring flavonoids quercetin and kaempferol on in vitro osteoclastic bone resorption. Biochem Pharmacol. 2003;65:35–42. doi:10.1016/s0006-2952(02)01445-412473376
  • Hocking LJ, Whitehouse C, Helfrich MH. Autophagy: a new player in skeletal maintenance? J Bone Miner Res. 2012;27:1439–1447. doi:10.1002/jbmr.166822706899
  • Florencio-Silva R, Sasso GR, Simoes MJ, et al. Osteoporosis and autophagy: what is the relationship? Rev Assoc Med Bras. 2017;63:173–179. doi:10.1590/1806-9282.63.02.17328355379
  • Fu LL, Cheng Y, Liu B. Beclin-1: autophagic regulator and therapeutic target in cancer. Int J Biochem Cell Biol. 2013;45:921–924. doi:10.1016/j.biocel.2013.02.00723420005
  • Lamark T, Svenning S, Johansen T. Regulation of selective autophagy: the p62/SQSTM1 paradigm. Essays Biochem. 2017;61:609–624. doi:10.1042/EBC2017003529233872
  • Nollet M, Santucci-Darmanin S, Breuil V, et al. Autophagy in osteoblasts is involved in mineralization and bone homeostasis. Autophagy. 2014;10:1965–1977. doi:10.4161/auto.3618225484092
  • Dutta D, Xu J, Kim JS, Dunn WA, Leeuwenburgh C. Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity. Autophagy. 2013;9:328–344. doi:10.4161/auto.2297123298947
  • Pierrefite-Carle V, Santucci-Darmanin S, Breuil V, Camuzard O, Carle GF. Autophagy in bone: self-eating to stay in balance. Ageing Res Rev. 2015;24:206–217. doi:10.1016/j.arr.2015.08.00426318060
  • Lin NY, Chen CW, Kagwiria R, et al. Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy-induced bone loss. Ann Rheum Dis. 2016;75:1203–1210. doi:10.1136/annrheumdis-2015-20724026113650
  • Dawodu D, Patecki M, Hegermann J, Dumler I, Haller H, Kiyan Y. oxLDL inhibits differentiation and functional activity of osteoclasts via scavenger receptor-a mediated autophagy and cathepsin K secretion. Sci Rep. 2018;8:11604. doi:10.1038/s41598-018-29963-w30072716
  • Charlier E, Relic B, Deroyer C, et al. Insights on molecular mechanisms of chondrocytes death in osteoarthritis. Int J Mol Sci. 2016;17:2146. doi:10.3390/ijms17122146
  • Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol. 2019;20:175–193. doi:10.1038/s41580-018-0089-830655609
  • Nolting J-F, Möbius W, Köster S. Mechanics of individual keratin bundles in living cells. Biophys J. 2014;107:2693–2699. doi:10.1016/j.bpj.2014.10.03925468348
  • Goldstein MG, Li Z. Heat-shock proteins in infection-mediated inflammation-induced tumorigenesis. J Hematol Oncol. 2009;2:5. doi:10.1186/1756-8722-2-519183457
  • Chen E, Xue D, Zhang W, Lin F, Pan Z. Extracellular heat shock protein 70 promotes osteogenesis of human mesenchymal stem cells through activation of the ERK signaling pathway. FEBS Lett. 2015;589:4088–4096. doi:10.1016/j.febslet.2015.11.02126608032
  • Li C, Sunderic K, Nicoll SB, Wang S. Downregulation of heat shock protein 70 impairs osteogenic and chondrogenic differentiation in human mesenchymal stem cells. Sci Rep. 2018;8:553. doi:10.1038/s41598-017-18541-129323151
  • Inaba M, Terada M, Nishizawa Y, et al. Protective effect of an aldose reductase inhibitor against bone loss in galactose-fed rats: possible involvement of the polyol pathway in bone metabolism. Metabolism. 1999;48:904–909. doi:10.1016/s0026-0495(99)90227-510421234
  • Chan CL, Chen JY, Shih MC, et al. L-caldesmon alters cell spreading and adhesion force in RANKL-induced osteoclasts. J Biomed Sci. 2019;26:12. doi:10.1186/s12929-019-0555-430678675
  • Kumar A, Singh AK, Gautam AK, et al. Identification of kaempferol-regulated proteins in rat calvarial osteoblasts during mineralization by proteomics. Proteomics. 2010;10:1730–1739. doi:10.1002/pmic.20090066620162559
  • Khedgikar V, Kushwaha P, Gautam J, et al. Kaempferol targets Krt-14 and induces cytoskeletal mineralization in osteoblasts: A mechanistic approach. Life Sci. 2016;151:207–217. doi:10.1016/j.lfs.2016.03.00926956522
  • Resende FA, Vilegas W, Dos Santos LC, Varanda EA. Mutagenicity of flavonoids assayed by bacterial reverse mutation (Ames) test. Molecules. 2012;17:5255–5268. doi:10.3390/molecules1705525522565478