Letter to the editor
Recent studies on kaempferol and its biological and pharmacological activities
Jae Kwang Kim1, Sang Un Park21Division of Life Sciences and Bio-Resource and Environmental Center, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea
2Department of Crop Science, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Korea
EXCLI J 2020;19:Doc627
Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one) is a natural flavonol exhibiting different metabolic functions. It is most commonly found in a variety of plants and plant derived foods including grapes, kale, bean, broccoli, tomatoes, spinach, tea, and ginkgo biloba leaves (Cid-Ortega and Monroy-Rivera, 2018; Devi et al., 2015).
The biosynthesis of kaempferol is completed in four major steps. In the first step, a phenylpropanoid metabolic pathway occurs in which phenylalanine is converted into 4-coumaroyl-CoA. Subsequently, 4-coumaroyl-CoA is combined with three molecules of malonyl-coA to form naringenin chalcone (a tetrahydroxychalcone) through the action of chalcone synthase. In the third step, naringenin chalcone is exchanged with naringenin, and its hydroxyl group is involved in the formation of dihydrokaempferol. Finally, dihydrokaempferol, which has a double bond, is converted into kaempferol (Calderón-Montaño et al., 2011; Santos-Buelga et al., 2019).
Several papers have reported the positive effects of dietary kaempferol in reducing the risk of chronic diseases, such as cancer, liver injury, obesity, and diabetes (Imran et al., 2019; Wong et al., 2019). Kaempferol exhibits anti-inflammatory properties and has been used to cure many acute and chronic inflammation-induced diseases, such as intervertebral disc degeneration and colitis, post-menopausal bone loss, and acute lung injury (Ren et al., 2019). Herein, we summarize the most recent published findings on the biological and pharmacological activities of kaempferol (Table 1(Tab. 1); References in Table 1: Adhikary et al., 2018; Alkhalidy et al., 2018; Beg et al., 2018; Chen et al., 2020; Chien et al., 2019; Cui et al., 2019; Da et al., 2019; Du et al., 2018; El-Kott et al., 2020; Fernández-Del-Río et al., 2017; Gao et al., 2018; Gao et al., 2019; Gómez-Zorita et al., 2017; Guo et al., 2017; Han et al., 2018; Jiang et al., 2019; Kim et al., 2018; Kim, 2017; Kouhestani et al., 2018; Lei et al., 2019; Li et al., 2017; Li et al., 2018; Li et al., 2019; Liu et al., 2017; Mahobiya et al., 2018; Ming et al., 2017; Moradzadeh et al., 2018; Özay et al., 2019; Pan et al., 2018; Qian et al., 2019 ; Rabha et al., 2018; Santos et al., 2019; Sharma and Nam, 2019; Suchal et al., 2017; Torres-Villarreal et al., 2019; Varshney et al., 2017; Vishwakarma et al., 2018; Wang et al., 2018; Wang et al., 2019; Wu et al., 2017; Wu et al., 2018; Yang et al., 2019; Yao et al., 2019; Yeon et al., 2019; Zhang and Ma, 2019; Zhang et al., 2017; Zhang et al., 2019; Zhao et al., 2017; Zhao et al., 2020; Zhong et al., 2018; Zhou et al., 2018; Zhu et al., 2018; Zhuang et al., 2017).
This research was supported by Golden Seed Project (213006051WTE11) funded by the Ministry of Agriculture, Food and Rural Affairs (MAFRA), the Ministry of Oceans and Fisheries (MOF), the Rural Development Administration (RDA), and the Korea Forest Service (KFS), Republic of Korea.
Conflict of interest
The authors declare no conflict of interest.
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9. Cui S, Tang J, Wang S, Li L. Kaempferol protects lipopolysaccharide-induced inflammatory injury in human aortic endothelial cells (HAECs) by regulation of miR-203. Biomed Pharmacother. 2019;115:108888.
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12. Du W, An Y, He X, Zhang D, He W. Protection of kaempferol on oxidative stress-induced retinal pigment epithelial cell damage. Oxid Med Cell Longev. 2018;2018:1610751.
13. El-Kott AF, Bin-Meferij MM, Eleawa SM, Alshehri MM. Kaempferol protects against cadmium chloride-induced memory loss and hippocampal apoptosis by increased intracellular glutathione stores and activation of PTEN/AMPK induced inhibition of Akt/mTOR signaling. Neurochem Res. 2020;45:295-309.
14. Fernández-Del-Río L, Nag A, Gutiérrez Casado E, Ariza J, Awad AM, Joseph AI, et al. Kaempferol increases levels of coenzyme Q in kidney cells and serves as a biosynthetic ring precursor. Free Radic Biol Med. 2017;110:176-87.
15. Gao W, Wang W, Peng Y, Deng Z. Antidepressive effects of kaempferol mediated by reduction of oxidative stress, proinflammatory cytokines and up-regulation of AKT/β-catenin cascade. Metab Brain Dis. 2019;34:485-94.
16. Gao Y, Yin J, Rankin GO, Chen YC. Kaempferol induces G2/M cell cycle arrest via checkpoint kinase 2 and promotes apoptosis via death receptors in human ovarian carcinoma A2780/CP70 cells. Molecules. 2018;23:E1095.
17. Gómez-Zorita S, Lasa A, Abendaño N, Fernández-Quintela A, Mosqueda-Solís A, Garcia-Sobreviela MP, et al. Phenolic compounds apigenin, hesperidin and kaempferol reduce in vitro lipid accumulation in human adipocytes. J Transl Med. 2017;15:237.
18. Guo H, Lin W, Zhang X, Zhang X, Hu Z, Li L, et al. Kaempferol induces hepatocellular carcinoma cell death via endoplasmic reticulum stress-CHOP-autophagy signaling pathway. Oncotarget. 2017;8:82207-16.
19. Han X, Liu CF, Gao N, Zhao J, Xu J. Kaempferol suppresses proliferation but increases apoptosis and autophagy by up-regulating microRNA-340 in human lung cancer cells. Biomed Pharmacother. 2018;108:809-16.
20. Imran M, Rauf A, Shah ZA, Saeed F, Imran A, Arshad MU, et al. Chemo-preventive and therapeutic effect of the dietary flavonoid kaempferol: A comprehensive review. Phytother Res. 2019;33:263-75.
21. Jiang R, Hao P, Yu G, Liu C, Yu C, Huang Y, et al. Kaempferol protects chondrogenic ATDC5 cells against inflammatory injury triggered by lipopolysaccharide through down-regulating miR-146a. Int Immunopharmacol. 2019;69:373-81.
22. Kim GD. Kaempferol inhibits angiogenesis by suppressing HIF-1α and VEGFR2 activation via ERK/p38 MAPK and PI3K/Akt/mTOR signaling pathways in endothelial cells. Prev Nutr Food Sci. 2017;22:320-6.
23. Kim TW, Lee SY, Kim M, Cheon C, Ko SG. Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells. Cell Death Dis. 2018;9:875.
24. Kouhestani S, Jafari A, Babaei P. Kaempferol attenuates cognitive deficit via regulating oxidative stress and neuroinflammation in an ovariectomized rat model of sporadic dementia. Neural Regen Res. 2018;13:1827-32.
25. Lei X, Guo J, Wang Y, Cui J, Feng B, Su Y, et al. Inhibition of endometrial carcinoma by Kaempferol is interceded through apoptosis induction, G2/M phase cell cycle arrest, suppression of cell invasion and upregulation of m-TOR/PI3K signalling pathway. J BUON. 2019;24:1555-61.
26. Li Q, Hu X, Xuan Y, Ying J, Fei Y, Rong J, et al. Kaempferol protects ethanol-induced gastric ulcers in mice via pro-inflammatory cytokines and NO. Acta Biochim Biophys Sin (Shanghai). 2018;50:246-53.
27. Li Q, Wei L, Lin S, Chen Y, Lin J, Peng J. Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway. Mol Med Rep. 2019;20:728-34.
28. Li Y, Ding Z, Wu C. Mechanistic study of the inhibitory effect of kaempferol on uterine fibroids in vitro. Med Sci Monit. 2017;22:4803-8.
29. Liu Y, Gao L, Guo S, Liu Y, Zhao X, Li R, et al. Kaempferol alleviates angiotensin II-induced cardiac dysfunction and interstitial fibrosis in mice. Cell Physiol Biochem. 2017;43:2253-63.
30. Mahobiya A, Singh TU, Rungsung S, Kumar T, Chandrasekaran G, Parida S, et al. Kaempferol-induces vasorelaxation via endothelium-independent pathways in rat isolated pulmonary artery. Pharmacol Rep. 2018;70:863-74.
31. Ming D, Wang D, Cao F, Xiang H, Mu D, Cao J, et al. Kaempferol inhibits the primary attachment phase of biofilm formation in Staphylococcus aureus. Front Microbiol. 2017;8:2263.
32. Moradzadeh M, Tabarraei A, Sadeghnia HR, Ghorbani A, Mohamadkhani A, Erfanian S, et al. Kaempferol increases apoptosis in human acute promyelocytic leukemia cells and inhibits multidrug resistance genes. J Cell Biochem. 2018;119:2288-97.
33. Özay Y, Güzel S, Yumrutaş Ö, Pehlivanoğlu B, Erdoğdu İH, Yildirim Z, et al. Wound healing effect of kaempferol in diabetic and nondiabetic rats. J Surg Res. 2019;233:284-96.
34. Pan D, Li N, Liu Y, Xu Q, Liu Q, You Y, et al. Kaempferol inhibits the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes by blocking activation of the MAPK pathway. Int Immunopharmacol. 2018;55:174-82.
35. Qian J, Chen X, Chen X, Sun C, Jiang Y, Qian Y, et al. Kaempferol reduces K63-linked polyubiquitination to inhibit nuclear factor-κB and inflammatory responses in acute lung injury in mice. Toxicol Lett. 2019;306:53-60.
36. Rabha DJ, Singh TU, Rungsung S, Kumar T, Parida S, Lingaraju MC, et al. Kaempferol attenuates acute lung injury in caecal ligation and puncture model of sepsis in mice. Exp Lung Res. 2018;44:63-78.
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38. Santos JMS, Lins TLBG, Barberino RS, Menezes VG, Gouveia BB, Matos MHT. Kaempferol promotes primordial follicle activation through the phosphatidylinositol 3-kinase/protein kinase B signaling pathway and reduces DNA fragmentation of sheep preantral follicles cultured in vitro. Mol Reprod Dev. 2019;86:319-29.
39. Santos-Buelga C, González-Paramás AM, Oludemi T, Ayuda-Durán B, González-Manzano S. Plant phenolics as functional food ingredients. Adv Food Nutr Res. 2019;90:183-257.
40. Sharma AR, Nam JS. Kaempferol stimulates WNT/β-catenin signaling pathway to induce differentiation of osteoblasts. J Nutr Biochem. 2019;74:108228.
41. Suchal K, Malik S, Khan SI, Malhotra RK, Goyal SN, Bhatia J, et al. Molecular pathways involved in the amelioration of myocardial injury in diabetic rats by kaempferol. Int J Mol Sci. 2017;18:E1001.
42. Torres-Villarreal D, Camacho A, Castro H, Ortiz-Lopez R, de la Garza AL. Anti-obesity effects of kaempferol by inhibiting adipogenesis and increasing lipolysis in 3T3-L1 cells. J Physiol Biochem. 2019;75:83-8.
43. Varshney R, Gupta S, Roy P. Cytoprotective effect of kaempferol against palmitic acid-induced pancreatic β-cell death through modulation of autophagy via AMPK/mTOR signaling pathway. Mol Cell Endocrinol. 2017;448:1-20.
44. Vishwakarma A, Singh TU, Rungsung S, Kumar T, Kandasamy A, Parida S, et al. Effect of kaempferol pretreatment on myocardial injury in rats. Cardiovasc Toxicol. 2018;18:312-28.
45. Wang H, Chen L, Zhang X, Xu L, Xie B, Shi H, et al. Kaempferol protects mice from d-GalN/LPS-induced acute liver failure by regulating the ER stress-Grp78-CHOP signaling pathway. Biomed Pharmacother. 2019;111:468-75.
46. Wang J, Li T, Feng J, Li L, Wang R, Cheng H, et al. Kaempferol protects against gamma radiation-induced mortality and damage via inhibiting oxidative stress and modulating apoptotic molecules in vivo and vitro. Environ Toxicol Pharmacol. 2018;60:128-37.
47. Wong SK, Chin KY, Ima-Nirwana S. The osteoprotective effects of kaempferol: the evidence from in vivo and in vitro studies. Drug Des Devel Ther. 2019;13:3497-14.
48. Wu P, Meng X, Zheng H, Zeng Q, Chen T, Wang W, et al. Kaempferol attenuates ROS-induced hemolysis and the molecular mechanism of its induction of apoptosis on bladder cancer. Molecules. 2018;23:E2592.
49. Wu Y, Zhang Q, Zhang R. Kaempferol targets estrogen-related receptor α and suppresses the angiogenesis of human retinal endothelial cells under high glucose conditions. Exp Ther Med. 2017;14:5576-82.
50. Yang YL, Cheng X, Li WH, Liu M, Wang YH, Du GH. Kaempferol attenuates LPS-induced striatum injury in mice involving anti-neuroinflammation, maintaining BBB integrity, and down-regulating the HMGB1/ TLR4 pathway. Int J Mol Sci. 2019;20:E491.
51. Yao X, Jiang H, NanXu Y, Piao X, Gao Q, Kim NH. Kaempferol attenuates mitochondrial dysfunction and oxidative stress induced by H(2)O(2) during porcine embryonic development. Theriogenology. 2019;135:174-80.
52. Yeon MJ, Lee MH, Kim DH, Yang JY, Woo HJ, Kwon HJ, et al. Anti-inflammatory effects of kaempferol on helicobacter pylori-induced inflammation. Biosci Biotechnol Biochem. 2019;83:166-73.
53. Zhang F, Ma C. Kaempferol suppresses human gastric cancer SNU-216 cell proliferation, promotes cell autophagy, but has no influence on cell apoptosis. Braz J Med Biol Res. 2019;52:e7843.
54. Zhang N, Zhao S, Hong J, Li W, Wang X. Protective effects of kaempferol on D-ribose-induced mesangial cell injury. Oxid Med Cell Longev. 2019;2019:7564207.
55. Zhang R, Ai X, Duan Y, Xue M, He W, Wang C, et al. Kaempferol ameliorates H9N2 swine influenza virus-induced acute lung injury by inactivation of TLR4/MyD88-mediated NF-κB and MAPK signaling pathways. Biomed Pharmacother. 2017;89:660-72.
56. Zhao L, Sun J, Shi S, Qin X, Zhang K, Xu J. Kaempferol protects retinal ganglion ceils from high-glucose-induced injury by regulating vasohibin-1. Neurosci Lett. 2020;716:134633.
57. Zhao Y, Tian B, Wang Y, Ding H. Kaempferol sensitizes human ovarian cancer cells-OVCAR-3 and SKOV-3 to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis via JNK/ ERK-CHOP pathway and up-regulation of death receptors 4 and 5. Med Sci Monit. 2017;23:5096-105.
58. Zhong X, Zhang L, Li Y, Li P, Li J, Cheng G. Kaempferol alleviates ox-LDL-induced apoptosis by up-regulation of miR-26a-5p via inhibiting TLR4/NF-κB pathway in human endothelial cells. Biomed Pharmacother. 2018;108:1783-9.
59. Zhou B, Jiang Z, Li X, Zhang X. Kaempferol's protective effect on ethanol-induced mouse primary hepatocytes injury involved in the synchronous inhibition of SP1, Hsp70 and CYP2E1. Am J Chin Med. 2018;46:1093-10.
60. Zhu G, Liu X, Li H, Yan Y, Hong X, Lin Z. Kaempferol inhibits proliferation, migration, and invasion of liver cancer HepG2 cells by down-regulation of microRNA-21. Int J Immunopathol Pharmacol. 2018;32:2058738418814341.
61. Zhuang Z, Ye G, Huang B. Kaempferol alleviates the interleukin-1β-induced inflammation in rat osteoarthritis chondrocytes via suppression of NF-κB. Med Sci Monit. 2017;23:3925-31.
Table 1: Recent studies on the biological and pharmacological activities of kaempferol