Journal of Biomedical Translational Research
Research Institute of Veterinary Medicine, Chungbuk National University
Review Article

Functions of flavonoids in three Korean native varieties of Artemisia species

Hun Hwan Kim1,https://orcid.org/0000-0002-4983-2321, Preethi Vetrivel1,https://orcid.org/0000-0002-9252-0817, Sang Eun Ha1https://orcid.org/0000-0002-4964-8700, Pritam Bhagwan Bhosale1https://orcid.org/0000-0003-1691-7844, Ho Jeong Lee2https://orcid.org/0000-0001-9646-195X, Jin-A Kim3https://orcid.org/0000-0001-8514-3243, Kwang Il Park1https://orcid.org/0000-0002-0199-8090, Seong Min Kim1,*https://orcid.org/0000-0003-3359-7504, Gon Sup Kim1,*https://orcid.org/0000-0001-7048-458X
1Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
2Biological Resources Research Group, Gyeongnam Department of Environment Toxicology and Chemistry, Korea Institute of Toxicology (KIT), Jinju 52834, Korea
3Department of Physical Therapy, International University of Korea, Jinju 52833, Korea
*Corresponding author: Seong Min Kim, Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea Tel: +82-55-772-2346, E-mail: ksm4234@naver.com
*Corresponding author: Gon Sup Kim, Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea Tel: +82-55-772-2346, E-mail: gonskim@gnu.ac.kr

These authors equally contributed to this work.

© Research Institute of Veterinary Medicine, Chungbuk National University. All rights reserved.

Received: Mar 02, 2020; Accepted: Mar 25, 2020

Abstract

The development of drugs from natural plant sources is at growing interest due to the limitations of chemical drugs in terms of side effects and cost-effective factors of natural medicines. Among the various components contained in natural plant materials, flavonoids are of increasing interest because of their extended biological benefits. Flavonoids are classified into various types according to their structure and possess different activities depending on the structure. In this study, the flavonoids contained in Artemisia, native to Korea were examined and reviewed. HPLC chromatograms of three Artemisia species (Artemisiaannua L., Artemisia iwayomogi and Artemisia argyi H.) were examined from published sources and their component analysis by MS data were summarized. The various flavonoids of Artemisia were classified into 12 types according to the main structure, and 10 flavonoids based on various activities were examined. The 10 flavonoids were identified as quercetin, kaempferol, rhamnetin, diosmetin, luteolin, methoxyflavone, catechin, apigenin, malvidin and genkwanin with extensive reported studies till date. The ten flavonoids examined have been reported to be effective in preventing and treating various diseases and exhibit activities such as anti-cancer, anti-inflammatory, antioxidant, anti-viral, anti-obesity, anti-diabetic and anti-Alzheimer. The collective results from the reported studies suggest that the three types of Korean native Artemisia, contains various flavonoids with beneficial activities and may have therapeutic effects against diseases.

Keywords: flavonoids; polyphenols; Artemisia; natural plant; diseases

Introduction

Researchers have shown an interesting trend in pharmaceutical development since the 21st century, to develop drugs from natural plant materials [1, 2]. The reason for the need of natural drugs is due to the limitations of expensive chemical drugs and its long-term side effects. Among the different secondary metabolites present natural materials, flavonoids are of importance due to their high biological benefits [3]. Flavonoids were named in the Latin word flavus, which means yellow, and is present in most plants [4, 5]. Flavonoids are known to be synthesized in certain parts of plants for a long time, providing color, fragrance and moisture to fruits and flowers, consequently helping to grow and develop seeds, spores and seedlings, and to protect against plaque [6, 7]. Flavonoids are natural compounds linked by three carbon chains, usually C6-C3-C6, and consist of an oxygenated heterocyclic ring (Fig. 1) [3]. The main classes of flavonoids are flavone, flavanone, flavan, flavonol, isoflavone, isoflavanone, isoflavan, flavanonol and anthocyanidin [8]. Natural flavonoids, especially their glucosides, are the most abundant polyphenols and more than 15,000 species are present in plants and are usually present in stems, flowers, leaves and fruits in the form of glycosides such as glucosides, galactoside, rhamnosides, arabinoside and rutinoside [911]. According to various reported studies, flavonoids have shown to exhibit anticancer [1214], anti-diabetic [1517], antioxidant [1820], anti-inflammatory [2123], and it also has been shown to play an important role in treating influenza [24], and managing obesity [25].

jbtr-21-2-39-g1
Fig. 1. Basic chemical structure of different types of flavonoid.
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Flavonoids in plants play a preliminary role in protecting themselves from UV [26], frost and provide drought resistance, which has a beneficial effect on the plant on seasonal protection factors [27]. Flavonoids have a positive effect on human life as well in the treatment and prevention of various diseases. Flavonoids exhibit various roles in executing the antioxidant activity, metabolic regulation of carcinogens, and anti-inflammatory properties. In particular, the potential for preventing tumor cell proliferation is noteworthy [14]. Flavonoids prevent DNA damage from a variety of carcinogens, resulting in chemical prevention and protection [12], affecting chromatin structure contributing to both gene transcription and translation modifications [13]. Flavonoids show effective regulation of lipid metabolism by reducing the serum triglycerides, cholesterol, Low-density lipoprotein (LDL) and esterified fatty acids suggestive of anti-diabetic and anti-obesity activity [16]. Further, flavonoids are used as an agonist in various therapeutic strategies as anti-oxidants, cytoprotective and reported to treat inflammation and metabolism [1921].

Among the different plant sources containing flavonoids, the genus Artemisia is a very diverse and widely distributed plant with more than 500 species belongs to the family of Asteraceae (Compositae), mainly distributed in temperate regions of Asia, Europe and North America. It is an herb with extensively distributed medicinal properties and also used for purposes like preparation of tea, and used in edible purposes like spices and ingredients in cooking [28]. The present review paper examines the three varieties of Artemisia: Artemisiaannua L., Artemisiaiwayomogi and Artemisiaargyi H and its functions in different therapeutic applications. Therefore, this review provides wide knowledge to the scientific community about the different flavonoids contained in the three species of Artemesia and their functions.

Chromatogram of flavonoids and components contained in Artemisia

The total number of phenols and flavonoids contained in three species of Artemisia family were identified as 32 in Artemisia annua L., 37 in Artemisia iwayomogi and 14 in Artemisia argyi H., out of which flavonoids were 16 (Artemisia annua L.), 27 (Artemisia iwayomogi), 7 (Artemisia argyi H.) respectively (Fig. 2A–C). Flavonoids contained in three kinds of Artemisia were classified into 10 types according to the main structure, and functional type shown in Table 1. In addition, Fig. 2 represents the chromatogram obtained through HPLC analysis of the three species of Artemisia that has been completely studied [2931].

jbtr-21-2-39-g2
Fig. 2. HPLC chromatogram of three Artemisia extracts from published sources (A) Artemisia annua L., (B) Artemisia iwayomogi and (C) Artemisia argyi H. Adopted from (A) Song et al. with permission of Wiley [29], (B) Kim et al. with CC-BY-NC-ND [30] and Kim et al. with CC-BY-NC-ND [31].
Download Original Figure
Table 1. Structure of main flavonoids contained in Artemisia (Artemisia annua L., Artemisia iwayomogi, Artemisia argyi H.)
Name Structure Artemisia annua L. Artemisia iwayomogi Artemisia argyi H. Function of classification Remake
Quercetin jbtr-21-2-39-g3 O O O Flavonol [4147]
Kaempferol jbtr-21-2-39-g4 O O O Flavonol [4851]
Rhamnetin jbtr-21-2-39-g5 O O - Flavonol [5255]
Diosmetin jbtr-21-2-39-g6 O - - Flavone [5658]
Luteolin jbtr-21-2-39-g7 O O - Flavone [5961]
Methoxy flavone jbtr-21-2-39-g8 O O O Flavone [6264]
Catechin jbtr-21-2-39-g9 - O - Flavanol [6575]
Apigenin jbtr-21-2-39-g10 - O O Flavone [7678]
Malvidin jbtr-21-2-39-g11 - O - Anthocyanidin [7981]
Genkwanin jbtr-21-2-39-g12 - O - Flavone [8284]
Download Excel Table
Components present in Artemisia annua L. and its reported functions

Artemisia annua L. grows into yellow flowers with a strong camphor scent in the month of September to an average height of 2 m [32]. Artemisia annua L. has been reported with a variety of activities including anti-inflammatory, antipyretic, anticancer, antifungal, antiparasitic, antiulcer, and cytotoxic effects [33]. Also, the essential oils and polyphenols contained in this plant were analyzed and proved to have excellent effects as antibacterial, antifungal and antioxidant activity [29, 30]. The AAP (A. annua polysaccharide), a water-soluble polysaccharide contained in Artemisia annua L. has been shown to inhibit cancer cell proliferation through p65-dependent mitochondrial signaling pathways via the activation of caspase-3 and -9, downregulation of Bcl-2 protein, upregulation of Bax protein, and release of cytochrome C from mitochondria [34]. Interestingly, in natural combinational therapy development using Artemesia, the interaction between three important components say arteannuin B, arteannuic acid, and scopoletin of artemisinin and A. annua showed a 2.6-fold improvement in mice with Plasmodium yoeli infection. This demonstrated the potential of certain components of A. annua could develop artemisin-based natural combination therapies for the treatment of malaria [35]. Collectively, the studies performed previously on Artemisia annua L. component and functions, it shows various beneficial activities that can be applied in the pharmaceutical industry.

Components present in Artemisia iwayomogi and its reported functions

Artemisia iwayomogi grows as flowers with yellow pigments during the month of August, the fruits ripen from September to October, and it grows up to an average height of 1 m tall. Artemisia iwayomogi is reported to exhibit biological effects such as antioxidants and anti-inflammatory and shown to treat immune-related disorders such as hepatitis and saccharide [30]. An essential oil present in Artemisia iwayomogi known as AIEO (Artemisia iwayomogi essential oil) has been shown to induce apoptotic death of Keratin forming tumor cell (KB cell line) mediated by mitogen-activated protein kinase (MAPK). AIEO does not show an only imbalance in the mitochondrial Bcl-2 and Bax proteins but also induced the activation of caspases and cleavage of poly ADP ribose polymerase (PARP) [36]. Similarly, a carbohydrate fraction of Artemisia iwayomogi known as AIP significantly reduced the levels of IgE and eosinophils in serum eosinophils followed by downregulation of inflammatory cytokines Th2 and TNF-α in lung inflammatory disease. [37]. A recent study on the phenol and flavonoid components of Artemisia iwayomogi was analyzed from its flower extract and demonstrated for its anti-inflammatory effect in LPS-induced macrophages by inhibiting the NF-kB signaling pathway [30].

Components present in Artemisia argyi H. and its reported functions

Artemisia argyi H. is a perennial herb belongs to the class of Asteraceae, is widely distributed in most of the parts in Eastern Asia. Artemisia argyi H. has a higher composition of polyunsaturated fatty acids, total phenolic compounds, vitamin C and essential amino acids compared to other Artemisia varieties and has been reported to have an excellent radical scavenging effect [38]. Artemisia argyi is reported to exhibit a variety of biological activities, including antidiabetic, antioxidant, anticancer, anti-inflammatory, and antiallergic has been reported to have an excellent radical scavenging effect [39]. The flavone jaceosidin isolated from Artemisia argyi H. is known to inhibit the upregulation of COX-2 and MMP proteins, which are frequently expressed in various types of cancerous and transformed cells. [40]. The extract of Artemisia argyi H. show a protective effect by inhibiting the contrast-induced inflammatory response through activation of PPAR-γ (proliferator-activated receptor gamma), inhibition of MAPK phosphorylation and activation of caspase [39]. Polyphenols and flavonoids present in Artemisia argyi H. inhibits through the inhibition of nitric oxide production, nuclear factor-κB activation, mRNA expression of inducible nitric oxide synthase, tumor necrosis factor α and interleukin-1β, and phosphorylation of MAPKs in macrophages related to inflammation [31].

Functions of 10 identified flavonoids in the three species of Artemisia family
1) Quercetin

Quercetin belongs to the class of flavonol in flavonoids, which is rich in fruits, vegetables, leaves, seeds and grains, with a naturally bitter taste. Quercetin inhibits the inflammatory enzymes cyclooxygenase and lipoxygenase to reduce inflammatory mediators such as prostaglandins and leukotrienes and levels of inflammatory mediators such as NO synthase, COX-2 and CRP in human hepatocyte derived cell lines significantly [41, 42]. Quercetin is known to inhibit LDL oxidation, lower blood pressure, and prevents the development of cardiac hypertrophy [43, 44]. Quercetin also helps in the protection of membranes of red blood cells from the exposure to free radicals like tar in cigarette and prevent respiratory malfunctions [45]. Quercetin is also known to induce apoptosis and inhibit the growth of various cancer cells, and has been reported to be particularly effective in prostate cancer both in vitro and in vivo [46, 47].

2) Kaempferol

Kaempferol belongs to the class of flavonol in flavonoids widely distributed as yellow crystalline solids. Kaempferol shown reported functions in reducing the production of reactive oxygen species (ROS), Malondialdehyde (MDA) and superoxide dismutase (SOD) activity in virus-induced inflammation through inhibition of the TLR4 / Myd88-mediated NF-kb and MAPK pathways [48]. Kaempferol also showed to regulate the normal plasma glucose, insulin, lipid peroxidation products, enzyme and non-enzyme antioxidants in diabetic rats [49]. The phosphorylation of mammalian targets of AKT (protein kinase B) and rapamycin (mTOR) signaling pathways has been shown to blocked by kaempferol treatment at the early stages of fast production and lowered early lipogenic factors such as C / EBPβ, KLFs in lipid accumulation conditions of adipocytes and in vivo zebrafish models [50]. Kaempferol also significantly inhibited the protein levels of DNA methyltransferase (DNMT3B) in ubiquitin-proteasome pathway to prevent premature degradation of protein synthesis [51].

3) Rhamnetin

Rhamnetin is a type of O-methylated flavonol that is found in a variety of plants and fruits. Rhamnetin has been reported to show anti-tumor activities in human breast cancer cells by the induction of apoptosis via the miR-34a / notch-1 signaling pathway [52]. Additionally, rhamnetin treatment on human prostate cancer cells LNCaP and PC-3 have been reported to result in increasing resistance to oxidative stress and inhibiting the cancer progression [53]. Rhamnetin also contributes to be effective compared to small molecular kinase inhibitors Sorafenib, etoposide and paclitaxel in treating hepatocellular carcinoma with susceptible to HepG2, ADR and MDR cells [54]. Rhamnetin has shown strong anti-tuberculosis activity and effectively inhibits lung inflammation by suppressing the mRNA levels of tumor necrosis factor-a, IL-6, IL-12 and matrix metalloproteinase-1 and terminate the IFN-y mediated stimulation of CRK1 and p38 mitogen activated protein kinase in MRC-5 lung cells [55].

4) Diosmetin

Diosmetin is an O-methylated flavone and the aglycone part of the flavonoid glycosides diosmin occurs naturally in citrus fruits. Pharmacologically, diosmetin is reported to exhibit anticancer, antimicrobial, antioxidant, oestrogenic and anti-inflammatory activities [56]. Treatment with diosmetin on human prostate cancer cells significantly reduced the expression levels of cell cycle arrest markers cyclin D1, Cdk2, and Cdk4, accompanied by a decrease in apoptotic regulators c-Myc and Bcl-2 expression with an increase in Bax, p27Kip1 and FOXO3a protein expression. These results suggest the anti-cancer property of diosmetin in prostate cancer cells [57]. In addition, Diosmetin attenuates apoptosis in Sprague-Dawley rat retinal cells and in human retinal pigment epithelial (RPE) cells, and protects against diosmetin’s adverse effects on DNA damage and oxidative stress [58]. Apart from the anti-tumor effects, diosmetin has shown its therapeutic potential to improve renal damage by inhibiting the nuclear factor erythrocyte 2 related factor 2 / heme oxyenase-1 pathway [59].

5) Luteolin

Luteolin is a principal yellow dye compound that is obtained from the plant Reseda luteola, and has been used as a source of dye since the first millennium B.C. [60]. Aside of being a chromogenic agent, Luteolin also shows pharmacological action as anti-cancer agents in reported studies. Human liver cancer cell line SMMC-7721 treated with Luteolin shown to inhibit the cell viability, induced cell cycle arrest and induced apoptosis by increasing caspase 8 and decreasing bcl-2 expression.

In addition, luteolin also induced autophagic cell death by converting the protein LC3B-1 to LC3b-2 and increasing Beclin 1 expression in SMMC-7721 cells. Taken together, these results showed promising confirmations that luteolin can be used as an apoptotic inducer as well as an autophagic regulator in HCC treatment [61]. The anti-diabetic function of luteolin was identified in type 2 diabetes model KK-Ay mice which showed significant improvement in blood glucose, HbA1c, insulin and HOMR-IR levels respectively [62]. In vivo studies on memory impairment in streptozotocin (STZ) -induced Alzheimer’s rat models have been reported to significantly improve spatial learning and memory impairment by luteolin treatment [63].

6) Dimethoxyflavone

Dimethoxyflavone is a group of flavone which is structurally composed of 14 hydrogen atoms, 17 carbon atoms and 4 oxygen atoms, and the name differs depending on their binding position. Inflammatory studies in LPS-induced peritoneal inflammatory mice supplemented with 6,7-trihydroxy-5-methoxyflavone reported being effective as an anti-inflammatory agent by reducing the concentration of inflammatory cytokines (TNF-α and IL-1β) [64]. A study on oral administration of MKE (K. parviflora rhizome) containing three methoxyflavones to dyslipidemic rats has been reported that the levels of cholesterol, triglycerides and LDL cholesterol were significantly decreased and HDL levels were significantly increased showing the hypolipidemic potential of methoxyflavones [65]. The antioxidant activity of DHMF (5,7-dihydroxy-8-methoxyflavone) has been studied in vivo upon oral administration in rats which showed the reversal of decreased activity of enzymes such as SOD, catalase and glutathione peroxidase. In addition, inflammatory mediators such as TNF-α and IL-1b induced by LPS have also been reported to be inhibited by DHMF [66].

7) Catechin

Catechin belongs to the flavan-3-ol or simply the flavanol group, and is well-identified in various plants with the execution of a lot of significant activities as a secondary metabolite compound [67]. Catechin has shown to inhibit oxidative damage and reduces lipid peroxidation in vascular smooth muscle cells [68]. The anti-oxidant effects of catechin in mouse models has shown adverse effects by increasing the levels of enzymes SOD, catalase and glutathione peroxidase which plays an important role in ROS elimination [69]. Green tea containing high amounts of catechin has been reported to increase glutathione levels in plasma and tissues [70] and to participate in vitamin E, which supplements glutathione function [71]. In addition, catalase expression has been reported to increase in the aorta of hypertensive rats fed with green tea containing catechin for a period of two weeks [72]. Green tea catechin also showed to inhibit tumor growth and metastatic breast cancer mouse cells [73]. It also has an effect on reducing the formation of tumor blood vessels in breast cancer [74]. Notably, Epigallocatechin gallate increases the expression of p53, p21, and NF-kB, inducing apoptosis in vascular smooth muscle cells, preventing the development of atherosclerosis [75, 76]. Studies also suggest catechin inhibits the morphological and functional degeneration in the brain [77] and protects against accelerated memory degeneration in aged mouse models [78].

8) Apigenin

Apigenin belongs to the flavone group, which is an aglycone of glycosides found in many plants, and it appears as a yellowish solid crystal [79]. Apigenin inhibits the expression of TNF-α induced NK-kB activation which is responsible for the activation of transcription factors associated with COX2 and iNOS synthesis in inflammation of mouse macrophages [80]. Anti-tumor studies with apigenin in vivo reduced tumor growth and size in vivo with a lower Ki-67 index in tumor-induced mice. Results showed apigenin inhibits proliferation by inducing DNA damage, cell cycle arrest on G2 / M, p53 accumulation and apoptosis [81]. Apigenin also reduced endometriosis cell proliferation by inducing cell cycle arrest and apoptosis by regulating the ERK1 / 2, JNK and AKT cell signaling pathways [82].

9) Malvidin

Malvidin is a flavone glycoside primarily present in the pigment of plants, and it has potential functionality in protecting cells from oxidative stress and its related diseases [83]. Treatment with Malvidin inhibits H2O2-induced oxidative stress by blocking the lipid peroxidation and increased the cell viability in human fibroblast cells. In addition, the oxidative stress-related proteins COX-2 (Cyclooxygenase-2) and iNOS (inducible nitric oxide synthase) were downregulated [84]. Malvidin also significantly inhibited colony formation and induced apoptosis in HTC-116, colon cancer cells with the downregulation of cell cycle-related proteins in a concentration-dependent manner, leading to arrest of the G2 / M phase [85].

10) Genkwanin

Genkwanin is a flavonoid belongs to the flavone group, which is a derivative of apigenin [86]. Genkwanin exerts an excellent anti-inflammatory effect by reducing the pro-inflammatory mediators such as iNOS, TNF-a, IL-1b, and IL6 without affecting the cytotoxicity of macrophages [87]. Genkwanin also showed downregulation of serum TNF-a, IL-6 and NO levels with reduction of foot swelling, arthritis index, inflammation of joint tissues and bone destruction in arthritis model rats. In addition, it has been reported to inhibit the activation of JAK / STAT and NF-kB signaling pathways in the synovial tissue of arthritis rats [88]. Genkwanin significantly inhibited cell proliferation in human colon colorectal cancer cells HT-29 and SW-480 and reduced inflammatory cytokine IL-8 secretion, and apparently improved visible gut histopathology was observed microscopically. These reports suggest the potential antitumor activity through enhancing the immune function by the reduction of inflammatory cytokines [89].

Conclusion

In summary, this review paper examines three species of Artemisia native to Korea (Artemisia annua L., Artemisia iwayomogi, Artemisia argyi H.). In brief, the flavonoids contained in three Artemisia varieties examined by chromatography and classified into 12 types according to the main structure are reported based on studies. Subsequently, the physiological activities of the classified flavonoids were quoted on their various activities such as antioxidant, anti-inflammatory, antiviral, anti-cancer, metastasis suppression and anti-obesity.

Thus, the review gives a extensive knowledge on the three native varieties of Artemisia in Korea and their therapeutic values in the prevention and treatment of various diseases which aids in research for the development of naturopathies using Artemisia.

Acknowledgements

This study was supported by the National Research Foundation of Korea funded by Ministry of Science and ICT (grant nos. 2012M3A9B8019303 and 2020R1A2B5B01001807).

References

1.

Cerella C, Teiten MH, Radogna F, Dicato M, Diederich M. From nature to bedside: pro-survival and cell death mechanisms as therapeutic targets in cancer treatment. Biotechnol Adv 2014;32:1111-1122.

2.

Schnekenburger M, Dicato M, Diederich M. Plant-derived epigenetic modulators for cancer treatment and prevention. Biotechnol Adv 2014;32:1123-1132.

3.

Xiao J. Dietary flavonoid aglycones and their glycosides: which show better biological significance? Crit Rev Food Sci Nutr 2017;57:1874-1905.

4.

Prasad S, Phromnoi K, Yadav VR, Chaturvedi MM, Aggarwal BB. Targeting inflammatory pathways by flavonoids for prevention and treatment of cancer. Planta Med 2010;76:1044-1063.

5.

Castellarin SD, Gaspero GD. Transcriptional control of anthocyanin biosynthetic genes in extreme phenotypes for berry pigmentation of naturally occurring grapevines. BMC Plant Biol 2007;7:46.

6.

Havsteen BH. The biochemistry and medical significance of the flavonoids. Pharmacol Ther 2002;96:67-202.

7.

Griesbach RJ. Biochemistry and genetics of flower color. Plant Breed Rev 2005;25:89-114.

8.

Saito K, Yonekura-Sakakibara K, Nakabayashi R, Higashi Y, Yamazaki M, Tohge T, Fernie AR. The flavonoid biosynthetic pathway in Arabidopsis: structural and genetic diversity. Plant Physiol Biochem 2013;72:21-34.

9.

Veitch NC, Grayer RJ. Flavonoids and their glycosides, including anthocyanins. Nat Prod Rep 2011;28:1626-1695.

10.

Kong DY. Flavonoids. In: Xu R, Ye Y, Zhao W (eds.). Introduction to natural products chemistry. New York, NY: CRC Press; 2012. p. 169-187.

11.

Oualid T, Artur MSS. Advances in C-glycosylflavonoid research. Curr Org Chem 2012;16:859-896.

12.

George VC, Dellaire G, Rupasinghe HPV. Plant flavonoids in cancer chemoprevention: role in genome stability. J Nutr Biochem 2017;45:1-14.

13.

Russo GL, Ungaro P. Epigenetic mechanisms of quercetin and other flavonoids in cancer therapy and prevention. Epigenetics Cancer Prev 2019;8:187-202.

14.

Venturelli S, Burkard M, Biendl M, Lauer UM, Frank J, Busch C. Prenylated chalcones and flavonoids for the prevention and treatment of cancer. Nutrition 2016;32:1171-1178.

15.

Li P, Tang Y, Liu L, Wang D, Zhang L, Piao C. Therapeutic potential of buckwheat hull flavonoids in db/db mice, a model of type 2 diabetes. J Funct Foods 2019;52:284-290.

16.

Varshney R, Mishra R, Das N, Sircar D, Roy P. A comparative analysis of various flavonoids in the regulation of obesity and diabetes: an in vitro and in vivo study. J Funct Foods 2019;59:194-205.

17.

Zeka K, Ruparelia K, Arroo RRJ, Budriesi R, Micucci M. Flavonoids and their metabolites: prevention in cardiovascular diseases and diabetes. Diseases 2017;5:19.

18.

Bendaif H, Melhaoui A, Bouyanzer A, Hammouti B, Ouadi YE. The study of the aqueous extract of leaves of Pancratium foetidum Pom as: characterization of polyphenols, flavonoids, antioxidant activities and ecofriendly corrosion inhibitor. J Mater Environ Sci 2017;8:4475-4486.

19.

Vazquez LC, Alanon ME, Robledo VR, Coello MSP, Gutierrez IH, Maroto MCD, Jordan J, Galindo MF, Jimenez MMA. Bioactive flavonoids, antioxidant behaviour, and cytoprotective effects of dried grapefruit peels (Critrus paradisi Macf.). Oxid Med Cell Longev 2016;8915729.

20.

Dulf FV, Vodnar DC, Socaciu C. Effects of solid-state fermentation with two filamentous fungi on the total phenolic contents, flavonoids, antioxidant activities and lipid fractions of plum fruit (Prunus domestica L.) by-products. Food Chem 2016;209:27-36.

21.

Cano FJP, Castell M. Flavonoids, inflammation and immune system. Nutrients 2016;8:659.

22.

Leyva-Lopez N, Gutierrez-Grijalva EP, Ambriz-Perez DL, Heredia JB. Flavonoids as cytokine modulators: a possible therapy for inflammation-related diseases. Int J Mol Sci 2016;17:921.

23.

Goya L, Martin MA, Sarria B, Ramos S, Mateos R, Bravo L. Effect of cocoa and its flavonoids on biomarkers of inflammation: studies of cell culture, animals and humans. Nutrients 2016;8:212.

24.

Bang S, Li W, Ha TKQ, Lee C, Oh WK, Shim SH. Anti-influenza effect of the major flavonoids from Salvia plebeia R. Br. via inhibition of influenza H1N1 virus neuraminidase. Nat Prod Res 2018;32:1224-1228.

25.

Hossain MK, Dayem AA, Han J, Yin Y, Kim K, Saha SK, Yang GM, Choi HY, Cho SG. Molecular mechanisms of the anti-obesity and anti-diabetic properties of flavonoids. Int J Mol Sci 2016;17:569.

26.

Takahashi A, Ohnishi T. The significance of the study about the biological effects of solar ultraviolet radiation using the exposed facility on the international space station. Biol Sci Space 2004;18:255-260.

27.

Samanta A, Das G, Das S. Roles of flavonoids in plants. Int J Pharm Sci Tech 2011;6:12-35.

28.

Torrell M, Cerbah M, Siljak-Yakovlev S, Valles J. Molecular cytogenetics of the genus Artemisia (Asteraceae, Anthemideae): fluorochrome banding and fluorescence in situ hybridization. I. subgenus seriphidium and related taxa. Plant Syst Evol 2003;239:141-153.

29.

Song Y, Desta KT, Kim GS, Lee SJ, Lee WS, Kim YH, Jin JS, El-Aty AMA, Shin HC, Shim JH, Shin SC. Polyphenolic profile and antioxidant effects of various parts of Artemisia annua L. Biomed Chromatogr 2016;30:588-595.

30.

Kim SM, Preethi V, Kim HH, Ha SE, Saralamma VVG, Kim GS. Artemisia iwayomogi (Dowijigi) inhibits lipopolysaccharide-induced inflammation in RAW264.7 macrophages by suppressing the NF-kB signaling pathway. ExpTher Med 2020;19:2161-2170.

31.

Kim SM, Lee SJ, Saralamma VVG, Ha SE, Preethi V, Desta KT, Choi JY, Lee WS, Chin SC, Kim GS. Polyphenol mixture of a native Korean variety of Artemisia argyi H. (Seomae mugwort) and its anti-inflammatory effects. Int J Mol Med 2019;44:1741-1752.

32.

Kreitschitz A, Valles J. New or rare data on chromosome numbers in several taxa of the genus Artemisia (Asteraceae) in Poland. Folia Geobotan 2003;38:333-343.

33.

Yan L, Xiong C, Xu P, Zhu J, Yang Z, Ren H, Luo Q. Structural characterization and in vitro antitumor activity of A polysaccharide from Artemisia annua L. (Huang Huahao). Carbohydr Polym 2019;213:361-369.

34.

Cavar S, Maksimovic M, Vidic D, Paric A. Chemical composition and antioxidant and antimicrobial activity of essential oil of Artemisia annua L. from Bosnia. Ind Crops Prod 2012;37:479-485.

35.

Jing L, Chao Z, Muxin G, Wang M. Combination of artemisinin-based natural compounds from Artemisia annua L. for the treatment of malaria: pharmacodynamic and pharmacokinetic studies. Phytother Res 2018;32:1415-1420.

36.

Cha JD, Jeong MR, Kim HY, Lee JC, Lee KY. MAPK activation is necessary to the apoptotic death of KB cells induced by the essential oil isolated from Artemisia iwayomogi. J Ethnopharmacol 2009;123:308-314.

37.

Lee JA, Sung HN, Jeon CH, Gill BC, Oh GS, Youn HJ, Park JH. A carbohydrate fraction, AIP1 from Artemisia iwayomogi suppresses pulmonary eosinophilia and Th2-type cytokine production in an ovalbumin-induced allergic asthma. Down regulation of TNF-α expression in the lung. Int Immunopharmacol 2008;8:117-125.

38.

Kim JK, Shin EC, Lim HJ, Choi SJ, Kim CR, Suh SH, Kim CJ, Park GG, Park CS, Kim HK, Choi JH, Song SW. Characterization of nutritional composition, antioxidative capacity and sensory attributes of Seomae mugwort, a native Korean variety of Artemisia argyi H. Lev. & Vaniot. J Anal Methods Chem 2015;2015:916346.

39.

Lee D, Kim CE, Park SY, Kim KO, Hiep NT, Lee D, Jang HJ, Lee JW, Kang KS. Protective effect of Artemisia argyi and its flavonoid constituents against contrast-induced cytotoxicity by iodixanol in LLC-PK1 cells. Int J Mol Sci 2018;19:1387.

40.

Jeong MA, Lee KW, Yoon DY, Lee HJ. Jaceosidin, a pharmacologically active flavone derived from Artemisia argyi, inhibits phorbol-ester-induced upregulation of COX-2 and MMP-9 by blocking phosphorylation of ERK-1 and -2 in cultured human mammary epithelial cells. Ann NY Acad Sci 2007;1095:458-466.

41.

Xiao X, Shi D, Liu L, Wang J, Xie X, Kang T, Deng W. Quercetin suppresses cyclooxygenase-2 expression and angiogenesis through inactivation of P300 signaling. PLoS One 2011;6:e22934.

42.

Garcia-Mediavilla V, Crespo I, Collado PS, Esteller A, Sanchez-Campos S, Tunon MJ, Gonzalez-Gallego J. The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol 2007;557:221-229.

43.

Chopra M, Fitzsimons PEE, Strain JJ, Thurnham DI, Howard AN. Nonalcoholic red wine extract and quercetin inhibit LDL oxidation without affecting plasma antioxidant vitamin and carotenoid concentrations. Clin Chem 2000;46: 1162-1170.

44.

Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T. Quercetin reduces blood pressure in hypertensive subjects. J Nutr 2007;137:2405-2411.

45.

Begum AN, Terao J. Protective effect of quercetin against cigarette tar extract-induced impairment of erythrocyte deformability. J Nutr Biochem 2002;13:265-272.

46.

Akan Z, Garip AI. Antioxidants may protect cancer cells from apoptosis signals and enhance cell viability. Asian Pac J Cancer Prev 2013;14:4611-4614.

47.

Yang F, Song L, Wang H, Wang J, Xu Z, Xing N. Quercetin in prostate cancer: chemotherapeutic and chemopreventive effects, mechanisms and clinical application potential: review. Oncol Rep 2015;33:2659-2668.

48.

Zhang R, Ai X, Duan Y, Xue M, He W, Wang C, Xu T, Xu M, Liu B, Li C, Wang Z, Zhang R, Wang G, Tian S, Liu H. 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;89:660-672.

49.

Al-Numair KS, Chandramohan G, Veeramani C, Alsaif MA. Ameliorative effect of kaempferol, a flavonoid, on oxidative stress in streptozotocin‐induced diabetic rats. Redox Rep 2015;20:198-209.

50.

Lee YJ, Choi HS, Seo MJ, Jeon HJ, Kim KJ, Lee BY. Kaempferol suppresses lipid accumulation by inhibiting early adipogenesis in 3T3‐L1 cells and zebrafish. Food Funct 2015;6:2824-2833.

51.

Qiu W, Lin J, Zhu Y, Zhang J, Zeng L, Su M, Tian Y. Kaempferol modulates DNA methylation and downregulates DNMT3B in bladder cancer. Cell Physiol Biochem 2017; 41:1325-1335.

52.

Lan L, Wang Y, Pan Z, Wang B, Yue Z, Jiang Z, Li L, Wang C, Tang H. Rhamnetin induces apoptosis in human breast cancer cells via the miR-34a/Notch-1 signaling pathway. Oncol Lett 2019;17:676-682.

53.

Patel R, Pakradooni R, Oak C, Bhaskaran N, Shukia S. Rhamnetin enhances anti-proliferative and apoptotic effects on prostate cancer cells. Am Assoc Cancer Res 2016;76: 3507.

54.

Jia H, Yang Q, Wang T, Cao Y, Jiang QY, Ma HD, Sun HW, Hou MX, Yang YP, Feng F. Rhamnetin induces sensitization of hepatocellular carcinoma cells to a small molecular kinase inhibitor or chemotherapeutic agents. Biochim Biophys Acta Gen Subj 2016;1860:1417-1430.

55.

Kim MJ, Jeon D, Kwak C, Ryoo S, Kim Y. Rhamnetin exhibits anti-tuberculosis activity and protects against lung inflammation. Bull Korean Chem Soc 2016;37:1703-1709.

56.

Kanika P, Manoj G, Vijay T, Dinesh KP. A review on pharmacological and analytical aspects of diosmetin: a concise report. Chin J Integr Med 2013;19:792-800.

57.

Oak C, Khalifa AO, Isali I, Bhaskaran N, Walker E, Shukla S. Diometin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest. Int J Oncol 2018;53:835-843.

58.

Shen Z, Shao J, Dai J, Lin Y, Yang X, Ma J, He Q, Yang B, Yao K, Luo P. Diosmetin protects against retinal injury via reduction of DNA damage and oxidative stress. Toxicol Rep 2016;3:78-86.

59.

Yang K, Li WF, Yu JF, Yi C, Huang WF. Diosmetin protects against ischemia/reperfusion-induced acute kidney injury in mice. J Surg Res 2017;214:69-78.

60.

Aziz N, Kim MY, Cho JY. Anti-inflammatory effects of luteolin: a review of in vitro, and in silico studies. J Ethnopharmacol 2018;225:342-358.

61.

Cao Z, Zhang H, Cai X, Fang W, Chai D, Wen Y, Chen H, Chu F, Zhang Y. Luteolin promotes cell apoptosis by inducing autophagy in hepatocellular carcinoma. Cell Physiol Biochem 2017;43:1803-1812.

62.

Zang Y, Igarashi K, Li Y. Anti-diabetic effects of luteolin and luteolin-7-O-glucoside on KK-Ay mice. Biosci Biotechnol Biochem 2016;80:1580-1586.

63.

Wang H, Wang H, Cheng H, Che Z. Ameliorating effect of luteolin on memory impairment in an Alzheimer’s disease model. Mol Med Rep 2016;13:4215-4220.

64.

Lima JCS, de Oliveira RG, Silva VC, de Sousa Jr PT, Violante IMP, Macho A, de Oliveira Martins DT. Anti-inflammatory activity 4’-6,7-trihydroxy-5-methoxyflavone from Fridericia chica (Bonpl.) L. G. Lohmann. Nat Prod Res 2018;34:726-730.

65.

Somintara S, Sripanidkulchai B, Pariwatthanakun C, Sripanidkulchai K. Hypolipidemic effect of methoxyflavone-enriched extract of Kaempferia parviflora in cholesterol-induced dyslipidemic rats. Songklanakarin J Sci Technol 2019;42:305-310.

66.

Sun HL, Peng ML, Lee SS, Chen CJ, Chen WY, Yang ML, Kuan YH. Endotoxin-induced acute lung injury in mice is protected by 5,7-dihydroxy-8-methoxyflavone via inhibition of oxidative stress and HIF-1α. Environmental Toxicology 2015;31:1700-1709.

67.

Chung SY, Wang H. Cancer preventive activities of tea catechins. Molecules 2016;21:1679.

68.

Branen L, Hovgaard L, Nitulescu M, Bengtsson E, Nilsson J, Jovinge S. Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 2004;24:2137-2142.

69.

Khan SG, Katiyar SK, Agarwal R, Mukhtar H. Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in drinking water to SKH-1 hairless mice: possible role in cancer chemoprevention. Cancer Res 1992;52:4050-4052.

70.

Anandh Babu PV, Sabitha KE, Shyamaladevi CS. Therapeutic effect of green tea extract on oxidative stress in aorta and heart of streptozotocin diabetic rats. Chem Biol Interact 2006;162:114-120.

71.

Zhu QY, Huang Y, Tsang D, Chen ZY. Regeneration of alpha-tocopherol in human low-density lipoprotein by green tea catechin. J Agric Food Chem 1999;47:2020-2025.

72.

Negishi H, Xu JW, Ikeda K, Njelekela M, Nara Y, Yamori Y. Black and green tea polyphenols attenuate blood pressure increases in stroke-prone spontaneously hypertensive rats. J Nutr 2004;134:38-42.

73.

Baliga MS, Meleth S, Katiyar SK. Growth inhibitory and antimetastatic effect of green tea polyphenols on metastasis-specific mouse mammary carcinoma 4T1 cells in vitro and in vivo systems. Clin Cancer Res 2005;11:1918-1927.

74.

Rodenberg JM, Brown PH. A novel look into estrogen receptor-negative breast cancer prevention with the natural, multifunctional signal transduction inhibitor deguelin. Cancer Prev Res 2009;2:915-918.

75.

Lin YL, Lin JK. (−)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-kappaB. Mol Pharmacol 1997;52:465-472.

76.

Chen XQ, Hu T, Han Y, Huang W, Yuan HB, Zhang YT, Du Y, Jiang YW. Preventive effects of catechins on cardiovascular disease. Molecules 2016;21:1759.

77.

Unno K, Takabayashi F, Kishido T, Oku N. Suppressive effect of green tea catechins on morphologic and functional regression of the brain in aged mice with accelerated senescence (SAMP10). Exp Gerontol 2004;39:1027-1034.

78.

Unno K, Takabayashi F, Yoshida H, Choba D, Fukutomi R, Kikunaga N, Kishido T, Oku, N, Hoshino M. Daily consumption of green tea catechin delays memory regression in aged mice. Biogerontology 2007;8:89-95.

79.

Tang D, Chen K, Huang L, Li J. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opin Drug Metab Toxicol 2017;13;323-330.

80.

Liang YC, Huang YT, Tsai SH, Lin-Shiau SY, Chen CF, Lin JK. Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis 1999;20:1945-1952.

81.

Meng S, Zhu Y, Li JF, Wang X, Liang Z, Li SQ, Xu X, Chen H, Liu B, Zheng XY, Xie LP. Apigenin inhibits renal cell carcinoma cell proliferation. Oncotarget 2017;8:19834-19842.

82.

Park S, Lim W, Bazer FW, Song G. Apigenin induces ROS dependent apoptosis and ER stress in human endometriosis cells. J Cell Physiol 2017;233:3055-3065.

83.

Huang W, Zhu Y, Li C, Sui Z, Min W. Effect of bluberry anthocyanins malvidin and glycosides on the antioxidant properties in endothelial cells. Oxid Med Cell Longev 2016;1591803.

84.

Seo HR, Choi MJ, Choi JM, Ko JC, Ko JY, Cho EJ. Malvidin protects WI-38 human fibroblast cells against stress-induced premature senescence. J Cancer Prev 2016; 21:32-40.

85.

Xu H, Zhang J, Huang H, Liu L, Sun Y. Malvidin induced anticancer activity in human colorectal HCT-116 cancer cells involves apoptosis, G2/M cell cycle arrest and upregulation of p21WAFI. Int J Clin Exp Med 2018;11:1734-1741.

86.

Hakobyan A, Arabyan E, Kotsinyan A, Karalyan Z, Sahakyan H, Arakelov V, Nazaryan K, Ferreira F, Zakaryan. Inhibition of African swine fever virus infection by genkwanin. Antivir Res 2019;167:78-82.

87.

Gao Y, Liu F, Fang L, Cai R, Zong C, Qi Y. Genkanin inhibits proinflammatory mediators mainly through the regulation of miR-101/MKP-1/MAPK pathway in LPS-activated macrophages. PLoS ONE 2014;9:e96741.

88.

Bao Y, Sun YW, Ji J, Gan L, Zhang CF, Wang CZ, Yuan CS. Genkwanin ameliorates adjuvant-induced arthritis in rats through inhibiting JAK/STAT and NF-kB signaling pathways. Phytomedicine 2019;63:153036.

89.

Wang X, Song ZJ, He X, Zhang RQ, Zhang CF, Li F, Wang CZ, Yuan CS. Antitumor and immunomodulatory activity of genkwanin on colorectal in the APCMin/+ mice. Int Immunopharmacol 2015;29:701-707.