An insight into the health-promoting effects of taxifolin (dihydroquercetin)

Phytochemistry 166 (2019) 112066

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Review

An insight into the health-promoting effects of taxifolin (dihydroquercetin) Christudas Sunil, Baojun Xu

T

*

Food Science and Technology Program, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Flavonoids Taxifolin Dihydroquercetin

Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin) is a flavonoid commonly found in onion, milk thistle, French maritime pine bark and Douglas fir bark. It is also used in various commercial preparations like Legalon™, Pycnogenol®, and Venoruton®. This review focuses on taxifolin’s biological activities and related molecular mechanisms. Published literatures were gathered from the scientific databases like PubMed, SciFinder, ScienceDirect, Wiley Online Library, Google Scholar, and Web of Science up to January 2019. Taxifolin showed promising pharmacological activities in the management of inflammation, tumors, microbial infections, oxidative stress, cardiovascular, and liver disorders. The anti-cancer activity was more prominent than other activities evaluated using different in vitro and in vivo models. Further research on the pharmacokinetics, in-depth molecular mechanisms, and safety profile using well-designed randomized clinical studies are suggested to develop a drug for human use.

1. Introduction Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin) is a flavonoid commonly found in milk thistle (Wallace et al., 2005), onions (Slimestad et al., 2007), Douglas fir bark (Kiehlmann and Edmond, 1995) and French maritime pine bark (Rohdewald, 2002). It is also commonly found in many plants. As a single compound it is used rarely but it is found in different preparations like silymarin (Legalon™), Pycnogenol® and Venoruton® (Blumenthal and Busse, 1998) along with silybin A, silybin B, isosilybin A, isosilybin B, silychristin, isosilychristin and silydianin (Ding et al., 2001). Taxifolin is an important component of dietary supplements and used as functional food having rich antioxidant. It was first isolated from Douglas fir bark (Pseudotsuga taxifolia (Lindl.) Britton) and later Dahurian and Siberian larch (Larix sibirica Ledeb. and Larix gmelinii (Rupr.) Kuzen.), syn Larix dahurica Turcz. ex

Trautv. (Pinaceae) (Pew, 1948). It exists in both trans - and cis - forms (Nifant'ev et al., 2006), soluble in water-alcohol solutions and polar solvents. (+) trans-Dihydroquercetin oxidizes more actively, donates hydrogen atoms and form the oxidation product quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4- one) (Rogozhin and Peretolchin, 2009). The structure-activity relationship of both compounds differs in the presence/absence of a C2, C3-double bond in the C-ring (Silva et al., 2002). As a therapeutic agent, taxifolin attracts more and more interest to the researchers. Thereby this review aims to summarize the various pharmacological effects with their mechanism of action (Table 1).

Abbreviations: ABTS, 2,2′-azino-di-(3-ethylbenzthiazoline sulfonic acid); ACAT, Acyl CoA: cholesterol acyltransferase; ActD, Actinomycin D; AKT, AKT, serine/ threonine kinase 1; Akt, Protein kinase B; ARE, Antioxidant –response element; BACE1, β-site APP cleaving enzyme 1; C99, C-terminal fragment β; CDKs, Cyclindependent kinases; CHOP, C/EBP homologous protein; COX, Cyclooxygenase; DGAT, Diacylglycerol acyltransferase; DMPD, N,N-dimethyl-ρ-phenylenediamine; DPPH, 2,2-diphenyl-1-picrylhydrazyl; EGFR, Epidermal growth factor receptor; eIf2α, The α subunit of eukaryotic initiation factor 2; ER, Endoplasmic reticulum; EWS, Ewing's sarcoma; GCLM, glutamate–cysteine ligase modifier; GRP78, Glucose-regulated protein 78 kDa; GSTA2, Glutathione S-transferase A2; GSTM1, Glutathione S-transferase M1; HDL, High-density lipoprotein; HMG-CoA reductase, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; HO-1, Heme oxygenase-1; ICAM-1, Intercellular adhesion molecule-1; IFN-γ, Interferon gamma; IL, Interleukin; iNOS, Inducible-nitric oxide synthase; JAK2, Janus kinase; JNK, c-JunNterminal kinase; Keap1, Kelch-like ECH-associating protein 1; LDL, Low-density lipoprotein; MIC, Minimum inhibitory concentration; MPO, Myeloperoxidase; MTP, Microsomal triglyceride transfer protein; NF-κB, Nuclear factor-kappa B; NQO1, NAD(P)H quinine oxidoreductase 1; Nrf2, NF-E2 p45-related factor 2; PARP, Poly (ADP-ribose) polymerase; PERK, Pancreatic ER kinase-like; PGE2, Prostaglandin E2; PI3K, Phosphoinositide 3-kinase; RANKL, Receptor activator of nuclear factor-;κB ligand; ROS, Reactive oxygen species; SIRT1, Sirtuin 1; SKP-;2, S-;phase kinase associated protein 2; SOD2, Superoxide Dismutase 2; STAT3, Signal transducer and activator of transcription 3; SUV, Solar-UV; TG, Triglycerides; TNF-α, Tumor necrosis factor-alpha; TXNRD1, Thioredoxin reductase 1 * Corresponding author. 2000, Jintong Road, Tangjiawan, Zhuhai, Guangdong, 519087, China. E-mail address: [email protected] (B. Xu). https://doi.org/10.1016/j.phytochem.2019.112066 Received 1 May 2019; Received in revised form 7 July 2019; Accepted 11 July 2019 0031-9422/ © 2019 Elsevier Ltd. All rights reserved.

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Table 1 Health promoting effects and bioactivities of taxifolin. Activity

Method and doses

Results

References

Antiinflammatory

Cerebral ischemia-reperfusion injury in rats (0.1 and 1.0 μg/kg) Ovariectomy-induced osteoporosis on C57BL/6 mice (50 mg/kg) In vitro evaluation of osteoclastogenesis on RAW264.7 cells (25, 50, 100, 150, 200, 400, and 600 μmol/L) In vivo mouse calvarial osteolysis model (1 and 10 mg/kg) Gel dilution test (0.5, 1.0, 2.0 and 5.0%)

Modulated NF-κB activation Suppressed the NF-κB activation, protein kinase activation by C-Fos and mitogen, and reduced the expression of osteoclast-specific genes, including Trap, Cathepsin K, Mmp-9, Nfatc1, C-Fos and Rank Inhibited the osteoclast differentiation induced by RANKL Suppressed the NF-κB signaling pathway and inhibited the osteoclastogenesis

Wang et al. (2006) Cai et al. (2018) Zhang et al. (2019)

St. epidermis (5.0%), zone of inhibition-21.33 ± 0.82 mm)

Microplate Alamar blue assay (0.2–100 μg/ml) In silico molecular docking

M. tuberculosis H37Rv, MIC of ≤12.5 μg/ml. Interaction with Mtb DNA gyrase and isoleucyl-tRNA synthetase

Microdilution broth method (3.5–225 μg/ml)

Inhibition of Streptococcus sobrinus IC50 - 21.8 ± 1.7 and glucosyltransferase IC50 - 53.0 ± 0.7 μg/ml Increased levels of bilirubin, total protein concentration, activities of alkaline phosphate, gamma-glutamyl transferase, alanine aminotransferase and aspartate aminotransferase Decreased the tissue lactate dehydrogenase activity, protein carbonyl content, lipid peroxidation and xanthine oxidase activity Blocked the JFH-1 virus-induced oxidative stress

Artem’Eva et al., 2015 Davis et al., 2018Davis et al., 2018 Kuspradini et al. (2009) Tapas et al. (2008)

Antimicrobial Anti-TB

Hepatoprotective

Rotenone-induced hepatotoxicity (0.25, 0.5 and 1 mg/kg)

PBMC isolation and proliferation assay HCV NS5B polymerase assays Huh7 human hepatoma cells Hepatitis induced by tetrachloromethane (100 mg/kg) Con A-induced liver injury (5 mg/kg) TNF-α-induced apoptosis in HepG2 Cell (200 μM)

APAP-induced liver injury (4, 20 or 40 mg/kg)

Cardiovascular

20% casein cholesterol diet along with taxifolin (0.1% and 0.05%) to rats Rat fed with cholesterol-free diet (0.05%) Cell culture study using HepG2 cells (200 μM) Cell culture study using HepG2 cells (200 μM)

Human healthy volunteers Cell culture study using H9c2 cells (2.5, 5, 10, 20, 40 and 80 μM) Isolated rat hearts Langendorff perfusion (20 μM)

Antiangiogenic effect

Anticancer

Chick chorioallantoic membrane assay, dorsal skinfold chamber and tube formation assay (40 μM, 80 μM, 120 μM) Quinone reductase assay HCT 116 cells (60 μM) Ames Salmonella microsome/mutagenicity assay (100 μl) Colorectal cancer cell lines and in an HCT116 xenograft model (10–100 μM) Cytotoxicity of TAX in JB6 P+ Cells and HepG2-C8 Cells (10–40 μM) 12-O-tetradecanoyl phorbol-13-acetate-induced JB6 P+ cells and JB6-shNrf2 cells transformation (10–40 μM) ARE-Luciferase reporter activity (5–40 μM) Immunofluorescence microscopy and flow cytometric analysis of Human Ewing’s sarcoma cells MTT assay (25, 50, and 100 μM) U2OS and Saos-2 osteosarcoma cell lines U2OS xenograft tumors model 1, 2-Dimethylhydrazine -induced mouse colon carcinogenesis (4 μg/kg) In silico molecular docking studies Sulpiride-induced benign prostatic hyperplasia (10 mg/kg)

Decreased lipid peroxidation Reduced the infiltration of CD4+ and CD8+ T cells in the injured liver tissues, down-regulation of pro-inflammatory cytokines, chemokine, apoptosis factors Inhibited the activation of caspase-3, caspase-7, and caspase-8, reduced the phosphorylation of NF-kB/p65 Downregulation of TNF-α and IL-6, increased mRNA expression of Nrf2 and SOD2, Bax downregulation, overexpression of Bcl-2 and Procaspase3 Normalized the serum and liver lipid concentrations Lowered the total liver cholesterol; reduced serum and liver thiobarbituric acid reactive substance concentration Inhibited the cholesterol synthesis by 86%; inhibit the activity of HMGCoA reductase by 47% at 200 mM Reduced the apoB secretion by 63%, inhibited the microsomal TG synthesis by 37%, decrease in diacylglycerol acyltransferase activity by 35% Lowered total LDL cholesterol level Inhibited the apoptotic pathway and the expression of pro-apoptotic proteins CHOP, Caspase-12, and p-JNK. Delayed the onset of ERs by reducing GRP78, p-PERK, and p-eif2α expression levels and by increasing HO-1 expression and Nrf2 binding to antioxidant response elements Inhibited new blood vessels and vessels branches per area, reduced the numbers and diameter of blood vessels, inhibition of tube formation on matrigel matrix Reduced quinone reductase activity; upregulated chemopreventive phase II enzymes and an antioxidant enzyme Inhibited benzidine and iron-mediated lipid peroxidation Cytochrome P-450 and peroxidase inhibition and chelation Reticence of cell growth

Polyak et al. (2010)

Teselkin et al. (2000) Chen et al. (2018a)

Chen et al. (2017)

Itaya & Igarashi (1992) Igarashi et al. (1996) Theriault et al. (2000) Casaschi et al., 2004

Kostyuk et al. (2003) Shu et al. (2019)

Wasimul et al., 2015

Lee et al. (2007) Makena and Chung (2007) Razak et al. (2018)

Stimulated the ARE-luciferase activity; up-regulated mRNA and protein levels of Nrf2; downstream genes HO-1 and NQO1

Kuang et al. (2017)

Inhibited cell viability and decreased EWS expression

Hossain and Ray, 2014

Arrested the G1 phase of the cell cycle Inhibited tumor growth Increased serum marker enzyme levels (CEA and LDH) and mast cell infiltration, inhibited NF-κB and Wnt signaling by down-regulating the levels of TNF-α, COX-2, β-catenin, and cyclin-D1 TAX exhibits strong binding affinity with Nrf2, β-catenin, and TNF-α Reduction of proliferative activity

Chen et al. (2018b) Manigandan et al. (2015)

Borovskaya et al. (2015)

(continued on next page) 2

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Table 1 (continued) Activity

Method and doses

Results

References

Anti-Alzheimer

N2a Swe cells cell culture study (10–50 μM) NF-κB p65 transcription factor assay STAT3 siRNA and SIRT1 siRNA transfection assays

Park et al. (2016)

Anti -toxoplasmosis

CCK-8 cell cytotoxicity assay (0, 0.6, 0.8, 4, 8, and 10 μg/ml) Anti-T. gondii and T. gondii infected cytotoxicity assay (0.6, 4, and 8 μg/ml) DNA-comet assay and chromosome aberrations counting (15, 150, and 2000 mg/kg)

Reduced the increased phosphorylated JAK2 at Tyr1007/1008 (P-JAK), phosphorylated STAT3 at Tyr 705 (P-STAT3) expressions and increased expressions of BACE1 mRNA and protein Elevated the decreased cytosol IκBα expression and reduced the increased nuclear NF-κB p65 level and nuclear NF-κB p65 DNA Stimulated SIRT1 protein expression Pyrimethamine with taxifolin significantly inhibited the tachyzoites

No DNA damages in mouse bone marrow, blood, liver, and rectal cells

Zhanataev et al. (2008)

Genotoxic study

2. Pharmacological activities

Abugri et al., 2018

Wang et al. (2006) have reported that taxifolin can modulate the NF-κB activation in rats with cerebral ischemia-reperfusion injury. Administration of taxifolin at the doses of 0.1 and 1.0 μg/kg, i.v. 60 min after middle cerebral arterial occlusion bettered infarction by 42% and 62%, respectively. Furthermore, taxifolin inhibited the infiltration of leukocyte and the expressions of COX-2 and iNOS in the brain with cerebral ischemic reperfusion injury. In addition, taxifolin also prevented the expressions of Mac-1 and ICAM-1. The enhanced activity of NF-κB was also inhibited by taxifolin. They proved this activity of taxifolin is due to its antioxidative effect, thereby modulates the activation of NF-κB. Recently in a study, taxifolin proved to be effective against osteoclastogenesis evaluated using both in vitro and in vivo models (Cai et al., 2018). Taxifolin suppressed the NF-κB activation, protein kinase activation by C-Fos and mitogen, and also reduced the expression of osteoclast-specific genes, including Trap, Cathepsin K, Mmp-9, Nfatc1, CFos, and Rank. Furthermore, taxifolin repressed the osteoclast activity by improving the ovariectomized-induced bone loss and decreased the levels of interleukin-6, interleukin-1β, necrosis factor-α, and RANKL in serum. Very recently it has been found that taxifolin inhibited the osteoclast differentiation induced by RANKL without cytotoxicity evaluated by in vitro study (Zhang et al., 2019). In addition to that, taxifolin significantly suppressed the expression of RANKL-induced gene, tartrate-resistant acid phosphatase, matrix metalloproteinase-9 nuclear factor of activated T-cells 1 and cathepsin K, and F-actin ring formation. In the study, Taxifolin also suppressed the NF-κB signaling pathway and inhibited the osteoclastogenesis. In support of this in in vivo study, taxifolin also prevented the bone loss evaluated in mouse calvarial osteolysis model.

2.1. Antioxidant activity Flavonoids are important compounds found in many plants, including edible fruits and vegetables. Flavonoids have attracted significant interests in the scientific arena because of their versatility of uses and health-promoting effects. They have the ability to chelate transition metal ions, to scavenge free radicals and to interact with enzymes proved to be an effective antioxidant. The presence of hydroxyl group (–OH) bonded to the aromatic ring in phenolic compounds especially flavonoids are reactive and responsible for antioxidant activity. The flavonoid compound taxifolin also proved to be a potent antioxidant (Kurth and Chan, 1951). Kolhir et al. (1996) first reported taxifolin’s antioxidant activity along with the capillary protector action. Interestingly, it has been found that taxifolin is 3.4 times more effective at 100 mg/kg and 4.9 times at 300 mg/kg dose than quercetin. Taxifolin also showed in vivo antioxidant effect evaluated in hepatitis induced by tetrachloromethane on Wistar rats (Teselkin et al., 2000). In the study, taxifolin treated rats showed antioxidant activity by decreased lipid peroxidation in the serum and liver reacting with thiobarbituric acid. Salah et al. (1995) have pointed that the presence of 5- and 7-OH groups with 4-oxo function in the A and C rings are responsible for radical scavenging effect and the stability is provided by the O-dihydroxy structure in the B ring. Taxifolin, due to its antioxidant activity it showed a neuroprotective effect by inhibiting the oxidative neuronal injuries on rat cortical cells. In support of this, it also inhibited the peroxidation of lipids and scavenged the DPPH free radicals (Dok-Go et al., 2003). In FRAP assay, taxifolin also showed good reducing capacity. Further, on analysis of oxidation potentials using electrochemical method, cyclic voltammetry, taxifolin showed a well-defined quasi-reversible anodic peak with Eap values ranging between +0.30 and + 0.46 V. The electrochemical data were in good agreement with the results obtained by the FRAP assay (Firuzi et al., 2005). Chobot et al. (2016) have also proved that the antioxidant activity of taxifolin is due to the electrochemical redox potentials, especially that of the ring A hydroxyl groups evaluated by deoxyribose degradation assay. In another study, taxifolin inhibited the decrease in H2O2-induced cell viability, cell apoptosis, and intracellular ROS generation in human RPE (ARPE-19) cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. With context to this, taxifolin inhibited the H2O2-induced poly (ADP-ribose) polymerase cleavage. Followed by treatment with taxifolin induced the translocation of Nrf2 to the nucleus by activating the mRNA and the protein expression. Besides the phase II enzyme’s (NQO1, HO-1, GCLM, and GCLC) mRNA and protein levels were also increased (Xie et al., 2017).

2.3. Cardiovascular activity In hyperlipidemia mainly increased the level of cholesterol or LDL cholesterol is the major cause and development of atherosclerosis and coronary heart diseases. However, studies have proved that flavonoids have a potential role in reducing blood lipid levels by preventing HMGCoA reductase or by limiting the availability of TG by influencing the apolipoprotein ratio (Weidmann, 2012). Similarly, taxifolin also showed antihyperlipidemic activity which was evaluated by feeding rats with a diet containing 20% casein cholesterol along with taxifolin (0.1% and 0.05%) for 21 days. Taxifolin treatment normalized lipid levels in the serum and liver, and excretion of lipids in fecal of rats fed with the cholesterol-enriched diet (Itaya and Igarashi, 1992). Followed by the in vivo study also proved the reduced level of total liver cholesterol along with the reduction in thiobarbituric acid reactive substance concentration in both serum and liver (Igarashi et al., 1996). The apolipoproteins ApoB and ApoA-I act as ligands for LDL and HDL receptors, respectively. ApoB carry’s cholesterol to the tissues whereas ApoA-I promotes the excretion by the efflux of cholesterol from the tissues to the liver. The risk of cardiovascular diseases can be measured from the superiority of the apoB/apoA-I ratio (Walldius et al., 2001; Yusuf et al., 2004). In recent years, it has been found by cell culture

2.2. Anti-inflammatory activity Flavonoids are well known with an anti-inflammatory activity which has been reported by several researchers (Gupta et al., 1971). 3

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studies several flavonoids have reduced the apoB production (Borradaile et al., 1999; Yee et al., 2002). This is due to the effect of flavonoids on the enzymes like HMG-CoA reductase, acyl CoA: cholesterol acyltransferase, microsomal triglyceride transfer protein, and diacylglycerol acyltransferase (Casaschi et al., 2002; Wu et al., 1996). In a study, taxifolin pretreatment with HepG2 cells inhibited the cholesterol synthesis by 86% at 200 mM observed within 24 h. Further, it has been found that taxifolin at 47% inhibited the HMG-CoA reductase activity. In addition, taxifolin also suppressed the cellular cholesterol esterification, and triacylglycerol and phospholipid syntheses significantly. The ApoA-I secretion was also increased by 36% and labeled apoB in the medium was reduced by 61%. The study proved that taxifolin decreased the hepatic lipid synthesis by decreasing and increasing the apoB and apoA-I secretion (Theriault et al., 2000). Another study by Casaschi et al. (2004) also proved that taxifolin at 200 μM reduced the apoB secretion in HepG2 cells by 63% and also microsomal TG synthesis by 37%. The reduction in the activities of DGAT (35%) and MTP (41%) proved that taxifolin through the activity on DGAT and MTP reduced the secretion of apoB and limited the availability of TG. New research results suggest that the cardioprotective effect of HDL may lose due to oxidative and compositional changes by myeloperoxidase induced by reactive nitrogen species (ONOO−, NO2 −; NO2•) (Gaut et al., 2002). This has been proved by the study of Kostyuk et al. (2003) confirmed that dihydroquercetin lowered the total LDL cholesterol levels by scavenging of MPO-derived from NO2 radicals in blood serum of healthy human volunteers. Recently taxifolin also showed the cardioprotective effect by acting against the ischemia-reperfusion injury by inhibiting oxidative stress and endoplasmic reticulum stressinduced apoptosis via the PI3K/Akt pathway. This has been proved in a recent study, taxifolin pretreatment changed the cardiac dysfunction, enhanced the activity of antioxidant enzymes, lipid peroxidation reduction, free radical scavenging. Adding to that, taxifolin inhibited the expression of pro-apoptotic proteins CHOP, Caspase-12, and p-JNK thereby inhibited the apoptotic pathway. Furthermore, taxifolin delayed the onset of endoplasmic reticulum stress by reducing the expression levels of GRP78, p-PERK, and p-eiF2α, and by increasing the expression of HO-1 and binding of Nrf2 to antioxidant response elements (Shu et al., 2019).

HepG2 cells. In the study, taxifolin significantly reduced the alanine transaminase and aspartate transaminase levels in serum and also reduced the infiltration of CD4+ and CD8+ T cells in the injured liver tissues. Furthermore, taxifolin down-regulated the pro-inflammatory cytokines like TNF-α, IFN-γ, IL-2, IL-4, and IL-10, apoptosis factors like Fas and FasL, the chemokine osteopontin, transcription factors that regulate Th cell differentiation (T-bet and GATA-3), perforin, granzyme B. In in vitro study, taxifolin prevented the apoptosis (TNF-α/ActD-induced) by inhibiting the caspase-3, caspase-7 and caspase-8 activation on HepG2 cells. Taxifolin showed these effects through the modulation of the caspase and NF-kB pathways (Chen et al., 2018a). Taxifolin also showed the hepatoprotective effect on liver injury by acetaminophen in the mouse. The levels of alanine transaminase and aspartate transaminase in serum were lessened after taxifolin treatment. Further, taxifolin showed downregulation of TNF-α and IL-6, increased mRNA expression of Nrf2 and SOD2, Bax down-regulation, over-expression of Bcl-2 and procaspase-3 (Chen et al., 2017). 2.5. Anticancer activity Flavonoids exert anticancer effects by multiple mechanisms: Suppression of metabolizing enzymes mainly Cytochrome P450, inhibition of cell cycle regulators (CDKs) thereby arresting the cell cycle at G1 phase or G2/M phase, activation of phase II metabolizing enzymes to inhibit the reactive oxygen species formation, induction of apoptosis and prevention of angiogenesis by the inhibition of vascular endothelial and basic fibroblast growth factors. The chemopreventive activity of taxifolin by ARE mechanism was reported by Lee et al. (2007). Glutathione S-transferase A2 and NADPH: quinone oxidoreductase 1 are the major phase II detoxifying enzymes encode in the promoter regions of ARE in the gene (Favreau and Pickett, 1991; Friling et al., 1990). In the study, taxifolin showed significant quinone reductase activity and low cytotoxicity (chemoprevention index 5.75) in HCT 116 cells. Further, they have analyzed the regulation of taxifolin on selected 3096 human genes in 3K human cancer chip by the DNA microarray technique. The results revealed that 60 μM of taxifolin upregulated 65 genes, including few chemopreventive phase II enzymes like NQO1 and GSTM1 and TXNRD1 (the antioxidant enzyme) and down-regulated 363 genes. Hence it was confirmed that taxifolin possesses chemopreventive action through ARE-dependent mechanism (Fig. 2) (Lee et al., 2007). In another study, taxifolin showed inhibitory effect on mutations induced by benzidine and found that salmonella TA102 tester strain was non-cytotoxic (Makena and Chung, 2007). Further, taxifolin also showed benzidine inhibition and iron-mediated lipid peroxidation. From the study, it has been found that taxifolin act by activating enzymes such as cytochrome P-450 and peroxidase and the chelation of iron present in the cytochrome P-450 in the rat liver S9 mix. This study proved another mechanism by which taxifolin works as discussed before (Fig. 2). Taxifolin (10–100 μM) also reported for antitumor activity on colorectal cancer cell lines (HCT116 and HT29) with IC50 values of 51.3 and 43.5 and 66.1 and 43.5 μM at 24 h and 48 h, respectively by Razak et al. (2018). Also, by flow cytometric analysis, it has been found that taxifolin at 40 and 60 μM the G2-phase cell cycle distribution for HCT116 was 44.61% and 59.52% and for HT 29 was 47.72% and 57.72%, respectively. The HCT116 xenograft model also proved the antitumor effect of taxifolin by cell growth arrest, controlling the cell cycle phase G2 and apoptosis. The expression of the βcatenin gene, AKT gene, and survivin gene was also suppressed by taxifolin (Fig. 2). ROS-induced oxidative stress has been implicated in the pathogenesis of carcinogenesis (Narendhirakannan and Hannah, 2013). In oxidative stress, the transcription of the cytoprotective genes occurs with the help of Nrf2 with the regulation of the adaptor protein, Keap1 (Cullinan et al., 2004; Wu et al., 2014). Keap1 and Nrf2 interaction disrupted under stress conditions and accumulates in the cell nucleus. Then, Nrf2 binds to the ARE in the promoter region of some phase II

2.4. Hepatoprotective activity Quercetin, rutin, catechin, naringenin, venoruton, and apigenin are the flavonoids reported for their hepatoprotective activities (Tapas et al., 2008). Taxifolin is used as an important component of hepatoprotective drug silymarin (Legalon®). The hepatoprotective activity of taxifolin was reported by several researchers. Taxifolin at the doses of 0.25, 0.5 and 1 mg/kg b. wt. showed hepatoprotective activity evaluated along with catechin (5, 10 and 20 mg/kg) and quercetin (5, 10 and 20 mg/kg) in hepatotoxic rats induced by rotenone. Taxifolin significantly increased the levels of total protein concentration, bilirubin, activities of alanine aminotransferase, alkaline phosphate, gammaglutamyl transferase, and aspartate aminotransferase. The activities of superoxide dismutase, myeloperoxidase and glutathione transferase, glutathione level and ferric reducing antioxidant power were significantly increased (Tapas et al., 2008). From the study it was found that at lower doses taxifolin showed comparable activity to quercetin and superior activity over catechin. The variation in C ring’s C2-C3 double bond in taxifolin is responsible for the antioxidant related hepatoprotective activity (Fig. 1) (Akinmoladun et al., 2018). Further taxifolin also offered protection against hepatitis by its antioxidative defenses as discussed before under antioxidant section (Teselkin et al., 2000). In a study by Polyak et al. (2010) screened taxifolin along with six major flavonolignans on Huh7 human hepatoma cells and the study proved taxifolin blocked the JFH-1 virus-induced oxidative stress. Recent pretreatment with taxifolin protected the hepatic injured mice induced by concanavalin A and apoptosis induced by TNF-α/ActD in 4

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Fig. 1. Structure of quercetin and taxifolin.

with EGFR and PI3K and inhibited their kinase activities in ATP competition and in the in vitro kinase assay. Further, taxifolin suppressed the phosphorylation of EGFR and Akt induced by UVB and also the signaling pathways in JB6 P+ skin epidermal cells of the mouse. Taxifolin reduced the expression levels of COX-2 and PGE2 induced by UVB. The study reported that taxifolin topical treatment to the dorsal skin significantly suppressed the tumor incidence, volume, and multiplicity. In addition to that taxifolin showed a significant reduction in EGFR and Akt phosphorylation in SUV- induced tumor in mouse skin (Fig. 3). Hossain and Ray, (2014) studied the anti-tumor effect of taxifolin on Ewing's sarcoma cell lines and animal models. The expression of EWS was knock downed using plasmid vector encoding EWS short hairpin RNA (shRNA). In SK-N-MC and RD-ES cell lines, EWS shRNA plus taxifolin inhibited 80% cell viability and decreased the expression of mRNA and protein levels of EWS. Additionally, it has been found that knockdown of EWS expression was related to the removal of DNA methylation from the p53 promoter, promoting p53, Puma, and Noxa

enzyme genes and to expressed Nrf2 downstream enzymes (Kobayashi et al., 2009; McMahon et al., 2010). HO-1 and NQO-1 are the enzymes which protect against oxidation (Fig. 2). Taxifolin also evaluated for the effect of activating the Nrf2 pathway to prevent cancer in JB6 P+ cells (Kuang et al., 2017). Taxifolin on JB6 P+ cells found to inhibit the formation of colony by12-O-tetradecanoyl phorbol-13-acetate (TPA)induction. In addition to that taxifolin stimulated the ARE-luciferase activity in HepG2-C8 cells and upregulated the Nrf2 mRNA and protein levels and downregulated the genes of HO-1 and NQO1, in JB6 P+ cells. Taxifolin also inhibited the expression levels of proteins like histone deacetylase and DNA methyltransferase. Moreover, it was revealed that taxifolin can induce Nrf2 expression and by demethylation of JB6 P+ cells it can downstream the target genes in JB6 P+ cells. From the study, it has been proved that taxifolin showed skin cancer effect by Nrf2 activation through the epigenetic pathway. Another study on JB6 P+ mouse skin epidermal cells by Oi et al. (2012) have proved that taxifolin acts on the potential targets like EGF receptor, PI3K, and Src. Taxifolin at the ATP-binding pocket interacted

Fig. 2. Taxifolin act through the antioxidant-response element and cytochrome P-450 enzymes mechanisms. 5

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Fig. 3. Taxifolin induce apoptosis with activation of extrinsic and intrinsic pathways, EGF receptor, PI3K and Src.

accumulation of amyloid-β. In addition, treatment with taxifolin significantly reduced the levels of amyloid-β oligomers on mouse brain in vivo (Saito et al., 2017).

expression. Thereby, taxifolin in cell lines induced the highest amount of apoptosis through the activation of extrinsic and intrinsic pathways. In animal models, EWS shRNA with taxifolin inhibited the growth of Ewing's sarcoma tumors by inhibition of differentiation inhibitors and angiogenic and invasive factors and also induction of activation of caspase-3 for apoptosis (Fig. 3). Taxifolin exhibited anti-cancer effects on U2OS and Saos-2 osteosarcoma cell lines by inhibiting the proliferation and diminishing colony formation. Further, in vivo intraperitoneal administration of taxifolin in nude mice bearing U2OS xenograft tumors, significantly inhibited tumor growth. In addition, taxifolin arrested the G1 phase of the cell cycle in U2OS and Saos-2 cell lines. The expression levels of AKT, SKP-2, v-myc avian myelocytomatosis viral oncogene homolog (cmyc) and phosphorylated (p-Ser473) AKT were reduced by taxifolin in U2OS and Saos-2 cell lines (Chen et al., 2018b). Taxifolin curbs colon carcinogenesis by NF-kB-mediated Wnt/b-catenin signaling through the up-regulation of Nrf2 pathway. Taxifolin also down-regulated the TNFα, COX-2, β-catenin, and cyclin-D1 thereby inhibited the NF-κB and Wnt signaling pathway (Manigandan et al., 2015). It is also reported that taxifolin injection reduced the proliferative activity on Wistar rats with benign prostatic hyperplasia (Borovskaya et al., 2015).

2.7. Antimicrobial activity Globally, the antimicrobial agent’s resistance has become an increasing problem nowadays (Cushnie and Lamb, 2005). Flavonoids with phenolic groups from plant source have been well known with antimicrobial activity (Cowan, 1999). They work by the mechanism of inhibition of function of the cytoplasmic membrane, synthesis of nucleic acids and energy metabolism (Cushnie and Lamb, 2005). Taxifolin (0.5, 1.0, 2.0 and 5.0%) also showed antimicrobial activity evaluated against Escherichia coli VL-613, Staphylococcus epidermidis ATCC 14990, Pseudomonas aeruginosa 98, M. luteus АТСС 10240, Micrococcus luteus (lysodeicticus) АТСС 4698, using gel dilution test. S. epidermidis was found to be high sensitive (Zone of inhibition 21.33 ± 0.82 mm) to 5.0% of taxifolin (Artem’Eva et al., 2015). Adding to that taxifolin also showed antimicrobial effect on dental pathogen, S. sobrinus. Taxifolin inhibited the growth of S. sobrinus and glucosyltransferase with an IC50 value of 21.8 and 53.0 μg/ml, respectively (Kuspradini et al., 2009). Futhermore, taxifolin was also active against M. tuberculosis H37Rv with a MIC of ≤12.5 μg/ml. The activity evaluated by in silico molecular docking and dynamics stimulation showed a good number of interactions with active amino acids of Mtb DNA gyrase and isoleucyltRNA synthetase (Davis et al., 2018).

2.6. Anti-Alzheimer activity Along with other pharmacological properties taxifolin also reported having anti-Alzheimer property. Particularly, in a study taxifolin alone and in combination with cilostazol significantly attenuated the increased Aβ and C99 levels in N2a Swe cells. In addition to that taxifolin and cilostazol also elevated the decreased cytosol IκBα expression and reduced the increased nuclear NF-κB p65 level and nuclear NF-κB p65 DNA binding activity significantly. From the study, it has been found that taxifolin and cilostazol strongly inhibited amyloidogenesis in a synergistic manner by suppressing P-JAK2/P-STAT3-coupled NF-κBlinked BACE1 expression via the upregulation of SIRT1 (Park et al., 2016). In another study, taxifolin inhibited the formation of amyloid-β oligomer and restores the vascular integrity and memory in cerebral amyloid angiopathy. Further, taxifolin in Tg-SwDI mice treated mice, significantly reduced the cerebrovascular pan-amyloid-β and

2.8. Antiangiogenic activity Taxifolin showed an antiangiogenic effect by inhibiting new blood vessels and vessels branches per area of chick chorio allantoic membrane assay. Taxifolin also showed in vitro antiangiogenic effect by inhibition of tube formation on Matrigel matrix that involved in human umbilical vein endothelial cells evaluated using tube formation assay (Wasimul et al., 2015). In the study, taxifolin showed significant inhibitory activity against tachyzoites in vitro with IC50 of 1.39 μg/mL (p ≤ 0.05) with the combination of pyrimethamine. 6

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apolipoprotein B metabolism by the citrus flavanones hesperetin and naringenin. Lipids 34, 591–598. Cai, C., Liu, C., Zhao, L., Liu, H., Li, W., Guan, H., Zhao, L., Xiao, J., 2018. Effects of taxifolin on osteoclastogenesis in vitro and in vivo. Front. Pharmacol. 9, 1286. Casaschi, A., Rubio, B.K., Maiyoh, G.K., Theriault, A.G., 2004. Inhibitory activity of diacylglycerol acyltransferase (DGAT) and microsomal triglyceride transfer protein (MTP) by the flavonoid, taxifolin, in HepG2 cells: Potential role in the regulation of apolipoprotein B secretion. Atherosclerosis 176, 247–253. Casaschi, A., Wang, Q., Dang, K., Richards, A., Theriault, A., 2002. Intestinal apolipoprotein B secretion is inhibited by the flavonoid quercetin: Potential role of microsomal triglyceride transfer protein and diacylglycerol acyltransferase. Lipids 37, 647–652. Chen, X., Guu, N., Xue, C., Li, B.R., 2018. Plant flavonoid taxifolin inhibits the growth, migration and invasion of human osteosarcoma cells. Mol. 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2.9. Genotoxic activity Zhanataev et al. (2008) have reported the genotoxic properties of taxifolin by DNA-comet assay and chromosome aberrations counting. In the study, no DNA damages in mouse bone marrow, blood, liver, and rectal cells were found after administration of taxifolin at the doses of 0.15 and 1.5 mg/kg for 5 times or 15, 150 and 2000 mg/kg once in doses. In addition to that, there was no effect on the level of chromosome aberrations in mouse bone marrow cells. Taxifolin also showed an antifibrotic effect evaluated on chronic nonbacterial inflammation of the prostatic gland in rats. 3. Conclusion and future perspectives In this review, various pharmacological properties of taxifolin especially, antioxidant, anticancer, antimicrobial, anti-Alzheimer, hepatoprotective and cardioprotective were summarized. The most important observation is taxifolin showed better activity in vitro studies, but data coupled with in vivo studies are lacking. Surprisingly, taxifolin showed effective anticancer, hepatoprotective and cardioprotective activities through multiple mechanisms. This has been proved due to the lipid-peroxidation of taxifolin that results in the chemopreventative and chemotherapeutic actions. The most striking observation is that the absence of C2, C3-double bond in the C ring of taxifolin compared to its oxidation product quercetin and many other flavonoids with identical hydroxylation pattern lacks antioxidant potency. Quercetin has been recognized as a multipotent compound effective against various diseases, but taxifolin has been overlooked as an unimportant impurity of some flavonoid compounds. But the evidence provided from the research data proved taxifolin as a potent anticancer agent. However, this review highlights the various pharmacological activities of taxifolin mainly acting through various molecular mechanisms. Further research into the exact mechanism on human systems with disease pathology both in- vitro and in vivo will provide a beneficial drug for human use. Funding This study is jointly supported by two research grants R201714 and R201914 from Beijing Normal University-Hong Kong Baptist University United International College. Conflicts of interest The authors declare no conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.phytochem.2019.112066. References Abugri, D.A., Witola, W.H., Russell, A.E., Troy, R.M., 2018. In vitro activity of the interaction between taxifolin (dihydroquercetin) and pyrimethamine against Toxoplasma gondii. Chem. Biol. Drug Des. 91, 194–201. Akinmoladun, A.C., Oladejo, C.O., Josiah, S.S., Famusiwa, C.D., Ojo, O.B., Olaleye, M.T., 2018. Catechin, quercetin and taxifolin improve redox and biochemical imbalances in rotenone-induced hepatocellular dysfunction: Relevance for therapy in pesticide-induced liver toxicity? Pathophysiology 25, 365–371. Artem'Eva, O.A., Pereselkova, D.A., Fomichev, YuP., 2015. Dihydroquercetin, the bioactive substance, to be used against pathogenic microorganisms as an alternative to antibiotics. Agric. Biol. 50, 513–519. Blumenthal, M., Busse, W.R., 1998. The Complete German Commission E. Monographs: Therapeutic Guide to Herbal Medicines. American Botanical Council, Austin, Tex. Borovskaya, T.G., Krivova, N.A., Zaeva, O.B., Fomina, T.I., Kamalova, S.I., Poluektova, M.E., Vychuzhanina, A.V., Shchemerova, Y.A., Grigor'eva, V.A., Goldberg, V.E., Plotnikov, M.B., 2015. Dihydroquercetin effects on the morphology and antioxidant/ prooxidant balance of the prostate in rats with sulpiride-induced benign hyperplasia. Bull. Exp. Biol. Med. 158, 513–516. Borradaile, N.M., Carroll, K.K., Kurowska, E.M., 1999. Regulation of HepG2 cell

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Sunil is a post-doctoral research fellow of Beijing Normal University-Hong Kong Baptist University United International College, China. He obtained Doctor of Philosophy in Pharmacology, awarded from the University of Madras, Chennai, India in 2013. He is a recipient of Senior Research Fellowship (2011–2013) India Council of Medical Research (ICMR), Government of India, New Delhi, India and also recipient of Early Career Research Award (2016) Department of science and technology, Science, Engineering & Research Board, New Delhi, India. Dr. Sunil has been awarded one year of post-doctoral research fellowship from the University of KwaZulu-Natal, Pietermaritzburg, South Africa. He has published 30 international peer-reviewed papers in reputed journals. His research has been focused on evaluating the anticancer and anti-diabetic effects of various isolated and synthesized compounds using in vitro and in vivo models.

BaojunXu is a Full Professor in Beijing Normal UniversityHong Kong Baptist University United International College (UIC), Zhuhai Scholar Distinguished Professor, Program Director of Food Science and Technology Program, Associate Director of UIC Key Lab -Laboratory for Health Promotion Mechanism of Medicinal Food and Folk Remedy, author of 172 peer-reviewed papers. Dr. Xu received Ph.D in Chungnam National University, South Korea. He conducted postdoctoral research work in North Dakota State University, Purdue University, and Gerald P. Murphy Cancer Foundation during 2005–2009. Dr. Xu is serving as Associate Editor-in-Chief of Food Science and Human Wellness, the Editorial Board member of several international journals. He received inaugural President’s Award for Research of UIC in 2016.

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