key: cord-0885755-1ya21ch7
authors: Kashyap, Dharambir; Sharma, Ajay; Tuli, Hardeep Singh; Sak, Katrin; Punia, Sandeep; Mukherjee, Tapan K.
title: Kaempferol – A dietary anticancer molecule with multiple mechanisms of action: Recent trends and advancements
date: 2017-01-18
journal: J Funct Foods
DOI: 10.1016/j.jff.2017.01.022
sha: 8574b815f71d9a6eb4c0d61dbdce8da79c80a437
doc_id: 885755
cord_uid: 1ya21ch7

The consumption of diet-based naturally bioactive metabolites is preferred to synthetic material in order to avert health-associated disorders. Among the plant-derived polyphenols, kaempferol (KMF) is considered as a valuable functional food ingredient with a broad range of therapeutic applications such as anti-cancer, antioxidant and anti-inflammatory uses. KMF acts on a range of intracellular as well as extracellular targets involved in the cell signaling pathways that in turn are known to regulate the hallmarks of cancer growth progressions like apoptosis, cell cycle, invasion or metastasis, angiogenesis and inflammation. Importantly, the understanding of mechanisms of action of KMF-mediated therapeutic effects may help the scientific community to design novel strategies for the treatment of dreadful diseases. The current review summarizes the various types of molecular targets of KMF in cancer cells as well as other health-associated disorders. In addition, this review also highlights the absorption, metabolism and epidemiological findings.

The interest of scientific community to identify and characterize bioactive constituents from various plant extracts for suitable use in pharmaceutical industry or in composition of functional foods is significantly increasing. Today, it is generally accepted that nutrition plays an important role in the prevention of different chronic diseases and decreasing the risk factors by virtue of its functional ingredients. Among the broad category of plantderived bioactive compounds, flavonoids are found to possess multiple health benefits. Therefore they are being considered as a medicinally important class of dietary molecules (Ravishankar, Rajora, Greco, & Osborn, 2013) . These plant-based secondary metabolites are known to represent a number of structurally diverse classes of polyphenols with potential pharmacological activities, including anticancer, anti-inflammatory, antioxidant, and anti-pathogenic properties (Rajendran et al., 2014; Ravishankar et al., 2013) . Indeed, numerous in vitro and in vivo studies have reported the ability of flavonoids to interfere in different stages of carcinogenesis like migration, invasion, metastasis, and angiogenesis (Ravishankar et al., 2013) . Moreover, epidemiological studies have shown that long-term and regular consumption of dietary items rich in flavonoids, such as fruits and vegetables, are associated with the lower risk of malignancy developments (Batra & Sharma, 2013; Kozlowska & Szostak-Wegierek, 2014; Tena et al., 2013) . The daily intake of flavonoids among humans is still greatly variable, ranging from about twenty milligrams to virtually one gram (Jaramillo-Carmona et al., 2014) . Although, flavonoids are characterized by a common skeleton of diphenyl propane, they can be further subdivided into flavanols, flavonols, flavones, flavanones, isoflavones and anthocyanins based on the peculiarities in their chemical structures (Batra & Sharma, 2013; Kozlowska & Szostak-Wegierek, 2014; Sak, 2014; Tena et al., 2013) .

Kaempferol (KMF), a well characterized natural flavonol, is present in 80% of plant-based foods, including broccoli, kale, cabbage, leek, tomato, beans, grapes, strawberries, apples, and tea Chen et al., 2013; Jaramillo-Carmona et al., 2014; Kim & Choi, 2013; Rajendran et al., 2014) . It has been reported that KMF has potential to significantly modulate a variety of signaling pathways that are involved in many adverse clinico-pathological conditions (Batra & Sharma, 2013; Jaramillo-Carmona et al., 2014; Kim & Choi, 2013; Rajendran et al., 2014) . In contrast to the standard chemotherapeutic drugs utilized in cancer treatment at present, KMF showed minimal side effects evidenced in the different experiments along with its effective synergistic ability in combination with various synthetic cytotoxic drugs Chen et al., 2013; Kim & Choi, 2013; Rajendran et al., 2014) . However, essential efforts are still needed to uncover its unexplored health benefits. This review highlights the multiple molecular targets of KMF that are involved in a variety of cellular signaling pathways. In addition to this, the review also discusses synergistic studies of KMF with other known therapeutic drugs along with its pharmacokinetics and epidemiological findings.

(3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4Hchromen-4-one) was initially discovered in Camellia sinensis (tea tree) and is abundant in different genera of plants such as Capparis spinosa (Capers) and Crocus sativus (Saffron) (Calderon-Montano, Burgos-Moron, Perez-Guerrero, & Lopez-Lazaro, 2011; Devi et al., 2015 ; Mercader-Ros et al., 2013, chap. 1). Table 1 summarizes the list of all sort of natural sources of KMF (see Fig. 1 ).

The biosynthetic approach of KMF is known to involve the condensation of cinnamoyl-CoA (1) and malonyl-CoA (2) in the presence of chalcone synthase, a catalytic enzyme, which results in the formation of naringenin-chalcone (3). Chalcone has been considered as the most widely studied precursor for a variety of flavanol synthesis. Further, chalcone isomerase mediates isomerisation reactions and leads to the formation of naringenin (flavanone) (4). In the next step, the hydroxylation is known to occur at C3 position of naringenin by flavanone 3-dioxygenase which leads to the synthesis of dihydrokaempferol (5). In the last step, flavonol synthase mediated exordium of a double bond at the C2-C3 position occurs in the dihydrokaempferol skeleton which results in the formation of KMF (Devi et al., 2015) (Fig. 2) . Naturally, KMF is also known to exist in conjugate forms with different sugar molecules such as rutinose, rhamnose, glucose and galactose that cause the formation of glycosidic combinations of KMF, such as astragalin (kaempferol-3-O-glucoside), kaempferol-3-beta-D-galactoside, kaempferol-3-rutinoside. Besides these, other derivatives, such as kaempferol methyl ether, kaempferol dimethyl ether, kaempferol trimethyl ether and kaempferol sulphate have also been noted (Calderon-Montano et al., 2011; Murakami & Tanaka, 1988) .

Chemically, KMF is synthesized by complex reaction having many steps: (a) cross aldol condensation of 2,4,6trimethoxyacetophenone (6) and 4-methoxybenzaldehyde (7) with KOH, (b) ortho-demethylation of 2,4,6,4 0 -tetramethoxychalcone (8) in the presence of AlCl 3 , (c) I 2 -mediated oxidative cyclization of 2-hydroxy-4,6,4 0 -trimethoxychalcone (9), (d) methylation of 5-hydroxy-7-methoxy-2-(4-methoxyphenyl)chromen-4-one by Me 2 SO 4 (10), (e) oxidative hydroxylation of 5,7-dimethoxy-2-(4methoxyphenyl)chromen-4-one (11) catalysed by DDO, (f) BBr 3 controlled catalytic demethylation of 3-hydroxy-5,7-dimethoxy-2 -(4-methoxyphenyl)chromen-4-one (12) (Lee & Wu, 2001) (Fig. 3A) .

Another convenient method for KMF synthesis involves the reaction of x-benzoyloxyphloracetophenone (13), p-(acetyloxy)

benzoic anhydride (14), sodium p-acetyloxybenzoate (15) in the presence of triethylamine at 160-165°C for 8 h, followed by mechanical stirring and aqueous KOH treatment that results in the formation of desired product (Ichikawa, Pamukcu, & Bryan, 1982) (Fig. 3B ).

Recent in vitro and in vivo studies have shown the antiproliferative and proapoptotic activities of KMF against various types of cancers including breast (Azevedo et al., 2015; Kim, Hwang, & Choi, 2016; Liao et al., 2016) , ovarian (Luo, Rankin, Li, Depriest, & Chen, 2011) , lung (Kuo et al., 2015) , pancreas (Zhang, Chen, Li, Chen, & Yao, 2008) , esophagus (Yao et al., 2016) , stomach , colon , prostate (Halimah et al., 2015) , bladder (Dang et al., 2015) , kidney (Song et al., 2014) and others. Most of these studies demonstrate that the mechanism of KMF is dependent on the inhibition of proliferation of various cancer cells either via cell cycle arrest or induction of apoptosis (Kuo et al., 2015; Liao et al., 2016) . KMF-dependent inhibition of cancer proliferation is mediated through arrest of the different phases of cell cycle (Fig. 4) and inhibition of cell cycle transition points Table 1 An overview about the sources of KMF and its derivatives.

including G0/G1 transition in esophagus squamous cell carcinoma (Yao et al., 2016) or G2/M transition in HT-29 human colon cancer cells . KMF additionally inhibits the expression of various cyclins like cyclin D1 and cyclin E in breast cancer cells (Kim et al., 2016) , cyclin B1 in gastric cancer cells and renal cell carcinoma (Song et al., 2014 cyclin D, cyclin E and cyclin A in colon cancer cells and cyclin-dependent kinases like CDK4 and CDK2 . KMF treatment has also been known to up-regulate the CDK inhibitors including p21 and p27 (Fig. 4) . Furthermore, results of these studies demonstrate that KMFdependent arrest of G0/G1 or G2/M transition is possibly due to inhibition of epidermal growth factor receptor (EGFR) activity, hexokinase-2 expression (Yao et al., 2016) , inhibition of the activity of estrogen (Kim et al., 2016) or uptake of glucose (Azevedo et al., 2015) . Of note, growth factors, hormones, glucose and hexokinases are positive regulators of cell cycle. A large body of evidence indicates that KMF induces cancer cells apoptosis by activating the apoptosis-related signaling pathways (Fig. 5) . Xu, Liu, Li, Wu, and Liu (2008) have indicated mitochondria in human cervical cancer cells (Hela cells) and HEK293 cells (embryonic kidney cells) as the source of KMF-dependent activation of intrinsic apoptotic signaling (Xu et al., 2008) . Further, studies by Kang et al. (2009) have substantiated that KMF could cause apoptosis MCF-7 breast cancer cells with estrogen receptor (ER) by activating intrinsic apoptosis signaling pathway and by downregulation of PLK1 expression (Kang et al., 2009) . Similarly, have shown that in gastric cancer cells KMF decreases the expression level of an anti-apoptotic protein Bcl 2 on the mitochondrial membrane and concomitant induction of pro-apoptotic protein Bax release from mitochondria . Very recently, by utilizing a number of cancer cell lines, including human breast carcinoma (MCF-7) cells, human stomach carcinoma (SGC-7901) cells, human cervical carcinoma (Hela) cells and human lung carcinoma (A549) cells Laio et al. have attested that mitochondrial dysfunction is the major reason of KMF-dependent apoptosis induction in these cancer cells (Liao et al., 2016) . How-ever, a number of other independent studies claimed that TNF cognate apoptosis-inducing ligand (TRAIL) is related to KMFdependent apoptosis in cancer cells. Of note, the proinflammatory cytokine TNF-a, and TRAIL are cognate to the activation of extrinsic apoptosis signaling pathway. For example, Yoshida et al. (2008) , have shown that KMF-dependent apoptosis in colon cancer cell lines is mediated by inducing TRAIL (Yoshida et al., 2008) . Likewise, TRAIL-KMF, mediated apoptosis is the result of suppression of survivin in human glioma cells (Siegelin, Reuss, Habel, Herold-Mende, & von Deimling, 2008) . Besides, KMF may also affect and inhibit various pro-survival molecules, i.e. Akt, PI(3)K, ERK 1/2 in the downstream signaling pathways (Kim et al., 2016; Kuo et al., 2015) . KMF also suppresses cancer metastasis in osteosarcoma cells and induces autophagy (programmed cell survival) in human hepatic cancer cells (Huang et al., 2013) . It has been shown that carcinoma cells activate AMP-activated protein kinase-dependent autophagy as the survival response to KMF-mediated energetic impairment (Filomeni et al., 2010) . In summary, KMF decreases the number of various cancer cells through a multiprong mechanisms that include the arrest of the cell cycle, activation of proapoptotic proteins, inhibition of antiapoptotic proteins and by attenuating the phosphorylation and activity of prosurvival proteins (e.g. Akt) and activation of programmed cell survival or autophagy. 

Cancer cells exhibit high metabolic rate to fulfil their energy requirements that in turn is found to be associated with the neovascularization (angiogenesis). A number of studies have reported the involvement of a variety of transcriptional (ERK 1/2, Akt, and MAPK) and growth factors (VEGF and FGF) in the tumour microenvironment for the neovascularization (Kashyap, Rajkumar Mondal, Tuli, Gaurav Kumar, & Sharma, 2016; Kashyap, Sonam Mittal, Sak, Singhal, & Tuli, 2016; Kumar, Mittal, Sak, & Tuli, 2016; Tuli, Sandhu, Sharma, & Gandhi, 2014) . These factors are being targeted as therapeutic approach for the cure of cancer in advanced stages (Fig. 6) . Treatment of Huh7 cell with KMF under hypoxic (low oxygen tension) condition inhibits the HIF-1a protein through the inactivation of p44/42 MAPK pathways which could be possible ways of cancer inhibition (Mylonis, Lakka, Tsakalof, & Simos, 2010) . In a study conducted by Luo et al. (2009) using human ovarian cancer cells, they suggested that KMF can inhibit angiogenesis significantly by altering the VEGF expression through both HIF dependent and independent (ESRRA) pathways (Luo et al., 2009) . In context to their previous studies Luo et al. (2012a Luo et al. ( , 2012b and Luo, Rankin, Juliano, Jiang, and Chen (2012) further proposed a novel angio-prevention mechanism of KMF via down-regulation of ERK-NFjB-cMyc-p21-VEGF signaling pathway (Luo et al., 2012a (Luo et al., , 2012b Luo, Rankin, et al., 2012) . In in vitro (HUVECs model) and in vivo studies (zebrafish model), Liang et al. (2015) demonstrated the anti-angiogenic effect of KMF via VEGF and FGF angiogenic promoters inactivation that are further known to interact with tyrosine kinase-associated angiogenic receptors. Fig. 6 summarizes the various above discussed molecular targets of KMF in the inhibition of cancer angiogenesis and further research is required to explore the remaining details of its mechanisms of action. 

Metastasis is considered as a hallmark of uncontrolled proliferation of the tumour cells at primary site followed by the invasion to the nearby tissue and invasion to the distant organs via bloodstream. The EMT proteins (Epithelial-Mesenchymal-Transitions), such as E-cadherin, vimentin, fibronectin, matrix metalloproteases (MMPs) are known to play a paramount role in the process of metastasis by trailing the cell-cell contacts (Short, Suarez-Zayas, & Gomez, 2016; Tulotta et al., 2016; Zhu, Guo, Wu, & Wei, 2016) . Therefore, EMT proteins are considered as promising targets to combat tumour metastasis. The STAT3 is another most widely studied transcription factor associated with cancer metastasis and survival which has been found to be suppressed by KMF treatment in human prostate cancer cells (DU145) (Kwon, Kang, Kang, & Yoon, 2010) . In a study by Chen et al. (2013) , the anti-metastatic effect of KMF in human osteosarcoma cells (OS) was investigated by inhibiting the DNA binding activity of a transcription factor called activator protein (AP-1) which resulted in reduced expression of MMP-2 & 9 . Moreover, the other associated molecules, including ERK 1/2 and p38 were also found to be down-regulated under KMF treatment (Fig. 6) . Similarly, ERK 1/2mediated down-regulation of MMPs has observed in KMF-treated human tongue squamous cancer cells (SCC4) (Lin et al., 2013) . In another study, KMF suppressed the transforming growth factor-b1 (TGF-b1) induced human non-small cell lung cancer (NSCLC, A549) transition from epithelial-to-mesenchymal (EMT) and migration by abolishing Akt1-mediated Smad3 phosphorylation (Eunji, Park, Choi, Jeon, & Kim, 2015) . Correspondingly, Hang, Zhao, Chen, Sun, and Zhang (2015) observed the modulation of EMT-cognate proteins, including E-cadherin and vimentin in KMF-treated non-minuscule lung cancer cells (Hang et al., 2015) .

Inflammation is known to be adopted by the tissues against various endogenous and exogenous pathogens. However, chronic inflammation has been considered to be associated with the progression of various diseases, including cancer, arthritis, and neurodegeneration (Tuli, Chaudhary, Beniwal, & Sharma, 2015; Tuli, Kashyap, Bedi, et al., 2015; . KMF has been proven to be a potent inhibitor of proinflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (Kong, Luo, Li, Zhou, & He, 2013a , 2013b Liu, Xiao, & Fang, 2014) . The anti-inflammatory mechanisms of KMF are mainly mediated (Fig. 7) by the down-regulation of several transcription factors, such as NF-jB (nuclear factor kappa B) and STAT that have ability to stimulate the activation of inflammatory molecules (Hamalainen, Nieminen, Vuorela, Heinonen, & Moilanen, 2007) . Garcia-Mediavilla et al. (2007) examined the anti-inflammatory potential of KMF in the human hepatocyte-derived cell line and proved that KMF was able to reduce the expression of C-reactive protein (CRP), COX-2, and iNOS via alterations in NF-jB pathway. Osteopontin (OPN), a reactive oxygen species (ROS)-dependent cytokine, which engenders and activates the p38 MAPK and NF-jB signaling, has been found to be down-regulated in aldosterone-induced human umbilical vein endothelial cells (HUVECs) by KMF (Liu et al., 2014) . Comparably, KMF treatment in lipopolysaccharide (LPS)-induced macrophages revealed the consequential down-regulation of COX-2, iNOS and TNF-a (tumour necrosis factor-a) both at transcriptional and translational levels via inhibition of NF-jB and AP-1 transcription factor (Kim, Kim, Moh, & Kang, 2015; Kim, Park, et al., 2015) . Moreover, the protein Fig. 6 . This figure summarized the KMF-mediated anti-angiogenic and anti-metastatic effects. HIF-1a which initiates neovascularization under hypoxic condition in tumour is found to be inhibited by the KMF. VEGF and its receptor VEGFR mediated activation of endothelia cells are also attenuated in the presence of KMF. Furthermore, KMF inhibits the Akt/mTOR/p07S6K, a well resolved signaling pathways in the neovascularization during the tumour progression. It also inhibits the STAT3 or its phosphorylation that have been required for the signaling cascades via HIF-1a activation. Inflammatory mediators like iNOS which activates the VEGF are noticed as down-regulated by KMF. Moreover KMF also inhibits the MMPs (MMP 2 & 9) via inhibition of MAPK/Akt pathways, both of these enzymes are important for the ECM remodelling during the cancer progression and facilitate the cancer metastasis. kinase cascade mechanisms governed by Src, Syk, IRAK1, and IRAK4 that are usually involved in the activation of NF-jB and AP-1 transcriptional factors can also be blocked by KMF. The docking studies have substantiated the homogeneous binding energies of KMF as that of MG-132 which is considered to be a potent NF-jB inhibitor (Kadioglu, Nass, Saeed, Schuler, & Efferth, 2015) . Therefore, evidences are suggesting that KMF may have great potential as an anti-inflammatory drug and could be introduced for in vivo trial.

Reactive Oxygen Species (ROS) generated by enzymatic reactions during metabolism are the major source of harmful oxidative stress (Adegoke & Forbes, 2015; Hazra, Sarma, & Sanyal, 2004) . Although human body has antioxidant enzymes as a defenses mechanism that constantly neutralizes the ROS, the excess concentrations of ROS become fatal and cause cellular dysfunction, oxygen toxicity, senescent, stroke, autoimmune diseases, cancer, Parkinson's disease, infection and arteriosclerosis (Adegoke & Forbes, 2015; Melo et al., 2015) . Studies have been performed using various funtional foods with antioxidant agents that may be availed to dispense ROS (Gao, Yang, & Xu, 1999; Kim et al., 2003) . These results showed that flavonols could be effective secondary metabolites against oxidative stress (Yoshida et al., 2008) . KMF directly scavenges peroxynitrite (reactive nitrogen species) and hydroxyl radicals at low concentration whereas at high concentrations it enhances the expression of antioxidant enzymes (Calderon-Montano et al., 2011) . The proposed mechanisms of action of KMF as a potent antioxidant have been reported to be associated with its up-regulatory effect on antioxidant response elements (ARE)-mediated antioxidative enzymes (Fig. 8) , such as heme oxygenase, catalase and superoxide dismutases (SODs) under the control of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathways (Saw et al., 2014) . KMF can also be utilized in the inhibition of platelet aggregation and LDL (Low-Density Lipoprotein) oxidative susceptibility (Kowalski, Samojedny, Paul, Pietsz, & Wilczok, 2005) . Choe et al. (2012) extracted and purified KMF from the roots of Rhodiola sachalinensis and anticipated its antioxidant potential (Choe et al., 2012) . Similarly, Wahab et al. (2014) extracted KMF from the beans of Cassia alata to study its antioxidant properties. KMF has additionally been found to bulwark myocardial ischemia/reperfusion (I/R) injury in rats by incrementing the calibers of SOD and decrementing the activity of P-GSK-3b . In a study, utilizing 1,2dimethyl hydrazine induced male Wistar rats, Nirmala and Ramanathan (2011) investigated that KMF treatment not only lowered down the erythrocyte lysate and thiobarbituric acid reactive substances (TBARS) but additionally up-regulated the antioxidant enzymes, including catalase, SOD, and glutathione peroxidase (Gpx) levels (Nirmala & Ramanathan, 2011) . Likewise, hepatoprotective effect of KMF glycosides has been investigated against Fig. 7 . This figure elaborates the anti-inflammatory activity of KMF. KMF prevents the proteasome degradation of IKb which forms complex with NF-rb and stops its translocation in the nucleus. It also directly prevents the translocation of the NF-rb in the nucleus and its binding to the DNA which otherwise activates the expression of various inflammatory genes. KMF inhibits the phosphorylation of the STAT6 which results in the inhibition of its translocation to nucleus thereby suppressing the activation of various inflammatory genes. carbon tetrachloride-induced liver injuries in mice by uplifting the oxidative stress scavenging potential (Wang, Sun, Jiang, Xie, & Zhang, 2015; Wang, Tang, & Zhang, 2015) . In osteoblast-like MC3T3-E1 cells, KMF inverted the antimycin A (AMA)-induced toxicity by averting the disruption of mitochondrial membrane potential and accumulation of intracellular calcium ions and ROS via P(I) 3K-Akt-CREB pathway (Choi, 2011) .

Data about phytochemicals have proved that the synergistic properties of different flavonoids may not only be utilized to enhance the potential of chemotherapeutic drugs, but also to reduce the ineluctable side effects Tuli, Kumar, Sandhu, Sharma, & Kashyap, 2015; Tuli, Sharma, Sandhu, & Kashyap, 2013) . In this scenario, KMF could act as a promising molecule to boost the therapeutic potential of the chemotherapy by refining the pharmacokinetics as well as by subsisting side effects of the therapy. A coalescence of quercetin, kaempferol and naringenin was found to be significantly more efficacious antiproliferative agent against mouse liver cancer cells Hepa-1c1c7 and human prostate cancer cells LNCaP (Campbell, King, Harmston, Lila, & Erdman, 2006) . In a study utilizing male SD rat models, Xu, Yang, Zheng, Zhu, and Zhu (2006) observed that KMF improves the pharmacokinetics of nifedipine by reducing the drug metabolic processes (Xu et al., 2006) . Similarly, the pharmacokinetics of tamoxifen has also been found to be altered by KMF via inhibition of drug metabolizing enzymes, including CYP3A (Piao, Shin, & Choi, 2008) . Besides inhibiting the activity of phase I CYPs enzymes, KMF additionally works as an inhibitor of multidrug resistance protein 1 (MDR1) or P-glycoproteins when co-administrated with etoposide and quercetin in rats and in human leukemic cells K562/A, respectively (Li, Li, & Choi, 2009; Yanqiu et al., 2013) . The neuroprotective effects of quercetin, KMF and biapigenin have been investigated against kainate and N-methyl-D-aspartate-induced neuronal cell death by Silva, Oliveira, Dias, and Malva (2008) . Utilizing ovarian cancer cell lines, Luo et al. investigated that KMF intensified the apoptotic effect of cisplatin by significantly down-regulating cmyc gene expression (Luo, Daddysman, Rankin, Jiang, & Chen, 2010) . Thus, drug combinations could co-act and potentiate the control of intricate biological disorders. Besides governing these promising pharmacological effects, KMF has additionally been known to promote other organ protective effects as summarized in Table 2 .

Although countless physiologically important functions of KMF have been described, poor bioavailability restricts its further clinical applications.

Flavonols are naturally dynamic polyphenolic compounds that are found in plants and plant-inferred nourishments of human diet. Their absorption as well as bioavailability in the blood is found to influence their ability to impact the cellular health. After intake, flavonoids undergo to metabolic processes as results of which they are enzymatically conjugated with sulphate, methyl or glycuronyl moieties. Different methodologies, including estimation of dietary intake, determination of plasma or urinary level, have been used to study the absorption and bioavailability potential of flavonoids. In the USA and Netherlands, KMF gives an important contribution to the daily consumption of flavonoids (25-33%), with a mean intake Mechanistically, KMF dissociates the Nrf2 from its repressor Keap1, prevent its degradation and facilitates its translocation to nucleus. KMF also stabilize the mitochondrial membrane potential and helps to reduce the ROS release in the cytoplasm. Decrease TNF-a, IL-6, and NF-jb, inhibit JNK and p38 protein, reduce expression of Bax and Caspase-3, increase Bcl-2 and activate ERK1/ERK2, prosurvival kinase Wistar rat 20 mg/kg Kapil et al. (2016) Activate BMP signaling pathway, induces miR-21 expression, downregulates DOCK4, 5, and 7 and antagonizes the PDGFmediated pro-migratory effect VSMC cells 50 lM Kim et al. (2015) Inhibit intrinsic and extrinsic pathways of apoptosis, and regulate SIRT1 expression Khedgikar et al. (2016) Enhance the expression of chondrogenic marker genes, such as collagen type I, collagen type X, OCN, Runx 2, Sox 9, induced ERK, and increase expression of BMP-2 ATDC5 cells 5 lM Nepal, Li, Cho, Park, and Soh (2013) 5

Neuro-protection Inhibit STAT 3, NF-kb activation, interleukin 1b, intercellular adhesion molecule 1, MMP 9, iNOS, myeloperoxidase, and TNF-a Arthritis-protection Inhibit RANKL-mediated phosphorylation of ERK 1/2, p38, JNK MAP kinases, and expressions of c-Fos and NFATc1

Mice 100 lM Lee, Lee, Sung, and Yoo (2014) Inhibit expression of MMP-1, MMP-3, COX-2, PGE2, phosphorylation of ERK-1/2, p38, JNK, and activation of NFjb RASF cells 100 lM Yoon et al. (2013) (continued on next page) of 6-10 mg/day (Hertog, Hollman, Katan, & Kromhout, 1993; Sampson, Rimm, Hollman, De Vries, & Katan, 2002) . Though, studies have been done concerning the assimilation of other flavonoids, like quercetin, the data on the bioavailability of KMF has still remained to elucidate. DeVries et al. (1998) , conducted a 7-days study by utilizing tea and onions-based diet in a group of volunteers to quantify the concentrations of KMF in plasma and urine (DeVries et al., 1998) . Their results revealed that KMF was excreted in about 2.5% of its consumed quantity which was higher than for quercetin (0.5%) after 4 h of dose ingestion. Similarly, using healthy humans as subject models, DuPont, Day, Bennett, Mellon, and Kroon (2004) have also reported the similar concentration (0.05 mM) of KMF in plasma after 4 h of intake of endive-based diet, containing up to 246 mg of KMF per kg (DuPont et al., 2004) . In another study, researchers observed the KMF excrete about 0.9% of the total consumed flavonoids from broccoli (Nielsen, Kall, Justesen, Schou, & Dragsted, 1997) . Furthermore, the absorption rate of KMF from small intestine mainly depends on the microbial hydrolysis of b-glucuronide before aglycone uptake. Rowland, Wiseman, Sanders, Adlercreutz, and Bowey (2000) , reported that variation in the gut microflora population alters the absorption rate of KMF by modulating the process of hydrolysis of conjugates and alterations in aglycone ring (Rowland et al., 2000) . Chromatographic studies revealed the presence of early absorption peak preferentially due to the absorption of kaempferol-3-glucoside. Nemeth et al. (2003) , investigated that kaempferol-3-glucoside is the most preferred substrate for lactasephlorizin hydrolase, as compared to kaempferol-3-(6-malonyl)-glu coside and kaempferol-3-glucuronide (Nemeth et al., 2003) . Being hydrophilic in nature, kaempferol-3-glucuronide is found to be absorbed directly from the small intestine. KMF glucosides are preferentially absorbed via mechanisms of active transport and deglycosylation processes as reported for quercetin absorption (Day, Gee, DuPont, Johnson, & Williamson, 2003; Day et al., 2000; Gee et al., 2000; Nemeth et al., 2003) . Hydroxylation is a phase I cytochrome P450 dependent enzymatic activity that is known to be involved in the metabolism of KMF. In a study, Nielsen, Breinholt, Justesen, Cornett, and Dragsted (1998) , investigated the hydroxylation capability of microsomes toward flavonols and flavones (Nielsen et al., 1998) . Like quercetin, KMF may also be subjected to basic phase II metabolic conjugation in accumulation with glucuronide or sulphate (Day et al., 2001) . It is essential to identify KMF metabolites to know the various circulating forms of this moiety. DuPont et al. (2004) , has observed the conjugated form of KMF metabolite i.e. kaempferol-3-glucuronide (55-80%) in the circulating plasma (DuPont et al., 2004) . Another form of metabolite subsists as kaempferol-7-sulphate which could be due to the action of human hepatocytes (Day et al., 2001) . These evidences have suggested the lesser bioavailability of KMF in the bloodstream, which needs to be improved with the aim to utilize the full therapeutic potential of KMF. Using G. biloba extractphospholipid complexes (GBP) of KMF, Chen et al. (2010) , have shown the increase in oral bioavailability of flavonoids including quercetin and KMF in a rat model (Chen et al., 2010) . Similarly, Wang, Sun, et al. (2015) and Wang, Tang, et al. (2015) , investigated that phospholipid complex (TFH-PC) of KMF may not only increase the bioavailability (172%) but also increase the solubility (22.0 folds) in comparison to total intake of flavonoids (Wang, Sun, et al., 2015; Wang, Tang, et al., 2015) . Another approach to improve the bioavailability of the therapeutically active flavonols is to explore the effect of the supplemented food matrix ingredients. So far, very limited data are reported about the effect of food ingredients on absorption and bioavailability of KMF. It has been found that the total absorption and bioavailability of flavonoids are Tsai et al. (2011) 14

Anti-fungal Reversion of resistant C. albicans by suppression of CDR1, CDR2, and MDR1

C. albicans z2003 128-256 lg/mL Shao, Zhang, Wang, Li, and Wang (2015) Foot associated with the composition of carbohydrate based food matrix. Rodriguez-Mateos, Oruna-Concha, Kwik-Uribe, Vidal, and Spencer (2012) , demonstrated that the maltitol and sucrose were found to increase and decrease the absorption of flavonoids by altering the activity of catechol-O-methyltransferase (Rodriguez-Mateos et al., 2012) . Also, the methylation of flavonoids, such as genistein and KMF, appeared to modulate the metabolism as well as transportation of these wonderful molecules. Cao, Jing, Wu, and Shi (2013) , indicated that the methylation of KMF not only enhances its transporting ability but also increases its hydrophobicity which further assists in the absorption, bioavailability, and binding affinity to both HSA (human serum albumin) and ovalbumin (Cao et al., 2013) . Furthermore, route of administration and nanotechnology-mediated implementations in the drug delivery may also ameliorate the bioavailability of KMF. In 2009, Barve et al. reported that the half-life of KMF was 3-4 h and 1-2 h, respectively, after intravenous (10 and 25 mg/kg) and oral (100 and 250 mg/kg) dosages of KMF in male SD (Sprague-Dawley) rats (Barve et al., 2009) . In a study, Luo et al. (2012a Luo et al. ( , 2012b and Luo, Rankin, et al. (2012) , observed that encapsulated poly (ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) and poly(DL-lactic acid-co-glycolic acid) drug dosages were found to be more efficacious than KMF alone (Luo et al., 2012a (Luo et al., , 2012b Luo, Rankin, et al., 2012) . Similarly, nano-suspension of KMF was found to improve its bioavailability as well as solubility by increasing the Cmax and Area under the curve (AUC 0-1 ) value (Qian et al., 2016) . Therefore, the data confirmed the significance of bioavailability and solubility of flavonoids to exert their bioactivity and indicated that improving these important pharmacokinetic parameters may probably further enhance the biological efficacy and potential physiological capacity of KMF.

Epidemiological studies about association between kaempferolrich foods intake and decrease in risk of certain types of cancer have shown the variable results depending on several factors, including population type, sample size, food composition, databases used, and other concurrent lifestyle determinants.

No association between consumption of KMF and total invasive cancer risk was found among middle-aged and older women in the Women's Health Study (Wang et al., 2009 ). However, among 66,940 women included in the Nurses' Health Study, Gates et al. observed a significant (40%) reduction in ovarian cancer incidence for the highest versus the lowest quintile of KMF intake (Gates et al., 2007) . On the other hand, a large-scale case-control study showed non-significant (21%) reduction in the incidence of ovarian cancer among women who were at highest quintile of KMF intake (Gates et al., 2009) . Similarly, a non-significant (27%) decrease in ovarian cancer risk was noted to be associated with a high KMF intake in a rather small case-control study (124 ovarian cancer cases and 696 population-based controls) conducted in the western New York (McCann, Freudenheim, Marshall, & Graham, 2003) .

In addition, there was no evidence showing a relationship between KMF intake and breast cancer risk described in the Nurses Health Study II (Adebamowo et al., 2005) , whereas a low consumption of KMF was significantly associated with decreased risk of estrogen receptor (ER) negative-neoplasias compared to ERpositive tumour among premenopausal women (Touillaud et al., 2005) . An inverse association of KMF intake with advanced stage (stage III/IV or stage IV, but not non-advanced) prostate cancer in the Netherlands Cohort Study was also described (Geybels et al., 2013) . Although there was no remarkable relationships between high KMF intake and colorectal cancer risk among women from the Nurses' Health Study and men from the Health Professionals Follow-Up Study (Lin et al., 2006) , a statistically significant reduction in the risk of advanced adenoma recurrence was observed in Polyp Prevention Trial (Bobe, Sansbury, et al., 2008) . Furthermore, consumption of higher dose of KMF was found to be protective against gastric cancer in a case-control study conducted in the Spain (Garcia-Closas, Gonzalez, Agudo, & Riboli, 1999) . KMF intake was also significantly associated with decreased risk of pancreatic cancer among current smokers (but not among never or former smokers) in the large Multiethnic Cohort Study with participants from Hawaii and California (Nothlings, Murphy, Wilkens, Henderson, & Kolonel, 2007) and among male smokers who were not consuming supplements of vitamin E or b-carotene in the a-Tocopherol, b-Carotene Cancer Prevention Study (Bobe, Weinstein, et al., 2008) . Moreover, high intakes of KMF were inversely associated with the development of lung tumour in a casecontrol study carried out in Los Angeles County, manifesting still only among tobacco smokers and not among non-smokers (Cui et al., 2008) . The data of a case-control study of lung cancer in women in Spain exhibited a non-significant association for the highest vs. lowest tertile intake of KMF (Garcia-Closas, Agudo, Gonzalez, & Riboli, 1998) .

Consequently, in the above-presented findings, consuming KMF rich diet may be related to lower cancer risk which could be feasible in specific tumour types and in certain populations. More epidemiological studies with larger cohorts are required to further investigate the potential role of kaempferol-rich foodstuffs in prevention of chronic diseases, such as cancer.

Functional foods have always been known to upgrade health benefits due to their broad spectrum of biological functions and interactions. Evidences have suggested the salutary effects of dietary KMF in plummeting the peril of lethal diseases, such as cancer. Current chemotherapeutic agents are known to pose serious health risks which could be solved by utilizing natural bioactive metabolites like KMF. However, the scientific community should always endeavour to ameliorate the potency of such wondrous molecules. As the structure of KMF revealed the availability of electron donor atoms, such as oxygen which can make the co-ordinate bond with metal atoms and resulting metal complexes of KMF may further boost its biological activity (Kashyap, Rajkumar Mondal, et al., 2016; Kashyap, Sonam Mittal, et al., 2016; . Computational implements like QSAR models can be acclimated to explore the unknown molecular interactions of KMF with recognized cellular receptors (Bose, Michael, Prashanth, & Chitraa, 2015) . Synergistic amalgamations with other promising natural bioactive molecules could also be visually perceived as another prospective of future study to enhance the therapeutic potential of KMF . Moreover, the role of KMF in modulating the expression and activity of drug metabolizing enzymes, such as CYPs could also avail the scientific communities to come forward to design novel strategies with subsisting chemotherapeutic agents (Bibi, 2008; Huang, Liangli, & Thomas, 2014; Zhang, Zheng, Zhu, Shen, & Zhu, 2006a , 2006b . Such approaches might be auxiliary in reducing the KMF-associated toxic (Canada, Watkins, & Nguyen, 1989; Silva et al., 1997) effects by lowering the requisite of active dosages. Furthermore, novel derivatives of KMF could additionally be an option to ameliorate the potency as well as dose-associated toxicity of this molecule. Rho and his colleagues have designed KMF predicated rhamnosides and purposed them as a paramount moiety in the obviation of inflammatory disorders (Rho et al., 2011) . Lower potency of a drug has also been found to be associated with its poor solubility and low bioavailability that can further be amended by utilizing the modern nanotechnology implements (Kuldeep & Ganju, 2014; Pinho, Martin, Graca, & Mariana, 2014) . Luo et al. (2012a Luo et al. ( , 2012b and Luo, Rankin, et al. (2012) , have designed a novel nano-formulation for KMF utilizing Poly DL-lactic acid-coglycolic acid, nanoparticles with amended bioavailability and cytotoxic effect against ovarian cancer (Luo et al., 2012a (Luo et al., , 2012b Luo, Rankin, et al., 2012) . Moreover, the acerbic and astringent taste of most of the flavonoids could additionally be overcome by utilizing the nanotechnology mediated encapsulation processes which may further enhance their applicability on the more astronomically immense scale in aliment items (Munin and Edwards-Levy, 2011) . Thus, KMF could prove to be a promising therapeutic agent and is certainly worth of further molecular studies.

None.

Dietary flavonols and flavonol-rich foods intake and the risk of breast cancer

Challenges and advances in quantum dot fluorescent probes to detect reactive oxygen and nitrogen species: A review

Influence of kaempferol, a flavonoid compound, on membrane-bound ATPases in streptozotocin-induced diabetic rats

The chemopreventive effect of the dietary compound kaempferol on the MCF-7 human breast cancer cell line is dependent on inhibition of glucose cellular uptake

Metabolism, oral bioavailability and pharmacokinetics of chemopreventive kaempferol in rats

Anti-cancer potential of flavonoids: Recent trends and future perspectives

In vitro anti-HIV-1 activities of kaempferol and kaempferol-7-O-glucoside isolated from Securigera securidaca

Role of cytochrome P450 in drug interactions

Dietary flavonoid and colorectal adenoma recurrence in the Polyp Prevention Trial

Flavonoid intake and risk of pancreatic cancer in male smokers (Finland)

Kaempferol inhibits Entamoeba histolytica growth by altering cytoskeletal functions

Kaempferol derivatives as a potent inhibitor of Karilysin, an important virulence factor of Tanerella forsythia

Influence of kaempferol on TGF-b1/ Smads signal path in liver tissue of mice with Schistosoma japonicum infection

A review on the dietary flavonoid kaempferol

Synergistic effects of flavonoids on cell proliferation in Hepa-1c1c7 and LNCaP Cancer Cell Lines

The toxicity of flavonoids to guinea pig enterocytes

Methylation of genistein and kaempferol improves their affinities for proteins

A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention

Kaempferol suppresses cell metastasis via inhibition of the ERK-p38-JNK and AP-1 signaling pathways in U-2 OS human osteosarcoma cells

Comparative pharmacokinetics and bioavailability studies of quercetin, kaempferol and isorhamnetin after oral administration of Ginkgo biloba extracts, Ginkgo biloba extract phospholipid complexes and Ginkgo biloba extract solid dispersions in rats

Kaempferol regulates MAPKs and NF-jB signaling pathways to attenuate LPS-induced acute lung injury in mice

Kaempferol induces cell cycle arrest in HT-29 human colon cancer cells

The antioxidant and anti-inflammatory effects of phenolic compounds isolated from the root of Rhodiola sachalinensis A

Kaempferol protects MC3T3-E1 cells through antioxidant effect and regulation of mitochondrial function

Stimulatory effect of naturally occurring flavonols quercetin and kaempferol on alkaline phosphatase activity in MG-63 human osteoblasts through ERK and estrogen receptor pathway

Dietary flavonoid intake and lung cancer -A population-based casecontrol study

Dietary compound kaempferol inhibits airway thickening induced by allergic reaction in a bovine, serum albumin-induced model of asthma

Kaempferol suppresses bladder cancer tumor growth by inhibiting cell proliferation and inducing apoptosis

Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase

Absorption of quercetin-3-glucoside and quercetin-4 0-glucoside in the rat small intestine: The role of lactase phlorizin hydrolase and the sodium-dependent glucose transporter

Human metabolism of dietary flavonoids: Identification of plasma metabolites of quercetin

Kaempferol and inflammation: From chemistry to medicine

Plasma concentrations and urinary excretion of the antioxidant flavonols querceti and kaempferol as biomarkers for dietary intake

Kaempferol-3-glucuronide, in humans

Kaempferol suppresses transforming growth Factor-b1-Induced Epithelial-to-Mesenchymal transition and migration of A549 lung cancer cells by inhibiting Akt1-mediated Phosphorylation of Smad3 at Threonine-1791

Carcinoma cells activate AMP-activated protein kinase-dependent autophagy as survival response to kaempferol-mediated energetic impairment

Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi

Intake of specific carotenoids and flavonoids and the risk of lung cancer in women in

Intake of specific carotenoids and flavonoids and the risk of gastric cancer in Spain

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

A prospective study of dietary flavonoid intake and incidence of epithelial ovarian cancer

Flavonoid intake and ovarian cancer risk in a population-based case-control study

Intestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway

Dietary flavonoid intake, black tea consumption, and risk of overall and advanced stage prostate cancer

Neuroprotection of kaempferol by autophagy in models of rotenonemediated acute toxicity: Possible implications for Parkinson's disease

Blockade of airway inflammation by kaempferol via disturbing Tyk-STAT signaling in airway epithelial cells and in asthmatic mice. Evid Based Complement

Kaempferol protects cardiomyocytes against anoxia/reoxygenation injury via mitochondrial pathway mediated by SIRT1

Induction of caspase cascade pathway by kaempferol-3-O-rhamnoside in LNCaP prostatecancer cell lines

Anti-inflammatory effects of flavonoids: Genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages

Small molecule kaempferol promotes insulin sensitivity and preserved pancreatic b-cell mass in middle-aged obese diabetic mice

Kaempferol modulates the metastasis of human non-small cell lung cancer cells by inhibiting epithelial-mesenchymal transition

Separation methods of quinonoid constituents of plants used in Oriental traditional medicines

Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherlands

Kaempferol ameliorates symptoms of metabolic syndrome by regulating activities of liver X receptor-b

Antidepressant effect of kaempferol, a constituent of saffron (Crocus sativus) petal, in mice and rats

Expression of the xenobiotic metabolizing enzyme cytochrome P450 1B1 alters anti-inflammatory activity of quercetin, kaempferol and taxifolin in macrophage and monocyte

Kaempferol induces autophagy through AMPK and AKT signaling molecules and causes G2/M arrest via downregulation of CDK1/cyclin B in SK-HEP-1 human hepatic cancer cells

A convenient method for the synthesis of Kaempferol

Distribution of kaempferol glycosides and their function in plants

Effect of kaempferol on the production and gene expression of monocyte chemoattractant protein-1 in J774.2 macrophages

Combination of quercetin and kaempferol enhances in vitro cytotoxicity on human colon cancer (HCT-116) cells. Records of Natural Products

Kaempferol is an anti-inflammatory compound with activity towards NF-jB pathway proteins

Downregulation of PLK-1 expression in kaempferol-induced apoptosis of MCF-7 cells

Kaempferol attenuates myocardial ischemic injury via inhibition of MAPK signaling pathway in experimental model of myocardial ischemiareperfusion injury

Molecular targets of gambogic acid in cancer: Recent trends and advancements

Molecular mechanisms of action of quercetin in cancer: Recent advances

Ursolic acid (UA): A metabolite with promising therapeutic potential

Kaempferol targets RSK2 and MSK1 to suppress ultraviolet radiation-induced skin cancer

Kaempferol targets Krt-14 and induces cytoskeletal mineralization in osteoblasts: A mechanistic approach

Anti-cancer effect and underlying mechanism(s) of kaempferol, a phytoestrogen, on the regulation of apoptosis in diverse cancer cell models

Treatment with kaempferol suppresses breast cancer cell growth caused by estrogen and triclosan in cellular and xenograft breast cancer models

Kaempferol inhibits vascular smooth muscle cell migration by modulating BMP-mediated miR-21 expression

Anti-oxidant activities of the extracts from the herbs of Artemisia apiacea

The dietary flavonoid kaempferol mediates anti-inflammatory responses via the Src, Syk, IRAK1, and IRAK4 molecular targets

The anti-inflammatory effect of kaempferol on early atherosclerosis in high cholesterol fed rabbits

The anti-inflammatory effect of kaempferol on early atherosclerosis in high cholesterol fed rabbits. Lipids in Health Disease

Effect of kaempferol on the production and gene expression of monocyte chemoattractant protein-1 in J774.2 macrophages

Flavonoids -Food sources and health benefits

Formulation and characterization of kaempferol nanoparticles

Molecular mechanisms underlying chemopreventive potential of curcumin: Current challenges and future perspectives

Isothiocyanates: A class of bioactive metabolites with chemopreventive potential

Radiosensitization of non-small cell lung cancer by kaempferol

Effect of Keampferol on the migration and invasion of DU145 human prostate cancer cells

Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity

Kaempferol inhibits IL-1b-stimulated, RANKL-mediated osteoclastogenesis via downregulation of MAPKs, c-Fos, and NFATc1

Total synthesis of Kaempferol and methylated Kaempferol derivatives

Enhanced bioavailability of etoposide after oral or intravenous administration of etoposide with kaempferol in rats

Neuroprotective effect of kaempferol against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease

Kaempferol identified by zebrafish assay and fine fractionations strategy from Dysosma versipellis inhibits angiogenesis through VEGF and FGF pathways

Protective effects of kaempferol against reactive oxygen species-induced hemolysis and its antiproliferative activity on human cancer cells

Kaempferol reduces matrix metalloproteinase-2 expression by downregulating ERK1/2 and the activator protein-1 signaling pathways in oral cancer cells

Flavonoid intake and colorectal cancer risk in men and women

Anti-inflammatory properties of kaempferol via its inhibition of aldosterone signaling and aldosterone-induced gene expression

Neuroprotective effect of kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-kB and STAT3 in transient focal stroke

Kaempferol enhances cisplatin's effect on ovarian cancer cells through promoting apoptosis caused by down regulation of cMyc

Kaempferol nanoparticles achieve strong and selective inhibition of ovarian cancer cell viability

Kaempferol nanoparticles achieve strong and selective inhibition of ovarian cancer. Cell viability

Kaempferol inhibits VEGF expression and in vitro angiogenesis through a novel ERK-NFjB-cMyc-p21 pathway

Kaempferol induces apoptosis in ovarian cancer cells through activating p53 in the intrinsic pathway

Kaempferol Inhibits Angiogenesis and VEGF expression through both HIF dependent and independent pathways in human ovarian cancer cells

Kaempferol alleviates insulin resistance via hepatic IKK/NF-jB signal in type 2 diabetic rats

Risk of human ovarian cancer is related to dietary intake of selected nutrients, phytochemicals and food groups

Antiplasmodial properties of kaempferol-3-o-rhamnoside isolated from the leaves of schima wallichii against chloroquine-resistant Plasmodium falciparum

Winery by-products: Extraction optimization, phenolic composition and cytotoxic evaluation to act as a new source of scavenging of reactive oxygen species

Biological activities of Kaempferol: Effect of cyclodextrins complexation on the properties of Kaempferol

Protective effects of kaempferol against cardiac sinus node dysfunction via CaMKII deoxidization

Encapsulation of natural polyphenolic compounds; a review

Occurrence, structure and taxonomic implications of Fern constituents

The dietary flavonoid kaempferol effectively inhibits HIF-1 activity and hepatoma cancer cell viability under hypoxic conditions

Deglycosylation by small intestinal epithelial cell beta-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans

Kaempferol induces chondrogenesis in A TDC5 cells through activation of ERK/BMP-2 signaling pathway

In vitro biotransformation of flavonoids by rat liver microsomes

Human absorption and excretion of flavonoids after broccoli consumption

Effect of kaempferol on lipid peroxidation and antioxidant status in 1,2-dimethyl hydrazine induced colorectal carcinoma in rats

Flavonols and pancreatic cancer risk: The multiethnic cohort study

Kaempferol stimulates gene expression of low-density lipoprotein receptor through activation of Sp1 in cultured hepatocytes

Kaempferol acts through mitogen-activated protein kinases and protein kinase B/AKT to elicit protection in a model of neuroinflammation in BV2 microglial cells

Inhibitory kinetics and mechanism of kaempferol on a-glucosidase

Effects of oral kaempferol on the pharmacokinetics of tamoxifen and one of its metabolites, 4-hydroxytamoxifen

Cyclodextrins as encapsulation agents for plant bioactive compounds

Production, characterization and evaluation of kaempferol nanosuspension for improving oral bioavailability

Kaempferol, a potential cytostatic and cure for inflammatory disorders

Flavonoids as prospective compounds for anti-cancer therapy

Kaempferol and kaempferol rhamnosides with depigmenting and antiinflammatory properties

Kaempferol has osteogenic effect in ovariectomized adult Sprague-Dawley rats

Influence of sugar type on the bioavailability of cocoa flavanols

Interindividual variation in metabolism of soy isoflavones and lignans: Influence of habitual diet on equal production by the gut microflora

Cytotoxicity of dietary flavonoids on different human cancer types

Flavonol and flavone intakes in US health professionals

The berry constituents quercetin, kaempferol, and pterostilbene synergistically attenuate reactive oxygen species: Involvement of the Nrf2-ARE signaling pathway

Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus

The roles of CDR1, CDR2, and MDR1 in kaempferol-induced suppression with fluconazole-resistant Candida albicans

Cell adhesion and invasion mechanisms that guide developing axons

The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin

Quercetin, kaempferol and biapigenin from Hypericum perforatum are neuroprotective against excitotoxic insults

Involvement of rat cytochrome 1A1 in the biotransformation of kaempferol to quercetin: Relevance to the genotoxicity of kaempferol

Kaempferol inhibits endoplasmic reticulum stress-associated mucus hypersecretion in airway epithelial cells and ovalbumin-sensitized mice

Kaempferol inhibits gastric cancer tumor growth: An in vitro and in vivo study

Kaempferol induces cell cycle arrest and apoptosis in renal cell carcinoma through EGFR/ p38 signaling

Antidepressant-like effect of kaempferol and quercitirin, isolated from opuntia ficus-indica var

Consumption of the dietary flavonoids quercetin, luteolin and kaempferol and overall risk of cancer -A review and meta-analysis of the epidemiological data

Anti-Japanese-encephalitis-viral effects of kaempferol and daidzin and their RNAbinding characteristics

Kaempferol exhibits progestogenic effects in ovariectomized rats

Effect of dietary intake of phytoestrogens on estrogen receptor status in premenopausal women with breast cancer

Kaempferol inhibits enterovirus 71 replication and internal ribosome entry site (IRES) activity through FUBP and HNRP proteins

Microbial pigments as natural color sources: Current trends and future perspectives

Molecular aspects of metal oxide nanoparticle (MO-NPs) mediated pharmacological effects

Cordycepin: A Cordyceps metabolite with promising therapeutic potential

Molecular aspects of melatonin (MLT)-mediated therapeutic effects

Apoptotic effect of cordycepin on A549 human lung cancer cell line

Pharmacological and therapeutic potential of Cordyceps with special reference to

Anti-angiogenic activity of the extracted fermentation broth of an entomopathogenic fungus, Cordyceps militaris 3936

Cordycepin: A bioactive metabolite with therapeutic potential

Imaging cancer angiogenesis and metastasis in a zebrafish embryo model

Luteolin and kaempferol from Cassia alata, antimicrobial and antioxidant activity of its methanolic extracts

Dietary intake of selected flavonols, flavones, and flavonoid-rich foods and risk of cancer in middle-aged and older women

Hepatoprotective effect of kaempferol against alcoholic liver injury in mice

Hepatoprotective effects of kaempferol 3-Orutinoside and kaempferol 3-O-glucoside from Carthamus tinctorius L. on CCl4-induced oxidative liver injury in mice

Kaempferol-7-O-beta-D-glucoside (KG) isolated from Smilax china L. rhizome induces G2/M phase arrest and apoptosis on HeLa cells in a p53-independent manner

Effect of kaempferol on the pharmacokinetics of nifedipine in rats. Zhejiang Da Xue Xue Bao Yi Xue Ban

The effects of quercetin and kaempferol on multidrug resistance and the expression of related genes in human erythroleukemic K562/A cells

Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway

Kaempferol inhibits IL-1b-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of COX-2, PGE2 and MMPs

Kaempferol sensitizes colon cancer cells to TRAIL-induced apoptosis

Neuroprotective effect of kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-jB and STAT3 in transient focal stroke

Kaempferol protects HIT-T15 pancreatic beta cells from 2-deoxy-Dribose-induced oxidative damage

Kaempferol promotes transplant tolerance by sustaining CD4+FoxP3+ regulatory T cells in the presence of calcineurin inhibitor

Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells

Effects of kaempferol and quercetin on cytochrome 450 activities in primarily cultured rat hepatocytes

Effects of kaempferol and quercetin on cytochrome 450 activities in primarily cultured rat hepatocytes. Zhejiang Da Xue Xue Bao Yi Xue Ban

Protective effects of Kaempferol against myocardial ischemia/reperfusion injury in isolated rat heart via antioxidant activity and inhibition of glycogen synthase kinase-3b

ANGPTL4 correlates with NSCLC progression and regulates Epithelial-Mesenchymal transition via ERK pathway