Chemo-preventive and therapeutic effect of the dietary flavonoid kaempferol: A comprehensive review

Full text

REVIEW
Chemo‐preventive and therapeutic effect of the dietary
flavonoid kaempferol: A comprehensive review
Muhammad Imran
1
|Abdur Rauf
2
|Zafar Ali Shah
2
|Farhan Saeed
3
|Ali Imran
3
|
Muhammad Umair Arshad
3
|Bashir Ahmad
4
|Sami Bawazeer
5
|Muhammad Atif
6
|
Dennis G. Peters
7
|Mohammad S. Mubarak
8
1
University Institute of Diet & Nutritional
Sciences, Faculty of Allied and Health
Sciences, The University of Lahore‐Pakistan
2
Department of Chemistry, University of
Swabi Anbar, Swabi, Pakistan
3
Faculty of Home and Food Sciences,
Government College University, Faisalabad,
Pakistan
4
Center of Biotechnology and Microbiology,
University of Peshawar, Peshawar, Pakistan
5
Department of EMS. Paramedic, College of
Public Health and Health Informatics, Umm
Al‐Qura University, Makkah, Saudi Arabia
6
Department of Clinical Laboratory Sciences,
College of Applied Medical Sciences, Jouf
University, Sakaka, Saudi Arabia
7
Department of Chemistry, Indiana University,
Bloomington, Indiana, USA
8
Department of Chemistry, The University of
Jordan, Amman, Jordan
Correspondence
Muhammad Imran, University Institute of Diet
and Nutritional Sciences, Faculty of Allied and
Health Sciences, The University of Lahore,
Lahore, Pakistan.
Email: mic_1661@yahoo.com
Abdur Rauf, Department of Chemistry,
University of Swabi Anbar‐23430, KPK,
Pakistan.
Email: mashaljcs@yahoo.com
Mohammad S. Mubarak, Department of
Chemistry, The University of Jordan, Amman
11942, Jordan.
Email: mmubarak@ju.edu.jo
Kaempferol, a natural flavonoid present in several plants, possesses a wide range of
therapeutic properties such as antioxidant, anticancer, and anti‐inflammatory. It has
a significant role in reducing cancer and can act as a therapeutic agent in the treat-
ment of diseases and ailments such as diabetes, obesity, cardiovascular diseases, oxi-
dative stress, asthma, and microbial contamination disorders. Kaempferol acts through
different mechanisms: It induces apoptosis (HeLa cervical cancer cells), decreases cell
viability (G2/M phase), downregulates phosphoinositide 3‐kinase (PI3K)/AKT (protein
kinase B) and human T‐cell leukemia/lymphoma virus‐I (HTLV‐I) signaling pathways,
suppresses protein expression of epithelial‐mesenchymal transition (EMT)‐related
markers including N‐cadherin, E‐cadherin, Slug, and Snail, and metastasis‐related
markers such as matrix metallopeptidase 2 (MMP‐2). Accordingly, the aim of the
present review is to collect information pertaining to the effective role of kaempferol
against various degenerative disorders, summarize the antioxidant, anti‐inflammatory,
anticancer, antidiabetic, and antiaging effects of kaempferol and to review the prog-
ress of recent research and available data on kaempferol as a protective and chemo-
therapeutic agent against several ailments.
KEYWORDS
anticancer, antidiabetic, cardioprotective, kaempferol, mechanisms of action, oxidative stress
1|INTRODUCTION
Health benefits related to consumption of fruits and vegetables
attracted the attention of researchers and investigators owing to the
presence of bioactive compounds and to their effect on human health
(Ghosh, Dey, & Saha, 2014). These compounds exert anticancer, anti-
diabetic, anti‐obesity, cardioprotective, anti‐inflammatory, antiallergic,
and antiplatelet activities (Jose, Sudhakaran, Kumar, Jayaraman, &
Variyar, 2014). Flavonoids are hydroxylated phenolic substances hav-
ing a benzo‐γ‐pyrone structure. They are widely present in plants in
response to microbial infection and are synthesized by a
phenylpropanoid pathway (Mahomoodally, Gurib‐Fakim, & Subratty,
2005). Health endorsing perspectives of flavonoids have been corre-
lated with their intake. According to estimates, the intake in humans
ranges from 20 to 1,000 mg/day, depending upon the consumption
pattern of the population (Scalbert & Williamson, 2000; Wang et al.,
Received: 27 July 2018 Revised: 24 September 2018 Accepted: 16 October 2018
DOI: 10.1002/ptr.6227
Phytotherapy Research. 2018;1–13. © 2018 John Wiley & Sons, Ltd.wileyonlinelibrary.com/journal/ptr 1

2009). As flavonoids like kaempferol are abundantly present in leafy
vegetables, apples, onions, broccoli, and berries, their consumption is
higher in all populations owing to the presence of this source in all
food guide models across the globe. Moreover, higher bioactivity
and therapeutic potential of flavonoids have been elucidated by their
higher heat stability and minor losses during cooking and frying oper-
ations. However, storage conditions alongside dietary interactions
may prove lethal for its bioavailability (Arts & Hollman, 2005; Moon,
Wang, & Morris, 2006).
Bioactivities of flavonoids depend mainly on their degree of
hydroxylation, structural class, other substitutions and conjugations,
and degree of polymerization (Heim, Tagliaferro, & Bobilya, 2002). In
addition, flavonoids exhibit antioxidant activity and neutralize the
effects of free radicals due to the presence of hydroxyl groups, and they
chelate metal ions (Kumar & Pandey, 2013). Recent epidemiological
findings suggest that higher dietary intake of flavonoid may be
inversely associated with risk of mortality (Godos, Castellano, Ray,
Grosso, & Galvano, 2018), diabetes (Liu et al., 2014), cardiovascular dis-
eases (Hooper et al., 2008), certain cancers (Grosso et al., 2017), and
depressive mood disorders (Chang et al., 2016; Godos et al., 2018).
Kaempferol (3,5,7‐trihydroxy‐2‐[4‐hydroxyphenyl]‐4H‐1‐benzopyran‐
4‐one, Figure 1) is a yellow bioactive flavonoid, which is present in
many edible plants such as tea, cabbage, broccoli, endive, kale, beans,
tomato, strawberries, leek, and grapes (Calderón‐Montaño, Burgos‐
Morón, Pérez‐Guerrero, & López‐Lázaro, 2011). As an anti‐oxidant,
kaempferol counteracts production of superoxide ions and lowers the
formation of reactive oxygen and nitrogen species. It also scavenges
Fenton‐generated hydroxyl radical, peroxynitrite, and hydroxyl radicals
(L. Wang et al., 2006). Furthermore, kaempferol suppresses the activity
of xanthine oxidase and enhances the activities of catalase, heme
oxygenase‐1, and superoxide dismutase (Heijnen, Haenen, Van Acker,
Van der Vijgh, & Bast, 2001; Klaunig & Kamendulis, 2004). Kaempferol
additionally exerts anticancer activity through several pathways such as
inhibition of angiogenesis and expression of vascular endothelial
growth factor (VEGF), induction of apoptosis, regulation of hypoxia‐
inducible factor 1‐alpha (HIF‐1α), induction of G2/M cell cycle arrest,
and caspase‐3‐dependent apoptosis (Huang et al., 2013; Kang et al.,
2010). Owing to the numerous uses of kaempferol as a chemothera-
peutic agent in the treatment of several ailments, this review focuses
on present knowledge about its effect in reducing the risk, preventing
and treating diseases (including cancer), along with its mechanisms of
action. Different databases such as MEDLINE (PubMed), Google
Scholar, Science Direct, and SciFinder have been employed to obtain
recent relevant references pertaining to the bioactivity and uses of
kaempferol as a chemotherapeutic agent by adapting the systematic
review methodology. Shown inTable 1 is a list of diseases treated with
or prevented by kaempferol, with mechanisms of action and a list of
related references.
2|HEALTH PERSPECTIVES
2.1 |Anticancer properties
Genomic DNA methylation plays a pivotal role in the progression and
development of bladder cancer. In this respect, kaempferol, as a che-
mopreventive agent, has been found to modulate DNA methylation,
to suppress the protein levels of DNA methyltransferases (DNMT3B)
and to induce 103 differential DNA methylation positions (dDMPs)
associated with genes 50 hypermethylated and 53 hypomethylated.
Additionally, it induces a premature degradation of DNMT3B by sup-
pressing the protein synthesis with cycloheximide (CHXv) (Qiu et al.,
2017). In a recent investigation, Kashafi and coworkers reported that
kaempferol (12–100 μM) induces apoptosis and cell death in HeLa
cervical cancer cells in a dose‐dependent fashion. These researchers
also found that treatment with kaempferol leads to reduction in cell
viability and downregulation of PI3K/AKT and hTERT pathways
(Kashafi, Moradzadeh, Mohamadkhani, & Erfanian, 2017). Similarly,
in MCF‐7 breast cancer cell line, research findings revealed that
kaempferol, at a dose of 25 μM, inhibits the protein expression of
EMT‐related markers including N‐cadherin, Slug, E‐cadherin, and Snail
and suppresses metastasis‐related markers such as MMP‐2, 9, cathep-
sin B, and D (Lee, Choi, & Hwang, 2017). The anti‐oncogenic role of
dietary flavonoid intake is further divulged by a meta‐analysis in which
a systematic search in electronic databases published up to June 2016
(143) was performed. The outcomes showed that the flavonoids con-
sumption has significant effect in different kinds of cancer prevention
(Grosso et al., 2017).
In human umbilical vein endothelial cells (HUVECs), Lee et al.
(2016) showed that kaempferol induces sub‐G1 phase cell population,
activates the caspase signals such as caspase‐3, ‐8, and ‐9 and triggers
apoptosis in a dose‐dependent manner. Additionally, it stimulates
death receptor signals (death receptor 4 [DR4], Fas/CD95, and DR5)
by enhancing the expressions of phosphorylated ataxia telangiectasia
mutated (ATM) and phosphorylated p53 pathways (Lee et al., 2016).
In a similar fashion, research by Liao and colleagues revealed that
kaempferol displays anticancer activity against different human cancer
cell lines, such as the human stomach carcinoma (SGC‐7901), human
breast carcinoma (MCF‐7), human lung carcinoma (A549), and human
cervical carcinoma (Liao et al., 2016). On the other hand, Tu, Bai, Cai,
and Deng (2016) showed that orally administered kaempferol, dose‐
dependently suppresses the spread of human cervical cancer by induc-
ing cell apoptosis, intracellular free calcium elevation, and mitochon-
drial membrane potential disruption (Tu et al., 2016). In HCCC9810
and QBC939 cells, kaempferol suppressed proliferation, reduced
colony formation, and induced apoptosis. Additionally, it (a) decreased
Bcl‐2 expression, (b) increased Fas, Bax expressions, (c) enhanced
cleaved‐caspase 3, cleaved‐caspase 8, cleaved‐caspase 9, and
cleaved‐PARP, (d) down‐regulated levels of phosphorylated TIMP2,
AKT, and MMP2, and (e) inhibited the number and volume of metasta-
sis foci in lung metastasis model (Qin, Cui, Yang, & Tong, 2016).
Similarly, research findings showed that kaempferol markedly sup-
presses 17β‐estradiol (E2), induces apoptosis, causes cell cycle arrest,
upregulates the expressions of bax and p21, downregulates the
expressions of cyclin E, cyclin D1, and cathepsin D. It additionally
FIGURE 1 Structure of kaempferol
2IMRAN ET AL.

TABLE 1 Health perspectives of kaempferol
Disorders Mechanisms References
Anticancer Modulation of DNA methylation, induced 103 differential DNA methylation positions
(dDMPs).
Suppression of protein levels of DNA methyltransferases (DNMT3B)
(Qiu et al., 2017).
Reduces cell viability, and down‐regulates PI3K/AKT and hTERT pathways. (Kashafi et al., 2017).
Inhibition of N‐cadherin, E‐cadherin, Slug, Snail, and MMP‐2, 9, and cathepsin B, D. (Lee et al., 2017).
Induction of sub‐G1 phase cell population.
Activation of caspase signals such as caspase‐3, ‐8, and ‐9
(Lee et al., 2016).
Reduces levels of Bcl‐2, enhances Fas and Bax expressions, and increases cleaved‐
caspase 3, cleaved‐caspase 8, cleaved‐caspase 9, and cleaved‐PARP.
Down‐regulation of phosphorylated TIMP2, AKT, and MMP2 levels.
(Qin et al., 2016).
Induction of cell apoptotic cell death, intracellular free calcium elevation, and
mitochondrial membrane potential disruption.
Tu et al., 2016
Oxidative Stress Suppresses the activity of ASK1/MAPK signaling pathways (JNK1/2 and p38). (Feng et al., 2017;
Choung et al., 2017).
Enhances the concentrations of superoxide dismutase, catalase, glutathione peroxidase,
and glutathione‐S‐transferase.
Increases plasma insulin level.
(Al‐Numair, Veeramani,
Alsaif, & Chandramohan,
2015).
Lowers aspartate aminotransferase, alanine aminotransferase, malondialdehyde (MDA).
Decreases activity of hepatic microsomal enzyme cytochrome 2E1 (CYP2E1) expression.
(Wang et al., 2015)
Enhancement of Bid, Bcl‐2, MAPK, and AIF. (Yang et al., 2014)
Increases mRNA and protein expression of Nrf2‐regulated genes. (Saw et al., 2014).
Cardiovascular
Role
Suppresses advanced glycation end products (AGEs)‐receptor.
Reduces levels of IL‐6, TNF‐α, and NF‐κB.
Activates ERK1/2 and inhibits active c‐JNK and p38 proteins.
Lowers expressions of Caspase‐3 and Bax, TUNEL positive cells.
(Suchal et al., 2017).
Reduces levels of proapoptotic proteins (Caspase‐3 and Bax), TUNEL positive cells. (Suchal, et al., 2016)
Reduces levels of cytoplasm cytochrome C, cleaved caspase‐3, lactate dehydrogenase,
and creatine kinase
Lowers tumor necrosis factor‐alpha (TNF‐α), and malondialdehyde
Zhou et al., 2015
Decreases expression of nicotinamide adenine dinucleotide phosphate‐oxidase 4 (Nox4),
OPN, NF‐κB, inhibitor of NF‐κB alpha phosphorylation (P‐IκBα), IL‐6, and alphavbeta3
(αvβ3) integrin
(Xiao et al., 2016;
Yang et al., 2014).
Antidiabetic Inhibits cell proliferation, migration, migration distance, and sprouting.
Down‐regulates the expression of PI3K
Inhibits the activation of Src, Erk1/2, and Akt1.
(Xu et al., 2017)
Lowers p62 expression, up regulated the AMPK, and down‐regulates the mTOR
phosphorylation.
(Varshney et al., 2017;
Zeng et al., 2015)
Decreases SREBP‐1c expression.
Lowers PPAR‐γ, and serum HbA1c levels.
Zeng et al., 2015)
Suppresses the phosphorylation of insulin receptor substrate‐1 (IRS‐1), IkB kinase β
(IKKβ), and IkB kinase α(IKKα).
(Luo et al., 2015;
Peng et al., 2016)
Anti‐inflammatory Inhibits the release of IL‐1β, TNF‐α,IL‐18, and IL‐6. (Tang et al., 2015)
Decreases expressions of TSLP, inhibits the up‐regulation of toll‐like receptor 4 (TLR4),
phosphorylation level of IκBα.
(Nam et al., 2017).
Suppresses myeloid differentiation factor 88 (MyD88), and NF‐κB p65 DNA binding
activity.
(Zhang et al., 2017).
Anti‐aging Improves motor coordination, and enhanced striatal dopamine. (Li & Pu, 2011).
Inhibits fibrilogenesis and secondary structural transformation of the peptide. (Sharoar et al., 2012)
Antiallergic Inhibits COX2‐mediated production of prostaglandin D2 and prostaglandin F2α.
Lowers α‐SMA expression, blocked BSA inhalation‐induced epithelial cell excrescence
and smooth muscle hypertrophy.
Dampens the antigen‐challenged activation of Syk‐phospholipase Cγ(PLCγ) pathway.
(Shin et al., 2015)
Inhibits enhancement of TNF‐αprotein levels and Th2 cytokines (IL‐4, IL‐5, and IL‐13).
Suppresses phosphorylation Akt and eosinophilia.
(Chung et al., 2015)
Inhibits Mucin gene expression and represses PQ phosphorylation of ERKs and c‐JNK. (Podder et al., 2014).
Inhibits tunicamycin‐induced ER stress and attenuates the induction of XBP‐1 and
IRE1α.
(Park et al., 2015)
Antiplatelet
aggregation
Inhibits enzymatic activities of thrombin, FXaas, and fibrin polymer formation.
Attenuates the phosphorylation of ERK1/2, p38, c‐JNK1/2, and phosphoinositide 3‐
kinase (PI3K)/PKB (AKT).
(Choi et al., 2015)
Bone disorders Induces apoptotic cell death and decreases viability of mitosis‐associated nuclear antigen
(Ki67).
Lowers levels of MMP‐3 and MMP‐13 enzymes.
(Zhu et al., 2017)
Suppresses IL‐1β‐stimulated and RANKL‐mediated osteoclast differentiation
Inhibits RANKL‐mediated phosphorylation of ERK 1/2, JNK MAP kinases, p38, and
expressions of NFATc1 and c‐Fos
(Lee et al., 2014;
Nepal et al., 2013).
Suppresses the proliferation and migration of VSMC
Activates BMP signaling pathway, down‐regulates DOCK4, 5, and 7, and induces miR‐21
expression.
(Kim et al., 2015)
(Kim et al., 2016)
(Continues)
IMRAN ET AL.3

caused reduction of the phosphorylation of AKT, IRS‐1, ERK, and
MEK1/2 in MCF‐7 breast cancer cells of in vivo xenografted mouse
model (Jo, Park, Choi, Jeon, & Kim, 2015; Kim, Hwang, & Choi,
2016). In addition, Lee and Kim (2016) reported that kaempferol
exhibits anticancer activity against different human pancreatic cancer
cell lines such as Miapaca‐2, Panc‐1, and SNU‐213 in a dose‐
dependent fashion. Moreover, it lowered viability, induced apoptosis,
inhibited migratory activity, and mediated by inhibition of ERK1/2,
EGFR‐related Src, and AKT pathways (Lee & Kim, 2016). In regulatory
T cells (Tregs), kaempferol significantly enhanced the inhibitory effect
of proliferation, increased the FOXP3 expression level, protected from
the pathological symptoms of collagen‐induced arthritis, and also
decreased the PIM1‐mediated FOXP3 phosphorylation at S422 in
rat model (Lin et al., 2015).
In human leukemia HL‐60 cells, kaempferol dose‐dependently
exhibited multiple mechanisms such as induction of DNA damage,
enhancement DNA condensation (Comet tail), reduction of
phosphate‐ataxia‐telangiectasia, protein expression associated with
DNA repair system, including phosphate‐ataxia‐telangiectasia mutated
(p‐ATM), DNA‐dependent serine/threonine protein kinase (DNA‐PK),
Rad3‐related (p‐ATR), O(6)‐methylguanine‐DNA methyltransferase
(MGMT), 14‐3‐3 proteins sigma (14‐3‐3σ), p53, and MDC1 protein
expressions, as well as enhanced protein expression of p‐H2AX and
p‐p53 (Wu et al., 2015). Similarly, findings of Azevedo et al. (2015)
highlighted the protective role of kaempferol against the proliferation
of MCF‐7 cells through inhibition of H‐deoxy‐D‐glucose (3 H‐DG)
uptake, lowering GLUT1 mRNA levels, increasing extracellular lactate
levels, and suppressing MCT1‐mediated lactate cellular uptake
(Azevedo et al., 2015). In human fibrosarcoma HT‐1080 cells,
kaempferol at a concentration of 30 μM showed significant reduction
in matrix metalloproteinase‐9 (MMP)‐9 secretion, JNK phosphoryla-
tion, and IκBαphosphorylation and inhibited phorbol‐12‐myristate‐
13‐acetate (PMA)‐induced MMP‐9 expression by blocking activation
of AP‐1 and NF‐κB (Choi et al., 2015).
In a similar fashion, treatment with kaempferol inhibited prolifera-
tion of gastric cancer cell lines MKN28 and SGC7901 through multiple
mechanisms; it (a) induced apoptotic cell death, (b) exhibited cell cycle
arrest, (c) suppressed tumor growth, (d) decreased cyclin B1, Cdk1, and
Cdc25C expressions, (e) lowered Bcl‐2 and enhanced Bax expressions,
(f) upregulated cleaved caspase‐3 and ‐9, (g) promoted Poly (ADP‐
ribose) polymerase (PARP) cleavage, and (h) decreased p‐Akt, p‐ERK
and cyclooxygenase‐2 (COX‐2) expression levels (Song et al., 2015).
Furthermore, kaempferol‐3‐O‐rhamnosidedose, a derivative of
kaempferol, suppressed cell proliferation rate, induced caspase‐
cascade pathway, upregulated the expression of caspase‐3, caspase‐
8, caspase‐9, and PARP proteins in LNCaP human prostate cancer cell
lines in a concentration‐dependent manner (Halimah et al., 2015).
Treatment of HT‐29 rat cells with different doses of kaempferol
(0–60 μmol/L) resulted in induction of apoptosis, an increase in chro-
matin condensation, and fragmentation of DNA in a dose‐dependent
manner. It also increased the levels of cleaved caspase‐3 and
caspase‐7 and cleaved PARP. Furthermore, it caused (a) enhancement
in mitochondrial membrane permeability and cytosolic cytochrome c
concentrations, (b) reduction in Bcl‐xL proteins expression, (c) increase
of the pro‐apoptotic protein Bik, (d) reduction of Akt activation and
Akt activity, (e) enhancement of mitochondrial Bad, (f) increase of
membrane‐bound FAS ligand, (g) decrease of uncleaved caspase‐8
activity, and (h) enhancement of caspase‐8 activity (Lee et al., 2014).
In a similar fashion, Cho and Park (2013) conducted a study on the
proliferation of HT‐29 cancer cells treated with different doses of
kaempferol (0–60 μmol/L). These researchers found that kaempferol
significantly decreases viable cell numbers, [
3
H] thymidine incorpora-
tion into DNA, causes G1 and G2/M cell cycle arrest, inhibits protein
expressions (cyclin A, cyclin E, cyclins D1, CDK2, CDK4), inhibits
CDK2 and CDK4 activities, and reduces phosphorylation of retino-
blastoma protein. Moreover, it lowers expressions of Cdc2, Cdc25
C`, and cyclin B1 proteins (Cho & Park, 2013).
A paper published by Yao et al. (2014) explored the inhibitory role
of kaempferol against human squamous cell carcinoma (SCC) and
SUV‐treated mouse skin. These researchers found that kaempferol
inhibits mitogen and stress‐activated protein kinase (MSK) and 90‐
kDa ribosomal S6 kinase (RSK) proteins, lowers SUV‐induced phos-
phorylation of histone H3 and c‐Fos, and attenuates SUV‐induced
phosphorylation of cAMP‐responsive element binding protein (CREB)
and histone H3 (Yao et al., 2014). On the other hand, researchers
found that kaempferol exhibits a cytotoxic effect on the proliferation
of bladder cancer cells by inducing apoptosis, causing cell cycle arrest,
inhibiting tumor growth, lowering levels of growth‐related markers,
and enhancing the expression of apoptosis markers. Moreover, it sup-
presses invasion and metastasis and downregulates the c‐Met/p38
signaling pathway (Dang et al., 2015; Nepal et al., 2013). Kaempferol
additionally reduces the viability, tumor growth, and tumor size in dif-
ferent human cancer cell lines including pharynx (FaDu cell line), met-
astatic lymph node (PCI‐15B cell line), oral cavity carcinoma (PCI‐13
cell line), and explanted FaDu cells (Swanson, Choi, Helton, Gairola,
& Valentino, 2014). Other studies verified the preventive role of
kaempferol against renal cell carcinoma (RCC) lines (786‐O and 769‐
P cells) through multiple mechanisms such as inhibition of cell growth,
induction of apoptotic cell death and cell cycle arrest, upregulation of
p21 and downregulation of cyclin B1 expressions, inhibition of
TABLE 1 (Continued)
Disorders Mechanisms References
Increases expression of the osteoblast‐activated factors RUNX‐2, BMP‐2, osterix,
collagen I, and SQSTM1/p62
Anti‐obesity Reduces expressions of lipin1, FASN, LPAATθ(lysophosphatidic acid acyltransferase),
SREBP‐1C (fatty acid synthetic proteins), and DGAT1 (triglyceride synthetic enzymes).
Blocks the mammalian target of mTOR, and phosphorylation of AKT (protein kinase B).
Attenuates C/EBPαand peroxisome proliferator‐activated receptor γ(PPARγ).
(Lee et al., 2015).
Lowers the expression of adipogenic transcription factors (Pparγ, Cebpβ, Srebp1, Rxrβ,
Lxrβ, and Rorα)
(Park et al., 2012).
4IMRAN ET AL.

activation of EGFR/p38 signaling pathways, and activation of PARP
cleavages (Song et al., 2014). Flavonoids such as kaempferol are more
promising in cancer inhibition then the flavanols owing to their struc-
tural diversity. In this context, the number of OH on the B ring influ-
ences the binding and inhibition (Debashis et al., 2017). Likewise,
observations made by Das, Majumder, and Saha (2017) concluded that
the DNA binding ability of flavonols has been attributed to their struc-
ture. Moreover, Pal, Dey, and Saha (2014) showed another mechanism
by which flavonoids may be helpful in the prevention of cancer. They
examined the catalase inhibitory activity of green tea and suggested
that its anti‐cancer property is mainly defined by ROS accumulation
due to catalase inhibition as depicted in Figure 2.
2.2 |Cardiovascular effect
A paper published by Suchal and coworkers (Suchal et al., 2017) indi-
cated that kaempferol is effective against myocardial ischemia‐
reperfusion (IR) injury in diabetic male albino Wistar rats. It markedly
decreases hyperglycemia, suppresses advanced glycation end prod-
ucts (AGEs)‐receptor for advanced glycation end products (RAGE) axis
activation, maintains hemodynamic function, preserves morphological
alterations, and normalizes oxidative stress. It additionally lowers IL‐
6, TNF‐α, and NF‐κB levels, activates ERK1/2, and inhibits c‐JNK
and p38 proteins. Likewise, kaempferol attenuated apoptosis by
reducing the expression of pro‐apoptotic proteins including caspase‐
3 and Bax and by increasing the level of antiapoptotic protein Bcl‐2.
Additionally, it enhanced the level of antiapoptotic protein (Bcl‐2). In
an earlier publication, Suchal et al. (2016) found that kaempferol (a)
lowers the expressions of IL‐6, TNF‐α, and NFκB, (b) suppresses p38
and JNK proteins, (c) activates ERK1/ERK2, (d) induces apoptosis, (e)
reduces levels of pro‐apoptotic proteins (caspase‐3 and Bax), TUNEL
positive cells, and (f) increases the level of antiapoptotic proteins
(Bcl‐2) in the IR model of myocardial injury (Suchal et al., 2016).
Hooper and coworkers conducted a meta‐analysis review to correlate
the cardiovascular protective role of flavonoids. They included data
from MEDLINE, EMBASE, and Cochrane databases that were further
processed by inclusion and exclusion validity and finally carried out
the meta‐analysis. They included 133 clinical trials and confirmed that
the dose dependent cardioprotective effect was observed for differ-
ent flavonoids (Hooper et al., 2008).
Regulation of osteopontin (OPN)‐related signaling pathways is
linked with aldosterone hormone by promoting activation of NF‐κB
in primary human umbilical vein endothelial cells (HUVECs). On the
other hand, kaempferol was found to lower production of ROS,
TNF‐α, OPN, NF‐κB, inhibitor of NF‐κB alpha phosphorylation (P‐
IκBα), IL‐6, and reduced nicotinamide adenine dinucleotide
phosphate‐oxidase 4 (Nox4), αvβ3 integrin, and P‐IκBαexpressions
(Xiao, Lu, Liu, & Luo, 2016). In a similar fashion, Zhou et al. (2015)
showed that kaempferol prevents myocardial I/R injury in rats by
decreasing the levels of TUNEL‐positive cell rate and by reducing
myocardial infarct size. It also reduces levels of cytoplasm cytochrome
C, cleaved caspase‐3, lactate dehydrogenase, creatine kinase, TNF‐α,
and malondialdehyde and improves the left ventricular developed
pressure and its maximum up/down rate (±dp/dt max). Moreover,
kaempferol increased the concentrations of glutathione/glutathione
disulfide, superoxide dismutase, phospho‐GSK‐3β(P‐GSK‐3β), and
total glycogen synthase kinase‐3β(Zhou et al., 2015).
Research findings revealed that kaempferol prevents
anoxia/reoxygenation (A/R)‐induced injury of cardiomyocytes by
increasing cell viability, lowering LDH release, reducing A/R‐induced
ROS generation, loss of Δψm, and release of cytochrome c from mito-
chondria into cytosol. Furthermore, it upregulated human silent infor-
mation regulator Type 1 expression, suppressed the A/R‐stimulated
mPTP opening, activated caspase‐3, and enhanced the expression of
Bcl‐2 (Guo et al., 2015). Similarly, it repressed the vascular smooth
muscle cell (VSMC) proliferation and migration and modulated the
microRNA expression levels and BMP4 signaling pathway. It addition-
ally induced apoptotic cell death, activated the BMP signaling path-
way, downregulated DOCK4, 5, and 7, induced miR‐21 expression,
and antagonized PDGF‐mediated pro‐migratory effect (Kim et al.,
2015). Moreover, intraperitoneal administration of streptozotocin
(STZ; 40 mg/kg BW) induced diabetes in adult male albino rats,
whereas kaempferol (100 mg/kg BW) exhibited significant reduction
in activities of total ATPases, Na(+)/K(+)‐ATPase, Ca(2+)‐ATPase, and
Mg(2+)‐ATPase in erythrocytes and tissues (Al‐Numair et al., 2015).
FIGURE 2 Anticancer mechanism illustration of kaempferol showing its effects on the MAPK Pathway, cell cycle, and angiogenesis. [Colour
figure can be viewed at wileyonlinelibrary.com]
IMRAN ET AL.5

In myocardial infarction (MI) of male Wistar rats, oral intake of
kaempferol (5, 10, and 20 mg/kg/day, i.p.) caused substantial enhance-
ment in arterial pressure, reduction in left ventricular pressure, and left
ventricular end‐diastolic pressure and increased the concentrations of
catalase, superoxide dismutase, and glutathione. Reduction in levels of
malondialdehyde, serum IL‐6, TNF‐αlevels, cardiac injury markers
(creatine kinase‐MB and lactate dehydrogenase), and Bax/Bcl‐2 ratio
were reported after treatment with kaempferol (Suchal et al., 2016a).
In a similar fashion, a group of researchers investigated the effective
role of kaempferol on the relaxation of porcine coronary artery
smooth muscle cells. These researchers found that kaempferol
increases relaxations, which are endothelium derived, produced by
exogenous NO or due to endothelium‐dependent hyperpolarization,
possibly by activation of KCa 1.1 channels (Xu, Leung, Leung, &
Man, 2015). On the other hand, Tang and colleagues investigated
the effect of kaempferol (12.5 and 25 μg/mL) on lipopolysaccharide
(LPS) plus ATP‐induced cardiac fibroblasts and showed that it signifi-
cantly suppresses the release of IL‐1β, TNF‐α,IL‐6, and IL‐18 and
inhibits the activation of Akt and NF‐κB (Tang et al., 2015).
2.3 |Antidiabetic perspective
Diabetic retinopathy is one of the most prevalent microvascular com-
plications of diabetes. In human retinal endothelial cells (HRECs), glu-
cose at a concentration of 25 mM enhances the mRNA expression
levels of placenta growth factor (PGF) and VEGF, as well as the con-
centrations of secreted VEGF and PGF. Administration of kaempferol
at the rate of 5–25 μM, under high‐glucose conditions, markedly
inhibited cell proliferation, migration distance, and growth of HRECs.
Furthermore, kaempferol suppressed the activation of Src, Erk1/2,
and Akt1 and downregulated the expression of PI3K (Xu, Zhao, Peng,
Xie, & Liu, 2017). Varshney and coworkers recently studied the
cytoprotective effect of kaempferol against palmitic acid‐induced pan-
creatic β‐cell death through modulation of autophagy via the
AMPK/mTOR signaling pathway. These researchers found that
kaempferol causes an increase in cell viability and apoptotic cell death
activities and improves the expressions of LC3 puncta and LC3‐II pro-
tein. These results suggest that kaempferol exerts a cytoprotective
role against lipotoxicity by activation of autophagy via the
AMPK/mTOR pathway (Varshney, Gupta, & Roy, 2017). Likewise,
the beneficial impact of dietary consumption of kaempferol has been
elucidated by the early meta‐analysis carried out by Liu et al. (2014).
They carried out the meta‐analysis to access relationship between dia-
betes onset and flavonoids consumption. They utilized a fixed effect
model to calculate the summary of risk and included the cohort stud-
ies from 2013. The outcomes significantly reflected the inverse asso-
ciation between flavonoids consumption and diabetes onset.
Research findings showed that treatment of diabetic rats with
kaempferol at doses of 50 and 150 mg/kg, dose‐dependently
improved blood lipids and insulin and suppressed the phosphorylation
of insulin receptor substrate‐1 (IRS‐1), IkB kinase β(IKKβ), and IkB
kinase α(IKKα) via the hepatic IKK/NF‐κB signaling pathway (Luo
et al., 2015; Peng, Zhang, Liao, & Gong, 2016). Furthermore, earlier
findings of Alkhalidy et al. (2015) indicated that kaempferol can cause
significant improvement in hyperglycemia, glucose tolerance, and
blood insulin levels in high‐fat fed obese mice. These results suggest
that kaempferol can act as an antidiabetic agent by improving periph-
eral insulin sensitivity and protecting against pancreatic β‐cell dysfunc-
tion (Alkhalidy et al., 2015). On the other hand, Zang and coworkers
found that treatment of C57BL/6J mice fed a high‐fat diet reverses
the effect of this food on parameters such as the adipose tissue, body
weight, triglyceride concentration, blood glucose level, peroxisome
proliferator‐activated receptor (PPAR‐γ), sterol regulatory element‐
binding protein (SREBP‐1c) expression, and serum HbA1c (hemoglobin
A[1c]) levels (Zang, Zhang, Igarashi, & Yu, 2015). In INS‐1E cells and
human islets, Zhang and colleagues showed that kaempferol promotes
cell viability, suppresses apoptosis, and decreases caspase‐3 activity. It
additionally prevents downregulation of antiapoptotic proteins Bcl‐2
and Akt induced by lipotoxicity. Kaempferol also improved insulin
secretion and synthesis and increased pancreatic and duodenal
homeobox‐1 (PDX‐1) expression. Furthermore, it restored activation
of protein kinase A (PKA) and production of cyclic adenosine
monophosphate (cAMP) and CREB phosphorylation and its regulated
transcriptional activity in β‐cells via upregulation of the PDX‐1/
cAMP/PKA/CREB signaling pathway (Zhang et al., 2013).
2.4 |Oxidative stress
A recent publication by Feng and coworkers indicated that kaempferol
protects against cardiac hypertrophy by lowering cardiomyocyte areas
and interstitial fibrosis, along with improving cardiac functions and
decreasing apoptosis. Kaempferol exerts this protective role by
inhibiting the ASK1/MAPK signaling pathway and by regulating oxida-
tive stress (Feng, Cao, Zhang, & Wang, 2017). In a similar fashion, a
team of scientists investigated the hepato‐protective role of
kaempferol against alcoholic liver injury in mice. These researchers
found that kaempferol can significantly lower oxidative stress and lipid
peroxidation and can improve the antioxidative defense activity. In
addition, it considerably lowers both the expression level and activity
of hepatic CYP2E1 (Wang et al., 2015). In male albino Wistar rats,
alcohol‐induced oxidative stress increases the level of γ‐glutamyl
transferase (GGT) and lowers the concentrations of enzymatic antiox-
idants such as superoxide dismutase, catalase, and glutathione perox-
idase. However, research findings revealed that treatment with
kaempferol reverses these changes (Shakya, Manjini, Hoda, &
Rajagopalan, 2014). In STZ‐induced diabetic rats, kaempferol at a dose
of 100 mg/kg BW lowered plasma glucose, thiobarbituric acid reactive
substances, lipid hydroperoxides, conjugated dienes, and levels of vita-
mins E and C. It additionally increased glutathione‐S‐transferase and
insulin plasma level (Al‐Numair et al., 2015).
Saw and coworkers studied the antioxidative stress role of
kaempferol, quercetin, and pterostilbene, alone and in combination,
in addition to the involvement of the Nrf2‐ARE signaling pathway.
These researchers showed that each of these compounds exhibited
remarkable free‐radical scavenging activity in the DPPH assay,
attenuated intracellular ROS levels, and had synergistic effects when
used in combination. Furthermore, these compounds induced antioxi-
dant response element (ARE) and improved the mRNA and protein
6IMRAN ET AL.

expression of Nrf2‐regulated genes (Saw et al., 2014). In a similar fash-
ion, Yang and colleagues investigated the therapeutic role of
kaempferol against glutamate‐treated hippocampal neuronal cells
(HT22). These researchers found that supplementation with
kaempferol at the rate of 25 μM shows substantial enhancement in cell
viability, regulation of expression levels of proteins such as Bid, Bcl‐2,
mitogen‐activated protein kinase (MAPK), and apoptosis‐inducing
factor (Yang, Kim, Jun, & Song, 2014).
In male Wistar rats, research by Haidari, Keshavarz, Shahi,
Mahboob, and Rashidi (2011) showed that kaempferol (5 mg/kg)
reduces the levels of serum uric acid and inhibits the activity of xan-
thine oxidoreductase in a dose‐dependent fashion (Haidari et al.,
2011). On the other hand, Gao and coworkers examined the antioxi-
dative and antiapoptotic properties, along with the chemo‐protective
mechanism of kaempferol. In House Ear Institute‐Organ of Corti 1
(HEI‐OC1) cells, these workers showed that kaempferol protects cells
against cisplatin‐induced apoptosis in a dose‐dependent manner.
Additionally, kaempferol‐induced HO‐1 expression protected against
cell death though the c‐Jun N‐terminal kinase (JNK) pathway and
through Nrf2 translocation. Furthermore, kaempferol enhanced the
concentration of glutathione and the expression of glutamate‐cysteine
ligase catalytic (GCLC) subunit (Gao et al., 2010). Similarly, kaempferol
protected beta cells from 2‐deoxy‐D‐ribose (dRib)‐induced oxidative
damage and suppressed dRib‐induced intracellular ROS, apoptosis,
and lipid peroxidation (Lee et al., 2010). Likewise, a group of
researchers (Lagoa et al., 2009; Qu et al., 2009) reported that supple-
mentation of kaempferol provides protection against 3‐nitropropionic
acid (NPA)‐induced neurodegeneration in Wistar rats. In addition,
kaempferol reduced motor deficit, delayed mortality, and increased
levels of glutathione and protein nitrotyrosines. Furthermore, a study
by Lopez and colleagues highlighted the preventive role of kaempferol
against nitrosative‐oxidative stress through enhancing apoptotic cell
death and PARP degradation and caspase‐9 activity (López‐Sánchez
et al., 2007).
2.5 |Anti‐inflammatory properties
Kaempferol exhibits anti‐inflammatory activity and thus has a thera-
peutic potential for the treatment of inflammatory diseases. In human
airway epithelial BEAS‐2B cells and eosinophils, kaempferol markedly
inhibited LPS‐induced eotaxin‐1 protein expression, attenuated
TNFα‐induced expression of epithelial intracellular cell adhesion
molecule‐1 and eosinophil integrin β2, and diminished TNFα‐induced
airway inflammation by attenuating monocyte chemo‐attractant
protein‐1 transcription, possibly by disturbing NF‐κB signaling (Gong,
Shin, Han, Kim, & Kang, 2012). In a similar fashion, Tang and
coworkers examined the anti‐inflammatory effect of kaempferol on
lipopolysaccharide (LPS) plus ATP‐induced cardiac fibroblasts, along
with the underlying mechanisms of action. These researchers showed
that kaempferol considerably suppresses the release of TNF‐α,IL‐1β,
IL‐6, and IL‐18 and inhibits activation of NF‐κB and Akt in LPS plus
ATP‐induced cardiac fibroblasts (Tang et al., 2015). In lipopolysaccha-
ride (LPS)‐treated RAW264.7 cells and peritoneal macrophages,
kaempferol exhibited inhibitory activity on the production of nitric
oxide (NO), COX‐2, and synthase (iNOS). It additionally reduced the
NF‐κB‐mediated enhancement of luciferase, activity, phosphorylation
of IκBα, and nuclear translocation of p50 and p65 (Jeong et al., 2014).
Recent in vivo and in vitro studies by Zhang et al. (2017) revealed
that kaempferol attenuates pulmonary edema, myeloperoxidase
activity, pulmonary capillary permeability, and numbers of inflamma-
tory cells. It additionally reduced the production of ROS and
malondialdehyde, enhanced superoxide dismutase activity, and
lowered the overproduction of IL‐1β, TNF‐α, and IL‐6. Furthermore,
it decreased H9N2 viral titer, and it inhibited the upregulation of toll‐
like receptor 4 (TLR4), phosphorylation level of IκBα, myeloid differen-
tiation factor 88 (MyD88), NF‐κB p65 DNA binding activity, NF‐κB
p65, and phosphorylation level of MAPKs. These results suggest that
kaempferol displays a protective effect on H9N2 virus‐induced inflam-
mation by suppressing TLR4/MyD88‐mediated NF‐κB and MAPKs
pathways (Zhang et al., 2017). In addition, kaempferol has been found
to (a) attenuate IL‐32‐induced monocyte differentiation to product
macrophage‐like cells, (b) decrease production and mRNA expression
of pro‐inflammatory cytokines such as thymic stromal lymphopoietin
(TSLP), IL‐1β, TNF‐α, and IL‐8, (c) inhibit the IL‐32‐induced activation
of p38 and nuclear factor‐κB in THP‐1 cells, and (d) ameliorate the
lipopolysaccharide‐induced production of the inflammatory mediators
TSLP, IL‐1β, TNF‐α,IL‐8, and nitric oxide of macrophage‐like cells dif-
ferentiated by IL‐32 (Nam, Jeong, & Kim, 2017).
In LPS‐treated macrophages, sodium nitroprusside‐(SNP)‐treated
RAW264.7 cells and peritoneal macrophages, kaempferol inhibited
the release of prostaglandin E2 (PGE2) and nitric oxide (NO), neutral-
ized production of radicals, downregulated the cellular adhesion of
U937 cells to fibronectin (FN), and diminished mRNA expression levels
of inflammatory genes TNF‐α, encoding iNOS and COX‐2. In addition,
treatment with kaempferol caused a decrease in AP‐1(c‐Fos and
c‐Jun) and NF‐κB (p50 and p65) levels and inhibited Syk, Src, and
IRAK1 (S. H. Kim et al., 2015). Furthermore, Lin et al. (2015) explored
the anti‐inflammatory role of kaempferol against collagen‐induced
arthritis in experimental rats. Results showed that kaempferol
enhances the levels of FOXP3 in T cells and decreases PIM1‐mediated
FOXP3 phosphorylation at S422 (Lin et al., 2015). Shown in Figure 3 is
the anti‐inflammatory mechanism associated with kaempferol.
2.6 |Antiaging role
In the mouse model of Parkinson's disease, 1‐methyl‐4‐phenyl‐
1,2,3,6‐tetrahydropyridine (MPTP) induces the disease, whereas
kaempferol (a) enhanced the activity of glutathione peroxidase, cata-
lase, and superoxide dismutase, (b) reduced malondialdehyde levels,
(c) improved motor coordination, (d) elevated striatal dopamine and
its metabolite levels, and (e) prevented the loss of TH‐positive neurons
in the substantia nigra (Li & Pu, 2011). In pheochromocytoma cells
(PC12), kaempferol reversed amyloid beta peptide (Abeta)‐induced
impaired performance (Roth, Schaffner, & Hertel, 1999). Similarly,
kaempferol‐3‐O‐rhamnoside exhibits an anti‐amyloidogenic Aβ42‐
mediated cytotoxicity effect through several mechanisms such as sup-
pression of fibrilogenesis and secondary structural transformation of
the peptide (Sharoar et al., 2012).
IMRAN ET AL.7

2.7 |Antiallergic effect
Shin and coworkers employed an in vitro model of dinitrophenylated
bovine serum albumin (DNP‐BSA)‐sensitized rat basophilic leukemia
(RBL‐2H3) mast cells, and an in vivo model of BSA‐challenged asth-
matic mice to explore the antiallergic effect of kaempferol. These
researchers found that kaempferol (a) markedly lowers anti‐α‐smooth
muscle actin (α‐SMA) expression, (b) inhibits COX2‐mediated produc-
tion of prostaglandin D2 and prostaglandin F2α, (c) deters the antigen‐
induced mast‐cell activation of cytosolic phospholipase A2 response
to protein kinase Cμand extracellular signal‐regulated kinase (ERK),
(d) blocks bovine serum albumin (BSA) inhalation‐induced epithelial
cell excrescence and smooth muscle hypertrophy, and (e) dampens
the antigen‐challenged activation of the Syk‐phospholipase Cγ(PLCγ)
pathway (Shin et al., 2015). In similar fashion, Park et al. (2015) studied
the inhibitory role of kaempferol in the bronchial airway and lung of
BALB/c mice sensitized with ovalbumin (OVA). They showed that
orally administrated kaempferol is greater than or equal to 10 mg/kg
inhibits mucus secretion and goblet cell hyperplasia, whereas treat-
ment with 20 μM kaempferol dampened the TGF‐βand tunicamycin
promoted MUC5AC induction. Kaempferol additionally inhibited
tunicamycin‐induced ER stress and attenuated the induction of
XBP‐1 and IRE1αin epithelial tissues of OVA‐challenged mice
(Park et al., 2015).
Chung and colleagues have recently explored the antiasthmatic
role of kaempferol through multiple mechanisms such as lowering
the elevated inflammatory cell numbers, inhibiting the enhancement
of TNF‐αprotein levels and Th2 cytokines (IL‐4, IL‐5, and IL‐13), and
suppressing the phosphorylation of Akt and eosinophilia. Moreover,
kaempferol blocks the total immunoglobulin (Ig) E levels in the serum
and bronchoalveolar lavage fluid (Chung et al., 2015). Furthermore,
kaempferol affects protection from the human Paraquat (PQ)‐exposed
bronchial epithelium BEAS‐2B cells by inhibiting mucin gene expres-
sion via NF‐κB. It additionally suppresses the PQ phosphorylation of
ERK and c‐JNK (Podder, Song, Song, & Kim, 2014). In BEAS‐2B cells
of BALB/c mice, kaempferol suppressed the lipopolysaccharide
(LPS)‐induced bronchial EMT. It exhibited a significant inhibitory effect
on the TGF‐β‐induced EMT process by reversing E‐cadherin expres-
sion and by retarding the induction of N‐cadherin and α‐smooth mus-
cle actin (α‐SMA). Kaempferol also inhibited epithelial excrescency,
collagen deposition, and goblet hyperplasia, and it suppressed TGF‐β
entailed epithelial protease‐activated receptor‐1 (Gong et al., 2014).
A study conducted by Gong et al. (2013) revealed that administra-
tion of kaempferol at less than or equal to 20 μM in BALB/c mice sen-
sitized with OVA inhibited LPS‐induced IL‐8 production through the
TLR4 activation, suppressed eotaxin‐1 induction, attenuated the
upregulated CXCR2 expression and macrophage inflammatory
protein‐2 production, and allayed the airway tissue levels of eotaxin‐
1 and eotaxin receptor CCR3 in a dose‐dependent manner. It addition-
ally suppressed the IL‐8‐inflamed Tyk2 activation and prevented acti-
vation of the STAT1/3 signaling concomitant and down‐regulated the
expression of Tyk‐inhibiting SOCS3 (Gong et al., 2013). On the
other hand, Medeiros et al. (2009) reported that kaempferol, in
BALB/c mice ovalbumin (OVA)/alum, dose‐dependently lowered the
total leukocyte and eosinophil counts in bronchoalveolar lavage fluid.
It also lowered the B220(+), CD4(+), MHC class II, CD40 molecule
expressions, inhibited mucus production, and ameliorated the airway
hyper responsiveness (AHR). Moreover, it impaired Th2 cytokine pro-
duction (IL‐5 and IL‐13) and did not induce a Th1 pattern of inflamma-
tion (Medeiros et al., 2009).
2.8 |Antiplatelet aggregation capacity
In animal models, including thrombin‐induced acute thromboembo-
lism, collagen/epinephrine, and FeCl
3
‐induced carotid arterial throm-
bus models, kaempferol markedly suppressed enzymatic activities of
thrombin, FXaas, and fibrin polymer formation. Similarly, kaempferol
attenuated the phosphorylation of ERK‐1/2, p38, c‐JNK‐1/2, and
phosphoinositide 3‐kinase (PI3K)/PKB (AKT) and protected against
FIGURE 3 Anti‐inflammatory mechanism associated with kaempferol [Colour figure can be viewed at wileyonlinelibrary.com]
8IMRAN ET AL.

thrombosis development (Choi et al., 2015). In vitro and in prolonged
in vivo thrombotic response in carotid arteries of mice, kaempferol
caused inhibited production of superoxide anion stimulated by colla-
gen, suppressed NOX activation and collagen‐induced phosphoryla-
tion of p47 (phox), and led to ROS‐dependent inactivation of SH2
domain‐containing protein tyrosine phosphatase‐2 (SHP‐2). It also
suppressed the specific tyrosine phosphorylation of key components
(Vav1, Syk, PLCγ2, and Btk) of collagen receptor signaling pathways,
and it attenuated the downstream responses, including P‐selectin
surface exposure, cytosolic calcium elevation, and integrin‐αIIbβ3
activation (Wang et al., 2015).
2.9 |Bone health promoting capacity
Effect of kaempferol on bone marrow‐derived mesenchymal stem
cells differentiation and inflammation has been recently investigated.
Results revealed that kaempferol improves cell viability and inhibits
cell apoptosis and cell proliferation induced by lipopolysaccharide
(LPS). In addition, kaempferol elevated the LPS‐induced level of
chondrogenic markers (SOX‐9, collagen II and aggrecan), and lowered
the level of matrix‐degrading enzymes,i.e., matrix metalloprotease
(MMP)‐3 and MMP‐13. These results highlight the protective effects
of kaempferol against osteoporosis and obesity (Zhu et al., 2017).
Kim et al. (2016) showed that kaempferol (10 μM) promotes the pro-
liferation, differentiation, and mineralization of osteoblasts. It addi-
tionally increased the expression of the osteoblast‐activated factors
RUNX‐2, BMP‐2, osterix, collagen I, induced autophagy, and enhanced
levels of the autophagy‐related factors beclin‐1, the conversion of
LC3‐II from LC3‐I, and SQSTM1/p62 (Kim et al., 2016). It also sup-
presses the proliferation and migration of VSMC by modulating the
microRNA expression levels and BMP4 signaling pathway, activating
the BMP signaling pathway, inducing miR‐21 expression, and down‐
regulating DOCK4, 5, and 7 (Kim et al., 2015). On the other hand,
research findings showed that kaempferol inhibits IL‐1β‐stimulated
RANKL‐mediated osteoclast differentiation. Additionally it suppresses
IL‐1β‐stimulated RANKL‐mediated phosphorylation of ERK 1/2, p38,
and JNK MAP kinases, and suppresses the expressions of NFATc1
and c‐Fos (Lee, Lee, Sung, & Yoo, 2014).
Release of inflammatory cytokines such as MMP‐1, MMP‐3, and
COX‐2 from rheumatoid arthritis synovial fibroblasts is associated
with articular bone and cartilage destruction. On the other hand,
kaempferol significantly inhibits production of nitric oxide synthase
and COX‐2 enzymes, proliferation of both unstimulated and IL‐1β‐
stimulated RASFs, formation of prostaglandin E2 (PGE2) as well as
mRNA and protein expression of MMP‐1, and MMP‐3. Moreover,
kaempferol reduced the phosphorylation of p38, ERK‐1/2,& JNK,
and activation of NF‐κB induced by IL‐1β(Gupta et al., 2013). Several
studies conducted by different investigators reported that utilization
of kaempferol (5.0 μM) against primary rat calvarial osteoblasts
enhanced the alkaline phosphatase activity and mineralization of the
cells. These studies included cytoskeletal proteins, chaperone extracel-
lular matrix protein, intracellular signaling protein, and proteins
involved in glycolysis and cell‐matrix interactions. In addition, it up‐
regulated the HSP‐70 and cytokeratin‐14 levels, and down‐regulated
the aldose reductase and caldesmon expression. In osteoblasts,
kaempferol altered cellular metabolism by slowing the polyol pathway
(Trivedi et al., 2009).
Trivedi and colleagues investigated the anti‐osteoclastogenic role
of kaempferol. They found that kaempferol in rat primary osteoblasts
markedly attenuates adipocyte formation and shows lower serum ALP
(bone turnover marker) and higher bone mineral density (BMD) in the
trabecular regions (proximal tibia, femur neck, and vertebrae) (Trivedi
et al., 2008). Furthermore, in MG‐63 cultured human osteoblasts,
kaempferol significantly enhanced the activity of alkaline phosphatase.
This process involves activation of the extracellular regulated kinase
(ERK) pathway, and activation of the estrogen receptor (ER) (Prouillet
et al., 2004).
FIGURE 4 Metabolic effect of kaempferol
indicating the mechanism associated with its
antidiabetic, anti‐obesity, cardiovascular and
oxidative damage protective perspective.
[Colour figure can be viewed at
wileyonlinelibrary.com]
IMRAN ET AL.9

2.10 |Anti‐obesity effect
Research by Lee and colleagues showed that kaempferol inhibits lipid
accumulation in adipocytes and zebrafish. It decreases the expression
levels of LPAATθ(lysophosphatidic acid acyltransferase), SREBP‐1C
(fatty acid synthetic proteins) lipin1, DGAT1 (triglyceride synthetic
enzymes), and FASN. Results also revealed that kaempferol delays cell
cycle progression from the S to G2/M phase, blocks mammalian target
of rapamycin (mTOR) and phosphorylation of AKT (protein kinase B),
and regulates cyclins in a dose‐dependent manner. In addition,
kaempferol down‐regulates the CCAAT‐enhancer binding proteins β
(C/EBPβ) and pro‐early adipogenic factors such as Krüppel‐like factors
(KLFs) 4 and 5, and up‐regulates the anti‐early adipogenic factors
(pref‐1(preadipocyte factor‐1), and KLF2). Moreover, attenuation of
late adipogenic factors such as C/EBPαand peroxisome proliferator‐
activated receptor γ(PPARγ) by kaempferol was reported (Lee et al.,
2015). On the other hand, a group of researchers confirmed the find-
ings that kaempferol plays an inhibitory role against 3T3‐L1 adipo-
cytes through multiple mechanisms such as (a) reduction of the
levels of adipogenic transcription factors (Cebpβ, Pparγ, Rxrβ, Srebp1,
Rorα, Lxrβ) and genes involved in triglyceride biosynthesis (Agpat2,
Gpd1, Dgat2) and (b) enhancement of lipolysis‐related genes (Lsr,
Tnfα, and Cel). Furthermore, kaempferol considerably repressed the
rosiglitazone‐induced PPARγtranscriptional activity (Park et al.,
2012). Displayed in Figure 4 is the metabolic effect of kaempferol indi-
cating the mechanism associated with its antidiabetic, anti‐obesity,
cardiovascular, and oxidative damage protective perspectives.
3|CONCLUSIONS
Chemo‐preventive and chemotherapeutic roles of compounds derived
from natural sources (plants and animals) have been gaining popularity
and attracting the attention of medicinal chemists, pharmacologists,
and dieticians due to the many benefits of these substances to human
health. These naturally derived compounds can also be used in the
fight against diseases such as cardiovascular disorders, cancer insur-
gence, and immune dysfunction, diabetes, oxidative stress, among
others. In addition, conventional therapies such as the use of natural
products in treating diseases, has attracted the attention of the scien-
tific and medical communities due to their lesser side effects and cost
in comparison with synthetic drugs. Kaempferol, a widely used dietary
flavonoid found in plant foods, such as tea, cabbage, broccoli, endive,
kale, beans, tomato, strawberries, leek, and grapes is considered as
one of the most abundant antioxidants in the human diet, and plays
a significant role in scavenging radicals and inflammation. Its efficacy,
a broad range of activity, and low toxicity compared with other exam-
ined compounds, make it an attractive chemical in the fight against
diseases (including cancer). In this review, we have shown through
documented research that kaempferol offers a widespread range of
preventive and therapeutic options against several diseases, along
with a description of the various mechanisms by which this compound
exerts its action. In short, this review reveals that kaempferol can be
an important complementary medicine for the prevention and treat-
ment of different illnesses, owing to its natural origin, safety, and
low cost relative to synthetic drugs. However, further studies (includ-
ing clinical trials on humans) of this natural compound are needed to
establish its efficacy and safety.
CONFLICT OF INTEREST
Authors declare no conflict of interest.
ORCID
Mohammad S. Mubarak http://orcid.org/0000-0002-9782-0835
REFERENCES
Alkhalidy, H., Moore, W., Zhang, Y., McMillan, R., Wang, A., Ali, M., …
Liu, D. (2015). Small molecule kaempferol promotes insulin sensitivity
and preserved pancreatic β‐cell mass in middle‐aged obese diabetic
mice. Journal of Diabetes Research,2015.
Al‐Numair, K. S., Chandramohan, G., Veeramani, C., & Alsaif, M. A. (2015).
Ameliorative effect of kaempferol, a flavonoid, on oxidative stress in
streptozotocin‐induced diabetic rats. Redox Report,20(5), 198–209.
Al‐Numair, K. S., Veeramani, C., Alsaif, M. A., & Chandramohan, G. (2015).
Influence of kaempferol, a flavonoid compound, on membrane‐bound
ATPases in streptozotocin‐induced diabetic rats. Pharmaceutical Biol-
ogy,53(9), 1372–1378.
Arts, I. C., & Hollman, P. C. (2005). Polyphenols and disease risk in epidemi-
ologic studies. The American Journal of Clinical Nutrition,81,
317S–325S.
Azevedo, C., Correia‐Branco, A., Araújo, J. R., Guimarães, J. T., Keating, E.,
& Martel, F. (2015). The chemopreventive effect of the dietary com-
pound kaempferol on the MCF‐7 human breast cancer cell line is
dependent on inhibition of glucose cellular uptake. Nutrition and Can-
cer,67(3), 504–513.
Calderón‐Montaño, J. M., Burgos‐Morón, E., Pérez‐Guerrero, C., & López‐
Lázaro, M. (2011). A review on the dietary flavonoid kaempferol. Mini
Reviews in Medicinal Chemistry,11(4), 298–340.
Chang, S. C., Cassidy, A., Willett, W. C., Rimm, E. B., O'Reilly, E. J., &
Okereke, O. I. (2016). Dietary flavonoid intake and risk of incident
depression in midlife and older women. The American Journal of Clinical
Nutrition,104(3), 704–714.
Cho, H. J., & Park, J. H. Y. (2013). Kaempferol induces cell cycle arrest in
HT‐29 human colon cancer cells. Journal of Cancer Prevention,18(3),
257–263.
Choi, J. H., Park, S. E., Kim, S. J., & Kim, S. (2015). Kaempferol inhibits
thrombosis and platelet activation. Biochimie,115, 177–186.
Choi, Y. J., Lee, Y. H., & Lee, S. T. (2015). Galangin and kaempferol suppress
phorbol‐12‐myristate‐13‐acetate‐induced matrix metalloproteinase‐9
expression in human fibrosarcoma HT‐1080 cells. Molecular Cell,
38(2), 151–155.
Chung, M. J., Pandey, R. P., Choi, J. W., Sohng, J. K., Choi, D. J., & Park, Y.
(2015). Inhibitory effects of kaempferol‐3‐O‐rhamnoside on
ovalbumin‐induced lung inflammation in a mouse model of allergic
asthma. International Immunopharmacology,25(2), 302–310.
Dang, Q., Song, W., Xu, D., Ma, Y., Li, F., Zeng, J., …Li, L. (2015).
Kaempferol suppresses bladder cancer tumor growth by inhibiting cell
proliferation and inducing apoptosis. Molecular Carcinogenesis,54(9),
831–840.
Das, A., Majumder, D., & Saha, C. (2017). Correlation of binding efficacies
of DNA to flavonoids and their induced cellular damage. Journal of
Photochemistry and Photobiology B: Biology,170, 256–262.
Feng, H., Cao, J., Zhang, G., & Wang, Y. (2017). Kaempferol attenuates car-
diac hypertrophy via regulation of ASK1/MAPK signaling pathway and
oxidative stress. Planta Medica,83(10), 837–845.
Gao, S. S., Choi, B.‐M., Chen, X. Y., Zhu, R. Z., Kim, Y., So, H., …Kim, B. R.
(2010). Kaempferol suppresses cisplatin‐induced apoptosis via
10 IMRAN ET AL.

inductions of heme oxygenase‐1 and glutamate‐cysteine ligase cata-
lytic subunit in HEI‐OC1 cells. Pharmaceutical Research,27(2),
235–245.
Ghosh, D., Dey, S. K., & Saha, C. (2014). Antagonistic effects of black tea
against gamma radiation‐induced oxidative damage to normal lympho-
cytes in comparison with cancerous K562 cells. Radiation and
Environmental Biophysics,53(4), 695–704.
Godos, J., Castellano, S., Ray, S., Grosso, G., & Galvano, F. (2018). Dietary
polyphenol intake and depression: Results from the Mediterranean
healthy eating, lifestyle and aging (MEAL) study. Molecules,23(5).
Gong, J. H., Cho, I. H., Shin, D., Han, S. Y., Park, S.‐H., & Kang, Y. H. (2014).
Inhibition of airway epithelial‐to‐mesenchymal transition and fibrosis
by kaempferol in endotoxin‐induced epithelial cells and ovalbumin‐
sensitized mice. Laboratory Investigation,94(3), 297–308.
Gong, J. H., Shin, D., Han, S. Y., Kim, J. L., & Kang, Y. H. (2012). Kaempferol
suppresses eosionphil infiltration and airway inflammation in airway
epithelial cells and in mice with allergic asthma. The Journal of Nutrition,
142(1), 47–56.
Gong, J. H., Shin, D., Han, S. Y., Park, S. H., Kang, M. K., Kim, J. L., & Kang,
Y. H. (2013). Blockade of airway inflammation by kaempferol via
disturbing Tyk‐STAT signaling in airway epithelial cells and in asthmatic
mice. Evidence‐based Complementary and Alternative Medicine, 2013.
Grosso, G., Godos, J., Lamuela‐Raventos, R., Ray, S., Micek, A., Pajak, A., …
Galvano, F. (2017). A comprehensive meta‐analysis on dietary flavo-
noid and lignan intake and cancer risk: Level of evidence and
limitations. Molecular Nutrition & Food Research,61(4), 1600930.
Grosso, G., Micek, A., Godos, J., Pajak, A., Sciacca, S., Galvano, F., &
Giovannucci, E. L. (2017). Dietary flavonoid and lignan intake and mor-
tality in prospective cohort studies: Systematic review and dose‐
response meta‐analysis. American Journal of Epidemiology,185(12),
1304–1316.
Guo, Z., Liao, Z., Huang, L., Liu, D., Yin, D., & He, M. (2015). Kaempferol
protects cardiomyocytes against anoxia/reoxygenation injury via mito-
chondrial pathway mediated by SIRT1. European Journal of
Pharmacology,761, 245–253.
Gupta, G. K., Kumar, A., Khedgikar, V., Gautam, J., Nagar, G. K., Gupta, V.,
…Mishra, P. R. (2013). Osteogenic efficacy enhancement of kaempferol
through an engineered layer‐by‐layer matrix: A study in ovariectomized
rats. Nanomedicine,8(5), 757–771.
Haidari, F., Keshavarz, S. A., Shahi, M. M., Mahboob, S. A., & Rashidi, M. R.
(2011). Effects of parsley (Petroselinum crispum) and its flavonol constit-
uents, kaempferol and quercetin, on serum uric acid levels, biomarkers
of oxidative stress and liver Xanthine oxidoreductase aactivity
inOxonate‐induced hyperuricemic rats. Iranian Journal of Pharmaceuti-
cal Research,10(4), 811–819.
Halimah, E., Diantini, A., Destiani, D. P., Destiani, I. S., Pradipta, H. S.,
Sastramihardja, K. L., …Hiroshi, K. (2015). Induction of caspase cascade
pathway by kaempferol‐3‐O‐rhamnoside in LNCaP prostate cancer cell
lines. Biomedical Reports,3(1), 115–117.
Heijnen, C., Haenen, G., Van Acker, F., Van der Vijgh, W., & Bast, A. (2001).
Flavonoids as peroxynitrite scavengers: The role of the hydroxyl
groups. Toxicology In Vitro,15(1), 3–6.
Heim, K. E., Tagliaferro, A. R., & Bobilya, D. J. (2002). Flavonoid antioxi-
dants: Chemistry, metabolism and structure‐activity relationships.
Journal of Nutritional Biochemistry,13(10), 572–584.
Hooper, L., Kroon, P. A., Rimm, E. B., Cohn, J. S., Harvey, I., Le Cornu, K. A.,
…Cassidy, A. (2008). Flavonoids, flavonoid‐rich foods, and cardiovas-
cular risk: A meta‐analysis of randomized controlled trials.
The American Journal of Clinical Nutrition,88(1), 38–50.
Huang, W. W., Tsai, S. C., Peng, S. F., Lin, M. W., Chiang, J. H., Chiu, Y. J., …
Yang, J. S. (2013). 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. Interna-
tional Journal of Oncology,42(6), 2069–2077.
Jeong, H. Y., Sung, G. H., Kim, J. H., Yoon, J. Y., Yang, Y., Park, J. G., …Cho,
J. Y. (2014). Syk and Src are major pharmacological targets of a Cerbera
manghas methanol extract with kaempferol‐based anti‐inflammatory
activity. Journal of Ethnopharmacology,151(2), 960–969.
Jo, E., Park, S. J., Choi, Y. S., Jeon, W. K., & Kim, B. C. (2015). Kaempferol
suppresses transforming growth factor‐β1–induced epithelial‐to‐
mesenchymal transition and migration of A549 lung cancer cells by
inhibiting Akt1‐mediated phosphorylation of Smad3 at threonine‐179.
Neoplasia,17(7), 525–537.
Jose, J., Sudhakaran, S., Kumar, S., Jayaraman, S., & Variyar, E. J. (2014). A
comparative evaluation of anticancer activities of flavonoids isolated
from Mimosa pudica,Aloe vera and Phyllanthus niruri against human
breast carcinoma cell line (MCF‐7) using MTT assay. International
Journal of Pharmacy and Pharmaceutical Sciences,6(2), 319–322.
Kang, J. W., Kim, J. H., Song, K., Kim, S. H., Yoon, J. H., & Kim, K. S. (2010).
Kaempferol and quercetin, components of Ginkgo biloba extract (EGb
761), induce caspase‐3‐dependent apoptosis in oral cavity cancer cells.
Phytotherapy Research,24(1), 213–217.
Kashafi, E., Moradzadeh, M., Mohamadkhani, A., & Erfanian, S. (2017).
Kaempferol increases apoptosis in human cervical cancer HeLa cells
via PI3K/AKT and telomerase pathways. Biomedicine and Pharmaco-
therapy,89, 573–577.
Kim, I. R., Kim, S. E., Baek, H. S., Kim, B. J., Kim, C. H., Chung, I. K., …Shin, S.
H. (2016). The role of kaempferol‐induced autophagy on differentia-
tion and mineralization of osteoblastic MC3T3‐E1 cells. Evidence‐
based Complementary and Alternative Medicine,16(1), 333.
Kim, K., Kim, S., Moh, S. H., & Kang, H. (2015). Kaempferol inhibits vascular
smooth muscle cell migration by modulating BMP‐mediated miR‐21
expression. Molecular and Cellular Biochemistry,407(1‐2), 143–149.
Kim, S. H., Hwang, K. A., & Choi, K. C. (2016). Treatment with kaempferol
suppresses breast cancer cell growth caused by estrogen and triclosan
in cellular and xenograft breast cancer models. The Journal of
Nutritional Biochemistry,28,70–82.
Kim, S. H., Park, J. G., Lee, J., Yang, W. S., Park, G. W., Kim, H. G., …Cho, J.
Y. (2015). The dietary flavonoid Kaempferol mediates anti‐
inflammatory responses via the Src, Syk, IRAK1, and IRAK4 molecular
targets. Mediators of Inflammation,2015, Article ID 904142.
Klaunig, J. E., & Kamendulis, L. M. (2004). The role of oxidative stress in
carcinogenesis. Annual Review of Pharmacology and Toxicology,44,
239–267.
Kumar, S., & Pandey, A. K. (2013). Phenolic content, reducing power and
membrane protective activities of Solanum xanthocarpum root
extracts. VEGETOS: An International Journal of Plant Research,26(1),
301–307.
Lagoa, R., Lopez‐Sanchez, C., Samhan‐Arias, A. K., Gañan, C. M., Garcia‐
Martinez, V., & Gutierrez‐Merino, C. (2009). Kaempferol protects
against rat striatal degeneration induced by 3‐nitropropionic acid.
Journal of Neurochemistry,111(2), 473–487.
Lee, C. F., Yang, J. S., Tsai, F. J., Chiang, N. N., Lu, C. C., Huang, Y. S., …
Chen, F. A. (2016). Kaempferol induces ATM/p53‐mediated death
receptor and mitochondrial apoptosis in human umbilical vein endothe-
lial cells. International Journal of Oncology,48(5), 2007–2014.
Lee, G. A., Choi, K. C., & Hwang, K. A. (2017). Kaempferol, a phytoestrogen,
suppressed triclosan‐induced epithelial‐mesenchymal transition and
metastatic‐related behaviors of MCF‐7 breast cancer cells.
Environomental Toxicology and Pharmacology,49,48
–57.
Lee, H. S., Cho, H. J., Yu, R., Lee, K. W., Chun, H. S., & Park, J. H. Y. (2014).
Mechanisms underlying apoptosis‐inducing effects of Kaempferol in
HT‐29 human colon cancer cells. International Journal of Molecular
Sciences,15(2), 2722–2737.
Lee, J., & Kim, J. H. (2016). Kaempferol inhibits pancreatic cancer cell
growth and migration through the blockade of EGFR‐related pathway
in vitro. PLoS One,11(5), e0155264.
Lee, W. S., Lee, E. G., Sung, M. S., & Yoo, W. H. (2014). Kaempferol inhibits
IL‐1β‐stimulated, RANKL‐mediated osteoclastogenesis via downregu-
lation of MAPKs, c‐Fos, and NFATc1. Inflammation,37, 1221–1230.
IMRAN ET AL.11

Lee, Y. J., Choi, H. S., Seo, M. J., Jeon, H. J., Kim, K. J., & Lee, B. Y. (2015).
Kaempferol suppresses lipid accumulation by inhibiting early adipogen-
esis in 3T3‐L1 cells and zebrafish. Food & Function,6(8), 2824–2833.
Lee, Y. J., Suh, K. S., Choi, M. C., Chon, S., Oh, S., Woo, J. T., …Kim, Y. S.
(2010). Kaempferol protects HIT‐T15 pancreatic beta cells from 2‐
deoxy‐D‐ribose‐induced oxidative damage. Phytotherapy Research,
24(3), 419–423.
Li, S., & Pu, X. P. (2011). Neuroprotective effect of kaempferol against a
1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine‐induced mouse model
of Parkinson's disease. Biological and Pharmaceutical Bulletin,34(8),
1291–1296.
Liao, W., Chen, L., Ma, X., Jiao, R., Li, X., & Wang, Y. (2016). Protective
effects of kaempferol against reactive oxygen species‐induced hemoly-
sis and its antiproliferative activity on human cancer cells. European
Journal of Medicinal Chemistry,114,24–32.
Lin, F., Luo, X., Tsun, A., Li, Z., Li, D., & Li, B. (2015). Kaempferol enhances
the suppressive function of Treg cells by inhibiting FOXP3 phosphory-
lation. International Immunopharmacology,28(2), 859–865.
Liu, Y. J., Zhan, J., Liu, X. L., Wang, Y., Ji, J., & He, Q. Q. (2014). Dietary fla-
vonoids intake and risk of type 2 diabetes: A meta‐analysis of
prospective cohort studies. Clinical Nutrition,33(1), 59–63.
López‐Sánchez, C., Martín‐Romero, F. J., Sun, F., Luis, L., Samhan‐Arias, A.
K., García‐Martíne, V., & Gutiérrez‐Merino, C. (2007). Blood micromo-
lar concentrations of kaempferol afford protection against
ischemia/reperfusion‐induced damage in rat brain. Brain Research,
1182, 123–137.
Luo, C., Yang, H., Tang, C., Yao, G., Kong, L., He, H., & Zhou, Y. (2015).
Kaempferol alleviates insulin resistance via hepatic IKK/NF‐κB signal
in type 2 diabetic rats. International Immunopharmacology,28(1),
744–750.
Mahomoodally, M. F., Gurib‐Fakim, A., & Subratty, A. H. (2005). Antimicro-
bial activities and phytochemical profiles of endemic medicinal plants
of Mauritius. Pharmaceutical Biology,43(3), 237–242.
Medeiros, K., Faustino, L., Borduchi, E., Nascimento, R. J., Silva, T. M.,
Gomes, E., …Russo, M. (2009). Preventive and curative glycoside
kaempferol treatments attenuate the TH2‐driven allergic airway dis-
ease. International Immunopharmacology,9(13), 1540–1548.
Moon, Y. J., Wang, X., & Morris, M. E. (2006). Dietary flavonoids: Effects
on xenobiotic and carcinogen metabolism. Toxicology In Vitro,20,
187–210.
Nam, S.‐Y., Jeong, H.‐J., & Kim, H.‐M. (2017). Kaempferol impedes IL‐32‐
induced monocyte‐macrophage differentiation. Chemico‐Biological
Interactions,274, 107–115.
Pal, S., Dey, S. K., & Saha, C. (2014). Inhibition of catalase by tea catechins
in free and cellular state: A biophysical approach. PLoS One,9(7),
e102460.
Park, S. H., Gong, J. H., Choi, Y. J., Kang, M. K., Kim, Y. H., & Kang, Y. H.
(2015). Kaempferol inhibits endoplasmic reticulum stress‐associated
mucus hypersecretion in airway epithelial cells and ovalbumin‐
sensitized mice. PLoS One,10(11), 143526.
Park, U. H., Jeong, J. C., Jang, J. S., Sung, M. R., Youn, H., Lee, S. J., …Um, S.
J. (2012). Negative regulation of adipogenesis by kaempferol, a compo-
nent of Rhizoma Polygonati falcatum in 3T3‐L1 cells. Biological and
Pharmaceutical Bulletin,35(9), 1525–1533.
Peng, X., Zhang, G., Liao, Y., & Gong, D. (2016). Inhibitory kinetics and
mechanism of kaempferol on α‐glucosidase. Food Chemistry,190,
207–215.
Podder, B., Song, K. S., Song, H. Y., & Kim, Y. S. (2014). Cytoprotective
effect of kaempferol on paraquat‐exposed BEAS‐2B cells via modulat-
ing expression of MUC5AC. Biological and Pharmaceutical Bulletin,
37(9), 1486–1494.
Prouillet, C., Mazière, J. C., Maziere, C., Wattel, A., Brazier, M., & Kamel, S.
(2004). Stimulatory effect of naturally occurring flavonols quercetin
and kaempferol on alkaline phosphatase activity in MG‐63 human
osteoblasts through ERK and estrogen receptor pathway. Biochemical
Pharmacology,67(7), 1307–1313.
Qin, Y., Cui, W., Yang, X., & Tong, B. (2016). Kaempferol inhibits the
growth and metastasis of cholangiocarcinoma in vitro and in vivo. Acta
Biochimica et Biophysica Sinica,48(3), 238–245.
Qiu, W., Lin, J., Zhu, Y., Zeng, L., Su, M., & T ian, Y. (2017). Kaempferol mod-
ulates DNA methylation and downregulates DNMT3B in bladder
cancer. Cellular Physiology and Biochemistry,41(4), 1325–1335.
Qu, W., Fan, L., Kim, Y. C., Ishikawa, S., Iguchi‐Ariga, S. M., Pu, X. P., &
Ariga, H. (2009). Kaempferol derivatives prevent oxidative stress‐
induced cell death in a DJ‐1‐dependent manner. Journal of Pharmaco-
logical Sciences,110(2), 191–200.
Roth, A., Schaffner, W., & Hertel, C. (1999). Phytoestrogen kaempferol
(3,4′,5,7‐tetrahydroxyflavone) protects PC12 and T47D cells from
β‐amyloid–induced toxicity. Journal of Neuroscience Research,57(3),
399–404.
Saw, C. L. L., Guo, Y., Yang, A. Y., Paredes‐Gonzalez, X., Ramirez, C., Pung,
D., & Kong, A. N. (2014). The berry constituents quercetin, kaempferol,
and pterostilbene synergistically attenuate reactive oxygen species:
Involvement of the Nrf2‐ARE signaling pathway. Food and Chemical
Toxicology,72, 303–311.
Scalbert, A., & Williamson, G. (2000). Dietary intake and bioavailability of
polyphenols. The Journal of Nutrition,130, 2073S–2085S.
Shakya, G., Manjini, S., Hoda, M., & Rajagopalan, R. (2014). Hepatoprotec-
tive role of kaempferol during alcohol‐and ΔPUFA‐induced oxidative
stress. Journal of Basic and Clinical Physiology and Pharmacology,25(1),
73–79.
Sharoar, M. G., Thapa, A., Shahnawaz, M., Ramasamy, V. S., Woo, E. R.,
Shin, S. Y., & Park, I. S. (2012). Keampferol‐3‐O‐rhamnoside abrogates
amyloid beta toxicity by modulating monomers and remodeling oligo-
mers and fibrils to non‐toxic aggregates. Journal of Biomedical Science,
19(1), 104.
Shin, D., Park, S. H., Choi, Y. J., Kim, Y. H., Antika, L. D., Habibah, N. U., …
Kang, Y. H. (2015). Dietary compound Kaempferol inhibits airway
thickening induced by allergic reaction in a bovine serum albumin‐
induced model of asthma. International Journal of Molecular Sciences,
16(12), 29980–29995.
Song, H., Bao, J., Wei, Y., Chen, Y., Mao, X., Li, J., …Xue, Y. (2015).
Kaempferol inhibits gastric cancer tumor growth: An in vitro and
in vivo study. Oncology Reports,33(2), 868–874.
Song, W., Dang, Q., Xu, D., Chen, Y., Zhu, G., Wu, K., …Li, L. (2014).
Kaempferol induces cell cycle arrest and apoptosis in renal cell carci-
noma through EGFR/p38 signaling. Oncology Reports,31(3),
1350–1356.
Suchal, K., Malik, S., Gamad, N., Malhotra, R. K., Goyal, S. N., Chaudhary, U.,
…Arya, D. S. (2016). Kaempferol attenuates myocardial ischemic injury
via inhibition of MAPK signaling pathway in experimental model of
myocardial ischemia‐reperfusion injury. Oxidative Medicine and Cellular
Longevity,2016. 7580731
Suchal, K., Malik, S., Gamad, N., Malhotra, R. K., Goyal, S. N., Bhatia, J., &
Arya, D. S. (2016a). Kampeferol protects against oxidative stress and
apoptotic damage in experimental model of isoproterenol‐induced car-
diac toxicity in rats. Phytomedicine,23(12), 1401–1408.
Suchal, K., Malik, S., Khan, S. I., Malhotra, R. K., Goyal, S. N., Bhatia, J., …
Arya, D.‐S. (2017). Molecular pathways involved in the amelioration
of myocardial injury in diabetic rats by kaempferol. International Journal
of Molecular Sciences,18(5). https://doi.org/10.3390/ijms18051001
Swanson, H. I., Choi, E. Y., Helton, W. B., Gairola, C. G., & Valentino, J.
(2014). Impact of apigenin and kaempferol on human head and neck
squamous cell carcinoma. Oral Surgery, Oral Medicine, Oral Pathology,
Oral Radiology,117(2), 214–220.
Tang, X. l., Liu, J. X., Dong, W., Li, P., Li, L., Hou, J. C., …Ren, J. G. (2015).
Protective effect of kaempferol on LPS plus ATP‐induced inflammatory
response in cardiac fibroblasts. Inflammation,38(1), 94–101.
Trivedi, R., Kumar, A., Gupta, V., Kumar, S., Nagar, G. K., Romero, J. R., …
Chattopadhyay, N. (2009). Effects of Egb 761 on bone mineral density,
bone microstructure, and osteoblast function: Possible roles of querce-
tin and kaempferol. Molecular and Cellular Endocrinology,302(1), 86–91.
12 IMRAN ET AL.

Trivedi, R., Kumar, S., Kumar, A., Siddiqui, J. A., Swarnkar, G., Gupta, V., …
Chattopadhyay, N. (2008). Kaempferol has osteogenic effect in ovari-
ectomized adult Sprague‐Dawley rats. Molecular and Cellular
Endocrinology,289(1‐2), 85–93.
Tu, L. Y., Bai, H. H., Cai, J. Y., & Deng, S. P. (2016). The mechanism of
kaempferol induced apoptosis and inhibited proliferation in human cer-
vical cancer SiHa cell: From macro to nano. Scanning,38(6), 644–653.
Varshney, R., Gupta, S., & Roy, P. (2017). Cytoprotective effect of
kaempferol against palmitic acid‐induced pancreatic β‐cell death
through modulation of autophagy via AMPK/mTOR signaling pathway.
Molecular and Cellular Endocrinology,448,1–20.
Wang, L., Lee, I. M., Zhang, S. M., Blumberg, J. B., Buring, J. E., & Sesso, H.
D. (2009). Dietary intake of selected flavonols, flavones, and flavonoid‐
rich foods and risk of cancer in middle‐aged and older women.
The American Journal of Clinical Nutrition,89(3), 905–912.
Wang, L., Tu, Y. C., Lian, T.‐W., Hung, J. T., Yen, J. H., & Wu, M. J. (2006).
Distinctive antioxidant and antiinflammatory effects of flavonols.
Journal of Agricultural and Food Chemistry,54(26), 9798–9804.
Wang, M., Sun, J., Jiang, Z., Xie, W., & Zhang, X. (2015). Hepatoprotective
effect of kaempferol against alcoholic liver injury in mice. The American
Journal of Chinese Medicine,43, 241–254.
Wang, S. B., Jang, J. Y., Chae, Y. H., Min, J. H., Baek, J. Y., Kim, M., …Chang,
T. S. (2015). Kaempferol suppresses collagen‐induced platelet activa-
tion by inhibiting NADPH oxidase and protecting SHP‐2 from
oxidative inactivation. Free Radical Biology & Medicine,83,41–53.
Wu, L. Y., Lu, H. F., Chou, Y. C., Shih, Y. L., Bau, D. T., Chen, J. C., …Chung,
J. G. (2015). Kaempferol induces DNA damage and inhibits DNA repair
associated protein expressions in human promyelocytic leukemia
HL‐60 cells. The American Journal of Chinese Medicine,43, 365–382.
Xiao, H. B., Lu, X. Y., Liu, Z. K., & Luo, Z. F. (2016). Kaempferol inhibits the
production of ROS to modulate OPN–αvβ3 integrin pathway in
HUVECs. Journal of Physiology and Biochemistry,72(2), 303–313.
Xu, X., Zhao, C., Peng, Q., Xie, P., & Liu, Q. (2017). Kaempferol inhibited
VEGF and PGF expression and in vitro angiogenesis of HRECs under
diabetic‐like environment. Brazilian Journal of Medical and Biological
Research,50(3), e5396.
Xu, Y. C., Leung, S. W., Leung, G. P., & Man, R. Y. (2015). Kaempferol
enhances endothelium‐dependent relaxation in the porcine coronary
artery through activation of large‐conductance Ca(2+) ‐activated K(+)
channels. British Journal of Pharmacology,172(12), 3003–3014.
Yang, E. J., Kim, G. S., Jun, M., & Song, K. S. (2014). Kaempferol attenuates
the glutamate‐induced oxidative stress in mouse‐derived hippocampal
neuronal HT22 cells. Food & Function,5(7), 1395–1402.
Yao, K., Chen, H., Liu, K., Langfald, A., Yang, G., Zhang, Y., …Dong, Z.
(2014). Kaempferol targets RSK2 and MSK1 to suppress UV
radiation‐induced skin cancer. Cancer Prevention Research,7(9),
958–967.
Zang, Y., Zhang, L., Igarashi, K., & Yu, C. (2015). The anti‐obesity and anti‐
diabetic effects of kaempferol glycosides from unripe soybean leaves in
high‐fat‐diet mice. Food & Function,6(3), 834–841.
Zhang, Y., Zhen, W., Maechler, P., & Liu, D. (2013). Small molecule
kaempferol modulates PDX‐1 protein expression and subsequently
promotes pancreatic β‐cell survival and function via CREB. J Nutr
Biochem,24(4), 638–646.
Zhang, R., Ai, X., Duan, Y., Xue, M., He, W., Wang, C., …Liu, H. (2017).
Kaempferol ameliorates H9N2 swine influenza virus‐induced acute
lung injury by inactivation of TLR4/MyD88‐mediated NF‐κB and
MAPK signaling pathways. Biomedicine & Pharmacotherapy,89,
660–672.
Zhou, M., Ren, H., Han, J., Wang, W., Zheng, Q., & Wang, D. (2015).
Protective effects of kaempferol against myocardial
ischemia/reperfusion injury in isolated rat heart via antioxidant activity
and inhibition of glycogen synthase kinase‐3. Oxidative Medicine and
Cellular Longevity,2015.
Zhu, J., Tang, H., Zhang, Z., Zhang, Y., Qiu, C., Zhang, L., …Li, F. (2017).
Kaempferol slows intervertebral disc degeneration by modifying
LPS‐induced osteogenesis/adipogenesis imbalance and inflammation
response in BMSCs. International Immunopharmacology,43, 236–242.
How to cite this article: Imran M, Rauf A, Shah ZA, et al.
Chemo‐preventive and therapeutic effect of the dietary flavo-
noid kaempferol: A comprehensive review. Phytotherapy
Research. 2018;1–13. https://doi.org/10.1002/ptr.6227
IMRAN ET AL.13