Kaempferol and inflammation: From chemistry to medicine

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Pharmacological Research

jo u r n al ho me p a g e :ww w . e l s e v i e r . c o m / l o c a t e / y p h r s

Review

Kaempferol and inﬂammation: From chemistry to medicine

Kasi Pandima Devi a

Q1

, Dicson Sheeja Malar a , Seyed Fazel Nabavi b , Antoni Sureda c , Jianbo Xiao d,e , Seyed Mohammad Nabavi b,∗∗,1 , Maria Daglia f,∗,1

aDepartmentofBiotechnology,ScienceCampus,AlagappaUniversity,Karaikudi630004,TamilNadu,India

bAppliedBiotechnologyResearchCenter,BaqiyatallahUniversityofMedicalSciences,POBox193955487,Tehran,Iran

cResearchGrouponCommunityNutritionandOxidativeStress,UniversityofBalearicIslands,andCIBERobn(PhysiopathologyofObesityandNutrition), E-07122PalmadeMallorca,BalearicIslands,Spain

dStateKeyLaboratoryofQualityResearchinChineseMedicine,MacauUniversityofScienceandTechnology,Taipa,Macau

eInstitutfürPharmazieundLebensmittelchemie,UniversitätWürzburg,AmHubland,97074Würzburg,Germany

fDepartmentofDrugSciences,MedicinalChemistryandPharmaceuticalTechnologySection,UniversityofPavia,27100Pavia,Italy

a r t i c l e i n f o

Articlehistory:

Received1March2015

Receivedinrevisedform5May2015 Accepted6May2015

Availableonlinexxx

Keywords:

Anti-inﬂammatoryactivity Flavonoids

Kaempferol

Pro-inﬂammatorycytokines

a b s t r a c t

Inflammationisanimportantprocessofhumanhealingresponse,whereinthetissuesrespondtoinjuries inducedbymanyagentsincludingpathogens.Itischaracterizedbypain,rednessandheatintheinjured tissues.Chronicinflammationseemstobeassociatedwithdifferenttypesofdiseasessuchasarthritis, allergies,atherosclerosis,andevencancer.Inrecentyearsnaturalproductbaseddrugsareconsidered asthenoveltherapeuticstrategyforpreventionandtreatmentofinflammatorydiseases.Amongthe differenttypesofphyto-constituentspresentinnaturalproducts,flavonoidswhichoccurinmanyveg- etablefoodsandherbalmedicinesareconsideredasthemostactiveconstituent,whichhasthepotency toameliorateinflammationunderbothinvitroandinvivoconditions.Kaempferolisanaturalflavonol presentindifferentplantspecies,whichhasbeendescribedtopossesspotentanti-inflammatoryproper- ties.Despitethevoluminousliteratureontheanti-inflammatoryeffectsofkaempferol,onlyverylimited reviewarticleshasbeenpublishedonthistopic.Hencethepresentreviewisaimedtoprovideacrit- icaloverviewontheanti-inflammatoryeffectsandthemechanismsofactionofkaempferol,basedon thecurrentscientificliterature.Inaddition,emphasisisalsogivenonthechemistry,naturalsources, bioavailabilityandtoxicityofkaempferol.

1. Introduction Q2

Inﬂammationisoneofthemostimportantbiologicalresponses inthevasculartissuescausedbydifferentpathogens,irritantsor celldamages

[1,2]. Inflammation is associated with pain, redness and heat, which usually reduces the normal functions of affected tissues [3]. It is considered as a protective mechanism of living organisms against pathogen-induced tissue damage [4,5]. Inflam- mation is classified into two major groups: acute and chronic, and it is well known that chronic inflammation is associated with differ- ent diseases such as arthritis, allergy, atherosclerosis, cancer,

etc.

[6–9]. Inflammation is the consequence of immune system activation as well as unwanted immune response in which, different immune cell types such as mast cells, T cells, B cells, NK cells, and neutrophils are involved [10–14]. It has also been reported that activities of some regulatory enzymes such as protein kinase C (PKC), phosphatidylinositol kinase (PIK), phosphodiesterase, phos- pholipase A2 (PLA2), tyrosine kinases, lipoxygenases (LOX) and cyclooxygenases (COX) play important roles in the initiation and progression of inflammation and immune response [14–16]. These regulatory enzymes have a crucial role in the endothelial cell activation which is also involved in the inflammatory response [14,16].

COX is known to be one of the most important inflammatory mediators that release arachidonic acid (AA), a precursor of eicosanoids like prostaglandins and prostacyclins, which have crucial roles in the progression and regulation of inflammation [17–19]. It has also been reported that, nitric oxide synthesized by the different isoforms of the inducible nitric oxide synthase (iNOS) and phosphorylation of protein kinases also play a key role in inflammation [20,21]. Furthermore, phosphodiesterases cause cell activation

via

changing the intracellular 3

,5

-cyclic monophosphate levels through which it alters the expression of pro-inﬂammatory cytokines and chemokines [22–24].

Both steroidal and non-steroidal anti-inﬂammatory drugs are currently used for the treatment of acute inﬂammation [25,26].

However, these drugs are not entirely effective in the treatment of chronic inﬂammation and related disorders [27,28] and show adverse effects [27,29]. Therefore, the search and discovery for new effective anti-inﬂammatory substances with low adverse effects are mandatory [27].

During the last two decades, much attention has been focused on dietary products as a rich source for drug discovery and development [30–32]. Special emphasis has been given to fruits and vegetables, which are rich sources of natural bioactive compounds, that can reduce the severity of inflammatory diseases through reg- ulating the expression of pro-inflammatory cytokines as well as eicosanoid production [33–35]. Apart from fruits and vegetables, herbal medicines are also under high consideration because of their richness in natural bioactive compounds including phenols and flavonoids [31,36–39]. Based on the traditional medicinal practices, much attention has been paid in examining the biological effects of herbs, plants, especially edible species, due to their negligible adverse effects [32,40–43].

Several ﬂavonoids have been reported to suppress inﬂamma- tion both

invitro

and

invivo

[44–46]. It has been reported that ﬂavonoids reduce the production of eicosanoids through inhibi- tion of the activities of PLA2, COX and LOX [16,47–49]. In addition, ﬂavonoids are inhibitors of phosphodiesterases, protein kinases, histamine releasing, and modulators of the transcription of genes

resulting in anti-inflammatory activities [15,16,50]. Kaempferol, a flavonol widely found in different vegetables is known to be one of the most active and important natural anti-inflammatory compounds [51–54]. Though numerous scientific reports are available on the anti-inflammatory activities of kaempferol, only negligible number of review articles are available on the anti-inflammatory role of kaempferol. Therefore, in the present article, we critically review the available information on anti-inflammatory actions of kaempferol and its possible mechanisms of action.

1.1. Chemistryofkaempferol

According to Fig. 1, kaempferol contains diphenylpropane struc- ture, which is responsible for its hydrophobic property [55].

Kaempferol is synthesized through 4-coumaroyl-CoA condensa- tion with three malonyl-CoA under the catalytic action of chalcone synthase producing naringenin chalcone [55,56]. Thereafter, under the catalytic effects of chalcone isomerase, naringenin-chalcone is transformed into the flavanone called naringenin [55]. In the next step, a hydroxyl group is added to naringenin (at C3 position) to produce dihydrokaempferol, under the activity of flavanone 3-dioxygenase [55,56]. In the final step, kaempferol is produced through the introduction of a double bond at the C2–C3 position in the dihydrokaempferol skeleton by the activity of flavonol synthase [55] (Fig. 2). In plants, different sugars such as rutinose, rham- nose, glucose, and galactose are bonded to kaempferol to produce glycosidic form of kaempferol such as astragalin (kaempferol-3-O- glucoside) [55,57].

1.2. Sourcesofkaempferol

Kaempferol is widely distributed in different genera such as

Delphinium,Camellia,Berberis,Citrus,Brassica,Allium,Malus,etc.

[58–65]. In these plants, kaempferol is bonded to different glyco- side moieties [55]. It has been also identiﬁed in different medicinal plants like

Acacianilotica

(L.) Delile,

Aloevera

(L.) Burm.f.,

Crocus sativus

L.,

Euphorbiapekinensis

Rupr.,

Ginkgobiloba

L.,

Hypericum perforatum

L.,

Phyllanthusemblica

L.,

Ribesnigrum

L., and

Rosmar- inusofﬁcinalis

L, which are the most common medicinal plants which contain high amounts of kaempferol [55,66–73]. In addition, kaempferol is widely identiﬁed in different edible plants [63,72,74].

Table 1 summarizes the most important and common edible plant sources of kaempferol.

O

OH

OH HO

OH 2 3 5 4

6 7

8

2' 3'

4'

5' 6'

Fig.1.Chemicalstructureofkaempferol.

38

39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95

96 97 98 99 100 101 102 103 104

105

106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121

122

123 124 125 126 127 128 129 130 131 132 133 134

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HO O

S O

CoA

HO O

S O

CoA

HO O

S O

CoA

HO

S O

CoA

Chalconesynthase

OH

O

OH

OH HO

Chalcone isomerase

O

OH

OH HO

O

OH

OH HO

OH Flavanone3-dioxygenase

Dihydrokaempferol Naringenin

O

OH

OH HO

OH

Flavonol synthase Kaempferol

Naringenin chalcone Malonyl-CoA

4-coumaroyl-CoA

Fig.2.Biosynthesisofkaempferol.

1.3. Bioavailabilityandmetabolism

The bioavailability of ingested natural substances is corre- lated with the extent of their absorption as well as their oral clearance rates [75,76]. It is well known that factors such as per- meability, lipophilicity, uptake and efflux by transporters affect the amounts of each compound which is taken up by the mesen- teric architecture and sent to liver tissues through intestinal cells [77–79]. Kaempferol is poorly absorbed, with an extremely poor oral bioavailability and it is commonly metabolized into the forms of methyl, sulfate or glucuronide [80–82]. The efflux of kaempferol is reported to restrict its use as an anticancer agent [82,83]. How- ever, it has been reported that the combination of kaempferol with other anticancer agents increases the anticancer affinity [83].

For example, the combination of kaempferol with quercetin significantly increases the anticancer effects of quercetin through blocking the efflux of quercetin [84]. In addition, the consumption of kaempferol has been reported to significantly increase the cytotoxic effects of cisplatin [83,85]. Therefore, it can be concluded that although the bioavailability of kaempferol is very poor, it seems that, kaempferol increases the bioavailability of different anticancer drugs [83].

1.4. Toxicity

Kaempferol, as the other flavonoids, has numerous bioactivi- ties that can be beneficial or detrimental depending on specific circumstances [86]. Kaempferol is reported to possess mutagenic and genotoxic effects [87,88]. It has been well known that the genotoxic effects of kaempferol are due to its

invitro

pro-oxidant activity [89–91]. Kaempferol reduces free radicals through hydrogen dona- tion and is transformed to a phenoxyl radical [92,93]. The phenoxyl radical can react with another free radicals to show antioxidant activity and becomes a stable form and/or can interact with oxygen to show pro-oxidant effect and produce reactive oxygen species [94]. In addition, pro-oxidant activities of kaempferol has a close correlation with its capacity to reduce metals ions [95,96]. It has been reported that reduced metals produce hydroxyl radicals through Fenton reaction and cause lipid peroxidation [97,98].

Under

invivo

conditions, the pro-oxidant activity of kaempferol is mediated by regulation of the activities of antioxidant and pro- oxidant enzymes [99]. It has also been reported that transformation of kaempferol by CYP1A1 enzymes is a key factor for its mutageni- city [89,100]. Despite to numerous

invitro

studies on genotoxic and carcinogenic effects of kaempferol, there are no data from

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Family Genus Species Commonname References

Amaryllidaceae Allium Alliumcepa Onion [64]

Alliumschoenoprasum Chives [175]

Amaranthaceae

Armoracia

Armoraciarusticana Horseradish [176]

Brassicaceae

Brassicacampestris Chinesecabbage [177]

Brassicajuncea Mustard [177]

Brassica

Brassicanapus Rutabagas [178]

Brassicaoleracea Broccoli [178]

Brassicarapa Turnipgreens [179]

Lepidium Lepidiumsativum Cress [180]

Raphanus Raphanussativus Radishes [181]

Apiaceae

Angelica Angelicakeiskei Ashitaba [182]

Foeniculum Foeniculumvulgare Fennel [183]

Levisticum Levisticumofﬁcinale Lovage [180]

Petroselinum Petroselinumcrispum Parsley [184]

Asteraceae Lactuca Lactucasativa Lettuce [185]

Amaranthaceae Spinacia Spinaciaoleracea Spinach [186]

Fabaceae

Vigna Vignaunguiculata Cowpea [187]

Vicia Viciafaba Broadbeans [188]

Phaseolus Phaseolusvulgaris Greenbeans [189]

Rosaceae

Rubus Rubusfruticosus Blackberries [190]

Rubusidaeus Raspberry [72]

Fragaria Fragariavesca Strawberry [191]

Malus Malusdomestica Apple [192]

Solanaceae

Lycium Lyciumbarbarum Gojiberries [193]

Lyciumchinense [63]

Solanum Solanumlycopersicum Tomatoes [194]

Solanumnigrum Nightshade [195]

Ericaceae Vacciniumvitis-idaea Cowberries [196]

Vacciniumoxycoccos [72]

Rutaceae Citrus Citrusparadisi Grapefruit [197]

Theaceae Camellia Camelliasinensis Tea [198]

Cucurbitaceae Cucumis Cucumissativus Cucumber [199]

Anacardiaceae Pistacia Pistaciavera Pistachio [200]

Vitaceae Vitis Vitisrotundifolia Muscadinegrapes [201]

Vitisvinifera Grapes [202]

Oleaceae Olea Oleaeuropaea Olivetree [203]

invivo

studies evidencing these effects. It can be hypothesized that low bioavailability of kaempferol may prevent from its geno- toxicity. However, it has been reported that kaempferols cause some additional adverse effects. For example, the consumption of kaempferol reduces the iron bioavailability and/or reduces the levels of folic acid in the cells and consequently, it may cause some abnormal effects in iron and/or folic acid deﬁcient patients [83,101].

1.5. Kaempferolandinﬂammation

The mechanisms by which kaempferol exerts its anti- inﬂammatory activities, as outlined in Fig. 3 are explained below.

1.5.1. Kaempferolasananti-oxidant

Oxidative stress is an unbalanced condition between cellular oxidants and antioxidants, which result in poor abolition of reactive oxygen and nitrogen species (ROS and RNS) formed in the cells [102]. ROS and the closely related RNS interact with biomolecules ensuing modifications and damages in proteins, lipids and DNA [103]. These changes attract the inflammatory mediators resulting in the stimulation of inflammatory mechanisms and causing detrimental effects in cells. ROS are generated in inflammatory cells including neutrophils and macrophages and are accompanied by the production of superoxide anions resulting in cellular damages [104]. Kaempferol is reported to have excellent antioxidant activity and can react with H

₂

O

₂

, HOCl, superoxide, nitric oxide

etc.

in cell free

in vitro

assays [105]. Erben-Russ et al. reported the radical scavenging activity of kaempferol [106]. Peroxynitrite which is involved in lipid peroxidation is shown to be inhibited by kaempferol isolated

form

Ginkgobiloba

leaves [107]. Kaempferol also protected HIT- T15 pancreatic beta cells from 2-deoxy-

d

-ribose-induced oxidative damage through the attenuation of lipid peroxidation and thereby decreased the progression of type II diabetes [108]. Strong attenuation of cytokine induced ROS in human umbilical vein endothelial cells and glutamate induced ROS production in neuronal HT22 cells by kaempferol have been reported [53,109]. Park et al. reported a marked reduction in phagocytosis after kaempferol administration to microglial cells treated with LPS in a concentration-dependent manner [110]. Nuclear factor (erythroid-derived 2)-like-2 (Nrf- 2) inhibition upon exposure to toxic chemicals or its impaired functions lead to the over expression of ROS [111]. The activation of redox sensitive transcription factor Nrf-2 further stimulates the activation of Hemeoxygenase-1 (HO-1) and protects the cells from oxidative damages [112]. Studies from Saw et al. showed that kaempferol supplementation in HepG2-C8 cells treated with H

2

O

2

induced the level of Nrf-2 and reduced ROS forma- tion [113]. Similarly, kaempferol also protected RAW264.7 cells from toxicity induced by LPS through the activation of HO-1, thereby suppressing the iNOS and nitric oxide expression levels [114].

1.5.2. Kaempferolasamodulatorofpro-inﬂammatoryenzyme activities

Prostaglandins (PG) are inflammatory mediators generated through the metabolism of arachidonic acid (AA) by COX at the site of inflammation [115]. Production of PG is further amplified in the presence of large amounts of nitric oxide, whose production is accelerated by the expression of iNOS in inflamed tissues [116]. Other enzymes which are known to modulate AA pathway, are PLA2 and LOX.

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185

186 187

188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204

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226 227 228 229 230 231 232 233 234

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Fig.3.Kaempferolanti-inﬂammatoryactivitymechanismsofaction.

Kaempferol showed potent inhibition of COX-1 and 2 enzymes in

invitro

cell free assay systems [117]. Human hepatocyte-derived Chang Liver cells co-incubated with kaempferol and cytokine mixture showed a decline in the expression level of iNOS and COX-2 in a concentration-dependent manner [118]. Another study by Lee et al.

demonstrated that kaempferol inhibited the expression of COX-2 by curbing Src-kinase activity caused by UVB exposure [119]. Stud- ies by various groups have also reported the inhibition of LOX by kaempferol under

invitro

and

invivo

conditions [120,121]. LOX plays a major role in the derivatization of leukotrienes (LT) from AA pathway which is involved in various inﬂammatory disorders including asthma, rheumatoid arthritis, inﬂammatory bowel disease

etc.

[122,123].

The physiological and pathophysiological role of nitric oxide is determined by the expression pattern of iNOS [124]. Over the past few decades, the role of nitric oxide has been evolved as an important biological mediator and its beneﬁcial role in neurolog- ical function, defense mechanisms

etc.,

have been widely studied.

Despite of these beneﬁcial roles, the excessive production of nitric oxide was shown to be associated with various disease compli- cations, especially with inﬂammatory diseases [125]. Nitric oxide

has been shown to interact with transition metal ions and mod- ify the activity of various enzymes like catalase resulting in the accumulation of H

₂

O

₂

and toxicity. Also, nitric oxide interacts with superoxide anion resulting in the formation of peroxy nitrite which acts as a powerful oxidant leading to DNA damage, LDL oxidation, inhibition of mitochondrial respiration, apoptosis and cell death [126–128]. Nitric oxide is also shown to induce the production of TNF-

␣

, a pro-inﬂammatory cytokine [129]. Kaempferol has been reported to hinder nitric oxide production induced by LPS in J774 cells and RAW264.7 cells, thereby lowering inﬂammatory response [54,130]. Also, kaempferol treatment is found to attenuate diabetic neuropathic pain induced by intraperitoneal injection of strepto- zotocin in Swiss mice which is mediated through the reduction in the levels of nitric oxide, IL-1

␤

and TNF-

␣

[131].

1.5.3. Modulationofgeneexpressioninvolvedininﬂammation

Several cellular mechanisms like mitogen activated protein kinase (MAPK), protein kinase C (PKC), phosphatidylinositol 3- kinases (PI3K) and Janus kinase-Signal Transducer and Activator of Transcription (JAK/STAT) pathways involved in modulating the expression levels of inﬂammatory mediators which are

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these kinases are involved in the regulation and expression of various transcription factors like NF-

␬

B and activator protein-1 (AP-1) [132]. Protein kinase C is a serine/threonine protein kinase which is involved in a myriad of cellular function. Of the several identiﬁed PKC isozymes, PKC

␪

is shown to be involved in the inﬂamma- tory response by controlling the transactivation of NF-

␬

B, AP-1 and nuclear factor of activated T-cells (NFAT) [133]. Inhibition of this particular isozyme is reported to reduce inflammatory mediated diseases [134]. Inflammation and allergic reactions induced by anti-IgE in human umbilical cord blood-derived cultured mast cells were noticeably declined upon treatment with kaempferol due to the inhibition of the release of pro-inflammatory cytokines, which in turn is due to the inhibition of PKC

␪

phosphorylation and intracellular Ca

²⁺

increase [135].

MAPK’s are a family of serine/threonine protein kinases, that includes extracellular signal-regulated kinase 1 and 2 (Erk1/2), c- jun N-terminal kinase (JNK) and p38 [136,137]. In response to inﬂammatory stimuli, the pathway being activated result in the expression of target genes including TNF-

␣

, IL-1

␤

, COX-2, and collagenases [138,139]. Kaempferol was shown to suppress the expression of LPS-induced MAPK pathway in human monocytic cell line THP-1, which in turn reduced the inﬂammatory burden by inhibiting the production of monocyte-derived chemokine (MDC), interferon gamma induced protein 10 (IP-10), growth related oncogene-alpha (GRO-

␣

) and IL-8 [140]. Also, kaempferol treatment to murine microglial BV2 cells and rheumatoid arthritis synovial ﬁbroblast cells signiﬁcantly inhibited LPS and IL-1

␤

- induced JNK and p38 phosphorylation, which were involved in the production of nitric oxide, PGE2 and iNOS expression [141].

LPS-induced lung injury in BALB/c mice was shown to activate the phosphorylation of ERK, p38 and JNK and thereby mediates the expression of pro-inﬂammatory mediators, ROS and myeloperoxi- dase (MPO). However, treatment with kaempferol suppressed the activation of ERK, p38 and JNK pathways and alleviated the harmful effects [142].

Growing experimental evidence also indicates the role of PI3K as an important mediator in inflammatory signaling cascade [143,144]. PI3K when activated results in the phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2) to form phosphatidylinositol(3,4,5)-trisphosphate (PIP3) and further results in the activation of Akt, which subsequently leads to cytokines production [145]. Kaempferol and 8-prenylkaempferol treatment has been shown to inhibit PI3K and Akt phosphorylation which is induced upon LPS, LPS plus ATP stimulation and RANTES (influenza A virus-induced regulated activation, normal T cell expressed and secreted) production in murine microglial BV2 cells, cardiac fibroblasts and A549 cells respectively, and protected the cells from the activation of inflammatory factors [110,146,147]. Aberrantly activated JAK/STAT pathway upon various stimuli has also been reported in inflammation which further leads to the activation of genes coding for inflammatory mediators [148]. Inflammation induced by LPS in airway epithelial cells was significantly inhibited by kaempferol treatment

via

the blockade of Tyk-STAT signaling pathway. Kaempferol efficiently disturbed the transactivation of STAT3 and inhibited further activation of inflammatory cytokines [149]. Neuroinflammation in rats caused due to transient focal ischemia resulted in the upregulation of STAT3 and NF-

␬

B, while the animals treated with kaempferol showed a marked decline in the phosphorylation of these transcription factors and reduced the inﬂammatory burden [150].

1.5.4. Inhibitionoftranscriptionfactors

The transcription factor NF-

␬

B, which is associated with oxidative stress and is responsible for the activation of inﬂammatory mediator genes including TNF-

␣

, IL-6, IL-8, iNOS and COX-2, is

plasm until it is triggered by the inﬂammatory stimuli [151–153].

Accumulating evidence indicates the role of kaempferol in atten- uating NF-

␬

B mediated inﬂammation in various model systems.

Kaempferol treatment in human umbilical vein endothelial cells (HUVEC) was shown to inhibit cytokine induced expression of redox sensitive factors NF-

␬

B and AP-1 [53]. Moreover, kaempferol acts as an efficient inhibitor of LPS and cytokine-associated airway inflammation, a characteristic of allergic asthma in human airway epithelial BEAS-2B cells, ovalbumin induced allergic changes in BALB/c mice and LPS plus ATP induced inflammation in cardiac fibroblasts through the blockade of NF-

␬

B signaling pathways [146,154]. Kaempferol also has shown protection against post- menopausal bone loss in mouse calvarial osteoblast cell line MC3T3-E1 through blockade of TNF-

␣

-induced translocation of NF- kB subunit p65 from the cytoplasm to the nucleus [155]. Studies by Kim et al. have indicated that advanced glycation end products (AGE) production and its binding to its receptor RAGE induced the degradation of I

␬

B

␣

and thereby induced the expression of NF-

␬

B upon aging in rats. These effects were signiﬁcantly reverted back on kaempferol treatment to rats which inhibited the degradation of I

␬

B

␣

and reduced age related NF-

␬

B activation [156]. TNF-

␣

was shown to activate IKK which in turn leads to the phosphorylation and degradation of I

␬

B, and further induces the expression of NF-

␬

B in HEK293 cells. However, kaempferol treatment inhibited the translocation of NF-

␬

B p65 subunit and reduced the inﬂammatory stimulus in cells [157].

1.5.5. Effectofkaempferolonadhesionmolecules

Endothelial adhesion molecules like intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), selectins, integrins and monocyte chemotactic protein-1 (MCP- 1) play a crucial role in inﬂammation through the interactions between circulating leukocytes and endothelial cells [158,159].

ICAM-1 and VCAM-1 belong to the Ig superfamily, are upregulated during inﬂammation and help in leukocyte recruitment, migration and activation of T cells [160,161]. TNF-

␣

induces inflammation fol- lowing the increase in ICAM-1 mRNA and protein expression, which is noticeably reduced upon treatment with kaempferol in A549 cells [162]. Studies by Crespo et al. also reveal that the inflammatory cascade induced by the treatment of cytokine mixture in HUVEC cells resulted in increase in the expression of VCAM-1, ICAM-1, E- selectin and other inflammatory mediators whereas, treatments with kaempferol significantly attenuated their expression [53].

Kaempferol treatment in high cholesterol induced atherosclerosis rabbit models showed a remarkable reduction in the gene and protein expression of E-selectin, ICAM-1, VCAM-1 and MCP-1.

Attraction of monocytes and their entry into the endothelial space is promoted by MCP-1 [163]. Reactive C protein (CRP), a biomarker for inflammation was shown to induce the expression of adhesion molecules [164]. Kaempferol supplementation in Chang liver cells reduced the level of CRP both at mRNA and protein level which was provoked upon cytokine treatment [162]. Dietary intake of flavonoids including, kaempferol in a study carried out on US adults has revealed that there is an inverse correlation between the level of flavonoid consumption and serum CRP level indicating their role in reducing the risk of inflammation [165].

1.5.6. Inhibitionofmatrixmetalloproteinasesbykaempferol

Matrix metalloproteinases (MMP’s) belong to the family of zinc-containing endopeptidases involved in tissue remodeling and degradation of extracellular matrix (ECM); the expression of which is regulated by cytokines, hormones and growth factors [166–170].

The physiological levels of MMP’s are maintained under the con- trol of tissue inhibitors of metalloproteinases (TIMP’s) [171]. The imbalance between MMP’s and TIMP’s are involved in various

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pathological conditions including inﬂammation. Pro-inﬂammatory cytokines including IL-1

␤

, TNF-

␣

, IFN-

␥

were reported to stimu- late the expression of MMP’s through NF-

␬

B activation [172,173].

Studies by Yoon et al. showed an increase in expression of MMP at both mRNA and protein level upon IL-1

␤

treatment and a signif- icant reduction upon kaempferol supplementation in rheumatoid arthritis synovial ﬁbroblast cells [141]. Kaempferol treatment in oral cancer cells SCC4 has shown a marked reduction in MMP-2 and increase in TIMP-2 levels along with the downregulation of ERK1/2 and AP-1 signaling pathways [174].

2. Conclusion

Chronic inﬂammation is directly related with many diseases, including cancer, allergies, arthritis, diabetes, cardiovascular dis- eases,

etc.

There is a close correlation between consumption of flavonoids and reduction in the risk of inflammation related diseases. Therefore, much attention has been paid to flavonoids as novel therapeutic strategy. It has been well known that health promoting beneficial effects of flavonoids is due to their potent anti-inflammatory actions along with their antioxidant activities. Kaempferol is one of the most common flavonoids widely distributed in different herbal sources. Numerous scientific reports showed that kaempferol has beneficial role on different inflammatory-related diseases such as cancers, cardiovascular, and neurodegenerative diseases. These beneficial anti-inflammatory actions of kaempferol are due to its potent effect in the inhibition of inflammatory cell function as well as inhibition in the expression of pro-inflammatory cytokines and chemokines. However, most of the research has been performed at doses far beyond oral bioavailability of kaempferol. Therefore, it seems very difficult to make a decision and/or come to a definite conclusion about the most effective dose of kaempferol. Therefore, further studies are needed to evaluate the most effective dose of kaempferol for clinical trials and should be aimed to solve problems related to low bioavailability, permeability and safe dosage.

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