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Flavonoids as Anti-Inflammatory and Analgesic Drugs: Mechanisms of Action and Perspectives in the Development of Pharmaceutical Forms

January 2012
Studies in Natural Products Chemistry 36:297-330

DOI:10.1016/B978-0-444-53836-9.00026-8

Authors:

Waldiceu A Verri

Universidade Estadual de Londrina

Fabiana TMC Vicentini

Farmacore

Marcela Baracat

Universidade Estadual de Londrina

Sandra R Georgetti

Universidade Estadual de Londrina

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Flavonoids are polyphenolic compounds with very diverse roles. In this chapter, we examined the bioactivity and potential of flavonoids as anti-inflammatory and analgesic drugs and the perspectives on their applicability and pharmaceutical development. Further, the mechanisms of action of flavonoids are addressed, for example, their effects on cytokine production, oxidative stress, and inhibition of protein kinases. In addition, the role of these mechanisms in inflammation and pain, and the structure-activity relationship are discussed.

ntracellular targets of flavonoids in inflammation. A variety of inflammatory stimuli

…

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Chapter 9

Flavonoids as Anti-Inflammatory

and Analgesic Drugs:

Mechanisms of Action and

Perspectives in the

Development of Pharmaceutical

Forms

Waldiceu A. Verri Jr.*, Fabiana T.M.C. Vicentini

{

, Marcela M. Baracat

{

Sandra R. Georgetti

{

, Renato D.R. Cardoso*, Thiago M. Cunha

}

Sergio H. Ferreira

}

, Fernando Q. Cunha

}

, Maria J.V. Fonseca

{

and

Rubia Casagrande

{

Departamento de Ciencias Patologicas, Centro de Ciencias Biologicas, Universidade Estadual

de Londrina, Rod. Celso Garcia Cid, Campus Universitario, Londrina, Parana, Brazil

{

Department of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao

Preto, Sao Paulo, Brazil

{

Departamento de Ciencias Farmaceuticas, Centro de Ciencias da Saude, Universidade Estadual

de Londrina, Londrina, Parana, Brazil

}

Department of Pharmacology, School of Medicine of Ribeirao Preto, University of Sao Paulo,

Ribeirao Preto, Sao Paulo, Brazil

INTRODUCTION

Flavonoids constitute a large group of aromatic amino acids widely

distributed in the plant kingdom [1–3]. In fact, flavonoids are important com-

ponents of the human diet. The intake of flavonoids can range between 50 and

800mg/day, depending on the consumption of vegetables and fruits [4–6].

Flavonoids are free radical scavengers (chain-breaking antioxidants) because

they are highly reactive as hydrogen or electron donors, which has led to their

potential use as therapeutic drugs [2,3,5,7–9].

In this chapter, we will discuss the current knowledge on the anti-inflammatory

and analgesic effects and mechanisms of flavonoids. The basic chemistry of

Bioactive Natural Products, Vol. 36. DOI: 10.1016/B978-0-444-53836-9.00026-8

flavonoids, structure–activity relationship, preclinical evidence and models, and

the development of pharmaceutical forms for their administration are also

addressed.

CHEMISTRY AND CLASSIFICATION

Flavonoids are formed in plants from the aromatic amino acids phenylalanine

and malonate. As shown in Fig. 1, the basic flavonoid structure is the flavan

nucleus, which consists of 15 carbon atoms arranged in three rings (C-6–C-3–

C-6) that are labeled A, B, and C. The various classes of flavonoids differ in

the level of oxidation and the pattern of substitution of the C ring, whereas indi-

vidual compounds within a class differ in the pattern of substitution of the

A and B rings as presented in Fig. 2. The flavonoid classes are flavones, flava-

nones, isoflavones, flavonols, flavanonols, flavan-3-ols, anthocyanidins, chal-

cones, and aurones. The dimerization of flavonoids has also been shown [10].

Flavonoids are primarily found in plants as glycosides, whereas aglycones

(the forms lacking sugar moieties) are found less frequently. At least eight

different monosaccharides or combinations of these (di- or trisaccharides)

can bind to different hydroxyl groups of the flavonoid aglycone [11].T

most common sugar moieties include D-glucose and L-rhamnose. The glyco-

sides are typically O-glycosides with the sugar moiety bound to the hydroxyl

group at the C-3 or C-7 position [12].

ANTI-INFLAMMATORY AND ANALGESIC FLAVONOIDS AND

THEIR MECHANISMS

Inflammation involves the development of four phenomena: edema, pain, ery-

thema, and an increase in temperature/fever. Depending on the intensity of

these cardinal signs, there can be loss of function. Although it is not a cardinal

inflammatory sign, the recruitment and activity of cells during inflammation

is important for the host response against infections and tissue repair. The

development of inflammation is initiated by the release of mediators of differ-

ent structures/classes through many cellular sources. Regarding the cellular

sources, resident cells, including macrophages and mast cells, are the first to

26⬘

5⬘

4⬘

3⬘

2⬘

1⬘

FIGURE 1 Core structure of flavonoids.

Studies in Natural Products Chemistry298

respond to inflammatory stimuli, and they communicate to the other cells of

the host by producing inflammatory mediators, which have been shown to

organize the host response and indicate what cells should be recruited to the

inflammatory foci and what activity should be performed by these cells.

A didactic description of inflammatory mediators examines those that are pro-

duced by cells and those that are produced from components present in the

plasma. The mediators produced by cells are serotonin, histamine, cytokines

and chemokines, nitric oxide (NO), reactive oxygen species (ROS), and lipid

mediators, such as prostanoids, leukotrienes, and lipoxins. Those derived from

components present in the plasma include bradykinin and members of the

complement and coagulation system [13].Flavonoids interfere with these

molecules at various degrees, depending on the concentration/doses of flavo-

noids used in vitro and in vivo. In the following sections, we will discuss the

anti-inflammatory and analgesic mechanisms of flavonoids as antioxidants,

3⬘Flavones

Luteolin

Apigenin

Chrysin

Baicalein

Baicalin

OHOH

Flavonones

Flavonols

Flavanolol

4⬘4⬘3⬘765

5⬘4⬘3⬘75

Quercetin

Kaempferol

Galangin

Fisetin

Myricetin

Isoquercetin

Myricetrin

Rutin

O9C12H21

4⬘3⬘75

Taxifolin OH OH OH OH

Hesperetin

Narigenin

OH OCH3

4⬘3⬘5

3⬘

4⬘

5⬘

3⬘

4⬘

OOH

3⬘

4⬘

FIGURE 2 (A) Structural characteristics of flavonoids.

continued

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 299

inhibitors of cytokine production and cyclooxygenase (COX) expression, and

inhibitors of a variety of intracellular pathways.

Antioxidant Effect of Flavonoids and Structure–Activity

Relationship

Many of the biological functions of flavonoids are attributed to their antioxi-

dant effects. The mechanisms are related to the neutralization of ROS, such as

peroxide anions, superoxide anion, hydroxyl radicals, lipid peroxides, and

hydroperoxides. Flavonoids also prevent oxidation of low-density lipopro-

teins, which have been implicated in atherosclerosis [14].

3⬘

4⬘

5⬘

3⬘

4⬘

Isoflavones

Flavan-3-ols

Anthocyanidins

Chalcones

Aurones

Genistein

(+)-catechin bOH

aOH

OH OH OH OH

aOH OH OH OH OH

OH OH OH OH

(-)-epicatechin

Auresidin

Leptosidin

(-)-epigallocatechin

gallate

Procyanidins

Cyanidin

Cyanin

Pelargonidin

Butein

2-hidroxychalcone

OH OH OH

Genistin OH Oglc OH

Daidzein OH OH

Daidzin Oglc OH

Biochanin A OHOH OCH3

Formononetin OH OCH3

Dehydroequol OH OH

Equol OH OH

Isoequol OH OH

4⬘75

3573⬘4⬘

O-glc

OH OH OH OH

3573⬘

OH OH OHOH

353⬘4⬘

4⬘

OH OH OH OH

OH OCH3OH OH

467 3⬘4⬘

5⬘

FIGURE 2—cont’d (B) Structural characteristics of flavonoids.

Studies in Natural Products Chemistry300

The prominent antioxidant activity of flavonoids is related to their low

redox potential (0.23<E7<0.75) [15]; therefore, they are thermodynamically

able to reduce free radicals with redox potentials between 2.13 and 1.0V.

Structure–activity studies of flavonoids have shown that three main compo-

nents are important for their activity: (1) o-dihydroxy on the B ring confers

the high stability to the flavonoid after the H atom donation, forming a phe-

noxyl radical by participating in the electron delocalization; (2) the presence

of 2,3-double bound bond in conjugation with a 4-oxo group on the C ring

allows for the dislocation of an electron from the phenoxyl radicals on the

B ring to the C ring; and (3) the 3-hydroxy group in combination with the

2,3-double bound increases the resonance stabilization for electron dislocation

across the molecule [16]. Flavonoids have been shown to chelate metals,

which is a characteristic associated with the presence of o-dihydroxy group

in the B ring, 3-hydroxy and 4-oxo groups in the C ring, and 5-hydroxy and

4-oxo groups in the C and A rings as shown in Fig. 1. Variations in these

structures resulted in variations in activity. It is noteworthy to mention that

quercetin is considered a standard flavonoid because it contains these three

structures related to flavonoids activity (Fig. 1). Figure 2 shows the basic

structure of the other members of the flavonoid family with substituent groups

forming some prominent flavonoids.

Flavonoids have also been shown to inhibit xanthine oxidase, which is

involved in the production of superoxide anion and hydrogen peroxide. There-

fore, this is a likely antioxidant mechanism of flavonoids [17].

Interestingly, flavonoids can also exert pro-oxidant activities, which are

related to the presence of hydroxyl groups, especially in the B ring. Further,

the unsaturated 2,3-bond and 4-oxo arrangement of flavones may promote the

formation of ROS induced by divalent copper in the presence of oxygen. These

data suggest that the same structural attributes that increased the antioxidant

capacity could also exacerbate oxidative stress and the damage to functional

and structural cellular molecules [18].

Inhibition of Production and Activity of Cytokines and Other

Related Molecules by Flavonoids

There is evidence that free radicals could activate oxidative stress sensitive

transcription factors, such as nuclear factor kB (NF-kB). NF-kB is known

as a pro-inflammatory transcription factor that induces the production of

COX-2, cytokines, and other pro-inflammatory molecules. In this vein, free

radicals are also pro-inflammatory molecules. Further, this is reciprocal

because cytokines, such as tumor necrosis factor a(TNFa), have been shown

to activate nicotinamide adenine dinucleotide phosphate-oxidase (NADPH

oxidase) to produce superoxide anion, which, in turn, could activate NF-kB,

although this relationship was not found in every cell and experimental condi-

tion [19].This could be one mechanism for the inhibition of cytokine produc-

tion or cytokine-dependent inflammation by flavonoids. Cytokines induce the

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 301

production of other cytokines and chemokines, and the inhibition of cytokine

effects limits this amplification system [20]. Cytokines have been shown to

induce the production of prostanoids, such as prostaglandin E

(PGE

), from

COX-2 and have been shown to induce NF-kB activation, resulting in

increased COX-2 expression (enzyme that produced prostaglandin). Thus, this

modulation of cytokines and NF-kB activity might explain other effects of

flavonoids, such as the inhibition of prostaglandin synthesis [19,21,22].

An interesting study investigated the mechanisms of baicalin (7-glucuro-

nic acid 5,6-dihydroxy-flavone), which is a flavonoid derived from Scutel-

laria baicalensis Georgi. Baicalin acts through an NF-kB-independent

mechanism and selectively binds to chemokines (subtype of cytokines), such

as stromal cell-derived factor (SDF), IL-8, MIP-1b, MCP-2, and C lymphotac-

tin without interacting with fractalkine (CX3C chemokine), neurotactin, or

other cytokines, such as TNFaand IFNg. Baicalin does not compete with che-

mokines for receptor binding; thus, it is not a receptor antagonist. Therefore,

the anti-inflammatory mechanism of baicalin could be attributed to selectively

binding/scavenging chemokines and limiting their biological activity [23].

In addition, studies have shown that flavonoids also induced the expression

of anti-inflammatory molecules, such as IL-1 receptor antagonist (IL-1ra), as

shown for luteolin in alveolar macrophages. Luteolin has been shown to

increase IL-1ra mRNA expression in alveolar macrophages without affecting

the mRNA expression of the anti-inflammatory cytokine IL-10 [24].

Therefore, flavonoids can inhibit NF-kB-dependent cytokine production,

act as a scavenger of some chemokines or induce the expression of anti-

inflammatory cytokines, such as IL-1ra. This role is important in inflamma-

tion because cytokines and chemokines initiate the inflammatory response.

Cytokines and chemokines activate and induce the increased expression of

adhesion molecules allowing the rolling of leukocytes over the endothelium,

which is necessary for their recruitment. Chemokines are important for the

selective recruitment of leukocytes during a variety of inflammatory condi-

tions. Cytokines are also involved in the development of fever by inducing

the production of prostaglandins, which act on EP3 (subtype of PGE

recep-

tor) [25] receptors to alter the activity of warm and cold sensitive neurons

in the hypothalamus to induce thermodysregulation. Another component of

inflammation is pain, which results from the activation and sensitization of

nociceptors (neurons transmitting the painful stimulus). Cytokines can

directly modulate nociceptor activity via their receptors. Thus, during inflam-

mation, flavonoids function to inhibit pro-inflammatory cytokine production

and inducing anti-inflammatory cytokines or scavenging chemokines. As

described for baicalin, the scavenging effects were selective for some chemo-

kines and were similar to those observed with soluble receptors or anti-cytokine

antibodies. In this sense, because not all flavonoids may present the same

effects described for the general form, every flavonoid must be analyzed sepa-

rately in different in vivo and/or in vitro assays.

Studies in Natural Products Chemistry302

Cytokines have also been shown to increase the expression of inducible

nitric oxide synthase (iNOS), which is responsible for NO synthesis in inflam-

matory states [26].The inhibition of iNOS-derived NO production is an

important anti-inflammatory mechanism of flavonoids because excessive

NO production is one of the components responsible for tissue destruction

in inflammation. In contrast, flavonoids, such as baicalin, increased the

expression of heme oxygenase-1 (HO-1) during ischemia/reperfusion injury

model, which mediated the reduction of NF-kB localization in the nucleus

(active NF-kB) and inhibition of IkB degradation. Therefore, the reduction

of TNFa, IL-6, and COX-2 mRNA expression was observed [27].

Flavonoids modulate the activity of other enzymes, such as myeloperoxidase,

which is an enzyme found in neutrophils and macrophages that produce the

microbicidal molecule hypochlorite. Flavonoids, such as myricitrin and quer-

cetin, are substrates for myeloperoxidase and inactivate it in vitro and in vivo

[22,28,29].

During inflammation, cytokines activate and increase the expression of

adhesion molecules, which are responsible for the interactions between leuko-

cytes and endothelial cells resulting in the sequence of rolling, firm adhesion

and transmigration of leukocytes culminating in leukocyte recruitment toward

the inflammatory foci. The three main groups of adhesion molecules include

selectins, integrins, and adhesion molecules of the immunoglobulin super

family. Their expression was reduced by the treatment with flavonoids

[30–33].

Thus, flavonoids affect the biology of cytokines/chemokines and other

systems, such as iNOS/NO and HO-1, to different extents and mechanisms.

Figure 3 summarizes these data.

Effect of Flavonoids on the Production of Lipid Mediators

It has been shown that flavonoids inhibit the peroxidase active site of COX-1,

COX-2, and 5-lipoxygenase (5-LO) [62], resulting in inhibition of prostanoids

(prostaglandins and tromboxanes) and leukotrienes production, respectively.

In fact, flavonoids inhibited the production of PGE

, which was consistent

with the inhibition of COX activity. In addition to the inhibition of the

COX-2 peroxidase active site [62], there is evidence that flavonoids inhibited

the NF-kB-dependent expression of COX-2 [63].

The inhibition of COX has the potential to be used as clinical activity

because of the use of selective and nonselective COX inhibitors, which have

been classified as nonsteroidal anti-inflammatory drugs (NSAIDs). Prosta-

glandins contributed to edema as a consequence of increased vascular perme-

ability and modulated the activity of neurons responsible for painful stimuli

perception and thermal regulation [13].It is noteworthy that COX-1 inhibitors

have side effects, such as an increase in gastric and intestinal ulcers, because

prostaglandins have been shown to increase protective mucus production, and

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 303

JAK

CYTOPLASMNUCLEUS

HO-1

5-LO

COX-1

MAP3K

NF-kB

c-Jun

AP-1

NF-kB

activated

-Proinflammatory mediators;

-Proinflammatory enzymes (COX-2; iNOS);

-Immune regulation;

-Lymphocyte Differentiation.

JNK1,2,3

MAP2K

MAPK 317

ROS

IKK

IKBp38

c-Fos

IKB

Ub-proteasome

STAT

NADPH

ERK 1/2

CHEMOKINES

ROS

FIGURE 3 Intracellular targets of flavonoids in inflammation. A variety of inflammatory stimuli

activate cells via receptors to produce inflammatory mediators that regulate the inflammatory pro-

cess. This cellular activation depends on intracellular signaling pathways. Receptor-independent

mechanisms also exist, such as those activated by UV radiation. Some examples of flavonoid clas-

ses regulating inflammation by modulating/blocking JAK (janus kinase)/STAT (signal transducers

and activators of transcription), MAPKs (mitogen-activated protein kinases), AP-1 (activating

protein 1) and NF-kB (nuclear factor kB) pathways are shown. These data support that the flavo-

noid apigenin (flavone) inhibited the expression of 1–2 [34] and 7–10 [35,36], decreased 13 [37]

production and inhibited the phosphorylation of 4–6 [38]. Delphinidin (anthocyanidins) inhibited

4–6, 9, 11–12 [39,40]. The epigallocatechin gallate (aflavan-3-ols) suppressed 12 and 9 activation

[41], phosphorylation of 5 and 6 [42], upregulated 13 [43] and inhibited 16 [44]. The isoflavone

genistein also inhibited the activation of 2–4 and 12 [45] and upregulates 13 [43]. Naringenin

(flavonones) suppressed the activation of 1–4, 6, and 8 pathways and the downstream signal trans-

ducer of 2 and 12 [34,46,47] and induced production of 13 [48]. Quercetin (flavonols) modulated

1–2 [49] and 12–13 pathways [32,50], reduced the expression of 14 and 16 [32,51], inhibited 11

[52] degradation and attenuated the activation of points 3–10 [32,53]. Butein (chalcone) inhibited

11 degradation [54] and 1–2, 4–6, and 12 activation [54,55]. Taxifolin (flavonolol) inhibited the

activation of 1–3 and 6 [56,57]. Baicalein reduced 1–2, 4–6, 11, and 15 [29,58,59] activation

and scavenged 16 [60]. Fisetin (flavonol) targeted 4 [61] and increased 13 expression [61].In

addition to the inhibition of COX-2 expression, flavonoids also inhibited the peroxidase site of

COX-2 [62]. Finally, all flavonoids have antioxidant activities and, therefore, inhibited 17. This

is a general scheme of flavonoid targets [13,14,18]. However, it is important to note that not all

cellular mechanisms are shown, and the flavonoids present in this study may have other targets

that are not presented in this figure.

Studies in Natural Products Chemistry304

treatment with COX-2 inhibitors increased the cardiovascular risk because the

COX-2-derived PGE

produced by endothelial cells present anti-aggregating

and vascular relaxing activities [64,65]. However, because the activity of fla-

vonoids do not rely exclusively on the inhibition of COX enzymes but affect

other pathways concomitantly to COX inhibition, they do not present these

common side effects of NSAIDs that target COX enzymes. In fact, flavonoids

have opposite effects compared to the COX inhibitors. The treatment with

extracts containing flavonoids and/or flavonoid-rich fractions of extracts

reduced the gastric lesions induced by NSAIDs, such as aspirin and indometh-

acin, or even promoted tissue healing [66,67]. Studies have also shown that

isolated flavonoids, such as rutin, reduced ulcers [68]. Moreover, in a rando-

mized clinical trial, a cream containing quercetin caused pain relief and

aphthous ulcer healing [69]. The analgesic mechanisms are discussed in a

separated section.

Regarding leukotrienes, there are 5-LO inhibitors and leukotriene receptor

antagonists available for clinical use. Because inhibition of leukotriene

synthesis [62] is a possible mechanism of action for some flavonoids, it is

possible that flavonoids inhibit inflammatory conditions that depend on leuko-

trienes. In fact, isoquercitrin inhibited leukotriene-induced airway contraction

in guinea pigs [70], and genistein inhibited leukotriene synthesis in eosino-

phils in asthma [71]. Further, flavonoids have additional mechanisms. Nari-

genin reduced mucus secretion by modulating ROS production and inhibited

NF-kB activity via epidermal growth factor receptor (EGFR)/phosphatidyli-

nositol 3-kinase (PI3K)-Akt/extracellular-regulated kinase (ERK) mitogen

activated protein kinase (MAP kinases) signaling in human airway epithelial

cells [72], quercetin induced a bronchodilator effect in an acute asthma model

[73], and apigenin reduced allergen-induced airway inflammation [74]. There-

fore, it is likely that flavonoids could represent a possible therapeutic approach

in asthma and in leukotriene-related diseases because leukotriene synthesis

inhibitors and receptor antagonists are in clinical use. Further, flavonoids have

a low toxicity, whereas leukotriene inhibitors have neurological side effects

and induce liver toxicity (more information on leukotriene inhibitors can be

found at www.fda.gov); therefore, flavonoids are safer than leukotriene

synthesis inhibitors and receptor antagonists.

Flavonoids can also modulate other lipid mediators. Isoflavones, such as

genistein and daidzein, inhibited the hydrolysis of anandamide by fatty acid

amide hydrolase (FAAH) at low micromolar concentrations. Among the

flavonoids tested by Thors et al.[75],kaempferol was the most potent and

was shown to inhibit FAAH in a competitive manner. The implications of

this mechanism of action included the reduced degradation of endocannabi-

noids and, therefore, the enhancement of the activation of cannabinoid

receptors. The consequences would be the increase in the analgesic effect of

endogenous and exogenous cannabinoids in cancer and inflammatory pain

[76–78].

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 305

Inhibition of Intracellular Signaling Pathways by Flavonoids

During Inflammation and Possible Implications Regarding Their

Antioxidant Effects

During inflammation, a variety of signaling pathways can be activated

depending on the inflammatory mediators, type of antigen and type of cell.

For example, PI3K and the three main MAP kinases, ERK, p38, and c-Jun

N-terminal kinase (JNK), are triggered during inflammation and may be

responsible for NADPH oxidase activation/oxidative burst, leukocyte recruit-

ment and activation of transcription factors, such as NF-kB and activating

protein-1 (AP-1) [79].In inflammation, inhibition of one MAP kinase reduced

the production of free radicals and inflammatory mediators. For instance,

TNFa-induced superoxide anion production via NADPH oxidase activation

depends on three pathways: (i) PI3K-induced PKC (protein kinase C) d,

(ii) PI3K/ERK-induced PKCd, and (iii) p38 activation of NADPH oxidase

in a PKCd-independent manner. As a consequence, inhibition of MAP kinases

reduced superoxide anion production [80]. Therefore, because a variety of fla-

vonoids have been shown to inhibit MAP kinases, including p38, JNK, and

ERK [72,81,82], it is possible that flavonoids do not act as antioxidants only

by scavenging free radicals but also by inhibiting NADPH oxidase-dependent

production of superoxide anion and other ROS. Further, excessive NADPH

oxidase activation may lead to tissue lesions; thus, flavonoids could limit tis-

sue lesions. Because these MAP kinases and PI3K pathways lead to NF-kB

and/or AP-1 activation and, consequently, pro-inflammatory mediators (e.g.,

cytokines) and enzymes (e.g., COX-2), their inhibition by flavonoids also

reduced the production of these inflammatory mediators [24,29,72,83].

Leukocyte recruitment is an important feature of inflammation because

leukocytes, such as neutrophils, must reach the inflammatory foci to phagocy-

tose and eliminate the foreign antigen. However, excessive leukocyte recruit-

ment and activation, in general, resulted in tissue lesions. Therefore, it is

important to limit the leukocyte recruitment to reduce tissue lesions. In auto-

immune diseases, leukocytes have a major role in tissue destruction, and inhi-

biting their recruitment was shown to be beneficial [84,85].MAP kinases and

PI3K are also activated during leukocyte recruitment with different kinases

activated based on the inflammatory stimulus and leukocyte. Because flavo-

noids inhibit the activation of those kinases, this is a possible mechanism that

is involved in flavonoid inhibition of leukocyte recruitment. Nevertheless, the

efficacy of each flavonoid in each inflammatory condition needs to be demon-

strated [72,81,82].

Intracellular signaling pathways are involved in flavonoid-induced activa-

tion of antioxidant mechanisms. In human umbilical vein endothelial cells

(HUVECs), it was demonstrated that treatment with small interfering

RNA (siRNA) and pharmacological inhibitors targeting PKCdand p38

MAPK attenuated HO-1 induction by fisetin (flavonol). The fisetin-induced

Studies in Natural Products Chemistry306

HO-1 expression was dependent on increased nuclear factor (erythroid-derived

2)-like 2 (Nrf2) translocation and antioxidant response element (ARE), as

detected by luciferase activity. Consistent with this, the treatment with an

HO-1 inhibitor reduced the inhibitory effect of fisetin for H

production [86].

Therefore, several models were able to demonstrate that the signaling

pathways were inhibited by flavonoids. It was difficult to present all signaling

pathways affected by flavonoids. In this vein, some additional intracellular

mechanisms targeted by flavonoids are summarized in Fig. 3.

Structure–Activity Relationship of Flavonoids in Inflammation

There are some slight differences in the intracellular pathways inhibited by

the different classes of flavonoids, but they share many similar targets as

shown in Fig. 3.Unfortunately, the majority of studies that examined the

activity of flavonoids did not investigate the structure–activity relationship.

However, there were several studies that did examine this relationship.

Tran et al.[87] synthesized derivatives from 20-hydroxychalcone and

investigated their effect on lipopolysaccharide (LPS)-induced PGE

synthesis

in macrophages. They concluded that the structure required the combination

of at least two alkoxy groups on the B ring of chalcones (see Fig. 2 for the basic

structure) where one group was substituted at position 4 and the other group

was substituted at positions 3 or 5 of B ring, which may enhance the inhibitory

activity of PGE

production. The benzyloxy moiety plays an important role in

establishing strong interactions between chalcone and COX-2. Importantly,

the inhibition of PGE

production from RAW 264.7 cells by 2-hydroxychalcone

derivatives was not associated with their cytotoxicity, which further corrobo-

rates the safety of flavonoids.

Interestingly, previous studies have found the effects of flavonols (kaemp-

ferol, quercetin, and myricetin) and flavones (flavone, chrysin, apigenin,

luteolin, baicalein, and baicalin) on the TNFa-stimulated ICAM-1 (adhesion

molecule) expression. Among the flavonoids tested, quercetin, kaempferol,

chrysin, apigenin, and luteolin inhibited TNFa-induced ICAM-1 expression.

These results suggest that the activity was independent of the flavonoid class

(flavonols and flavones) (Fig. 2). The TNFa-induced expression of ICAM-1

was dependent on the activation of MAP kinases (ERK, JNK, and p38),

NF-kB, and AP-1. Apigenin and luteolin (flavones) inhibited TNFa-induced

activation of all MAP kinases, AP-1, and IKK/NF-kB pathways. In compari-

son, kaempferol (flavonols) and chrysin (flavones) only inhibited JNK and

AP-1 activity. Further, kaempferol (flavonols) and chrysin (flavones) showed

similar mechanisms of action, whereas flavones (apigenin and luteolin com-

pared to chrysin) signaled through a unique mechanism. Thus, the flavonoid

class does not define the mechanism of action, but the –OH group at positions

5 and 7 of the A ring and at position 4 of the B ring is an important structural

component for determining the flavonoid mechanisms of action (see Fig. 2 for

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 307

the basic structure). Further, the presence of an –OH group at position 3 of the

B ring reduced the activity, whereas the –OH group at position 5 of the B ring

abolished the activity [29].

Previous studies have also shown that kaempferol had increased activity

than quercetin regarding the inhibition of the expression of adhesion mole-

cules (VCAM-1, ICAM-1, and L-selectin) [32],which was consistent with

the data mentioned above [29]. However, quercetin showed increased inhibi-

tion of iNOS and COX-2 protein expression and NF-kB and AP-1 than

kaempferol [32]. These compounds differ by the presence of the –OH at posi-

tion 3 in the B ring in quercetin. This structural difference was considered to

be predictive of the reduced activity in the study of Chen et al.[29],as

described above. In contrast, the –OH group at positions 3 and 4 in the B ring

found in quercetin conferred high stability to the flavonoid after H atom dona-

tion, forming a phenoxyl radical by participating in the electron delocaliza-

tion, and represents one out of three possible antioxidant mechanisms of

flavonoids, as described above [16]. Because iNOS and COX-2 could be

induced by transcription factors, including NF-kB and AP-1, and that free

radicals activate NF-kB, the presence of the –OH group at positions 3 and 4

in the B ring and the resulting antioxidant effect might account for the inhibi-

tion of gene expression and NF-kB and AP-1 activation by LPS [32]. There-

fore, it is likely that depending on the experimental model, the –OH groups

may result in contrasting data regarding the structure–activity relationship.

Analgesic Flavonoids

The sensitization of primary sensory neurons is essential to inflammatory

pain. Nonetheless, previously, the sensitization of nociceptors was believed

to be the result of the excitatory action of a “soup” of various inflammatory

mediators released at the site of inflamed or damaged tissue. However, this

hypothesis was challenged by the discovery of the mechanism of action of

NSAIDs by Vane’s group [88] and by the demonstration, in humans and in

animals, that eicosanoids were primarily responsible for nociceptor sensitiza-

tion and not overt pain [89]. In addition to PGE

, other inflammatory media-

tors, including sympathetic amines, endothelin, substance P, bradykinin, and

NGF, also possessed the same nociceptor-sensitizing property. These media-

tors acted directly on neuronal receptors, triggering molecular mechanisms

that facilitated the electrical activity of the neuronal membrane. Although

our understanding of the molecular mechanisms of nociceptor sensitization

is not complete, there is a general agreement that the stimulation of

G-protein-coupled receptors by inflammatory mediators activate the enzyme

adenylate cyclase to produce cyclic adenosine monophosphate (cAMP). This

substance, in turn, triggers the activation of a group of protein kinases [protein

kinase A (PKA) and C (PKC)], which leads to the phosphorylation of ion

channels in the membrane. These data were a result of a facilitation of the

Studies in Natural Products Chemistry308

inward sodium current via tetrodotoxin (TTX)-resistant Na

channels, a facil-

itation of inward Ca

2þ

currents, and an inhibition of outward K

currents.

This sequence of events is the basic peripheral mechanism of hyperalgesia,

a state in which a slight or normally non-noxious thermal, mechanical, or

chemical stimulus becomes painful [21].

We refer to the mediators that act directly on the primary nociceptor as

“final mediators,” which was in contrast with “intermediate” mediators

released during inflammation by resident and migrating cells or by plasma,

which stimulated the release of the final mediators. Whereas the inflammatory

signs and symptoms were similar, the resident and migrating cells and the

intermediate and final mediators varied depending on the time frame, the type

of tissue, and the type of inflammatory stimuli. In general, measurements of

mediators in exudates or inflamed tissues at a single time point gave a dis-

torted picture of the evolution of the pathological process and suggested a

disorganized “soup” of cells and mediators. In fact, sequential release of

inflammatory mediators or cellular events observed after a challenge by

inflammatory stimuli could be observed only by performing a series of mea-

surements. Commonly, it is this temporal and pathophysiological hierarchy

that allowed the researcher to discover the site of action of existing drugs or

to propose targets for new drug development [21].

Studies have shown that flavonoids have analgesic effects. They have been

shown to inhibit both inflammatory and neuropathic pain through mechanisms

involving the inhibition of cytokine production (e.g., IL-1b) and prostaglandin

and inducing NO production and endogenous opioid-dependent mechanisms.

These data were demonstrated for quercetin and other flavonoids (e.g., myri-

citrin, hesperidin, and dihydroxy flavones) in models of overt pain-like behav-

ior, such as acetic acid and phenyl-p-benzoquinone-induced abdominal

contortions and in the formalin test, in models of mechanical hyperalgesia

induced by carrageenan and in thermal hyperalgesia in streptozotocin-induced

diabetes [90–95].Depending on the experimental model, flavonoids inhibited

the production of intermediate and directly acting nociceptive mediators in

inflammatory pain [93] as well as directly antagonized nociceptor sensitiza-

tion by activating neuronal mechanisms, including the release of endogenous

opioids in streptozotocin-induced diabetic neuropathy [90]. Previous studies

have demonstrated that myrecetin reduced, in a concentration- and p38-

dependent manner, the K

currents in dorsal root ganglia (DRG) neurons

using whole cell patch-clamp recordings. This effect does not induce analge-

sia. Therefore, it is unlikely that the analgesic mechanism of a flavonoid

would depend on the direct modulation of K

currents in neurons [96].In

contrast, studies have shown that the inhibition of TNFa-induced activation

of MAP kinase, p38, in DRG neurons reduced the activation of TTX-resistant

channels, such as Nav 1.8, that have been implicated in inflammatory

and neuropathic pain [21]. Thus, the inhibition of these Na

currents is

an analgesic mechanism [97]. Together with the data demonstrating that

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 309

flavonoids inhibited MAP kinase activation [81], it would be appropriate to

determine whether flavonoids reduce TTX-resistant sodium channels currents

in DRG neurons.

In support of the involvement of the inhibition of oxidative stress in flavo-

noids analgesic mechanisms of action, quercetin has been shown to inhibit car-

rageenan-induced mechanical hyperalgesia and the accompanying reduction in

the decreased glutathione levels [92].Interestingly, baicalin reduced streptozo-

tocin-induced neuropathic pain by inhibiting p38 activation, oxidative–nitrosa-

tive stress, and 12/15-lipoxygenase overexpression and activation without

affecting glucose levels [98]. Therefore, as discussed for other inflammatory

signs, it is likely that flavonoids function through more than one mechanism.

Further, glucocorticosteroids (steroidal anti-inflammatory drugs) increased the

blood glucose levels, which is a relevant side effect for diabetic patients. In this

sense, the ability of baicalin to reduce pain without affecting glucose levels

indicates that it would be a potential treatment option for diabetic patients’ pain

management [98].

Structure modifications are also an interesting approach to increase the activ-

ity of flavonoids. El-Sabbagh et al.[99] synthesized 2,3-dihydroquinazolin-4

(1H)-one derivatives bearing chalcone moieties. One compound showed a signif-

icant analgesic effect in the acetic acid-induced writhing test and in the reduction

of carrageenan-induced paw edema compared to celecoxib (a commonly used

NSAID that selectively inhibits COX-2), and it also exhibited a similar loss

of gastric effects, as compared to celecoxib, which were reduced compared to

COX-1 inhibitors, such as indomethacin. Therefore, structural modifications

of flavonoids could be a promising approach to increase their analgesic and

anti-inflammatory activities. However, it remains to be determined whether the

side effects are also maintained in very low levels.

Evidence of Flavonoids Effects in Human Inflammatory Diseases

and Human Cell Models of Disease

To further corroborate the data discussed above on the anti-inflammatory

effects, mechanisms and structure–activity relationship of flavonoids, studies

support their use in in vitro models to evaluate inflammatory signaling using

human cells and in human diseases.

Dietary supplementation of quercetin at 900mg/day for 4 weeks did not

change the blood biomarkers of inflammation and disease severity of rheuma-

toid arthritis patients [100].However, there are some concerns to be mentioned.

Quercetin has poor oral absorption, and therefore, optimized pharmaceutical

formulation might help increase its absorption. The patients were recommended

to refrain from ingesting nutritional antioxidants because their ingestion nor-

mally ranged between 50 and 800mg/day [4–6]. Thus, the treatment with quer-

cetin at the dose tested would only replenish the deficit of intake. Moreover,

only one dose was tested and the period was short. Further, these patients were

Studies in Natural Products Chemistry310

under conventional medical treatments that made it difficult to observe the

additional anti-inflammatory effects with quercetin treatment [100].

In contrast, quercetin has been shown to inhibit phorbol 12-myristate 13-

acetate (PMA)- and calcium ionophore A23187 (PMACI)-induced gene

expression and the production of TNFa, IL-1b, IL-6, and IL-8 in a human

mast cell line. Quercetin also attenuated PMACI-induced activation of NF-k

B and p38 MAP kinase in mast cells [101].Because mast cells play an impor-

tant role in the pathogenesis of rheumatoid arthritis, modulation of the produc-

tion of inflammatory mediators by these cells could be a target of quercetin

[85]. Further data regarding rheumatoid arthritis demonstrated that hesperitin

and myricetin also reduced IL-1b-induced production of metalloprotease and

IL-6 in human synovial cell line in a JNK and JNK- and p38-dependent man-

ner, respectively [102,103]. Luteolin also reduced IL-1b-induced cytokine and

metalloprotease activation by inhibiting MAP kinases, NF-kB, and AP-1 in a

human synovial sarcoma cell line [104].

In another autoimmune disease, lupus, patients need alternatives to ster-

oids and cytotoxic drugs. Apigenin inhibited autoantigen-presenting and stim-

ulatory functions of antigen presenting cells (APCs) necessary for the

activation and expansion of autoreactive Th1 and Th17 cells and B cells in

lupus. Apigenin also has been shown to cause apoptosis of hyperactive lupus

APCs and T and B cells by inhibiting expression of NF-kB-regulated anti-

apoptotic molecules, especially COX-2 and cellular caspase-8 (FLICE)-like

inhibitory protein (c-FLIP), which are hyper-expressed by lupus immune cells.

Increasing the bioavailability of dietary plant-derived COX-2 and NF-kB

inhibitors, such as apigenin, could be valuable for suppressing inflammation

in lupus and other Th17-mediated diseases, such as rheumatoid arthritis,

Crohn’s disease, and psoriasis, and in the prevention of inflammation-based

tumors overexpressing COX-2 (colon and breast) [105].

Interestingly, one study addressed the effect of flavonoid intake in chronic

diseases. People with an increased quercetin intake had a lower mortality from

ischemic heart disease. The incidence of cerebrovascular disease was lower

with a higher intake of kaempferol, naringenin, and hesperetin. Men with

increased quercetin intake had a lower lung cancer incidence, and men

with higher myricetin intake had a lower prostate cancer risk. The incidence

of asthma was lower with increased quercetin, naringenin, and hesperetin

intakes. A trend toward a reduction in the risk of type 2 diabetes was asso-

ciated with higher quercetin and myricetin intakes [106].Therefore, there

are data suggesting a protective role of flavonoids in human disease and/or

human cell systems. Of note, the effects of flavonoids, as shown in humans

[106], might depend on long-term treatment.

Evidence also suggests that flavonoids might be useful to reduce the exces-

sive inflammatory responses induced in the presence of bacterial (e.g., LPS

and fMLP) products by inhibiting the activation of MAP kinases, PI3K, and

NF-kB and inhibiting the production of pro-inflammatory cytokines and NO

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 311

[107–109]. Further, long-term ultraviolet-induced skin inflammation has been

shown to contribute to cancer development, and flavonoids have been shown

to reduce the inflammatory state by mechanisms that are discussed in the sec-

tion regarding topical formulation development [110–113].

DEVELOPMENT OF ORAL FORMULATIONS

CONTAINING FLAVONOIDS

Encapsulation of Flavonoids

The research and application of flavonoids have been areas of great interest in

the functional foods, nutraceutical and pharmaceutical industries due to their

high spectrum of biological activities, including antioxidant, anti-inflammatory,

antibacterial, and antiviral functions [86–118].However, the effectiveness of

nutraceutical products, including flavonoids, in preventing diseases is depen-

dent on preserving the bioavailability of the active ingredients. This can be

difficult because only a small proportion of the molecules remain available

following oral administration due to insufficient gastric residence time, low

permeability and/or solubility within the gut, and their instability under condi-

tions encountered in food processing and storage (temperature, oxygen, and

light) or in the gastrointestinal tract (pH, enzymes, and in the presence of other

nutrients) [119].

In fact, flavonoids have weak water solubility and could undergo degradation

in the acidic stomach environment. These properties cause low flavonoid dissolu-

tion rates from solid, oral dosage forms, such as capsules and tablets, from meals

or from the partial degradation in the harsh pH conditions of the gastric environ-

ment, resulting in a low absorption and bioavailability. Thus, to encapsulate flavo-

noids in gastro-resistant polymers to transport them directly to the intestine may

improve their bioavailability after oral administration [120].To increase the

effectiveness of flavonoids, formulations must provide protective mechanisms

that can maintain the active molecular form until the time of consumption and

deliver this form to the physiological target within the organism [121].

Most of the bioactive food components were administered in encapsulated

forms to overcome the drawbacks of their instability, alleviate unpleasant

tastes or flavors, and improve the bioavailability and half-life of the com-

pound in vivo and in vitro [122–129].

Microencapsulation is defined as a process in which tiny particles or dro-

plets of the active ingredient(s) are surrounded by a coating or embedded in a

homogeneous or heterogeneous matrix, generally of polymeric materials, to

give small capsules that may range from sub-microns to several millimeters

in size with many useful properties [130].Nanoencapsulation involves the for-

mation of active, loaded particles with diameters ranging from 1 to 1000 nm

[129]. The term nanoparticle is a collective name for both nanospheres and

nanocapsules. Nanospheres have a matrix type structure. Active particles

Studies in Natural Products Chemistry312

may be absorbed at the sphere surface or encapsulated within the particle.

Nanocapsules are vesicular systems in which the active particle is confined

to a cavity consisting of an inner liquid core surrounded by a polymeric mem-

brane [131]. Compared to micron-sized particles, nanoparticles provide a

greater surface area and have the potential to increase the solubility due to a

combination of large interfacial adsorption of the core compound, enhanced

bioavailability, and improved controlled release, which enabled better preci-

sion targeting of the encapsulated materials [130,132].

The encapsulation, depending on the polymers and technology used, may

stabilize these labile compounds and extend their shelf-life. From an industrial

perspective, encapsulated powders would be easy to handle and to use in food

and pharmaceutical processing, keeping their initial flavonoid content,

bioactivity, and safety for prolonged storage. In nano- and microsystems,

stabilization occurred because the wall/coating material acts as a physical

barrier; therefore, for this reason, the shelf-life of the encapsulated drugs

was prolonged. Moreover, polymers may modulate the release rate and

solubility in intestinal fluid [120,133–135].

Various techniques have been used for encapsulation, including spray-dry-

ing, spray freezing, extrusion, coacervation, liposome entrapment, inclusion

complexation, lyophilization, and emulsion [136,137,133].

Spray-Drying

Spray-drying encapsulation is commonly used in pharmaceutical and bio-

chemical fields and in the food industry due to the large availability of equip-

ment and for the ease of industrialization. It is also a mild, “one-step”

processing operation to move from a liquid feed into a powder product

[138,139].The spray-drying process is an economical, flexible, continuous

operation that produces particles of good quality. The typical shape of

spray-dried particles is spherical, with a mean size range of 10–100 mm

[137]. Because the fast solvent evaporation keeps the droplet temperature

far below the drying air temperature, spray-drying is strongly recommended

for heat sensitive materials, such as flavonoids [114]. Ersus and Yurdagel

[140] microencapsulated the flavonoid anthocyanin pigments of the black car-

rot by spray-drying using maltodextrins as a carrier and coating agents to pro-

tect the flavonoids from oxidation. The ethanolic extracts of black carrots that

were dried with high air inlet temperatures (>160–180C) caused greater

anthocyanin losses, whereas the maltodextrin of 20–21 DE (Glucodry

210)

gave the highest anthocyanin content powder at the end of drying process

[140]. The maltodextrin could also be mixed with arabic gum as wall mate-

rial. A mixture of maltodextrin (60%) and arabic gum (40%) has been used

for encapsulation of procyanidins from grape seeds [141]. The encapsulation

efficiency was up to 89%, and the procyanidin was not changed during dry-

ing. The stability of the products was improved by spray-drying.

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 313

Other flavonoids, such as naringin and rutin, that present different struc-

tures and physicochemical characteristics were microencapsulated by spray-

drying using cellulose-derived polymers [142].The protective ability of cellu-

lose derivatives was based either on the ability to form amorphous matrices

loading drugs during the spray-drying process or on their pH dependent solu-

bility. Cellulose acetate phthalate (CAP) was as insoluble and stable in acidic

gastric fluid as in its nonionized form. It becomes soluble, swellable, and dis-

integrable as the phthalic acid groups ionized above pH 6 in intestinal fluid

[143]. However, these results showed that satisfactory, gastro-resistant micro-

systems were produced only for the more soluble glycosides, such as rutin and

naringin [142,144]. Nevertheless, in the development of gastro-resistant

microparticles containing low-solubility, the ingredients required a compro-

mise between the enhancement of the dissolution rate and protection in the

gastric environment. An incomplete flavonoid release in the simulated intesti-

nal fluid was observed for the slightly water-soluble, such as quercetin

[142,144]. Sansone et al.[120] produced naringenin and quercetin gastro-

resistant microparticles by spray-drying and investigated the effects of the

combined use of CAP as coating polymer and three different materials

(sodium dodecylbenzensulfonate, tween-85, and sodium carboxymethylcellu-

lose crosslinked) that were able to enhance the dissolution test. The presence

of a combination of CAP and surfactants or swelling agents in the formulations

produced microparticles with a good resistance at a low gastric fluid pH and

complete flavonoid release in the intestinal environment. The spray-drying

technique and the process conditions selected have produced good encapsula-

tion efficiencies and product yields. Chitosan has also been used as a wall mate-

rial in spray-drying of olive leaf extract (OLE) [145]. Another wall material

successfully used for encapsulation of polyphenol was the protein–lipid

(sodium caseinate–soy lecithin) emulsion, which has been used in spray-drying

of grape seed extract, apple polyphenol extract, and olive leaf extract [146].

Therefore, there is an increase in groups attempting to develop gastro-resistant

formulations containing flavonoids to increase their availability.

Coacervation

Complex coacervation is commonly associated with no definite forms and is

an expensive method for encapsulating food ingredients [147]; however, this

process should be related to the potential benefits it might offer, especially

to high value, labile functional ingredients, such as the encapsulation of flavo-

noids [148]. The size of the capsule and its characteristics can be varied by

changing the pH, the ion concentration, the ratio of matrix molecule and the

bioactive component, and the type of matrix. The technique is primarily

driven by electrostatic interactions, but hydrophobic interactions are also

involved [136,148,149]. This is immobilization rather than encapsulation

technology and is, therefore, mostly proposed and applied for bioactive food

Studies in Natural Products Chemistry314

molecules rather than for bioactive, living cells. The technique is applied for

flavors, oils, and for some water-soluble bioactive molecules [119].

The studies on encapsulation of flavonoids by coacervation used wall

materials, such as calcium alginate and calcium alginate-chitosan, to encapsu-

late yerba mate extract [125], gelatin to encapsulate () epigallocatechin gal-

late [150], glucan to encapsulate black currant extract [151], and propolis

extract was encapsulated using pectin and soy protein [126]. Other coacerva-

tion coating systems such as gliadin, heparin/gelatin, carrageenan, soy protein,

polyvinyl alcohol, gelatin/carboxymethylcellulose, b-lactoglobulin/gum aca-

cia, and guar gum/dextran have also been studied [147]. However, most of

the core materials in these studies were essential oils rather than flavonoids.

Liposomes

Liposomes are spherical bilayers that enclose bioactive molecules. The lipo-

somes are formed by dispersion of polar lipids (mostly phospholipids) in an

aqueous solution. Liposomes can be utilized in the entrapment, release of

water-soluble, lipid-soluble, and amphiphilic materials [152].Bioactive

agents encapsulated into liposomes can be protected from digestion in the

stomach and showed significant levels of absorption in the gastrointestinal tract,

leading to the enhancement of bioactivity and bioavailability [153]. A variety of

liposome techniques have been employed for the encapsulation of flavonoids,

such as film evaporation, sonication, reverse phase evaporation, melting, and

freezing–thawing [154]. The encapsulating efficiency of liposomes was highest

when they were prepared by freezing–thawing, followed by thin film evapora-

tion, then reverse phase evaporation, whereas melting and sonication have the

lowest efficiency. Liposomal systems prepared by sonication, melting, and

reverse phase evaporation displayed better dispersion.

The nature of the core materials is another factor that affects the efficiency

of liposome encapsulation. The isomers of (þ)-catechin and ()-epicatechin

entrapped in liposomes showed similar encapsulation levels and release rates

[155].However, another type of catechin, ()-epigallocatechin-3-gallate

(EGCG), has been observed to have an increased level of encapsulation

for the same liposome system. EGCG contains a galloyl group, indicating

a greater lipophilicity. Hence, it is possible that EGCG was more effective

when localized within the liposome bilayers, thereby increasing the

entrapment.

There is evidence of quercetin liposomes prepared from egg phosphatidyl-

choline/cholesterol (2:1). A lower dose (20 mg/kg body weight) and a faster

rate of absorption were observed with intranasal quercetin liposomes when

compared with oral quercetin (300mg/kg body weight). These results suggest

that intranasal delivery of quercetin in the form of liposomes to the brain

could allow for a reduction in the dose to reduce the potential of toxicity of

the quercetin [156].

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 315

Inclusion Encapsulation—Cyclodextrins

Cyclodextrins can envelop molecular structures by forming molecular inclu-

sion complexes. Cyclodextrins have a hydrophobic interior and a hydrophilic

exterior. The hydrophobic interior of the capsule can be varied in size by

varying the number of glucose units of the cyclodextrin molecules

[157,158].It has been applied to increase the solubility of hydrophobic mole-

cules and to protect molecules from inactivation or degradation.

The inclusion of hesperetin and hesperidin in (2-hydroxypropyl)-b-cyclodextrin

(HP-b-CD) [159];quercetin and myricetin in HP-b-CD, maltosyl-b-CDs, and

b-CDs [160]; kaempferol, quercetin, and myricetin in HP-b-CD [161]; 3-hydro-

xyflavone (3-OHeF), morin, and quercetin in a- and b-CDs [162]; and rutin in

b-CD [163] have been studied, and their water solubility improved by

encapsulation. In addition, their antioxidant activities were shown to be

increased in these CD-encapsulated systems. The improved antioxidant efficacy

of the inclusion complex may be a result of the protection of the flavonoid

against rapid oxidation by free radicals [161], which may, in part, be explained

by an increase in their solubility in the biological moiety [163]. The encapsula-

tion efficacy of CD inclusion was affected by the core materials. In general, the

higher the hydrophobicity and the smaller the molecule, the greater the affinity

for the CD was.

Freeze-Drying

Freeze-drying is an industrial process used to ensure the long-term stability

and to preserve the original properties of pharmaceutical and biological pro-

ducts [164]. Freeze-drying, also known as lyophilization or cryodesiccation,

is a process used for the dehydration most heat-sensitive materials and aro-

mas. Freeze-drying works by freezing the material, reducing the surrounding

pressure, and adding enough heat to allow the frozen water in the material

to sublimate directly from the solid phase to the gas phase. Encapsulation

by freeze-drying is achieved as the core materials homogenize in matrix solu-

tions and then co-lyophilize, resulting in uncertain forms.

Due to the long dehydration period required (generally 20 h), this technol-

ogy is rarely applied but may serve as a solution of specific encapsulation

issues for encapsulating water-soluble essences and natural aromas and drugs

[137].Freeze-dried samples of pomace containing anthocyanin and maltodex-

trin have shown good shelf life stability during storage at 50C/0.5 water

activity for up to 2 months [165]. Laine et al.[166] encapsulated phenolic-

rich cloudberry extract by freeze-drying, using maltodextrins as wall materi-

als. The microencapsulated cloudberry extract offered better protection for

phenolics during storage, whereas the antioxidant activity remained the same

or even improved slightly. However, studies have shown that freeze-drying

induced encapsulation was unable to improve stability or bioactivity. When

Studies in Natural Products Chemistry316

Hibiscus anthocyanin extract was encapsulated in pullulan by freeze-drying,

the free anthocyanins were shown to have 1.5–1.8 times faster degradation

than the pullulan–anthocyanin co-lyophilized materials [167]. These results

showed that they can be both free and co-lyophilized with pullulan, Hibiscus

anthocyanins exhibited good antiradical activity throughout storage, and no

significant differences were observed between the materials, suggesting that

the encapsulation might not be necessary if the Hibiscus anthocyanin extract

is to be freeze dried.

DEVELOPMENT OF TOPICAL FORMULATIONS

CONTAINING FLAVONOIDS

The UV components of sunlight are now recognized as major environmental

factors that are deleterious to human health. Acute exposure to ultraviolet

radiation (UVR) from the sun is harmful to the skin, causing sunburn, immune

suppression, DNA damage, and connective tissue degradation. Accumulated

damage resulting from chronic sun exposure has been shown to cause skin

cancer and premature skin aging (photoaging) [168].The genesis of skin dis-

eases due to UVR exposure is a result of the generation of free radicals and

mobilization of transition metal ions, and, thus, inflammation [22].

In principle, the conscientious use of sunscreens/blocks or protective

clothing should prevent UV exposure to the skin. Nevertheless, as epidemio-

logical studies have indicated that the use of sunscreen and sun block are not

completely effective in preventing UV-induced skin injuries, further

approaches are needed to more effectively protect human skin against UV-

caused damage [169].Instead of only blocking the UVR from being absorbed

by the skin, as is usually found with UV absorbers and sunscreens, the skin

could also be protected by preventing the formation of the photooxidants that

result in radical damage and cutaneous diseases [170].

There is increased interest in the identification of natural product sources

for novel anti-inflammatory and antioxidant compounds that might prove to

be of superior efficacy in preventing and/or treating the skin from the photo-

damage [171,172].Naturally occurring agents are considered to be less toxic

and more effective approaches in controlling various human malignancies

[173,174]; thus, a new concept in cosmetics research and development is

the use of the so-called “biological filters,” such as the potent antioxidants,

vitamins, and flavonoids, which can have protective effects against UVR

and may also have biologically relevant filtering activity [175].

In addition to their innate antioxidant activity, flavonoids, which are

widely distributed in medicinal plants, are known as natural anti-inflammatory

agents [176],which strongly suggest the potential of these compounds to

antagonize critical UV-induced damaging events. Therefore, their topical

use may provide the necessary photoprotection in addition to human

sunscreens.

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 317

The topical delivery of bioactive substances is a powerful strategy to avoid

possible systemic toxicity and, at the same time, to restrict the therapeutic

effects to specific tissues [177] because it is the considered route of adminis-

tration of agents against the UV-induced skin damages. Nevertheless, the

most difficult aspect of a topical delivery system is to overcome the barrier

of the stratum corneum (SC) against foreign substances [178,179]. Further,

most flavonoids are highly lipophilic substances, and their penetration across

the SC (epidermis’ outermost layer) and into viable skin layers may be diffi-

cult due to their affinity for SC components (principally lipophilic in nature)

and the tendency to be retained in this layer [180].

Therefore, adequate cutaneous absorption is known to be an essential

requirement for topically applied photoprotective agents [181],andthevehicle

in which the drug is applied could effectively influence its release from a topi-

cal pharmaceutical preparation [177]. When a delivery system is applied topi-

cally to the skin, the active agent must be released from its carrier (vehicle)

before it contacts the epidermal surface and be available for penetration into

the SC and lower layers of the skin [182,183]. Thus, the percutaneous absorp-

tion of a drug could be influenced by the partition of the active agent between

the vehicle and SC, which was influenced by active agent–vehicle–skin

interactions [184].

In addition, to propose the topical application of flavonoids or delivery

systems containing these agents, extensive in vivo studies are required to test

the long-term treatment effects of the proposed agents, their half-life and the

optimum dose for beneficial effects. Recently, many studies were designed to

evaluate the in vivo efficacy against the UV-induced damage of different

flavonoids when topically applied.

Quercetin, the best studied and one of the most common flavonoids found

in nature, which was shown to have a poor ability to permeate through excised

human skin [177],has been incorporated into different delivery systems to

inhibit the oxidative skin damage and the inflammatory processes induced

by the solar UVR.

Among the first studies that incorporated quercetin into two different

oil-in-water emulsions, with a distinct lipid content, was developed by Casa-

grande et al.[22,177],and they evaluated their potential application as a topi-

cal carrier system for the delivery of this flavonoid. The in vivo results

suggested that these functionally stable formulations containing quercetin

may be used as a topical active product to control UVB-induced skin damage.

Based on these promising results, further studies investigated the design of

novel administration forms to increase the quercetin effectiveness when topi-

cally applied. In this context, quercetin was incorporated into a liquid, crystal-

line formulation, and the influence of this carrier in the in vitro antioxidant

activity of this flavonoid was evaluated. Vehicles having a liquid, crystalline

structure allowed for an easier diffusion of biologically active substances

through the skin have a considerable solubilizing capacity for both oil- and

water-soluble compounds; in addition, liquid crystals were thermodynamically

Studies in Natural Products Chemistry318

stable and could be stored for long periods of time without phase separation

[185]. In fact, Scalia and Mezzena [186]demonstrated that the incorporation

of quercetin in lipid microparticles improved the photo- and chemical stability

of the flavonoid, and the biocompatibility of the lipoparticle carrier system

represents an additional advantage for the development of quercetin-based pro-

ducts for skin care.

In addition, quercetin was also incorporated into water-in-oil (w/o) micro-

emulsion and evaluated regarding its protective effect against UVB-induced

damage in the hairless mouse skin. These results confirmed the possible use-

fulness of topical formulations containing quercetin to prevent UVB radiation

skin as suggested by Casagrande et al.[22].However, the incorporation into

the w/o microemulsion optimized the effects of the flavonoid because a dose

approximately sixfold smaller produced the same in vivo results obtained with

nonionic emulsion containing quercetin. The optimization was due to the sig-

nificant increase in quercetin skin penetration caused by its incorporation into

w/o microemulsion [21]. Further, by evaluating the effects of this w/o micro-

emulsion incorporating quercetin in UV-induced erythema formation and

histopathological changes, we suggest that the protective effects of this for-

mulation on UV-induced responses was not secondary to the interference of

UV transmission (i.e., blocking the UVB radiation from being absorbed by

the skin), as is usually performed with UVB absorbers and sunscreens, but

was due to different biological effects of this flavonoid [168].

Microemulsion systems, which represent pharmaceutically versatile formu-

lations for various applications, have received increasing attention during recent

years because they have several advantages, such as ease of manufacturing,

thermodynamic stability, and high solubilizing power, that allow for the

incorporation of large amounts of poorly soluble compounds and increased drug

permeation rates [179,187].

This type of formulation was also employed as a carrier of another flavo-

noid with lipophilic characteristics. Hesperetin, a flavanone compound, which

has been demonstrated to have protective effects for skin damage [188],was

incorporated into microemulsions for topical whitening products after UVR.

This in vivo study demonstrated that hesperetin-loaded microemulsions showed

significant topical whitening effects and diminished skin irritations when com-

pared with the nontreated group. The authors suggested that the observed

inhibition on the irritation effect might be due to the anti-inflammatory effect

of flavonoids [178]. It was also observed that there was an in vivo protective

effect of hesperetin that was incorporated into a cream formulation when

combined with a combination of the penetration enhancers, such as menthol,

linoleic acid, and lecitin [179].

The evaluation of the in vivo effect of different extracts where flavonoids

were among the main chemical constituents has also been shown. Typically,

as a first step, the extracts that have previously been shown to have anti-

inflammatory and antioxidant activities, in addition to other pharmacological

properties, were incorporated into a topical administration forms, and its

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 319

release and its skin penetration were evaluated to select the most promising

system to deliver the studied active agent.

Gebre-Mariam et al.[182] incorporated the extract of Melilotus elegans

into three different types of formulations (hydrophilic, amphiphilic, and lipo-

philic cream) and evaluated the release profiles of the kaempferol glycosides

from these formulations. As expected, the faster and higher release was

obtained by employing the lipophilic cream in which the glycoside forms of

flavonoids, due to their polarity, have less affinity for the cream base.

The postirradiation, topical application of lotions containing increasing

levels of the plant extract, pycnogenol B, significantly inhibited the acute

inflammation-edema response to solar-simulated UVR [190].

The potential of a topical preparation (SK Ato Formula) containing flavo-

noid mixtures from S. baicalensis Georgi roots and Ginkgo biloba L. leaves

with an extract of Gentiana scabra Bunge roots was evaluated in an animal

model of chronic skin inflammation. In this study, the animals were treated

with 12-O-tetradecanoylphorbol-13-acetate for 7 consecutive days to induce

a chronic skin inflammation, and when topically applied in this model, the

studied formulation reduced these responses. Further, it inhibited PGE

gener-

ation and suppressed the expression of pro-inflammatory genes, COX-2, and

IL-1bin the skin lesion [176].

Reseada luteola L., which is a natural source of luteolin (flavone), was

used to obtain a luteolin-rich extract to be investigated in the prevention or

treatment of inflammatory skin diseases (e.g., sunburn). Due to poor solubility

of the Reseada extract, a nanoparticular soluble state of the extract (s-RE) was

used and clinically assessed on its anti-inflammatory properties in a standar-

dized test model in human volunteers in vivo. These results showed that topi-

cal application of a solubilized luteolin-rich extract from R. luteola effectively

reduced UVB-induced skin inflammation [189].

Fonseca et al.[172] investigated the potential use of extracts from Calen-

dula officinalis L. (also known as marigold), which is used primarily for cuta-

neous and internal inflammatory diseases of several origins that was added in

various topical formulations to prevent or to treat the UVB irradiation-induced

skin damage. The topical application of the gel formulation containing C. offi-

cinalis reduced the histological skin changes induced by UVB irradiation,

providing a photoprotective effect in the hairless mice.

Studies have shown that topically applied isoflavones and their metabo-

lites may offer protection from UV-induced inflammation and immunosup-

pression [191].The topical administration may also be a suitable route for

soy isoflavones to obtain systemic bioavailability because of their rapid clear-

ance from the plasma [192].

Widyarini et al.[193] assessed the effect of several red clover (Trifolium

pratense) isoflavones on UVR-induced skin inflammation that was measured

as the edema component of this reaction by the increase in the irradiated skin-

fold thickness and on the systemic suppression of immune function measured

as the contact hypersensitivity response. This study had shown that topical

Studies in Natural Products Chemistry320

application of lotions containing genistein, equol, isoequol, or dehydroequol

provided protection not only against UVR-induced cutaneous inflammation

observed as the sunburn reaction but also against photoimmune suppression,

which was evident as a defective contact hypersensitivity reaction that was

initiated by the UV-irradiated skin.

Several isoflavonoid derivatives have been identified as metabolites produced

from dietary isoflavones by the gastrointestinal microflora in humans and found to

have various potent biological activities [189].Studies that have focused on

equol ([S]-40,7-dihydroxyisoflavane) because it was shown that its contribution

to the protection against solar-simulated UVR-induced erythemal-associated

edema and immunosuppression [190] showed a potential role in the prevention

of human skin cancer [190] by acting as a sunscreen and, thus, inhibiting DNA

photodamage [191] when topically applied as a lotion.

Soybeans are a rich source of flavonoids called isoflavones, with the most

potent isoflavones being genistein and daidzein and the soybean cake, a bypro-

duct obtained during the processing of soybean oil that has been shown to be a

rich source of isoflavones and other functional components. Chiu et al.[194]

found that isoflavone extract from soybean cake could decrease the early acti-

vation of the signaling pathway in response to UVB and could prevent skin cell

apoptosis, erythema, and inflammation reactions. Thus, this extract might be a

good candidate for an anti-photoaging agent in skin care that has many advan-

tages, such as convenience, economy, and environmental protection.

Propolis is a resinous material that honeybees (Apis mellifera L.) collect

from various plant species and mix with wax and other substances. In general,

it is a complex mixture of different constituents, including flavonoids, aro-

matic acids and esters, aldehydes and ketones, fatty acids and esters, terpenes,

steroids, amino acids, polysaccharides, hydrocarbons, alcohols, hydroxyben-

zene, and several other compounds in trace amounts [195].Although its

composition varies with the source, most samples share significant similarity

in their overall chemical nature, and approximately 50% of the raw propolis is

represented by resin, composed of flavonoids and related phenolic acids

[196]. Many of these constituents were biologically active and were involved

in a broad spectrum of pharmacological properties of propolis, with the main

properties being antimicrobial, immunomodulatory, and anti-inflammatory

[197,198]. It has been suggested that these properties may arise from complex

mechanisms or synergistic interactions between compounds [199]. The topical

application of a crude de-waxed ethanolic extract of “Sydney” propolis in the

Skh:hr-1 albino hairless mouse was effective in reducing inflammation,

immunosuppression, and oxidative damage caused by UV exposure [171].

In contrast, although Fonseca et al.[199] had demonstrated that oral treat-

ment of the hairless mice with two Brazilian propolis extracts (green and

brown) prevented irradiation-induced oxidative stress by preventing GSH

depletion, the topical pretreatment of animals with solutions containing both

propolis extracts was not effective. The low topical effectiveness of both

extracts could be explained by poor diffusion of the active compounds

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 321

through the SC and viable epidermis of mouse skin. To this end, topical for-

mulations that diffuse more effectively through the skin could be developed

and additional studies should be performed.

Finally, the topical application of dermocosmetic formulations containing

an association of vitamins and bioflavonoids showed relevant biological activ-

ity in terms of photoprotection, demonstrating the potentiality of using the

association of active substances with different mechanisms of action against

the UV-induced skin damages [147].

In conclusion, the above-mentioned findings suggest that the in vivo topi-

cal application of flavonoids has the potential to antagonize critical damaging

events, such as the inflammatory reaction, induced by UVR and could be

developed as dermatological and cosmetic products in addition to sunscreens

that would provide photoprotection for humans.

CONCLUSIONS

In this chapter, we described evidence that demonstrated the anti-inflamma-

tory and analgesic effects of flavonoids by mechanisms involving the inhibi-

tion of oxidative stress, cytokines and lipid mediators production, scavenging

chemokines, NF-kB, AP-1, JAK/STAT, MAP kinases and PI3K activation,

IkB degradation, myeloperoxidase, and stimulation of endogenous opioids

release, NO production, IL-1ra, and HO-1 expression. There have been stud-

ies that examined the structure–activity relationship of flavonoids, but there

have not been conclusive data. Further, there has been an increased focus

on developing novel formulations and pharmaceutical forms that could

improve the stability and absorption of flavonoids for oral administration

and that could be incorporated into topical formulations for the protection

against UV radiation-induced skin damage. Finally, the use of flavonoids

may represent a better pharmacological approach compared to current thera-

pies because flavonoids do not act by a single mechanism, but they have been

shown to inhibit the activity and expression of pro-inflammatory enzymes

(e.g., COX-1, COX-2, and 5-LO), inhibit cytokine production and scavenge

them, inhibit intracellular signaling pathways essential for inflammation/pain

induction (e.g., MAP kinases and PI3K), transcription factors (e.g., NF-kB

and AP-1), and oxidative stress while presenting a better profile regarding

side effects, such as gastrointestinal and renal lesions, as compared to nonse-

lective and selective COX-2 inhibitors, respectively. Moreover, steroidal anti-

inflammatory drugs increased blood glucose levels, and there is evidence that

it does not occur, at least for some flavonoids, suggesting a better profile for

diabetic patients. Thus, flavonoids represent a promising class of drugs for

anti-inflammatory and analgesic use, and there is increasing attention on the

development of pharmaceutical forms of flavonoids. Further studies using

human cells and long-term clinical trials are necessary to confirm their

usefulness.

Studies in Natural Products Chemistry322

ACKNOWLEDGMENTS

We thank the financial support of Fundac¸a

˜o de Amparo a Pesquisa do Estado de Sa

˜o Paulo

(FAPESP), Conselho Nacional de Desenvolvimento Cientı

´fico e Tecnolo

´gico (CNPq),

Coordenac¸a

˜o de Aperfeic¸oamento de Pessoal de Nı

´vel Superior (CAPES), Fundac¸a

˜o

Arauca

´ria and Governo do Estado do Parana

´/SETI, Brazil.

ABBREVIATIONS

5-LO 5-lipoxygenase

AP-1 activating protein-1

APCs antigen presenting cells

CAP cellulose acetate phthalate

cFLIP cellular caspase-8 (FLICE)-like inhibitory protein

COX cyclooxygenase

DRG dorsal root ganglia

EGCG ()-epigallocatechin-3-gallate

EP3 PGE

receptor 3

ERK extracellular signal-regulated kinase

FAAH fatty acid amide hydrolase

GSH reduced glutathione

IKK IkB kinase

IL interleukin

iNOS inducible nitric oxide synthase

JNK Jun N-terminal Kinase

MAP kinases mitogen-activated protein kinases

MCP-2 monocyte chemotatic protein-2

MIP-1bmacrophage inflammatory protein-1

NADPH oxidase nicotinamide adenine dinucleotide phosphate-oxidase

NF-kBnuclear factor kB

NO nitric oxide

NSAIDS nonsteroidal anti-inflammatory drugs

PGE

prostaglandin E

PI3K phosphoinositide 3-kinase

PMA phorbol 12-myristate 13-acetate

PMACI PMA calcium ionophore A23187

ROS reactive oxidative species

SC stratum corneum

SDF stromal cell-derived factor

Th T helper

UVR ultraviolet radiation

w/o water-in-oil

Chapter 9Flavonoids as Anti-Inflammatory and Analgesic Drugs 323

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Jul 2023
INT J PHARMACEUT

Improved therapies for inflammatory bowel diseases are sorely needed. Novel therapeutic agents and the development of controlled release systems for targeted tissue delivery are interesting approaches to overcome these barriers. We investigated the activity of trans-chalcone (T) in acetic acid-induced colitis in mice and developed, characterized, and determined the therapeutic effect of pectin/casein polymer microcapsules containing T (MT) in a colitis mouse model. In vitro, compound release was achieved in simulated intestinal fluid but not in the simulated gastric fluid. In vivo, since T at the dose of 3 mg/kg but not 0.3 mg/kg ameliorated colitis, we next tested the effects of MT at 0.3 mg/kg (non-effective dose). MT, but not free T at 0.3 mg/kg, significantly improved colitis outcomes such as neutrophil recruitment, antioxidant capacity, cytokine production, and NF-kB activation. This translated into reduced macro and microscopic damage in the colon. T release from the microcapsules is mediated by a pH-dependent and pectinase-regulated mechanism that provide controlled and prolonged release of T. Moreover, MT lowered the required dose for T therapeutic effect, indicating that could be a suitable pharmaceutical approach to colitis treatment. This is the first demonstration that T or MT is effective at reducing the signs of colitis.

Natural Flavonoids as Potential Therapeutics in the Management of Diabetic Wound: A Review

Article

Apr 2023
CURR TOP MED CHEM

Flavonoids are important bioactive phenolic compounds abundant in plants and exhibit different therapeutic potentials. A wound is a significant problem in diabetic individuals. A hyperglycaemic environment alters the normal wound-healing process and increases the risk of microbial infection, leading to hospitalization, morbidity, and amputation. Flavonoids are an important class of phytochemicals with excellent antioxidant, anti-inflammatory, antimicrobial, antidiabetic, antitumor, and wound healing property. Quercetin, hesperidin, curcumin, kaempferol, apigenin, luteolin, morin, etc. have shown their wound healing potential. Flavonoids effectively exhibit antimicrobial activity, scavenge reactive oxygen species, augment endogenous antioxidants, reduce the expression and synthesis of inflammatory cytokines (i.e. IL-1β, IL-6, TNF-α, NF-κB), inhibit inflammatory enzymes, enhance anti-inflammatory cytokine (IL-10), enhance insulin section, reduce insulin resistance, and control blood glucose level. Several flavonoids like hesperidin, curcumin, quercetin, rutin, naringin, and luteolin have shown their potential in managing diabetic wounds. Natural products that maintain glucose haemostatic, exert anti-inflammatory activity, suppress/inhibit microbial growth, modulate cytokines, inhibit matrix metalloproteinase (MMP), stimulate angiogenesis and extracellular matrix, and modulate growth factor can be considered as a potential therapeutic lead to treat diabetic wound. Flavonoids were found to play a positive role in management of diabetic wounds by regulating MMP-2, MMP-8, MMP-9, MMP-13, Ras/Raf/ MEK/ERK, PI3K/Akt, and nitric oxide pathways. Therefore, it can be assumed that flavonoids could be potential therapeutics to prevent devastating effects of diabetic wounds. This paper focused on the potential role of flavonoids in managing diabetic wounds and discussed their possible mechanism of action.

Utilization of plant extracts to control the safety and quality of fried foods-A review

Article

Apr 2023
COMPR REV FOOD SCI F

Frying is one of the most common methods of preparing foods. However, it may lead to the formation of potentially hazardous substances, such as acrylamide, heterocyclic amines, trans fatty acids, advanced glycation end products, hydroxymethyl furfural and polycyclic aromatic hydrocarbons, and adversely alter the desirable sensory attributes of foods, thereby reducing the safety and quality of fried foods. Currently, the formation of toxic substances is usually reduced by pretreatment of the raw materials, optimization of process parameters, and the use of coatings. However, many of these strategies are not highly effective at inhibiting the formation of these undesirable reaction products. Plant extracts can be used for this purpose because of their abundance, safety, and beneficial functional attributes. In this article, we focus on the potential of using plant extracts to inhibit the formation of hazardous substances, so as to improve the safety of fried food. In addition, we also summarized the effects of plant extracts, which inhibit the production of hazardous substances, on food sensory aspects (flavor, color, texture, and taste). Finally, we highlight areas where further research is required.

Controlled drug delivery with nanoparticles: Current possibilities and future trends

Article

Jan 1995
EUR J PHARM BIOPHARM

Numerous investigations have shown that the distribution profile of a drug can be modified at the cellular and tissular level by entrapment in submicronic colloidal systems (nanoparticles). This review provides an update on the technologies available for nanoparticles preparation. Their in vivo fate after intravascular administration is discussed, especially the strategies which are currently considered to avoid the uptake by the reticuloendothelial system. The paper also provides information about the existence of nanoparticles translocation after oral administration. Further, toxicological aspects are examined. Finally, the last part of this review is focused on the application of nanoparticles in therapeutics.

Flavonoids inhibit tumor necrosis factor-alpha-induced up-regulation of intercellular adhesion molecule-1 (ICAM-1) in respiratory epithelial cells through activator protein-1 and nuclear factor-kappa B: Structure-activity relationships

Article

Sep 2004

Intercellular adhesion molecule-1 (ICAM-1) has been implicated in the processes of inflammation and carcinogenesis. Flavonoids, which are polyphenolic compounds with a wide distribution throughout the plant kingdom, have potent anti-inflammatory properties. We investigated the effects of flavonols ( kaempferol, quercetin, and myricetin) and flavones ( flavone, chrysin, apigenin, luteolin, baicalein, and baicalin) on the tumor necrosis factor-alpha (TNF-alpha)-stimulated ICAM-1 expression. Among those flavonoids tested, kaempferol, chrysin, apigenin, and luteolin are active inhibitors of ICAM-1 expression. Additional experiments suggested that apigenin and luteolin were actively inhibiting the IkappaB kinase (IKK) activity, the IkappaBalpha degradation, the nuclear factor-kappaB (NF-kappaB) DNA-protein binding, and the NF-kappaB luciferase activity. TNF-alpha-induced ICAM-1 promoter activity was attenuated using an activator protein-1 (AP-1) site deletion mutant, indicating the involvement of AP-1 in ICAM-1 expression. AP-1-specific DNA-protein binding activity was increased by TNF-alpha, and the supershift assay identified the components of c-fos and c-jun. Extracellular signal-regulated kinase (ERK) and p38 were involved in the c-fos mRNA expression, and c-Jun NH2-terminal kinase (JNK) was involved in the c-jun mRNA expression. All three mitogen-activated protein kinase ( MAPK) activities were inhibited by apigenin and luteolin. In comparison, kaempferol and chrysin only inhibited the JNK activity. The inhibitory effects of apigenin and luteolin on ICAM-1 expression are mediated by the sequential attenuation of the three MAPKs activities, the c-fos and c-jun mRNA expressions, and the AP-1 transcriptional activity. IKK/NF-kappaB pathway is also involved; however, kaempferol- and chrysin-mediated inhibitions are primarily executed through the attenuation of JNK activity, c-jun mRNA expression, and AP-1 activity. The structure-activity relationships are also explored, and the important role of -OH group at positions 5 and 7 of A ring and at position 4 of B ring is noted. Finally, our results suggested that AP-1 seems to play a more significant role than NF-kappaB in the flavonoid-induced ICAM-1 inhibition.

Rutin and quercetin gastro-resistant microparticles obtained by spray-drying technique

Article

Dec 2005
J DRUG DELIV SCI TEC

Quercetin and rutin gastro-resistant microparticles were prepared by spray-drying using cellulose acetate trimellitate (CAT) or cellulose acetate phthalate (CAP) as coating polymers. The influence of parameters such as the initial organic or aqueous feed solutions and polymer/drug ratio on the particle yield, behaviour and morphology was investigated. By spray-drying 2% buffer aqueous feed solutions in different polymer/drug ratio (1:1, 3:1 and 5:1) microparticles loaded with rutin were obtained. The microsystems were characterized by scanning electron microscopy (SEM), fluorescence microscopy (FM), and differential scanning calorimetry (DSC). In vitro dissolution studies, carried out using a pH change method, showed a typical biphasic drug release trend due to the pH dependent solubility of the enteric polymers.

Thermal, mechanical and functional properties of cellulose acetate phthalate (CAP) coatings obtained from neutralized aqueous solutions

Article

Feb 1995
INT J PHARMACEUT

This study investigated the thermal, mechanical and functional properties of cellulose acetate phthalate (CAP) film coatings obtained from neutralized aqueous solutions. A novel salt forming agent, 2-amino-2-methyl-l-propanol (MAP), was used for the neutralization and dissolution of CAP in water. Triethylcitrate (TEC) was used as the plasticizer at 10–35% levels. Thermal and mechanical properties of free films plasticized with 10–35% TEC were evaluated by thermogravimetric analysis (TGA), thermal mechanical analysis (TMA) and dynamic mechanical spectroscopy (DMS). The physical stability of CAP/MAP films stored at 40 and 50°C was compared to ammoniated CAP films with respect to dissolution times in pH 6.8 buffer. Plasticized CAP/MAP films were also sprayed at three weight gains (6, 8 and 10%) onto acetylsalicylic acid (ASA) tablets (650 mg) using pan coating technology. The functional properties of the films were assessed for enteric integrity in 0.1 N HCI, drug release in pH 6.8 phosphate buffer and water permeability. Results have shown that CAP/MAP films plasticized with 25–35% TEC released ≤1% ASA after 2 h in 0.1 N HCl and > 95% after 1 h in buffer, thereby demonstrating their excellent functional properties. These films had high permeability to water/acid which makes them unsuitable for acid-labile drugs, since water/HCl would penetrate rapidly into the tablet core and degrade the drug. Neither the Tg nor E′ values differed significantly for films that showed satisfactory functional properties. Films were stiff and brittle with E′ values in the range of 2–3 × 109 Pa and Tg values of 108–112°C. TEC appeared to have limited solubility in the CAP/MAP polymer with reduced plasticization effects at concentrations higher than 20–25%. CAP/MAP free films were found to be superior to ammoniated CAP films with respect to extent of aging when stored at 40°C. The results clearly showed the potential use of plasticized CAP/MAP films as an enteric film former for pharmaceutical products.

(−)-Epigallocatechin-3-gallate inhibits monocyte chemotactic protein-1 expression in endothelial cells via blocking NF-κB signaling

Article

May 2007
LIFE SCI

Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes and plays a key role in various inflammatory responses, including atherosclerosis. In this study, we examined the effect of (−)-epigallocatechin-3-gallate (EGCG), a major green tea catechin, on the expression of MCP-1 in human endothelial ECV304 cells. EGCG markedly inhibited the phorbol 12-myristate 13-acetate (PMA)-induced MCP-1 mRNA and protein levels in a dose-dependent manner. EGCG was also found to reduce the MCP-1 transcriptional activity. The upregulation of MCP-1 by PMA was significantly inhibited by blockade of P38 mitogen-activated protein kinase (MAPK) and NF-κB, but not by blockade of extracellular-signal-regulated kinase and c-Jun N-terminal kinase pathway. Furthermore, The PMA-induced p38 MAPK and NF-κB activation were obviously attenuated after pretreating ECV304 cells with EGCG. The conditioned media from the endothelial ECV304 cells treated with PMA could remarkably stimulate the migration of THP-1 monocytes and this effect was partially abrogated by MCP-1 neutralizing antibodies. Moreover, the media from the EGCG-pretreated ECV304 cells lost the stimulatory activity for THP-1 migration. These results suggest that EGCG may exert an anti-inflammatory effect in endothelial cells by controlling MCP-1 expression, at least in part, mediated through the suppression of p38 MAPK and NF-κB activation.

Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivties, bioavailability, and epidemiology

Article

Oct 2004
NUTR RES

Iris Erlund

The bioactivities, dietary sources, bioavailability, metabolism, and epidemiology of 3 flavonoids, quercetin, hesperetin, and naringenin, are reviewed. The use of their plasma concentrations as biomarkers of dietary intake is also discussed. The compounds were chosen because of their significant dietary intakes and promising bioactivities, and in the case of quercetin, because epidemiological studies suggest protection against cardiovascular disease.

Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-??B and p38 MAPK in HMC1 human mast cell line

Article

May 2007

Objective and design: Mast cell-mediated allergic inflammation is involved in many diseases such as asthma, sinusitis, and rheumatoid arthritis. Mast cells induce production of pro-inflammatory cytokines with immune regulatory properties. We investigated the effect of quercetin on the expression of pro-inflammatory cytokines in human mast cell line, HMC-1. Methods: HMC-1 cells were stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 (PMACI). Results: Quercetin decreased the gene expression and production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 in PMACI-stimulated HMC-1 cells. Quercetin attenuated PMACI-induced activation of NF-kappaB and p38 mitogen-activated protein kinase. Conclusion: Our study provides evidence that quercetin may suitable for the treatment of mast cell-derived allergic inflammatory diseases.

Quercetin inhibits IL-1 beta-induced ICAM-1 expression in pulmonary epithelial cell line A549 through the MAPK pathways

Article

Sep 2009
MOL BIOL REP

Quercetin is a herbal flavonoid derived from various foods of plant origin and widely used as a major constituent of nutritional supplements. Quercetin has been shown to have anti-inflammatory properties and can play a role in anti-inflammatory procedure. Intercellular adhesion molecule-1 (ICAM-1) is one of the important pro-inflammatory factors, especially in early phage of inflammation. However, the mechanisms regulating ICAM-1 expression by quercetin in human A549 cells were still unclear. In this study, the inhibitory effect of quercetin on ICAM-1 expression by interleukin-1 beta (IL-1 beta)-stimulated A549 cells was investigated, and the roles of mitogen-activated protein kinases (MAPK) pathways were explored. Quercetin attenuated IL-1 beta-induced expression of ICAM-1 mRNA and protein in a dose-dependent manner. The experiment suggested that quercetin actively inhibited inhibitory protein of nuclear factor-kappa B (I kappa B) degradation, and nuclear factor-kappa B (NF-kappa B) activity. The c-fos and c-jun, components of activator protein-1 (AP-1), were mediated by MAPK pathways. ERK and p38 were involved in the c-fos mRNA expression, and JNK was involved in the c-jun mRNA expression. The inhibitory effect of quercetin on ICAM-1 expression was mediated by the sequential attenuation of the c-fos and c-jun mRNA expressions. These inhibitory effects were partially inhibited by SB203580, a specific inhibitor of p38 MAPK, but not by PD98059, a specific inhibitors of extracellular signal-regulated kinase (ERK), and SP600125, a specific inhibitor of c-Jun-N-terminal kinase (JNK). Taken together, these results suggest that quercetin negatively modulating ICAM-1 partly dependent on MAPK pathways.

The role of antioxidant phytonutrients in the prevention of diseases

Article

Jan 2003

The authors investigated the in vitro antioxidant properties of nine selected flavonoid aglycons, namely quercetin, kaempferol, myricetin, apigenin, luteolin, daidzein, genistein, formononetin and biochanin A. The in vitro antioxidant power of flavonoids basically depends on their chemical structure. The concentration of those flavonoids in vegetables and fruits frequently consumed in Hungary was examined by a RP-HPLC method. Referring to the total flavonoid content, rich sources were onions, parsnip, spinach, different parts of celery, and lentils. Among the fruits berries were very rich sources of flavonoids (blackberry, red current). The flavonoid intake was estimated in two groups, first included more than 500 schoolboys and girls aged 12-15 years, and the second group was about 200 healthy adults aged 25-60 years. The average dietary flavonoid intake of the children and the adults was 19.5±26.6 and 18.8±28.9 mg/day, respectively. The flavonoid intake showed high differences among the subjects. The consumption of flavonoids in the children's group was from 0 to 179 mg/day, and in the adults¢ group from 0.5 to 310 mg/day. Although two groups in our study did not represent exactly the total Hungarian population it is supposed that the average daily flavonoid intake of the population is not different from these data. The estimated Hungarian intake is very similar to that of others published in the literature.

Procyanidins: Extraction and micro-encapsulation

Article

Sep 2007

As by-products of grape juice and wine production, grape seeds are a rich source of procyanidins but are usually discarded as waste. We have treated grape seeds with supercritical fluid extraction to remove the oils and have extracted the procyanidins from the residues. In order to extend the shelf life, micro-encapsulating methods for procyanidins were studied: the use of gum arabic and maltodextrin as wall materials (the contents of arabic gum and maltodextrin were 40% and 60%, respectively). The raw materials were then mixed (the ratio of core substance to wall material was 30:70 w/w and the content of the slurry was 20% w/v). After homogenisation, spray drying was used to prepare microcapsules. The micro-encapsulation efficiency was up to 88.84%. Analysis of the product showed that the procyanidin was not changed during the processing and the procyanidin microcapsule membrane was uninterrupted and with fairly good integrity. The stability of the products was also obviously improved. Copyright © 2007 Society of Chemical Industry

Flavonoids as Anti-Inflammatory and Analgesic Drugs: Mechanisms of Action and Perspectives in the Development of Pharmaceutical Forms

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