Next Article in Journal
Schizandrin Protects Primary Rat Cortical Cell Cultures from Glutamate-Induced Apoptosis by Inhibiting Activation of the MAPK Family and the Mitochondria Dependent Pathway
Previous Article in Journal
Anthraquinones of the Roots of Pentas micrantha
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 18
Issue 1
10.3390/molecules18010322
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Molecular Mechanism Underlying Anti-Inflammatory and Anti-Allergic Activities of Phytochemicals: An Update

by
Yuva Bellik
1,2,
Laïd Boukraâ
1,3,*,
Hasan A. Alzahrani
3,4,
Balkees A. Bakhotmah
3,5,
Fatiha Abdellah
1,
Si M. Hammoudi
1 and
Mokrane Iguer-Ouada
2
1
Laboratory of Research on Local Animal Products, Ibn-Khaldoun University of Tiaret, Tiaret 14000, Algeria
2
Faculty of Nature and Life Sciences, Abderrahmane Mira University, Béjaia 06000, Algeria
3
Mohammad Hussein Al Amoudi Chair for Diabetic Foot Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
4
Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
5
Department of Nutrition Food Sciences, Arts and Design College, King Abdulaziz University, Jeddah 21589, Saudi Arabia
*
Author to whom correspondence should be addressed.
Molecules 2013, 18(1), 322-353; https://doi.org/10.3390/molecules18010322
Submission received: 13 September 2012 / Revised: 6 December 2012 / Accepted: 14 December 2012 / Published: 27 December 2012
(This article belongs to the Section Natural Products Chemistry)
Browse Figures
Versions Notes

Abstract

:
The resort worldwide to edible medicinal plants for medical care has increased significantly during the last few years. Currently, there is a renewed interest in the search for new phytochemicals that could be developed as useful anti-inflammatory and anti-allergic agents to reduce the risk of many diseases. The activation of nuclear transcription factor-kappa B (NF-κB) has now been linked to a variety of inflammatory diseases, while data from numerous studies underline the importance of phytochemicals in inhibiting the pathway that activates this transcription factor. Moreover, the incidence of type I allergic disorders has been increasing worldwide, particularly, the hypersensitivity to food. Thus, a good number of plant products with anti-inflammatory and anti-allergic activity have been documented, but very few of these compounds have reached clinical use and there is scant scientific evidence that could explain their mode of action. Therefore, this paper intends to review the most salient recent reports on the anti-inflammatory and anti-allergic properties of phytochemicals and the molecular mechanisms underlying these properties.

1. Introduction

Plants have been the basis of many traditional medicine systems throughout the World for thousands of years and still remain as the main new source of structurally important chemical substances that lead to the development of innovative drugs [1,2]. The use of medicinal plants for the treatment of many diseases is associated with folk medicine from different parts of the World [3,4]. Nowadays, the search for new anti-inflammatory and anti-allergic agents from the huge array of medicinal plant resources is intensifying [5]. In fact, a variety of bioactive components have been shown to modulate inflammatory responses [6]. The inflammatory response is a critical protective reaction to irritation, injury, or infection, characterised by redness, heat, swelling, loss of function and pain [7]. Redness and heat result from an increase in blood flow, swelling is associated with increased vascular permeability, and pain is the consequence of activation and sensitisation of primary afferent nerve fibres [8].
The understanding of the cellular and molecular mechanisms involved in the inflammatory process has increased considerably in recent decades and this has permitted the discovery of many promising targets for the development of new drugs to treat chronic inflammatory diseases [8]. A great number of inflammatory mediators including kinins, platelet-activating factor (PAF), prostaglandins, leukotrienes, amines, purines, cytokines, chemokines and adhesion molecules, has been found to act on specific targets, leading to the local release of other mediators from leukocytes and the further attraction of leukocytes, such as neutrophils, to the site of inflammation [6].
The constant advent of new findings from immunohistochemical, biochemical, molecular and functional animal models, together with clinical trials, has greatly increased the interest in the study of the mechanisms that underlie the inflammatory process [8]. Recently, roles have been identified for several inflammatory cells and for a large number of inflammatory mediators in important pathologies not previously known to be linked to inflammation, such as Alzheimer’s disease and cardiovascular disorders including atherosclerosis, as well as cancer, reviewed in Akiyama et al. [9] and Libby et al. [10].
Natural products have long been, over the years, contributed to the development of modern therapeutic drugs [11]. Evidence exists that drugs derived from natural products can modulate various inflammatory mediators (arachidonic acid metabolites, peptides, cytokines, excitatory amino acids, etc.), the production and/or action of second messengers (cGMP, cAMP, protein kinases, and calcium), the expression of transcription factors such as AP-1, NF-κB, and proto-oncogenes (c-jun, c-fos, and c-myc), and the expression of key pro-inflammatory molecules such as inducible NO synthase (iNOS), cyclooxygenase (COX-2), cytokines (IL-1β, TNF-α), neuropeptides and proteases [6,7,8].
In parallel, the allergic process has an important inflammatory component in which mast cell activation and degranulation are the first phenomena observed. During this process, mast cells release several inflammatory mediators including histamine (5-HT), platelet aggregating factor (PAF), leukotrienes, and a variety of cytokines [12,13]. Hypersensitivity type I, an allergic reaction, is an IgE mediated immune response, resulting in histamine secretion from mast cells and blood basophils. The early phase reaction of allergy occurs within minutes after allergen exposure, whereas the late phase reaction occurs hours later and involves in cytokines secretion such as TNF-α and IL-4 [14].
The discovery of drugs that can be used for the treatment of inflammatory and allergic diseases is important in human health. Drug discovery from plants involves a multidisciplinary approach combining botanical, ethnobotanical, phytochemical and biological techniques [2]. Several natural product drugs of plant origin are in clinical use and some are undergoing Phase II and Phase III clinical trials [2,3,4,5]. This review highlights the current patents about the potential benefits and effectiveness of phytochemicals that have shown experimental or clinical anti-inflammatory or anti-allergic activities, the possible mechanism of action and their therapeutic value.

2. Major Classes of Phytochemicals

Plants are rich in a wide variety of secondary metabolites, the great majority of which do not appear to participate directly in growth and development [15]. Based on their biosynthetic origins, phytochemicals can be classified as carotenoids, phenolics, alkaloids, nitrogen-containing compounds, and organosulfur compounds. Interestingly, an important classification has been depicted by Liu [16] gathering nearly most of dietary phytochemical classes and the structures of their main chemically relevant components (Figure 1).
Molecules 18 00322 g001 550
Figure 1. Classification of dietary phytochemicals [16].
Figure 1. Classification of dietary phytochemicals [16].
Molecules 18 00322 g001
Phytochemicals, although noted for the complexity of their chemical structures and biosynthetic pathways, they have been widely perceived as biologically insignificant and have historically received little attention from most plant biologists. Organic chemists, however, have long been interested in these novel phytochemicals and have investigated their chemical properties extensively since the 1850s [15]. At present numerous studies have established that the phytochemical content of plants contributes to their protective effects against acute, chronic, and degenerative diseases [17,18,19].

3. Molecular Mechanism Underlying Phytochemicals

3.1. Inflammation

Wide ranges of phytoconstituents were responsible for anti-inflammatory activity including phenolics, alkaloids, and terpenoids [19]. However, efforts have focused on a class of compounds to elucidate the mechanisms of action of herbs, characterize and establish their potential utility as therapeutic agents in the treatment of inflammatory diseases.
Several mechanisms of action have been proposed to explain the anti-inflammatory actions of phytoconstituents, it consist broadly in: (1) Antioxidative and radical scavenging activities; (2) Modulation of cellular activities of inflammation-related cells (mast cells, macrophages, lymphocytes, and neutrophils); (3) Modulation of proinflammatory enzyme activities such as phospholipase A2 (PLA2), cyclooxygenase (COX), and lipoxygenase (LOX) and the nitric oxide (NO) producing enzyme, nitric oxide synthase (NOS); (4) Modulation of the production of other proinflammatory molecules; (5) Modulation of proinflammatory gene expression.
The Table 1 and Table 2 summarize the most studied and well-known phytochemicals including polyphenols (Figure 2), alkaloids (Figure 3), and terpenes (Figure 4) compounds with anti-inflammatory activities and their cellular and molecular mechanism. It should be noted that several other reports demonstrating the similar results are not represented here.
Molecules 18 00322 g002 550
Figure 2. Chemical structures of polyphenols. Modified from Vauzour [20].
Figure 2. Chemical structures of polyphenols. Modified from Vauzour [20].
Molecules 18 00322 g002
Table
Table 1. Anti-inflammatory activities of phytochemicals.
Table 1. Anti-inflammatory activities of phytochemicals.
Target pathwayEffectsCompoundsMechanism of actionReferences
Antioxidative and radical scavenging activities Promoting antioxidant enzymes activity Quercetin, resveratrol, curcumin, hydroxytyrosol, catechin, luteolinIncreasing the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), γ-glutamylcysteine synthetase (γ-GCS) NADPH:quinone oxidoreductase-1 (NQO1) and heat shock proteins 70 (HSP70) expression[21,22,23,24,25,26,27,28,29,30]
Inhibiting pro-oxidant enzymes activity Epigallocatechin, ECG, EGCGInhibiting lipoxygenase and cyclooxygenase[31]
Typheramide, alfrutamide, (−)-epicatechin, procyanidinInhibiting the activities of 5- lipoxygenase, 12-lipoxygenase and 15-lipoxygenase[32,33]
Curcumin, resveratrol, lupeolDecreasing the activity of iNOS and myeloperoxidase (MPO) level[24,30,34]
Ellagic acid gallic, acid corilagin, luteolinInhibiting tyrosinase and xanthine oxidase[35,36]
ResveratrolInhibiting O-acetyltransferase and sulfotransferase activities[37]
Prevent free radical attacks Epicatechin, rutin, mannitolScavenging hydroxyl radical (OH.)[38]
Ellagic acid gallic, acid corilagin, luteolin, β-carotene, tetrandrineScavenging superoxide radical (O2.)[35,36,39,40]
Quercetin, curcumin, lycopeneDecreasing MDA and lipoperoxidation[22,30,41]
Enhancing endogenous antioxidant moleculesQuercetin, resveratrol, catechin, proanthocyanidin B4, β-caroteneElevating cellular GSH content[21,24,26,42]
Modulation of cellular activities of inflammation-related cellsInhibition of enzymes involved in signaling transduction and cell activation processes (T cell, B lymphocyte) or cytokine production GenisteinInhibition of tyrosine protein kinaseinducing anti-proliferative effects on T cell, reducing IL-2 secretion and IL-2R expression[43,44]
Quercetin, kaempferol, apigenin, chrysin, luteolinInhibition of tyrosine protein kinaseinducing anti-proliferative effects on M-CSF-activated macrophages[45]
Inhibition of arachidonic acid release from membranes (degranulation) QuercetinInhibiting lysosomal enzyme release from stimulated neutrophil (elastase, β-glucuronidase)[46,47,48]
Impairing lysosomal enzyme release from polymorphonuclear leukocytes[47,49,50]
RutinReducing the polymorphonuclear neutrophils chemotaxis to FMLP[51]
Modulation of arachidonic acid (AA) related enzymes Inhibition of arachidonic acid metabolism Quercetin, kaempferol, myricetin, hesperetin, naringenin, quercetagetin, kaempferol-3-galactoside, scutellarein, ochnaflavone, amentoflavone, ginkgetin, morelloflavone, bilobetin, triptolide, papyriflavonol AInhibition of PLA2 activity[50,51,52,53,54,55,56,57,58,59]
Inhibition of proinflammatory enzymes (COX, LOX and NOS) from different sources Luteolin, 3',4'-dihydroxyflavone, galangin, morin, apigenein, chrysin, quercetin, myricetin, morusin, kuwanon C, sanggenon D, broussoaurone A, cycloheterophyllin, broussochalcone A broussoflavonol F, catechin, EGCG, resveratrol, xanthomicrol, cirsiliol, hypolaetin, diosmetin, tectorigenin, kuraridin, kurarinone, sophoraflavanone G, morusin, sanggenon B, kazinol B, rutaecarpine, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dlGG), curcumin, 4'-Me-gallocatechin, lonchocarpol A, tomentosanol D, catechins, catechins gallateInhibited COX activity[6,58,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74]
Sophoraflavanone G, kenusanone A, kuraridin, papyriflavonol A, sanggenon B, sanggenon D, boswellic acid, diphyllin acetylapiosideInhibited 5-LOX activity[69,75,76,77]
Quercetin, kaempferol, fisetin, quercetagetin-7-O-glucoside, hibifolin, hypolaetin, sideritoflavone, 5,6,7-trihydroxyflavone (baicalein)Inhibited 12-LOX activity[6,78]
Kaempferol, quercetin, myricetin, morin, cirsiliol, artoninsInhibited 5-LOX and 12-LOX activity[79,80,81,82]
QuercetinInhibited eNOS activity[83]
Modulation of the production of other proinflammatory molecules Inhibition of proinflammatory cytokines from different sources FormononetinInhibited iNOS activity[84]
Genistein, apigenin, quercetin, morin, wogonin, soyisoflavones, daidzein, glycitein, dlGG, paeonolInhibited NO production[71,85,86,87,88,89]
Genistein, quercetin, wogonin, baicalein, luteolin, nobiletin, paeonol, chlorogenic acid, hematein, aucubin, catalposide, tetrandrine, fangchinoline, colchicines, piperlactam SInhibited cytokine production : IL-1β, IL-6, TNF-α[89,90,91,92,93,94,95,96,97,98,99,100,101]
Curcumin, amoradicin, genistein, silybin, quercetin, wogonin, rutin, luteolin, eriodictyol, hesperitin, EGCG, geraniin, corilagin, pinoresinol, woorenoside, lariciresinol glycoside, terpinen-4-ol, physalin B, triptolide, lupeol, [6]-shogaol, vitamin D, cepharanthine, fangchinoline, adenosineInhibited TNF-α production[34,98,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123]
Apigenin, wogonin, bacaleinInhibited IL-6 and IL-8 production[124,125]
Genistein, ilicic acid, inuviscolide acid, tryptanthrinInhibited LTB4 production[126,127,128]
Saikosaponins, masticaienonic acid, masticadienolic acid, morolic acidReducing LTC4 production[128,129,130,131]
Chrysin, flavone, galangin, kaempferol, quercetin, salidroside, syringin, phillyrin, coniferin, tryptanthrinInhibited TXB2 production[79,128,132]
Lupeol, paeonol, quercetin, salidroside, syringin, phillyrin, tectorigenin, tectoridin, platycodin D, β-turmerone, ar-turmerone, rutaecarpineInhibited PGE2 production[34,89,105,132,133,134,135,136]
Modulation of proinflammatory gene expression Inhibition of the expression of various inflammation-related proteins/enzymes, by suppressing activation of transcription factors such as NF-κB and AP-1 Baicalein, oroxylin A, baicalin, skullcapflavone IIInhibited eotaxin production[137]
Rutin, bilobetin, ginkgetin, isoginkgetin, ochnaflavone, morusin, kuwanon C, kazinol B, sanggenon B and D, echinoisoflavanone, wogonin, apigenin, kaempferol, genistein, chrysin, luteolin, quercetin, myricetin, flavone, tectorigenin, nobiletin, oroxylin A, galangin, EGCG, isoliquiritigenin, silymarin, curcumin, flavones, daidzein, glycitein, isorhamnetin, naringenin, pelargonidin, soyisoflavones, wogonin, resveratrol, triptolide, lupeol, butyrate, zeaxanthin, β-caroteneInhibited iNOS expression[56,84,87,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157]
Bilobetin, ginkgetin, paeonol, tectorigenin, tectoridin, platycodin D, apigenin, genistein, kaempferol, quercetin, myricetin, nobiletin, rhamnetin, eriodictyol, luteolin, fisetin, phloretin, wogonin, galangin, oroxylin A, lupeol, isoliquiritigenin, amentoflavone, butyrate, ursolic acid, iridoid, pendunculariside, agnuside, ferulic acid, [6]-Gingerol, resveratrol, EGCGInhibited COX-2 expression[56,89,133,134,140,141,142,143,147,154,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172]
Lycopene, dlGG, wogonin, genistein, apigenin, kaempferol, myricetin, oroxylin, silymarin, β-carotene, resveratrol, quercetin, avicins, parthenolide, chlorogenic acid, triptolide, capsaicin, butyrate, luteolin, curcuminInhibition of NF-κB activation[41,71,87,90,140,142,145,148,157,171,173,174,175,176,177,178,179,180,181]
Hematein, casearinols A and B, casearinones A and B, colchicineInhibited the expression of ICAM-1 and VCAM-1 on the surface of different cells[95,182,183]
Molecules 18 00322 g003 550
Figure 3. Chemical structures of alkaloids. Adapted from Gautam and Jachak [7].
Figure 3. Chemical structures of alkaloids. Adapted from Gautam and Jachak [7].
Molecules 18 00322 g003
Molecules 18 00322 g004 550
Figure 4. Chemical structures of terpenoids. Adapted from Gautam and Jachak [7].
Figure 4. Chemical structures of terpenoids. Adapted from Gautam and Jachak [7].
Molecules 18 00322 g004
Table
Table 2. Phytochemicals with anti-inflammatory effects and their clinical efficiencies.
Table 2. Phytochemicals with anti-inflammatory effects and their clinical efficiencies.
Herbal formulation/CompoundIndicationClinical efficiencyReferences
CurcuminAntirheumatic
  • - Exerted an antirheumatic activity comparable to that of phenylbutazone
[184]
Active constituents of honeysuckle (Lonicera japonica) stemAnti-inflammatory and analgesic effect
  • - Prevented croton oil induced-mice ear edema
  • - Inhibited arachidonic acid-induced mice ear edema
  • - Inhibited writhing reaction in mice induced by acetic acid
[185]
Cocoa extracts containing polyphenols enriched with procyanidinsCOX and/or lipooxygenase (LOX) modulators, NO or NO-synthase modulators, as non-steroidal anti-inflammatory agents, platelet aggregation modulators, antioxidants, inhibitors of oxidative DNA damage and DNA topoisomerase II inhibitor
  • - Inhibition of the COX-1 and COX-2 activities from ram seminal vesicle and sheep placenta
  • - Inhibition of DNA topoisomerase II
  • - Effect on LPS-induced nitrite production by γ-interferon-primed monocytes/macrophages
  • - Effective on cancer cells such as: KB Nasopharyngeal/HeLa cell line, HCT-116 cell line, ACHN renal cell line, A-549 lung cell line, SK-5 melanoma cell line, MCF-7 breast cell line, CCRF-CEM T-cell leukemia cell line, MDA MB231 breast cell line, PC-3 prostate cancer cell line, Hela cervical cancer cell line, SKBR-3 breast cancer cell line, CRFK normal kidney cell line, MDCK normal kidney line, canine GH normal kidney cell line
[186]
Composition comprising: Ajuga turkestanica, Panax quinquefolius, Rhodiola rosea root, Glycyrrhiza glabra, Morinda citrifolia fruit, Uncaria tomentosa inner bark, Capsicum frutescens, chondroitin sulfate, Curcuma longa, Dioscorea villosa, glucosamine sulfate, Harpagophytum procumbens and Tribulus terrestrisTreating arthritis and its symptoms, rheumatoid arthritis and osteoarthritis as well as any inflammatory condition of the joints and their symptoms, pain swelling, heat, redness and limitation of movement
  • - The formulation is revealed to be an excellent alternative for the handling of osteoarthritic patients with femoropatteral knee, chondromalacia and meniscopathy
[187]
Synergistic mixture of standardized Boswellia serrata extract, glucosamine salts, and curcuminoids. The composition optionally containing bromelain, chondroitin, methylsulphonylmethane, resveratrol, extracts of white willow and ginger, and quercetin.Treating and controlling inflammatory diseases, preventing and curing cancer
  • - Protective effect on adjuvant induced arthritis in winstar albino rats
[188]
Extracts of Vitex leucoxylon and its constituents: corosolic acid, agnuside and 6-O-caffeoylarbutinInflammatory diseases, diabetic conditions, liver disorders and free radical mediated diseases
  • - Anti-inflammatory activity by preventing carrageenin induced paw edema in albino wistar rats
[189]
Carotenoids, and xanthophyll carotenoids, or analogs or derivatives of astaxanthin, lutein, zeaxanthin, lycoxanthin, lycophyll, or lycopeneReduce the adverse side effects associated with administration of COX-2 selective inhibitor drugs. Reduce peroxidation of low density lipoprotein (LDL) and other lipids in the serum and plasma cell membranes, and reduce the incidence of deleterious clinical cardiovascular events of subjects undergoing COX-2 selective inhibitor drug therapy
  • - Inhibition of the superoxide anion
  • - Decrease of the lag time for LDL conjugated diene formation and increase of the levels of thiobarbituric-acid-reactive-substances (TBARS)
  • - Increase of isoprostane formation from lipid vesicles enriched with arachidonic acid
  • - Increase in electron density associated with the upper hydrocarbon core of the membrane
[190]
Two herbal compositions. The first composition comprises Radix Clematidis, Radix Angelicae Pubescentis, Rhizoma et Radix Notopterygii, Radix Saposhnikoviae, and Radix Gentianae Macrophyllae. The second composition comprises Rhizoma Chuanxiong, Radix Angelicae Sinensis, Cortex Eucommiae, and Radix Achyranthis BidentataeasPreventive and therapeutic effects on alleviating symptoms associated with inflammatory and rheumatic diseases
  • - Effective on patients with rheumatoid arthritis and lack severe side effects
[191]
[5-hydroxy-7-methoxy-2-(4'-methoxyphenyl}-4-oxo-4H-chromen-8-yl] sulfonic acid monoester obtainable by extraction of plant material selected from Sidastrum acuminatum, Sidastrum burrerense, Sidastrum E.G. Baker, Sidastrum kicranthum, Sidastrum lodiegense, Sidastrum multiflorum, Sidastrum micranthum, Sidastrum paniculatum, Sidastrum strictum, Sidastrum tehuacanum or Sidastrum quinquenerviumInhibits the arachidonic acid cascade
  • - Antiinflammatory properties keratinocyte monolayer PGE 2 model
  • - Induction of gene expression by transglutaminase which plays a crucial role in the formation of jacket surrounding the keratinocytes
[192]
Oil-soluble licorice extractInhibitory effect on: hyaluronidase activity, hexosaminidase release, platelet aggregation, and phospholipase A2 activity, and which is suitably used especially as an external preparation for skin
  • - Inhibitory effect on hyaluronidase activity of bovine testis
  • - Inhibitory effect on hexosaminidase release from rat basophilic leukemia cells - Inhibitory effect on rabbit platelet aggregation
  • - Inhibitory effect on phospholipase A2 activity of rat leukemia cells
[193]
Extracts or fractions of Aphanamixis polystachyaDiseases mediated by 5-lipoxygenase enzyme
  • - Inhibition of 5-Lipoxygenase activity
  • - Inhibition of tyrosinase activity
  • - Anti-oxidant and anti-inflammatory activities by acting on the following target molecules : nitrite, TNF-α, IL-1β and the levels of lipid peroxidation and glutathoine in the liver of Freund complete adjuvant induced arthritis model of Sprague Dawley rats
[194]
Extracts and fractions from Hypericum gentianoidesInhibition of inflammation, PGE2-mediated disease, disorder or condition, a COX-mediated disease, disorder or condition, or an infection of HIV
  • - Reduced LPS-induced COX-2 enzyme in RAW 264.7 macrophages
  • - Reduced LPS-induced PGE2 in RAW 264.7 macrophages
  • - Reduced HIV infection in vitro
[195]
Compositions containing one or more of a flavone or flavonoid glycoside a non-bovine heavily sulfated proteoglycan, an unrefined olive kernel extract, a hexosamine sulfate, a histamine-1 and histamine-3 receptor agonist, an antagonist of CRH, a long-chain unsaturated fatty acid, a phospholipid, Krill oil, a polyamine, glutiramer acetate and interferon Treatment of inflammatory conditions. Inhibitors of mast cell activation and secretion in the brain as in multiple sclerosis
  • - Increased the absorption of a proteoglycan (chondroitin sulfate) from the intestine into the general circulation in Sprague-Dawley rats
[196]
Berry extract containing stable anthocyaninTreating inflammation, oxidative damage, or cancer
  • - Inhibition of proliferation of HT-29 human colorectal cancer cells
  • - Ihibition of IL-12 release from murine dendritic cells
[197]
Free-B-Ring flavonoids from Scutellaria baicalensisTreatment of COX-2 mediated diseases and conditions
  • - Inhibition of COX-1 of THP-1 cells and COX-2 of HOSC cells
[198]
The inflammatory process can be initiated by various inflammatory stimuli including viruses, chemicals, and reactive oxygen/nitrogen species, which subsequently increases the synthesis and secretion of proinflammatory cytokines. Moreover, the unchecked activation of NF-κB/AP-1 and the production of TNF-α signaling have provided compelling evidence about the critical role for these factors in coupling inflammation and many chronic diseases. Phytochemicals have been shown to modulate various points in these inflammatory processes [6]. These modulations serve as controlling points where the amplification of the inflammatory processes can be disconnected and thereby reduce subsequent diseases risk.

3.2. Allergy

The allergic process has an important inflammatory component. Hypersensitivity reactions can be divided into four types:
Type I: Called immediate or anaphylactic hypersensitivity mediated by IgE. Mast cells and basophils play a central role in immediate allergic inflammation through releasing chemical mediators such as histamine and cysteinyl leukotrienes, cytokines and chemokines. The reaction may involve skin (eczema), eyes (conjunctivitis), nasopharynx (rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis).
Type II: Known as antibody-mdiated cytotoxicity mediated by antibodies of the IgM or IgG classes and complement. Antibodies directed against cell surface antigens causes cell damage such as hemolytic disease of the newborn (Rh disease) and myasthenia gravis (MG).
Type III: Known as immune complex hypersensitivity mediated by IgG or IgM classes. The reaction may be general (serum sickness) or may involve individual organs including skin (systemic lupus erythematosus), joints (rheumatoid arthritis) or other organs.
Type IV: Known as cell mediated or delayed type hypersensitivities. These reactions are mediated by CD4+T cells, and involved in the pathogenesis of many autoimmune diseases (multiple sclerosis). Another form of delayed hypersensitivity is contact dermatitis (poison ivy).
Therapeutic intervention in allergic disease has thus commonly focused on suppressing IgE production and blocking the action of histamine, thus regulating the expression and/or release of cytokines, chemokines, adhesion molecules, and or/inflammatory mediators. Below (Table 3 and Table 4) are summarized some of the most studied and well-known phytochemicals with anti-allergic effects and their mode of action. Here, too, several other reports demonstrating the similar results are not represented.
Table
Table 3. Anti-allergic activities of phytochemicals.
Table 3. Anti-allergic activities of phytochemicals.
Target pathwayEffectsCompoundsMechanism of actionRef.
Effect on IgE-mediated Hypersensitivity (Type I)Inhibition of chemical mediator release and cytokine production by mast, basophil or T cellsLuteolin, quercetin, baicaleinInhibited the release of histamine, leukotrienes and prostaglandin D2 Inhibited IgE-mediated TNF-α and IL-6 production[199]
Luteolin, quercetin, baicalein, apigeninInhibited the p44/42 MAPK phosphorylation in response to crosslinkage of FcεRI[200]
TetrandrineSuppression of prostaglandin and leukotriene generation[201]
Coixol, pseudoephedrine, mallotophilippen A and BInhibited the release of histamine[202,203,204]
Apigenin, luteolin, 3.6-dihydroxy flavones, fisetin, kaempferol, quercetin, myricetinInhibition of the hexosaminidase release Suppression of cysteinyl leukotriene synthesis[205]
Flavone, quercetinInhibition of transport ATPase in histamine secretion[206,207]
IsoquercitrinInhibited carbachol and leukotriene D4 production[208]
Cirsiliol (3',4',5-trihydroxy-6,7-dimethoxy flavone)Suppressed cysteinyl leukotrienes release[80]
Ayanin, luteolin, apigenin, diosmetin, fisetin, ombuin, quercetin, kaempferol (other compounds see Table 1)Suppression of IL-4 synthesis (other cytokines see Table 1)[209]
Inhibition of signal transduction and gene expression in mast, basophil or T cells Preventing allergic asthmaMallotophilippen A and B (other compounds see Table 1)Inhibited iNOS gene expression (other enzymes see Table 1)[204]
Luteolin, apigenin, fisetinSuppressed CD40 ligand expression[209,210]
NobiletinReduced eotaxin expression[211]
Luteolin, apigenin, fisetinInhibited AP-1 and NFAT activation[210]
Dietary polyphenolsInterfer with activated T-helper 2[212]
Quercetin, provinol, flavin-7Anti-inflammatory effects in experimental allergic asthma[213,214,215]
Effect on cell-mediated hypersensitivity (type IV)Preventing contact dermatitisPolyphenol (extract from the bark of Acacia mearnsii) Inhibited itching in atopic dermatitis by preventing the skin from drying [216]
Polyphenols and anthocyanins derived from Vaccinium uliginosum LImprove atopic dermatitis disease in mice by reducing the Th2/Th1 ratio, IL-4 and IL-13 (as Th2 cytokines), IFN-γ, and IL-12 (as a Th1 cytokine) in spleens Decreased gene expression, such as IL-4, IL-5, CCR3, eotaxin-1, IL-12, IFN-γ, MCP-1, and IL-17, and suppressed Th 17[217]
Attenuating autoimmune disordersImproving multiple sclerosis (MS) diseaseDietary polyphenols, carotenoids, curcuminInhibited neuroinflammation in MS Inhibited the differentiation and expansion of Th17 cells in circulation induced by inflammatory cascade; Enhanced the expression of ZO-1; Down-regulated expression of CXC chemokines and receptor; Decreased Th17 cells to transmigrate across the blood brain barrier and the inhibition of autoreactive T cells transmigration can reduce neuroinflammation; Blocked IL17 and others, which lead to centtral system nervous tissue destruction in MS[218,219,220]
Table
Table 4. Phytochemicals with anti-allergic effects and their clinical efficiencies.
Table 4. Phytochemicals with anti-allergic effects and their clinical efficiencies.
Herbal formulations/CompoundsIndicationClinical efficiencyRef.
Seeds of Cucurbita moschata and flowers of Carthamus tinctorius and at least one crude drug selected from Plantago asiatica, Lonicera japonica, Glycyrrhiza uralensis, Coix lachrymal-jobi var. ma-yuen, Zingiber officinale, Curcuma longa, Curcuma zedoaria and Artemisia argyi.Prevention or therapy of pollen allergy, allergic rhinitis, atopic dermatitis, asthma or urticariaAnimal trials: Inhibiting the production of total IgE antibodies in the blood of mice sensitized with cedar pollen Human trials: Therapeutic effects on patients suffering from cedar pollen allergy[221]
Formulation(s) comprises of Tinospora cardifolia, Piper longum, Albizia lebbeck and Curcuma amadaTreatment of allergyDecreased the histamine release (mast cell degranulation) in rats-Reduced lipid peroxidation and superoxide dismutase activity, and increased catalase activity in tissues (liver, kidney and heart) rats[222]
The composition comprises at least one of the following ingredients: luteolin from Perilla leaf or seed, Cinnamon, Kiwi, Picao preto, Hesperidin, Acerola cherry, Guaco, Holy Basil, Kakadu, Solamum, Rosmarinic acid, Tinospora and AframomumInhibits and/or mitigates an allergic response Inhibition of the IgE secretion by U266 human myeloma cells-Reduction of the IgE receptor expression by RBL-2H3 cells-Inhibiting or preventing the release of mediators such as histamine, PGD 2 and LTC4 by RBL-2H3 cells [223]
Flavonoid and/or a flavonoid derivative (Troxerutin or Veneruton®)Treating symptoms of common cold, allergic rhinitis and infections relating to the respiratory tractShowed success results on different patients suffering from common cold symptoms-Reduced the symptom score after treatment of patients suffering from allergic airway conditions[224]
Kaempferol, apigeninTreatment of contact dermatisInhibited iNOS induction produced in contact dermatitis[225]
DehydrocorydalineTreatment of hypersensivities reactionsInhibited the induction phase of picryl chloride-induced contact dermatitisin mice[226]
Despite the promising use of plant products for medicinal purposes for the evidences discussed above, it is worth noting that many of the dietary phytochemicals or natural products are not without cytotoxic effect and can originate various allergic reactions. The well known allergenic phytoconstituents are sesquiterpene lactones and furanocoumarins. Many of plants containing sesquiterpene lactones cause allergic contact dermatitis and effective treatments are scarce. Other natural products such as flavonoids [227], alkaloids [228,229], and terpenoids [230,231] can also cause allergic reactions. Phenolics such as: anethol, atranorin, catechols, cinnamon, cinnamic derivatives, benzoic acid, curcumin, eugenol, isoeugenol, litreol, ginkgolic acid, resorcinols, oak moss resin, tertiaery-butylhydroquinone, urushiol, usnic acid. Alkaloids such as: atropine, pilocarpine, quinine, thebaine, codeine, and terpenoids such as: abietic acid, alantolactone, artesunate, asiaticoside, asiatic and madecassic acids, carvone, citral, β-cyclocostunolide, dehydroabietic acid, eucalyptol, farnesol, geraniol, limonene, α-pinene, phellandrene, linalool, menthol, myrrh, parthenolide, polygodial, sesquiterpenes, sesquiterpenes, thymol (reviewed in Rios et al. [232]). While flavonoids are only weakly antigenic and usually do not induce immune reactions after consumption or therapeutic application, antibodies against flavonoids have been found in human blood [227]. Adverse side effects of polyphenol intake on cardiovascular diseases have been also reported. A high consumption of polyphenol (2 g chlorogenic acid per day during 1 week) significantly increased homocysteinemia [233,234]. The consumption of tea has been associated with a higher bone mineral density [235]. A recent randomized crossover trial [236] revealed that moderate consumption of red wine reduced erythrocyte superoxide dismutase activity. Another randomized double-blind, placebo-controlled trial showed that the combination of vitamin C and grape-seed polyphenols increases blood pressure [237].

4. Conclusions

Phytochemicals show both anti-inflammatory and anti-allergic activities in vitro and in vivo. Several cellular action mechanisms are proposed to explain their mode of action. Any single mechanism could not explain all of their in vivo activities. They probably have multiple cellular mechanisms acting on multiple sites of cellular machinery. The continual efforts will provide new insight into the anti-inflammatory and anti-allergic activities of phytochemicals, and eventually lead to development of a new class of anti-inflammatory and anti-allergic agents. However, the concern and difficulties related to the investigation of herbal medicines have precluded the financial incentives that could be provided to pharmaceutical industries. As a function of such difficulties, few herbal drugs have been studied adequately and well-controlled double-blind clinical trials to prove their safety and efficacy have been lacking. The trend today, especially in an industrial setting, is to seek bioactive compounds from plants that will serve as lead compounds for synthetic or semisynthetic development, and knowledge of the main pharmacologically active plant compounds is an essential requirement to standardize procedures for obtaining herbal remedies in order to replace crude products with modern pharmacological formulations.

Acknowledgments

The authors acknowledge the funding of this study by Mohammad Hussein Al-Amoudi Chair for Diabetic Foot Research and also the Deanship of Scientific Research, at King Abdulaziz University.

References

  1. Fabricant, D.S.; Farnsworth, N.R. The value of plants used in traditional medicine for drug discovery. Environ. Health Perspect. 2001, 109, 69–75. [Google Scholar]
  2. Jachak, S.M.; Saklani, A. Challenges and opportunities in drug discovery from plants. Curr. Sci. 2007, 92, 1251–1257. [Google Scholar]
  3. Harvey, A. Strategies for discovering drugs from previously unexplored natural products. Drug Discov. Today 2000, 5, 294–300. [Google Scholar] [CrossRef]
  4. Bakhotmah, B.A.; Alzahrani, H.A. Self-reported use of complementary and alternative medicine (CAM) products in topical treatment of diabetic foot disorders by diabetic patients in Jeddah, Western Saudi Arabia. BMC Res. Notes 2010, 2010, 254. [Google Scholar]
  5. Bellik, Y.; Hammoudi, S.M.; Abdellah, F.; Iguer-Ouada, M.; Boukraâ, L. Phytochemicals to prevent inflammation and allergy. Recent Pat. Inflamm. Allergy Drug Discov. 2012, 6, 147–158. [Google Scholar] [CrossRef]
  6. Kim, Y.S.; Young, M.R.; Bobe, G.; Colburn, N.H.; Milner, J.A. Bioactive food components, inflammatory targets, and cancer prevention. Cancer Prev. Res. 2009, 2, 200–208. [Google Scholar] [CrossRef]
  7. Gautam, R.; Jachak, S.M. Recent developments in anti-infammatory natural products. Med. Res. Rev. 2009, 29, 767–820. [Google Scholar] [CrossRef]
  8. Calixto, J.B.; Otuki, M.F.; Santos Adair, R.S. Anti-inflammatory compounds of plant origin. Part I. Action on arachidonic acid pathway, nitric oxide and nuclear factor κB (NF-κB). Planta Med. 2003, 69, 973–983. [Google Scholar] [CrossRef]
  9. Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G.M.; Cooper, N.R.; Eikelenboom, P.; Emmerling, M.; Fiebich, B.L.; et al. Inflammation and Alzheimer’s disease. Neurobiol. Aging 2000, 21, 383–421. [Google Scholar]
  10. Libby, P.; Ridker, P.M.; Maseri, A. Inflammation and atherosclerosis. Circulation 2002, 105, 1135–1143. [Google Scholar] [CrossRef]
  11. Cragg, G.M.; Newman, D.J.; Snader, K.M. Natural products in drug discovery and development. J. Nat. Prod. 1997, 60, 52–60. [Google Scholar]
  12. Brito, F.A.; Lima, L.A.; Ramos, M.F.S.; Nakamura, M.J.; Cavalher-Machado, S.C.; Siani, A.C.; Henriques, M.G.M.O.; Sampaio, A.L.F. Pharmacological study of anti-allergic activity of Syzygium cumini (L.) Skeels. Braz. J. Med. Biol. Res. 2007, 40, 105–115. [Google Scholar]
  13. Nettis, E.; Colanardi, M.C.; Ferrannini, A.; Tursi, A. Antihistamines as important tools for regulating inflammation. Curr. Med. Chem. Anti Inflamm. Anti Allergy Agents 2005, 4, 81–89. [Google Scholar] [CrossRef]
  14. Tewtrakul, S.; Itharat, A. Anti-allergic substances from the rhizomes of Dioscorea membranacea. Bioorg. Med. Chem. 2006, 14, 8707–8711. [Google Scholar] [CrossRef]
  15. Croteau, R.; Kutchan, T.M.; Lewis, N.G. Natural Products (Secondary Metabolites). In Biochemistry & Molecular Biology of Plants; Buchanan, B., Gruissem, W., Jones, R., Eds.; Wiley: Hoboken, NJ, USA, 2000; Volume 24, pp. 1250–1318. [Google Scholar]
  16. Liu, R.H. Potential synergy of phytochemicals in cancer prevention: Mechanism of action. J. Nutr. 2004, 134, 3479S–3485S. [Google Scholar]
  17. Calabrese, V.; Cornelius, C.; Dinkova-Kostova, A.T.; Iavicoli, I.; Di Paola, R.; Koverech, A.; Cuzzocrea, S.; Rizzarelli, E.; Calabrese, E.J. Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity. Biochim. Biophys. Acta. 2012, 1822, 753–783. [Google Scholar]
  18. Nichenametla, S.N.; Taruscio, T.G.; Barney, D.L.; Exon, J.H. A Review of the effects and mechanisms of polyphenolics in cancer. Crit. Rev. Food Sci. Nutr. 2006, 46, 161–183. [Google Scholar]
  19. Arya, V.; Arya, M.L. A Review on anti-inflammatory plant barks. Int. J. Pharm.Tech. Res. 2011, 3, 899–908. [Google Scholar]
  20. Vauzour, D. Dietary polyphenols as modulators of brain functions: Biological actions and molecular mechanisms underpinning their beneficial effects. Oxid. Med. Cell. Longev. 2012. [Google Scholar] [CrossRef]
  21. Alía, M.; Ramos, S.; Mateos, R.; Granado-Serrano, A.B.; Bravo, L.; Goya, L. Quercetin protects human hepatoma HepG2 against oxidative stress induced by tert-butyl hydroperoxide. Toxicol. Appl. Pharmacol. 2006, 212, 110–118. [Google Scholar] [CrossRef]
  22. Pandey, K.B.; Rizvi, S.I. Protective effect of resveratrol on markers of oxidative stress in human erythrocytes subjected to in vitro oxidative insult. Phytother. Res. 2010, 24, S11–S14. [Google Scholar] [CrossRef]
  23. Scharf, G.; Prustomersky, S.; Knasmuller, S.; Schulte-Hermann, R.; Huber, W.W. Enhancement of glutathione and g-glutamylcysteine synthetase, the rate limiting enzyme of glutathione synthesis, by chemoprotective plant-derived food and beverage components in the human hepatoma cell line HepG2. Nutr. Cancer 2003, 45, 74–83. [Google Scholar] [CrossRef]
  24. Gulcin, I. Antioxidant properties of resveratrol: A structure-activity insight. Innovat. Food Sci. Emerg Tech. 2010, 11, 210–218. [Google Scholar] [CrossRef]
  25. Fki, I.; Sahnoun, Z.; Sayadi, S. Hypocholesterolemic effects of phenolic extracts and purified hydroxytyrosol recovered from olive mill wastewater in rats fed a cholesterol-rich diet. J. Agric. Food. Chem. 2007, 55, 624–631. [Google Scholar]
  26. Du, Y.; Guo, H.; Lou, H. Grape seed polyphenols protect cardiac cells from apoptosis via induction of endogenous antioxidant enzymes. J. Agric. Food. Chem. 2007, 55, 1695–1701. [Google Scholar]
  27. Rodrigo, R.; Miranda, A.; Vergara, L. Modulation of endogenous antioxidant system by wine polyphenols in human disease. Clin. Chim. Acta 2011, 412, 410–424. [Google Scholar]
  28. Leung, H.W.; Kuo, C.L.; Yang, W.H.; Lin, C.H.; Lee, H.Z. Antioxidant enzymes activity involvement in luteolin-induced human lung squamous carcinoma CH27 cell apoptosis. Eur. J. Pharmacol. 2006, 534, 12–18. [Google Scholar] [CrossRef]
  29. Vanhees, K.; van Schooten, F.J.; Moonen, E.J.; Maas, L.M.; van Waalwijk van Doorn-Khosrovani, S.B.; Godschalk, R.W.L. Maternal intake of quercetin during gestation alters ex vivo benzo[a]pyrene metabolism and DNA adduct formation in adult offspring. Mutagenesis 2012, 27, 445–451. [Google Scholar] [CrossRef]
  30. Shen, S.Q.; Zhang, Y.; Xiang, J.J.; Xiong, C.L. Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes. World J. Gastroenterol. 2007, 13, 1953–1961. [Google Scholar]
  31. Hong, J.; Smith, T.J.; Ho, C.T.; August, D.A.; Yang, C.S. Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. Biochem. Pharmacol. 2001, 62, 1175–1183. [Google Scholar]
  32. Park, J.B. Effects of typheramide and alfrutamide found in Allium species on cyclooxygenases and lipoxygenases. J. Med. Food 2011, 14, 226–231. [Google Scholar]
  33. Schewe, T.; Sadik, C.; Klotz, L.O.; Yoshimoto, T.; Kuhn, H.; Sies, H. Polyphenols of cocoa: Inhibition of mammalian 15-lipoxygenase. Biol. Chem. 2001, 382, 1687–1696. [Google Scholar]
  34. Fernandez, M.A.; de las Heras, B.; Garcia, M.D.; Saenz, M.T.; Villar, A. New insights into the mechanism of action of the anti-inflammatory triterpene lupeol. J. Pharm. Pharmacol. 2001, 53, 1533–1539. [Google Scholar]
  35. Rangkadilok, N.; Sitthimonchai, S.; Worasuttayangkurn, L.; Mahidol, C.; Ruchirawat, M.; Satayavivad, J. Evaluation of free radical scavenging and antityrosinase activities of standardized longan fruit extract. Food Chem. Toxicol. 2007, 45, 328–336. [Google Scholar] [CrossRef]
  36. Leopoldini, M.; Russo, N.; Toscano, M. The molecular basis of working mechanism of natural polyphenolic antioxidants. Food Chem. 2011, 125, 288–306. [Google Scholar] [CrossRef]
  37. Cadenas, S.; Barja, G. Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3. Free Radic. Biol. Med. 1999, 26, 1531–1537. [Google Scholar] [CrossRef]
  38. Hanaski, Y.; Ogawa, S.; Fukui, S. The correlation between active oxygen scavenging and antioxidative effects of flavonoids. Free Radic. Biol. Med. 1994, 16, 845–850. [Google Scholar]
  39. Mascio, P.D.; Murphy, M.E.; Sies, H. Antioxidant defense systems: The role of carotenoids, tocopherols, and thiols. Am. J. Clin. Nutr. 1991, 53, 194S–200S. [Google Scholar]
  40. Chen, Y.; Tsai, Y.H.; Tseng, S.H. The potential of tetrandrine as a protective agent for ischemic stroke. Molecules 2011, 16, 8020–8032. [Google Scholar] [CrossRef]
  41. Srinivasan, M.; Sudheer, A.R.; Pillai, K.R.; Kumar, P.R.; Sudhakaran, P.R.; Menon, V.P. Lycopene as a natural protector against gamma-radiation induced DNA damage, lipid peroxidationand antioxidant status in primary culture of isolated rat hepatocytes in vitro. Biochim. Biophys. Acta 2007, 1770, 659–665. [Google Scholar] [CrossRef]
  42. Yang, S.C.; Huang, C.C.; Chu, J.S.; Chen, J.R. Effects of β-carotene on cell viability and antioxidant status of hepatocytes from chronically ethanol-fed rats. Br. J. Nutr. 2004, 92, 209–215. [Google Scholar] [CrossRef]
  43. Manna, S.K. Double-edged sword effect of biochanin to inhibit nuclear factor kappaB: Suppression of serine/threonine and tyrosine kinases. Biochem. Pharmacol. 2012, 15, 1383–1392. [Google Scholar]
  44. Trevillyan, J.M.; Lu, Y.L.; Atluru, D.; Phillips, C.A.; Bjorndahl, J.M. Differential inhibition of T cell receptor signal transduction and early activation events by selective inhibitor of protein-tyrosine kinase. J. Immunol. 1990, 145, 3223–3230. [Google Scholar]
  45. Comalada, M.; Ballester, I.; Bailon, E.; Sierra, S.; Xaus, J.; Galvez, J.; de Medina, F.S.; Zarzuelo, A. Inhibition of pro-inflammatory markers in primary bonemarrow-derived mouse macrophages by naturally occurring flavonoids: Analysis of the structure-activity relationship. Biochem. Pharmacol. 2006, 72, 1010–1021. [Google Scholar] [CrossRef]
  46. Pečivová, J.; Mačičková, T.; Sviteková, K.; Nosá, R. Quercetin inhibits degranulation and superoxide generation in PMA stimulated neutrophils. Interdiscip. Toxicol. 2012, 5, 81–83. [Google Scholar]
  47. Kanashiro, A.; Souza, J.G.; Kabeya, L.M.; Azzolini, A.E.; Lucisano-Valim, Y.M. Elastase release by stimulet neutrophils inhibited by flavonoids: Importance of the catechol group. Z. Naturforsch. C 2007, 62, 357–361. [Google Scholar]
  48. Tordera, M.; Ferrandiz, M.L.; Alcaraz, M.J. Influence of anti-inflammatory flavonoids on degranulation and arachidonic acid release in rat neutrophils. Z. Naturforsch.C 1994, 49, 235–240. [Google Scholar]
  49. Berton, G.; Schneider, C.; Romeo, D. Inhibition by quercetin of activation of polymorphonuclear leukocyte functions. Stimulus-specific effects. Biochim. Biophys. Acta 1980, 595, 47–55. [Google Scholar] [CrossRef]
  50. Lee, T-P.; Matteliano, M.L.; Middletone, E. Effect of quercetin on human polymorphonuclear leukocyte lysosomal enzyme release and phospholipid metabolism. Life Sci. 1982, 31, 2765–2774. [Google Scholar] [CrossRef]
  51. Selloum, L.; Bouriche, H.; Tigrine, C.; Boudoukha, C. Anti-inflammatory effect of rutin on rat paw oedema, and on neutrophils chemotaxis and degranulation. Exp. Toxicol. Pathol. 2003, 54, 313–318. [Google Scholar] [CrossRef]
  52. Lanni, C.; Becker, E.L. Inhibition of neutrophil phospholipase A2 by p-bromophenylacyl bromide, nordihydroguaiaretic acid, 5,8,11,14-eicosatetrayenoic acid and quercetin. Int. Arch. Allergy Appl. Immunol. 1985, 76, 214–217. [Google Scholar] [CrossRef]
  53. Chiou, Y.L.; Lin, S.R.; Hu, W.P.; Chang, L.S. Quercetin modulates activities of Taiwan cobra phospholipase A2 via its effects on membrane structure and membrane-bound mode of phospholipase A2. J. Biosci. 2012, 37, 277–87. [Google Scholar] [CrossRef]
  54. Gil, B.; Sanz, M.J.; Terencio, M.C.; Ferrandiz, M.L.; Bustos, G.; Paya, M.; Gunasegaran, R.; Alcaraz, M.J. Effects of flavonoids on Naja naja and human recombinant synovial phospholipase A2 and inflammatory responses in mice. Life Sci. 1994, 54, PL333–PL338. [Google Scholar] [CrossRef]
  55. Chang, H.W.; Baek, S.H.; Chung, K.W.; Son, K.H.; Kim, H.P.; Kang, S.S. Inactivation of phospholipase A2 by naturally occurring biflavonoid, ochnaflavone. Biochem. Biophys. Res. Commun. 1994, 205, 843–849. [Google Scholar]
  56. Gil, B.; Sanz, M.J.; Terencio, M.C.; Gunasegaran, R.; Paya, M.; Alcaraz, M.J. Morelloflavone, a novel biflavonoid inhibitor of human secretory phospholipase A2 with anti-inflammatory activity. Biochem. Pharmacol. 1997, 53, 733–740. [Google Scholar]
  57. Baek, S.H.; Yun, S.S.; Kwon, T.K.; Kim, J.R.; Chang, H.W.; Kwak, J.Y.; Kim, J.H.; Kwun, K.B. The effects of two new antagonists of secretory PLA2 on TNF-α, iNOS, and COX-2 expression in activated macrophages. Shock 1999, 12, 473–478. [Google Scholar] [CrossRef]
  58. Hong, J.; Bose, M.; Ju, J.; Ryu, J.H.; Chen, X.; Sang, S.; Lee, M.J.; Yang, C.S. Modulation of arachidonic acid metabolism by curcumin and related beta diketone derivatives: Effects on cytosolic phospholipase A(2), cyclooxygenases and 5-lipoxygenase. Carcinogenesis 2004, 25, 1671–1679. [Google Scholar] [CrossRef]
  59. Kwak, W.-J.; Moon, T.C.; Lin, C.X.; Rhyn, H.G.; Jung, H.; Lee, E.; Kwon, D.Y.; Son, K.H.; Kim, H.P.; Kang, S.S.; et al. Papyriflavonol A from Broussonetia papyrifera inhibits the passive cutaneous anaphylaxis reaction and has a secretory phospholipase A2-inhibitory activity. Biol. Pharm. Bull. 2003, 26, 299–302. [Google Scholar] [CrossRef]
  60. Bauman, J.; von Bruchhausen, F.V.; Wurm, G. Flavonoids and related compounds as inhibitors of arachidonic acid peroxidation. Prostaglandins 1980, 20, 627–639. [Google Scholar] [CrossRef]
  61. Landorfi, R.; Mower, R.L.; Steiner, M. Modification of platelet function and arachidonic acid metabolism by biflavonoids. Structure-activity relations. Biochem. Pharmacol. 1984, 33, 1525–1530. [Google Scholar] [CrossRef]
  62. Akhtar, N.; Haqqi, T.M. Epigallocatechin-3-gallate suppresses the global interleukin-1beta-induced inflammatory response in human chondrocytes. Arthritis Res. Ther. 2011, 13, R93. [Google Scholar] [CrossRef]
  63. Kimura, Y.; Okuda, H.; Nomura, T.; Fukai, T.; Arichi, S. Effects of phenolic constituents from the mulberry tree on arachidonate metabolism in rat platelets. J. Nat. Prod. 1986, 49, 639–644. [Google Scholar] [CrossRef]
  64. Lin, C.N.; Lu, C.M.; Lin, H.C.; Fang, S.C.; Shieh, B.J.; Hsu, M.F.; Wang, J.P.; Ko, F.N.; Teng, C.M. Novel antiplatelet constituents from Formosan Moraceous plants. J. Nat. Prod. 1996, 59, 834–838. [Google Scholar] [CrossRef]
  65. Gerhauser, C.; Klimo, K.; Heiss, E.; Neumann, I.; Gamal-Eldeen, A.; Knauft, J.; Liu, G.Y.; Sitthimonchai, S.; Frank, N. Mechanism-based in vitro screening of potential cancer chemopreventive agents. Mutat. Res. 2003, 523-524, 163–172. [Google Scholar] [CrossRef]
  66. Csaki, C.; Keshishzadeh, N.; Fischer, K.; Shakibaei, M. Regulation of inflammation signaling by resveratrol in human chondrocytes in vitro. Biochem. Pharmacol. 2008, 75, 677–687. [Google Scholar]
  67. Ferrandiz, M.L.; Ramachandran Nair, A.G.; Alcaraz, M.J. Inhibition of sheep platelet arachidonatemetabolism by flavonoids from Spanish and Indian medicinal herbs. Pharmazie 1990, 45, 206–208. [Google Scholar]
  68. You, K.M.; Jong, H.; Kim, H.P. Inhibition of cyclooxygenase/lipoxygenase from human platelets by polyhydroxylated/methoxylated flavonoids isolated from the several medicinal plants. Arch. Pharm. Res. 1999, 22, 18–24. [Google Scholar] [CrossRef]
  69. Chi, Y.S.; Jong, H.; Son, K.H.; Chang, H.W.; Kang, S.S.; Kim, H.P. Effects of naturally occurring prenylated flavonoids on arachidonic acid metabolizing enzymes: Cylooxygenases and lipoxygenases. Biochem. Pharmacol. 2001, 62, 1185–1191. [Google Scholar] [CrossRef]
  70. Moon, T.C.; Murakami, M.; Kudo, I.; Son, K.H.; Kim, H.P.; Kang, S.S.; Chang, H.W. A new class of Cox-2 inhibitor, rutaecarpine from Evoida rutaecarpa. Inflamm. Res. 1999, 48, 621–625. [Google Scholar] [CrossRef]
  71. Hou, C.-C.; Chen, Y.-P.; Wu, J.-H.; Huang, C.-C.; Wang, S.-Y.; Yang, N.-S.; Shyur, L.-F. A Galactolipid possesses novel cancer chemopreventive effects by suppressing inflammatory mediators and mouse B16 melanoma. Cancer Res. 2007, 67, 6907–6915. [Google Scholar] [CrossRef]
  72. Noreen, Y.; Serrano, G.; Perera, P.; Bohlin, L. Flavan-3-ols isolated from some medicinal plants inhibiting COX-1 and COX-2 catalysed prostaglandin biosynthesis. Planta Med. 1998, 64, 520–524. [Google Scholar] [CrossRef]
  73. Jang, D.S.; Cuendet, M.; Hawthorne, M.E. Prenylated flavonoids of the leaves of Macaranga conifera with inhibitory activity against cyclooxygenase-2. Phytochemistry 2002, 61, 867–872. [Google Scholar] [CrossRef]
  74. Likhiwitayawuid, K.; Sawasdee, K.; Kirtikara, K. Flavonoids and stilbenoids with COX-1 and COX-2 inhibitory activity from Dracaena loureiri. Planta Med. 2002, 68, 841–843. [Google Scholar] [CrossRef]
  75. Sailer, E.R.; Subramanian, L.R.; Rall, B.; Hoernlein, R.F.; Ammon, H.P.; Safayhi, H. Acetyl-11-keto-beta-boswellic acid (AKBA): Structure requirements for binding and 5-lipoxygenase inhibitory activity. Br. J. Pharmcol. 1996, 117, 615–618. [Google Scholar] [CrossRef]
  76. Safayhi, H.; Boden, S.E.; Schweizer, S.; Ammon, H.P. Concentration-dependent potentiating and inhibitory effects of Boswellia extracts on 5-lipoxygenase product formation in stimulated PMNL. Planta Med. 2000, 66, 110–113. [Google Scholar] [CrossRef]
  77. Prieto, J.M.; Giner, R.M.; Recio, M.M.C.; Schinella, G.; Manez, S.; Rios, J.L. Diphyllin acetylapioside, a 5-lipoxygenase inhibitor from Haplophyllum hispanicum. Planta Med. 2002, 68, 359–360. [Google Scholar] [CrossRef]
  78. Nakadate, T.; Yamamoto, S.; Aizu, E.; Kato, R. Effects of flavonoids and antioxidants on 12-O-tetradecanoylphorbol 13-acetate induced epidermal ornithine decarboxylase induction and tumor promotion in relation to lipoxygenase inhibition by these compounds. Gann 1984, 75, 214–222. [Google Scholar]
  79. Laughton, M.J.; Evans, P.J.; Moroney, M.A.; Hoult, J.R.S.; Halliwell, B. Inhibition of mammalian 5-lipoxygenase and cyclooxygenase by flavonoids and phenolic dietary additives. Biochem. Pharmacol. 1991, 42, 1673–1681. [Google Scholar] [CrossRef]
  80. Kim, H.P.; Indu, M.; Iversen, L.; Ziboh, V.A. Effects of naturally occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pigs. Prostaglandins Leukot. Essent. Fatty Acids 1998, 58, 17–24. [Google Scholar] [CrossRef]
  81. Yoshimoto, T.; Furukawa, M.; Yamamoto, S.; Horie, T.; Watanabe-Kohno, S. Flavonoids: Potent inhibitors of arachidonate 5-lipoxygenase. Biochem. Biophys. Res. Commun. 1983, 116, 612–618. [Google Scholar] [CrossRef]
  82. Reddy, G.R.; Ueda, N.; Hada, T.; Sackeyfio, A.C.; Yamamoto, S.; Hana, Y. A prenylatedflavone, artonin E, as arachidonate 5-lipoxygenase inhibitor. Biochem. Pharmacol. 1991, 41, 115–118. [Google Scholar] [CrossRef]
  83. Kinaci, M.K.; Erkasap, N.; Kucuk, A.; Koken, T.; Tosun, M. Effects of quercetin on apoptosis, NF-κB and NOS gene expression in renal ischemia/reperfusion injury. Exp. Ther. Med. 2012, 3, 249–254. [Google Scholar]
  84. Wang, Y.; Zhu, Y.; Gao, L.; Yin, H.; Xie, Z.; Wang, D.; Zhu, Z.; Han, X. Formononetin attenuates IL-1β-induced apoptosis and NF-κB activation in INS-1 cells. Molecules 2012, 17, 10052–10064. [Google Scholar] [CrossRef]
  85. Sadowska-Krowicka, H.; Mannick, E.E.; Oliver, P.D.; Sandoval, M.; Zhang, X.J.; Eloby-Childess, S.; Clark, D.A.; Miller, M.J. Genistein and gut inflammation: Role of nitric oxide. Proc. Soc. Exp. Biol. Med. 1998, 217, 351–357. [Google Scholar]
  86. Soliman, K.F.A.; Mazzio, E.A. In vitro attenuation of nitric oxide production in C6 astrocyte cell culture by various dietary compounds. Proc. Soc. Exp. Biol. Med. 1998, 218, 390–397. [Google Scholar]
  87. Kim, H.; Kim, Y.S.; Kim, S.Y.; Suk, K. The plant flavonoid wogonin suppresses death of activated C6 rat glial cells by inhibiting nitric oxide production. Neurosci. Lett. 2001, 309, 67–71. [Google Scholar] [CrossRef]
  88. Kao, T.K.; Ou, Y.C.; Raung, S.L.; Lai, C.Y.; Liao, S.L.; Chen, C.J. Inhibition of nitric oxide production by quercetin in endotoxin/cytokine-stimulated microglia. Life Sci. 2010, 86, 315–321. [Google Scholar] [CrossRef]
  89. Fu, P.K.; Wu, C.L.; Tsai, T.H.; Hsieh, C.L. Anti-Inflammatory and anticoagulative effects of paeonol on LPS-induced acute lung injury in rats. Evid. Based Complement. Alternat. Med. 2012. [Google Scholar] [CrossRef]
  90. Geng, Y.; Zhang, B.; Lotz, M. Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. J. Immunol. 1993, 151, 6692–6700. [Google Scholar]
  91. Yoon, J.S.; Chae, M.K.; Lee, S.Y.; Lee, E.J. Anti-inflammatory effect of quercetin in a whole orbital tissue culture of Graves’ orbitopathy. Br. J. Ophthalmol. 2012, 96, 1117–1121. [Google Scholar] [CrossRef]
  92. Jang, S.; Dilger, R.N.; Johnson, R.W. Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J. Nutr. 2010, 140, 1892–1898. [Google Scholar] [CrossRef]
  93. Lin, N.; Sato, T.; Takayama, Y.; Mimaki, Y.; Sashida, Y.; Yano, M.; Ito, A. Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem. Pharmacol. 2003, 65, 2065–2071. [Google Scholar] [CrossRef]
  94. Krakauer, T. The polyphenol chlorogenic acid inhibits staphylococcal exotoxin-induced inflammatory cytokines and chemokines. Immunopharmacol. Immunotoxicol. 2002, 24, 113–119. [Google Scholar] [CrossRef]
  95. Hong, J.J.; Jeong, T.S.; Choi, J.H.; Park, J.H.; Lee, K.Y.; Seo, Y.J.; Oh, S.R.; Oh, G.T. Hematein inhibits tumor necrotic factor-alpha-induced vascular cell adhesion molecule-1 and NF-kappaB-dependent gene expression in human vascular endothelial cells. Biochem. Biophys. Res. Commun. 2001, 281, 1127–1133. [Google Scholar] [CrossRef]
  96. Jeong, H.J.; Koo, H.N.; Na, H.J.; Kim, M.S.; Hong, S.H.; Eom, J.W.; Kim, K.S.; Shin, T.Y.; Kim, H.M. Inhibition of TNF-alpha and IL-6 production by Aucubin through blockade of NF-kappaB activation RBL-2H3 mast cells. Cytokine 2002, 18, 252–259. [Google Scholar] [CrossRef]
  97. An, S.J.; Pae, H.O.; Oh, G.S.; Choi, B.M.; Jeong, S.; Jang, S.I.; Oh, H.; Kwon, T.O.; Song, C.E.; Chung, H.T. Inhibition of TNF-alpha, IL-1beta, and IL-6 productions and NF-kappa B activation in lipopolysaccharide-activated RAW 264.7 macrophages by catalposide, an iridoid glycoside isolated from Catalpa ovata G. Don (Bignoniaceae). Int. Immunopharmacol. 2002, 2, 1173–1181. [Google Scholar] [CrossRef]
  98. Choi, H.S.; Kim, H.S.; Min, K.R.; Kim, Y.; Lim, H.K.; Chang, Y.K.; Chung, M.W. Antiinflammatory effects of fangchinoline and tetrandrine. J. Ethnopharmacol. 2000, 69, 173–179. [Google Scholar] [CrossRef]
  99. Onai, N.; Tsunokawa, Y.; Suda, M.; Watanabe, N.; Nakamura, K.; Sugimoto, Y.; Kobayashi, Y. Inhibitory effects of bisbenzylisoquinoline alkaloids on induction of proinflammatory cytokines, interleukin-1 and tumor necrosis factor-alpha. Planta Med. 1995, 61, 497–501. [Google Scholar] [CrossRef]
  100. Kiraz, S.; Ertenli, I.; Arici, M.; Calguneri, M.; Haznedaroglu, I.; Celik, I.; Pay, S.; Kirazli, S. Effects of colchicine on inflammatory cytokines and selectins in familial Mediterranean fever. Clin. Exp. Rheumatol. 1998, 16, 721–724. [Google Scholar]
  101. Chiou, W.F.; Peng, C.H.; Chen, C.F.; Chou, C.J. Anti-inflammatory propertiesof piperlactam S: Modulation of complement 5a-induced chemotaxis and inflammatory cytokines production in macrophages. Planta Med. 2003, 69, 9–14. [Google Scholar] [CrossRef]
  102. Sun, J.; Han, J.; Zhao, Y.; Zhu, Q.; Hu, J. Curcumin induces apoptosis in tumor necrosis factor-alpha-treated HaCaT cells. Int. Immunopharmacol. 2012, 13, 170–174. [Google Scholar] [CrossRef]
  103. Ding, J.; Polier, G.; Köhler, R.; Giaisi, M.; Krammer, P.H.; Li-Weber, M. Wogonin and related natural flavones overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein resistance of tumors by down-regulation of c-FLIP protein and up-regulation of TRAIL receptor 2 expression. J. Biol. Chem. 2012, 2, 641–649. [Google Scholar]
  104. Wadsworth, T.L.; McDonald, T.L.; Koop, D.R. Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-α. Biochem.Pharmacol. 2001, 62, 963–974. [Google Scholar] [CrossRef]
  105. Morikawa, K.; Nonaka, M.; Narahara, M.; Torii, I.; Kawaguchi, K.; Yoshikawa, T.; Kumazawa, Y.; Morikawa, S. Inhibitory effect of quercetin on carrageenan-induced inflammation in rats. Life Sci. 2003, 74, 709–721. [Google Scholar] [CrossRef]
  106. Dien, M.V.; Takahashi, K.; Mu, M.M.; Koide, N.; Sugiyama, T.; Mori, I.; Yoshida, T.; Yokochi, T. Protective effect of wogonin on endotoxin-induced lethalshock in D-galactosamine-sensitized mice. Microbiol. Immunol. 2001, 45, 751–756. [Google Scholar]
  107. Takahashi, K.; Morikawa, A.; Kato, Y.; Sugiyama, T.; Koide, N.; Mu, M.M.; Yoshida, T.; Yokochi, T. Flavonoids protect mice from two types of lethal shock induced by endotoxin. FEMS Immunol. Med. Microbiol. 2001, 31, 29–33. [Google Scholar] [CrossRef]
  108. Shin, D.K.; Kim, M.H.; Lee, S.H.; Kim, T.H.; Kim, S.Y. Inhibitory effects of luteolin on titanium particle-induced osteolysis in a mouse model. Acta Biomater. 2012, 8, 3524–3351. [Google Scholar] [CrossRef]
  109. Kim, J.E.; Son, J.E.; Jang, Y.J.; Lee, D.E.; Kang, N.J.; Jung, S.K.; Heo, Y.S.; Lee, K.; Lee, H.J. Luteolin, a novel natural inhibitor of TPL2 kinase, inhibits tumor necrosis factor-α-induced cyclooxygenase-2 expression in JB6 mouse epidermis cell. J. Pharmacol. Exp. Ther. 2011, 338, 1013–1022. [Google Scholar] [CrossRef]
  110. Ueda, H.; Yamazaki, C.; Yamazaki, M. A hydroxyl group of flavonoids affects oral anti-inflammatoryactivity and inhibition of systemic tumor necrosis factor-α production. Biosci. Biotechnol. Biochem. 2004, 68, 119–125. [Google Scholar] [CrossRef]
  111. Li, Y.C.; Yeh, C.H.; Yang, M.L.; Kuan, Y.H. Luteolin suppresses inflammatory mediator expression by blocking the Akt/NFκB pathway in acute lung injury induced by lipopolysaccharide in mice. Evid. Based Complement. Alternat. Med. 2012. [Google Scholar] [CrossRef]
  112. Kumazawa, Y.; Kawaguchi, K.; Takimoto, H. Immunomodulating effects of flavonoids on acute and chronic inflammatory responses caused by tumor necrosis factor α. Curr. Pharm. Des. 2006, 12, 4271–4279. [Google Scholar] [CrossRef]
  113. Okabe, S.; Suganuma, M.; Imayoshi, Y.; Taniguchi, S.; Yoshida, T.; Fujiki, H. New TNFα releasing inhibitors, geraniin and corilagin, in leaves of Acer nikoense, Megusurino-Ki. Biol. Pharm. Bull. 2001, 10, 1145–1148. [Google Scholar]
  114. Cho, J.Y.; Park, J.; Yoo, E.S.; Yoshikawa, K.; Baik, K.U.; Lee, J.; Park, M.H. Inhibitory effect of lignans from the rhizomes of Coptis japonica var. dissecta on tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW264.7 cells. Arch. Pharmacol. Res. 1998, 21, 12–16. [Google Scholar] [CrossRef]
  115. Cho, J.Y.; Baik, K.U.; Yoo, E.S.; Yoshikawa, K.; Park, M.H. In vitro anti-inflammatory effects of neolignan woorenosides from the rhizomes of Coptis japonica. J. Nat. Prod. 2000, 63, 1205–1209. [Google Scholar] [CrossRef]
  116. Hart, P.H.; Brand, C.; Carson, C.F.; Riley, T.V.; Prager, R.H.; Finlay-Jones, J.J. Terpinen-4-ol, themain component of the essential oil of Malaleuca alternifolia (tea tree oil), suppresses inflammatory mediator production by activated human monocytes. Inflamm. Res. 2000, 49, 619–626. [Google Scholar] [CrossRef]
  117. Soares, M.B.; Bellintani, M.C.; Ribeiro, I.M.; Tomassini, T.C.; Ribeiro dos Santos, R. Inhibition of macrophage activation and lipopolysaccaride-induced death by seco-steroids purified from Physalis angulata L. Eur. J. Pharmacol. 2003, 459, 107–112. [Google Scholar] [CrossRef]
  118. Lin, N.; Sato, T.; Ito, A. Triptolide, a novel diterpenoid triepoxide from Tripterygium wilfordii Hook. F., suppresses the production and gene expression of pro-matrix metalloproteinases 1 and 3 and augments those of tissue inhibitors of metalloproteinases 1 and 2 in human synovial fibroblasts. Arthritis Rheum. 2001, 44, 193–2200. [Google Scholar]
  119. Liacini, A.; Sylvester, J.; Zafarullah, M. Triptolide suppresses proinflammatory cytokine-induced matrix metalloproteinase and aggrecanase-1 gene expression in chondrocytes. Biochem. Biophys. Res. Commun. 2005, 327, 320–327. [Google Scholar] [CrossRef]
  120. Ha, S.K.; Moon, E.; Ju, M.S.; Kim, D.H.; Ryu, J.H.; Oh, M.S.; Kim, S.Y. 6-Shogaol, a ginger product, modulates neuroinflammation: A new approach to neuroprotection. Neuropharmacology 2012, 63, 211–223. [Google Scholar] [CrossRef]
  121. Shany, S.; Levy, Y.; Lahav-Cohen, M. The effects of 1α, 24(S)-dihydroxyvitamin D2 analog on cancer cell proliferation and cytokine expression. Steroids 2001, 66, 319–325. [Google Scholar] [CrossRef]
  122. Ono, M.; Tanaka, N.; Moriyasu, T. Anti-inflammatory action of cepharanthine ointment ingredient in experimental animals: Studies on chronic inflammation and TNF-alpha production. Ensho 1994, 14, 425–429. [Google Scholar] [CrossRef]
  123. Parmely, M.J.; Zhou, W.W.; Edwards, C.K., III; Borcherding, D.R.; Silverstein, R.; Morrison, D.C. Adenosine and a related carbocyclic nucleoside analogue selectively inhibit tumor necrosis factor-alpha production and protect mice against endotox challenge. J. Immunol. 1993, 151, 389–396. [Google Scholar]
  124. Gerritsen, M.E.; Carley, W.W.; Ranges, G.E.; Shen, C.P.; Phan, S.A.; Ligon, G.F.; Perry, C.A. Flavonoids inhibit cytokine-induced endothelial cell adhesion protein gene expression. Am. J. Pathol. 1995, 147, 278–292. [Google Scholar]
  125. Nakamura, N.; Hayasaka, S.; Zhang, X.Y.; Nagaki, Y.; Matsumoto, M.; Hayasaka, Y.; Terasawa, K. Effects of baicalin, baicalein and wogonin on interleukin-6 and interleukin-8 expression, and nuclear factor-κB binding activities induced by interleukin-1β in human retinal pigmant epithelial cell line. Exp. Eye Res. 2003, 77, 195–202. [Google Scholar] [CrossRef]
  126. Atluru, D.; Jackson, T.M.; Atluru, S. Genistein, a selective protein tyrosine kinase inhibitor, inhibits interleukin-2 and leukotriene B4 production from human mononuclear cells. Clin. Immunol. Immunopathol. 1991, 59, 379–387. [Google Scholar] [CrossRef]
  127. Hernandez, V.; del Carmen Recio, M.; Manez, S.; Prieto, J.M.; Giner, R.M.; Rios, J.L. A mechanistic approach to the in vivo anti-inflammatory activity of sesquiterpenoid compounds isolated from Inula viscosa. Planta Med. 2001, 67, 726–731. [Google Scholar] [CrossRef]
  128. Danz, H.; Stoyanova, S.; Thomet, O.A.; Simon, H.U.; Dannhardt, G.; Ulbrich, H.; Hamburger, M. Inhibitory activity of tryptanthrin on prostaglandin and leukotriene synthesis. Planta Med. 2002, 68, 875–880. [Google Scholar] [CrossRef]
  129. Bermejo, B.P.; Abad Martinez, M.J.; Silvan Sen, A.M.; Sanz Gomez, A.; Fernandez Matellano, L.; Sanchez Contreras, S.; Diaz Lanza, A.M. In vivo and in vitro anti-inflammatory activity of saikosaponins. Life Sci. 1998, 63, 1147–1156. [Google Scholar] [CrossRef]
  130. Bermejo, B.P.; Diaz Lanza, A.M.; Silvan Sen, A.M.; de Santos Galindez, J.; Fernandez Matellano, L.; Sanz Gomez, A.; Abad Martinez, M.J. Effects of some iridoids from plant origin on arachidonic acid metabolism in cellular systems. Planta Med. 2000, 66, 324–328. [Google Scholar] [CrossRef]
  131. Giner-Larza, E.M.; Manez, S.; Giner, R.M.; Recio, M.C.; Prieto, J.M.; Cerda-Nicolas, M.; Rios, J.L. Anti-inflammatory triterpenes from Pistacia terebinthus galls. Planta Med. 2002, 68, 311–315. [Google Scholar] [CrossRef]
  132. Diaz Lanza, A.M.; Abad Martinez, M.J.; Fernandez Matellano, L.; Recuero Carretero, C.; Villaescusa Castillo, L.; Silvan Sen, A.M.; Bermejo Benito, P. Lignan and phenylpropanoid glycosides from Phillyrea latifolia and their in vitro anti-inflammatory activity. Planta Med. 2001, 67, 219–223. [Google Scholar] [CrossRef]
  133. Kim, Y.P.; Yamada, M.; Lim, S.S.; Lee, S.H.; Ryu, N.; Shin, K.H. Inhibition of tectorigenin and tectoridin of prostaglandin E2 production and cyclooxygenase-2 induction in rat peritoneal macrophages. Biochim. Biophys. Acta 1999, 1438, 399–407. [Google Scholar] [CrossRef]
  134. Kim, Y.P.; Lee, E.B.; Kim, S.Y.; Li, D.; Ban, H.S.; Lim, S.S.; Shin, K.H.; Ohuchi, K. Inhibition of prostaglandin E2 production by platycodin D isolated from the root of Platycodon grandiflorum. Planta Med. 2001, 67, 362–364. [Google Scholar] [CrossRef]
  135. Hong, C.H.; Noh, M.S.; Lee, W.Y.; Lee, S.K. Inhibitory effects of natural sesquiterpenoids isolated from the rhizomes of Curcuma zedoaria on prostaglandin E2 and nitric oxide production. Planta Med. 2002, 68, 545–547. [Google Scholar] [CrossRef]
  136. Woo, H.G.; Lee, C.H.; Noh, M.S.; Lee, J.J.; Jung, Y.S.; Baik, E.J.; Moon, C.H.; Lee, S.H. Rutaecarpine, a quinazolinocarboline alkaloid, inhibits prostaglandin production in RAW26.7 macrophages. Planta Med. 2001, 67, 505–509. [Google Scholar] [CrossRef]
  137. Nakajima, T.; Imanishi, M.; Yamamoto, K.; Cyong, J.C.; Hirai, K. Inhibitory effect of baicalein, a flavonoid in Scutellaria root, on eotaxin production by human dermal fibroblasts. Planta Med. 2001, 67, 132–135. [Google Scholar] [CrossRef]
  138. Chi, Y.S.; Cheon, B.S.; Kim, H.P. Effect of wogonin, a plant flavones from Scutellaria radix, on the suppression of cyclooxygenase and the induction of inducible nitric oxide synthase in lipopolysaccharide-treated RAW 26.7 cells. Biochem. Pharmacol. 2001, 61, 1195–1203. [Google Scholar] [CrossRef]
  139. Kim, H.K.; Cheon, B.S.; Kim, Y.H.; Kim, S.Y.; Kim, H.P. Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW 264.7 and their structural-activity relationships. Biochem. Pharmacol. 1999, 58, 759–765. [Google Scholar] [CrossRef]
  140. Liang, Y.C.; Huang, Y.T.; Tsai, S.H.; Lin-Shiau, S.Y.; Chen, C.F.; Lin, J.K. Suppression of inducible cyclooxygenase and inducible nitricoxide synthase by apigenin and related flavonoids in mousemacrophages. Carcinogenesis 1999, 20, 1945–1952. [Google Scholar] [CrossRef]
  141. Murakami, A.; Nakamura, Y.; Torikai, K.; Tanaka, T.; Koshiba, T.; Koshimizu, K.; Kuwahara, S.; Takahashi, Y.; Ogawa, K.; Yano, M.; Tokuda, H.; et al. Inhibitory effect of citrus nobiletin onphorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res. 2000, 60, 5059–5066. [Google Scholar]
  142. Chen, Y.C.; Yang, L.L.; Lee, T.J.F. Oroxylin A inhibition of lipopolysaccharide-induced iNOS and COX-2 gene expression via suppression of nuclear factor-κB activation. Biochem. Pharmacol. 2000, 59, 1445–1457. [Google Scholar] [CrossRef]
  143. Raso, G.M.; Meli, R.; di Carlo, G.; Pacillio, M.; di Carlo, R. Inhibiton of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1. Life Sci. 2001, 68, 921–931. [Google Scholar] [CrossRef]
  144. Shen, S.C.; Lee, W.R.; Lin, H.Y.; Huang, H.C.; Ko, C.H.; Yang, L.L.; Chen, Y.C. In vitro and in vivo inhibitory activities of rutin, wogonin, andquercetin on lipopolysaccharide-induced nitric oxide andprostaglandin E2 production. Eur. J. Pharmacol. 2002, 446, 187–194. [Google Scholar] [CrossRef]
  145. Singh, R.; Ahmed, S.; Islam, N.; Goldberg, V.M.; Haqqi, T.M. Epigallocatechin-3-gallate inhibits interleukin-1β-induced expression of nitric oxide synthase and production of nitric oxide in human chondrocytes. Suppression of nuclear factor κB by degradation of the inhibitor of nuclear factor κB. J. Rheumatol. 2002, 46, 2079–2086. [Google Scholar]
  146. Chan, M.M.; Fong, D.; Ho, C.T.; Huang, H.T. Inhibition of induciblenitric oxide synthase gene expression and enzyme activity byepigallocatechin gallate, a natural product from green tea. Biochem. Pharmacol. 1997, 54, 1281–1286. [Google Scholar] [CrossRef]
  147. Takahashi, T.; Takasuka, N.; Ligo, M.; Baba, M.; Nishino, H.; Tsuda, H. Isoliquilitigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development. Cancer Sci. 2004, 95, 448–453. [Google Scholar] [CrossRef]
  148. Kang, J.S.; Jeon, Y.J.; Kim, H.M.; Han, S.H.; Yang, K.H. Inhibition of inducible nitric-oxide synthase expression by silymarin in lipopolysaccharide-stimulated macrophages. J. Pharmacol. Exp. Ther. 2002, 302, 138–144. [Google Scholar] [CrossRef]
  149. Chan, M.M.; Huang, H.I.; Fenton, M.R.; Fong, D. In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties. Biochem. Pharmacol. 1998, 55, 1955–1962. [Google Scholar] [CrossRef]
  150. Hamalainen, M.; Nieminen, R.; Vuorela, P.; Heinonen, M.; Moilanen, E. Anti-inflammatory effects of flavonoids: Genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaBactivations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with theirinhibitory effect on iNOS expression and NO production in activated macrophages. Mediators Inflamm. 2007, 2007, 45673. [Google Scholar]
  151. Lee, H.; Kim, Y.O.; Kim, H.; Kim, S.Y.; Noh, H.S.; Kang, S.S. Flavonoid wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia. FASEB J. 2003, 17, 1943–1944. [Google Scholar]
  152. Qureshi, A.A.; Guan, X.Q.; Reis, J.C.; Papasian, C.J.; Jabre, S.; Morrison, D.C.; Qureshi, N. Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor. Lipids Health Dis. 2012, 11, 76. [Google Scholar] [CrossRef]
  153. Wang, B.; Ma, L.; Tao, X.; Lipsky, P.E. Triptolide, an active component of the Chinese herbal remedy Tripterygium wilfordii Hook F, inhibits production of nitric oxide by decreasing inducible nitric oxide synthase gene transcription. Arthritis Rheum. 2004, 50, 2995–3003. [Google Scholar] [CrossRef]
  154. Suh, N.; Honda, T.; Finlay, H.J.; Barchowsky, A.; Williams, C.; Benoit, N.E.; Xie, Q.W.; Nathan, C.; Gribble, G.W.; Sporn, M.B. Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages. Cancer Res. 1998, 58, 717–723. [Google Scholar]
  155. Stempelj, M.; Kedinger, M.; Augenlicht, L.; Klampfer, L. Essential role of the JAK/STAT1 signalingpathway in the expression of inducible and its regulation by butyrate. J. Biol. Chem. 2007, 282, 9797–804. [Google Scholar]
  156. Palombo, P.; Fabrizi, G.; Ruocco, V. Beneficial long-term effects of combined oral/topical antioxidanttreatment with the carotenoids lutein and zeaxanthin on humanskin: A double-blind, placebo-controlled study. Skin Pharmacol. Physiol. 2007, 20, 199–210. [Google Scholar] [CrossRef]
  157. Kang, N.J.; Shin, S.H.; Lee, H.J.; Lee, K.W. Polyphenols as small molecular inhibitors of signaling cascades in carcinogenesis. Pharmacol. Ther. 2011, 130, 310–324. [Google Scholar] [CrossRef]
  158. Hooshmand, S.; Soung do, Y.; Lucas, E.A.; Madihally, S.V.; Levenson, C.W.; Arjmandi, B.H. Genistein reduces the production of proinflammatory molecules in human chondrocytes. J. Nutr. Biochem. 2007, 18, 609–614. [Google Scholar]
  159. Kwak, W.J.; Han, C.K.; Son, K.H.; Chang, H.W.; Kang, S.S.; Park, B.K.; Kim, H.P. Effects of ginkgetin from Ginkgo biloba leaves on cyclooxygenases and in vivo skin inflammation. Planta Med. 2002, 68, 316–321. [Google Scholar] [CrossRef]
  160. Mutoh, M.; Takahashi, M.; Fukuda, K.; Komatsu, H.; Enya, T.; Matsushima-Hibiya, Y.; Mutoh, H.; Sugimura, T.; Wakabayashi, K. Suppression by flavonoids of cyclooxygenase-2 promotor-dependent transcriptional activity incolon cancer cells: Structural-activity relationship. Jpn. J. Cancer Res. 2000, 91, 686–691. [Google Scholar] [CrossRef]
  161. Chen, C.Y.; Peng, W.H.; Tsai, K.D.; Hsu, S.L. Luteolin suppresses inflammation-associated gene expression by blocking NF-kappaB and AP-1 activation pathway in mouse alveolar macrophages. Life Sci. 2007, 81, 1602–1614. [Google Scholar] [CrossRef]
  162. Wakabayashi, I.; Yasui, K. Wogonin inhibits inducible prostaglandin E2 production in macrophages. Eur. J. Pharmacol. 2000, 406, 477–481. [Google Scholar] [CrossRef]
  163. Park, B.K.; Heo, M.Y.; Park, H.; Kim, H.P. Inhibition of TPA-inducedcyclooxygenase-2 and skin inflammation in mice by wogonin, a plant flavone from Scutellaria radix. Eur. J. Pharmacol. 2001, 425, 153–157. [Google Scholar] [CrossRef]
  164. Banerjee, T.; Valacchi, G.; Ziboh, V.A.; van der Vliet, A. Inhibitionof TNFα-induced cyclooxygenase-2 expression by amentoflavonethrough suppression of NF-κB activation in A549 cells. Mol. Cell. Biochem. 2002, 238, 105–110. [Google Scholar] [CrossRef]
  165. Tong, X.; Yin, L.; Joshi, S.; Rosenberg, D.W.; Giardina, C. Cyclooxygenase-2 regulation in colon cancer cells: Modulation of RNA polymerase II elongation by histone deacetylase inhibitors. J. Biol. Chem. 2005, 280, 15503–15509. [Google Scholar]
  166. Subbaramaiah, K.; Michaluart, P.; Sporn, M.B.; Dannenberg, A.J. Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Cancer Res. 2000, 60, 2399–2404. [Google Scholar]
  167. Suksamrarn, A.; Kumpun, S.; Kirtikara, K.; Yingyongnarongkul, B.; Suksamrarn, S. Iridoids with anti-inflammatory activity from Vitex peduncularis. Planta Med. 2002, 68, 72–73. [Google Scholar] [CrossRef]
  168. Hirata, A.; Murakami, Y.; Atsumi, T.; Shoji, M.; Ogiwara, T.; Shibuya, K.; Ito, S.; Yokoe, I.; Fujisawa, S. Ferulic acid dimer inhibits lipopolysaccharide-stimulated cyclooxygenase-2 expression in macrophages. In Vivo 2005, 19, 849–853. [Google Scholar]
  169. Kim, S.O.; Kundu, J.K.; Shin, Y.K.; Park, J.H.; Cho, M.H.; Kim, T.Y.; Surh, Y.J. [6]-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF-κB in phorbol ester stimulated mouse skin. Oncogene 2005, 24, 2558–2567. [Google Scholar] [CrossRef]
  170. Kim, J.K.; Kim, Y.; Na, K.M.; Surh, Y.J.; Kim, T.Y. [6]-Gingerol prevents UVB-induced ROS production and COX-2 expression in vitro and in vivo. Free Radic. Res. 2007, 41, 603–614. [Google Scholar] [CrossRef]
  171. Kundu, J.K.; Shin, Y.K.; Kim, S.H.; Surh, Y.J. Resveratrol inhibits phorbol ester-induced expression of COX-2 and activation of NF-κB in mouse skin by blocking IκB kinase activity. Carcinogenesis 2006, 27, 1465–1474. [Google Scholar] [CrossRef]
  172. Peng, G.; Dixon, D.A.; Muga, S.J.; Smith, T.J.; Wargovich, M.J. Green tea polyphenol (−)-epigallocatechin-3-gallate inhibits cyclooxygenase-2 expression in colon carcinogenesis. Mol. Carcinog. 2006, 45, 309–319. [Google Scholar] [CrossRef]
  173. Donnelly, L.E.; Newton, R.; Kennedy, G.E.; Fenwick, P.S.; Leung, R.H.F.; Ito, K.; Russell, R.E.K.; Barnes, P.J. Anti-inflammatory effects of resveratrol in lung epithelial cells: Molecular mechanisms. Am. J. Physiol. Lung Cell. Mol. Physiol. 2004, 287, L774–L783. [Google Scholar] [CrossRef]
  174. Haridas, V.; Arntzen, C.J.; Gutterman, J.U. Avicins, a family of triterpenoid saponins from Acacia victoriae (Bentham), inhibit activation of nuclear factor-kappaB by inhibiting both its nuclear localization and ability to bind DNA. Proc. Natl. Acad. Sci.USA 2001, 98, 11557–11562. [Google Scholar]
  175. Sheehan, M.; Wong, H.R.; Hake, P.W.; Malhotra, V.; O’Connor, M.; Zingarelli, B. Parthenolide, an inhibitor of the nuclear factor-kappaB pathway, ameliorates cardiovascular derangement and outcome in endotoxicshock in rodents. Mol. Pharmacol. 2002, 61, 953–963. [Google Scholar] [CrossRef]
  176. Feng, R.; Lu, Y.; Bowman, L.L.; Qian, Y.; Castranova, V.; Ding, M. Inhibition of AP-1, NF-kB and MAPKs and induction of phase 2 detoxifying enzyme activity by chlorogenic acid. J. Biol. Chem. 2005, 280, 2888–2895. [Google Scholar]
  177. Qiu, D.; Zhao, G.; Aoki, Y.; Shi, L.; Uyei, A.; Nazarian, S.; Ng, J.C.-H.; Kao, P.N. Immunosuppressant PG490(triptolide) inhibits T-cell interleukin-2 expression at the levelof purine-box/nuclear factor of activated T-cells and NFkappaB transcriptional activation. J. Biol. Chem. 1999, 274, 13443–13450. [Google Scholar]
  178. Han, S.S.; Keum, Y.S.; Chun, K.S.; Surh, Y.J. Suppression of phorbol ester-induced NF-jB activation by capsaicin in cultured human promyelocytic leukemia cells. Arch. Pharm. Res. 2002, 25, 475–479. [Google Scholar] [CrossRef]
  179. Lührs, H.; Gerke, T.; Müller, J.G.; Melcher, R.; Schauber, J.; Boxberge, F.; Scheppach, W.; Menzel, T. Butyrate inhibitsNF-κB activation in lamina propria macrophagesof patients with ulcerative colitis. Scand. J. Gastroenterol. 2002, 37, 458–466. [Google Scholar] [CrossRef]
  180. Kim, J.S.; Jobin, C. The flavonoid luteolin prevents lipopolysaccharide-induced NK-kappaB signaling and gene expressionby blocking I-kappaB kinase activity in intestinal epithelial cellsand bone-marrow derived dendritic cells. Immunology 2005, 115, 373–387. [Google Scholar]
  181. Jobin, C.; Bradham, C.A.; Russo, M.P.; Juma, B.; Narula, A.S.; Brenner, D.A.; Sartor, R.B. Curcumin blocks cytokine-mediated NF-κB activation and pro-inflammatory gene expression by inhibiting inhibitory factor I-κB kinase activity. J. Immunol. 1999, 163, 3474–3483. [Google Scholar]
  182. Hunter, M.S.; Corley, D.G.; Carron, C.P.; Rowold, E.; Kilpatrick, B.F.; Durley, R.C. Four new clerodane diterpenes from the leaves of Casearia guianensis which inhibit the interaction of leukocyte function antigen 1 with intercellular adhesion molecule 1. J. Nat. Prod. 1997, 60, 894–899. [Google Scholar] [CrossRef]
  183. Asahina, A.; Tada, Y.; Nakamura, K.; Tamaki, K. Colchicine and griseofulvin inhibit VCAM-1 expression on human vascular endothelial cells-evidence for the association of VCAM-1 expression with microtubules. J. Dermatol. Sci. 2001, 25, 1–9. [Google Scholar] [CrossRef]
  184. Goel, A.; Kunnumakkara, A.B.; Aggarwal, B.B. Curcumin as “Curecumin”: From kitchen to clinic. Biochem. Pharmacol. 2008, 75, 787–809. [Google Scholar] [CrossRef]
  185. Kwak, W.J.; Cho, Y.B.; Han, C.K.; Shin, H.J.; Ryu, K.H.; Yoo, H.; Rhee, H.I. Extraction and purification method of active constituents from stem of Lonicera japonica thunb, its usage for anti-inflammatory and analgesic drug. US20087314644, 1 January 2008. [Google Scholar]
  186. Kealey, K.S.; Snyder, R.M.; Romanczyk, L.J.; Geyet, H.M.; Myers, M.E.; Whitacre, E.J.; Schmitz, H.H. Treatment of inflammation. US20080188550, 7 August 2008. [Google Scholar]
  187. Olalde Rangel, J.A. Arthritis phyto-nutraceutical synergistic composition. US20087416748, 26 August 2008. [Google Scholar]
  188. Gokaraju, G.R.; Gokaraju, R.R.; Gottumukkala, V.S.; Golakoti, T. Dietary supplement formulation for controlling inflammation and cancer. US20087455860, 25 December 2008. [Google Scholar]
  189. Gokaraju, G.R.; Gokaraju, R.R.; Gottumukkala, V.S.; Somepalli, V. Pharmaceutically Active Extracts of Vitex Leucoxylon, a Process of Extracting the Same and a Method of Treating Diabetes and Inflammatory Diseases Therewith. US20080199543, 21 August 2008. [Google Scholar]
  190. Lockwood, S.F.; Mason, P.R. Use of carotenoids and/or carotenoid derivatives/analogs for reduction/inhibition of certain negative effects of COX inhibitors. US20080293679, 27 November 2008. [Google Scholar]
  191. Li, Y. Herbal compositions for prevention and treatment of rheumatic and inflammatory diseases and method of preparing the same. US20097553506, 3 July 2009. [Google Scholar]
  192. Buchholz, H.; Wirth, C.; Carola, C.; Alves Fontes, R. Flavonoid derivates. US20097588783, 15 September 2009. [Google Scholar]
  193. Miyake, Y.; Yoko, I. Anti-inflammatory agent. US20100120903, 13 May 2010. [Google Scholar]
  194. Gokaraju, G.R.; Gokaraju, R.R.; Golakoti, T.; Chirravuri, V.R.; Alluri, V.K.R.; Bhupathiraju, K. Use of Aphanamixis polystacha extracts or fractions against 5-lipoxygenase mediated diseases. US20100178288, 15 July 2010. [Google Scholar]
  195. Hillwig, M.L. Anti-inflammatory and anti-HIV compositions and methods of use. US20107854946, 21 December 2010. [Google Scholar]
  196. Theoharides, T.C. Anti-inflammatory compositions for treating multiple sclerosis. US20117906153, 15 March 2011. [Google Scholar]
  197. Mumper, R.J.; Dai, J.; Gallicchio, V.S. Berry preparations and extracts. US20117964223, 21 June 2011. [Google Scholar]
  198. Jia, Q.; Nichols, T.C.; Rhoden, E.E.; Walte, S. Identification of Free-B-Ring flavonoids as potent COX-2 inhibitors. US20110245333, 6 October 2011. [Google Scholar]
  199. Kimata, M.; Shichijo, M.; Miura, T.; Serizawa, I.; Inagaki, N.; Nagai, H. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin. Exp. Allergy 2000, 30, 501–508. [Google Scholar]
  200. Yano, S.; Tachibana, H.; Yamada, K. Flavones suppress the expression of the high-affinity IgE receptor Fc epsilon RI in human basophilic KU812 cells. J. Agric. Food Chem. 2005, 53, 1812–1817. [Google Scholar] [CrossRef]
  201. Wu, S.J.; Ng, L.T. Tetrandrine inhibits proinflammatory cytokines, iNOS and COX-2 expression in human monocytic cells. Biol. Pharm. Bull. 2007, 30, 59–62. [Google Scholar] [CrossRef]
  202. Otsuka, H.; Hirai, Y.; Nagao, T.; Yamasaki, K. Antiinflammatory activity of benzoxazinoids from roots of Coix lachryma-jobi var. ma-yuen. J. Nat. Prod. 1988, 51, 74–79. [Google Scholar] [CrossRef]
  203. Wang, M.; Huang, Y.J.; Zhang, T.H.; Tong, Z.Q. Anti-allergic, anti-histamine and anti-inflammatory effects ofcompound pseudoephedrine. J. Shenyang Pharm. Univ. 1996, 132, 129–133. [Google Scholar]
  204. Daikonya, A.; Katsuki, S.; Wu, J.-B.; Kitanaka, S. Anti-allergic agents from natural sources (41)): Anti-allergic activity of new phloroglucinol derivatives from Mallotus philippensis (Euphorbiaceae). Chem. Pharm. Bull. 2002, 50, 1566–1659. [Google Scholar] [CrossRef]
  205. Cheong, H.; Ryu, S.Y.; Oak, M.H.; Cheon, S.H.; Yoo, G.S.; Kim, K.M. Studies of structure activity relationship of flavonoids for the anti-allergic actions. Arch. Pharm. Res. 1998, 21, 478–480. [Google Scholar] [CrossRef]
  206. Fewtrell, C.M.; Gomperts, B.D. Effect of flavone inhibitors on transport ATPases on histamine secretion from rat mast cells. Nature 1977, 265, 635–636. [Google Scholar] [CrossRef]
  207. Middleton, E.J.; Drzewiecki, G.; Krishnarao, D. Quercetin: An inhibitor of antigen-induced human basophil histamine release. J. Immunol. 1981, 127, 546–550. [Google Scholar]
  208. Fernandez, J.; Reyes, R.; Ponce, H.; Oropeza, M.; Vancalsteren, M.R.; Jankowski, C.; Campos, M.G. Isoquercitrin from Argemone platyceras inhibits carbachol and leukotriene D4-induced contraction in guinea-pig airways. Eur.J. Pharmacol. 2005, 522, 108–115. [Google Scholar] [CrossRef]
  209. Kawai, M.; Hirano, T.; Higa, S.; Arimitsu, J.; Maruta, M.; Kuwahara, Y.; Ohkawara, T.; Hagihara, K.; Yamadori, T.; Shima, Y.; et al. Flavonoids and related compounds as anti-allergic substances. Allergol. Int. 2007, 56, 113–123. [Google Scholar] [CrossRef]
  210. Hirano, T.; Arimitsu, J.; Higa, S.; Naka, T.; Ogata, A.; Shima, Y.; Fujimoto, M.; Yamadori, T; Ohkawara, T.; Kuwabara, Y.; et al. Luteolin, a flavonoid, inhibits CD40 ligand expression by activated human basophils. Int. Arch. Allergy Immunol. 2006, 140, 150–156. [Google Scholar] [CrossRef]
  211. Wu, Y.Q.; Zhou, C.H.; Tao, J.; Li, S.N. Antagonistic effects of nobiletin, a polymethoxyflavonoid, on eosinophilic airway inflammation of asthmatic rats and relevant mechanisms. Life Sci. 2006, 78, 2689–2696. [Google Scholar] [CrossRef]
  212. Magrone, T.; Jirillo, E. Influence of polyphenols on allergic immune reactions: Mechanisms of action. Proc. Nutr. Soc. 2012, 71, 316–321. [Google Scholar] [CrossRef]
  213. Joskova, M.; Franova, S.; Sadloňova, V. Acute bronchodilator effect of quercetin in experimental allergic asthma. Bratisl. Lek. Listy 2011, 112, 9–12. [Google Scholar]
  214. Fraňova, S.; Strapkova, A.; Mokry, J.; Šutovska, M.; Joškova, M.; Sadloňova, V.; Antošova, M.; Pavelčikova, D.; Fleškova, D.; Nosaľova, G. Pharmacologic modulation of experimentally induced allergic asthma. Interdiscp. Toxicol. 2011, 4, 27–32. [Google Scholar] [CrossRef]
  215. Joskova, M.; Sadlonova, V.; Nosalova, G.; Novakova, E.; Franova, S. Polyphenols and their components in experimental allergic asthma. Adv. Exp. Med. Biol. 2013, 756, 91–98. [Google Scholar] [CrossRef]
  216. Ikarashi, N.; Sato, W.; Toda, T.; Ishii, M.; Ochiai, W.; Sugiyama, K. Inhibitory effect of polyphenol-rich fraction from the bark of Acacia mearnsii on itching associated with allergic dermatitis. Evid. Based Complement. Alternat. Med. 2012. [Google Scholar] [CrossRef]
  217. Kim, M.J.; Choung, S.Y. Mixture of polyphenols and anthocyanins from Vaccinium uliginosum L. alleviates DNCB-induced atopic dermatitis in NC/Nga Mice. Evid. Based Complement Alternat. Med. 2012. [Google Scholar] [CrossRef]
  218. Riccio, P.; Rossano, R.; Liuzzi, G.M. May diet and dietary supplements improve the wellness of multiple sclerosis patients? A molecular approach. Autoimmune Dis. 2010, 2010, 249842. [Google Scholar]
  219. Riccio, P. The molecular basis of nutritional intervention inmultiplesclerosis: A narrative review. Complement.Ther. Med. 2011, 19, 228–237. [Google Scholar] [CrossRef]
  220. Xie, L.; Li, X.K.; Takahara, S. Curcumin has bright prospects for the treatment of multiplesclerosis. Int. Immunopharmacol. 2011, 11, 323–330. [Google Scholar] [CrossRef]
  221. Yoshida, S. Preventive or therapeutic agent for pollen allergy, allergic rhinitis, atopic dermatitis, asthma or urticaria, or health food for prevention or improvement or reduction of symptoms thereof. US20046811796, 2 November 2004. [Google Scholar]
  222. Palpu, P.; Rao, C.V.; Rawat, A.K.S.; Ojha, S.K.; Reddy, G.D. Anti-allergic herbal formulation. US20087344739, 18 March 2008. [Google Scholar]
  223. Menon, G.R.; Fast, D.J.; Krempin, D.W.; Goolsby, J.N. Anti-Allergy composition and related method. US20087384654, 10 June 2008. [Google Scholar]
  224. Frimman Berg, K. Method of treating symptoms of common cold, allergic rhinitis and infections relating to the respiratory tract. US20118003688, 23 August 2011. [Google Scholar]
  225. Olszanecki, R.; Gebska, A.; Kozlovski, V.I.; Gryglewski, R.J. Flavonoids and nitric oxide synthase. J. Physiol. Pharmacol. 2002, 53, 571–584. [Google Scholar]
  226. Matsuda, H.; Tokuoka, K.; Wu, J.; Shiomoto, H.; Kubo, M. Inhibitory effects of dehydrocorydaline isolated from Corydalis Tuber against type I-IV allergic models. Biol. Pharm. Bull. 1997, 20, 431–434. [Google Scholar] [CrossRef]
  227. Havsteen, B.H. The biochemistry and medical significance of the flavonoids. Pharmacol. Ther. 2002, 96, 67–202. [Google Scholar] [CrossRef]
  228. Carboni, G.P.; Contri, P.; Davalli, R. Allergic contact dermatitis from apomorphine. Contact Derm. 1997, 36, 177–178. [Google Scholar] [CrossRef]
  229. Waclawski, E.R.; Aldridge, R. Occupational dermatitis from thebaine and codeine. Contact Derm. 1995, 33, 51. [Google Scholar]
  230. Tanaka, S.; Otsuki, T.; Matsumoto, Y.; Hayakawa, R.; Sugiura, M. Allergic contact dermatitis from enoxolone. Contact Derm. 2001, 44, 192. [Google Scholar] [CrossRef]
  231. Basketter, D.A.; Wright, Z.M.; Colson, N.R.; Patlewicz, G.Y.; Pease, C.K. Investigation of the skin sensitizing activity of linalool. Contact Derm. 2002, 47, 161–164. [Google Scholar] [CrossRef]
  232. Ríos, J.L.; Bas, E.; Recio, M.C. Effects of natural products on contact dermatitis. Curr. Med. Chem. Anti Inflamm. Anti Allergy Agents 2005, 4, 65–80. [Google Scholar] [CrossRef]
  233. Olthof, M.R.; Hollman, P.C.; Zock, P.L.; Katan, M.B. Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans. Am. J. Clin. Nutr. 2001, 73, 532–538. [Google Scholar]
  234. Muller, T.; Woitalla, D.; Hauptmann, B.; Fowler, B.; Kuhn, W. Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson’s disease. Neurosci. Lett. 2001, 308, 54–56. [Google Scholar] [CrossRef]
  235. Hegarty, V.M.; May, H.M.; Khaw, K.T. Tea drinking and bone mineral density in older women. Am. J. Clin. Nutr. 2000, 71, 1003–1425. [Google Scholar]
  236. Estruch, R.; Sacanella, E.; Mota, F.; Chiva-Blanch, G.; Antúnez, E.; Casals, E.; Deulofeu, R.; Rotilio, D.; Andres-Lacueva, C.; Lamuela-Raventos, R.M.; et al. Moderate consumption of red wine, but not gin, decreases erythrocyte superoxide dismutase activity: A randomised crossover trial. Nutr. Metab. Cardiovasc. Dis. 2011, 21, 46–53. [Google Scholar] [CrossRef]
  237. Ward, N.C.; Hodgson, J.M.; Croft, K.D.; Burke, V.; Beilin, L.J.; Puddey, I.B. The combination of vitamin C and grape-seed polyphenols increases blood pressure: A randomized, double-blind, placebo-controlled trial. J. Hypertens. 2005, 23, 427–434. [Google Scholar] [CrossRef]

Share and Cite

MDPI and ACS Style

Bellik, Y.; Boukraâ, L.; Alzahrani, H.A.; Bakhotmah, B.A.; Abdellah, F.; Hammoudi, S.M.; Iguer-Ouada, M. Molecular Mechanism Underlying Anti-Inflammatory and Anti-Allergic Activities of Phytochemicals: An Update. Molecules 2013, 18, 322-353. https://doi.org/10.3390/molecules18010322

AMA Style

Bellik Y, Boukraâ L, Alzahrani HA, Bakhotmah BA, Abdellah F, Hammoudi SM, Iguer-Ouada M. Molecular Mechanism Underlying Anti-Inflammatory and Anti-Allergic Activities of Phytochemicals: An Update. Molecules. 2013; 18(1):322-353. https://doi.org/10.3390/molecules18010322

Chicago/Turabian Style

Bellik, Yuva, Laïd Boukraâ, Hasan A. Alzahrani, Balkees A. Bakhotmah, Fatiha Abdellah, Si M. Hammoudi, and Mokrane Iguer-Ouada. 2013. "Molecular Mechanism Underlying Anti-Inflammatory and Anti-Allergic Activities of Phytochemicals: An Update" Molecules 18, no. 1: 322-353. https://doi.org/10.3390/molecules18010322

Article Metrics

Back to TopTop