This article was downloaded by: [University of Leeds]On: 04 September 2013, At: 14:22Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,37-41 Mortimer Street, London W1T 3JH, UK

Critical Reviews in Food Science and NutritionPublication details, including instructions for authors and subscription information:http://www.tandfonline.com/loi/bfsn20

Recent Advances in Biologically Active Compoundsin Herbs and Spices: A Review of the Most EffectiveAntioxidant and Anti-Inflammatory Active PrinciplesLaura Rubi a , Maria-Jos Motilva a & Maria-Paz Romero aa Department of Food Technology, XaRTA-UTPV, Escola Tcnica Superior dEnginyeriaAgrria , Universitat de Lleida, Avda/Alcalde Rovira Roure 191, 25198 Lleida , SpainAccepted author version posted online: 06 Jul 2012.Published online: 14 Jun 2013.

To cite this article: Laura Rubi , Maria-Jos Motilva & Maria-Paz Romero (2013) Recent Advances in Biologically ActiveCompounds in Herbs and Spices: A Review of the Most Effective Antioxidant and Anti-Inflammatory Active Principles, CriticalReviews in Food Science and Nutrition, 53:9, 943-953, DOI: 10.1080/10408398.2011.574802

To link to this article: http://dx.doi.org/10.1080/10408398.2011.574802

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the Content) containedin the publications on our platform. However, Taylor & Francis, our agents, and our licensors make norepresentations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of theContent. Any opinions and views expressed in this publication are the opinions and views of the authors, andare not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon andshould be independently verified with primary sources of information. Taylor and Francis shall not be liable forany losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoeveror howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use ofthe Content.

This article may be used for research, teaching, and private study purposes. Any substantial or systematicreproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in anyform to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions

Critical Reviews in Food Science and Nutrition, 53:943953 (2013)Copyright C Taylor and Francis Group, LLCISSN: 1040-8398 / 1549-7852 onlineDOI: 10.1080/10408398.2011.574802

Recent Advances in BiologicallyActive Compounds in Herbs andSpices: A Review of the MostEffective Antioxidant andAnti-Inflammatory Active Principles

LAURA RUBI O, MARIA-JOS E MOTILVA, and MARIA-PAZ ROMERODepartment of Food Technology, XaRTA-UTPV, Escola Te`cnica Superior dEnginyeria Agra`ria, Universitat de Lleida,Avda/Alcalde Rovira Roure 191, 25198 Lleida, Spain

Spices, like vegetables, fruit, and medicinal herbs, are known to possess a variety of antioxidant effects and other biologicalactivities. Phenolic compounds in these plant materials are closely associated with their antioxidant activity, which is mainlydue to their redox properties and their capacity to block the production of reactive oxygen species. More recently, their abilityto interfere with signal transduction pathways involving various transcription factors, protein kinases, phosphatases, andother metabolic enzymes has also been demonstrated. Many of the spice-derived compounds which are potent antioxidantsare of great interest to biologists and clinicians because they may help protect the human body against oxidative stressand inflammatory processes. It is important to study the bioactive compounds that can modulate target functions relatedto defence against oxidative stress, and that might be used to achieve health benefits individually. In the present review,an attempt has been made to summarize the most current scientific evidence about the in vitro and in vivo effects of thebioactive compounds derived from herbs and spices, focused on anti-inflammatory and antioxidant effects, in order to providescience-based evidence for the traditional uses and develop either functional foods or nutraceuticals.

Keywords Spices, herbs, antioxidant activity, terpenes, phenolic acids, flavonoids

INTRODUCTION

Spices and herbs are common food adjuncts, which have beenused as flavoring, seasoning, and coloring agents and some-times as preservative, throughout the world for thousands ofyears, especially in India, China, and many other southeasternAsian countries. While bringing color and taste to the food,some spices have long been considered to possess medicinalvalue and have been effectively used in the indigenous systemsof medicine (Nadkarni and Nadkarni, 1976). Apart from thetraditional use, a host of beneficial physiological effects havebeen brought to the fore by extensive animal studies during thepast three decades (Srinivasan, 2005a). Among these are theirbeneficial influences on lipid metabolism (Naidu et al., 2002;

Address correspondence to Dr. Maria-Jose Motilva, Department of FoodTechnology, XaRTA-UTPV, Escola Te`cnica Superior dEnginyeria Agra`ria,Universitat de Lleida, Avda/Alcalde Rovira Roure 191, 25198 Lleida, Spain.E-mail: motilva@tecal.udl.es

Manjunatha et al., 2007), efficacy as antidiabetics (Tundis et al.,2010), antimicrobial (Lai et al., 2004), digestive stimulant ac-tion (Platel et al., 2004), anticarcinogenic potential (Lampe,2003), antioxidant property, and anti-inflammatory (Srinivasan,2005b).

Much of the earlier studies on herbs and spices have viewedtheir bioactive compounds from the perspective of antioxidants.The antioxidant property of these molecules was later explainedon the basis of the availability of OH and the system of conju-gated double bonds present in these molecules. However, manyother effects such as anti-inflammatory, antitumor, antiathero-genic abilities could not be explained solely on the basis oftheir antioxidant properties. Investigations into the mechanismof action of these molecules have thrown light on the fact thatpolyphenols may not merely exert their effects as free radi-cal scavengers, but may also modulate cellular-signaling pro-cesses during inflammation or may themselves serve as signal-ing agents (Aggarwal and Shisodia, 2004).

943

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013

944 L. RUBI O ET AL.

Table 1 Recent advances in biological activities of phenolic terpenes in herbs and spices

Active principle Molecule Origin studied Biological activity Reference

MonoterpenesThymol Oregano, thyme Inhibits LDL oxidation in vitro Kulisic et al., 2007

Prevents peroxynitrite-induced formationin vitro

Prieto et al., 2007

Anti-inflammatory: Inhibits oxLDLinduced proinflammatory cytokinessecretion (TNF-, IL-1b, IL-6), andincreases the anti-inflammatory cytokineIL-10 in vitro

Ocana-Fuentes et al., 2010

Carvacrol Oregano, thyme Inhibits LDL oxidation in vitro Kulisic et al., 2007Prevents in vitro peroxynitrite-induced

formationPrieto et al., 2007

DiterpenesCarnosic acid Rosemary, sage Protects lipid membranes against oxidative

damage in vitroLaura et al., 2010Perez-Fons et al., 2006

Anti-inflammatory: Inhibits the formationof pro-inflammatory leukotrienes and5-LOX

Mueller et al., 2010

Carnosol Rosemary, sage Protects lipid membranes against oxidativedamage in vitro

Laura et al., 2010Perez-Fons et al., 2006

Anti-inflammatory: Inhibits the formationof pro-inflammatory leukotrienes and5-LOX

Poeckel et al., 2008Mueller et al., 2010

Rosmanol Rosemary, sage Anti-inflammatory: Inhibits the activationof NF-kB and STAT3

Lai et al., 2009

Epirosmanol Rosemary Inhibits lipid peroxidation in the cellmembrane and human LDL

Inhibits the formation of apo B in LDL Hui-Hui et al., 2001

Moreover, the most recent and large Antioxidant FoodDatabase (Carlsen et al., 2010) developed from the analysis of3,100 foods, beverages, spices, and herbs, shows that the mostantioxidant-rich products in the human diet are spices and herbs,some of them exceptionally high. The elevated concentration ofantioxidants observed in several dried herbs compared to freshsamples, is a normal consequence of the drying process leavingmost of the antioxidants present in the fresh vegetal tissue intactin the dried end product. They are phytochemically complexand variable geographically within a species or taxon but withmajor contributions from the Apiaceae and Lamiaceae.

The active principles in spices and herbs with biologicalactivities are none other than secondary metabolites produced byplants. The most recent phytochemicals isolated from herbs andspices include: phenolic terpenes (thymol, carvacrol, carnosicacid, carnosol, and rosmanol; Table 1), hidroxycinnamic acids

and derivates (caffeic acid, ferulic acid, p-coumaric, rosmarinicacid, eugenol, and curcumin; Table 2), flavonoids (quercetin,luteolin, and apigenin; Table 3), among others.

To-date, randomized controlled trials considering the intakeof single antioxidants have provided no evidence of health ben-efit effects. So, if an advantage is to be obtained, it might bestcome from consuming a battery of antioxidants, such as occurnaturally in certain foods (Howlett, 2008). However, it is impor-tant to study individually bioactive compounds that can modu-late target functions related to defense against oxidative stressand inflammation, and that might be used to achieve such ben-efits. Oxidative damage and inflammatory processes at the cel-lular and subcellular level is now considered to be an importantevent in disease processes like cardiovascular diseases (CVD),inflammatory disease, carcinogenesis, and ageing, so the use ofherbs and spices as source of bioactive compounds to combat

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013

RECENT ADVANCES IN BIOLOGICALLY ACTIVE COMPOUNDS IN HERBS AND SPICES 945

Table 2 Recent advances in biological activities of hidroxycinnamic acids and derivatives in herbs and spices

Active principle Molecule Origin studied Biological activity Reference

Ferulic acid Mint Inhibits LDL peroxidation in vitro Cheng et al., 2007

Caffeic acid Sage, parsley, lemon balm,thyme, oregano

Inhibits LDL peroxidation in vitro Cheng et al., 2007

p-coumaric Oregano Inhibits LDL oxidation and reduces LDLcholesterol in vivo

Zang et al., 2000

Eugenol Clove, basil Inhibits LDL oxidation in vitro and in vivo

Antioxidative organs protection effects

Teissedre et al., 2000Ito et al., 2005Nagababu et al., 2010Shukri et al., 2010

Rosmarinic acid Oregano, sage, basil,rosemary, thyme, mint

Anti-inflammatory: Increases secretion of theanti-inflammatory cytonkine IL-10 Reducesexpression of iNOS and COX-2 protein

Mueller et al., 2010Shen et al., 2010

Curcumin Turmeric Anti-inflammatory: Reduction of NF-kB, COX-2,and proinflammatory cytokines such as IL-1,IL-6, and TNF- in vitro and in vivo

Antioxidant: Increase in PPAR , glutathione,Haem oxygenase-1, superoxide dismutase, andROS; reduction of NO synthase

Reduction in colonic NF-kB inducible NOsynthase and various measures of oxidativestress such as myeloperoxidase and lipidperoxidation in vivo

Inhibition of LDL oxidation in vitro

Epstein et al., 2010

Aggarwal et al., 2009

Akhilender Naidu et al.,2002

oxidation warrants further attention. In the present review, anattempt has been made to summarize the most current scientificevidences about the in vitro and in vivo effects of the bioactivecompounds derived from herbs and spices, focused on antioxi-dant and anti-inflammatory activities.

Antioxidant Activity

Reactive oxygen spices (ROS) are considered the major con-tributors to many of the diseases associated with ageing, includ-ing CVDs, cancer, cataracts, age-related decline in the immunesystem, and degenerative diseases of the nervous system suchas Parkinsons and Alzheimers disease (Howlett, 2008). Thesefree radicals generated in vivo damage many targets, includ-ing lipids, proteins, DNA, and small molecules. The bodysinnate defenses need to be supported by a wide variety of small-molecular-weight antioxidants found in the diet, and many of

them are of plant origin. Hence, natural antioxidant moleculescan counter ROS directly or boost regenerative systems to re-store antioxidant capacity (Naghavi et al., 2003).

Spices, like vegetables, fruit, and medicinal herbs, are knownto possess a variety of antioxidant effects and properties (Zhenget al., 2001). The antioxidant effect of phenolic compounds ismainly due to their redox properties and their capacity to blockthe production of ROS formed in several in vitro and in vivosystems. This is the result of various possible mechanisms: free-radical scavenging activity, transition-metal-chelating activity,and/or singlet-oxygen-quenching capacity. It has been demon-strated in in vitro and in vivo models, that the antioxidant activityof these bioactive compounds found in herbs and spices couldplay an important role in suppressing cell growth, viral repli-cation, inhibiting allergy and arthritis, preventing cancer andheart diseases, and abrogating several other pathological con-ditions responsible for the early stages of multiple pathologies(Aggarwal et al., 2002).

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013

946 L. RUBI O ET AL.

Table 3 Recent advances in biological activities of flavonoids in herbs and spices

Activeprinciple Molecule Origin studied Biological activity Reference

Quercetin Dill Anti-inflammatory: Inhibits iNOS, COX-2, and CRP,and downregulates NF-kB and TNF- secretionROS scavenging in vitro and in vivoAnti-inflammatory effects in vitro and in vivoModulation of gene expression in vitro

Garca-Mediavilla et al.,2007

Boots et al., 2008

Apigenin Parsley Anti-inflammatory: Suppression of inducible NOsynthase Inhibition of LOX and COX-2 ReductionIL-6 secretion and TNF- and expression of iNOS

Lee et al., 2010Mueller et al., 2010

Luteolin Thyme, mint Decreases the levels of serum total cholesterol,triacylglycerols, LDL-c and increases the level ofserum HDL-c

Feng et al., 2011

Recently, a growing bulk of experimental evidence indicatesthat the cellular effects of nonenzymatic antioxidants do not sim-ply depend on their free radical chain-breaking activity. Prac-tically all of them have repeatedly been shown to act also atseveral key sites in the complex network of functional signalingwithin tissues and cells, involving various transcription factors,protein kinases, phosphatases, and other metabolic enzymes(Leonarduzzi et al., 2010). For instance, overexpression of an-tioxidant enzymes can block activation of the nuclear transcrip-tion factors NF-B and AP-1, the stress-activated protein ki-nases, and apoptosis. Thus, nonenzymatic antioxidants appear tocontribute to maintaining cellular behavior and function withinthe physiological range, and might protect against atypical cellproliferation; but especially they may effectively downregulatethe inflammatory process. Thus, antioxidant ingredients derivedfrom the spices, by blocking transcription factors and kinases,have potential for blocking various diseases, including cancerand CVDs, two major causes of death in developed countries.

From a prevention standpoint, the antioxidant properties ofherbs and spices are of particular interest in view of the im-pact of the oxidative modification of low-density lipoproteincholesterol (LDL-c) in the development of atherosclerosis. Ithas also been reported that various spice-derived ingredients arepotent inhibitors of lipid peroxidation in cell and human LDL(Akhilender Naidu et al., 2002).

These multiple potential mechanisms of antioxidant actionmake the diverse group of phenolic compounds in herbs andspices an interesting target in the search for health beneficialphytochemicals. In this review, various biological activities thathave been assigned to the antioxidant ingredients derived from

herbs and spices are listed in Tables 13 and extended to everygroup of bioactive compounds.

Anti-Inflammatory Activity

Various spice- and herb-derived compounds have also beenshown to exhibit anti-inflammatory activity and a review of themost recent studies is presented here. Different studies havedemonstrated an association between the typical Western dietrich in refined starches, sugars, saturated and transfatty acidsand poor in fruit, vegetables, fibre, -omega-3 fatty acids andwhole grains, and an increased tendency toward inflammatorydisorders and related diseases, such as CVDs, arthritis, or dia-betes (Giugliano et al., 2006). In order to reduce inflammation,a diet rich in fruits and vegetables has been negatively corre-lated with various diseases that are associated with inflamma-tory disorders. In this sense, several dietary polyphenols wereshown to ameliorate inflammatory stages via diverse mecha-nisms (Gonzalez-Gallego et al., 2010).

Chronic inflammation plays an important role in the devel-opment of atherosclerosis, a progressive disease characterizedby the accumulation of lipids and fibrous elements in the largearteries. This inflammation is the mechanism with which thebody responds to the interactions between modified lipopro-teins, monocytes, macrophages, T-cells, and arterial endothelialcells (Libby, 2008). Activated leukocytes, endothelial cells, andmacrophages produce proinflammatory cytokines including in-terleukin (IL)-1b, IL-6, as well as tumor necrosis factor-alpha(TNF-) and anti-inflammatory cytokines, like the cytokine

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013

RECENT ADVANCES IN BIOLOGICALLY ACTIVE COMPOUNDS IN HERBS AND SPICES 947

IL-10 (Li et al., 2005). These cells also produce proinflam-matory enzymes, the inducible forms of nitric oxide sintase(iNOS) and cyclooxygenase (COX), which are responsible forincreasing the levels of nitric oxide (NO) and prostaglandins(PEG2), and are known to be involved in various chronic dis-eases, including multiple sclerosis and colon cancer (Yan et al.,2007). The NF-B transcription factor also plays an importantrole in the inflammatory response by regulating the expressionof various genes encoding proinflammatory cytokines, adhesionmolecules, chemokines, growth factors, and inducible enzymes,such as COX-2 (Hanada et al., 2002). The use of plants withpharmaceutical properties has received increased interest nowa-days from both the homeopathic and allopathic branches. Be-sides, these medicinal plants play an important role in publichealth, especially in developing countries.

Although inflammation is primarily a protective response(against microorganisms, toxins, or allergens, for example),chronic and uncontrolled inflammation becomes detrimental totissues. Since ancient times, in various cultures worldwide, in-flammatory disorders and related diseases have been treated withplants or plant-derived formulations (Krishnaswamy, 2008).Over the last decade, the anti-inflammatory activity of severalspice ingredients and isolated compounds has already been sci-entifically demonstrated and this review pretends to summarizethe most recent advances obtained from the in vitro and in vivostudies.

BIOACTIVE COMPOUNDS IN HERBS AND SPICES

The antioxidant and anti-inflammatory activities of herbs andspices have been related with three main groups of compounds:terpenes, phenolic acids, and flavonoids.

Terpenes

Terpenes form structurally and functionally different classes.They are made from combinations of several 5-carbon-base (C5)units called isoprene. The biosynthesis of the terpenes consistsof synthesis of the isopentenyldiphosphate (IPP) as a precursor,repetitive addition of IPPs to form the prenyldiphosphate pre-cursor of the various classes of terpenes, modification of the al-lylicprenyldiphosphate by terpene-specific synthetases to formthe terpene skeleton, and finally, secondary enzymatic modifi-cation (redox reaction) of the skeleton to attribute functionalproperties to the different terpenes. We will focus here on themain terpenes in herbs and spices, these being the monoterpenesand diterpenes.

The monoterpenes (C10) are formed from the couplingof two isoprene units (C10). They are the most representa-tive molecules, constituting 90% of the essential oils, and interms of health, the most important are thymol and carvacrol(Table 1). The antioxidant properties of thymol and carvacrol

have been demonstrated in several studies, suggesting theiruse as nutraceutical ingredients in the development of novelfunctional foods. The derivatives of thymol and carvacrol havebeen described as antioxidant according to the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging method (Mastelicet al., 2008). Essential oils from oregano and their components(carvacrol and thymol) inhibited 3-nitrotyrosine formation, abiomarker of oxidative stress, supporting the nutraceutical valueof oregano and the potential of thymol and carvacrol for pre-venting the formation of toxic products by the action of reactivenitrogen species (Prieto et al., 2007).

Also, thymol and carvacrol act in preventing the autoxidationof lipids (Yanishlieva et al., 2006). In another recent study, theantioxidative effect of essential oils from oregano and thyme,and aqueous tea extracts, on the oxidation susceptibility of LDLhas been studied (Kulisic et al., 2007). The results indicate adose-dependent protective effect of both the essential oils andthe aqueous tea extracts on the copper-induced LDL oxidation.The protective effect is assigned to the presence of phenolicmonoterpenes, thymol and carvacrol, which are identified as thedominant compounds. The strong protective effect of aqueoustea infusions is proposed to be the consequence of the presenceof both components and large amounts of other polyphenols,like rosmarinic acid and various flavonoids. These findings mayhave implications for the effect of these compounds on LDL invivo.

A recent study showed the possible anti-inflammatory effectsof these two components based on the decrease in proinflam-matory TNF-, IL-1b, and IL-6 cytokines synthesis, as well asan increase in the production of the anti-inflammatory cytokineIL-10 (Ocana-Fuentes et al., 2010). These results may suggestan anti-inflammatory effect of oregano extracts and their com-pounds in a cellular model of atherosclerosis.

Carnosic acid and carnosol, the main diterpenes in aromaticherbs, together with rosmarinic acid, a hydroxycinnamic acidester, are the main antioxidant compounds present in rosemary(Wellwood et al., 2004; Penuelas et al., 2005). Among the herbalextracts reported to have antioxidative activity, rosemary is oneof the most widely used and commercialized plant extracts,not only as a culinary herb for flavoring but also as an an-tioxidant in processed foods and cosmetics (Zheng et al., 2001).Carnosic acid and carnosol, together with such other isoprenoidsas sterols, tocopherols, or carotenoids, play a photoprotectiverole and are considered as bioactive constituents. Carnosic acidis originated from IPP via methylerythritol phosphate. It is lo-cated in chloroplasts and intracellular membranes, as is carnosol,formed from the oxidative degradation of carnosic acid (Almelaet al., 2006).

The antioxidant activity of rosemary extracts and their re-spective major compounds (carnosic acid, carnosol, and ros-marinic acid) was analyzed in a study by Laura et al. (2010)and compared by using different in vitro systems. Whereasrosmarinic acid, carnosic acid, and carnosol exhibited simi-lar antioxidant activity in a phospholipid membrane-free as-say, carnosol behaved as an extremely potent antioxidant in a

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013

948 L. RUBI O ET AL.

membrane-based assay (46 times stronger than the rest of thecompounds). This differential antioxidant behavior suggests thatfactors other than the radical scavenging capability may be in-volved. All of the diterpenes induced changes on the lipid orderand packing of phospholipid model membranes. These effectsmay contribute to membrane stabilization and the interruptionof radical propagation, which may cooperate with the electrondonor ability of rosemary diterpenes to protect the membranesagainst oxidative damage (Laura et al., 2010).

In a very recent study the anti-inflammatory activity of vari-ous fruits, herbs, and spices has been demonstrated (Muelleret al., 2010). Sage, a herb rich in carnosol and carnosicacid, presented anti-inflammatory activity, improving the anti-inflammatory profile of the secreted cytokines and inhibitingnotably the expression of the proinflammatory enzyme, iNOS.According to the literature, carnosic acid and carnosol can in-hibit the formation of proinflammatory leukotrienes and LOX-5(Poeckel et al., 2008). Based on the positive results of theireffects on cytokine profiles and inhibition of iNOS and COX-2 expression, several plant extracts tested in this study couldpotentially be used as food supplements with the purpose ofproviding anti-inflammatory effects.

The pharmacokinetics and the absolute bioavailability ofcarnosic acid in rats have also been examined (Yan et al., 2009).The absorption of carnosic acid was slow (Tmax = 125.6 min-utes) after i.g. administration (90 mg/kg). However, the max-imum plasma concentration was high and retained for a longtime. The absolute bioavailability of carnosic acid was alsohigh [F(%) = 65.09], which would be a useful feature in futureclinical applications of the drug as an antioxidant.

Recent studies (Lai et al., 2009) demonstrated that rosmanol,another natural diterpene from rosemary, downregulates inflam-matory iNOS and COX-2 gene expression by inhibiting the acti-vation of NF-B and STAT3 through interfering with the activa-tion of phosphatidylinositol 3-kinases (PI3K/Akt) and MAPKsignaling. Taken together, rosmanol with carnosic acid mightcontribute to the potent anti-inflammatory effect of rosemaryand may have the potential to be developed into an effectiveanti-inflammatory agent.

Hidroxycinamic Acids and Derivates

Hydroxycinnamates or phenylpropanoids (C6C3 com-pounds) are secondary plant metabolites of phenylalanine, andto a lesser extent, of tyrosine via the action of phenylalanineammonia lyase or tyrosine ammonia lyase, respectively. Hy-droxycinamic acids are important simple phenols as they areprecursors for the synthesis of many other complex phenols.They are found in almost all food groups, although they areabundant in cereals, legumes, oilseeds, fruits, vegetables, bev-erages, and herbs and spices (Robbins, 2003).

The latest studies into the antioxidant and anti-inflammatoryactivities of hidroxycinnamates derived from herbs and spicesare summarized in Table 2. Recently, the in vitro and in vivo an-

tioxidant activity of hydroxycinnamates was reviewed and therevision concluded that these phenolic compounds may exerta myriad of health benefits thus ameliorating chronic diseasesassociated with oxidative damage such as cancers, CVDs, hyper-tension, and neurodegenerative disorders (Shahidi et al., 2010).

Among these, the inhibition of LDL peroxidation by supple-mentation of antioxidants has become one of the most attractivetherapeutic strategies for preventing atherosclerosis. A study byCheng et al. (2007) used the in vitro peroxidation of LDL as amodel to evaluate the free radical-induced damage of biologicalmembranes and the protective effect of hydroxycinnamic acidderivatives, that is, caffeic acid, chlorogenic acid, sinapic acid,ferulic acid, and p-coumaric acid. The kinetic analysis of theantioxidation process demonstrates that these hydroxycinnamicacid derivatives are effective antioxidants against both AAPH-and Cu2+-induced LDL peroxidation with the activity sequenceof caffeic acid chlorogenic acid > sinapic acid > ferulicacid > p-coumaric acid, and caffeic acid chlorogenic acid >sinapic acid ferulic acid p-coumaric acid, respectively. Caf-feic acid, one of the most effective antioxidants in this study, isfound in great amounts in a number of Mediterranean culinaryherbs, including sage, parsley, thyme, and oregano (Wojdyoet al., 2007).

p-Coumaric acid has an important presence in oregano (Shanet al., 2005) and there is evidence that it has an antioxidanteffect in vivo, protecting LDL oxidation and reducing LDLlevels in serum (Zang et al., 2000). In this study, rats wereadministered with p-coumaric acid in drinking water at low andhigh doses for 10, 21, and 31 days, and the oral administrationof 317 mg/day for 30 days significantly inhibited LDL oxidationand reduced LDL levels. Blood levels of 8-epiprostaglandin F2were monitored as a marker of LDL oxidation. If p-coumaric isan efficient antioxidant for LDL, it may play a key role in thepurported effect of oxidized lipoprotein on platelet activity toslow the progression of atherosclerosis.

Eugenol (4-allyl-2 methoxyphenol), the major component ofcloves (Shan et al., 2005), is known for its aroma and medicinalvalues. In a very recent study the antioxidant activity of eugenolwas evaluated by the degree of protection offered against freeradical-mediated lipid peroxidation using both in vitro and invivo models (Nagababu et al., 2010). The in vitro lipid per-oxidation was induced in mitochondria by (Fe(II)-ascorbate) or(Fe(II) + H2O2), and eugenol completely inhibited both iron andFenton reagent-mediated lipid peroxidation. The inhibitory ac-tivity of eugenol was about five times higher than that observedfor -tocopherol. The in vivo lipid peroxidation-mediated liverdamage was induced by administration of CCl4 to rats. Eugenolsignificantly inhibited the rise in serum glutamic oxalacetictransaminase activity and cell necrosis. The protective action ofeugenol has been found to be due to interception of secondaryradicals derived from endoplasmic reticulum lipids rather thaninterfering with primary radicals of CCl4(CCl3/CCl3OO).

In several previous studies, there is also evidence of the invitro inhibition of LDL oxidation by eugenol. The activitiesof 23 selected essential oils in inhibiting the copper-catalyzed

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013

RECENT ADVANCES IN BIOLOGICALLY ACTIVE COMPOUNDS IN HERBS AND SPICES 949

oxidation of human LDL were determined in vitro (Teissedreet al., 2000) and antioxidant activity average levels from dif-ferent plant varieties showed that when eugenol is the majorcomponent, the inhibition of LDL oxidation ranged between68% (clove) and 100% (St. Thomas Bay). In a study by Ito et al.(2005), the antioxidant action of eugenol compounds was ana-lyzed in relation to the role of transition metals. Iron-mediatedlipid peroxidation and autoxidation of Fe2+ ion were markedlyinhibited by isoeugenol, and less effectively by eugenol. Copper-dependent oxidation of LDL was potently inhibited by eugenoland isoeugenol to the same extent. This study evidenced that an-tioxidant properties of eugenol compounds can be explained byforming complexes with reduced metals. The potent inhibitoryeffect of isoeugenol on lipid peroxidation may be related to thedecreased formation of perferryl ion or the iron-oxygen chelatecomplex as the initiating factor of lipid peroxidation by keepingiron at a reduced state. Inhibition of LDL oxidation by eugenolcompounds could be due to the suppression of free radical cas-cade of lipid peroxidation in LDL by reducing copper ion. An-other recent study (Shukri et al., 2010) attempts to evaluatethe organ and tissue protective in vivo effects of dietary cloves(Eugenia aromaticum) in chronic hyperglycaemia. The cloves(equivalent to 100 mg total eugenol + eugenyl acetate per kgbody weight/day) were administered orally to streptozotocin-induced diabetic rats. Dietary supplementation with cloves re-duced tissue injuries, especially in the lens and cardiac muscles,and to a lesser extent in the liver, but not the kidneys. Addi-tionally, the cloves treatment significantly reduced blood sugarincreases and lipid peroxidation in rats by restoring the antiox-idant enzyme levels. Cloves inhibited hyperglycaemia-inducedoxidative tissue damage and cataract formation in the eye lens.This study also demonstrates the in vivo antioxidative organprotective effects of clove in diabetics.

Rosmarinic acid, a hidroxycinamic acid derivate, is an es-ter of caffeic acid and 3,4-dihydroxy-phenyllactic acid typicallyfound in Lamiaceae plants, such as basil (Ocimum spp.), rose-mary (Rosmarinus spp.), thyme (Thymus spp.), mint (Menthaspp.), and oregano (Origanum spp.) (Petersen et al., 2003). Thecharacterization of 26 spice extracts and their phenolic con-stituents showed that all spices in the Lamiaceae family testedcontained very high concentrations of rosmarinic acid, mostlyranging from 1086 to 2563 mg/100 g of dry-weight being themajor phenol in the Lamiaceae spices (Shan et al., 2005). Ros-marinic acid has two ortho-dihydroxy groups (catechol struc-tures), which is the most important structural feature for strongantioxidant activity in phenolic compounds. This compoundmay function as an antioxidant, scavenging superoxide, hy-droxyl radicals, and inhibiting oxidation of LDLs (Nakamuraet al., 1998; Fuhrman et al., 2000). In addition, there is re-cent scientific evidence about the anti-inflammatory activity ofrosmarinic acid. It has been recently demonstrated that in alipopolysaccharide-stimulated macrophage model, rosmarinicacid may contribute to the reduction of the inflammatory re-sponse by increasing the secretion of IL-10 (Mueller et al.,2010). Many anti-inflammatory studies have been performed on

oregano extracts where the water-soluble extract was reportedto inhibit COX-2 secretion in humane epithelial carcinoma cells(Lemay, 2006), and it also exhibited anti-inflammatory activ-ities in mouse models of stress-induced gastritis and contacthypersensitivity (Yoshino et al., 2006). However, these anti-inflammatory studies were all performed on oregano crude ex-tracts without any information as to which compounds may beresponsible. Recently, all of these compounds were elucidatedcoupled with bioactivity-guided isolation, and one of the anti-inflammatory constituents identified was rosmarinic acid (Shenet al., 2010). It was then subjected to the LPS-induced nitrite pro-duction assay and Western blotting of LPS-induced iNOS andCOX-2 protein levels in murine cells, and all showed strongeror comparable anti-inflammatory activities compared withindomethacin, a recognized anti-inflammatory agent used asa control.

Curcumin (diferuloylmethane), a polyphenolic compoundderived from the dietary spice turmeric (also an ingredient ofcurry powder), has been used for centuries as a treatment forinflammatory diseases. Extensive research within the past twodecades has shown that curcumin, a complex molecule withmultiple biological targets, mediates its anti-inflammatory ef-fects through the downregulation of inflammatory transcriptionfactors (such as NF-kB), enzymes (such as COX-2 and LOX-5),and cytokines (such as TNF-, IL1, and IL-6) (Aggarwal et al.,2009). Most recent studies about its biological activities are sum-marized in Table 2. Because of the crucial role of inflammationin most chronic diseases, the potential of curcumin has been ex-amined in neoplastic, neurological, cardiovascular, pulmonary,and metabolic diseases. It is known that bis-,-unsaturated -diketone, two methoxy groups, two phenolic hydroxy groups,and two double-conjugated bonds might play an essential rolein the antiproliferative and anti-inflammatory activities assignedto curcumin (Sandur et al., 2007).

A recent publication by Epstein et al. (2010) reviewed theevidence for the therapeutic potential of curcumin from in vitrostudies, animal models and human clinical trials, and concludethat in complex multifactorial illnesses, such as systemic in-flammatory diseases and cancer, an agent like curcumin thatacts at a number of different cellular levels, perhaps offers abetter chance of effective prophylaxis or treatment. The wealthof in vitro and preclinical data has provided a strong basis fromwhich to progress to the trailing of curcumin in humans. Manyof the molecular efficacies of curcumin demonstrated in cell cul-ture systems and animal models are comparable to those seenin human subjects. The anti-inflammatory targets of curcuminincluding reduction of NF-kB, COX-2, and proinflammatorycytokines such as IL-1, IL-6, and TNF-, translate into clini-cal anti-inflammatory efficacy with improvement of rheumatoidarthritis, psoriasis, postoperative inflammation, chronic ante-rior uveitis, and orbital inflammatory pseudo-tumors (Epsteinet al., 2010). Concordant with the finding that high concen-trations of curcumin are achievable in gastrointestinal tissue,curcumin shows clinical benefits in some diseases, such as irri-table bowel syndrome (Bundy et al., 2004) and gastric ulceration

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013

950 L. RUBI O ET AL.

(Prucksunand et al., 2001). The in vitro findings of enhancedPPAR- expression and modulation of NOS, glutathione, andother antioxidant activities are supported by the clinical powerof curcumin to lower serum cholesterol (Soni et al., 1992) andimprove the endothelial function in type 2 diabetes mellitus(Usharani et al., 2008).

There is also evidence that curcumin significantly inhibitsboth the initiation and propagation phases of LDL oxida-tion measured by thiobarbituric acid reactive substances assay(TBARS) and by relative electrophoretic mobility of LDL onagarose gel (Akhilender Naidu et al., 2002). These data suggestthat curcumin, which constitute about 14% of turmeric, couldbe an effective antioxidant and offer protection against oxida-tion of human LDL, although it requires further investigationson in vivo models.

Its nontoxicity (Aggarwal et al., 2003) and good tolerabilityin human subjects, in combination with strong promising resultsfrom cell line, animal, and early human clinical studies supportthe ongoing research and development of curcumin as a pre-ventive and disease-modifying agent. Nevertheless, curcuminexhibits poor bioavailability in humans (Anand et al., 2007).Major reasons that could contribute to the low concentration ofcurcumin in plasma and tissue could be related with its poorabsorption, its rapid metabolism through conjugation, and itsrapid systemic elimination (Garcea et al., 2005). To improve thebioavailability of curcumin, numerous approaches have beentested (Anand et al., 2007). These involve, first, the use ofpipeline that interferes with glucuronidation; second, the useof liposomal curcumin; third, curcumin nanoparticles; fourth,the use of curcumin phospholipid complex; and fifth, the use ofstructural analogues of curcumin (e.g., EF-24). The latter hasbeen reported to have a rapid absorption with a peak plasmahalf-life.

Despite the lower bioavailability, the therapeutic efficacy ofcurcumin against various human diseases, including cardiovas-cular and neurological diseases (Aggarwal et al., 2009), diabetes(Usharani et al., 2008), arthritis (Venkatesha et al., 2011), can-cer (Garcea et al., 2005), and Crohns disease (Claramunt et al.,2009) has been documented. Enhanced bioavailability of cur-cumin in the near future is likely to bring this promising naturalproduct to the forefront of therapeutic agents for the treatmentof human disease.

Flavonoids

Most classes of flavonoids are found in herbs and spices. Fre-quently, these include relatively uncommon aglycones and/orcommon aglycones with comparatively uncommon substitutionpatterns. Flavonoids do not generally exceed 0.20.4 g/kgin Lamiaceae herbs but reach 1.53 g/kg in Apiaceae herbs,3.5 g/kg in cloves, and 7 g/kg in bay leaf (Shan et al., 2005).Although flavonoids make a rather small contribution to the totalantioxidant capacity of the spice extracts because of their lowconcentrations, in this review they are not discriminated becauseit has been shown that they are very powerful antioxidants with

interesting biological activities, which are reviewed in Table 3.There is a large body of evidence from epidemiological stud-ies that long-term administration of flavonoids can decrease,or at least, tend to decrease, the incidence of CVDs and theirconsequences (Aherne et al., 2002; Mennen et al., 2004).

Besides their antioxidant properties, many reports have fo-cused on the possible role of flavonoids in the modulation ofROS-dependent cell-signaling pathways, emphasizing that theirbeneficial effects may be ascribed to other than simple antioxi-dant activity. Direct interactions between polyphenols and sig-naling proteins may occur, likely because of flavonoids hy-drophobicity and the presence of multiple hydroxyls on thefavonoid rings, which enable hydrogen bonding to occur withprotein functional groups (Fraga, 2007).

Flavonols are the most ubiquitous flavonoids in foods, beingquercetin the most common flavanol present in different planttissues. Among herbs and spices, quercetin is found in a greatamount in dill (Proestos et al., 2005). The flavonoid quercetinhas been proven to be an excellent antioxidant that also possessesanti-inflammatory, antiproliferative, and gene expression chang-ing capacities in vitro. Within the flavonoid family, quercetin isthe most potent scavenger of ROS, including O2, and RNS-like NO ONOO (Heijnen et al., 2002). These antioxidativecapacities of quercetin are attributed to the presence of twoantioxidant pharmacophores within the molecule that have theoptimal configuration for free radical scavenging, that is, thecatechol group in the B ring and the OH group at position 3 onthe AC ring.

Quercetin is known also to possess strong anti-inflammatorycapacities. Several in vitro studies, using different cell lines,have shown that this molecule is capable of inhibiting LPS-induced cytokine production. For instance, quercetin inhibitsLPS-induced TNF- production in macrophages (Manjeet et al.,1999) and LPS-induced IL-8 production in lung cells (A549)(Geraets et al., 2007). Moreover, in glial cells, it was even shownthat quercetin can inhibit LPS-induced mRNA levels of two cy-tokines, that is, TNF- and IL-1 (Bureau et al., 2008). A possibleexplanation for these anti-inflammatory effects of quercetin maybe found in the interplay between oxidative stress and inflamma-tion. ROS are not only involved in the occurrence of oxidativestress, but also in the promotion of inflammatory processes viaactivation of transcription factors, such as NF-B and activatorprotein (AP)-1, which induce the production of cytokines likeTNF-. Indeed, it has already been shown that quercetin can in-hibit the production as well as the gene expression of TNF- viamodulation of NF-B in human peripheral blood mononuclearcells (Nair et al., 2006). In another recent study, it is suggestedthat the modulation of iNOS, COX-2, and C-reactive protein(CRP) by quercetin may contribute to the anti-inflammatory ef-fects of these in Chang Liver cells, via mechanisms likely toinvolve blockade of NF-B activation and the resultant upreg-ulation of the proinflammatory genes (Garca-Mediavilla et al.,2007).

Until now, only the antioxidative and anti-inflammatoryeffects of quercetin have been shown in vivo as well.Interestingly, these two effects of quercetin appear to be more

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013

RECENT ADVANCES IN BIOLOGICALLY ACTIVE COMPOUNDS IN HERBS AND SPICES 951

pronounced when the respective basal levels of the occurring ox-idative stress and inflammation are high. This indicates that theuse of quercetin supplementation is especially fruitful in peoplesuffering from a disease that is associated with both processes,such as hypertension (Boots et al., 2008).

Flavones are much less common than flavonols in fruits,vegetables, and herbs. Flavones consist chiefly of glycosides ofluteolin and apigenin. One of the most important edible sourcesof flavones identified to date in herbs and spices is parsley,which contains a great amount of apigenin (2 g/kg) (Justesenet al., 1998). Luteolin is also the main flavonoid in thyme andmint (Proestos et al., 2005). Both compounds have been linkedto antioxidant and anti-inflammatory effects. In a recent study,the anti-inflammatory activities of several flavonoids were eval-uated (Lee et al., 2010). Luteolin and apigenin strongly inhib-ited LPS-induced nitrite production in a dose-dependent man-ner, mainly due to the suppression of inducible NO synthase.Luteolin showed the strongest inhibitory activities on 15-LOXand a potent inhibition on COX-2 reaction. Recently, differentcompounds from plant extracts were also tested in the LPS-stimulated macrophage model to see their anti-inflammatoryresponse, and luteolin and apigenin reduced IL-6 and TNF-secretions, and also reduced the expression of iNOS and COX-2 (Mueller et al., 2010). These findings further the idea that a dietrich in fruits, herbs, and spices may contribute to the reductionof inflammation and help prevent related diseases.

The hypolipidemic effect of these compounds was alsoproven in hyperlipidemic rats induced by high fat diet, combinedwith the oral administration of Perilla frutescens, a herb usedin traditional Chinese medicine. The main flavonoids presentin this herb are luteolin and apigenin. The results of this studyshowed that P. frutescens was highly effective at decreasingthe levels of serum total cholesterol, triacylglycerols, LDL-c,and adipose tissue accumulation and in increasing the level ofserum high-density lipoprotein cholesterol (HDL-c; Feng et al,2011). In conventional therapy, steroidal and nonsteroidal anti-inflammatory drugs that inhibit COX are used to treat acuteinflammation, but are unsuccessful at curing chronic inflam-matory diseases, such as rheumatoid arthritis or osteoarthritis.Furthermore, these compounds exhibit several undesirable sideeffects. Therefore, alternative treatments with safer compoundsare needed (Yoon et al., 2005).

CONCLUSIONS

Research on the structure activity relationships in spice com-ponents has become an exciting field as these compounds playa major role in the culinary, industrial, and pharmacologicalfields. A range of bioactive compounds in herbs and spices hasbeen studied for antioxidant and anti-inflammatory propertiesin vitro and in vivo animal models, but the challenge lies in in-tegrating this knowledge to ascertain whether these effects canbe observed in humans, and within defined cuisines.

In summary, as several metabolic diseases and ageing-relateddegenerative disorders are closely associated with oxidative andinflammatory processes in the body, the use of herbs and spices,or their bioactive principles, as a source of antioxidants tocombat oxidation warrants further attention. Immediate studiesshould focus on validating the antioxidant capacity of herbs andspices, as well as testing their effects on markers of oxidationand inflammation. Based on the positive results from the latestresearch in this field, several of the plant extracts tested couldpotentially be used as food supplements to provide beneficialeffects.

ACKNOWLEDGMENTS

This work was supported by the Spanish Ministry of Educa-tion and Science financing the project AGL2009-13517-C13-02and the University of Lleida through the L. Rubio grant.

ABBREVIATIONS

ROS = Reactive oxygen speciesCVD = Cardiovascular diseasesROI = Reactive oxygen intermediatesNF- B = Nuclear factorBTNF- = Tumor necrosis factorCOX = CyclooxygenaseLOX = LipooxygenaseIL = InterleukinLDL-c = Low-density lipoprotein cholesterolLPS = LipopolysaccharideHDL-c = High-density lipoprotein cholesterolNO = Nitric oxideoxLDL = Oxidised low-density lipoproteinPPAR = Peroxisome proliferator activated receptoriNOS = Inducible nitric oxide synthaseSTAT3 = Signal transducer and activator of transcription 3MAPK = Mitogenactivated-proteinkinasesCRP = C- reactive protein

REFERENCES

Aggarwal, B., et al. (2002). Spices as potent antioxidants with therapeuticpotential. In: Handbook of Antioxidants. Cadenas, E. and Packer, L., Eds.,Ch. 22. University of Southern California School of Pharmacy, Los Angeles.Marcel Dekker, Inc.

Aggarwal, B. B., et al. (2003). Anticancer potential of curcumin: Preclinicaland clinical studies. Anticancer Res. 23:363398.

Aggarwal, B. B., et al. (2009). Pharmacological basis for the role of curcumin inchronic diseases: An age-old spice with modern targets. Trends Pharmacol.Sci. 30:8594.

Aggarwal, B. B. and Shisodia, S. (2004). Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: Reasoning forseasoning. Ann NY Acad Sci. 1030:434441.

Aherne, S. A., et al. (2002). Dietary flavonols: Chemistry, food content, andmetabolism. Nutrition 18:7581.

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013

952 L. RUBI O ET AL.

Akhilender Naidu, K., et al. (2002). Inhibition of human low density lipoproteinoxidation by active principles from spices. Mol. Cell. Biochem. 229:1923.

Almela, L., et al. (2006). Liquid chromatograpic-mass spectrometric analysisof phenolics and free radical scavenging activity of rosemary extract fromdifferent raw material. J. Chromatogr. A 1120:221229.

Anand, P., et al. (2007). Bioavailability of curcumin: Problems and promises.Mol. Pharm. 4:807818.

Boots, A. W., et al. (2008). Health effects of quercetin: From antioxidant tonutraceutical. Eur. J. Pharmacol. 585:325337.

Bundy, R., et al. (2004). Turmeric extract may improve irritable bowel syn-drome symptomology in otherwise healthy adults: A pilot study. J. Altern.Complement. Med. 10:10151018.

Bureau, G., et al. (2008). Resveratrol and quercetin, two natural polyphenols,reduce apoptotic neuronal cell death induced by neuroinflammation. J. Neu-rosci. Res. 86:403410.

Carlsen, M. H., et al. (2010). The total antioxidant content of more than 3100foods, beverages, spices, herbs and supplements used worldwide. Nutr. J. 9:3.

Cheng, J., et al. (2007). Antioxidant activity of hydroxycinnamic acid deriva-tives in human low density lipoprotein: Mechanism and structure-activityrelationship. Food Chem. 104:132139.

Claramunt, R. M., et al. (2009). Synthesis and biological evaluation of curcum-inoid pyrazoles as new therapeutic agents in inflammatory bowel disease:Effect on matrix metalloproteinases. Bioorg. Med. Chem. 17:12901296.

Epstein, J., et al. (2010). Curcumin as a therapeutic agent: The evidence fromin vitro, animal and human studies. Br. J. Nutr. 103:15451557.

Feng, L., et al. (2011). Hypolipidemic and antioxidant effects of total flavonoidsof Perilla Frutescens leaves in hyperlipidemia rats induced by high-fat diet.Food Res. Int. 44:404409.

Fraga, C. G. (2007). Plant polyphenols: How to translate their in vitro antioxidantactions to in vivo conditions. IUBMB Life. 59:308315.

Fuhrman, B., et al. (2000). Lycopene synergistically inhibits LDL oxidationin combination with vitamin E, glabridin, rosmarinic acid, carnosic acid, orgarlic. Antioxid. Redox Signal. 2:491506.

Garcea, G., et al. (2005). Consumption of the putative chemopreventive agentcurcumin by cancer patients: Assessment of curcumin levels in the colorectumand their pharmacodynamic consequences. Cancer Epidemiol. BiomarkersPrev. 14:120125.

Garca-Mediavilla, V., et al. (2007). The anti-inflammatory flavones quercetinand kaempferol cause inhibition of inducible nitric oxide synthase,cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclearfactor kappaB pathway in Chang Liver cells. Eur. J. Pharmacol. 557:221229.

Geraets, L., et al. (2007). Dietary flavones and flavonoles are inhibitorsof poly(ADP-ribose) polymerase-1 in pulmonary epithelial cells. J. Nutr.137:21902195.

Giugliano, D., et al. (2006). The effects of diet on inflammation. Emphasis onthe metabolic syndrome. J. Am. Coll. Cardiol. 48:677685.

Gonzalez-Gallego, J., et al. (2010). Fruit polyphenols, immunity and inflam-mation. Br. J. Nutr. 104:S3S15.

Hanada, T., et al. (2002). Regulation of cytokine signaling and inflammation.Cytokine Growth Factor Rev. 13:413421.

Heijnen, C. G. M., et al. (2002). Protection of flavonoids against lipid per-oxidation: The structure activity relationship revisited. Free Radic. Res.36:575581.

Howlett, J. (2008). Functional foodsFrom science to health claims. In: ILSIEurope Concise Monograph Series. (Peter Aggett, ed. University of CentralLancashire (UK)). ILSI Europe, Brussels.

Hui-Hui, Z., et al. (2001). Antioxidant properties of phenolic diterpenes fromRosmarinus officinalis. Acta Pharmacol. Sin. 22:10941098.

Ito, M., et al. (2005). Antioxidant action of eugenol compounds: Role of metalion in the inhibition of lipid peroxidation. Food Chem. Toxicol. 43:461466.

Justesen, U., et al. (1998). Quantitative analysis of flavonols, flavones, andflavanones in fruits, vegetables and beverages by high-performance liquidchromatography with photo-diode array and mass spectrometric detection. J.Chromatogr. A, 799:101110.

Krishnaswamy, K. (2008). Traditional Indian spices and their health signifi-cance. Asia Pac. J. Clin. Nutr. 17:265268.

Kulisic, T., et al. (2007). The effects of essential oils and aqueous tea infusionsof oregano (Origanumvulgare L. spp. hirtum), thyme (Thymus vulgaris L.)and wild thyme (Thymus serpyllum L.) on the copper-induced oxidation ofhuman low-density lipoproteins. Int. J. Food Sci. Nutr. 58:8793.

Lai, C., et al. (2009). Rosmanol potently inhibits lipopolysaccharide-inducediNOS and COX-2 expression through downregulating MAPK, NF-B, STAT3and C/EBP signaling pathways. J. Agric. Food Chem. 57:1099010998.

Lai, P. K., et al. (2004). Antimicrobial and chemopreventive properties of herbsand spices. Curr. Med. Chem. 11:14511460.

Lampe, J. W. (2003). Spicing up a vegetarian diet: Chemopreventive effects ofphytochemicals. Am. J. Clin. Nutr. 78:579S583S.

Laura, P., et al. (2010). Relationship between the antioxidant capacity andeffect of rosemary (Rosmarinus officinalis L.) polyphenols on membranephospholipid order. J. Agric. Food Chem. 58:161171.

Lee, J. (2010). Caffeic acid derivatives in dried Lamiaceae and Echinacea pur-purea products. J. Funct. Foods 2:158162.

Lee, J., et al. (2010). Evaluation of antioxidant and inhibitory activities fordifferent subclasses flavonoids on enzymes for rheumatoid arthritis. J. FoodSci. 75:H212H217.

Lemay, M. (2006). Anti-inflammatory phytochemicals: In vitro and ex vivoevaluation. In: Phytochemicals, pp 4160. Meskin, M. S., Bidlack, W. R. andRandolph, R. K., Eds., CRC Press, Boca Raton, FL.

Leonarduzzi, G., et al. (2010). Targeting tissue oxidative damage by meansof cell signaling modulators: The antioxidant concept revisited. Pharmacol.Ther. 128:336374.

Li, H. X., et al. (2005). Effects of interleukin-10 on expression of inflammatorymediators and anti-inflammatory mediators during acute lung injury in rats.Zhongguo Wei Zhong Bing JiJiu Yi Xue. 17:338341.

Libby, P. (2008). Role of inflammation in atherosclerosis associated withrheumatoid arthritis. Am. J. Med. 121:S21S31.

Manjeet, K. R., et al. (1999). Quercetin inhibits LPS-induced nitric oxide and tu-mor necrosis factor- production in murine macrophages. Int. J. Immunophar-macol. 21:435443.

Manjunatha, H., et al. (2007). Hypolipidemic and antioxidant effects of di-etary curcumin and capsaicin in induced hypercholesterolemic rats. Lipids.42:11331142.

Mastelic, J., et al. (2008). Comparative study on the antioxidant and biologicalactivities of carvacrol, thymol, and eugenol derivatives. J. Agric. Food Chem.56:39893996.

Mennen, L. I., et al. (2004). Consumption of foods rich in flavonoids is relatedto a decreased cardiovascular risk in apparently healthy French women. J.Nutr. 134:923926.

Mueller, M., et al. (2010). Anti-inflammatory activity of extracts from fruits,herbs and spices. Food Chem. 122:987996.

Nadkarni, K. M. and Nadkarni, A. K. (1976). Indian Materia Medica. PopularPrakashan Pvt. Ltd, Mumbai, India.

Nagababu, E., et al. (2010). Assessment of antioxidant activity of eugenol invitro and in vivo. Methods Mol. Biol. 610:165180.

Naghavi, M., et al. (2003). From vulnerable plaque to vulnerable patient:A call for new definitions and risk assessment strategies. Circulation.108:16641672.

Naidu, K. A., et al. (2002). Inhibition of human low density lipoprotein oxidationby active principles from spices. Mol. Cell. Biochem. 229:1923.

Nair, M. P., et al. (2006). The flavonoid quercetin inhibits proinflammatorycytokine (tumor necrosis factor alpha) gene expression in normal peripheralblood mononuclear cells via modulation of the NF- system. Clin. VaccineImmunol. 13:319328.

Nakamura, Y., et al. (1998). Superoxide scavenging activity of rosmarinicacid from perillafrutescens britton var. acuta f. viridis. J. Agric. Food Chem.46:45454550.

Ocana-Fuentes, A., et al. (2010). Supercritical fluid extraction of oregano (Ori-ganumvulgare) essentials oils: Anti-inflammatory properties based on cy-tokine response on THP-1 macrophages. Food and Chem. Toxicol. 48:15681575.

Penuelas, J., et al. (2005). Isoprenoids: An evolutionary pool for photoprotec-tion. Trends Plant Sci. 10:166169.

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013

RECENT ADVANCES IN BIOLOGICALLY ACTIVE COMPOUNDS IN HERBS AND SPICES 953

Perez-Fons, L., et al. (2006). Rosemary (Rosmarinus officinalis) diterpenesaffect lipid polymorphism and fluidity in phospholipid membranes. Arch.Biochem. Biophys. 453:224236.

Petersen, M., et al. (2003). Rosmarinic acid. Phytochemistry. 62:121125.Pizzale, L., et al. (2002). Antioxidant activity of sage (Salvia officinalis and S

fruticosa) and oregano (Origanumonites and O indercedens) extracts relatedto their phenolic compound content. J. Sci. Food Agric. 82:16451651.

Platel, K., et al. (2004). Digestive stimulant action of spices: A myth or reality?Indian J. Med. Res. 119:167179.

Poeckel, D., et al. (2008). Carnosic acid and carnosol potently inhibit human 5-lipoxygenase and suppress pro-inflammatory responses of stimulated humanpolymorphonuclear leukocytes. Biochem. Pharmacol. 76:9197.

Prieto, J. M., et al. (2007). In vitro activity of the essential oils of Origanumvul-gare, Saturejamontana and their main constituents in peroxynitrite-inducedoxidative processes. Food Chem. 104:889895.

Proestos, C., et al. (2005). RP-HPLC analysis of the phenolic compounds ofplant extracts. Investigation of their antioxidant capacity and antimicrobialactivity. J. Agric. Food Chem. 53:11901195.

Prucksunand, C., et al. (2001). Phase II clinical trial on effect of the longturmeric (Curcuma longa Linn) on healing of peptic ulcer. Southeast AsianJ. Trop. Med. Public Health. 32:208215.

Reichling, J., et al. (2009). Essential oils of aromatic plants with antibacte-rial, antifungal, antiviral, and cytotoxic propertiesAn overview. Forsch.Komplementarmed. 16:7990.

Robbins, R. J. (2003). Phenolic acids in foods: An overview of analyticalmethodology. J. Agric. Food Chem. 51:28662887.

Sandur, S. K., et al. (2007). Curcumin, demethoxycurcumin, bisdemethoxy-curcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independentmechanism. Carcinogenesis. 28:17651773.

Shahidi, F., et al. (2010). Hydroxycinnamates and their in vitro and in vivoantioxidant activities. Phytochem. Rev. 9:147170.

Shan, B., et al. (2005). Antioxidant capacity of 26 spice extracts and character-ization of their phenolic constituents. J. Agric. Food Chem. 53:77497759.

Shen, D., et al. (2010). LC-MS method for the simultaneous quantitation ofthe anti-inflammatory constituents in oregano (Origanum Species). J. Agric.Food Chem. 58:71197125.

Shukri, R., et al. (2010). Cloves protect the heart, liver and lens of diabetic rats.Food Chem. 122:11161121.

Soni, K. B., et al. (1992). Effect of oral curcumin administration on serum perox-ides and cholesterol levels in human volunteers. Indian J. Physiol. Pharmacol.36:273275.

Srinivasan, K. (2005a). Spices as influencers of body metabolism: An overviewof three decades of research. Food Res. Int. 38:7786.

Srinivasan, K. (2005b). Role of spices beyond food flavoring: Nutraceuticalswith multiple health effects. Food Rev. Int. 21:167188.

Teissedre, P. L., et al. (2000). Inhibition of oxidation of human low-densitylipoproteins by phenolic substances in different essential oils varieties. J.Agric. Food Chem. 48:38013805.

Tundis, R., et al. (2010). Natural products as alpha-amylase and alpha-glucosidase inhibitors and their hypoglycaemic potential in the treatmentof diabetes: An update. Mini Rev. Med. Chem. 10:315331.

Usharani, P., et al. (2008). Effect of NCB-02, atorvastatin and placebo on en-dothelial function, oxidative stress and inflammatory markers in patients withtype 2 diabetes mellitus: A randomized, parallel-group, placebo-controlled,8-week study. Drugs R. D., 9:243250.

Venkatesha, S. H., et al. (2011). Herbal medicinal products target definedbiochemical and molecular mediators of inflammatory autoimmune arthritis.Bioorg. Med. Chem. 19:2129.

Wellwood, C. R. L., et al. (2004). Relevance of carnosic acid concen-trations to the selection of rosemary, Rosmarinusofficinalis (L.), acces-sions for optimization of antioxidant yield. J. Agric. Food Chem. 52:61016107.

Wojdyo, A., et al. (2007). Antioxidant activity and phenolic compounds in 32selected herbs. Food Chem. 105:940949.

Yan, J., et al. (2007). BLIMP1 regulates cell growth through repression of p53transcription. Proc. Natl. Acad. Sci. U.S.A. 104:18411846.

Yan, H., et al. (2009). High-performance liquid chromatography method fordetermination of carnosic acid in rat plasma and its application topharma-cokinetic study. Biomed. Chromatogr. 23:776781.

Yanishlieva, N. V., et al. (2006). Natural antioxidants from herbs and spices.Eur. J. Lipid Sci. Technol. 108:776793.

Yoon, J., et al. (2005). Molecular targets of dietary polyphenols with anti-inflammatory properties. Yonsei Med. J. 46:585596.

Yoshino, K., et al. (2006). Antioxidant and antiinflammatory activities oforegano extract. J. Health Sci. 52:169173.

Zang, L., et al. (2000). Effect of antioxidant protection by p-coumaric acid onlow-density lipoprotein cholesterol oxidation. Am. J. Physiol. - Cell Physiol.279:C954C960.

Zheng, W., et al. (2001). Antioxidant activity and phenolic compounds inselected herbs. J. Agric. Food Chem. 49:51655170.

Zheng, S., et al. (2006). Crocetin attenuates atherosclerosis in hyper-lipidemic rabbits through inhibition of LDL oxidation. J. Cardiovasc.Pharmacol.,47:7076.

Dow

nloa

ded

by [U

nivers

ity of

Lee

ds] a

t 14:2

2 04 S

eptem

ber 2

013