Review Article Therapeutic Potential of Dietary Phenolic …downloads.hindawi.com/journals/aps/2015/823539.pdf · · 2015-11-24Review Article Therapeutic Potential of Dietary Phenolic

Review ArticleTherapeutic Potential of Dietary Phenolic Acids

Venkata Saibabu1 Zeeshan Fatima1 Luqman Ahmad Khan2 and Saif Hameed1

1Amity Institute of Biotechnology Amity University Haryana Gurgaon Manesar 122413 India2Department of Biosciences Jamia Millia Islamia New Delhi 110025 India

Correspondence should be addressed to Saif Hameed saifhameedyahoocoin

Received 26 May 2015 Revised 3 August 2015 Accepted 18 August 2015

Academic Editor Robert Gogal

Copyright copy 2015 Venkata Saibabu et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Although modern lifestyle has eased the quality of human life this lifestylersquos related patterns have imparted negative effects onhealth to acquiremultiple diseasesMany synthetic drugs are invented during the lastmillennium butmost if not all of them possessseveral side effects and proved to be costly Convincing evidences have established the premise that the phytotherapeutic potentialof natural compounds and need of search for novel drugs from natural sources are of high priority Phenolic acids (PAs) are a classof secondary metabolites spread throughout the plant kingdom and generally involved in plethora of cellular processes involvedin plant growth and reproduction and also produced as defense mechanism to sustain various environmental stresses Extensiveresearch on PAs strongly suggests that consumption of these compounds hold promise to offer protection against various ailmentsin humans This paper focuses on the naturally derived PAs and summarizes the action mechanisms of these compounds duringdisease conditions Based on the available information in the literature it is suggested that use of PAs as drugs is very promisinghowever more research and clinical trials are necessary before these bioactive molecules can be made for treatment Finally thisreview provides greater awareness of the promise that natural PAs hold for use in the disease prevention and therapy

1 Introduction

Since ancient times plants and their products have beenused as folk medicine in different parts of the world It isbelieved that over 400000 tropical flowering plant specieshave healing properties [1] Several studies on medicinalplants determined the variety of compounds contributing totreatment of life-threatening diseases such as diabetes cancerand infections Numbers of methods have been introducedfor qualitative and quantitative analysis of plant secondarymetabolites such as polyphenols alkaloids saponins glyco-sides resins oleoresins sesquiterpene and lactones Thesesecondary compounds are involved in plant growth devel-opment reproduction and disease resistance Phenolic acids(PAs) are among the most common bioactive compoundsthroughout plant kingdom which have role in growthreproduction and defense against environmental stress andmicroorganisms [2 3] The antioxidant activities of PAs areextensively implemented in food industry as preservativessince antiquity They also have function in plethora of

important biological activities such as antiageing reducingthe risk of life-threatening diseases such as HIV diabetesCVDs and cancer Bulk information available about potentialhealth benefits regarding PAs has led to an increased interestin PAs and this review illustrates the role that PAs possess inimportant biological conditions (Figure 1) A comprehensiveliterature search was conducted in PubMed and GoogleScholar by using the following mesh keywords (1) phenolicacids (2) antioxidants (3) anticancer (4) cardioprotective(5) antiulcer (6) anti-diabetic (7) antimicrobial and (8)hepatoprotectiveThus the aim of the present paper is to sys-tematically review and summarize the literature supportingthe health benefits of PAs at a common platform

2 Phenolic Acids ClassificationOccurrence and Bioavailability

PAs are aromatic carboxylic acids naturally appearing in theplant kingdom The term phenolic acid describes a phenolring that possesses at least one carboxylic acid functionality

Hindawi Publishing CorporationAdvances in Pharmacological SciencesVolume 2015 Article ID 823539 10 pageshttpdxdoiorg1011552015823539

2 Advances in Pharmacological Sciences

Phenolic acids Antioxidant

AntimicrobialAntidiabetic

Anticancer

Neuroprotective

Cardioprotective

Hepatoprotective

Anti-inflammation

ABCA1eNOS LDL level Paraoxonase 1

CAT TBARSSODGPx MDA levelsNrf2JNK

Membrane AMPKGLUT4G-6-Pase

iNOSCOX-2

AChEBChEMDA level

p38 JNK

Caspases 3 and 9 Myc

Bax PI3Akt

permeability PPAR-120574

IL-1120573 IL-6

IL-1120573 IL-6

TNF-120572

TNF-120572

TNF-120572

NF-120581B

NF-120581B

NF-120581B

PKC120572

I120581B-120572

TGF-120573

IL-1120573 IL-6 and IL-8

Figure 1 Key factors involved in health beneficial effects of natural PAs

However in case of plant metabolites these refer to a distinctgroup of organic acids which contains two distinguishingcarbon frameworks hydroxybenzoic and hydroxycinnamicacid structures PAs are usually subclassified into benzoicacids containing seven carbon atoms (C6-C1) and cinnamicacids with nine carbon atoms (C6-C3)

PAs are widely distributed in the plant kingdom andfound in a wide variety of nuts and fruits such as raspberriesgrapes strawberries walnuts cranberries and black cur-rants These are secondary metabolites derived from pheny-lalanine and tyrosine via shikimatechorismate pathwayHowever these compounds exist predominantly as hydrox-ybenzoic acids which include gallic acid (GA) salicylic acid(SA) protocatechuic acid (PCA) ellagic acid (EA) and gen-tisic acid (GeA) and hydroxycinnamic acids which includep-coumaric acid (p-CA) caffeic acid (CA) ferulic acid (FA)chlorogenic acid (CGA) and sinapic acids (SA) or alterna-tively may occur as conjugated forms (Figure 2)

The chemical properties of PAs in terms of availability ofthe phenolic hydroxyl groups predict their activity in vitroThe effective in vivo potential of PAs depends on multiplefactors such as quantity of the compound ingested absorbedandor metabolized plasma andor tissue concentrationstype and amount of single PA and synergistic effects How-ever the chemical structure of phenolic compounds differ-ently affects all the factors described above For instancesulfate derivatives of FA and CA showed lower activitieswhen compared with the antioxidant activities of the parentalphenolic acids indicating the importance of the phenolicacids and their metabolites [4]

3 Antioxidant Properties

Biological system generates reactive oxygen species (ROS) asthe byproduct of various metabolic activities and mitochon-dria are said to be major site responsible for ROS productionThese free radicals are highly unstable or reactive and cancause direct damage to cell components such as nucleic acidslipids and proteins [5] ROS is themajor contributor tomanydiseases which include CVDs cancer age-related declinein the immune system and degenerative diseases such asParkinsonrsquos and Alzheimerrsquos disease Human body possessesseveral stress response enzymes including superoxide dismu-tase (SOD) and catalase (CAT) to counteract radical-induceddamage PAs counteract both ROS and RNS-induced celldamage by their direct free radical scavenging activity aswell as the upregulation of the HOBVR system superoxidedismutase (SOD) and catalase (CAT) whose final aim is todetoxify ROS and RNS

Oxidative stress has been implicated in the pathogenesisof multiple cardiovascular complications Antioxidant role ofFA in cardioprotection is well studied [6] In hypersensitiverats treatment with FA for 4ndash12 weeks increased SOD andCAT activities FA treatment also increased SOD and CATlevels inmyocardium and pancreatic tissue of streptozotocin-induced diabetic rats in dose and time dependentmanner [7]

Antioxidant activities of PCA along with known anti-oxidant Trolox were measured in vitro using various anti-oxidant assays including 11-diphenyl-2-picrylhydrazyl(DPPH∙) 221015840-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)(ABTS+∙) superoxide anion radicals (O

2

minus∙) and hydroxyl

Advances in Pharmacological Sciences 3

Protocatechuic acid Vanillic acidGallic acid

Salicylic acidEllagic acid

OH

OH

HO

O

OH

OHHO

HO

O

OH

HO

O

OCH3

OH

OH

OOH

OH

OH

HO

OO

O O

(a) Hydroxybenzoic acids

O

OH

HO

OCH3

O

OH

HO

OH

O

OH

HO

OH

HO

O

OCH3

H3CO

OH

OH

OHHO

HO

O

HO

OHOH

OH

OH

OH

O O

O

Caffeic acid Ferulic acid

Quinic acid

Sinapic acid

p-Coumaric acidChlorogenic acid

(b) Hydroxycinnamic acids

Figure 2 Structural classification of natural PAs discussed in the review

radical (∙OH) scavenging activity ferric ions (Fe3+) andcupric ions (Cu2+) reducing power ferrous ions (Fe2+) andcupric ions (Cu2+) chelating activity The antioxidant activityof PCA could be attributed to both its transition metalions chelation and by free radicals scavenging via donatinghydrogen atom (H∙) or electron [8]

Oral administration of vanillic acid (VA) at high doses(100mgkg) increased the antioxidant status by reducing lipidperoxidation and increased the SOD CAT and glutathioneperoxidase (GPx) activities and reduced glutathione (GSH)levels in cisplatin induced nephrotoxicity in albino rats [9]Similarly GA consumption diminished this harmful effectvia its antioxidant action by inhibiting the initiation andorpropagation of the lipid peroxidation [10] In the later studies

same group investigated the antioxidant properties of GAderived from Peltiphyllum peltatum against sodium fluoride(NaF-) induced hepatotoxicity in rats [11] Pretreatment ofanimals with GA could mitigate the NaF-induced hepatotox-icity through suppression of lipid peroxidation expressed inreduced Thiobarbituric Acid Reactive Substances (TBARS)levels restoration of GPx levels CAT and SOD corroboratingits antioxidative role

Antioxidant properties of PAs depend on not only theirdirect activity as a scavenger but also their capacity tostrengthen the endogenous antioxidant defenses Nuclearfactor erythroid 2- (NFE2-) related factor 2 (Nrf2) is a keytranscription factor which strictly regulates the antioxidantdetoxifying enzyme genes by antioxidant response elements


present in the promoter region of those genes [12] PAs such asPCA have been demonstrated to induce the ARE-dependentantioxidantdetoxifying phase II enzymes such as GR andGPx by activating the transcription factor Nrf2 through JNK-mediated phosphorylation [13] Similarly PCA induces anti-apoptotic mechanism that likely related to the activation ofthe JNK-mediated survival signals that strengthen the cellularantioxidant defenses rather than antioxidant power of PCAPAs induce phase II hepatic antioxidant enzyme and increasethe antioxidant status of liver [14] PAs including GEA GAp-CA and FA selectively induce hepatic mRNA transcriptsfor CuZnSOD GPx and catalase likely through upregulationof gene transcription as well as the Nrf2 transcription factorindicating their potential antioxidant role in liver [15]

4 Antiulcer Activity

Gastric ulcer is a recurrent chronic illness caused by bothendogenous and exogenous factors which include pepsinstress and noxious factors such as nonsteroidal anti-inflam-matory drugs Helicobacter pylori bacteria smoking andalcohol consumption [16]Natural PAs have been investigatedfor their antiulcer activities which are apparent from wideranges of studies in experimental animals GA has beenreported to be antiulcer in aspirin plus pylorus ligationmodel GA exerts this effect by improving mucosal defensivewith activation of antioxidant parameters and inhibition ofsome toxic oxidant parameters Similarly GA in combinationwith famotidine an antiulcer drug synergistically protectedthe experimentally induced peptic ulcermodels [17] Animalstreated with low dose combinations like GA (50mgkg) +FM (10mgkg) along with high dose GA (100mgkg) + FM(10mgkg) showed significant ulcer protective effect inducedby aspirin plus pylorus ligation

Gastroprotective properties of another phenolic acid EAhave also been reported EA arewell documented in acute andchronic ulcer rat models [18]The gastroprotective propertiesof EA are partly due to increased endogenous production ofnitric oxide which is an antioxidant effect by replenishingnon-protein-sulfhydryls and attenuation of TNF-120572 whereasin indomethacin ulcer gastroprotective properties are partlydue to attenuation of elevated levels of TNF-120572 interferon-120574and interleukins 4 and 6

5 Antidiabetic Activity

Impairment in glucose metabolism leads to physiologicalimbalance with the onset of the hyperglycemia and subse-quently diabetes mellitus which can be either type 1 or type 2It is well known that several physiological parameters of thebody get altered in the diabetic conditions Long term effectsof diabetes may cause development of specific complicationssuch as retinopathy nephropathy neuropathy foot ulcerssexual dysfunctions and cardiovascular complications

Insulin stimulates glucose transport by inducing thetranslocation of glucose transporter 4 (GLUT4) to the plasmamembrane which is mediated by two major pathways aninsulin independent AMPK pathway and an insulin depen-dent PI3K pathway The antidiabetic effects of natural PAs

are well documented as evident from wide range of studiesCGA could enhance the glucose uptake in L6 myotubes viaincreasing expression of GLUT4 and PPAR-120574 transcript [19]Similarly PCA also exerts its insulin-like activity in humanomental adipocytes PCA induces the glucose uptake asso-ciated with enhanced GLUT4 translocation and increasedPPARg transcript [20] GA derived from sea buckthorn leafextract stimulated GLUT4 translocation and glucose trans-port in a concentration dependent manner with maximumstimulation at 10 120583M concentration [21] Further the roleof atypical protein kinase Cfk is revealed in GA mediatedGLUT4 translocation and glucose uptake

Similarly CGA stimulates glucose transport in bothskeletal muscle isolated from mice and L6 skeletal musclecells [22] Furthermore in L6 myotubes CGA increased glu-cose transport via GLUT4 transporter and in skeletal musclevia the activation of AMPK CGA lowered AUC glucoseinhibited hepatic glucose-6-phosphatase (G-6-Pase) expres-sion and improved skeletal muscle glucose uptake and lipidprofiles in Leprdbdb mice Mechanistically CGA activatedAMPK leading to suppression of hepatic glucose productionand fatty acid biosynthesis Inhibition and knockdown ofAMPK abrogating these metabolic alterations suggested thatCGA can improve glucose and lipid metabolism via theactivation of AMPK Another phenolic acid p-CAmodulatedglucose and lipid metabolism via AMPK activation in L6skeletal muscle cells [23] p-CA also promoted fatty acid 120573-oxidation decreased oleic acid-induced triglyceride accumu-lation and enhanced glucose uptake proving its beneficialeffects in improving or treating metabolic disorders

6 Cardioprotective Activity

Cardiac disease is the major cause of morbidity and mor-tality among the noncommunicable diseases Implication ofcardiovascular complications including cardiomyopathy indiabetes can be attributed to hyperlipidemia hyperglycemiaand oxidative stress which promote atherosclerosis [24ndash26]Cardiovascular complications are higher in diabetic patientsthan nondiabetics [27] Cardioprotective role of the twophenolic acids caffeic acid (CA) and ellagic acid (EA) hasbeen reported in STZ-induced diabetic mice Treatment withCA or EA markedly elevated the insulin secretion whichmight attenuate the dyslipidemia improved glycemic controland diminished cardiac oxidative stress [28]

Atherosclerosis is a chronic inflammatory disease char-acterized by accumulation of leukocytes in the vascularwall Platelets play essential role in formation of atheroscle-rotic plaques and thrombosis by coaggregating with leuko-cytes via P-selectin glycoprotein ligand-1 (PSGL-1) and P-selectin interactions [29 30] GA has been found to possessantiatherosclerotic activity by inhibiting platelet activationand its association with leukocytes P-selectin expressionstimulated by ADP which is likely to be through decreasingintracellular Ca2+ mobilization via regulating the signalsof PKC120572p38MAPK and AktGSK3120573 [31] Protocatechuicaldehyde (structurally similar to PCA) isolated from rootof Salvia miltiorrhiza attenuated PDGF-induced prolifera-tion and migration of VSMCs via (PI3K)Akt and MAPK


kinase pathways which regulate key enzymes associated withmigration and proliferation of VSMCs [32] It is reported thatFA effectively reduced copper ion induced LDL oxidationand facilitated the uptake and degradation of cholesterol inthe liver p-CA is known to protect the LDL from ROS byscavenging ∙OH in vivo and thereby reduce lipid peroxidationand serum LDL cholesterol levels [33]

Cardioprotective activities of EA have also been inves-tigated EA effectively reduces oxidative stress lowers thelevels of plasma lipids and inhibits lipid peroxidation EAreduced the uptake of oxidized LDL in murine macrophagesby downregulating membrane expression of SR-B1 [34] SR-B1 is a membrane receptor on macrophages responsible forthe internalization of oxidized LDL that promotes cellularaccumulation of cholesterol [35] Similarly EA also promotescholesterol efflux in lipid-loaded macrophages by inducingmembrane receptor ABCA1 expression ABCA1 is a mem-brane transporter abundant in macrophages and plays acrucial role in cholesterol homeostasis thereby protectingagainst atherosclerosis [36] Salicylic acid (SA) treatment hasbeen reported to prevent complications of atheroscleroticcardiovascular disease such as myocardial infarction andocclusive stroke [37] These effects of SA are attributed to itsplatelet-inhibitory function and stimulation of Paraoxonase 1an enzyme that protects the serum lipids from oxidation andcan reduce macrophage foam cell formation and attenuatesatherosclerosis development [38]

Hypertension is the most common cardiovascular dis-order mainly affected by lifestyle and dietary habits [39]Nitric oxide (NO) plays a key role in the physiologic controlof blood pressure and myocardial injury Alterations in NOsynthesis or bioavailability can cause vasoconstriction andmight be involved in the pathogenesis of hypertension VAhas been proven to act against cardiovascular complicationsaroused due to hypertension [40] VA normalized hyper-tension and left ventricular function in N120596-nitro-L-argininemethyl ester (L-NAME) induced hypertensive rat models L-NAME isNO synthase inhibitor which causes reduction in itsactivity leading to hypertension and arteriosclerosis [41ndash43]Vanillic acid (VA) possessed cardioprotective effect which isevident by lowered cardiac marker enzymes (CK CK-MBand LDH) left ventricular functions improved tissue nitricoxide metabolite levels and upregulated mRNA expressionof eNOS in L-NAME induced hypertensive rat

7 Anticancer Activity

Cancer is one of the leading causes of the deaths worldwideand chemotherapy is mainly used to treat cancer How-ever occurrence of severe side effects of the drugs led tosearch for alternatives Phytochemicals exert their anticanceractivities by protecting critical cellular components (DNAproteins and lipids) from oxidative insult and interfere withproliferative activity and induction of apoptosis of cancercells Epidemiological and experimental studies confirmedthat consumption of dietary products such as fruits andvegetables may have significant impact on the developmentof different types of cancers EA is proven to be capable ofdecreasing oxidative stress a hallmark of developing cancer

EA downregulates the expression and activity of PKC120572 inlymphoma bearing mice via decreasing the oxidative stressas evident by reduced lipid peroxidation and protein car-bonylation [44] Similarly EA downregulates the expressionof oncogene Myc and upregulates tumor suppressor geneTGF-120573 in lymphoma bearing mice EA also exerts apoptosisthrough targeting PI3KAkt kinases that in turn resulted inattenuation of its downstream Bcl-2 family proteins in 12-dimethyl hydrazine- (DMH-) induced rat colon carcinogen-esis [45] EA could stimulate the apoptosis by decreasing NF-120581B activity thus activating the mitochondrial death pathwayassociated with caspase 3 activation and cytochrome Crelease [46] Additionally EA also lowers the expression ofcyclins against inflammation mediated cell proliferation bydownregulation ofNF-120581B in EA-administered rats Inductionof apoptosis features were observed in prostate cancer usingthe transgenic rat for adenocarcinoma of prostate (TRAP)model and human prostate cancer cell line (LNCaP) Thesefindings showed that EA inhibits the early stage of prostatecarcinogenesis through induction of apoptosis via activationof caspase 3 [47] Similarly inactivation of phosphatidylinositol 3-kinase (PI3K)Akt pathway Bcl-2 downregulationand increased expression of Bax caspase 3 and cytochromec increased annexin V apoptotic cells and DNA fragmen-tation were observed in human adenocarcinoma cells [46]Cytotoxic effects of EAhave been reported inTSGH8301 [48]Cells treated with EA resulted in arresting cell cycle at G0G1promoted ROS and Ca2+ production activities of caspases9 and 3 and decreased the level of ΔΨ119898 EA and Embelinisolated from Ardisia japonica at low concentrations syner-gistically increased the apoptosis thereby decreasing the pro-liferation in vitro Similarly EA alone or in combination withEmbelin alone decreased tumor size and tumor cellularity ina subcutaneous xenograft mouse model of pancreatic cancer

Angiogenesis is a critical process in tumor developmentand metastasis PAs have been showed to inhibit the angio-genesis in various cancer cell lines and in vivo Caffeic acidphenethyl ester (CAPE) a major medicinal component ofpropolis showed dose dependent VEGF secretion in MDA-231 cells and formation of capillary-like tubes by endothelialcells implicate on antiangiogenesis [49] Antiangiogenicactions of p-CA have been studied in the ECV304 humanendothelial cell line p-CA reduced the mRNA levels of twoimportant angiogenic factors VEGF and bFGF that stimulatepermeability proliferation and tube formation of endothelialcells [50]

Tumor metastasis is a complex cascade that is accompa-nied by metalloproteinase (MMP) upregulation and extra-cellular matrix degradation Metastasis allows cancer cells toproliferate and invade blood or lymphatic system furtherenhancing cancer cell invasion and worsening prognosisPomegranate juice (Punica granatum) and its three con-stituents luteolin ellagic acid and punicic acid (L + EA +P) have been shown to interfere with multiple biologicalprocesses such as suppression of cell growth increased celladhesion inhibition of cell migration and inhibition ofchemotaxis towards proteins (SDF1120572) involved in breast can-cer metastasis [51] Similarly L + EA + P exhibited beneficialeffect on metastasis of prostate cancer in SCID mouse tumor


model and 119875119905119890119899minusminus K-rasG12D prostate tumors Studies wereconducted by injecting luciferase-expressing human PCacells in the region of the prostate ectopically and monitoredthe tumor progressionwith bioluminescence imagingweeklyResults revealed that L + E + P inhibit PC-3M-luc primarytumor growth and suppress the CXCL12CXCR4 implicatedas therapeutic target for metastasis [52] Further L + E +P significantly inhibited the growth and metastasis in vivoGA is known to inhibit metastasis and invasive growth ofgastric cancer cells via increased expression of RhoB down-regulation of AKTsmall GTPase signals and inhibition ofNF-120581B activity [53]

8 Anti-Inflammatory Activity

Inflammation is the complex biological process of vasculartissues to harmful stimuli such as pathogens chemical irri-tants and damaged cells or tissue It is a protective attemptby the organism in which immune system plays a major roleInflammatory response includes (1) migration of immunecells from blood vessels and release of mediators at the siteof damage followed by (2) recruitment of inflammatory cells(3) release of ROS RNS and proinflammatory cytokinesto eliminate foreign pathogens and (4) repairing injuredtissuesThough acute inflammation is rapid and self-limitingprolonged inflammation causes various chronic disorders[54] The link between chronic inflammation and variousdiseases such as cancer metabolic disorder type II diabetesarthritis autoimmune diseases neurological diseases pul-monary diseases and cardiovascular complications is wellknown Among other natural bioactive compounds PAs arewidely recognized for their anti-inflammatory properties inwide range disease conditions

Platelets are key mediators of inflammation that maytrigger an inflammatory response in vessel wall early in thedevelopment of atherosclerosis and contribute to the desta-bilization of advanced atherosclerotic lesions [55] CGA pos-sesses antiplatelet activity by reducing release of atheroscle-rotic-related inflammatory mediators (sP-selectin IL-1120573sCD40L and CCL5) and inhibits in vivo thrombus for-mation [56] In addition antiplatelet and antithromboticeffects shown by CGA are associated with A

2A receptor acti-vation Similarly CGA induced an anti-inflammatory effectin lipopolysaccharide- (LPS-) inflamed murine RAW 2647macrophage cells through (1) suppression of proinflamma-tory cytokines such as IL-1120573 TNF-120572 and IL-6 as well asthe chemokine CXCL1 through downregulation of NF-120581B(2) decreased NO production mediated by downregulationof iNOS and (3) inhibition of an important adhesionmoleculeNinjurin 1 (Ninj 1) [57] CA attenuated LPS-inducedNO production possibly by inhibiting phosphorylation ofp38MAPK and JNK12 suggesting that CA selectively inhibitdifferent LPS-induced proinflammatory signaling cascadesin RAW 2647 macrophages [58] Further CGA showedantiosteoarthritis (anti-OA) properties in IL-1120573-stimulatedchondrocytes [54] CGA suppressed the production of NOand PGE2 via downregulating the expression of iNOS andCOX-2 which are implicated in the pathogenesis of OA

[59] In another study CGA leads to attenuation in TLR4-mediated inflammatory responses such as NO and PGE2production in LPS-treated RAW 2647 cells and improvesHClEtOH-induced acute gastritis symptoms [60]

9 Neuroprotective Activity

Neuroprotection means prevention of nerve cells from dyingand usually involves an intervention of drug treatment It is amechanism used to protect neuronal injury or degenerationof CNS following acute disorders The goal of neuroprotec-tion is to limit neuronal dysfunction after injury and attemptto maintain the possible integrity of cellular interactions inthe brain resulting in undisturbed neural function There arewide ranges of natural compounds from plants and in partic-ular PAs have been the focus of research These compoundsmay act as free radical scavengers antiexcitotoxic agentsapoptosis inhibitors and so forth Two hydroxycinnamicacids CGA and CA have been shown to be associated withanti-Alzheimerrsquos properties [61] Mechanistically these prop-erties could be attributed to inhibition of BChE and AChEactivities thus butyrylcholine breaks down and slows downacetylcholine in vitro Furthermore CGA and CA decreasethemalondialdehyde (MDA) formeddue to prooxidants suchas FeSO

4

sodium nitroprusside and quinolinic acid Recentstudies demonstrated the novel evidence explaining the neu-rological effects of CGA Voltage gated potassium channels(Kv) play crucial role in the electrophysiological processesof sensory neurons and have been identified as potentialtherapeutic targets for inflammation and neuropathic paindisorders The effects of CGA on the two main subtypes ofKv in trigeminal ganglion (TG) neurons namely the IKVand IKA channels are also highlighted [62] Upon CGAtreatment activation and inactivation currents of both IKVand IKA were significantly shifted toward depolarizationwhich implies that Kv is triggered at a lower threshold witha prolonged duration thus enhancing Kv activities in bothIKA and IKV channels This would gradually decreasethe excitability of neurons during trigeminal hyperalgesicconditions in neuropathic and inflammatory pain

Functional restoration of injured spinal cord by self-assembled nanoparticles composed of FA modified glycolchitosan (FA-GC) has been investigated to a considerableextent [63] These nanoparticles protected primary neuronsfrom glutamate-induced excitotoxicity in vitro In additionsignificant recovery in locomotor function was observed in aspinal cord contusion injury rat model that was intravenouslyadministered FA-GCnanoparticles at 2 h after injury Furtherhistological analysis revealed that FA-GC treatment signifi-cantly preserved axons and myelin and also reduced cavityvolume inflammatory response and astrogliosis at the lesionsite

The accumulation of A120573 deposit owing to the metabolicdisorders in the brain is key step in the pathogenesis ofAlzheimerrsquos disease (AD) A120573 can stimulate chronic neu-roinflammation response andworsen the neurological degra-dation Two genes namely presenilins 1 and 2 (PS1 andPS2) genes or the amyloid-protein precursor (APP) plays animportant role in the processing of A120573 PCA derived from


Radix Salviae Miltiorrhizae has been found to have a pro-tective effect on improving cognitive deficits in STZ-inducedAD rats [64] The Morris water maze test revealed that PCA(100mgkg) significantly prolonged the mean latency timeand the path length of A120573PPPS1 mice PCA reduced thenumber of A120573 positive expressions in the hippocampus andcerebral cortex of A120573PPPS1 mice by immunocytochemicalassaywithCongo red staining and decreased remarkablyAPPexpression levels by western blot analysis In addition PCAimproves the cognitive deficits of AD animal by decreasingthe levels of inflammatory cytokines including TNF-120572 IL-1120573IL-6 and IL-8

10 Hepatoprotective Activity

Liver diseases are a major health problem which causes highmortality andmorbidity affecting the human of all ages Liverdiseases are classified as autoimmune hepatitis alcoholicliver disease and viral hepatitis Despite advances in modernmedicine still there is lack of effective drug that completelycures liver complications Therefore there is urgent need forsearch of effective drugs to replace current drugs Natural PAsare undoubtedly valuable as a source of newmedicinal agentsHepatoprotective effect of EA in concanavalin A- (Con A-)induced hepatitis mice model has been evaluated [65]Pretreatment with EA significantly decreased the expressionlevels of the toll-like receptor 4 (TLR4) and TLR2 implicatedin hepatitis possibly by inflammation Further EA decreasedthe expression of inflammatory cytokines and in turn inhibitthe phosphorylation of MAPK and nuclear translocation ofNF-120581B This may account for a reduction in TNF-120572 IL-6and IL-1120573 expression by inhibition of NF-120581B-mediated tran-scriptional activation and I120581B-120572 degradation and preventionof JNK p38 and ERK MAPK phosphorylation

Resistin is a hormone implicated in enhanced hepaticsteatosis via downregulation of content and activities ofmitochondria [38] EA reduced serum resistin levels andimproved hepatic steatosis and serum lipid profile in high-fatfed obese diabetic KK-Aymice [66] EA supplementation alsoimproved hepatic steatosis by reducing triglycerides whichplay key role in liver steatosis and ameliorated serum HDLCand non-HDLC levels which might be caused by reducedserum resistin levelsMoreover EA upregulatedmRNA levelsof PPARa and its target genes including cpt1a suggesting thatEA acts as transcriptional activator of PPARa in the liver

11 Antiaging Activity

Aging is the accumulation of changes over time associ-ated with increasing susceptibility to different diseases andultimately leading to death Several hypotheses have beenproposed to explain how aging occurs However manyevidences led to the general acceptance of the oxidative stresstheory that the accumulation of molecular damage causedby reactive oxygen species is a major factor in aging PCAderived from dried fruits of Alpinia oxyphylla Miq showedstrong ability to attenuate ageing alterations of antioxida-tive defense systems in spleen and liver male Sprague-Dawley rats [67] Intraperitoneal injection of PCA showed

effects on splenic weight antioxidant enzyme activities andMDA levels in spleen and liver of rats PCA isolated fromVeronica peregrine exhibited significant antiaging effects onCaenorhabditis elegans model system [68] In the presenceof PCA lifespan of the wild-type worms increased in a dosedependent manner PCA also improved tolerance of wormsagainst heat shock and osmotic and oxidative stress whichmight result in extension of lifespan Pharyngeal pumpingrate and progeny production are the two factors evidencedfor prolonged lifespan and improved longevity Interestinglyboth factors were significantly reduced after PCA exposureIn addition PCA-treated agedworms showed improved bodymovement compared to untreated controls suggesting PCAcould enhance health span as well as lifespan

12 Antimicrobial Activity

Illnesses resulting from pathogens and the emergence ofresistance to conventional antibiotics are vital concern inpublic health and demand new antimicrobial compounds[69 70] Plants do not possess immune system like animalsbut instead synthesize phenolic compounds in response to thepresence of pathogens herbivores and insects [71] Researchon natural products has demonstrated significant progress inthe discovery of novel compounds with antimicrobial activity[72ndash74]

The antibacterial activities of PAs have been demon-strated in various studies on different pathogens Veronicamontana L water extract and its main phenolic constituentPCA showed being highly effective against the growth ofListeria monocytogeneswhich causes listeriosis which occursmostly in elderly people immune-compromised patientsand pregnant women [75 76] The mechanism of actionof PCA towards L monocytogenes appears to be alter-ation of permeability of bacterial cytoplasmic membraneAntibacterial activity and mode of action of two phenolicacids have been investigated on E coli P aeruginosa Saureus and L monocytogenes It was found that FA andGA had antimicrobial activity against the bacteria testedwith MIC of 500mgmL for P aeruginosa 1500mgmL forE coli 1750mgmL for S aureus and 2000mgmL for Lmonocytogenes with GA Similarly FA showed the antimi-crobial activity with MIC of 100mgmL for E coli and Paeruginosa and 1100mgmL and 1250mgmL for S aureusand L monocytogenes respectively CGA has been shown tohave potent antibacterial and antibiofilm properties againstemerging nosocomial pathogen SmaltophiliaTheminimuminhibitory concentrationwas shown to be 8 to 16120583gmLminus1 anddose-dependently reduced the adhesion of S maltophilia topolystyrene plate Influence of subinhibitory concentrationsof CGA on virulence associated factors of enterotoxigenicS aureus has been investigated [77] At subinhibitory con-centrations (125mgmL) CGA significantly inhibited thehemolysis and coagulase titter Reduced binding to fibrinogenand decreased production of SEA (an enterotoxin) wereobserved at concentrations ranging from 116MIC to 12MICFinally CAmarkedly inhibited the expression of sea hla andagr genes in S aureus [78]


13 Conclusion

The new lifestyles adopted by people have considerablyenhanced the risk of acquiring various diseases Extensiveresearch on natural PAs provides new insight into thecomprehension of the cellular and molecular mechanismsresponsible for the immense potential therapeutic activityof these compounds against a number of human diseasesHowever evidence of such properties has been collectedfrom cellular and animal models while clinical studies arestill lacking It is worth mentioning that further studies andclinical trials are needed to fully establish the preventive andtherapeutic effectiveness of PAs and also to prove their safetyfor human consumptionMoreover natural PAs also have thepotential to drive the flux of funds to the corporate sectorfor investment in drug development which eventually mayinfluence the quality of life for many patients Certainly moreintricate molecular mechanisms need to be investigated tofurther enhance their widespread usage and pharmaceuticalpotential

Conflict of Interests

The authors declare that they have no conflict of interests

Authorsrsquo Contribution

Venkata Saibabu andZeeshan Fatima had equal contribution

Acknowledgments

SaifHameed thanks Science and Engineering Research Board(SERB) New Delhi (SRFTLS-122012) for Young Scientistaward The authors thank Professor Rajendra Prasad Direc-tor of Amity Institute of Biotechnology for encouragement

References

[1] T Odugbemi ldquoMedicinal plants as antimicrobialsrdquo in Outlineand Pictures of Medicinal Plants from Nigeria pp 53ndash64 Uni-versity of Lagos Press 2006

[2] I K Valentine V K Maria and B Bruno ldquoPhenolic cycle inplants and environmentrdquo Journal of Cell amp Molecular Biologyvol 2 no 1 pp 13ndash18 2003

[3] A A Elzaawely T D Xuan and S Tawata ldquoEssential oils kavapyrones and phenolic compounds from leaves and rhizomess ofAlpinia zerumbet and their antioxidant activityrdquo Food Chemem-istry vol 103 no 2 pp 486ndash494 2007

[4] A Piazzon U Vrhovsek D Masuero F Mattivi F Mandojand M Nardini ldquoAntioxidant activity of phenolic acids andtheir metabolites synthesis and antioxidant properties of thesulfate derivatives of ferulic and caffeic acids and of the acyl glu-curonide of ferulic acidrdquo Journal of Agricultural and FoodChem-istry vol 60 no 50 pp 12312ndash12323 2012

[5] A Cherubini C Ruggiero M C Polidori and P MecoccildquoPotential markers of oxidative stress in strokerdquo Free RadicalBiology and Medicine vol 39 no 7 pp 841ndash852 2005

[6] S Roy S K Metya S Sannigrahi N Rahaman and F AhmedldquoTreatment with ferulic acid to rats with streptozotocin-induced diabetes effects on oxidative stress pro-inflammatory

cytokines and apoptosis in the pancreatic120573 cellrdquoEndocrine vol44 no 2 pp 369ndash379 2013

[7] M A Alam C Sernia and L Brown ldquoFerulic acid improvescardiovascular and kidney structure and function in hyperten-sive ratsrdquo Journal of Cardiovascular Pharmacology vol 61 no 3pp 240ndash249 2013

[8] X Li X Wang D Chen and S Chen ldquoAntioxidant activity andmechanism of protocatechuic acid in vitrordquo Functtional Food inHealth and Disease vol 7 pp 232ndash244 2011

[9] G Sindhu E Nishanthi and R Sharmila ldquoNephroprotectiveeffect of vanillic acid against cisplatin induced nephrotoxicity inwistar rats a biochemical and molecular studyrdquo EnvironmentalToxicology and Pharmacology vol 39 no 1 pp 392ndash404 2015

[10] S M Nabavi S Habtemariam S F Nabavi et al ldquoProtectiveeffect of gallic acid isolated from Peltiphyllum peltatum againstsodiumfluoride-induced oxidative stress in ratrsquos kidneyrdquoMolec-ular and Cellular Biochemistry vol 372 no 1-2 pp 233ndash2392013

[11] S F Nabavi S Habtemariam A Sureda A HajizadehMoghad-dam M Daglia and S M Nabavi ldquoIn vivo protective effects ofgallic acid isolated from peltiphyllum peltatum against sodiumfluoride-induced oxidative stress in rat erythrocytesrdquo Arhivesof Industrial Hygiene and Toxicolog vol 64 no 4 pp 553ndash5592013

[12] W W Wasserman and W E Fahl ldquoFunctional antioxidantresponsive elementsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 94 no 10 pp 5361ndash5366 1997

[13] R Varı M DrsquoArchivio C Filesi et al ldquoProtocatechuic acidinduces antioxidantdetoxifying enzyme expression throughJNK-mediatedNrf2 activation inmurinemacrophagesrdquo Journalof Nutritional Biochemistry vol 22 no 5 pp 409ndash417 2011

[14] R Varı B Scazzocchio C Santangelo et al ldquoProtocatechuicacid prevents oxLDL-induced apoptosis by activating JNKNrf2survival signals inmacrophagesrdquoOxidativeMedicine and Cellu-lar Longevity vol 2015 Article ID 351827 11 pages 2015

[15] C-T Yeh and G-C Yen ldquoInduction of hepatic antioxidantenzymes by phenolic acids in rats is accompanied by increasedlevels of multidrug resistance-associated protein 3 mRNAexpressionrdquo Journal of Nutrition vol 136 no 1 pp 11ndash15 2006

[16] A F Syam M Sadikin S I Wanandi and A A Rani ldquoMolec-ularmechanismonhealing process of peptic ulcerrdquoActaMedicaIndonesiana vol 41 no 2 pp 95ndash98 2009

[17] K Asokkumar S Sen M Umamaheswari A T Sivashan-mugam and V Subhadradevi ldquoSynergistic effect of the combi-nation of gallic acid and famotidine in protection of rat gastricmucosardquo Pharmacological Reports vol 66 no 4 pp 594ndash5992014

[18] A M S E S Beserra P I Calegari M D C Souza et alldquoGastroprotective and ulcer-healing mechanisms of ellagic acidin experimental ratsrdquo Journal of Agricultural and Food Chem-istry vol 59 no 13 pp 6957ndash6965 2011

[19] P K Prabhakar and M Doble ldquoSynergistic effect of phyto-chemicals in combination with hypoglycemic drugs on glucoseuptake in myotubesrdquo Phytomedicine vol 16 no 12 pp 1119ndash1126 2009

[20] B Scazzocchio R Varı C Filesi et al ldquoCyanidin-3-O-120573-glucoside and protocatechuic acid exert insulin-like effects byupregulating PPAR120574 activity in human omental adipocytesrdquoDiabetes vol 60 no 9 pp 2234ndash2244 2011

[21] C N Vishnu Prasad T Anjana A Banerji andA Gopalakrish-napillai ldquoGallic acid induces GLUT4 translocation and glucose


uptake activity in 3T3-L1 cellsrdquo FEBS Letters vol 584 no 3 pp531ndash536 2010

[22] K W Ong A Hsu and B K H Tan ldquoChlorogenic acid stim-ulates glucose transport in skeletalmuscle viaAMPKactivationa contributor to the beneficial effects of coffee on diabetesrdquoPLoSONE vol 7 no 3 Article ID e32718 2012

[23] S-A Yoon S-I Kang H-S Shin et al ldquop-Coumaric acidmodulates glucose and lipid metabolism via AMP-activatedprotein kinase in L6 skeletal muscle cellsrdquo Biochemical andBiophysical Research Communications vol 432 no 4 pp 553ndash557 2013

[24] J W Baynes ldquoRole of oxidative stress in development of com-plications in diabetesrdquoDiabetes vol 40 no 4 pp 405ndash412 1991

[25] N S Dhalla G N Pierce I R Innes and R E BeamishldquoPathogenesis of cardiac dysfunction in diabetes mellitusrdquoCanadian Journal of Cardiology vol 1 no 4 pp 263ndash281 1985

[26] K C Tomlinson S M Gardiner R A Hebden and T BennettldquoFunctional consequences of streptozotocin-induced diabetesmellitus with particular reference to the cardiovascular systemrdquoPharmacological Reviews vol 44 no 1 pp 103ndash150 1992

[27] J Herlitz A Hjalmarson K Swedberg L Ryden and FWaagstein ldquoEffects on mortality during five years after earlyintervention with metoprolol in suspected acute myocardialinfarctionrdquo Acta Medica Scandinavica vol 223 no 3 pp 227ndash231 1988

[28] P-C Chao C-C Hsu and M-C Yin ldquoAnti-inflammatory andanti-coagulatory activities of caffeic acid and ellagic acid incardiac tissue of diabetic micerdquo Nutrition amp Metabolism vol 6article 33 2009

[29] G Davı and C Patrono ldquoPlatelet activation and atherothrom-bosisrdquoTheNew England Journal of Medicine vol 357 no 24 pp2482ndash2494 2007

[30] P Aukrust B Halvorsen T Ueland et al ldquoActivated plateletsand atherosclerosisrdquo Expert Review of Cardiovascular Therapyvol 8 no 9 pp 1297ndash1307 2010

[31] S-S Chang V S Y Lee Y-L Tseng et al ldquoGallic acid attenuatesplatelet activation and platelet-leukocyte aggregation involvingpathways of Akt and GSK3120573rdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 683872 8 pages2012

[32] C Y Moon C R Ku Y H Cho and E J Lee ldquoProtocate-chuic aldehyde inhibits migration and proliferation of vascularsmoothmuscle cells and intravascular thrombosisrdquoBiochemicaland Biophysical Research Communications vol 423 no 1 pp116ndash121 2012

[33] L-Y Zang G Cosma H Gardner X Shi V Castranova and VVallyathan ldquoEffect of antioxidant protection by p-coumaric acidon low-density lipoprotein cholesterol oxidationrdquoTheAmericanJournal of PhysiologymdashCell Physiology vol 279 no 4 pp C954ndashC960 2000

[34] S-H Park J-L Kim E-S Lee et al ldquoDietary ellagic acid atten-uates oxidized LDL uptake and stimulates cholesterol efflux inmurine macrophagesrdquo Journal of Nutrition vol 141 no 11 pp1931ndash1937 2011

[35] P Yue Z Chen F Nassir et al ldquoEnhanced hepatic apoA-Isecretion and peripheral efflux of cholesterol and phospholipidin CD36 null micerdquo PLoS ONE vol 5 no 3 Article ID e99062010

[36] M Xu H Zhou K C B Tan R Guo S W M Shiu andY Wong ldquoABCG1 mediated oxidized LDL-derived oxysterolefflux frommacrophagesrdquoBiochemical and Biophysical ResearchCommunications vol 390 no 4 pp 1349ndash1354 2009

[37] D H Mouhamed A Ezzaher L Gaha W Douki and M FNajjar ldquoIn vitro ffects of salicylic acid on plasma paraoxonase1 activityrdquo Journal of Drug Metabolism amp Toxicology vol 4 no2 article 148 3 pages 2013

[38] L Zhou X Yu Q Meng et al ldquoResistin reduces mitochondriaand induces hepatic steatosis in mice by the protein kinaseCprotein kinase Gp65PPAR gamma coactivator 1 alpha path-wayrdquo Hepatology vol 57 no 4 pp 1384ndash1393 2013

[39] S Kumar P Prahalathan and B Raja ldquoVanillic acid a potentialinhibitor of cardiac and aortic wall remodeling in l-NAMEinduced hypertension through upregulation of endothelialnitric oxide synthaserdquo Environmental Toxicology and Pharma-cology vol 38 no 2 pp 643ndash652 2014

[40] L H Opie P J Cammerford B J Gerch and M A PfefferldquoControversies in ventricular remodellingrdquoTheLancet vol 367no 9507 pp 356ndash367 2006

[41] H C D Souza G Ballejo M C O Salgado V J Dias Da Silvaand H C Salgado ldquoCardiac sympathetic overactivity anddecreased baroreflex sensitivity in L-NAME hypertensive ratsrdquoThe American Journal of PhysiologymdashHeart and CirculatoryPhysiology vol 280 no 2 pp H844ndashH850 2001

[42] O Pechanova I Bernatova P Babal et al ldquoRed wine polyphe-nols prevent cardiovascular alterations in L-NAME-inducedhypertensionrdquo Journal of Hypertension vol 22 no 8 pp 1551ndash1559 2004

[43] S Mishra and M Vinayak ldquoAnti-carcinogenic action of ellagicacid mediated via modulation of oxidative stress regulatedgenes in Dalton lymphoma bearing micerdquo Leukemia amp Lym-phoma vol 52 no 11 pp 2155ndash2161 2011

[44] S Umesalma and G Sudhandiran ldquoEllagic acid preventsrat colon carcinogenesis induced by 1 2 dimethyl hydrazinethrough inhibition of AKT-phosphoinositide-3 kinase path-wayrdquo European Journal of Pharmacology vol 660 no 2-3 pp249ndash258 2011

[45] S Srigopalram I A Jayraaj B Kaleeswaran et al ldquoEllagic acidnormalizes mitochondrial outer membrane permeabilizationand attenuates inflammation-mediated cell proliferation inexperimental liver cancerrdquoApplied Biochemistry andBiotechnol-ogy vol 173 no 8 pp 2254ndash2266 2014

[46] C-C Ho A-C Huang C-S Yu et al ldquoEllagic acid inducesapoptosis in TSGH8301 human bladder cancer cells through theendoplasmic reticulum stress- and mitochondria-dependentsignaling pathwaysrdquo Environmental Toxicology vol 29 no 11pp 1262ndash1274 2014

[47] S Umesalma P Nagendraprabhu andG Sudhandiran ldquoEllagicacid inhibits proliferation and induced apoptosis via the Aktsignaling pathway in HCT-15 colon adenocarcinoma cellsrdquoMolecular and Cellular Biochemistry vol 399 no 1-2 pp 303ndash313 2015

[48] J Wu C Omene J Karkoszka et al ldquoCaffeic acid phenethylester (CAPE) derived from a honeybee product propolisexhibits a diversity of anti-tumor effects in pre-clinical modelsof human breast cancerrdquo Cancer Letters vol 308 no 1 pp 43ndash53 2011

[49] C-S Kong C-H Jeong J-S Choi K-J Kim and J-W JeongldquoAntiangiogenic effects of P-coumaric acid in human endothe-lial cellsrdquo Phytotherapy Research vol 27 no 3 pp 317ndash323 2013

[50] A Rocha L Wang M Penichet and M Martins-GreenldquoPomegranate juice and specific components inhibit cell andmolecular processes critical for metastasis of breast cancerrdquoBreast Cancer Research and Treatment vol 136 no 3 pp 647ndash658 2012


[51] L Wang W Li M Lin et al ldquoLuteolin ellagic acid andpunicic acid are natural products that inhibit prostate cancermetastasisrdquo Carcinogenesis vol 35 no 10 pp 2321ndash2330 2014

[52] H-H Ho C-S Chang W-C Ho S-Y Liao C-HWu and C-J Wang ldquoAnti-metastasis effects of gallic acid on gastric cancercells involves inhibition of NF-120581B activity and downregulationof PI3KAKTsmall GTPase signalsrdquo Food and Chemical Toxi-cology vol 48 no 8-9 pp 2508ndash2516 2010

[53] M-H Pan C-S Lai and C-T Ho ldquoAnti-inflammatory activityof natural dietary flavonoidsrdquo Food and Function vol 1 no 1pp 15ndash31 2010

[54] S Massberg C Schulz and M Gawaz ldquoRole of platelets inthe pathophysiology of acute coronary syndromerdquo Seminars inVascular Medicine vol 3 no 2 pp 147ndash161 2003

[55] E Fuentes J Caballero M Alarcon A Rojas and I PalomoldquoChlorogenic acid inhibits human platelet activation andthrombus formationrdquo PLoS ONE vol 9 no 3 Article IDe90699 2014

[56] S J Hwang Y-W Kim Y Park H-J Lee and K-W Kim ldquoAnti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW2647 cellsrdquo Inflammation Research vol 63 no1 pp 81ndash90 2014

[57] M C Bufalo I Ferreira G Costa et al ldquoPropolis and itsconstituent caffeic acid suppress LPS-stimulated pro-inflam-matory response by blocking NF-120581B and MAPK activation inmacrophagesrdquo Journal of Ethnopharmacology vol 149 no 1 pp84ndash92 2013

[58] W-P Chen and L-D Wu ldquoChlorogenic acid suppresses inter-leukin-1120573-induced inflammatory mediators in human chon-drocytesrdquo International Journal of Clinical and ExperimentalPathology vol 7 no 12 pp 8797ndash8801 2014

[59] R Studer D Jaffurs M Stefanovic-Racic P D Robbins andC H Evans ldquoNitric oxide in osteoarthritisrdquo Osteoarthritis andCartilage vol 7 no 4 pp 377ndash379 1999

[60] W S Yang D Jeong Y-S Yi et al ldquoIRAK14-targeted anti-inflammatory action of caffeic acidrdquoMediators of Inflammationvol 2013 Article ID 518183 12 pages 2013

[61] G Oboh O M Agunloye A J Akinyemi A O Ademiluyiand S A Adefegha ldquoComparative study on the inhibitory effectof caffeic and chlorogenic acids on key enzymes linked toAlzheimerrsquos disease and some pro-oxidant induced oxidativestress in ratsrsquo brain-in vitrordquo Neurochemical Research vol 38no 2 pp 413ndash419 2013

[62] Y J Zhang X W Lu N Song et al ldquoChlorogenic acid altersthe voltage-gated potassium channel currents of trigeminalganglion neuronsrdquo International Journal of Oral Science vol 6no 4 pp 233ndash240 2014

[63] W Wu S-Y Lee X Wu et al ldquoNeuroprotective ferulic acid(FA)-glycol chitosan (GC) nanoparticles for functional restora-tion of traumatically injured spinal cordrdquo Biomaterials vol 35no 7 pp 2355ndash2364 2014

[64] Y Song T Cui N Xie X Zhang Z Qian and J Liu ldquoPro-tocatechuic acid improves cognitive deficits and attenuatesamyloid deposits inflammatory response in aged A120573PPPS1double transgenic micerdquo International Immunopharmacologyvol 20 no 1 pp 276ndash281 2014

[65] J H Lee J H Won J M Choi et al ldquoProtective effectof ellagic acid on concanavalin A-induced hepatitis via toll-like receptor and mitogen-activated protein kinasenuclearfactor 120581B signaling pathwaysrdquo Journal of Agricultural and FoodChemistry vol 62 no 41 pp 10110ndash10117 2014

[66] Y Yoshimura S Nishii N Zaima T Moriyama and Y Kaw-amura ldquoEllagic acid improves hepatic steatosis and serum lipidcomposition through reduction of serum resistin levels andtranscriptional activation of hepatic ppara in obese diabeticKK-A119910 micerdquo Biochemical and Biophysical Research Communi-cations vol 434 no 3 pp 486ndash491 2013

[67] X Zhang G-F Shi X-Z Liu L-J An and S Guan ldquoAnti-ageing effects of protocatechuic acid fromAlpinia on spleen andliver antioxidative system of senescent micerdquo Cell Biochemistryand Function vol 29 no 4 pp 342ndash347 2011

[68] Y S Kim H W Seo M-H Lee D K Kim H Jeon and D SCha ldquoProtocatechuic acid extends lifespan and increases stressresistance in Caenorhabditis elegansrdquo Archives of PharmacalResearch vol 37 no 2 pp 245ndash252 2014

[69] S Hameed and Z Fatima ldquoNovel regulatory mechanismsof pathogenicity and virulence to combat MDR in Candidaalbicansrdquo International Journal ofMicrobiology vol 2013ArticleID 240209 10 pages 2013

[70] J Tanwar S Das Z Fatima and S Hameed ldquoMultidrugresistance an emerging crisisrdquo Interdisciplinary Perspectives onInfectious Diseases vol 2014 Article ID 541340 7 pages 2014

[71] MM Cowan ldquoPlant products as antimicrobial agentsrdquoClinicalMicrobiology Reviews vol 12 no 4 pp 564ndash582 1999

[72] M A Ansari Z Fatima and S Hameed ldquoSesamol a naturalphenolic compound with promising anticandidal potentialrdquoJournal of Pathogens vol 2014 Article ID 895193 12 pages 2014

[73] S Das J Tanwar S Hameed and Z Fatima ldquoAntimicro-bial potential of epigallocatechin-3-gallate (EGCG) a greentea polyphenolrdquo Journal of Biochemical and PharmacologicalResearch vol 2 no 3 pp 167ndash174 2014

[74] M A Ansari A Anurag Z Fatima and S Hameed ldquoNaturalphenolic compounds a potential antifungal agentrdquo inMicrobialPathogens and Strategies for Combating Them Science Tech-nology and Education vol 1 pp 1189ndash1195 Formatex ResearchCenter 2013

[75] D S Stojkovic J Zivkovic M Sokovic et al ldquoAntibacterialactivity of Veronica montana L extract and of protocatechuicacid incorporated in a food systemrdquo Food and Chemical Toxi-cology vol 55 pp 209ndash213 2013

[76] J C Low andW Donachie ldquoA review of Listeria monocytogenesand listeriosisrdquoThe Veterinary Journal vol 153 no 1 pp 9ndash291997

[77] A Karunanidhi R Thomas A Van Belkum and V NeelaldquoIn vitro antibacterial and antibiofilm activities of chlorogenicacid against clinical isolates of Stenotrophomonas maltophiliaincluding the trimethoprimsulfamethoxazole resistant strainrdquoBioMed Research International vol 2013 Article ID 392058 7pages 2013

[78] G Li M Qiao Y Guo X Wang Y Xu and X Xia ldquoEffect ofsubinhibitory concentrations of chlorogenic acid on reducingthe virulence factor production by Staphylococcus aureusrdquoFoodborne Pathogens and Disease vol 11 no 9 pp 677ndash6832014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of


StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


Medicinal ChemistryInternational Journal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Autoimmune Diseases


Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of


Pharmaceutics


MEDIATORSINFLAMMATION

of


Phenolic acids Antioxidant

AntimicrobialAntidiabetic

Anticancer

Neuroprotective

Cardioprotective

Hepatoprotective

Anti-inflammation

ABCA1eNOS LDL level Paraoxonase 1

CAT TBARSSODGPx MDA levelsNrf2JNK

Membrane AMPKGLUT4G-6-Pase

iNOSCOX-2

AChEBChEMDA level

p38 JNK

Caspases 3 and 9 Myc

Bax PI3Akt

permeability PPAR-120574

IL-1120573 IL-6

IL-1120573 IL-6

TNF-120572

TNF-120572

TNF-120572

NF-120581B

NF-120581B

NF-120581B

PKC120572

I120581B-120572

TGF-120573

IL-1120573 IL-6 and IL-8

Figure 1 Key factors involved in health beneficial effects of natural PAs

However in case of plant metabolites these refer to a distinctgroup of organic acids which contains two distinguishingcarbon frameworks hydroxybenzoic and hydroxycinnamicacid structures PAs are usually subclassified into benzoicacids containing seven carbon atoms (C6-C1) and cinnamicacids with nine carbon atoms (C6-C3)

PAs are widely distributed in the plant kingdom andfound in a wide variety of nuts and fruits such as raspberriesgrapes strawberries walnuts cranberries and black cur-rants These are secondary metabolites derived from pheny-lalanine and tyrosine via shikimatechorismate pathwayHowever these compounds exist predominantly as hydrox-ybenzoic acids which include gallic acid (GA) salicylic acid(SA) protocatechuic acid (PCA) ellagic acid (EA) and gen-tisic acid (GeA) and hydroxycinnamic acids which includep-coumaric acid (p-CA) caffeic acid (CA) ferulic acid (FA)chlorogenic acid (CGA) and sinapic acids (SA) or alterna-tively may occur as conjugated forms (Figure 2)

The chemical properties of PAs in terms of availability ofthe phenolic hydroxyl groups predict their activity in vitroThe effective in vivo potential of PAs depends on multiplefactors such as quantity of the compound ingested absorbedandor metabolized plasma andor tissue concentrationstype and amount of single PA and synergistic effects How-ever the chemical structure of phenolic compounds differ-ently affects all the factors described above For instancesulfate derivatives of FA and CA showed lower activitieswhen compared with the antioxidant activities of the parentalphenolic acids indicating the importance of the phenolicacids and their metabolites [4]

3 Antioxidant Properties

Biological system generates reactive oxygen species (ROS) asthe byproduct of various metabolic activities and mitochon-dria are said to be major site responsible for ROS productionThese free radicals are highly unstable or reactive and cancause direct damage to cell components such as nucleic acidslipids and proteins [5] ROS is themajor contributor tomanydiseases which include CVDs cancer age-related declinein the immune system and degenerative diseases such asParkinsonrsquos and Alzheimerrsquos disease Human body possessesseveral stress response enzymes including superoxide dismu-tase (SOD) and catalase (CAT) to counteract radical-induceddamage PAs counteract both ROS and RNS-induced celldamage by their direct free radical scavenging activity aswell as the upregulation of the HOBVR system superoxidedismutase (SOD) and catalase (CAT) whose final aim is todetoxify ROS and RNS

Oxidative stress has been implicated in the pathogenesisof multiple cardiovascular complications Antioxidant role ofFA in cardioprotection is well studied [6] In hypersensitiverats treatment with FA for 4ndash12 weeks increased SOD andCAT activities FA treatment also increased SOD and CATlevels inmyocardium and pancreatic tissue of streptozotocin-induced diabetic rats in dose and time dependentmanner [7]

Antioxidant activities of PCA along with known anti-oxidant Trolox were measured in vitro using various anti-oxidant assays including 11-diphenyl-2-picrylhydrazyl(DPPH∙) 221015840-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)(ABTS+∙) superoxide anion radicals (O

2

minus∙) and hydroxyl




OH

OH

HO

O

OH

OHHO

HO

O

OH

HO

O

OCH3

OH

OH

OOH

OH

OH

HO

OO

O O


O

OH

HO

OCH3

O

OH

HO

OH

O

OH

HO

OH

HO

O

OCH3

H3CO

OH

OH

OHHO

HO

O

HO

OHOH

OH

OH

OH

O O

O


Quinic acid

Sinapic acid







































4
















13 Conclusion






Acknowledgments


References























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of




OH

OH

HO

O

OH

OHHO

HO

O

OH

HO

O

OCH3

OH

OH

OOH

OH

OH

HO

OO

O O


O

OH

HO

OCH3

O

OH

HO

OH

O

OH

HO

OH

HO

O

OCH3

H3CO

OH

OH

OHHO

HO

O

HO

OHOH

OH

OH

OH

O O

O


Quinic acid

Sinapic acid







































4
















13 Conclusion






Acknowledgments


References























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of
































4
















13 Conclusion






Acknowledgments


References























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



















4
















13 Conclusion






Acknowledgments


References























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of










4
















13 Conclusion






Acknowledgments


References























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of













13 Conclusion






Acknowledgments


References























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


13 Conclusion






Acknowledgments


References























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

Documents

Review Article Therapeutic Potential of Dietary Phenolic …downloads.hindawi.com/journals/aps/2015/823539.pdf · · 2015-11-24Review Article Therapeutic Potential of Dietary Phenolic