UNIVERSITI PUTRA MALAYSIA

MALIK ADEWOYIN

FPSK(m) 2014 50

CINNAMATE-ZINC LAYERED HYDROXIDE NANOCOMPOSITE ATTENUATES INFLAMMATORY RESPONSE IN RAW 264.7

MACROPHAGES STIMULATED BY LIPOPOLYSACCHARIDE

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CINNAMATE-ZINC LAYERED HYDROXIDE NANOCOMPOSITE

ATTENUATES INFLAMMATORY RESPONSE IN RAW 264.7

MACROPHAGES STIMULATED BY LIPOPOLYSACCHARIDE

By

MALIK ADEWOYIN

Thesis Submitted to the School of Graduate Studies, Universiti Putra Malaysia, in

Fulfillment of the Requirements for the Degree of Master of Science

September 2014

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COPYRIGHT

All material contained within the thesis, including without limitation text, logos, icons,

photographs and all other artwork, is copyright material of Universiti Putra Malaysia

unless otherwise stated. Use may be made of any material contained within the thesis

for non-commercial purposes from the copyright holder. Commercial use of material

may only be made with the express, prior, written permission of Universiti Putra

Malaysia.

Copyright © Universiti Putra Malaysia

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DEDICATION

This thesis is dedicated to the entire members of Adewoyin and Olowoporoku family.

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Abstract of thesis presented to the Senate of Universiti Putra Malaysia in fulfilment of

the requirements for the Degree of Master of Science

CINNAMATE-ZINC LAYERED HYDROXIDE (ZCA) NANOCOMPOSITE

ATTENUATES INFLAMMATORY RESPONSE IN RAW 264.7

MACROPHAGES STIMULATED BY LIPOPOLYSACCHARIDE (LPS)

By

MALIK ADEWOYIN

September 2014

Chairman: Associate Professor Sharida Fakurazi, PhD

Faculty: Medicine and Health Sciences

Cinnamic acid (CA) is a phytochemical originally derived from Cinnamomum cassia, a

plant with anti-inflammatory, antioxidant, antitumour and antiulcerogenic activity. The

intercalation of CA with a nano carrier, zinc layered hydroxide (ZLH) produced

cinnamate zinc layered hydroxide (ZCA), which has been previously characterized. The

intercalation is expected to improve the solubility and cell specificity of CA. Also, the

nano carrier will protect CA from degradation and sustain its release. Nevertheless, the

aim of the research is to evaluate the efficacy CA-ZLH in an in vitro model using RAW

264.7 macrophage cell line.In this study, the anti-inflammatory activity of ZCA, CA

and ZLH and their capacity to modulate the release of NO, PGE2, IL-6, TNF-α, IL-1β

and IL-10 in lipopolysaccharide-induced RAW 264.7 cells were evaluated.

Additionally, the expression of pro-inflammatory enzymes cyclooxygenase-2, iNOS

and transcription factor NF-κB were examined. Cytotoxicity tests were conducted to

determine the concentration of ZCA, CA and ZLH toxic to RAW 264.7 cells. This was

followed by treatment of confluent RAW 264.7 with ZCA, CA and ZLH for one hour

prior to stimulation of cells with lipopolysaccharide (LPS) for 24 hours to trigger an

inflammatory response. Griess reagent was added to an equal volume of culture

supernatant to determine the amount of NO produced in the treated and control groups

of cells. ELISA was used to measure levels of cytokines (TNF-α, IL-6, IL-1β, Il-10) and

PGE2produced by cells pretreated with ZCA, CA and ZLH, followed by activation with

LPS for 30 minutes, 2 hours, 4 hours and 24 hours. Cell lysates from ZCA, CA and

ZLH- treated cells were also used for Western blotting analysis to evaluate protein

expression of COX-2, iNOS and NF-κB.The cytotoxicity test conducted showed that

cells exposed to 2.5, 5 and 10 µg/ml each of ZCA, CA and ZLH displayed more than

90% cell viability. These three concentrations were selected for subsequent assays. NO

produced in cells treated with ZCA and CA were significantly lower than samples

treated with LPS alone. In the cytokine assay, ZCA and CA also displayed significant

inhibitory effect after 24 hours after LPS stimulation against pro-inflammatory

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cytokines such as TNF-α, IL-1β and IL-6 and another inflammatory marker PGE2. The

only anti-inflammatory cytokine in the design, IL-10 was significantly upregulated by

ZCA as well as CA. Western blot analysis showed samples treated with ZCA and CA

significantly inhibited the protein expression of COX-2, iNOS and NF-κB. Even

thoughZCA is composed of only40.4% of CA, it displayed higher anti-inflammatory

activity than 100% CA. However, ZLH did not show any significant activity. The

enhanced activity of ZCA may be associated with the intercalation which has reduced

the compound to a nano size.

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Abstrak tesis yang dikemukakan kepada Senat Universiti Putra Malaysia sebagai

memenuhi keperluan untuk Ijazah Master Sains

CINNAMATE - ZINC BERLAPIS HIDROKSIDA (ZCA) NANOKOMPOSIT

MELEMAH TINDAK BALAS KERADANGAN DALAM MAKROFAJ RAW

264.7 DIRANGSANG OLEH LIPOPOLISAKARIDA (LPS)

Oleh

MALIK ADEWOYIN

September 2014

Pengerusi: Profesor Madya Sharida Fakurazi , PhD

Fakulti: Perubatan dan Sains Kesihatan

Asid Cinnamic (CA) adalah fitokimia asalnya diperoleh daripada Cinnamomum cassia,

tumbuhan dengan anti-inflamasi, antioksidan, antitumor dan aktiviti anti-

ulsergenik.Interkalasi CA dengan pembawa nano, zink berlapis hidroksida (ZLH) yang

dihasilkan zink cinnamate berlapis hidroksida (ZCA), yang telah dicirikan sebelum ini.

Interkalasi itu dijangka meningkatkan keterlarutan dan spesifisiti sel CA. Juga,

pembawa nano akan melindungi CA daripada degradasi dan mengekalkan

pelepasannya. Walau bagaimanapun, tujuan penyelidikan ini adalah untuk menilai

keberkesanan CA-ZLH secara in vitro menggunakan titisan sel makrofaj RAW 264.7.

Dalam kajian ini, aktiviti anti-inflamasi daripada ZCA, CA dan ZLH dan kemampuan

mereka untuk memodulasi pembebasan NO, PGE2 , IL-6, TNF- -1β dan IL-10

dalam lipopolisakarida dicetus sel-sel RAW 264.7 telah dinilai. Tambahan lagi,

ungkapan pro-radang enzim sikloksigenase-2, iNOS dan faktor transkripsi NF-κB telah

diperiksa.Ujian sitotoksik telah dijalankan untuk menentukan kepekatan ZCA, CA dan

ZLH toksik kepada sel-sel RAW 264.7. Ini diikuti dengan pertemuan sel-sel RAW

264.7 yang dirawat dengan ZCA, CA dan ZLH selama satu jam sebelum ransangan sel

dengan lipopolisakarida (LPS) selama 24 jam untuk mencetuskan tindak balas

keradangan . Reagen Griess ditambah kepada jumlah kultur supernatan yang sama

untuk menentukan jumlah NO terhasil di dalam kumpulan-kumpulan sel yang dirawat

dan dikawal. ELISA telah digunakan untuk mengukur tahap sitokin (TNF- -6, IL-

1β, Il-10) dan PGE2 yang dihasilkan oleh sel-sel dengan pre-rawat ZCA, CA dan ZLH,

diikuti dengan pengaktifan dengan LPS untuk 30 minit, 2 jam, 4 jam dan 24 jam. Sel

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lysates daripada ZCA, CA dan ZLH-terawat juga telah digunakan untuk analisis Blot

Western untuk menilai ungkapan protein COX-2, iNOS dan NF-κB. Ujian sitotoksik

yang dijalankan menunjukkan bahawa sel-sel terdedah kepada 2.5, 5 dan 10μg/ml setiap

ZCA, CA dan ZLH dipaparkan lebih daripada 90% viabiliti sel. Ketiga-tiga kepekatan

telah dipilih untuk ujian berikutnya. NO dihasilkan dalam sel-sel yang dirawat dengan

ZCA dan CA adalah jauh lebih rendah daripada sampel yang mengandungi LPS sahaja.

Dalam cerakin sitokin itu, ZCA dan CA juga menunjukkan kesan mencegah yang ketara

selepas 24 jam terhadap sitokin pro-radang seperti TNF-α, IL-1β dan IL-6 dan satu lagi

penanda radang PGE2. Satu-satunya sitokin antiinflamasi dalam reka bentuk, IL-10

telah ketara terregulasi oleh ZCA serta CA. Analisis Blot Western menunjukkan sampel

yang mengandungi ZCA dan CA ketara menghalang ungkapan protein COX-2, iNOS

dan NF-κB. Walaupun ZCA terdiri daripada hanya 40.4% daripada CA tetapi ia

memaparkan aktiviti anti-inflamasi lebih tinggi daripada 100% CA. Walau

bagaimanapun, ZLH tidak menunjukkan sebarang aktiviti yang ketara. Aktiviti ZCA

yang dipertingkatkan boleh dikaitkan dengan interkalasi yang telah mengurangkan

kompaun kepada saiz nano.

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ACKNOWLEDGEMENTS

All praises and gratitude are due to almighty Allah, our nourisher and sustainer. I thank

Him for his favours during my stay in this beautiful country. May the knowledge

benefit me and the entire humanity. I am indebted to my supervisor, Associate Prof Dr.

(Datin) Sharida Fakurazi who taught me the fundamentals of research and scientific

writing. Her constructive criticism of this write up has made it an excellent and

interesting read. I also appreciate the contribution of my co-supervisor, Prof Dr. Mohd

Zobir Hussien whose landmark in the field of Nanotechnology has created a

collaborative advantage for those of us in the Life Sciences to explore. The immense

contribution of Sumaiyah Megat Mohsin who was responsible for the synthesis of the

nanohybrid used for this research cannot be overemphasized.

I would also like to thank Dr. Arul for sharing his experience in Proteomics and other

laboratory techniques. All officers of Laboratory of Vaccine and Immunotherapeutics

have played a supportive role towards the successful completion of this research. To all

I say ‘Terima kasih’. The laboratory is a place of research and reflection. Companions

like Abubakar, Aminu, Shafinaz, Aimi, Karthi and Tiqah have assisted me in dousing

the tension and keeping a smiling face.

Life outside the four walls of the laboratory would have been frustrating without the

affection and companionship of fellow Nigerians. Moral support from Abdwasiu Arolu,

Dr. Jaji, Abualhaji Mansur,Al-Hassan,Abdulhakeem Oladele, Abdulhakeem Olaniyi

Abdulhafees, Binyamin and many others epitomizes the concept of Islamic

brotherhood. I will forever remain grateful to all of you.

However, I would like to thank my parents and siblings for their love and concern. May

Allah strengthen the family ties. I do not know how to express my gratitude to my wife,

Deola for her sacrifices. May Allah shower His blessings on her in this world and the

hereafter. To my children, Rufaidah and Ahmad, I love you all. Lastly, I would like to

show my gratitude to brothers in Mushin for keeping the home front safe and crisis free.

May Allah reward you abundantly.

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This thesis was submitted to the Senate of Universiti Putra Malaysia and has been

accepted as fulfillment of the requirement for the degree of Doctor of Philosophy. The

members of the Supervisory Committee were as follows:

Sharida Fakurazi, PhD

Associate Professor

Faculty of Medicine and Health Sciences

Universiti Putra Malaysia

(Chairman)

Mohd Zobir Hussein, PhD

Professor

Institute of Advanced Technology

Universiti Putra Malaysia

(Member)

_____________________________

BUJANG BIN KIM HUAT, PhD

Professor and Dean

School of Graduate Studies

Universiti Putra Malaysia

Date:

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Declaration by graduate student

I hereby confirm that:

this thesis is my original work

quotations, illustrations and citations have been duly referenced

the thesis has not been submitted previously or comcurrently for any other degree

at any institutions

intellectual property from the thesis and copyright of thesis are fully-owned by

Universiti Putra Malaysia, as according to the Universiti Putra Malaysia

(Research) Rules 2012;

written permission must be owned from supervisor and deputy vice –chancellor

(Research and innovation) before thesis is published (in the form of written, printed

or in electronic form) including books, journals, modules, proceedings, popular

writings, seminar papers, manuscripts, posters, reports, lecture notes, learning

modules or any other materials as stated in the Universiti Putra Malaysia

(Research) Rules 2012;

there is no plagiarism or data falsification/fabrication in the thesis, and scholarly

integrity is upheld as according to the Universiti Putra Malaysia (Graduate Studies)

Rules 2003 (Revision 2012-2013) and the Universiti Putra Malaysia (Research)

Rules 2012. The thesis has undergone plagiarism detection software

Signature:___________________ Date: ___________________

Name and Matric No: Malik Adewoyin GS33378

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TABLE OF CONTENTS

Page

ABSTRACT i

ABSTRAK iii

ACKNOWLEDGEMENTS v

APPROVAL vi

DECLARATION viii

LIST OF TABLES x

TABLE OF FIGURES xiii

LIST OF ABBREVIATIONS xiv

CHAPTER

1 INTRODUCTION 1

1.1 Problem statement 2

1.2 Justification 3

1.3 Hypothesis 3

1.4 Objectives of Study 3

1.4.1 Main objective 3

1.4.2 Specific objectives 3

2 LITERATURE REVIEW 4

2.1 Inflammation 4

2.1.1 LPS pro-inflammatory signaling 5

2.1.2 Genesis of chronic inflammation 6

2.1.3 Chronic inflammation and inflammatory diseases 7

2.1.4 Experimental model of inflammation 7

2.2 Pro-inflammatory mediators 8

2.2.1 Nitric oxide 8

2.2.2 Prostaglandin E2 (PGE2) 9

2.2.3 Tumour necrosis factor alpha (TNF-α) 10

2.2.4 Interleukin-1β (IL-1β) 10

2.2.5 Interleukin-6 (IL-6) 10

2.3 Inhibition of pro-inflammatory mediators 11

2.4 Anti-inflammatory cytokine 12

2.4.1 Interleukin- 10 (IL-10) 12

2.5 Nuclear factor kappa B (NF-KB) 12

2.6 The macrophage in inflammation 13

2.7 Chemistry of cinnamic acid 13

2.7.1 Natural sources of cinnamic acid 15

2.7.2 Pharmacological properties of cinnamic acid 15

2.7.3 Therapeutic limitations of cinnamic acid 16

2.8 Nanotechnology and Medicine 16

2.8.1 Pharmacological advantage of nano delivery system 18

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3 MATERIALS AND METHODS 21

3.1 Materials synthesis and characterization 21

3.2 Cell line, Chemicals and Reagents 21

3.3 Cell culture 22

3.3.1 Cell Thawing 22

3.3.2 Preparation of cell stock 22

3.3.3 Cell passaging 22

3.4 MTT assay for cell viability 23

3.5 Determination of Nitric oxide Production 23

3.6 Determination of cytokines level via enzyme linked

immunosorbent assay (ELISA)

23

3.7 Determination of PGE2 production 24

3.8 Preparation of Samples for Western’s blotting 25

3.9 Protein quantification 25

3.10 Gel casting for sodium dodecyl sulphate- polyacrylamide gel

electrophoresis (SDS – PAGE)

25

3.11 Western blotting 26

3.12 Statistical analysis 27

4 RESULTS 28

4.1 Effects of ZCA, CA and ZLH on cell viability 28

4.2 Effects of Cinnamate-zinc layered hydroxide (ZCA) on LPS –

induced nitric oxide (NO) production

29

4.3 Reduced production of PGE2 in RAW 264.7 cells stimulated

with LPS

30

4. 4 Effect of Cinnamate-zinc layered hydroxide (ZCA) on LPS

induced IL-6 production

31

4.5 Effect of Cinnamate-zinc layered hydroxide (ZCA) on LPS-

activated production of TNF alpha

34

4.6 The downregulatory effect Cinnamate- zinc layered hydroxide

(ZCA) on LPS induced production of IL-1β

36

4.7 Effects of Cinnamate zinc layered hydroxide (ZCA) on IL-10

in LPS-activated RAW 264.7 cells

37

4. 8 Effects of Cinnamate zinc layered hydroxide (ZCA) on LPS-

induced iNOS expressions

40

4.9 Effect of Cinnamate-zinc layered hydroxide (ZCA) on LPS-

induced COX-2 expression

41

4.10 Effect of ZCA on LPS-induced NF-κB expression 43

5 DISCUSSION 45

6 CONCLUSION AND RECOMMENDATIONS FOR FUTURE

STUDIES

50

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REFERENCES 51

BIODATA OF STUDENT 88

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LIST OF FIGURES

Figure Page

2a Toll-like receptor signaling 6

2b Inhibition of Pro-inflammatory enzymes 12

2c Structure of cinnamic acid 14

2d Nanomedicine application areas 17

2e Types of nanocarriers 19

2f FESEM image of ZCA 20

4.1 Effect of ZCA,CA and ZLH on RAW 264.7 viability 29

4.2 Inhibitory effect of ZCA on LPS-induced NO production in

RAW 264.7 macrophages

30

4.3 Inhibitory effect of ZCA on LPS-induced production of PGE2

on RAW 264.7 macrophages

31

4.4 Inhibitory effect ZCA on LPS-induced production of IL-6 on

RAW 264.7 macrophages

33

4.5 Inhibitory effect of ZCA on LPS-induced production of TNF-α

on RAW 264.7 macrophages

36

4.6 Inhibitory effect of CA and ZCA on LPS-induced production of

IL-1β on RAW 264.7 macrophages

37

4.7 Upregulatory effect of ZCA on LPS-induced suppression of IL-

10 in RAW 264.7 macrophages

39

4.8 Inhibitory effect of ZCA and CA on LPS induced iNOS protein

expression

41

4.9 Inhibitory effect of ZCA and CA on LPS induced COX-2

protein expression

42

4.10 Inhibitory effect of ZCA and CA on LPS induced NF-κB protein

expression

44

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LIST OF ABBREVIATIONS

AP-1 Activator protein 1

ATCC American Type Culture Collection

CA Cinnamic acid

C/ABP CCAAT/ enhancer binding protein

COX-2 Cyclooxygenase 2

CR Control release

DAMP Damage associated molecular pattern

DEX Dexamethazone

DMEM Dulbecco's Modified Eagle's Medium

DMSO Dimethyl sulfoxide

DNA Deoxyribonucleic acid

ds RNA Double stranded ribonucleic acid

ECL Enhanced Chemiluminescence

eNOS/NOS3 Endothelial nitric oxide synthase

FBS Fetal bovine serum

FESEM Field emission electron microscopy

IFN-γ Interferon gamma

IκB Inhibitory kappa B

IκBE Inhibitor kappa B epsilon

IKK Inhibitor kappa B kinases

IL-10 Interleukin 10

IL-12 Interleukin 12

IL-1β Interleukin 1 beta

IL-2 Interleukin 2

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IL-23 Interleukin 23

IL-6 Interleukin 6

iNOS Inducible nitric oxide synthase

JAK Janus kinase

JNK Jun N-terminal kinase

KDA Kilo Dalton

Km Michealis constant

LDH Layered double hydroxide

LPS Lipopolysaccharide

MAF Macrophage activating factor

MAPK Mitogen activated protein kinase

MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NADP Nicotinamide adenine dinucleotide phosphatase- reductase

NADPH Nicotinamide adenine dinucleotide phosphatase-oxidase

NEDD Naphylethylene diamine dihydrochloride

NF-KB Nuclear factor kappa B

NLR Nod-like receptors

nNOS/ NOS1 Neuronal nitric oxide synthase

NO Nitric oxide

NP Nanoparticle

O2 Oxygen gas

PAMP Pathogen associated molecular pattern

PBS Phosphate buffered saline

PGE2 Prostaglandin E2

PGG2 Prostaglandin G2

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PGH2 Prostaglandin H2

PGHS Prostaglandin H synthase

PLA2 Phosphatase A2

PPR Pattern recognition receptors

PVDF Polyvinylidene difluoride

RNA Ribonucleic acid

ROS Reactive oxygen specie

RPM Revolutions per minute

SDS-PAGE Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SE Standard error

SEM Scanning electon microscope

TB Transfer buffer

TEMED Tetramethylethylenediamine

TGFβ Transforming growth factor beta

TLR Toll like receptors

TMB Tetramethylbenzidine

TNF-α Tumour necrosis factor alpha

TREG The regulatory T cells

TXA2 Thromboxane A2

UV Ultraviolet

ZCA Cinnamate zinc layered hydroxide

ZLH Zinc layered hydroxide

ZnO Zinc

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CHAPTER 1

INTRODUCTION

Inflammation is an inherent beneficial process through which offending factors are

removed, and tissue structure and normal physiological function are restored(Nathan

2002). The body is continuously surveyed by the immune system for the presence of

invaders. Any contact with an attack is neutralized by an involuntary, discrete and

localized inflammatory response. However, insufficient inflammatory response may

result in immunodeficiency, which may finally lead to infection or cancer. On the other

hand, excessive responses may result in chronic inflammatory diseases such as

rheumatoid arthritis, diabetes and Alzheimer’s disease. Inflammation can also manifest

in the bloodstream causing sepsis, septic shock syndrome, severe trauma and

meningitis. Nevertheless, anti-inflammatory responses that are rapid, redundant,

localized, reversible, adaptive to variation in input and coordinated by the nervous

system restores homeostasis and health (Tracey et al., 1986; Tracey et al., 1987).

When inflammation is provoked by a pathogen, pattern recognition receptors expressed

by macrophages stimulate resident macrophages to begin innate immune response.

Commonly referred to astoll like receptors (TLR), they recognize microbial pathogens

through their molecular structures. Responses mediated by TLR influence the

activation of NF-κB in relation with a set of pro-inflammatory cytokine genes, most

especially IL-1 and TNF-α. Activated macrophages possess an enhanced capacity to

eliminate microbes and cancer cells. They are bigger with a large number of

pseudopods and obviously ruffled plasma membrane, producing various biologically

activeproducts that, if uncontrolled, result in the damage of tissues and chronic

inflammation. However, recent research outcomes associated the consumption of

phenolic compounds with the prevention and low risk of many degenerative diseases

which are associated with inflammation like atherosclerosis, cancer and cardiovascular

diseases (Scalbertet al., 2005)

Cinnamomum cassia, an evergreen tree of Lauraceae family has long been associated

with cure for inflammatory disease, dyspepsia, blood circulation disturbances and

gastritis. Its extracts contain phenolics like cinnamic alcohol, cinnamic aldehyde,

coumarin and cinnamic acid (Heetal., 2005; Sunget al., 2011). It has been established

that Cinnamomum cassia has many pharmacological properties like anti-

inflammatory(Hong et al,2002) antipyretic (Grover et al.2002), antitumor(Lee et

al.,2005) and anti ulcerogenic activity(Sunget al., 2011). Recently, each of the active

compounds has been subjected to further screening to identify their individual qualities.

Cinnamic acid (CA), one of the phytocompounds derived from the plant,demonstrated

in both in vivo and in vitro experiments significant anti-inflammatory potential (Liao et

al., 2012). Patra et al (2012) were able to confirm its antioxidant property in which it

protected the bone marrow and spleen cells in a dose- dependent pattern, from

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cyclophosphamide- induced oxidative stress. It has also been found to be an antitumor

(Akaoet al., 2003).

Many other important biological activities have been attributed to CA, including

inhibition of the malarial agent Plasmodium falciparum (Kanaani and Ginsburg, 1992),

of low Km mitochondrial aldehyde dehydrogenase in rats (Poole et al., 1993), and of

mushroom tyrosinase (Lee,2002). This compound has also been reported to be of

potential value as a natural product for the treatment of cancer, and it has demonstrated

antimicrobial activity against microorganisms such as rumen bacteria (Theodorou et al.,

1987). Despite its various pharmacological properties, activity of CA has been found to

be lower than cinnamyl aldehyde and p-coumaric acid (COU) which might be due its

high metabolic rate (Liao et al. 2012; Garrait et al. 2006).

However, therapeutic efficacy of CA could be improved by intercalating the compound

with a nanoparticle (NP). CA has been intercalated with zinc layered hydroxide (ZLH)

to produce a nanohybrid, cinnamate-zinc layered hydroxide (ZCA). The carrier, ZLH

was synthesized from the hydrolysis of zinc oxide (ZnO). Then, cinnamate anion was

intercalated into ZLH interlayer spaces giving rise to ZCA (shown in Fig. 1a and b)

which has been successfully characterized by another group in the laboratory. The

character of the nanocomposite is described in Chapter 3(Mohsin et al., 2013).Drug

intercalation with nanoparticle ensures controlled drug delivery by increasing drug

localization to specific cells, tissues or organs (Ferrari, 2005; Riehemann et al., 2009).

The efficacy, stability and solubility of drugs can be boosted by intercalating it with a

nanoparticle. Nanoparticles also have the potential to decrease toxicity and enhance

sustained release(Merisko-Liversidge and Liversidge, 2008).

Generally, NP sizes are between 10 to 1000nm. The drug is dissolved, encapsulated,

entrapped or adjoined to a NP matrix based on the method of preparation. Recently,

biodegradable polymeric NPs have received considerable recognition aspotential drug

delivery tools with respect to their applications as DNA carriers in gene therapy, their

capability to target particular tissues/organs, their relevance in the control release (CR)

of pharmacologically- active agents, and in their ability to deliver peptides, proteins and

genes via a peroral course of administration (Langer, 2000; Lanza et al., 2011)

1.1 Problem statement

The number of drugs designed to fight inflammation far more exceed any other category

of drugs because chronic and low level inflammations are associated with acute and

chronic diseases. However,non-specificity of action, degradation of drug en routebefore

reaching the target site and poor solubility in the medium of deliveryare the major

limitationsof conventional drugs (Rawat et al., 2006; Jain 2007; Surendiran et al.,

2009).Cinnamic acid has been found to exhibit lower activity than some its derivatives

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especially cinnamyl aldehyde and p-coumaric acid which may be associated with its

comparably high rate of metabolism (Liao et al. 2012; Garrait et al. 2006).

1.2 Justification

Nanotechnology offers the alternative of designing new drugs with higher cell

specificity and unconventional drug-release systems that act selectively on certain

targets and shield the drug from degradation. This permits the administration of smaller,

yet more effective doses, reducing adverse effects. Moreover, nanotechnology can also

be used to modify drug formulations, improving drug solubility and changing the

pharmacokinetics to sustain the release of the drug, thus prolonging its bioavailability

(Surendiran et al., 2009)

1.3 Hypothesis

This study is designed to assess the hypothesis that intercalation of cinnamic acid with

ZLH will enhance the anti-inflammatory activity of cinnamic acid.

1.3 Objectives of Study

1.3.1 Main objective

The main objective of this study is to evaluate the antiinflammatory activity of

cinnamate-zinc layered hydroxide (ZCA), cinnamic acid (CA) and zinc layered

hydroxide (ZLH) in lipopolysaccharide (LPS)- induced inflammation using RAW 264.7

cell line.

1.3.2 Specific objectives

The specific objectives of the study are to:

1. Determine the concentration ofZCA, CA and ZLH that will induce cytotoxicity in

RAW 264.7 cells.

2. Evaluate the action of ZCA, CA and ZLH on the production of some

inflammatory cytokines and biomarkers in LPS-induced inflammation.

3. Determine the effect of ZCA, CA and ZLH on the expression of inducible

inflammatory enzymes and NF-κB in RAW 264.7 cells through western blotting

technique.

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REFERENCES

Anselmi, Cecilia, Marisanna Centini, Maria Maggiore, Nicola Gaggelli, Marco

Andreassi, Anna Buonocore, Giangiacomo Beretta, and Roberto Maffei Facino.

"Non-covalent inclusion of ferulic acid with α-cyclodextrin improves photo-

stability and delivery: NMR and modeling studies." Journal of pharmaceutical

and biomedical analysis 46, no. 4 (2008): 645-652.

Abbas, Abul K., Andrew HH Lichtman, and Shiv Pillai. Cellular and molecular

immunology. Elsevier Health Sciences, 1994.

Aderem, Alan, and Richard J. Ulevitch."Toll-like receptors in the induction of the

innate immune response."Nature 406, no. 6797 (2000): 782-787.

Adisakwattana, Sirichai, Preecha Moonsan, and Sirintorn Yibchok-Anun."Insulin-

releasing properties of a series of cinnamic acid derivatives in vitro and in

vivo." Journal of agricultural and food chemistry 56, no .17 (2008): 7838-7844.

Aggarwal, Bharat B., and Jordan U. Gutterman.Human cytokines. 1992.

Agusti, A. W. K. M., W. MacNee, K. Donaldson, and M. Cosio. "Hypothesis: does

COPD have an autoimmune component?." Thorax 58, no. 10 (2003): 832-834.

Ahmad, Nosheen, Li C. Chen, Marion A. Gordon, Jeffrey D. Laskin, and Debra L.

Laskin. "Regulation of cyclooxygenase-2 by nitric oxide in activated hepatic

macrophages during acute endotoxemia." Journal of leukocyte biology 71, no. 6

(2002): 1005-1011.

Ait-Oufella, Hafid, Benoît L. Salomon, Stéphane Potteaux, Anna-Karin L. Robertson,

Pierre Gourdy, Joffrey Zoll, Régine Merval et al. "Natural regulatory T cells

control the development of atherosclerosis in mice." Nature medicine 12, no. 2

(2006): 178-180..

Ajat, Md, M. Mohd, Khatijah Yusoff, and Mohd Zobir Hussein."Synthesis of

glutamate-zinc-aluminium-layered double hydroxide nanobiocomposites and

cell viability study."Current Nanoscience 4, no. 4 (2008): 391-396.

Akao, Yukihiro, Hiroe Maruyama, Kenji Matsumoto, Kenji Ohguchi, Kumi Nishizawa,

Takashi Sakamoto et al "Cell growth inhibitory effect of cinnamic acid

derivatives from propolis on human tumor cell lines." Biological and

Pharmaceutical Bulletin 26, no. 7 (2003): 1057-1059.

Alberto, Aragón-Muriel, and Polo-Cerón Dorian."Synthesis, characterization, thermal

behavior, and antifungal activity of La (III) complexes with cinnamates and 4-

methoxyphenylacetate."Journal of Rare Earths 31, no. 11 (2013): 1106-1113.

© COPYRIG

HT UPM

52

Alderton, W., C. H. Cooper, and R. Knowles. "Nitric oxide synthases: structure,

function and inhibition." Biochem. J 357 (2001): 593-615.

Appoloni, Olivier, Elisabeth Dupont, M. Vandercruys, M. Andriens, Jean Duchateau,

and Jean-Louis Vincent."Association of tumor necrosis factor-2 allele with

plasma tumor necrosis factor-alpha levels and mortality from septic shock."The

American journal of medicine 110, no. 6 (2001): 486-488.

Arizaga, Gregorio Guadalupe Carbajal, Kestur Gundappa Satyanarayana, and Fernando

Wypych. "Layered hydroxide salts: synthesis, properties and potential

applications." Solid State Ionics 178, no. 15 (2007): 1143-1162.

Arnardottir, Snjolaug, Helene Alexanderson, Ingrid E. Lundberg, and Kristian Borg.

"Sporadic inclusion body myositis: pilot study on the effects of a home exercise

program on muscle function, histopathology and inflammatory reaction."

Journal of rehabilitation medicine 35, no. 1 (2003): 31-35.

Azad, Neelam, Yon Rojanasakul, and Val Vallyathan. "Inflammation and lung cancer:

roles of reactive oxygen/nitrogen species." Journal of Toxicology and

Environmental Health, Part B 11, no. 1 (2008): 1-15.

Barone, Eugenio, Vittorio Calabrese, and Cesare Mancuso."Ferulic acid and its

therapeutic potential as a hormetin for age-related diseases."Biogerontology 10,

no. 2 (2009): 97-108.

Barton, Gregory M. "A calculated response: control of inflammation by the innate

immune system." The Journal of clinical investigation 118, no. 2 (2008): 413-

419.

Bartsch, Helmut, and Jagadeesan Nair. "Chronic inflammation and oxidative stress in

the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage,

and repair." Langenbeck's Archives of Surgery 391, no. 5 (2006): 499-510.

Bauer, Laura Ann, Nira S. Birenbaum, and Gerald J. Meyer."Biological applications of

high aspect ratio nanoparticles."Journal of Materials Chemistry 14, no. 4

(2004): 517-526.

Benelli, R., G. Lorusso, A. Albini, and D. M. Noonan."Cytokines and chemokines as

regulators of angiogenesis in health and disease."Current pharmaceutical design

12, no. 24 (2006): 3101-3115.

Berg, Daniel J., Natalie Davidson, Ralf Kühn, Werner Müller, Satish Menon, Gina

Holland, L. Thompson-Snipes, Michael W. Leach, and Donna Rennick.

"Enterocolitis and colon cancer in interleukin-10-deficient mice are associated

with aberrant cytokine production and CD4 (+) TH1-like responses." Journal of

Clinical Investigation 98, no. 4 (1996): 1010.

© COPYRIG

HT UPM

53

Berleth, Erica S., Srikanth Nadadur, Alicia D. Henn, Cheryl Eppolito, Satoshi Shiojiri,

Hira L. Gurtoo, M. Jane Ehrke, and Enrico Mihich. "Identification,

characterization, and cloning of TIP-B1, a novel protein inhibitor of tumor

necrosis factor-induced lysis."Cancer research 59, no. 21 (1999): 5497-5506.

Berriozabal, Gemma, and Yolanda R. de Miguel. "Synthesis and characterisation of

silica nanoparticles bearing different functional groups obtained via a two‐stage

method." physica status solidi (c) 7, no. 11‐12 (2010): 2692-2696.

Beutler, B., and A. Cerami."The common mediator of shock, cachexia, and tumor

necrosis."Adv Immunol 42 (1988): 213-231.

Bogdan, Christian. "Nitric oxide and the immune response."Nature immunology 2, no.

10 (2001): 907-916.

Boltaña, Sebastian, Nerea Roher, Frederick W. Goetz, and Simon A. MacKenzie.

"PAMPs, PRRs and the genomics of gram negative bacterial recognition in

fish." Developmental & Comparative Immunology 35, no. 12 (2011): 1195-

1203.

Bosschaerts, Tom, Martin Guilliams, Benoît Stijlemans, Yannick Morias, Daniel Engel,

Frank Tacke, Michel Herin, Patrick De Baetselier, and Alain Beschin. "Tip-DC

development during parasitic infection is regulated by IL-10 and requires

CCL2/CCR2, IFN-γ and MyD88 signaling." PLoS pathogens 6, no. 8 (2010):

e1001045.

Boulaiz, Houria, Pablo J. Alvarez, Alberto Ramirez, Juan A. Marchal, Jose Prados,

Fernando Rodríguez-Serrano, Macarena Perán, Consolación Melguizo, and

Antonia Aranega. "Nanomedicine: Application areas and development

prospects." International journal of molecular sciences 12, no. 5 (2011): 3303-

3321.

Brannon-Peppas, Lisa, and James O. Blanchette."Nanoparticle and targeted systems for

cancer therapy."Advanced drug delivery reviews 64 (2012): 206-212.

Brennan, F. M., R. N. Maini, and M. Feldmann. "TNFα—a pivotal role in rheumatoid

arthritis?." Rheumatology 31, no. 5 (1992): 293-298.

Bulut, Asiye Safak, Esra Erden, Serpil Dizbay Sak, Hatice Doruk, Nazmiye Kursun,

and Dilek Dincol. "Significance of inducible nitric oxide synthase expression in

benign and malignant breast epithelium: an immunohistochemical study of 151

cases." Virchows Archiv 447, no. 1 (2005): 24-30.

Camussi, Giovanni, and Enrico Lupia. "The future role of anti-tumour necrosis factor

(TNF) products in the treatment of rheumatoid arthritis." Drugs 55, no. 5 (1998):

613-620.

© COPYRIG

HT UPM

54

Charo, Israel F., and Mark B. Taubman."Chemokines in the pathogenesis of vascular

disease."Circulation research 95, no. 9 (2004): 858-866.

Charo, Israel F., and Richard M. Ransohoff."The many roles of chemokines and

chemokine receptors in inflammation."New England Journal of Medicine 354,

no. 6 (2006): 610-621.

Chen, Helen HW, Cheng-Yang Chou, Yuan-Hua Wu, Wei-Ting Hsueh, Chiung-Hui

Hsu, How-Ran Guo et al. "Constitutive STAT5 activation correlates with better

survival in cervical cancer patients treated with radiation therapy." International

Journal of Radiation Oncology* Biology* Physics 82, no. 2 (2012): 658-666.

Chen, Yen-Ling, Shao-Tsung Huang, Fang-Ming Sun, Yu-Ling Chiang, Chia-Jung

Chiang, Chiung-Man Tsai, et al "Transformation of cinnamic acid from trans-to

cis form raises a notable bactericidal and synergistic activity against multiple-

drug resistant Mycobacterium tuberculosis." European Journal of

Pharmaceutical Sciences 43, no. 3 (2011): 188-194.

Cheng, R., S. Glynn, et al. (2010)."Nitric oxide and redox inflammation in

cancer."Advances in Molecular Toxicology 4: 157-182.

Cheng, Xingguo, and Liisa Kuhn."Chemotherapy drug delivery from calcium phosphate

nanoparticles."International journal of nanomedicine 2, no. 4 (2007): 667.

Chiong, Hoe Siong, Yoke Keong Yong, Zuraini Ahmad, Mohd Roslan Sulaiman,

Zainul Amiruddin Zakaria, Kah Hay Yuen et al. "Cytoprotective and enhanced

anti-inflammatory activities of liposomal piroxicam formulation in

lipopolysaccharide-stimulated RAW 264.7 macrophages." International journal

of nanomedicine 8 (2013): 1245.

Choi, Soo-Jin, Jae-Min Oh, and Jin-Ho Choy. "Biocompatible nanoparticles intercalated

with anticancer drug for target delivery: pharmacokinetic and biodistribution

study." Journal of nanoscience and nanotechnology 10, no. 4 (2010): 2913-

2916.

Chou, Tz-Chong, Earl Fu, and E. Shen. "Chitosan inhibits prostaglandin E2 formation

and cyclooxygenase-2 induction in lipopolysaccharide-treated RAW 264.7

macrophages." Biochemical and biophysical research communications 308, no.

2 (2003): 403-407.

Choy, Cheuk-Sing, Chien-Ming Hu, Wen-Ta Chiu, Carlos-Shu Kei Lam, Yih Ting,

Shin-Han Tsai et al. "Suppression of lipopolysaccharide-induced of inducible

nitric oxide synthase and cyclooxygenase-2 by Sanguis Draconis, a dragon's

blood resin, in RAW 264.7 cells." Journal of ethnopharmacology 115, no. 3

(2008): 455-462.

© COPYRIG

HT UPM

55

Choy, Jin‐Ho, Jiwon Shin, Seung‐Yong Lim, Jae‐Min Oh, Mi‐Hwa Oh, and Sangsuk

Oh. "Characterization and stability analysis of zinc oxide nanoencapsulated

conjugated linoleic acid." Journal of food science 75, no. 6 (2010): 63-68.

Choy, Jin-Ho, Seo-Young Kwak, Jong-Sang Park, Yong-Joo Jeong, and Josik Portier.

"Intercalative nanohybrids of nucleoside monophosphates and DNA in layered

metal hydroxide." Journal of the American Chemical Society 121, no. 6 (1999):

1399-1400.

Chou, Tz-Chong, Earl Fu, and E. Shen. "Chitosan inhibits prostaglandin E2 formation

and cyclooxygenase-2 induction in lipopolysaccharide-treated RAW 264.7

macrophages." Biochemical and biophysical research communications 308, no.

2 (2003): 403-407.

Cipolletta, Daniela, Markus Feuerer, Amy Li, Nozomu Kamei, Jongsoon Lee, Steven E.

Shoelson, Christophe Benoist, and Diane Mathis. "PPAR-[ggr] is a major driver

of the accumulation and phenotype of adipose tissue Treg cells." Nature(2012).

Clària, Joan, Ana González-Périz, Cristina López-Vicario, Bibiana Rius, and Esther

Titos. "New insights into the role of macrophages in adipose tissue inflammation

and fatty liver disease: modulation by endogenous omega-3 fatty acid-derived

lipid mediators." Frontiers in immunology2 (2011).

Cook, John A., David Gius, David A. Wink, Murali C. Krishna, Angelo Russo, and

James B. Mitchell. "Oxidative stress, redox, and the tumor

microenvironment."In Seminars in radiation oncology, vol. 14, no. 3, (2004) pp.

259-266.

WB Saunders, Compare, Debora, and Gerardo Nardone. "The bacteria-hypothesis of

colorectal cancer: pathogenetic and therapeutic implications." Translational

Gastrointestinal Cancer 3, no. 1 (2013): 44-53.

Copray, J. C. V. M., I. Mantingh, N. Brouwer, K. Biber, B. M. Küst, R. S. B. Liem, I.

Huitinga, F. J. H. Tilders, A-M. Van Dam, and H. W. G. M. Boddeke.

"Expression of interleukin-1 beta in rat dorsal root ganglia."Journal of

neuroimmunology 118, no. 2 (2001): 203-211.

Cursino, Ana Cristina Trindade, José Eduardo Ferreira da Costa Gardolinski, and

Fernando Wypych. "Intercalation of anionic organic ultraviolet ray absorbers

into layered zinc hydroxide nitrate." Journal of colloid and interface science

347, no. 1 (2010): 49-55.

Dalli, Jesmond, and Charles N. Serhan. "Specific lipid mediator signatures of human

phagocytes: microparticles stimulate macrophage efferocytosis and pro-

resolving mediators." Blood 120, no. 15 (2012): 60-72.

© COPYRIG

HT UPM

56

De Oliveira Niero, E. L. and G. M. Machado-Santelli (2013). "Cinnamic acid induces

apoptotic cell death and cytoskeleton disruption in human melanoma cells."

Journal of experimental & clinical cancer research: 32, no 1(2013): 31-38.

De Santa, Francesca, Vipin Narang, Zhei Hwee Yap, Betsabeh Khoramian Tusi,

Thomas Burgold, Liv Austenaa et al. "Jmjd3 contributes to the control of gene

expression in LPS‐activated macrophages." The EMBO journal 28, no. 21

(2009): 3341-3352.

De Visser, Karin E., Alexandra Eichten, and Lisa M. Coussens. "Paradoxical roles of

the immune system during cancer development."Nature reviews cancer 6, no. 1

(2006): 24-37.

De Vries, R. P., B. Michelsen, C. H. Poulsen, P. A. Kroon, R. H. Van Den Heuvel, C.

B. Faulds, G. Williamson, J. P. Van Den Hombergh, and J. Visser. "The faeA

genes from Aspergillus niger and Aspergillus tubingensis encode ferulic acid

esterases involved in degradation of complex cell wall polysaccharides." Applied

and environmental microbiology 63, no. 12 (1997): 4638-4644.

Dekker, Mark J., SoJung Lee, Robert Hudson, Katherine Kilpatrick, Terry E. Graham,

Robert Ross, and Lindsay E. Robinson. "An exercise intervention without

weight loss decreases circulating interleukin-6 in lean and obese men with and

without type 2 diabetes mellitus." Metabolism 56, no. 3 (2007): 332-338.

Dinarello, C. A. "Reduction of inflammation by decreasing production of interleukin-1

or by specific receptor antagonism." International journal of tissue reactions 14,

no. 2 (1991): 65-75.

Dinarello, Charles A. "Biologic basis for interleukin-1 in disease." Blood 87, no. 6

(1996): 2095-2147.

Dobson, J. (2006). "Gene therapy progress and prospects: magnetic nanoparticle-based

gene delivery." Gene therapy 13(4): 283-287.

Dubois, Raymond N., Steven B. Abramson, Leslie Crofford, Rajnish A. Gupta, Lee S.

Simon, Leo BA Van De Putte, and Peter E. Lipsky. "Cyclooxygenase in biology

and disease."The FASEB journal 12, no. 12 (1998): 1063-1073.

Dugoua, Jean-Jacques, Dugald Seely, Dan Perri, Kieran Cooley, Taryn Forelli, Edward

Mills et al "From type 2 diabetes to antioxidant activity: a systematic review of

the safety and efficacy of common and cassia cinnamon bark This article is one

of a selection of papers published in this special issue (part 1 of 2) on the Safety

and Efficacy of Natural Health Products." Canadian journal of physiology and

pharmacology 85, no. 9 (2007): 837-847.

© COPYRIG

HT UPM

57

Ekmekcioglu, Suhendan, Julie A. Ellerhorst, Victor G. Prieto, Marcella M. Johnson,

Lyle D. Broemeling, and Elizabeth A. Grimm. "Tumor iNOS predicts poor

survival for stage III melanoma patients." International journal of cancer 119, no.

4 (2006): 861-866.

Ekmekcioglu, Suhendan, Julie Ellerhorst, Christine M. Smid, Victor G. Prieto, Mark

Munsell, Antonio C. Buzaid, and Elizabeth A. Grimm. "Inducible nitric oxide

synthase and nitrotyrosine in human metastatic melanoma tumors correlate with

poor survival." Clinical Cancer Research 6, no. 12 (2000): 4768-4775.

Emerich, Dwaine F., and Christopher G. Thanos."Targeted nanoparticle-based drug

delivery and diagnosis."Journal of drug targeting 15, no. 3 (2007): 163-183.

Escoubet-Lozach, Laure, Christopher Benner, Minna U. Kaikkonen, Jean Lozach, Sven

Heinz, Nathan J. Spann, Andrea Crotti et al. "Mechanisms establishing TLR4-

responsive activation states of inflammatory response genes." PLoS genetics 7, no.

12 (2011): e1002401.

Esposito, Emanuela, and Salvatore Cuzzocrea."The role of nitric oxide synthases in

lung inflammation."Current opinion in investigational drugs (London, England:

2000) 8, no. 11 (2007): 899-909.

Farrell, Adrian J., David R. Blake, R. M. Palmer, and S. Moncada. "Increased

concentrations of nitrite in synovial fluid and serum samples suggest increased

nitric oxide synthesis in rheumatic diseases." Annals of the rheumatic diseases 51,

no. 11 (1992): 1219-1222.

Feghali, C. A., K. L. Bost, D. W. Boulware, and L. S. Levy. "Mechanisms of

pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts

cultured from affected skin sites of patients with scleroderma." The Journal of

rheumatology 19, no. 8 (1992): 1207-1211.

Ferdinandy, Peter, and Richard Schulz."Nitric oxide, superoxide, and peroxynitrite in

myocardial ischaemia‐reperfusion injury and preconditioning."British journal of

pharmacology 138, no. 4 (2003): 532-543.

Ferrari, Mauro. "Cancer nanotechnology: opportunities and challenges." Nature

Reviews Cancer 5, no. 3 (2005): 161-171.

Ferrari, R. "The role of TNF in cardiovascular disease."Pharmacological research 40,

no. 2 (1999): 97-105.

Feynman, Richard. "The man who dared to think small."Science 254, no. 29 (1991): 1.

Fialkow, Lea, Yingchun Wang, and Gregory P. Downey."Reactive oxygen and nitrogen

species as signaling molecules regulating neutrophil function."Free Radical

Biology and Medicine 42, no. 2 (2007): 153-164.

© COPYRIG

HT UPM

58

Filippi, C. M., and M. G. Von Herrath."IL‐10 and the resolution of infections."The

Journal of pathology 214, no. 2 (2008): 224-230.

Fletcher, Gerald F., Gary Balady, Steven N. Blair, James Blumenthal, Carl Caspersen,

Bernard Chaitman, Stephen Epstein et al. "Statement on Exercise: Benefits and

Recommendations for Physical Activity Programs for All Americans A Statement

for Health Professionals by the Committee on Exercise and Cardiac Rehabilitation

of the Council on Clinical Cardiology, American Heart Association." Circulation

94, no. 4 (1996): 857-862.

Foti, Mario C., Carmelo Daquino, and Corrada Geraci."Electron-transfer reaction of

cinnamic acids and their methyl esters with the DPPH radical in alcoholic

solutions."The Journal of organic chemistry 69, no. 7 (2004): 2309-2314.

Fujiwara, Nagatoshi, and Kazuo Kobayashi."Macrophages in inflammation."Current

Drug Targets-Inflammation & Allergy 4, no. 3 (2005): 281-286.

Funk, C. D. "Prostaglandins and leukotrienes: advances in eicosanoid biology."

Science 294 no. 5548 (2001): 1871-1875.

Gabay, Cem. "Interleukin-6 and chronic inflammation."Arthritis research and therapy

8, no. 2 (2006): S3.

Gabriel Heaney, Liam, John Thomas Lindsay, and Lorcan Patrick Augustine

McGarvey. "Inflammation in chronic obstructive pulmonary disease:

implications for new treatment strategies." Current medicinal chemistry 14, no.

7 (2007): 787-796.

Garrait, Ghislain, Jean-François Jarrige, Stéphanie Blanquet, Erick Beyssac, Jean-

Michel Cardot, and Monique Alric. "Gastrointestinal absorption and urinary

excretion of trans-cinnamic and p-coumaric acids in rats."Journal of agricultural

and food chemistry 54, no. 8 (2006): 2944-2950.

Goodman, Julie E., Lorne J. Hofseth, S. Perwez Hussain, and Curtis C. Harris. "Nitric

oxide and p53 in cancer‐prone chronic inflammation and oxyradical overload

disease." Environmental and molecular mutagenesis 44, no. 1 (2004): 3-9.

Graf, Ernst. "Antioxidant potential of ferulic acid."Free Radical Biology and Medicine

13, no. 4 (1992): 435-448.

Groneberg, David A., Michael Giersig, Tobias Welte, and Ulrich Pison."Nanoparticle-

based diagnosis and therapy."Current drug targets 7, no. 6 (2006): 643-648.

Grover, J. K., S. Yadav, and V. Vats. "Medicinal plants of India with anti-diabetic

potential." Journal of ethnopharmacology 81, no. 1 (2002): 81-100.

© COPYRIG

HT UPM

59

Guardia, Teresita, Alejandra Ester Rotelli, Américo Osvaldo Juarez, and Lilian

Eugenia Pelzer. "Anti-inflammatory properties of plant flavonoids. Effects of

rutin, quercetin and hesperidin on adjuvant arthritis in rat." Il farmaco 56, no. 9

(2001): 683-687.

Gupta, M., U. K. Mazumder, P. Gomathi, and V. Thamil Selvan. "Antiinflammatory

evaluation of leaves of Plumeria acuminata." BMC Complementary and

alternative medicine 6, no. 1 (2006): 36-44.

Hagemann, Thorsten, Toby Lawrence, Iain McNeish, Kellie A. Charles, Hagen Kulbe,

Richard G. Thompson et al "“Re-educating” tumor-associated macrophages by

targeting NF-κB." The Journal of experimental medicine 205, no. 6 (2008):

1261-1268.

Hargreaves, Diana C., Tiffany Horng, and Ruslan Medzhitov."Control of inducible

gene expression by signal-dependent transcriptional elongation."Cell 138, no. 1

(2009): 129-145.

He, Zhen-Dan, Chun-Feng Qiao, Quan-Bin Han, Chuen-Lung Cheng, Hong-Xi Xu,

Ren-Wang Jiang, Paul Pui-Hay But, and Pang-Chui Shaw. "Authentication and

quantitative analysis on the chemical profile of cassia bark (cortex cinnamomi)

by high-pressure liquid chromatography."Journal of agricultural and food

chemistry 53, no. 7 (2005): 2424-2428.

Henriksen, P. A., and D. E. Newby. "Therapeutic inhibition of tumour necrosis factor α

in patients with heart failure: cooling an inflamed heart." Heart 89, no. 1 (2003):

14-18.

Higashimoto, Yuji, Yuko Yamagata, Satoshi Taya, Takuya Iwata, Morihiro Okada,

Tadashi Ishiguchi et al "Systemic inflammation in chronic obstructive

pulmonary disease and asthma: Similarities and differences." Respirology 13,

no. 1 (2008): 128-133.

Hirano, T. "The Biology of Interleukin-6 (Part 1 of 2)." (2010): 153-166.

Hirano, Toshio, Tetsuya Taga, Tadashi Matsuda, Masahiko Hibi, Sachiko Suematsu, Bo

Tang, et al "Interleukin 6 and its receptor in the immune response and

hematopoiesis." The International Journal of Cell Cloning 8, no. S1 (1990):

155-167.

Hirano, Toshio. "Interleukin-6 and its relation to inflammation and disease."Clinical

immunology and immunopathology 62, no. 1 (1992): S60-S65.

Hirota, Hisao, Hiroshi Kiyama, Tadamitsu Kishimoto, and Tetsuya Taga."Accelerated

Nerve Regeneration in Mice by upregulated expression of interleukin (IL) 6 and

IL-6 receptor after trauma."The Journal of experimental medicine 183, no. 6

(1996): 2627-2634.

© COPYRIG

HT UPM

60

Hoentjen, Frank, R. Balfour Sartor, Michitaka Ozaki, and Christian Jobin. "STAT3

regulates NF-κB recruitment to the IL-12p40 promoter in dendritic cells." Blood

105, no. 2 (2005): 689-696.

Hoffman, Ilse, Séverine Vermeire, Gert Van Assche, and Paul Rutgeerts."Infliximab for

pediatric Crohn's disease."Drugs of today (Barcelona, Spain: 1998) 44, no. 8

(2008): 615-628.

Hong, Chae Hee, Sun Kyung Hur, O-Jin Oh, Sun Sook Kim, Kyung Nam, and Sang

Kook Lee. "Evaluation of natural products on inhibition of inducible

cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse

macrophage cells."Journal of Ethnopharmacology 83, no. 1 (2002): 153-159.

Hoskins, John A. "The occurrence, metabolism and toxicity of cinnamic acid and

related compounds."Journal of applied toxicology 4, no. 6 (1984): 283-292.

Hotamisligil, G. S. "The role of TNFα and TNF receptors in obesity and insulin

resistance." Journal of internal medicine 245, no. 6 (1999): 621-625.

Hotamisligil, Gökhan S. "Inflammation and metabolic disorders."Nature 444, no. 7121

(2006): 860-867.

Howe, L. R., K. Subbaramaiah, A. M. Brown, and A. J. Dannenberg. "Cyclooxygenase-

2: a target for the prevention and treatment of breast cancer." Endocrine-related cancer

8, no. 2 (2001): 97-114.

Huang, Da-Wei, and Szu-Chuan Shen. "Caffeic acid and cinnamic acid ameliorate

glucose metabolism via modulating glycogenesis and gluconeogenesis in

insulin-resistant mouse hepatocytes." Journal of Functional Foods 4, no. 1

(2012): 358-366.

Huang, Qingrong, Hailong Yu, and Qiaomei Ru."Bioavailability and delivery of

nutraceuticals using nanotechnology." Journal of Food Science 75, no. 1 (2010):

R50-R57.

Hussein, Mohd Zobir, Samer Hasan Al Ali, Zulkarnain Zainal, and Muhammad Nazrul

Hakim. "Development of antiproliferative nanohybrid compound with controlled

release property using ellagic acid as the active agent." International journal of

nanomedicine 6 (2011): 1373.

Hussein, H., H. Hussain, M. S. Salbiah, O. Muhaini, Y. L. Low, and P. K. Beh. "| use

of drugs for rheumatological and bone disorders." Malaysian statistics on

medicines 2007 (2007): 109.

Hwang, Sung-Ho, Yang-Su Han, and Jin-Ho Choy. "Intercalation of functional organic

molecules with pharmaceutical, cosmeceutical and neutraceutical functions into

layered double hydroxides and zinc basic salts." Bulletin-Korean Chemical

Society 22, no. 9 (2001): 1019-1022..

© COPYRIG

HT UPM

61

I kappa B: a specific inhibitor of the NF-kappa B transcription factor Barbe, C., J.

Bartlett, et al. (2004). "Silica Particles: A Novel Drug‐Delivery System."

Advanced Materials 16(21): 1959-1966.

Jeanjean, A. P., S. M. Moussaoui, J-M.Maloteaux, and P. M. Laduron. "Interleukin-1β

induces long-term increase of axonally transported opiate receptors and

substance P." Neuroscience 68, no. 1 (1995): 151-157.

Jeffrey, J. E. and R. M. Aspden. "Cyclooxygenase inhibition lowers prostaglandin E."

Arthritis research & therapy no. 9 (2007): R129.

Jung, Kyung Hee, Eunyoung Ha, Mi Ja Kim, Hye-Jin Won, Long Tai Zheng, Hye

Kyung Kim, Seung Jae Hong, Joo Ho Chung, and Sung-Vin Yim. "Suppressive

effects of nitric oxide (NO) production and inducible nitric oxide synthase

(iNOS) expression by< i> Citrus reticulata</i> extract in RAW 264.7

macrophage cells." Food and chemical toxicology 45, no. 8 (2007): 1545-1550.

Juskewitch, Justin E., Jeffrey L. Platt, Bruce E. Knudsen, Keith L. Knutson, Gregory J.

Brunn, and Joseph P. Grande. "Disparate roles of marrow-and parenchymal cell-

derived TLR4 signaling in murine LPS-induced systemic

inflammation."Scientific reports 2 (2012).

Kanaani, J. A. M. I. L., and H. A. G. A. I. Ginsburg."Effects of cinnamic acid

derivatives on in vitro growth of Plasmodium falciparum and on the

permeability of the membrane of malaria-infected erythrocytes."Antimicrobial

agents and chemotherapy 36, no. 5 (1992): 1102-1108.

Kang, Sang-Rim, Dae-Yong Han, Kwang-Il Park, Hyeon-Soo Park, Yong-Bae Cho,

Hu-Jang Lee, Won-Sup Lee et al. "Suppressive Effect on Lipopolysaccharide-

Induced Proinflammatory Mediators by Citrus aurantium L. in Macrophage

RAW 264.7 Cells via NF-𝜅 B Signal Pathway." Evidence-Based

Complementary and Alternative Medicine 2011 (2010).

Kang, Young Soo, Subhash Risbud, John F. Rabolt, and Pieter Stroeve."Synthesis and

characterization of nanometer-size Fe3O4 and γ-Fe2O3 particles."Chemistry of

Materials 8, no. 9 (1996): 2209-2211.

Kasetti, Ramesh Babu, Shaik Abdul Nabi, Sirasangandla Swapna, and Chippada

Apparao."Cinnamic acid as one of the antidiabetic active principle (s) from the

seeds of Syzygium alternifolium."Food and Chemical Toxicology 50, no. 5

(2012): 1425-1431.

Kasuga, Kie, Rong Yang, Timothy F. Porter, Nitin Agrawal, Nicos A. Petasis, Daniel

Irimia et al "Rapid appearance of resolvin precursors in inflammatory exudates:

novel mechanisms in resolution." The Journal of Immunology 181, no. 12

(2008): 8677-8687.

© COPYRIG

HT UPM

62

Kawanishi, Noriaki, Hiromi Yano, Yuka Yokogawa, and Katsuhiko Suzuki. "Exercise

training inhibits inflammation in adipose tissue via both suppression of

macrophage infiltration and acceleration of phenotypic switching from M1 to

M2 macrophages in high-fat-diet-induced obese mice." Exercise immunology

review16 (2010).

Kawasaki, Ernest S., and Audrey Player."Nanotechnology, nanomedicine, and the

development of new, effective therapies for cancer."Nanomedicine:

Nanotechnology, Biology and Medicine 1, no. 2 (2005): 101-109.

Keystone, Edward C. "Tumor necrosis factor-α blockade in the treatment of

rheumatoid arthritis."Rheumatic Disease Clinics of North America 27, no. 2

(2001): 427-443.

Kim, Hee Kee, Bong Sun Cheon, Young Ha Kim, Sung Yong Kim, and Hyun Pyo

Kim.

"Effects of naturally occurring flavonoids on nitric oxide production in the macrophage

cell line RAW 264.7 and their structure–activity relationships." Biochemical

pharmacology 58, no. 5 (1999): 759-765.

Kim, I. D. and B. J. Ha (2009). "Paeoniflorin protects RAW 264.7 macrophages from

LPS-induced cytotoxicity and genotoxicity." Toxicology in Vitro 23(6): 1014-

1019

Kim, Hee Kee, Bong Sun Cheon, Young Ha Kim, Sung Yong Kim, and Hyun Pyo

Kim. "Effects of naturally occurring flavonoids on nitric oxide production in the

macrophage cell line RAW 264.7 and their structure–activity

relationships."Biochemical pharmacology 58, no. 5 (1999): 759-765.

Kim, Jong-Bin, Ah-Reum Han, Eun-Young Park, Ji-Yeon Kim, Woong Cho, Jun Lee,

Eun-Kyoung Seo, and Kyung-Tae Lee."Inhibition of LPS-Induced iNOS, COX-

2 and Cytokines Expression by Poncirin through the NF-.KAPPA.B Inactivation

in RAW 264.7 Macrophage Cells."Biological and Pharmaceutical Bulletin 30,

no. 12 (2007): 2345-2351.

Kleinert, H., A. Pautz, et al. (2004). "Regulation of the expression of inducible nitric

oxide synthase."European journal of pharmacology 500(1): 255-266.

Knowles, Richard G., and Salvador Moncada.Nitric oxide synthases in

mammals.Biochemical Society, 1994.

Kong, Yeon Hee, Youn Ock Jo, Chang-Won Cho, Dongwook Son, Soojin Park,

Jeonghae Rho et al. “Inhibitory effects of cinnamic acid on melanin biosynthesis

in skin.”Biological & pharmaceutical bulletin 31, no. 5 (2008): 946-948..

© COPYRIG

HT UPM

63

Koo, Otilia M., Israel Rubinstein, and Hayat Onyuksel. "Role of nanotechnology in

targeted drug delivery and imaging: a concise review." Nanomedicine:

Nanotechnology, Biology and Medicine 1, no. 3 (2005): 193-212.

Kubes, P., M. Suzuki, and D. N. Granger. "Nitric oxide: an endogenous modulator of

leukocyte adhesion." Proceedings of the National Academy of Sciences 88, no.

11 (1991): 4651-4655.

Kukowska-Latallo, Jolanta F., Kimberly A. Candido, Zhengyi Cao, Shraddha S.

Nigavekar, Istvan J. Majoros, Thommey P. Thomas et al "Nanoparticle targeting

of anticancer drug improves therapeutic response in animal model of human

epithelial cancer." Cancer research 65, no. 12 (2005): 5317-5324.

Kumar, Himanshu, Taro Kawai, and Shizuo Akira."Pathogen recognition by the innate

immune system."International reviews of immunology 30, no. 1 (2011): 16-34.

Kumar, V., A. K. Abbas, N. Fausto, R. Mitchell, and Robbins Basic Pathology.

"Saunders." (2003).

Kupferminc, M. J., A. M. Peaceman, et al"Tumor necrosis factor-α is elevated in

plasma and amniotic fluid of patients with severe preeclampsia." American

journal of obstetrics and gynecology 170 no.6 (1994): 1752-1759.

Kurumbail, Ravi G., Anna M. Stevens, James K. Gierse, Joseph J. McDonald,

Roderick A. Stegeman, Jina Y. Pak et al. "Structural basis for selective

inhibition of cyclooxygenase-2 by anti-inflammatory agents." Nature 384, no.

6610 (1996): 644-648.

Langenbach, Robert, Charles Loftin, Christopher Lee, and Howard Tiano.

"Cyclooxygenase knockout mice: models for elucidating isoform-specific

functions." Biochemical pharmacology 58, no. 8 (1999): 1237-1246.

Leak, Jessica A. "Herbal medicine: is it an alternative or an unknown? A brief review

of popular herbals used by patients in a pain and symptom management practice

setting."Current review of pain 3, no. 3 (1999): 226-236.

Lebovic, Dan I., Frauke Bentzien, Victor A. Chao, Evelyn N. Garrett, Y. Gloria Meng,

and Robert N. Taylor. "Induction of an angiogenic phenotype in endometriotic

stromal cell cultures by interleukin-1β." Molecular human reproduction 6, no. 3

(2000): 269-275.

Lee, A., M. G. Cooper, et al. "Effects of nonsteroidal anti-inflammatory drugs on

postoperative renal function in adults with normal renal function." Cochrane

Database Syst Rev 2. Art. No.: CD002765.(2007) DOI: 10.1002/ 14651858.

CD002765. pub3.

© COPYRIG

HT UPM

64

Lee, H.-S."Tyrosinase inhibitors of Pulsatilla cernua root-derived materials."Journal of

agricultural and food chemistry 50(6): (2002) 1400-1403.

Lee, Seung Ho, Sun Young Lee, Dong Ju Son, Heesoon Lee, Hwan Soo Yoo, Sukgil

Song, Ki Wan Oh, Dong Cho Han, Byoung Mog Kwon, and Jin Tae Hong.

"Inhibitory effect of 2′-hydroxycinnamaldehyde on nitric oxide production

through inhibition of NF-κB activation in RAW 264.7 cells."Biochemical

pharmacology 69, no. 5 (2005): 791-799.

Levesque, Marc C., Youwei Chen, Bethany E. Beasley, Charles W. O’Loughlin, Jon P.

Gockerman, Joseph O. Moore et al "Chronic lymphocytic leukemia cell CD38

expression and inducible nitric oxide synthase expression are associated with

serum IL-4 levels." Leukemia research 30, no. 1 (2006): 24-28.

Levy, Bruce D., Clary B. Clish, Birgitta Schmidt, Karsten Gronert, and Charles N.

Serhan. "Lipid mediator class switching during acute inflame

mation: signals in resolution." Nature immunology 2, no. 7 (2001): 612-619.

Liao, Jung-Chun, Jeng-Shyan Deng, Chuan-Sung Chiu, Wen-Chi Hou, Shyh-Shyun

Huang, Pei-Hsin Shie et al "Anti-inflammatory activities of Cinnamomum cassia

constituents in vitro and in vivo."Evidence-Based Complementary and

Alternative Medicine 2012 (2012).

Li, Fusu, Lan Jin, Jingbin Han, Min Wei, and Congju Li. "Synthesis and Controlled

Release Properties of Prednisone Intercalated Mg− Al Layered Double

Hydroxide Composite." Industrial & Engineering Chemistry Research 48, no.

12 (2009): 5590-5597.

Lin, W.-W.and M. Karin "A cytokine-mediated link between innate immunity,

inflammation, and cancer." Journal of Clinical Investigation 1175(2007): 1175-

1183.

Lin, Yu-Li, and Jen-Kun Lin. "(−)-Epigallocatechin-3-gallate blocks the induction of

nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of

transcription factor nuclear factor-κB." Molecular Pharmacology 52, no. 3

(1997): 465-472.

Li, Long-Gang, and Hui-Mian Xu."Inducible nitric oxide synthase, nitrotyrosine and

apoptosis in gastric adenocarcinomas and their correlation with a poor

survival."World J Gastroenterol 11, no. 17 (2005): 2539-2544.

Lippross, Sebastian, Bjoern Moeller, Holger Haas, Mersedeh Tohidnezhad, Nadine

Steubesand, Christoph Jan Wruck, Bodo Kurz, Andreas Seekamp, Thomas Pufe,

and Deike Varoga. "Intraarticular injection of platelet‐rich plasma reduces

inflammation in a pig model of rheumatoid arthritis of the knee joint."Arthritis

& Rheumatism 63, no. 11 (2011): 3344-3353.

© COPYRIG

HT UPM

65

Liu, Lei, W. Robert Hudgins, Sonsoles Shack, Mu Quan Yin, and Dvorit Samid.

"Cinnamic acid: a natural product with potential use in cancer intervention."

International journal of cancer 62, no. 3 (1995): 345-350.

Liu, Xiong, James G. Worden, Qiu Dai, Jianhua Zou, Jinhai Wang, and Qun Huo.

"Monofunctional Gold Nanoparticles Prepared via a

Noncovalent‐Interaction‐Based Solid‐Phase Modification Approach." Small 2,

no. 10 (2006): 1126-1129.

Liu, Ying‐Mei, Shuenn‐Jyi Sheu, Shiow‐Hua Chiou, Hsien‐Chang Chang, and

Yuh‐Pan Chen."Capillary electrophoretic analyses of alkaloids in commercial

samples of Coptidis Rhizoma."Phytochemical Analysis 5, no. 5 (1994): 256-260.

Locksley, Richard M., Nigel Killeen, and Michael J. Lenardo."The TNF and TNF

receptor superfamilies-integrating mammalian biology."Cell 104, no. 4 (2001):

487-501.

Luo, Jun-Li, Shin Maeda, Li-Chung Hsu, Hideo Yagita, and Michael Karin. "Inhibition

of NF-κB in cancer cells converts inflammation-induced tumor growth mediated

by TNFα to TRAIL-mediated tumor regression." Cancer cell 6, no. 3 (2004):

297-305.

Lotito, A. P. N., M. N. Muscará, et al. (2004). "Nitric oxide-derived species in synovial

fluid from patients with juvenile idiopathic arthritis."The Journal of

rheumatology 31(5): 992-997.

MacKenzie, Simon, Josep V. Planas, and Frederick W. Goetz. "LPS-stimulated

expression of a tumor necrosis factor-alpha mRNA in primary trout monocytes

and in vitro differentiated macrophages." Developmental & Comparative

Immunology 27, no. 5 (2003): 393-400.

Maier, Steven F., Eric P. Wiertelak, David Martin, and Linda R. Watkins. "Interleukin-1

mediates the behavioral hyperalgesia produced by lithium chloride and

endotoxin." Brain research 623, no. 2 (1993): 321-324.

Mäki-Petäjä, K. M., J. Cheriyan, et al. (2008). "Inducible nitric oxide synthase activity

is increased in patients with rheumatoid arthritis and contributes to endothelial

dysfunction." International journal of cardiology 129(3): 399-405.

Migita, K., S. Yamasaki, et al. (2001)."The role of peroxynitrite in cyclooxygenase-2

expression of rheumatoid synovium."Clinical and experimental rheumatology

20(1): 59-62.

Mallat, Ziad, Sandrine Besnard, Micheline Duriez, Virginie Deleuze, Florence

Emmanuel, Michel F. Bureau et al. "Protective role of interleukin-10 in

atherosclerosis." Circulation research 85, no. 8 (1999): 17-24.

© COPYRIG

HT UPM

66

Marletta, Michael A. "Nitric oxide synthase: aspects concerning structure and

catalysis." Cell 78, no. 6 (1994): 927-930.

Masamoto, Yukimitsu, Yoshiyuki Murata, Kimiye Baba, Yasuaki Shimoishi, Mikiro

Tada, and Kyoya Takahata. "Inhibitory effects of esculetin on melanin

biosynthesis." Biological & pharmaceutical bulletin 27, no. 3 (2004): 422-430.

Matsumoto, Manabu, Mutsuo Furihata, Atsushi Kurabayashi, Keijiro Araki, Shiro

Sasaguri, and Yuji Ohtsuki."Association between inducible nitric oxide synthase

expression and p53 status in human esophageal squamous cell

carcinoma."Oncology 64, no. 1 (2002): 90-96.

McCartney-Francis, Nancy, Janice B. Allen, Diane E. Mizel, Jorge E. Albina, Q. W.

Xie, Carl F. Nathan, and Sharon M. Wahl. "Suppression of arthritis by an

inhibitor of nitric oxide synthase."The Journal of experimental medicine 178,

no. 2 (1993): 749-754.

Merisko-Liversidge, Elaine M., and Gary G. Liversidge. "Drug nanoparticles:

formulating poorly water-soluble compounds." Toxicologic pathology 36, no. 1

(2008): 43-48.

Mezei, Orsolya, William J. Banz, Richard W. Steger, Michael R. Peluso, Todd A.

Winters, and Neil Shay. "Soy isoflavones exert antidiabetic and hypolipidemic

effects through the PPAR pathways in obese Zucker rats and murine RAW

264.7 cells." The Journal of nutrition 133, no. 5 (2003): 1238-1243.

Milligan, Erin D., Evan M. Sloane, Stephen J. Langer, Pedro E. Cruz, Marucia Chacur,

Leah Spataro, Julie Wieseler-Frank et al. "Controlling neuropathic pain by

adeno-associated virus driven production of the anti-inflammatory cytokine,

interleukin-10." Mol Pain 1, no. 9 (2005).

Mira, Jean-Paul, Alain Cariou, Franck Grall, Christophe Delclaux, Marie-Reine Losser,

Fahrad Heshmati et al. "Association of TNF2, a TNF-α promoter polymorphism,

with septic shock susceptibility and mortality: a multicenter study." Jama 282,

no. 6 (1999): 561-568.

Mitchell, Jane A., and Timothy D. Warner. "Cyclo‐oxygenase‐2: pharmacology,

physiology, biochemistry and relevance to NSAID therapy." British journal of

pharmacology 128, no. 6 (1999): 1121-1132.

Mitchell, Jane A., Pravit Akarasereenont, Christoph Thiemermann, Roderick J. Flower,

and John R. Vane."Selectivity of nonsteroidal antiinflammatory drugs as

inhibitors of constitutive and inducible cyclooxygenase."Proceedings of the

National Academy of Sciences 90, no. 24 (1993): 11693-11697.

© COPYRIG

HT UPM

67

Mody, Vicky V., Rodney Siwale, Ajay Singh, and Hardik R. Mody."Introduction to

metallic nanoparticles."Journal of Pharmacy and Bioallied Sciences 2, no. 4

(2010): 282.

Mohsin, Sumaiyah Megat Nabil, Mohd Zobir Hussein, Siti Halimah Sarijo, Sharida

Fakurazi, Palanisamy Arulselvan, and Taufiq-Yap Yun Hin. "Synthesis of

(cinnamate-zinc layered hydroxide) intercalation compound for sunscreen

application."Chemistry Central Journal 7, no. 1 (2013): 1-12.

Mollace, Vincenzo, Carolina Muscoli, Emanuela Masini, Salvatore Cuzzocrea, and

Daniela Salvemini."Modulation of prostaglandin biosynthesis by nitric oxide

and nitric oxide donors."Pharmacological reviews 57, no. 2 (2005): 217-252.

Moncada, Salvador, Sergio H. Ferreira, and John R. Vane."Inhibition of prostaglandin

biosynthesis as the mechanism of analgesia of aspirin-like drugs in the dog knee

joint."European journal of pharmacology 31, no. 2 (1975): 250-260.

Moore, Kevin W., Rene de Waal Malefyt, Robert L. Coffman, and Anne O'Garra.

"Interleukin-10 and the interleukin-10 receptor."Annual review of immunology

19, no. 1 (2001): 683-765.

Mosmann, Tim R., and Kevin W. Moore.“ The role of IL-10 in crossregulation of TH1

and TH2 responses” Parasitology Today 7, no. 3 (1991): 49-53.

Mosser, David M., and Justin P. Edwards."Exploring the full spectrum of macrophage

activation."Nature Reviews Immunology 8, no. 12 (2008): 958-969.

Mulligan, Michael S., Joan M. Hevel, Michael A. Marletta, and Peter A. Ward. "Tissue

injury caused by deposition of immune complexes is L-arginine dependent."

Proceedings of the National Academy of Sciences 88, no. 14 (1991): 6338-6342.

Mungrue, Imran N., Robert Gros, Xiaomang You, Asif Pirani, Azar Azad, Tamas

Csont, Richard Schulz, Jagdish Butany, Duncan J. Stewart, and Mansoor

Husain. "Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite

generation, heart block, and sudden death." Journal of Clinical Investigation

109, no. 6 (2002): 735-743.

Munin, Aude, and Florence Edwards-Lévy."Encapsulation of natural polyphenolic

compounds; a review."Pharmaceutics 3, no. 4 (2011): 793-829.

Murakami, Akira, and Hajime Ohigashi."Targeting NOX, INOS and COX‐2 in

inflammatory cells: Chemoprevention using food phytochemicals."International

journal of cancer 121, no. 11 (2007): 2357-2363.

Mylonas, Katie J., Meera G. Nair, Lidia Prieto-Lafuente, Daniel Paape, and Judith E.

Allen. "Alternatively activated macrophages elicited by helminth infection can

© COPYRIG

HT UPM

68

be reprogrammed to enable microbial killing." The Journal of immunology 182,

no. 5 (2009): 3084-3094.

Nagai, Yoshinori, Sachiko Akashi, Masakazu Nagafuku, Masato Ogata, Yoichiro

Iwakura, Shizuo Akira,et al "Essential role of MD-2 in LPS responsiveness and

TLR4 distribution." Nature immunology 3, no. 7 (2002): 667-672.

Nahrevanian, H. "Involvement of nitric oxide and its up/down stream molecules in the

immunity against parasitic infections." Brazilian Journal of Infectious Diseases

13 no. 6 (2009): 440-448.

Nakagawa, T., and T. Yokozawa."Direct scavenging of nitric oxide and superoxide by

green tea."Food and Chemical Toxicology 40, no. 12 (2002): 1745-1750.

Nanjundaiah, Siddaraju M., Harish Nayaka Mysore Annaiah, and Shylaja M.

Dharmesh. "Gastroprotective effect of ginger rhizome (Zingiber officinale)

extract: role of Gallic acid and Cinnamic acid in H+, K+-ATPase/H. pylori

inhibition and anti-oxidative mechanism." Evidence Based Complementary and

AlternativeMedicine 2011 (2009): 27-34.

Nathan, Carl, and Aihao Ding."Nonresolving inflammation."Cell 140, no. 6 (2010):

871-882.

Nathan, Carl. "Points of control in inflammation."Nature 420, no. 6917 (2002): 846-

852.

Ng, Lean-Teik, and Shu-Jing Wu."Antiproliferative activity of cinnamomum cassia

constituents and effects of pifithrin-alpha on their apoptotic signaling pathways

in Hep G2 Cells."Evidence-Based Complementary and Alternative Medicine

2011 (2011) Article ID 492148, 6 pages

O’Farrell, Norah, Andrew Houlton, and Benjamin R. Horrocks. "Silicon nanoparticles:

applications in cell biology and medicine." International journal of

Nanomedicine 1, no. 4 (2006): 451.

Odegaard, Justin I., Roberto R. Ricardo-Gonzalez, Matthew H. Goforth, Christine R.

Morel, Vidya Subramanian, Lata Mukundanet al. "Macrophage-specific

PPAR&ggr; controls alternative activation and improves insulin resistance."

Nature 447, no. 7148 (2007): 1116-1120.

Omar Alvarado, Thomas J. Fellers and Michael W. Davidson - National High Magnetic

Field Laboratory, 1800 East Paul Dirac Dr., The Florida State University,

Tallahassee, Florida, 32310.

© COPYRIG

HT UPM

69

Orive, Gorka, Eduardo Anitua, José Luis Pedraz, and Dwaine F. Emerich. "Biomaterials

for promoting brain protection, repair and regeneration." Nature Reviews

Neuroscience 10, no. 9 (2009): 682-692.

Orucevic, Amila, Stephen Hearn, and Peeyush K. Lala."The role of active inducible

nitric oxide synthase expression in the pathogenesis of capillary leak syndrome

resulting from interleukin-2 therapy in mice."Laboratory investigation; a

journal of technical methods and pathology 76, no. 1 (1997): 53-65.

O'Sullivan, Brendan, Angus Thompson, and Ranjeny Thomas."NF-κB as a therapeutic

target in autoimmune disease."Expert Opinion on Therapeutic Targets, 11, no. 2

(2007) : 111-122

Özer, Ö., Başak Mutlu, and Sevim Tömek. "Development and in vitro evaluation of

topically applied cinnamic acid formulations." Die Pharmazie-An International

Journal of Pharmaceutical Sciences 62, no. 2 (2007): 138-144.

Ozkan, Mihrimah. "Quantum dots and other nanoparticles: what can they offer to drug

discovery?" Drug Discovery Today 9, no. 24 (2004): 1065-1071.

Pahl, Heike L. "Activators and target genes of Rel/NF-kappaB transcription factors."

Oncogene 18, no. 49 (1999): 6853-6866.

Pankhurst, Quentin A., J. Connolly, S. K. Jones, and J. Dobson."Applications of

magnetic nanoparticles in biomedicine."Journal of physics D: Applied physics

36, no. 13 (2003): R167.

Park, Ji-Won, Ok-Kyoung Kwon, Ha-young Jang, Hyeok Jeong, Sei-Ryang Oh,

Hyeong-Kyu Lee, Sang-Bae Han, and Kyung-Seop Ahn. "A leaf methanolic

extract of Wercklea insignis attenuates the lipopolysaccharide-induced

inflammatory response by blocking the NF-κB signaling pathway in RAW 264.7

macrophages." Inflammation 35, no. 1 (2012): 321-331.

Park, Man, Chang-Il Lee, Young Jin Seo, Sang Ryung Woo, Dongill Shin, and Jyung

Choi. "Hybridization of the natural antibiotic, cinnamic acid, with layered

double hydroxides (LDH) as green pesticide."Environmental Science and

Pollution Research 17, no. 1 (2010): 203-209.

Patra, Kartick, Samadrita Bose, Shehnaz Sarkar, Jyotirmoy Rakshit, Samarjit Jana, Avik

Mukherjee et al "Amelioration of cyclophosphamide induced myelosuppression

and oxidative stress by cinnamic acid." Chemico-biological interactions 195, no.

3 (2012): 231-239.

Pelletier, Jean-Pierre, V. Lascau-Coman, D. Jovanovic, J. C. Fernandes, P. Manning, J.

R. Connor et al "Selective inhibition of inducible nitric oxide synthase in

© COPYRIG

HT UPM

70

experimental osteoarthritis is associated with reduction in tissue levels of

catabolic factors." The Journal of rheumatology 26, no. 9 (1999): 2002-2014.

Philip, Mary, Donald A. Rowley, and Hans Schreiber."Inflammation as a tumor

promoter in cancer induction."In Seminars in cancer biology,Academic Press

vol. 14, no. 6(2004): 433-439.

Pilichos, Charalambos J., Ilias A. Kouerinis, George C. Zografos, Dimiris P. Korkolis,

Athena A. Preza, Maria Gazouli, Evangelos I. Menenakos et al. "The effect of

nitric oxide synthases inhibitors on inflammatory bowel disease in a rat model."

in vivo 18, no. 4 (2004): 513-516.

Poole, Charles P., and Frank J. Owens."Introduction to nanotechnology."Cambridge

University Press Vol. 30, no 5 (2003): 165-184.

Popov, Andrei M., Yurii E. Lozovik, Silvana Fiorito, and L’Hocine

Yahia."Biocompatibility and applications of carbon nanotubes in medical

nanorobots."International journal of nanomedicine 2, no. 3 (2007): 361.

Ramanan, P. N., and M. N. Rao."Antimicrobial activity of cinnamic acid

derivatives."Indian Journal of Experimental Biology 25 no1 (1987): 42-3

Rao, Chinthalapally V., Dhimant Desai, Barbara Simi, Nalini Kulkarni, Shantu Amin,

and Bandaru S. Reddy. "Inhibitory effect of caffeic acid esters on

azoxymethane-induced biochemical changes and aberrant crypt foci formation

in rat colon."Cancer research 53, no. 18 (1993): 4182-4188.

Rawat, Manju, Deependra Singh, S. Saraf, and Swarnlata Saraf. "Nanocarriers:

promising vehicle for bioactive drugs." Biological and Pharmaceutical Bulletin

29, no. 9 (2006): 1790.

Ricciotti, E. and G. A. FitzGerald (2011)."Prostaglandins and

inflammation."Arteriosclerosis, thrombosis, and vascular biology 31(5): 986-

1000.

Ridker, Paul M., Nader Rifai, Meir J. Stampfer, and Charles H. Hennekens."Plasma

concentration of interleukin-6 and the risk of future myocardial infarction

among apparently healthy men."Circulation 101, no. 15 (2000): 1767-1772.

Roca, Francisco J., Iván Mulero, Azucena López-Muñoz, Maria P. Sepulcre, Stephen A.

Renshaw, José Meseguer et al. "Evolution of the inflammatory response in

vertebrates: Fish TNF-α is a powerful activator of endothelial cells but hardly

activates phagocytes." The Journal of Immunology 181, no. 7 (2008): 5071-

5081.

Ross, Russell. "Atherosclerosis—an inflammatory disease."New England journal of

medicine 340, no. 2 (1999): 115-126.

© COPYRIG

HT UPM

71

Rudge, S., C. Peterson, C. Vessely, J. Koda, S. Stevens, and L. Catterall. "Adsorption

and desorption of chemotherapeutic drugs from a magnetically targeted carrier

(MTC)." Journal of Controlled Release 74, no. 1 (2001): 335-340.

Rutschman, Robert, Roland Lang, Matthias Hesse, James N. Ihle, Thomas A. Wynn,

and Peter J. Murray. "Cutting edge: Stat6-dependent substrate depletion

regulates nitric oxide production." The Journal of Immunology 166, no. 4

(2001): 2173-2177.

Sabat, Robert, Gerald Grütz, Katarzyna Warszawska, Stefan Kirsch, Ellen Witte,

Kerstin Wolk et al "Biology of interleukin-10." Cytokine & growth factor

reviews 21, no. 5 (2010): 331-344.

Sabat, Robert. "IL-10 family of cytokines."Cytokine & growth factor reviews 21, no. 5

(2010): 315-324.

Saleem, Mohammad, Farrukh Afaq, Vaqar Mustafa Adhami, and Hasan Mukhtar.

"Lupeol modulates NF-κB and PI3K/Akt pathways and inhibits skin cancer in

CD-1 mice." Oncogene 23, no. 30 (2004): 5203-5214.

Scalbert, Augustin, Claudine Manach, Christine Morand, Christian Rémésy, and Liliana

Jiménez."Dietary polyphenols and the prevention of diseases."Critical reviews

in food science and nutrition 45, no. 4 (2005): 287-306.

Schottelius, Arndt JG, Marty W. Mayo, R. Balfour Sartor, and Albert S. Baldwin.

"Interleukin-10 signaling blocks inhibitor of κB kinase activity and nuclear

factor κB DNA binding." Journal of Biological Chemistry 274, no. 45 (1999):

31868-31874.

Schweizer, A., U. Feige, A. Fontana, K. Müller, and C. A. Dinarello. "Interleukin-1

enhances pain reflexes. Mediation through increased prostaglandin E2

levels."Agents and actions 25, no. 3-4 (1988): 246-251.

Serbina, Natalya V., Thais P. Salazar-Mather, Christine A. Biron, William A. Kuziel,

and Eric G. Pamer. "TNF/iNOS-producing dendritic cells mediate innate

immune defense against bacterial infection." Immunity 19, no. 1 (2003): 59-70.

Serhan, Charles N., Sue D. Brain, Christopher D. Buckley, Derek W. Gilroy,

Christopher Haslett, Luke AJ O’Neill et al. "Resolution of inflammation: state

of the art, definitions and terms." The FASEB journal 21, no. 2 (2007): 325-332.

Shaikh, J., D. D. Ankola, V. Beniwal, D. Singh, and M. N. V. Kumar. "Nanoparticle

encapsulation improves oral bioavailability of curcumin by at least 9-fold when

compared to curcumin administered with piperine as absorption enhancer."

European Journal of Pharmaceutical Sciences 37, no. 3 (2009): 223-230.

© COPYRIG

HT UPM

72

Shan, Bin, Yizhong Z. Cai, Mei Sun, and Harold Corke. "Antioxidant capacity of 26

spice extracts and characterization of their phenolic constituents." Journal of

agricultural and food chemistry 53, no. 20 (2005): 7749-7759.

Shaul, Philip W. "Regulation of endothelial nitric oxide synthase: location, location,

location." Annual Review of Physiology 64, no. 1 (2002): 749-774.

Shen, Jing, Run-Tian Wang, Li-Wei Wang, Yao-Chu Xu, and Xin-Ru Wang. "A novel

genetic polymorphism of inducible nitric oxide synthase is associated with an

increased risk of gastric cancer." World Journal of Gastroenterology 10, no. 22

(2004): 3278-3283.

Shenoy, Dinesh, Wei Fu, Jane Li, Curtis Crasto, Graham Jones, Charles DiMarzio et al.

"Surface functionalization of gold nanoparticles using hetero-bifunctional poly

(ethylene glycol) spacer for intracellular tracking and delivery." International

journal of nanomedicine 1, no. 1 (2006): 51-61

Shimizu, N., T. Naoe, Y. Kawazoe, H. Sakagami, H. Nakashima, T. Murakami, and N.

Yamamoto."Lignified materials as medicinal resources. VI. Anti-HIV activity of

dehydrogenation polymer of p-coumaric acid, a synthetic lignin, in a quasi-in-

vivo assay system as an intermediary step to clinical trials." Biological &

pharmaceutical bulletin 16, no. 4 (1993): 434-436.

Sindrilaru, Anca, Thorsten Peters, Stefan Wieschalka, Corina Baican, Adrian Baican,

Henriette Peter et al. "An unrestrained proinflammatory M1 macrophage

population induced by iron impairs wound healing in humans and mice." The

Journal of clinical investigation 121, no. 3 (2011): 985.

Singh, J. and A. Suruchi. "AntiTNF-α strategy: Present status of this therapeutic

paradigm." Indian Journal of Pharmacology 36 no 1(2004).

Slowing, Igor I., Juan L. Vivero-Escoto, Chia-Wen Wu, and Victor S-Y.Lin.

"Mesoporous silica nanoparticles as controlled release drug delivery and gene

transfection carriers."Advanced drug delivery reviews 60, no. 11 (2008): 1278-

1288.

Smith, William L., David L. DeWitt, and R. Michael Garavito. "Cyclooxygenases:

structural, cellular, and molecular biology." Annual review of biochemistry 69,

no. 1 (2000): 145-182.

Smith, William L., R. Michael Garavito, and David L. DeWitt."Prostaglandin

endoperoxide H synthases (cyclooxygenases)-1 and− 2."Journal of Biological

Chemistry 271, no. 52 (1996): 33157-33160.

Stefanovic‐Racic, M., J. Stadler, and C. H. Evans."Nitric oxide and arthritis."Arthritis &

Rheumatism 36, no. 8 (1993): 1036-1044.

© COPYRIG

HT UPM

73

Stender, Joshua D., Gabriel Pascual, Wen Liu, Minna U. Kaikkonen, Kevin Do,

Nathanael J. Spann, Michael Boutros, Norbert Perrimon, Michael G. Rosenfeld,

and Christopher K. Glass. "Control of proinflammatory gene programs by

regulated trimethylation and demethylation of histone H4K20."Molecular cell

48, no. 1 (2012): 28-38.

Stober, Carmel B., Uta G. Lange, Mark TM Roberts, Antonio Alcami, and Jenefer M.

Blackwell. "IL-10 from regulatory T cells determines vaccine efficacy in murine

Leishmania major infection." The Journal of Immunology 175, no. 4 (2005):

2517-2524.

Stout, Robert D., and Jill Suttles. "Functional plasticity of macrophages: reversible

adaptation to changing microenvironments." Journal of leukocyte biology 76,

no. 3 (2004): 509-513.

Stout, Robert D., Chuancang Jiang, Bharati Matta, Illya Tietzel, Stephanie K. Watkins,

and Jill Suttles. "Macrophages sequentially change their functional phenotype in

response to changes in microenvironmental influences." The Journal of

Immunology 175, no. 1 (2005): 342-349.

Sun, Dongmei, Xiaoying Zhuang, Xiaoyu Xiang, Yuelong Liu, Shuangyin Zhang,

Cunren Liu et al. "A novel nanoparticle drug delivery system: the anti-

inflammatory activity of curcumin is enhanced when encapsulated in

exosomes." Molecular Therapy 18, no. 9 (2010): 1606-1614.

Sun, L. K., P. Wahl, G. Bilic, and R. P. Wüthrich."CD44-mediated cyclooxygenase-2

expression and thromboxane A2 production in RAW 264.7

macrophages."Inflammation Research 50, no. 10 (2001): 496-499.

Sun, Min-Hua, Xi-Chun Han, Ming-Ku Jia, Wei-Dong Jiang, Min Wang, Hong Zhang

et al. "Expressions of inducible nitric oxide synthase and matrix

metalloproteinase-9 and their effects on angiogenesis and progression of

hepatocellular carcinoma." World journal of gastroenterology: WJG 11, no. 38

(2005): 5931-5937.

Sun, W., Q.He, L. Lu, and H. Liu. "Synthesis and properties of layered double

hydroxides intercalated with cinnamic acid series organic UV ray absorbents."

Materials chemistry and physics 107, no. 2 (2008): 261-265.

Sung, Yoon-Young, Taesook Yoon, Ja Young Jang, Sang-Joon Park, Gi-Hoon Jeong,

and Ho Kyoung Kim. "Inhibitory effects of Cinnamomum cassia extract on

atopic dermatitis-like skin lesions induced by mite antigen in NC/Nga mice."

Journal of ethnopharmacology 133, no. 2 (2011): 621-628.

© COPYRIG

HT UPM

74

Surendiran, A., S. Sandhiya, S. C. Pradhan, and C. Adithan."Novel applications of

nanotechnology in medicine."Indian Journal of Medical Research 130, no. 6

(2009).

Sutterwala, Fayyaz S., Gary J. Noel, Padmini Salgame, and David M. Mosser."Reversal

of proinflammatory responses by ligating the macrophage Fcγ receptor type

I."The Journal of experimental medicine 188, no. 1 (1998): 217-222.

Sutterwala, Fayyaz S., Gary J. Noel, Raphael Clynes, and David M. Mosser."Selective

suppression of interleukin-12 induction after macrophage receptor ligation."The

Journal of experimental medicine 185, no. 11 (1997): 1977-1985.

Sweitzer, S., D. Martin, and J. A. DeLeo. "Intrathecal interleukin-1 receptor antagonist

in combination with soluble tumor necrosis factor receptor exhibits an anti-

allodynic action in a rat model of neuropathic pain." Neuroscience 103, no. 2

(2001): 529-539.

Tabas, Ira, and Christopher K. Glass. "Anti-inflammatory therapy in chronic disease:

challenges and opportunities." Science 339, no. 6116 (2013): 166-172.

Tak, P. P. and G. S. Firestein (2001). "NF-κB: a key role in inflammatory diseases."

Journal of Clinical Investigation 107(1): 7-11.

Tan, P. L., S. Farmiloe, S. Yeoman, and J. D. Watson."Expression of the interleukin 6

gene in rheumatoid synovial fibroblasts."The Journal of rheumatology 17, no.

12 (1990): 1608-1612.

Tergaonkar, Vinay. "NFκB pathway: A good signaling paradigm and therapeutic

target." The international journal of biochemistry & cell biology 38, no. 10

(2006): 1647-1653.

Theodorou, M. K., D. J. Gascoyne, D. E. Akin, and R. D. Hartley."Effect of phenolic

acids and phenolics from plant cell walls on rumenlike fermentation in

consecutive batch culture."Applied and environmental microbiology 53, no. 5

(1987): 1046-1050.

Thiemermann, Christoph, and John Vane. "Inhibition of nitric oxide synthesis reduces

the hypotension induced by bacterial lipopolysaccharides in the rat in vivo."

European journal of pharmacology 182, no. 3 (1990): 591-595.

Thomson, A. W.” The cytokine handbook”, Academic Press (1994)

Tian, Bing, and Allan R. Brasier."Identification of a nuclear factor kappa B-dependent

gene network."Recent Progress in Hormone Research 58, no. 1 (2003): 95-130.

Tilley, Stephen L., Thomas M. Coffman, and Beverly H. Koller."Mixed messages:

modulation of inflammation and immune responses by prostaglandins and

thromboxanes."Journal of Clinical Investigation 108, no. 1 (2001): 15-23.

© COPYRIG

HT UPM

75

Tracey, Kevin J., Bruce Beutler, Stephen F. Lowry, James Merryweather, Stephen

Wolpe, Ian W. Milsark et al. "Shock and tissue injury induced by recombinant

human cachectin." Science 234, no. 4775 (1986): 470-474.

Tracey, Kevin J., Yuman Fong, David G. Hesse, Kirk R. Manogue, Annette T. Lee,

George C. Kuo et al "Anti-cachectin/TNF monoclonal antibodies prevent septic

shock during lethal bacteraemia." Nature 330, no. 6149 (1987): 662-664.

Tsirogianni, Afrodite K., Niki Maria Moutsopoulos, and Haralampos M.

Moutsopoulos. "Wound healing: immunological aspects." Injury 37, no. 1

(2006): S5-S12.

Üçeyler, Nurcan, Regine Valenza, Michael Stock, Robert Schedel, Günter Sprotte, and

Claudia Sommer."Reduced levels of antiinflammatory cytokines in patients with

chronic widespread pain."Arthritis & Rheumatism 54, no. 8 (2006): 2656-2664.

Van Snick, Jacques. "Interleukin-6: an overview." Annual review of immunology 8, no.

1 (1990): 253-278.

Vieira, P., R. de Waal-Malefyt, M. N. Dang, K. E. Johnson, R. Kastelein, D. F.

Fiorentino et al. "Isolation and expression of human cytokine synthesis

inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading

frame BCRFI." Proceedings of the National Academy of Sciences 88, no. 4

(1991): 1172-1176.

Villalta, S. Armando, Chiara Rinaldi, Bo Deng, Grace Liu, Brian Fedor, and James G.

Tidball. "Interleukin-10 reduces the pathology of mdx muscular dystrophy by

deactivating M1 macrophages and modulating macrophage phenotype." Human

molecular genetics 20, no. 4 (2011): 790-805.

Vincent, Jean Louis. "Afelimomab."International journal of clinical practice 54, no. 3

(2000): 190-193.

Voronov, Elena, Dror S. Shouval, Yakov Krelin, Emanuela Cagnano, Daniel

Benharroch, Yoichiro Iwakura et al. "IL-1 is required for tumor invasiveness

and angiogenesis." Proceedings of the National Academy of Sciences 100, no. 5

(2003): 2645-2650.

Wagner, Volker, Anwyn Dullaart, Anne-Katrin Bock, and Axel Zweck."The emerging

nanomedicine landscape."Nature biotechnology 24, no. 10 (2006): 1211-1218.

Wahba, Nahed M., Amany S. Ahmed, and Zedan Z. Ebraheim."Antimicrobial effects of

pepper, parsley, and dill and their roles in the microbiological quality

enhancement of traditional Egyptian Kareish cheese."Foodborne pathogens and

disease 7, no. 4 (2010): 411-418.

© COPYRIG

HT UPM

76

Wang, Wei, Meng Luo, Yujie Fu, Song Wang, Thomas Efferth, and Yuangang Zu.

"Glycyrrhizic acid nanoparticles inhibit LPS-induced inflammatory mediators in

264.7 mouse macrophages compared with unprocessed glycyrrhizic acid."

International journal of nanomedicine 8 (2013): 1377.

Wang, Ying, Zhiyong Tang, and Nicholas A. Kotov."Bioapplication of

nanosemiconductors."Materials Today 8, no. 5 (2005): 20-31.

Warren, J. S. "Interleukins and tumor necrosis factor in inflammation." Critical reviews

in clinical laboratory sciences 28 no1 (1990): 37-59.

Wieseler-Frank, Julie, Steven F. Maier, and Linda R. Watkins."Glial activation and

pathological pain."Neurochemistry international 45, no. 2 (2004): 389-395.

Woo, Kyung Jin, Yong-Jin Jeong, Hiroyasu Inoue, Jong-Wook Park, and Taeg Kyu

Kwon. "Chrysin suppresses lipopolysaccharide-induced cyclooxygenase-2

expression through the inhibition of nuclear factor for IL-6 (NF-IL6) DNA-

binding activity." FEBS letters 579, no. 3 (2005): 705-711.

WoOng, Cho, Nam JooWon, Kang HyunJun, T. Windono, Seo EunKyoung, and Lee

KyungTae. "Zedoarondiol isolated from the rhizoma of Curcuma heyneana is

involved in the inhibition of iNOS, COX-2 and pro-inflammatory cytokines via

the downregulation of NF-κB pathway in LPS-stimulated murine macrophages."

International Immunopharmacology 9, no. 9 (2009): 1049-1057.

Wouters, E. F. M. "Management of severe COPD." The Lancet 364, no. 9437 (2004):

883-895.

Wu, Xinying, Yanbin Tan, Hui Mao, and Minming Zhang."Toxic effects of iron oxide

nanoparticles on human umbilical vein endothelial cells."International journal

of nanomedicine 5 (2009): 385-399.

Wynn, Thomas A. "Fibrotic disease and the TH1/TH2 paradigm." Nature Reviews

Immunology 4, no. 8 (2004): 583-594.

Xiao, Wenbin, Hong Hong, Yuko Kawakami, Clifford A. Lowell, and Toshiaki

Kawakami."Regulation of myeloproliferation and M2 macrophage programming

in mice by Lyn/Hck, SHIP, and Stat5."The Journal of clinical investigation 118,

no. 3 (2008): 924.

Xu, Zhi Ping, and Guo Qing Lu. "Hydrothermal synthesis of layered double hydroxides

(LDHs) from mixed MgO and Al2O3: LDH formation mechanism." Chemistry

of materials 17, no. 5 (2005): 1055-1062.

Xu, Zhi Ping, Tara L. Walker, Kerh-lin Liu, Helen M. Cooper, GQ Max Lu, and Perry

F. Bartlett."Layered double hydroxide nanoparticles as cellular delivery vectors

© COPYRIG

HT UPM

77

of supercoiled plasmid DNA."International journal of nanomedicine 2, no. 2

(2007): 163-171.

Yada-Hashimoto, Namiko, Yukihiro Nishio, Masahide Ohmichi, Jun Hayakawa, Seiji

Mabuchi, Koji Hisamoto, et al. "Estrogen and raloxifene inhibit the monocytic

chemoattractant protein-1-induced migration of human monocytic cells via

nongenomic estrogen receptor [alpha]." Menopause 13, no. 6 (2006): 935-941.

Yan, Hong Qu, Miguel Alcaros Banos, Patrick Herregodts, Robert Hooghe, and

Elisabeth L. Hooghe‐Peters. "Expression of interleukin (IL)‐1β, IL‐6 and their

respective receptors in the normal rat brain and after injury." European journal

of immunology 22, no. 11 (1992): 2963-2971.

Yang, Jianhong, Shucai Li, Caifeng Xie, Haoyu Ye, Huan Tang, Lijuan Chen, and

Aihua Peng."Anti-inflammatory activity of ethyl acetate fraction of the seeds

of< i> Brucea Javanica</i>."Journal of ethnopharmacology 147, no. 2 (2013):

442-446.

Yao, Masahiro, Minoru Yoshida, Takeshi Kishida, Noboru Nakaigawa, Masaya Baba,

Kazuki Kobayashi et al. "VHL tumor suppressor gene alterations associated

with good prognosis in sporadic clear-cell renal carcinoma." Journal of

theNational Cancer Institute 94, no. 20 (2002): 1569-1575.

Zandi, Ebrahim, Y. I. Chen, and Michael Karin. "Direct phosphorylation of IκB by

IKKα and IKKβ: discrimination between free and NF-κB-bound substrate."

Science 281, no. 5381 (1998): 1360-1363.

Zedler, Siegfried, and Eugen Faist."The impact of endogenous triggers on trauma-

associated inflammation."Current opinion in critical care 12, no. 6 (2006): 595-

601.

Zhang, J.-M.and J. An "Cytokines, inflammation and pain." International

anesthesiology clinics 45 no. 2 (2007): 27.

Zhang, L. P., and Z. Z. Ji."Synthesis, antiinflammatory and anticancer activity of

cinnamic acids, their derivatives and analogues."Acta Pharmaceutica Sinica 27

(1992): 823-823.

Zhang, L., F. X. Gu, J. M. Chan, A. Z. Wang, R. S. Langer, and O. C. Farokhzad.

"Nanoparticles in medicine: therapeutic applications and developments."

Clinical Pharmacology & Therapeutics 83, no. 5 (2008): 761-769.