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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
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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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