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CHAPTER 1

INTRODUCTION

1.0General Background

As the world developed, the emerging of new diseases and the number of drug

resistant pathogens are increases. The diet habit has also contributed as significant

increases of patients that harbouring the non pathogenic born diseases such as

cardiovascular disease, diabetes, stroke, and cancer. Atherosclerosis is a major driver

of cardiovascular disease in humans and occurs with greater frequency with

increasing age, diabetes, smoking, and hypertension (Beckman et al., 2002). It is the

main causes of mortality and morbidity in developed countries (Fishbein and

Fishbein, 2009). In Malaysia, the atherosclerosis is identified as the main cause of

death in 2010 and become the top two causes of death in industrialized countries in

China (Zhiyong, 2011). It is an ageing disease with a fastest progress from 40 to 49

years. Atherosclerosis is an inflammatory progressive disease, which begins in the

first decade of life and develops silently over decades before clinical manifestations

(Lusis, 2000). Atherosclerosis is the build up of plaque on the inside walls of

arteries. Plaque is made up of low density lipoprotein (LDL), macrophages, smooth

muscle cells, platelets, and other substances. It may narrow the lumen of a blood

vessel and restrict blood flow. Plaque rupture can induce the formation of thrombus

(blood clot) and block blood flow. This will result in ischemic stroke or heart attack

(Frink, 2002).


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There are three different stages of atherosclerosis that led to the "clogging" of

arteries; firstly, the fatty streak which consists of smooth muscle cells, which are

filled with cholesterol and macrophages ; a type of immune system "scavenger" cell

that removes harmful substances, such as excess cholesterol particles, from the

bloodstream (Thompson, 2010). The fatty streak alone does not cause any symptoms

but, over time, can develop into a more advanced form of atherosclerosis called

fibrous plaque, secondly, the formation of fibrous plaque in the inner layer of arteries

which consist of large numbers of smooth muscle cells, macrophages, and

lymphocytes (a type of white blood cell that typically responds to an infection or

injury). These cells are all filled with cholesterol. As the fibrous plaque grows, it

projects into the space inside the artery where the blood is flowing and lastly the

complicated lesion where the fibrous plaque breaks open, exposing the cholesterol

and connective tissue underneath. This rupture provokes a strong clotting reaction

from your blood, such as when you have a cut. The combination of fibrous plaque

and the blood clot is called a complicated lesion (Healthwise, 2010). Although there

already have the established drugs used to treat those diseases such lipid lowering

therapy and the statin but there still have some problem arise such patient suffered

from the side effect (Azevedo et al., 2008).

1.2 Significant of study

New drugs discovery from various sources including marine is urge to substitute the

current drug in the market such statin that exhibited side effect on the patients which

causing liver failure. Expert estimate that the biological diversity in marine

ecosystems is higher than the tropical rain forest (Haefner, 2003). Therefore, marine
http://www.webmd.com/heart-disease/what-is-atherosclerosishttp://www.webmd.com/cholesterol-management/default.htmhttp://www.webmd.com/heart/anatomy-picture-of-bloodhttp://www.webmd.com/a-to-z-guides/blood-clotshttp://www.webmd.com/a-to-z-guides/blood-clotshttp://www.webmd.com/heart/anatomy-picture-of-bloodhttp://www.webmd.com/cholesterol-management/default.htmhttp://www.webmd.com/heart-disease/what-is-atherosclerosis


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It was demonstrated that SR-B1 promoter contained a binding site for peroxisome

proliferator activated receptor gamma (PPAR), a ligand dependent transcription

factor that is activated by TZD (ligand). Therefore, in order to determine the assay

developed was fully functional, transfected cells were then treated with

rosiglitazone, a derivative of TZD as positive control. The chimeric constructs

containing PPRE and SR-B1 promoter, respectively, that were ligated to reporter

gene (luciferase gene), were used and transfected to human liver, HepG2 cell line.

The crude or compounds that increased the PPRE and SR-B1 promoter activities

(based on luciferase activity) were identified to have the potential as therapeutic

agent against atherosclerosis. Previously, research on PPRE conducted, the

peroxisome proliferator activated receptors (PPARs), PPAR,, , and , are ligand-

activated transcription factors belonging to the nuclear hormone superfamily that

also includes the retinoic acid and thyroid hormone receptors. Upon ligand binding,

PPARs form heterodimers with one of the three retinoid X receptor proteins which

then bind to PPAR response elements (PPRE) within the promoter regions of target

genes. They have been shown to regulate diverse cell functions, including adipocyte

differentiation, control of inflammation, fatty acid metabolism, cell cycle control,

and the development of atherosclerosis (Willson, et al , 2001). A variety of

endogenous and exogenous ligands for PPARs have been identified (Guan Y, 2001).

PPAR is the target for the hypolipidemic fibrate drugs, and PPAR the target for

the antidiabetic thiazolidinediones.


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1.3 The scope of Study

The Rhizophora apiculata and Acanthus ebracteatus were chosen to for further

investigation towards atherosclerosis disease. Both species do not show the

cytotoxicity activity against HepG2 cell line. This study also focused on cytotoxicity

screening for methanolic crude, fraction and their pure compound. Furthermore,

isolated and identified the bioactive compound from Rhizophora apiculata and

determined the ability of secondary metabolites towards the transcriptional activity

of PPRE and SR-B1 promoter.

2.0OBJECTIVES:

i. To determine the lower cytotoxicity activity of selected mangrove plant extract

ii. To determine the biological activities of extract and chemical constituent from

Rhizopora apiculata and Acanthus ebracteatus against atherosclerosis using SRBI

techniques

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