KARYA TULIS AKHIR

PENGARUH EKSTRAK KULIT MANGGIS

(Garcinia mangostana Linn) SEBAGAI ANTI INFLAMASI

PADA TIKUS MODEL ATEROSKLEROTIK

Oleh :

RP SALVA REVERENTIA YURISTA

08020113

UNIVERSITAS MUHAMMADIYAH MALANG

FAKULTAS KEDOKTERAN

2011

HASIL PENELITIAN

PENGARUH EKSTRAK KULIT MANGGIS

(Garcinia mangostana Linn) SEBAGAI ANTI INFLAMASI

PADA TIKUS MODEL ATEROSKLEROTIK

KARYA TULIS AKHIR

Diajukan kepada

Universitas Muhammadiyah Malang

untuk memenuhi Salah Satu Persyaratan

dalam menyelesaikan Program Sarjana

Fakultas Kedokteran

Oleh :

RP SALVA REVERENTIA YURISTA

08020113

UNIVERSITAS MUHAMMADIYAH MALANG

FAKULTAS KEDOKTERAN

2011

LEMBAR PENGESAHAN

LAPORAN HASIL PENELITIAN

Telah disetujui sebagai hasil penelitian

untuk memenuhi persyaratan

Pendidikan Sarjana Fakultas Kedokteran

Universitas Muhammadiyah Malang

12 Oktober 2011

Pembimbing I

Prof. Dr. dr. Djanggan Sargowo, Sp.PD, Sp.JP(K)

Pembimbing II

dr. Fathiyah Safithri, M.Kes

Mengetahui,

Dekan Fakultas Kedokteran

Universitas Muhammadiyah Malang

dr. Irma Suswati, M.Kes

LEMBAR PENGUJIAN

Karya Tulis Akhir oleh RP Salva Reverentia Yurista ini

telah diuji dan dipertahankan di depan Tim Penguji

pada tanggal 12 Oktober 2011.

Tim Penguji

Prof. Dr. dr. Djanggan Sargowo, Sp.PD, Sp.JP(K) Ketua

dr. Fathiyah Safithri, M.Kes Anggota

Prof. Dr. dr. Djoni Djunaedi, Sp.PD, KPTI Anggota

KATA PENGANTAR

Puji syukur saya ucapkan kepada Tuhan Yang Maha Esa, karena atas

berkat dan rahmat-Nya, penulis telah berhasil menyelesaikan usulan penelitian

yang berjudul “Pengaruh Ekstrak Kulit Manggis (Garcinia Mangostana Linn)

sebagai Anti Inflamasi pada Tikus Model Aterosklerotik”. Dalam penyelesaian

karya tulis akhir ini tidak lepas dari bimbingan dan bantuan dari semua pihak,

untuk itu penulis ingin mengucapkan terima kasih yang tak terhingga kepada :

1. dr. Irma Suswati, M.Kes selaku Dekan Fakultas Kedokteran Universitas

Muhammadiyah Malang atas kesabaran dan ilmu yang diberikan kepada

penulis.

2. dr. Meddy Setiawan, Sp.PD selaku Pembantu Dekan I Fakultas

Kedokteran UMM yang telah membekali ilmu hingga terselesaikannya

karya tulis akhir ini.

3. dr. Fathiyah Safithri, M.Kes selaku Pembantu Dekan II Fakultas

Kedokteran UMM sekaligus pembimbing II atas bimbingan, ilmu,

dukungan, dan saran yang telah diberikan dalam penyusunan karya tulis

akhir ini.

4. dr. Iwan Sys Indrawanto, Sp.KJ selaku Pembantu Dekan III Fakultas

Kedokteran UMM yang terus memberi semangat dan ilmu bagi penulis.

5. Prof. Dr. dr. Djanggan Sargowo, Sp.PD, Sp.JP(K) selaku pembimbing I

yang berkenan memberikan waktu untuk memberikan bimbingan,

semangat, ilmu, dan pengarahan dari awal hingga terselesaikannya karya

tulis akhir ini.

6. Prof. Dr. dr. Djoni Djunaedi, Sp.PD, KPTI selaku penguji yang telah

banyak memberikan waktu, ilmu, arahan, dan saran demi kesempurnaan

karya tulis akhir ini.

7. dr. Mochamad Bahrudin, Sp.S selaku dosen wali atas saran, ilmu, dan

arahan studi yang diberikan selama ini.

8. Seluruh dosen Fakultas Kedokteran UMM yang telah membekali penulis

berbagai ilmu hingga terselesaikannya karya tulis ini.

9. Papa Dr. RP Henky, SH, MH dan mama yang tidak pernah berhenti

memberikan dukungan dan doa bagi penulis. Terimakasih telah menjadi

orang tua yang sempurna.

10. Kakak, adik, dan seluruh keluarga besar S. Hadikoesumo.

11. Ir. Adlis Achir Abdullah, MS dan keluarga atas segala bantuan dan

dukungan yang diberikan kepada penulis.

12. Staf TU dan para laboran FK UMM yang telah banyak membantu penulis.

13. Seluruh staf CVCU RSU dr. Saiful Anwar Malang dan staf Laboraturium

Farmakologi FK Universitas Brawijaya yang telah memberikan banyak

bantuan bagi penulis.

14. Dicky dan Elok selaku tim terbaik.

15. Teman-teman terbaik angkatan 2008 yang selalu memberikan motivasi

bagi penulis.

16. Semua pihak yang tidak mungkin disebutkan satu-persatu.

Karya tulis akhir ini masih jauh dari kesempurnaan. Dengan kerendahan

hati penulis mohon maaf yang sebesar-besarnya dan mengharapkan saran dan

kritik yang membangun. Semoga karya tulis ini dapat menambah wawasan dan

bermanfaat bagi semua pihak.

Malang, Oktober 2011

Penulis

ABSTRAK

Yurista, RP Salva Reverentia. 2011. Pengaruh Ekstrak Kulit Manggis (Garcinia

mangostana Linn) sebagai Anti Inflamasi pada Tikus Model

Aterosklerotik. Fakultas Kedokteran, Universitas Muhammadiyah Malang.

Pembimbing: (1) Prof. Dr. dr. Djanggan Sargowo, Sp.PD, Sp.JP (K) , (2)

dr. Fathiyah Safithri, M.Kes.

Latar Belakang: Aterosklerosis merupakan penyakit inflamasi yang ditandai

dengan peningkatan aktivitas imunologis, dimana respon imun berperan pada

setiap fase aterosklerosis. Hal terpenting pada aterogenesis adalah nuclear factor-

κB (NF- κB) yang meregulasi aktivasi molekul adhesi (ICAM-1) dan sekresi

sitokin pro-inflamasi seperti tumor necrosis factor (TNF-α) interleukin-1 (IL-1),

dan interleukin-6 (IL-6)

Tujuan : Membuktikan aktivitas anti inflamasi dari esktrak kulit manggis pada

tikus model aterosklerotik.

Metode : Sampel penelitian ini menggunakan 30 ekor tikus putih (Rattus

novergicus Strain wistar), dibagi dalam 5 kelompok dengan enam tikus di

masing-masing kelompok. Kelompok I merupakan kelompok normal; Kelompok

II merupakan kelompok tikus yang diberi diet aterosklerotik selama 90 hari;

kelompok III, IV, dan V merupakan kelompok perlakuan tikus yang diberi diet

aterosklerotik dan ekstrak kulit manggis per oral (200mg/kg; 400 mg/kg, 800

mg/kg) selama 90 hari. Setelah 90 hari perlakuan, dilakukan pengambilan sampel

darah untuk pemeriksaan kadar TNF-α dan IL-1 menggunakan metoda Elisa.

Pengambilan jaringan aorta juga dilakukan untuk mengamati ekspresi NF-kB,

ICAM-1, dan IL-6 menggunakan teknik immunohistokimia.

Hasil : Pemberian ekstrak kulit manggis (800 mg/kg) signifikan menurunkan

kadar TNF-α, dan IL-1, serta menurunkan ekspresi NF-kB, ICAM-1, dan IL-6.

Kesimpulan: Ekstrak kulit manggis (Garcinia mangostana Linn) memiliki

aktivitas anti inflamasi dengan menurunkan kadar TNF-α dan IL-1, serta

menurunkan ekspresi NF-kB, ICAM-1, and IL-6 yang mencegah perkembangan

aterosklerosis.

Kata kunci: Aterosklerosis, Garcinia mangostana Linn, anti inflamasi, TNF-α,

IL-1, IL-6, NF-kB, ICAM-1.

ABSTRACT

Yurista, RP Salva Reverentia. 2011. Effect of Extract from Pericarp of

Mangosteen (Garcinia Mangostana Linn) as Anti-Inflammatory Agent in

Rat Models with Atherosclerosis. Faculty of Medicine, University of

Muhammadiyah Malang. Advisors: (1) Prof. Dr. dr. Djanggan Sargowo,

Sp.PD, Sp.JP (K), (2) dr. Fathiyah Safithri, M.Kes

Background : Atherosclerosis is an inflammatory disease characterized by

intense immunological activity, which immune responses participate in every

phase of atherosclerosis. On fundamental importance in atherogenesis is nuclear

factor-κB (NF- κB) that regulates activation of adhesion molecules (ICAM-1) and

secretion of pro-inflammatory cytokines such as tumor necrosis factor (TNF-α)

interleukin-1 (IL-1), and interleukin-6 (IL-6).

Objectives : The extract from pericarp of mangosteen (Garcinia mangostana

Linn ) were carried out to investigate for anti-inflammatory activity in rat models

with atherosclerosis.

Methods: The subjects of the study were 30 albino rats of (Rattus novergicus

Strain wistar), divided into 5 groups with six rats in each group. Group I

comprises normal healthy rats remains untreated for 90 days; Group II comprises

of high cholesterol diet induced atherosclerotic rats for 90 days; Group III, IV,

and V comprise of high cholesterol diet induced atherosclerosis and were

administered extract from pericarp of mangosteen orally (200mg/kg; 400 mg/kg,

800 mg/kg) daily for 90 days. After 90 days treatment, rats were decapitated and

blood was sample collected from the aorta for determination level of TNF-α and

IL-1 by ELISA. Aorta was taken to observe the expression of NF-kB, ICAM-1,

and IL-6 using immunohistochemical techniques.

Results : Oral administration (800 mg/kg) of the extract from pericarp of

mangosteen significantly decreased the level of TNF-α, and IL-1 and also

reduced the expression of NF-kB, ICAM-1, and IL-6.

Conclusion: These results suggest that the extract from pericarp of mangosteen

(Garcinia mangostana Linn) possess anti-inflammatory actions by reducing level

of TNF-α, IL-1, and also reduce the expression of NF-kB, ICAM-1, and IL-6 that

prevent the development of atherosclerosis.

Keywords: Atherosclerosis, Garcinia mangostana Linn, anti-inflammatory, TNF-

α, IL-1, IL-6, NF-kB, ICAM-1.

DAFTAR ISI

HALAMAN JUDUL ....................................................................................... i

LEMBAR PENGESAHAN ............................................................................. ii

LEMBAR PENGUJIAN .................................................................................. iii

KATA PENGANTAR ..................................................................................... iv

ABSTRAK. ...................................................................................................... vii

ABSTRACT.. ................................................................................................... viii

DAFTAR ISI .................................................................................................... ix

DAFTAR TABEL ............................................................................................ xiii

DAFTAR GAMBAR. ...................................................................................... xiv

DAFTAR SINGKATAN. ................................................................................ xvi

DAFTAR LAMPIRAN .................................................................................... xviii

BAB 1 PENDAHULUAN .............................................................................. 1

1.1 Latar Belakang ................................................................................ 1

1.2 Rumusan Masalah ........................................................................... 4

1.3 Tujuan Penelitian ............................................................................ 4

1.3.1 Tujuan Umum ........................................................................ 4

1.3.2 Tujuan Khusus ....................................................................... 4

1.4 Manfaat Penelitian ........................................................................... 4

1.4.1 Manfaat Akademik ................................................................. 4

1.4.2 Manfaat Klinis ....................................................................... 4

BAB 2 TINJAUAN PUSTAKA ..................................................................... 6

2.1 Aterosklerosis .................................................................................. 5

2.1.1 Definisi Aterosklerosis ........................................................... 5

2.1.2 Patogenesis Aterosklerosis ..................................................... 7

2.1.3 Dislipidemia dan Aterosklerosis ............................................ 8

2.1.4 Proses Inflamasi pada Aterosklerosis karena Peningkatan

LDL ........................................................................................ 12

2.1.5 Peran Makrofag pada Pembentukan Plak Aterosklerosis ...... 14

2.1.6 Aktivasi Sel T dan Aterogenesis ............................................ 17

2.1.7 Peran Nuclear Faktor kappa B (NF-κB) pada

Disfungsi Endotel ................................................................... 20

2.1.8 Peran TNF-α, IL-1, dan IL-6 pada Disfungsi Endotel ........... 22

2.1.9 Inflamasi sebagai Target Terapi Aterosklerosis .................... 24

2.2 Manggis (Garcinia mangostana Linn) ............................................ 25

2.2.1 Taksonomi .............................................................................. 25

2.2.2 Morfologi Tanaman ................................................................ 26

2.2.3 Komponen Manggis (Garcinia mangostana Linn) ................ 27

2.2.4 Penelitian Mengenai Manfaat Kulit Manggis ........................ 30

2.2.5 Peran Manggis sebagai Anti Inflamasi Alami ....................... 31

BAB 3 KERANGKA KONSEP DAN HIPOTESIS .................................... 34

3.1 Kerangka Konsep ............................................................................ 34

3.2 Hipotesis .......................................................................................... 35

BAB 4 METODE PENELITIAN .................................................................. 36

4.1 Rancangan Penelitian ...................................................................... 36

4.2 Tempat dan Waktu Penelitian ......................................................... 36

4.3 Populasi dan Sampel ....................................................................... 36

4.3.1 Populasi .................................................................................. 36

4.3.2 Sampel .................................................................................... 36

4.3.3 Estimasi Besar Sampel ........................................................... 36

4.3.4 Karakteristik Sampel Penelitian ............................................. 38

4.4 Bahan dan Alat Penelitian ............................................................... 38

4.4.1 Bahan ..................................................................................... 38

4.4.2 Alat ......................................................................................... 39

4.5 Variabel dan Definisi Operasional .................................................. 40

4.5.1 Variabel .................................................................................. 40

4.5.2 Definisi Operasional .............................................................. 41

4.6 Alur Penelitian ................................................................................. 43

4.7 Prosedur Penelitian .......................................................................... 44

4.7.1 Pembagian Kelompok Tikus .................................................. 44

4.7.2 Adaptasi ................................................................................. 44

4.7.3 Pemberian Diet Aterosklerotik............................................... 44

4.7.4 Pemberian Ekstrak Kulit Manggis (Garcinia Mangostana

Linn) ....................................................................................... 45

4.7.5 Proses Anastesi dan Pembedahan Hewan Coba .................... 47

4.7.6 Pemeriksaan Pemeriksaan Kadar IL-1, IL-6 dan TNF-α ....... 48

4.7.7 Pengamatan ekspresi ICAM-1 ............................................... 49

4.7.8 Pengamatan Hasil ................................................................... 52

4.7.9 Analisis Data .......................................................................... 52

BAB 5 HASIL PENELITIAN DAN ANALISA DATA. ......................... 54

5.1 Pemeriksaan Kadar IL-1 . ......................................................... 55

5.2 Pemeriksaan Kadar TNF-α. ...................................................... 57

5.3 Pengamatan Ekspresi IL-6........................................................ 59

5.4 Pengamatan Ekspresi ICAM-1. ................................................ 61

5.5 Pengamatan Ekspresi NF-κB ................................................... 63

BAB 6 PEMBAHASAN. ............................................................................ 67

BAB 7 KESIMPULAN DAN SARAN. .................................................... 73

DAFTAR PUSTAKA. .................................................................................... 74

LAMPIRAN…. ............................................................................................... 80

DAFTAR TABEL

Tabel Halaman

5.1 Pengaruh pemberian ekstrak kulit manggis terhadap rerata kadar

IL-1(pg/ml) ............................................................................................... 55

5.2 Pengaruh pemberian ekstrak kulit manggis terhadap rerata kadar

TNF-α (pg/ml) .......................................................................................... 57

5.3 Pengaruh pemberian ekstrak kulit manggis terhadap ekspresi IL-6 (sel/

lapang pandang) ........................................................................................ 59

5.4 Pengaruh pemberian ekstrak kulit manggis terhadap ekspresi ICAM-1

(sel/lapang pandang) ................................................................................. 61

5.5 Pengaruh pemberian ekstrak kulit manggis terhadap eskpresi NF-κB

(sel/lapang pandang) ................................................................................. 63

DAFTAR GAMBAR

Gambar Halaman

2.1 Komposisi Selular Plak Aterosklerosis ...................................................... 6

2.2 Karakteristik Kelas Lipoprotein Utama. .................................................... 9

2.3 Klasifikasi Lipoprotein .............................................................................. 10

2.4 Klasifikasi Fraksi Lipid menurut NCEP ATP III 2001.............................. 11

2.5 Dislipidemia dan Aterosklerosis ................................................................ 11

2.6 Penyakit yang Terkait dengan Aktivasi NF-κB ......................................... 14

2.7 Rekruitmen dan Aktivasi Sel Imun ............................................................ 15

2.8 Peran Makrofag pada Inflamasi Arteri....................................................... 17

2.9 Efek Aktivasi Sel T pada Inflamasi Plak ................................................... 19

2.10 Peran Translokasi NF-κB pada Aterogenesis .......................................... 20

2.11 Struktur NF-κB/DNA complex : p50 dan p65 ......................................... 21

2.12 Skema NF-κB pada Inflamasi .................................................................. 21

2.13 Ilustrasi NF-κB pathways terhadap respon LPS,TNF dan Antigen ......... 22

2.14 Peran Agen Inflamasi pada Disfungsi Endotel ........................................ 23

2.15 Kaskade Sitokin ....................................................................................... 24

2.16 Target Terapi Aterosklerosis .................................................................... 25

2.17 Buah Manggis .......................................................................................... 26

2.18 Struktur Buah dan Pohon Manggis .......................................................... 26

2.19 Kandungan Nutrisi Manggis. ................................................................... 28

2.20 Struktur Kimia Xanthone pada Kulit Manggis ........................................ 29

2.21 Isolasi Xanthone pada Kulit Manggis. ..................................................... 30

2.22 Aktivitas Anti Inflamasi dan Anti Alergi pada Manggis. ........................ 33

5.1 Grafik Rerata Kadar IL-1 pada Berbagai Kelompok. ................................ 55

5.2 Kurva Persamaan Dosis ekstrak kulit manggis terhadap Kadar IL-1. ........ 56

5.3 Grafik Rerata Kadar TNF-α pada Berbagai Kelompok. ............................ 57

5.4 Kurva Persamaan Dosis ekstrak kulit manggis terhadap Kadar TNF-α. ... 58

5.5 Grafik Rerata Ekspresi IL-6 pada Berbagai Kelompok ............................. 59

5.6 Kurva Persamaan Dosis ekstrak kulit manggis terhadap Ekspresi IL-6 .... 60

5.7 Gambaran mikroskopis aorta tikus putih dengan perbesaran 200 kali. ..... 61

5.8 Grafik Rerata Ekspresi ICAM-1 pada Berbagai Kelompok. ..................... 62

5.9 Kurva Persamaan Dosis ekstrak kulit manggis terhadap Ekspresi

ICAM-1. ................................................................................................. 63

5.10 Gambaran mikroskopis aorta tikus putih dengan perbesaran 200 kali. ... 64

5.11 Grafik Rerata Ekspresi NF-κB pada Berbagai Kelompok. ...................... 64

5.12 Kurva Persamaan Dosis ekstrak kulit manggis terhadap Ekspresi

NF-κB ..................................................................................................... 65

DAFTAR SINGKATAN

AGE : Advance glycation endproduct

APC : Antigen presenting cell

ATP : Adenosine triphosphat

BSA : Bovine serum albumin

CD40 : Cluster of differentiation 40

CD40L : CD40 ligand

CD154 : Cluster of differentiation 154

COX : Cyclooxygenase

CRP : C-reactive protein

CXCL : CXC-chemokine ligand

CX3CR-1 : CX3-chemokine receptor-1

DAB : Diamino benzidine

DNA : Deoxyribonucleic acid

ELISA : Enzyme linked immunosorbent assay

HSP : Heat-shock protein

HRP : Horseradish peroxidase

ICAM-1 : Intracellular adhesion molecule-1

IFN- γ : Interferon gamma

IKK α : Inhibitor kappa B kinase alpha

IKK β : Inhibitor kappa B kinase beta

IkB : Inhibitor kappa B

IDL : Intermediate density lipoprotein

IL-1 : Interleukin-1

IL-4 : Interleukin-4

IL-6 : Interleukin-6

IL-10 : Interleukin-10

iNOS : inducible nitric oxide synthase

IP-10 : Inducible protein-10

ITAC-11 : IFN-inducible T-cell α-chemoattractant

kDa : kilo Dalton

LDL : Low density lipoprotein

LOX-1 : Lectin-like receptor for oxidized LDL

LPS : Lipopolysaccharide

M-CSF : Macrophage colony-stimulating factor

mRNA : messenger RNA

MCP-1 : Monocyte chemoattractant protein-1

Mig : Monokine induced by IFN- γ

MMPs : Matrix metalloproteinases

NF-kB : Nuclear factor kappa B

NKT : Natural killer-T cell

NO : Nitric oxide

ox-LDL : Oxidized low density lipoprotein

PBS : Phosphate buffered saline

PGE2 : Prostaglandins E2

RANTES : Regulated and T-cell expressed secreted

ROS : Reactive oxygen species

TF : Tissue factor

TG : Trigliserida

TGF-β : Transforming growth factor- β

Th1 : Type 1 helper cell

Th2 : Type 2 helper cell

TLR : Toll-like receptor

TMB : Tetra methyl benzidine

TNF-α : Tumor necrosis factor alpha

Treg : regulatory T cell

VCAM : Vascular cell adhesion molecule

VLA4 : Very late antigen 4

VLDL : Very low density lipoprotein

VEGF : Vascular endothelial growth factor

DAFTAR LAMPIRAN

Lampiran Halaman

1. Analisis Kadar IL-1 ..................................................................................... 80

2. Analisis Kadar TNF-α ................................................................................. 83

3. Analisis Ekspresi IL-6 .................................................................................. 86

4. Analisis Ekspresi ICAM-1 .......................................................................... 89

5. Analisis Ekspresi NF-κB .............................................................................. 92

6. Confirmation Dr.Salva Reverentia FK Muhammadiyah ............................. 95

7. Indonesian Oral Acceptance Letter .............................................................. 96

8. Kosultasi Tugas Akhir ................................................................................. 97

DAFTAR PUSTAKA

Assman, G., Cullen, P., Fruchart, J-C., Greten, H., Riesen, W., Eckardstein, A.V.

2004. Treatment guidelines for dyslipidemia. In : Task Force Symposium.

Zürich : International Task Force for Prevention of Coronary Heart Disease.

Bai, X.C., Lu, D., Liu, A.L., Zhang, Z.M., Li, X.M., Zou, Z.P., Zeng, W.S.,

Cheng, B.L., Luo, S.Q. 2005. Reactive oxygen species stimulates receptor

activator of NF-κB ligand expression in osteoblast. J Biol Chem. 280(17):

44975-44987.

Baldwin, Jr. A.S. 2001. The transcription factor NF-κB and human disease. J Clin

Invest. 107(1): 1-6.

Bandyopadhyay, U., Das, D., Banerjee, R.K. 1999. Reactive oxygen species:

Oxidative damage and pathogenesis. Curr Sci. 77(5): 658-666.

Blanco-Vaca, F., Escola-Gil, J.C.., Martin Campos, J.M., Julve, J. 2001. Role of

apoA-II in lipid metabolism and atherosclerosis:advances in the study of an

enigmatic protein. J Lipid Res. 42: 1727-1739.

Boyle, J.J. 2005. Macrophage activation in atherosclerosis: pathogenesis and

pharmacology of plaque rupture. CurrVasc Pharmacol. 3: 63-8.

Brand, K. and Page, S. 1997. Impaired endothelial and smooh muscle cell

function in oxidative stress role of NF-kB in atherogenesis. Exp Physiol. 82:

287-304.

Brown, C.T. 2005. Penyakit Aterosklerotik Koroner. In : Price S.A. and Wilson,

L.M. Patofisiologi : Konsep Klinis Proses-Proses Penyakit. Jakarta: EGC, pp:

576-612.

Browne, D., Meeking, D., Shaw, K., Cummings, M. 2003. Endothelial

dysfunction and pre-symptomaticatherosclerosis in type 1 diabetes –

pathogenesis and identification. Br J Diabetes Vasc Dis. 3: 27-34.

Bumrungpert, Akkarach. 2009. Bioavailability and inhibitory effects on

inflammation and insulin resistance of xanthones from Garcinia mangostana

l. (mangosteen) in human adipocytes. Mahidol University.

Calcagni, E. and Elenkov, I. 2006. Stress system activity, innate and T helper

cytokines, and susceptibility to immune-related diseases. N.Y. Acad Sci. 1069:

62-76.

Chait, A., Han, C.Y., Oram, J.F., Heinecke, J.W. 2005. Lipoprotein-associated

inflammatory proteins: markers or mediators of cardiovascular disease?. J

Lipid Res. 46: 389-403.

Chen, J. Liu, Y., Liu, H., Hermonat P.L., Mehta, J.L. 2006. Molecular dissection

of Angiotensin II–activated human LOX-1 promoter. Arterioscler Thromb

Vasc Biol. 26: 1163-1168.

Chen, G-L., Yang, L-L., Wang, C-C. 2007. Anti-inflammatory activity of

mangostins from Garcinia mangostana. Food Chem Toxicol. 46: 688-693.

Chiba, T., Kondo, Y., Shinozaki, S., Kaneko, E., Ishigami, A., Maruyama, N.,

Umezawa, K., Shimokado, K. 2006. A selected NF-κB inhibitor, DHMEQ,

reduced atherosclerosis in ApoE deficient mice. J Thromb Haemost. 13(6):

308-313.

Chomnawang, M.T., Surassmo, S., Nukoolkarn, V.S., Gristnapan, W. 2007.

Effect of Garcinia mangostana on inflammation caused by Propionibacterium

acnes. Fitoterapia. 78: 401-408.

Collins, T. 2001. NF-κB is pivotal mediator mediator or innocent bystander in

atherogenesis. J Clin Invest. 107(03) : 732-735.

Curtiss, L. 2009. Reversing Atherosclerosis?. N Eng J Med. 360 (11) : 1144-1146.

Davis, C., Fischer, J., Ley, K., Sarembock, I.J. 2003. The role of inflammation in

vascular injury and repair. J Thromb Haemost. 1: 1699-1709.

Davis, N.E. 2005. Atherosclerosis-an inflammatory process. J Insur Med. 37: 72-

75.

Diaz , M.N., Frei, B., Vita, J.A., Keaney, J.F,Jr. 1997.Mechanisms of disease:

antioxidants and atherosclerotic heart disease. N Engl J Med. 337(6): 408-416.

Dwek, A.C. 2003. A review of mangosteen. Chem Pharm Bull. 51: 857-866.

Dzau, V.J., Braun-Dullaeus, R.C., Sedding, D.G. 2002. Vascular proliferation and

atherosclerosis: new perspectives andtherapeutic strategies. Nat Med. 8(11):

1249-1256.

Eberlein, M., Scheibner, K.A., Black, K.E., Collins, S.L., Chan-Li, Y., Powell,

J.D., Horton, M.R. 2008. Anti-oxidant inhibition of hyaluronan fragment-

induced inflammatory gene expression. J Inflamm. 5: 20.

El-Melegy, N.T., Mohamed, N.A., Sayed, M.M. 2008. Oxidative modification of

low-density lipoprotein in relation to dyslipidemia and oxidant status in

children with steroid sensitive nephrotic syndrome. Pediatric Res. 63(4): 404-

409.

Frank, P.G. and Lisanti, M.P. 2008. ICAM-1 : role in inflammation and in

regulation of vascular permeability. Am J Physiol Heart Circ Physiol. 295:

H926-H297.

Franklin, H. and Epstein,M.D. 1997. Nuclear Factor-κB, a pivotal transcription

factor in chronic inflammatory disease. N Eng J Med. 336:1066-1015.

Fruchart, J.C. and Lille. 2003. In : Task Force Symposium. Scuol : International

Task Force for Prevention Coronary Heart Disease.

Gareus, R., Kotsaki, E., Xanthoulea, S., van der Made, I., Gijbels, M.J.J.,

Kardakis, R., Polykratis, A., Kollias, G., de Winther, P.J., Pasparakis, M.

2008. Endothelial Cell-Specific NF-κB Inhibition Protects Mice from

Atherosclerosis. Cell Metabolism. 8: 372–383.

Greaves, D.R. and Channon, K.M. 2002. Inflammation and immune responses in

atherosclerosis. Trends Immunol. 23(11): 535-541.

Hansson, G.K. 2005. Mechanisms of disease : inflammation, atherosclerosis,and

coronary artery disease. N Eng J Med. 352:1685-95.

Hansson, G.K. 2009. Atherosclerosis-an immune disease. Atherosclerosis. 202: 2-

10.

Hansson, G.K. and Libby, P. 2006. The immune response inatherosclerosis: a

double-edged sword. Nature. 6: 508-519.

Havenoja, T. 2000. Fisiologia do sistema circulatorio. BBA. 1488:189-210.

Hotamisligil, G.S. 2010. Endoplasmic stress and atherosclerosis. Nature med.

16:369-399.

Huang, Y.L., Chen, C.C., Chen, Y.J., Huang, R.L., Shieh, B.J. 2001.

Threexanthones anda benzophenone from Garcinia mangostana. J Nat Prod.

64: 903-906.

Introna, M. and Mantovani, A. 1997. Early activation signals in endothelial cells :

stimulation by cytokines. Arterioscler Thromb Vasc Biol. 17:423-428.

Jiang, D.J., Dai, Z., Li, Y.J. 2004. Pharmacological Effects of Xanthones as

Cardiovascular Protective Agents. Cardiovasc Drug Rev. 22(2): 91-102.

Jung, H.A., Su, B.N., Keller, W.J., Mehta, R.G., Kinghorn, D. 2006.

AntioxidantXanthones from pericarp of Garcinia mangostana (Mangosteen).

J Agric Food Chem. 54: 2077-2082.

Karatzis, E.N. 2005. The Role of Inflammatory Agents in Endothelial Function

and their Contribution to Atherosclerosis. Hell J Cardiol. 46: 232-239.

Kleemann, R., Zadelaar, S., Kooistra, T. 2008. Cytokines and atherosclerosis: a

comprehensive review of studies in mice. Cardiovasc Res. 79: 360-376.

Kopins, L. and Lowenstein, C. 2010. In the clinic dyslipidemia. Ann Intern Med.

153(3): ITC2-1-ITC2-16.

Ledebur, H.C. and Parks, T.P. 1995.Transcriptional regulation of intracellular

adhesion molecule-1 by inflammatory cytokines in the human endothelial

cells : essential roles of a variant NF-κB sites and p65 homodimers. J Biol

Chem. 270(2): 933-943.

Libby, P. 2002. Inflammation in atherosclerosis. Nature. 420: 868-874.

Libby, P., Ridker, P.M., Hansson, G.K. 2009. Inflammation in atherosclerosis :

from pathophysiology to practice. J Am Coll Cardiol. 54: 2129-38.

Libby, P., Ridker, P.M., Maseri, A. 2002. Inflammation in atherosclerosis.

Circulation. 105:1135-1143.

Lindemann, S., Kramer, B., Seizer, M.P., Gawaz, M. 2007. Platelets,

inflammation and atherosclerosis. J Thromb Haemost. 5(1): 203-11.

Mach, F. 2005. Inflammation is a crucial feature of atherosclerosis and a potential

target to reduce cardiovascular events. Handb Exp Pharmacol. 170: 697-722.

McPherson, R. , Frohlich, J., Fodor, G., Genest J. 2006. Recommendations for the

diagnosis and treatment of dyslipidemia and prevention of cardiovascular

disease. Can J Cardiol. 22(11): 913 – 927.

Muller, W.A. 2003. Leucocyte-endothelial cell interaction in leukocyte

transmigration and the inflammatory response. Trends Immunol. 24: 237-334.

Naka, T., Nishimoto, N., Kishimoto, T. 2002. The Paradigm of IL-6: from basic

science to medicine. Arthritis Res. 4(suppl 3): S233-S242.

Nakatani, K., Yamakuni, T., Kondo, N., Arakawa, T., Oosawa, K., Shimura, S.,

Inoue, H., Ohizumi, Y. 2004. Mangostin Inhibits inhibitor kappa B kinase

activity and decreases Lipopolysaccharide–induced cyclooxygenase-2 gene

expression in C6 Rat Glioma cells. Mol Pharmacol. 66:667-674.

Napoli, C. and Lerman, L.O. 2001. Involvement of Oxidation-Sensitive

Mechanisms in the Cardiovascular Effects of Hypercholesterolemia. Mayo

Clin Proc. 2001. 76:619-631.

Ndengele, M.M., Muscoli, C., Wang, Z.Q., Doyle, T.M. 2005. Superoxide

potentiates NF-kB activation and modulates endotoxin-induced cytokine

production in alveolar macrophages. SHOCK. 23(2): 186-193.

Nishikori, M. 2005. classical and alternative NF-κB activation pathways and their

roles in lymphoid malignancies. J Clin Exp Hematopathol. 45(1): 15-24.

Packard, R.R.S., Libby, P. 2008. Inflammation in atherosclerosis: from vascular

biology to biomarker discovery and risk prediction. Clin Chem. 54(1): 24-38.

Pedraza-Chaverri, J., Cardenaz-Rodriguez, N., Orozco-Ibarra, M., Perez-Rojas, J.

2008. Medicinal properties of mangosteen (Garcinia mangostana). Food Chem

Toxicol. 46: 3227-3239.

Porth, C.M. 2007. Essential of pathophysiology. 2nd

ed. Philadelphia : Lippincott

Williams and Wilkins, pp: 254-273.

Read, M.A., Whitley, M.Z. Williams, A.J., Collins, T. 1994. NF-κB and IκBα: an

inducible regulatory system in endothelial activation. J Exp Med. 179: 503-

512.

Reanmongkol, W. and Wattanapiromsakul, C. 2008. Evaluation of the analgesic,

antipyretic and anti-inflammatory activitiesof the extracts from the pericarp of

Garcinia mangostana Linn. inexperimental animals. Songklanakarin J. Sci.

Technol. 30 (6): 739-745.

Ross, R. 1999. Mechanism of disease: atherosclerosis-an inflammatory process. N

Eng J Med. 340(2): 115-126.

Sargowo, D. 2003. Disfungsi endotel pada penyakit kardiovaskular. Malang :

Bayumedia Publishing Malang, pp : 33-50.

Shi, Q., Vandeberg, J.L., Jett, C., Rice, K., Leland, M.M., Talley, L., Kushwaha,

R.S., Rainwater, D.L., Vandeberg, J.L., Wang, X.L. 2005. Arterial endothelial

dysfunction in baboons fed a high-cholesterol, high-fat diet. Am J Clin Nutr.

82:751–9.

Sonis, S.T. 2002. The biologic role for Nuclear Factor-kappaB in disease and its

potential involvement in mucosal injury associated with anti neoplastic

therapy. Crit Rev Oral Med. 13(5): 380-389.

Spagnoli, L.G., Bonanno, E., Sangiorgi, G., Mauriello, A. 2007. Role of

inflammation in atherosclerosis. J Nucl Med. 48: 1800-1815.

Stocker, R. and Keaney, J.F, Jr. 2004. Role of oxidative modifications in

atherosclerosis. Physiol Rev. 84 :1381-1478.

Tak, P.P. and Firestein, G.S. 2001. NF-κB: a key role in inflammatory diseases. J

Clin Invest. 107(1): 6-11.

Tedgui, A. and Mallat, Z. 2006. Cytokines in atherosclerosis : pathogenic and

regulatory pathways. Physiol Rev. 86: 515–581.

Tewtrakula, S., Wattanapiromsakul, C., Mahabusarakam, W. 2009. Effects of

compounds from Garcinia mangostana on inflammatory mediators in

RAW264.7 macrophage cells. J Ethnopharmacol. 121: 379-382.

Vohra, R.S., Murphy, J.E., Walker, J.H., Ponnambalam, S., Homer-

Vanniasinkam, S. 2006. TheLOX-1 scavenger receptor and atherosclerotic

plaque rupture. FASEB J. 21: 743-7.

Wang, R., Ding, G., Liang, W., Chen, C., Yang, H. 2010. Role of LOX-1 and

ROS in oxidized low-density lipoprotein induced epithelial-mesenchymal

transition of NRK52E. Lipids in Health and Disease. 9:120.

Wang, S., Kotamraju, S., konorev, E., Kalivendi, S., Joseph, J., Kalyanaraman, B.

2002. Activation of nuclear factor-κB during doxorubicin-induced apoptosis

in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen

peroxide. Biochem J. 367: 729–740.

Wolfrum, S., Teupser, D., Tan, M., Chen, K.Y., Breslow, J.L. 2007. The

proliferative effect of A20 on atherosclerosis in apolipoprotein E-deficient

mice is associated with reduced expression of NF-κB target genes. Proc Nat

Acad Sci USA. 104(47) : 18601-18606.

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