Oleh: LILLY NURFITRIA RAMADHANI 201110330311075 · PDF filedr. Dian Yuliartha, Sp.PA, atas...

20
KARYA TULIS AKHIR PERBEDAAN POTENSI EKSTRAK JINTAN HITAM (Nigella sativa) TOPIKAL BERBAGAI DOSIS DENGAN NATRIUM DIKLOFENAK TOPIKAL DALAM MENURUNKAN EKSPRESI TUMOR NECROSIS FACTOR α (TNFα) PADA KORNEA TIKUS PUTIH JANTAN (Rattus novergicus strain wistar) MODEL INFLAMASI Oleh: LILLY NURFITRIA RAMADHANI 201110330311075 UNIVERSITAS MUHAMMADIYAH MALANG FAKULTAS KEDOKTERAN 2015

Transcript of Oleh: LILLY NURFITRIA RAMADHANI 201110330311075 · PDF filedr. Dian Yuliartha, Sp.PA, atas...

KARYA TULIS AKHIR

PERBEDAAN POTENSI EKSTRAK JINTAN HITAM (Nigella sativa)

TOPIKAL BERBAGAI DOSIS DENGAN NATRIUM DIKLOFENAK

TOPIKAL DALAM MENURUNKAN EKSPRESI TUMOR NECROSIS

FACTOR α (TNFα) PADA KORNEA TIKUS PUTIH JANTAN (Rattus

novergicus strain wistar) MODEL INFLAMASI

Oleh:

LILLY NURFITRIA RAMADHANI

201110330311075

UNIVERSITAS MUHAMMADIYAH MALANG

FAKULTAS KEDOKTERAN

2015

HASIL PENELITIAN

PERBEDAAN POTENSI EKSTRAK JINTAN HITAM (Nigella sativa) TOPIKAL

BERBAGAI DOSIS DENGAN NATRIUM DIKLOFENAK TOPIKAL DALAM

MENURUNKAN EKSPRESI TUMOR NECROSIS FACTOR α (TNFα) PADA

KORNEA TIKUS PUTIH JANTAN (Rattus novergicus strain wistar)

MODEL INFLAMASI

KARYA TULIS AKHIR

Diajukan kepada

Universitas Muhammadiyah Malang

Untuk Memenuhi Salah Satu Persyaratan

Dalam Menyelesaikan Program Sarjana

Fakultas Kedokteran

Oleh :

LILLY NURFITRIA RAMADHANI

201110330311075

UNIVERSITAS MUHAMMADIYAH MALANG

FAKULTAS KEDOKTERAN

2015

i

LEMBAR PENGESAHAN

ii

LEMBAR PENGUJIAN

iii

KATA PENGANTAR

Puji syukur kehadirat Allah SWT Yang Maha Pengasih lagi Maha

Penyayang, Yang Maha Pemberi semua nikmat, kebaikan, dan kekuatan selama

proses pelaksanaan, Yang Maha Menyimpan rahasia hikmah di balik semua

peristiwa, Yang Maha Memudahkan, dan atas karunia-Nya, penulisan tugas akhir

ini dapat selesai dengan baik. Shalawat serta salam selalu tercurahkan kepada

Rasulullah Muhammad shalallahu alaihi wasallam, keluarganya dan para

sahabatnya yang telah berjasa membawa syiar dakwah Islam ke seluruh dunia.

Penelitian tugas akhir ini berjudul “ Perbandingan Pemberian Ekstrak

Jintan Hitam (Nigella sativa) Topikal dengan Natrium Diklofenak Topikal

Terhadap Penurunan Ekspresi Tumor Necrosis Factor α (TNFα) Pada Kornea

Tikus Putih Jantan (Rattus novergicus strain wistar) Model Inflamasi”. Tugas

akhir ini diajukan untuk memenuhi persyaratan Pendidikan Sarjana Fakultas

Kedokteran Universitas Muhammadiyah Malang.

Pada kesempatan ini, penulis ingin menyampaikan terimakasih kepada :

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

Muhammadiyah Malang atas ilmu dan bimbingannya selama di Fakultas

Kedokteran UMM.

2. dr. Moch. Ma’roef, Sp.OG, selaku Pembantu Dekan I Fakultas Kedokteran

UMM atas kesediaan waktu dan penyampaian ilmu yang sangat bermanfaat

bagi masa depan para mahasiswa FK UMM.

3. dr. Rahayu, Sp.S, selaku Pembantu dekan II Fakultas Kedokteran UMM

yang senantiasa bersabar dalam membimbing dan mengajarkan ilmunya

kepada kami.

iv

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

semangat dalam menyampaikan ilmu dan motivasi yang membangun

semangat kami selama menjalani pendidikan di Fakultas Kedokteran.

5. dr. Alfa Sylvestris Sp.M, selaku pembimbing 1, atas kesabaran, kebaikan

hati, serta kesediaan dalam meluangkan waktu dalam membimbing hingga

dapat menyelesaikan penelitian ini dengan baik.

6. dr. Diah Hermayanti Sp.PK, selaku pembimbing 2, atas kesabaran, kebaikan

hati, serta kesediaan dalam meluangkan waktu dalam membimbing penulis

hingga dapat menyelesaikan penelitian ini dengan baik.

7. dr. Isbandiyah Sp.PD, selaku penguji tugas akhir ini, atas segala masukan

dan arahan yang sangat bermanfaat dalam pengerjaan tugas akhir ini dan

kesediaan waktu, sehingga tugas ini dapat diselesaikan dengan baik.

8. dr. Dian Yuliartha, Sp.PA, atas kebaikan dan kesediaan meluangkan waktu

untuk membantu dalam proses pengamatan hasil penelitian.

9. Ibu, bapak, atas doa dan lelah yang diberikan dari pagi hingga pagi lagi,

serta dukungan moril dan materil yang tak pernah putus agar tugas ini dapat

selesai dengan baik. Mas Adi dan Bagus, terimakasih sudah menjadi kakak

dan adik terbaik yang membuat penulis selalu ingin kembali ke rumah.

10. Seluruh staf TU dan laboran, Mas Miftah dan Pak Joko yang bersedia

membantu setiap tahapan proses penelitian hingga penyelesaian tugas akhir

ini.

11. Pak wibi, ibu fitri dan seluruh staf Laboratorium Biokima UB, yang

bersedia membantu setiap tahapan proses penelitian hingga penyelesaian

tugas akhir ini.

v

12. Kawan seperjuangan “Grup Jintan Hitam” Imaniyah, Muqsit, Rofwiun

13. Sahabat-sahabat terbaik yang menjadi keluarga selama di Malang,

Imaniyah, Dwi, Friska, Hakimah, Laksita, Jeanny, Kinanthi, Putrinda,

Mariyah, Tari, Alfi, Mba Dwi, Linda, Dea terimakasih atas kebersamaan

yang sederhana, bantuan, kesabaran, motivasi, dukungan, dan semua yang

telah diberikan.

14. Sejawat FK UMM angkatan 2011, Adorables, atas dukungan, bantuan, dan

kerjasamanya. Semoga kelak dapat menjadi dokter-dokter profesional yang

barokah, sukses dunia akhirat, dan senantiasa dalam ketaatan kepada Allah

SWT.

15. Semua pihak yang terlibat secara langsung maupun tidak langsung,

terimakasih atas bantuan dan dukungannya.

Penulis menyadari bahwa tugas akhir ini masih jauh dari kata

sempurna. Oleh karena itu, penulis sangat mengharapkan saran dan

masukan yang membangun. Dengan mengharapkan Keridhaan-Nya, semoga

karya tulis ini dapat menambah wawasan keilmuan dan bermanfaat bagi

semua pihak.

Malang, 27 Agustus 2015

Penulis

viii

DAFTAR ISI

LEMBAR PENGESAHAN .................................................................................. i LEMBAR PENGUJIAN ...................................................................................... ii

KATA PENGANTAR ........................................................................................ iii ABSTRAK .......................................................... Error! Bookmark not defined.

ABSTRACT ........................................................ Error! Bookmark not defined. DAFTAR ISI .................................................................................................... viii

DAFTAR TABEL ............................................................................................... x DAFTAR GAMBAR .......................................................................................... xi

DAFTAR LAMPIRAN ...................................................................................... xii DAFTAR SINGKATAN .................................................................................. xiii

BAB 1 PENDAHULUAN ................................................................................... 1 1.1 Latar Belakang .................................................................................. 1

1.2 Rumusan Masalah ............................................................................. 3

1.3 Tujuan Penelitian .............................................................................. 3

1.3.1 Tujuan Umum .......................................................................... 3

1.3.2 Tujuan Khusus ......................................................................... 3

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

1.4.1 Manfaat Akademis ................................................................... 4

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

BAB 2 TINJAUAN PUSTAKA ........................................................................... 5

2.1 Jintan Hitam (Nigella sativa)............................................................. 5

2.1.1 Taksonomi dan Deskripsi Jintan Hitam (Nigella sativa) ........... 5

2.1.2 Kandungan Biji Jintan Hitam (Nigella sativa) .......................... 6

2.1.3 Ekstrak Jintan Hitam (Nigella sativa) Sebagai Anti-inflamasi ... 7

2.1.4 Fixed oil pada Jintan Hitam (Nigella sativa) ............................. 8

2.1.5 Thymoquinone pada Jintan Hitam (Nigella sativa) .................... 9

2.2 Kornea ............................................................................................ 10

2.2.1 Histologi dan Fisiologi Kornea ............................................... 10

2.2.2 Imunologi Kornea .................................................................. 12

2.3 Inflamasi Kornea............................................................................. 14

2.3.1 Inflamasi Kornea Akibat Trauma Alkali (NaOH) ................... 16

2.3.2 Peran TNFα pada Inflamasi Steril Kornea .............................. 19

2.4 Non-steroidal Anti-inflammatory Drug (NSAID) ............................ 21

BAB 3 KERANGKA KONSEPTUAL DAN HIPOTESIS ................................. 23 3.1 Kerangka Konseptual ...................................................................... 23

3.2 Hipotesis ......................................................................................... 25

BAB 4 METODOLOGI PENILITIAN .............................................................. 26 4.1 Rancangan Penelitian ...................................................................... 26

ix

4.2 Tempat dan Waktu Penelitian ......................................................... 26

4.3 Populasi dan Sampel ....................................................................... 26

4.3.1 Populasi ................................................................................. 26

4.3.4 Teknik Pengambilan Sampel .................................................. 28

4.3.5 Karakteristik Sampel Penelitian .............................................. 28

4.3.6 Variabel Penelitian ................................................................. 28

4.3.7 Definisi Oprasional Variabel Penelitian .................................. 28

4.4 Alat dan Bahan Penelitian ............................................................... 29

4.4.1 Alat ........................................................................................ 29

4.4.2 Bahan ..................................................................................... 30

4.5 Prosedur Penelitian ......................................................................... 31

4.5.1 Pembuatan Ekstrak Jintan Hitam (Nigella sativa) Topikal

Tetes Mata.............................................................................. 31

4.5.2 Sediaan Natrium Diklofenak 1% tetes mata topikal ................ 32

4.5.3 Perlakuan Sampel ................................................................... 32

4.5.4 Adaptasi ................................................................................. 33

4.5.5 Pengambilan Sampel Kornea .................................................. 33

4.5.7 Penghitungan Ekspresi TNFα ................................................. 37

4.6 Analisis Statistik ............................................................................. 37

4.7 Alur Penelitian ................................................................................ 38

4.8 Penguburan Tikus Percobaan .......................................................... 39

BAB 5 HASIL PENELITIAN DAN ANALISIS DATA .................................... 40

5.1 Hasil Penelitian ............................................................................... 40

5.2 Analisis Data .................................................................................. 41

5.2.1 Uji Normalitas ........................................................................ 41

5.2.2 Uji Statistik Non-Parametric Kruskal-Wallis .......................... 41

5.2.3 Uji Post Hoc Mann-Whitney .................................................. 42

BAB 6 PEMBAHASAN .................................................................................... 44

BAB 7 KESIMPULAN DAN SARAN .............................................................. 48 7.1 Kesimpulan ..................................................................................... 48

7.2 Saran............................................................................................... 48

DAFTAR PUSTAKA ........................................................................................ 49 LAMPIRAN ...................................................................................................... 55

x

DAFTAR TABEL

Tabel Halaman

2.1 Bahan Aktif Nigella sativa ………...…………………………….………. 7

2.2 Klasifikasi trauma alkali .............................................................................. 18

2.3 Fase penyembuhan pada defek kornea akibat trauma alkali ....................... 19

4.1 Scoring TNF α untuk Analisis Semikuantitatif............................................. 29

5.1 Hasil Pengamatan Ekspresi TNFα pada kornea tikus putih jantan

(Rattus novergicus strain wistar) Model Inflamasi..................................... 40

5.2 Hasil Uji Normalitas (Shapiro-Wilk)............................................................ 41

5.3 Hasil Uji Kruskal-Wallis............................................................................... 42

5.4 Perbandingan Nilai Asymp. Sig. dari Uji Mann-Whitney

Semua Kelompok Uji ................................................................................... 42

xi

DAFTAR GAMBAR

Gambar Halaman

2.1 Tanaman, bunga dan biji (Nigella sativa) .................................................... 5

2.2 Usulan jalur biosintesis thymoquinone dalam biji (Nigella sativa) .............. 9

2.3 Potongan melintang kornea .......................................................................... 11

2.4. Konsep mekanis migrasi neutrofil ke daerah cedera kornea ...................... 13

2.5 Mekanisme inflamasi steril ........................................................................... 18

4.1 Lokasi pengambilan sampel kornea .............................................................. 33

4.2 Gambaran TNFα dalam pewarnaan imunohistokimia ................................. 37

5.1 Grafik Hasil Pengamatan Ekspresi TNFα pada Kornea Tikus Putih

Jantan (Rattusnovergicus strain wistar) ...................................................... 40

xii

DAFTAR LAMPIRAN

Lampiran Halaman

Lampiran 1 Data Primer Hasil Penelitian .......................................................… 55

Lampiran 2 Analisis Data Statistik .................................................................… 56

Lampiran 3 Dokumentasi Penelitian ................................................................... 63

Lampiran 4 Determinasi Tanaman Jintan hitam ................................................. 65

Lampiran 5 Surat Keterangan Ekstrak Jintan Hitam ......................................... 66

Lampiran 6 Surat Keterangan Penelitian Lab. Biokimia UB ............................. 67

Lampiran 7 Surat Keterangan Penelitian Lab. Biomedik UMM ....................... 68

Lampiran 8 Surat Keterangan Kelaikan Etik ...................................................... 69

Lampiran 9 Surat Keterangan Pembacaan PA .................................................... 70

Lampiran 10 Kartu Konsultasi Tugas Akhir ....................................................... 71

xiii

DAFTAR SINGKATAN

CME : cystoids macular edema

COX : cyclooxygenase

COX2 : cyclooxygenase 2

DAMPs : damage-associated molecular patterns

EGFR : epidermal growth factor receptor

GM-CSF : granulocyte-macrophage colony-stimulating factor

HMGB1 : high-mobility group box 1

IFNγ : Interferon γ

IL-1 : interleukin 1

IL1-R : IL-1 receptor

IL-1β : interleukin-1β

IL-6 : Interleukin 6

iNOS : inducible nitric oxide synthase

LC : langerhans cell

LT : leukotrien

MAPKs : mitogen-activated protein kinase

MMP 9 : matrix metalloproteinase 9

NK : natural killer

NLRP3 : nucleotide-binding oligomerization domain (NOD)-like receptor

and pyrin domain-containing 3

NO : nitric oxide

NOD : nucleotide-binding oligomerization domain

xiv

NSAID : nonsteroidal antiinflammatory drug

PBS : phosphate buffered saline

PEE : punctate epithelial erosion

PEK : punctate epithelial keratitis

PG : prostaglandin

PGD₂ : prostaglandin D₂

PGE₂ : prostaglandin E₂

PGF₂ : prostaglandin F₂

PGI₂ : prostaglandin I₂

PRR : pathogen recognition receptor

RAGE : receptor for advanced glycation end-product

ROI : reactive oxygen intermediates

TIO : tekananan intraokular

TLRs : toll-like receptor

TNFα : tumor necrosis factor α

TXA₂ : tromboxsan A₂

WHO : world health organization

49

DAFTAR PUSTAKA

Abelson, Mark B. 2011. It’s Time to Think About the Blink : In addition to

defending the eye from particles and allergens, the blink can help

diagnose certain diseases as well. Available at :

http://www.reviewofophthalmology.com/content/d/therapeutic_topics/c/28

665/#sthash.IOewbtgm.dpuf (25 Agustus 2015)

Ahmad A, Husain A, Mujeeb M. et al . 2013. A Review on Therapeutic Potential

of Nigella sativa: A Miracle Herb. Asian Pasific Journal of Tropical

Biomedicine. 3(5): 337-352. DOI: 10.1016/S2221-1691(13)60075-1 (1

Maret 2015)

Al Obeed O.A, Alkhayal K.A, Al Sheikh A. et al . 2014. Increased Expression of

Tumor Necrosis Factor-α is Associated with Advanced Colorectal Cancer

Stages. World J Gastroenterol. 20(48):18390-18396. DOI:10.3748/wjg.

v20.i48.18390 (14 April 2015)

Alemi M, Sabouni F, Sanjarian F. et al . 2012. Anti-inflammatory Effect of Seeds

and Callus of Nigella sativa L. Extracts on Mix Glial Cells with Regard to

Their Thymoquinone Content. AAPS PharmSciTech. Vol. 14, no. 1. DOI:

10.1208/s12249-012-9899-8. (23 November 2014)

Al-Mutheffer E.A. 2010, The Effect of Local Aplication Black Seed (Nigella

sativa) Oil on Wound Healing in Rabbits. Al-Anbar J. Vet. Sci. Vol: 3,

No. (1) (25 Maret 2015)

American Academy of Ophtalmology Cornea/Eksternal Disease Pannnel.

Preferred Practice Pattern®Guideline. Corneal Ectasia. San Francisco,

CA: American Academy of Ophtalmology; 2013. Available at:

www.aao.org/ppp (10 Februari 2015)

Biolegend. 2008. Immunohistochemistry Protocol for Parrafin-Embedded

Sections. Available at: http://www.biolegend.com/media_assets/support_

protocol/BioLegend_IHC_Paraffin.pdf (10 Desember 2014)

Botnick I, Xue W, Bar E. et al . 2012. Distribution of Primary and Specialized

Metabolites in Nigella sativa Seed, a Spice with Vast Traditional and

Historitical Uses. Molecules. 17, 10159-10177. ISSN 1420-3049 (15

Maret 2015)

Boudreau, Lee. 2011. Principles of Immunohistochemistry : Queen’s Laboratory

For Molecular Pathology. Available at : http://www.path.queensu.ca/

qlmp/sites/default/files/Principles_of_ImmunoHisto_Chemistry%20(1).pd

f (25 Agustus 2015)

Brunton L.L, Parker K.L, Blumenthal D.K. et al . 2010. Goodman & Gilman :

Manual Farmakologi dan Terapi. Jakarta : EGC. Hal 1055

50

Burns A.R, Li Z and Smith W. 2005. Neutrophil Migration in the Wounded

Cornea: The Role of the Keratocyte from Cullen Symposium on Corneal

and Ocular Surface Inflammation. The Ocular Surface. Vol: 3, No. (4).

pp:s-173-s-176 (31 Agustus 2014)

Cade F, Paschalis E.I, Regatieri C.V. et al. 2013. Alkali Burn to the Eye:

Protection Using TNF- a Inhibition. Cornea; 0 pp:1–8. Available at:

www.corneajrnl.com (4 Agustus 2015)

Chehl N, Chipitsyna G, Gong Q. et al. 2009. Anti-inflammatory effects of the

Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells.

HPB 11, 373–381 DOI:10.1111/j.1477-2574.2009.00059.x (4 Agustus

2015)

Chen G.Y and Nunez G. 2010. Sterile Inflammation : Sensing and Reacting to

Damage. Nat Rev Immunol. 10(12): 826–837. DOI: 10.1038/nri2873. (25

Maret 2015)

Choi J.A, Choi J.S and Joo C.K. 2011. Effect of Amniotic Membrane Suspension

in The Rat Alkali Burn Model. Molecular vision; 17:404-412. http://

www.molvis.org/molvis/v17/a45 (25 Maret 2015)

Colatrella N and Varanelli J.R. 2013. Chemical Injuries to the Cornea : Not Your

Typical Epithelial Defect. Advance Ocular Care (25 Maret 2015)

Crane A.M, Hua H.U, Coggin A.D. et al. 2012. Biocemistry and Molecular

Biology : Mass Spectrometric Analyses of Phosphatidylcholine in Alkali-

Exposed Corneal Tissue. IOVS. Vol. 53, No. 11. pp: 7122-7130 (25 Maret

2015)

Cursifen C. 2009. Immune Privilege and Angiogenic Privilege of the Cornea.

Cornea, Conjungtiva and Refractive Surgery Course Book EUPO. pp: 85-

93 Tersedia: www.eupo.eu (1 Maret 2015)

Dana, Reza. 2007. Comparison of Topical Interleukin-1 Vs Tumor necrosis

Factor-alpha Blockade with Corticosteroid Therapy on Murine Corneal

Inflammation, Neovascularization, and Transplant Survival. An American

Ophthalmological Society Thesis: Published. (8 Mei 2015)

Ellenberg D, Azar D.T, Hallak J.A. et al . 2010. Novel Aspects of Corneal

Aniogenic and Lymphangiogenc Privilege. Prog Retin Eye Res. 29(3):

208-248. DOI:10.1016/j.preteyers. 2010.01.002 (25 Maret 2015)

Erdumus M, Yagci R, Yilmaz B. et al . 2007. Inhibitory Effect of Topical

Thymoquinone on corneal Neovascularization. Cornea. Vol: 26, No. (6)

pp : 715-719 (29 Agustus 2014)

Eva Paul Riordan. 2009. Anatomi & Embriologi Mata in : Vaughan & Asbury

Oftamologi Umum (Edisi 17). Jakarta : EGC. pp: 8,10

51

Flach A.J and Fraunfelder F.W. 2009. Obat-Obat Mata, in : Vaughan & Asbury

Oftamologi Umum (Edisi 17). Jakarta : EGC. pp: 68

Fredriksson L, Herpers B, Benedetti G. et al . 2011. Diclofenac Inhibits Tumor

Necrosis Factor-α-induced Nuclear Factor-κB Activation Causing

Synergistic Hepatocyte Apoptosis. Hepatology. Vol: 53, No.(6).

DOI:10.1002/hep.24314 (14 Mei 2015)

Frey H, Schroeder N, Jensen T.M. et al . 2013. Biological Interplay between

Proteoglycans and Their Innate Immune Receptor in Inflammation. FEBS

Journal 280: 2165-2179. DOI:10.1111/febs.12145 (25 Mei 2015)

Gagen, Debjani. 2011. Cellular and Molecular Mechanisms of Corneal

Inflammation and Wound Healing. Disertation Doctor of Philosophy in

Physiological Optics at Faculty of the College of Optometry Houston

University: Published. (11 Oktober 2014)

Giambelluca M.S, Robert-Labelle E, Bertheu-Mailhot G. et al. 2013. Post

transcriptional regulation of tumour necrosis factor alpha biosynthesis:

Relevance to the pathophysiology of rheumatoid arthritis. OA

Inflammation 01;1(1):3 pp:1-6 (4 Agustus 2015)

Islam M.H, Ahmad I.Z and Salman M.T. 2012. Antibacterial Activity of Nigella

sativa Seed in Various Germination Phase on Clinical Bacterial Strain

Isolated From Human Patient. E3 Journal of Biotechnology and

Pharmaceutical Research. Vol. 4(1), pp 8-13. ISSN 2141-7474 (1 Maret

2015)

Joussen A.M, Rohrscheneider K, Reichling J et al. 2008. Treatment of Corneal

Neovascularization with Dietary Iso¯avonoidsand Flavonoids. Exp. Eye

Res. 71, 483-487 (4 Agustus 2015)

Kanski J.J and Bowling B. 2011. Clinical Ophtalmology : a systematic Approach

(7th

ed). Elsevier Limited. pp: 168-172

King T.C. 2007. Inflammation, inflammatory Mediators and Immune-Mediated

Disease in Elsevier’s Integrated : Pathology. MosbyElsevier. pp: 21-57

Kresno, Siti Boedina. 2013. Imunologi: Diagnosis dan Prosedur Laboratorium

(edisi kelima). Jakarta: Badan Penerbit FKUI. pp: 117,130,221

Lin K.J, Loi M.X, Lien G.S. et al . 2013. Topical Administration of Orbital Fat-

Derived Stem Cell Promotes corneal Tissue Regeneration. Stem Cell

Research & Therapy. 4;72. pp: 1-12 Available at: http://stemcellres.com/

content/4 /3/72 (9 Mei 2015)

Lu P, Li L, Liu G. et al . 2012. Critical Role of TNF-a-Induced Macrophage

VEGF and iNOS Production in the Experimental Corneal

Neovascularization. IOVS. Vol: 53, No (7), pp.3516-3525. DOI:

10.1167/iovs. 10-5548 (25 Mei 2015)

52

Lucia E.W. 2011. Eksperimen Farmakologik Orientasi Preklinik (Edisi Prabu).

Surabaya: Sandira Surabaya. pp: 22-30.

Marrazzo G, Bellner L, Halilovic A. et al . 2011. The Role of Neutrophils in

Corneal Wound Healing in HO-2 Null Mice. PLoS ONE 6(6):e21180. doi:

10.1371/journal .pone.00211 80 (7 Mei 2015)

McKenzie M and Whitley W. 2012. Review of Cornea and Contact Lens: a

Closer Look at Corneal Inflammation. Available at: http://www.reviewof

contactlenses.com/content/d/irregular_cornea/c/37560/ (25 maret 2015)

Mescher, Anthony L. 2013. Junqueira’s basic Histology: Text & Atlas (edition:

13th). McGraw-Hill eBooks. pp: 483

Moroi S.E and Lichter P.R. 2007. Goodman & Gilman : Manual Farmakologi

dan Terapi vol.2 Edisi 10. Jakarta : EGC. Hal 1795

Newton, K and Dixit, V.M. 2012. Signaling in Innate Immunity and

Inflammation. Cold Spring Harb Perspect Biol. 4:a006049. DOI: 10.1101

/cshperspect .a006049. (30 Maret 2015)

Niederkorn J.Y. 2011. Cornea: Window to Ocular Immunology. Curr Immunol

Rev. 7(3):328-335.DOI: 10.2174/157339511796196539 (25 Maret 2015)

Paarakh, Padma M. 2010. Nigella sativa Linn.- A Comprehensive Review. Indian

Journal of Natural Product and Resources. Vol. 1(4), pp.409-429 (16

Maret 2015)

Pareira R.V, Kumar A, Pandey B.N. et al . 2012. Radioprotection by Macerated

Extract of Nigella sativa in Normal Tissues of Fibrosarcoma Bearing

Mice. Indian J Pharm Sci. 74(5): 403-414. DOI: 10.4103/0250-

474X.108415. Available at: http://www.ncbi.nlm.nih.gov/

pmc/articles/PMC3660866/ (21 Mei 2015)

Rajsekhar S and Kuldeep B. 2011. Pharmacognosy and Pharmachology of

Nigella sativa - a Review. International Research Journal of Pharmacy.

2(11), 36-39. ISSN 2230-8407 (15 Maret 2015)

Ridwan, Endi. 2013. Etika Pemanfaatan Hewan Percobaan dalam Penelitian

Kesehatan. J Indon Med Assoc. Vol: 63, No: 3 (25 Maret 2015)

Russo A, Costagliola C, Delcassi L. et al . 2013. Topical Nonsteroidal Anti-

Inflammatory Drugs for Macular Edema. Mediator of Inflamation, ID

476525. Avalaible at : http://dx.doi.org/10.1155/2013/476525 (28 Maret

2015)

Sakimoto T, Yamada A and Sawa M. 2009. Release of Soluble Tumor Necrosis

Factor Receptor 1 from Corneal epithelium by TNF-α-Converting

Enzyme-Dependent Ectodomain Shedding. IOVS 2009. Vol. 5, No. 10. Pp:

53

4618-4621. Available at : http://iovs.arvojournals.org/pdfaccess.ashx?

url=/data/Journals/IOVS/933243 (22 Mei 2015)

Salem M.L. 2005. Immunomodulatory and Theurapeutic Properties of the Nigella

sativa L. seed. International Immunopharmacology. 5: 1749-1770 (27

April 2015)

Salim L.Z.A, Mohan S, Othman R. et al .2013. Tymoquinone Induce

Mitochondria-Mediated apoptosis in Acute Lymphoblastic Leukaemia in

Vitro. Molecules ;18, 11219-11240. ISSN 1420-3049 (16 Maret 2015)

Saryono. 2011. Metodologi Penelitian Kesehatan Penuntun Praktis Bagi Pemula.

Mitra Cendika Press. Yogyakarta. pp.42-43.

Sawazaki R, Ishihara T, Usui S. et al . 2014. Diclofenac Protects Cultured Human

Corneal Epithelial Cell Against Hyperosmolarity and Ameliorates

Corneal Surface Damage in a Rat Model of Dry Eye. Invest Ophthalmol

Vis Sci 55:2547–2556. DOI:10.1167/iovs.13-13850 (14 Mei 2015)

Seif , Ansam Aly. 2014. Nigella Sativa reverses osteoporosis in ovariectomized

rats. BMC Complementary and Alternative Medicine 2014, 14:22 pp: 1-8

doi:10.1 186/1472 -6882-14-2 2 (4 Agustus 2015)

Sethi G, Ahn K.S and Aggarwal B.B. 2008. Targeting Nuclear Factor-κB

Activation Pathway by Thymoquinone: Role in Suppression of

Antiapoptotic Gene Products and Enhancement of Apoptosis. Mol Cancer

Res; 6(6). DOI 10.1158/1541-7786-MCR-07-2088. (2 November 2014)

Subijanto A.A and Diding H.P.2008. Pengaruh Minyak Biji Jinten Hitam (Nigella

Sativa L.) terhadap Derajat Inflamasi Saluran Napas. Majalah Kedokteran

Indonesia. Vol. 58, no.(6). pp.200-204. (25 April 2015)

Sylvestris A, Ma’roef M, Azizi R.N. et al . 2012. Pengaruh Pemberian Ekstrak

Jintan Hitam (Nigella sativa) terhadap Proses Inflamasi konjungtiva dan

Kornea (Interlukin 1 / IL-1 dan Matrix Matalloproteinase 9 / MMP-9 dan

Proses Epitelisasi Kornea (Epidermal Growth Factor Receptor / EGFR)

pada tikus putih (Rattus novergicus strain wistar) yang diovariektomi

(Hipoestrogen). Laporan Hasil Penelitian Program Hibah Kompetisi

Peningkatan Kualitas Pendidikan Dokter (PKH-PKDD) Fakultas

Kedokteran Universitas Muhammadiyah Malang: dipublikasikan.

Tripathi T and Alizadeh H.2014. Role of Protease-Activated Receptor 2 (PAR2)

in Ocular Infection and Inflammation. Receptors & Clinical Investigaion.

1: e291. Available at: http://www.smartscitech.com/index.php/rci (7 April

2015)

Venkatachallam S.K.T, Pattekhan H, Divakar S. et al . 2010. Chemical

Composition of Nigella sativa L. Seed Extracts Obtained by Supercritical

Carbon Dioxide. J Food Sci Technol. 47(6): 598-605. DOI:10.1007/

s13197-010-0109-y. (8 Mei 2014)

54

Waseem M and Humayun S. 2009. Comparison of Anti-Inflammatory Activity of

Dexamethasone and Diclofenac Sodium Eye Drops in

Phacoemulsification. Journal of the College of Physician and Surgeon

Pakistan. Vol. 19 (9): 570-574. (12 Februari 2015)

Willoughby C.E, Ponzin D, Ferrari S. et al . 2010. Anatomy and Physiology of

the Human Eye: Effect of Mucopolysaccharidoses Disease on Structure

and Function-A Review. Clinical and Experimental Opthalmology. 38: 2-

11. DOI: 10.1111/j.1442-9071.2010.02363.x (25 maret 2015)

World Health Organization. 2010. Visual Impairentment and Blindness 2010

(online).Tersedia:http://www.who.int/blindness/data_maps/VIFACTSHEE

TGLODAT2010full.pdf (5 November 2014)

Yanai K, Huang J, Kadonosono K. et al .2013. Corneal Sensitivity After Topical

Bromfenac Sodium Eye-drop Instillation. Clinical Ophtalmology .7 :741-

744. (12 Februari 2015)

Yi K, Chung T.Y, Hyon J.Y. et al . 2011. Combined Treatment with Antioxidants

and Immunosupressants on Cytokine Release by Human Peripheral Blood

Mononuclear Cells-Chemically Injured Keratocyte Reaction. Molecular

Vision; 17: 2665-2671. Available at: http://www.molvis.org/molvis/

v17/a288 (25 Maret 2015)

Zhang, Xiaoyan. 2013. Genetic Variation in Prediction of Drug Efficacy and

Toxicity. Clinic Pharmacol Biopharmaceut 2: e113. DOI: 10.4172/2167-

065X.1000e113 (5 Agustus 2015)