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Abstrak :
Latar belakang : Overtraining berdampak buruk terhadap kesehatan karena dapat menyebabkan kematian mendadak pada atlet muda. Berdasarkan data epidemiologi ditemukan bahwa kejadian kematian mendadak (suddent cardiac death) pada atlet muda, penyebab paling banyak adalah gangguan kardiovaskular. Tubuh melakukan adaptasi terhadap beban berlebih, berupa remodelling (morfologi dan elektrofisiologi). Remodeling elektrofisiologis yaitu perubahan pada gap junction, berupa perubahan ekspresi Cx43 yang yang mengakibatkan gangguan penghantaran konduksi listrik. Selama latihan fisik dapat terbentuk ROS yang akan menginduksi permeabilitas mitokondria sehingga terjadi kebocoran sitokrom c, selanjutnya akan mengaktifkan kaskade apoptosis. Metode : Penelitian ini dilakukan pada 6 jaringan kardiomiosit tikus Wistar kelompok kontrol dan overtraining. Ekspresi Cx43 dan caspase-3 diamati melalui pulasan imunohistokimia dan diukur dengan image J. Hasil : Hasil penelitian ini menunjukkan peningkatan bermakna pada ekspresi Cx43 total overtraining (43644.57±27711.03) dibandingkan kelompok kontrol (13002.37±3705.41). Tidak ditemukan perbedaan bermakna ekspresi caspase-3 pada kedua kelompok meskipun diperoleh hasil lebih tinggi pada kelompok overtraining (14.15%±10.54%) dibandingkan kelompok kontrol (2,63%±3.56%). Kesimpulan : Overtraining meningkatkan ekspresi Cx43 total tetapi tidak terbukti meningkatkan caspase-3 pada kardiomiosit ventrikel kiri tikus. ......Background: overtraining has bad effect for health, overtraining can cause sudden death in young athlete, reports of sudden death incidences in young athlete claim that cardiovascular disease is the cause. The heart can face the excess load by remodeling as it?s adaptation mechanism. There is 2 type remodeling, morphology and electrophysiology. Remodeling electrophysiology is a change on Cx43 expression which can interfere the heart?s electrical conduction. Free radical which formed from physical exercise can induce mitochondrial permeability that lead leakage of cytochrome c, so that so that activate the apoptosis cascade. Methods: This study conducted on 12 Wistar rat?s cardiomyocytes tissue that divided into control and overtraining group. Cx43 expression and caspase-3 was observed through immunohistochemical staining and measured by image J. Results: There was significant increase in the expression of Cx43 total overtraining (43644.57 ± 27711.03) compared to the control group (13002.37 ± 3705.41). Found no significant differences in the expression of caspase-3 in both groups although the result was higher in the group of overtraining (14,15% ± 10,54%) compared to the control group (2,63% ± 3,56%). Conclusion: Overtraining increase total Cx43 expression but not proven to increase caspase-3 in the rat left ventricular cardiomyocytes.

Abstrak :
Latar Belakang: Alopesia androgenetik (AAG), merupakan kelainan rambut yang mengganggu secara psikososial bagi sebagian besar lelaki. Pengobatan yang ada saat ini masih terbatas. Kinin secara empirik telah digunakan sebagai zat penumbuh rambut. Namun belum ada penelitian untuk menilai mekanisme kerja dan efektivitas kinin topikal terhadap pertumbuhan rambut. Metode: Kajian in silico molecular docking dan molecular dynamic simulation dilakukan untuk menilai afinitas kinin terhadap enzim 5α-reduktase dengan kontrol finasterid. Uji hambatan kinin terhadap 5α-reduktase secara in vitro dinyatakan sebagai nilai IC50 kinin, dengan finasterid sebagai pembanding. Pada percobaan in vivo, 28 ekor mencit C57BL/6 dibagi secara acak menjadi 7 kelompok terdiri dari 4 ekor. Kelompok (A) testosteron (alopesia),yang di suntik 1 mg testosteron secara subkutan,(B) testosteron+finasterid 2%(C) kelompok normal, dan kelompok (D-G) testosteron+kinin 0,5%,1%,1,5% dan 2 %. Dioles bahan uji sesuai kelompok setiap hari selama 28 hari. Luas dan panjang rambut dinilai secara visual setiap minggu. Pemeriksaan histologi (morfologi dan kepadatan folikel rambut), pemeriksaan imunohistokimia kaspase-3, pemeriksaan ELISA PGE2 dan pemeriksaan MDA dilakukan setelah 28 hari. Hasil : Hasil in silico menunjukkan kinin mempunyai afinitas yang cukup baik terhadap 5β-reduktase, meskipun lebih rendah dibanding finasterid (ΔG kinin -31,67 kj/mol dan ΔG finasterid -42,89 kj/mol dari hasil penambatan molekuler; serta ΔG kinin -6,32±12,84 kj/mol dan ΔG finasterid -11,17±18,92 kj/mol dari hasil simulasi dinamika molekuler. Hasil pengukuran hambatan enzim 5α-reduktase didapatkan IC50 kinin 10,6 ±1,40 uM dan IC50 finasterid 0,623 ± 0,14 nM. Luas area pertumbuhan rambut semua kelompok perlakuan kinin lebih luas dibandingkan kelompok alopesia dan berbeda bermakna pada pada minggu ke-3 dan ke-4. Gambaran histopatologi morfologi rambut semua kelompok didominasi fase anagen . Rasio anagen: telogen kelompok perlakuan kinin lebih tinggi dibandingkan kelompok alopesia. Kepadatan folikel rambut kelompok perlakuan kinin lebih tinggi secara bermakna daripada kelompok alopesia. Kinin 0,5%, 1%, dan finasterid menurunkan ekspresi kaspase-3. PGE2 meningkat pada semua kelompok perlakuan kinin, tertinggi pada kinin 2%. dan berbeda bermakna terhadap kelompok alopesia. Pemberian kinin tidak mampu menurunkan kadar MDA. Kesimpulan: Pemberian kinin pada mencit jantan yang diinduksi testosteron mempunyai efek menumbuhkan rambut, meningkatkan kepadatan folikel rambut. Kinin menghambat enzim 5α-reduktase, meningkatkan kadar PGE2, menurunkan ekspresi Kaspase-3, tetapi tidak menurunkan MDA. Kinin potensial dikembangkan sebagai penumbuh rambut. Background: Androgenetic alopecia (AGA), is a hair disease which lead to negative psychological effects in most of its sufferers. Currently, treatments of AGA are limited to topical minoxidil and oral finasterid, which possess many side effects. Quinine had empirically used as herbal hair grower, but its mechanism of action and effectiveness are not studied yet. Methods: Molecular docking was done to analyse the inhibition affinity of the 5β-reductase enzyme of both quinine and finasteride as control. Further, an in vitro test for inhibition of 5α-reductase was carried out by measuring the IC50 on both compounds. The experimental study used male C57BL/6 mice aged 7 weeks. Mice were randomly divided into 7 groups of 4 animals, namely (A) testosterone (alopecia group) which was performed subcutaneous injection of 1 mg testosterone on the back of mice (B) testosterone+2% finasterid, (C) normal group, (D-G) testosterone+0.5%, 1% , 1.5% and 2% quinine. Application of the test material on the back of the mice was carried out daily for 28 days. Hair growth assessment was done visually by assessing hair growth area every week. Histologic examination ( hair morphology and density of hair follicles), immunohistochemical examination of caspase-3, ELISA examination for PGE2, and lipid peroxidase by MDA examination were carried out after 28 days. Results: The results of molecular docking showed that quinine had a good affinity for 5β-reductase, but it was lower than finasterid (ΔG quinine = -31.67 kJ/mol vs ΔG finasterid = 42.89 kJ/mol and from dynamic simulation ΔG quinine -6,32±12,84 kj/mol and ΔG finasteride -11,17±18,92 kj/mol). The IC50 of quinine was 10.6 ± 1.40 uM, while finasterid was 0.623 ± 0.14 nM.The area of hair growth in the quinine treatment group was wider than the alopecia group and showed significance on the 3rd and 4th week. Histopathological features all of the groups was dominated by the anagen phase. The anagen:telogen ratio of the alopecia group was lower than that of the quinine group. The density of hair follicles in the treatment group and the alopecia group was statistically significant.The administration of 0.5% and 1% quinine, as well as finasterid, decreased the expression of caspase-3. PGE2 was increased in the quinine treatment group and significant compared to the alopecia group. MDA levels were higher in quinine compared to alopecia group. Conclusion: Quinine was efficacious in promoting hair growth in AGA mouse models. It is inhibited 5α-reductase enzyme, increasing PGE2, decreasing caspase-3. However it was unable to suppress MDA levels. Hence, topical quinine has the potential to be further developed into a herbal medicine for hair growth.

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[ABSTRAK
Pendahuluan: Penurunan kadar Zink (Zn) pada prostat berkorelasi dengan peningkatan skor Gleason adenokarsinoma prostat dan menyebabkan rendahnya Caspase-3 sebagai eksekutor apoptosis. Tingkat ekspresi transporter Zn pada sel tumor prostat berhubungan dengan tingkat keganasannya. ZnT-1 merupakan transporter Zn ke luar sel prostat, sedangkan ZIP-1 merupakan transporter Zn ke dalam sel prostat. Ekspresi ZIP-1 turun pada adenokarsinoma prostat. Korelasi ZnT-1, ZIP-1 dan Caspase-3 diduga berpengaruh dalam karsinogenesis prostat, sehingga berpotensi untuk menjadi faktor prognosis adenokarsinoma prostat. Tujuan: Mempelajari korelasi ekspresi ZnT-1 dan aktivasi Caspase-3 terhadap skor Gleason, menganalisis korelasi ekspresi ZIP-1, ZnT-1 dan aktivasi Caspase- 3, serta mengetahui profil ekspresi ZnT-1 pada jaringan adenokarsinoma prostat yang berbeda skor Gleason, dibandingkan dengan jaringan Benign Prostatic Hyperplasia (BPH), Desain: Studi retrospektif analitik potong lintang. Metode: Sampel penelitian ini adalah 31 blok parafin prostat yang dikelompokkan menjadi BPH, adenokarsinoma prostat skor Gleason ≤ 7 dan skor Gleason > 7. Ekspresi ZnT-1 dinilai dengan pulasan imunohistokimia. Data ekspresi ZIP-1 dan Caspase-3 merupakan data sekunder dari penelitian Septiawan et al. Hasil: Ekspresi ZnT-1 berkorelasi dengan skor Gleason adenokarsinoma prostat. Ekspresi ZIP-1 berkorelasi dengan aktivasi Caspase-3 pada adenokarsinoma prostat dan adenokarsinoma prostat skor Gleason ≤ 7. Ekspresi ZnT-1 berkorelasi dengan ekspresi ZIP-1 pada adenokarsinoma prostat skor Gleason > 7. Ekspresi ZIP-1 berkorelasi kuat dengan aktivasi Caspase-3 pada adenokarsinoma prostat skor Gleason 8. Ekspresi ZnT-1 pada adenokarsinoma prostat skor Gleason > 7 lebih rendah dibandingkan pada skor Gleason ≤ 7, tetapi tidak dapat dianalisis kemaknaan perbedaannya dengan BPH karena hanya diperoleh 1 sampel BPH pada penelitian ini. Kesimpulan: Transporter Zn berpotensi untuk menjadi faktor prognosis adenokarsinoma prostat.

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ABSTRACT
Background: Decreased levels of Zinc ( Zn ) in the prostate correlates with an increase in the grade Gleason score of prostate adenocarcinoma and decrease in Caspase-3 as apoptosis executor. Zn transporter expression levels in prostate tumor cells associates with the level of malignancy. The ZnT-1 is Zn exporter, while the ZIP-1 is Zn importer of prostate cells. ZIP-1 expression drops on adenocarcinoma prostate. Correlation ZnT-1, ZIP-1 and Caspase-3 allegedly influential in prostate carcinogenesis and potential to be prognostic factor of prostate adenocarcinoma. Objective: To analyze the correlation ZnT-1 and Caspase-3 activation of the gleason score, to analyze the correlation of the expression of ZIP-1, ZnT-1 and Caspase-3 activation in adenocarcinoma prostate, and to study the profile expression of ZnT-1 in prostate adenocarcinoma with different grading of Gleason scores, compared with benign prostatic hyperplasia (BPH), Design: A cross-sectional retrospective study analytic . Methodology: The sample is 31 paraffin blocks were grouped into BPH, prostate adenocarcinoma Gleason scored ≤ 7 and prostate adenocarcinoma Gleason scored > 7. Samples are analyzed expression of ZnT-1 by immunohistochemical staining. ZIP-1 and Caspase-3 expression is secondary data of Septiawan et al?s immunohistochemical staining. Results: ZnT-1 expression correlated with gleason score. ZIP-1 correlated with the activation of Caspase-3 in prostate adenocarcinoma and prostate adenocarcinoma Gleason score ≤ 7. ZnT-1 correlated with ZIP-1 in prostate adenocarcinoma Gleason score > 7. ZnT-1 expression in prostate adenocarcinoma Gleason scored > 7 was lower than prostate adenocarcinoma Gleason score ≤ 7, but could not be analyzed the difference significance with BPH because there was only 1 BPH sample in this research. Conclusion: Zn transporters have the potential to be a prognostic factor of prostate adenocarcinoma.;Background: Decreased levels of Zinc ( Zn ) in the prostate correlates with an increase in the grade Gleason score of prostate adenocarcinoma and decrease in Caspase-3 as apoptosis executor. Zn transporter expression levels in prostate tumor cells associates with the level of malignancy. The ZnT-1 is Zn exporter, while the ZIP-1 is Zn importer of prostate cells. ZIP-1 expression drops on adenocarcinoma prostate. Correlation ZnT-1, ZIP-1 and Caspase-3 allegedly influential in prostate carcinogenesis and potential to be prognostic factor of prostate adenocarcinoma. Objective: To analyze the correlation ZnT-1 and Caspase-3 activation of the gleason score, to analyze the correlation of the expression of ZIP-1, ZnT-1 and Caspase-3 activation in adenocarcinoma prostate, and to study the profile expression of ZnT-1 in prostate adenocarcinoma with different grading of Gleason scores, compared with benign prostatic hyperplasia (BPH), Design: A cross-sectional retrospective study analytic . Methodology: The sample is 31 paraffin blocks were grouped into BPH, prostate adenocarcinoma Gleason scored ≤ 7 and prostate adenocarcinoma Gleason scored > 7. Samples are analyzed expression of ZnT-1 by immunohistochemical staining. ZIP-1 and Caspase-3 expression is secondary data of Septiawan et al?s immunohistochemical staining. Results: ZnT-1 expression correlated with gleason score. ZIP-1 correlated with the activation of Caspase-3 in prostate adenocarcinoma and prostate adenocarcinoma Gleason score ≤ 7. ZnT-1 correlated with ZIP-1 in prostate adenocarcinoma Gleason score > 7. ZnT-1 expression in prostate adenocarcinoma Gleason scored > 7 was lower than prostate adenocarcinoma Gleason score ≤ 7, but could not be analyzed the difference significance with BPH because there was only 1 BPH sample in this research. Conclusion: Zn transporters have the potential to be a prognostic factor of prostate adenocarcinoma.;Background: Decreased levels of Zinc ( Zn ) in the prostate correlates with an increase in the grade Gleason score of prostate adenocarcinoma and decrease in Caspase-3 as apoptosis executor. Zn transporter expression levels in prostate tumor cells associates with the level of malignancy. The ZnT-1 is Zn exporter, while the ZIP-1 is Zn importer of prostate cells. ZIP-1 expression drops on adenocarcinoma prostate. Correlation ZnT-1, ZIP-1 and Caspase-3 allegedly influential in prostate carcinogenesis and potential to be prognostic factor of prostate adenocarcinoma. Objective: To analyze the correlation ZnT-1 and Caspase-3 activation of the gleason score, to analyze the correlation of the expression of ZIP-1, ZnT-1 and Caspase-3 activation in adenocarcinoma prostate, and to study the profile expression of ZnT-1 in prostate adenocarcinoma with different grading of Gleason scores, compared with benign prostatic hyperplasia (BPH), Design: A cross-sectional retrospective study analytic . Methodology: The sample is 31 paraffin blocks were grouped into BPH, prostate adenocarcinoma Gleason scored ≤ 7 and prostate adenocarcinoma Gleason scored > 7. Samples are analyzed expression of ZnT-1 by immunohistochemical staining. ZIP-1 and Caspase-3 expression is secondary data of Septiawan et al?s immunohistochemical staining. Results: ZnT-1 expression correlated with gleason score. ZIP-1 correlated with the activation of Caspase-3 in prostate adenocarcinoma and prostate adenocarcinoma Gleason score ≤ 7. ZnT-1 correlated with ZIP-1 in prostate adenocarcinoma Gleason score > 7. ZnT-1 expression in prostate adenocarcinoma Gleason scored > 7 was lower than prostate adenocarcinoma Gleason score ≤ 7, but could not be analyzed the difference significance with BPH because there was only 1 BPH sample in this research. Conclusion: Zn transporters have the potential to be a prognostic factor of prostate adenocarcinoma.;Background: Decreased levels of Zinc ( Zn ) in the prostate correlates with an increase in the grade Gleason score of prostate adenocarcinoma and decrease in Caspase-3 as apoptosis executor. Zn transporter expression levels in prostate tumor cells associates with the level of malignancy. The ZnT-1 is Zn exporter, while the ZIP-1 is Zn importer of prostate cells. ZIP-1 expression drops on adenocarcinoma prostate. Correlation ZnT-1, ZIP-1 and Caspase-3 allegedly influential in prostate carcinogenesis and potential to be prognostic factor of prostate adenocarcinoma. Objective: To analyze the correlation ZnT-1 and Caspase-3 activation of the gleason score, to analyze the correlation of the expression of ZIP-1, ZnT-1 and Caspase-3 activation in adenocarcinoma prostate, and to study the profile expression of ZnT-1 in prostate adenocarcinoma with different grading of Gleason scores, compared with benign prostatic hyperplasia (BPH), Design: A cross-sectional retrospective study analytic . Methodology: The sample is 31 paraffin blocks were grouped into BPH, prostate adenocarcinoma Gleason scored ≤ 7 and prostate adenocarcinoma Gleason scored > 7. Samples are analyzed expression of ZnT-1 by immunohistochemical staining. ZIP-1 and Caspase-3 expression is secondary data of Septiawan et al?s immunohistochemical staining. Results: ZnT-1 expression correlated with gleason score. ZIP-1 correlated with the activation of Caspase-3 in prostate adenocarcinoma and prostate adenocarcinoma Gleason score ≤ 7. ZnT-1 correlated with ZIP-1 in prostate adenocarcinoma Gleason score > 7. ZnT-1 expression in prostate adenocarcinoma Gleason scored > 7 was lower than prostate adenocarcinoma Gleason score ≤ 7, but could not be analyzed the difference significance with BPH because there was only 1 BPH sample in this research. Conclusion: Zn transporters have the potential to be a prognostic factor of prostate adenocarcinoma.;Background: Decreased levels of Zinc ( Zn ) in the prostate correlates with an increase in the grade Gleason score of prostate adenocarcinoma and decrease in Caspase-3 as apoptosis executor. Zn transporter expression levels in prostate tumor cells associates with the level of malignancy. The ZnT-1 is Zn exporter, while the ZIP-1 is Zn importer of prostate cells. ZIP-1 expression drops on adenocarcinoma prostate. Correlation ZnT-1, ZIP-1 and Caspase-3 allegedly influential in prostate carcinogenesis and potential to be prognostic factor of prostate adenocarcinoma. Objective: To analyze the correlation ZnT-1 and Caspase-3 activation of the gleason score, to analyze the correlation of the expression of ZIP-1, ZnT-1 and Caspase-3 activation in adenocarcinoma prostate, and to study the profile expression of ZnT-1 in prostate adenocarcinoma with different grading of Gleason scores, compared with benign prostatic hyperplasia (BPH), Design: A cross-sectional retrospective study analytic . Methodology: The sample is 31 paraffin blocks were grouped into BPH, prostate adenocarcinoma Gleason scored ≤ 7 and prostate adenocarcinoma Gleason scored > 7. Samples are analyzed expression of ZnT-1 by immunohistochemical staining. ZIP-1 and Caspase-3 expression is secondary data of Septiawan et al’s immunohistochemical staining. Results: ZnT-1 expression correlated with gleason score. ZIP-1 correlated with the activation of Caspase-3 in prostate adenocarcinoma and prostate adenocarcinoma Gleason score ≤ 7. ZnT-1 correlated with ZIP-1 in prostate adenocarcinoma Gleason score > 7. ZnT-1 expression in prostate adenocarcinoma Gleason scored > 7 was lower than prostate adenocarcinoma Gleason score ≤ 7, but could not be analyzed the difference significance with BPH because there was only 1 BPH sample in this research. Conclusion: Zn transporters have the potential to be a prognostic factor of prostate adenocarcinoma.;Background: Decreased levels of Zinc ( Zn ) in the prostate correlates with an increase in the grade Gleason score of prostate adenocarcinoma and decrease in Caspase-3 as apoptosis executor. Zn transporter expression levels in prostate tumor cells associates with the level of malignancy. The ZnT-1 is Zn exporter, while the ZIP-1 is Zn importer of prostate cells. ZIP-1 expression drops on adenocarcinoma prostate. Correlation ZnT-1, ZIP-1 and Caspase-3 allegedly influential in prostate carcinogenesis and potential to be prognostic factor of prostate adenocarcinoma. Objective: To analyze the correlation ZnT-1 and Caspase-3 activation of the gleason score, to analyze the correlation of the expression of ZIP-1, ZnT-1 and Caspase-3 activation in adenocarcinoma prostate, and to study the profile expression of ZnT-1 in prostate adenocarcinoma with different grading of Gleason scores, compared with benign prostatic hyperplasia (BPH), Design: A cross-sectional retrospective study analytic . Methodology: The sample is 31 paraffin blocks were grouped into BPH, prostate adenocarcinoma Gleason scored ≤ 7 and prostate adenocarcinoma Gleason scored > 7. Samples are analyzed expression of ZnT-1 by immunohistochemical staining. ZIP-1 and Caspase-3 expression is secondary data of Septiawan et al’s immunohistochemical staining. Results: ZnT-1 expression correlated with gleason score. ZIP-1 correlated with the activation of Caspase-3 in prostate adenocarcinoma and prostate adenocarcinoma Gleason score ≤ 7. ZnT-1 correlated with ZIP-1 in prostate adenocarcinoma Gleason score > 7. ZnT-1 expression in prostate adenocarcinoma Gleason scored > 7 was lower than prostate adenocarcinoma Gleason score ≤ 7, but could not be analyzed the difference significance with BPH because there was only 1 BPH sample in this research. Conclusion: Zn transporters have the potential to be a prognostic factor of prostate adenocarcinoma., Background: Decreased levels of Zinc ( Zn ) in the prostate correlates with an increase in the grade Gleason score of prostate adenocarcinoma and decrease in Caspase-3 as apoptosis executor. Zn transporter expression levels in prostate tumor cells associates with the level of malignancy. The ZnT-1 is Zn exporter, while the ZIP-1 is Zn importer of prostate cells. ZIP-1 expression drops on adenocarcinoma prostate. Correlation ZnT-1, ZIP-1 and Caspase-3 allegedly influential in prostate carcinogenesis and potential to be prognostic factor of prostate adenocarcinoma. Objective: To analyze the correlation ZnT-1 and Caspase-3 activation of the gleason score, to analyze the correlation of the expression of ZIP-1, ZnT-1 and Caspase-3 activation in adenocarcinoma prostate, and to study the profile expression of ZnT-1 in prostate adenocarcinoma with different grading of Gleason scores, compared with benign prostatic hyperplasia (BPH), Design: A cross-sectional retrospective study analytic . Methodology: The sample is 31 paraffin blocks were grouped into BPH, prostate adenocarcinoma Gleason scored ≤ 7 and prostate adenocarcinoma Gleason scored > 7. Samples are analyzed expression of ZnT-1 by immunohistochemical staining. ZIP-1 and Caspase-3 expression is secondary data of Septiawan et al’s immunohistochemical staining. Results: ZnT-1 expression correlated with gleason score. ZIP-1 correlated with the activation of Caspase-3 in prostate adenocarcinoma and prostate adenocarcinoma Gleason score ≤ 7. ZnT-1 correlated with ZIP-1 in prostate adenocarcinoma Gleason score > 7. ZnT-1 expression in prostate adenocarcinoma Gleason scored > 7 was lower than prostate adenocarcinoma Gleason score ≤ 7, but could not be analyzed the difference significance with BPH because there was only 1 BPH sample in this research. Conclusion: Zn transporters have the potential to be a prognostic factor of prostate adenocarcinoma.]

Abstrak :
[Pendahuluan: Proses karsinogenesis adenokarsinoma prostat terjadi akibat disregulasi kadar zinc dalam sel. Molekul zinc intrasel berperan dalam metabolisme aerob mitokondria dan induksi apoptosis. Penyerapan zinc diatur oleh protein ZIP1, berperan meningkatkan kandungan zinc sitoplasmik intrasel dengan membawa zinc dari cairan ekstrasel. Kadar zinc yang tinggi dan ekspresi protein ZIP1 banyak ditemukan pada epitel prostat normal, sedangkan pada kanker prostat ditemukan sedikit atau tidak ada ekspresi protein ZIP1. Penurunan ekspresi ZIP1 diduga dapat menghambat apoptosis, serta memacu perkembangan adenokarsinoma prostat. Penelitian ini bertujuan menganalisis korelasi ekspresi protein ZIP1 dan Caspase- 3 pada jaringan adenokarsinoma prostat berdasarkan Gleason score yang berbeda. Metode: Desain studi analitik retrospektif dengan desain potong lintang. Sampel penelitian ini adalah 31 sediaan blok parafin adenokarsinoma prostat yang memenuhi kriteria inklusi. Sediaan dipulas menggunakan teknik imunohistokimia untuk mengetahui ekspresi protein ZIP1 dan caspase-3. Ekspresi protein pada pulasan slide dihitung menggunakan program imageJ. Gleason score sebagai data sekunder yang didapatkan dari laporan kasus. Korelasi ekspresi kedua protein berdasarkan Gleason score dianalisis dengan uji korelasi Pearson menggunakan SPSS 11.5. Hasil: Rerata positivitas ekspresi ZIP1 pada adenokarsinoma prostate adalah 35% dan rerata positivitas caspase-3 adalah 33%. Terdapat korelasi positif bermakna antara ekspresi ZIP1 dan caspase-3 (r = 0.379 , p = 0,018). Terdapat korelasi positif antara ekspresi ZIP1 dan caspase-3 pada kelompok intermediate grade (r = 0.73, p = 0.01) dan korelasi lemah tidak bermakna pada kelompok high grade (r = 0.04, p = 0.48). Kesimpulan: Terdapat korelasi positif antara ekspresi ZIP1 dan ekspresi caspase- 3 pada adenokarsinoma prostat. ......, Introduction: Carcinogenesis of adenocarcinoma of the prostate occurs due to dysregulation of zinc level within the cells. Intracellular zinc molecules contributes to mitochondrial aerobic metabolism. Its influx is regulated by a transporter protein ZIP1, whose non-presence is predicted to inhibit apoptosis, thus leads to the development of prostate adenocarcinoma. This study was aimed to analyze the correlation of ZIP1 and Caspase-3 expression in prostate adenocarcinoma with respect to its grading as represented by Gleason Score. Methods: This was a cross-sectional, retrospective analytical study on 31 formalyn-fixed, paraffin-embedded tissue that meet inclusion criteria. The specimen was stained using immunohistochemical technique for ZIP1 and Caspase-3. Protein expression of each case were counted using ImageJ analysis. Gleason score were acquired as secondary data from the cases’ reports. The correlation of their expression with respect of Gleason score were analyzed with Pearson’s correlation using SPSS 11.5. Results: Mean expression level of ZIP1 and Caspase-3 in prostate adenocarcinoma were 35% and 33%, respectively. There was a significantly positive correlation between ZIP1 and Caspase-3 expression (r=0.379; p=0.018). However, their correlation was stronger in intermediate-grade group (r=0.73; p=0.01) and the correlation was much weaker in high-grade group (r=0.04; p=0.48). Conclusion: There was a positive correlation between ZIP1 and caspase-3 expression in adenocarcinoma prostate.]

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ABSTRAK
Nama : Elvira YunitaProgram Studi : Program Magister Ilmu BiomedikJudul : Efek In Vitro Andrografolida terhadap Apoptosis Jalur Intrinsik pada Sel Punca Kanker Payudara Manusia yang Dipaparkan Rotenon: Tinjauan Ekspresi Caspase-9, Caspase-3 dan Survivin. Latar belakang: Andrografolida ANDRO merupakan senyawa bioaktif utama yang berasal dari sambiloto, Andrographis paniculata. Penelitian in silico yang telah dilakukan menunjukan ANDRO mempengaruhi apoptosis intrinsik dengan berinteraksi dengan survivin, caspase-9 dan caspase-3. Penelitian lain menunjukkan bahwa Breast Cancer Stem Cell BCSC memiliki survival rate yang lebih tinggi setelah dipaparkan dengan rotenon jika dibandingkan dengan non-BCSC. Oleh karena itu penelitian ini bertujuan untuk menganalisis apoptosis jalur intrinsik pada BCSC yang telah dipaparkan rotenon dan ANDRO.Metode: BCSC dipaparkan dengan 50 ?M rotenon selama 6 jam dan kemudian sel dipaparkan dengan ANDRO 0.075 mM, 0.15 mM, 0.3 mM dan 0.6 mM selama 24 jam. RNA sel diisolasi dan diikuti dengan pengukuran ekspresi mRNA caspase-9 dan 3 dengan qRT-PCR. Protein sel akan digunakan untuk pengukuran ekspresi protein survivin total dan survivin terfosforilasi. Selain itu, Apoptosis sel juga diukur dengan flowcytomety.Hasil: Perlakuan dengan rotenon dan ANDRO dapat meningkatkan ekspresi mRNA caspase-9 dan caspase-3 yang juga disertai dengan penurunan viabilitas. Paparan ANDRO dengan konsentrasi rendah hingga 0.015 mM pada BCSC yang telah diberikan rotenon dapat menurunkan ekspresi mRNA survivin. Dosis yang lebih tinggi dapat meningkatkan ekspresi mRNA survivin. Ekspresi protein survivin mengalami peningkatan yang disertai dengan penurunan rasio survivin yang teraktivasi. Selain itu, persentase apoptosis setelah paparan rotenon dan ANDRO hingga 0.3 mM ANDRO juga mengalami peningkatan seiring dengan bertambahnya konsentrasi ANDRO yang dipaparkan dose dependent manner .Kesimpulan: Paparan rotenon dan ANDRO dapat menginduksi kematian sel melalui apoptosis jalur intrinsik pada BCSC. Selain itu, ANDRO juga diusulkan sebagai senyawa yang potensial menjadi agen terapi pendamping bagi pasien-pasien yang menjalani kemoterapi maupun radioterapi.

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ABSTRACT Name Elvira YunitaStudy Program Biomedical ScienceTitle In Vitro Effect of Andrographolide on the intrinsic pathway of apoptosis in rotenone induced human breast cancer stem cells Focus on caspase 9, caspase 3 and survivin expression Background Andrographolide ANDRO is an active compound of Andrographis paniculata, has been suggested to have an anti cancer property. Our in silico study has shown that ANDRO could interact with survivin, caspase 9 and caspase 3 which influence the intrinsic apoptotic pathway. We have also demonstrated that human breast cancer stem cells BCSCs could survive better than their counterpart non BCSCs after rotenone treatment. In this study, we aimed to investigate whether andrographolide could induced apoptotic of rotenone induced BCSCs.Method Human BCSCs ALDH cells were first induced by 50 M rotenone for 6 hours and treated with 0.075 mM, 0.15 mM, 0.3 mM dan 0.6 mM of ANDRO for 24 hours. Total RNA from the cells was isolated, followed by determination of survivin, caspase 9 and caspase 3 m RNA expression level using Real Time RT PCR technique. Protein from the cells used to examine expression of survivin and phosphorylated survivin. Besides, examining of apoptotic cell also measured by flowcytometry.Result Treatment of rotenone and ANDRO drastically increase caspase 9 and caspase 3 expression, leading to the decrease of cell viability. Low concentration of ANDRO treatment until 0.15 mM could supress survivin expression, but gradually increased higher than the control in line with the increasing of ANDRO concentration. Survivin protein expression was increased following by decreasing ratio of activated survivin. Besides, percentage of apoptosis after rotenone and ANDRO treatment until 0.3 mM of ANDRO treatment also increased in line with increasing ANDRO concentration dose dependent manner .Conclusion Rotenone and ANDRO treatment could induced apoptotic intrinsic in BCSCs. Thus, we propose that andrographolide as potential compound that could be used as a novel co chemoradiation therapy and radiotherapy targeted to BCSCs.

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Latar Belakang: Penggunaan doksorubisin untuk terapi kanker masih menjadi pilihan utama karena terbukti poten.Namun, terjadinya resistensi pada sel kanker terhadap kemoterapi merupakan salah satu penghambat keberhasilan dari pengobatan ini. Sel punca kanker payudara berperan pada terjadinya resistensi terapi yang ditandai dengan adanya peningkatan ekspresi survivin. Survivin adalah protein bifungsional yang dapat menekan apoptosis dan mengatur pembelahan sel. Penelitian terbaru menyarankan untuk mengkombinasikan terapi kanker konvensional dengan senyawa aktif bahan alam untuk mencegah resistensi sel kanker terhadap kemoterapi seperti andrografolida. Oleh karena itu senyawa andrografolida diharapkan dapat digunakan sebagai kemosensitizer terhadap doksorubisin. penelitian ini bertujuan untuk menganalisis peran andrografolida dalam mengatasi resistensi dan meningkatkan efektivitas doksorubisin pada sel punca kanker payudara melalui penekanan aktivitas survivin pada jalur apoptosis intrinsik. Metode: Sel punca kanker payudara (CD24-/CD44+) diberikan doksorubisin 0,1μM. Setelah 14 hari perlakuan maka dilakukan kombinasi doksorubisin 0,1μM dan andrografolida 0,285 mM hingga hari ke-22. Setiap 2 hari, sel dipanen dan dihitung dengan metode eksklusi trypan blue. Analisis ekspresi mRNA Caspase-9, Caspase-3, dan Survivin dilakukan dengan qRT-PCR, sedangkan uji apoptosis dilakukan dengan metode flow cytometry. Hasil: Pemberian doksorubisin tunggal dapat mengurangi viabilitas sel punca kanker payudara (CD24-/CD44+). Setelah 12 hari pemberian, viabilitas sel punca kanker payudara (CD24-/CD44+). dan ekspresi mRNA survivin meningkat, tetapi ekspresi mRNA caspase 9 dan caspase 3 ditekan. Sedangkan kombinasi doksorubisin dan andrografolida dapat menurunkan viabilitas sel punca kanker payudara (CD24- /CD44+) pada hari ke 16, sejalan dengan penurunan ekspresi survivin mRNA dan peningkatan ekspresi mRNA caspase-9 dan caspase-3. Kesimpulan: Andrografolida dapat berfungsi sebagai kemosensitizer untuk meningkatkan apoptosis intrinsik pada sel punca kanker payudara yang telah diberikan doksorubisin berulang. ......Background: Doxorubicin is still the main option for cancer treatment because it has proven to be effective. However, the resistance of cancer cells to chemotherapy is one of the obstacles to the success of this treatment. Breast cancer stem cells play a role in the development of treatment resistance, which is indicated by the increase in survivin expression. Survivin is a bifunctional protein that suppresses apoptosis and regulates cell division. Recent studies had suggested using additional substances to prevent cancer cell resistance to chemotherapy such as andrographolide. Hence, andrographolide compounds are expected to be used as chemosensitizer against the doxorubicin. This study aimed to analyze the role of andrographolide to overcome the resistance and improve the effectiveness of doxorubicin in human BCSC through suppressing survivin activity on the intrinsic apoptosis pathway. Method: BCSCs (CD24-/CD44+) were treated with 0.1μM doxorubicin. After 14 days of treatment, the cells were treated with a combination of 0.1μM doxorubicin and 0.285 mM andrographolide until the 22nd day. Every 2 days, the cells were harvested and counted by using the trypan blue exclusion method. The analysis of Caspase-9, Caspase-3, and Survivin mRNA expression was performed by using qRT-PCR, while apoptotic assay was done using flow cytometry. Result: The single treatment of doxorubicin could reduce BCSCs viability. After 12 days of treatment, the survivin mRNA expression was increased following BCSCs viability, but the caspase 9 and caspase 3 mRNA expressions were suppressed. Meanwhile, the combination of doxorubicin and andrographolide could decrease BCSCs viability on the 16th day, in line with the decreased expression of survivin mRNA, there was an improvement of caspase-9 and caspase-3 mRNA expression levels. Conclusion: Andrographolide could be considered as chemosensitizer to increase intrinsic apoptosis in breast cancer stem cells that given repeated doxorubicin administration.

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Latar Belakang: Tujuan dari penelitian ini adalah untuk mengetahui pengaruh stres oksidatif pada ketahanan hidup spermatozoa manusia melalui peningkatan ekspresi caspase 3 dan aktivasi Akt. Informasi ini berhubungan dengan infertilitas laki-laki yang menurunkan viabilitas dan parameter kinetik spermatozoa. Metode: Spermatozoa manusia diperoleh dari donor normozoospermia. Spermatozoa dimurnikan menggunakan larutan percoll. Spermatozoa dari seminal plasma dilarutkan dalam media Bigger, Whitter, dan Whittingham (BWW). Kemudian, spermatozoa diinkubasi dengan hidrogen peroksida (H2O2) 50 M, 100 M, 150 M, 200 M dan 250 M selama 2 jam. Stres oksidatif diuji dengan uji malondialdehid (MDA). Viabilitas diperiksa dengan larutan eosin Y. Parameter motilitas diukur dengan Computer Assisted Sperm Analyzer (CASA). Deteksi protein western blot akan dilakukan dengan antibodi anti-caspase-3 untuk mengenali caspase-3 dan antibodi phosphodetect yang mengenali fosforilasi Akt. Hasil: Setelah inkubasi H2O2 selama 2 jam, terdapat efek H2O2 terhadap penurunan viabilitas dan motilitas (VAP, VSL, VCL) secara signifikan. Selain itu, viabilitas dan motilitas memiliki hubungan positif dengan proses apoptosis dan ketahanan hidup spermatozoa dengan menggunakan caspase 3 (meningkat) dan fosforilasi Akt (menurun) secara signifikan. Kesimpulan: Stres oksidatif dapat menurunkan viabilitas dan kinetik spermatozoa melalui peningkatan ekspresi caspase-3 dan penurunan aktivitas Akt

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ABSTRACT
Background: The purposes of this study was to evaluate the effect of oxidative stress on survival of human spermatozoa through releasing apoptotic process, This information has correlated with idiopathic infertility that decrease viability and motility parameters spermatozoa. Methods: Human spermatozoa were obtained from normozoospermic volunteer donors. Spermatozoa was purified using discontinuous Percoll. Spermatozoa from the plasma seminal dissolved in Bigger, Written, and Whittingham (BWW) medium. Then, spermatozoa were incubated with 50 M, 100 M, 150 M, 200 M dan 250 M hydrogen peroxide (H2O2) for 2-h. Oxidative stress were assed by malondialdehyde (MDA) assay. Viability was examined by eosin Y solution. Kinectic parameters were assessed by Computer Assisted Sperm Analyzer (CASA). Detection of perotein in the western blot was examined with anti-caspase-3 antibodies to recognize caspase-3 activity and phsophodetect antibody that recognizes the phosphorylation of Akt. Results: After 2-h incubation H2O2, there was dose dependent effect of H2O2 on viability and motility parameters significantly decrease. Therefore, viability and kinetic were positive relationship on apoptotic and survival effect by using caspase-3 activation (increase) and akt (decrease) significantly. Conclusions: Oxidative stress can decreases viability and kinetic spermatozoa through increase caspse 3 and decrease Akt activation

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Latar Belakang: Glioblastoma multiforme (GBM) merupakan tumor intrakranial yang sangat agresif dengan prognosis buruk meskipun telah diberikan terapi standar yang optimal. Kerusakan untai ganda DNA spontan dianggap berhubungan dengan ketidakstabilan genomik serta progresivitas kanker. Penelitian ini bertujuan untuk memperoleh parameter molekuler baru sebagai faktor prognostik yang diharapkan dapat digunakan dalam praktik klinis rutin pada GBM. Penelitian ini melakukan analisis korelasi antara miRNA-328 dengan gamma-H2AX (petanda kerusakan untai ganda DNA) serta perannya terhadap caspase-3 (petanda apoptosis), jalur PI3K/Akt (jalur sinyal teraktivasi), faktor klinis, dan kesintasan pada GBM. Metode: Penelitian kohort retrospektif menggunakan jaringan tersimpan dari 26 pasien GBM yang diambil sebelum mendapat terapi lengkap. Jaringan dari 7 pasien glioma grade 1 digunakan sebagai kontrol. Analisis miRNA-328 menggunakan metode two-step qRT-PCR; analisis gamma-H2AX, PI3K, Akt, dan caspase-3 menggunakan metode Sandwich ELISA. Uji eksperimental in vitro menggunakan cell line GBM, U-87 MG, yang ditransfeksi dengan miRNA-328 untuk menganalisis peran miRNA-328 terhadap aktivitas ?-H2AX, caspase-3, serta viabilitas sel. Hasil: Terdapat perbedaan bermakna pada konsentrasi miRNA-328, gamma-H2AX, PI3K, Akt antara kelompok GBM dengan glioma grade 1 (p<0,05). Pada kelompok GBM diperoleh korelasi negatif antara miRNA-328 dengan gamma-H2AX dan Akt (p<0,05); korelasi positif antara gamma-H2AX dengan PI3K, Akt, serta caspase-3 (p<0,05). Korelasi positif antara gamma-H2AX dengan ukuran tumor (p<0,05). Analisis Kaplan–Meier menunjukkan bahwa pada kelompok GBM dengan konsentrasi miRNA-328 tinggi memiliki kesintasan lebih tinggi dibandingkan kelompok dengan konsentrasi miRNA-328 rendah (p<0,05); sedangkan pada kelompok GBM dengan konsentrasi gamma-H2AX tinggi memiliki kesintasan lebih rendah dibandingkan kelompok dengan konsentrasi gamma-H2AX rendah (p<0,05). Hasil analisis univariat cox regression menunjukkan miRNA-328 dan gamma-H2AX memiliki peran sebagai faktor prognostik potensial pada GBM (p<0,05), sedangkan analisis bivariat menunjukkan potensi miRNA-328 sebagai faktor prognostik independen (p<0,05). Hasil uji in vitro menunjukkan bahwa konsentrasi miRNA-328 berbanding terbalik dengan gamma-H2AX dan viabilitas sel; konsentrasi miRNA-328 berbanding lurus dengan caspase-3; konsentrasi gamma-H2AX berbanding terbalik dengan caspase-3; serta konsentrasi gamma-H2AX berbanding lurus dengan viabilitas sel GBM. Kesimpulan: MiRNA-328 dan gamma-H2AX sebagai parameter molekuler memiliki potensi sebagai faktor prognostik yang berpengaruh terhadap kesintasan sehingga diharapkan penggunaannya dalam praktik klinis rutin dapat meningkatkan respons terapi serta prognosis pada pasien GBM. Penelitian lebih lanjut dengan metode kohort prospektif serta penelitian in vivo guna mendukung hasil penelitian ini. ......Background: Glioblastoma multiforme is an intracranial tumor which has very aggressive behavior with poor prognosis even though optimal standard therapy has been given. The spontaneous DNA double-strand breaks have association with genomic instability and tumor progression. The objective of this study is to obtain the new molecular parameters that can be used in routine clinical practice as potential prognostic factors in GBM. This study analyzed the correlation between miRNA-328 and gamma-H2AX (marker of spontaneous DNA double-strand breaks) as well as their roles in caspase-3 (marker of apoptosis), PI3K/Akt pathway (activated signal transduction pathway), clinical factors, and survival in GBM. Methods: A cohort retrospective study using pre-treatment tumor tissue specimens from 26 patients with GBM before undergoing complete therapy. Tumor tissue specimens from 7 patients with grade 1 glioma were used as controls in this study. The two-step qRT-PCR method was used to analyze the concentration of miRNA-328 and the Sandwich ELISA methods were used to analyze the concentrations of gamma-H2AX, PI3K, Akt, caspase-3. Results: The comparison analyses between GBM group and grade 1 glioma group showed significant differences in miRNA-328, ?-H2AX, PI3K, and Akt concentrations (p<0.05). In GBM group, the results of statistical analyses showed negative correlations between miRNA-328 and gamma-H2AX, as well as Akt (p<0.05); positive correlations between ?-H2AX and PI3K, Akt, caspase-3 (p<0.05). Kaplan–Meier analysis in GBM showed that the high-concentration miRNA-328 group had a higher survival rate than the low-concentration miRNA-328 group (p<0.05); and the high-concentration gamma-H2AX group had a lower survival rate than the low-concentration gamma-H2AX group (p<0.05). The univariate cox regression analysis showed the potential roles of miRNA-328 and gamma-H2AX as prognostic factors in GBM (p<0.05), however the bivariate analysis showed miRNA-328 had potency as an independent prognostic factor (p<0.05). Conclusion: MiRNA-328 and gamma-H2AX as molecular parameters have potency as prognostic factors that effect the survival rate so that the routine clinical application of these parameters can be expected to improve the therapy response and prognosis in GBM patients. Further studies with cohort prospective method and in vivo study to support the results of this study.

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Latar Belakang: Penyakit arteri perifer (PAP) merupakan penyakit yang sering dijumpai serta memiliki morbiditas dan mortalitas yang bermakna. Iskemia tungkai akut merupakan salah satu PAP yang menyebabkan stres retikulum endoplasma dan kematian sel melalui apoptosis atau autofagia. Aktivasi Caspase secara berurutan memainkan peran penting dalam suatu fase apoptosis sei. Sementara itu, Beclin-l memiliki peran utama dalam autofagia. Endotelin-1 (ET -1) sebagai faktor transkripsi Monocyte Chemoattractant Protein-1 (MCP-1) telah diteliti dengan baik dalam perkembangan aterosklerosis tetapi tidak pada iskemia tungkai. Tujuan penelitian ini adalah untuk mengetahui peran ET-1 dalam patogenesis iskemia tungkai akut melaIui MCPIP, Beclin-1, dan Caspase-3. Bahan dan Metode: Tiga belas kelinci umur 5 bulan galur Selandia Bam White (NZW) dipilih untuk penelitian ini. Arteri femoralis kanan semua kelinci kemudian diikat dan dilakukan reseksi pembedahan sampai alirannya hilang, dikonfirmasi oIeh Doppler Laser Fluximetry. Semua kelinci kemudian secara acak dialokasikan untuk kelompok perlakuan dengan pemberian intravena ECE-1 inhibitor (CGS26303) 5 mglkg berat badanlhari selama 26 hari dan kelompok kontrol. Jaringan diambiI dari daerah otot iskemik dan dilakukan pemeriksaan untuk ekspresi protein MCPIP, Beclin-1 untuk biomarker autofagia serta Caspase-3 untuk biomarker apoptosis menggunakan imunohistokimia. Ekspresi gen diperiksa menggunakan real time polymerase chain reaction (RT-PCR) dan dinyatakan sebagai ekspresi gen relatif. Hasil: Selama periode follow-up, 2 kelinci mati karena infeksi. Oleh karena itu, tersisa 11 kelinci yang menjadi subjek penelitian ini. Empat kelinci dialokasikan untuk kelompok kontrol sementara 7 kelinci diberikan ECE-I sebagai kelompok perlakuan. Semua kelompok perlakuan positif memiliki antibodi terhadap MCPIP, Beclin-1, dan Caspase-3 tetapi tidak untuk kelompok kontrol (p = 0,003). Meskipun demikian, ekspresi gen relatif dari MCP1P, Beclin-1 dan Caspase-3 ditemukan bervariasi antara 2 kelompok dan tidak berbeda bermakna seeara statistik. Simpulan: Pada iskemia tungkai akut, ET-1 diduga memiliki peran penting dalam mengatur MCP1P, Beelin-1, dan Caspase-3. Jalur tersebut merupakan suatu alternatif baru mekanisme kematian sei. Intervensi melalui inhibisi ET -1 diduga dapat menunda proses kematian sel. ......Background: Peripheral arterial disease (PAD) is common and causes significant morbidity and mortality. Acute limb ischemia is one of the PAD that will develops endoplasmic reticulum stress and subsequently cell death through apoptosis or autophagy. Sequential activation of Caspases plays a major role in the execution phase of cell apoptosis while Beclin-I has a central role in autophagy. Endothelin-I (ET -1) as atranscription factor of Monocyte Chemoattractant Protein-I (MCP-1) has been well studied in the progression of atherosclerosis but not in limb ischemia. The aim of the study is to investigate the role of ET -1 in the pathogenesis of acute limb ischemia through MCPIP, Beclin-1 and Caspase-3 . Materials and Methods: Thirteen of 5-month-old New Zealand White (NZW) rabbits are chosen for this study. The right femoral artery of all rabbits are ligated and resected surgically until its flow disappear and confirmed by laser Doppler Fluximetry. All are then randomly. allocated for intravenous administration of ECE-I inhibitor (CGS26303) 5 mglkg body weight/day for 26 days (n=7) and control group (n=6). The tissue taken from ischemic muscle area was examined for protein expression of MCPIP, Beclin-1 for autophagy biomarker as well as Caspase-3 for apoptotic biomarker using immunohistochemistry technique. Gene expressions are examined using real time Polymerase Chain Reaction (PCR) and expressed as relative gene expression. Result: During period of follow-up, 2 rabbits died because of infection. Therefore there were still remain II rabits for subject of this study. Four were allocated for non-intervention as control group while 7 were for ECE-1 administration as intervention group. All of the intervention group has positive on antibody for MCPIP, Beclin-I and Caspase-3 but not for the control group (p = 0.003). However, the relative gene expression on MCPIP, Becline-1 and Caspase-3 varied between 2 groups and were not statistically different. Conclusion: In acute limb ischemia, ET-1 maya play major role in regulating MCPIP, Beclin-l and Caspase-3. This pathway may be proposed as a new alternative mechanism of cell death in this situation. Intervention of ET-I may delay the process of cell death.

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Latar belakang: Malaria merupakan penyakit parasitik yang masih banyak ditemukan di Indonesia Timur. Inflamasi akibat infeksi malaria memicu stress oksidatif sehingga terjadi apoptosis sel yang berlebihan yang berhubungan dengan ekspresi protein Caspase-3 sebagai protein eksekutor apoptosis. Pemberian sambiloto dan spirulina yang memiliki efek antiinflamasi dan antioksidan dapat berpotensi mencegah kerusakan sel epitel kolon media mencit yang diinduksi Plasmodium berghei. Tujuan: Penelitian ini bertujuan untuk melihat adanya pengaruh pemberian kombinasi sambiloto dan spirulina terhadap ekspresi Caspase-3 pada sel epitel kolon media mencit yang diinduksi Plasmodium berghei. Metode: Penelitian ini merupakan penelitian ekperimental yang menggunakan materi biologi tersimpan kolon media mencit Swiss Webster jantan. Kelompok uji berupa AP (Sambiloto 200 mg/KgBB), AP+PS (sambiloto 200 mg/KgBB dan bubuk spirulina 130 mg/KgBB), AP+ES (sambiloto 200 mg/KgBB dan ekstrak spirulina 26 mg/KgBB), kontrol negatif (carboxymethil cellulose 0,5%) dan kontrol positif (Dihidroartemisinin Piperakuin 195 mg/KgBB). Setelah diberikan terapi selama 28 hari, mencit diterminasi lalu dilakukan pewarnaan imunohistokimia anti-Caspase-3 pada jaringan kolon. Spesimen dilihat menggunakan mikroskop cahaya dengan perbesaran 400x sebanyak lima lapang pandang. Analisis data menggunakan piranti ImageJ® dengan melihat persentase ekspresi Caspase 3 lalu dianalisis menggunakan SPSS 20.0 Hasil: Uji hipotesis One Way ANOVA diperoleh hasil signifikan (p<0,05). Berdasarkan uji Post-hoc Bonferroni diperoleh kelompok AP+PS (148,54 +/- 17,23) berbeda signifikan (p<0,05) dengan kelompok AP dan kontrol negatif. Selain itu, kelompok AP+PS menunjukkan efek yang tidak berbeda dengan kontrol positif (162,66 +/- 7,01; p=0,952). Simpulan: Pemberian ekstrak sambiloto dan serbuk spirulina menunrunkan ekspresi Caspase-3 pada sel epitel kolon media mencit terinduksi Plasmodium berghei. ......Background: Malaria is a parasitic disease that is still widely found in Indonesia, Inflammation caused by malaria infection can trigger oxidative stress which can lead to excessive cell apoptosis associated with protein Caspase-3 expression as an apoptosis executor protein. The administration of sambiloto and spirulina which have anti-inflammatory and antioxidant effects can potentially prevent Plasmodium berghei-induced damage to the colonic epithelial cells of mice. Aim: This study aims to determine the effect of giving a combination of sambiloto and spirulina on the expression of Caspase-3 in mice colonic epithelial cells induced by Plasmodium berghei. Methods: This study is an experimental study using biological material stored in colon media of male Swiss Webster mice. The test groups were AP (Sambiloto 200 mg/KgBB), AP + PS (sambiloto 200 mg/KgBB and spirulina powder 130 mg/KgBB), AP + ES (sambiloto 200 mg / KgBB and spirulina extract 26 mg/KgBB), negative control. (carboxymethil cellulose 0.5%) and positive control (Dihydroartemisinin Piperakuin 195 mg/KgBW). After 28 days of therapy, the mice were terminated and then stained with anti-Caspase-3 immunohistochemicals on the colonic tissue. Specimens were viewed using a light microscope with a magnification of 400x for five fields of view. Data analysis using the ImageJ® tool by looking at the percentage of Caspase 3 expression then analyzed using SPSS 20.0. Results: The One Way ANOVA hypothesis test obtained significant results (p <0.05). Based on the Bonferroni Post-hoc test, it was found that the AP + PS group (148.54 +/- 17.23) was significantly different (p <0.05) from the AP group and negative control. In addition, the AP + PS group showed no different effects from the positive control (162.66 +/- 7.01; p = 0.952) Conclusion: Provision of sambiloto extract and spirulina powder reduced the expression of Caspase-3 in colonic epithelial cells of Plasmodium berghei induced mice.