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Latar Belakang: Cisplatin telah menjadi terapi lini pertama untuk kanker ovarium, namun efek samping terbesar cisplatin adalah peningkatan resistensi sel kanker yang menyebabkan hepatotoksisitas pada sel normal. Kurkumin terbukti memiliki sifat hepatoprotektif, tetapi efek terapeutik kurkumin terbatas karena memiliki bioavailabilitas yang rendah. Penggunaan kitosan nanopartikel pada kurkumin telah terbukti meningkatkan bioavailabilitas kurkumin sehingga efektivitasnya lebih besar. Penelitian ini dilaksanakan untuk melihat pengaruh nanokurkumin terhadap hepatotoksisitas akibat pemberian cisplatin. Tujuan: Membandingkan pengaruh kurkumin dan nanopartikel kurkumin untuk digunakan sebagai ko-kemoterapi dengan cisplatin pada kanker ovarium tikus yang ditinjau melalui jalur apoptosis, khususnya marker Bax dan Kaspase-3. Metode: Penelitian ini merupakan penelitian eksperimental in vivo pada model kanker ovarium tikus betina galur Wistar yang diinduksi 7,12-dimethybenzen[a]anthracene (DMBA) dan dilaksanakan di Departemen Farmakologi dan Terapeutik Fakultas Kedokteran Universitas Indonesia sejak bulan Juni 2019 hingga Juni 2020. Cisplatin diberikan dalam dosis sebesar 4 mg/kgBB secara intraperitoneal. Kurkumin dan nanokurkumin diberikan dalam dosis oral sebesar 100 mg/kgBB. Organ tersimpan hepar yang diambil dari 25 ekor tikus terbagi menjadi 5 kelompok perlakuan, yaitu kelompok tikus normal, model kanker ovarium tikus, terapi cisplatin, terapi cisplatin + kurkumin, dan terapi cisplatin + nanokurkumin. Setelah dikelompokkan, dilakukan homogenisasi sampel yang terpilih. Lalu, RNA Bax dan Kaspase-3 diisolasi dari homogenat sampel organ hepar dan cDNA kedua gen disintesis. Kemudian, tingkat ekspresi mRNA Bax dan Kaspase-3 pada hepar diukur menggunakan qRT-PCR. Data ekspresi mRNA Bax dan Kaspase-3 dianalisis dan diuji korelasi antarkelompok menggunakan aplikasi SPSS. Hasil: Tidak ada perbedaan yang signifikan antara kelima kelompok pada tingkat ekspresi mRNA Bax (p=0,372) dan Kaspase-3 (p=0,111). Kesimpulan: Tidak ditemukan pengaruh kurkumin dan nanokurkumin terhadap ekspresi mRNA Bax dan Kaspase-3 organ hepar pada model kanker ovarium tikus setelah pemberian terapi cisplatin.

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Background: Cisplatin has become the first-line therapy for ovarian cancer, but it has a side effect of increasing cancer cell resistance which causes hepatotoxicity in normal cells. Curcumin has been shown to have hepatoprotective properties, but its therapeutic effect is limited because of its low bioavailability. The use of chitosan nanoparticles in curcumin has been shown to increase the bioavailability of curcumin. This research was conducted to see the effect of nanocurcumin on hepatotoxicity due to cisplatin administration. Aim: Comparing the effect of curcumin and curcumin nanoparticles as co-chemotherapy with cisplatin in rat ovarian cancer that is evaluated through apoptotic pathways, specifically Bax and Kaspase-3 markers. Methods: This research is an in vivo experimental study on a female ovarian cancer model of Wistar rats induced 7,12-dimethybenzen[a]anthracene (DMBA) and was carried out in the Department of Pharmacology and Therapeutics of the Faculty of Medicine, University of Indonesia from June 2019 to June 2020. Cisplatin is given in doses of 4 mg/kgBW intraperitoneal. Curcumin and nanocurcumin are given in oral doses of 100 mg/kgBW. Stored liver organs which was taken from 25 rats was divided into 5 treatment groups which are normal, ovarian cancer model, cisplatin therapy, cisplatin + curcumin therapy, and cisplatin + nanocurcumin therapy group. After the samples are grouped, homogenization of the selected sample is carried out. Then, the Bax and Kaspase-3 RNA were isolated from the homogenate samples and the cDNA of the two genes was synthesized. Then, the levels of Bax and Kaspase-3 mRNA expressions in the liver were measured using qRT-PCR. Bax and Kaspase-3 mRNA expressions were analyzed and tested intergroup correlations using the SPSS application. Results: There were no significant differences between the five groups in the expression levels of Bax mRNA (p=0,372) and Kaspase-3 (p=0,111). Conclusion: This study shows no effect of curcumin and nanocurcumin on the expression of Bax and Caspase-3 liver organ mRNA in rat ovarian cancer models after cisplatin therapy.

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"Salah satu obat antikanker yang sekarang paling efektif digunakan sebagai kemoterapi kanker ovarium adalah cisplatin. Namun, cisplatin memiliki banyak efek samping pada berbagai organ, salah satunya hepar. Hepatotoksisitas akibat cisplatin menyebabkan terbatasnya dosis kemoterapi cisplatin. Salah satu faktor kunci patofisiologi kerusakan akut hepar adalah inflamasi. Kurkumin merupakan senyawa alami yang memiliki sifat antiinflamasi tetapi bioavailabilitasnya rendah. Untuk itu, diformulasikan nanokurkumin untuk meningkatkan bioavailabilitasnya. Meskipun begitu, efek kurkumin dan nanokurkumin dalam memodulasi jalur inflamasi hepatotoksisitas akibat cisplatin pada kanker ovarium belum diamati. Penelitian ini bertujuan untuk membandingkan pengaruh kurkumin dan nanokurkumin sebagai ko-kemoterapi terhadap hepatotoksisitas cisplatin dalam jalur inflamasi. Penelitian in vivo dilakukan pada tikus Wistar betina yang diinduksi DMBA untuk mendapatkan model kanker ovarium. Kemudian, tikus-tikus diberi perlakuan terapi dengan cisplatin secara intraperitoneal (4 mg/kgBB/minggu) dan kombinasinya dengan kurkumin (100 mg/kgBB/hari) dan nanokurkumin (100 mg/kgBB/hari) per oral. Tikus-tikus tersebut dibagi menjadi kelompok: tikus normal, model kanker ovarium saja, terapi cisplatin, terapi cisplatin + kurkumin, dan terapi cisplatin + nanokurkumin. Setelah 1 bulan, tikus di-sacrifice dan organ hepar disimpan beku. Ekspresi mRNA relatif NF-κB dan IL-1β serta kadar protein IL-6 diukur dengan metode qt RT-PCR dan ELISA secara berurutan. Data hasil pengukuran IL-6 dan data hasil transformasi logaritma NF-κB dan IL-1β dianalisis menggunakan uji one-way ANOVA, menggunakan perangkat lunak SPSS20. Tidak terdapat perbedaan signifikan secara statistik antar kelompok perlakuan dalam mRNA NF-κB (p=0,503), mRNA IL-1β (p=0,237), dan protein IL-6 (p=0,157). Tidak ada perbedaan yang signifikan antara kurkumin dan nanokurkumin dalam memodulasi jalur inflamasi hepatotoksisitas cisplatin pada model kanker ovarium tikus.

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Up to now, one of the most effective anticancer drug as ovarian cancer chemotherapy is cisplatin. Nevertheless, cisplatin has many side effects on several organs, one of which is liver. Cisplatin-induced hepatotoxicity causes limited cisplatin chemotherapy dose. One of the pathophysiological key factor of acute liver injury is inflamation. Curcumin is natural compound which has antiinflamation properties but the bioavailability is low. To overcome it, nanocurcumin is made to increase its bioavailability. Nonetheless, curcumin and nanocurcumin effect on modulating inflammatory pathway toward cisplatin-induced hepatotoxicity in ovarian cancer rat model has not been observed. This study aims to compare the effect of curcumin and nanocurcumin as co-chemotherapy toward cisplatin-induced hepatotoxicity in inflammatory pathway. An in vivo study was done on female Wistar rats induced by DMBA to achieve ovarian cancer model. Then, rats was treated with cisplatin intraperitoneally (4 mg/kgBW/week) and the combination with per oral curcumin (100 mg/kgBW/day) and nanocurcumin (100 mg/kgBW/day). Those rats were divided into groups, which are normal rat, only ovarian cancer model, cisplatin therapy, cisplatin + curcumin therapy, and cisplatin + nanocurcumin therapy. After 1 month, rats are sacrificed and liver organs are stored frozen. mRNA relative expression of NF-κB and IL-1β as well as protein level of IL-6 was measured using qt RT-PCR and ELISA method, respectively. The result data from the measurement of IL-6 and the data from logarithmic transformation of NF-κB and IL-1β was analysed using one-way ANOVA test using SPSS20 software. There is no significant differences between groups in mRNA NF-κB (p=0.503), mRNA IL-1β (p=0.237), and protein IL-6 (p=0.157). There is no significant differences between curcumin and nanocurcumin in modulating inflammatory pathway of cisplatin-induced hepatotoxicity in ovarian cancer rat model."

"Latar Belakang: Cisplatin, agen kemoterapi pilihan untuk kanker ovarium, bersifat hepatotoksik dengan menginduksi stres oksidatif. Kurkumin adalah agonis jalur Nrf2/Keap1 yang penting dalam respons terhadap stres oksidatif, namun bioavailabilitasnya buruk. Pemberian kurkumin dalam bentuk nanopartikel meningkatkan bioavailabilitasnya dalam tubuh dan distribusinya ke organ target. Penelitian ini bertujuan untuk mengetahui pengaruh nanopartikel kurkumin terhadap hepatotoksisitas cisplatin melalui modulasi jalur Nrf2/Keap1 dilihat dari kadar MDA dan ekspresi gen jalur Nrf2/Keap1. Metode: 25 ekor tikus Wistar betina dikelompokkan menjadi 5 kelompok yaitu kelompok normal, 4 kelompok model kanker ovarium yang diinduksi DMBA yang dibagi menjadi kelompok tanpa terapi, monoterapi cisplatin 4 mg/KgBB intraperitoneal, ko-kemoterapi cisplatin dan kurkumin konvensional 100 mg/KgBB per oral, serta ko-kemoterapi cisplatin dan nanopartikel kurkumin dalam kitosan 100mg/KgBB per oral selama 1 bulan. Tikus dikorbankan dan hepar disimpan beku. Pengukuran MDA dilakukan dengan metode spektrofotometri, sementara analisis gen jalur Nrf2/Keap1 dilakukan dengan prosedur qRT-PCR. Hasil: Uji parametrik ANOVA dan post-hoc Tukey menunjukkan adanya penurunan kadar MDA hepar secara bermakna antara kelompok ko-kemoterapi kurkumin konvensional dan ko-kemoterapi nanokurkumin dengan kelompok monoterapi cisplatin (p=0,000 dan p=0,005). Tidak ada perbedaan bermakna antarkelompok pada ekspresi relatif mRNA Keap1 (p=0,190). Tidak ada perbedaan bermakna antara kelompok ko-kemoterapi kurkumin konvensional dengan nanokurkumin terkait ekspresi relatif Nrf2 (p=0,990), HO-1 (p=0,513), dan NQO-1 (p=1,000). Kesimpulan: Pemberian kurkumin menurunkan kadar MDA jaringan hepar dibanding kelompok monoterapi cisplatin. Tidak ada perbedaan bermakna antara kurkumin konvensional dan nanokurkumin dalam melemahkan hepatotoksisitas cisplatin dilihat dari MDA dan ekspresi gen jalur Nrf2/Keap1.

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Introduction: Cisplatin induces hepatotoxicity by oxidative stress-related mechanism. Curcumin activates the Nrf2/Keap1 pathway, modulating cellular response to oxidative stress, but its bioavailability is poor. The administration of curcumin in nanoparticles may increase the bioavailability and distribution of curcumin into tissues. This research aimed to assess the attenuation of cisplatin- induced hepatotoxicity through the modulation of Nrf2/Keap1 pathway by nanocurcumin.

Methods: 25 female Wistar rats were divided into a normal group and four ovarian cancer models by DMBA induction (further classified into a no treatment group, cisplatin monotherapy [4 mg/KgBW i.p.], co-administration of cisplatin and conventional curcumin [100 mg/KgBW p.o.], and co-administration of cisplatin and curcumin-loaded chitosan nanoparticles [100mg/KgBW p.o.]) for a month. The livers of the sacrificed animals were frozen. MDA level was measured by spectrophotometry, while the analysis of Nrf2/Keap1 pathway was done using qRT-PCR.

Results: The ANOVA parametric test showed significant differences between groups in hepatic MDA level ((p<0,001). MDA level was markedly reduced in groups receiving conventional (p<0,001) and nanocurcumin (p=0,005), though there were no significant differences between the administration of conventional and nanocurcumin in MDA level (p=0,277). There were no significant differences between groups in Keap1 relative mRNA expression (p=0,190). No statistically significant differences were observed between groups receiving conventional curcumin and nanocurcumin in the relative gene expression Nrf2 (p=0,990), HO-1 (p=0,513), and NQO-1 (p=1,000) mRNAs.

Conclusion: Curcumin did attenuate cisplatin-induced hepatotoxicity, but no significant differences were observed in hepatic MDA level and relative expression of genes in the Nrf2/Keap1 pathway between conventional curcumin and nanocurcumin administration. "

"Latar belakang: Dikarenakan fungsinya, hati merupakan organ yang rentan mengalami hepatotoksisitas. Oleh karena itu, senyawa yang diduga memiliki efek hepatoprotektif banyak diteliti. Salah satu bahan tersebut berupa minyak bekatul, yakni ekstrak minyak dari lapisan luar beras. Kandungan bahan aktifnya banyak dimanfaatkan dalam bidang kesehatan termasuk pada penyakit hati sehingga diduga minyak bekatul memiliki efek hepatoprotektif yang melindungi dan menyembuhkan hati dari hepatotoksisitas. Tujuan: Membuktikan bahwa minyak bekatul memiliki sifat hepatoprotektif terhadap hepatotoksisitas. Metode: Uji eksperimental pada 6 kelompok tikus Sprague dawley. Hepatotoksisitas diinduksi oleh CCl4 dengan dosis 0,55 g/KgBB sebanyak 1 kali secara oral. Minyak bekatul diberikan dalam 2 dosis untuk kelompok tikus yang berbeda, yakni 500 μL dan 1,5 mL. Pemberian minyak bekatul dilakukan setiap hari selama 8 minggu sebelum (preventif) atau setelah (kuratif) induksi hepatotoksisitas. Jarak antara induksi hepatotoksisitas dan pemberian minyak bekatul adalah 48 jam. Marker hepatotoksisitas yang diukur berupa serum ALT. Hasil: Kelompok yang diberikan minyak bekatul, baik sebagai agen preventif dan agen kuratif serta baik dalam dosis 500 μL dan 1,5 mL memiliki level serum ALT yang lebih rendah dibandingkan kelompok yang hanya diberikan CCl4 (p < 0,05). Simpulan: Minyak bekatul memiliki sifat hepatoprotektif baik sebagai agen preventif maupun kuratif terhadap hepatotoksisitas diinduksi CCl4.

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Background: Liver is prone to hepatotoxicity because of its function. For this reason, compounds that may have hepatoprotective attribute are searched extensively. One of those compounds is rice bran oil, an extract from the rice’s outer layer. Rice bran oil has many active components that are found to be beneficial in medical treatment, including liver disease. Therefore oil rice brain is thought to have hepatoprotective properties that may protect and cure liver from hepatotoxivity.

Aim: Evaluate rice bran oil’s hepatoprotective properties against hepatotoxicity.

Methods: This experimental study used six different groups of Sprague dawley. Hepatotoxicity in mouse is induced using 0,5g/KgBW of single-dose CCl4 orally. Rice bran oil was given in 2 separate doses, 500 μL dan 1,5 mL. Rice bran oil was administered for 8 weeks before (in preventive group) and after (in curative group) hepatotoxicity induction with 48 hours interval separating those two interventions. Serum ALT was investigated to evaluate hepatotoxicity.

Results: Group administered with rice bran oil as a preventive agent and curative agent with either 500 μL or 1,5 mL dose have low levels of serum ALT compared to CCl4 control group (p < 0,05).

Conclusion: Rice bran oil has hepatoprotective properties, both as a preventive agent and a curative agent against CCl4 induced hepatotoxicity."

"Latar belakang: Cisplatin merupakan pilihan utama terapi kanker ovarium saat ini, namun memiliki efek samping diantaranya adalah hepatotoksisitas. Salah satu patofisiologi hepatotoksisitas ini adalah melalui jalur inflamasi dan fibrosis. Kurkumin merupakan senyawa yang memiliki efek antiinflamasi dan antifibrosis, namun memiliki bioavailabilitas yang rendah. Pemberian nanopartikel kurkumin diteliti dapat meningkatkan bioavailabilitas kurkumin dalam tubuh. Tujuan: Penelitian ini bertujuan untuk mengetahui pengaruh nanokurkumin pada hepatotoksisitas akibat cisplatin, ditinjau dari kadar TNF-α dan TGF-β1 pada jaringan hati. Metode: Penelitian in vivo dilakukan pada tikus betina galur Wistar yang dibagi menjadi 5 kelompok perlakuan (1 kelompok normal/sham, dan 4 kelompok diinduksi DMBA untuk mendapatkan model kanker ovarium). Tikus model kanker ovarium diberikan perbedaan perlakuan lagi yaitu satu kelompok tidak diterapi, satu kelompok diterapi cisplatin 4 mg/kgBB secara intraperitoneal, satu kelompok diterapi cisplatin dan kurkumin konvensional 100 mg/kgBB oral, dan satu kelompok diterapi cisplatin dan nanopartikel kurkumin 100 mg/kgBB per oral. Setelah satu bulan pemberian terapi, tikus dikorbankan dan disimpan beku organ hatinya. Pengukuran kadar TNF-α dan TGF-β1 jaringan hati dilakukan dengan metode ELISA. Hasil: Tidak terdapat perbedaan yang signifikan antar kelompok perlakuan pada kadar TNF-α (p=0.675), dan tidak terdapat perbedaan yang signifikan antara kelompok terapi kurkumin dan nanokurkumin pada kadar TGF-β1 (p=0.992). Simpulan: Pemberian nanokurkumin tidak memengaruhi kadar TNF-α dan TGF-β1 di jaringan hati tikus model kanker ovarium yang mendapat terapi cisplatin.

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Introduction: Cisplatin is currently the main choice for ovarian cancer therapy, but it has side effects including hepatotoxicity. One of the pathophysiology of cisplatin-induced hepatotoxicity is through inflammation and fibrosis. Curcumin is a compound that has anti-inflammatory and antifibrosis effects, but has a low bioavailability. The administration of curcumin nanoparticles under study can increase the bioavailability of curcumin in the body. Goals: This study aims to determine the effect of nanocurcumin on cisplatin-induced hepatotoxicity, in terms of levels of TNF-α and TGF-β1 in liver tissue.

Methods: In vivo research was carried out on female Wistar rats divided into 5 treatment groups (1 normal/sham group, and 4 groups induced by DMBA to obtain ovarian cancer models). The ovarian cancer model mice were further classified where one group got no treatment, one group treated with cisplatin 4 mg/kgBW intraperitoneally, one group was treated with cisplatin and conventional curcumin 100 mg/kgBW orally, and one group was treated with cisplatin and curcumin nanoparticles 100 mg/kgBW orally. After one month of therapy, the mice were sacrificed and kept their liver frozen. The measurement of TNF-α and TGF-β1 levels in liver tissue was carried out by the ELISA method.

Results: There was no significant difference between treatment groups in TNF-α levels (p = 0.675), and there was no significant difference between the curcumin and nanocurcumin therapy groups in TGF-β1 levels (p = 0.992).

Concluson: Nanocurcumin therapy did not affect TNF-α and TGF-β1 level in liver tissue in ovarian cancer model mice receiving cisplatin therapy."