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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 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."

"Latar belakang: Kanker ovarium diduga dapat menyebabkan penurunan fungsi dan kerusakan ginjal. Cisplatin salah satu terapi kanker ovarium bersifat nefrotoksik. Kerusakan ginjal ini terjadi melalui berbagai mekanisme, salah satunya adalah peningkatan ekspresi ETAR. Kurkumin diduga mampu menurunkan ekspresi ETAR pada jaringan ginjal yang rusak. Penelitian ini bertujuan untuk mengetahui efek ko-kemoterapi kurkumin pada cisplatin terhadap ekspresi ETAR serta gambaran histopatologi jaringan ginjal pada tikus model kanker ovarium. Metode: 24 tikus wistar betina dibagi menjadi empat kelompok: Kelompok normal sham (N), kanker ovarium tanpa perlakuan (Ca), kanker ovarium yang mendapat 4 mg/KgBB cisplatin (Cis), dan kanker ovarium yang mendapat 4 mg/KgBB cisplatin +100 mg/KgBB kurkumin (Cis+Cur). Setelah 3 minggu tikus dikorbankan, ginjal tikus diambil untuk pengamatan histopatolgi serta ekspresi mRNA ETAR. Hasil: Pada pengamatan histopatologi Masson Trichrome ditemukan fokus fibrosis pada kelompok tikus Ca dan Cis. Melalui qRT-PCR diketahui bahwa ekspresi mRNA pada kelompok Ca dan Cis relatif sama, namun meningkat masing-masing sebesar 133% (2,33 kali lipat) dan 123% (2,23 kali lipat) dibandingkan dengan kelompok normal. Sedangkan pada kelompok Cis+Cur terdapat penurunan ekspresi mRNA sebesar 31,5% (0.315 lebih rendah) dan 34,4% (0.344 lebih rendah) berurutan dibanding kelompok Cis dan Cur. Tidak ditemukan perbedaan bermakna secara statistik antar kelompok uji. Kesimpulan: Kanker ovarium dapat memicu kerusakan ginjal pada tiku dibuktikan dengan peningkatan ekspresi mRNA ETAR dan fokus fibrosis. Pemberian cisplatin pada dosis terapeutik tidak meningkatkan ekspresi mRNA ETAR pada jaringan tikus model kanker ovarium, meski demikian pemberian kurkumin sebagai ko-kemoterapi menurunkan ekspresi mRNA ETAR dan fokus fibrosis meskipun tidak bermakna secara statistik.

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Background: Ovarian cancer is believed can lead to renal functional deterioration Furthermore, cisplatin as chemotherapeutic agent has nephrotoxic effects. Increased expression of the Endothelin A receptor (ETAR) is thought to be one of the mechanisms. Curcumin is believed to have protective effects in injured kidney. This study is to evaluate the co-chemotherapy effects of curcumin for cisplatin upon ETAR expression and histopathological appearances in rats’ kidney. Method: Total of 24 wistar rats, devided into four treatment groups: normal group (N), ovarian cancer without treatment group (Ca), ovarian cancer which received cisplatin 4 mg/kgBW group (Cis), and ovarian cancer which received cisplatin 4 mg/kgBW + 100 mg/kgBW curcumin group (Cis+Cur). Kidney tissue specimen was obtained for histopathological examination and ETAR messenger ribonucleic acid (mRNA) expression. Results: Fibrosis foci were found at kidney tissue of Ca and Cis group. The mRNA expression level among Ca and Cis group were relatively equivalent; however increased by 133% (2,33 fold) and by 123% (2,23 fold), respectively compared to N group. Meanwhile, the Cis + Cur group decreased by 31.5% (0.315 lower) and 34.4 % (0.344 lower) compared to Cis and Ca group respectively. There are no statistical significant among the experiment groups. Conclusion: Ovarian cancer is associated with kidney injury, demonstrated by increased of ETAR mRNA and fibrosis foci formation. Therapeutic dose cisplatin do not increased ETAR mRNA in the kidney of ovarian cancer rat. Curcumin administration as co-chemotherapeutic agent result in the decrease of ETAR mRNA level and the decrease of fibrosis foci formation."

"Kemoterapi dengan cisplatin merupakan modalitas utama pada terapi pada kanker ovarium, walaupun telah diketahui toksisitasnya pada berbagai organ termasuk ginjal. Kurkumin, senyawa fenolik yang diperoleh dari Curcuma longa, diketahui memiliki efek proteksi pada ginjal akibat cisplatin pada berbagai model toksisitas in vivo. Namun, efek kurkumin pada ginjal dibatasi oleh bioavailabilitasnya yang rendah. Kelompok penelitian kami telah berhasil mengembangkan formulasi kurkumin nanopartikel baru yang telah terbukti memperbaiki efikasi cisplatin pada model kanker ovarium. Namun, belum diketahui apakah formulasi kurkumin nanopartikel ini juga dapat memperbaiki fungsi dan kondisi inflamasi pada ginjal yang disebabkan oleh cisplatin.Metode Sebanyak 24 ekor tikus Wistar betina dibagi menjadi: 6 ekor tikus normal (sham treatment) dan 18 ekor tikus yang diinduksi menjadi kanker ovarium dengan DMBA. Tikus kanker ovarium dibagi menjadi 3 kelompok masing-masing 6 ekor yang menerima cisplatin 4 mg/kgBB/minggu atau cisplatin 4 mg/kgBB/minggu +kurkumin 100 mg/kgBB/hari atau cisplatin 4 mg/kgBB/minggu + nanokurkumin 100 mg/kgBB/hari. Terapi diberikan selama 4 minggu, kemudian dilakukan terminasi dan diambil darah dan organ ginjal untuk analisis penanda fungsi ginjal dan inflamasi.Hasil Nanokurkumin dapat menurunkan kadar ureum serum signifikan dibandingkan kelompok cisplatin, namun tidak mempengaruhi kadar kreatinin dan sedikit menurunkan kadar neutrophil gelatinase-associated lipocalin (NGAL). Nanokurkumin tidak berhasil menurunkan kadar penanda inflamasi: TNF-, IL-1β dan IL-6.KesimpulanNanokurkumin memiliki kecenderungan untuk memperbaiki beberapa penanda fungsi ginjal dalam darah pada model kanker ovarium yang diberikan cisplatin, namun tidak mempengaruhi kadar penanda inflamasi di ginjal.

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The effects of nanocurcumin on kidney function and inflammatory

markers in rat model of ovarian cancer treated with cisplatin

Cisplatin remains the main modality of treatment for ovarian cancer, despite its known toxic effects to various organs, including the kidney. Curcumin, a phenolic compound derived from Curcuma longa, was known to have a renoprotective effect on cisplatin- induced in vivo models. However, the beneficial effect of curcumin on the kidney is limited by its low bioavailability. Our research group has successfully developed a novel curcumin nanoparticle formulation that has been shown to improve the efficacy of cisplatin in ovarian cancer models. However, it is not yet known whether this curcumin nanoparticle formulation can also improve kidney function and inflammatory conditions caused by cisplatin in ovarian cancer models.

Method

A total of 24 female Wistar rats were divided into: 6 normal rats (sham treatment) and 18 rats induced to develop ovarian cancer with DMBA. Ovarian cancer rats were divided into 3 groups of 6 each receiving cisplatin 4 mg/kgBW/week or cisplatin 4 mg/kgBW/week + curcumin 100 mg/kgBW/day or cisplatin 4 mg/kgBW/week + nanocurcumin 100 mg/day. kgBB/day. Therapy was given for 4 weeks, then terminated and blood and kidney were taken for analysis of markers of kidney function and inflammation.

Results

Nanocurcumin lowered serum urea levels significantly compared to the cisplatin group. However, nanocurcumin did not alter creatinine levels and slightly reduced serum neutrophil gelatinase-associated lipocalin (NGAL) concentrations. Nanocurcumin was did not affect the inflammatory markers studied: TNF-, IL-1β and IL-6.

Conclusion

Nanocurcumin has a tendency to improve several markers of kidney function in cisplatin- treated ovarian cancer models. However, the effect was not associated by the alteration of inflammatory cytokines in the kidney."

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Latar belakang: Kurkumin memiliki aktivitas antikanker yang poten, namun profil farmakokinetik dan ketersediaan kurkumin di organ target sangat rendah. Nanopartikel kurkumin dibuat untuk meningkatkan aktivitas kurkumin sehingga dapat meningkatkan efek obat pada proses angiogenesis dan proliferasi sel pada tikus model kanker ovarium.

Metode: Nanopartikel kurkumin dibuat dengan metode gelasi ionik menggunakan kitosan sebagai polimer. Profil farmakokinetika kurkumin dan nanokurkumin dilakukan pada tikus dengan pemberian dosis oral sebesar 100 mg/kgBB. Sampel darah diambil pada sembilan  waktu dan konsentrasi kurkumin dalam plasma dianalisis menggunakan UPLC-MS/MS. Pengujian nanokurkumin sebagai ko-kemoterapi secara in vivo pada kanker ovarium dilakukan pada tikus model kanker ovarium dengan induksi DMBA. Tikus model kanker ovarium diberikan terapi cisplatin atau kombinasi cisplatin dan kurkumin, atau kombinasi cisplatin dan nanokurkumin. Efek antikanker dilihat dari pengukuran marker antiproliferasi (Ki67), marker apoptosis serta jalur sinyal TGF-b/PI3K/Akt dan IL-6/JAK/STAT3.

Hasil: Diperoleh ukuran partikel nanokurkumin sebesar 19,43±11,24 nm, dengan efisiensi penjerapan 99,97%, dan loading capacity 11,34%. Sifat mukoadhesif nanokurkumin lebih baik dibandingkan dengan kurkumin. Evaluasi profil farmakokinetik pada tikus diperoleh bahwa nanokurkumin meningkatkan AUC, Cmax, Tmax dan menurunkan klirens. Pada uji aktivitas in vivo,  pemberian cisplatin dan ko-kemoterapi nanokurkumin menyebabkan penurunan yang signifikan pada volume dan berat ovarium. Penemuan ini sesuai dengan penurunan ekspresi protein TGF-β, PI3K dan p-Akt/Akt. Efek ko-kemoterapi nanokurkumin juga dapat dapat menurunkan ekspresi protein IL-6, JAK, dan p-STAT3/STAT3. Pemberian cisplatin dan nanokurkumin juga menyebabkan peningkatan marker apoptosis yang signifikan seperti Bax, kaspase-9 dan kaspase-3 serta menurunkan ekspresi Bcl-2.

Kesimpulan: Nanokurkumin dapat memperbaiki profil farmakokinetika kurkumin, sehingga dapat diaplikasikan pada strategi ko-kemoterapi kanker ovarium dengan menghambat proliferasi melalui penghambatan jalur sinyal PI3K/Akt, JAK/STAT3, peningkatan apoptosis marker Bax, kaspase-3 dan kaspase-9 serta menurunkan ekspresi Bcl-2.

Kata kunci: kurkumin, kitosan, nanopartikel, kanker ovarium, PI3K/Akt, JAK/STAT

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Background: Curcumin has a potent anticancer activity. However, its systemic bioavailability and its concentration in organ is extremely low. The modification of curcumin to curcumin nanoparticles was expected to increase the activity of curcumin on angiogenesis and cell proliferation process in rat ovarian cancer.

Methods: Nanocurcumin were made using ionic gelation methods. The pharmacokinetic profiles of curcumin particles and nanoparticles were then assessed in rats by administering a single oral dose of 100 mg/kg BW. Blood samples were taken from nine predetermined time points, and curcumin plasma concentrations were then analyzed using UPLC-MS/MS. Nanocurcumin was tested as a co-chemotherapy in vivo and was carried out on ovarian cancer animal models, induced with 7,12-dimethylbenz(a)anthracene (DMBA). The ovarian cancer animal models were then treated with cisplatin, or cisplatin and curcumin, or combination of cisplatin with nanocurcumin. The anticancer effect of nanocurcumin as co-chemotherapy was investigated with the measurement of antiproliferation marker (Ki67), apoptotic markers as well as the expression of TGF-b/PI3K/Akt dan IL-6/JAK/STAT3.

Result: The particle size of the curcumin nanoparticles obtained were 19,43±11,24 nm. Entrapment efficiency (EE) of curcumin nanoparticles were exceeding 99.97%, and drug loading capacity (DLC) was 11.34%. The mucoadhesive properties of the nanoparticles were superior to that of curcumin particles. Pharmacokinetic evaluation in rats revealed that curcumin nanoparticles resulted in an increase of AUC, Cmax, Tmax, and lower Cl. The administration of cisplatin and nanocurcumin co-chemotherapy caused a significant reduction in ovarian volume and weight. These findings followed with decreased protein expression of TGF-β, PI3K and p-Akt/Akt. The co-chemotherapy effect nanocurcumin is also investigated as a mechanism of action via IL-6, JAK, p-STAT3/STAT3 expressions.  Treatments of cisplatin and nanocurcumin resulted in a significant increase in apoptotic markers such as Bax, caspase-9, and caspase-3 expressions and decreased Bcl-2 expression.

Conclusion: Nanocurcumin is an effective formulation to improve pharmacokinetics profile. Nanocurcumin as a co-chemotherapy  can be considered as a potential co-chemotherapy in ovarian cancer. The improved mechanism of actions are shown by the proliferation inhibition, downregulation of PI3K/Akt, JAK/STAT3 signaling pathways, and Bcl-2 expression and increasing apoptosis through the expression of Bax, caspase-9 and caspase-3.

Keywords: curcumin, chitosan, nanoparticles, ovarian cancer, PI3K/Akt, JAK/STAT

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"Latar belakang : Cisplatin adalah pilihan utama dalam penatalaksanaan kanker ovrium secara farmakologi. Namun, disisi lain cisplatin dapat menyebabkan kerusakan ginjal. Kerusakan ginjal akibat Cisplatin salah satunya terjadi karena perubahan aktivitas sistem endotelin ginjal sebagai pengatur hemodinamik ginjal. Secara teori kerusakan ini dapat dikurangi dengan pemberian ko-kemoterapi cisplatin yang memiliki sifat renoprotektif. Salah satu agen renoprotektif adalah Kurkumin. Salah satu manfaat kurkumin dapat mengurangi kerusakan ginjal karena bersifat renoprotektif. Penelitian ini bertujuan untuk mengetahui efek pemberian kurkumin sebagai ko-kemoterapi cisplatin terhadap ekspresi reseptor endothelin B (ETBR) dan gambaran hitopatologi pada ginjal tikus model kanker ovarium.Metode: Dua puluh empat tikus Wistar betina (150-200 gram) berusia 5 minggu dikelompokan menjadi empat kelompok: Normal (N), Kanker Ovarium tanpa pemberian obat (Ca), Cisplatin (Cis) adalah kelompok tikus kanker ovarium yang mendapat terapi cisplatin 4mg/KgBB selama tiga minggu, Cisplatin+Kurkumin (Cis+Cur) adalah kelompok tikus kanker ovarium yang diberi cisplatin 4mg/KgBB+ curcumin 100mg/KgBB selama tiga minggu. Setelah memasuki minggu ke-24, tikus dikorbankan dan diambil jaringan ginjal untuk dilakukan pengamatan secara histologi dan molekular.Hasil: gambaran histologi ginjal menunjukan perubahan struktur abrnomal. Akan tetapi perubahan struktur menuju kerusakan ginjal pada penelitian ini tidak signifikan. Selanjutnya, pengamatan ekspresi ETBR didapati ekspresi tertinggi pada kelompok tikus normal (N) dan terendah pada kelompok tikus dengan pemberian Cisplatin dan Kurkumin (Cis+Cur) dengan nilai p pada uji ANOVA Satu Arah sebesar 0.087 (signifikan jika p<0,05).Kesimpulan: pemberian kurkumin sebagai ko-kemoterapi cisplatin pada tikus model kanker ovarium tidak menyebabkan perubahan struktur histologi yang bermakna dan tidak menyebabkan peningkatan ekspresi ETBR yang signifikan.

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Background: Cisplatin is the main choice in pharmacological treatment of ovarian cancer. However, cisplatin can cause kidney damage. One of the causes of kidney damage due to cisplatin occurs due to changes in the activity of the renal endothelin system as a renal hemodynamic regulator. In theory, this damage can be reduced by giving cisplatin co-chemotherapy which has renoprotective properties. One of the renoprotective agents is curcumin. One of the benefits of curcumin is to reduce kidney damage because it is renoprotective. This study aims to determine the effect of curcumin administration as co-chemotherapy of cisplatin on endothelin B receptor expression (ETBR) and the histopathological description of ovarian cancer model rats.

Methods: Twenty-four female Wistar rats (150-200 grams) aged 5 weeks were grouped into four groups: Normal (N), Ovarian Cancer without drug administration (Ca), Cisplatin (Cis) is a group of ovarian cancer mice receiving 4mg/KgBB cisplatin therapy for three weeks, Cisplatin + Curcumin (Cis + Cur) is a group of ovarian cancer mice that were given cisplatin 4mg / KgBB + curcumin 100mg / KgBB for three weeks. After entering the 24th week, the rats were sacrificed and kidney tissue was taken for histological and molecular observation.

Result: The histology of the kidneys showed an abnormal structural change. However, the structural changes leading to kidney damage in this study were not significant. Furthermore, observations of ETBR expression found the highest expression in the normal (N) group

of rats and the lowest in the group of rats given Cisplatin and Curcumin (Cis + Cur) with a p value in the One Way ANOVA test of 0.087 (significant if p <0.05).

Conclusion: giving curcumin as co-chemotherapy of cisplatin in ovarian cancer model mice did not cause significant changes in histological structure and did not cause a significant increase in ETBR expression"

"Nefrotoksisitas merupakan efek samping utama yang membatasi penggunaan cisplatin sebagai obat anti-tumor. Kurkumin memeliki beberapa aktivitas farmakologis salah satunya, yaitu sebagai nefroprotektor. Akan tetapi kurkumin kurang larut di dalam air, sehingga digunakan nanokurkumin yang lebih mudah larut/terdispersi dalam air. Tujuan penelitian ini adalah untuk mengetahui efek kurkumin dan nanokurkumin terhadap nefrotoksisitas tikus yang diinduksi cisplatin melalui jalur ERK1/2. Perlakuan hewan coba dilakukan selama 10 hari, menggunakan tikus Sprague Dawley yang dibagi menjadi 5 kelompok, n=6, yaitu kelompok normal, cisplatin CIS, Cisplatin kurkumin 100 mg/kgBB/hari p.o Cis Kurku100, Cisplatin nanokurkumin 50 mg/kgBB/hari p.o Cis Nanokur50, Cisplatin nanokurkumin 100 mg/kgBB/hari p.o Cis Nanokur100 . Pada hari ke-7 dilakukan injeksi cisplatin 7 mg/kgBB, i.p dan 72 jam setelah injeksi cisplatin dilakukan pengambilan darah dan organ ginjal. Cisplatin dosis tunggal pada kelompok CIS menyebabkan peningkatan kadar BUN dan kreatinin dalam plasma, kadar MDA, peningkatan rasio ekspresi BCL-2/Bax, serta peningkatan rasio ekspresi protein p-ERK/ERK secara signifikan, dibandingkan kelompok normal. Pemberian kurkumin 100 mg/kgBB dan nanokurkumin 100 mg/kgBB berperan sebagai antioksidan untuk mencegah progresifitas nefrotoksisitas akibat cisplatin, dilihat melalui terjadinya penurunan kadar BUN dan kreatinin dalam plasma, penurunan kadar MDA, dan peningkatan rasio ekspresi gen BCL-2/Bax secara signifikan dibandingkan kelompok CIS, serta penurunan rasio ekspresi protein p-ERK/ERK secara signifikan dibandingkan kelompok CIS. Cisplatin dosis tunggal 7 mg/kgBB dapat menyebabkan nefrotoksisitas pada tikus yang menyerupai AKI Acute Kidney Injury pada manusia. Kurkumin 100 mg/kgBB cenderung memiliki efek nefroprotektor yang lebih baik dalam mencegah progresifitas nefrotoksisitas akibat cisplatin melalui jalur stress oksidatif dan apoptosis.

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Nephrotoxicity is the major limitation for the clinical use of cisplatin as an antitumor. Curcumin has some pharmacological activity, one of them as nephroprotector. However, curcumin less soluble in water, so it is used nanocurcumin which is readily dispersed in aqueous media. The purpose of this study is to investigate the effects of curcumin and nanocurcumin against ciplatin induced nephrotoxicity in rats through ERK1 2 pathway. This study conducted for 10 days treatment, five groups n 6 of male Sprague Dawley rats were examined normal, cisplatin CIS 7 mg kgBW, Cis curcumin Cis Curcu100 100 mg kg BW day, Cisplatin nanocurcumin 50 mg kg BW day Cis Nanocur50, and Cisplatin nanocurcumin 100mg kg BW day Cis Nanocur100 . After 72 h following injection cisplatin, specimens were collected. This study resulted a single dose of cisplatin in CIS group caused a significant increased in plasma BUN, plasma creatinine, MDA levels, decreased ratio expression of BCL 2 Bax gene, and increased ratio of p ERK ERK as compared to normal group. Pre treatment with curcumin 100 mg kgBW and nanocurcumin 50 and 100 mg kgBW acts as an antioxidant to prevent progression of nephrotoxicity cisplatin, were reduced plasma BUN levels, plasma creatinine levels, MDA levels in kidney, increased GSH level in kidney, increased ratio expression of BCL 2 Bax gene in kidney, and decreased ratio of p ERK ERK protein in kidney compared with cisplatin induced nephrotoxicity rats without treatment. Cisplatin with single dose 7 mg kgBW is able to induced nephrotoxicity in rats that mimicked acute kidney injury in human. Curcumin 100 mg kgBW tend to have a better nephroprotector effect in preventing the progression of cisplatin induced nephrotoxicity through oxidative stress pathways and apoptosis. "

"Pendahuluan: Hampir 85% kasus karsinoma ovarium terjadi overekspresi endothelin-1 (ET-1) yang memodulasi persinyalan tumorigenesis dan metastasis. Disisi lain, cisplatin sebagai kemoterapi kanker ovarium menimbulkan efek samping dan resistensi terapi. Berbagai penelitian menunjukkan kurkumin berpotensi sebagai antikanker yang meningkatkan efikasi cisplatin dan menekan overekspresi ET-1 pada lini sel nonkanker. Namun, belum banyak penelitian yang mengidentifikasi penekanan ekspresi ET-1 oleh kurkumin dalam regimen terapi bersama cisplatin di kanker ovarium. Oleh karena itu, penelitian ini bertujuan melihat efek ko-kemoterapi kurkumin bersama cisplatin pada kanker ovarium terkait ekspresi relatif mRNA ET-1. Metode: Jaringan ovarium tersimpan dari 24 tikus betina galur Wistar dibagi kedalam 4 kelompok: tikus yang hanya dibedah dan diberi aquadest (sham), tikus yang diimplantasi DMBA tanpa intervensi terapi, tikus yang diimplantasi DMBA dan diberi terapi tunggal cisplatin intraperitoneal 4 mg/kgBB/minggu, tikus yang diimplantasi DMBA dengan diberi terapi cisplatin 4 mg/kgBB/minggu dan kurkumin oral 100 mg/kgBB/hari. Implantasi DMBA dilakukan selama 28 minggu dan intervensi pada hewan coba selama 4 minggu. Setelah itu, jaringan ovarium tersimpan dianalisis ekspresi relatif mRNA ET-1 dengan mesin qRT-PCR menggunakan metode Livak-Schmittgen (2(-Ct)). Hasil: Didapatkan rerata ekspresi relatif mRNA ET-1 [p=0,021] pada kelompok sham (0,349±0,24), kelompok DMBA (3,117±1,532), kelompok DMBA+cisplatin (0,993±0,651), dan kelompok DMBA+kurkumin+cisplatin (0,117±0,081). Ketiga kelompok tidak memiliki perbedaan bermakna dibandingkan sham. Meski demikian, terdapat perbedaan bermakna pada kelompok kombinasi cisplatin serta ko-kemoterapi kurkumin dengan kelompok tanpa intervensi terapi [p=0,019]. Kesimpulan: Terjadi penurunan ekspresi relatif mRNA endothelin-1 di jaringan ovarium model tikus yang diinduksi DMBA setelah pemberian kombinasi cisplatin dan ko-kemoterapi kurkumin.

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Introduction: Endothelin-1 overexpression happens in 85% ovarian carcinoma cases that modulate metastatic and tumorigenesis. Meanwhile, cisplatin as ovarian cancer chemotherapy cause side effects and therapy resistances. Prior studies show potential effect of curcumin as an anticancer could enhance cisplatin efficacy and attenuate ET-1 overexpression in non-cancer cell lines. However, not many studies have identified suppression effect of ET-1 expression by curcumin with cisplatin in ovarian cancer. Therefore, this study is conducted to identify the effect of curcumin with cisplatin in ovarian cancer treatment especially its relation to relative expression of ET-1 mRNA.

Methods: Frozen ovarian tissue samples from 24 female Wistar rats were divided into 4 groups: a group that only operated on and treated with distilled-water (sham), group with DMBA-implantation, group with DMBA-implantation and intraperitoneal cisplatin 4mg/kgBW/week, group with DMBA-implantation and cisplatin with same dose as before plus oral curcumin 100mg/kgBW/day. After 28 weeks of DMBA-implantation and 4 weeks of intervention, frozen ovarian tissue samples were taken to measure its relative expression of ET-1 mRNA level with qRT-PCR machine.

Results: The mean of relative expression of ET-1 mRNA level [p=0,021] in frozen tissue sample of sham group (0,349±0,24), DMBA-implantation group (3,117±1,532), DMBA+cisplatin-treated group (0,993±0,651), and DMBA+curcumin+cisplatin-treated group (0,117±0,081). This study shows those 3 groups did not have significant difference compared with sham. But among group with cisplatin+curcumin-treated compared to DMBA-implantation shows a significant difference (p=0,019).

Conclusion: The relative expression of ET-1 mRNA in ovarian tissue of DMBA-induced rats model decreases after given by a combination of cisplatin+curcumin co-chemotherapy."

"Latar Belakang: Cisplatin, agen kemoterapi utama dalam terapi kanker ovarium,memiliki sifat hepatotoksik karena menginduksi stres oksidatif. Kurkumin dapatmeningkatkan kadar atau aktivitas antioksidan endogen seperti enzim superoksidadismutase dan glutation. Formulasi nanopartikel kurkumin dapat meningkatkanbioavailabilitas kurkumin dan distribusinya pada organ target. Penelitian inibertujuan untuk mengetahui pengaruh nanokurkumin terhadap hepatotoksisitasakibat cisplatin melalui regulasi antioksidan endogen SOD dan GSH. Metode: 25ekor tikus galur Wistar betina dibagi ke dalam 1 kelompok sham dan 4 kelompokmodel kanker ovarium yang diinduksi DMBA pada penelitian in-vivo ini. Empatkelompok tersebut adalah kelompok tanpa terapi, cisplatin 4 mg/KgBBintraperitoneal, cisplatin dengan kurkumin konvensional 100 mg/KgBB per oral,atau cisplatin dengan nanopartikel kurkumin dalam kitosan 100 mg/KgBB per oral.Setelah perlakuan selama 1 bulan, hepar tikus diambil dan disimpan beku.Pengukuran aktivitas SOD, kadar GSH, dan kadar GSSG dilakukan dengan metodespektrofotometri. Hasil: Uji statistik pada kadar GSH, GSSG, dan aktivitas SODmenunjukkan peningkatan yang signifikan pada kelompok ko-kemoterapikurkumin konvensional dibanding monoterapi cisplatin (p<0.05). Tidak adaperbedaan yang bermakna antarkelompok pada rasio GSH/GSSG (p>0.05) dantidak ditemukan perbedaan bermakna antara kedua kelompok ko-kemoterapi padasemua variabel (p>0.05). Kesimpulan: Kurkumin konvensional dan nanokurkuminsetara dalam meregulasi antioksidan endogen SOD dan GSH pada tikus modelkanker ovarium yang mendapat cisplatin.

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Introduction: As the primary chemotherapeutic agent of choice for ovarian cancer,

cisplatin has hepatotoxic properties via oxidative stress induction. Curcumin can

increase the levels and activities of endogenous antioxidants like superoxide

dismutase enzyme and glutathione. Formulation of curcumin nanoparticles

increases its bioavailability and target organ distribution. This research aims to

elucidate the effects of nanocurcumin on cisplatin-induced hepatotoxicity via

regulation of endogenous antioxidants, SOD and GSH. Method: 25 Wistar female

rats were grouped into 1 sham group and 4 DMBA-induced ovarian cancer model

groups in this in-vivo study. Four cancer model groups were further divided into

no-treatment, 100 mg/KgBW intraperitoneal cisplatin therapy, cisplatin with oral

100 mg/KgBW conventional curcumin, and cisplatin with oral 100 mg/KgBW

curcumin nanoparticle in chitosan group. The liver of the rats were taken and frozen

after one month of treatment. Spectrophotometry was used to measure the activities

of SOD, levels of GSH, and levels of GSSG. Results: Statistic tests on levels of

GSH, GSSG, and activity of SOD showed significant increase in the curcumin cochemotherapy

against cisplatin monotherapy (p<0.05). There was no significant

difference within the groups of GSH/GSSG ratio (p>0.05) and no significant

difference was found between the curcumin co-chemotherapy and nanocurcumin

co-chemotherapy groups in all the variables (p>0.05). Conclusion: Conventional

curcumin and nanocurcumin administration are similar in regulating endogenous

antioxidants SOD and GSH on rats with ovarian cancer model treated with cisplatin."

"Latar belakang: Terdapat peningkatan 80% ekspresi reseptor endothelin A dan 40% ekspresi endothelin B pada kanker ovarium. Peningkatan ekspresi reseptor endothelin A terbukti berperan dalam menyebabkan progresifitas dan metastasi kanker ovarium. REB berperan sebagai klirens endothelin-1 dan meningkatkan proses apoptosis. Cisplatin sebagai lini pertama pengobatan kanker ovarium memiliki efek samping dan berisiko mengembangkan kanker ovarium resistensi cisplatin. Kurkumin sebagai salah satu bahan alami terbukti memiliki potensi sebagai antikanker dan dapat meingkatkan efikasi cisplatin. Tujuan: penelitian ini adalah untuk melihat efektifitas kombinasi kurkumin dan cisplatin sebagai tatalaksana alternatif kanker ovarium dilihat dari ekspresi relatif mRNA reseptor endothelin A dan reseptor endothelin B. Metode: Homogenasi jaringan ovarium tersimpan yang dilanjutkan dengan sentrifugasi. Cairan supernatan diambil untuk dilakukan purifikasi. RNA yang terfurifikasi diubah menjadi cDNA. Selanjutnya, analisis dilakukan menggunakan mesin qRT-PCR, dengan metode Livak-Schmittgen 2(-Ct). Hasil: Ekspresi mRNA reseptor endothelin B pada kelompok normal (7,376±1,407), DMBA +Cis (1,701±1,096), DMBA+Cis+Cur (7,391±2,261), DMBA (0,649±0,221), dengan p<0,05. Hasil bermakna pada kelompok DMBA dan DMBA+Cis+Kur dengan p=0,014. Ekspresi mRNA reseptor endothelin A pada kelompok normal (0,698±0,366), DMBA+Cis (5,311±2,737), DMBA+Cis+Kur (7,502±2,476), DMBA (10,970±3,883), dengan p<0,05. Namun antar kelompok DMBA dan kelompok DMBA+Cis+Kur atau DMBA+Cis tidak ditemukan hasil bermakna p>0,05. Simpulan: Kombinasi kurkumin dan cisplatin yang diberikan pada tikus model kanker ovarium yang diinduksi DMBA, dapat memengaruhi jalur reseptor endothelin melalui peningkatan ekspresi relatif mRNA reseptor endothelin B, dan kecendrungan penurunan ekspresi reseptor endothelin A.

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Background: There was an 80% increase in endothelin A receptor expression and 40% endothelin B expression in ovarian cancer. Increased expression of endothelin A receptors has been shown to play a role in causing progression and metastasis of ovarian cancer. REB acts as endothelin-1 clearance and increases the apoptotic process. Cisplatin as the first line of ovarian cancer treatment has side effects and the risk of developing cisplatin- resistant ovarian cancer. Curcumin as a natural ingredient is proven to have potential as an anticancer and can increase the efficacy of cisplatin. The purpose of this study was to determine the effectiveness of the combination of curcumin and cisplatin as an alternative treatment for ovarian cancer in terms of the relative expression of endothelin A and endothelin B receptor mRNAs. Methods: Homogenation of stored ovarian tissue followed by centrifugation. The supernatant fluid is taken for purification. The purified RNA is converted into cDNA. Furthermore, the analysis was performed using a qRT- PCR machine, with the Livak-Schmittgen methode 2(-Ct). Results: The expression of mRNA endothelin B receptor in normal (7.376 ± 1.407), DMBA + Cis (1.701 ± 1.096), DMBA + Cis + Cur (7.391 ± 2.261), DMBA (0.649 ± 0.221) groups, with p <0.05. The results were significant in the DMBA and DMBA + Cis + Kur groups with p = 0.014. The expression of endothelin A receptor mRNA in normal (0.698 ± 0.366), DMBA + Cis (5.311 ± 2.737), DMBA + Cis + Kur (7.502 ± 2.476), DMBA (10.970 ± 3.883) groups, with p <0.05. However, between the DMBA group and the DMBA + Cis + Kur or DMBA + Cis group there were no significant results found with p> 0.05. Conclusion: The combination of curcumin and cisplatin given to DMBA-induced ovarian cancer model mice can affect the endothelin receptor pathway through an increase in the relative expression of endothelin B receptor mRNA, and a tendency to decrease the expression of endothelin A receptors."