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Abstrak :

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

Abstrak :
Latar belakang: Nanopartikel perak (AgNPs) telah banyak diteliti karena aktivitas anti-inflamasinya yang berpotensi digunakan sebagai obat yang bekerja secara lokal di saluran gastrointestinal (GI) untuk pengobatan kolitis ulseratif. Namun, disolusi AgNPs secara masif dalam kondisi asam di lambung berpotensi menyebabkan serapan sistemik dan toksisitas. Pendekatan rasional harus dirancang untuk penargetan kolon secara selektif. Metode: Biomolekul alginat dipilih sebagai agen penstabil untuk radiosintesis dan penghantaran AgNPs karena bersifat biokompatibel, sensitif pH, dan polianionik. Radiosintesis dioptimalkan menggunakan Central Composite Design – Response Surface Methodology (CCD-RSM) yang melibatkan 20 percobaan tanpa penambahan isopropanol sebagai scavenger radikal hidroksil. Stabilitas nanosuspensi dievaluasi selama penyimpanan pada suhu 4°C kondisi gelap selama 40 hari. Disolusi AgNPs secara in vitro ditentukan dalam simulasi cairan lambung pH 1,2 selama 120 menit. Kemudian, serapan sistemik dan toksisitas AgNPs terstabilisasi alginat ditentukan setelah pemberian oral dosis berulang 14 hari pada mencit sehat dengan dosis bervariasi (2,5, 5,0, dan 10,0 mg/kg BB). Hasil: Radiosintesis berhasil mensintesis AgNPs terstabilisasi alginat tanpa penambahan isopropanol. Kondisi optimal diperoleh pada dosis iradiasi 20 kGy, konsentrasi precursor ion perak 7,78 mM, dan konsentrasi alginat 1,2 % (b/v) yang menghasilkan nilai konversi 65,43 % dengan konsentrasi AgNPs 480,9 ppm. Morfologi AgNPs berbentuk bulat dengan ukuran 10,25 ± 5,03 nm. Menariknya, alginat berperan ganda sebagai agen penstabil sekaligus agen pereduksi selama radiosintesis. Alginat juga berperan menstabilkan nanosuspensi hingga 67 ± 5 hari, dan meminimalkan disolusi pada kondisi asam pH 1.2 hingga kurang dari 1,5 % dalam periode disolusi 120 menit. Setelah administrasi oral dosis berulang 14 hari dosis 2,5 mg/kg BB, mencit sehat tidak menunjukkan tanda toksisitas. Perak tidak terdeteksi pada organ dalam, sedangkan penilaian hstopatologis untuk hepar dan kolon tidak berbeda bermakna dengan kelompok kontrol. Kesimpulan: Alginat berperan penting dalam radiosintesis AgNPs tanpa penambahan isopropanol. Alginat juga berperan sebagai agen penstabil yang baik untuk menjaga stabilitas selama penyimpanan dan mencegah disolusi dalam kondisi asam. Dosis 2,5 mg/kg BB dapat digunakan sebagai dosis referensi untuk penelitian lebih lanjut mengenai toksisitas/bioaktivitas AgNPs sebagai obat yang bekerja secara lokal di saluran gastrointestinal (GI) untuk pengobatan kolitis ulseratif. ......Background: Silver nanoparticles (AgNPs) have been extensively investigated due to their anti-inflammatory activity which potentially used as locally-acting drug in the gastrointestinal (GI) tract for treatment of ulcerative colitis. However, massive dissolution of AgNPs in acidic stomach potentially lead to systemic uptake and toxicity. Rational approaches must be designed for selectively targeting the colon. Methods: Biomolecule alginate was chosen as stabilizing agent for radiosynthesis and delivery of AgNPs due to its biocompatibility, pH sensitiveness, and polyanionic nature. Radiosynthesis was optimized using central composite design – response surface methodology (CCD-RSM) which involved 20 run experiments without addition of isopropanol as a hydroxyl radical scavenger. The stability of nanosuspension was evaluated during storage at 4°C under dark for 40 days. The in vitro dissolution of AgNPs was determined in simulated gastric fluid pH 1.2 for 120 min. Then, systemic uptake and toxicity of alginate-stabilized AgNPs were determined upon 14 days repeated dose oral administration in healthy mice at varied dose (2.5, 5.0, and 10.0 mg/kg BW). Results: Radiosynthesis had successfully synthesized alginate AgNPs without addition of isopropanol. The optimal condition was found at dose of 20 kGy, precursor silver ion of 7.78 mM, and alginate concentration of 1.2 % (w/v) which resulted the conversion yield of 65.43 % with concentration of AgNPs at 480.9 ppm. The AgNPs was spherical in shape at size of 10.25 ± 5.03 nm. Interestingly, alginate played dual role as stabilizing and reducing agent during radiosynthesis. The alginate allowed stabilization of nanosuspension for 67 ± 5 days, and also minimized the acid dissolution down to 1.5 % during 120 min dissolution time. Upon 14 days repeated dose oral administration of AgNPs at dose 2.5 mg/kg BW, the healthy mice did not showed toxicity sign. Silver was not detected in internal organ, while hstopathological scoring for liver and colon is not significantly different with control group. Conclusion: Alginate plays important role in radiosynthesis of AgNPs without addition of isopropanol. It also acts as good stabilizing agent for maintaining stability during storage and preventing dissolution in acidic condition. Dose of 2.5 mg/kg BW can be used as a reference dose for further research on toxicity/bioactivity of AgNPs as locally-acting drug in the gastrointestinal (GI) tract for treatment of ulcerative colitis.

Abstrak :
Latar belakang: Moringa oleifera (MO) secara luas telah dimanfaatkan oleh masyarakat Indonesia sebagai bahan makanan dan juga obat tradisional. M. oleifera telah terbukti memiliki berbagai efek farmakologi diantaranya efek neuroprotektif. Tujuan penelitian ini untuk menganalisis efek neuroprotektif dan mekanisme dasar dari ekstrak etanol 70% daun (MOE) dan minyak biji M. oleifera (MOO) pada mencit yang mengalami depresi, kecemasan dan fungsi kognitif akibat induksi stres kronik. Metode: Dalam penelitian ini kami menguji analisis fitokimia MOE dengan LC-MS dan MOO dengan GC-MS. Dua puluh empat mencit jantan dengan berat badan 25-30 g, dibagi secara acak menjadi 6 kelompok yaitu kelompok normal (mencit normal diberi 0,5% CMC), WIRS (mencit stres dengan induksi WIRS+CMC 0,5%), kelompok WIRS+MOE400 (mencit stres+ MOE 400 mg/kg BB), WIRS+MOE800 (mencit stres + MOE 800 mg/kg BB), WIRS+MOO1 (mencit stress + MOO 1 ml/kg BB), dan WIRS+MOO2 (mencit stress + MOO 2 ml/kg BB). Pemberian MOE dan MOO diberikan secara oral selama 23 hari. Induksi WIRS dilakukan pada hari 1 sampai 15 selama 2 jam, dan hari ke 16 dilakukan selama 6 jam. Selanjutnya dilakukan uji perilaku dengan open field test untuk prilaku kecemasan, forced swim test untuk perilaku depresif, dan uji memori dengan Y-maze test dan novel objective recognition test. Pada hari ke-24 mencit dikorbankan dan diambil darah serta jaringan otak untuk dianalisis lebih lanjut. Hasil: MOE mengandung 5,8% (b/b) total fenol dan 2,70% (b/b) total flavonoid, sedangkan MOO mengandung 0,04% (b/b) total fenol, tetapi flavonoid tidak terdeteksi. GC-MS menghasilkan MOO yang mengandung senyawa asam lemak, sterol, vitamin E dan senyawa aromatik, sedangkan MOE didominasi oleh senyawa flavonoid, asam lemak dan alkaloid juga ditemukan. Pemberian MOE 400 mg/kg BB dan MOO 2 mL/kg BB, kadar protein dan ekspresi BDNF meningkatkan signifikan (p<0,050) dibanding kelompok WIRS, selanjutnya MOE 800 mg/kg BB dan MOO 1 dan 2 mL/kg BB aktivitas asetilkolinesterase (AChE) menurun signifikan (p<0,05) dibandingkan kelompok WIRS. MOE 400 dan 800 mg/kg BB dan MOO 1 mL/kg BB, tingkat depresi dan kecemasan menurun signifikan serta memori meningkat signifikan dibandingkan kelompok WIRS. Sedangkan MOO 2 mL/kg BB tingkat kecemasan tidak berbeda dari kelompok WIRS. Kesimpulan: MOE dan MOO memiliki efek neuroprotektif dengan memperbaiki fungsi kognitif dan menurunkan tingkat depresi dan kecemasan melalui mekanisme penghambatan aktivitas AChE dan meningkatkan kadar protein dan ekspresi mRNA BDNF. ......Background: Moringa oleifera (MO) has been widely used by Indonesian people as a functional food and as traditional medicine. M. oleifera has been shown to have various pharmacological effects including neuroprotective effects. The aim of this study was to analyze the neuroprotective effects and the basic mechanisms of 70% ethanol extract (MOE) and seed oil of M. oleifera (MOO) in mice depression-like behavior, anxiety-like behavior, and cognitive decline due to chronic stress induction. Methods: In this study we examine the phytochemical analyze of MOE by LC-MS and MOO by GC-MS. Twenty-four male mice with a body weight of 25-30 g, were randomly divided into 6 groups. Normal group (normal mice given 0.5% CMC), WIRS (stressed mice with induced water immersion restraint stress/WIRS+CMC 0.5%) group, WIRS+MOE400 (stressed mice+ MOE 400 mg/kg BW) group, WIRS+MOE800 (stress mice + MOE 800 mg/kg BW) group, and WIRS+MOO1 (stress mice + MOO 1 ml/kg BW) group, and WIRS+MOO2 (stress mice + MOO 2 ml/kg BW) group. The MOE and MOO were orally administration for 23 days. MOE and MOO were administered orally for 23 days. WIRS induction was performed for 2 hours on days 1 to 15, and for 6 hours on day 16. The open field test for anxious behavior, the forced swim test for depressive behavior, and a memory test using the Y-maze test and the novel objective recognition test were then performed sequentially on days 17-23. On day 24th the mice were sacrificed and the blood as well as the brain tissue were collected for further analyze. Results: MOE contained 5.8% (w/w) of total phenols and 2.70% (w/w) of total flavonoids, while MOO contained 0.04% (w/w) of total phenols, but no flavonoids were detected. GC-MS produced MOO which contained fatty acid compounds, sterols, vitamin E and aromatic compounds, while MOE which was dominated by flavonoids, fatty acids, and alkaloids, were also found. Giving MOE 400 mg/kg BW and MOO 2 mL/kg BW, protein levels and expression of BDNF increased significantly (p<0.050) compared to the WIRS group, then MOE 800 mg/kg BW and MOO 1 and 2 mL/kg BW acetylcholinesterase activity (AChE) decreased significantly (p<0.05) compared to the WIRS group. MOE 400 and 800 mg/kg BW and MOO 1 mL/kg BW, the levels of depression and anxiety decreased significantly, and memory increased significantly compared to the WIRS group. Whereas MOO 2 mL/kg BW the anxiety level was not different from the WIRS group. Conclusion: MOE and MOO have neuroprotective effects by improving cognitive function and reducing levels of depression and anxiety through mechanisms of inhibiting acetylcholinesterase activity and increasing protein levels and BDNF mRNA expression.