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"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.

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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."

"Salah satu pendekatan pengobatan terapi kanker yaitu dengan mengeksplorasi tanaman obat yang mengandung satu atau lebih senyawa yang secara khusus menargetkan sel kanker dengan efek samping yang lebih sedikit. Kopi (Coffea sp.) dilaporkan memiliki sifat antikanker. Dalam budidaya kopi, dihasilkan sekitar 50-60% limbah kulit buah (kaskara). Saat ini olahan kaskara banyak diproduksi sebagai produk makanan dan suplemen karena mengandung protein, polisakarida, dan senyawa aktif, hal ini akan menjadi pendekatan yang menjanjikan untuk mengembangkan terapi kanker yang dapat ditargetkan secara khusus pada sel kanker. Penelitian ini bertujuan untuk memperoleh senyawa metabolit sekunder dari kaskara kopi robusta yang beraktivitas sitotoksik dan mengevaluasi mekanisme kematiaannya terhadap sel Hela dan sel MCF-7 secara in vitro dan in silico serta menentukan kadar senyawa aktifnya. Kaskara kopi robusta diekstraksi menggunakan pelarut etanol 70%, dan dievaluasi mutu ekstrak berdasarkan parameter spesifik dan non spesifik. Selanjutnya dilakukan fraksinasi bertingkat menggunakan pelarut n-heksana, etil asetat, dan metanol-air. Fraksi dilanjutkan isolasi secara kolom kromatografi dan dilakukan pemurnian hingga diperoleh isolat dan dikarakterisasi dengan 1H-NMR, 13C-NMR, 2D-NMR, LC-MS, UV-Vis dan FT-IR serta diuji aktivitas sitotoksik terhadap sel Hela dan sel MCF-7 secara in vitro dan in silico terhadap protein target Caspase 3 dan Caspase 9. Penetapan kadar senyawa aktif dilakukan dengan KCKT-PDA. Hasil penelitian menunjukkan bahwa ekstrak kaskara kopi robusta memenuhi syarat mutu Farmakope Herbal Indonesia. Hasil pemurnian dan elusidasi kaskara kopi robusta diperoleh sepuluh senyawa: Cas 01: friedelin, Cas 04: asam ursolat,,Cas 06: lufeol merupakan golongan triterpenoid; Cas 02: stigmasterol, Cas 03: beta sitosterol merupakan golongan steroid; Cas 05: tricalysiolide B merupakan golongan diterpenoid; Cas 07: kafein merupakan turunan alkaloid; Cas 08: asam klorogenat, Cas 09: asam kafeat merupakan golongan fenolik, dan Cas 10: katekin yang merupakan golongan flavonoid. Hasil uji aktivitas sitotoksik secara in vitro terhadap kanker serviks (Sel Hela) dan kanker payudara (sel MCF-7) menunjukkan bahwa senyawa kontrol positif (cisplatin) memberikan hasil IC50 19,85 ± 0,14 µg/mL terhadap sel Hela dan IC50 25,87 ± 0,17 µg/mL terhadap sel MCF-7. Senyawa Cas 04 memberikan potensi paling aktif sebagai antikanker yang ditunjukkan dengan data terhadap kanker serviks (Sel Hela) dengan kategori toksik (IC50 25,85 ± 0,17 µg/mL) dan kanker payudara (sel MCF-7) dengan kategori sangat toksik (IC50 12,83 ± 0,15 µg/mL); delapan senyawa (Cas 01, Cas 02, Cas 03, Cas 06, Cas 07, Cas 08, Cas 09, dan Cas 10) masuk dalam kategori toksik dan satu senyawa (Cas 05) dalam kategori kurang toksik. Senyawa teraktif (asam ursolat) menginduksi persinyalan apoptosis melalui jalur intrinsik dengan peningkatan ekspresi gen pada caspase 3 dan caspase 9 yang diukur dengan metode RT-qPCR. Kadar senyawa aktif dalam ekstrak kaskara kopi robusta diperoleh hasil kadar senyawa lufeol sebesar 0,087 ± 0,015%; stigmasterol sebesar 0,126 ± 0,046%; asam ursolat 0,627 ± 0,002%; friedelin 0,539 ± 0,137%; kafein sebesar 3,203 ± 0,069%; asam klorogenat sebesar 0,679 ± 0,003%; asam kafeat sebesar 0,153± 0,003% dan senyawa katekin sebesar 0,359 ± 0,012%. Aktivitas in silico dari senyawa hasil isolasi terhadap protein target caspase 3 dan caspase 9 memperlihatkan bahwa sembilan senyawa (friedelin, beta-sitosterol, stigmasterol, asam ursolat, lufeol, kafein, asam klorogenat, asam kafeat, katekin) menghasilkan skor penambatan lebih negatif dari kontrol positif serta melibatkan pembentukan ikatan hidrogen, ikatan hidrofobik dan ikatan alkil dalam interaksi pengikatan antara senyawa dengan caspase 3 dan caspase 9. Kesepuluh senyawa hasil isolasi telah dilaporkan terkandung dalam genus Coffea dan keluarga Rubiaceae, tetapi beberapa senyawa (friedelin, asam ursolat, lufeol, tricalysiolide B) baru dilaporkan pertama kali dari bagian kaskara kopi robusta.

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One approach to cancer therapy treatment is to explore medicinal plants that contain one or more compounds that specifically target cancer cells with fewer side effects. Coffee (Coffea sp.) is reported to have anticancer properties. In coffee cultivation, around 50-60% of fruit skin waste (kaskara) is produced. Currently, processed cascara is widely produced as food products and supplements because it contains protein, polysaccharides, and active compounds. This will be a promising approach for developing cancer therapy that can be targeted specifically at cancer cells. This research aims to obtain secondary metabolite compounds from Robusta coffee beans that have cytotoxic activity and evaluate the mechanism of their death on Hela cells and MCF-7 cells in vitro and in silico and determine the levels of active compounds. Robusta coffee beans were extracted using 70% ethanol solvent, and the quality of the extract was evaluated based on specific and non-specific parameters. Next, multilevel fractionation was carried out using the solvents n-hexane, ethyl acetate, and methanol-water. The fraction was then isolated using column chromatography and purified until an isolate was obtained and characterized by 1H-NMR, 13C-NMR, 2D-NMR, LC-MS, UV-Vis and FT-IR and tested for cytotoxic activity against Hela cells and MCF-7 cells. In vitro and in silico against the target proteins caspase 3 and caspase 9. Determination of active compound levels was carried out using HPLC-PDA. The research results show that robusta coffee kascara extract meets the quality requirements of the Indonesian Herbal Pharmacopoeia. The results of the purification and elucidation of robusta coffee cascara obtained ten compounds: Cas 01: friedelin, Cas 04: ursolic acid, Cas 06: lupeol is a triterpenoid group; Cas 02: stigmasterol, Cas 03: beta-sitosterol is a class of steroids; Cas 05: tricalysiolide B is a diterpenoid group; Cas 07: caffeine is an alkaloid derivative; Cas 08: chlorogenic acid, Cas 09: caffeic acid which is a phenolic group, and Cas 10: catechin which is a flavonoid group. The results of the in vitro cytotoxic activity test against cervical cancer (Hela cells) and breast cancer (MCF-7 cells) showed that the positive control compound (cisplatin) gave an IC50 of 19.85 ± 0.14 µg/mL against Hela cells and an IC50 of 25.87 ± 0.17 µg/mL against MCF-7 cells. The Cas 04 compound provides the most active potential as an anticancer as shown by data against cervical cancer (Hela cells) in the toxic category (IC50 25.85 ± 0.17 µg/mL) and breast cancer (MCF-7 cells) in the very toxic category ( IC50 12.83 ± 0.15 µg/mL); eight compounds (Cas 01, Cas 02, Cas 03, Cas 06, Cas 07, Cas 08, Cas 09, and Cas 10) are in the toxic category and one compounds (Cas 06) are in the less toxic category. The active compound (ursolic acid) induces apoptotic signaling through the intrinsic pathway with increased gene expression for caspase 3 and caspase 9 as measured by the RT-qPCR method. The levels of active compounds in robusta coffee cascara extract resulted in lufeol compound levels of 0.087 ± 0.015%; stigmasterol was 0.126 ± 0.046%; ursolic acid 0.627 ± 0.002%; friedelin 0.539 ± 0.137%; caffeine of 3.203 ± 0.069%; chlorogenic acid of 0.679 ± 0.003%; caffeic acid was 0.153 ± 0.003% and catechin compounds were 0.359 ± 0.012%. The in silico activity of the isolated compounds against the target proteins caspase 3 and caspase 9 showed that nine compounds (friedelin, beta-sitosterol, stigmasterol, ursolic acid, lupeol, caffeine, chlorogenic acid, caffeic acid, catechin) produced docking scores that were more negative than the control positive and involves the formation of hydrogen bonds, hydrophobic bonds and alkyl bonds in the binding interaction between the compound and caspase 3 and caspase 9. The ten isolated compounds have been reported to be contained in the genus Coffea and the Rubiaceae family, but several compounds (friedelin, ursolic acid, lupeol, tricalysiolide B) have only been reported for the first time from the cascara part of robusta coffee."

"Analog Kurkumin Indazol merupakan senyawa analog berpotensi dikembangkan sebagai antikanker. Penelitian ini bertujuan untuk memperoleh senyawa baru analog kurkumin tetrahidro-indazol yang mempunyai akivitas penghambatan antikanker yang selektif. Penelitian diawali skrining in silico 186 senyawa disain didasarkan pada penapisan model farmakofor dan terpilih 14 senyawa, dilanjutkan penambatan molekular menghasilkan 10 senyawa hit. Kemudian dilakukan sintesis dengan reaksi kondensasi Clasein-Schmidth, dihasilkan enam analog indazole baru dari kurkumin dan dievaluasi aktivitas sitotoksiknya menggunakan uji proliferasi metil tiazolil tetrazolium terhadap sel kanker MCF-7, HeLa, WiDr, dan Vero. Struktur senyawa dikarakterisasi dengan FTIR, NMR, dan spektral massa. Hasil penelitian menunjukkan bahwa senyawa yang disintesis lebih aktif terhadap sel WiDr dibandingkan dengan sel MCF-7 dan HeLa. Aktivitas sitotoksik senyawa 3b, 3c, 3d, 5a terhadap sel WiDr lebih aktif dibandingkan kurkumin dan tamoxifen. Evaluasi lebih lanjut terhadap sel Vero (sel normal) untuk menentukan selektivitasnya menunjukkan beberapa senyawa hasil sintesis lebih selektif (nilai IS > 2) dibandingkan tamoxifen dan doksorubisin (nilai SI < 2,00). Tiga senyawa (3a, 3b, dan 3c) menunjukkan IS tinggi terhadap sel WiDr yaitu 3,74, 5,27, dan 4,39. Di antara senyawa yang disintesis, 3b menunjukkan aktivitas sitotoksik tertinggi, terutama terhadap garis sel WiDr (IC50 = 27,20 M) dengan selektivitas yang sangat baik (SI = 5,27).

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Indazole Analogs of Curcumin is an analog compound that has the potential to be developed as an anticancer. This study aims to obtain a new compound analogue of curcumin tetrahydro-indole which has selective anticancer inhibitory activity. The research began with the design of the curcumin analog compound tetrahydro-indazole in silico based on a pharmacophore model and 14 compounds were selected, then continued molecular docking to produce 10 hit compounds. Then the synthesis was carried out using the Clasein-Schmidth condensation reaction and produced a series of six novel indazole analogs of curcumin and evaluated their cytotoxic activity against MCF-7, HeLa, WiDr, and Vero cells. The structure of the compound was characterized by FTIR, NMR, and mass spectral. The results showed that the synthesized compound was more active against WiDr cells than MCF-7 and HeLa cells. The cytotoxic activity of compounds 3b, 3c, 3d, 5a against WiDr cells was more active than curcumin and tamoxifen. Further evaluation of Vero cells to determine their selectivity showed that some of the compounds synthesized were more selective (SI value>2) than tamoxifen and doxorubicin. Three compounds (3a, 3b, and 3c) showed high SI against WiDr cells, namely 3.74, 5.27, and 4.39. Among the synthesized compounds, 3b showed the highest cytotoxic activity, especially against the WiDr cell line (IC50 = 27.20 M) with excellent selectivity (SI = 5.27)."