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"Munculnya resistansi parasit yang cepat terhadap obat antimalaria yang tersedia saat ini telah menarik perhatian dalam penemuan obat. Andrografolida (ANDRO), suatu senyawa yang diisolasi dari tanaman obat Andrographis panniculata Nees, memperlihatkan sifat antimalaria secara in vitro dan in vivo, tetapi mekanisme kerjanya yang tepat belum dipahami. Penelitian ini bertujuan untuk menjelaskan mekanisme yang mendasari sifat antimalaria dari ANDRO terhadap parasit malaria hewan pengerat, Plasmodium berghei. Parasit diinjeksikan pada mencit BALB/c dan kemudian diberi perlakuan dengan ANDRO dan butionin sulfoksimin (BSO) sebagai kontrol pada konsentrasi berbeda secara ex vivo. Selanjutnya dilakukan pengukuran beberapa parameter status oksidatif, seperti konsentrasi GSH, rasio GSH/GSSG, rasio NADPH/NADP+, aktivitas spesifik dan ekspresi mRNA tioredoksin reduktase (TrxR), kadar malondialdehid (MDA) dan pertumbuhan parasit ex vivo. Pengaruh ANDRO terhadap detoksifikasi hem juga diukur secara in vitro ( cell-parasite free).Hasil menunjukkan bahwa ANDRO mendeplesi GSH tetapi meningkatkan rasio GSH/GSSG. Rasio NADPH/NADP+ dan aktivitas spesifik TrxR mengalami penurunan pada semua konsentrasi yang diuji tetapi ekspresi mRNA TrxR sedikit meningkat pada konsentrasi yang lebih rendah dan meningkat bermakna pada 60 M. ANDRO memperlihatkan efek yang berbeda terhadap pertahanan antioksidan parasit dibandingkan BSO dan peningkatan stres oksidatif tidak menyebabkan peningkatan kadar MDA. Andrografolida juga menghambat pertumbuhan parasit ex vivo dan mengganggu polimerisasi hem dengan IC50 367±171 M serta menghambat degradasi hem bergantung GSH, hambatan maksimal dihasilkan pada konsentrasi 15 g/mL. Kesimpulan, ANDRO menghasilkan aktivitas antimalaria dengan mengganggu sistem pertahanan antioksidan parasit yang dibuktikan dengan penurunan konsentrasi GSH dan aktivitas enzim TrxR. ANDRO memiliki potensi untuk dikembangkan menjadi antimalaria baru baik sebagai obat tunggal atau dalam kombinasi dengan obat antimalaria lainnya.

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The rapid emergence of parasite resistance to currently available antimalarial drugs has re-newed interest on drug discovery. Andrographolides, a compound isolated from the medicinal plant, Andrographis panniculata, Nees, exhibited antimalarial properties in vitro and in vivo but its precise mechanism of action remains elusive. The present study aims to elucidate the mechanism (s) underlying the antimalarial property of the andrographolides in the rodent malarial parasite, Plasmodium berghei. The parasite was initially propagated in BALB/c mice and subsequently be propagated ex vivo in the presence of different concentrations of andrographolide and buthionin sulphoximine (BSO) as control. Several parameters of the oxidative status, such as GSH concentration, GSH/GSSG ratio, NADPH/NADP+ ratio, specific activity and mRNA expression of thioredoxin reductase (TrxR), malondialdehyde (MDA) level and the parasite growth ex vivo were measured. Effect of the andrographolide on heme polymerization and GSH-dependent heme degradation were also tested using cell-free assay system.The results indicated that the andrographolide depleted the GSH but increased the GSH/GSSG ratio. The NADPH/NADP+ ratio and the specific activity of the TrxR were decreased at all tested concentrations but expression of TrxR mRNA slightly increased at lower concentrations and increased significantly at 60 M. Andrographolide exerted a different effect on the antioxidant defense of the parasite than that BSO and increase in oxidative stress did not result in the increase of the MDA level. Andrographolide also inhibited the parasite growth ex vivo and interfered with the heme polymerization with IC50 of 367±171 M and GSH-dependent heme degradation with maximum concentration of 15 g/mL. In conclusion, andrographolide exerted its antimalarial properties through interference with the parasite oxidant defense system as evidenced by GSH depletion and decrease thioredoxin reductase enzyme activity. Andrographolide is potentially developed into a novel antimalaria either as a single prescription or in combination with other antimalarial drug."

"[ABSTRAKMalaria merupakan salah satu penyakit yang sering terjadi di negara tropis dansubtropis. Penyakit malaria banyak terjadi di sebagian besar wilayah Indonesia,seperti Irian Jaya, Nusa Tenggara Barat (NTB) dan Nusa Tenggara Timur (NTT).Berdasarkan data terakhir WHO pada tahun 2013, tercatat sebanyak 198 jutakasus malaria di seluruh dunia, dengan jumlah kematian sebanyak 584.000 jiwa.Pengobatan yang pernah ada untuk jenis malaria Plasmodium falciparum adalahklorokuin, sulfadoksin – pirimetamin, kinin, meflokuin dan artemisinin. Akantetapi, meningkatnya resistensi parasit pada obat antimalaria, melemahkan upayapengendalian malaria. Penambatan molekuler sebagai salah satu metodependekatan in silico telah digunakan pada pencarian senyawa berkhasiat untukmenangani malaria. Dalam satu dekade terakhir, diketahui bahwa senyawaturunan kurkumin memiliki efek sinergis dengan artemisinin terhadapPlasmodium berghei secara in vivo. Pada penelitian ini, dilakukan penambatanmolekuler senyawa turunan kurkumin baru terhadap enzim target antimalaria.Penambatan dilakukan menggunakan piranti lunak AutoDock. Berdasarkan hasilpenambatan, didapatkan senyawa terbaik yang berpotensi sebagai obat antimalariabaru, yang dapat menyerang di sisi aktif tertentu dari Plasmodium falciparum,yaitu : 1,4-dihidrodiazepin-6-morfolinometil kurkumin pada enzim PfDHFR danPirimidin-2-on-5-morfolinometil kurkumin pada enzim PfDHODH.

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ABSTRACTMalaria is a disease that often occurs in tropical and subtropical countries.Prevalent of malaria in most parts of Indonesia, such as Irian Jaya, West NusaTenggara (NTB) and East Nusa Tenggara (NTT). Based on the WHO's last data in2013, there were 198 million cases of malaria worldwide, with the number ofdeaths by 584,000 inhabitants. Treatment for this type of Plasmodium falciparummalaria is chloroquine, sulfadoxine - pyrimethamine, quinine, mefloquine andartemisinin. However, increasing parasite resistance to the antimalarial drug,making malaria control efforts become effortless. Molecular docking as onemethod in silico approaches have been used in the search for efficaciouscompounds addressing malaria. In the last decade, it is known that the compoundcurcumin analogues have synergistic effect with artemisinin against Plasmodiumberghei in vivo. In this study, we employed docking of new molecular compoundscurcumin derivates as antimalarial target enzymes. Molecular docking isperformed using Autodock. Based on the docking result, best compound isobtained as a potential new antimalarial drug, which can be attacked in certainactive side of Plasmodium falciparum, which is 1,4-dihydrodiazepin-6-morpholinomethyl curcumin on PfDHFR enzyme dan Pyrimidin-2-one-5-morpholinomethyl curcumin on PfDHODH enzyme., Malaria is a disease that often occurs in tropical and subtropical countries.Prevalent of malaria in most parts of Indonesia, such as Irian Jaya, West NusaTenggara (NTB) and East Nusa Tenggara (NTT). Based on the WHO's last data in2013, there were 198 million cases of malaria worldwide, with the number ofdeaths by 584,000 inhabitants. Treatment for this type of Plasmodium falciparummalaria is chloroquine, sulfadoxine - pyrimethamine, quinine, mefloquine andartemisinin. However, increasing parasite resistance to the antimalarial drug,making malaria control efforts become effortless. Molecular docking as onemethod in silico approaches have been used in the search for efficaciouscompounds addressing malaria. In the last decade, it is known that the compoundcurcumin analogues have synergistic effect with artemisinin against Plasmodiumberghei in vivo. In this study, we employed docking of new molecular compoundscurcumin derivates as antimalarial target enzymes. Molecular docking isperformed using Autodock. Based on the docking result, best compound isobtained as a potential new antimalarial drug, which can be attacked in certainactive side of Plasmodium falciparum, which is 1,4-dihydrodiazepin-6-morpholinomethyl curcumin on PfDHFR enzyme dan Pyrimidin-2-one-5-morpholinomethyl curcumin on PfDHODH enzyme.]"