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Abstrak :
ABSTRAK
Dengue merupakan salah satu penyakit serius pada manusia yang disebabkan oleh infeksi virus dengue (DENV). Namun, pengembangan senyawa antiviral DENV sering menghadapi masalah dikarenakan belum ada obat yang efektif menangani semua jenis serotipe DENV. Penghambatan melalui host enzim virus yang terlibat dalam siklus hidup DENV dapat menjadi pendekatan potensial dalam penemuan obat dengue dan juga menghindari resisten antiviral. Host retikulum endoplasma (RE) alpha-gukosidase II adalah salah satu target enzim dalam host RE DENV yang berperan penting dalam pelipatan glikoprotein DENV. Dalam penelitian ini digunakan sekitar 67.609 senyawa bahan alam yang telah diketahui aktivitas biologisnya dari pangkalan data InterBioScreen (IBS) sebagai kandidat inhibitor host RE alpha-gukosidase II. Proses penapisan untuk mendapatkan inhibitor terbaik dilakukan melalui tiga tahap simulasi penambatan molekul yaitu virtual screening, rigid docking, dan flexible docking. Titik farmakofor untuk proses penapisan diperoleh dari analisis Protein-Ligand Interaction Fingerprint (PLIF) menggunakan delapan protein alpha-glukosidase II dengan ligan yang berbeda-beda. Berdasarkan proses penapisan tersebut, sebanyak 32 ligan memiliki nilai Root Mean Square Deviation (RMSD) dan Gbinding yang diinginkan, dan lima ligan memiliki interaksi molekul paling baik untuk menghambat host RE alpha-glukosidase II sebagai target enzim. Sifat farmakologi kelima ligan dianalisis melalui uji ADME-Tox menggunakan perangkat lunak Toxtree, SwissADME, admetSAR, dan pkCSM. Ligan terbaik yaitu STOCK1N-86400 memiliki sifat farmakologi terbaik, interaksi hidrogen terbanyak dengan asam amino penting Asp564, Asp640, dan Met565 pada situs aktif host RE alpha-glukosidase II, dan Gbinding paling rendah dibandingkan standar. Hasil simulasi dinamika molekul juga menunjukkan ligan tersebut stabil pada suhu 310K.

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ABSTRACT
Dengue is one of the crucial diseases in human caused by dengue virus (DENV) infection. However, the development of DENV antiviral is often facing a problem because no effective drug to treat infection caused by all DENV serotypes. The inhibition of enzyme host of virus involved in DENV life cycle can be a potential approach in dengue drug discovery, and also avoiding antiviral resistance. Host endoplasmic reticulum (ER) alpha-glucosidase II is one of the enzymes target in host DENV ER that plays an important role in the DENV glycoprotein folding. In this research, about 67.609 natural products that have been known for their biological activities were acquired from InterBioScreen (IBS) database as candidate host alpha-glucosidase II inhibitor. The screening process was done by three protocol of molecular docking simulation: virtual screening, rigid docking, and flexible docking. Pharmacophore features in screening were obtained from Protein-Ligand Interaction Fingerprint (PLIF) analysis using eight -glucosidase II proteins with different ligands. Based on that screening process, about 32 ligands have a desirable value of Root Mean Square Deviation (RMSD) and Gbinding, and five ligands have a good molecular interaction to inhibit host ER alpha-glucosidase II as enzyme target. Pharmacological properties of the five ligands were analyzed through ADME-Tox test using Toxtree, SwissADME, admetSAR, and pkCSM software. The best ligand, STOCK1N-86400 has the best pharmacological properties, the highest number of hydrogen interaction with critical amino acids Asp564, Asp640, and Met565 in host ER alpha-glucosidase II active site, and the lower Gbinding from standard. The result of molecular dynamic simulation also showed that ligand is stable at a temperature of 310 K.

Abstrak :
Latar Belakang: Sindrom metabolik (MetS) melibatkan endoplasmic reticulum stress (ER stress) di dalam patogenesisnya. 6-gingerol diketahui memiliki banyak efek farmakologi yang berpotensi untuk pengobatan MetS. Studi ini bertujuan untuk meneliti efek modulasi 6-gingerol terhadap MetS melalui jalur ER stress dan menentukan dose-response relationship. Metode: Pembuatan model MetS menggunakan tikus Sprague-Dawley jantan yang diberikan diet high-fat high fructose (HFHF) selama 16 minggu dan diinjeksi streptozotocin intraperitoneal dosis 22 mg/kgBB pada minggu ke-8. Dua puluh lima ekor tikus dibagi menjadi kelompok diet standar, kontrol negatif (HFHF) dan 3 kelompok perlakuan yang masing-masing diberikan 6-gingerol dosis 50, 100 dan 200 mg/kgBB selama 8 minggu. Setelah tikus dikorbankan, dilakukan pemeriksaan kadar glukosa darah puasa, HOMA-IR, kolesterol total, HDL, LDL, trigliserida; serta parameter ER stress yaitu GRP78 dan IRE1, serta pemeriksaan histopatologik hati. Hasil: Hasil studi menunjukkan 6-gingerol dapat mengurangi berat badan, menurunkan glukosa darah puasa, memperbaiki resistensi insulin, menurunkan kadar kolesterol total, LDL dan trigliserida serta mengurangi secara signifikan akumulasi lipid dan apoptosis hepatosit (p<0,05). Perbaikan terhadap kelainan metabolik tersebut terjadi melalui downregulasi ekspresi protein GRP78 dan IRE1 pada pemberian dosis 200mg/kgBB secara bermakna (p<0,05). Kesimpulan: Studi ini berhasil membuktikan efek modulasi 6-gingerol pada sindrom metabolik secara dose-dependent melalui jalur ER stress. ......Background: Metabolic syndrome (MetS) implicates ER stress in its pathogenesis. 6-gingerol is known to have many potential pharmacological effects for treating MetS. This study aims to investigate the modulating effect of 6-gingerol on MetS via the ER stress pathway and determine the dose-response relationship. Methods: To induce MetS, male Sprague-Dawley rats were fed high-fat high fructose (HFHF) diet for 16 weeks and injected with low-dose intraperitoneal streptozotocin (22 mg/kg BW) at week 8. Twenty-five rats were divided into a standard diet group, negative control (HFHF), and three treatment groups with 6-gingerol doses of 50, 100, and 200 mg/kg BW for eight weeks, respectively (given after eight weeks of induction). At the end of the study, all rats were sacrificed. Then the following tests were carried out, including fasting blood glucose, HOMA-IR, total cholesterol, HDL, LDL, and triglyceride levels; and ER stress parameters (GRP78 and IRE1), also a histopathological examination of liver. Results: 6-gingerol can reduce body weight, lower fasting blood glucose and improve insulin resistance, reduce total cholesterol, LDL, and triglyceride levels, and significantly reduced lipid accumulation and apoptosis in hepatocytes (p<0,05). Improvement of these metabolic abnormalities occurred through downregulation of GRP78 protein expression, IRE1 (dose of 200 mg/kgBW) significantly (p<0.05). Conclusion: This study proved the modulating effect of 6-gingerol on metabolic syndrome in a dose-dependent manner through the ER stress pathway.

Abstrak :
This book primarily focuses on the pathophysiology of ER stress. It introduces the molecular bases of ER stress, the emerging relevance of the ER-mitochondria cross-talk, the signaling pathways engaged and cellular responses to ER stress, including the adaptive Unfolded Protein Response (UPR), autophagy as well as cell death. Next the book addresses the role of ER stress in physiology and in the etiology of relevant pathological conditions, like carcinogenesis and inflammation, neurodegeneration and metabolic disease. The last chapter describes how ER stress pathways can be targeted for therapeutic benefit. Altogether, this book will provide the reader with an exhaustive view of ER stress biology and the latest insights in the role of ER stress in relevant human diseases.