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Abstrak :
Otak merupakan organ yang memiliki kebutuhan oksigen dan glukosa tertinggi di tubuh. Rendahnya tekanan oksigen pada otak dapat memicu terjadinya kerusakan pada sel otak bahkan kematian sel. Hipoksia merupakan kondisi penurunan kadar oksigen pada organ, jaringan atau sel. Hipoksia yang diberikan pada kadar dan waktu tertentu dapat menimbulkan respons adaptasi tubuh sehingga kondisi hipoksia dapat ditanggulangi. Salah satu respons adaptasi yang dilakukan adalah autofagi. Autofagi adalah suatu proses degradasi dan daur ulang molekul sitoplasmik dan organel seperti mitokondria dengan bantuan lisosom yang berperan dalam menjaga homeostasis seluler. Penelitian ini dilakukan untuk mengetahui efek pemberian hipoksia hipobarik intermiten terhadap aktivitas autofagi sel melalui ekspresi protein LC3 dan mTOR pada jaringan otak tikus. Penelitian ini menggunakan sampel jaringan otak tikus jenis Sprague-Dawley. Tikus dibagi dalam lima kelompok, yaitu kelompok kontrol, kelompok hipoksia 1 kali (HHI 1), HHI 2, HHI 3 dan HHI 4. Setiap kelompok hipoksia akan dimasukan dalam hypobaric chamber dan dibawa sampai ketinggian 25.000 kaki selama 5 menit. Tikus kemudian dikorbankan dan dilakukan pengukuran ekspresi protein LC3 dan mTOR menggunakan metode ELISA. Ekspresi protein LC3 juga dianalisis dengan IHK. Hasil menunjukkan bahwa pemberian perlakuan hipoksia hipobarik intermiten mampu meningkatkan ekspresi protein LC3 dan mempertahankan ekspresi mTOR. Hasil pulasan IHK menunjukkan ekspresi protein LC3 lebih tinggi pada bagian cerebellum otak dibandingkan dengan bagian cerebrum pada setiap kelompok. ......The brain is an organ with the highest demand for oxygen and glucose in the body. Insufficient oxygen pressure in the brain can lead to damage to brain cells and even cell death. Hypoxia is a condition characterized by a decrease in the oxygen levels in organs, tissues, or cells. Hypoxia, when applied at specific levels and durations, can induce adaptive responses in the body, allowing it to cope with the hypoxic conditions. One such adaptive response is autophagy. Autophagy is a cellular process involving the degradation and recycling of cytoplasmic molecules and organelles, including mitochondria, facilitated by lysosomes. This process plays a crucial role in maintaining cellular homeostasis. This study aimed to investigate the effects of intermittent hypobaric hypoxia on autophagic activity in brain cells by assessing the expression of proteins LC3 and mTOR during hypoxic conditions. The experimental subjects were Sprague-Dawley rats, and they were divided into five groups: a control group, and four groups subjected to intermittent hypobaric hypoxia (IHH) for varying durations (IHH1, IHH2, IHH3, and IHH4). Each IHH group was exposed to a hypobaric chamber at an altitude of 25,000 feet for 5 minutes. Subsequently, the rats were sacrificed, and the expression of LC3 and mTOR proteins was measured using ELISA. The LC3 protein expression was also analyzed through immunohistochemistry (IHC). The results showed that intermittent hypobaric hypoxia treatment increased the expression of LC3 protein and maintained mTOR expression. Additionally, IHC feedback indicated higher LC3 protein expression in the cerebellum region compared to the cerebrum in each experimental group.

Abstrak :
ABSTRAK
Preeklamsia merupakan masalah kesehatan maternal yang berdampak luas pada kesehatan manusia. Defek plasentasi merupakan faktor predisposisi utama preeklamsia yang mengakibatkan spektrum kematian sel apoptosis, aponekrosis dan autofagi. Autofagi juga berperan sebagai mekanisme ketahanan selular melalui nutrisi sebagai regulator utama. Penelitian ini bertujuan untuk mengetahui peran nutrisi dan autofagi sebagai ketahanan selular pada patomekanisme preeklamsia . Penelitian ini merupakan penelitian dengan desain potong lintang yang dilakukan terhadap 4 kelompok yakni; hamil normal, preeklamsia awitan lanjut, preeklamsia awitan dini dan PJT dengan jumlah sampel 10 pasien tiap kelompok. Dilakukan analisis nutrisi secara kualitatif dan kuantitatif untuk zat nutrisi vitamin D, kalsium dan seng serta zat nutrisi sebagai marka inflamasi yaitu vitamin A dan mineral besi. Dilakukan pemeriksaan marka kematian sel LDH dan pemeriksaan marka autofagi LC3, Beclin-1, kegagalan autofagi rasio LC3/Beclin-1 serta marka nutrisi plasenta VDR. Selama periode Agustus hingga Oktober 2015 terdapat 40 pasien yang mengikuti penelitian di RSUPN Cipto Mangunkusumo dan RS Budi Kemuliaan Jakarta. Terdapat perbedaan bermakna ekspresi LC3 dan Beclin-1 serta rasio LC3/Beclin-1 di antara kelompok penelitian. Kelompok preeklamsia awitan dini dan PJT memiliki ekspresi LC3 dan Beclin-1 tertinggi, sedangkan kelompok hamil normal dan preeklamsia awitan lanjut memiliki rasio LC3/Beclin-1 tertinggi. Terdapat korelasi antara kegagalan autofagi dengan LDH. Terdapat defisiensi vitamin D, kalsium dan seng serta terdapat peningkatan retinol dan ferrum sebagai marka inflamasi pada kelompok kehamilan patologis. Terdapat mekanisme up regulation ekspresi nutrisi plasenta reseptor vitamin D VDR pada kelompok preeklamsia awitan lanjut dan awitan dini , sementara ditemukan ekspresi VDR yang rendah pada kelompok PJT. Terdapat korelasi negatif antara rasio LC3/Beclin-1 dengan marka nutrisi maternal terutama kelompok preeklamsia awitan lanjut dan awitan dini. Terdapat korelasi bermakna antara rasio LC3/Beclin-1 dengan ekspresi VDR sebagai marka nutrisi plasenta pada kelompok preeklamsia awitan dini. Autofagi berperan dalam proses kematian sel dan ketahanan selular trofoblas. Terdapat peran nutrisi yang berkorelasi dengan proses autofagi pada patomekanisme preeklamsia. Kata kunci : Autofagi, kematian sel, ketahanan selular, nutrisi, preeklamsia.

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ABSTRACT
Preeclampsia is a maternal health problem which largely affects human well being. Placentation defects is the main predisposition factor of preeclampsia which cause cell death spectrum of apoptotic, aponecrosis, and autophagy. Autophagy also has a role as cellular survival mechanism as well through nutrition as main regulator. This research aims to understand the roles of nutrition and autophagy as cellular survival in pathomechanism of preeclampsia. The research has cross sectional study design which was conducted to four groups of pregnancy normal pregnancy, late onset preeclampsia, early onset preeclampsia, and intrauterine growth restriction IUGR with 10 samples for each group. Qualitative and quantitative nutrition analysis was done for vitamin D, calcium and zinc. The same methods was done to nutrients as inflammatory markers which is vitamin A and iron. Assessment was done for cell death marker LDH, autophagy markers LC3, Beclin 1, autophagy failure ratio of LC3 Beclin 1, and placenta nutrition marker VDR. During the period of August to October 2015 there were 40 patients participated in research which was conducted in RSUPN Cipto Mangunkusumo and RS Budi Kemuliaan Jakarta. Analysis shows statistically significant difference between groups of the expression of LC3 and Beclin 1 and ratio of LC3 Beclin 1 as well. Early onset preeclampsia and IUGR group showed the highest LC3 and Beclin 1 expression, while normal pregnancy and late onset preeclampsia group showed the highest ratio of LC3 Beclin 1. There was a correlation between autophagy failure and LDH. There were deficiencies of vitamin D, calcium and zinc and the increase of retinol and iron as inflammatory markers in pathological pregnancy. There was up regulation of vitamin D receptor VDR expression in early and late onset preeclampsia, while low expression of VDR in placenta of IUGR group. There was negative correlation between ratio of LC3 Beclin 1 and maternal nutrition markers particularly in preeclampsia group. There was significant correlation between the ratio of LC3 Beclin 1 and expression of placenta VDR as nutrition marker in early onset preeclampsia group. Autophagy plays a role in the spectrum of cell death and cellular survival in trophoblast. There is role of nutrition in correlation with autophagy process in pathomechanism of preeclampsia Keywords Autophagy, cell death, cellular survival, nutrition, preeclampsia

Abstrak :
Latar belakang: Prevalensi populasi gemuk dewasa terus meningkat di seluruh dunia, termasuk Indonesia. Hal ini penting terkait perkembangan penyakit degeneratif. Perbedaan perilaku adiposit dengan awitan obesitas yang dimulai sejak kecil atau sejak dewasa belum diketahui secara jelas. Penelitian ini bertujuan untuk menganalisis perbedaan jumlah, ukuran, tingkat hipoksia, glikolisis anaerobik, autofagi, biogenesis dan fungsi mitokondria adiposit viseral tikus coba. Metode: Tiga puluh lima ekor tikus Sprague-Dawley jantan, usia 4 minggu, BB 65–110 gram, secara acak dibagi menjadi kelompok perlakuan 8 dan 28 pekan. Kelompok 8 pekan terbagi 3 kelompok: PRK8 (pakan rendah kalori 8 pekan), PTL8 (pakan tinggi lemak 8 pekan), PS8 (pakan standar 8 pekan) sebagai kontrol. Kelompok 28 pekan terbagi 4 kelompok: PRK28 (PRK 8 pekan + PTL 20 pekan), PS28 (PS 8 pekan + PTL 20 pekan), PTL28 (PTL 28 pekan) dan kontrol (PS 28 pekan). Jumlah dan ukuran adiposit dianalisis pada pekan 8 dan 28 (histopatologi). Pemeriksaan ekspresi mRNA Hif-1α, Hif-2α, Lc3 (RT-qPCR); kadar HIF-1α, HIF-2α, PGC1α, MnSOD, LC3 (ELISA); dan aktivitas LDH (pemeriksaan enzimatis) dilakukan pada akhir pekan 28. Hasil: BB kelompok PRK8 lebih rendah dibandingkan PS8 (p = 0,008), BB kelompok PTL8 lebih tinggi dibandingkan PS8 (p = 0,008). Jumlah adiposit tidak berbeda bermakna, namun ukuran sel kelompok PRK8 lebih kecil dibandingkan PS8 dan PTL8 (p = 0,000). BB kelompok PRK28, PS28 dan PTL28 lebih tinggi bermakna dibandingkan kontrol. BB PTL28 didapatkan paling tinggi, namun kenaikan BB akibat pemberian PTL 20 pekan terjadi pada kelompok PRK28. Jumlah adiposit PRK28 paling sedikit namun paling hipertrofi. Kadar HIF-1α PRK28 meningkat dibandingkan PTL28 (p = 0,046) dan kontrol (p = 0,029). Kadar HIF-2α PRK28 meningkat dibandingkan PS28 (p = 0,045) dan PTL28 (p = 0,022). Adiposit PTL28 juga hipertrofi, disertai peningkatan ekspresi mRNA HIF-2α. Kadar PGC1α PRK28 meningkat dibandingkan PS28 (p = 0,000), PTL28 (p = 0,000) dan kontrol (p = 0,000). Aktivitas MnSOD PRK28 meningkat dibandingkan PTL28 (p = 0,038) dan PS28 (p = 0,015). Aktivitas LDH tidak berbeda bermakna pada seluruh kelompok. Ekspresi mRNA Lc3 PRK28 meningkat dibandingkan PTL28 (p = 0,037) dan kontrol (p = 0,047) namun tidak ada perbedaan pada kadar protein LC3. Simpulan: Ditemukan perbedaan respons adiposit viseral pada kelompok tikus gemuk dewasa yang berbeda status gizi pada masa pertumbuhan. Adiposit tikus yang kurus pada masa pertumbuhan didapatkan hipertrofi dan hipoksia; disertai peningkatan gen autofagi, biogenesis dan fungsi mitokondria. Adiposit tikus yang gemuk sejak kecil didapatkan hipertrofi disertai peningkatan ekspresi gen hipoksia.

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Background: The prevalence of obesity in adults is increasing worldwide. This is problematic since obesity is associated with degenerative diseases. Nowadays, Indonesia is facing an interesting phenomenon, where there are adults who have been obese since childhood and others who conversely were undernourished while young. The biological differences of these two types of obesities are not well understood. This study aims to analyse the difference in the size, number, hypoxic state, anaerobic glycolysis, autophagic activity, biogenesis and mitochondrial functions of rat visceral adipocytes that differ in nutritional state at youth. Method: Thirty five four-week-old male Sprague-Dawley rats were randomly divided into 8-week and 28-week treatment groups. The 8-week groups consist of groups given a low-caloric diet (LCD8), a high-fat diet (HFD8), a standard chow diet (SD8) as control. The 28-week groups consist of groups given LCD for 8 weeks + HFD for 20 weeks (LCD28), SD for 8 weeks + HFD for 20 weeks (SD28), HFD for 28 weeks (HFD28), and SD for 28 weeks as control. The size and number of visceral adipocytes were analyzed at week 8 and 28 by histopathological examination. The levels of Hif-1α, Hif-2α and Lc3 mRNA (RT-qPCR), HIF-1α, HIF-2α, PGC1α, MnSOD, LC3 (ELISA); and the lactate dehydrogenase activity (enzymatic analysis) were analyzed at week 28. Result: The LCD8 significantly had the lowest BW and the HFD8 had the highest. There was no difference in the number of adipocytes, but the LCD8 adipocytes were tiny in size. At week 28, there was a significant increase of BW in all the treatment groups compared to control. The highest BW was found in the HFD28 group, but the highest BW increase was found in LCD28. The LCD28 had the least amount of adipocytes, but the size was the largest, with the significant increase of HIF-1α and HIF-2α. Although the HFD28 adipocytes were hypertrophic, there was an increase in the Hif-2α mRNA expression but not in the protein level. The PGC1α level and the MnSOD activity of the LCD28 were significantly higher than the other groups. There was no difference in the lactate dehydrogenase activity between all groups. The Lc3 mRNA of the LCD28 was increased significantly, but not in the level of LC3 protein. Conclusion: There were differences in the visceral adipocyte characteristics of obese adult rats which differ in nutritional state at a young age. Adipocytes of the obese adult rats which were undernourished were hypertrophic, hypoxic, and had increased autophagic gene expression, biogenesis and mitochondrial functions. The adipocytes of rats which were obese since young were hypertrophic and had increased hypoxic gene expression.