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"Latar Belakang: Pada proses regenerasi jaringan terjadi ketidakseimbangan antara kebutuhan oksigen dengan suplai oksigen yang menyebabkan jaringan mengalami hipoksia relatif. Keadaan hipoksia diduga memiliki peran penting dalam proses regenerasi jaringan. Pada penelitian ini, dianalisis ekspresi protein dan gen yang berperan mengatasi keadaan hipoksia (HIF-1α dan HIF-2α), protein yang berperan dalam suplai oksigen (Cygb), protein yang menstimulasi biogenesis mitokondria (PGC-1α) serta enzim yang mampu menangkal radikal bebas (MnSOD) pada regenerasi jaringan. Regenerasi jaringan ekor pada cecak rumah (Hemidactylus platyurus) digunakan sebagai model dalam penelitian ini, karena merupakan hewan yang paling dekat secara taksonomi dengan mamalia yang memiliki daya regenerasi tinggi, dibandingkan vertebrata lain dengan kemampuan sama. Diharapkan penelitian ini dapat menjadi model dalam mempelajari proses regenerasi dalam upaya pengembangan terapi penyembuhan luka. Metode: Penelitian bersifat eksperimental deskriptif menggunakan jaringan 30 ekor cecak hasil regenerasi pada hari ke 1; 3; 5; 8; 10; 13; 17; 21; 25; dan 30 setelah autotomi dengan 3 kali pengulangan pada setiap pengamatan. Cecak diperoleh dari lingkungan laboratorium Zoologi Puslit Biologi LIPI Cibinong. Analisis ekspresi gen dilakukan dengan metoda qRT-PCR; analisis ekspresi protein dinilai dengan metoda Western Blot dan imunohistokimia, serta dilakukan analisis struktur histologi jaringan dengan pewarnaan hematoksilin-eosin. Penelitian dilakukan di Laboratorium Departemen Biokimia & Biologi Molekuler FKUI; laboratorium Histologi FKUI, laboratorium PRVKP FKUI, dan laboratorium Patologi Anatomi FKH IPB. Penelitian dalam kurun waktu tahun 2015-2018. Hasil penelitian: Grafik pertumbuhan jaringan ekor cecak menghasilkan pola pertumbuhan yang lambat pada 13 hari pertama, pertumbuhan yang sangat cepat hari ke 13 sampai ke 21, dan kembali lambat sampai hari ke 30. Pada awal pertumbuhan, ekspresi HIF-1α dan HIF-2α tinggi menunjukkan jaringan dalam keadaan hipoksia. Tingginya ekspresi Cygb selama proses regenerasi jaringan dari awal hingga akhir pengamatan menunjukkan perannya untuk mengakomodasi oksigen selama proses regenerasi berlangsung. Ekspresi PGC-1α yang tinggi di awal proses dan tetap dipertahankan sampai akhir pengamatan berperan untuk mempertahankan agar energi untuk proses regenerasi dapat terpenuhi melalui biogenesis mitokondria. Tingginya ekspresi MnSOD dalam jaringan pada awal regenerasi diduga memiliki peranan yang berkaitan dengan netralisasi senyawa radikal dalam jaringan. Kesimpulan: HIF 1α, HIF 2α, Cygb, PGC 1α dan MnSOD masing-masing memiliki peran penting tersendiri dalam proses regenerasi jaringan.

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Background: In tissue regeneration there is an imbalance between oxygen demand and supply causes the tissue to experience relative hypoxia. Hypoxia is thought to have an important role in the tissue regeneration. This research analyzed the expression of proteins and genes that play role in overcoming hypoxia (HIF-1α dan HIF-2α); the protein involved in oxygen supply (Cygb); the protein that stimulates mitochondrial biogenesis (PGC-1α); and the enzyme counteract free radicals (MnSOD). The regeneration of house gecko's tail (Hemidactylus platyurus) was used as a model in this research, because it is the taxonomically closest animal to mammals that have a high capability in regeneration, compared to other vertebrates with the same ability. Hence, this study might become a model in studying tissue regeneration as an effort in developing a wound healing treatment. Method: The research was performed in a descriptive experimental way, using 30 geckos, having undergone regeneration on day 1; 3; 5; 8; 10; 13; 17; 21; 25; and 30 after autotomy. The experiment used 3 repetitions for each observation. House geckos were obtained from the laboratory building of Zoology Research Center of Indonesian Institute of Sciences (LIPI) Cibinong and its surrounding area. The analysis for gene expression was performed using qRT-PCR method; the analysis for protein expression was undertaken using Western Blot method and immunohistochemistry. In addition to these, the structure analysis for the tissue histology was performed using Haematoxilyn and Eosin (H&E) staining method. The study was conducted in the Laboratory of the Department of Molecular Biochemistry & Biology FKUI; Laboratory of the Department of Histology FKUI; laboratory of the Institute of Human Virology & Cancer Biology FKUI; and laboratoty of Phatology Anatomy of Animal Medicine, Institute of Agriculture Bogor, in the year 2015-2018.Results: The graph for the growth of the gecko tail tissue exhibits a slow growth pattern for the first 13 days, followed by a very swift growth between day 13 to 21, returning to slow growth afterwards until day 30. In the early growth stage, the expression of HIF1α and HIF-2α were increased which showed the tissue was in hypoxia state. HIF protein regulates the contributing to the tissue regeneration process, leading to the increasing growth of tissue with the correlation values of r=-0,853 for HIF-1α; r=-0,75 The substantial expression of Cygb observed throughout the process of tissue regeneration indicates its role in accommodating oxygen in the regeneration process. The expression of PGC-1α was observed to be high in the early stages of the process and remain so until the process ends. This indicates its function in maintaining that sufficient energy provided by mitochondrial biogenesis is available for the regeneration process. The high level of MnSOD expression in the tissue in the early stage of regeneration is thought to relate to its role in neutralizing radicals inside the tissue. Conclusion: HIF 1α, HIF 2α, Cygb, PGC 1α and MnSOD have their own important roles in the tissue regeneration process."

"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."

"Olahraga aerobik terbukti mampu meningkatkan struktur dan fungsi kognitif. Data tentang jenis olahraga aerobik yang terbaik untuk menjaga keseimbangan oksidatif, serta memicu angiogenesis dan neuroplastisitas di berbagai regio otak masih terbatas. Penelitian ini menganalisis pengaruh olahraga aerobik halang rintang terhadap kadar neuroglobin otak, protein pemicu angiogenesis, neuroplastisitas di hipokampus dan korteks prefrontal, serta fungsi memori relasional. Mencit Mus musculus CBS-Swiss strain jantan berusia 10 bulan dilatih berlari di roda berjalan yang diberi halang rintang, berlari dengan kecepatan 10 m/menit, 30 menit/hari, 5 hari/minggu sambil melewati halang rintang untuk setiap 78 cm. Tiga jenis halang rintang diganti setiap 3 hari. Kelompok pembanding adalah mencit yang berlari dengan kecepatan dan waktu yang sama, namun tanpa halang rintang, serta kelompok kontrol yang tidak berolahraga. Kadar neuroglobin otak tidak berbeda bermakna pada tiga kelompok mencit. Latihan lari halang rintang memberikan efek lebih baik dibanding lari tanpa halang rintang pada kadar developmentally regulated brain protein-A (drebrin-A) di hipokampus. Kedua kelompok olahraga memiliki efek yang lebih baik dibanding kontrol pada ekspresi vascular endothelial growth factors (VEGF), kadar drebrin-A, dan paired associative cognitive test. Olahraga aerobik kompleks memicu neuroplastisitas yang lebih baik dibanding aerobik sederhana di hipokampus. Kedua tipe olahraga aerobik mampu meningkatkan angiogenesis dan neuroplastisitas di otak, dan meningkatkan kemampuan memori relasional. Olahraga aerobik tidak meningkatkan kadar neuroglobin secara bermakna. Hal ini menunjukkan bahwa intensitas olahraga aerobik memberikan efek hipoksia yang dapat ditoleransi oleh jaringan otak.

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Aerobic exercise has been proven to improve of cognitive structure and function. Study about the type of aerobic exercise affects on angiogenesis, neuroplasticity and oxidative homeostasis in brain?s specific regions is still limited. The present study was conducted to investigate the effects of hurdle aerobic exercise on brain neuroglobin level, angiogenesis and neuroplasticity proteins in hippocampus and prefrontal cortex, and relational memory among middle aged CBS-Swiss strain mice. Mice, age 10 months were subjected to hurdle running wheel for 8 weeks. They ran at speed of 10 m/min, 30 min/day, and 5 days/week with hurdles for every 78 cm. Three types of hurdles were changed for every 3 days. Another group of same age mice ran at same speed, time, and period, without hurdle as comparison, while other control group never exercises. The hurdle group exercise has significant higher level of developmentally regulated brain protein-A (drebrin- A) in hippocampus compared to non-hurdle group. Both of exercise groups have significant higher ability on paired associative cognitive test, and they have significant higher expression of vascular endothelial growth factor (VEGF) and higher level of drebrin-A compared to control. Neuroglobin level was not significant different among of all groups. More complex aerobic exercise has better effect on hippocampus neuroplasticity. Both of aerobic exercise has better effect on angiogenesis and neuroplasticity in the brain, and also on cognitive function. Aerobic exercise does not resulting high hypoxic stress and could be tolerated by brain."

"Pendahuluan: Hipoksia plasenta pada bayi prematur menyebabkan stres oksidatif yang merusak protein penaut endotel kapiler plasenta. Kerusakan pada kapiler plasenta diharapkan dapat menggambarkan perubahan permeabiltas kapiler otak yang menyebabkan perdarahan intraventrikel.Metode: Penelitian observasional potong lintang terhadap 58 sampel plasenta bayi prematur. Hipoksia dinilai dari saturasi vena umbilikal, respon jaringan terhadap hipoksia dari kadar HIF-1α, stres oksidatif dari kadar malondialdehid (MDA) dan glutation (GSH). Integritas lapisan endotel dinilai dengan histomorfologi, ekspresi protein N-kaderin dan okludin dengan imunohistokimia, Glial fibrillary acidic protein (GFAP) sebagai petanda kerusakan perivaskular astrosit dan perdarahan intraventrikel dinilai dengan ultrasonografi kepala.Hasil: Kadar HIF-1α lebih tinggi tidak bermakna pada kelompok hipoksia dibandingkan kelompok non hipoksia (uji t tidak berpasangan, p = 0,122); Kadar MDA jaringan plasenta lebih tinggi tidak bermakna sedangkan GSH lebih rendah tidak bermakna (Mann Whitney, p = 0,414 dan p = 0,810). Gambaran histomorfologi lebih tidak utuh tidak bermakna (Chi-square, p = 0,066), sedangkan ekspresi N-kaderin dan okludin lebih rendah bermakna (Chi-square, p = 0,001). Kadar GFAP serum lebih tinggi bermakna (Mann Whitney, p = 0,05). Korelasi tidak bermakna antara ekspresi N-kaderin dan okludin dengan perdarahan intraventrikel (Spearman?s rho, p = 0,869 dan p = 0,341).Kesimpulan: Hipoksia pada plasenta menyebabkan perubahan ekspresi protein penaut endotel kapiler plasenta, secara molekuler sudah menyebabkan perubahan permeabilitas lapisan endotel kapiler plasenta tetapi secara struktural belum. Perubahan ekspresi protein penaut endotel kapiler plasenta tidak berhubungan dengan perdarahan intraventrikel.

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Introduction: Plasental hypoxia in premature infants causes oxidative stress which inflicts damage to endothelial protein junction of placental capillary. It is expected that damaged of placental capillary can demonstate permeability changes in brain capillary that can cause intraventricular hemorrage.

Method:.a cross sectional observational study conducted on 58 placenta of premature infants. Hypoxia is determined by umbilical venous saturation. Tissue response to hypoxia determined by the level of HIF-1α, stress oxidative by the level of malondialdehide (MDA) and glutation (GSH). Endothelial layer integtrity by histomorfologi overview, N-cadherine and occludin by immunohistochemistry. Glial fibrillary acidic protein (GFAP) as perivascular astrocyte disruption marker and intraventricular hemorrhage carried by head ultrasound.

Result: The levels of HIF-1α was not significantly higher in hypoxia group compared to non hypoxia group (unpaired t test, p = 0,122); The level of placental MDA was not significantly hingher while GSH was not significantly lower (Mann Whitney, p = 0,414 and p = 0,810). Histomorpological overview was not significantly not intact (Chi-square, p = 0,066), while the expression of N-cadherine and occludin were significantly lower (Chi-square = 0,001). There was not significant correlation between protein junction expression with intravenrticular hemorrhage (Spearman?s rho, p = 0,869 and p = 0,341).

Conclution: Hypoxia causes lower expression of N-cadherin and occludin, moleculary it cause placental endothelial capillary permeability but structurally it does not. Protein expression changes does not correlate with intraventricular hemorrhage."

"Latar belakang: Sitoglobin (Cygb) adalah protein pengangkut O2 yang diekspresikan oleh fibroblas dan fibroblast like cells aktif. Keperluan O2 dan energi meningkat pada fibrosis akibat proliferasi fibroblas dan sintesis kolagen. Pada fibrosis terjadi hipoksia yang ditandai oleh stabilisasi hypoxia inducible factor-1α (HIF-1α), yang kemudian membentuk HIF-1 yang merupakan faktor transkripsi untuk ekspresi protein adaptasi (termasuk Cygb). Diduga Cygb berperan dalam suplai O2 pada fibrosis. Tujuan penelitian ini adalah untuk memperoleh informasi mengenai peran Cygb pada hipoksia jaringan fibrosis dengan keloid sebagai model.Metode: Penelitian bersifat observasional deskriptif. Sampel keloid diperoleh melalui biopsi, sedangkan kontrol preputium diperoleh melalui sirkumsisi, masing-masing 10 sampel jaringan. Pengukuran ekspresi mRNA Cygb, HIF-1α, kolagen I dan III dilakukan dengan real time RT-PCR; kadar protein Cygb dan HIF-1α dengan ELISA; dan ekspresi protein Cygb, HIF-1α, FGF, kolagen I dan III di lapisan dermis dengan imunohistokimia (IHK). Pengukuran kadar MDA dan GSH (tingkat stres oksidatif) serta kadar hidroksiprolin (untuk pematangan kolagen) dengan spektrofotometri, sedangkan pengukuran kepadatan kolagen dengan pewarnaan Van Gieson. Data dianalisis secara statistik menggunakan uji-t.Hasil: Pada keloid dibandingkan preputium, ekspresi mRNA Cygb meningkat 8,7 kali, protein Cygb meningkat bermakna (1,196 Vs 0,779 ng/mg protein dan 95% Vs 63% ; p <0,05). Ekspresi mRNA HIF-1α meningkat 5,1 kali, protein HIF-1α meningkat bermakna (0,201 Vs 0,122 ng/mg protein dan 80% Vs 38%; p <0,05). Terdapat korelasi kuat antara ekspresi protein HIF-1α dan mRNA Cygb (Pearson; R = 0,649; p <0,01). Ekspresi protein FGF keloid meningkat bermakna (78% Vs 41%; p <0,05). Demikian pula ekspresi mRNA prokolagen I dan III keloid meningkat bermakna (35 kali dan 27,1 kali), serta ekspresi protein kolagen I dan III (61% Vs 37% dan 39% Vs. 16%; p <0,05). Juga terdapat korelasi kuat antara protein HIF-1α dengan FGF, prokolagen I dan III (Pearson; R= 0,878; R=0,960; dan R=0884; p<0,01). Kadar hiroksiprolin lebih tinggi pada keloid (0,297 Vs 276 ng/mg protein; p >0,05) dan pematangan kolagen lebih tinggi bermakna (1,2 kali; p <0,05). Cygb berkorelasi kuat dengan pematangan kolagen (kadar hidroksiprolin) (Pearson; R = 0,790; p <0,001).Kesimpulan: Cygb berperan pada hipoksia jaringan fibrosis yang ditandai dengan peningkatan ekspresinya. Peran Cygb terkait dengan ekspresi HIF-1α yang berkorelasi dengan peningkatan FGF, pro/kolagen I dan III yang merupakan faktor penting pada fibrosis. Cygb juga berperan pada pematangan kolagen.

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Background: Cytoglobin (Cygb) is an O2 carrier protein expressed by fibroblasts and active fibroblast like cells. O2 and energy demand increased in fibrosis due to proliferation of fibroblasts and synthesis of collagen. In fibrosis hypoxia occurred which is characterized by stabilization of hypoxia inducible factor-1α (HIF-1α), which later forming the HIF-1, a transcription factor for the expression of adaptation protein (including Cygb). Cygb alleged role in the supply of O2 in fibrosis. The purpose of this study was to obtain information about Cygb role in fibrosis hypoxia with keloid tissue as a model.Methods: This was an observational descriptive study. Keloid samples were obtained from biopsy, while the preputium as control were obtained from circumcision, 10 tissue samples each. Measurement of Cygb, HIF-1α, collagen I and III mRNA expression were carried out by real time RT?PCR. Cygb and HIF-1α protein level were measured by ELISA; while Cygb, HIF-1α, FGF, and collagen I and III protein expressions in the dermis layer by immunohistochemistry (IHC). Measurement of MDA and GSH levels (oxidative stress) and hydroxyprolin concentration (marker of mature collagen) by spectrophotometry, while the collagen density measurement with van Gieson staining. Data were analyzed statistically using t-test.Results: In keloid compared preputium, Cygb mRNA expression increased 8.7 times compared to preputium, Cygb protein increased significantly (1.196 Vs 0.779 ng/mg protein and 95% Vs 63%, p <0.05). HIF-1α mRNA expression increased by 5.1 times in keloid tissue, and protein HIF-1α increased significantly (0.201 Vs 0.122 ng/mg protein and 80% Vs 38%, p <0.05). There is a strong correlation between the expression of HIF-1α protein and Cygb mRNA (Pearson; R = 0.649, p <0.01). Keloid FGF protein expression increased significantly (78% Vs 41%; p <0.05). Similarly, mRNA expression of procollagen I and III keloid increased significantly (35 times and 27.1 times), and protein expression of collagen I and III (61% Vs 37% and 39% Vs 16%, p <0.05). There is also a strong correlation between HIF-1α protein with FGF, procollagen I and III (Pearson, R = 0.878, R = 0.960; and R = 0.884, p <0.01). Hydroxyprolin concentration were higher in keloid (0.297 Vs 0.276 ng/mg protein; p >0.05) and collagen maturation was significantly higher (1.2 times, p <0.05). Cygb is correlated with maturation of collagen (hydroxyproline levels) (Pearson, R = 0.790, p <0.001).Conclusion: Cygb play role in fibrosis hypoxia which is characterized by its increased expression. Cygb role is associated with the expression of HIF-1α which are correlated with increased FGF, pro/collagen I and III, which are important factor in fibrosis. Cygb also play a role in the maturation of collagen."

"Pendahuluan: Penelitian dilakukan untuk mengetahui peran senyawa flavonoid mangiferin dalam meningkatkan ekspresi mRNA HIF-1α dan sebagai pencekal besi dalam menstabilkan HIF-1α pada lini sel HepG2 dan menganalisis interaksi mangiferin dengan prolil hidroksilase (PHD2) secara simulasi docking.Metode: Sel HepG2 dikultur hingga >80% konfluen dan selanjutnya diberikan mangiferin konsentrasi 25-200μM. Kuersetin digunakan sebagai pembanding flavonoid mangiferin yang bekerja di dalam inti sel, sedangkan DFO dan CuCl2 digunakan sebagai pembanding daya ikat terhadap besi. Ekspresi mRNA HIF-1α ditentukan dengan real time RT- PCR/q-PCR, dan stabilisasi protein HIF-1α ditentukan mengunakan teknik ELISA. Simulasi docking dilakukan terhadap protein PHD2 dengan mangiferin, CuCl2, deferoksamin (DFO), dan campuran mangiferin+ kuersetin.Hasil: Uji viabilitas sel menggunakan metode MTS dengan pemberian mangiferin, kuersetin, campuran mangiferin-kuersetin, DFO dan CuCl2 (25-200μM) memperlihatkan hasil diatas 85%. Ekspresi mRNA HIF-1α dengan mangiferin, kuersetin, mangiferin+kuersetin, dan DFO menunjukkan hasil sedikit lebih tinggi dibanding kontrol. Konsentrasi protein HIF-1α pada pemberian mangiferin, kuersetin, mangiferin-kuersetin, DFO dan CuCl2 lebih tinggi dibanding kontrol. Simulasi docking mangiferin terhadap PHD2 memperlihatkan ΔG= -16,22, dan DFO menunjukkan ΔG= -17,15. Terdapat interaksi antara mangiferin, dan DFO dengan besi dan asam amino pada situs katalitik domain PHD2, sedangkan CuCl2 tidak berinteraksi dengan residu asam amino pada domain PHD2, tetapi langsung menggantikan Fe. Efek penghambatan terhadap PHD2 oleh mangiferin dan kuersetin disebabkan oleh delokalisasi elektron melalui kompleks transfer elektron.Kesimpulan: Mangiferin dapat meningkatkan ekspresi mRNA HIF-1α dan meningkatkan protein HIF-1α, menurun protein PHD2 dan menurunkan protein HO-HIF-1α pada lini sel HepG2 secara in vitro. Analisis docking terdapat interaksi antara mangiferin, dan DFO dengan besi dan asam amino PHD2. Mangiferin memiliki stabilitas pengkikatan dengan besi yang berdekatan dengan DFO.

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Introduction: This research was conducted to determine the role of flavanoid mangiferin to increase expression HIF-1α mRNA, and as an iron chelator to stabilize protein HIF-1α in cell line HepG2 and analyzes the interaction of mangiferin with prolil hidroksilase (PHD2) by docking simulation.

Methods: HepG2 cells were cultured and treated by mangiferin with concentration between 25-200μM. Quercetin is used as a comparison mangiferin flavonoid that works in the nucleus and DFO, CuCl2 is used as a comparison to iron-binding. HIF- 1α mRNA expression was determined by real time RT-PCR/q-PCR, and the stability HIF-1α protein were measured by the increase in HIF-1α protein, decreased PHD2 protein and decreased HO-HIF-1α using ELISA. Docking simulation was conducted between PHD2 protein and mangiferin, CuCl2, desferoxamine (DFO), and quercetin.

Results: Cell viability with MTS assay showed that cell exposure with 25μM-200μM concentrations of mangiferin, quercetin, mangiferin+quercetin mixture, DFO, and CuCl2 is above 85%. HIF-1α mRNA expression was slightly higher than in controls with mangiferin, quercetin, mangiferin quercetin mixture and DFO. HIF-1α protein concentration and ratios vs untreated controls were above 1 with mangiferin, quercetin, mangiferin quercetin mixture, DFO, and CuCl2. Docking simulation mangiferin with PHD2 showed ΔG= -16,22. Docking simulation with DFO showed ΔG= -17,15, and interact mangiferin, and DFO with iron in the catalytic site of PHD2 and with amino acid residues, whereas CuCl2 does not react with amino acid residues in the PHD2 domain, but directly replaces Fe. The inhibitory effect to PHD2 by mangiferin and quercetin is considered by electron delocalisation through an electron transfer complex.

Conclusion: Mangiferin can increase HIF-1α mRNA expression and HIF-1α protein levels in HepG2 cell line by in vitro. Binding interaction with iron and PHD2 amino acids occurs by mangiferin and DFO. Mangiferin has stability iron binding a similar with DFO."

"Latar belakang: Paparan hipoksia subletal (Hypoxia conditioning) diyakini memiliki efek neuroprotektif yang dapat meningkatkan resistensi sel dengan cara menginduksi perubahan ekspresi gen dan jalur sinyal intraseluler yang mengakibatkan adaptasi intraseluler melalui proses eritropoiesis, angiogenesis, transport glukosa dan glikolisis anaerobik melalui aktivitas gen HIF- 1 alpha. Penelitian mengenai hipoksia hipobarik intermiten (HHI) telah membuktikan bahwa induksi HHI menurunkan kerusakan jaringan otak pada korteks, dan meningkatkan densitas mikrovaskuler. HHI juga memicu respons neuroplastisitas pada sel otak sebagai upaya agar fungsi sel otak tidak terganggu. Tujuan: Menganalisis efek hipoksia hipobarik intermitten (HHI) terhadap neuroplastisitas jaringan otak dengan mengamati perubahan fungsi motorik dan kognitif serta peningkatan protein PSD95 sebagai respons adaptasi pasca induksi hipoksia hipobarik intermitten. Metode: 25 tikus Sprague-Dawley, dibagi menjadi 4 kelompok diinduksi HHI dan 1 kelompok sebagai kelompok kontrol.Induksi dilakukan dengan hypobaric chamber di Lakespra TNI AU dengan interval induksi 1 minggu selama 4 kali (hari-1, 8, 15 dan 22). Setelah induksi, kelompok itu diuji untuk parameter fisiologis menggunakan balok berjalan untuk mengukur fungsi motorik dan Y Maze untuk mengukur fungsi kognitif. Jaringan otak diambil untuk pemeriksaan reseptor neurotransmitter glutamat dan GABA serta protein PSD95. Hasil: kelompok perlakuan dengan 1,2,3,4 kali paparan hipoksia hypobarik tidak menunjukkan perbedaan yang signifikan dalam fungsi neuromotor kompleks, fungsi kognitif dan PSD 95 dibandingkan dengan kelompok kontrol (p> 0,05). Ekspresi reseptor GABA dan glutamat menurun secara signifikan di induksi pertama, namun meningkat secara signifikan pada kelompok induksi kedua dan ketiga dan untuk akhirnya menurun mendekati rerata kelompok kontrol. Kesimpulan: HHI menginduksi proses neuroplastisitas sebagai respon adaptasi terhadap paparan hipoksia hipobarik intermiten pada tikus Sprague-Dawley.

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Background: Sublethal exposure to hypoxia known as hypoxia preconditioning is believed to have neuroprotective effect. Hypoxia preconditioning induces changes in gene expression and intracellular signaling pathways that lead to the emergence of intracellular adaptation through the process of erythropoiesis, angiogenesis, glucose transport and anaerobic glycolysis through HIF- 1 alpha gene activity. Intermittent hypobaric hypoxic conditions (IHH) which occurs at high altitude such as during flight, is a common condition that causes exposure to hypoxia preconditioning. HHI induction decreased brain cortical tissue damage, and increased microvascular density. The aim of the present study is to investigate the effect of hypoxic preconditioning on the function of neuronal cells.

Aims: to investigate the neuroplasticity responses after intermittent hypobaric hypoxia induction on cerebral function (complex neuromotor function,cognitive function, PSD95 and neurotransmitter transduction).

Method: A total of 25 Sprague-Dawley rats were divided into 4 groups of IHH and 1 group as control. The 4 IHH groups were exposed to intermittent hypobaric hypoxia in Indonesian Air Force Institute of Aviation Medicine hypobaric chamber, by 1 week interval for 4 times (day-1, 8, 15 and 22). After the induction, the groups were evaluated for physiological parameters using walking beam to measure the complex neuromotor function and Y maze to measure the cognitive function. The brain was taken for immunochemistry and ELISA analysis.

Results: the group treated with 1,2,3,4 times exposure to hypobaric hypoxia shows no significant differences in complex neuromotor function,cognitive function and PSD95 compare to control group ( p>0.05). The level of GABA and glutamate receptor decreased significantly in induction 1, but raised significantly in group induction 2 and 3 compare to control group.

Conclution: IHH induced neuroplasticity as adaptation respons to hypobaric intermittent hypoxia in Sprague-Dawley rats."

"ABSTRAKProgram latihan untuk penatalaksanaan Diabetes Melitus DM tipe 2 harus dipastikan aspek keamanannya, selain juga efektif dan bermanfaat. Melalui penelitian dua tahap dilakukan perancangan latihan fisik yang dievaluasi dengan randomized controlled trial RCT .Program latihan 12 minggu mengombinasikan high intensity interval training HIIT dan latihan beban tiga dan dua kali per minggu dengan peningkatan intensitas bertahap. HIIT terdiri atas perbandingan 1 : 4 menit high intensity exercise HIE dan low intensity exercise LIE . Latihan beban terdiri atas sembilan latihan untuk batang tubuh, ekstremitas atas, dan bawah. RCT diikuti 42 penyandang DM tipe 2 berusia 35 ndash;64 tahun, yang dialokasikan menjadi kelompok eksperimen dengan latihan sesuai rancangan dan kelompok kontrol dengan continuous cardiorespiratory training. Pemeriksaan tingkat kebugaran VO2max , kontrol glikemik HbA1c , dan stres oksidatif MDA dan SOD dilakukan di awal dan akhir program.Pasca latihan didapatkan nilai rerata VO2max kelompok eksperimen 38,13 5,93 mL/kg.min lebih tinggi dibandingkan kontrol 32,09 5,24 mL/kg.min , p = 0,004, serta stres oksidatif menurun MDA eksperimen ? -0,14 0,39 nmol/mL dibandingkan kontrol ? 0,18 0,26 nmol/mL , p = 0,011; SOD eksperimen median ? 0,47 U/mL IQR 0,08-0,74 U/mL dibandingkan kontrol ? 0,14 0,35 U/mL , p = 0,036 . HbA1c kelompok eksperimen menunjukkan penurunan ? -0.43 1.01 , namun tidak bermakna. Skor komposit efek latihan lebih tinggi pada kelompok eksperimen 8,72 1,27 dibandingkan kontrol 7,20 1,08 , p = 0,001.Dengan demikian disimpulkan bahwa program latihan pada penelitian ini memberi manfaat dan dapat diimplementasikan dengan aman. Kata kunci: HIIT dan latihan beban; program latihan berbasis pasien; stres oksidatif; T2DM

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ABSTRACTExercise programs for patients with Type 2 Diabetes Mellitus T2DM must be demonstrably safe, effective, and beneficial. Objectives. In this two-step study, a training program was designed and implemented in a randomized controlled trial RCT to meet the above criteria.The 12-week exercise program combined high intensity interval training HIIT three times per week and resistance training twice weekly , with gradually increased intensity. The HIIT element comprised 1 minute of high intensity exercise HIE and 4 minutes of low intensity exercise LIE . The resistance training element comprised nine exercises for core, upper, and lower extremities. The 42 T2DM patients who participated in the RCT were aged 35 ndash;64 years. Participants were randomly allocated to the experimental EXP group for the new training program and to the control KTR group for continuous cardiorespiratory training. Fitness level VO2max , glycemic control HbA1c , and oxidative stress MDA and SOD were measured before and after the exercise program.VO2max was higher in EXP 38.13 5.93 mL/kg.min than in KTR 32.09 5.24 mL/kg.min; p = 0.004 . Overall oxidative stress decreased in EXP MDA EXP ? -0.14 0.39 nmol/mL as compared to KTR ? 0.18 0.26 nmol/mL; p = 0.011 and SOD EXP median ? 0.47 U/mL IQR 0.08-0.74 U/mL as compared to KTR ? 0.14 0.35 U/mL; p = 0.036 . EXP HbA1c also decreased, although not significantly ? -0.43 1.01 . EXP composite effects score was significantly higher 8.72 1.27 than for KTR 7.20 1.08; p = 0.001 .The exercise program for T2DM patients was shown to be safe, with significant benefits.Keywords: glycemic control; HIIT and resistance training; oxidative stress; patient-based training program; physical fitness; T2DM"

"ABSTRAKLatar Belakang: Hipertrofi jantung dapat timbul akibat stres patologis misal hipoksia yang merupakan respon jantung sebagai mekanisme homeostatis yang diperlukan untuk menormalkan stres dinding ventrikel kiri dan mempertahankan curah jantung. Hipoksia sistemik kronik merupakan stres lingkungan yang berat. Respon spesifik jantung terhadap stres jantung terlihat pada peningkatan kadar peptida di dalam plasma, yang membantu jantung dalam menghadapi beban yang meningkat. Menurut sejumlah peneliti, kadar Apelin berhubungan erat dengan disfungsi ventrikel. Apelin merupakan preproprotein dengan 77 asam amino yang disekresikan dari keluarga adipokine, berperan dalam mempertahankan performa jantung pada beban tekanan kronik. Pada tingkat molekular, respons adaptasi diperantarai oleh perubahan ekspresi gen. Tujuan penelitian: Menganalisis pola ekspresi gen Apelin dan gen BNP pada hipertrofi ventrikel akibat induksi hipoksia sistemik kronik dengan mengukur konsentrasi Apelin-13 dan konsentrasi BNP-45. Penelitian bersifat eksperimental menggunakan 28 ekor tikus Sprague-Dawley jantan, umur 8-12 minggu yang dibagi dalam 7 kelompok n=4 ekor/kelompok , terdiri dari kelompok kontrol normoksia, O2 atmosfir dan kelompok perlakuan hipoksia dalam sungkuphipoksia, 8 O2, masing-masing selama 6 jam, 1, 3, 5, 7 dan 14 hari . Parameter stres oksidatif akibat hipoksia jantung, dilakukan dengan pengukuran kadar malondialdehid MDA dan histopatologi dengan pewarnaan HE. Selain itu juga dilakukan pengukuran protein Apelin-13 dan BNP-45 menggunakan metoda ELISA dan pengukuran ekspresi relatif mRNA Apelin dan BNP-45 jantung, menggunakan real time RT-PCR kuantitatif dengan rumus Livak. Hasil penelitian: ekspresi relatif Apelin-13 di jantung menurun pada awal hipoksia dan kemudian meningkat mulai hari ke-3 sampai hari ke-14. Peningkatan kadar MDA yang signifikan terjadi sejak hipoksia 7 hari. Korelasi MDA terhadap peningkatan ekspresi relatif Apelin adalah kuat r=0.750 dan signifikan p=0.000 . Korelasi BNP-45 terhadap Apelin-13 adalah sangat kuat r=0.943 dan signifikan p=0.000 . Dapat disimpulkan bahwa adanya peningkatan MDA, peningkatan ekspresi relatif dan protein Apelin-13 dan peningkatan ekspresi relatif dan protein BNP-45 pada jaringan jantung mempunyai korelasi yang signifikan dan kuat, sesuai dengan peningkatan lamanya perlakuan hipoksia.

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ABSTRACTBackground: Cardiac hypertrophy can result from pathological stress eg hypoxia as a response to ventricular wall stress and to maintain cardiac output. Chronic systemic hypoxia is a severe environmental stress. During cardiac stress certain peptides are release by the heart into the plasma, which help the heart to compensate the increased myocardial load. According to several authors, apelin levels are increased during cardiac dysfunction. Apelin is a preproprotein with 77 amino acids from adipokine, which contributes to maintaining cardiac performance at chronic stress loads. At the molecular level, the adaptation response is mediated by changes in gene expression. Objective: To analyze the expression pattern of Apelin-13 and BNP-45 on ventricular hypertrophy due to induction of chronic systemic hypoxia by measuring Apelin-13 and BNP-45 concentrations. The experimental study used 28 male Sprague-Dawley rats, 8-12 weeks old divided into 7 groups 4 per group , consisting of control group normoxia, atmospheric O2 and 4 hypoxia treatment groups, which underwent systemic hypoxia in hypoxic chamber containing 8 oxygen, respectively for 6 hours, 1, 3, 5, 7 and 14 days . The presence of oxidative stress due to cardiac hypoxia was determined by malondialdehyde MDA and cardiac structural alteration was examined by HE staining. Apelin-13 and BNP-45 proteins were determined using the ELISA method and the relative expression of cardiac Apelin and BNP-45 mRNA were determined using quantitative RT-PCR real time with Livak formula. Results: Relative expression of Apelin-13 in the heart decreased early in hypoxia and then increased from day 3 to day 14. Significant increases in MDA levels occurred after 7 days hypoxia. There was a strong and significant correlation between MDA levels and Apelin relative expression r = 0.750, p = 0.001 . Similar results were obtained for of BNP-45 and Apelin-13 r = 0.943, p = 0.001 . From the results, it can be concluded that during chronic systemic hypoxia there was an increase in oxidative stress, relative expression and Apelin-13 proteins and relative expression and BNP-45 protein of the rat cardiac tissue."

"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."