Disertasi

Potensi Ekstrak Hibiscus Sabdariffa L. Dalam Mencegah Gagal Tumbuh Janin Melalui Peran Jalur IGF-1 Dan Fungsi Transpor Plasenta Pada Model Tikus Bunting Dengan Restriksi Nutrisi = The Potential ofHibiscus Sabdariffa L. Extract In Preventing Fetal Growth Restriction Through the IGF-1 Signaling Pathway and Placental Transport Function in Maternal Feed-Restriction Pregnant Rat Model.

Latar Belakang Kekurangan gizi maternal selama kehamilan merupakan faktor utama terjadinya hambatan pertumbuhan janin, yang terutama disebabkan oleh penurunan insulinlike growth factors (IGFs) dan terganggunya fungsi transpor nutrisi plasenta. Hibiscus sabdariffa L. (HSL) memiliki berbagai senyawa bioaktif yang berpotensi memodulasi jalur pertumbuhan, namun mekanisme kerjanya pada kondisi restriksi nutrisi maternal belum sepenuhnya dipahami. Metode Penelitian eksperimental ini menggunakan 25 ekor tikus Wistar bunting yang diberikan restriksi pakan sebesar 50% selama kehamilan. Hewan coba dibagi menjadi lima kelompok: kontrol normal, kontrol restriksi, serta tiga kelompok restriksi yang menerima ekstrak HSL dosis 5, 10, dan 20 mg/kgBB/hari. Terminasi kehamilan dilakukan pada hari ke-18 melalui seksio sesarea. Pemeriksaan meliputi kadar IGF-1 maternal dan GLUT1 (ELISA), ekspresi gen IGF-1, IGF-1R, GLUT1, dan SNAT1 (qRT-PCR), ekspresi protein AKT dan MAPK (Western blot), kadar glukosa darah janin, profil asam amino janin (LC-MS/MS), serta pengukuran berat plasenta, berat janin, dan panjang janin. Analisis in silico dilakukan melalui molecular docking dan molecular dynamics untuk mengevaluasi stabilitas interaksi senyawa aktif HSL dengan IGF-1R dan AKT. Hasil Kelompok restriksi yang menerima ekstrak HSL dosis 10 mg/kgBB/hari menunjukkan hasil paling optimal, ditandai dengan peningkatan bermakna berat janin (1453 vs 833 mg) dan panjang janin (22,97 vs 19,05 mm) dibandingkan kelompok restriksi. Peningkatan tersebut disertai dengan peningkatan signifikan ekspresi gen IGF-1R (3,277 vs 1,006) dan SNAT1 (7,519 vs 0,362). Ekspresi IGF- 1 plasenta, berat plasenta, aktivasi AKT, serta beberapa asam amino janin cenderung meningkat, meskipun belum mencapai signifikansi statistik. Analisis in silico menunjukkan bahwa ellagic acid, N-feruloyl serotonin, quercetin-3-Orutinose, dan tiliroside memiliki afinitas ikatan paling kuat terhadap IGF-1R dan AKT. Simulasi molecular dynamics mengonfirmasi bahwa kompleks senyawa– protein tersebut stabil selama simulasi, dengan fluktuasi RMSD yang rendah dan interaksi hidrogen yang persisten. Kesimpulan Ekstrak Hibiscus sabdariffa L., khususnya pada dosis 10 mg/kgBB/hari, berpotensi memperbaiki pertumbuhan janin pada kondisi restriksi nutrisi maternal melalui aktivasi jalur IGF-1R–AKT dan peningkatan ekspresi transporter asam amino SNAT1 di plasenta.
Kata kunci: Restriksi nutrisi maternal, Hibiscus Sabdariffa L., IGF-1, transpor plasenta, pertumbuhan janin.


Background Maternal undernutrition during pregnancy is a major cause of fetal growth restriction, primarily through reduced insulin-like growth factor (IGF) availability and impaired placental nutrient transport. Hibiscus sabdariffa L. (HSL) contains bioactive compounds with growth-modulating properties, its mechanism of action under maternal feed restriction remains unclear. Methods This experimental study involved 25 pregnant Wistar rats subjected to a 50% dietary restriction throughout gestation. Animals were divided into five groups: a normal control, a restricted control, and three restricted groups treated with HSL extract at doses of 5, 10, and 20 mg/kg body weight/day. Pregnancy was terminated on gestational day 18 by caesarean section. Maternal IGF-1 and GLUT1 levels were measured by ELISA. Placental expression of IGF-1, IGF-1R, GLUT1, and SNAT1 was assessed using qRT-PCR, while AKT and MAPK protein expression was evaluated by Western blotting. Fetal blood glucose levels, fetal amino acid profiles (LC-MS/MS), placental weight, fetal weight, and fetal length were also analyzed. In silico analyses included molecular docking and molecular dynamics simulations to assess the stability of interactions between HSL bioactive compounds and IGF-1R and AKT. Results The restricted group treated with HSL at 10 mg/kg body weight/day showed the most favorable outcomes, with significantly increased fetal weight (1453 vs 833 mg) and fetal length (22.97 vs 19.05 mm) compared with the restricted control group. These improvements were accompanied by significantly higher placental gene expression of IGF-1R (3.277 vs 1.006) and SNAT1 (7.519 vs 0.362). Placental IGF-1 expression, placental weight, AKT activation, and selected fetal amino acid levels showed an increasing trend, although statistical significance was not reached. In silico results demonstrated that ellagic acid, N-feruloyl serotonin, quercetin-3-O-rutinose, and tiliroside exhibited the strongest binding affinity to IGF-1R and AKT. Molecular dynamics simulations further confirmed the stability of these ligand–protein complexes, indicated by low RMSD fluctuations and sustained intermolecular interactions. Conclusion Hibiscus sabdariffa L. extract, particularly at a dose of 10 mg/kg body weight/day, may enhance fetal growth under maternal nutrient restriction by activating the IGF-1R–AKT signaling pathway and upregulating placental amino acid transport via SNAT1.
Keywords: Maternal feed-restricted, Hibiscus Sabdariffa L., IGF-1, placental transport, fetal growth