Maghfirah Savitri, Trina Ekawati Tallei, Ahmad Akroman Adam, Nur Balqis Maulydia, Fatimawali Fatimawali, Gadis Sabrina Tanjung, Muhammad Firdaus, Rony Abdi Syahputra, Fahrul Nurkolis
Obesity and type 2 diabetes are interconnected metabolic disorders characterized by hyperglycemia, dyslipidemia, and insulin resistance. Marine red algae like Hydropuntia edulis offer promising multitarget bioactive compounds. This study evaluated the antidiabetic and anti-obesity potential of H. edulis extract (HEE) through a comprehensive approach combining untargeted LC-HRMS metabolomics, network pharmacology, molecular docking, in vitro enzyme assays, and in vivo validation in a diabetic zebrafish model. Metabolomic profiling revealed over 300 metabolites, including amino acids, peptides, phosphorylated intermediates, and fatty acid amides. Network pharmacology analysis identified key metabolic targets, including DPP4, SI, and MGAM, which are involved in carbohydrate digestion and glucose homeostasis. Among the compounds, 2,6-piperidinedicarboxylic acid showed strong and stable binding to the DPP-4 active site, supported by docking studies, MM/GBSA energy estimation, and 100-ns molecular dynamics simulation. Structural analyses (PCA, SASA, DCCM) confirmed complex stability and favorable interaction dynamics under physiological conditions. In vitro, HEE inhibited α-amylase, α-glucosidase, and DPP-4 in a dose-dependent manner. In vivo, HEE significantly lowered fasting blood glucose, reduced weight gain (p < 0.01), improved lipid profiles, and modulated key proteins involved in insulin and lipid signaling—downregulating DPP-4 and SREBP-1c, while upregulating GLP-1 and AKT1—mirroring the effects of metformin. These findings demonstrated the multitarget efficacy of HEE in modulating both digestive and endocrine pathways involved in metabolic regulation. The rich metabolite profile of H. edulis supports its potential as a functional food for metabolic syndrome. Further studies are needed to isolate active compounds and assess their pharmacokinetics, safety, and efficacy in mammals. © 2025 Elsevier Ltd
Robert Wolter Monginsidi Army Hospital, North Sulawesi, Manado, Indonesia; Department of Biology, Faculty of Medicine, Sam Ratulangi University, North Sulawesi, Manado, 95113, Indonesia; Department of Biology, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University, North Sulawesi, Manado, 95115, Indonesia; Cosmo Dental Care, North Sulawesi, Manado, 95115, Indonesia; of Mathematics and Applied Sciences, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia; Pharmacy Study Program, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University, North Sulawesi, Manado, 95115, Indonesia; Research Center for Marine and Land Bioindustry, National Research and Innovation Agency (BRIN), North Lombok, 83352, Indonesia; Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, 20155, Indonesia; Master of Basic Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta, 55281, Indonesia; Medical Research Center of Indonesia, Surabaya, Indonesia
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