{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T20:09:22Z","timestamp":1770149362865,"version":"3.49.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004728","name":"VIT University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004728","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:italic>Curcuma angustifolia<\/jats:italic> Roxb. is a therapeutic herb and a member of the Zingiberaceae family. A potential bioactive fraction was isolated from the methanolic extract of <jats:italic>Curcuma angustifolia<\/jats:italic> rhizome using column chromatography, and it was characterised using <jats:sup>1<\/jats:sup>H-NMR, GCMS and FTIR analyses. The bioactive fraction showed no toxic effects on the HepG2 cell line and it demonstrated inhibition of \u03b1-amylase and \u03b1-glucosidase enzymes <jats:italic>in vitro with<\/jats:italic> IC<jats:sub>50<\/jats:sub> values of 2.75 \u00b1 0.09 and 4.9 \u00b1 0.07\u00a0\u00b5M, respectively. Molecular docking analysis also showed that nerolidol, the major constituent of the bioacive fraction inhibits \u03b1-amylase and \u03b1-glucosidase enzymes competitively, supporting <jats:italic>in vitro<\/jats:italic> antihyperglycemic activity. ADMET analysis showed that nerolidol has the necessary physicochemical parameters for drug-likeness. It also complies with Lipinski\u2019s rule, indicating that its chemical structure is appropriate for designing safe and bioavailable oral drug. The antidiabetic efficacy of the isolated bioactive fraction was validated in type 2 diabetic albino wistar rats induced with a high-fat diet and a low dose (35\u00a0mg\/kg bw) of streptozotocin. After 28\u00a0days of intervention, the lower and higher doses of the bioactive fraction (100 and 200\u00a0mg\/kg BW) substantially decreased fasting blood glucose levels and ameliorated hyperglycemia, glucose intolerance, insulin resistance, and hyperlipidemia. The higher dose of bioactive fraction significantly ameliorated liver, kidney, and lipid profiles compared to the standard drug metformin and exhibited lower toxicity in the liver, kidney, pancreas, and epididymal adipose tissue than the lower dose of the bioactive fraction. Gene expression studies revealed that the bioactive fraction upregulated AMPK through downregulating PKA, a mechanism similar to the action of metformin. The results indicate that the isolated bioactive fraction could be a natural alternative to synthetic antidiabetic medications.<\/jats:p>","DOI":"10.3389\/fphar.2025.1570533","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T05:37:52Z","timestamp":1747201072000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Bioactive fraction isolated from Curcuma angustifolia rhizome exerts anti-diabetic effects in vitro, in silico and in vivo by regulating AMPK\/PKA signaling pathway"],"prefix":"10.3389","volume":"16","author":[{"given":"P.","family":"Kavya","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Gayathri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3240","DOI":"10.3390\/ijms21093240","article-title":"The metformin mechanism on gluconeogenesis and AMPK activation: the metabolite perspective","volume":"21","author":"Agius","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"21642","DOI":"10.1021\/acsomega.3c01027","article-title":"Antioxidant, hypoglycemic, antilipidemic, and protective effect of polyherbal emulsion (F6-SMONSECCE) on alloxan-induced diabetic rats","volume":"8","author":"Akhtar","year":"2023","journal-title":"ACS Omega"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.3390\/ph16101368","article-title":"Synergistic antihyperglycemic and antihyperlipidemic effect of polyherbal and allopolyherbal formulation","volume":"16","author":"Alhamhoom","year":"2023","journal-title":"Pharmaceuticals"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.3390\/antiox10111695","article-title":"The blood \u2013 brain barrier, oxidative stress, and insulin resistance","volume":"10","author":"Banks","year":"2021","journal-title":"Antioxidants"},{"key":"B5","doi-asserted-by":"publisher","first-page":"5179","DOI":"10.3390\/ijms21155179","article-title":"Biological properties, bioactive constituents, and pharmacokinetics of some capsicum spp. and capsaicinoids","volume":"21","author":"Batiha","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"452","DOI":"10.3389\/fphar.2018.00452","article-title":"Metformin mitigates fibrosis and glucose intolerance induced by doxorubicin in subcutaneous adipose tissue","volume":"9","author":"Biondo","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"116446","DOI":"10.1016\/j.trac.2021.116446","article-title":"Human artificial membranes in (bio)analytical science: potential for in vitro prediction of intestinal absorption-A review","volume":"145","author":"Carrasco-Correa","year":"2021","journal-title":"Trac. Trends Anal. Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"4649","DOI":"10.1038\/s41598-017-04631-7","article-title":"Liver fat, hepatic enzymes, alkaline phosphatase and the risk of incident type 2 diabetes: a prospective study of 132,377 adults","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.aaf.2022.04.003","article-title":"Glycolysis and gluconeogenesis are involved of glucose metabolism adaptation during fasting and re-feeding in black carp (Mylopharyngodon piceus)","volume":"9","author":"Dai","year":"2024","journal-title":"Aquac. Fish."},{"key":"B10","doi-asserted-by":"publisher","first-page":"133964","DOI":"10.1016\/j.molstruc.2022.133964","article-title":"Rational design of novel pyridine-based drugs candidates for lymphoma therapy","volume":"1270","author":"Daoui","year":"2022","journal-title":"J. Mol. Struct."},{"key":"B11","doi-asserted-by":"publisher","first-page":"103964","DOI":"10.1016\/j.sjbs.2024.103964","article-title":"In vitro and in silico studies of the potential cytotoxic, antioxidant, and HMG CoA reductase inhibitory effects of chitin from Indonesia mangrove crab (Scylla serrata) shells","volume":"31","author":"Fajriaty","year":"2024","journal-title":"Saudi J. Biol. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"106114","DOI":"10.1016\/j.phrs.2022.106114","article-title":"Mitochondria as an important target of metformin: the mechanism of action, toxic and side effects, and new therapeutic applications","volume":"177","author":"Feng","year":"2022","journal-title":"Pharmacol. Res."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.29219\/fnr.v65.3602","article-title":"Synergistic antitumor effect of resveratrol and sorafenib on hepatocellular carcinoma through PKA\/AMPK\/eEF2K pathway","volume":"65","author":"Gao","year":"2021","journal-title":"Food Nutr. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"12827","DOI":"10.3390\/ijms222312827","article-title":"The MTT assay: utility, limitations, pitfalls, and interpretation in bulk and single-cell analysis","volume":"22","author":"Ghasemi","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3220","DOI":"10.1111\/1750-3841.15438","article-title":"Activity-guided isolation of \u03b1-amylase, \u03b1-glucosidase, and pancreatic lipase inhibitory compounds from Rhus coriaria L","volume":"85","author":"G\u00f6k","year":"2020","journal-title":"J. Food Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"100535","DOI":"10.1016\/j.cdc.2020.100535","article-title":"Isolation, characterization and drug-likeness analysis of bioactive compounds from stem bark of Warburgia ugandensis Sprague","volume":"29","author":"Gonfa","year":"2020","journal-title":"Chem. Data Collect."},{"key":"B17","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/s10020-023-00721-7","article-title":"Liraglutide attenuates type 2 diabetes mellitus - associated non - alcoholic fatty liver disease by activating AMPK\/ACC signaling and inhibiting ferroptosis","volume":"29","author":"Guo","year":"2023","journal-title":"Mol. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"116963","DOI":"10.1016\/j.jep.2023.116963","article-title":"Metabolite profiling and biochemical investigation of the antidiabetic potential of Loranthus pulverulentus Wall n -butanol fraction in diabetic animal models","volume":"318","author":"Hafeez","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B19","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1002\/9781119697473.ch3","article-title":"The global burden of diabetes","volume-title":"Textbook of diabetes","author":"Harding","year":"2024"},{"key":"B20","doi-asserted-by":"publisher","first-page":"103816","DOI":"10.1016\/j.sjbs.2023.103816","article-title":"Effect of PENN-DIABEX, a novel polyherbal formulation, in high fat diet streptozotocin-induced diabetic rats","volume":"30","author":"Hassan","year":"2023","journal-title":"Saudi J. Biol. Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.puhe.2024.05.009","article-title":"The burden of type 2 diabetes mellitus in Latin America, 1990\u20132019: findings from the Global Burden of Disease study","volume":"233","author":"Ilic","year":"2024","journal-title":"Public Health"},{"key":"B22","doi-asserted-by":"publisher","first-page":"3344","DOI":"10.3390\/ijms19113344","article-title":"Interactive roles for AMPK and glycogen from cellular energy sensing to exercise metabolism","volume":"19","author":"Janzen","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"4945","DOI":"10.1007\/s00018-019-03152-y","article-title":"Regulation of AMPK activity by type 10 adenylyl cyclase: contribution to the mitochondrial biology, cellular redox and energy homeostasis","volume":"76","author":"Jayarajan","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.drudis.2019.10.014","article-title":"A drug-likeness toolbox facilitates ADMET study in drug discovery","volume":"25","author":"Jia","year":"2020","journal-title":"Drug Discov. Today"},{"key":"B25","doi-asserted-by":"publisher","first-page":"09603271221126487","DOI":"10.1177\/09603271221126487","article-title":"Antidiabetic effects of nerolidol through promoting insulin receptor signaling in high-fat diet and low dose streptozotocin-induced type 2 diabetic rats","volume":"41","author":"Jiang","year":"2022","journal-title":"Hum. \\and Exp. Toxicol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"115158","DOI":"10.1016\/j.biopha.2023.115158","article-title":"A sulfonamide chalcone AMPK activator ameliorates hyperglycemia and diabetic nephropathy in db\/db mice","volume":"165","author":"Kaewin","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B27","doi-asserted-by":"publisher","first-page":"109462","DOI":"10.1016\/j.foodres.2020.109462","article-title":"Potential anti-diabetic properties of Merlot grape pomace extract: an in vitro, in silico and in vivo study of \u03b1-amylase and \u03b1-glucosidase inhibition","volume":"137","author":"Kato-Schwartz","year":"2020","journal-title":"Food Res. Int."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e202301788","DOI":"10.1002\/cbdv.202301788","article-title":"Phytochemical profiling and assessment of antidiabetic activity of Curcuma angustifolia rhizome methanolic extract: an in vitro and in silico analysis","volume":"21","author":"Kavya","year":"2024","journal-title":"Chem. and Biodivers."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1458505","DOI":"10.3389\/fchem.2024.1458505","article-title":"Phytochemical analysis, identification of bioactive compounds using GC-MS, in vitro and in silico hypoglycemic potential, in vitro antioxidant potential, and in silico ADME analysis of Chlorophytum comosum root and leaf","volume":"12","author":"Kavya","year":"2024","journal-title":"Front. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.jtcme.2022.03.003","article-title":"Formulation and evaluation of SGLT2 inhibitory effect of a polyherbal mixture inspired from Ayurvedic system of medicine","volume":"12","author":"Kumar","year":"2022","journal-title":"J. Tradit. Complement. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"32182","DOI":"10.1074\/jbc.M110.134890","article-title":"AMPK-Dependent repression of hepatic gluconeogenesis via disruption of CREB\u00b7CRTC2 complex by orphan nuclear receptor small heterodimer partner","volume":"285","author":"Lee","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"117104","DOI":"10.1016\/j.jep.2023.117104","article-title":"Hyperglycemia effect of Pinctada martensii hydrolysate in diabetic db\/db mice","volume":"319","author":"Li","year":"","journal-title":"J. Ethnopharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"129809","DOI":"10.1016\/j.ijbiomac.2024.129809","article-title":"Antidiabetic effects and mechanism of \u03b3-polyglutamic acid on type II diabetes mice","volume":"261","author":"Li","year":"","journal-title":"Int. J. Biol. Macromol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"788","DOI":"10.3390\/toxics10120788","article-title":"Applications of in silico models to predict drug-induced liver injury","volume":"10","author":"Lin","year":"2022","journal-title":"Toxics"},{"key":"B35","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1038\/s41594-022-00799-3","article-title":"Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate","volume":"29","author":"McCorvie","year":"2022","journal-title":"Nat. Struct. Mol. Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"9120259","DOI":"10.1155\/2022\/9120259","article-title":"Antiobesity activity of two polyherbal formulations in high-fat diet-induced obese C57bl\/6J mice","volume":"2022","author":"Pandeya","year":"2022","journal-title":"Biomed. Res. Int."},{"key":"B37","doi-asserted-by":"publisher","first-page":"103631","DOI":"10.1016\/j.sjbs.2023.103631","article-title":"Antioxidant properties and cytotoxic effects of selected edible plants in Southeast Asia for further use as phytogenic antioxidant additives","volume":"30","author":"Pasri","year":"2023","journal-title":"Saudi J. Biol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"117032","DOI":"10.1016\/j.jep.2023.117032","article-title":"Antidiabetic effects of polyherbal mixture made of Centaurium erythraea, Cichorium intybus and Potentilla erecta","volume":"319","author":"Petrovi\u0107","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"36856","DOI":"10.1021\/acsomega.2c05544","article-title":"Polyoxygenated cyclohexenes from uvaria grandiflora with multi-enzyme targeting properties relevant in type 2 diabetes and obesity","volume":"7","author":"Quimque","year":"2022","journal-title":"ACS Omega"},{"key":"B40","doi-asserted-by":"publisher","first-page":"113836","DOI":"10.1016\/j.molliq.2020.113836","article-title":"Validation of the antidiabetic potential of isolated and nanoemulsified endophytic fungal metabolite 2,4,6-triphenylaniline through AMPK activation pathway","volume":"316","author":"Ranganathan","year":"2020","journal-title":"J. Mol. Liq."},{"key":"B41","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/s13530-020-00056-4","article-title":"In silico prediction of toxicity and its applications for chemicals at work","volume":"12","author":"Rim","year":"2020","journal-title":"Toxicol. Environ. Health Sci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"S128","DOI":"10.22377\/ijgp.v11i01.884","article-title":"The in-vitro antidiabetic activity of Phoenix roebelenii leaf extract","volume":"11","author":"Roy","year":"2017","journal-title":"Int. J. Green Pharm."},{"key":"B43","doi-asserted-by":"publisher","first-page":"112956","DOI":"10.1016\/j.biopha.2022.112956","article-title":"Downregulation of hepatic fat accumulation, inflammation and fibrosis by nerolidol in purpose built western-diet-induced multiple-hit pathogenesis of NASH animal model","volume":"150","author":"Sabir","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B44","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1038\/414799a","article-title":"Insulin signalling and the regulation of glucose and lipid metabolism","volume":"414","author":"Saltiel","year":"2001","journal-title":"Nature"},{"key":"B45","doi-asserted-by":"publisher","first-page":"14","DOI":"10.4103\/1735-5362.278711","article-title":"Synthesis and inhibitory activity of N-acetylpyrrolidine derivatives on \u03b1-glucosidase and \u03b1-amylase","volume":"15","author":"Sansenya","year":"2020","journal-title":"Res. Pharm. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/1873-3468.13666","article-title":"Glycogen storage disease type Ib: role of glucose-6- phosphate transporter in cell metabolism and function","volume":"594","author":"Sim","year":"2020","journal-title":"FEBS Lett."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s13205-022-03309-w","article-title":"Amelioration of hyperglycemia and hyperlipidemia in a high - fat diet - fed mice by supplementation of a developed optimized polyherbal formulation","volume":"12","author":"Sunil","year":"2022","journal-title":"3 Biotech."},{"key":"B48","doi-asserted-by":"publisher","first-page":"100804","DOI":"10.1016\/j.jaim.2023.100804","article-title":"Acute and sub-chronic toxicity of Liberin, an anti-diabetic polyherbal formulation in rats","volume":"14","author":"Suvarna","year":"2023","journal-title":"J. Ayurveda Integr. Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1007\/s00044-020-02607-3","article-title":"Anti-urease and cytotoxic activity of 1-Nitro-2-phenylethane and Nerolidol; two major compounds isolated from the seeds of Dennettia tripetala","volume":"29","author":"Ugheighele","year":"2020","journal-title":"Med. Chem. Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e001953","DOI":"10.1136\/bmjdrc-2020-001953","article-title":"Predictive utilities of lipid traits, lipoprotein subfractions and other risk factors for incident diabetes: a machine learning approach in the Diabetes Prevention Program","volume":"9","author":"Varga","year":"2021","journal-title":"BMJ Open Diabetes Res."},{"key":"B51","doi-asserted-by":"publisher","first-page":"111532","DOI":"10.1016\/j.biopha.2021.111532","article-title":"FTZ attenuates liver steatosis and fibrosis in the minipigs with type 2 diabetes by regulating the AMPK signaling pathway","volume":"138","author":"Wang","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"B52","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/s41392-023-01352-4","article-title":"Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus","volume":"8","author":"Wang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"B53","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s12902-019-0400-5","article-title":"Association of insulin, C-peptide and blood lipid patterns in patients with impaired glucose regulation","volume":"19","author":"Wang","year":"2019","journal-title":"BMC Endocr. Disord."},{"key":"B54","doi-asserted-by":"publisher","first-page":"115374","DOI":"10.1016\/j.bcp.2022.115374","article-title":"Activated AMPK mitigates diabetes-related cognitive dysfunction by inhibiting hippocampal ferroptosis","volume":"207","author":"Xie","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"2335","DOI":"10.1007\/s13300-018-0519-9","article-title":"Correlation between different stages of diabetic nephropathy and neuropathy in patients with T2DM: a cross-sectional controlled study","volume":"9","author":"Xu","year":"2018","journal-title":"Diabetes Ther."},{"key":"B56","doi-asserted-by":"publisher","first-page":"116732","DOI":"10.1016\/j.lfs.2019.116732","article-title":"Linderane protects pancreatic \u03b2 cells from streptozotocin (STZ) -induced oxidative damage","volume":"233","author":"Zhang","year":"2019","journal-title":"Life Sci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1570533\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T05:37:53Z","timestamp":1747201073000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1570533\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,14]]},"references-count":56,"alternative-id":["10.3389\/fphar.2025.1570533"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1570533","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,14]]},"article-number":"1570533"}}