In this study, two high-content flavonoid derivatives [3–8 biapigenin (HM 104) and quercetin-3-O-β-d-galactopyranoside (HM 111)] were obtained through the bioactivity-guided isolation of antidiabetic compounds from Hypericum monogynum flowers. HM 104 and HM 111 exhibited good glucose consumption in fatty acid-induced insulin-resistant HepG2 cells. Moreover, both active compounds enhanced glucose uptake by restoring the expression of key regulators of glucose metabolism, including insulin receptor substrate 1, phosphoinositide 3-kinase, protein kinase B, and glucose transporter type 4, and by mitigating the expression of forkhead box O1 and the factors involved in gluconeogenesis. They upregulate the phosphorylation of glycogen synthase kinase-3β, which may affect glycogen synthesis. Furthermore, the production of reactive oxygen species was decreased by the two compounds. This study provides novel mechanistic insights into the protective effects of flavonoid derivatives isolated from H. monogynum flowers in preventing and managing insulin resistance and associated metabolic disorders.
Get full access to this article
View all access options for this article.
References
1.
TangvarasittichaiS. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes, 2015; 6(3):456–480; doi: 10.4239/wjd.v6.i3.456
2.
TönniesT, RathmannW, HoyerA, et al.Quantifying the underestimation of projected global diabetes prevalence by the International Diabetes Federation (IDF) Diabetes Atlas. BMJ Open Diabetes Res Care, 2021; 9(1):e002122; doi: 10.1136/bmjdrc-2021-002122
3.
JugranAK, RawatS, DevkotaHP, et al.Diabetes and plant‐derived natural products: From ethnopharmacological approaches to their potential for modern drug discovery and development. Phytother Res, 2021; 35(1):223–245; doi: 10.1002/ptr.6821
4.
BaileyCJ, FlattPR, ConlonJM. An update on peptide-based therapies for type 2 diabetes and obesity. Peptides, 2023; 161:170939; doi: 10.1016/j.peptides.2023.170939
5.
HulettNA, ScalzoRL, ReuschJE. Glucose uptake by skeletal muscle within the contexts of type 2 diabetes and exercise: An integrated approach. Nutrients, 2022; 14(3):647; doi: 10.3390/nu14030647
6.
GerichJE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: Therapeutic implications. Diabet Med, 2010; 27(2):136–142; doi: 10.1111/j.1464-5491.2009.02894.x
7.
HattingM, TavaresCD, SharabiK, et al.Insulin regulation of gluconeogenesis. Annals of the New York Academy of Sciences, 2018; 1411(1):21–35; doi: 10.1111/nyas.13435
8.
GuoX, LiH, XuH, et al.Glycolysis in the control of blood glucose homeostasis. Acta Pharmaceutica Sinica B, 2012; 2(4):358–367; doi: 10.1016/j.apsb.2012.06.002
9.
KeaneKN, CruzatVF, CarlessiR, et al.Molecular events linking oxidative stress and inflammation to insulin resistance and β-cell dysfunction. Oxid Med Cell Longev, 2015; 2015(1):181643; doi: 10.1155/2015/181643
10.
NewsholmeP, HaberE, HirabaraS, et al.Diabetes associated cell stress and dysfunction: Role of mitochondrial and non‐mitochondrial ROS production and activity. J Physiol, 2007; 583(Pt 1):9–24; doi: 10.1113/jphysiol.2007.135871
11.
AliMY, ZaibS, RahmanMM, et al.Didymin, a dietary citrus flavonoid exhibits anti-diabetic complications and promotes glucose uptake through the activation of PI3K/Akt signaling pathway in insulin-resistant HepG2 cells. Chem Biol Interact, 2019; 305:180–194; doi: 10.1016/j.cbi.2019.03.018
12.
LiuH, GuanH, TanX, et al.Enhanced alleviation of insulin resistance via the IRS-1/Akt/FOXO1 pathway by combining quercetin and EGCG and involving miR-27a-3p and miR-96–5p. Free Radic Biol Med, 2022; 181:105–117; doi: 10.1016/j.freeradibiomed.2022.02.002
13.
WangK, WangH, LiuY, et al.Dendrobium officinale polysaccharide attenuates type 2 diabetes mellitus via the regulation of PI3K/Akt-mediated glycogen synthesis and glucose metabolism. Journal of Functional Foods, 2018; 40:261–271; doi: 10.1016/j.jff.2017.11.004
14.
WatsonRT, PessinJE. Bridging the GAP between insulin signaling and GLUT4 translocation. Trends Biochem Sci, 2006; 31(4):215–222; doi: 10.1016/j.tibs.2006.02.007
15.
KloverPJ, MooneyRA. Hepatocytes: Critical for glucose homeostasis. Int J Biochem Cell Biol, 2004; 36(5):753–758; doi: 10.1016/j.biocel.2003.10.002
16.
BechmannLP, HannivoortRA, GerkenG, et al.The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol, 2012; 56(4):952–964; doi: 10.1016/j.jhep.2011.08.025
17.
ChabowskiA, Żendzian‐PiotrowskaM, KonstantynowiczK, et al.Fatty acid transporters involved in the palmitate and oleate induced insulin resistance in primary rat hepatocytes. Acta Physiol (Oxf), 2013; 207(2):346–357; doi: 10.1111/apha.12022
18.
BodenG, ShulmanG. Free fatty acids in obesity and type 2 diabetes: Defining their role in the development of insulin resistance and β‐cell dysfunction. Eur J Clin Invest, 2002; 32 (Suppl 3):14–23; doi: 10.1046/j.1365-2362.32.s3.3.x
19.
LiYN, ZengYR, YangJ, et al.Chemical constituents from the flowers of Hypericum monogynum L. with COX-2 inhibitory activity. Phytochemistry, 2022; 193:112970; doi: 10.1016/j.phytochem.2021.112970
20.
XuWJ, ZhuMD, WangXB, et al.Hypermongones A–J, rare methylated polycyclic polyprenylated acylphloroglucinols from the flowers of Hypericum monogynum. J Nat Prod, 2015; 78(5):1093–1100; doi: 10.1021/acs.jnatprod.5b00066
21.
ZengYR, LiYN, ZhangZZ, et al.Hypermoins A–D: Rearranged nor-polyprenylated acylphloroglucinols from the flowers of Hypericum monogynum. J Org Chem, 2021; 86(10):7021–7027; doi: 10.1021/acs.joc.0c02880
22.
ZengYR, WangLP, HuZX, et al.Chromanopyrones and a flavone from Hypericum monogynum. Fitoterapia, 2018; 125:59–64; doi: 10.1016/j.fitote.2017.12.013
23.
MoraisFS, CanutoKM, RibeiroPR, et al.Chemical profiling of secondary metabolites from Himatanthus drasticus (Mart.) Plumel latex with inhibitory action against the enzymes α-amylase and α-glucosidase: In vitro and in silico assays. J Ethnopharmacol, 2020; 253:112644; doi: 10.1016/j.jep.2020.112644
24.
LinlanT, ShuangyuX, ZhangZ, et al.Bioassay-guided isolation of α-Glucosidase inhibitory constituents from Hypericum sampsonii. Chin J Nat Med, 2023; 21(6):443–453; doi: 10.1016/S1875-5364(23)60472-8
25.
WobserH, DornC, WeissTS, et al.Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells. Cell Res, 2009; 19(8):996–1005; doi: 10.1038/cr.2009.73
26.
LiS, WangC, WangM, et al.Antidepressant like effects of piperine in chronic mild stress treated mice and its possible mechanisms. Life Sci, 2007; 80(15):1373–1381; doi: 10.1016/j.lfs.2006.12.027
27.
JiangL, NumonovS, BobakulovK, et al.Phytochemical profiling and evaluation of pharmacological activities of Hypericum scabrum L. Molecules, 2015; 20(6):11257–11271; doi: 10.3390/molecules200611257
28.
CongF, JoshiKR, DevkotaHP, et al.Dhasingreoside: New flavonoid from the stems and leaves of Gaultheria fragrantissima. Nat Prod Res, 2015; 29(15):1442–1448; doi: 10.1080/14786419.2014.1003932
29.
FuM, ShenW, GaoW, et al.Essential moieties of myricetins, quercetins and catechins for binding and inhibitory activity against α-Glucosidase. Bioorg Chem, 2021; 115:105235; doi: 10.1016/j.bioorg.2021.105235
30.
HsinKY, GhoshS, KitanoH. Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology. PLoS One, 2013; 8(12):e83922; doi: 10.1371/journal.pone.0083922
31.
MannaP, AchariAE, JainSK. 1, 25 (OH) 2-vitamin D 3 upregulates glucose uptake mediated by SIRT1/IRS1/GLUT4 signaling cascade in C2C12 myotubes. Mol Cell Biochem, 2018; 444(1–2):103–108; doi: 10.1007/s11010-017-3235-2
32.
WangJ, WuT, FangL, et al.Anti-diabetic effect by walnut (Juglans mandshurica Maxim.)-derived peptide LPLLR through inhibiting α-glucosidase and α-amylase, and alleviating insulin resistance of hepatic HepG2 cells. J Functional Foods, 2020; 69:103944; doi: 10.1016/j.jff.2020.103944
33.
LiY, TangY, ShiS, et al.Tetrahedral framework nucleic acids ameliorate insulin resistance in type 2 diabetes mellitus via the PI3K/Akt pathway. ACS Appl Mater Interfaces, 2021; 13(34):40354–40364; doi: 10.1021/acsami.1c11468
34.
ZhangY, YanLS, DingY, et al.Edgeworthia gardneri (Wall.) Meisn. Water extract ameliorates palmitate induced insulin resistance by regulating IRS1/GSK3β/FoxO1 signaling pathway in human HepG2 hepatocytes. Front Pharmacol, 2019; 10:1666; doi: 10.3389/fphar.2019.01666
35.
RenZ, XieZ, CaoD, et al.C-Phycocyanin inhibits hepatic gluconeogenesis and increases glycogen synthesis via activating Akt and AMPK in insulin resistance hepatocytes. Food Funct, 2018; 9(5):2829–2839; doi: 10.1039/C8FO00257F
36.
SatoT, WatanabeY, NishimuraY, et al.Acute fructose intake suppresses fasting-induced hepatic gluconeogenesis through the AKT-FoxO1 pathway. Biochem Biophys Rep, 2019; 18:100638; doi: 10.1016/j.bbrep.2019.100638
37.
XingYQ, LiA, YangY, et al.The regulation of FOXO1 and its role in disease progression. Life Sci, 2018; 193:124–131; doi: 10.1016/j.lfs.2017.11.030
38.
LiZ, LaiZW, ChristianoR, et al.Global analyses of selective insulin resistance in hepatocytes caused by palmitate lipotoxicity. Mol Cell Proteomics, 2018; 17(5):836–849; doi: 10.1074/mcp.RA117.000560
39.
RodgersJT, PuigserverP. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A, 2007; 104(31):12861–12866; doi: 10.1073/pnas.0702509104
40.
MaZ, LiuH, WangW, et al.Paeoniflorin suppresses lipid accumulation and alleviates insulin resistance by regulating the Rho kinase/IRS-1 pathway in palmitate-induced HepG2Cells. Biomed Pharmacother, 2017; 90:361–367; doi: 10.1016/j.biopha.2017.03.087
41.
Cichoż-LachH, MichalakA. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol, 2014; 20(25):8082–8091; doi: 10.3748/wjg.v20.i25.8082
42.
ZhangY, KhanM, YuanT, et al.Preparation and characterization of D. opposita Thunb polysaccharide-zinc inclusion complex and evaluation of anti-diabetic activities. Int J Biol Macromol, 2019; 121:1029–1036; doi: 10.1016/j.ijbiomac.2018.10.068
43.
HermanMA, KahnBB. Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony. J Clin Invest, 2006; 116(7):1767–1775; doi: 10.1172/JCI29027
OrmazabalV, NairS, ElfekyO, et al.Association between insulin resistance and the development of cardiovascular disease. Cardiovasc Diabetol, 2018; 17(1):122; doi: 10.1186/s12933-018-0762-4
46.
GuptaP, TaiyabA, HassanMI. Emerging role of protein kinases in diabetes mellitus: From mechanism to therapy. Adv Protein Chem Struct Biol, 2021; 124:47–85; doi: 10.1016/bs.apcsb.2020.11.001
47.
WuJ, ChenM, ShiS, et al.Hypoglycemic effect and mechanism of a pectic polysaccharide with hexenuronic acid from the fruits of Ficus pumila L. in C57BL/KsJ db/db mice. Carbohydr Polym, 2017; 178:209–220; doi: 10.1016/j.carbpol.2017.09.050
48.
FranciniF, SchinellaGR, RíosJL. Activation of AMPK by medicinal plants and natural products: Its role in type 2 diabetes mellitus. Mini Rev Med Chem, 2019; 19(11):880–901; doi: 10.2174/1389557519666181128120726
49.
GrossD, Van Den HeuvelA, BirnbaumM. The role of FoxO in the regulation of metabolism. Oncogene, 2008; 27(16):2320–2336; doi: 10.1038/onc.2008.25
50.
FridlyandL, PhilipsonL. Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes Obes Metab, 2006; 8(2):136–145; doi: 10.1111/j.1463-1326.2005.00496.x
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
