Novel Protein Tyrosine Phosphatase 1B Inhibitor-Geranylated Flavonoid from Mulberry Leaves Ameliorates Insulin Resistance

Abstract

Mulberry leaf is a common vegetable with a variety of beneficial effects, such as hypoglycemic activity. However, the underlying mechanism of its hypoglycemic effect have not been fully revealed. In this study, two flavonoid derivatives were isolated from mulberry leaves, a new geranylated flavonoid compound (1) and its structural analogue (2). The structures of compounds 1 and 2 were elucidated using spectroscopic analysis. To study the potential hypoglycemic properties of these compounds, their regulatory effects on protein tyrosine phosphatase 1B (PTP1B) were investigated. In comparison to oleanolic acid, compounds 1 and 2 showed significant inhibitory activities (IC 50 = 4.53 ± 0.31 and 10.53 ± 1.76 μM) against PTP1B, the positive control (IC 50 = 7.94 ± 0.76 μM). Molecular docking predicted the binding sites of compound 1 to PTP1B. In insulin-resistance HepG2 cell, compound 1 promoted glucose consumption in a dose-dependent manner. Furthermore, western blot and polymerase chain reaction analyses indicated that compound 1 might regulate glucose consumption through the PTP1B/IRS/PI3K/AKT pathway. In conclusion, geranylated flavonoids in mulberry leaves inhibite PTP1B and increase the glucose consumption in insulin-resistant cells. These findings provide an important basis for the use of mulberry leaf flavonoids as a dietary supplement to regulate glucose metabolism.

Ferulic Acid Ameliorates Hepatic Inflammation and Fibrotic Liver Injury by Inhibiting PTP1B Activity and Subsequent Promoting AMPK Phosphorylation

“…Interestingly, FA had no effect on PTP1B expression in hepatocytes, macrophages as well as HSCs, with or without the presence of different model drugs ( Supplementary Figures S5A–E ). Lines of evidence indicated that PTP1B dephosphorylated multiple protein kinases and caused the modulation of multiple signaling pathways ( Niu et al, 2020 ). Given that the regulatory effects of PTP1B on AMPK activation were not only affected by its expression but also relied on its phosphatase activity, FA might mediate AMPK phosphorylation through the regulation of PTP1B activity.…”

“…There are several critical amino acid residues (Arg221, Ala217, Asp 48, Asp181, Gly183, Gly220, Lys116, Phe182 and Tyr46) of PTP1B were found to directly interact with potential inhibitors isolated from natural products (Jung et al, 2017;Sharma et al, 2020;Hu et al, 2021). Notably, Arg221 exerts an important function in optimizing salt bridge interactions with the phosphate bound to the catalytic site and stabilizing the phosphoryl-enzyme intermediator (Niu et al, 2020). Here we reported that Arg221 might play a vital role in the inhibition of PTP1B by FA.…”

Potential Molecular Targets of Oleanolic Acid in Insulin Resistance and Underlying Oxidative Stress: A Systematic Review

“…In addition, ROS-induced activation of the NF-кB pathway in skeletal muscle of HFD-fed mice has been associated with increased expression of PTP1B [ 55 ], a negative regulator of insulin signaling [ 56 ]. In this line, the transfection with PTP1B to HepG2 cells by Niu et al [ 57 ] decreased the transcription of IRS1 and GLUT4. Considering that several authors have previously reported inhibitory activities of OA and its derivatives on PTP1B [ 56 , 58 , 59 , 60 ], one of the possible mechanisms by which OA improves insulin sensitivity could be through inhibiting PTP1B.…”

Nineteen New Flavanol–Fatty Alcohol Hybrids with α-Glucosidase and PTP1B Dual Inhibition: One Unusual Type of Antidiabetic Constituent from Amomum tsao-ko

“…In the ROESY spectra, correlations of H-13 with H-11 and H-2 supported the 11β-H and 13β-H in 10; correlations of H-11 with H 2 -14 and H-13 with H-2′/6′ indicated the 11β-H and 13α-H in 11; correlations of H-11/H-13 and H-13/H-2′(6′) verified the 11α-H and 13α-H in 12; correlations of H-11 with H 2 -14 and H-13 with H-2 suggested the 11α-H and 13β-H in 13. Thus, the structures of 10−13 were deduced and named as tsaokoflavanol J (10), tsaokoflavanol K (11), tsaokoflavanol L ( 12), and tsaokoflavanol M (13), respectively.…”

“…According to the mode of action, the currently used oral hypoglycemic drugs are mainly classified as biguanides, α-glucosidase inhibitors, insulin secretagogues, insulin sensitizers, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. ,− Among them, α-glucosidase inhibitors, for example, acarbose, miglitol, and voglibose, are considered promising antidiabetic drugs that can be used alone or in combination with other types of drugs, whereas the undesirable gastrointestinal side effects and weight gain are inevitable . It is well accepted that protein tyrosine phosphatase 1B (PTP1B) plays a key role in negatively regulating insulin action by dephosphorylation of activated insulin receptors and downstream substrate proteins, and thus, PTP1B inhibitors are fascinating candidates for developing antidiabetic agents. − However, the clinical use of PTP1B inhibitors is severely impeded by their poor membrane permeability and weak selectivity against T-cell protein tyrosine phosphatase (TCPTP), the most similar protein to PTP1B . Therefore, compounds with α-glucosidase and/or PTP1B inhibitory effects will provide valuable clues in searching for new antidiabetic candidates.…”