Oleanolic acid induces a dual agonist action on PPARγ/α and GLUT4 translocation: A pentacyclic triterpene for dyslipidemia and type 2 diabetes

Loza-Rodríguez, Hilda; Estrada‐Soto, Samuel; Alarcón-Aguilar, Francisco Javier; Huang, Fengyang; Aquino‐Jarquín, Guillermo; Fortis-Barrera, Ángeles; Giacoman-Martínez, Abraham; Almanza-Perez, Julio César

doi:10.1016/j.ejphar.2020.173252

Cited by 40 publications

(24 citation statements)

References 43 publications

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“…Lipid metabolism disorders are closely related to the cardiovascular diseases and T2DM [20], and TC/HDL-C ratio is a reasonable blood lipid index in predicting the cardiovascular risk of T2DM patients.…”

Section: Discussionmentioning

confidence: 99%

Study on the Mechanism of Lupenone for Treating type 2 Diabetes by Integrating Pharmacological Evaluation and Network Pharmacology

Wang

et al. 2021

Preprint

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Background: Lupenone (LUP) is the active ingredient of Rhizoma Musae, which has good anti-diabetes effects, but the underlying mechanism is unclear. In this study, animal experiments combined with network pharmacology were used to explore the mechanism of LUP for treating diabetes. Methods: Type 2 diabetic rats with insulin resistance (IR) were induced by a high-fat diet and streptozotocin. the fasting blood glucose (FBG), index of oxidative stress, blood lipids, and IR-related targets in skeletal muscle and adipose were detected. a network pharmacology-based strategy was also adopted to clarify the mechanism of LUP for treating diabetes by improving IR. Results: LUP decreased the FBG levels and synthesis of glycogen, improved oxidative stress and lipid metabolism disorders, and increased the gene and protein expression of insulin receptor, insulin receptor substrate (IRS)-1, IRS-2, glucose transporter type 4 (GLUT-4) in skeletal muscle and peroxisome proliferator-activated receptor γ, IRS-1, IRS-2, GLUT-4 in adipose. Network pharmacology analysis revealed that LUP improves IR by multiple targets (like INS, TP53, TNF, SRC and ESR1) and signal pathways. Conclusion: These results suggested that the mechanism of LUP for treating diabetes is closely related to improving IR. LUP has the potential to develop as a new drug for the treatment of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Study on the Mechanism of Lupenone for Treating type 2 Diabetes by Integrating Pharmacological Evaluation and Network Pharmacology

Wang

et al. 2021

Preprint

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“…Twenty-four hours after compound 1 treatment revealed a similar decrease of glucose to that induced by metformin treated group, showing a significant decrease at 1, 3 and 8 days D r a f t 13 compared to vehicle group (p < 0.05). On the other hand, glucose measured 5 h after daily treatment significantly lowered glycemia in diabetic mice treated with compound 1 and metformin, which indicate its effectiveness in experimental diabetes treatment, i.e., it might be by insulin sensitization in tissues (Loza-Rodriguez et al, 2020;García-Díaz et al, 2016). It is important to mention that along the treatment, mice weight was monitored; however, we did not find any significant change between diabetic groups (data do not show).…”

Section: Sub-acute Antidiabetic Assaymentioning

confidence: 98%

“…Also, triglycerides and total cholesterol were significantly diminished by compound 1, while HDL and VLDL were not modified. The fact that compound 1 produced an important antidiabetic action could be attributable to inhibition of PTP-1B, and also to a possible increase in the expression of PPAR-, inducing insulin sensitization (Loza-Rodriguez et al, 2020;Thangavel et al, 2017). In this context, insulin action in adipose tissue involves the stimulation of glucose uptake and the inhibition of lipolysis, two processes classically considered to be the earliest defects detected in insulin resistance (Fernández-Veledo et al, 2008).…”

Section: Sub-acute Antidiabetic Assaymentioning

confidence: 99%

“…Therefore, there is a continuum interest to develop new drugs, focused on treatment of metabolic disorders such as T2D and dyslipidemia. In this regard, the pentacyclic triterpenic acids show plenty of biological activities, such as antidiabetic, antiinflammatory, antimicrobial, antiviral, cardioprotective, etc (Guzmán-Ávila et al, 2018;Liu, 2005; D r a f t 4 Loza- Rodriguez et al, 2020;Ramírez-Espinosa et al, 2011;Ramírez-Espinosa et al, 2013;Ramírez-Espinosa et al, 2014;Somova et al, 2003;Jung et al, 2007).…”

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confidence: 99%

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PPARα/γ, adiponectin, and GLUT4 overexpression induced by moronic acid methyl ester influenced glucose and triglyceride levels of experimental diabetic mice

Estrada‐Soto

Cerón-Romero

Navarrete‐Vázquez

et al. 2022

Can. J. Physiol. Pharmacol.

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The current study aimed to determine the antidiabetic and antidyslipidemic activities of moronic acid methyl ester (1) by in vivo, in vitro, in silico and molecular biology studies. Compound 1 was evaluated to establish its dose-dependent antidiabetic and antihyperglycemic (50 mg/kg) activities, in diabetic and normoglycemic male CD1 mice, respectively. Also, compound 1 was subjected to a sub-acute study (50 mg/kg/day for eight days) to determine blood biochemical profiles and the expression of PTP-1B, GLUT4, PPAR-α, PPAR-γ, adiponectin, IL-1β, and MCP1 in adipose tissue of animals after treatment. Different doses in acute administration of 1 decreased glycemia (p < 0.05), compared with vehicle, showing greater effectiveness in the range 50-160 mg/kg. Also, the oral glucose tolerance test (OGTT) showed that 1 induced a significant antihyperglycemic action by opposing the hyperglycemic peak (p < 0.05). Moreover, 1 subacute administration decrease glucose and triglycerides levels after treatment (p < 0.05); while the expression of PPAR-α and γ, adiponectin and GLUT4 displayed an increase (p< 0.05) compared with the diabetic control group. In conclusion, compound 1 showed antihyperglycemic, antidiabetic and antidyslipidemic effects in normal and diabetic mice, probably due to insulin sensitization through increase mRNA expression of GLUT4, PPAR-α, PPAR-γ and adiponectin genes.

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“…The dried stems of A. trifoliata have also been used in traditional Chinese medicine for antineoplastic activity, activating blood circulation, facilitating diuresis, and suppressing urinary stones and oligogalactia (ChPC, 2015) in China for hundreds of years [20] . Recently, phytochemical investigations have been conducted on the stem and fruit sections of this plant, which contain a variety of bioactive constituents; triterpenoids, phenolics, flavonoids, and lignans have been identified, and some exhibit important bioactivity properties, including antioxidant, antimicrobial, antitumor, and antidiabetic activities [21–24] . However, previous studies mainly concentrated on the α‐glucosidase inhibitory activity of A. trifoliata and its chemical constituents, but the mechanism of action underlying these effects remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Natural Triterpenoids Isolated from Akebia trifoliata Stem Explants Exert a Hypoglycemic Effect via α‐Glucosidase Inhibition and Glucose Uptake Stimulation in Insulin‐Resistant HepG2 Cells

Bian

Yang

Elango

et al. 2021

Chemistry & Biodiversity

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The inhibition of α‐glucosidase activity is a prospective approach to attenuate postprandial hyperglycemia in the treatment of type 2 diabetes mellitus (T2DM). Herein, the inhibition of α‐glucosidase by three compounds T1–T3 of Akebia trifoliata stem, namely hederagenin (T1), 3‐epiakebonoic acid (T2), and arjunolic acid (T3) were investigated using enzyme kinetics and molecular docking analysis. The three triterpenoids exhibited excellent inhibitory activities against α‐glucosidase. T1–T3 showed the strongest inhibition with IC50 values of 42.1±5.4, 19.6±3.2, and 11.2±2.3 μM, respectively, compared to the acarbose positive control (IC50=106.3±8.2). Enzyme inhibition kinetics showed that triterpenoids T1–T3 demonstrated competitive, mixed, and noncompetitive‐type inhibition against α‐glucosidase, respectively. The inhibition constant (Ki) values were 21.21, 7.70, and 3.18 μM, respectively. Docking analysis determined that the interaction of ligands T1–T3 and α‐glucosidase was mainly forced by hydrogen bonds and hydrophobic interactions, which could result in improved binding to the active site of the target enzyme. The insulin resistant (IR)‐HepG2 cell model used in this study (HepG2 cells exposed to 10−7 M insulin for 24 h) and glucose uptake assays showed that compounds T1–T3 had no cytotoxicity with concentrations ranging from 6.25 to 25 μM and displayed significant stimulation of glucose uptake in IR‐HepG2 cells. Thus, triterpenoids T1–T3 showed dual therapeutic effects of α‐glucosidase inhibition and glucose uptake stimulation and could be used as potential medicinal resources to investigate new antidiabetic agents for the prevention or treatment of diabetes.

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Oleanolic acid induces a dual agonist action on PPARγ/α and GLUT4 translocation: A pentacyclic triterpene for dyslipidemia and type 2 diabetes

Cited by 40 publications

References 43 publications

Study on the Mechanism of Lupenone for Treating type 2 Diabetes by Integrating Pharmacological Evaluation and Network Pharmacology

Study on the Mechanism of Lupenone for Treating type 2 Diabetes by Integrating Pharmacological Evaluation and Network Pharmacology

PPARα/γ, adiponectin, and GLUT4 overexpression induced by moronic acid methyl ester influenced glucose and triglyceride levels of experimental diabetic mice

Natural Triterpenoids Isolated from Akebia trifoliata Stem Explants Exert a Hypoglycemic Effect via α‐Glucosidase Inhibition and Glucose Uptake Stimulation in Insulin‐Resistant HepG2 Cells

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