trans‐ferulic acid attenuates hyperglycemia‐induced oxidative stress and modulates glucose metabolism by activating AMPK signaling pathway in vitro

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) is a potent metabolic regulator and an attractive target for antidiabetic activators. Here we report for the first that, trans-ferulic acid (TFA) is a potent dietary bioactive molecule of hydroxycinnamic acid derivative for the activation of AMPK with a maximum increase in phosphorylation (2.71/2.67 ± 0.10; p < .001 vs. high glucose [HG] control) in hyperglycemia-induced human liver cells (HepG2) and rat skeletal muscle cells (L6), where HG suppresses the AMPK pathway. It was also observed that TFA increased activation of AMPK in a doseand time-dependent manner and also increased the phosphorylation of acetyl-CoA carboxylase (ACC), suggesting that it may promotes fatty acid oxidation; however, pretreatment with compound C reversed the effect. In addition, TFA reduced the level of intracellular reactive oxygen species (ROS) and nitric oxide (NO) induced by hyperglycemia and subsequently increased the level of glutathione. Interestingly, TFA also upregulated the glucose transporters, GLUT2 and GLUT4, and inhibited c-Jun N-terminal protein kinase (JNK1/2) by decreasing the phosphorylation level in tested cells under HG condition. Our studies provide critical insights into the mechanism of action of TFA as a potential natural activator of AMPK under hyperglycemia. Practical applicationsHydroxycinnamic acid derivatives possess various pharmacological properties and are found to be one of the most ubiquitous groups of plant metabolites in almost all dietary sources. However, the tissue-specific role and its mechanism under hyperglycemic condition remain largely unknown. The present study showed that TFA is a potent activator of AMPK under HG condition and it could be used as a therapeutic agent against hyperglycemia in type 2 diabetes.

Machine Learning-Based Analysis Reveals Triterpene Saponins and Their Aglycones in Cimicifuga racemosa as Critical Mediators of AMPK Activation

“…From the non-triterpene compounds, the cinnamic, benzoic, or fukiic acid derivatives were clearly classified as active. A literature search supported this classification for synaptic acid [ 36 ], P-coumaric acid [ 11 ], isoferulic acid [ 37 ], protocatechuic acid [ 37 ], and protocatechuic aldehyde [ 38 ]. Compounds such as cimiracemates, cimiphenones, cimifugic acid derivatives, and actealactone were likewise classified as active.…”

Anti-Hyperuricemic Effect of Anserine Based on the Gut–Kidney Axis: Integrated Analysis of Metagenomics and Metabolomics

“…D-gluconic acid has toxin-reducing and antioxidant abilities, wherein it can improve diabetic kidney tubular damage by inhibiting inositol oxygenase, preventing mitochondrial damage and apoptosis and reducing oxidative stress through the ascorbic acid and aldehyde metabolic pathway, thereby improving kidney function [ 38 ]. Moreover, ferulic acid has been shown to lighten oxidative stress through the activation of the AMPK signalling pathway in vitro [ 39 ]. Pipecolic acid is an intermediate in the lysine degradation pathway, with an enhanced lysine degradation pathway indicating enhanced levels of oxidative stress in the host [ 40 ].…”

New Insights on Dietary Polyphenols for the Management of Oxidative Stress and Neuroinflammation in Diabetic Retinopathy

“…Increased phosphorylation of AMPK, upregulation of GLUT2 and GLUT4, and inhibition of JNK1/2 activity. [128] HUVEC cells incubated in a hyperglycemic medium.…”

“…Hyperglycemia induces oxidative stress and decreases AMPK phosphorylation. Sigh and Patil [ 128 ] showed that trans-FA increased cellular phosphorylation of AMPK in cultured HepG2 and L6 cells exposed to high glucose in a time-dependent manner, besides causing upregulation of GLUT2 and GLUT4 and inhibition of JNK1/2 activity.…”