Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity

Abstract

Ferulic acid, a bacterial metabolite of anthocyanins, seems likely to be a primary mediator of the health benefits associated with anthocyanin-rich diets, and has long been employed in Chinese cardiovascular medicine. In rodent studies, it has exerted wide-ranging antioxidant and anti-inflammatory effects, the molecular basis of which remains rather obscure. However, recent studies indicate that physiologically relevant concentrations of ferulic acid can boost expression of Sirt1 at mRNA and protein levels in a range of tissues. Sirt1, a class III deacetylase, functions to detect a paucity of oxidisable substrate, and in response works in various ways to promote cellular survival and healthful longevity. Sirt1 promotes ‘cell cleansing’ and cell survival by boosting autophagy, mitophagy, mitochondrial biogenesis, phase 2 induction of antioxidant enzymes via Nrf2, and DNA repair—while inhibiting NF-kB-driven inflammation, apoptosis, and cellular senescence, and boosting endothelial expression of the protective transcription factor kruppel-like factor 2. A deficit of the latter appears to mediate the endothelial toxicity of the SARS-CoV-2 spike protein. Ferulic acid also enhances the activation of AMP-activated kinase (AMPK) by increasing expression and activity of its activating kinase LKB1—whereas AMPK in turn amplifies Sirt1 activity by promoting induction of nicotinamide phosphoribosyltranferase, rate-limiting for generation of Sirt1’s obligate substrate NAD+. Curiously, AMPK acts by independent mechanisms to potentiate many of the effects mediated by Sirt1. Hence, it is proposed that ferulic acid may exert complementary or synergistic health-promoting effects when used in conjunction with clinically useful AMPK activators, such as the nutraceutical berberine. Additional nutraceuticals which might have potential for amplifying certain protective effects of ferulic acid/berberine are also discussed.

Integrating experimental model, LC-MS/MS chemical analysis, and systems biology approach to investigate the possible antidiabetic effect and mechanisms of Matricaria aurea (Golden Chamomile) in type 2 diabetes mellitus

“…Moreover, AMPK increases fatty acid oxidation in the liver and decreases de novo fatty acid synthesis, cholesterol synthesis, and lipogenesis by inhibiting sterol regulatory element binding protein 1c (SREBF1), HMG CoA reductase (HMGCR), and Acetyl-coA carboxylase (ACACA). In agreement with our proposal, previous studies have shown that MA ingredients, including Apigenin, luteolin, quercetin, ferulic acid, chlorogenic acid, isoorientin, naringenin, and resveratrol, ameliorate hyperglycemia and hyperlipidemia through activation of the AMPK signaling pathway and SIRT1 ( Ong et al, 2012 ; Jin et al, 2015 ; Tsai et al, 2018 ; Joshi et al, 2019 ; DiNicolantonio et al, 2022 ). Our network analysis also revealed an increase in adiponectin and leptin production, which may activate AMPK signaling.…”

Heterozygous Loss of KRIT1 in Mice Affects Metabolic Functions of the Liver, Promoting Hepatic Oxidative and Glycative Stress

“…In this regard, it is noteworthy that both mTOR activation and FoxO1 inhibition were originally linked to loss of KRIT1 function and shown to be associated with increased cellular ROS levels and susceptibility to oxidative stress via downregulation of autophagy and antioxidant defenses [ 15 , 19 ]. On the other hand, both AMPK and Sirt1 are known to play a positive role in the maintenance of cellular homeostasis and antioxidant defenses by opposing the actions of the Akt/mTOR pathway and promoting autophagy [ 95 , 99 , 100 ]. However, while AMPK and Sirt1 cooperate in orchestrating FoxO1-mediated compensatory responses to transient metabolic and oxidative stress for the maintenance of cell functions, these responses may result in inefficiency in chronic stress conditions.…”

Preclinical findings: The pharmacological targets and molecular mechanisms of ferulic acid treatment for COVID-19 and osteosarcoma via targeting autophagy

“…Moreover, the GO and KEGG enrichment assays revealed that biological processes were distinctly enriched in the positive regulation of tumor necrosis factor production, particularly the positive regulation of tumor necrosis factor superfamily cytokine production. More data have suggested that ferulic acid might inhibit autophagy-dependent cell proliferation in cancers ( 32 ) as well as inflammation-related SARS-CoV-2 infection ( 33 ). Following the use of the molecular docking analysis, we ultimately identified the core ferulic acid target proteins against OS and COVID-19, namely, STAT3, MAPK1, and PIK3R1.…”