Cells Free Full-Text AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review

AMPK-independent regulation of macrophage pro- vs. anti-inflammatory transcriptional responses by AICAR is not limited to NFκB-mediated transcription, but also extends to the cytokine-responsive transcription factor STAT3. Fresh pancreatic and liver tissues and blood samples were collected for biochemical analysis. The levels of serum amylase and lipase were measured by assay kit (C , A , Nanjing Jiancheng Bioengineering Institute, Nanjing, China) to evaluate the degree of pancreatitis. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured with commercial kit (C , C , Nanjing Jiancheng Bioengineering Institute, Nanjing, China) to evaluate the degree of liver injury and function. The contents of malondialdehyde (MDA) and superoxide dismutase (SOD) in pancreas and liver homogenate were determined with commercial kit (A , A , Nanjing Jiancheng Bioengineering Institute, Nanjing, China).

3. Insulin Resistance Test

This is consistent with a previous study in breast cancer demonstrating that p-EGFR activates MUC1 by phosphorylating MUC1 [29]. This indicates that JAK1/EGFR-MUC1 might form a positive feedback loop to promote tumour cell proliferation and survival. Our current and previous findings indicate that AICAR prevents transcriptional activation by LPS or ER stress inducers without altering upstream signaling20. We considered that AICAR may interfere with a general component of the transcriptional activation machinery independently of the nature of a distinct transcription factor and activation stimulus.

9. Organ Weight

• Since then, the compound that has been widely used as an AMPK-agonist was an exogenous dephosphorylated AICA riboside that should be properly abbreviated AICAr.
• AMPK-independent regulation of macrophage pro- vs. anti-inflammatory transcriptional responses by AICAR is not limited to NFκB-mediated transcription, but also extends to the cytokine-responsive transcription factor STAT3.
• It plays an important role in various biological processes via its interactions with and deacetylation of many transcriptional regulators, such as forkhead transcription factor (FOXO) [25], p53 [26], nuclear factor-κB (NF-κB) [27], and PGC-1α [28].
• We conclude that because AICAR is already used in the clinic, the development of novel therapies using AICAR to promote AMPK phosphorylation is promising for future medical interventions of PALI.
• In this follow-up study, we further investigated the effects of AICAR/Compound C treatment on T cell responses.
• In Netherlands clinical trials, AICAR has been shown to help prevent cardiac ischemia after a heart attack.

VX-509 (Lot #S754101, Cat #S7541), ABT-702 (Cat #S6619), and osimertinib (Cat #S7297) were purchased from Selleck Chemicals. Pierce protease and phosphatase inhibitor mini tablets (Lot #WD319834, Cat #A32959) were from Thermo Fisher Scientific and utilised for protein extraction. Macrophages were treated with 100 ng/ml LPS and 1 mM AICAR and labelled with 5 µM 2′,7′-dichlorodihydrofluorescein diacetate (Thermo Fisher Scientific) for the last 20 min of LPS treatment. Median fluorescence intensity (MFI) of the FITC channel was recorded on a LSRII/Fortessa flow cytometer.

AICAR was tested in several clinical trials aiming to use it as an adenosine mimetic to ameliorate ischemia-reperfusion damage following coronary bypass surgery36. Our data point to potent anti-inflammatory effects of AICAR in combination with adenosine kinase inhibition. Although it is unlikely that this application of AICAR will find its way to the clinic, a mechanistic understanding how AICAR interferes with pro-inflammatory transcriptional activation may guide attempts to structurally alter this molecule to create optimized anti-inflammatory drugs. Pancreatic and liver tissues were collected, fixed immediately in 4% paraformaldehyde for 24 h, dehydrated in a graded ethanol series, and then embedded in paraffin.

AICAr as an “Exercise in a Pill”

However, treatment with either AICAR or Compound C inhibited cytokine production irrespective of AMPK expression in T cells (middle and right panels, Figure S5). Furthermore, we measured cytokine production in supernatants collected from anti-CD3/CD28-activated T cells and demonstrated that both Compound C and AICAR inhibited levels of IL-2, Testosterone cypionate original IFNγ and TNFα regardless of AMPK expression (Figure ​(Figure5).5). Thus, our data indicate that, although AMPK is critical in promoting cytokine production in Ca2+- and TCR-activated T cells, the cytokine-inhibitory effects of AICAR/Compound C on T cells are independent of AMPK. Although AICAR/Compound C have been commonly used as an agonist/antagonist of AMPK, respectively, whether or not they are able to activate/inhibit AMPK in T cells remains unclear [18, 30, 34].