AICAR Improves Outcomes of Metabolic Syndrome and Type 2 Diabetes Induced by High-Fat Diet in C57Bl 6 Male Mice PMC

AICAR has also been suggested by researchers to have anti-inflammatory potential and may improve physical performance in certain experimental models. To explain the broad effect of AICAR on transcriptional activation we considered the interaction with general component of the transcription machinery. However, this is unlikely to be the case, since STAT6-dependent and HIF-evoked gene expression remained unaltered in AICAR-treated cells. AICAR also did not affect elevation of PPARγ mRNA expression during monocyte to macrophage differentiation19.

• Recent studies have revealed some of the metabolic changes observed due to exercise training can be stimulated pharmacologically (22, 30).
• Total number of tubule formations per frame was assessed at 40× optical zoom with a digital inverted compound microscope and ImageJ analysis software (National Institutes of Health, Bethesda, MD).
• Thus, as a cell permeable nucleoside, AICAR has high therapeutic value for the treatment of PALI.
• Additionally, heart rate was analyzed over the hour period from the arterial pressure measurements using LabChart 7.0.

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

In general, it can be concluded that AICAR, administered starting from the seventh week of the study, contributes to the reduction in absolute body weight and weight gain in animals receiving HFD. Before the mode of action via AMPK was appreciated, AICAr-mediated protection of myocardium was ascribed only to the effects of adenosine on vasodilation and inhibition of platelet aggregation and neutrophil activation [13,54]. Later studies provided the link between the activation of AMPK and AICAr-mediated effects on glucose and glycogen metabolism in heart muscle [30,55]. Having shown transcription factor-specific inhibition of transcriptional activation by AICAR, we questioned the ability of AICAR to interfere with binding of transcription factors to DNA using electrophoretic mobility shift (EMSA) assays. Nuclear extracts were prepared from macrophages stimulated with LPS, IL-6 or cultured under hypoxia to achieve nuclear accumulation of NFκB, STAT3, or HIF1α, respectively. Subsequently, nuclear extracts were incubated with oligonucleotides containing NFκB, STAT3 and HIF1-binding sequences in the presence or absence of AICAR.

9. Organ Weight

In 2012, the RED-CABG trial was stopped early after interim data failed to indicate a reduction in morbidity or mortality among intermediate- to high-risk patients receiving AICAr versus placebo [15]. In 1995, 5-amino-4-imidazolecarboxamide (AICA) ribonucleoside or riboside was first proposed to be used as the activator of AMP-kinase (AMPK) in intact cells or, in other words, to play the same role that phorbol esters had in dissecting signaling pathways regulated by protein kinase C [1]. 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. However, in more than 1700 articles that can be retrieved from PubMed on AMPK and AICA riboside, AICAr is often abbreviated as AICAR, although the AICAR acronym should be reserved for AICA ribotide or the phosphorylated form that is a physiological, endogenous precursor in de novo purine synthesis [4]. The nomenclature is additionally complicated because the other name used for the endogenous substance or AICAR is ZMP [5]. Moreover, the search of the literature reveals the common use of acadesine instead of AICAr [4,6,7,8,9,10,11,12,13,14,15,16,17,18,19].

Immunoprecipitated DNA was recovered using PCR purification kit (Qiagen) and analysed using quantitative PCR. Primers corresponding to human IFNβ promoter (5′-GGGAGAAGTGAAAGTGGGAAA-3′, 5′-CAGGAGAGCAATTTGGAGGA-3′) or IκB (5′-GACGACCCCAATTCAAATCG-3′, 5′-TCAGGCTCGGGGAATTTCC-3′) and IL-8 promoters (5′-GTTGTAGTATGCCCCTAAGAG-3′, 5′-GCCTTTGCATATATCAGACAG-3′) were used for analysis. Although AICAR did not influence nuclear RelA accumulation in response to LPS, it blocked RelA binding to cognate DNA elements of LPS-induced genes as proven by ChIP assays. This may be sufficient to prevent transcriptional activation, since NFκB activation is a critical event during LPS transcriptional responses for most of its target genes25. AICAR has been used safely in human studies up to concentrations of 25 mg/kg with minimal side effects [8]. AICAR may provide mild side effects at the recommended dosages of 50 mg per day, however, extreme overdose of AICAR can be dangerous since it can affect blood flow to the heart.

IL-4 predominantly acts via signal transducer and activator of transcription 6 (STAT6) transcription factor, while IL-6 and IL-10 induce target gene expression through STAT3. HIF1α can be pharmacologically activated by the prolyl hydroxylase inhibitor dimethyloxalylglycine Clomid 50 mg Hubei Huangshi Nanshang (DMOG). Since activated AMPK attenuates STAT3-dependent transcription induced by IL-6 or IL-49,29, we blocked AICAR conversion to ZMP using ABT-702. Figure 4 shows that the ability of AICAR to inhibit activation of gene expression is stimulus-dependent.

In 2003, Campas et al. reported that AICAr activates AMPK and induces apoptosis in primary samples of B-cell chronic lymphocytic leukemia (CLL) in vitro [11]. Two years later, an epidemiological study revealed that metformin, another AMPK activator had a protective role in the development of cancer, and thus, invigorated interest in the possible use of AMPK agonists in the treatment of cancer [109]. In the meantime, many other studies described the beneficial effects of AICAr, especially in hematological malignancies, and most of these effects turned out to be AMPK-independent.