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

Depending on the experimental setting, different studies demonstrated that AMPK is either dispensable, or can influence IFNγ production in T cells [33-35, 45-47]. While it is known that AMPK is dispensable for T cell development, AMPK deficiency has been shown to impair the generation of memory T cells [45]. By specific deletion of AMPK in T cells using a genetic approach, our studies reveal several important functions of AMPK in T cells. 3) AICAR and Compound C exert both AMPK-dependent and independent effects in T cells depending on different functional context. In the context of T cell early activation and cytokine production, both AICAR and Compound C inhibit these events independent of AMPK.

Thus, as a cell permeable nucleoside, AICAR has high therapeutic value for the treatment of PALI. Importantly, this study provides new insight into the mechanisms underlying the improvement of hepatic oxidative stress and inflammation in PALI by AICAR. AMPK activation promotes the nuclear accumulation of Nrf2, which partially mediates antioxidant effects and inhibits NLRP3 inflammasome activation and thus is important for AICAR protection against PALI (Figure 9). 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 conclusion, chronic AICAR treatment of rats for 14 successive days significantly increased NAMPT and PGC-1α protein expression levels in red and white gastrocnemius muscles. GLUT4 protein expression levels were also increased, and mitochondrial biogenesis was enhanced in skeletal muscles following AICAR treatment.

Phosphorylation analysis by intracellular staining

• The decrease in the distance traveled in the center by the animals treated with HFD indirectly indicates a higher level of anxiety compared to the animals kept on an STD.
• This indicates that JAK1/EGFR-MUC1 might form a positive feedback loop to promote tumour cell proliferation and survival.
• Long-term AICAR administration induced a considerable decrease in fasting plasma levels of insulin and glucose in this animal model for insulin resistance.
• Figure 5A–C shows increased oligonucleotide binding to stimulated nuclear extracts as compared to extracts prepared from untreated cells.

Moreover, Nrf2 deficiency dramatically weakened these beneficial effects of AICAR in L-arginine-induced PALI mice. Thus, AICAR protects against PALI at least in part through Nrf2-mediated antioxidant effects and inhibition of NLRP3 inflammasome activation. Skeletal muscle AMPK is known to be activated by exercise [10, 11]; secretory factors including leptin [12], adiponectin [13], interleukin-6 [14], and brain-derived neurotrophic factor [15]; and antidiabetic drugs [16, 17]. It is also activated by the adenosine analog 5-aminoimidazole-4-carboxamide-1-β-d-ribofranoside (AICAR); AICAR activation of AMPK stimulates glucose uptake and fatty acid oxidation in skeletal muscle cells [18]. AICAR treatment has also been found to enhance the expression of metabolic components, including glucose transporter 4 (GLUT4) and monocarboxylate transporters 1 and 4 proteins; increase hexokinase activity; and stimulate mitochondrial biogenesis in skeletal muscle [19–22]. Activation of AMPK has been linked to upregulated expression of metabolic regulators, such as silent information regulator of transcription 1 (SIRT1), peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), and nicotinamide phosphoribosyltransferase (NAMPT) [21, 23, 24].

Western blot

Our data showed that MUC1-CT is highly expressed, mainly localising at the cell membrane and cytoplasm (Fig. 2e). AICAR treatment dramatically decreased MUC1-CT expression in H441 cells, consistent with our western blot data (Fig. 2e). Previous studies showed that MUC1-CT could induce the expression of downstream targets, including connective tissue growth factor (CTGF/CCN2), enolase 1 (ENO1), and phosphoglucomutase 2 (PGM2) [84, 85]. To validate this, we performed a qRT-PCR analysis in H1975 cells and demonstrated decreased gene expression of CTGF, PGM2, and ENO1 treated with various doses of AICAR (Fig. 2f). These data suggest that AICAR treatment degrades MUC1/MUC1-CT protein and decreases gene transcription of MUC1 downstream targets. We designed our study so as to compare AICAR-induced metabolic alterations in red and white muscles.

This result suggests an increased degradation of adipose tissue and thus supports previous long-term AICAR experiments performed on lean rats demonstrating a reduction in intra-abdominal fat content (34). Even if a minor but barely detectable activation occurs, the decrease in fat mass is most likely ascribable to events taking place outside the adipose tissue, keeping the proposed antilipolytic effect of AICAR in mind (31). Instead, an increased rate of whole-body fatty acid oxidation (e.g., in liver and skeletal muscle) induced daily by AICAR injection could be a partial explanation for our findings. Also of note is that two previous studies on rat skeletal muscles have shown that acute AICAR exposure upregulates mRNA of uncoupling protein (UCP)-2 (40) and UCP-3 (40,41). Alternatively, our data on retroperitoneal and epididymal fat mass might reflect a simple redistribution of the adipose tissue with no quantitative change in total fat content. 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is an established pharmacological activator of AMP-activated protein kinase (AMPK).

The aim of the study was to investigate the effect of AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on the consequences of metabolic syndrome and type 2 diabetes induced by the consumption of a high-fat diet (HFD) in male C57Bl/6 mice. Additionally, the animals from group 6 were administered Methotrexate (MTX) at a dose of 1 mg/kg in parallel with AICAR, which slows down the metabolism of AICAR. The animals were recorded with signs of metabolic syndrome and type 2 diabetes mellitus by recording their body weights, glucose and insulin levels, and the calculating HOMA-IRs.

Mucin 1 (MUC1) is a transmembrane glycoprotein consisting of N-terminal alpha and C-terminal beta subunits (MUC1-CT) [22]. Previous studies have shown that the active subunit MUC1-CT is involved in tumorigenesis in lung and other cancers [23,24,25,26,27,28]. The protein–protein interaction study has demonstrated that epidermal growth factor receptor (EGFR) phosphorylates and activates MUC1-CT [29]. Upregulated MUC1-CT binds to and activates downstream effectors, such as signal transducer and activator of transcription 3 (STAT3), resulting in increased cell proliferation [30].

In Europe clinical trials, AICAR has been shown to help prevent cardiac ischemia after a heart attack. This product is for in vitro research use only and is not intended for use in humans or animals. Working concentrations and length of treatment can vary depending on the desired effect, but it is typically used at 0.5-2mM for 30 minutes-24 hours. Unpaired, two-tailed Student’s t test was Drostanolone costs performed for the comparison of results from different treatments. FA was responsible for designing the experiment, writing the protocol and report, conducting the search, screening potentially eligible studies, extracting and analysing data, interpreting results, and updating reference lists.

Methotrexate, a well-known cytostatic drug, inhibits purine de novo synthesis and potentiates the ability of exogenous AICAr to increase the level of ZMP by inhibiting AICART (Figure 3). Consequently, methotrexate enhances the ability of AICAr to activate AMPK and to inhibit the growth of human cancer cell lines [107], and promote glucose uptake and lipid oxidation in skeletal muscle [108]. No matter whether being AMPK-dependent or independent, metabolic effects of AICAr may be of relevance for the potential treatment of type 2 diabetes [41]. AICAr induces hypoglycemia in vivo [42,43] and the effect is abolished in mice lacking AMPK [32,33,35], suggesting that the effect can be more ascribed to AMPK-dependent entry of glucose than to AMPK-independent effects of AICAr on the inhibition of gluconeogenesis. In addition, AICAr may help to reduce peripheral resistance to insulin action because AICAr acts to reduce the storage of fatty acids in adipose tissue [37].