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

AICAR has been also reported to increase angiogenesis and vascularization by inducing VEGFa expression in a fashion similar to exercise [32], although not necessarily acting through AMPK activation, rather via independent, alternative, and still unclear mechanisms [33]. When AICAR is present, it stimulates AMPK even without the cells experiencing an actual Trenbolone tablets buy in USA energy deficit. Activation of AMPK leads to increased uptake and utilization of glucose by muscles, enhances fat oxidation, and stimulates the production of mitochondrial enzymes. Metformin is a compound that belongs to the biguanidine class, commonly used in clinical treatment as an anti-diabetic drug.

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]. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr) has been one of the most commonly used pharmacological modulators of AMPK activity. The majority of early studies on the role of AMPK, both in the physiological regulation of metabolism and in cancer pathogenesis, were based solely on the use of AICAr as an AMPK-activator. Even with more complex models of AMPK downregulation and knockout being introduced, AICAr remained a regular starting point for many studies focusing on AMPK biology. However, there is an increasing number of studies showing that numerous AICAr effects, previously attributed to AMPK activation, are in fact AMPK-independent. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is an intermediate in the generation of inosine monophosphate and analog of adenosine monophosphate (AMP) that is capable of stimulating AMP-dependent protein kinase (AMPK) activity.

The AMP-activated protein kinase is an enzyme and a protein that may play a regulatory role in several metabolic pathways. Its expression has been observed in several tissues, including the skeletal muscles, liver, and brain. In all these tissues, it is considered to exert a potential net effect on lipogenesis and may inhibit cholesterol synthesis and ketogenesis. It may also modulate insulin secretion and skeletal muscle fatty acid oxidation with glucose uptake.

AICAR Administration and Dosage:

It should also be noted that in young mice, longer (14 days) treatment failed to improve spatial memory and neurogenesis, raising the possibility of negative consequences of chronic administration [39]. AICAr-induced apoptosis and concurrent activation of AMPK were described in childhood acute lymphoblastic leukemia (ALL) cell lines [110], as well as in B cells isolated from patients with mantle cell lymphoma and splenic marginal zone lymphoma [7]. In chronic myelogenous leukemia (CML) cell lines [12] and primary samples [111], AICAr had antiproliferative effects, but AMPK knock-down by shRNA failed to prevent the effect of AICAr, indicating an AMPK-independent mechanism [12]. In azacytidine (Aza)-resistant myelodysplastic syndrome and acute myeloid leukemia (MS/AML) cell lines and primary samples, 2 mM AICAr blocked proliferation, and these initial findings led to a phase I/II clinical trial using AICAr in 12 patients with Aza-refractory MDS/AML patients.

Metformin

Unsurprisingly, Western blot results showed that sodium taurocholate infusion significantly reduced the ratio of p-AMPK/AMPK in liver tissues. As expected, this ratio was further reduced by CC treatment, suggesting that CC treatment successfully inhibited AMPK phosphorylation levels in the liver tissues of SAP rats (Figure 5A). Interestingly, treatment with CC significantly exacerbated sodium taurocholate-induced pancreatic injury in rats, as evidenced by further increased acinar necrosis and inflammatory cell infiltration (Figure 5B). Evaluation of the pancreatitis score in pancreatic sections also revealed that CC treatment was accompanied by more severe pancreatic injury than SAP (Figure 5D). We also observed that administration of CC in rats augmented SAP-induced edema, necrosis and structural disorder in hepatic lobules with further increased liver injury scores compared with SAP rats (Figures 5C,D). In addition, the amplitude of SAP-induced elevation of serum levels of both ALT and AST, two markers of liver injury, in CC-treated rats was higher than that in the SAP groups (Figure 5E).

Peptide AICAR: Possible Side Effects

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. 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).

In particular, oral resveratrol administration increases oxygen consumption, aerobic capacity and insulin sensitivity in a high-fat diet regimen [102–104]. Resveratrol also has well-known antioxidant capabilities, both in vitro and, to a minor extent, in vivo [106]. Such a protective effect contributes to resveratrol’s capability of improving cardiovascular functions.