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

In human aortic endothelial cells, AICAr stimulated AMPK activity and nitric oxide (NO) production, and the effects were proved to be AMPK-dependent since the effects were inhibited by the expression of a dominant-negative (DN) AMPK mutant [60]. Similar AMPK-dependent effects on NO production were observed in response to hypoxia [61], and studies performed in the knockout of the upstream kinase LKB1 confirmed the important role of AMPK in angiogenesis [62]. When it comes to enhancing athletic performance and improving training results, many athletes and fitness enthusiasts turn to supplements and peptides to give them an edge.

Table 9

This review aims to give an overview of the present knowledge on AMPK-dependent and AMPK-independent effects of AICAr on metabolism, hypoxia, exercise, nucleotide synthesis, and cancer, calling for caution in the interpretation of AICAr-based studies in the context of understanding AMPK signaling pathway. This cutting-edge peptide is designed to enhance endurance, improve fat metabolism, and boost overall athletic performance. With its unique properties and proven benefits, AICAR 50 mg is a game-changer for both beginners and advanced bodybuilders. The central goal of this study was to investigate the pharmacological activation of AMPK by AICAR as a therapeutic strategy for the treatment of PALI. Our findings demonstrated that AICAR activates AMPK, which leads to Nrf2-mediated antioxidant stress and inhibition of NLRP3-related inflammation, and thus improving PALI. This study indicated that AMPK exerted an essential role in the pathological processes of PALI and presented the first evidence that pharmacological activation of AMPK by AICAR ameliorates PALI, suggesting that AICAR may be a promising therapeutic agent for the treatment of PALI.

The Effects of AICAR 50 mg Peptide Sciences

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]. The cell cycle analyses of AICAr-arrested cells in some studies revealed an increase in the proportion of cells in the G0/G1 phase, as would be expected from the mechanism of cell cycle arrest in response to AMPK activation and mTORC1 inhibition [23].

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

• Male SD rats (220–250 g, age 7–8 weeks) were obtained from the Experimental Animal Center of Wenzhou Medical University.
• The concentration of the resulting solution was 100 mg/mL, the volume of administration was 10 mL/kg, and the dose administered was 500 mg/kg.
• 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.
• Adenosine is a potent vasodilator that plays a key role in reducing ischemia/reperfusion injury, but the applications for systemic adenosine are limited owing to peripheral hemodynamic actions [13].

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).

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Adenosine is a potent vasodilator that plays a key role in reducing ischemia/reperfusion injury, but the applications for systemic adenosine are limited owing to peripheral hemodynamic actions [13]. As shown in Figure 1, AICAr shares structural similarities with adenosine, and therefore, can increase the extracellular concentrations of adenosine by competing for the nucleoside transporter [20]. In addition, AICAR increases intracellular concentrations by inhibiting adenosine deaminase and increasing the production of adenosine rather than inosine from ATP catabolism.

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]. As a cell-permeable nucleotide, AICAr enters the cells through adenosine transporters [20] and becomes phosphorylated by adenosine kinase into AICAR [21]. AICAR or ZMP activates AMPK but it is 40- to 50- fold less potent than AMP in AMPK activation and accumulates in high concentrations in the cytoplasm [1], so that it was always likely that AICAr may have several AMPK-independent effects.

In all the AICAR-treated animals, the visually assessed body fat was lower compared to untreated HFD animals. Additionally, all the animals treated with AICAR had a significantly reduced mass of adipose tissue surrounding the epididymis, relative to the animals on HFD without treatment. AICAR administered against the background of HDJ, on the contrary, improved the functional morphology of the liver—reduced the accumulation of glycogen in hepatocytes. AICAR, introduced from the first day of the study, reduced the content of lipid inclusions in the cytoplasm. Methotrexate administration had no effect on the therapeutic activity of AICAR in the study.

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. To further determine the roles of AICAR in PALI, we next investigated whether replenishment of AICAR can rescue the damaged antioxidant system in sodium taurocholate-induced SAP rats. Notably, AICAR supplementation further augmented the hepatic expression levels of HO-1 and NQO-1 after sodium taurocholate treatment in rats (Figures 3A–E). Furthermore, the detection results of hepatic tissues in sodium taurocholate-induced SAP rats showed that the levels of MDA were significantly elevated, whereas the concentrations of SOD were strikingly decreased, suggesting that the antioxidant capacity of the liver in sodium taurocholate-induced SAP rats was disrupted. However, treatment with AICAR significantly restored the antioxidant abilities of the liver, as evidenced by an obvious elevation in hepatic concentrations of SOD and a marked decline in the hepatic levels of MDA (Figure 3F). These data suggest that AICAR supplementation prevents sodium taurocholate-induced PALI in rats by increasing antioxidant activities in the liver.

These findings suggest that AICAR markedly alters the nuclear accumulation of Nrf2 and inhibits NLRP3 inflammasome activation in sodium taurocholate-induced PALI rats by activating AMPK phosphorylation. Thus, we speculate that Nrf2 and NLRP3 inflammasome pathway may mediate essential parts in the protective roles of AICAR against oxidative stress and inflammation in sodium taurocholate-induced PALI rats. The initial body weight of the animals in all groups at the beginning of the study did not differ. By the end of the fourth week of the study (Day 28), there was a significant increase in body weight relative to the control group in groups 3 (HFD + vehicle), 5 (HFD Insulin order from bulksteroid.net + AC 7), and 6 (HFD + AC + MTX) (26.8 ± 2.0 g, 26.4 ± 1.7 g and 26.7 ± 1.9 g, respectively, versus 24.7 ± 1.1 g in the STD + vehicle group). This difference in weight remained unchanged throughout the lifetime phase of the study, i.e., the absolute weight of all the animals treated with HFD was significantly different from the weight of control animals from the fourth week of the study (Table 1). At the same time, the body weight, as well as the increase in body weight of animals from group 4, which received AICAR against the background of HFD starting from the first day, did not differ from that in group 3, which received HFD and the vehicle (Table 1 and Table 2).