AICAR, an AMPK activator, protects against cisplatin-induced acute kidney injury through the JAK STAT SOCS pathway

Although the effects of AICAR and Compound C on T cell activity has been studied 30, 33-37, whether these effects are dependent or independent of AMPK is still unclear. Here, using AMPK-deficient T cells, we investigated the effects of AICAR and Compound C on T cell survival and function. We found that AICAR promoted, but Compound C inhibited, Ca2+ signaling-induced T cell death in an AMPK-dependent manner.

In group 5 (HFD + AC 7), at week 11, there was a significant decrease in body weight gain relative to group 3 (HFD + vehicle) (38.6 ± 12.7% versus 52.0 ± 14.9%), which indicates that that AICAR treatment from seventh week of the study, helps to reduce body weight gain. The rate of weight gain in animals treated with HFD was significantly increased relative to the control starting from the fifth week of the study. This increase was maintained throughout the study in all animals on HFD, with the exception of the group 5 animals treated with AICAR from week 7 of the study.

Figure 6. Treatment of AICAR and Compound C inhibits mTOR signaling in T cells.

It appears that AMPK and SIRT1 can activate each other and feed off ensuing signaling between them. Which one is the upstream or downstream signal may depend on different types of cells or biological pathways. In regulation of the macrophage inflammation, we previously found that AMPK antagonizes inflammation through SIRT1 by increasing the SIRT1 activator NAD+11.

The tubes were then centrifuged on a SW60 Ti rotor (Beckman) at 150,000 g for 4 h at 4 °C and the fractions at the top of 12% OptiPrep solution were collected as the crude lysosome fractions. The fractions were diluted with two volumes steroids of PBS, followed by centrifugation at 20,000 g for 20 min. Since the FTase-Ras-Erk pathway is highly operant in the aging mesenchymal fibroblasts 9, we hypothesized that AMPK may exert its effects at least partially via downregulation of the Erk pathway. We found that when mesenchymal fibroblasts derived from aged hearts were treated with 0.5 mM of AICAR, phosphorylated Erk was reduced by 30% (Figure 2D).

• As a central metabolic regulator that reacts to an increase in AMP/ATP ratio, AMPK restricts growth and proliferation in response to energetic or nutritional stress.
• For example, it increases the usage of fat for energy and causes cells to make more mitochondria (the cells’ powerhouses or energy creators).
• Physiological AMPK activation involves phosphorylation of Thr-172 within the activation loop of the KD in the AMPKα catalytic subunit.
• All the animals after an overnight fast were measured for the initial glucose level, after which a 40% glucose solution at a dose of 2 mg/kg was injected into the stomach with a probe and the amount of glucose was measured 30, 60, 90, and 120 min after administration.
• Peptide Hub is not an outsourcing facility as defined under 503B of the Federal Food, Drug, and Cosmetic Act.

Figure 3. AICAR and Compound C suppress T cell activation in an AMPK-independent manner.

To examine the effects of AICAR and NAM on the proliferation of MSCs, we estimated the cell numbers in each treatment group by MTT assay (Fig.1b). MSCs of different study groups at P10 were harvested, and MTT assay was done on the third and seventh days after seeding. Although compared to the control group, there was no significant increase in the estimated number of cells after 3 days, the cell proliferation after 7 days was dramatically increased with concomitant use of AICAR and NAM or each compound alone (AICAR or NAM) compared to the control group.

CE-MS-based analysis of AMP, ADP, and ATP

One reason for this decrease was the administration of widespread tyrosine kinase inhibitors (TKIs) that block mutant EGFR signalling as the first-line therapy in patients harbouring EGFR mutations 40,41,42. In a preclinical setting, introducing mutant EGFR into mouse alveolar epithelial cells induces malignant phenotypes comparable to human lung adenocarcinoma. It demonstrates objective responses to EGFR induction or inactivation with changed protein expression for phosphorylated (p-EGFR) and total EGFR 43, 44.

However, in recent years, direct AMPK activators have been identified and tested in preclinical models, and a small number have entered clinical trials. Despite these advances, which disease(s) represent the best indications for therapeutic AMPK activation and the long-term safety of such approaches remain to be established. After an initial 5-µCi bolus, 3-3H-glucose was infused at 0.05 µCi/min for 2 hrs to measure basal glucose turnover. A 2-hr hyperinsulinemic-euglycemic clamp were conducted with a prime and continuous infusion of insulin at a rate of 2.5 mU/kg/min, coupled with a variable infusion of 40% glucose to maintain blood glucose at 6 mM. Blood glucose was measured via tail bleed every 5 minutes in the 1st hour to achieve stable blood glucose levels and every 10 minutes until the end of the 2-hour clamp to maintain constant blood glucose levels.