AMPK-dependent and independent effects of AICAR and compound C on T-cell responses

However, mounting evidence indicates AICAR and Compound C are able to regulate cellular functions via AMPK-independent mechanisms 19, 22-30. In addition, Compound C has been shown to inhibit activities of many other kinases, such as ERK8, ALK2, Src, Lck, etc, besides AMPK 31, 32. Thus, pharmacological application of AICAR or Compound C may result in both AMPK-dependent and independent effects in different types of cells. Fourteen-week-old male, lean (L; 31.3 g body wt) wild-type andob/ob (O; 59.6 g body wt) mice are injected with the AMP-activated kinase (AMPK) activator AICAR (A) at 0.5 mg/g per day or saline control (C) for 14 days.

Repeated AMPK Activation by AICAR Increases SIRT3 and MnSOD Protein in an AMPK- and PGC-1α-Dependent Manner

AICAR, which is the analog of AMP, binds to the same site on AMPK and activates it by mimicking the energy deprivation that is normally determined by AMP to ATP ratio (Fig.6a, b) 26, 49, 51. Apparently there is a discrepancy between the mixed effect of resveratrol and the positive effect of AICAR since they both activate the same SIRT1, PGC1α axis pathway 18, 24, 49. The underlying mechanism for this inconsistency remains unclear and requires further thorough investigation. Nevertheless, we suggest that the positive effects of resveratrol on patients cells might be masked by some additional negative effects. Notably, resveratrol was reported to inhibit the mitochondrial FoF1 ATPsynthase (complex V) and oxygen consumption while depleting ATP content 50, 51.

Nuclear Protein Extraction

• First, AICAR can induce apoptosis in B-cell chronic lymphocytic leukemia cells 35 and kill chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death 36.
• At lower concentrations, i.e., when bound to double-stranded DNA in the cytoplasm and nucleus, Acridine Orange emits green fluorescence 11.
• Chemical reagents that target AMPK activity have been widely used to investigate cellular functions of AMPK 7-10.
• This decreased sensitivity and phosphorylation level is attributed either to the increased action of the corresponding phosphatases or to the decreased activity or access of upstream kinases on this residue 49, 51, 58, 63.
• Additionally, whereas 0.5 mM AICAR tripled the Caspase-3-positive cells in mouse embryonic stem cell culture, it increased the cell cycle progression to the extent that the net proliferation was higher than the controls 34.

On the basis of AUC values (Figure 3B), the combination of radiation treatment and AICAR resulted in greater than additive inhibition of growth. The inhibition of spheroid growth can be observed in representative images of spheroids at the end of the experiment in Figure 3C. The activation of AMPK by AICAR in LNCaP cells, indicated by phosphorylation of ACC, was unaffected by administration of 2 Gy X-rays (Figure 3D).

AICAR Treatment Markedly Increases the Antioxidant Abilities of the Liver in Sodium Taurocholate-Induced SAP Rats

In turn, AMPK cannot be efficiently activated anymore, causing a gradual decline in autophagy. An additional reduction of autophagy https://pilates.com.my/2024/12/26/understanding-parabolan-a-comprehensive-guide-5/ leads to the accumulation of dysfunctional mitochondria, which also increases the cellular ROS level. These are only a small part of the vicious cycle that eventually leads to cellular senescence 48, 49, 53,54,55, 64, 65. The compounds tested were polyphenols, and other compounds with reported effects on ROS production and mitochondrial biogenesis.

Thus, these results further indicate that AMPK is not involved in T cell activation. In line with other studies that reported AMPK-independent activity of AICAR/Compound on cellular physiology 19, 24-27, 44 , our data provide new evidence that these reagents inhibit T cell activation in an AMPK-independent manner. AICAR/Compound C is commonly used as an agonist/antagonist to study AMPK-dependent cellular pathways.

Although the mechanism of action of this compound is poorly defined, it has been found to be beneficial in a number of diseases including cancer, neurodegenerative diseases and metabolic diseases 30–33. All of the above mentioned compounds have been documented to exert positive effects, however to our knowledge, they have not been systematically screened in OXPHOS deficient patient’s cells together in the same system. To further elucidate the role of AMPK in PALI, we treated rats with the AMPK inhibitor Compound C (CC, 13.8 mg/kg) by intraperitoneal injection to block the phosphorylation of AMPK in liver tissues, followed by sodium taurocholate infusion. Unsurprisingly, Western blot results showed that sodium taurocholate infusion significantly reduced the ratio of p-AMPK/AMPK in liver tissues.

Pharmacological activator of AMPK, 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) attenuated the psychosine-mediated down-regulation of AMPK and restored altered biosynthesis of lipids. AICAR treatment also down-regulated psychosine induced expression of proinflammatory cytokines and inducible nitric oxide synthase in primary astrocytes. This study delineates an explicit role for AMPK in psychosine induced inflammation in astrocytes without directly affecting the cell death of oligodendrocytes. AICAR (5-Aminoimidazole-4-carboxamide riboside or acadesine) is an AMP-activated protein kinase (AMPK) agonist, its activity in human gallbladder cancer cells was evaluated here.