AICAR suppresses TNF-α-induced complement factor B in RPE cells Scientific Reports

AICAr-mediated inhibition of mTORC1 requires the phosphorylation of protein raptor 77. The best way to assess the role of AMPK in the effects of AICAr in vivo could be provided by AMPK knockout mice. However, a decrease in gluconeogenesis and an inhibition of oxidative phosphorylation (OXPHOS) can be observed in response to AICAr in mice lacking both AMPKα1 and α2 isoforms 38,39,40. To verify our hypothesis, we used Nrf2 KO mice and WT mice to conduct a comparative study in an L-arginine-induced PALI model with or without AICAR treatment. We found that knockout of Nrf2 limited the ability of AICAR to reduce the severity of PALI in mice (Figures 7A–E).

AICAR treatment also reduces EGFR protein stability and activity as well as MUC1-CT expression. Clinically, higher expression of MUC1 correlates with less overall and disease-free survival in lung adenocarcinoma patients at advanced stages. AICAR treatment inhibits cancer cell line-derived lung xenograft tumour growth in mice. AICAR treatment blocks 3D organoid growth from EGFR-mutant patient-derived xenograft and transgenic mouse lung tumour tissues. Combinational treatment with AICAR and EGFR and JAK inhibitors further decreases organoid formation.

Cell cultures were maintained in the continuous culture for about 5weeks for a further five passages (P10). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Support for this study was provided by the Novo Nordisk Foundation Center for Basic Metabolic Research and the Novo Nordisk Foundation (Excellence Project Award) to JTT.

These data suggest that AICAR induces cytotoxicity by increasing cell apoptosis in EGFR-mutant lung cancer cells. Western blot assay demonstrated significant increases in phosphorylated H2AX (γ-H2AX), phosphorylated p53 (p-p53), and p21Cip1 in 0.4 mM AICAR-treated cells than in vehicle-treated cells, suggesting AICAR treatment increases DNA damage 74,75,76 (Fig. 1i). These data are consistent with a previous study showing AICAR-induced cell apoptosis in acute lymphoblastic leukaemia 10. As expected, the expression levels of γ-H2AX, p-p53, and p21Cip1 did not change significantly in AICAR-treated A549 cells (Fig. 1j).

AICAR and metformin protect INS-1E cells from palmitate-induced apoptosis

Significant improvements can be witnessed in the performance during endurance-type exercise, by converting fast-twitch muscle fibres to the more energy-efficient, fat-burning, slow-twitch type. Plasma AICAR was increased in the majority of horses after racing did not correlate with age, gender, or performance in this population. When administered intravenously, AICAR acutely decreased mean arterial blood pressure despite a compensatory increase in cardiac output and heart rate. It highlights how peptides like MOTS-c, AMPK, AICAR, and FTPP can influence metabolic pathways, improve insulin sensitivity, and enhance glucose homeostasis. These peptides offer innovative therapeutic options by targeting underlying biochemical processes, providing hope for improved diabetes care and outcomes. In summary, AICAR is a compound used to activate AMPK, while AMPK is the enzyme that regulates energy balance within cells.

AICAR Treatment Studies

MK designed the concept of the study and experiments, performed the experiments, analyzed the data, did the statistical analysis, drafted the manuscript, and designed the figures. MS performed the experiments, contributed to the data gathering and statistical analysis, and did the critical revision on the materials and methods section. MM did the qRT-PCR, analyzed the data, did the statistical analysis, and designed the appropriate figures for qRT-PCR results. AT, TT, MF, and AM provided technical and material support, supervised the process of acquisition of the data, and analyzed the data.

• We detected only a partial correlation between individual responses in fibroblasts and residual enzymatic complex I activity in muscle, genotype or clinical presentation (Table and Fig. 2).
• When treated with either AICAR, NAM, or their combination, the frequency of Bcl-2-positive cells increased and that of Bax- and Caspase-3-positive MSCs dropped significantly.
• Potential side effects may include fatigue, muscle weakness, changes in blood sugar levels, or effects on liver function.
• Prostate cancer is the most commonly diagnosed cancer amongst men and the second most common cause of cancer death in men 1.

Following that, to detect the extracellular calcium deposits, we stained the cells with Alizarin Red S (Sigma-Aldrich) for 20 min. For quantification, the Alizarin Red S was eluted by 5% sodium dodecyl sulfate in 0.5 N HCL for 15 min, and the optical density was evaluated at 405 nm, using NanoDrop 2000c Spectrophotometer (Thermo Fisher Scientific) 11. Human MSCs were isolated from the adipose tissue of three different healthy individuals, and informed consent was obtained according to the Shiraz University of Medical Sciences ethics committee guidelines 27, 28.

We think this is because treatment with AICAR and NAM can increase the proliferation of the cells, https://vam.vn/steroids-an-overview-of-use-benefits-risks-and/ which might show a greater level of lipid accumulation in the treatment groups after Oil Red O staining. In line with our findings, Gharibi et al. previously showed that while treating MSCs with rapamycin resulted in an increased level of lipid accumulation in the cells, it had an insignificant effect on the markers of adipogenesis 11. Additionally, as demonstrated by Jaiswal et al., differentiation of MSCs to the osteogenic and adipogenic lineages is mechanistically related 45. Together, these findings propose an inverse relation between osteogenic and adipogenic differentiation of MSCs in aging 11. To evaluate the morphology of MSCs, the surface area of the cells was determined, using the technique described in the “Materials and methods” section. Of note, MSCs treated with AICAR alone showed the characteristic morphology of young MSCs, like the AICAR+NAM group, while NAM-treated cells exhibited morphological features of senescent MSCs (Fig. 2a, b).

Krabbe disease (KD) is an inherited neurological disorder caused by the deficiency of galactocerebrosidase activity resulting in accumulation of psychosine, which leads to energy depletion, loss of oligodendrocytes, induction of gliosis, and inflammation by astrocytes in CNS. In this study, for the first time, we report the regulation of ‘cellular energy switch,’ AMP-activated protein kinase (AMPK), by psychosine in oligodendrocytes and astrocytes. Psychosine treatment significantly down-regulated AMPK activity, resulting in increased biosynthesis of lipids including cholesterol and free fatty acid in oligodendrocytes cell line (MO3.13) and primary astrocytes.

Recently AICAR was also reported to be favorable in cytochrome c oxidase deficiency 47, 48. 5-Aminoimidazole-4-carboxamide ribotide (AICAR) was found to be the most beneficial compound improving growth and ATP content while decreasing ROS production. AICAR also increased mitochondrial biogenesis without altering mitochondrial membrane potential (Δψ). Fluorescence microscopy data supported increased mitochondrial biogenesis and activation of the AMP activated protein kinase (AMPK). Other compounds such as; bezafibrate and oltipraz were rated as favorable while polyphenolic phytochemicals (resverastrol, grape seed extract, genistein and epigallocatechin gallate) were found not significant or detrimental. Although the results have to be verified by more thorough investigation of additional OXPHOS parameters, preliminary rapid screening of potential therapeutic compounds in individual patient’s fibroblasts could direct and advance personalized medical treatment.