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AMPK: Potential Therapeutic Target for Alzheimer’s Disease Bentham Science

AMPK: Potential Therapeutic Target for Alzheimer’s Disease Bentham Science

AMPK: Potential Therapeutic Target for Alzheimer’s Disease Bentham Science

A similar pattern was obtained when α1AMPK activity was monitored after treatment of IEC-6 cells with increasing concentrations of adenosine and the K0.5 value of the adenosine effect was 0.47 μM (Fig. 2C). Thus, the effect triggered by this nucleoside is physiologically relevant, since it occurs within the range of adenosine concentrations found in body fluids. Adenosine in peripheral blood has been reported to occur at concentrations of 0.3-1 μM (Lasley et al., 1998; Pasini et al., 1996; Saadjian et al., 2002); however, in the intestinal lumen and the portal vein it is likely to achieve higher levels. Moreover, it is accepted that adenosine can also be produced by ectonucleotidase action on nucleotides, thus leading to high local nucleoside concentrations (Che et al., 1997; Roman and Fitz, 1999). To confirm that extracellular adenosine induces an increase in AMP intracellular concentration, the adenine nucleotide content was measured at different times after addition of 10 μM adenosine.

  • Lysates were filtered (70 μm pore size) and 5 × 105 cells were stained by Aqua-Live-Dead (Thermo Fisher, Waltham, MA, USA) and relevant antibodies for characterisation (see ESM Table 1 and ESM Table 2 for antibody details).
  • If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account.
  • The rate of whole body glucose turnover was estimated using a continuous infusion of [3-3H]-glucose at 0.1 µCi/min.
  • The cells were then evaluated after 4 days of stimulation by phase contrast microscopy (Olympus).

Nuclear and cytoplasmic extracts were prepared using the NE-PER nuclear and cytoplasmic extraction reagent kit (Pierce Biotechnology Inc.) according to the manufacturer’s instructions. Total protein extract and Western blotting (WB) analysis were conducted as described previously [2]. “A number of anti-doping organizations, including the International Olympic Committee, store doping control samples of their events for eight years for potential future retesting and detection as anti-doping science advances,” Donze said. In 2004, he made headlines for engineering “marathon mice.” By injecting a single gene into the nucleus of a fertilized egg, he created mice born with more efficient muscles, faster metabolisms and stronger hearts.

Activation of AMPK Affects GLUT1 and GYS1 mRNA Abundance and Glucose Uptake

The alterations in insulin action in skeletal muscle are likely to be involved in the mechanism of our findings on whole-body glucose homeostasis. Moreover, it has previously been shown that acute in vivo AICAR exposure can decrease endogenous glucose production in normal rats (26). Recently, this decrease has also been demonstrated in insulin-resistant obese Zucker rats (31). These observations are consistent with the potential influence of AICAR on the regulation of hepatic gluconeogenesis, as suggested by in vitro studies of isolated hepatocytes and hepatoma cells (29,30). Therefore, an altered endogenous glucose production may contribute to the observed changes in glucose and insulin homeostasis. This pro-inflammatory cascade of events could be blocked by anti-oxidants such as NAC and vitamin E as well as by neutral sphingomyelinase inhibitor (3-o-methyl sphingomyelin) [12, 19, 30].

  • Cell viability and apoptosis were measured in AICAR-treated EGFR-mutant and wild-type lung cells.
  • Although it could be argued that extracellular adenosine modulates AMPK through purinergic activation, this is unlikely in our cell system.
  • Peptides were synthesised on an Activotec P11 peptide synthesiser (Activotec, Cambridge, UK) on pre-loaded LL Wang resin, using N(a)-Fmoc amino acids including Fmoc-Cys (StBu)-OH, with HATU as the coupling reagent.
  • However, with these two peptides in combination, at equimolar concentrations (7.5 μM each), Aβ (1–42) induced approximately twice the amount of nitric oxide release and correspondingly higher iNOS expression as compared to Aβ (1–40) (lane 11 vs. lane 14).
  • We also detected a tenfold increase in the interaction of cyclo-CRVLAR with p110α Kd 33.7 ± 3.7 µM (Fig. 1E, Supplementary Fig. 3A).

Subsequent studies revealed that PGC-1α, a gene involved in the co-activation of mitochondrial biogenesis and metabolic processes, was significantly upregulated by MOTS-c, suggesting its functional involvement [52]. MOTS-c inhibits ROS production by activating PGC-1α, resulting in an anti-inflammatory effect (decreases levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6, while increasing the levels of anti-inflammatory cytokine IL-10). PGC-1α knockdown reversed the inhibitory effect of MOTS-c on ROS production while increasing the levels of TNF-α, IL-1β and IL-6, as well as reducing IL-10 levels [52]. As a key downstream molecule of MOTS-c, AMPK mediates a variety of effects such as metabolic homeostasis, insulin resistance, fat accumulation, exercise, inflammation, osteoporosis, cardiovascular protection, and aging [7, 9, 44,45,46,47,48,49].

AICAR Research and Fertility

High levels of bad cholesterol (LDL) cause macrophage proliferation, increasing the risk of cardiovascular events, including heart attacks. A study has shown that AICAR may slow the spread of cardiovascular disease and reduce heart attacks. Research shows that AICAR has excellent absorption in mice and has few adverse effects. Only qualified medical professionals or academic researchers should buy AICAR peptides. Recent clinical trials [i] highlight the importance of AICAR in cellular-level inflammation.

Thyroid cancer cell research has also suggested that AICAR may induce apoptosis in cancer cells by p21 induction and caspase-3 activations, potentially causing inhibition of cancer cell proliferation. Additional AICAR research reveals that healthy and diabetic mice exhibited impaired inflammatory responses in metabolic diseases. Improvements in insulin sensitivity, lipid metabolism, energy balance, and inflammatory symptoms have also been shown in scientific studies using AICAR.

Patient-derived xenograft tumours specimens

The SREBP-2 precursor levels slightly decreased in response to AICAR at 12 h and were significantly decreased by 24 h (Fig 2B). However, the nuclear active form of SREBP-2 exhibited a significant decrease during the AICAR treatment period (Fig 2C). Since MUC1 and EGFR regulate each other mutually, we asked if AICAR treatment would reduce both expression levels. In H1975 cells treated with AICAR for 1 and 2 h, expression levels for p-EGFR, EGFR, and MUC1-CT decreased significantly (Fig.4f). A previous study showed that lung tumour cells are featured with high EGFR protein stability [50]. Our data suggest that AICAR not only inactivates MUC1-CT and EGFR activity but may also degrade EGFR protein stability, thus providing a new strategy to block EGFR-driven oncogenesis.

Preparation of nuclear extracts and electrophoretic mobility shift assay (EMSA)

This is also suggested by the reversal of the enhanced glycolytic response by supplementation of folic acid in the culture medium [7]. Interestingly, AMPK is also necessary for MOTS-c stress-responsive nuclear translocation. Subcellular isolation and immunofluorescence imaging showed that pharmacological and genetic interventions that inhibit AMPK activity prevent the stress-induced nuclear translocation of MOTS-c, which rapidly enters the nucleus within 1 h after metformin and AICAR treatment [36]. This suggests that AMPK both promotes the nuclear translocation of MOTS-c and mediates its physiological effects, forming a positive feedback loop. To translate our rodent data to human pathophysiology, we investigated if AICAR could reduce WAT inflammation in humans.

AICAR is under investigation as a potential adjunct to chemotherapeutics because it can increase their effectiveness, thus allowing for lower doses of these toxic drugs that cause hair loss, nausea, and worse. After the first round of chemotherapy, there is often a marked increase in the resistance of cancer cells to chemotherapeutic drugs. The current thinking is that AICAR or a similar molecule could slow cancer cell metabolism and make those cells more susceptible to environmental insults and thus less resistant to standard chemotherapy5.

AICAR attenuated HFD-induced adipose inflammation independent of adiponectin

As in skeletal muscle, hepatic glucose metabolism is also potentially regulated by the AMPK system. Thus, under in vitro conditions, it has been demonstrated that AICAR exposure in rat hepatoma cells and isolated hepatocytes leads to a downregulation of gluconeogenetic enzymes and suppressed gluconeogenesis, respectively (29,30). These findings are supported by observations demonstrating a decreased rate of endogenous glucose production after in vivo AICAR exposure (26,31). Thus, pharmacological AMPK activation in liver tissue might also mimic the possible acute effects of high-intensity exercise and might potentially decrease the hepatic glucose output as well as reduce sterol and fatty acid synthesis. PC-12 cells (Fig. 10), following stimulation with NGF, showed extensive neuronal growth forming a network reminiscent of neuronal extensions (Fig 10B).