AICAR phosphate AICAR磷酸盐阿卡地新磷酸盐 AMPK激活剂 CAS 681006-28-0

AICAR did not influence early activation of the NFκB signalling pathway as seen by an unaltered IκB kinase (IKK) phosphorylation (Fig.2A). Following LPS stimulation, phosphorylation as well as nuclear translocation of the NFκB family member RelA (p65) also remained intact in the presence of AICAR (Fig. 2B). AICAR had also no effect towards activation of three major MAPK branches by LPS, since we observed similar phosphorylation of extracellular signal-regulated kinase (ERK), p38 MAPK, and nuclear c-Jun in macrophages stimulated with LPS in the presence or absence of AICAR (Fig. 2A,B). Interestingly, in animal studies with obese mice, AICAR showed all of the peptide benefits for obese diet-induced mice, yet the healthy lean mice did not reap any of the benefits of insulin sensitivity or an increase in glucose uptake. That being said, the application in bodybuilding does not seem very suitable, as these mechanisms are targeted at the out-of-shape and overweight, so if you are not a top-level endurance athlete.

Cell Data

Conclusively, AICAR interferes with DNA binding of NFκB and STAT3 to modulate inflammatory responses. According to this hypothesis selective co-activation of AMPK and PPARδ would induce gene expression changes that mimic those triggered by combined exercise and PPARδ as well as VP16-PPARδ over-expression. To investigate this possibility, we compared the transcriptional changes induced in skeletal muscle by combined exercise and GW1516 treatment with that of combined AMPK activator (the cell permeable AMP analog AICAR) and GW1516 treatment.

Biological Activity

AMPK acts as an energy regulator and is activated during exercise or other circumstances that use up cellular energy. Despite the introduction of numerous biologic agents for the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, low-dose methotrexate therapy remains the gold standard in RA therapy. Methotrexate is generally the first-line drug for the treatment of RA, psoriatic arthritis and other forms of inflammatory arthritis, and it enhances the effect of most biologic agents in RA. Understanding the mechanism of action of methotrexate could be instructive in the appropriate use of the drug and in the design of new regimens for the treatment of RA.

Hyperinsulinemic-euglycemic Clamp Study

Given the numerous benefits of exercise on general health, identification of orally active agents that mimic or potentiate the genetic effects of endurance exercise is a long standing, albeit elusive medical goal. High doses of certain natural extracts such as resveratrol can improve endurance (Lagouge et al 2006). The aerobic effects of resveratrol are thought to dependent on activation of SIRT1-PGC1α coactivator complex in skeletal muscle. However, the downstream transcriptional factor(s) targeted by SIRT1/PGC1α in mediating these effects are not known. More importantly, both SIRT1/PGC1α and resveratrol each activate multiple targets and thus whether there is a specific signaling pathway that can be selectively activated by a synthetic drug to improve endurance is not known.

“In a recent study, we made a side-by-side comparison between effects of short- and long-term AICAR administration and exercise regimens, on gastrocnemius muscle and brain in young C57Bl/6 male mice. Both interventions induced similar AMPK pathway activation in skeletal muscle after both short (3–7 days) and longer (14 days) administration. Interestingly, 4 weeks of drug treatment decreased epididymal fat mass to body weight ratio and increased oxygen consumption without changing body weight, supporting the speculation that AICAR may positively regulate endurance. In summary, our experimental results indicated that AICAR inhibits cell growth, induces apoptosis, attenuates cell migration, enhances chemosensitivity to docetaxel, and suppresses the activation of the AMPK/mTOR-dependent signaling pathway. These results suggest that AICAR appears as a new potential anticancer agent for treating prostate cancer. AICAr-induced apoptosis and concurrent activation of AMPK were described in childhood acute lymphoblastic leukemia (ALL) cell lines 110, as well as in B cells isolated from patients with mantle cell lymphoma and splenic marginal zone lymphoma 7.

Docetaxel chemotherapy was administered to patients with metastatic castration-resistant prostate cancer (CRPC) for a decade, and demonstrated ability to improve the median overall survival by around 3 months 5,6. Currently, there is no effective therapy for recurrent prostate cancer; hence, a novel therapeutic method for CRPC is needed. The diverse effects of AICAR on metabolism, muscle function, cancer growth, and cardioprotection underscore its potential for therapeutic applications. Future research should focus on M-JECT 100 mg Muscule Pharm buy online further elucidating the mechanisms of AICAR action and exploring its efficacy in clinical settings. The activation of AMPK by AICAR leads to a cascade of downstream effects, including the inhibition of anabolic processes and the stimulation of catabolic pathways. Research in thyroid cancer cells indicates that AICAR may also operate by causing apoptosis (programmed cell death).

• 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.
• Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%.
• AICAR‘s cardioprotective effects have been explored in various studies, particularly its ability to protect heart muscle during surgery.
• Mechanistically, AMPK-independent actions of AICAR are poorly understood and warrant further investigation.
• We previously showed that α1AMPK is abundantly expressed in fat tissue, while the expression of α2AMPK is low in fat tissue 11.

Cells were cultured in RPMI 1640 medium (PNT1A, RWPE1, BPH1, LNCaP, C4-2, and 22Rv1) or F-12 medium (PC3), supplemented with antibiotics (100 U/mL penicillin and 100 U/mL streptomycin) and 10% (v/v) FBS in a humidified atmosphere of 5% CO2 at 37 °C and passaged every 2–3 days to maintain growth. To examine whether AICAR affects the therapeutic efficiency of docetaxel-based therapy in prostate cancer, 22Rv1 cells were treated with various doses (0, 0.5 and 1 mM) of AICAR in the presence or absence of docetaxel for 24 h. As shown in Figure 5, AICAR exhibited synergistic effect with docetaxel treatment in prostate cancer cells. AICAR has been found to possess anti-cancer properties, inhibiting the growth of cancer cells both in vitro and in vivo.

(C) The expression of mTOR, cMYC, phosphor-p70S6K and p70S6K was determined by western blot. The western blotting results are representative of results obtained in three separate experiments. (D) Proposed mechanism of the anticancer effects induced by AICAR in 22Rv1 prostate cancer cells. TGF-β signaling is well known as a key regulator of many biological processes in prostate cancer including inducing EMT, migration and metastasis 28. To examine whether AICAR affects TGF-β-induced EMT, migration, and invasion activities in prostate cancer cells, 22Rv1 cells were treated with 5 ng/mL TGF-β and various concentrations (0, 0.25, and 0.5 mM) of AICAR. As shown in Figure 4A, AICAR inhibited TGF-β-induced EMT through inhibiting the expression of mesenchymal marker, N-cadherin, and enhancing the expression of epithelial marker, E-cadherin.

To detect the synergistic effects of AICAR, cells were treated with different doses of the AICAR (0, 0.5, and 1 mM) combined with different doses of docetaxel for 24 and 48 h. Prostate cancer is the most common cancer and the second leading cause of cancer-related death among men in the United States 1. Current treatment options for prostate cancer include surgery, hormonal therapy, chemotherapy, radiation therapy, radiofrequency ablation, high-intensity focused ultrasound, cryotherapy, and cancer vaccine 2,3. Androgen deprivation therapy (ADT) by surgical or chemical castration has been the mainstay of treatment for advanced prostate cancer in the past few decades. However, the majority of androgen-sensitive prostate cancer patients will eventually develop resistance to ADT within 1 to 3 years and the disease will become androgen-independent 4.

Numerous doping detection methods (here, here, here, here, and here) have not only established a baseline for endogenous AICAR production, but can also detect high levels of AICAR long after you’ve given your blood sample. Ronald Evans, author of the 2008 paper that sparked mainstream media attention, notified the World Anti-Doping Agency (WADA) about AICAR’s performance-enhancing effects BEFORE the paper was published. Biohacker beware… unless you’re a top-tier endurance athlete who self-experiments and isn’t entering a competition anytime soon (you’ll soon see why), there’s not much reason to test AICAR. The sooner we stop thinking of AICAR as a PED (performance-enhancing drug) and more as a life-optimizing Golden Age agent, the faster we can start giving it to people in dire need.