Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • br Authors Contributions br Role of the Funding Source

    2018-10-23


    Authors\' Contributions
    Role of the Funding Source This commentary was supported by institutional funds (grant number: 1010601ctBoe15; University of Rome Tor Vergata, Rome, Italy).
    Conflict of Interest
    The discovery that caloric restriction enhances lifespan and that sirtuins 1 (Sirt1) may mediate these effects ushered in a renaissance of research into the development of novel small molecule activators targeting this highly conserved family of deacetylases (). Subsequent findings that the polyphenol resveratrol, a substance enriched in the skin of red and purple fruits and most notably red wine, was a potent Sirt1 activator created further excitement around developing more specific agonists towards this new molecular target for anti-aging therapies (). It has now been over a decade since the first synthesis and characterization of potent, novel, small molecule, Sirt1 activating compounds (STACs) and their reported ability to improve glucose tolerance and insulin sensitivity in rodent models of obesity and type 2 diabetes (T2D) (). Since this time, STACs (, SRT501, SRT1720, SRT2104) have been shown to improve lipid profiles, glucose tolerance, lifespan and healthspan in rodents (). Clinical trials with these activators for a variety of conditions are currently underway or completed (, , , , , , ). However, the development of STACs for clinical use has not been without controversy, and a major question regarding their use has centered on their specificity for Sirt1. These concerns were initially raised when the utility of the fluorescent cell-free assays used to identify direct Sirt1 activation was questioned (). Further questions were raised by findings that Sirt1 was dispensable for the beneficial metabolic effects of resveratrol, and that these activities were mediated by adenosine monophosphate (AMP)-activated protein kinase (AMPK) in some (), but not all studies (). Like Sirt1, AMPK is a highly conserved protein that has evolved to sense cellular energy status. Activation of AMPK in response to alterations in mu receptor antagonist nucleotides leads to the inhibition of energy consuming and actuating energy producing processes. Activation of AMPK holds exciting potential as a therapeutic target, as evidenced by the clinical effectiveness of metformin and salsalate, which activate AMPK indirectly by inhibiting mitochondrial function (). This potential has sparked significant interest and progress in developing new, direct AMPK activators. Notably, AMPK activation produces many of the same effects as those observed with STACs, such as improved glucose homeostasis (), increased mitochondrial biogenesis () and, at least in the case of metformin, improved healthspan and lifespan (). In the April 2017 issue of , present evidence that, similar to resveratrol, the beneficial metabolic effects of STACs may also require AMPK. The authors show that AMPK activation by SRT1720 does not require Sirt1 in C2C12 muscle cells and Sirt1 knockout (KO) animals. Assays in mouse embryonic fibroblasts (MEFs) or in skeletal muscle of muscle-specific Sirt1 KO mice indicate that SRT1720 competes with cyclic AMP (cAMP); this competition inhibits recombinant cAMP-degrading phosphodiesterases . Using pharmacological inhibitors and siRNA gene manipulation in C2C12 and HeLa cells, the authors find that SRT1720-mediated activation of AMPK occurs through cAMP-Epac1 signaling involving the release of sarcoplasmic reticulum calcium and subsequent activation of calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ) and protein kinase A (PKA). This mechanism of action is very similar to that previously demonstrated for resveratrol by the same authors ().
    Introduction For men and women worldwide, liver cancer ranks as the second and sixth leading cause of cancer deaths, respectively (Torre et al., 2015). In 2012, there were an estimated 782,500 new cases of liver cancer and 745,500 deaths worldwide, and the incidence of the disease is rising (Torre et al., 2015). Hepatocellular carcinoma (HCC) account for >90% of primary liver cancer cases, and epidemiological studies have revealed that chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, exposure to aflatoxin, alcohol consumption, cigarette smoking, diabetes, and susceptibility genetic factors are major risk factors for HCC (Donato et al., 2002; El-Serag, 2012; Yang et al., 2011). The prognosis for HCC patients is poor: the 5-year survival rate for localized HCC patients is 30.5%, and this rate drops below 5% for those with distant metastases according to the Surveillance, Epidemiology, and End Results (SEER) database (El-Fattah et al., 2017; Oweira et al., 2017). For patients at early disease stages, liver resection is the most effective treatment methods; however, fewer than 30% of HCC patients are eligible for this treatment, and approximately 70% of them will relapse within 5years of treatment (Intaraprasong et al., 2016). Thus, it is necessary to identify those prognostic factors and systematically evaluate patient characteristics to guide the postoperative treatments and surveillance, which may improve the prognosis of HCC patients.