• 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
  • We also examined possible involvement of


    We also examined possible involvement of the NF-κB signaling pathway in GSK-3 inhibitor-induced suppression of PGE2 production, whereas GSK-3 inhibitors did not have a significant effect on IκB phosphorylation/degradation or NF-κB nuclear translocation. These results are consistent with a previous paper reporting that suppression of GSK-3β inhibited NF-κB-mediated transcription without affecting degradation of IκB or translocation of NF-κB [30]. Martin et al. suggested that a possible mechanism of this phenomenon is that the inhibition of GSK-3 enhanced the ability of cAMP response element-binding protein (CREB) allowing it to remove the coactivator CREB-binding protein (CBP) from NF-κB, resulting in the inhibition of NF-κB/CBP-mediated activation of pro-inflammatory gene transcription in human monocytes [18]. Thus, GSK-3 inhibitors could suppress the inflammatory NF-κB signaling pathway by this mechanism in our SGX523 synthesis without affecting either IκB phosphorylation/degradation or NF-κB nuclear translocation. In addition to TPA-treated THP-1 cells, we examined effect of GSK-3 inhibitions on PGE2 production using mouse peritoneal macrophages. As shown in Fig. 8, pharmacological and genetic inhibition of GSK-3 decreased PGE2 production of the macrophages. These results confirmed that GSK-3 had an important role in PGE2 production in the macrophages. Further, we demonstrated the effect of GSK-3 inhibitors on PGE2 production in vivo for the first time, using an acute inflammation model. Again, we found that both pharmacological and genetic inhibition of GSK-3 significantly decreased PGE2 production in the inflammatory air pouches, confirming the involvement of GSK-3 in PGE2 production in vivo. Taken together, these results suggested that GSK-3 inhibitors could be useful for the treatment of inflammatory diseases. Since most NSAIDs are non-specific COX inhibitors, they cause several adverse reactions induced by COX-1 inhibition, such as gastro-intestinal and renal damage and bleeding. To avoid these side effects, COX-2-specific inhibitors such as rofecoxib and celecoxib were developed [31]. However, long-term treatment with COX-2-specific inhibitors has been shown to increase thromboembolic cardiovascular events owing to the inhibition of prostacyclin production [32]. Therefore, it is natural that not COX-2 but mPGES-1, an enzyme downstream to COX in the PGE2 synthesis cascade, is a promising target for a novel anti-inflammation agent [33]. As shown in this study, although GSK-3 inhibitors inhibited mPGES-1 expression, they also suppressed COX-2 expression. Thus, GSK-3 inhibitors may not be appropriate for systemic application, if we are concerned about thromboembolic adverse reactions due to COX-2 inhibition. However, despite this effect, they could be useful as local application drugs. We previously reported that GSK-3 inhibitors accelerated bone regeneration [34]. Therefore, GSK-3 inhibitors could be locally applicable for the treatment of diseases that exhibit inflammatory reactions and bone absorption, such as rheumatoid arthritis and periodontitis.
    Conflict of interest
    Acknowledgements We thank Prof. Akihiko Takashima (Dept. of Aging Neurobiology, National Center for Genetics and Gerontology) for kindly providing GSK-3β+/− mice. We thank the technical support by the Research Support Center, Graduate School of Medical Sciences, Kyushu University. This work was supported by KAKENHI (Grant numbers: 25460334).
    Introduction Diabetes mellitus (DM) is a multifactorial, noncommunicable, and complex metabolic disorder constituting a major public health issue throughout the world. Epidemiological studies have reported that the prevalence of DM worldwide was estimated to be 2.8% in 2000 and 4.4% in 2030, and the total number diabetics is prognosticating to rise from 210million in 2010 to 366million in 2030 (American Diabetes Association, 2015). DM is divided into two broad etopathogenetic categories, type 1 and type 2. Type 1 DM (also called insulin-dependent diabetes) occurs when the pancreatic β-cells stops making or makes a little amount of insulin, whereas type 2 DM (also called non-insulin dependent diabetes) occurs when β-cells do not make enough or the body has trouble using the insulin (American Diabetes Association, 2015). One of the most important factors contributing to DM is dysfunction and death of pancreatic β-cells (the major insulin secretion cells). When β-cell dysfunction which induces by apoptosis and a decrease in its' mass, it can induce to impaired insulin secretion and lead to the onset of pathogenetic processes of DM (Ley et al., 2014). Although several studies have reported that environmental stimulus and toxic insults (such as low and high glucose, hypoxia, lipotoxicity, chemicals, and heavy metals) can induce dysfunction and apoptosis of β-cells (Chang et al., 2013, Kover et al., 2015, Pedraza et al., 2012, Yang et al., 2016, Zhou et al., 2015), the exact mechanism involved in these is still not fully understood.