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Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes
These compounds bind to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates and improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Expand
(S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme
A novel series of 14-membered macrocycles containing a N-N'-bridged bisindolylmaleimide moiety and related ATP dependent kinase inhibition profiles is provided and compared to the profile for staurosporine, a nonselective PKC inhibitor. Expand
Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC β Inhibitor
The vascular complications of diabetes mellitus have been correlated with enhanced activation of protein kinase C (PKC). LY333531, a specific inhibitor of the β isoform of PKC, was synthesized andExpand
Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth.
VEGF appears to mediate its mitogenic effects partly through the activation of the PLCgamma and PKC pathway, involving predominately PKC-beta isoform activation in endothelial cells. Expand
SIRT1 Exerts Anti-Inflammatory Effects and Improves Insulin Sensitivity in Adipocytes
It is shown that treatment of 3T3-L1 adipocytes with a SIRT1 activator attenuated tumor necrosis factor alpha-induced insulin resistance and gene expression profiles showed that Sirt1 expression was inversely related to inflammatory gene expression. Expand
Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic
The results suggest that the activation of PKC, predominately the beta isoform by hyperglycemia in the mesangial cells and glomeruli can partly contribute to early renal dysfunctions by alteration of prostaglandin production and Na+-K+ ATPase activity as well as the chronic pathological changes by the overexpression of TGF-beta1 and extracellular matrix components genes. Expand
Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor.
It is demonstrated that intravitreal injection of VEGF rapidly activates protein kinase C in the retina at concentrations observed clinically, inducing membrane translocation of PKC isoforms alpha, betaII, and delta and >threefold increases in retinal vasopermeability in vivo. Expand
Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor.
When administered orally, LY333531 ameliorated the glomerular filtration rate, albumin excretion rate, and retinal circulation in diabetic rats in a dose-responsive manner, in parallel with its inhibition of PKC activities. Expand
Protein tyrosine phosphatase 1B inhibitors for diabetes
PTP1B is reviewed as a novel target for type 2 diabetes, and the challenges in developing small-molecule inhibitors of this phosphatase are looked at. Expand
Crystal Structures of Human SIRT3 Displaying Substrate-induced Conformational Changes
The first sets of crystal structures of human SIRT3, an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2, and a reaction intermediate structure trapped by a thioacetyl peptide, provide insights into the conformational changes induced by the two substrates required for the reaction. Expand