Combined caudate lobe and high hilar resection (CCHR) is technically safe and oncologically justifiable and could be adopted with a high cure rate as a one-stage resection procedure for most patients with Bismuth type IV HC whose total bilirubin level is less than 20 mg/L and whose direct bilirubin is more than 60% of total bilirubin.
Background: To study the effect of parecoxib, a novel cyclooxygenase-2 selective inhibitor, on the radiation response of colorectal cancer (CRC) cells and its underlying mechanisms. Materials and Methods: Both in vitro colony formation and apoptosis assays as well as in vivo mouse xenograft experiments were used to explore the radiosensitizing effects of parecoxib in human HCT116 and HT29 CRC cells. Results: Parecoxib sensitized CRC cells to radiation in vitro with a sensitivity enhancement ratio of 1.32 for HCT116 cells and 1.15 for HT29 cells at a surviving fraction of 0.37. This effect was partially attributable to enhanced apoptosis induction by parecoxib combined with radiation, as illustrated using an in vitro apoptosis assays. Parecoxib augmented the tumor response of HCT116 xenografts to radiation, achieving growth delay more than 20 days and an enhancement factor of 1.53. In accordance with the in vitro results, parecoxib combined with radiation resulted in less proliferation and more apoptosis in tumors than radiation alone. Radiation monotherapy decreased microvessel density (MVD) and microvessel intensity (MVI), but increased the hypoxia level in xenografts. Parecoxib did not affect MVD, but it increased MVI and attenuated hypoxia. Conclusions: Parecoxib can effectively enhance radiation sensitivity in CRC cells through direct effects on tumor cells and indirect effects on tumor vasculature.
Introduction:
Metabolic remodeling is critically involved in the pathogenesis of cardiac fibrosis. Glycolytic switch provides rapid energy production and biosynthetic intermediates to support proliferation and collagen synthesis of fibroblast. Sirtuin 5 (Sirt5) is a protein lysine de-succinylase that impacts diverse metabolic pathways.
Objective:
This study aimed to determine the function and mechanism of Sirt5 in cardiac fibroblast activation and cardiac fibrosis.
Methods and Results:
SIRT5 expression was examined in human and mouse myocardia, and was found to be downregulated in fibrotic myocardial tissues compared to non-fibrotic tissues. In a mouse model of myocardial infarction, Sirt5-knockout (KO) mice showed more severe cardiac fibrosis compared with wild-type mice. The aggravating cardiac fibrosis of Sirt5-KO mice were also found after transverse aortic constriction or angiotensin II plus phenylephrine-infusion. Proliferation and collagen synthesis of cardiac fibroblasts (CFBs) were both significantly enhanced by SIRT5 deficiency after AngII/PE-infusion
in vivo
and transform growth factor (TGF)-β1-treatment
in vitro
, but were attenuated by overexpression of Sirt5
in vitro
. Moreover, Sirt5 deficiency enhanced a metabolic switch from oxidative phosphorylation to glycolysis in the isolated CFBs, and inhibition of glycolysis diminished the effect of Sirt5 deficiency on CFBs activation. Mechanistically, lysine succinylome analysis identified phosphoenolpyruvate carboxykinase 2 (Pck2), a rate-limiting enzyme in glycolysis pathway, as the protein mostly succinylated after Sirt5 deficiency. Activity of Pck2 was significantly inhibited by Sirt5 deficiency-mediated hypersuccinylation both
in vivo
and
in vitro
. K489R mutation of Pck2 diminished its succinylation and the reduction of its enzymatic activity mediated by Sirt5 deficiency, which also blunted the effect of Sirt5 deficiency on CFBs activation.
Conclusions:
Sirt5 deficiency enhances a metabolic reprogramming from oxidative phosphorylation to glycolysis in CFBs by succinylating Pck2, which promotes CFBs activation and aggravates cardiac fibrosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.