The enhancement of endogenous neurogenesis has been suggested in the treatment of traumatic brain injury (TBI); however, the factors that trigger the process of adult neurogenesis following TBI remain elusive. In the adult mammalian central nervous system, there are 2 neurogenic regions: the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles, both of which maintain relatively quiescent states in a stable microenvironment. However, once stimulated by intrinsic and extrinsic events, relevant signals are activated in these 2 regions. In this study, in order to explore the mechanisms behind endogenous neurogenesis following TBI, we investigated potential factors regulating this process. We observed that the expression of survivin, an anti-apoptotic protein, increased in a time-dependent manner in the hippocampus in a mouse model of TBI. In addition, the number of survivin (+) cells, as well as that of BrdU (+) cells increased in the SGZ of the dentate gyrus (DG) in the hippocampus following TBI, as shown by immunofluorescence double staining; the co-localization of survivin and BrdU was shown in the merged images. The expression of survivin was also significantly increased in the doublecortin (DCX) (+) immature neurons in the DG of the hippocampus soon after the induction of TBI. Taken together, these data confirm the connection between the expression of survivin and adult neurogenesis following TBI; our data also suggest the therapeutic potential of upregulating survivin expression as a novel strategy for the effective treatment of TBI.
Aim: To examine the inhibitory effects of adenosine monophosphate-activated protein kinase (AMPK) activation on cardiac hypertrophy in vitro and to investigate the underlying molecular mechanisms. Methods: Cultured neonatal rat cardiomyocytes were treated with the specifi c AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and the specifi c AMPK antagonist Compound C, and then stimulated with phenylephrine (PE). The Muscle RING fi nger 1 (MuRF1)-small interfering RNA (siRNA) was transfected into cardiomyocytes using Lipofectamine 2000. The surface area of cultured cardiomyocytes was measured using planimetry. The protein degradation was determined using high performance liquid chromatography (HPLC). The expression of β-myosin heavy chain (β-MHC) and MuRF1, as well as the phosphorylation levels of AMPK and Forkhead box O 1 (FOXO1), were separately measured using Western blot or real-time polymerase chain reaction. Results: Activation of AMPK by AICAR 0.5 mmol/L inhibited PE-induced increase in cardiomyocyte area and β-MHC protein expression and PE-induced decrease in protein degradation. Furthermore, AMPK activation increased the activity of transcription factor FOXO1 and up-regulated downstream atrogene MuRF1 mRNA and protein expression. Treatment of hypertrophied cardiomyocytes with Compound C 1 μmol/L blunted the effects of AMPK on cardiomyocyte hypertrophy and changes to the FOXO1/MuRF1 pathway. The effects of AICAR on cardiomyocyte hypertrophy were also blocked after MuRF1 was silenced by transfection of cardiomyocytes with MuRF1-siRNA. Conclusion: The present study demonstrates that AMPK activation attenuates cardiomyocyte hypertrophy by modulating the atrophyrelated FOXO1/MuRF1 signaling pathway in vitro.
The aim of the present study was to examine the role of sirtuin 3 (Sirt3)-autophagy in regulating myocardial energy metabolism and inhibiting myocardial hypertrophy in angiotensin (ang) ii-induced myocardial cell hypertrophy. The primary cultured myocardial cells of neonatal Sprague dawley rats were used to construct a myocardial hypertrophy model induced with ang ii. Following the activation of Sirt3 by resveratrol (res), Sirt3 was silenced using small interfering (si)rna-Sirt3, and the morphology of the myocardial cells was observed under an optical microscope. reverse transcription-polymerase chain reaction was used to detect the mrna expression of the following myocardial hypertrophy markers; atrial natriuretic peptide (anP), brain natriuretic peptide (BnP), Sirt3, medium-chain acyl-coa dehydrogenase (Mcad) and pyruvate kinase (PK). Western blot analysis was used to detect the protein expression of Sirt3, light chain 3 (lc3) and Beclin1. ang ii may inhibit the protein expression of Sirt3, lc3 and Beclin1. res, an agonist of Sirt3, may promote the protein expression of Sirt3, lc3 and Beclin1. res inhibited the mrna expression of anP and BnP, and reversed the ang ii-induced myocardial cell hypertrophy. The addition of sirna-Sirt3 decreased the protein expression of Sirt3, lc3 and Beclin1, increased the mrna expression of anP and BnP, and weakened the inhibitory effect of res on myocardial cell hypertrophy. res promoted the mrna expression of Mcad, inhibited the mrna expression of PK, and reversed the influence of Ang II on myocardial energy metabolism. siRNA-Sirt3 intervention significantly decreased the effect of res in eliminating abnormal myocardial energy metabolism. in conclusion, Sirt3 may inhibit ang ii-induced myocardial hypertrophy and reverse the ang ii-caused abnormal myocardial energy metabolism through activation of autophagy.
By combining the Pax6(m/+) genetic background with an high-fat diet environment, we developed a novel diabetic model to mimic human type 2 diabetes. This model is characterized by impaired insulin secretion, caused by the Pax6 mutation, and high-fat diet-induced insulin resistance and therefore provides an ideal tool for research on type 2 diabetes pathogenesis and therapies.
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