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Lan H.-C.,Academia Sinica, Taiwan | Lan H.-C.,Institute of Biology and Anatomy | Wu C.-F.,Academia Sinica, Taiwan | Wu C.-F.,National Yang Ming University | And 3 more authors.
Journal of Biological Chemistry

SF-1 is a key transcription factor for all steroidogenic genes. It up-regulates the expression of the steroidogenic Cyp11a1 gene in the adrenal in a pathway stimulated by cAMP through HIPK3-mediated JNK/c-Jun phosphorylation. In the present study, we have investigated the factors mediating cAMP-dependent HIPK3 action to potentiate the activity of SF-1 for Cyp11a1 transcription in mouse adrenocortical Y1 cells. We found Daxx, a HIPK kinase substrate in the apoptosis pathway, was phosphorylated by HIPK3 at Ser-669 in response to cAMP stimulation. Daxx participated in SF-1-dependent Cyp11a1 expression as shown by experiments involving both overexpression and down-regulation via a dominant negative Daxx mutant. The S669A mutant of Daxx, which could not be phosphorylated by HIPK3, lost the ability to potentiate SF-1 activity for Cyp11a1 expression. The enhancement of SF-1 activity by Daxx required JNK and c-Jun phosphorylation. Thus, Daxx functioned as a signal transducer linking cAMP-stimulated HIPK3 activity with JNK/c-Jun phosphorylation and SF-1-dependent Cyp11a1 transcription for steroid synthesis. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Huang K.-H.,Taipei Medical University | Pai M.-H.,Taipei Medical University | Wu C.-H.,Institute of Biology and Anatomy | Liu J.-J.,Taipei Medical University | Yeh S.-L.,Taipei Medical University

Background & aims: Arginine (Arg) was shown to have immunomodulatory effect and inhibits advanced glycation end product (AGE) formation in in vitro studies. This study investigated the effects of dietary Arg supplementation on renal receptor of AGE (RAGE) expressions and oxidative damage in diabetic rats. Methods: There were 1 normal control (NC) group and 2 diabetic groups in this study. Rats in the NC group were fed with a chow diet. One diabetic group (DM) was fed a common semipurified diet, while the other diabetic group received a diet in which part of the casein was replaced by Arg (DM-Arg) for 8 wk. Diabetes was induced by an intraperitoneal injection of nicotinamide followed by streptozotocin. Rats with blood glucose levels exceeding 180 mg/dL were considered diabetic. Blood samples were collected at the baseline and 8 wk. Kidneys of the animals were harvested at the end of the study for further analysis. Results: Plasma fructosamine contents were significantly higher in the diabetic groups than in the NC group. The DM group had higher fructosamine than the DM-Arg group. Kidney nitrotyrosine concentrations and nuclear factor-κB p65 protein expressions were significantly lower in the DM-Arg group than in the DM group. The result of immunohistochemical staining also showed that the expressions of RAGE in the kidneys were significantly lower in the DM-Arg group than in the DM group. Conclusions: These results suggest that dietary Arg supplementation may decrease renal RAGE expressions and oxidative damage in rats with type 2 diabetes. © 2010 European Society for Clinical Nutrition and Metabolism. Source

Huang W.-C.,Taipei Veterans General Hospital | Huang W.-C.,Graduate Institute of Medical science | Huang W.-C.,National Yang Ming University | Kuo H.-S.,Taipei Veterans General Hospital | And 13 more authors.
Journal of Gene Medicine

Background: Following spinal cord injury, the delivery of neurotrophic factors to the injured spinal cord has been shown to promote axonal regeneration and functional recovery. In previous studies, we showed that acidic fibroblast growth factor (aFGF) is a potent neurotrophic factor that promotes the regeneration of axotomized spinal cord or dorsal root ganglion neurones. Methods: We constructed a recombinant adeno-associated virus (AAV) vector to express human aFGF and evaluated aFGF expression and function in AAV-aFGF-infected PC12 cells. We analyzed AAV-green fluorescent protein (GFP) tropism and AAV-mediated aFGF expression in contused spinal cords. Animals received behavioural testing to evaluate the functional recovery. Results: Overexpression of aFGF was shown in AAV-aFGF-infected PC12 cells in a dose-dependent manner. Concurrently, neurite extension and cell number were significantly increased in AAV-aFGF infected cells. AAV-mediated GFP expression persisted for at least 5 weeks in contused spinal cords, and the most prominently transduced cells were neurones. Contusive injury reduced endogenous aFGF expression in spinal cords. Overexpression of aFGF was demonstrated in AAV-aFGF transduced spinal cords compared to AAV-GFP transduced spinal cords at 3 and 14 days post-injury. Evaluation of motor function revealed that the improvement of AAV-aFGF-treated rats was prominent. Both AAV-aFGF- and recombinant human aFGF-treated rats revealed significantly better recovery at 5 weeks post-injury, compared to vehicle- and AAV-GFP-treated rats. Conclusions: These data suggest that supplement of aFGF improve the functional recovery of spinal cord-contused rats and that AAV-aFGF-mediated gene transfer could be a clinically feasible therapeutic approach for patients after nervous system injuries. © 2011 John Wiley & Sons, Ltd. Source

Shyu H.-Y.,Neurology Section | Shyu H.-Y.,Institute of Biology and Anatomy | Fong C.-S.,Buddhist Dalin Tzu Chi General Hospital | Fong C.-S.,Tzu Chi University | And 6 more authors.
Clinica Chimica Acta

Background: γ-Glutamyl carboxylation, a reaction essential for the biosynthesis of vitamin K-dependent coagulation factors, requires the participation of the γ-glutamyl carboxylase (GGCX), vitamin K epoxide reductase (VKORC1), and NAD(P)H:quinone oxidoreductase (NQO1). We evaluated the role of these genotype polymorphisms in patients with large-artery atherosclerotic stroke. Methods: In this hospital-based case-control study, 117 patients who were categorized as having large-artery atherosclerotic stroke and 115 age- and gender-matched controls were recruited. Genotyping determination for the GGCX1 (Gln325Arg), NQO1 (Pro187Ser), and VKORC1 (rs9923231) polymorphisms was performed. The associations of genotype with ischemic stroke (IS) risk were examined. Results: A higher genotypic frequency of NQO1 C609T was found in the controls than in the patients, manifesting a 0.47-fold risk reduction in IS (95% CI=0.25-0.87). A tendency toward a reduced IS risk was statistically significant in those subjects who carried a greater number of the NQO1, GGCX, and VKORC1 polymorphisms (aOR=0.58, P trend=0.005). The synergistic effect of multiple genes on risk reduction was more significant in a subset of patients who were not alcoholics and who were non-smokers (P<0.05). Conclusions: Compartmentation of coagulation factor metabolism may account for the preferential role of NQO1, GGCX, and VKORC1 polymorphisms to lower the risk for large-artery atherosclerotic stroke. © 2010 Elsevier B.V. Source

Lin Y.-H.,National Taiwan University of Science and Technology | Fu K.-Y.,National Defense Medical Center | Hong P.-D.,National Taiwan University of Science and Technology | Ma H.,Veteran General Hospital | And 10 more authors.
Annals of Plastic Surgery

ABSTRACT: Embryonic stem cells (ESCs) are pluripotent cells that can differentiate into various cell types, including keratinocyte-like cells, within suitable microniches. In this study, we aimed to investigate the effects of culture media, cell coculture, and a tissue-engineering biocomposite on the differentiation of mouse ESCs (MESCs) into keratinocyte-like cells and applied these cells to a surgical skin wound model. MESCs from BALB/c mice (ESC26GJ), which were transfected using pCX-EGFP expressing green fluorescence, were used to track MESC-derived keratinocytes. Weak expression of the keratinocyte early marker Cytokeratin 14 (CK-14) was observed up to 12 days when MESCs were cultured in a keratinocyte culture medium on tissue culture plastic and on a gelatin/collagen/polycaprolactone (GCP) biocomposite. MESCs cocultured with human keratinocyte cells (HKCs) also expressed CK-14, but did not express CK-14 when cocultured with human fibroblast cells (HFCs). Furthermore, CK-14 expression was observed when MESCs were cocultured by seeding HKCs or HFCs on the same or opposite side of the GCP biocomposite. The highest CK-14 expression was observed by seeding MESCs and HKCs on the same side of the GCP composite and with HFCs on the opposite side. To verify the effectiveness of wound healing in vivo, adipose-derived stem cells were applied to treat surgical wounds in nude mice. An obvious epidermis multilayer and better collagen deposition during wound healing were observed, as assessed by Masson staining. This study demonstrated the potential of keratinocyte-like differentiation from mesenchymal stem cells for use in promoting wound closure and skin regeneration. Copyright © 2013 Lippincott Williams & Wilkins. Source

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