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Chuang Y.-F.,Taipei Medical University | Yang H.-Y.,Taipei Medical University | Ko T.-L.,Taipei Medical University | Hsu Y.-F.,Landseed Hospital | And 3 more authors.
Biochemical Pharmacology | Year: 2014

Inflammation and vascular perturbations are increasingly implicated in the pathogenesis of neurodegenerative diseases. Prevailing evidence suggests that valproic acid (VPA), an antiepileptic and mood stabilizer, exhibits not only neuro-protective effects, but also anti-inflammatory effects in neurodegenerative diseases. However, the underlying mechanism contributing to VPA's suppression of inflammatory responses remains unclear. In this study, we explored the inhibitory action of VPA on cyclooxygenase (COX)-2 expression in bEnd.3 mouse brain microvascular endothelial cells exposed to lipopolysaccharide (LPS), a pro-inflammatory stimulus. The LPS-induced increases in COX-2 protein level and COX-2 promoter-luciferase activity were significantly suppressed by VPA. VPA inhibited p38MAPK and JNK phosphorylation in LPS-stimulated bEnd.3 cells. Treatment of cells with a p38MAPK inhibitor (p38MAPK inhibitor III) or a JNK signaling inhibitor (JNK inhibitor II) significantly inhibited LPS-induced COX-2 expression. VPA inhibited LPS-induced NF-κB subunit p65 phosphorylation and κB-luciferase activity. LPS-increased p65 and C/EBPβ binding to the COX-2 promoter region was attenuated in the presence of VPA. In addition, VPA suppression of p38MAPK, JNK and p65 phosphorylation, and subsequent COX-2 expression was restored in cells transfected with mitogen-activated protein kinase phosphatase-1 (MKP-1) dominant negative (DN) mutant. VPA also caused increases in MKP-1 acetylation and MKP-1 phosphatase activity in bEnd.3 cells. In conclusion, VPA may cause MKP-1 activation to dephosphorylate p38MAPK and JNK, leading to decrease in p65 and C/EBPβ binding to the COX-2 promoter region and COX-2 down-regulation in LPS-stimulated bEnd.3 cells. The present study therefore supports the therapeutic value of VPA in alleviating brain inflammatory processes. © 2014 Elsevier Inc. Source

Wu S.-Y.,Graduate Institute of Medical science | Wu C.-P.,Landseed Hospital | Kang B.-H.,Institute of Aerospace and Undersea Medicine | Li M.-H.,Institute of Aerospace and Undersea Medicine | And 2 more authors.
Critical Care Medicine | Year: 2012

Objective: Although ischemia-reperfusion injury is a major determinant of primary graft dysfunction after lung transplantation, an approach to extend preoperative lung preservation to postoperative protection has not yet been defined. The purpose of this study was to determine the protective effects of and the signal pathway regulated by hypercapnic acidosis in ischemia- reperfusion-induced lung injury. Design: Animal study. Setting: Animal care facility procedure room in a medical center. Subjects: Adult male Sprague-Dawley rats. Interventions: Lung injury was induced in a clinically relevant ex vivo animal model. Animals were divided into a control group (FICO2, 5%; n = 6), ischemia-reperfusion group (FICO2, 5%; n = 6), and hypercapnic acidosis (ischemia-reperfusion + hypercapnic acidosis) group (FICO2, 10%; n = 6). Measurements and Main Results; Ischemia-reperfusion caused significant increases in alveolar lavage and perfusate tumor necrosis factor-α, inflammatory cell infiltration, lung tissue malondialdehyde, bronchoalveolar lavage fluid protein concentration and lactate dehydrogenase activity, lung weight gain, and infiltration coefficient. Ventilation with 10% CO2 significantly suppressed the inflammatory response and attenuated lung ischemia-reperfusion injury. Our results also showed that hypercapnic acidosis significantly inhibited the ischemia-reperfusion-induced phosphorylation and nuclear translocation of nuclear factor-κB. This was associated with elevation of inhibitor of nuclear factor-κB-α level and reduced IκB kinase-β phosphorylation, suggesting a suppression of IκB kinase and thus IκB-α activation. Conclusions: Hypercapnic acidosis may attenuate lung ischemia-reperfusion injury by suppressing the activation of the IκB kinase-nuclear factor-κB pathway. Copyright © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins. Source

Chen T.-A.,Landseed Hospital | Horng J.-T.,Asia University, Taiwan | Horng J.-T.,National Central University | Lin W.-C.,National Central University
International Journal of Clinical Oncology | Year: 2013

Background: The risk of metachronous colorectal cancer in patients with colorectal cancer is higher than the rate of sporadic colorectal cancer in the average population. We conducted a large-scale, population-based study, with many more clinical cases than in previously published studies, to calculate the incidence of metachronous colorectal cancer. Methods: This is a retrospective study based on data obtained from the Taiwan Cancer Registry from 1988 to 2007. Between 1988 and 2002, we analyzed 70,906 patients who were diagnosed with colon or rectal cancer and traced the occurrence of metachronous lesions with at least 5 years of follow-up. Results: Of these patients, 1,192 (730 males, 462 females; mean age 62.73 ± 12.92 years) developed metachronous cancers. The 15-year cumulative incidence of metachronous cancer was 1.68%. Within 2 years of the index cancer, 51.69% of the metachronous cancers appeared, and 61.27% of the metachronous cancers appeared within 3 years. Conclusions: Most metachronous lesions were noted within 3 years of initial diagnosis of the index cancer. Surveillance colonoscopy to ensure the absence of metachronous disease is essential for patients after curative surgery within 1 year, especially for those patients who did not receive complete colonoscopy before their first operation for colorectal cancer. © 2012 Japan Society of Clinical Oncology. Source

Huang Y.-H.,Taipei Medical University | Yang H.-Y.,Taipei Medical University | Hsu Y.-F.,Landseed Hospital | Chiu P.-T.,Taipei Medical University | And 2 more authors.
Angiogenesis | Year: 2014

Formation of lymphatic capillaries by lymphatic endothelial cells (LECs) occurs both in normal tissues as well as in pathological processes including tumor metastasis. Interleukin-6 (IL-6), a potent pro-inflammatory cytokine, has been shown to be highly elevated in various cancers. IL-6 has also been shown to increase tumor lymphangiogenesis through vascular endothelial growth factor-C (VEGF-C) induction in tumor cells. Although lymphangiogenesis is associated with lymph node metastasis and also resistance to conventional therapy in various cancers, the precise mechanisms of lymphangiogenesis in LECs remain unclear. This study aimed to investigate the signaling cascade involved in IL-6-induced VEGF-C expression in murine LECs (SV-LEC). The VEGF-C mRNA and protein levels were increased in SV-LECs exposed to IL-6. IL-6 time-dependently induced Src phosphorylation and downstream phosphorylation of ERK1/2 and p38MAPK. In contrast, PP2, an inhibitor of Src signaling, abrogated IL-6's effects on ERK1/2 and p38MAPK phosphorylation. IL-6 exposure also led to increase in VEGF-C promoter-luciferase activity as well as C/EBPβ- and κB-luciferase activities. VEGF-C promoter-, C/EBPβ- and κB-luciferase activities were all suppressed by Src, ERK1/2 or p38MAPK signaling blockades despite presence of IL-6. Finally, C/EBPβ and p65 binding to the VEGF-C promoter region were increased after IL-6 exposure in SV-LECs. Taken together, we report a Src-mediated ERK1/2 and p38MAPK activation resulting in C/EBPβ and p65 binding to the promoter region of VEGF-C, leading to VEGF-C expression in IL-6-exposed SV-LECs. © 2013 Springer Science+Business Media Dordrecht. Source

Yang H.-H.,Chi Mei Medical Center | Yang H.-H.,Southern Taiwan University of Science and Technology | Hou C.-C.,Landseed Hospital | Lin M.-T.,Chi Mei Medical Center | Chang C.-P.,Southern Taiwan University of Science and Technology
American Journal of Respiratory Cell and Molecular Biology | Year: 2012

Dextromethorphan (DM) has been shown to protect against endotoxic shock in mice. Heatstroke resembles sepsis in many respects. The objective of this study was to examine the heat-induced acute lung inflammation and injury in rats with or without DM, and for comparison with those of the rats with MK-801 (an N-methyl-Daspartate receptor antagonist), SA4503 (a sigma-1 receptor agonist), or fluoxetine (a serotonin reuptake inhibitor). Heatstroke was induced by exposing the anesthetized rats to heat stress (43°C for 68 min). At 68 minutes after start of heat stress, animals treated with vehicle medium,DM(10-30 mg/kg of body weight, intramuscular), MK-801 (1mg/kg of bodyweight, intraperitoneal), SA4503 (1mg/kg of body weight, intraperitoneal), or fluoxetine (5 mg/kg of body weight, intraperitoneal)wereallowedtorecoverat roomtemperature (26°C). As comparedwith vehicle-treated heatstroke rats (25-31 min; n=8),DM(30mg/kg)-treatedheatstrokerats andMK-801(1mg/kg)- treated heatstroke rats had significantly greater survival time (193-209 min [n=7] and 121-133 min [n=8], respectively). However, the survival times for the SA4503-treated heatstroke rats (28-34 min; n=8) or the fluoxetine-treated heatstroke rats (20-26 min; n=8) were not significantly different from the vehicle-treated heatstroke rats. DM treatment significantly: (1) reduced acute lung injury, including edema, neutrophils infiltration, and hemorrhage scores; (2) decreased acute pleurisy; and (3) decreased bronchoalveolar fluid levels of the proinflammatory cytokines, and ischemia and oxidative damage markers during heatstroke. Our results indicate that DM therapymay improve outcomes of heatstroke in rats by antagonizing the N-methyl-D-aspartate receptors. Copyright © 2012 by the American Thoracic Society. Source

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