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Chen Y.-H.,Graduate Institute of Aerospace and Undersea Medicine | Yu J.,Genomics Research Center | Yu J.,Academia Sinica, Taiwan
Developmental Dynamics | Year: 2012

Background: Parthenogenetic mammalian embryos were reported to die in utero no later than the 25-somite stage due to abnormal development of both embryonic and extraembryonic lineages. Interestingly, it has been shown that parthenogenetic ICM cells tend to differentiate more into primitive endoderm cells and less into epiblast and ES cells. Hence we are interested in studying the molecular mechanisms underlying lineage defects of parthenotes. Results: We found that parthenote inner cell masses (ICMs) contained decreased numbers of Sox2+/Nanog+ epiblast cells but increased numbers of Gata4+ primitive endoderm cells, indicating an unusual lineage segregation. We demonstrate for the first time that the increased Gata4 level in parthenotes may be explained by the strong up-regulation of Fgf3 and Fgfr2 phosphorylation. Inhibition of Fgfr2 activation by SU5402 in parthenotes restored normal Nanog and Gata4 levels without affecting Fgf3, indicating that Fgf3 is upstream of Fgfr2 activation. In parthenote trophectoderm, we detected normal Cdx2 but ectopic Gata4 expression and reduced Elf5 and Tbr2(Eomes) levels. Conclusions: Taken together, our work provides for the first time the insight into the molecular mechanisms of the developmental defects of parthenogenetic embryos in both the trophectoderm and ICM. © 2012 Wiley Periodicals, Inc.

Lin K.-T.,Tri Service General Hospital | Lin C.-S.,Tri Service General Hospital | Lee S.-Y.,Graduate Institute of Aerospace and Undersea Medicine | Huang W.-Y.,Tri Service General Hospital | Chang W.-K.,National Defense Medical Center
Medicine (United States) | Year: 2016

Esophageal cancers account for majority of synchronous or metachronous head and neck cancers. This study examined the risk of esophageal cancer following percutaneous endoscopic gastrostomy (PEG) in head and neck cancer patients using the Taiwan National Health Insurance Research Database. From 1997 to 2010, we identified and analyzed 1851 PEG patients and 3702 sex-, age-, and index date-matched controls. After adjusting for esophagitis, esophagus stricture, esophageal reflux, and primary sites, the PEG cohort had a higher adjusted hazard ratio (2.31, 95% confidence interval [CI]=1.09-4.09) of developing esophageal cancer than the controls. Primary tumors in the oropharynx, hypopharynx, and larynx were associated with higher incidence of esophageal cancer. The adjusted hazard ratios were 1.49 (95% CI=1.01-1.88), 3.99 (95% CI=2.76-4.98), and 1.98 (95% CI=1.11-2.76), respectively. Head and neck cancer patients treated with PEG were associated with a higher risk of developing esophageal cancer, which could be fixed by surgically placed tubes. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Ho C.-L.,Taiwan Forestry Research Institute | Lin C.-Y.,National Ilan University | Ka S.-M.,Graduate Institute of Aerospace and Undersea Medicine | Chen A.,National Defense Medical Center | And 4 more authors.
PLoS ONE | Year: 2013

Bamboo vinegar (BV), a natural liquid derived from the condensation produced during bamboo charcoal production, has been used in agriculture and as a food additive, but its application to immune modulation has not been reported. Here, we demonstrated that BV has anti-inflammatory activities both in vitro and in vivo. BV reduced inducible nitric oxide synthase expression and nitric oxide levels in, and interleukin-6 secretion by, lipopolysaccharide-activated macrophages without affecting tumor necrosis factor-α secretion and cyclooxygenase-2 expression. The mechanism for the anti-inflammatory effect of BV involved decreased reactive oxygen species production and protein kinase C-α/δ activation. Furthermore, creosol (2-methoxy-4-methylphenol) was indentified as the major anti-inflammatory compound in BV. Impaired cytokine expression and NLR family, pyrin domain-containing 3 (NLRP3) inflammasome activation was seen in mice treated with creosol. These findings provide insights into how BV regulates inflammation and suggest that it may be a new source for the development of anti-inflammatory agents or a healthy supplement for preventing and ameliorating inflammation- and NLRP3 inflammasome-related diseases, including metabolic syndrome. © 2013 Ho et al.

Chang Y.-P.,National Ilan University | Ka S.-M.,Graduate Institute of Aerospace and Undersea Medicine | Hsu W.-H.,A-Life Medical | Chen A.,National Defense Medical Center | And 9 more authors.
Journal of Cellular Physiology | Year: 2015

The NLRP3 inflammasome is a caspase-1-containing multi-protein complex that controls the release of IL-1β and plays important roles in the development of inflammatory disease. Here, we report that resveratrol, a polyphenolic compound naturally produced by plants, inhibits NLRP3 inflammasome-derived IL-1β secretion and pyroptosis in macrophages. Resveratrol inhibits the activation step of the NLRP3 inflammasome by suppressing mitochondrial damage. Resveratrol also induces autophagy by activating p38, and macrophages treated with an autophagy inhibitor are resistant to the suppressive effects of resveratrol. In addition, resveratrol administration mitigates glomerular proliferation, glomerular sclerosis, and glomerular inflammation in a mouse model of progressive IgA nephropathy. These findings were associated with decreased renal mononuclear leukocyte infiltration, reduced renal superoxide anion levels, and inhibited renal NLRP3 inflammasome activation. Our data indicate that resveratrol suppresses NLRP3 inflammasome activation by preserving mitochondrial integrity and by augmenting autophagy. © 2014 Wiley Periodicals, Inc.

Ka S.M.,Graduate Institute of Aerospace and Undersea Medicine | Yeh Y.C.,A-Life Medical | Huang X.R.,Chinese University of Hong Kong | Chao T.K.,National Defense Medical Center | And 6 more authors.
Diabetologia | Year: 2012

Aims/hypothesis: The TGF-β/MAD homologue (SMAD) and nuclear factor κB (NF-κB) signalling pathways have been shown to play a critical role in the development of renal fibrosis and inflammation in diabetic nephropathy. We therefore examined whether targeting these pathways by a kidney-targeting Smad7 gene transfer has therapeutic effects on renal lesions in the db/db mouse model of type 2 diabetes. Methods: We delivered Smad7 plasmids into the kidney of db/db mice using kidney-targeting, ultrasound-mediated, microbubble-inducible gene transfer. The histopathology, ultrastructural pathology and pathways of TGF-β/SMAD2/3-mediated fibrosis and NF-κB-dependent inflammation were evaluated. Results: In this mouse model of type 2 diabetes, Smad7 gene therapy significantly inhibited diabetic kidney injury, compared with mice treated with empty vectors. Symptoms inhibited included: (1) proteinuria and renal function impairment; (2) renal fibrosis such as glomerular sclerosis, tubulo-interstitial collagen matrix abundance and renal inflammation, including Inos (also known as Nos2), Il1b and Mcp1 (also known as Ccl2) upregulation, as well as macrophage infiltration; and (3) podocyte and endothelial cell injury as demonstrated by immunohistochemistry and/or electron microscopy. Further study demonstrated that the improvement of type 2 diabetic kidney injury by overexpression of Smad7 was associated with significantly inhibited local activation of the TGF-β/SMAD and NF-κB signalling pathways in the kidney. Conclusions/interpretation: Our results clearly demonstrate that kidney-targeting Smad7 gene transfer may be an effective therapy for type 2 diabetic nephropathy, acting via simultaneous modulation of the TGF-β/SMAD and NF-κB signalling pathways. © 2011 Springer-Verlag.

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