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Cincinnati, OH, United States

Wang K.,Tongji University | Wang K.,Wuhan University | Dong H.-Q.,Tongji University | Wen H.-Y.,Tongji University | And 6 more authors.
Macromolecular Bioscience | Year: 2011

A novel amphiphilic four-armed [poly(ε-benzyloxycarbonyl-L-lysine)]2-block-poly(ethylene glycol)-block-[poly(ε-benzyloxycarbonyl-L-lysine)]2 hybrid copolymer has been prepared. The cytotoxicity study shows that the copolymer has good biocompatibility with no obvious inhibition effect on cell growth. The amphiphilic copolymers could self-assemble to form vesicles in aqueous solution. DOX · HCl, as a hydrophilic drug, can be loaded into the vesicles, and then successfully internalized by human breast cancer MCF-7 cells. Importantly, the DOX-loaded vesicles show a greatly improved drug release behavior with a zero-order release at the initial stage, suggesting a great potential as the carrier of hydrophilic drugs for controlled drug delivery. Novel vesicles self-assembled from amphiphilic star-armed [poly( ε-benzyloxycarbonyl-L-lysine)]2 -block-poly(ethylene glycol)-block-[poly(ε-benzyloxycarbonyl-L-lysine)]2 hybrid copolymer have been prepared. They display good biocompatibility and improved drug release behavior with a zero-order release at the initial stage, suggesting that they have potential as carriers of hydrophilic drugs for drug delivery. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Lager S.,University of Texas Health Science Center at San Antonio | Lager S.,Gothenburg University | Gaccioli F.,University of Texas Health Science Center at San Antonio | Ramirez V.I.,University of Texas Health Science Center at San Antonio | And 3 more authors.
Journal of Lipid Research | Year: 2013

Obese women have an increased risk to deliver large babies. However, the mechanisms underlying fetal overgrowth in these pregnancies are not well understood. Obese pregnant women typically have elevated circulating lipid levels. We tested the hypothesis that fatty acids stimulate placental amino acid transport, mediated via toll-like receptor 4 (TLR4) and mammalian target of rapamycin (mTOR) signaling pathways. Circulating NEFA levels and placental TLR4 expression were assessed in women with varying prepregnancy body mass index (BMI). The effects of oleic acid on system A and system L amino acid transport, and on the activation of the mTOR (4EBP1, S6K1, rpS6), TLR4 (IκBα, JNK, p38 MAPK), and STAT3 signaling pathways were determined in cultured primary human trophoblast cells. Maternal circulating NEFAs (n = 33), but not placental TLR4 mRNA expression (n = 16), correlated positively with BMI ( P > 0.05). Oleic acid increased trophoblast JNK and STAT3 phosphorylation ( P > 0.05), whereas mTOR activity was unaffected. Furthermore, oleic acid doubled trophoblast system A activity ( P > 0.05), without affecting system L activity. siRNA-mediated silencing of TLR4 expression prevented the stimulatory effect of oleic acid on system A activity. Our data suggest that maternal fatty acids can increase placental nutrient transport via TLR4, thereby potentially affecting fetal growth.Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.. Source

Jones H.N.,University of Cincinnati | Jones H.N.,Center for Molecular Fetal Therapy | Jansson T.,University of Cincinnati | Jansson T.,University of Texas Health Science Center at San Antonio | And 2 more authors.
Diabetes | Year: 2010

OBJECTIVE - Maternal adiponectin levels are reduced and placental nutrient transporters are upregulated in obesity and gestational diabetes mellitus; however, the effects of adiponectin on placental function are unknown. We hypothesized that adiponectin regulates placental amino acid transport. RESEARCH DESIGN AND METHODS - Human primary trophoblast cells were cultured and incubated with globular adiponectin (gAd) or full-length adiponectin (fAd) alone or in combination with insulin. System A and L amino acid transport and SNAT1, SNAT2, and SNAT4 isoform expression was measured. The activity of the AMP-activated protein kinase (AMPK), phosphatidylinositol 3 kinase-AKT, and peroxisome proliferator-activated receptor-α (PPARα) signaling pathways was determined. RESULTS - In the absence of insulin, gAd stimulated AMPK Thr172 phosphorylation, SNAT2 protein expression, and system A activity. This effect appeared to be mediated by interleukin-6 release and signal transducer and activator of transcription 3 (STAT3) signaling because gAd failed to stimulate system A in cells in which STAT3 had been silenced using small interfering RNA. fAd alone had no effect on system A activity or SNAT expression. Insulin increased AKT and insulin receptor substrate 1 (IRS-1) phosphorylation, system A activity, and SNAT2 expression. When combined with insulin, gAd did not affect system A activity or SNAT expression. In contrast, fAd abolished insulin-stimulated AKT Thr308 and IRS-1 Tyr612 phosphorylation, system A activity, and SNAT2 expression. Furthermore, fAd increased PPARα expression and PPARα (Ser21) phosphorylation. CONCLUSIONS - In contrast to the insulin-sensitizing actions of adiponectin in liver and muscle reported in the literature, fAd attenuates insulin signaling in primary human trophoblast cells. As a result, fAd inhibits insulin-stimulated amino acid transport, which may have important implications for placental nutrient transport and fetal growth in pregnancy complications associated with altered maternal adiponectin levels. © 2010 by the American Diabetes Association. Source

Yu L.,Columbia University | Wynn J.,Columbia University | Cheung Y.H.,Columbia University | Shen Y.,Columbia University | And 12 more authors.
Human Genetics | Year: 2013

Congenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm occurring as either an isolated defect or in association with other anomalies. Genetic factors including aneuploidies and copy number variants are important in the pathogenesis of many cases of CDH, but few single genes have been definitively implicated in human CDH. In this study, we used whole exome sequencing (WES) to identify a paternally inherited novel missense GATA4 variant (c.754C>T; p.R252W) in a familial case of CDH with incomplete penetrance. Phenotypic characterization of the family included magnetic resonance imaging of the chest and abdomen demonstrating asymptomatic defects in the diaphragm in the two "unaffected" missense variant carriers. Screening 96 additional CDH patients identified a de novo heterozygous GATA4 variant (c.848G>A; p.R283H) in a non-isolated CDH patient. In summary, GATA4 is implicated in both familial and sporadic CDH, and our data suggests that WES may be a powerful tool to discover rare variants for CDH. © 2012 Springer-Verlag Berlin Heidelberg. Source

Leung A.,Center for Molecular Fetal Therapy | Crombleholme T.M.,Aurora University | Keswani S.G.,Center for Molecular Fetal Therapy
Current Opinion in Pediatrics | Year: 2012

Purpose of Review: The mid-gestation fetus is capable of regenerative healing with wound healing indistinguishable from surrounding skin. This review aims to evaluate the current knowledge of how the mid-gestation fetus heals without scar and the implications of these findings in efforts to recapitulate the fetal regenerative phenotype in the postnatal environment. Recent Findings: It has been over 30 years since the empirical observation that the fetus heals without scar; yet, the underlying mechanisms of this phenomenon have not been elucidated. Fetal wound healing is characterized by a distinct growth factor profile, an attenuated inflammatory response with an anti-inflammatory cytokine profile, an extracellular matrix rich in type III collagen and hyaluronan, attenuated biomechanical stress, and a potential role for stem cells. Current therapies to minimize scarring in postnatal wounds have attempted to recapitulate singular aspects of the fetal regenerative phenotype and have met with varying degrees of clinical success. We now have the molecular tools to more completely comprehend the fundamental mechanisms of fetal regenerative wound repair, which has the potential to provide insights into the identification of therapeutic targets to minimize the scar formation. Summary: Successful therapies that help minimize postnatal scar formation can be realized through understanding the cellular and molecular mechanisms of fetal regenerative wound healing. These insights will have implications not only for cutaneous wound healing, but also potentially for any disease process characterized by excessive fibroplasia. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

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