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  1. Article ; Online: Copper-Binding Domain Variation in a Novel Murine Lysyl Oxidase Model Produces Structurally Inferior Aortic Elastic Fibers Whose Failure Is Modified by Age, Sex, and Blood Pressure

    Kit Man Tsang / Russell H. Knutsen / Charles J. Billington / Eric Lindberg / Heiko Steenbock / Yi-Ping Fu / Amanda Wardlaw-Pickett / Delong Liu / Daniela Malide / Zu-Xi Yu / Christopher K. E. Bleck / Jürgen Brinckmann / Beth A. Kozel

    International Journal of Molecular Sciences, Vol 23, Iss 6749, p

    2022  Volume 6749

    Abstract: Lysyl oxidase ( LOX ) is a copper-binding enzyme that cross-links elastin and collagen. The dominant LOX variation contributes to familial thoracic aortic aneurysm. Previously reported murine Lox mutants had a mild phenotype and did not dilate without ... ...

    Abstract Lysyl oxidase ( LOX ) is a copper-binding enzyme that cross-links elastin and collagen. The dominant LOX variation contributes to familial thoracic aortic aneurysm. Previously reported murine Lox mutants had a mild phenotype and did not dilate without drug-induced provocation. Here, we present a new, more severe mutant, Lox b 2b370.2Clo (c.G854T; p.Cys285Phe), whose mutation falls just N-terminal to the copper-binding domain. Unlike the other mutants, the C285F Lox protein was stably produced/secreted, and male C57Bl/6J Lox +/ C285F mice exhibit increased systolic blood pressure (BP; p < 0.05) and reduced caliber aortas ( p < 0.01 at 100mmHg) at 3 months that independently dilate by 6 months ( p < 0.0001). Multimodal imaging reveals markedly irregular elastic sheets in the mutant ( p = 2.8 × 10 −8 for breaks by histology) that become increasingly disrupted with age ( p < 0.05) and breeding into a high BP background ( p = 6.8 × 10 −4 ). Aortic dilation was amplified in males vs. females ( p < 0.0001 at 100mmHg) and ameliorated by castration. The transcriptome of young Lox mutants showed alteration in dexamethasone ( p = 9.83 × 10 −30 ) and TGFβ-responsive genes ( p = 7.42 × 10 −29 ), and aortas from older C57Bl/6J Lox +/ C285F mice showed both enhanced susceptibility to elastase ( p < 0.01 by ANOVA) and increased deposition of aggrecan ( p < 0.05). These findings suggest that the secreted Lox +/ C285F mutants produce dysfunctional elastic fibers that show increased susceptibility to proteolytic damage. Over time, the progressive weakening of the connective tissue, modified by sex and blood pressure, leads to worsening aortic disease.
    Keywords lysyl oxidase ; elastin ; collagen ; thoracic aortic aneurysm ; sex as a biological variable ; Fib-SEM ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 333
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Impact of retinoic acid exposure on midfacial shape variation and manifestation of holoprosencephaly in Twsg1 mutant mice

    Charles J. Billington / Brian Schmidt / Ralph S. Marcucio / Benedikt Hallgrimsson / Rajaram Gopalakrishnan / Anna Petryk

    Disease Models & Mechanisms, Vol 8, Iss 2, Pp 139-

    2015  Volume 146

    Abstract: Holoprosencephaly (HPE) is a developmental anomaly characterized by inadequate or absent midline division of the embryonic forebrain and midline facial defects. It is believed that interactions between genes and the environment play a role in the widely ... ...

    Abstract Holoprosencephaly (HPE) is a developmental anomaly characterized by inadequate or absent midline division of the embryonic forebrain and midline facial defects. It is believed that interactions between genes and the environment play a role in the widely variable penetrance and expressivity of HPE, although direct investigation of such effects has been limited. The goal of this study was to examine whether mice carrying a mutation in a gene encoding the bone morphogenetic protein (BMP) antagonist twisted gastrulation (Twsg1), which is associated with a low penetrance of HPE, are sensitized to retinoic acid (RA) teratogenesis. Pregnant Twsg1+/− dams were treated by gavage with a low dose of all-trans RA (3.75 mg/kg of body weight). Embryos were analyzed between embryonic day (E)9.5 and E11.5 by microscopy and geometric morphometric analysis by micro-computed tomography. P19 embryonal carcinoma cells were used to examine potential mechanisms mediating the combined effects of increased BMP and retinoid signaling. Although only 7% of wild-type embryos exposed to RA showed overt HPE or neural tube defects (NTDs), 100% of Twsg1−/− mutants exposed to RA manifested severe HPE compared to 17% without RA. Remarkably, up to 30% of Twsg1+/− mutants also showed HPE (23%) or NTDs (7%). The majority of shape variation among Twsg1+/− mutants was associated with narrowing of the midface. In P19 cells, RA induced the expression of Bmp2, acted in concert with BMP2 to increase p53 expression, caspase activation and oxidative stress. This study provides direct evidence for modifying effects of the environment in a genetic mouse model carrying a predisposing mutation for HPE in the Twsg1 gene. Further study of the mechanisms underlying these gene-environment interactions in vivo will contribute to better understanding of the pathogenesis of birth defects and present an opportunity to explore potential preventive interventions.
    Keywords Twisted gastrulation ; Twsg1 ; Bone morphogenetic protein ; Holoprosencephaly ; Retinoic acid ; Apoptosis ; Oxidative stress ; Medicine ; R ; Pathology ; RB1-214
    Subject code 571
    Language English
    Publishing date 2015-02-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Glycosylation of Twisted gastrulation is required for BMP binding and activity during craniofacial development

    CharlesJ.Billington / JulianeFiebig / LanPham / MuSun / TinaJaskoll / KimMansky

    Frontiers in Physiology, Vol

    2011  Volume 2

    Abstract: Twisted Gastrulation (TWSG1) is a conserved, secreted glycoprotein that modulates signaling of bone morphogenetic proteins (BMPs) in the extracellular space. Deletion of exon 4 of mouse Twsg1 (mTwsg1) is associated with significant craniofacial defects. ... ...

    Abstract Twisted Gastrulation (TWSG1) is a conserved, secreted glycoprotein that modulates signaling of bone morphogenetic proteins (BMPs) in the extracellular space. Deletion of exon 4 of mouse Twsg1 (mTwsg1) is associated with significant craniofacial defects. However, little is understood about the biochemical properties of the corresponding region of the protein. We have uncovered a significant role for exon 4 sequences as encoding the only two glycosylation sites of the mTWSG1 protein. Deletion of the entire exon 4 or mutation of both glycosylation sites within exon 4 abolishes glycosylation of mTWSG1. Importantly, we find that constructs with mutated glycosylation sites have significantly reduced BMP binding activity. We further show that glycosylation and activity of TWSG1 recombinant proteins vary markedly by cellular source. Non-glycosylated mTWSG1 made in E. coli has both reduced affinity for BMPs, as shown by surface plasmon resonance analysis, and reduced BMP inhibitory activity in a mandibular explant culture system compared to glycosylated proteins made in insect cells or murine myeloma cells. This study highlights an essential role for glycosylation in Twisted gastrulation action.
    Keywords Glycosylation ; BMP ; Mandibular explants ; MSX2 ; Surface plasmon resonance analysis ; Twisted gastrulation ; Physiology ; QP1-981 ; Science ; Q
    Language English
    Publishing date 2011-09-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Sustained Weight Loss with Vagal Nerve Blockade but Not with Sham

    Scott A. Shikora / Bruce M. Wolfe / Caroline M. Apovian / Mehran Anvari / David B. Sarwer / Robert D. Gibbons / Sayeed Ikramuddin / Christopher J. Miller / Mark B. Knudson / Katherine S. Tweden / Michael G. Sarr / Charles J. Billington

    Journal of Obesity, Vol

    18-Month Results of the ReCharge Trial

    2015  Volume 2015

    Abstract: Background/Objectives. Vagal block therapy (vBloc) is effective for moderate to severe obesity at one year. Subjects/Methods. The ReCharge trial is a double-blind, randomized controlled clinical trial of 239 participants with body mass index (BMI) of 40 ... ...

    Abstract Background/Objectives. Vagal block therapy (vBloc) is effective for moderate to severe obesity at one year. Subjects/Methods. The ReCharge trial is a double-blind, randomized controlled clinical trial of 239 participants with body mass index (BMI) of 40 to 45 kg/m or 35 to 40 kg/m with one or more obesity-related conditions. Interventions were implantation of either vBloc or Sham devices and weight management counseling. Mixed models assessed percent excess weight loss (%EWL) and total weight loss (%TWL) in intent-to-treat analyses. At 18 months, 142 (88%) vBloc and 64 (83%) Sham patients remained enrolled in the study. Results. 18-month weight loss was 23% EWL (8.8% TWL) for vBloc and 10% EWL (3.8% TWL) for Sham (P<0.0001). vBloc patients largely maintained 12-month weight loss of 26% EWL (9.7% TWL). Sham regained over 40% of the 17% EWL (6.4% TWL) by 18 months. Most weight regain preceded unblinding. Common adverse events of vBloc through 18 months were heartburn/dyspepsia and abdominal pain; 98% of events were reported as mild or moderate and 79% had resolved. Conclusions. Weight loss with vBloc was sustained through 18 months, while Sham regained weight between 12 and 18 months. vBloc is effective with a low rate of serious complications.
    Keywords Internal medicine ; RC31-1245
    Subject code 796
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Hindawi Publishing Corporation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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