scholarly journals 4-O-Methylhonokiol Influences Normal Cardiovascular Development in Medaka Embryo

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 475
Author(s):  
Santu Singha ◽  
Ilias Muhammad ◽  
Mohamed Ibrahim ◽  
Mei Wang ◽  
Nicole Ashpole ◽  
...  
Keyword(s):  
Wnt Signaling Pathway ◽  
Differential Sensitivity ◽  
Cardiovascular Development ◽  
Magnolia Grandiflora ◽  
Proinflammatory Mediators ◽  
Cardiac Ventricle ◽  
Exposure Windows ◽  
And Function ◽  
Medaka Embryo

Although 4-O-Methylhonokiol (MH) effects on neuronal and immune cells have been established, it is still unclear whether MH can cause a change in the structure and function of the cardiovascular system. The overarching goal of this study was to evaluate the effects of MH, isolated from Magnolia grandiflora, on the development of the heart and vasculature in a Japanese medaka model in vivo to predict human health risks. We analyzed the toxicity of MH in different life-stages of medaka embryos. MH uptake into medaka embryos was quantified. The LC50 of two different exposure windows (stages 9–36 (0–6 days post fertilization (dpf)) and 25–36 (2–6 dpf)) were 5.3 ± 0.1 μM and 9.9 ± 0.2 μM. Survival, deformities, days to hatch, and larval locomotor response were quantified. Wnt 1 was overexpressed in MH-treated embryos indicating deregulation of the Wnt signaling pathway, which was associated with spinal and cardiac ventricle deformities. Overexpression of major proinflammatory mediators and biomarkers of the heart were detected. Our results indicated that the differential sensitivity of MH in the embryos was developmental stage-specific. Furthermore, this study demonstrated that certain molecules can serve as promising markers at the transcriptional and phenotypical levels, responding to absorption of MH in the developing embryo.

scholarly journals The effect of in vitro exposure to antisense oligonucleotides on macrophage morphology and function

2011 ◽  
Vol 2 (1) ◽  
pp. 12 ◽  
Author(s):  
Ann Brasey ◽  
Raouf Igue ◽  
Loubna Djemame ◽  
Serge Séguin ◽  
Paolo Renzi ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Morphological Changes ◽  
Lower Airway ◽  
Functional Responses ◽  
Phagocytic Capacity ◽  
Proinflammatory Mediators ◽  
Functional Consequences ◽  
And Function

<p>Antisense oligonucleotides (AON) delivered via inhalation are in drug development for respiratory diseases. In rodents and monkeys, repeated exposure to high doses of inhaled phosphorothioate (PS) AON can lead to microscopic changes in the lungs, including accumulation of alveolar macrophages in the lower airway that have a <em>foamy</em> appearance. The functional consequences that result from this morphological change are unclear as there is controversy whether the vacuoles/inclusion bodies reflect normal clearance of the inhaled AON or are early indicators of lung toxicity. The morphological and functional responses of macrophage to PS AON were characterized <em>in vitro</em> using the comparator drug amiodarone, as a known inducer of foamy macrophages. Morphological changes of increased vacuolization with the presence of lamellated structures were observed in macrophages in response to both amiodarone and AON treatment. Functional responses to the drugs clearly differed with amiodarone treatment leading to apoptosis of cells and cell death, release of proinflammatory mediators IL-1RA, MIP-1<em>α </em>and TNF<em>α</em>, decrease in IP-10, a cytokine shown to be involved in protection against pulmonary fibrosis and altered phagocytosis capacity of the cells. In contrast, AON in concentrations up to 30 μM, had no effect on cell viability or apoptosis, had minimal effects on pro-inflammatory cytokines, increased IP-10 levels and did not alter the phagocytic capacity of the cells. Exposure of macrophages to AON<em> in vitro</em>, led to morphological changes of increased vacuolization, but did not lead to functional consequences which were observed with another vacuolization-inducing drug, suggesting that the <em>in vivo </em>phenotypic changes observed following inhalation of AON may be consistent with a clearance mechanism and not an activation or impairment of macrophages.</p>

scholarly journals Human rare variant and zebrafish CRISPR/Cas9-mediated mutant analyses reveal novel functions for API5, HSPB7, and LMO2 in heart failure

2021 ◽  
Author(s):  
Matthew J Winter ◽  
Yosuke Ono ◽  
Jonathan S Ball ◽  
Anna Walentinsson ◽  
Erik Michaelsson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Rare Variant ◽  
Drug Targets ◽  
Heart Function ◽  
Positive Control ◽  
Cardiovascular Development ◽  
Rare Variant Analysis ◽  
Drug Target Validation ◽  
And Function

The clinical heterogeneity of heart failure has challenged our understanding of the underlying genetic mechanisms of this disease. To gain further insights into this complex pathophysiology we combined human rare variant analysis and in vivo CRISPR/Cas9-mediated mutant phenotyping in zebrafish to identify and investigate the role of 3 genes. Whole-exome sequencing of patients identified API5, HSPB7, and LMO2 as causally associated with heart failure and these genes were further investigated, alongside the positive control gata5, using CRISPR/Cas9-mediated multi-locus in vivo mutation in zebrafish. Following effective somatic mutation, we observed multiple impacts on cardiovascular development and function in F0 embryos including reductions in ventricle size, pericardial oedema, and chamber malformation. In the case of lmo2, there was also a significant impact on heart function. Our analysis suggests novel functions for API5, HSPB7, and LMO2 in human cardiovascular disease and identifies them as potential drug targets. Our data also supports in vivo CRISPR/Cas9-mediated multi-locus gene mutation analysis in F0 zebrafish as a rapid and effective primary screen for assessing gene function, as part of an integrated multi-level drug target validation strategy.

Osseointegration interface of calcified bone and endosseous implants

1992 ◽  
Vol 50 (2) ◽  
pp. 1096-1097
Author(s):  
K.E. Krizan ◽  
J.E. Laffoon ◽  
M.J. Buckley
Keyword(s):  
Structure And Function ◽  
Titanium Implants ◽  
En Bloc ◽  
Endosseous Implants ◽  
Ultrastructural Studies ◽  
The Past ◽  
Cacodylate Buffer ◽  
One Year ◽  
And Function

With increase use of tissue-integrated prostheses in recent years it is a goal to understand what is happening at the interface between haversion bone and bulk metal. This study uses electron microscopy (EM) techniques to establish parameters for osseointegration (structure and function between bone and nonload-carrying implants) in an animal model. In the past the interface has been evaluated extensively with light microscopy methods. Today researchers are using the EM for ultrastructural studies of the bone tissue and implant responses to an in vivo environment. Under general anesthesia nine adult mongrel dogs received three Brånemark (Nobelpharma) 3.75 × 7 mm titanium implants surgical placed in their left zygomatic arch. After a one year healing period the animals were injected with a routine bone marker (oxytetracycline), euthanized and perfused via aortic cannulation with 3% glutaraldehyde in 0.1M cacodylate buffer pH 7.2. Implants were retrieved en bloc, harvest radiographs made (Fig. 1), and routinely embedded in plastic. Tissue and implants were cut into 300 micron thick wafers, longitudinally to the implant with an Isomet saw and diamond wafering blade [Beuhler] until the center of the implant was reached.

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

scholarly journals Gpr1 is an active chemerin receptor influencing glucose homeostasis in obese mice

2014 ◽  
Vol 222 (2) ◽  
pp. 201-215 ◽  
Author(s):  
Jillian L Rourke ◽  
Shanmugam Muruganandan ◽  
Helen J Dranse ◽  
Nichole M McMullen ◽  
Christopher J Sinal
Keyword(s):  
Adipose Tissue ◽  
Glucose Homeostasis ◽  
Stromal Vascular Fraction ◽  
Tolerance Test ◽  
Glucose Levels ◽  
Brown Adipose ◽  
Elevated Glucose ◽  
And Function ◽  
G Protein Coupled

Chemerin is an adipose-derived signaling protein (adipokine) that regulates adipocyte differentiation and function, immune function, metabolism, and glucose homeostasis through activation of chemokine-like receptor 1 (CMKLR1). A second chemerin receptor, G protein-coupled receptor 1 (GPR1) in mammals, binds chemerin with an affinity similar to CMKLR1; however, the function of GPR1 in mammals is essentially unknown. Herein, we report that expression of murineGpr1mRNA is high in brown adipose tissue and white adipose tissue (WAT) and skeletal muscle. In contrast to chemerin (Rarres2) andCmklr1,Gpr1expression predominates in the non-adipocyte stromal vascular fraction of WAT. Heterozygous and homozygousGpr1-knockout mice fed on a high-fat diet developed more severe glucose intolerance than WT mice despite having no difference in body weight, adiposity, or energy expenditure. Moreover, mice lackingGpr1exhibited reduced glucose-stimulated insulin levels and elevated glucose levels in a pyruvate tolerance test. This study is the first, to our knowledge, to report the effects ofGpr1deficiency on adiposity, energy balance, and glucose homeostasisin vivo. Moreover, these novel results demonstrate that GPR1 is an active chemerin receptor that contributes to the regulation of glucose homeostasis during obesity.

scholarly journals Development of a semi-automated segmentation tool for high frequency ultrasound image analysis of mouse echocardiograms

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kristi Powers ◽  
Raymond Chang ◽  
Justin Torello ◽  
Rhonda Silva ◽  
Yannick Cadoret ◽  
...  
Keyword(s):  
Image Analysis ◽  
Automated Analysis ◽  
Structure And Function ◽  
Ultrasound Images ◽  
Cardiac Structure ◽  
Short Axis ◽  
Pixel Intensity ◽  
Cardiac Structure And Function ◽  
And Function

AbstractEchocardiography is a widely used and clinically translatable imaging modality for the evaluation of cardiac structure and function in preclinical drug discovery and development. Echocardiograms are among the first in vivo diagnostic tools utilized to evaluate the heart due to its relatively low cost, high throughput acquisition, and non-invasive nature; however lengthy manual image analysis, intra- and inter-operator variability, and subjective image analysis presents a challenge for reproducible data generation in preclinical research. To combat the image-processing bottleneck and address both variability and reproducibly challenges, we developed a semi-automated analysis algorithm workflow to analyze long- and short-axis murine left ventricle (LV) ultrasound images. The long-axis B-mode algorithm executes a script protocol that is trained using a reference library of 322 manually segmented LV ultrasound images. The short-axis script was engineered to analyze M-mode ultrasound images in a semi-automated fashion using a pixel intensity evaluation approach, allowing analysts to place two seed-points to triangulate the local maxima of LV wall boundary annotations. Blinded operator evaluation of the semi-automated analysis tool was performed and compared to the current manual segmentation methodology for testing inter- and intra-operator reproducibility at baseline and after a pharmacologic challenge. Comparisons between manual and semi-automatic derivation of LV ejection fraction resulted in a relative difference of 1% for long-axis (B-mode) images and 2.7% for short-axis (M-mode) images. Our semi-automatic workflow approach reduces image analysis time and subjective bias, as well as decreases inter- and intra-operator variability, thereby enhancing throughput and improving data quality for pre-clinical in vivo studies that incorporate cardiac structure and function endpoints.

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