scholarly journals Cyclosporin inhibition of collagen remodeling is mediated by gelsolin

2007 ◽  
Vol 293 (3) ◽  
pp. C1049-C1058 ◽  
Author(s):  
Matthew W. C. Chan ◽  
Pamela D. Arora ◽  
Christopher A. McCulloch
Keyword(s):  
Extracellular Matrix ◽  
Actin Assembly ◽  
Loss Of Function ◽  
Wild Type ◽  
Connective Tissues ◽  
Collagen Binding ◽  
Collagen Remodeling ◽  
Periodontal Tissues ◽  
Collagen Accumulation ◽  
Collagen Phagocytosis

Cyclosporin A (CsA) inhibits collagen remodeling by interfering with the collagen-binding step of phagocytosis. In rapidly remodeling connective tissues such as human periodontium this interference manifests as marked tissue overgrowth and loss of function. Previous data have shown that CsA inhibits integrin-induced release of Ca2+ from internal stores, which is required for the binding step of collagen phagocytosis. Because gelsolin is a Ca2+-dependent actin-severing protein that mediates collagen phagocytosis, we determined whether gelsolin is a CsA target. Compared with vehicle controls, CsA treatment of wild-type mice increased collagen accumulation by 60% in periodontal tissues; equivalent increases were seen in vehicle-treated gelsolin-null mice. Collagen degradation by phagocytosis in cultured gelsolin wild-type fibroblasts was blocked by CsA, comparable to levels of vehicle-treated gelsolin-null fibroblasts. In wild-type cells treated with CsA, collagen binding was similar to that of gelsolin-null fibroblasts transfected with a gelsolin-severing mutant and treated with vehicle. CsA blocked collagen-induced Ca2+ fluxes subjacent to bound collagen beads, gelsolin recruitment, and actin assembly at bead sites. CsA reduced gelsolin-dependent severing of actin in wild-type cells to levels similar to those in gelsolin-null fibroblasts. We conclude that CsA-induced accumulation of collagen in the extracellular matrix involves disruption of the actin-severing properties of gelsolin, thereby inhibiting the binding step of collagen phagocytosis.

scholarly journals Gelsolin Mediates Collagen Phagocytosis through a Rac-dependent Step

2004 ◽  
Vol 15 (2) ◽  
pp. 588-599 ◽  
Author(s):  
Pamela D. Arora ◽  
Michael Glogauer ◽  
Andras Kapus ◽  
David J. Kwiatkowski ◽  
Christopher A. McCulloch
Keyword(s):  
Actin Filaments ◽  
Calcium Ionophore ◽  
Initial Contact ◽  
Β1 Integrin ◽  
Wild Type ◽  
Collagen Binding ◽  
Calcium Dependent ◽  
Collagen Phagocytosis ◽  
Α2β1 Integrin

The role of gelsolin, a calcium-dependent actin-severing protein, in mediating collagen phagocytosis, is not defined. We examined α2β1 integrin-mediated phagocytosis in fibroblasts from wild-type (WT) and gelsolin knockout (Gsn-) mice. After initial contact with collagen beads, collagen binding and internalization were 60% lower in Gsn- than WT cells. This deficiency was restored by transfection with gelsolin or with β1 integrin-activating antibodies. WT cells showed robust rac activation and increased [Ca2+]i during early contact with collagen beads, but Gsn- cells showed very limited responses. Transfected gelsolin in Gsn- cells restored rac activation after collagen binding. Transfection of Gsn- cells with active rac increased collagen binding to WT levels. Chelation of intracellular calcium inhibited collagen binding and rac activation, whereas calcium ionophore induced rac activation in WT and Gsn- cells. We conclude that the ability of gelsolin to remodel actin filaments is important for collagen-induced calcium entry; calcium in turn is required for rac activation, which subsequently enhances collagen binding to unoccupied α2β1 integrins.

Drug-Induced Gingival Overgrowth - A Review

1970 ◽  
pp. 26-29
Author(s):  
Mst Fatema Akhter ◽  
Shaheen Lipika Quayum ◽  
Afrin Bintal Ali ◽  
Zia Mamoon
Keyword(s):  
Extracellular Matrix ◽  
Collagen Synthesis ◽  
Immunosuppressive Agents ◽  
Channel Blockers ◽  
Gingival Fibroblasts ◽  
Connective Tissues ◽  
Drug Induced ◽  
Gingival Overgrowth ◽  
Collagen Phagocytosis ◽  
Synthesis And Degradation

Drug-induced gingival overgrowth is a side effect associated with 3 types of drugs: anticonvulsants (phenytoin), immunosuppressive agents (cyclosporine A), and various calcium channel blockers for cardiovascular diseases. Gingival overgrowth is characterized by the accumulation of extracellular matrix in gingival connective tissues, particularly collagenous components with various degrees of inflammation. Although the mechanisms of these disorders have not been elucidated, recent studies suggest that these disorders seem to be induced by the disruption of homeostasis of collagen synthesis and degradation in gingival connective tissue, predominantly through the inhibition of collagen phagocytosis of gingival fibroblasts. In this review, we focus on collagen metabolism in drug-induced gingival overgrowth, focusing on the regulation of collagen phagocytosis in fibroblasts. DOI: 10.3329/bjpp.v25i1.5743Bangladesh J Physiol Pharmacol 2009; 25(1&2) : 26-29

scholarly journals Apelin expression deficiency in mice contributes to vascular stiffening by extracellular matrix remodeling of the aortic wall

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Beatrice Romier ◽  
Cédric Dray ◽  
Laetitia Vanalderwiert ◽  
Amandine Wahart ◽  
Thinhinane Hocine ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Pulse Wave Velocity ◽  
Aortic Wall ◽  
Pulse Wave ◽  
Elastic Fibers ◽  
Cathepsin S ◽  
Wild Type ◽  
Collagen Accumulation ◽  
Vascular Stiffening

AbstractNumerous recent studies have shown that in the continuum of cardiovascular diseases, the measurement of arterial stiffness has powerful predictive value in cardiovascular risk and mortality and that this value is independent of other conventional risk factors, such as age, cholesterol levels, diabetes, smoking, or average blood pressure. Vascular stiffening is often the main cause of arterial hypertension (AHT), which is common in the presence of obesity. However, the mechanisms leading to vascular stiffening, as well as preventive factors, remain unclear. The aim of the present study was to investigate the consequences of apelin deficiency on the vascular stiffening and wall remodeling of aorta in mice. This factor freed by visceral adipose tissue, is known for its homeostasic role in lipid and vascular metabolisms, or again in inflammation. We compared the level of metabolic markers, inflammation of white adipose tissue (WAT), and aortic wall remodeling from functional and structural approaches in apelin-deficient and wild-type (WT) mice. Apelin-deficient mice were generated by knockout of the apelin gene (APL-KO). From 8 mice by groups, aortic stiffness was analyzed by pulse wave velocity measurements and by characterizations of collagen and elastic fibers. Mann–Whitney statistical test determined the significant data (p < 5%) between groups. The APL-KO mice developed inflammation, which was associated with significant remodeling of visceral WAT, such as neutrophil elastase and cathepsin S expressions. In vitro, cathepsin S activity was detected in conditioned medium prepared from adipose tissue of the APL-KO mice, and cathepsin S activity induced high fragmentations of elastic fiber of wild-type aorta, suggesting that the WAT secretome could play a major role in vascular stiffening. In vivo, remodeling of the extracellular matrix (ECM), such as collagen accumulation and elastolysis, was observed in the aortic walls of the APL-KO mice, with the latter associated with high cathepsin S activity. In addition, pulse wave velocity (PWV) and AHT were increased in the APL-KO mice. The latter could explain aortic wall remodeling in the APL-KO mice. The absence of apelin expression, particularly in WAT, modified the adipocyte secretome and facilitated remodeling of the ECM of the aortic wall. Thus, elastolysis of elastic fibers and collagen accumulation contributed to vascular stiffening and AHT. Therefore, apelin expression could be a major element to preserve vascular homeostasis.

scholarly journals VARIOUS MANIFESTATIONS OF HYPERPLASIA OF PERIODONTAL TISSUES IN CHILDREN

2013 ◽  
Vol 9 (3) ◽  
pp. 56-62
Author(s):  
Т. Закиров ◽  
T. Zakirov ◽  
Е. Бимбас ◽  
E. Bimbas ◽  
Т. Стати ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Oral Hygiene ◽  
Conservative Therapy ◽  
Genetic Disorder ◽  
Gingival Hyperplasia ◽  
Complex Treatment ◽  
Connective Tissues ◽  
Drug Induced ◽  
Gingival Overgrowth ◽  
Periodontal Tissues

There are many reasons for gingival hyperplasia in  children. Mostly, proper oral hygiene is sufficient to achieve normal healthy gingiva. In some situations, however, gingival hyperplasia is drug induced or can be a manifestation of a genetic disorder. In the latter, it may exist as an isolated abnormality or as part of a syndrome. Gingival overgrowth is characterized by the accumulation of extracellular matrix in gingival connective  tissues, particularly collagenous components with various degrees of inflammation. The complex treatment of gingival overgrowth can include conservative therapy and traditional or laser gingivectomy

scholarly journals Separate Functions of Gelsolin Mediate Sequential Steps of Collagen Phagocytosis

2005 ◽  
Vol 16 (11) ◽  
pp. 5175-5190 ◽  
Author(s):  
P. D. Arora ◽  
M.W.C. Chan ◽  
R. A. Anderson ◽  
P. A. Janmey ◽  
C. A. McCulloch
Keyword(s):  
Dominant Negative ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Actin Assembly ◽  
Actin Monomer ◽  
Collagen Binding ◽  
Phosphatidylinositol Phosphate ◽  
Catalytically Active ◽  
Collagen Phagocytosis

Collagen phagocytosis is a critical mediator of extracellular matrix remodeling. Whereas the binding step of collagen phagocytosis is facilitated by Ca2+-dependent, gelsolin-mediated severing of actin filaments, the regulation of the collagen internalization step is not defined. We determined here whether phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] regulation of gelsolin is required for collagen internalization. In gelsolin null fibroblasts transfected with gelsolin severing mutants, actin severing and collagen binding were strongly impaired but internalization and actin monomer addition at collagen bead sites were much less affected. PI(4,5)P2 accumulated around collagen during internalization and was associated with gelsolin. Cell-permeable peptides mimicking the PI(4,5)P2 binding site of gelsolin blocked actin monomer addition, the association of gelsolin with actin at phagosomes, and collagen internalization but did not affect collagen binding. Collagen beads induced recruitment of type 1 γ phosphatidylinositol phosphate kinase (PIPK1γ661) to internalization sites. Dominant negative constructs and RNA interference demonstrated a requirement for catalytically active PIPK1γ661 for collagen internalization. We conclude that separate functions of gelsolin mediate sequential stages of collagen phagocytosis: Ca2+-dependent actin severing facilitates collagen binding, whereas PI(4,5)P2-dependent regulation of gelsolin promotes the actin assembly required for internalization of collagen fibrils.

scholarly journals Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01948-20
Author(s):  
Dalin Rifat ◽  
Si-Yang Li ◽  
Thomas Ioerger ◽  
Keshav Shah ◽  
Jean-Philippe Lanoix ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Evidence ◽  
Clinical Samples ◽  
Loss Of Function ◽  
Wild Type ◽  
Content Type ◽  
Solid Media ◽  
High Level ◽  
Level Resistance

ABSTRACTThe nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10−5 CFU. Whole-genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, of which 91% occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance, namely, fbiC (56%), fbiA (15%), ddn (12%), fgd (4%), and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983 (fbiD), a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

scholarly journals Identification of a novel homozygous loss-of-function mutation in FUCA1 gene causing severe fucosidosis: A case report

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052110059
Author(s):  
Xinwen Zhang ◽  
Shaozhi Zhao ◽  
Hongwei Liu ◽  
Xiaoyan Wang ◽  
Xiaolei Wang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lysosomal Storage Disorder ◽  
Autosomal Recessive ◽  
Signs And Symptoms ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Wild Type ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Exon 1

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.

scholarly journals Somatic production of reactive oxygen species does not predict its production in sperm cells across Drosophila melanogaster lines

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Biz R. Turnell ◽  
Luisa Kumpitsch ◽  
Anne-Cécile Ribou ◽  
Klaus Reinhardt
Keyword(s):  
Reactive Oxygen Species ◽  
Drosophila Melanogaster ◽  
Reactive Oxygen ◽  
Future Research ◽  
Ros Production ◽  
Oxygen Species ◽  
Loss Of Function ◽  
Wild Type ◽  
Ros Scavenging ◽  
Transport Chain

Abstract Objective Sperm ageing has major evolutionary implications but has received comparatively little attention. Ageing in sperm and other cells is driven largely by oxidative damage from reactive oxygen species (ROS) generated by the mitochondria. Rates of organismal ageing differ across species and are theorized to be linked to somatic ROS levels. However, it is unknown whether sperm ageing rates are correlated with organismal ageing rates. Here, we investigate this question by comparing sperm ROS production in four lines of Drosophila melanogaster that have previously been shown to differ in somatic mitochondrial ROS production, including two commonly used wild-type lines and two lines with genetic modifications standardly used in ageing research. Results Somatic ROS production was previously shown to be lower in wild-type Oregon-R than in wild-type Dahomey flies; decreased by the expression of alternative oxidase (AOX), a protein that shortens the electron transport chain; and increased by a loss-of-function mutation in dj-1β, a gene involved in ROS scavenging. Contrary to predictions, we found no differences among these four lines in the rate of sperm ROS production. We discuss the implications of our results, the limitations of our study, and possible directions for future research.

Collagen remodeling in the extracellular matrix of the cardiomyopathic Syrian hamster heart as assessed by FTIR attenuated total reflectance spectroscopy

1999 ◽  
Vol 77 (11) ◽  
pp. 1843-1855 ◽  
Author(s):  
Pamela S Bromberg ◽  
Kathleen M Gough ◽  
Ian MC Dixon
Keyword(s):  
Genetic Algorithm ◽  
Extracellular Matrix ◽  
Discriminant Analysis ◽  
Left Ventricle ◽  
Linear Discriminant Analysis ◽  
Collagen Content ◽  
Diffuse Fibrosis ◽  
Collagen Deposition ◽  
Linear Discriminant ◽  
Collagen Remodeling

Collagen type I and III deposition in the cardiac extracellular matrix contributes significantly to myocardial dysfunction. Diffuse and focal fibrosis is believed to accompany human congestive cardiomyopathy (CCM) associated with congestive heart failure (CHF). The left ventricle collagen remodeling that occurs in the hamster model of CCM is marked by left ventricle fibrosis, hypertrophy and dilation, proceeded by CHF post 150 days of age. The objectives of our study were to (i) evaluate changes in collagen deposition in the right (RV) and left (LV) ventricular tissue of cardiomyopathic (CMP) and control (CON) myocardium using FTIR ATR spectroscopy, (ii) classify the normal and diseased heart tissue using linear discriminant analysis (LDA) aided by a genetic algorithm (GA) selection of spectroscopically diagnostic regions in the mid-IR region, (iii) rationalize the spectroscopic differences between left/right ventricle tissue as well as CON/CMP tissue according to the pathophysiology documented for the UM-X7.1 strain of CMP hamsters. The presence of collagen in the tissue was confirmed spectroscopically by observation of the collagen IR fingerprint in the 1000-1800 cm-1 region. Difference spectroscopy was utilized to substantiate which tissue under comparison exhibited pronounced collagen content. Multivariate analysis (LDA) was carried out on user-selected spectral subregions and compared to class separation based on spectral subregions chosen nonsubjectively by a GA. Our study confirmed that the animals experienced LV collagen remodeling denoted by focal rather than diffuse fibrosis. In addition, RV collagen remodeling, denoted by decreased RV collagen content, appeared to accompany the increased LV collagen deposition found for the CMP animals.Key words: FTIR spectroscopy, collagen, cardiomyopathy, genetic algorithm, linear discriminant analysis.

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