scholarly journals A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization

2011 ◽  
Vol 194 (2) ◽  
pp. 277-289 ◽  
Author(s):  
Zohreh Khavandgar ◽  
Christophe Poirier ◽  
Christopher J. Clarke ◽  
Jingjing Li ◽  
Nicholas Wang ◽  
...  
Keyword(s):  
Bone Mineralization ◽  
Skeletal Development ◽  
Specific Expression ◽  
Neutral Sphingomyelinase ◽  
Phosphodiesterase 3 ◽  
A Cell ◽  
Endocrine Factors ◽  
The Brain ◽  
Bone Abnormalities

A deletion mutation called fro (fragilitas ossium) in the murine Smpd3 (sphingomyelin phosphodiesterase 3) gene leads to a severe skeletal dysplasia. Smpd3 encodes a neutral sphingomyelinase (nSMase2), which cleaves sphingomyelin to generate bioactive lipid metabolites. We examined endochondral ossification in embryonic day 15.5 fro/fro mouse embryos and observed impaired apoptosis of hypertrophic chondrocytes and severely undermineralized cortical bones in the developing skeleton. In a recent study, it was suggested that nSMase2 activity in the brain regulates skeletal development through endocrine factors. However, we detected Smpd3 expression in both embryonic and postnatal skeletal tissues in wild-type mice. To investigate whether nSMase2 plays a cell-autonomous role in these tissues, we examined the in vitro mineralization properties of fro/fro osteoblast cultures. fro/fro cultures mineralized less than the control osteoblast cultures. We next generated fro/fro;Col1a1-Smpd3 mice, in which osteoblast-specific expression of Smpd3 corrected the bone abnormalities observed in fro/fro embryos without affecting the cartilage phenotype. Our data suggest tissue-specific roles for nSMase2 in skeletal tissues.

scholarly journals Anti-aggregation Effects of Phenolic Compounds on α-synuclein

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2444
Author(s):  
Kenjiro Ono ◽  
Mayumi Tsuji ◽  
Tritia R. Yamasaki ◽  
Giulio M. Pasinetti
Keyword(s):  
Phenolic Compounds ◽  
Gut Microbiota ◽  
Lewy Bodies ◽  
Hydroxybenzoic Acid ◽  
Dietary Polyphenols ◽  
Pathologic Features ◽  
Hydroxyphenylacetic Acid ◽  
A Cell ◽  
The Brain

The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson’s disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate αS aggregation and propagation. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies, we and other groups reported that phenolic compounds inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer-induced cellular and synaptic toxicities. Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. Our recent studies on the brain-penetrating polyphenolic acids 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-hydroxyphenylacetic acid (3-HPPA), which are derived from gut microbiota-based metabolism of dietary polyphenols, demonstrated an in vitro ability to inhibit αS oligomerization and mediate aggregated αS-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular αS seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-αS aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α-synucleinopathies.

Biodiversity as a source of new pharmacophores: A new theory of memory III

2005 ◽  
Vol 77 (1) ◽  
pp. 75-81 ◽  
Author(s):  
◽  
M. Iqbal Choudhary
Keyword(s):  
Natural Products ◽  
Anticancer Agents ◽  
Neurological Disorders ◽  
In Vitro Bioassay ◽  
Natural Sources ◽  
Chemical Basis ◽  
Antioxidant Agents ◽  
A Cell ◽  
The Brain

Several classes of natural products with significant inhibitory activity against target enzymes involved in several diseases have been identified. Spectrophotometer and high-throughput assays were used to assess the inhibition of prolyl endopeptidase (PEP), which led us to some novel inhibitors having potential as anticancer agents. Inhibition of cholinesterase enzymes has led to the discovery of new inhibitors with potential for use in Alzheimer’s disease and other neurological disorders. We have also discovered several potent antioxidant agents from natural sources by using a battery of antioxidant assays. Anti-inflammatory activity of a number of natural products was assayed through a cell-based in vitro bioassay. This article also contains a section on a slightly different topic of chemical basis of memory as presented during the lecture. The theory of the chemical basis of memory based on hydrogen bonding in the brain is further elaborated.

scholarly journals Adhesion, Invasion, and Translocation Characteristics of Listeria monocytogenes Serotypes in Caco-2 Cell and Mouse Models

2003 ◽  
Vol 69 (6) ◽  
pp. 3640-3645 ◽  
Author(s):  
Ziad W. Jaradat ◽  
Arun K. Bhunia
Keyword(s):  
Listeria Monocytogenes ◽  
Mouse Model ◽  
Cell Line ◽  
Mouse Bioassay ◽  
Adhesion Properties ◽  
Culture Model ◽  
A Cell ◽  
In Vitro Adhesion ◽  
The Brain

ABSTRACT Adhesion is a crucial first step in Listeria monocytogenes pathogenesis. In this study, we examined how the adhesion properties of serotypes correlate with their invasion efficiencies in a cell culture model (Caco-2) and in a mouse model. Adhesion characteristics of all 13 serotypes of L. monocytogenes (25 strains) were analyzed, which yielded three distinct groups (P < 0.05) with high-, medium-, and low-level-adhesion profiles. The efficiency of these strains in invading the Caco-2 cell line was analyzed, which produced two groups; however, the overall correlation (R 2) was only 0.1236. In the mouse bioassay, all selected strains, irrespective of their adhesion profiles, translocated to the liver and the spleen with almost equal frequencies that did not show any clear relationship with adhesion profiles. However, the serotypes with increased adhesion showed a slightly increased translocation to the brain (R 2 = 0.3371). Collectively, these results indicate that an in vitro adhesion profile might not be an accurate assessment of a strain's ability to invade a cultured cell line or organs or tissues in a mouse model.

A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization

2011 ◽  
Vol 208 (8) ◽  
pp. i25-i25
Author(s):  
Zohreh Khavandgar ◽  
Christophe Poirier ◽  
Christopher J. Clarke ◽  
Jingjing Li ◽  
Nicholas Wang ◽  
...  
Keyword(s):  
Bone Mineralization ◽  
Neutral Sphingomyelinase ◽  
A Cell

scholarly journals IGFBP-4 regulates adult skeletal growth in a sex-specific manner

2017 ◽  
Vol 233 (1) ◽  
pp. 131-144 ◽  
Author(s):  
David E Maridas ◽  
Victoria E DeMambro ◽  
Phuong T Le ◽  
Kenichi Nagano ◽  
Roland Baron ◽  
...  
Keyword(s):  
Growth Factor ◽  
Skeletal Development ◽  
Skeletal Growth ◽  
Insulin Like Growth Factor ◽  
Bone Maintenance ◽  
Specific Manner ◽  
A Cell ◽  
Gender Specific

Insulin-like growth factor-1 (IGF-1) and its binding proteins are critical mediators of skeletal growth. Insulin-like growth factor-binding protein 4 (IGFBP-4) is highly expressed in osteoblasts and inhibits IGF-1 actions in vitro. Yet, in vivo studies suggest that it could potentiate IGF-1 and IGF-2 actions. In this study, we hypothesized that IGFBP-4 might potentiate the actions of IGF-1 on the skeleton. To test this, we comprehensively studied 8- and 16-week-old Igfbp4−/− mice. Both male and female adult Igfbp4−/− mice had marked growth retardation with reductions in body weight, body and femur lengths, fat proportion and lean mass at 8 and 16 weeks. Marked reductions in aBMD and aBMC were observed in 16-week-old Igfbp4−/− females, but not in males. Femoral trabecular BV/TV and thickness, cortical fraction and thickness in 16-week-old Igfbp4−/− females were significantly reduced. However, surprisingly, males had significantly more trabeculae with higher connectivity density than controls. Concordantly, histomorphometry revealed higher bone resorption and lower bone formation in Igfbp4−/− females. In contrast, Igfbp4−/− males had lower mineralized surface/bone surface. Femoral expression of Sost and circulating levels of sclerostin were reduced but only in Igfbp4−/− males. Bone marrow stromal cultures from mutants showed increased osteogenesis, whereas osteoclastogenesis was markedly increased in cells from Igfbp4−/− females but decreased in males. In sum, our results indicate that loss of Igfbp4 affects mesenchymal stromal cell differentiation, regulates osteoclastogenesis and influences both skeletal development and adult bone maintenance. Thus, IGFBP-4 modulates the skeleton in a gender-specific manner, acting as both a cell autonomous and cell non-autonomous factor.

scholarly journals AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Anca Remes ◽  
Andreas H. Wagner ◽  
Nesrin Schmiedel ◽  
Markus Heckmann ◽  
Theresa Ruf ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Myocardial Hypertrophy ◽  
Cardiomyocyte Hypertrophy ◽  
Activated T Cells ◽  
Specific Expression ◽  
Adult Mice ◽  
Before And After ◽  
A Cell

AbstractPrevious studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.

scholarly journals Smpd3Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development

2016 ◽  
Vol 36 (17) ◽  
pp. 2282-2299 ◽  
Author(s):  
Jingjing Li ◽  
Garthiga Manickam ◽  
Seemun Ray ◽  
Chun-do Oh ◽  
Hideyo Yasuda ◽  
...  
Keyword(s):  
Bone Development ◽  
Skeletal Development ◽  
Loss Of Function ◽  
Endochondral Bone ◽  
Transgenic Expression ◽  
Phosphodiesterase 3 ◽  
Skeletal Phenotype ◽  
Metabolizing Enzyme ◽  
Bone Abnormalities ◽  
And Cartilage

Sphingomyelin phosphodiesterase 3 (SMPD3), a lipid-metabolizing enzyme present in bone and cartilage, has been identified to be a key regulator of skeletal development. A homozygous loss-of-function mutation called fragilitas ossium (fro) in theSmpd3gene causes poor bone and cartilage mineralization resulting in severe congenital skeletal deformities. Here we show thatSmpd3expression in ATDC5 chondrogenic cells is downregulated by parathyroid hormone-related peptide through transcription factor SOX9. Furthermore, we show that transgenic expression ofSmpd3in the chondrocytes offro/fromice corrects the cartilage but not the bone abnormalities. Additionally, we report the generation ofSmpd3flox/floxmice for the tissue-specific inactivation ofSmpd3using the Cre-loxPsystem. We found that the skeletal phenotype inSmpd3flox/flox; Osx-Cremice, in which theSmpd3gene is ablated in both late-stage chondrocytes and osteoblasts, closely mimics the skeletal phenotype infro/fromice. On the other hand,Smpd3flox/flox;Col2a1-Cremice, in which theSmpd3gene is knocked out in chondrocytes only, recapitulate thefro/fromouse cartilage phenotype. This work demonstrates thatSmpd3expression in both chondrocytes and osteoblasts is required for normal endochondral bone development.

Identification and characterization of a differentiation-specific antigen on normal and malignant murine erythroid cells

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 103-108 ◽  
Author(s):  
ER Bacon ◽  
AJ Sytkowski
Keyword(s):  
Cell Surface ◽  
Developmental Process ◽  
Specific Antigen ◽  
Erythroid Cells ◽  
Specific Expression ◽  
Mature Erythrocyte ◽  
Erythroleukemia Cells ◽  
A Cell ◽  
Murine Erythroleukemia

Rauscher murine erythroleukemia cells grow continuously in vitro and undergo terminal differentiation in response to the physiological inducer erythropoietin. In the course of this developmental process they express many erythroid-specific markers. In order to investigate the expression of cell surface determinants during Rauscher cell differentiation we generated monoclonal antibodies to uninduced cells. Using an anti-Rauscher cell monoclonal antibody, we have identified a cell surface determinant, designated ERY-1, that is present on normal murine erythroid cells. This determinant is apparently absent from the early progenitor BFU-E, but is present on the more mature progenitors CFU-E and CFC-E. It disappears during erythroid maturation and is absent from the mature erythrocyte. This pattern of ERY-1 expression is exhibited with remarkable fidelity during the erythropoietin-induced differentiation of Rauscher cells. Such differentiation-specific expression of the ERY-1 determinant suggests that it may play a functional role in erythropoiesis.

scholarly journals Identification and characterization of a differentiation-specific antigen on normal and malignant murine erythroid cells

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 103-108 ◽  
Author(s):  
ER Bacon ◽  
AJ Sytkowski
Keyword(s):  
Cell Surface ◽  
Developmental Process ◽  
Specific Antigen ◽  
Erythroid Cells ◽  
Specific Expression ◽  
Mature Erythrocyte ◽  
Erythroleukemia Cells ◽  
A Cell ◽  
Murine Erythroleukemia

Abstract Rauscher murine erythroleukemia cells grow continuously in vitro and undergo terminal differentiation in response to the physiological inducer erythropoietin. In the course of this developmental process they express many erythroid-specific markers. In order to investigate the expression of cell surface determinants during Rauscher cell differentiation we generated monoclonal antibodies to uninduced cells. Using an anti-Rauscher cell monoclonal antibody, we have identified a cell surface determinant, designated ERY-1, that is present on normal murine erythroid cells. This determinant is apparently absent from the early progenitor BFU-E, but is present on the more mature progenitors CFU-E and CFC-E. It disappears during erythroid maturation and is absent from the mature erythrocyte. This pattern of ERY-1 expression is exhibited with remarkable fidelity during the erythropoietin-induced differentiation of Rauscher cells. Such differentiation-specific expression of the ERY-1 determinant suggests that it may play a functional role in erythropoiesis.

Ultrastructure of melanocyte-keratinocyte interactions and pigment transfer in vitro

1978 ◽  
Vol 36 (2) ◽  
pp. 650-651
Author(s):  
Raul I. Garcia ◽  
Evelyn A. Flynn ◽  
George Szabo
Keyword(s):  
Direct Injection ◽  
Skin Pigmentation ◽  
Freeze Fracture ◽  
Pigment Granule ◽  
Time Lapse ◽  
Ultrastructural Level ◽  
Lanthanum Tracer ◽  
A Cell

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

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