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PubMed2007

Electron tomography of nascent herpes simplex virus virions.

Cells infected with herpes simplex virus type 1 (HSV-1) were conventionally embedded or freeze substituted after high-pressure freezing and stained with uranyl acetate. Electron tomograms of capsids attached to or undergoing envelopment at the inner nuclear membrane (INM), capsids within cytoplasmic vesicles near the nuclear membrane, and extracellular virions revealed the following phenomena. (i) Nucleocapsids undergoing envelopment at the INM, or B capsids abutting the INM, were connected to thickened patches of the INM by fibers 8 to 19 nm in length and < or =5 nm in width. The fibers contacted both fivefold symmetrical vertices (pentons) and sixfold symmetrical faces (hexons) of the nucleocapsid, although relative to the respective frequencies of these subunits in the capsid, fibers engaged pentons more frequently than hexons. (ii) Fibers of similar dimensions bridged the virion envelope and surface of the nucleocapsid in perinuclear virions. (iii) The tegument of perinuclear virions was considerably less dense than that of extracellular virions; connecting fibers were observed in the former case but not in the latter. (iv) The prominent external spikes emanating from the envelope of extracellular virions were absent from perinuclear virions. (v) The virion envelope of perinuclear virions appeared denser and thicker than that of extracellular virions. (vi) Vesicles near, but apparently distinct from, the nuclear membrane in single sections were derived from extensions of the perinuclear space as seen in the electron tomograms. These observations suggest very different mechanisms of tegumentation and envelopment in extracellular compared with perinuclear virions and are consistent with application of the final tegument to unenveloped nucleocapsids in a compartment(s) distinct from the perinuclear space.

Animals↗
PubMed1989

Role of lipids in calcification of cartilage.

This review addresses the role of lipids and membranes in biologic calcification and examines their regulation during endochondral ossification. The close association of lipids with mineral deposition has been well established. Early observations indicated that lipids, particularly phospholipids, can not be totally extracted from calcified tissues until the tissues are decalcified. Phospholipids associated with mineral are also enriched in extracellular membrane vesicles, called matrix vesicles. Numerous studies indicate that mineral deposits in calcifying cartilage are first seen in these phosphatidylserine and alkaline phosphatase enriched vesicles and that the process of endochondral calcification of epiphyseal growth plate is possibly mediated by them. Matrix vesicles, and the phospholipids present in them, appear to be involved in initial formation of calcium hydroxyapatite crystals via the interaction of calcium and phosphate ions with phosphatidylserine to form phospholipid:Ca:Pi complexes (CPLX). CPLX is present in tissues which are undergoing initial mineral deposition but are absent from nonmineralizing tissues. Evidence suggests that CPLX resides in the interior of matrix vesicles where the earliest mineral crystals are formed in association with the vesicle membrane. More recently, it has been determined that specific membrane proteins, called proteolipids, participate in CPLX formation and hydroxyapatite deposition, in part by structuring phosphatidylserine in an appropriate conformation. Phosphatidylserine involvement in the initiation of mineralization has been extensively investigated because of its extremely high binding affinity for Ca2+. In addition to structuring a specific phospholipid environment, proteolipids may also act as ionophores, promoting export of protons and import of calcium and phosphate, both requirements of biologic calcification.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1981

Current concepts of the physiology and biochemistry of calcification.

The current picture of the process of biological calcifications portrays the cells within the calcifying tissues as central factors controlling the deposition of mineral crystals in the extracellular matrix. The cell responds to hormones and second messengers, and other changes in its environment, regulating the concentration of ions within the extracellular matrix and secreting macromolecules whose properties determine the ability of the matrix to be calcified. The mitochondria within the cells accumulate calcium and phosphate, releasing these ions into the matrix as calcification progresses. Extracellular matrix vesicles, derived from the cells of some, but not all, calcifying matrices, provide sites for initial mineral deposition in many tissues. Among the macromolecules secreted by the cell, collagen provides the support for the hydroxyapatite crystals; proteoglycans serve to control the extent and/or progress of mineralization. The proteoglycans, glycoproteins, enzymes and the collagen itself, along with the cells, determine the nature of the matrix, while phosphoproteins, proteolipids, and phospholipids may serve as hydroxyapatite nucleators or as surfaces upon which apatite is deposited. but it is the interaction of many or all of these factors that determines the process of biological calcification and controls the properties of the calcified matrices.

Bone and Bones↗
PubMed1988

Direct effects of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 on growth zone and resting zone chondrocyte membrane alkaline phosphatase and phospholipase-A2 specific activities.

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] and 24,25-(OH)2D3 differentially affect the specific activity of alkaline phosphatase (ALPase) and phospholipase-A2 (PLA2) of plasma membranes and extracellular matrix vesicles produced by costochondral reserve zone and growth zone cartilage chondrocytes in culture. In the present study, growth zone and cartilage and reserve zone matrix vesicles and plasma membranes were isolated from confluent chondrocyte cultures and incubated with hormone for 3 and 24 h in vitro. Addition of 1,25-(OH)2D3 to GC matrix vesicles and plasma membranes resulted in dose-dependent increases in ALPase and PLA2 specific activities in both membrane fractions. Addition of 24,25-(OH)2D3 to RC membrane fractions stimulated matrix vesicle ALPase at 10(-7) and 10(-8) M and plasma membrane ALPase at 10(-8) M only. However, 24,25-(OH)2D3 inhibited matrix vesicle and plasma membrane PLA2 activity. The effects of the vitamin D metabolites were noticed after both 3 and 24 h. Neither hormone metabolite had any effect on these enzymes in membrane fractions from cultures of neonatal rat muscle mesenchymal cells, which do not calcify their matrix in vivo. These data suggest that 1,25-(OH)2D3 and 24,25-(OH)2D3 can directly affect chondrocyte membrane enzymes without genomic influence or protein synthesis and that membrane response depends on the stage of chondrocyte differentiation. Changes in PLA2 activity may change membrane fluidity and may be a mechanism by which the hormones affect cell membranes.

24,25-Dihydroxyvitamin D 3↗
PubMed1976

Lipids of matrix vesicles.

The association of lipids with biological mineral formation was first indicated by histochemical observations. This was later confirmed by biochemical studies which revealed that calcium was bound to acidic lipids at sites of early mineral deposition. The morphological locus of initial mineral formation has now been shown to be membrane-enclosed vesicles in the extracellular matrix. Recent studies on isolated vesicles have documented that they are rich in lipids very similar to those previously found to be associated with newly forming mineral. The vesicle lipids are enriched in cholesterol, free fatty acids, sphingomyelin, glycolipids, lysophospholipids, and phosphatidylserine, and depleted in phosphatidylcholine and -ethanolamine. This composition is like that of the plasma membrane of cells and supports electron microscopic evidence that the vesicles arise by budding from the chondrocyte surface membrane. Metabolic studies indicate that formation of the vesicles occurs relatively rapidly (i.e., in less than 6 hours) by biochemical processes involving both lipid synthesis and degradation. In vitro studies suggest that the vesicle lipids may be involved in the initial binding and phase separation of calcium phosphate, as well as its conversion to crystalline apatite; however, final elucidation of the mechanism of action remains to be attained.

Animals↗
PubMed1993

Cellular and subcellular distribution of HNK-1 immunoreactivity in the neural tube of Xenopus.

The HNK-1 antigen, a carbohydrate moiety bound to many cell adhesion and recognition molecules, is implicated in cell-cell and cell-substrate interactions during neural development. HNK-1 immunoreactivity (HNK1-IR) appears on neurons of the Xenopus neural tube very early in their development (Nordlander, Devel. Brain Res., 50:147-153, 1989). The distribution and onset of expression of the HNK-1 epitope on and within individual neurons is examined in this study. HNK-1 labels developing neurons and their processes, and focal areas of other structures which are directly contacted by neurons, such as neuroepithelial cell surfaces, basal lamina, and culture surfaces. HNK1-IR first appears in the Golgi apparatus and subsequently on the cell surface and in streams of punctate material directed toward the site of axon initiation and into the developing axon and its growth cone. The entire neuron is coated with a thin (20-30 nm) surface layer of HNK1-IR. In addition, the surface is dotted with small (100-250 nm) boluses of HNK1-IR material. Such boluses also occur within cytoplasmic vesicles, and extracellularly on basal lamina and culture substrata in proximity to neurons or their processes. The subcellar distribution of HNK1-IR in this tissue is compatible with a role for the HNK-1 epitope in axonal outgrowth and guidance.

Animals↗
PubMed1995

Mutational analysis of the putative leukotoxin transport genes in Actinobacillus actinomycetemcomitans.

The periodontal pathogen, Actinobacillus actinomycetemcomitans, produces leukotoxin, a protein that specifically lyses host defense cells. The leukotoxin is similar in sequence and operon organization to the Escherichia coli alpha-hemolysin and other members of the RTX family of toxins. However, unlike the other RTX toxins, the A. actinomycetemcomitans leukotoxin is not secreted from the cell and instead remains associated with the outer membrane. Nonetheless, the A. actinomycetemcomitans Ikt operon contains two genes, IktB and IktD, that appear analagous to the toxin localization genes found in the other Gram-negative bacteria. Thus, to determine the roles of these putative transport genes in A. actinomycetemcomitans, we have used insertional mutagenesis to generate mutant strains lacking functional LktB and/or LktD. When either IktD or both IktB and IktD were inactivated, the level of detectable leukotoxin protein in the cell decreased significantly. However, the IktB and IktD mutations had no effect on the levels of leukotoxin RNA. Thus, the lack of LktB and LktD proteins must affect LktA synthesis post-transcriptionally. It is proposed that this is an indirect effect of leukotoxin mislocalization in IktB- and IktD- mutants. Finally, analysis of the mutants revealed that LktB and LktD are not essential for the formation of extracellular membrane vesicles in A. actinomycetemcomitans.

Aggregatibacter actinomycetemcomitans↗
PubMed1976

Transmission microscopy of freeze dried, unstained epiphyseal cartilage of the guinea pig.

The question of the initial mineralization in the epiphyseal plate has been investigated to date in specimens prepared by conventional electron microscopical techniques. As conventional techniques can produce artifacts, either a loss of mineral substance or a secondary nucleation, the mineralization process was investigated using freeze dried, vacuum embedded growth cartilage which was neither contrasted not stained and which had a very short contact with water. The prevailing theory that the first mineralization begins within extracellular matrix vesicles and that the mineralization outside these vesicles is a secondary process was confirmed. Mineralized matrix vesicles were found in the fully mineralized long septa down to the opening zone. In several cases a mineralization could be observed in those transverse septa in which organic substance was present between the cells. The typical radial arrangement of the apatitic needles and platelets in the matrix vesicles could be explained by the formation of a mineralization in an ionotropic gel, the orientation of the matrix macromolecules to be produced by a vectorial influx of calcium ions and phosphate groups coming from different directions. Thin strands of mineral substance with low contrast, which follow the direction of the longitudinal septum, were assumed to be the mineralized collagen fibrils. In several needles dot-like formations were seen and the distance between the middle of neighbouring dots was found to lie mainly in the range 30-56 A, while the lateral separation distance between the middle of closely packed parallel chains and needles was found to lie mainly in the range 30-42 A. Parallel periodic structures which could be visualized in apatitic chains and needles 20-40 A in diameter were assumed to be the 8.2 A-(100)-lattice planes of apatite, being an indication that these formations already possess criteria of the apatite lattice.

Animals↗
PubMed1987

Cytochemical localization of alkaline and acid phosphatase in human vanishing bone disease.

This report is the first cytochemical investigation of vanishing bone disease "Gorham's Disease" (Gorham and Stout 1955). The ultrastructural localization of non-specific alkaline phosphatase and of specific and non-specific acid phosphatase activity was studied in slices of tissue removed from a patient with this rare disorder. Sodium beta-glycerophosphate and phosphorylcholine chloride were used as substrates. Alkaline phosphatase was present around the plasma membranes of osteoblasts and associated with extracellular matrix vesicles in new woven bone. This is consistent with the proposed role for this enzyme (Robison 1923) and for matrix vesicles (Bonucci 1967) in the mineralization of bone (Bernard and Marvaso 1981). Concentrations of specific secretory acid phosphatase reaction product in the cytoplasm of degenerating osteoblasts may contribute to the imbalance between bone formation and resorption. Osteoclasts, while few in number, showed non-specific and specific acid phosphatase activity. The Golgi apparatus and heterophagic lysosomes of mononuclear phagocytes were rich in non-specific acid phosphatase. This was also present in the Golgi lamellae and lysosomes of endothelial cells. Acid phosphatase cytochemistry suggests that mononuclear phagocytes, multinuclear osteoclasts and the vascular endothelium are involved in bone resorption in this disease.

Acid Phosphatase↗
PubMed1982

Effect of X-ray irradiation on primary mineralization in rat alveolar bone.

The effect of X-ray irradiation on the process of primary mineralization in bone was studied by biochemical and ultrastructural methods. A single dose of 1500R was administered to the head region of rats. The animals were examined immediately after irradiation and 1, 2 and 3 weeks later. Fractions of isolated cells and extracellular matrix vesicles were prepared from the maxillary alveolar bone of irradiated and untreated rats by collagenase digestion and differential centrifugation. The protein content and activities of vesicular phosphatases were determined in both fractions. A continuous decrease in the activity of alkaline phosphatase could be observed in both cell and matrix vesicle fractions during a three-week follow up after irradiation. Acid phosphatase activity decreased only in the vesicle fraction. Transmission electron microscopy of irradiated bone tissue revealed that many matrix vesicles were devoid of intact membranes and apatite crystals. Calcifying nodules were abundant in the matrix without their apparent fusion into larger mineralized structures. It is suggested that irradiation interferes with enzymatic processes associated with primary mineralization.

Alveolar Process↗
PubMed1996

Persistence of complexed acidic phospholipids in rapidly mineralizing tissues is due to affinity for mineral and resistance to hydrolytic attack: in vitro data.

Acidic phospholipids, complexed with calcium and inorganic phosphate, are components of extracellular matrix vesicles. Both the complexed acidic phospholipids and matrix vesicles have previously been shown to serve as hydroxyapatite (HA) nucleators in solution and when implanted in a muscle pouch. The present study supplies evidence that complexed acidic phospholipids can persist in mineralizing tissues both because of their affinity for HA and because of their resistance to hydrolysis by phospholipase A2. Calcium-phosphatidylserine-phosphate complex (CPLX-PS) synthesized with 14C-labeled phosphatidylserine (PS) was used to measure CPLX-PS affinity for HA using a Langmuir adsorption isotherm model. The affinity was shown to be higher and more specific than that of PS itself (K = 8.66 ml/mumol; N, the number of binding sites = 20.4 mumol/m2 as compared with previously reported values for PS of K = 3.33 ml/mumol, and N = 4.87 mumol/m2). Incorporated into synthetic liposomes and incubated in a calcium phosphate solution in which mineralization is induced by an ionophore, CPLX-PS showed behavior distinct from free PS. As previously reported, PS in these liposomes totally blocked HA formation. On the other hand, CPLX-PS in similar concentrations had a varied response, having no effect, slightly inhibiting, or actually promoting HA formation. CPLX-PS was also shown to be a poorer substrate for phospholipase A2 than PS, with Km = 4.63 mM for CPLX-PS and Km = 0.27 mM for PS; and Vmax = 0.029 ml/minute for CPLX-PS and Vmax = 0.066 ml/minute for PS. These data explain how complexed acidic phospholipids may persist in the growth plate and facilitate initial mineral deposition.

Calcification, Physiologic↗
PubMed2026

Recent advancements in exosomal content analysis: the future of liquid biopsy.

Exosomes are widely acknowledged as an essential agent that carries biomarkers for specific diseases, representing the molecular status of their parent cells and providing extremely useful diagnostic insights. They can be isolated from different body fluids and contain a range of cargo molecules, including proteins, lipids, metabolites, and nucleic acids. Recent advancements in technology have greatly accelerated exosome research. Proteomics provides protein signatures linked to many pathological conditions, enabling quick and clinically scalable diagnostic tools, whereas high-throughput RNA-sequencing can be used to perform detailed transcriptome profiling. Exosomal biomarkers are showing promising clinical results in early detection of neurological diseases, infectious and cardiovascular disorders, oncology, and other medical conditions, hence accelerating therapeutic monitoring. Despite these advances, several challenges continue to hinder clinical translation including the lack of standardized isolation protocol, variability in exosome yield and purity, biological heterogeneity, and limited large-scale clinical validation. Addressing these limitations will be critical for the successful integration of exosome-based liquid biopsy into routine clinical practice. Overall, exosomes having significant potential as diagnostic tool, represent a transformative horizon in biomedical liquid biopsy research to redefine the landscape of less-invasive diagnostics and tailored clinical applications.

Humans↗
PubMed1991

Depolarization produces an acidification of adrenal gland perfusates.

Stimulation of adrenal glands with a variety of agonists or high potassium produced an acidification of the perfusion medium. The magnitude of the transient pH decrease was similar to that found in other nervous structures, and depended on the buffering capacity of the perfusion medium. However, no alkaline transient could be detected in this tissue. This acidification required Ca2+ and occurred under conditions producing catecholamine release. Since firstly the acidification could not be directly correlated with the amount of catecholamine released and secondly the time-course of both phenomena was different, suggesting that the acidification did not only result from the exocytosis of the acidic content of the chromaffin vesicles. The extracellular acidification may in addition originate: (a) partly from the proton release from acidic proteins, (b) from an output of acid equivalents from the cytoplasmic medium, either by the Na+/H+ antiporter present in all animal cells [24], or another mechanism yet to be determined.

Acetylcholine↗
PubMed1989

Effect of glass-ceramic implants on primary calcification in rat tibial bone after injury.

Using histomorphometry and transmission electron microscopy the distribution of extracellular matrix vesicles around bone-bonding and non-bonding glass-ceramic implants in tibial bone healing was studied. Grouping of vesicles was performed according to type, diameter and distance to the calcified front. Most vesicles were 0.06-0.22 microns in diameter in both implants tested. The mean vesicular distance of matrix vesicles to the calcified front was statistically significantly lower in non-bonding material compared with KG Cera. The sequence of vesicle arrangement according to diameter was: 'empty', 'amorphous', 'crystal', 'rupture'. Empty vesicles were the smallest and rupture vesicles the largest. Distances of vesicles to the calcified front showed the same sequence of arrangement, while the rupture type was located nearest to the front. The findings support the widely acknowledged hypothesis on the role of matrix vesicles in mineralization. It was shown that mineralizing tissue around bone-bonding glass-ceramics contains more matrix vesicles, which are distributed further from the front with a lower degree of calcification. The parameters studied could serve as standard criteria for the evaluation of implant materials.

Animals↗
PubMed1992

Effect of titanium implants on primary mineralization following 6 and 14 days of rat tibial healing.

The effect of pure commercial titanium implants on the process of primary mineralization was studied. This was examined by insertion of titanium implants into rat tibial bone after ablation. The effects of the titanium were studied through the behaviour of extracellular matrix vesicles (MV). Methods of morphometric analysis at the TEM level were applied. The insertion of titanium implants was followed by an increase in the number of MV as well as vesicular diameter and by a decrease in vesicular distance from the calcified front when compared to normal healing. These results suggest that the process of MV maturation around titanium implants was delayed when compared to normal primary bone formation during bone healing. The delay in mineralization was compensated by an increase in vesicle production, resulting in an enhancement of primary mineralization by the titanium.

Animals↗
PubMed2024

Secretome Analysis Using Affinity Proteomics and Immunoassays: A Focus on Tumor Biology.

The study of the cellular secretome using proteomic techniques continues to capture the attention of the research community across a broad range of topics in biomedical research. Due to their untargeted nature, independence from the model system used, historically superior depth of analysis, as well as comparative affordability, mass spectrometry-based approaches traditionally dominate such analyses. More recently, however, affinity-based proteomic assays have massively gained in analytical depth, which together with their high sensitivity, dynamic range coverage as well as high throughput capabilities render them exquisitely suited to secretome analysis. In this review, we revisit the analytical challenges implied by secretomics and provide an overview of affinity-based proteomic platforms currently available for such analyses, using the study of the tumor secretome as an example for basic and translational research.

Humans↗
PubMed2003

Modulation of intercellular communication mediated at the cell surface and on extracellular, plasma membrane-derived vesicles by ionizing radiation.

The plasma membrane is a dynamic organelle whose function includes receptor-mediated signal transduction into the cell. Conversely, the plasma membrane is the origin of inter-cellular signaling. In addition to expressing and releasing growth factors in a soluble form(through exocytosis) and via proteolysis of cell surface components, membrane ligands may signal nearby cells through juxtacrine stimulation or by the exfoliation or shedding of plasma membrane-derived vesicles. Ionizing radiation (IR) has a profound effect on plasma membrane structure and function. IR-induced ultrastructural alterations are mediated via lipid interaction with water radiolysis products (e.g., hydroxyl radicals, hydrogen radicals, and hydrated electrons). Ionizing radicals act directly on lipid molecules to promote lipid hydro-peroxides and lipid hydroperoxide breakdown products (e.g., alpha, beta unsaturated aldehydes) that contribute to altered plasma membrane lipid composition. A change in lipid composition increases membrane lipid microviscosity and results in membrane fenestrations that enhance permeability to small molecules and ions. Reactive ionizing species also stimulate sphingomyelinase activity, leading to sphingomyelin hydrolysis and ceramide generation that further contributes to altered membrane lipid composition and cellular apoptosis. In addition, exposure to IR results in impaired rate of and cumulative shedding of plasma membrane-associated growth factors. Mechanisms of exfoliation are reviewed for normal cells and the impact of radiation on modulating signal transduction mediated by exfoliation is summarized.

Apoptosis↗