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1.
J Cell Physiol ; 226(9): 2438-47, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21660967

ABSTRACT

The Gi protein-associated A(3) adenosine receptor (A(3) AR) is a member of the adenosine receptor family. Selective agonists at the A(3) AR, such as CF101 and CF102 were found to induce anti-inflammatory and anti-cancer effects. In this study, we examined the differential effect of CF102 in pathological conditions of the liver. The anti-inflammatory protective effect of CF101 was tested in a model of liver inflammation induced by Concanavalin A (Con. A) and the anti-cancer effect of CF102 was examined in vitro and in a xenograft animal model utilizing Hep-3B hepatocellular carcinoma (HCC) cells. The mechanism of action was explored by following the expression levels of key signaling proteins in the inflamed and tumor liver tissues, utilizing Western blot (WB) analysis. In the liver inflammation model, CF102 (100 µg/kg) markedly reduced the secretion of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase in comparison to the vehicle-treated group. Mechanistically, CF102 treatment decreased the expression level of phosphorylated glycogen synthase kinase-3ß, NF-κB, and TNF-α and prevented apoptosis in the liver. This was demonstrated by decreased expression levels of Fas receptor (FasR) and of the pro-apoptotic proteins Bax and Bad in liver tissues. In addition, CF102-induced apoptosis of Hep-3B cells both in vitro and in vivo via de-regulation of the PI3K-NF-κB signaling pathway, resulting in up-regulation of pro-apoptotic proteins. Taken together, CF102 acts as a protective agent in liver inflammation and inhibits HCC tumor growth. These results suggest that CF102 through its differential effect is a potential drug candidate to treat various pathological liver conditions.


Subject(s)
Adenosine A3 Receptor Agonists/pharmacology , Adenosine/analogs & derivatives , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Liver/drug effects , Liver/pathology , Adenosine/pharmacology , Adenosine/therapeutic use , Adenosine A3 Receptor Agonists/therapeutic use , Animals , Anti-Inflammatory Agents/therapeutic use , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , Concanavalin A , Hepatitis/drug therapy , Hepatitis/pathology , Liver/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Receptor, Adenosine A3/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
2.
Arthritis Rheum ; 60(10): 3061-71, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19790055

ABSTRACT

OBJECTIVE: Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A(3) adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model. METHODS: OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 microg/kg given twice daily) was initiated. The A(3) adenosine receptor antagonist MRS1220 (100 microg/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O-fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses. RESULTS: CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-kappaB signaling pathway, resulting in down-regulation of tumor necrosis factor alpha. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes. CONCLUSION: CF101 deregulated the NF-kappaB signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA.


Subject(s)
Adenosine/analogs & derivatives , Anti-Inflammatory Agents/therapeutic use , Cartilage, Articular/pathology , Inflammation/drug therapy , Osteoarthritis/drug therapy , Osteoarthritis/pathology , Adenosine/adverse effects , Adenosine/pharmacology , Adenosine/therapeutic use , Adenosine A3 Receptor Antagonists , Animals , Anti-Inflammatory Agents/adverse effects , Anti-Inflammatory Agents/pharmacology , Apoptosis/drug effects , Apoptosis/physiology , Cartilage, Articular/drug effects , Cartilage, Articular/metabolism , Disease Models, Animal , Inflammation/metabolism , Inflammation/pathology , Iodoacetates/adverse effects , Male , NF-kappa B/metabolism , Osteoarthritis/chemically induced , Rats , Rats, Wistar , Signal Transduction/drug effects , Signal Transduction/physiology
3.
Cell Immunol ; 258(2): 115-22, 2009.
Article in English | MEDLINE | ID: mdl-19426966

ABSTRACT

The Gi protein associated A(3) adenosine receptor (A(3)AR) was recently defined as a novel anti-inflammatory target. The aim of this study was to look at A(3)AR expression levels in peripheral blood mononuclear cells (PBMCs) of patients with autoimmune inflammatory diseases and to explore transcription factors involved receptor expression. Over-expression of A(3)AR was found in PBMCs derived from patients with rheumatoid arthritis (RA), psoriasis and Crohn's disease compared with PBMCs from healthy subjects. Bioinformatics analysis demonstrated the presence of DNA binding sites for nuclear factor-kappaB (NF-kappaB) and cyclic AMP-responsive element binding protein (CREB) in the A(3)AR gene promoter. Up-regulation of NF-kappaB and CREB was found in the PBMCs from patients with RA, psoriasis and Crohn's disease. The PI3K-PKB/Akt signaling pathway, known to regulate both the NF-kappaB and CREB, was also up-regulated in the patients' PBMCs. Taken together, NF-kappaB and CREB are involved with the over-expression of A(3)AR in patients with autoimmune inflammatory diseases. The receptor may be considered as a specific target to combat inflammation.


Subject(s)
Arthritis, Rheumatoid/metabolism , Crohn Disease/metabolism , Psoriasis/metabolism , Receptor, Adenosine A3/biosynthesis , Adult , Cells, Cultured , Cyclic AMP Response Element-Binding Protein/genetics , Humans , I-kappa B Kinase/metabolism , Leukocytes, Mononuclear/metabolism , Middle Aged , NF-kappa B/metabolism , Promoter Regions, Genetic/physiology , Protein Binding , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , Receptor, Adenosine A3/genetics , Tumor Suppressor Proteins , Up-Regulation
4.
Biochem Pharmacol ; 76(4): 482-94, 2008 Aug 15.
Article in English | MEDLINE | ID: mdl-18602896

ABSTRACT

The A(3) adenosine receptor (A(3)AR) is over-expressed in inflammatory cells and was defined as a target to combat inflammation. Synthetic agonists to this receptor, such as IB-MECA and Cl-IB-MECA, exert an anti-inflammatory effect in experimental animal models of adjuvant- and collagen-induced arthritis. In this study we present a novel A(3)AR agonist, CF502, with high affinity and selectivity at the human A(3)AR. CF502 induced a dose dependent inhibitory effect on the proliferation of fibroblast-like synoviocytes (FLS) via de-regulation of the nuclear factor-kappa B (NF-kappaB) signaling pathway. Furthermore, CF502 markedly suppressed the clinical and pathological manifestations of adjuvant-induced arthritis (AIA) in a rat experimental model when given orally at a low dose (100 microg/kg). As is typical of other G-protein coupled receptors, the A(3)AR expression level was down-regulated shortly after treatment with agonist CF502 in paw and in peripheral blood mononuclear cells (PBMCs) derived from treated AIA animals. Subsequently, a decrease in the expression levels of protein kinase B/Akt (PKB/Akt), IkappaB kinase (IKK), I kappa B (IkappaB), NF-kappaB and tumor necrosis factor-alpha (TNF-alpha) took place. In addition, the expression levels of glycogen synthase kinase-3 beta (GSK-3beta), beta-catenin, and poly(ADP-ribose)polymerase (PARP), known to control the level and activity of NF-kappaB, were down-regulated upon treatment with CF502. Taken together, CF502 inhibits FLS growth and the inflammatory manifestations of arthritis, supporting the development of A(3)AR agonists for the treatment of rheumatoid arthritis.


Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/analogs & derivatives , Arthritis, Rheumatoid/drug therapy , NF-kappa B/metabolism , Protein Kinases/metabolism , Signal Transduction/drug effects , Synovial Membrane/pathology , Adenosine/pharmacology , Adenosine/therapeutic use , Animals , Arthritis/chemically induced , Arthritis/drug therapy , Arthritis/metabolism , Arthritis/pathology , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Disease Models, Animal , Humans , Inflammation/drug therapy , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats , Synovial Membrane/metabolism
5.
Int J Oncol ; 33(2): 287-95, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18636149

ABSTRACT

The A3 adenosine receptor (A(3)AR) is highly expressed in tumors and was suggested as a target for cancer treatment. In this study, we show that A(3)AR is highly expressed in tumor tissues and in peripheral blood mononuclear cells (PBMCs) derived from patients with HCC, as well as from HCC tumor-bearing rats. The high expression level of the receptor was directly correlated to overexpression of NF-kappaB, known as a transcription factor of A(3)AR. CF102, a synthetic highly selective agonist to A(3)AR induced a marked dose response inhibition of tumor growth in N1S1 HCC tumor rats, via de-regulation of the NF-kappaB and the Wnt signal transduction pathways, resulting in apoptosis of tumor cells. Taken together, A(3)AR is highly expressed in tumors and PBMCs of HCC patients and tumor-bearing rats. CF102 induced apoptosis and tumor growth inhibition. These data suggest A(3)AR as a novel targeted therapy to treat HCC.


Subject(s)
Adenosine/analogs & derivatives , Apoptosis/drug effects , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , NF-kappa B/drug effects , Wnt Proteins/drug effects , Adenosine/pharmacology , Adenosine A3 Receptor Agonists , Adult , Aged , Aged, 80 and over , Animals , Blotting, Western , Carcinoma, Hepatocellular/metabolism , Humans , Immunohistochemistry , In Situ Nick-End Labeling , Liver Neoplasms/metabolism , Male , Middle Aged , NF-kappa B/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Adenosine A3/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Wnt Proteins/metabolism
6.
Exp Cell Res ; 269(2): 230-6, 2001 Oct 01.
Article in English | MEDLINE | ID: mdl-11570815

ABSTRACT

Adenosine, a purine nucleoside, acts as a regulatory molecule, by binding to specific G-protein-coupled A(1), A(2A), A(2B), and A(3) cell surface receptors. We have recently demonstrated that adenosine induces a differential effect on tumor and normal cells. While inhibiting in vitro tumor cell growth, it stimulates bone marrow cell proliferation. This dual activity was mediated through the A3 adenosine receptor. This study showed that a synthetic agonist to the A3 adenosine receptor, 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyl-uronamide (Cl-IB-MECA), at nanomolar concentrations, inhibited tumor cell growth through a cytostatic pathway, i.e., induced an increase number of cells in the G0/G1 phase of the cell cycle and decreased the telomeric signal. Interestingly, Cl-IB-MECA stimulates murine bone marrow cell proliferation through the induction of granulocyte-colony-stimulating factor. Oral administration of Cl-IB-MECA to melanoma-bearing mice suppressed the development of melanoma lung metastases (60.8 +/- 6.5% inhibition). In combination with cyclophosphamide, a synergistic anti-tumor effect was achieved (78.5 +/- 9.1% inhibition). Furthermore, Cl-IB-MECA prevented the cyclophosphamide-induced myelotoxic effects by increasing the number of white blood cells and the percentage of neutrophils, demonstrating its efficacy as a chemoprotective agent. We conclude that A3 adenosine receptor agonist, Cl-IB-MECA, exhibits systemic anticancer and chemoprotective effects.


Subject(s)
Neoplasms/prevention & control , Neoplasms/therapy , Receptors, Purinergic P1/metabolism , Adenosine/analogs & derivatives , Adenosine/pharmacology , Administration, Oral , Animals , Antineoplastic Agents, Alkylating/pharmacology , Bone Marrow Cells/metabolism , Cell Cycle , Cell Division , Cyclophosphamide/pharmacology , Granulocyte Colony-Stimulating Factor/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , In Situ Hybridization, Fluorescence , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Male , Mice , Mice, Inbred C57BL , Neoplasms, Experimental , Protein Binding , Receptor, Adenosine A3 , Telomere/metabolism , Tumor Cells, Cultured
7.
Neoplasia ; 3(2): 125-31, 2001.
Article in English | MEDLINE | ID: mdl-11420748

ABSTRACT

Tumor metastases are extremely rare in striated muscles. Lately, we have found that muscle cell conditioned medium (MCM) inhibits the proliferation of various tumor cells while maintaining the growth of normal murine bone marrow cells. This dual activity was confirmed in vivo when the MCM was administered orally, i.e., it inhibited the development of tumor growth in mice and prevented the myelotoxic effects of chemotherapy. Adenosine was found to be one of the active components of MCM, inhibiting tumor cell growth while maintaining bone marrow cell proliferation in vitro. Adenosine is known to act as an important regulatory molecule through its binding to specific G-protein-associated A1, A(2a), A(2b) and A3 cell surface receptors. In distinction from MCM, adenosine did not suppress tumor development in mice and was not active as a chemoprotective agent when administered orally or intravenously. Thus, the in vivo activity of MCM could not be attributed to adenosine. In this study, MCM from which adenosine was enzymatically removed still retained its dual activity that was also found to be mediated through the A3 adenosine receptor (A3AR). This result led to the conclusion that natural agonists to A3AR were responsible for the activity of MCM. We further tested synthetic agonist to the A3AR and demonstrated that it possessed the same in vitro and in vivo activity profile as MCM. Taken together, muscle cells, in addition to adenosine, secrete natural agonists to A3AR. These agonists are stable nondegradable molecules and may contribute to the systemic anticancer and chemoprotective activity exerted by MCM. This group of molecules may account for the rarity of tumor metastases in muscle.


Subject(s)
Muscle Neoplasms/metabolism , Muscles/metabolism , Purinergic P1 Receptor Agonists , Adenosine/metabolism , Animals , Antineoplastic Agents/pharmacology , Bone Marrow Cells/metabolism , Cell Division , Culture Media, Conditioned/pharmacology , Dose-Response Relationship, Drug , Humans , Mice , Models, Chemical , Neoplasm Metastasis , Purinergic P1 Receptor Antagonists , Receptor, Adenosine A3 , Time Factors , Tumor Cells, Cultured
8.
J Cell Physiol ; 186(1): 19-23, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11147810

ABSTRACT

Adenosine is an ubiquitous nucleoside present in all body cells. It is released from metabolically active or stressed cells and subsequently acts as a regulatory molecule through binding to specific A1, A2A, A2B and A3 cell surface receptors. The synthesis of agonists and antagonists to the adenosine receptors and their cloning enabled the exploration of their physiological functions. As nearly all cells express specific adenosine receptors, adenosine serves as a physiological regulator and acts as a cardioprotector, neuroprotector, chemoprotector, and as an immunomodulator. At the cellular level, activation of the receptors by adenosine initiates signal transduction mechanisms through G-protein associated receptors. Adenosine's unique characteristic is to differentially modulate normal and transformed cell growth, depending upon its extracellular concentration, the expression of adenosine cell surface receptors, and the physiological state of the target cell. Stimulation of cell proliferation following incubation with adenosine has been demonstrated in a variety of normal cells in the range of low micromolar concentrations, including mesangial and thymocyte cells, Swiss mouse 3T3 fibroblasts, and bone marrow cells. Induction of apoptosis in tumor or normal cells was shown at higher adenosine concentrations (>100 microM) such as in leukemia HL-60, lymphoma U-937, A431 epidermoid cells, and GH3 tumor pituitary cell lines. It was further noted that the A3 adenosine receptor (A3AR) plays a key role in the inhibitory and stimulatory growth activities of adenosine. Modulation of the A3AR was found to affect cell growth either positively or negatively depending on the concentration of the agonist, similar to the effect described for adenosine. At nanomolar concentrations, the A3AR agonists possess dual activity, i.e., antiproliferative activity toward tumor cells and stimulatory effect on bone marrow cells. In vivo, these agonists exerted anti-cancer effects, and when given in combination with chemotherapy, they enhanced the chemotherapeutic index and acted as chemoprotective agents. Taken together, activation of the A3AR, by minute concentrations of its natural ligand or synthetic agonists, may serve as a new approach for cancer therapy.


Subject(s)
Adenosine/physiology , Neoplasms/pathology , Receptors, Purinergic P1/physiology , Animals , Cell Division/physiology , Humans , Receptor, Adenosine A3 , Reference Values , Signal Transduction/physiology
9.
Eur J Cancer ; 36(11): 1452-8, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10899660

ABSTRACT

In this study, we demonstrated several mechanisms exploring the inhibitory effect of low-dose adenosine on lymphoma cell growth. Adenosine, a purine nucleoside present in plasma and other extracellular fluids, acts as a regulatory molecule, by binding to G-protein associated cell-surface receptors, A1, A2 and A3. Recently we showed that low-dose adenosine released by muscle cells, inhibits tumour cell growth and thus attributes to the rarity of muscle metastases. In the present work, a cytostatic effect of adenosine on the proliferation of the Nb2-11C rat lymphoma cell line was demonstrated. This effect was mediated through the induction of cell cycle arrest in the G0/G1 phase and by decreasing the telomeric signal in these cells. Adenosine was found to exert its antiproliferative effect mainly through binding to its A3 receptor. The cytostatic anticancer activity, mediated through the A3 adenosine receptor, turns it into a potential target for the development of anticancer therapies.


Subject(s)
Adenosine/physiology , Lymphoma/pathology , Receptors, Purinergic P1/physiology , Animals , Apoptosis/physiology , Cell Division/physiology , DNA, Neoplasm/analysis , Purinergic P1 Receptor Antagonists , Rats , Receptor, Adenosine A3 , Telomere/chemistry , Tumor Cells, Cultured
10.
J Cell Physiol ; 183(3): 393-8, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10797314

ABSTRACT

Adenosine, a ubiquitous nucleoside, is released into the extracellular environment from metabolically active or stressed cells. It binds to cells through specific A1, A(2A), A(2B), and A3 G-protein-associated cell-surface receptors, thus acting as a signal-transduction molecule by regulating the levels of adenylyl cyclase and phospholipase C. In this study, we showed that adenosine stimulates the proliferation of murine bone marrow cells in vitro. Pharmacological studies, using antagonists to the adenosine receptors, revealed that this activity was mediated through the binding of adenosine to its A1 and A3 receptors. This result was further corroborated by showing that the two selective A1 and A3 receptor agonists, N-cyclopentyladenosine (CPA) and 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-be ta-D-ribofuranuronamide (IB-MECA) respectively, induced bone marrow cell proliferation in a manner similar to adenosine. Adenosine's interaction with its A1 and A3 receptors induced G-CSF production, which led to its stimulatory effect on bone marrow cells. These results were confirmed in vivo when we demonstrated that low-dose adenosine (0.25 mg/kg) acted as a chemoprotective agent. When administered after chemotherapy, it restored the number of leukocytes and neutrophils to normal levels, compared with the decline in these parameters after chemotherapy alone. It is suggested that low-dose adenosine, already in clinical use, may also be applied as a chemoprotective agent.


Subject(s)
Adenosine/pharmacology , Bone Marrow Cells/physiology , Granulocyte Colony-Stimulating Factor/biosynthesis , Receptors, Purinergic P1/physiology , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , Cell Cycle/drug effects , Cell Division/drug effects , Cells, Cultured , Cyclophosphamide/toxicity , Granulocyte Colony-Stimulating Factor/blood , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Purinergic P1 Receptor Antagonists , Quinazolines/pharmacology , Receptor, Adenosine A3 , Theobromine/analogs & derivatives , Theobromine/pharmacology , Triazoles/pharmacology , Xanthines/pharmacology
11.
Clin Exp Metastasis ; 17(6): 531-5, 1999.
Article in English | MEDLINE | ID: mdl-10763920

ABSTRACT

Tumor metastases are extremely rare in striated muscles. This is surprising given the fact that this tissue constitutes 60% of body weight. The present study focuses on small molecules produced and secreted by muscle cells which possess anti-cancer activity in vivo. Recently we have shown that a low molecular weight fraction (< 1000 Dalton) of skeletal muscle cell conditioned medium (muscle factor-MF), markedly inhibits the proliferation of carcinoma, sarcoma or melanoma cell lines in vitro. The MF exerts a cytostatic effect on tumor cell growth and arrests the cells in the G0/G1 of the cell cycle. However, normal cell proliferation, such as bone marrow and fibroblasts, was stimulated following incubation with MF. In this study, the effect of orally administered MF on melanoma and sarcoma growth was examined in mice. The administration of MF to mice inoculated intravenously with melanoma (B16-F10) or sarcoma (MCA-105) cells, resulted in a statistically significant inhibition of metastatic lung foci. In a different model, melanoma was induced in the foot pad and after development of a local lesion, the leg was amputated. A prolonged survival time was observed in the MF treated groups. Since the MF stimulated bone marrow cell proliferation in vitro, we decided to test its efficacy as an inhibitor of the myelotoxic effect exerted by chemotherapy, in vivo. MF, administered after chemotherapy, restored the number of white blood cells and yielded an increased percentage of neutrophils compared with the decline in these parameters after administration of chemotherapy alone. Thus, it is indicated that MF exerted a systemic anti tumor and chemoprotective effect when given orally. It can be concluded that it is bioavailable and is not biodegradable in the digestive system. MF may be considered as a potential therapy for the prevention of tumor spread.


Subject(s)
Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Muscle Proteins/administration & dosage , Sarcoma, Experimental/pathology , Administration, Oral , Animals , Antineoplastic Agents/adverse effects , Bone Marrow Cells/drug effects , Bone Marrow Cells/pathology , Cell Division/drug effects , Cell Line , Lung Neoplasms/drug therapy , Male , Mice , Mice, Inbred C57BL , Muscle Proteins/pharmacology , Sarcoma, Experimental/drug therapy
12.
Biull Eksp Biol Med ; 114(7): 86-8, 1992 Jul.
Article in Russian | MEDLINE | ID: mdl-1421323

ABSTRACT

Osteogenesis imperfecta (OI) is a disease with biochemical evidence of abnormality in collagen biosynthesis. We report here that expression of the OI phenotype extends to the level of dermal fibroblast morphology in vitro. Growth characteristics and morphology of control (n = 3) and 01 cell strains (n = 10) were compared. Our results show that (1) OI fibroblasts take longer time (16 days) than that with control cells (13 days) to reach stationary phase; (2) OI fibroblasts achieve a lower cell density (1.0 +/- 0.09) at stationary phase compared to control cells (1.47 +/- 0.1); p < 0.01; (3) cell shape (expressed as the width/length ratio) was also abnormal in OI cells: they have significantly increased ratios (p < 0.05) compared to control. These changes were associated with an increased level of fibronectin concentration and engorged cytoplasmic vesicles in dermal fibroblasts in vitro. We have reason to suspect that dysmorphology of fibroblasts may be related to aberrant collagen metabolism that leads to inadequacy of extracellular substratum, that in its turn hinders normal adhesion of cells as well as their spreading, morphology and fibronectin concentration.


Subject(s)
Fibroblasts/pathology , Osteogenesis Imperfecta/genetics , Skin/pathology , Adolescent , Adult , Cells, Cultured , Child , Child, Preschool , Collagen/metabolism , Cytoplasm/metabolism , Fibroblasts/metabolism , Fibronectins/metabolism , Humans , Infant , Middle Aged , Osteogenesis Imperfecta/metabolism , Osteogenesis Imperfecta/pathology , Phenotype , Skin/metabolism
13.
Ortop Travmatol Protez ; (9): 43-8, 1990 Sep.
Article in Russian | MEDLINE | ID: mdl-2095516

ABSTRACT

Properties of clonogenic stromal fibroblasts of bone marrow which are precursors of osteo- and chondrogenesis, of patients with different diseases of osteoarticular apparatus have been studied. Peculiarities of their reaction on growth-stimulating influence of nonstromal auto- and xenogeneic cells have been demonstrated. The possibilities of data application for studying of pathogenesis of hereditary osteochondrodysplasias as well as other groups of the skeleton affections are considered.


Subject(s)
Bone Diseases/etiology , Bone Marrow Cells , Joint Diseases/etiology , Adolescent , Adult , Aged , Arthritis/etiology , Arthritis/immunology , Bone Diseases/immunology , Bone Marrow/immunology , Cells, Cultured , Child , Child, Preschool , Colony-Forming Units Assay , Female , Humans , Joint Diseases/immunology , Male , Middle Aged , Osteochondrodysplasias/etiology , Osteochondrodysplasias/genetics , Osteoporosis/etiology , Osteoporosis/immunology
14.
Ortop Travmatol Protez ; (4): 27-32, 1989 Apr.
Article in Russian | MEDLINE | ID: mdl-2740128

ABSTRACT

The authors have carried out a search for morphological markers for diagnosing, differential diagnosis and medico-genetic consulting of 4 forms of osteochondrodysplasias. The cells and the intercellular substance of the cartilaginous graft plate from the upper flaring portion of the ileum of the patients were investigated. A common feature of most conditions were changes on the part of the granular endoplasmatic net, which points at a disturbance in the function of the synthesis apparatus and/or of the transport of the synthesized biopolymers. No morphological changes were revealed in the cartilaginous graft plate which were pathognomonic for spondyloepiphyseal dysplasia, achondroplasia and multiple exostosis chondrodysplasia. In one of the forms of pseudoachondroplasia (its severe dominant heritable variation) there were specific inclusions in the chondrocytes of the patients, which apparently were a morphological manifestation of disturbed assembly of proteoglycan aggregates which is the basis of the pathogenesis of pseudoachondroplasia. The possibility of using this morphological marker in the clinico-genetic classification of pseudoachondroplasia, in differential diagnosis of the disease in unclear cases as well as in medico-genetic consulting of the patients' families is discussed.


Subject(s)
Growth Plate/pathology , Osteochondrodysplasias/diagnosis , Child , Diagnosis, Differential , Genetic Counseling , Humans , Osteochondrodysplasias/classification , Osteochondrodysplasias/pathology
15.
Lab Delo ; (4): 58, 1989.
Article in Russian | MEDLINE | ID: mdl-2470972

ABSTRACT

The authors present an available method for preparing bacterial cells for examination in a scanning electron microscope. The method has been tried with clinical strains of S. aureus, P. aeruginosa, Acinetobacter calcoaceticus v. anitratus. Morphologic features of various types of microorganisms are described.


Subject(s)
Bacteria/ultrastructure , Microscopy, Electron, Scanning/methods , Humans
17.
Tsitol Genet ; 20(5): 330-4, 1986.
Article in Russian | MEDLINE | ID: mdl-3097896

ABSTRACT

Cytochemical studies of the peripheral blood leucocytes in patients suffering from mucopolysaccharidoses (MPS) have revealed metachromatic granules in the cell cytoplasm. Electron microscopy of these cells has shown multiple cytoplasmic vacuoles. It is supposed that metachromatic granules in blood leucocytes of patients with MPS observed in the photo-optical studies correspond to the vacuoles found under electron microscope. The obtained data have shown that peripheral blood leucocytes and skin fibroblasts have the common ultrastructure in MPS patients. The data of electron histochemical studies testify to that the vacuoles of skin fibroblasts are filled with glycosaminoglycans.


Subject(s)
Leukocytes/metabolism , Mucopolysaccharidoses/metabolism , Skin/metabolism , Adult , Child , Connective Tissue/metabolism , Connective Tissue/ultrastructure , Fibroblasts/metabolism , Fibroblasts/ultrastructure , Glycosaminoglycans/metabolism , Histocytochemistry , Humans , Leukocytes/ultrastructure , Microscopy, Electron , Mucopolysaccharidoses/pathology , Skin/ultrastructure
19.
Tsitol Genet ; 14(5): 21-6, 1980.
Article in Russian | MEDLINE | ID: mdl-6776669

ABSTRACT

Ultrastructure of skin fibroblasts was studied in patients with mucopolysaccharidoses of types IV and VI and their relatives. In MPS VI and keratan-nonexcreting form of MPS IV the cytoplasm of fibroblasts contained numerous vacuoles with material of various electron density. The ultrastructure of cell did not differ from the norm in the keratan-excreting form of MPS IV. Skin fibroblasts from parents and siblings with MPS VI were found to contain a large number of residue bodies. The possible usage of ultrastructural data for early diagnosis of MPS and in medical genetic consultation of families of the patients with MPS is discussed.


Subject(s)
Mucopolysaccharidoses/pathology , Mucopolysaccharidosis IV/pathology , Mucopolysaccharidosis VI/pathology , Skin/ultrastructure , Cytoplasm/ultrastructure , Fibroblasts/ultrastructure , Humans , Microscopy, Electron
20.
Arkh Anat Gistol Embriol ; 73(8): 47-52, 1977 Aug.
Article in Russian | MEDLINE | ID: mdl-907485

ABSTRACT

During early postnatal ontogenesis in the metaepiphyseal plate of the developing rat tibial bone, the borderline zone, the columnar cartilage zone and the zone of macrovesiculous cells differ in their cell composition, structure of basic substance and in functional and reactive potencies, which manifest themselves most distinctly after injection of growth-promoting hormones to the animals. The organic specificity of the metaepiphyseal borderline zone depends, first of all, on its intermediate position between the cartilage, fulfilling further bone growth lengthwise as an organ, and a developing endochondral bone substituting cartilage in the epiphysis. The borderline zone retains these features under hormonal effect. In the zone of columnar cells, it is reasonable to distinguish a layer of cuboidal cells--mature chondrocytes posessing great reactive and reparative possibilities, which become especially distincitive after prednisolon and TCT injection.


Subject(s)
Tibia/anatomy & histology , Animals , Animals, Newborn , Calcitonin/pharmacology , Microscopy, Electron , Prednisolone/pharmacology , Rats , Tibia/growth & development
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