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1.
AJNR Am J Neuroradiol ; 36(6): 1102-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25767187

RESUMO

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping allows overcoming several nonlocal restrictions of susceptibility-weighted and phase imaging and enables quantification of magnetic susceptibility. We compared the diagnostic accuracy of quantitative susceptibility mapping and R2* (1/T2*) mapping to discriminate between patients with Parkinson disease and controls. MATERIALS AND METHODS: For 21 patients with Parkinson disease and 21 age- and sex-matched controls, 2 radiologists measured the quantitative susceptibility mapping values and R2* values in 6 brain structures (the thalamus, putamen, caudate nucleus, pallidum, substantia nigra, and red nucleus). RESULTS: The quantitative susceptibility mapping values and R2* values of the substantia nigra were significantly higher in patients with Parkinson disease (P < .01); measurements in other brain regions did not differ significantly between patients and controls. For the discrimination of patients with Parkinson disease from controls, receiver operating characteristic analysis suggested that the optimal cutoff values for the substantia nigra, based on the Youden Index, were >0.210 for quantitative susceptibility mapping and >28.8 for R2*. The sensitivity, specificity, and accuracy of quantitative susceptibility mapping were 90% (19 of 21), 86% (18 of 21), and 88% (37 of 42), respectively; for R2* mapping, they were 81% (17 of 21), 52% (11 of 21), and 67% (28 of 42). Pair-wise comparisons showed that the areas under the receiver operating characteristic curves were significantly larger for quantitative susceptibility mapping than for R2* mapping (0.91 versus 0.69, P < .05). CONCLUSIONS: Quantitative susceptibility mapping showed higher diagnostic performance than R2* mapping for the discrimination between patients with Parkinson disease and controls.


Assuntos
Encéfalo/patologia , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Ferro/metabolismo , Imageamento por Ressonância Magnética/métodos , Doença de Parkinson/diagnóstico , Idoso , Mapeamento Encefálico/métodos , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/patologia , Sensibilidade e Especificidade , Substância Negra/patologia
2.
J Bone Joint Surg Br ; 87(5): 687-91, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15855373

RESUMO

We studied 52 patients, each with a lumbosacral transitional vertebra. Using MRI we found that the lumbar discs immediately above the transitional vertebra were significantly more degenerative and those between the transitional vertebrae and the sacrum were significantly less degenerative compared with discs at other levels. We also performed an anatomical study using 70 cadavers. We found that the iliolumbar ligament at the level immediately above the transitional vertebra was thinner and weaker than it was in cadavers without a lumbosacral transitional vertebra. Instability of the vertebral segment above the transitional vertebra because of a weak iliolumbar ligament could lead to subsequent disc degeneration which may occur earlier than at other disc levels. Some stability between the transitional vertebra and the sacrum could be preserved by the formation of either an articulation or by bony union between the vertebra and the sacrum through its transverse process. This may protect the disc from further degeneration in the long term.


Assuntos
Disco Intervertebral/patologia , Vértebras Lombares/patologia , Doenças da Coluna Vertebral/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Cadáver , Feminino , Humanos , Ílio , Instabilidade Articular/fisiopatologia , Ligamentos Articulares/patologia , Região Lombossacral , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Sacro , Fatores Sexuais
3.
J Med Primatol ; 31(3): 129-35, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12190853

RESUMO

In the last three decades, several monkeys reared in outdoor/indoor-outdoor breeding colonies and cages of the Primate Research Institute, Kyoto University, died of yersiniosis caused by Yersinia pseudotuberculosis, necessitating introduction of a method to detect the bacteria rapidly and thus allow preventive measures to be undertaken. A rapid nested polymerase chain reaction (PCR) method for identification of Y. pseudotuberculosis in fecal samples and a random amplified polymorphic DNA (RAPD)-PCR approach for distinguishing between bacterial strains were therefore developed. Yersinia pseudotuberculosis isolates from monkey specimens were found to be classifiable into several types. To determine the source of infection, hundreds of fecal samples of wild rats, pigeons, and sparrows were collected from around the breeding colonies and cages, and subjected to PCR analyses. Yersinia pseudotuberculosis was detected in 1.7% of the fecal samples of wild rats. The DNA fingerprints of the bacteria revealed by RAPD-PCR were the same as that of one strain isolated from macaques, suggesting the wild rat to be a possible source of infection.


Assuntos
Haplorrinos/microbiologia , Doenças dos Macacos/microbiologia , Técnica de Amplificação ao Acaso de DNA Polimórfico/métodos , Fatores de Virulência , Yersinia pseudotuberculosis/genética , Yersinia pseudotuberculosis/isolamento & purificação , Adesinas Bacterianas/genética , Animais , Animais Selvagens , Proteínas de Bactérias/genética , Primers do DNA , Fezes/microbiologia , Ratos , Yersinia pseudotuberculosis/classificação , Infecções por Yersinia pseudotuberculosis/microbiologia , Infecções por Yersinia pseudotuberculosis/transmissão , Infecções por Yersinia pseudotuberculosis/veterinária
4.
Bone ; 29(5): 458-66, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11704499

RESUMO

Recent experiments have shown that exogenous basic fibroblast growth factor (bFGF) enlarges fracture callus and accelerates the healing of osteotomized long bones. The actions of bFGF are mediated by four different transmembrane receptors (FGFR1-4). Among them, FGFR1 has a high affinity for bFGF, and gain-of-function mutations of the FGFR1 gene cause craniosynostosis in humans. Gene expression for FGFR1 has been analyzed in embryogenesis; however, in skeletal repair, detailed expression of FGFR1 has not been fully established. In the present study, a rat model of closed femoral fracture healing was used to quantify mRNA encoding the FGFR1 and to characterize cells expressing FGFR1 by in situ hybridization. Gene expression for FGFR1 was rapidly upregulated after fracture; its mRNA level on day 1 was 3.4-fold higher than that of unfractured femora. At this stage, a moderate signal for FGFR1 was detected in periosteal osteoprogenitor cells, inflammatory cells near fracture sites, and cells among muscle layers. FGFR1 mRNA reached peak expression when callus remodeling actively progressed (6.8-fold on day 14), and remained elevated even in the later stages of healing (6.3-fold on day 28). During the intermediate stage of fracture healing, a strong signal for FGFR1 was diffusely distributed in mature osteoblasts in the hard callus, and mature osteoclasts also expressed a weak signal for FGFR1. These results suggest that FGF/FGFR1 signaling has multifunctional roles during fracture healing and may regulate both osteoblasts and osteoclasts, contributing to bone formation and callus remodeling.


Assuntos
Consolidação da Fratura/fisiologia , Receptores Proteína Tirosina Quinases/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Animais , Calo Ósseo/fisiopatologia , Fêmur/lesões , Fêmur/fisiologia , Fator 2 de Crescimento de Fibroblastos/genética , Expressão Gênica/fisiologia , Hibridização In Situ , Masculino , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Ribonucleases , Transdução de Sinais/fisiologia
5.
J Orthop Res ; 19(5): 935-44, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11562144

RESUMO

Chondrogenesis is an essential component of endochondral fracture healing, though the molecular and cellular events by which it is regulated have not been fully elucidated. In this study, we used a rat model of closed fracture healing to determine the spatial and temporal expression of genes for cartilage-specific collagens. Furthermore, to determine the effects of basic fibroblast growth factor (bFGF) on chondrogenesis in fracture healing, we injected 100 microg recombinant human bFGF into the fracture site immediately after fracture. In normal calluses, pro-alpha1(II) collagen mRNA (COL2A1) was detected in proliferative chondrocytes beginning on day 4 after the fracture, and pro-alpha1(X) collagen mRNA (COL10A1) in hypertrophic chondrocytes beginning on day 7. In FGF-injected calluses, the cartilage enlarged in size significantly. On day 14, both COL2A1- and COL10A1-expressing cells were more widely distributed, and the amounts of COL2A1 and COL10A1 mRNAs were both approximately 2-fold increased when compared with uninjected fractures. Temporal patterns of expression for these genes were, however, identical to those found in normal calluses. The number of proliferating cell nuclear antigen-positive cells was increased in the non-cartilaginous area in the bFGF-injected calluses by day 4. The present molecular analyses demonstrate that a single injection of bFGF enhances the proliferation of chondroprogenitor cells in fracture callus, and thus contributes to the formation of a larger cartilage. However, maturation of chondrocytes and replacement of the cartilage by osseous tissue are not enhanced by exogenous bFGF, and this results in the prolonged cartilaginous callus phase. We conclude that, in the healing of closed fractures of long bones, exogenous bFGF has a capacity to enlarge the cartilaginous calluses, but not to induce more rapid healing.


Assuntos
Condrogênese/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacocinética , Consolidação da Fratura/efeitos dos fármacos , Fraturas Fechadas/tratamento farmacológico , Animais , Cartilagem/química , Cartilagem/fisiologia , Condrócitos/química , Condrócitos/fisiologia , Condrogênese/fisiologia , Modelos Animais de Doenças , Fraturas Fechadas/fisiopatologia , Expressão Gênica/efeitos dos fármacos , Radioisótopos do Iodo , Masculino , Pró-Colágeno/genética , Antígeno Nuclear de Célula em Proliferação/análise , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley
6.
Gan To Kagaku Ryoho ; 28(8): 1099-104, 2001 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-11525025

RESUMO

In this study, we demonstrated that toremifene citrate (TOR) inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVEC) in vitro. Moreover, TOR suppressed angiogenesis in rabbit cornea and lung metastasis of human fibrosarcoma HT-1080 cells in nude mice. The antiangiogenic activity in vitro was apparent at the concentration of 5 microM which is clinically achievable by oral administration of 120 mg/kg of TOR. These results suggest that clinical treatment with 120 mg/day of TOR might be expected to exhibit antiangiogenesis and antimetastasis effects, in addition to inhibition of estrogen-dependent tumor cell growth.


Assuntos
Inibidores da Angiogênese/farmacologia , Fibrossarcoma/patologia , Neoplasias Pulmonares/secundário , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Toremifeno/farmacologia , Animais , Neovascularização da Córnea/patologia , Estrogênios/fisiologia , Humanos , Camundongos , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Coelhos
7.
Inorg Chem ; 40(7): 1496-500, 2001 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-11261956

RESUMO

Three dipeptide complexes of the form K[Pt(IV)(dipep)Cl3] and two complexes of the form K[Pt(IV)(Hdipep)Cl4] were newly prepared and isolated. The platinum(IV) complexes containing the dipeptide were obtained directly by adding KI to H2[PtCl6] solution. The reaction using KI was rapidly completed and provided analytically pure yellow products in the form of K[Pt(dipeptide)Cl3] for H2digly, H2gly(alpha)-ala, H2alpha-alagly and H2di(alpha)-ala. The K[Pt(IV)(digly)Cl3] complex crystallizes in the monoclinic space group P2(1)/c with unit cell dimensions a = 10.540(3) A, b = 13.835(3) A, c = 8.123(3) A, beta = 97.01(2) degrees, Z = 4. The crystal data represented the first report of a Pt(IV) complex with a deprotonated peptide, and this complex has the rare iminol type diglycine(2-) coordinating to Pt(IV) with the bond lengths of the C2-N1 (amide) bond (1.285(13) A). The 195Pt NMR peaks of the K[Pt(IV)(dipep)Cl3] and the K[Pt(IV)(Hdipep)Cl4] complexes appeared at about 270 ppm and at about -130 ppm, respectively, and were predicted for a given set of ligand atoms. While the K[Pt(IV)(x-gly)Cl3] complexes, where x denotes the glycine or alpha-alanine moieties, were easily reduced to the corresponding platinum(II) complexes, the K[Pt(IV)(x-alpha-ala)Cl3] complexes were not reduced, but the Cl- ion was substituted for OH- ion in the reaction solution. The K[Pt(digly)Cl3] and K[Pt(gly-L-alpha-ala)Cl3] complexes inhibited the growth of Candida albicans, and the antifungal activities were 3- to 4-fold higher than those of cisplatin. The metabolism of glucose in C. albicans was strongly inhibited by K[Pt(digly)Cl3] and K[Pt(gly-L-alpha-ala)Cl3] but not by the antifungal agent fluconazole.


Assuntos
Antifúngicos/química , Candida albicans/efeitos dos fármacos , Dipeptídeos/química , Glucose/metabolismo , Compostos de Platina/química , Antifúngicos/farmacologia , Candida albicans/metabolismo , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Isótopos de Nitrogênio , Compostos de Platina/farmacologia
8.
Circulation ; 103(5): 736-42, 2001 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-11156887

RESUMO

BACKGROUND: ACE inhibition after myocardial infarction (MI) has been shown to have beneficial effects on cardiac anatomy and function. The purpose of this study was to examine the effects of ACE inhibition on cardiac gene expression after MI. METHODS AND RESULTS: Rats were randomized to receive captopril or no treatment 1 day after MI. Eight weeks later, cardiac function and hemodynamics were measured by use of indwelling catheters and perivascular flow probes. Myocardial gene expression was assessed with DNA microarrays and real-time reverse transcription-polymerase chain reaction. The ratios of heart and left ventricular weights to body weight were significantly increased by MI and normalized by captopril. Cardiac index and stroke volume index were lower in the untreated MI group than in sham controls but were normal in the MI+captopril group. Thirty-seven genes were found to be differentially expressed between the untreated MI group and sham controls; 31 were induced and 6 repressed. Captopril partially or completely inhibited changes in 10 of the genes. The 37 genes clustered into 11 functional groups, and 6 had >/=1 genes whose expression was modified by ACE inhibition. CONCLUSIONS: ACE inhibition after MI inhibits cardiac hypertrophy, preserves cardiac function, and attenuates changes in myocardial gene expression. Gene expression profiling reveals, however, that some elements of the pathophysiology may be unaffected by the treatment and be targets for new therapies.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Expressão Gênica/efeitos dos fármacos , Infarto do Miocárdio/genética , Peptidil Dipeptidase A/metabolismo , Doença Aguda , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Coração/fisiologia , Testes de Função Cardíaca , Frequência Cardíaca/efeitos dos fármacos , Masculino , Infarto do Miocárdio/enzimologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
9.
J Biol Chem ; 276(10): 7048-54, 2001 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-11092885

RESUMO

Mechanical loading is crucial for maintenance of bone integrity and architecture, and prostaglandins are an important mediator of mechanosensing. Cyclooxygenase-2 (COX-2), an inducible isoform of prostaglandin G/H synthase, is induced by mechanical loading-derived fluid shear stress in bone-forming cells such as osteoblasts and osteocytes. In this study, we investigated transcription factor and transcriptional regulatory elements responsible for the shear stress-induced COX-2 expression in osteoblastic MC3T3-E1 cells. When the cells were transfected with luciferase-reporter plasmids including the 5'-flanking region of the murine cox-2 gene, the fluid shear stress increased the luciferase activities, consistent with the induction of COX-2 mRNA and protein expression. Deletion analysis of the promoter region revealed that the shear stress-induced luciferase responses were regulated by two regions, -172 to -100 base pair (bp) and -79 to -46 bp, of the cox-2 promoter, in which putative cis-elements of C/EBP beta, AP-1, cAMP-response element-binding protein (CREB), and E box are included. Mutation of sites of C/EBP beta, AP-1, and/or cAMP-response element decreased the shear stress-induced luciferase activities, whereas mutation of the E box did not affect the responses. In an electrophoretic mobility shift assay, shear stress enhanced nuclear extract binding to double-stranded oligonucleotide probes containing C/EBP beta and AP-1-binding motifs, and the bands of the complexes were supershifted by the addition of antibody specific for each regulator. Although the binding activity of CREB toward its probe was unaffected by shear stress, the phosphorylation of CREB was enhanced by the stress. These data suggest that C/EBP beta, AP-1, and CREB play crucial roles in the shear stress-induced cox-2 expression in osteoblasts.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Isoenzimas/biossíntese , Osteoblastos/metabolismo , Prostaglandina-Endoperóxido Sintases/biossíntese , Fator de Transcrição AP-1/metabolismo , Animais , Sítios de Ligação , Western Blotting , Linhagem Celular , Núcleo Celular/metabolismo , Ciclo-Oxigenase 2 , Vetores Genéticos , Isoenzimas/genética , Luciferases/metabolismo , Camundongos , Mutação , Plasmídeos/metabolismo , Regiões Promotoras Genéticas , Prostaglandina-Endoperóxido Sintases/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Mecânico , Fatores de Tempo , Ativação Transcricional , Transfecção , Regulação para Cima
10.
Nihon Hoigaku Zasshi ; 54(2): 207-18, 2000 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-11060990

RESUMO

We report a method for estimation of age from teeth using the racemization of amino acids (racemization method). This method is based on the characteristics of the constant age-related increase in the amount of D-aspartic acid in dentin. We estimated age by measuring the ratio of D-aspartic acid to L-aspartic acid, i.e. the ratio of racemization ¿ratio of D/L, ln[(1 + D/L)/(1 - D/L)]¿. Because different D/L ratios have been obtained from different teeth in the same individuals and from different sites of dentin in the same tooth, we usually prepare bucco-lingual longitudinal sections at the central part of each tooth, and prepare samples of powdered whole dentin. This powder is then mixed and used to measure the D/L ratio in the dentin. To accurately estimate age from forensic specimens, we simultaneously measured the D/L ratios in more than four control teeth of the same type obtained from subjects of known age. Use of control teeth is necessary because it is sometimes difficult to maintain constant running conditions for gas chromatography to obtain reproducible values in different runs. Therefore, for every measurement, we determined an equation for calculating age from the D/L ratios of control teeth, and estimated the age of the specimen tooth by substituting in its D/L ratio. The most reliable results were obtained using samples of lower incisors or premolars, which are single-rooted teeth with a relatively small volume of dentin. Thus sampling of the dentin is easier than for other teeth. It is better to keep control teeth desiccated because racemization does not proceed readily under such conditions. The deviation from the actual age in the cases we examined was less than 3 years. Thus, racemization of amino acids can be used for accurate estimation of age from teeth.


Assuntos
Determinação da Idade pelos Dentes/métodos , Ácido Aspártico/química , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Estereoisomerismo
11.
Am J Physiol Heart Circ Physiol ; 279(6): H2994-3002, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11087257

RESUMO

This study determined the effects of exercise training on cardiac function, gene expression, and apoptosis. Rats exposed to a regimen of treadmill exercise for 13 wk had a significant increase in cardiac index and stroke volume index and a concomitant decrease in systemic vascular resistance compared with both age-matched and body weight-matched sedentary controls in the conscious state at rest. In exercise-trained animals, there was no change in the expression of several marker genes known to be associated with pathological cardiac adaptation, including atrial natriuretic factor, beta-myosin heavy chain, alpha-skeletal and smooth muscle actins, and collagens I and III. Exercise training, however, produced a significant induction of alpha-myosin heavy chain, which was not observed in rats with myocardial infarction. No histological features of cardiac apoptosis were observed in the treadmill-trained rats. In contrast, apoptotic myocytes were detected in animals with myocardial infarction. In summary, exercise training improves cardiac function without evidence of cardiac apoptosis and produces a pattern of cardiac gene expression distinct from pathological cardiac adaptation.


Assuntos
Adaptação Fisiológica/genética , Apoptose/fisiologia , Expressão Gênica/fisiologia , Coração/fisiologia , Condicionamento Físico Animal/fisiologia , Actinas/genética , Animais , Fator Natriurético Atrial/genética , Colágeno/genética , Ecocardiografia , Coração/crescimento & desenvolvimento , Ventrículos do Coração/crescimento & desenvolvimento , Hemodinâmica/fisiologia , Masculino , Fibras Musculares Esqueléticas/patologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Cadeias Pesadas de Miosina/genética , Ratos , Ratos Sprague-Dawley , Função Ventricular
12.
Bone ; 27(4): 479-86, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11033442

RESUMO

Bone morphogenetic proteins (BMPs) play an important role in various kinds of pattern formation and organogenesis during vertebrate development. In the skeleton, BMPs induce the differentiation of cells of chondrocytic and osteoblastic cell lineage and enhance their function. However, the action of BMPs on osteoclastic bone resorption, a process essential for pathophysiological bone development and regeneration, is still controversial. In this study, we examine the direct effect of BMPs on osteoclastic bone-resorbing activity in a culture of highly purified rabbit mature osteoclasts. BMP-2 caused a dose- and time-dependent increase in bone resorption pits excavated by the isolated osteoclasts. BMP-4 also stimulated osteoclastic bone resorption. The increase in osteoclastic bone resorption induced by BMP-2 was abolished by the simultaneous addition of follistatin, a BMP/activin binding protein that negates their biological activity. Just as it increased bone resorption, BMP-2 also elevated the messenger RNA expressions of cathepsin K and carbonic anhydrase II, which are key enzymes for the degradation of organic and inorganic bone matrices, respectively. Type IA and II BMP receptors (BMPRs), and their downstream signal transduction molecules, Smad1 and Smad5, were expressed in isolated osteoclasts as well as in osteoblastic cells, whereas type IB BMPR was undetectable. BMPs directly stimulate mature osteoclast function probably mediated by BMPR-IA and BMPR-II and their downstream molecules expressed in osteoclasts. The results presented here expand our understanding of the multifunctional roles of BMPs in bone development.


Assuntos
Proteínas Morfogenéticas Ósseas/farmacologia , Reabsorção Óssea , Osteoclastos/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Receptores de Fatores de Crescimento , Fator de Crescimento Transformador beta , Animais , Sequência de Bases , Proteína Morfogenética Óssea 2 , Receptores de Proteínas Morfogenéticas Ósseas , Proteínas Morfogenéticas Ósseas/metabolismo , Anidrases Carbônicas/genética , Primers do DNA , Microscopia Eletrônica de Varredura , Osteoclastos/metabolismo , Osteoclastos/ultraestrutura , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coelhos , Receptores de Superfície Celular/genética , Transdução de Sinais , Transativadores/metabolismo
13.
J Immunol ; 165(8): 4254-63, 2000 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11035059

RESUMO

Differentiation of osteoclasts, the cells primarily responsible for bone resorption, is controlled by a variety of osteotropic hormones and cytokines. Of these factors, receptor activator of NF-kappaB (RANK) ligand (RANKL) has been recently cloned as an essential inducer of osteoclastogenesis in the presence of M-CSF. Here, we isolated a stroma-free population of monocyte/macrophage (M/Mphi)-like hemopoietic cells from mouse unfractionated bone cells that were capable of differentiating into mature osteoclasts by treatment with soluble RANKL (sRANKL) and M-CSF. However, the efficiency of osteoclast formation was low, suggesting the requirement for additional factors. The isolated M/Mphi-like hemopoietic cells expressed TGF-beta and type I and II receptors of TGF-beta. Therefore, we examined the effect of TGF-beta on osteoclastogenesis. TGF-beta with a combination of sRANKL and M-CSF promoted the differentiation of nearly all M/Mphi-like hemopoietic cells into cells of the osteoclast lineage. Neutralizing anti-TGF-beta Ab abrogated the osteoclast generation. These TGF-beta effects were also observed in cultures of unfractionated bone cells, and anti-TGF-beta blocked the stimulatory effect of 1, 25-dihydroxyvitamin D(3). Translocation of NF-kappaB into nuclei induced by sRANKL in TGF-beta-pretreated M/Mphi-like hemopoietic cells was greater than that in untreated cells, whereas TGF-beta did not up-regulate the expression of RANK, the receptor of RANKL. Our findings suggest that TGF-beta is an essential autocrine factor for osteoclastogenesis.


Assuntos
Proteínas de Transporte , Glicoproteínas/fisiologia , Fator Estimulador de Colônias de Macrófagos/fisiologia , Glicoproteínas de Membrana , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores do Fator de Necrose Tumoral/fisiologia , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/fisiologia , Animais , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Separação Celular , Células Cultivadas , Sinergismo Farmacológico , Glicoproteínas/farmacologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Ligantes , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Osteoprotegerina , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Fator de Crescimento Transformador beta/farmacologia
14.
Antimicrob Agents Chemother ; 44(10): 2853-4, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10991871

RESUMO

A new platinum derivative of the form H[Pt(IV)(Hdigly)Cl(2)(OH)(2)] (Hdigly==glycylglycine) damaged the Candida albicans cell membrane and inhibited the growth of the cells. The cytotoxic activity of H[Pt(IV)(Hdigly)Cl(2)(OH)(2)] on mammalian cells was 10-fold lower than that of cis-diammine-dichloroplatinum (cisplatin). Substitution of platinum for peptides is effective for enhancement of antifungal activity and reduction of the toxicity to mammalian cells.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Testes de Sensibilidade Microbiana , Células Tumorais Cultivadas
15.
Kaibogaku Zasshi ; 75(5): 451-6, 2000 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-11155692

RESUMO

Although osteocytes are of the most abundant cells in bone, our knowledge about the role of osteocytes in bone metabolism is still poor compared with that about osteoblasts and osteoclasts, both being on the surface of bone. Osteocytes are terminally differentiated bone-forming cells. During bone formation, some of the osteoblasts lining the surface of bone are incorporated into the newly formed osteoid matrix and become osteocytes, while the other osteoblasts remain on the surface as lining cells. During this transition from osteoblasts to osteocytes, the cells lose numerous osteoblastic phenotypes and acquire osteocytic characteristics such as high expression of osteocalcin and particularly their specific morphology. Osteocytes are connected with each other in bone and with osteoblasts on the bone surface through canaliculi, forming cellular networks; and gap-junctions present at the contact sites mediate their intercellular communication. Several roles of osteocytes in bone have been proposed so far. Of them, based on the morphological characteristics of osteocytes, sensation of mechanical stress loaded onto bone is suspected to be one of their functions. One of the mechanical stresses on bone is fluid shear stress. Between the osteocyte's plasma membrane and the bone matrix is the periosteocytic space. This space exists both in the lacunae and in the canaliculi, and it is filled with extracellular fluid (ECF). Application of mechanical stress to bone locally deforms the tissue. This periodical deformation subsequently causes an increase in the flow of ECF in the periosteocytic space, resulting in shear stress on the surface of the osteocytes. Experimental studies demonstrated that bone cells were equivalently or more sensitive to the fluid shear stress than epithelial cells. Osteocytic cells cultured enhanced expression of prostaglandin (PG) G/H synthase-2 (COX-2) mRNA in response to shear stress. PGE2 is a potent regulator of proliferation and function of osteoblasts and osteoclasts. Therefore, a metabolic response by osteoblasts and osteoclasts lining the bone surface may be caused by PGE2 produced by osteocytes in response to shear stress when the prostanoid reaches the surface through the canaliculi. In conclusion, osteocytes play an important role in sensing extracellular mechanical stress, and the mechanical signals mediated by osteocytes may regulate the overall metabolism of cells in bone tissue.


Assuntos
Apoptose/fisiologia , Osteócitos , Estresse Mecânico , Animais , Comunicação Celular/fisiologia , Diferenciação Celular , Divisão Celular , Humanos , Osteócitos/citologia , Osteócitos/fisiologia , Estimulação Física , Prostaglandinas/metabolismo , Prostaglandinas/fisiologia
16.
J Bone Joint Surg Br ; 81(3): 508-15, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10872376

RESUMO

The multifunctional adhesion molecule CD44 is a major cell-surface receptor for hyaluronic acid (HUA). Recent data suggest that it may also bind the ubiquitous bone-matrix protein, osteopontin (OPN). Because OPN has been shown to be a potentially important protein in bone remodelling, we investigated the hypothesis that OPN interactions with the CD44 receptor on bone cells participate in the regulation of the healing of fractures. We examined the spatial and temporal patterns of expression of OPN and CD44 in healing fractures of rat femora by in situ hybridisation and immunohistochemistry. We also localised HUA in the fracture callus using biotinylated HUA-binding protein. OPN was expressed in remodelling areas of the hard callus and was found in osteocytes, osteoclasts and osteoprogenitor cells, but not in cuboidal osteoblasts which were otherwise shown to express osteocalcin. The OPN signal in osteocytes was not uniformly distributed, but was restricted to specific regions near sites where OPN mRNA-positive osteoclasts were attached to bone surfaces. In the remodelling callus, intense immunostaining for CD44 was detected in osteocyte lacunae, along canaliculi, and on the basolateral plasma membrane of osteoclasts, but not in the cuboidal osteoblasts. HUA staining was detected in fibrous tissues but little was observed in areas of hard callus where bone remodelling was progressing. Our findings suggest that OPN, rather than HUA, is the major ligand for CD44 on bone cells in the remodelling phase of healing of fractures. They also raise the possibility that such interactions may be involved in the communication of osteocytes with each other and with osteoclasts on bone surfaces. The interactions between CD44 and OPN may have important clinical implications in the repair of skeletal tissues.


Assuntos
Calo Ósseo/patologia , Fraturas do Fêmur/patologia , Consolidação da Fratura/fisiologia , Receptores de Hialuronatos/análise , Sialoglicoproteínas/análise , Animais , Remodelação Óssea/fisiologia , Ácido Hialurônico/análise , Masculino , Osteoclastos/patologia , Osteócitos/patologia , Osteopontina , Ratos , Ratos Sprague-Dawley
17.
J Med Chem ; 40(18): 2858-65, 1997 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-9288167

RESUMO

Novel N-substituted phthalimides (2-substituted 1H-isoindole-1,3-diones) were prepared, and their effects on tumor necrosis factor-alpha (TNF-alpha) production by human leukemia cell line HL-60 stimulated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or okadaic acid (OA) were examined. A structure-activity relationship study of the N-phenylphthalimides and N-benzylphthalimides revealed that their enhancing effect on TPA-induced TNF-alpha production by HL-60 cells and their inhibiting effect on OA-induced TNF-alpha production by HL-60 cells are only partially correlated.


Assuntos
Células HL-60/efeitos dos fármacos , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Ftalimidas/química , Ftalimidas/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HL-60/fisiologia , Humanos , Fatores Imunológicos/síntese química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Ácido Okadáico/farmacologia , Rotação Ocular , Ftalimidas/síntese química , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol/farmacologia
18.
J Forensic Sci ; 42(1): 137-9, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8988588

RESUMO

To determine the age of a subject from teeth accurately utilizing the racemization rates of amino acids, standard samples of the same tooth species from the same jaw are necessary as controls, as well as data for identification. However, standard teeth are generally stored in fixatives such as ethanol and formalin. We investigated and compared the degree of progression of racemization of dentinal aspartic acid in teeth stored in 95% ethanol, 10% formalin, or 10% neutral formalin fixatives. The racemization rate of dentinal aspartic acid in teeth stored in 10% neutral formalin was the highest, followed by that for teeth stored in 10% formalin then that for teeth stored in 95% ethanol. Teeth stored in these fixatives at 15 degrees C showed almost no progression of racemization. The racemization ratio (D/L ratio) in teeth extracted 10 years previously was almost unchanged from that at the time of extraction, and allowed an accurate evaluation of the subjects age at tooth extraction.


Assuntos
Determinação da Idade pelos Dentes/métodos , Aminoácidos/análise , Etanol/farmacologia , Fixadores/farmacologia , Formaldeído/farmacologia , Aminoácidos/química , Ácido Aspártico/análise , Ácido Aspártico/química , Dentina/química , Medicina Legal , Humanos , Pessoa de Meia-Idade , Racemases e Epimerases , Fatores de Tempo
19.
Bioorg Med Chem ; 5(11): 2095-102, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9416426

RESUMO

N-Substituted phthalimides (2-substituted 1H-isoindole-1,3-diones) were prepared and their inhibitory effects on tumor necrosis factor-alpha (TNF-alpha) production by human leukemia cell line THP-1 stimulated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or okadaic acid (OA) were examined. A structure-activity relationship study of these phthalimide analogues revealed that their inhibitory effects on TPA- and OA-induced TNF-alpha production by THP-1 cells are well correlated to each other, i.e. they may involve the same target molecule(s). An analysis by the use of phthalimide analogue-immobilized affinity gels indicated the existence of several phthalimide-binding proteins in THP-1 cell extract.


Assuntos
Leucemia Monocítica Aguda/metabolismo , Ftalimidas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ácido Okadáico/farmacologia , Ftalimidas/síntese química , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol/farmacologia , Células Tumorais Cultivadas
20.
Clin Exp Pharmacol Physiol ; 22(4): 311-3, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7671451

RESUMO

1. Intrarenal arterial infusion of hypertonic saline (HS) transiently increased and then gradually reduced renal blood flow (RBF) in anaesthetized dogs. Glomerular filtration rate (GFR) but not filtration fraction decreased at the end of the infusion. 2. In the presence of a potassium channel opener cromakalim (0.3 microgram/kg per min), HS infusion failed to reduce RBF; the initial increase in RBF was maintained throughout the infusion. Since cromakalim also prevented the decrease in GFR, HS infusion lowered filtration fraction. 3. The results suggest that cromakalim inhibits both pre-and postglomerular vasoconstriction induced by HS infusion.


Assuntos
Benzopiranos/farmacologia , Pirróis/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Cromakalim , Modelos Animais de Doenças , Diurese/efeitos dos fármacos , Cães , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hematócrito , Masculino , Canais de Potássio/efeitos dos fármacos , Circulação Renal/efeitos dos fármacos , Solução Salina Hipertônica/toxicidade , Sódio/urina
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