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Background: Gabapentinoid anticonvulsants are standard treatment for neuropathic pain and are often combined with opioids for treating cancer. It is assumed that this combination may heighten somnolence and respiratory depression due to the inhibitory effects of opioids on the central nervous system. Although pregabalin, a gabapentinoid, is known to increase somnolence frequency during opioid therapy, whether mirogabalin exerts similar effects on somnolence frequency under opioid therapy remains unknown. This study examined the signals of somnolence and respiratory depression in response to pregabalin and mirogabalin use by utilizing data from the Japanese Adverse Drug Event Report database and assessed their interaction with strong opioid analgesics. Methods: Information was obtained from the JADER database from April 2004 to August 2023 via the Pharmaceuticals and Medical Devices Agency website. The study focused on neuropathic pain medications, specifically "pregabalin" and "mirogabalin besilate." Adverse events were defined using preferred terms (PTs) from the Medical Dictionary for Regulatory Activities version 26.1. The PTs considered were "Somnolence (10041349)" and "Respiratory depression (10038678)." To investigate the effect of the combination of strong opioid analgesics with pregabalin and mirogabalin on the occurrence of somnolence, a multivariable logistic regression analysis was conducted. Results: Signals for somnolence were detected with the use of both drugs (pregabalin: information component (IC) [95% confidence intervals (CIs)]: 2.89 [2.70 to 3.08]; mirogabalin: IC [95% CIs] 2.50 [1.85 to 3.16]). When evaluating respiratory depression, a typical and serious adverse event of opioid analgesic use, a signal was detected with pregabalin use but not with mirogabalin use (pregabalin: (IC [95% CIs] 1.28 [0.83 to 1.73]; mirogabalin: IC [95% CIs] -0.15 [-2.20 to 1.89]). Multivariable analysis indicated that the use of strong opioid analgesics increased the occurrence of somnolence when combined with pregabalin but not when combined with mirogabalin (p = 0.004). Conclusion: While the safety of concomitant administation of mirogabalin with opioids remains controversial, caution should be exercised when using pregabalin, especially in combination with opioids for neuropathic pain, compared to that for mirogabalin.
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Analgésicos Opioides , Compuestos Bicíclicos con Puentes , Pregabalina , Insuficiencia Respiratoria , Somnolencia , Femenino , Humanos , Masculino , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Analgésicos/efectos adversos , Analgésicos/administración & dosificación , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/administración & dosificación , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/administración & dosificación , Compuestos Bicíclicos con Puentes/efectos adversos , Compuestos Bicíclicos con Puentes/administración & dosificación , Bases de Datos Factuales , Interacciones Farmacológicas , Japón/epidemiología , Neuralgia/tratamiento farmacológico , Neuralgia/inducido químicamente , Neuralgia/epidemiología , Pregabalina/efectos adversos , Insuficiencia Respiratoria/inducido químicamenteRESUMEN
Transurethral vaporization of the prostate in saline (TURisV) is an innovative endoscopic surgical modality for the treatment of benign prostatic hyperplasia (BPH) that vaporizes prostate tissue using a uniquely designed mushroom electrode. TURisV promises instant hemostatic tissue ablation under saline irrigation and offers clinical advantages for endoscopic BPH operations. From July 2008 to February 2009, TURisV was performed in 17 cases with clinically significant BPH. Median operation time was 127.0 min and median volume of vaporized prostate tissue was 41.1 g. Median International Prostate Symptom Score improved from 20 to 4 after 12 months. Median maximum flow rate increased from 5.3 mL/s to 13.8 mL/s after 12 months. Postoperative median residual urine improved from 48.0 mL to 7.0 mL after 12 months. No changes in hemoglobin or electrolyte levels were seen postoperatively. Our results suggest that TURisV is a safe and efficacious treatment for BPH.
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Hiperplasia Prostática/cirugía , Resección Transuretral de la Próstata/métodos , Anciano , Anciano de 80 o más Años , Electrodos , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Calidad de Vida , Cloruro de Sodio , Irrigación Terapéutica , Resección Transuretral de la Próstata/instrumentación , Resultado del Tratamiento , MicciónRESUMEN
OBJECTIVES: Calcifying cystic odontogenic tumour (CCOT) is a rare disorder of the jaw. A comparison between conventional radiographs and CT images in CCOTs has not been reported. The purposes of this study were to analyse conventional radiographs and CT images of CCOTs, establish CT images of CCOTs and assess the utility of CT in the diagnosis of CCOTs. METHODS: Nine patients with a histopathologically confirmed CCOT who had both conventional radiographs and CT images were enrolled. RESULTS: CT was superior to conventional radiographs in detecting buccolingual expansion, odontomas and radio-opaque bodies. CONCLUSION: The characteristic CT appearances of CCOT were that radio-opaque bodies were typically located in the periphery of the lesion and the shape of radio-opaque bodies was linear and/or spotted. CT was useful in diagnosing a CCOT.
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Neoplasias Maxilomandibulares/diagnóstico por imagen , Quiste Odontogénico Calcificado/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
OBJECTIVES: this study was undertaken to investigate the relationship between radiographic appearance and epithelial cell proliferations in keratocystic odontogenic tumours (KCOTs). METHODS: a retrospective radiographic analysis was performed on 284 cases of KCOT to gain insight into the radiographic characteristics. Expression of Ki-67 in 30 of the 284 cases was detected by the labelled streptavidin-biotin (LSAB) method and evaluated by an image analysis system. RESULTS: the radiographic presentation of KCOT was divided into four types: unilocular, multilocular, multiple and naevoid basal cell carcinoma syndrome (NBCCS). The expression of Ki-67 in NBCCS was significantly different from the solitary and multiple KCOTs (P = 0.018, 0.002). In multilocular KCOTs it was also significantly different from the unilocular and syndrome-associated lesions (P = 0.000). In contrast, no significant differences were observed between the solitary and multiple lesions (P = 0.220). CONCLUSIONS: a high correlation exists in KCOT between its biological behaviour and imaging features. The solitary KCOT seems less biologically aggressive and it should be classified as a cyst rather than a tumour. This means that more than half of KCOTs manifest themselves as ordinary cysts.
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Tumores Odontogénicos/diagnóstico por imagen , Tumores Odontogénicos/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular , Niño , Diagnóstico Diferencial , Femenino , Humanos , Técnicas para Inmunoenzimas , Queratinas , Antígeno Ki-67/análisis , Masculino , Persona de Mediana Edad , Quistes Odontogénicos/diagnóstico por imagen , Quistes Odontogénicos/metabolismo , Quistes Odontogénicos/patología , Tumores Odontogénicos/clasificación , Tumores Odontogénicos/metabolismo , Radiografía Panorámica , Estudios Retrospectivos , Adulto JovenRESUMEN
The purpose of this article is to report 20 cases of ossifying fibroma involving the jaw bone and to review the literature of this lesion. All the cases had adequate radiographs and clinical information. Varying shapes of the lesion including cystic lesion and mixed density lesion are presented, including two massive expansile lesions, which measured more than 10 cm.
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Fibroma Osificante/diagnóstico por imagen , Neoplasias Maxilomandibulares/diagnóstico por imagen , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Adulto JovenRESUMEN
A novel internal target has been developed, which will make electron scattering off short-lived radioactive nuclei possible in an electron storage ring. An "ion trapping" phenomenon in the electron storage ring was successfully utilized for the first time to form the target for electron scattering. Approximately 7 x 10(6) stable 133Cs ions were trapped along the electron beam axis for 85 ms at an electron beam current of 80 mA. The collision luminosity between the stored electrons and trapped Cs ions was determined to be 2.4(8) x 10(25) cm(-2) s(-1) by measuring elastically scattered electrons.
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OBJECTIVES: CD14, toll-like receptor 4 (TLR4) and MyD88 have been shown to mediate responsiveness in host cells to lipopolysaccharide. We investigated here the regulatory effects of inflammatory cytokines on the expression of membrane CD14 (mCD14), TLR4 and MyD88, and on subsequent responsiveness to lipopolysaccharide from Actinobacillus actinomycetemcomitans in human gingival fibroblasts. MATERIALS AND METHODS: Following treatment with either interleukin-1beta, tumor necrosis factor-alpha (TNF-alpha) or gamma-interferon (IFN-gamma), expression of mCD14/TLR4 and MyD88 was determined by flow cytometry and western blotting, respectively. After pretreatment with IFN-gamma, cells were pre-incubated with either anti-CD14 antibody MY4 or anti-TLR4 antibody HTA125 and subsequently treated with A. actinomycetemcomitans lipopolysaccharide. Then, phosphorylation of mitogen-activated protein (MAP) kinases and IkappaBalpha was examined by western blotting, and production of interleukin-6 and interleukin-8 was measured by their respective enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: IFN-gamma stimulated expression of mCD14, whereas -1beta and TNF-alpha did not. Expression of MyD88 but not TLR4 was also enhanced by IFN-gamma. The lipopolysaccharide activated MAP kinases, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38, and IkappaBalpha and stimulated production of interleukin-6 and interleukin-8. The lipopolysaccharide-stimulated interleukin-6 and interleukin-8 production was markedly inhibited by MY4 or HTA125. Pretreatment with IFN-gamma augmented the following activation of MAP kinases and IkappaBalpha and production of interleukin-6 and interleukin-8 in response to the lipopolysaccharide. CONCLUSIONS: These results suggest that the augmentation by IFN-gamma of the responsiveness to A. actinomycetemcomitans lipopolysaccharide, such as activation of MAP kinases and IkappaBalpha and terminal cytokine production in human gingival fibroblasts, may be partially mediated by up-regulation of CD14 and MyD88 expression.
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Antígenos de Diferenciación/biosíntesis , Encía/metabolismo , Interferón gamma/farmacología , Receptores de Lipopolisacáridos/biosíntesis , Lipopolisacáridos/farmacología , Glicoproteínas de Membrana/biosíntesis , Receptores de Superficie Celular/biosíntesis , Receptores Inmunológicos/biosíntesis , Proteínas Adaptadoras Transductoras de Señales , Aggregatibacter actinomycetemcomitans/fisiología , Análisis de Varianza , Western Blotting , Células Cultivadas , Activación Enzimática , Fibroblastos/metabolismo , Fibroblastos/microbiología , Regulación de la Expresión Génica/efectos de los fármacos , Encía/citología , Encía/microbiología , Humanos , Quinasa I-kappa B , Interleucina-6/biosíntesis , Interleucina-8/biosíntesis , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Factor 88 de Diferenciación Mieloide , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Toll-Like 4 , Receptores Toll-LikeRESUMEN
OBJECTIVES: We have recently developed a new device for measuring the spinnbarkeit of saliva called the Neva Meter. The purpose of this study was to evaluate this device and to measure spinnbarkeit as well as viscosity, another important property, in the resting saliva of 24 healthy adults. METHODS: We used polyvinyl alcohol (PVA) as a standard solution to establish the reproducibility of spinnbarkeit tests. We collected resting saliva from 24 employees of a business office (16 males and 8 females, average age: 37.8) and investigated the relationship between spinnbarkeit and viscosity. RESULTS: The spinnbarkeit of PVA increased along with the concentration of the solution, and the reproducibility of the values was acceptable. Spinnbarkeit of resting saliva showed a positive correlation with viscosity at a shear rate of 76.6 s(-1) (r = 0.55, P < 0.05) and 191.5 s(-1) (r = 0.59, p < 0.05). CONCLUSIONS: The newly developed Neva Meter was suitable for measuring the spinnbarkeit of saliva quickly and easily at the chair-side in the dental clinic. Results obtained using this new device may be important for understanding and evaluating the condition of the oral cavity.
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Saliva/fisiología , Adulto , Elasticidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Alcohol Polivinílico/química , Reproducibilidad de los Resultados , Reología/instrumentación , ViscosidadRESUMEN
OBJECTIVES: The purpose of this study was to clarify the CT features of odontogenic myxoma. METHODS: CT appearances were analysed in 17 patients with histologically verified odontogenic myxoma collected from five dental hospitals in Japan. RESULTS: On the CT images, tumour borders were generally well defined with a smooth margin both for bony and soft tissue structures in all patients. Cortical status was clearly evaluated using CT and the continuity was interrupted in nine patients. Intralesional trabeculations were observed in 13 patients. Of these 13, 6 patients showed the characteristic appearance of angular or straight trabeculations within the tumour. The trabeculations were frequently observed at the peripheral portion of the tumour. In three maxillary tumours, soft tissue margins were observed beyond the cortical margin and/or intralesional trabeculations. In 10 of the 13 lesions evaluated, the majority of the whole tumour area showed relatively lower density compared with surrounding muscles. CONCLUSION: CT clearly demonstrated characteristic features of odontogenic myxoma. CT analysis may contribute to establishing a consensus regarding the interpretation of conventional radiographic appearances in odontogenic myxoma.
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Tumores Odontogénicos/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Mandíbula/diagnóstico por imagen , Neoplasias Mandibulares/diagnóstico por imagen , Músculos Masticadores/diagnóstico por imagen , Maxilar/diagnóstico por imagen , Neoplasias Maxilares/diagnóstico por imagen , Persona de Mediana EdadRESUMEN
BMPs exert a negative growth effect on various types of cells. We have previously reported that BMP-2 inhibited the growth of HS-72 mouse hybridoma cells by inducing p21(CIP1/WAF1) expression. In the present study, we demonstrated that BMP-2 activated the mouse p21(CIP1/WAF1) promoter in HS-72 cells, and that a 29-base pair (b) region of the promoter (-1928/-1900 relative to the TATA box), conserved between mice and humans, was responsive to BMP-2 as well as expression of Smad1, Smad4, and constitutively active mutants of BMP type I receptors. Furthermore, an oligonucleotide containing the 29-b region was found to be associated with Smad4 and phosphorylated Smad1 in the nuclear extract of BMP-2-stimulated HS-72 cells. These results suggested that BMP-2 might activate p21(CIP1/WAF1) transcription by inducing a binding of Smad4 and Smad1 to the 29-b region in HS-72 cells.
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Linfocitos B/metabolismo , Proteínas Morfogenéticas Óseas/farmacología , Ciclinas/genética , Regiones Promotoras Genéticas , Receptores de Factores de Crecimiento , Proteínas Represoras , Factor de Crecimiento Transformador beta , Animales , Proteína Morfogenética Ósea 2 , Receptores de Proteínas Morfogenéticas Óseas , Células COS , Linaje de la Célula , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Hibridomas , Ratones , Proteínas Oncogénicas Virales/farmacología , Receptores de Superficie Celular/metabolismo , Elementos de Respuesta , Proteínas Smad , Proteína Smad1 , Proteína Smad4 , Células Madre/metabolismo , Transactivadores/genética , Transactivadores/metabolismo , TransfecciónRESUMEN
Bone tissues reportedly contain considerable amounts of activin A and follistatin, an activin A-binding protein. In the present study, we found that follistatin strongly inhibited osteoclast formation in cocultures of mouse bone marrow cells and primary osteoblasts induced by 1alpha,25 dihydroxyvitamin D(3), prostaglandin E(2), and interleukin-1alpha. Antibody aganist activin A also inhibited the osteoclast formation. Furthermore, activin A synergistically stimulated osteoclast differentiation mediated by receptor activator NF-kappaB ligand (RANKL). RT-PCR analysis revealed that osteoblasts produced not only activin A but also follistatin. Western blot analysis of a panel of phosphorylated proteins revealed that activin A stimulated the phosphorylation of p44/42 mitogen activated protein (MAP) kinase (ERK1/2) and p38 MAP kinase in macrophage colony-stimulating factor-dependent bone marrow macrophages (M-BMMPhis). In addition, phosphorylation of Smad2 was observed in M-BMMPhis stimulated with activin A. These findings indicate that the phosphorylation of p44/42 MAP kinase, p38 MAP kinase, and Smad2 is involved in activin A-enhanced osteoclast differentiation induced by RANKL. Taken together, these results suggest that both activin A and follistatin produced by osteoblasts may play an important role in osteoclast differentiation through MAP kinases and Smad2 signaling pathways.
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Proteínas de Unión al ADN/metabolismo , Inhibinas/farmacología , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Osteoclastos/citología , Osteoclastos/enzimología , Transactivadores/metabolismo , Receptores de Activinas , Activinas , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/enzimología , Proteínas Portadoras/farmacología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Células Cultivadas , Femenino , Folistatina , Expresión Génica/fisiología , Glicoproteínas/farmacología , Sustancias de Crecimiento/farmacología , Glicoproteínas de Membrana/farmacología , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Fosforilación , Ligando RANK , ARN Mensajero/análisis , Receptor Activador del Factor Nuclear kappa-B , Receptores de Factores de Crecimiento/genética , Receptores de Factores de Crecimiento/metabolismo , Proteína Smad2 , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Infection of murine macrophages in vitro with periodontopathic bacterium Actinobacillus actinomycetemcomitans induces apoptotic cell death. In this study, we investigated the involvement of caspases in apoptotic cell death of A. actinomycetemcomitans-infected macrophages. Two peptide inhibitors of caspases, benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone (Z-VAD-FMK) and benzyloxycarbonyl-Asp-Glu-Val-Asp (OMe)-fluoromethyl ketone (Z-DEVD-FMK), inhibited apoptotic cell death of murine macrophage cell line J774.1 infected with A. actinomycetemcomitans. During the process of apoptosis, interleukin-1beta (IL-1beta) was detected in the culture supernatants of J774.1 cells. IL-1beta secretion was blocked by the caspase-1 inhibitor, Z-VAD-FMK, indicating that caspase-1 is involved in not only the induction of apoptosis but also the IL-1beta secretion from A. actinomycetemcomitans-infected J774.1 cells. Immunoblot analysis revealed that the infection of A. actinomycetemcomitans to J774.1 cells induced the cleavage of retinoblastoma protein (Rb), suggesting that caspase-3 was activated by A. actinomycetemcomitans infection. The cytosol from A. actinomycetemcomitans-infected J774.1 cells induced Rb proteolysis in vitro, which was inhibited by the caspase-3 inhibitor, Z-DEVD-FMK. Furthermore, caspase-3-like activity was markedly increased in J774.1 cells infected with A.actinomycetemcomitans between 12 h and 24 h, which was subsequently inhibited by the addition of caspase-3 inhibitor, Z-DEVD-FMK. These findings indicate that caspase-3 induces apoptosis in J774.1 cells infected with A. actinomycetemcomitans. Taken together, these results suggest that caspase-1 and caspase-3 are involved in the induction of apoptosis in A. actinomycetemcomitans-infected macrophages.
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Aggregatibacter actinomycetemcomitans/fisiología , Apoptosis/fisiología , Caspasas/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiología , Clorometilcetonas de Aminoácidos/farmacología , Animales , Apoptosis/efectos de los fármacos , Inhibidores de Caspasas , Línea Celular , Inhibidores de Cisteína Proteinasa/farmacología , Immunoblotting , Interleucina-1/biosíntesis , Macrófagos/enzimología , Ratones , Oligopéptidos/farmacología , Proteína de Retinoblastoma/metabolismoRESUMEN
Osteoclasts, bone-resorbing multinucleated cells, develop from monocyte-macrophage lineage cells in the presence of osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) and macrophage colony-stimulating factor (M-CSF). M-CSF-dependent bone marrow macrophages (M-BMMPhis) from mouse bone marrow cells have been shown to differentiate into osteoclast-like multinucleated cells (OCLs) in the presence of soluble ODF/RANKL (sODF/RANKL) and M-CSF within 3 days. In this study, we found that stimulation of M-BMMPhis with sODF/RANKL induced a transient expression of cyclin-dependent kinase inhibitors (CDK inhibitors) p21(WAF1/CIP1) and p27(KIP1) by 24 h. The CDK inhibitor proteins disappeared by 48 h. Tumor necrosis factor alpha (TNF-alpha), which is reported to stimulate OCL differentiation, stimulated p21(WAF1/CIP1) and p27(KIP1) expression in M-BMMPhis as well. However, M-CSF alone did not stimulate the expression of the two CDK inhibitors. To clarify the role of p21(WAF1/CIP1) and p27(KIP1) in osteoclastogenesis, accumulation of these CDK inhibitors was aborted by antisense oligonucleotides. Treatment with p21(WAF1/CIP1) antisense oligonucleotide alone, or p27(KIP1) antisense oligonucleotide alone, showed a limited inhibitory effect on OCL formation. However, treatment with a mixture of these two antisense oligonucleotides strongly inhibited OCL formation. These results suggest that a combined modulation of the CDK inhibitors p21(WAF1/CIP1) and p27(KIP1) may be involved in osteoclast differentiation induced by ODF/RANKL.
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Proteínas de Ciclo Celular , Diferenciación Celular , Ciclinas/metabolismo , Inhibidores Enzimáticos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Osteoclastos/citología , Proteínas Supresoras de Tumor , Regulación hacia Arriba , Animales , Secuencia de Bases , Células de la Médula Ósea/citología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Ciclinas/genética , Cartilla de ADN , Femenino , Macrófagos/citología , Ratones , Proteínas Asociadas a Microtúbulos/genética , Oligonucleótidos Antisentido/farmacología , Osteoclastos/efectos de los fármacosRESUMEN
Bone morphogenetic proteins (BMPs), members of the transforming growth factor (TGF)-beta superfamily, are a group of related proteins that are capable of inducing the formation of cartilage and bone but are now regarded as multifunctional cytokines. We show in this report a novel function of BMPs in hematopoietic cells: BMP-2 induces apoptosis not only in human myeloma cell lines (U266, RPMI 8226, HS-Sultan, IM-9, OPM-2, and KMS-12 cells), but also in primary samples from patients with multiple myeloma. The mechanism of BMP-2-induced apoptosis was investigated with the use of U266 cells, which are dependent on the interleukin-6 autocrine loop. We showed that BMP-2 caused cell-cycle arrest in the G1 phase and the subsequent apoptosis of myeloma cells. BMP-2 up-regulated the expression of cyclin-dependent kinase inhibitors (p21(CIP1/WAF1) and p27(KIP1)) and caused hypophosphorylation of retinoblastoma (Rb) protein. In studies of apoptosis-associated proteins, BMP-2 was seen to down-regulate the expression of Bcl-x(L); however, BMP-2 had no effects on the expression of Bcl-2, Bax, or Bad. Therefore, BMP-2 induces apoptosis in various human myeloma cells by means of the down-regulation of Bcl-x(L) and by cell-cycle arrest through the up-regulation of p21(CIP1/WAF1) and p27(KIP1) and by the hypophosphorylation of Rb. Further analysis showed that the signal transducer and activator of transcription 3 (STAT3) was inactivated immediately after BMP-2 treatment. We conclude that BMP-2 would be useful as a novel therapeutic agent in the treatment of multiple myeloma both by means of its antitumor effect of inducing apoptotis and through its original bone-inducing activity, because bone lesions are frequently seen in myeloma patients.
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Apoptosis/efectos de los fármacos , Proteínas Morfogenéticas Óseas/farmacología , Proteínas de Unión al ADN/metabolismo , Fase G1/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Transactivadores/metabolismo , Factor de Crecimiento Transformador beta , Proteína Morfogenética Ósea 2 , Proteínas Morfogenéticas Óseas/uso terapéutico , Humanos , Mieloma Múltiple/metabolismo , Factor de Transcripción STAT3 , Transducción de Señal/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Nod1 is an Apaf-1-like molecule composed of a caspase-recruitment domain (CARD), nucleotide-binding domain, and leucine-rich repeats that associates with the CARD-containing kinase RICK and activates nuclear factor kappaB (NF-kappaB). We show that self-association of Nod1 mediates proximity of RICK and the interaction of RICK with the gamma subunit of the IkappaB kinase (IKKgamma). Similarly, the RICK-related kinase RIP associated via its intermediate region with IKKgamma. A mutant form of IKKgamma deficient in binding to IKKalpha and IKKbeta inhibited NF-kappaB activation induced by RICK or RIP. Enforced oligomerization of RICK or RIP as well as of IKKgamma, IKKalpha, or IKKbeta was sufficient for induction of NF-kappaB activation. Thus, the proximity of RICK, RIP, and IKK complexes may play an important role for NF-kappaB activation during Nod1 oligomerization or trimerization of the tumor necrosis factor alpha receptor.
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Proteínas Adaptadoras Transductoras de Señales , Proteínas Portadoras/metabolismo , FN-kappa B/metabolismo , Proteínas Quinasas/metabolismo , Proteínas/metabolismo , Transcripción Genética , Animales , Apoptosis , Proteínas Portadoras/genética , Línea Celular , Fibroblastos/citología , Fibroblastos/fisiología , Humanos , Quinasa I-kappa B , Ratones , Proteína Adaptadora de Señalización NOD1 , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas/genética , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Eliminación de Secuencia , Transducción de Señal/fisiología , TransfecciónRESUMEN
We have previously found that bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-beta family, induces cell-cycle arrest in the G1 phase and apoptotic cell death of HS-72 mouse hybridoma cells. In this study, we show that BMP-2 did not alter expression of cyclin D, cyclin E, cyclin-dependent kinase 2 (CDK2), CDK4, p27KIP1, p16INK4a, or p15INK4b, but enhanced expression of p21(CIP1/WAF1). Accumulation of p21(CIP1/WAF1) resulted in increased binding of p21(CIP1/WAF1) to CDK4 and concomitantly caused a profound decrease in the in vitro retinoblastoma protein (Rb) kinase activity of CDK4. Furthermore, the ectopic expression of human papilloma virus type-16 E7, an inhibitor of p21(CIP1/WAF1) and Rb, reverted G1 arrest induced by BMP-2. Expression of E6/E7, without increasing the p53 level, blocked inhibition of Rb phosphorylation and G1 arrest, but did not attenuate cell death in BMP-treated HS-72 cells. Taken together, these results suggest that inhibition of Rb phosphorylation by p21(CIP1/WAF1) is responsible for BMP-2-mediated G1 arrest and that BMP-2-induction of apoptosis might be independent of Rb hypophosphorylation.
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Apoptosis/fisiología , Linfocitos B/patología , Linfocitos B/fisiología , Proteínas Morfogenéticas Óseas/fisiología , Fase G1/fisiología , Proteínas Oncogénicas Virales/fisiología , Proteínas Represoras , Factor de Crecimiento Transformador beta , Animales , Proteína Morfogenética Ósea 2 , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/fisiología , Humanos , Hibridomas , Ratones , Proteínas E7 de Papillomavirus , Transducción de Señal/fisiologíaRESUMEN
A total of 74 strains of oral treponemes, which were isolated from subgingival plaque samples from patients with periodontitis, were taxonomically studied on the basis of biochemical characteristics, DNA-DNA hybridization, and 16S rRNA gene sequences. These organisms fermented carbohydrates and required rumen fluid or short-chain volatile fatty acids for growth. The isolates were divided into seven subgroups based on their biochemical characteristics. The levels of DNA relatedness among the representative strains of each subgroup and Treponema socranskii (including three subspecies) were greater than 78%, while the levels of DNA relatedness among these strains and other Treponema species, including T. denticola and "T. vincentii", were less than 15%. DNA-DNA hybridization indicated that all subgroups belonged to T. socranskii. This result correlated well with the cluster on the phylogenetic trees based on 16S rRNA sequences.