RESUMO
Periodontitis is an inflammatory disease that affects the supporting structures of teeth. The presence of a bacterial biofilm initiates a destructive inflammatory process orchestrated by various inflammatory mediators, most notably proinflammatory cytokines, which are upregulated in the gingival crevicular fluid, leading to the formation of periodontal pockets. This represents a well-characterized microbial change during the transition from periodontal health to periodontitis; interestingly, the gestational condition increases the risk and severity of periodontal disease. Although the influence of periodontitis on pregnancy has been extensively reviewed, the relationship between pregnancy and the development/evolution of periodontitis has been little studied compared to the effect of periodontitis on adverse pregnancy outcomes. This review is aimed at summarizing the findings on the pregnancy-proinflammatory cytokine relationship and discussing its possible involvement in the development of periodontitis. We address (1) an overview of periodontal disease, (2) the immune response and possible involvement of proinflammatory cytokines in the development of periodontitis, (3) how bone tissue remodelling takes place with an emphasis on the involvement of the inflammatory response and metalloproteinases during periodontitis, and (4) the influence of hormonal profile during pregnancy on the development of periodontitis. Finally, we believe this review may be helpful for designing immunotherapies based on the stage of pregnancy to control the severity and pathology of periodontal disease.
Assuntos
Bactérias/imunologia , Citocinas/biossíntese , Hormônios Esteroides Gonadais/fisiologia , Periodontite/imunologia , Remodelação Óssea , Feminino , Microbioma Gastrointestinal/fisiologia , Humanos , Metaloproteases/fisiologia , Periodontite/etiologia , Periodontite/microbiologia , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/imunologiaRESUMO
La integridad y la estabilidad de la interfase adhesivo/dentina en las restauraciones realizadas mediante resinas compuestas se encuentra constantemente comprometida por la hidrólisis progresiva de sus componentes hidrofílicos y la degradación de la matriz colágena, producida por la reactivación de una serie de endopeptidasas denominadas metaloproteinasas (MMP) y otras enzimas colagenolíticas que se encuentran fosilizadas en la matriz de la dentina. Esto lleva a la destrucción de la capa híbrida y facilita la penetración bacteriana en la interfase, el aumento de la hipersensibilidad posoperatoria y la formación de caries recurrentes. Estos problemas inciden además en la pérdida de retención de la restauración y se constituyen en el principal factor etiológico de los procesos inflamatorios que comprometen seriamente la salud de la pulpa dental. Debido a que la integridad de la matriz colágena es esencial para preservar la durabilidad de la adhesión de las restauraciones, se han intentado algunas estrategias, con el objeto de inhibir o al menos reducir en lo posible la acción de las enzimas colagenolíticas sobre la estabilidad de la interfase. A pesar de que algunas de las estrategias ensayadas hasta el momento han demostrado ser eficaces, aún se encuentran en una etapa netamente experimental y requieren ser más profundamente investigadas
Assuntos
Humanos , Adesivos Dentinários/química , Dentina , Infiltração Dentária/etiologia , Resinas Compostas/química , Cárie Dentária/etiologia , Colágeno/fisiologia , Sensibilidade da Dentina , Doenças da Polpa Dentária/etiologia , Hidrólise , Metaloproteases/fisiologiaRESUMO
La integridad y la estabilidad de la interfase adhesivo/dentina en las restauraciones realizadas mediante resinas compuestas se encuentra constantemente comprometida por la hidrólisis progresiva de sus componentes hidrofílicos y la degradación de la matriz colágena, producida por la reactivación de una serie de endopeptidasas denominadas metaloproteinasas (MMP) y otras enzimas colagenolíticas que se encuentran fosilizadas en la matriz de la dentina. Esto lleva a la destrucción de la capa híbrida y facilita la penetración bacteriana en la interfase, el aumento de la hipersensibilidad posoperatoria y la formación de caries recurrentes. Estos problemas inciden además en la pérdida de retención de la restauración y se constituyen en el principal factor etiológico de los procesos inflamatorios que comprometen seriamente la salud de la pulpa dental. Debido a que la integridad de la matriz colágena es esencial para preservar la durabilidad de la adhesión de las restauraciones, se han intentado algunas estrategias, con el objeto de inhibir o al menos reducir en lo posible la acción de las enzimas colagenolíticas sobre la estabilidad de la interfase. A pesar de que algunas de las estrategias ensayadas hasta el momento han demostrado ser eficaces, aún se encuentran en una etapa netamente experimental y requieren ser más profundamente investigadas (AU)
Assuntos
Humanos , Resinas Compostas/química , Dentina/efeitos dos fármacos , Infiltração Dentária/etiologia , Adesivos Dentinários/química , Metaloproteases/fisiologia , Colágeno/fisiologia , Hidrólise , Doenças da Polpa Dentária/etiologia , Sensibilidade da Dentina , Cárie Dentária/etiologiaRESUMO
A new homodimeric PII metalloproteinase, named BlatH1, was purified from the venom of the Central American arboreal viperid snake Bothriechis lateralis by a combination of anion-exchange chromatography, hydrophobic interaction chromatography, and gel filtration. BlatH1 is a glycoprotein of 84 kDa. The mature protein contains a metalloproteinase domain, with the characteristic zinc-binding motif (HEXXHXXGXXH) followed by the sequence CIM at the Met-turn. In the disintegrin domain, the tripeptide sequence TDN substitutes the characteristic RGD motif found in many disintegrins. BlatH1 hydrolyzed azocasein, gelatin and fibrinogen, and exerts a potent local and systemic hemorrhagic activity in mice. The hemorrhagic activity of BlatH1 is not inhibited by the plasma proteinase inhibitor α2-macroglobulin, although the SVMP is able to cleave this plasma inhibitor, generating a 90 kDa product. BlatH1 inhibits ADP- and collagen-induced human platelet aggregation (IC50 = 0.3 µM and 0.7 µM for ADP and collagen, respectively). This activity is abrogated when the enzyme is preincubated with the metalloproteinase inhibitor Batimastat, implying that it depends on proteolysis. In agreement, a synthetic peptide containing the sequence TDN of the disintegrin domain is unable to inhibit platelet aggregation. BlatH1 is a valuable tool to understand the structural determinants of toxicity in PII SVMPs.
Assuntos
Venenos de Crotalídeos/enzimologia , Metaloproteases/química , Proteínas de Répteis/química , Viperidae , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , Venenos de Crotalídeos/toxicidade , Hemorragia/induzido quimicamente , Humanos , Dose Letal Mediana , Pulmão/efeitos dos fármacos , Pulmão/patologia , Metaloproteases/fisiologia , Metaloproteases/toxicidade , Camundongos , Dados de Sequência Molecular , Agregação Plaquetária/efeitos dos fármacos , Estrutura Quaternária de Proteína , Proteólise , Proteínas de Répteis/fisiologia , Proteínas de Répteis/toxicidade , Análise de Sequência de Proteína , alfa-Macroglobulinas/químicaRESUMO
BACKGROUND: The venoms of several scorpion species have long been associated with pancreatitis in animal models and humans. Antarease, a Zn-metalloprotease from Tityus serrulatus, is able to penetrate intact pancreatic tissue and disrupts the normal vesicular traffic necessary for secretion, so it could play a relevant role in the onset of acute pancreatitis. METHODS: The cDNA libraries from five different scorpion species were screened for antarease homologs with specific primers. The amplified PCR products were cloned and sequenced. A structural model was constructed to assess the functionality of the putative metalloproteases. A phylogenetic analysis was performed to identify clustering patterns of these venom components. RESULTS: Antarease-like sequences were amplified from all the screened cDNA libraries. The complete sequence of the antarease from T. serrulatus was obtained. The structural model of the putative antarease from Tityus trivittatus shows that it may adopt a catalytically active conformation, sharing relevant structural elements with previously reported metalloproteases of the ADAM family. The phylogenetic analysis reveals that the reported sequences cluster in groups that correlate with the geographical localization of the respective species. CONCLUSIONS: Antareases are ubiquitous to a broad range of scorpion species, where they could be catalytically active enzymes. These molecules can be used to describe the evolution of scorpion venoms under different ecogeographic constrains. GENERAL SIGNIFICANCE: For the first time the complete sequence of the antareases is reported. It is demonstrated that antareases are common in the venom of different scorpion species. They are now proposed as targets for antivenom therapies.
Assuntos
Metaloproteases/química , Venenos de Escorpião/enzimologia , Sequência de Aminoácidos , Sequência de Bases , Metaloproteases/genética , Metaloproteases/fisiologia , Modelos Moleculares , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , FilogeografiaRESUMO
Pulmonary lymphangioleiomyomatosis is an uncommon disease of unknown etiology characterized by the proliferation of abnormal smooth muscle cells in the lungs, leading to parenchymal destruction and progressive respiratory failure. The natural history of this disease remains poorly understood, primarily seen in women of childbearing age. The diagnosis can be difficult because symptoms are nonspecific and very similar to other respiratory diseases like asthma, emphysema and bronchitis. Lymphangioleiomyomatosis may not be diagnosed until a pneumothorax, chylothorax, interstitial lung disease or angiomyolipomas are discovered. The recent advances in genetic and molecular research provide new hope to discover the intricate mechanism of disease and evaluate new therapies. Internists, primary care physicians and pulmonologists should be aware of this condition in order to avoid delay in the diagnosis and institute appropriate therapy. The clinical features, pathophysiology, molecular genetics and medical treatment will be reviewed.
Assuntos
Estrogênios , Neoplasias Pulmonares , Linfangioleiomiomatose , Neoplasias Hormônio-Dependentes , Diagnóstico por Imagem/métodos , Dispneia/etiologia , Estrogênios/fisiologia , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Transplante de Pulmão , Linfangioleiomiomatose/diagnóstico , Linfangioleiomiomatose/epidemiologia , Linfangioleiomiomatose/genética , Linfangioleiomiomatose/patologia , Linfangioleiomiomatose/terapia , Masculino , Metaloproteases/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias Hormônio-Dependentes/diagnóstico , Neoplasias Hormônio-Dependentes/epidemiologia , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/patologia , Neoplasias Hormônio-Dependentes/terapia , Pneumotórax/etiologia , Pneumotórax/cirurgia , Distribuição por Sexo , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/fisiologiaRESUMO
Metalloproteinases (MMPs) are involved in different physiological and pathological processes. They regulate several signaling pathways in cell growth, inflammation and angiogenesis. The MMPs modulate the complex tumor microenvironment and are involved in the early stages of carcinogenesis, tumor invasion and metastasic processes. MMPs participate in the processing of bioactive molecules such as cytokines, chemokines and growth factors. Their substrates are the extracellular matrix proteins and endogenous inhibitors (TIMPs) regulate their functions. The accurate balance between these two molecules, MMPs and TIMPs, is critical for maintaining homeostasis. Due to their role in cancer biology, MMPs are potential targets for future therapeutic strategies of this malignant disease.
Assuntos
Matriz Extracelular/metabolismo , Inibidores de Metaloproteinases de Matriz , Metaloproteases/fisiologia , Carcinogênese/metabolismo , Homeostase/fisiologia , Estrutura Molecular , Metástase Neoplásica , Microambiente Tumoral/fisiologiaRESUMO
Las metaloproteinasas (MMPs) intervienen en diversos procesos fisiológicos y patológicos del organismo. Regulan, por ejemplo, las vías de señalización que controlan el crecimiento celular, la inflamación y la angiogénesis. Cumplen funciones moduladoras en el complejo microambiente tumoral interviniendo en las etapas tempranas de la carcinogénesis, en la invasión y la producción de metástasis tumorales. Participan en el procesamiento de moléculas bioactivas como citoquinas, quemoquinas y factores de crecimiento. Las MMPs tienen como substrato a las proteínas de la matriz extracelular (MEC) y su actividad es regulada por inhibidores endógenos (TIMPs). El adecuado balance entre ambas moléculas es fundamental para mantener la homeostasis. Debido al papel que desempeñan en diferentes etapas de la biología del cáncer, son un blanco potencial para futuras estrategias en la terapéutica de esta enfermedad.
Metalloproteinases (MMPs) are involved in different physiological and pathological processes. They regulate several signaling pathways in cell growth, inflammation and angiogenesis. The MMPs modulate the complex tumor microenvironment and are involved in the early stages of carcinogenesis, tumor invasion and metastasic processes. MMPs participate in the processing of bioactive molecules such as cytokines, chemokines and growth factors. Their substrates are the extracellular matrix proteins and endogenous inhibitors (TIMPs) regulate their functions. The accurate balance between these two molecules, MMPs and TIMPs, is critical for maintaining homeostasis. Due to their role in cancer biology, MMPs are potential targets for fu ture therapeutic strategies of this malignant disease.
Assuntos
Matriz Extracelular/metabolismo , Inibidores de Metaloproteinases de Matriz , Metaloproteases/fisiologia , Carcinogênese/metabolismo , Homeostase/fisiologia , Estrutura Molecular , Metástase Neoplásica , Microambiente Tumoral/fisiologiaRESUMO
Las metaloproteinasas (MMPs) intervienen en diversos procesos fisiológicos y patológicos del organismo. Regulan, por ejemplo, las vías de señalización que controlan el crecimiento celular, la inflamación y la angiogénesis. Cumplen funciones moduladoras en el complejo microambiente tumoral interviniendo en las etapas tempranas de la carcinogénesis, en la invasión y la producción de metástasis tumorales. Participan en el procesamiento de moléculas bioactivas como citoquinas, quemoquinas y factores de crecimiento. Las MMPs tienen como substrato a las proteínas de la matriz extracelular (MEC) y su actividad es regulada por inhibidores endógenos (TIMPs). El adecuado balance entre ambas moléculas es fundamental para mantener la homeostasis. Debido al papel que desempeñan en diferentes etapas de la biología del cáncer, son un blanco potencial para futuras estrategias en la terapéutica de esta enfermedad.(AU)
Metalloproteinases (MMPs) are involved in different physiological and pathological processes. They regulate several signaling pathways in cell growth, inflammation and angiogenesis. The MMPs modulate the complex tumor microenvironment and are involved in the early stages of carcinogenesis, tumor invasion and metastasic processes. MMPs participate in the processing of bioactive molecules such as cytokines, chemokines and growth factors. Their substrates are the extracellular matrix proteins and endogenous inhibitors (TIMPs) regulate their functions. The accurate balance between these two molecules, MMPs and TIMPs, is critical for maintaining homeostasis. Due to their role in cancer biology, MMPs are potential targets for fu ture therapeutic strategies of this malignant disease.(AU)
Assuntos
Matriz Extracelular/metabolismo , Inibidores de Metaloproteinases de Matriz , Metaloproteases/fisiologia , Carcinogênese/metabolismo , Homeostase/fisiologia , Estrutura Molecular , Metástase Neoplásica , Microambiente Tumoral/fisiologiaRESUMO
Os tumores odontogênicos benignos compreendem um grupo de neoplasias originárias dos tecidos dentários. Pesquisas vêm buscando identificar moléculas envolvidas nos mecanismos moleculares que regulam a remodelação da matriz extracelular (MEC) e como isto influencia no comportamento localmente invasivo presente em alguns destes tumores. A Transição Epitélio-Mesenquimal (TEM conversão do fenótipo epitelial em mesenquimal) é bem caracterizada em diversos carcinomas, culminando em mestástase. MMPs são enzimas que degradam os componentes da MEC, geram moléculas bioativas, participam da TEM e o controle da remodelação da MEC dá-se pelo balanço entre elas, seus inibidores (TIMPs e RECK) e seu ativador (EMMPRIN). Assim, o objetivo deste trabalho foi delinear o perfil de expressão das MMPs (-2, -7, -9 e -14), seus inibidores (TIMPs -2, -3, -4 e RECK), seu ativador (EMMPRIN) e marcadores da TEM (Snail, Slug, N-caderina, Fibronectina, a-Actina de músculo liso e Vimentina) em Ameloblastomas (AB) e Tumores Odontogênicos Cístico Calcificantes (TOCC). Ainda, realizamos a comparação da expressão de cada molécula avaliada em cada compartimento celular (epitélio e estroma) e correlação entre as moléculas avaliadas no mesmo tumor. Utilizamos 19 casos de AB e 18 casos de TOCC (Serviço de Anatomia Patológica da FOUSP), localização das enzimas/proteínas por imunoistoquímica e analisadas nos compartimentos epitelial e estromal
Todas as proteínas/enzimas analisadas foram detectadas tanto nos AB quanto nos TOCC, sendo a maioria expressa em ambos os compartimentos. A N-caderina foi localizada apenas no epitélio dos AB e a Vimentina somente no estroma em ambos os tumores. Na comparação entre o epitélio x estroma dos ameloblastomas, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-2, MMP-7, EMMPRIN/CD147, Fibronectina, a-Actina de músculo liso, N-caderina, Vimentina, Snail e Slug. Na comparação entre o epitélio x estroma dos TOCC, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-9, RECK, EMMPRIN/CD147, Vimentina, N-caderina, Snail e Slug. Assim, entre o epitélio x estroma dos ameloblastomas e TOCC, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-2, MMP-7, MMP-9, RECK, EMMPRIN/CD147, Fibronectina, Vimentina, a-Actina de músculo liso, N-caderina, Snail e Slug. Esta é a primeira vez que a EMMPRIN, RECK, TIMP-3, TIMP-4, Ncaderina, Snail e Slug são descritas em TOCC e TIMP-3, TIMP-4, Snail e Slug em ameloblastomas. Concluímos que estas proteínas/enzimas estão diferencialmente expressas tanto no epitélio quanto no estroma destes tumores e sugerimos que estes podem participar do comportamento localmente invasivo.
Odontogenic tumors comprise a group of benign neoplasms originating from dental tissues. Research looking for identify molecules involved in the molecular mechanisms that regulate extracellular matrix remodeling (ECM) and how this impacts on locally invasive behavior present in some of these tumors. Epithelial-Mesenchymal Transition (EMT - conversion of epithelial phenotype into mesenchymal phenotype) is well characterized in several carcinomas, leaving to metastasis. MMPs are enzymes that degrade ECM components, generate bioactive molecules, participating in the EMT and control ECM remodeling is given by the balance between them, their inhibitors (TIMPs and RECK) and its activator (EMMPRIN). The aim of this study was evaluate expression profile of MMPs (-2, -7, -9 and - 14), their inhibitors (TIMPs -2, -3, -4 and RECK), its activator (EMMPRIN) and EMT markers (Snail, Slug, N-cadherin, Fibronectin, -smooth muscle actin and Vimentin) in ameloblastomas (AB) and Calcifying Cystic Odontogenic Tumor (CCOT). We also compared the expression of each molecule assessed in each cellular compartment (epithelium and stroma) and correlation between molecules evaluated in the same tumor. We used 19 AB cases and 18 CCOT cases from files of Pathology Laboratory (FOUSP), localization of enzymes/proteins and analyzed by immunohistochemistry in epithelial and stromal compartments
All proteins/enzymes were detected in both AB and CCOT, mostly expressed in both compartments. N-cadherin was localized only in the epithelium of AB and Vimentin only in stromal in both tumors. Comparing "epithelium vs stroma" of AB, we observed a statistically significant difference (p <0.05) for MMP-2, MMP-7, EMMPRIN/CD147, Fibronectin, -smooth muscle actin, N-cadherin, Vimentin, Snail and Slug. Comparing "epithelium vs stroma" of CCOT, we observed a statistically significant difference (p <0.05) for MMP-9, RECK, EMMPRIN/CD147, Vimentin, N-cadherin, Snail and Slug. Analizing epithelium vs stroma" between AB and CCOT, we observed a statistically significant difference (p <0.05) for MMP-2, MMP-7, MMP-9, RECK, EMMPRIN/CD147, Fibronectin, Vimentin , -smooth muscle actin, N-cadherin, Snail and Slug. This is the first time that EMMPRIN, RECK, TIMP-3, TIMP-4, N-cadherin, Snail and Slug are described in CCOT and TIMP-3, TIMP-4, Snail and Slug in AB. We conclude that these proteins/enzymes are differentially expressed in both epithelium and stroma of these tumors and suggest that they may participate locally invasive behavior.