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Despite the evolution of restorative dentistry, resin adhesion to the dentin surface still presents some obstacles. Among these obstacles are the metalloproteinase enzymes that hydrolyze unprotected collagen filaments and compromise adhesive restorations. Chlorhexidine (CHX) is an antimicrobial widely discussed nowadays to inhibit or delay the action of these enzymes. Therefore, the objective of this study was to evaluate, through the literature, the mechanism of action of chlorhexidine on metalloproteinase enzymes (MMPs) and its clinical impact on the adhesion of composite resin restorations. This research was carried out in the form of an integrative literature review, having a basic nature. For this purpose, Pubmed and Lilacs databases were used with the descriptors “chlorhexidine”, “metalloproteinase”, “hybrid layer”, “clorexidina”, “metaloproteinases” and “camada híbrida”, performing the random crossover and using the operator boolean AND. In view of what has been evaluated, chlorhexidine can be considered beneficial for its clinical use as it can chelate ions that are fundamental for the constancy and function of MMPs, in addition to altering their dimensional structure. However, there is still a need for further studies to evaluate the mechanisms of action of CHX in addition to extensive and in vivo studies regarding its use. A pesar de la evolución de la odontología restauradora, la adhesión de la resina a la superficie de la dentina aún presenta algunos obstáculos. Entre estos obstáculos se encuentran las enzimas metaloproteinasas que hidrolizan los filamentos de colágeno desprotegidos y comprometen las restauraciones adhesivas. La clorhexidina (CHX) es un antimicrobiano ampliamente discutido en la actualidad para inhibir o retrasar la acción de estas enzimas. Por lo tanto, el objetivo de este estudio fue evaluar, a través de la literatura, el mecanismo de acción de la clorhexidina sobre las enzimas metaloproteinasas (MMP) y su impacto clínico en la adhesión de las restauraciones de resina compuesta. Esta investigación se realizó en forma de revisión integradora de la literatura, teniendo un carácter básico. Para ello se utilizaron las bases de datos Pubmed y Lilacs con los descriptores “chlorhexidine”, “metalloproteinase”, “hybrid layer”, “clorexidina”, “metaloproteinases” y “camada híbrida, realizando el cruce aleatorio y utilizando el operador booleano AND. En vista de lo evaluado, la clorhexidina puede considerarse beneficiosa para su uso clínico ya que puede quelar iones fundamentales para la constancia y función de las MMP, además de alterar su estructura dimensional. Sin embargo, todavía es necesario realizar más estudios para evaluar los mecanismos de acción de CHX además de estudios extensos e in vivo con respecto a su uso. Apesar da evolução da odontologia restauradora, a adesão da resina na superfície dentinária ainda apresenta alguns obstáculos. Dentre esses obstáculos, encontram-se as enzimas metaloproteinases que hidrolisam os filamentos colágenos desprotegidos e comprometem as restaurações adesivas. A clorexidina (CHX) é um antimicrobiano amplamente discutido nos dias atuais para inibir ou retardar a ação destas enzimas. Diante disto, o objetivo deste trabalho foi avaliar, por meio da literatura, o mecanismo de ação da clorexidina sobre as enzimas metaloproteinases (MMPs) e sua repercussão clínica na adesividade das restaurações em resinas compostas. Essa pesquisa foi realizada na forma de revisão integrativa da literatura, tendo natureza básica. Para este fim, foram utilizadas as bases de dados Pubmed e Lilacs, com os descritores “chlorhexidine”, “metalloproteinase”, “hybrid layer”, “clorexidina”, “metaloproteinases” e “camada híbrida”, realizando o cruzamento aleatório e empregando o operador booleano AND. Perante o que foi avaliado, a clorexidina pode ser considerada benéfica para seu uso clínico pois consegue quelar íons fundamentais para a constância e função das MMPs, além de alterar a estrutura dimensional das mesmas. Entretanto, ainda existe a necessidade de mais estudos para avaliar os mecanismos de ação da CHX, além de estudos extensos e in vivo quanto ao seu uso.

Submitted by Daniella Santos (daniella.santos@ufma.br) on 2022-10-24T04:12:58Z No. of bitstreams: 1 FLAVIAMENDONÇA.pdf: 4286884 bytes, checksum: 88e5fd00c89331cbc1257e36fdde9606 (MD5) Made available in DSpace on 2022-10-24T04:12:58Z (GMT). No. of bitstreams: 1 FLAVIAMENDONÇA.pdf: 4286884 bytes, checksum: 88e5fd00c89331cbc1257e36fdde9606 (MD5) Previous issue date: 2022-07-01 Penile cancer (PC) is one of the most common male tumors, with a high incidence in Brazil and worldwide, especially in the state of Maranhão. This cancer has a great capacity to invade locally and metastasize to regional lymph nodes, which is the most important prognostic factor, since metastasis to regional lymph nodes and the depth of invasion greatly reduce patient survival. This study is justified by the need to understand the factors that condition the invasive capacity of penile cancer, among them the regulation of MMPs 2 by TIMPs 2 and 3 and the relationship that this regulation has with the progression of this cancer, conditioning the invasive capacity of tumor cells. The overall objective was to analyze the expression of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in the development of HPV+ and HPV penile cancer through morphological and molecular studies. This is an epidemiological, analytical, qualitative, retrospective and sectional study of historical series of cases of penile epidermoid carcinomas, performed on 75 samples of penile tumors stored in the Biobanco de Tumores e DNA do Maranhão (BTMA). Sociodemographic data were obtained through a questionnaire, clinical and histopathological data were collected through medical record analysis. The genomic DNA of the samples was extracted and polymerase chain reaction PCR/Nested for HPV detection and then electrophoresis in agarose gel. Positive samples were submitted to genotyping by the Anyplex method for viral type identification. To analyze the expression of MMPs 2 and TIMPs 2 and 3 real time PCR was performed. It was observed that the mean age of patients at diagnosis was approximately 64 years. Most (64.76%) were from the interior of Maranhão and considered themselves to be brown (62.67%). It was also observed that 44.44% of patients were married, 30.56% had incomplete elementary school education, and 26.30% were illiterate. When asked about lifestyle habits, most patients (51.61%) said they never use condoms (63.51) that they smoke or have smoked during their lifetime. The majority (81.09%) also stated that they have been or still are alcoholics. It was also observed in this study that 49% of the samples were positive for HPV, with HPV 16 present in 36% and HPV 11 in 49% of the samples. The gene expression analyzed in this study showed an association between penile cancer, HPV infection and decreased expression of TIMP3 (p = 0,0360 entre tumores HPV+ e HPV-). With these results we can conclude that there is a relationship between some lifestyle habits of patients and penile cancer, as well as an important association with HPV infection. And also, that there is a relationship between HPV+ penile cancer and the downregulation of MMP expression, provided by the reduced expression of TIMP3. O câncer de pênis (CP) faz parte dos tumores que acometem o sexo masculino, com crescente incidência no Brasil e no mundo, especialmente no estado do Maranhão. Este câncer apresenta grande capacidade de invadir localmente e metastatizar para os linfonodos regionais, o que constitui o fator prognóstico mais importante, pois as metástases nos linfonodos regionais e a profundidade da invasão reduzem muito a sobrevivência do paciente. O presente trabalho justifica-se pela necessidade de compreender os fatores que condicionam a capacidade invasora do câncer de pênis, dentre eles a regulação das MMPs 2 pelos TIMPs 2 e 3 e a relação que esta regulação apresenta com a progressão deste câncer, condicionando a capacidade invasora das células tumorais. O objetivo geral foi analisar a expressão de metaloproteinases (MMPs) e inibidores teciduais de metaloproteinases (TIMPs) no desenvolvimento do câncer de pênis HPV+ e HPV- através de estudos morfológicos e moleculares. Trata se de um estudo epidemiológico, do tipo analítico, quantitativo, retrospectivo e seccional de série histórica de casos de carcinomas epidermóides penianos, realizado em 75 amostras de tumores penianos armazenados no Biobanco de Tumores e DNA do Maranhão (BTMA). Dados sociodemográficos foram obtidos através de um questionário, dados clínicos e histopatológicos foram coletados por meio de análise de prontuário. O DNA genômico das amostras foi extraído e realizada a reação em cadeia de polimerase PCR/Nested para detecção do HPV e em seguida a eletroforese em gel de agarose. Amostras positivas foram submetidas a genotipagem pelo método Anyplex para identificação do tipo viral. Para análise da expressão das MMPs 2 e dos TIMPs 2 e 3 foi realizada PCR em tempo real. Observou-se que a média de idade dos pacientes ao diagnóstico foi de aproximadamente 64 anos. A maioria (64,76%) era procedente do interior do Maranhão e consideravam-se pardos (62,67%). Observou se ainda que 44,44% dos pacientes eram casados, 30,56% dos pacientes tinham ensino fundamental incompleto e 26,30% era analfabeto. Quando questionados sobre os hábitos de vida, a maioria dos pacientes (51,61%) afirmou nunca usa camisinha (63,51) que fuma ou já fumou durante a vida. A maioria (81,09%) também afirmou que já foi etilista ou ainda é. Foi observado também neste estudo que 49% das amostras eram positivas para o HPV, sendo que o HPV 16 estava presente em 36% e o HPV 11 em 49% das amostras. A expressão de genes analisada neste estudo demonstrou uma associação entre o câncer de pênis, a infecção pelo HPV e a diminuição da expressão do TIMP3 (p = 0,0360 entre tumores HPV+ e HPV-). Com estes resultados podemos concluir que há uma relação entre alguns hábitos de vida dos pacientes e o câncer peniano, bem como uma associação importante com a infecção pelo HPV. E ainda, que há uma relação entre o câncer de pênis HPV+ e a desregulação da expressão de MMP, proporcionada pela reduzida atividade de TIMP3.

Background Autologous hematopoietic stem cell transplantation (AHSCT) treats patients with severe and progressive systemic sclerosis (SSc). However, basic mechanisms associated with the therapeutic efficacy of the procedure are not entirely understood. We aimed to evaluate how AHSCT affects skin fibrosis in SSc patients. Methods Clinical data, serum, and skin samples from 39 SSc patients who underwent AHSCT were retrospectively evaluated. Skin biopsies were analyzed by immunohistochemistry with anti-MMP-1, -MMP-2, -MMP-3, -MMP-9, -TIMP-1, -α-SMA, -TGF-β, and -NF-κB p65 antibodies, and stained with hematoxylin and eosin and picrosirius red to assess skin thickness and collagen density, respectively. Serum samples were evaluated by Multiplex Assay for COL1A1, COL4A1, FGF-1, MMP-1, MMP-3, MMP-12, MMP-13, PDGF-AA, PDGF-BB, S100A9, and TIMP-1 levels and compared to healthy controls. Results After AHSCT, SSc patients showed clinical improvement in skin involvement, assessed by modified Rodnan’s skin score (mRSS). Histologically, collagen density and skin thickness decreased after AHSCT. Immunohistochemical analyses showed increased expression of MMP-2, MMP-3, MMP-9, and TIMP-1 after AHSCT, whereas expression of NF-κB p65 decreased. At baseline, serum levels of COL4A1 and S100A9 were higher than in healthy controls. Serum levels of S100A9 normalized after AHCST in SSc patients compared to controls. Serum levels of PDGF-AA, PDGF-BB, TIMP-1, and MMP-1 decreased, while COL1A1 increased after AHSCT in SSc patients. No changes were detected in MMP-3, MMP-12, MMP-13, and FGF-1 serum levels after AHSCT. Conclusions Our results suggest that the therapeutic effects of AHSCT on skin fibrosis are related to changes in molecules associated with connective tissue maintenance and inflammation in SSc.

Background: Melanoma is the most aggressive skin cancer, and BRAF (V600E) is the most frequent mutation that led to the development of BRAF inhibitors (BRAFi). However, patients treated with BRAFi usually present recidivism after 6-9 months. Curcumin is a turmeric substance, and it has been deeply investigated due to its anti-inflammatory and antitumoral effects. Still, the low bioavailability and biodisponibility encouraged the investigation of different analogs. DM-1 is a curcumin analog and has shown an antitumoral impact in previous studies. Methods: Evaluated DM-1 stability and cytotoxic effects for BRAFi-sensitive and resistant melanomas, as well as the role in the metalloproteinases modulation. Results: DM-1 showed growth inhibitory potential for melanoma cells, demonstrated by reduction of colony formation, migration and endothelial tube formation, and cell cycle arrest. Subtoxic doses were able to downregulate important Metalloproteinases (MMPs) related to invasiveness, such as MMP-1, -2 and -9. Negative modulations of TIMP-2 and MMP-14 reduced MMP-2 and -9 activity; however, the reverse effect is seen when increased TIMP-2 and MMP-14 resulted in raised MMP-2. Conclusion: These findings provide essential details into the functional role of DM-1 in melanomas, encouraging further studies in the development of combinatorial treatments for melanomas.

Resumen: Objetivos: Evaluar la resistencia de unión a la microtracción en dentina humana de un sistema adhesivo universal con clorhexidina en su composición, en modo de grabado y lavado en 2 pasos, y en modo de autograbado. Metodología: 20 terceros molares divididos aleatoriamente en 4 grupos según el tipo de sistema adhesivo utilizado (Single Bond Universal®, 3MESPE y Peak Universal Bond®, Ultradent Products) y modo de uso (grabado total y autograbado). Se confeccionaron cuerpos de prueba sometidos al ensayo de microtracción utilizando una máquina de ensayos universales. Resultados: No se encontraron diferencias estadísticamente significativas entre los cuatro grupos estudiados. Conclusiones: La resistencia de unión de una resina compuesta a dentina humana no fue afectada por el uso de un sistema adhesivo universal que contiene clorhexidina en su composición aplicado en los modos de grabado total y autograbado. Sumário: Objetivos: Avaliar a resistência de união á microtração na dentina humana de um sistema adesivo universal com clorexidina na sua composição, no modo de condicionamento total em dois passos e no modo autocondicionante. Metodologia: 20 terceiros molares foram divididos aleatoriamente em 4 grupos, de acordo com o tipo de sistema adesivo utilizado (Single Bond Universal®, 3MESPE e Peak Universal Bond®, Ultradent Products) e modo de uso (condicionamento total e autocondicionante). Os corpos de prova criados foram submetidos ao teste de microtração utilizando uma máquina de ensaios universal. Resultados: Não foram encontradas diferenças estatisticamente significativas entre os quatro grupos estudados. Conclusões: A resistência de união da resina composta à dentina humana não foi afetada pelo uso de um sistema adesivo universal contendo clorexidina em sua composição, aplicado nos modos de condicionamento total ou autocondicionamento. Abstract: Objectives: To evaluate the microtensile bond strength to human dentin of a chlorhexidine containing universal adhesive system applied in the total-etch and self-etch modes. Methods: 20 third molars were randomly divided into 4 groups according to the universal adhesive system (Single Bond Universal ®, 3M ESPE and Peak Universal Bond®, Ultradent) and application mode used (total-etch and self-etch). Specimens were performed and subjected to a microtensile bond strength using a MTS SANS universal testing machine. Results: No statistically significant differences were found in the microtensile bond strength between the four groups studied. Conclusions: The bond strength of a composite resin to human dentin was not affected by the use of a universal adhesive system containing chlorhexidine in its composition applied in the total-etch and self-etch mode.

The reversion-inducing cysteine-rich protein with kazal motifs (RECK) gene was described as a tumor suppressor gene two decades ago. Recently, novel alternatively spliced products of this gene have been identified. Of these, the transcript variant 3 (RECKVar3) was shown to display tumor-facilitating effects in astrocytoma cells in vitro, with a higher RECKVar3/canonical RECK expression ratio being correlated with lower survival rates of patients. However, the regulatory mechanisms through which the cell controls the production and maintenance of these alternative transcripts, as well as their expression in other tumor types, remain elusive. Thus, the aim of this study is to investigate the role of the alternatively spliced transcripts from the RECK gene in melanoma progression as well as their regulation mechanism. To this end, we analyzed data from the Cancer Genome Atlas network and experimental data obtained from a panel of cell lines to show that high levels of RECKVar3 are predictive of poor survival. We also show that the MAPK and PI3K signaling pathways clearly play a role in determining the alternative-to-canonical ratio in vitro. Finally, we show that overexpression of the RECKVar3 protein upregulates matrix metalloproteinases (MMP)-9 and MMP-14 mRNA, while downregulating their inhibitor, tissue inhibitor of metalloproteinase (TIMP)3, and that RECKVar3-specific knockdown in the 1205Lu melanoma cell line hampered upregulation of the MMP9 mRNA promoted by the MEK1/2 inhibitor U0126. Taken together, our data complement the evidence that the RECK gene has a dual role in cancer, contributing to better understanding of the signaling cues, which dictate the melanoma invasive potential.

Proanthocyanidin has been considered as a preventive agent against erosion because of its properties, which involves remineralization, reduction of demineralization and matrix metalloproteinases (MMPs) inhibition. Thus, the aim of this in situ study was t

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2022-02-21T21:11:24Z No. of bitstreams: 1 Guilherme Henrique Cardoso Fernandes.pdf: 1224058 bytes, checksum: 571512b4f4582f6cda131971250c46fe (MD5) Made available in DSpace on 2022-02-21T21:11:24Z (GMT). No. of bitstreams: 1 Guilherme Henrique Cardoso Fernandes.pdf: 1224058 bytes, checksum: 571512b4f4582f6cda131971250c46fe (MD5) Previous issue date: 2021-12-16 Rheumatoid Arthritis (RA) is a chronic inflammatory, autoimmune, systemic and progressive disease that leads to irreversible destruction of cartilage and bone. In vivo and in vitro experimental studies using photobiomodulation therapy have shown positive effects on the modulation of factors that cause disease progression. The objective of this work was to evaluate the effects of photobiomodulation therapy in the treatment of induced Rheumatoid Arthritis (RA) in vitro and in vivo, in relation to cellular, biochemical and functional aspects. Methodology applied in the in vitro step recovered cartilage-derived chondrocytes with induced Rheumatoid Arthritis. Chondrocytes were cultured in 96-well plates, considered healthy chondrocytes (CD) or derived from cartilages with induced RA, untreated (NT) or treated with PBM at different parameters, wavelength 810nm, 2J energy and 35, 50, 100mW of power and cell proliferation was evaluated. In the in vivo step, 25 male Wistar rats were used, divided into groups, CTL (control), RA (Rheumatoid Arthritis) and RA + PBM. For the induction of RA, 3 injections of the lesion-inducing solution (CIA) were used on days 0, 7 and 21 days after the last induction. For groups that received PBM treatment (808nm; 2J; 100mW) irradiation started immediately after the last induction. The strength (Fmax) and maximum deformation (Dmax) supported by the cartilage until the moment of rupture were evaluated. The quantification of the gene expression of MMPs 2, 9 and 13 is performed. Results: The results of the evaluation of cell proliferation showed that the NT group showed a reduction in cell proliferation after 48 hours. The groups irradiated with powers of 35mW and 100mW showed increased cell proliferation. Increased proliferation of RA chondrocytes treated with PBM and reduced Fmax and Dmax were observed in RA groups. PBM reduced the biomechanical changes caused by RA and the expression of MMPs 2,9 and 13, preventing disease progression. Conclusion: PBM promoted an improvement in the functional and biochemical characteristics, reducing the impact on cartilage resistance and reducing the expression of MMPs. The 810nm wavelengths at 2J energy were efficient in increasing cell proliferation and maintaining viability. Suggesting that it is an important therapy in the treatment of rheumatoid arthritis with no known side effects. A Artrite Reumatoide (AR) é uma doença crônica inflamatória, autoimune, sistêmica e progressiva, que leva à destruição irreversível da cartilagem e osso. Estudos experimentais in vivo e in vitro utilizando a terapia por fotobiomodulação têm demonstrado efeitos positivos sobre a modulação de fatores que causam a progressão da doença. O objetivo deste trabalho foi avaliar os efeitos da terapia por fotobiomodulação no tratamento da Artrite Reumatoide (AR) induzida in vitro e in vivo, em relação aos aspectos celulares, bioquímicos e funcionais. A Metodologia aplicada na etapa in vitro recuperou condrócitos derivados de cartilagem com Artrite Reumatoide induzida. Os condrócitos foram cultivados em placas de 96 poços, considerados condrócitos saudáveis (CD) ou derivados de cartilagens com AR induzida, não tratada (NT) ou tratada com PBM em diferentes parâmetros, comprimento de onda 810nm, 2J de energia e 35, 50, 100mW de potência e foi avaliada a proliferação celular. Na etapa in vivo foram utilizados 25 ratos machos Wistar, distribuídos em grupos, CTL (controle), AR (Artrite Reumatoide) e AR + PBM. Para a indução da AR, foi utilizado 3 injeções da solução (CIA) indutora da lesão nos dias 0, 7 e após 21 dias da última indução. Para os grupos que receberam tratamento por PBM (808nm; 2J; 100mW) a irradiação iniciou imediatamente após a última indução. Foi avaliada a força (Fmax) e deformação máxima (Dmax) suportada pela cartilagem até o momento da ruptura. E realizada a quantificação da expressão gênica das Mês 2, 9 e 13. Os resultados da avaliação da proliferação celular, demonstrou que o grupo NT apresentou redução da proliferação celular após 48h. Os grupos irradiados com as potências de 35mW e 100mW apresentaram aumento da proliferação celular. Foi observado aumento da proliferação dos condrócitos com AR tratados com PBM e redução da Fmax e Dmax nos grupos com AR. A PBM reduziu as alterações biomecânicas provocadas pela AR e a expressão das MMPs 2,9 e 13 evitando a progressão da doença. Conclusão: A PBM promoveu melhora nas características funcionais e bioquímica, reduzindo o impacto na resistência cartilagem e redução da expressão de MMPs. Os comprimentos de onda 810nm na energia de 2J foram eficientes no aumento da proliferação celular e manutenção da viabilidade. Sugerindo ser uma importante terapia no tratamento da artrite reumatoide com ausência de efeitos colaterais conhecidos.

Dissertação para obtenção do grau de Mestre no Instituto Universitário Egas Moniz Objetivo: Avaliar a presença de MMP ativas no FCG de pacientes com doença periodontal - grupo de estudo - por comparação a pacientes com saúde periodontal - grupo de controlo -, a fim de determinar se estas enzimas podem atuar como biomarcadores da doença. Metodologia: Participaram neste estudo cinco pacientes com saúde periodontal e cinco pacientes com periodontite. O fluido foi recolhido por Periopapers em sulcos gengivais e bolsas periodontais e quantificado no Periotron. A presença de MMP ativas nas amostras de FCG foi analisada por zimografia de colagénio. Resultados: O volume de FCG foi superior em bolsas periodontais (154 ± 38 (n=8)) do que em sulcos gengivais (26 ± 17 (n=10)). A incubação dos géis por um período de tempo alargado permitiu detetar um maior número de bandas proteolíticas previsivelmente correspondentes a formas enzimáticas inativas (pró-MMP-8/pró-MMP-13) e ativas (MMP-1/MMP-13 e MMP-2), tendo sido observadas diferenças entre os grupos estudados. Conclusão: A utilização de Periopapers e do Periotron constituiu um método adequado de recolha e quantificação de FCG. A atividade proteolítica das MMP apresentou diferenças entre os dois grupos estudados, o que revela que estas enzimas podem ser indicadas como biomarcadores da doença. Objective: To evaluate the presence of active MMPs in the GCF of patients with periodontal disease - study group - in comparison with patients with periodontal health - control group -, in order to determine whether these enzymes can act as biomarkers of the disease. Methodology: Five patients with periodontal health and five patients with periodontitis participated in this study. The fluid was collected by Periopapers in gingival sulcus and periodontal pockets and quantified in Periotron. The presence of active MMPs in GCF samples was analyzed by collagen zymography. Results: The volume of GCF was higher in periodontal pockets (154 ± 38 (n=8)) than in gingival sulcus (26 ± 17 (n=10)). The incubation of the gels for an extended period of time allowed to detect a greater number of proteolytic bands predictably corresponding to inactive (pro-MMP-8/pro-MMP-13) and active (MMP-1/MMP-13 and MMP-2) enzymatic forms, with differences between the studied groups being observed. Conclusion: The use of Periopapers and Periotron was an adequate method for collecting and quantifying GCF. The proteolytic activity of MMPs showed differences between the two groups studied, which reveals that these enzymes can be indicated as biomarkers of the disease.

Dissertação para obtenção do grau de Mestre no Instituto Universitário Egas Moniz A dentina é um substrato dentário de elevada importância biológica, sendo um tecido mineralizado dinâmico e sujeito a várias alterações, como tal é necessário preservar. Dado a biodinâmica dentinária e a evolução da medicina dentária conservadora, este tecido encara várias adversidades no que toca à adesão e ao impacto da cárie dentária. Os antioxidantes são elementos inibidores da ação de radicais livres, tem um papel muito importante sobre as metaloproteínases e agem sobre as fibras de colagénio. Tendo em conta todas estas características é possível associar a ação benéfica dos antioxidantes na dentina. Esta dissertação centra-se na resolução de um problema chave que é como diminuir a degradação da camada híbrida simultaneamente à existência da conservação do tecido dentinário. Através da análise das causas da evolução da carie dentária, degradação da camada híbrida e instabilidade da adesão a longo prazo, são avaliados vários estudos de diferentes autores sobre uso de antioxidantes na dentina e são observados os seus resultados. Objetivo: Avaliar qual a ação dos antioxidantes na dentina e classificar a sua ação como benéfica ou não para este tecido dentário. Dentin is a dental subtract of high biological relevance, being a dynamic mineralized tissue that is vulnerable to several alterations, therefore is necessary to preserve. given the dentinary biodynamic and the evolution of the conservative odontology, this tissue faces several adversities when it comes to the impact in dental cavities. Antioxidants are inhibiting elements towards the action of reactive oxygen species; they have an important role over the metalloproteinasis and act on the collagen fibers. Accounting all these characteristics it is possible to associate the beneficial action of the antioxidants in the Dentine. This dissertation is focused on the resolution of a key problem that is how to reduce the degradation of hybrid layer while keeping the conservation of the dental tissue. Due to analysis of the evolution of the dental cavity, degradation of the hybrid layer and instability of the long-term bonding, there are evalued several other studies over the use of antioxidants in the Dentine and their results are observed Objective: Evaluate the effect of antioxidants in the Dentine and to classify its action as benefic or not for the dental tissue

Objetivo: El objetivo del presente estudio es establecer el papel que desempeñan las Metaloproteinasas (MMPs) y la importancia de sus inhibidores en la adhesión. Metodología: Esta revisión se realizó con una estrategia de búsqueda exhaustiva de la literatura científica utilizando la base de datos PUBMED, ScienceDirect y Scielo, se utilizó las palabras clave “Metaloproteinasas”, “MMPs” y “Adhesión dental”, y conectores como “y”. Resultados: Durante la unión a la dentina, es beneficioso aplicar inhibidores de MMP capaces no solo de inhibir la descomposición del colágeno de la dentina en las capas híbridas, mejorando así la fuerza de la unión a la dentina, sino también de prevenir la caries secundaria. Conclusión: Durante la unión a la dentina, sería beneficioso aplicar inhibidores de MMP capaces no solo de inhibir la descomposición del colágeno de la dentina en las capas híbridas, mejorando así la fuerza de la unión a la dentina, sino también de prevenir la caries secundaria alrededor de la restauración. Las metaloproteinasas juegan un papel importante en la adhesión, sin embargo, compuestos como la clorhexidina, aunque estudiados, no han demostrado mejorar la adhesión durante un largo período de tiempo, a diferencia de la doxiciclina, cuyos estudios respaldan la mejora a largo plazo de la adhesión. Objective: The objective of this study is to establish the role of metalloproteinases (MMPs) and the importance of their inhibitors in development. Methodology: This review was carried out with an exhaustive search strategy of scientific literature using PUBMED, ScienceDirect and Scielo as databases, using “Metalloproteinases”, “MMPs” and “Dental adesão” as keywords, and connectors such as “e”. Results: During bonding to dentin, it is beneficial to apply MMP inhibitors capable of not inhibiting dentin collagen breakdown in hybrid beds, improving bond strength to dentin, but also preventing secondary lesions. Conclusion: During dentin collagen, it would be beneficial to apply MMP inhibitors capable of not only inhibiting dentin collagen breakdown in hybrid layers, as well as improving dentin bond strength, but also preventing secondary caries around the restoration. The metalloproteinases play an important role in the administration, however, compounds such as chlorhexidine, as studied, have not been shown to improve the administration for a long period of time, on the contrary to doxycycline, whose studies support a better administration over a long period of time. Objetivo: O objetivo deste estudo é estabelecer o papel das Metaloproteinases (MMPs) e a importância de seus inibidores na adesão. Metodologia: Esta revisão foi realizada com uma estratégia de busca exaustiva da literatura científica utilizando as bases de dados PUBMED, ScienceDirect e Scielo, utilizando as palavras-chave “Metalloproteinases”, “MMPs” e “Dental adesão”, e conectores como “e”. Resultados: Durante a adesão à dentina, é benéfico aplicar inibidores de MMP capazes de não apenas inibir a decomposição do colágeno dentinário nas camadas híbridas, melhorando assim a resistência da união à dentina, mas também prevenindo cáries secundárias. Conclusão: Durante a colagem em dentina, seria benéfico aplicar inibidores de MMP capazes de não apenas inibir a quebra do colágeno dentinário nas camadas híbridas, melhorando assim a resistência de união à dentina, mas também prevenindo cáries secundárias ao redor da restauração. As metaloproteinases desempenham um papel importante na adesão, no entanto, compostos como a clorexidina, embora estudados, não demonstraram melhorar a adesão por um longo período de tempo, ao contrário da doxiciclina, cujos estudos suportam a melhora da adesão a longo prazo.

Gracielle Vieira Ramos, 1, 2 Ivo Vieira de Sousa Neto, 3 Alessandra Choqueta Toledo-Arruda, 4, 5 Rita de Cassia Marqueti, 3 Rodolfo P Vieira, 6– 8 Milton A Martins, 5 Tânia F Salvini, 9 João Luiz Quaglioti Durigan 10 1Physical Therapy Division, University of Brasilia, Brasília, DF, Brazil; 2Department of Physical Therapy, University Paulista, Brasília, DF, Brazil; 3Laboratory of Molecular Analysis, Graduate Program of Sciences and Technology of Health, Universidade de Brasília, Brasília, DF, Brazil; 4Faculty of Physiotherapy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 5Department of Medicine Clinical (LIM 20), School of Medicine, University of São Paulo, São Paulo, Brazil; 6Universidade Brasil, Post-Graduation Program in Bioengineering, São Paulo, Brazil; 7Laboratory of Pulmonary and Exercise Immunology (LABPEI), Brazilian Institute of Teaching and Research in Pulmonary and Exercise Immunology (IBEPIPE) and Nove de Julho University (UNINOVE), São Paulo, SP, Brazil; 8Federal University of Sao Paulo, Post-Graduation Program in Sciences of Human Movement and Rehabilitation, São Paulo, Brazil; 9Department of Physical Therapy, Federal University of São Carlos, São Carlos, Brazil; 10Rehabilitation Sciences Graduation Program, University of Brasilia, Brasília, DF, BrazilCorrespondence: Gracielle Vieira RamosDepartment of Physical Therapy, University Paulista, Sgas Quadra 913, s/nº - Conjunto B - Asa Sul, Brasília, DF, Brazil, 70390-130 Email graciellevieiraramos@gmail.comBackground: Long-term cigarette smoke (CS) induces substantive extrapulmonary effects, including musculoskeletal system disorders. Exercise training seems to protect long-term smokers against fiber atrophy in the locomotor muscles. Nevertheless, the extracellular matrix (ECM) changes in response to aerobic training remain largely unknown. Thus, we investigated the effects of moderate treadmill training on aerobic performance, cross-sectional area (CSA), fiber distribution, and metalloproteinase 2 (MMP-2) activity on quadriceps muscle in mice exposed to chronic CS.Methods: Male mice were randomized into four groups: control or smoke (6 per group) and exercise or exercise+smoke (5 per group). Animals were exposed to 12 commercially filtered cigarettes per day (0.8 mg of nicotine, 10 mg of tar, and 10 mg of CO per cigarette). The CSA, fibers distribution, and MMP-2 activity by zymography were assessed after a period of treadmill training (50% of maximal exercise capacity for 60 min/day, 5 days/week) for 24 weeks.Results: The CS exposure did not change CSA compared to the control group (p> 0.05), but minor fibers in the frequency distribution (< 1000 μm 2) were observed. Long-term CS exposure attenuated CSA increases in exercise conditions (smoke+exercise vs exercise) while did not impair aerobic performance. Quadriceps CSA increased in mice nonsmoker submitted to aerobic training (p = 0.001). There was higher pro-MMP-2 activity in the smoke+exercise group when compared to the smoke group (p = 0.01). Regarding active MMP-2, the exercise showed higher values when compared to the control group (p = 0.001).Conclusion: Moderate treadmill training for 24 weeks in mice exposed to CS did not modify CSA, despite inducing higher pro-MMP-2 activity in the quadriceps muscle, suggesting limited effects on ECM remodeling. Our findings may contribute to new insights into molecular mechanisms for CS conditions.Keywords: physical exercise, chronic obstructive pulmonary disease, MMP-2, inflammation

Introduction To evaluate the relationship between the genetic polymorphism of matrix metalloproteinases 1 and 13 and posttraumatic elbow stiffness, as well as the association of other risk factors with this condition. Materials and methods We evaluated 20 patients with posttraumatic elbow stiffness and 12 controls with traumatic elbow disorders without contracture. Deoxyribonucleic acid (DNA) was obtained from buccal mucosa epithelial cells of the volunteers. The MMP-1 and MMP-13 genotypes were determined using PCR-restriction fragment length polymorphism assays. Results We did not find any significant differences in the frequency of genotypes and alleles between the test and control groups for the polymorphism of metalloproteinases 1 and 13. We observed that genotypes 1G/2G and 2G/2G of MMP-1 were present in 65% (13/20) of patients with articular stiffness and 50% (6/12) of controls (p = 0.599). Genotypes A/A and A/G of MMP-13 were obtained in 95% (19/20) of patients and 91.6% (11/12) of controls (p = 0.491). Among the prognostic factors for elbow stiffness, only immobilization time correlated positively. The mean immobilization time for cases and controls were 16 ± 10 days and 7 ± 7 days, respectively (p = 0.017). Conclusion The genetic polymorphism of MMP-1 at position -1607 and MMP-13 at position -77 was not associated with post-traumatic elbow stiffness. Level of Evidence III; Prognosis Study; Case-Control Study. RESUMO Introdução Avaliar a relação entre o polimorfismo genético das metaloproteinases 1 e 13 da matriz e a rigidez pós-traumática do cotovelo, assim como a associação de outros fatores de risco com essa condição. Material e método Foram avaliados 20 pacientes com rigidez pós-traumática do cotovelo e 12 controles com distúrbios traumáticos do cotovelo sem contratura. O ácido desoxirribonucleico (DNA) de voluntários foi obtido a partir de células epiteliais da mucosa bucal. Os genótipos MMP-1 e MMP-13 foram determinados usando ensaios de polimorfismo de comprimento de fragmento de restrição de PCR. Resultados Não encontramos diferença significativa na frequência de genótipos e alelos entre os grupos teste e controle para o polimorfismo das metaloproteinases 1 e 13. Observamos que os genótipos 1G/2G e 2G/2G de MMP-1 estavam presentes em 65% (13/20) dos pacientes com rigidez articular e 50% (6/12) dos controles (p = 0,599). Os genótipos A/A e A/G da MMP-13 foram obtidos em 95% (19/20) dos pacientes e 91,6% (11/12) dos controles (p = 0,491). Dentre os fatores prognósticos para rigidez de cotovelo, apenas o tempo de imobilização se correlacionou positivamente. O tempo médio de imobilização para casos e controles foi de 16 ± 10 dias e 7 ± 7 dias, respectivamente (p = 0,017). Conclusões O polimorfismo genético de MMP-1 na posição -1607 e MMP-13 na posição -77 não foi associado à rigidez pós-traumática do cotovelo. Nível de Evidência III; Estudos Prognósticos; Estudo de Caso-Controle.

Evaluate the effect of dentifrices or gels containing MMP inhibitors on dentine loss in situ. Acrylic palatal appliances containing bovine dentine blocks were divided into two rows, corresponding to the groups erosion (ERO) and erosion associated with abrasion (ERO+ABR). For ERO, the appliances were immersed in a cola drink for 5 min, 4 times/day, while for ERO+ABR, the blocks were brushed for 15 sec with a dentifrice slurry after the second and third erosive challenges. Ten volunteers took part in study 1 (S1), where the dentifrices evaluated contained 1100 ppm fluoride as NaF, 0.61% green tea extract, or 0.012% chlorhexidine digluconate. Thirteen volunteers participated in study 2 (S2), in which the treatment was performed only once (1 min) with gels containing 400 μM EGCG (EGCG400), 0.012% chlorhexidine, 1 mM FeSO4, 1.23% F (NaF), placebo, or received no treatment. Dentine loss was analyzed by profilometry (μm). Regarding S1, ERO+ABR induced significantly higher dentine loss compared with ERO and all dentifrices tested led to significantly lower dentine loss when compared with placebo. For S2, regardless of the conditions or times of evaluation, gels containing EGCG, CHX, or FeSO4 led to significantly less wear compared with the other groups. Both dentifrices and gels containing MMP inhibitors significantly reduced dentine loss. Dentifrices and gels containing MMP inhibitors are able to increase the protection against dentine wear, although gels have a better effect when compared with fluoride gel, lasting up to 10 days after a single application.

Proton pump inhibitors (PPI) are commonly used drugs that may increase the cardiovascular risk by mechanisms not entirely known. We examined whether the PPI omeprazole promotes vascular oxidative stress mediated by xanthine oxidoreductase (XOR) leading to activation of matrix metalloproteinases (MMPs) and vascular remodeling. We studied Wistar rats treated with omeprazole (or vehicle) combined with the XOR inhibitor allopurinol (or vehicle) for four weeks. Systolic blood pressure (SBP) measured by tail-cuff plethysmography was not affected by treatments. Omeprazole treatment increased the aortic cross-sectional area and media/lumen ratio by 25% (P 0.05). Omeprazole treatment decreased gastric pH and induced vascular remodeling accompanied by impaired endothelium-dependent aortic responses (assessed with isolated aortic ring preparation) to acetylcholine (P 0.05). Omeprazole increased vascular active MMP-2 expression and activity assessed by gel zymography and in situ zymography, respectively (P 0.05). Moreover, omeprazole enhanced vascular oxidative stress assessed in situ with the fluorescent dye DHE and with the lucigenin chemiluminescence assay (both P 0.05). All these biochemical changes caused by omeprazole were associated with increased vascular XOR activity (but not XOR expression assessed by Western blot) and treatment with allopurinol fully prevented them (all P 0.05). Importantly, treatment with allopurinol prevented the vascular dysfunction and remodeling caused by omeprazole. Our results suggest that the long-term use of omeprazole induces vascular dysfunction and remodeling by promoting XOR-derived reactive oxygen species formation and MMP activation. These findings provide evidence of a new mechanism that may underlie the unfavorable cardiovascular outcomes observed with PPI therapy. Clinical studies are warranted to validate our findings.

Dissertação para obtenção do grau de Mestre no Instituto Universitário Egas Moniz A reabilitação à base de implantes tem sofrido uma evolução e são cada vez mais os Médicos Dentistas que optam por este tipo de reabilitação. No entanto, é acompanhada por um conjunto de possíveis complicações que podem dificultar a reabilitação ou mesmo impossibilitá-la, como por exemplo, a peri-implantite. A peri-implantite é a doença inflamatória formada em redor da mucosa dos implantes que leva a uma perda de osso de suporte, que, caso extrema, obriga a explantação do implante. Devido à evolução da doença, que muitas vezes é severa, pretende-se procurar um biomarcador que possa melhorar o prognóstico dos implantes afetados através de um diagnóstico mais precoce. A presente revisão bibliográfica destina-se a descrever as evidências científicas sobre o papel das metaloproteinases recolhidas do fluído crevicular como marcador para o diagnóstico precoce da peri-implantite. A revisão foi elaborada a partir de pesquisa na literatura científica, recorrendo às bases de dados eletrónicas como PubMed, B-on, Cochrane e ScienceDirect, assim como a teses e dissertações disponíveis no Google Scholar ou ainda às listas de referências dos artigos consultados. As metaloproteinases, produzidas por neutrófilos, fibroblastos e osteoclastos estão presentes no fluído peri-implantar, e são de grande interesse nesta área pois são responsáveis pela degradação do colagénio tipo I, o principal componente da matriz extracelular. Diversos estudos já comprovaram o papel determinante das metaloproteinases na perda óssea, em especial da MMP-8 – colagenase principal da matriz. Como tal, o controlo da sua concentração ao longo da reabilitação implantosuportada permite prever ou detetar precocemente a destruição do osso de suporte do implante. Um método é recorrendo a testes point-of-care, que permitem analisar as concentrações de MMP de um modo simples, fidedigno e não invasivo possibilitando ao Médico Dentista determinar a suscetibilidade do paciente para a peri-implantite e adaptar o tratamento ao caso em questão. Implant-based rehabilitation has evolved and dentists are increasingly choosing this type of rehabilitation. However, it is accompanied by a set of possible complications that may hinder rehabilitation or even make it impossible, such as peri-implantitis. Peri-implantitis is an inflammatory disease formed around the mucosa of the implants that leads to a loss of supporting bone, which, if extreme, forces explantation of the implant. Due to the evolution of the disease, which is often severe, it is important to look for a biomarker that can improve the prognosis of affected implants through an earlier diagnosis. This bibliographic review aims to describe the role of metalloproteinases collected from crevicular fluid as a marker for the early diagnosis of peri-implantitis. The review was based on research in the scientific literature, using electronic databases such as PubMed, B-on, Cochrane and ScienceDirect, as well as the theses and dissertations available on Google Scholar or the reference lists of the articles consulted. Metalloproteinases, produced by neutrophils, fibroblasts and osteoclasts are present in the peri-implant fluid, and are of great interest in this area because they are responsible for the degradation of type I collagen, the main component of the extracellular matrix. Several studies have already proven the determinant role of metalloproteinases in bone loss, in particular MMP-8 – the main collagenase in the matrix. As such, the control of its concentration during the implant-supported rehabilitation allows to the early prediction or detection of the destruction of the implant support bone. One method is using point-of-care tests, which permit the analysis of MMP concentrations in a simple, reliable and non-invasive way allowing the Dentist to determine the patient's susceptibility to peri-implantitis and adapt the treatment to the case in question.

Remodelamento ventricular se refere ao processo fisiopatológico caracterizado por alterações da morfologia ventricular e que, freqüentemente, culmina em dilatação das cavidades cardíacas. O processo de dilatação ventricular pós-infarto ocorre após um dano isquêmico agudo e irreversível, sendo influenciado primordialmente por três fatores interdependentes: o tamanho do infarto, o estresse da parede ventricular e o processo de cicatrização tecidual. Os meiosmais eficientes de evitar ou minimizar o aumento nas dimensões ventriculares após um infarto são através da limitação do dano isquêmico e da redução da pós-carga e da tensão da parede ventricular. Recentemente, o papel da síntese e degradação da matriz extracelular nos processos relacionados com o remodelamento ventricular pós-infarto vem recebendo grande interesse. Amodulação da atividade de uma família de enzimas proteolíticas, as metaloproteinases, responsáveis pela degradação de proteínas da matriz extracelular, emergiu como uma estratégia terapêutica potencial para pacientes em risco de desenvolver quadros de falência miocárdica. Dados promissores, utilizando modelos de infarto experimental, sugerem que esse tipo deabordagem poderá ter um papel relevante no tratamento do remodelamento ventricular pósinfarto. De forma similar, diversos investigadores têm avaliado estratégias inovadoras de tratamento que se baseiam no conceito de que a regeneração do tecido miocárdico é factível e segura, envolvendo o uso de terapias com células pluripotentes. Inúmeros estudos experimentaisjá avaliaram o uso destas células em diferentes modelos de lesão miocárdica, demonstrando resultados consistentemente benéficos em aspectos funcionais. Estudos clínicos estão sendo desenvolvidos em todo o mundo, incluindo iniciativas no Brasil, para definir o papel destas estratégias de tratamento na reversão do remodelamento ventricular pós-infarto.Unitermos: Infarto agudo do miocárdio, remodelamento, metaloproteinases.

A high incidence of intentional or accidental paraquat (PQ) ingestion is related to irreversible lung fibrosis and no effective therapy is currently available. Vitamin D has emerged with promising results as an immunomodulatory molecule when abrogating the inflammatory responses of lung diseases. Therefore, we have investigated the role of vitamin D treatments on PQ-induced lung fibrosis in male C57/BL6 mice. Lung fibrosis was induced by a single injection of PQ (10 mg/kg; i.p.). The control group received PQ vehicle. Seven days later, after the PQ injection or the vehicle injection, the mice received vitamin D (5 μg/kg, i.p., once a day) or vehicle, for a further 7 days. Twenty-four hours after the last dose of vitamin D or the vehicle, the analysis were performed. The vitamin D treatments reduced the number of leukocytes in their BALF and they decreased the IL-6, IL-17, TGF-beta and MMP-9 levels and the abrogated collagenase deposits in their lung tissues. Conversely, the vitamin D treatments increased the resolvin D levels in their BALF. Moreover, their tracheal contractility was also significantly reduced by the vitamin D treatments. Altogether, the data that was obtained showed a promising use of vitamin D, in treating the lung fibrosis that had been induced by the PQ intoxications. This may improve its prognostic use for a non-invasive and low cost therapy.

Heart rate variability (HRV) has been extensively explored by traditional linear approaches (e.g., spectral analysis); however, several studies have pointed to the presence of nonlinear features in HRV, suggesting that linear tools might fail to account for the complexity of the HRV dynamics. Even though the prevalent notion is that HRV is nonlinear, the actual presence of nonlinear features is rarely verified. In this study, the presence of nonlinear dynamics was checked as a function of time scales in three experimental models of rats with different impairment of the cardiac control: namely, rats with heart failure (HF), spontaneously hypertensive rats (SHRs), and sinoaortic denervated (SAD) rats. Multiscale entropy (MSE) and refined MSE (RMSE) were chosen as the discriminating statistic for the surrogate test utilized to detect nonlinearity. Nonlinear dynamics is less present in HF animals at both short and long time scales compared with controls. A similar finding was found in SHR only at short time scales. SAD increased the presence of nonlinear dynamics exclusively at short time scales. Those findings suggest that a working baroreflex contributes to linearize HRV and to reduce the likelihood to observe nonlinear components of the cardiac control at short time scales. In addition, an increased sympathetic modulation seems to be a source of nonlinear dynamics at long time scales. Testing nonlinear dynamics as a function of the time scales can provide a characterization of the cardiac control complementary to more traditional markers in time, frequency, and information domains.NEW & NOTEWORTHY Although heart rate variability (HRV) dynamics is widely assumed to be nonlinear, nonlinearity tests are rarely used to check this hypothesis. By adopting multiscale entropy (MSE) and refined MSE (RMSE) as the discriminating statistic for the nonlinearity test, we show that nonlinear dynamics varies with time scale and the type of cardiac dysfunction. Moreover, as complexity metrics and nonlinearities provide complementary information, we strongly recommend using the test for nonlinearity as an additional index to characterize HRV.

To evaluate the gene expression of collagen, matrix metalloproteinases (MMPs) and inhibitors, cholinergic muscarinic receptors (CHRMs), and angiogenic and nerve growth factors (NGFs) in the bladder of patients with bladder outlet obstruction caused by benign prostatic hyperplasia (BPH).We analyzed bladder specimens from 43 patients with obstructive BPH undergoing transurethral resection of the prostate as compared to 10 age-matched controls with an International Prostatic Symptom Score of8 and a prostate volume of30 g. A bladder biopsy was performed for relative gene expression analysis with quantitative real-time polymerase chain reaction of collagens I and III, MMP-1, MMP-2, and MMP-9; tissue inhibitors of metalloproteinases (TIMPs) TIMP-1, TIMP-2, and reversion-inducing cysteine-rich protein with kazal motifs (RECK); CHRM2 and CHRM3; VEGF and CD105; and NGF and nerve growth factor receptor (NGFr).Patients with bladder outlet obstruction presented a statistically significant overexpression of collagens I and III, VEGF, CHRM2, and CHRM3. CD105, MMP-9, and TIMP-1 were underexpressed. Expressions of NGF, NGFr, MMP-1, MMP-2, TIMP-2, and RECK were heterogeneous. CHRM2 and CHRM3 were overexpressed in patients with persistent detrusor overactivity. Smokers presented an upregulation of NGFr and VEGF; dyslipidemic patients had an overexpression of NGFr.Bladder upregulation of collagens I and III on transcriptional level appears to be relevant in BPH. Muscarinic receptors CHRM2 and CHRM3 are also overexpressed, more so in patients with persistent detrusor overactivity. Upregulation of VEGF and NGFr, particularly in subjects with risk factors for atherosclerosis, reinforces the role of ischemia in BPH-induced modifications of the bladder.

Air pollution is known to exacerbate respiratory diseases and epidemiological studies have shown that women present more chronic respiratory symptoms than man exposed to traffic pollution, however, the reason why is unclear. This study evaluated the inflammatory differences in BALB/c mouse males (n=34) and females (n=111) in three phases of the estrous cycle that were exposed to ambient air (AA) or concentrated ambient particles (CAPs). Tracheal hyperreactivity to methacholine, bronchoalveolar lavage fluid (BALF) and immunohistochemical of airways and lung parenchyma were studied. Hyperreactivity increased in CAPs-exposed female mice compared with AA-exposed mice in estrus (p

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2021-11-04T13:57:20Z No. of bitstreams: 1 Eliane Martins Amadio.pdf: 2834140 bytes, checksum: be06d272762bb06059a06a9c2e0a6cd9 (MD5) Made available in DSpace on 2021-11-04T13:57:20Z (GMT). No. of bitstreams: 1 Eliane Martins Amadio.pdf: 2834140 bytes, checksum: be06d272762bb06059a06a9c2e0a6cd9 (MD5) Previous issue date: 2019-06-27 Photobiomodulation therapy (PBMT) has been indicated for wound healing through increased mitotic activity, number of fibroblasts, collagen synthesis and neovascularization; however, in unfavorable conditions such as protein malnutrition, photobiomodulation has not yet been fully studied. In view of the above, this study aimed to verify the effects of PBMT on healing in the proliferation phase in rats submitted to a hypoproteic diet. For this purpose 40 male rats (12 weeks) were used, of which 20 were normoproteic (25%) and 20 were submitted to 8% hypoproteic diet. The animals were divided into four experimental groups (n = 10) and submitted to cutaneous wound by means of 8 mm punch and treated by low intensity laser photobiomodulation (660 nm, 50 mW, 1.07 W / cm2, 0.028 cm2, 72 J / cm2, 2 J). The following analyzes were performed at the 7 and 14 days of the tissue repair process: semi-quantitative histopathological analysis (H&E), differentiation of the type I and III collagen I percentage by polarization of histological laminae stained with picrosirus red and labeling by immunohistochemistry of MMP- 3, MMP- 9 fibronectin and VEGF and test of mechanical resistance in machine universal test. . The results showed that there were significant differences between the normoproteic groups with lesion and their respective groups treated p

Introdução: A fotobiomodulação (FBM) vem sendo amplamente descrita na literatura com excelentes resultados que envolvem resolução de processos inflamatórios, alívios álgicos e reparos teciduais. Por possuir atuação nos sistemas biológicos de maneira atérmica, indolor e de baixo custo tem sido alvo de diversas pesquisas experimentais e clínicas, visando um maior esclarecimento de seus efeitos e um aumento de sua aplicabilidade clínica. Entretanto, pouco se conhece sobre possíveis efeitos adversos e respostas celulares indesejadas. Assim como os medicamentos possuem descrições de seus efeitos adversos, torna-se importante também o conhecimento desses possíveis efeitos na fototerapia. Objetivo: O presente trabalho teve como objetivo avaliar os níveis de mRNA de metaloproteinases-2, -9 e -13, bem como seu regulador (TIM-2) e expressão das proteínas MMP-13 e TIMP-2 em tecidos saudáveis presentes na articulação talocrural de camundongos após FBM. Métodos: Os animais foram distribuídos em 3 grupos (n=6): controle, 3J/cm-2 e 30J/cm-2. Os parâmetros do laser de baixa potência foram: 830 nm, 10 mW, 0,05 de área irradiada, doses de 3J/cm-2 e 30J/cm-2, tempo de irradiação de 15 e 150 segundos, respectivamente e emissão da luz em modo contínuo. As articulações foram irradiadas por 4 dias consecutivos, uma vez ao dia. Após a eutanásia, as articulações foram encaminhadas para dosagem dos níveis de mRNA de metaloproteinases (MMP-2, MMP-9, MMP-13) e seu regulador (TIMP-2), através de real time PCR e para imunocitoquímica de MMP-13 e TIMP-2. Resultados: Um aumento nos níveis relativos de mRNA para MMP-2 (p0,05). Com relação à expressão proteica, a MMP-13 apresentou marcação positiva e apenas nos condrócitos nas cartilagens articulares, embora sem diferença estatística (p>0,05). Já TIMP-2 não obteve marcação positiva em nenhum dos tecidos avaliados. Conclusão: Com isso, nossos resultados indicam que a PBM foi capaz de regular os níveis relativos de mRNA para MMP-2, mas não regular a expressão protéica de MMP-13 e TIMP-2 e essa regulação foi diretamente dependente da dose testada. Introduction: Photobiomodulation (PBM) has been widely described in the literature with excellent results involving resolution of inflammatory processes, pain relief and tissue repair. PBM has been applied in several experimental and clinical researches due to low cost, athermic effect and painless. However, it is not known about possible side-effects and unwanted cellular responses. Since anti-inflammatory drugs have elucidations about their side-effects, it is also important to know about these possible side-effects in phototherapy. Objective: The aim of this study was to evaluate the metalloproteinase-2, -9 and -13 mRNA relative levels as well as its regulator (TIM-2) and protein expressions of MMP-13 and TIMP- 2 in healthy tissues present in mice talocrural joint after PBM. Methods: Animals were divided into 3 groups (n = 6): control, 3Jcm-2 e 30Jcm-2. Low –level laser parameters were: 830 nm, 10 mW, 0.05 irradiated area, doses of 3Jcm-2 and 30Jcm-2, 15 and 150 seconds of irradiation, respectively, and continuous mode. The joints were irradiated for 4 consecutive days once a day. After euthanasia, the left joints were dissected and RNA extracted to quantify metalloproteinases mRNA levels (MMP-2, MMP-9, MMP-13) and its regulator (TIMP-2) by real time PCR. Right joints were dissected to immunocytochemestry analysis for MMP-13 and TIMP-2. Results: An increase in MMP-2 mRNA relative levels was observed at 30Jcm-2 group (p 0.05). Regarding protein expressions, MMP-13 demonstrated positive labeled cells, but only in chondrocytes from articular cartilages, although the cell quantification has not demonstrated statistical differences when compared with control group (p> 0.05). TIMP-2 did not present positive labeled cells for any tissues evaluated. Conclusion: Our results indicate that PBM was able to regulate mRNA levels for MMP-2, but it was not able to regulate MMP-13 and TIMP-2 proteins and this regulation was dose-dependent.

Submitted by Kalina CB/A (kalikros2@gmail.com) on 2021-12-13T17:45:47Z No. of bitstreams: 1 Dissertação - Aline de Almeida Azevedo - 2019 - Completa.pdf: 3559147 bytes, checksum: 197f713c8b3a9199df77794729805aa0 (MD5) Made available in DSpace on 2021-12-13T17:45:47Z (GMT). No. of bitstreams: 1 Dissertação - Aline de Almeida Azevedo - 2019 - Completa.pdf: 3559147 bytes, checksum: 197f713c8b3a9199df77794729805aa0 (MD5) Previous issue date: 2019-03-25 Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq Renovascular hypertension (RH) is caused by partial occlusion of the renal artery promoting renal ischemia and subsequent activation of the renin-angiotensin-aldosterone system (RAAS), a starting point for systemic arterial hypertension. RH is a progressive disease that, when untreated, leads to chronic kidney disease (CKD). Currently, there is no specific treatment in the advanced stages of the disease, since the only alternative is dialysis and/or renal transplantation. However, due to high cost of dialysis treatments and to the lack of available organs for transplantation, there is an imminent need for the development of new therapies. Mesenchymal stem cells (MSC) are excellent candidates for cell therapy because of their ability to reduce renal damage, through the synthesis and release of cytokines and growth factors, preserving renal function. However, it is necessary to elucidate the renal parenchyma remodeling through the epithelial-mesenchymal transition (EMT) in the presence of mesenchymal stem cells. The main objective of this work was to evaluate the effects of bone marrow MSC transplantation on the expression balance of metalloproteinases -2 and -9 and the inhibitors of tissue metalloproteinases -1 and -2 (TIMP) in the left kidney of rats with RH induced by 2 kidney- 1clip model (clipping of left renal artery – 2K1C). It was also analyzed morphological and functional alterations, basal membrane integrity, TNF-α (tumor necrosis factor alpha) and TGF-β (transforming growth factor beta) contents and tissue expression of CD68 (macrophage), IL-10 (interleukin), and α-SMA (smooth muscle alpha-actin). Male Wistar rats (n = 18) were divided into three groups: Sham, 2K1C and 2K1C+MSC (received transplantation after 4 weeks of clipping surgery). After 2 weeks of transplantation (week 6) the animals were euthanized and the kidneys were collected and processed for microscopy and western blotting. The 2K1C animals presented hypertension, with increased urea, creatinine and proteinuria, while there was a reduction of total serum proteins. The kidneys of these animals showed increased fibrosis, a basement membrane disruption, increased MMP-2 and -9, TNF-α and TGF-β expression, and increased CD68, α-SMA and TNF-α staining. After 15 days of MSC transplantation, the animals showed reduction of blood pressure, urea and proteinuria, and serum proteins normalization, showing that the therapy promoted renal function reestablishment. In addition, MSC transplantation reduced the renal content of MMP-2 and -9, and TGF-β, and the α-SMA staining, while increased TIMP-1 and -2 content, contributing to basal membrane restoration, reduction of fibrosis by TEM, and renal glomeruli and tubules restoration. We also observed reduction of TNF-α expression and staining, reduction of CD68 staining, and increase of IL-10 staining. These results suggest that MSC transplantation was able to improve morphological and functional aspects caused by RH, promoting an immunomodulatory effect and renal parenchyma remodeling, preventing the progression of fibrosis through TEM in an experimental model of CKD. A hipertensão renovascular (HR) é causada pela oclusão parcial da artéria renal, promovendo isquemia renal, e subsequente ativação do sistema renina-angiotensina-aldosterona (SRAA), um ponto de partida para hipertensão arterial sistêmica. A HR é uma doença progressiva e, quando não tratada, leva à doença renal crônica (DRC). No momento, não existe tratamento específico nas fases avançadas da doença, pois a única alternativa é a diálise e/ou transplante renal. Mas, devido ao alto custo dos tratamentos de diálise e à carência de órgãos disponíveis para o transplante, existe a necessidade iminente do desenvolvimento de novas terapias. As células-tronco mesenquimais (CTM) são excelentes candidatas para a terapia celular pela sua capacidade de reduzir a lesão renal, por meio da síntese e liberação de citocinas e fatores de crescimento, preservando a função renal. Porém, é necessário elucidar o remodelamento do parênquima renal através da transição epitélio-mesenquimal (TEM) na presença das CTM. O objetivo principal deste trabalho foi avaliar os efeitos do transplante de CTM sobre o equilíbrio da expressão de metaloproteinases -2 e -9 e dos inibidores de metaloproteinases-1 e -2 (TIMP) no rim esquerdo de ratos com HR induzida pelo modelo 2 rins 1 clipe (clipagem na artéria renal esquerda - 2R1C). Também foram analisadas as alterações morfológicas e funcionais, a integridade da membrana basal, os conteúdos de TNF-α (fator de necrose tumoral alfa) e TGF-β (fator de crescimento transformante beta) e a expressão tecidual de CD68 (macrófago), IL-10 (interleucina), e α-SMA (alfa actina de músculo liso). Ratos machos Wistar (n=18) foram divididos em três grupos: Sham, 2R1C e 2R1C+CTM (receberam transplante após 4 semanas da cirurgia de clipagem). Após 2 semanas do transplante (semana 6) os animais foram eutanasiados e os rins foram coletados e processados para microscopia de luz e western blotting. Os animais 2R1C apresentaram hipertensão arterial, com aumento de ureia, creatinina e proteinúria, enquanto houve redução de proteínas totais séricas. Os rins desses animais apresentaram fibrose, desestruturação da membrana basal, aumento do conteúdo de MMP-2 e -9, TNF-α e TGF-β e aumento da marcação de CD68, α-SMA e TNF-α. Após 15 dias de transplante de CTM os animais apresentaram redução na pressão arterial, da ureia e proteinúria e normalização de proteínas séricas, mostrando que a terapia promoveu restabelecimento da função renal. Além disso, o transplante de CTM reduziu o conteúdo renal de MMP-2 e -9, TGF-β e da marcação para α-SMA, enquanto aumentou o conteúdo de TIMP-1 e -2, contribuindo para restauração da membrana basal, redução da fibrose pela TEM, e restauração dos glomérulos e túbulos renais. Também observamos redução da expressão e marcação do TNF-α, redução da marcação de CD68 e aumento de IL-10. Estes resultados sugerem que o transplante de CTM foi capaz de melhorar aspectos morfológicos e funcionais causados pela HR, promovendo um efeito imunomodulador e o remodelamento do parênquima renal, impedindo a progressão da fibrose através da TEM em modelo experimental de DRC.

Conselho Nacional de Desenvolvimento Científico e Tecnológico O objetivo neste estudo foi quantificar e verificar o percentual de solubilidade do colágeno intramuscular (IMC), que possa modificar a qualidade da carne de bovinos Nelore castrados e não castrados abatidos aos 9, 13 e 16 meses. Além de investigar se possíveis diferenças na expressão dos genes fibrogênicos e dos marcadores da remodelação do colágeno estariam associadas a diferenças no conteúdo, na solubilidade e nos tipos de IMC. Foram utilizados trinta e seis bezerros Nelore (Bos taurus indicus), sendo a metade aleatoriamente selecionada para a castração cirúrgica uma semana antes do desmame. Os bovinos foram confinados e submetidos às mesmas condições experimentais, e seis animais de cada classe sexual foram distribuídos aleatoriamente para serem abatidos quando a média da idade atingisse 9,3 ± 0,09, 12,6 ± 0,05 e 15,7 ± 0,07 meses. Este estudo foi realizado seguindo delineamento inteiramente casualizado em esquema fatorial com 2 condições sexuais (castrado vs. não castrado) e 3 idades de abate (9, 13 e 16 meses). O conteúdo de colágeno total não diferiu entre os tratamentos e também não foram encontradas interações (P > 0,201). Os bovinos não castrados apresentaram maior porcentagem de colágeno solúvel (P = 0,034) que os castrados, porém não foram encontradas diferenças entre as idades (P = 0,187), e também não foram encontradas interações (P = 0,640). O percentual de área do colágeno tipo 1 (COL 1) não diferiu entre os tratamentos e também não foram encontradas interações (P > 0,239). Foram encontradas interações (P = 0,023) entre idade e sexo, onde novilhos abatidos aos 16 meses apresentaram menor percentual de área de colágeno tipo 3 (COL 3) e não foram encontrados efeitos nas classes sexuais (P = 0,400) e nas idades (P = 0,107). Foram encontradas interações (P = 0,049) entre idade e sexo, onde novilhos abatidos aos 16 meses apresentaram menor proporção de área de COL 3 e não foram encontrados efeitos nas classes sexuais (P = 0,400) e nas idades (P = 0,180). Não foram encontradas diferenças entre os genes fibrogênicos e dos genes marcadores da remodelação do colágeno, e também não foram encontradas interações (P > 0,220). Os resultados indicam que a expressão foi constante não interferindo as classes sexuais de animais castrados e não castrados nas idades avaliadas. Conclui-se que como os animais não castrados apresentaram maior percentual de colágeno solúvel, possivelmente devido ao maior remodelamento da matriz extracelular estimulado pela hipertrofia das fibras musculares, implicando na continuidade do crescimento muscular nessa condição sexual. A redução do percentual e da proporção de área do COL 3 pode estar associada ao menor turnover do perimísio em novilhos castrados Nelore aos 15 meses indicando estabilização do crescimento muscular. The objective of this study was to quantify and verify the percentage of solubility of intramuscular collagen (IMC), which could modify the quality of the meat of castrated and uncastrated Nelore cattle slaughtered at 9, 13 and 16 months. In addition to investigating whether possible differences in the expression of fibrogenic genes and of collagen markers remodeling would be associated with differences in content, solubility and IMC types. Thirty- six Nelore calves (Bos taurus indicus) were used, half of which were randomly selected for surgical castration one week before weaning. Animals were confined and submitted to the same experimental conditions, and six animals of each sex class were randomly assigned to slaughter when the mean age reached 9.3 ± 0.09, 12.6 ± 0.05 and 15.7 ± 0.07 months. This study was carried out in a completely randomized design in a factorial scheme with 2 sexual conditions (castrated vs. uncastrated) and 3 slaughter ages (9, 13 and 16 months). Total collagen content did not differ across treatments and no interactions were found (P> 0.201). However, no differences were found among the ages (P = 0.187) and no interactions were found (P = 0.640). The percentage of collagen type 1 (COL 1) did not differ between treatments and no interactions were found (P> 0.239). There were interactions (P = 0.023) between age and sex, where steers slaughtered at 16 months presented lower percentage of collagen type 3 (COL 3) and no effects were found for sex (P = 0.400) and ages (P = 0.107). There were interactions (P = 0.049) between age and sex, where steers slaughtered at 16 months presented a lower proportion of COL 3 area and no effects were found for sex classes (P = 0.400) and ages (P = 0.180). No differences were found among fibrogenic genes and marker genes for collagen remodeling, and no interactions were found (P> 0.220). The results indicate that expression was constant independent of sexual classes of castrated and uncastrated in the evaluated ages. It can be concluded that as the uncastrated presented a higher percentage of soluble collagen, possibly due to the greater remodeling of the extracellular matrix stimulated by the hypertrophy of the muscular fibers, it implies with the continuity of the muscular growth in this sexual condition. The reduction of the percentage and proportion of the area of COL 3 may be associated to the lower turnover of perimysium in Nellore steers at 15 months indicating stabilization of muscle growth.

Made available in DSpace on 2019-10-06T16:49:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-04-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Introduction: Preeclampsia affects 3–5% of pregnancies worldwide and is the primary cause of maternal-fetal and neonatal mortality. Previous studies show that alterations in maternal concentrations of angiogenic factors, such as PlGF, PDGF AA, ANG-1, and ANG-2, may play fundamental roles in the pathophysiology of the disease. Objective: Determine whether the PlGF, PDGF AA, ANG-1, and ANG-2 are predictors of preeclampsia occurrence in a prenatal cohort study. Patients and methods: This is a case-control study associated with a prospective cohort of pregnant women, with gestational ages between 20 and 25 weeks, composed of 30 pregnant women with preeclampsia (PE) and 90 healthy pregnant women (HP). The plasma concentrations of the markers were determined using the ELISA method. The comparison between the case and control groups was performed using the t test on the SAS® 9.4 software. Also, ROC curves were constructed to evaluate the predictive potential of the biomarkers. Results: Differences in the concentrations of PlGF, PDGF AA, ANG-1 and ANG-2, and the ANG-1/ANG-2 ratio were not observed between the PE and the HP groups. The predictive capacity of the biomarkers was assessed using ROC curves, in which the area under the curve for PlGF AUC = 0.55; PDGF AA AUC = 0.55; ANG-1 AUC = 0.47; ANG-2 AUC = 0.51, and the ANG-1/ANG-2 ratio AUC = 0.57. Conclusion: In pregnant women, with gestational ages between 20 and 25 weeks significant differences in biomarker concentrations between groups PE and HP were not observed. The ROC curves showed that the biomarkers were ineffective as preeclampsia predictors in the analyzed cohort. Department of Gynecology and Obstetrics Ribeirão Preto Medical School University of São Paulo, 3900 Bandeirantes Avenue Department of Health Sciences Ribeirão Preto Medical School University of São Paulo, 3900 Bandeirantes Avenue Department of Pharmacology Biosciences Institute State University of São Paulo (UNESP) Department of Childcare and Pediatrics Ribeirão Preto Medical School University of São Paulo, 3900 Bandeirantes Avenue Department of Pharmacology Biosciences Institute State University of São Paulo (UNESP) FAPESP: FAPESP

Submitted by REGINA APARECIDA DO NASCIMENTO (apnascimentofarma@hotmail.com) on 2019-01-11T12:20:18Z No. of bitstreams: 1 TESE COMPLETA -Regina.pdf: 3365859 bytes, checksum: 845a0bc96844ad6afc3de3847007ec6e (MD5) Approved for entry into archive by Luciana Pizzani null (luciana@btu.unesp.br) on 2019-01-14T11:49:12Z (GMT) No. of bitstreams: 1 ferro_bs_me_bot_par.pdf: 365777 bytes, checksum: 8e0fd3a5377fc68a4e733844981a46f8 (MD5) Made available in DSpace on 2019-01-14T11:49:12Z (GMT). No. of bitstreams: 1 ferro_bs_me_bot_par.pdf: 365777 bytes, checksum: 8e0fd3a5377fc68a4e733844981a46f8 (MD5) Previous issue date: 2018-12-05 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) O óxido nítrico (NO) é um gás produzido principalmente por células endoteliais, e durante a época gestacional, contribui para evitar aumento exacerbado da resistência vascular sistêmica (RVS), uma vez que, durante esse período, aumenta-se o volume sanguíneo e a frequência cardíaca. Quando, há disfunções endoteliais, reduz-se a biodisponibilidade de NO, provocando vasoconstrição e esta, por sua vez, consequentemente aumenta atividade das MMPs. Essa queda do NO e aumento das MMPs culminam em desordens hipertensivas gestacionais. Segundo estudos anteriores realizados em modelos de hipertensão em machos a doxiciclina, um antibiótico derivado das tetraciclinas, diminuiu a pressão arterial sistólica devido a sua capacidade de inibir a atividade das MMPs. No entanto, há escassez de trabalhos que desenvolveram estudos sobre os efeitos da doxicicilina em modelos animais de hipertensão gestacional. Por esse motivo, investigamos os efeitos da doxiciclina na inibição das MMPs na hipertensão gestacional, induzida pelo Nω-nitro-L-arginina-metil éster (LNAME) em ratas. Para tanto, realizamos zimografia para avaliar a atividade da MMP-2 e -9 na placenta, no útero e na aorta torácica. Ainda avaliamos a pressão arterial sistólica, o desenvolvimento feto-placentário e os metabólitos do NO. Também foi avaliada a capacidade antioxidante plasmática, os níveis plasmáticos de soluble fms-like tyrosine kinase-1 (sFlt-1) e o fator de crescimento placentário (PLGF). Nossos dados mostram que o tratamento com LNAME aumentou a pressão arterial e diminuiu a prole destes animais. Por outro lado, a doxiciclina preveniu a hipertensão gestacional induzida por L-NAME sem afetar a prole. Observou-se também uma diminuição da biodisponibilidade de NO em ratas hipertensas. O tratamento com doxiciclina atenuou o aumento da atividade da MMP-2 e -9, provocados pela hipertensão induzida por L-NAME. Concomitantemente, a doxiciclina restaurou o equilíbrio angiogênico por meio do aumento dos níveis de PLGF e redução dos níveis de sFlt-1. A doxiciclina também aumentou a capacidade antioxidante do plasma nas ratas hipertensas. Por causa disso, compreendemos que o aumento da atividade da MMP-2 e -9 deveu-se a uma redução do NO, causada pelo tratamento com L-NAME. Cabe ressaltar que o aumento da ativação de MMPs e o desequilíbrio angiogênico causados pelo modelo de hipertensão gestacional induzido por L-NAME estão associados ao aumento da pressão arterial sistólica, enquanto a doxiciclina restabeleceu todos esses parâmetros. Visto a importância do NO durante a gestação saudável, quanto durante a gestação hipertensiva devido a sua diminuição, realizamos um segundo estudo, em que avaliamos a atividade de MMP-2 e -9 em três diferentes períodos gestacionais: inicial (Early), intermediário (Mid) e tardio (Late). Nesse segundo estudo, observamos que a pressão arterial sistólica apresentou-se elevada nos três períodos gestacionais propostos, evidenciando-se principalmente nos dois últimos períodos (intermediário e tardio) em ratas hipertensas. Paralelamente, nesse mesmo grupo de animais, os níveis de NO plasmático apresentaram-se insuficientes, principalmente nos períodos gestacionais intermediário e tardio, em que há uma maior demanda de NO. Além disso, os parâmetros feto-placentários foram comprometidos em ratas hipertensas. Os níveis plasmáticos de malondialdeído e a atividade da MMP-2 e -9 apresentaram aumentos ao longo dos períodos gestacionais previamente adotados em ratas hipertensas. Em suma, os dados apresentados tanto no primeiro quanto no segundo estudo sugerem que o processo gestacional por si requer uma maior biodisponibilidade de NO e atuação do NO na modulação da atividade das MMPs ao longo da gestação, sendo essa demanda maior nos períodos finais da gestação. Nitric oxide (NO) is a gas produced mainly by endothelial cells, and during the gestational period contributes to avoid an exacerbated increase in systemic vascular resistance (SVR), since during this period, there is a rise in blood volume and heart rate. When there are endothelial dysfunctions, the bioavailability of NO is reduced, causing vasoconstriction and this, in turn, consequently increases the activity of MMPs. This decrease in NO and increase in MMPs culminates in gestational hypertensive disorders. According to previous studies in non-gestational hypertension models, doxycycline, an antibiotic derived from tetracyclines, lowered systolic blood pressure due to its ability to inhibit MMP activity. However, there is a shortage of works that have developed studies on the effects of doxycycline in animal models of gestational hypertension. For this reason, we investigated the effects of doxycycline on the inhibition of MMPs in gestational hypertension, induced by Nω-nitro-L-arginine-methyl ester (L-NAME) in rats. We performed a zymography to evaluate the activity of MMP-2 and -9 in the placenta, uterus and thoracic aorta. We also evaluated systolic blood pressure, fetalplacental development and NO metabolites. Plasma antioxidant capacity, plasma levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PLGF) were also evaluated. Our data shows that the treatment with L-NAME increased blood pressure and decreased the offspring of these animals. On the other hand, doxycycline prevented LNAME-induced gestational hypertension and the reduction of offspring. A decrease in NO bioavailability in hypertensive rats was also observed. Treatment with doxycycline attenuated the increased activity of MMP-2 and -9, caused by L-NAME-induced hypertension. Concomitantly, doxycycline restored the angiogenic balance by increasing PLGF levels and reducing levels of sFlt-1. Doxycycline also increased plasma antioxidant capacity in hypertensive rats. For this reason, we understand that the increased activity of MMP-2 and -9 was due to a reduction of NO caused by the treatment with L-NAME. It should be noted that the increase in MMP activation and angiogenic imbalance caused by the L-NAME-induced gestational hypertension model are associated with increased systolic blood pressure, while doxycycline reestablished all of these parameters. Considering the importance of NO during a healthy gestation and during a hypertensive pregnancy due to its decrease, we performed a second study, in which we evaluated the activity of MMP-2 and -9 in three different gestational periods: initial, intermediate and late. In this second study, we observed that systolic blood pressure was elevated in the three proposed gestational periods, evidencing mainly in the last two periods (intermediate and late) in hypertensive rats. At the same time, in this same group of animals, plasma NO levels were insufficient, especially in the intermediate and late gestational periods, where there is a greater demand for NO. In addition, the fetal-placental parameters were compromised in hypertensive rats. Plasma levels of malondialdehyde and MMP-2 and -9 activity increased gradually over the gestational periods previously adopted in hypertensive rats. In summary, the data presented in both the first and second studies suggests that the gestational process itself requires a greater bioavailability of NO, and NO action in the modulation of the MMP activity during pregnancy, being this demand is greater in the final periods of gestation. 16/18782-3