The study of Yangyinyiqi mixture anti bleomycin-induced pulmonary fibrosis on rats by intervening matrix metalloproteinase-9 and tissue inhibitors of matrix metallopreoteinases-1 / El estudio de la mezcla Yangyinyiqi en fibrosis pulmonar inducida por anti-bleomicina en ratas por intervención en la matriz metaloproteinasa-9 e inhibidores de tejido de matriz metaloproteinasa-1

To investigate effectsof Yangyinyiqi Mixture on pulmonary fibrosis caused by bleomycin. SD ratswere divided randomly into: model group(distilled water,1 mL·0.1 kg-1), dexamethasone acetate group (dexamethasone acetate, the dosage was reduced gradually), low-dose group (Yangyinyiqi Mixture, 11 g·kg-1), moderate-dose group (Yangyinyiqi Mixture, 22 g·kg-1), high-dose group (Yangyinyiqi Mixture, 44 g·kg-1) and control group (distilled water, 1 mL·0.1 kg-1). Yangyinyiqi Mixture and dexamethasone acetate were intragastrically administrated. Lung tissue was collected for histopathological examination. Compared with control group, collagen markedly increased and HYP content significantly increased on 7th day in model group (p<0.01). On 28th day, collagen was diffusely deposited, alveolar was destroyed, and HYP content significantly increased (p<0.01). Compared with model group, bleomycin-induced suffering injury caused MMP-9 expression levels to rapidly increase (7and 14 days, p<0.01). TIMP-1 markedly increased (7and 14 days, p<0.01) and stayed at a high level to28th day. Yangyinyiqi Mixture exerted an effect against pulmonary fibrosis, which could involved prevention of collagen deposition through inhibitingMMP-9 and TIMP-1 expression.

El trabajo investiga los efectos de la mezcla Yangyinyiqi sobre la fibrosis pulmonary causada por bleomicina. Ratas SD se dividieron aleatoriamente en: grupo modelo (agua destilada, 1 mL·0.1 kg-1), grupo acetate de dexametasona (acetate de dexametasona, la dosis se redujo gradualmente), grupo de dosis baja (mezcla Yangyinyiqi, 11 g·kg-1), grupo de dosis moderada (mezcla Yangyinyiqi, 22 g·kg-1), grupo de dosis alta (mezcla Yangyinyiqi, 44 g·kg-1) y grupo control (agua destilada, 1 Ml·0.1 kg-1). La mezcla de Yangyinyiqi y el acetate de dexametasona se administraron por vía intragástrica. Se recolectó tejido pulmonary para examen histopatológico. En comparación con el grupo control, el colágeno aumentó notablemente y el contenido de HYP aumentó significativamente el séptimo día en el grupo modelo (p<0.01). El día 28, el colágeno se depositó difusamente, se produjo destrucción alveolar y el contenido de HYP aumento significativamente (p<0.01). En comparación con el grupo modelo, la lesión inducida por bleomicina causó que los niveles de expression de MMP-9 aumentaron rápidamente (7 y 14 días, p<0.01). TIMP-1 aumentó notablemente (7 y 14 días, p<0.01) y se mantuvo en un nivel alto hasta el día 28. La mezcla Yangyinyiqi ejerció un efecto contra la fibrosis pulmonary, lo que podría implicar la prevención del deposito de colágenio mediante la inhibición de la expression de MMP-9 y TIMP-1.

The Identification of Immune-Related Plasma Proteins Associated with Spontaneous Preterm Delivery and Intra-Amniotic Infection in Women with Premature Cervical Dilation or an Asymptomatic Short Cervix

BACKGROUND: We aimed to investigate whether various immune-related plasma proteins, alone or in combination with conventional clinical risk factors, can predict spontaneous preterm delivery (SPTD) and intra-amniotic infection in women with premature cervical dilation or a short cervix (≤ 25 mm).METHODS: This retrospective study included 80 asymptomatic women with premature cervical dilation (n = 50) or a short cervix (n = 30), who underwent amniocentesis at 17–29 weeks. Amniotic fluid (AF) was cultured, and maternal plasma was assayed for interleukin (IL)-6, matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and complements C3a and C5a, using enzyme-linked immunosorbent assay (ELISA) kits. The primary outcome measures were SPTD at < 32 weeks and positive AF cultures.RESULTS: The plasma levels of IL-6, C3a, and C5a, but not of MMP-9 and TIMP-1, were significantly higher in women with SPTD at < 32 weeks than in those who delivered at ≥ 32 weeks. The women who delivered at < 32 weeks had more advanced cervical dilatation, and higher rates of antibiotic and tocolytic administration and were less likely to be given vaginal progesterone than those who delivered at ≥ 32 weeks. Using a stepwise regression analysis, a combined prediction model was developed, which included the plasma IL-6 and C3a levels, and cervical dilatation (area under the curve [AUC], 0.901). The AUC for this model was significantly greater than that for any single variable included in the predictive model. In the univariate analysis, plasma IL-6 level was the only significant predictor of intra-amniotic infection.CONCLUSION: In women with premature cervical dilation or a short cervix, maternal plasma IL-6, C3a, and C5a levels could be useful non-invasive predictors of SPTD at < 32 weeks. A combination of these biomarkers and conventional clinical factors may clearly improve the predictability for SPTD, as compared with the biomarkers alone. An increased plasma level of IL-6 predicted intra-amniotic infection.

Comparison of Corticosteroids by 3 Approaches to the Treatment of Chronic Rhinosinusitis With Nasal Polyps

PURPOSE: Corticosteroids are regarded as the mainstay of medical treatment of eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP). To date, a head-to-head comparison of the efficacy and safety of glucocorticoid preparations administered via different routes for the treatment of chronic rhinosinusitis with nasal polyps has not been reported. To compare the efficacy and safety of steroids administered via the oral, intranasal spray and transnasal nebulization routes in the management of ECRSwNP over a short course. METHODS: Overall, 91 patients with ECRSwNP were recruited prospectively and randomized to receive either oral methylprednisolone, budesonide inhalation suspension (BIS) via transnasal nebulization, or budesonide nasal spray (BNS) for 2 weeks. Nasal symptoms and polyp sizes were assessed before and after the treatment. Similarly, nasal polyp samples were evaluated for immunological and tissue remodeling markers. Serum cortisol levels were assessed as a safety outcome. RESULTS: Oral methylprednisolone and BIS decreased symptoms and polyp sizes to a significantly greater extent from baseline (P < 0.05) than BNS. Similarly, BIS and oral methylprednisolone significantly reduced eosinophils, T helper 2 cells, eosinophil cationic protein, interleukin (IL)-5, and expression of matrix metalloproteinases 2 and 9, and significantly increased type 1 regulatory T cells, IL-10, transforming growth factor-β, and tissue inhibitor of metalloproteinases 1 and 2 in nasal polyps to a greater extent than BNS. Post-treatment serum cortisol levels were significantly decreased by oral methylprednisolone compared to BIS or BNS, which did not significantly alter the cortisol levels. CONCLUSIONS: A short course of BIS transnasal nebulization is more efficacious compared to BNS in the management of ECRSwNP and is safer than oral methylprednisolone with respect to hypothalamic-pituitary-adrenal axis function.

Updating the role of matrix metalloproteinases in mineralized tissue and related diseases

Abstract Bone development and healing processes involve a complex cascade of biological events requiring well-orchestrated synergism with bone cells, growth factors, and other trophic signaling molecules and cellular structures. Beyond health processes, MMPs play several key roles in the installation of heart and blood vessel related diseases and cancer, ranging from accelerating metastatic cells to ectopic vascular mineralization by smooth muscle cells in complementary manner. The tissue inhibitors of MMPs (TIMPs) have an important role in controlling proteolysis. Paired with the post-transcriptional efficiency of specific miRNAs, they modulate MMP performance. If druggable, these molecules are suggested to be a platform for development of "smart" medications and further clinical trials. Thus, considering the pleiotropic effect of MMPs on mammals, the purpose of this review is to update the role of those multifaceted proteases in mineralized tissues in health, such as bone, and pathophysiological disorders, such as ectopic vascular calcification and cancer.

Circulating Tissue Inhibitor of Metalloproteinase-4 levels are not a Predictor of Preeclampsia in the period between 20 and 25 Weeks of Gestation / Níveis circulantes de inibidor tecidual da metaloproteinase tipo-4 não são um preditor de preeclampsia no período entre 20 e 25 semanas de gestação

Abstract Objective To evaluate whether the circulating level of tissue inhibitor of metalloproteinase- 4 (TIMP-4) in the period between 20 and 25 weeks of gestation is a predictor of preeclampsia. Methods We have performed a case-control study, nested in a prospective study cohort in Ribeirão Preto, in the state of São Paulo, Brazil. Of the 1,400 pregnant women evaluated between 20 and 25 weeks of gestation, 460 delivered in hospitals outside of our institution. Of the 940 pregnant women who completed the protocol, 30 developed preeclampsia. Healthy pregnant women (controls, n = 90) were randomly selected from the remaining 910 participants. From blood samples collected between 20 and 25 weeks of gestation, we performed a screening of 55 angiogenesis-related proteins in 4 cases and 4 controls. The protein TIMP-4 was the most differentially expressed between cases and controls. Therefore, wemeasured this protein in all cases (n = 30) and controls selected (n = 90). Results There were no differences in the plasma TIMP-4 levels of cases compared with controls (1,144 263 versus 1,160 362 pg/mL, respectively; p > 0.05). Conclusion Plasma TIMP-4 levels were not altered at 20 to 25 weeks of gestation, before the manifestation of clinical symptoms; therefore, they are not good predictors of the development of preeclampsia.

Resumo Objetivo Avaliar se o nível de inibidor tecidual de metaloproteinases tipo-4 (TIMP-4, na sigla em inglês) circulante no período entre 20 e 25 semanas de gestação é um preditor de preeclâmpsia. Métodos Foi realizado um estudo caso-controle aninhado em uma coorte de estudo prospectivo em Ribeirão Preto, São Paulo, Brasil. De 1.400 mulheres grávidas avaliadas entre 20 e 25 semanas de gestação, 460 tiveram parto em hospitais fora da nossa instituição. Das 940 gestantes que completaram o protocolo, 30 desenvolveram preeclâmpsia. Gestantes saudáveis (controles, n = 90) foram selecionadas aleatoriamente das 910 participantes restantes. A partir de amostras de sangue coletadas entre 20 e 25 semanas de gestação, foi realizada uma triagem de 55 proteínas relacionadas à angiogênese em 4 casos e 4 controles. A proteína TIMP-4 foi a mais diferentemente expressa entre os casos e os controles; portanto, medimos esta proteína em todos os casos (n = 30) e controles selecionados (n = 90). Resultados Não houve diferenças nos níveis plasmáticos de TIMP-4 nos casos em comparação com os controles (1.144 263 versus 1.160 362 pg/mL, respectivamente; p > 0,05). Conclusão Os níveis plasmáticos de TIMP-4 não foramalterados no período entre 20 e 25 semanas de gestação antes da manifestação dos sintomas clínicos; portanto, não são um bom preditor do desenvolvimento da preeclâmpsia.

Oxymatrine alleviates periodontitis in rats by inhibiting inflammatory factor secretion and regulating MMPs/TIMP protein expression

Abstract Purpose: To investigate the effect of oxymatrine on periodontitis in rats and related mechanism. Methods: Ninety SD rats were divided into control, model, 10, 20 and 40 mg/kg oxymatrine and tinidazole groups. The periodontitis model was established in later 5 groups. The 10, 20 and 40 mg/kg oxymatrine groups were intragastrically administrated with 10, 20 and 40 mg/kg oxymatrine, respectively. The tinidazole group was intragastrically administrated with 100 mg/kg tinidazole. The treatment duration was 4 weeks. The tooth mobility, gingival and plaque indexes, serum inflammatory factor levels and gingival tissue matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) protein levels were detected. Results: After treatment, compared with model group, in 40 mg/kg oxymatrine group the rat general conditions were obviously improved, the tooth mobility, gingival index and plaque index were significantly decreased (P<0.05), the serum tumor necrosis factor-α, interleukin-1β and prostaglandin E2 levels were significantly decreased (P<0.05), the MMP-2 and MMP-9 protein levels were significantly decreased (P<0.05), and the TIMP-2 protein level was significantly increased (P<0.05). Conclusions: Oxymatrine can alleviate the experimental periodontitis in rats. The mechanism may be related to its inhibiting inflammatory factor secretion and regulating MMPs/TIMP protein expression.

Segment­ specific expression of MMP/TIMP in the oviduct of llama (Lama glama) and gelatinolytic activity in the oviductal fluid / Expresión segmento específica de MMP/TIMP en el oviducto de llama (Lama glama) y actividad gelatinolítica en el fluido oviductal

Oviductal molecules have the potential to improve the reproductive biotechnologies. In camelids, knowledge and assessment of the oviductal environment are necessary to successfully develop species-specific reproductive technologies, especially because of the camelids reproductive particularities. Among the oviductal factors, the matrix metalloproteinases/tissue inhibitor of matrix metalloproteinases system (MMPs/TIMPs) should be investigated more thoroughly due to their participation in reproductive processes. Consequently, the current study assayed gene and protein expression of MMPs throughout the llama oviduct. MMPs zymogen and active forms in the oviductal fluid were also characterized. MMP2 and MMP9 transcripts were detected in ampulla, isthmus, utero-tubal junction and papilla, being MMP2 and MMP9 2.15 and 1.10 folds higher in papilla than in ampulla, respectively. In addition, differences in immunolocalization of MMP2 and MMP9 between the epithelial mucosa layers of the oviductal segments were observed. The presence of MMPs in the epithelium suggests their secretion into the oviductal lumen. Coincidently, bands of 62 and 94 kDa, corresponding to MMP2 and MMP9 were detected by zymography in the oviductal fluid. Treatment with an exogenous activator (APMA) suggests that they are present as proMMPs. TIMP2 and TIMP1, the specific inhibitors of MMP2 and MMP9, respectively, were expressed in each oviductal segment, indicating a well-regulated control of MMP proteolytic activity in the oviduct. These findings prove that the llama oviduct produces and secretes MMPs into the oviductal lumen, suggesting that these enzymes may have an unknown role in the preparation of the oviductal environment for gametes, fertilization and early embryo development in camelids.

Las moléculas oviductales tienen el potencial para mejorar las biotecnologías reproductivas. En los camélidos, debido a sus peculiares características reproductivas, el conocimiento del ambiente oviductal constituye una herramienta útil para el desarrollo de tecnologías reproductivas específicas para estas especies. Entre los factores oviductales de interés se encuentran las metaloproteasas de matriz (MMPs) y sus inhibidores específicos (TIMPs), los cuales han sido involucrados en diferentes procesos reproductivos. Por estas razones, en este trabajo se caracterizó la expresión génica y proteica de MMP2 y MMP9 en el oviducto de llama. Además, se analizó la presencia de las formas activas e inactivas (zimógenos) de estas enzimas en el fluido oviductal. Se observó que todos los segmentos oviductales, ámpula, istmo, unión útero-tubal y papila, expresan MMP2 y MMP9, siendo los niveles de expresión de MMP2 y MMP9 más elevados en papila respecto a ámpula; 2,15 y 1,10 veces respectivamente. Asimismo, se observaron diferencias en la distribución de las MMPs a nivel de la mucosa entre los segmentos oviductales. Consecuentemente, bandas con actividad gelatinolítica de 62 y 94 kDa, se detectaron en el fluido oviductal, las cuales corresponderían a las formas inactivas de la MMP2 y la MMP9, respectivamente. Los inhibidores específicos de MMP2 y MMP9; TIMP2 y TIMP1, también se detectaron en los segmentos oviductales, indicando su probable participación en la regulación de la actividad proteolítica de las MMPs en el oviducto de llama. En conjunto, los datos de este trabajo demuestran que el oviducto de la llama produce y secreta MMPs al lumen oviductal; sugiriendo que estas enzimas pueden participar en la preparación del ambiente oviductal para la recepción de los gametos, la fecundación y el desarrollo embrionario temprano en camélidos.

Relaxin Modulates the Expression of MMPs and TIMPs in Fibroblasts of Patients with Carpal Tunnel Syndrome

PURPOSE: The aim of this study was to investigate the anti-fibrotic effect of relaxin in subsynovial fibroblasts activated by transforming growth factor beta (TGF-β). MATERIALS AND METHODS: To test the anti-fibrotic effect of an adenovirus-relaxin construct (Ad-RLN) on subsynovial fibroblasts in vitro, cells from subsynovial connective tissue of patients with carpal tunnel syndrome were activated with TGF-β1 and exposed to Ad-RLN (as a therapeutic gene) or adenovirus-lacZ construct (as a marker gene) for four hours. Subsynovial fibroblast cultures without adenoviral exposure served as controls. RESULTS: We observed induction of gene expressions of collagen I, III and IV, as well as the abatement of alpha-smooth muscle actin (a-SMA) synthesis, Smad2 phosphorylation, and fibronectin at the protein level, in comparison to controls. In addition, protein expressions of matrix metalloproteinase (MMP) I was significantly induced, whereas the protein expressions of tissue inhibitor of metalloproteinases (TIMP) I and IV were reduced due to relaxin expression. CONCLUSION: RLN prevents excessive synthesis of extracellular matrix by reducing the expressions of its components, such as fibronectin, a-SMA, and phosphorylated Smad2, by increasing the expression of MMPs; and by decreasing the expression of TIMPs.

Relationship between matrix metalloproteinases and the occurrence and development of ovarian cancer

Ovarian cancer is one of the most malignant genital cancers, with a high mortality rate. Many researchers have suggested that matrix metalloproteinases (MMPs) have remarkably high expression in ovarian cancer tissues. MMPs are considered to be related to the occurrence, development, invasion and metastasis of ovarian cancer. Moreover, some studies have discovered that the unbalance between MMPs and tissue inhibitor of metalloproteinases (TIMPs) are associated with the malignant phenotype of tumors. This review summarizes the latest research progress of MMPs in ovarian cancer. The investigation of MMP mechanism in ovarian cancer will facilitate the development of effective anti-tumor drugs, and thereby improve the survival rate of patients with ovarian cancer.

Effect of Hijikia fusiforme extracts on degenerative osteoarthritis in vitro and in vivo models

BACKGROUND/OBJECTIVES: The inhibitory effect of Hijikia fusiforme (HF) extracts on degenerative osteoarthritis was examined in primary cultured rat cartilage cells and a monosodium iodoacetate (MIA)-induced osteoarthritis rat model. MATERIALS/METHODS: In vitro, cell survival and the expression of matrix metalloproteinases (MMPs), collagen type I, collagen type II, aggrecan, and tissue inhibitor of metalloproteinases (TIMPs) was measured after H2O2 (800 µM, 2 hr) treatment in primary chondrocytes. In vivo animal study, osteoarthritis was induced by intra-articular injection of MIA into knee joints of rats, and then RH500, HFE250 and HFE500 were administered orally once a day for 28 days. To determine the anti-inflammatory effects of HFE, nitric oxide (NO), prostaglandin E2 (PGE2) expression were measured. In addition, real-time PCR was performed to measure the genetic expression of MMPs, collagen type I, collagen type II, aggrecan, and TIMPs. RESULTS: In the in vitro assay, cell survival after H2O2 treatment was increased by HFE extract (20% EtOH). In addition, anabolic factors (genetic expression of collagen type I, II, and aggrecan) were increased by HFE extract (20% EtOH). However, the genetic expression of MMP-3 and 7, known as catabolic factors were significantly inhibited by treatment with HFE extract (20% EtOH). In the in vivo assay, anabolic factors (genetic expression of collagen type I, II, aggrecan, and TIMPs) were increased by oral administration of HFE extract. However, the genetic expression of MMP-3 and 7, known as catabolic factors, and production of NO and PGE2 were significantly inhibited by treatment with oral administration of HFE extract. CONCLUSIONS: HFE extract inhibited articular cartilage degeneration through preventing extracellular matrix degradation and chondrocyte injury.

Effect of Hijikia fusiforme extracts on degenerative osteoarthritis in vitro and in vivo models

BACKGROUND/OBJECTIVES: The inhibitory effect of Hijikia fusiforme (HF) extracts on degenerative osteoarthritis was examined in primary cultured rat cartilage cells and a monosodium iodoacetate (MIA)-induced osteoarthritis rat model. MATERIALS/METHODS: In vitro, cell survival and the expression of matrix metalloproteinases (MMPs), collagen type I, collagen type II, aggrecan, and tissue inhibitor of metalloproteinases (TIMPs) was measured after H2O2 (800 µM, 2 hr) treatment in primary chondrocytes. In vivo animal study, osteoarthritis was induced by intra-articular injection of MIA into knee joints of rats, and then RH500, HFE250 and HFE500 were administered orally once a day for 28 days. To determine the anti-inflammatory effects of HFE, nitric oxide (NO), prostaglandin E2 (PGE2) expression were measured. In addition, real-time PCR was performed to measure the genetic expression of MMPs, collagen type I, collagen type II, aggrecan, and TIMPs. RESULTS: In the in vitro assay, cell survival after H2O2 treatment was increased by HFE extract (20% EtOH). In addition, anabolic factors (genetic expression of collagen type I, II, and aggrecan) were increased by HFE extract (20% EtOH). However, the genetic expression of MMP-3 and 7, known as catabolic factors were significantly inhibited by treatment with HFE extract (20% EtOH). In the in vivo assay, anabolic factors (genetic expression of collagen type I, II, aggrecan, and TIMPs) were increased by oral administration of HFE extract. However, the genetic expression of MMP-3 and 7, known as catabolic factors, and production of NO and PGE2 were significantly inhibited by treatment with oral administration of HFE extract. CONCLUSIONS: HFE extract inhibited articular cartilage degeneration through preventing extracellular matrix degradation and chondrocyte injury.

Effects of in vitro continuous passaging on the phenotype of mouse hyaline chondrocytes and the balance of the extra- cellular matrix / 华西口腔医学杂志

<p><b>OBJECTIVE</b>This study aimed to investigate the effects of in vitro continuous passaging on the morphological phenotype and differentiation characteristics of mouse hyaline chondrocytes, as well as on the balance of the extracellular matrix (ECM).</p><p><b>METHODS</b>Enzymatic digestion was conducted to isolate mouse hyaline chondrocytes, which expanded over five passages in vitro. Hematoxylin-eosin stain was used to show the changes in chondrocyte morphology. Semi-quantitative polymerase chain reaction was performed to analyze the mRNA changes in the marker genes, routine genes, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) in chondrocytes. Zymography was carried out to elucidate changes in gelatinase activities.</p><p><b>RESULTS</b>After continuous expansion in vitro, the morphology of round or polygonal chondrocytes changed to elongated and spindled shape. The expression of marker genes significantly decreased (P < 0.05), and it was almost negatively expressed by P5 chondrocytes. By contrast, the down regulation of routine genes was insignificant. The gene expression levels of MMPs and TIMPs both decreased (P < 0.05), but the change in MMP-1 and TIMP-1 was not statistically significant (P > 0.05). Meanwhile, the ratio of MMPs/TIMPs was altered. At the protein level, the activities of gelatinases decreased after passaging, especially for P4 and P5 chondrocytes (P < 0.05).</p><p><b>CONCLUSION</b>Serially passaged chondrocytes dedifferentiated and lost specific phenotypic characteristics during in vitro expansion culture. Simultaneously, the anabolism and catabolism of the cartilage ECM became uncontrollable and led to the imbalance of ECM homeostasis. When hyaline chondrocytes are applied in research on relevant diseases or cartilage tissue engineering, P0-P2 chondrocytes should be used.</p>

Análise comparativa da expressão e atividade das metaloproteinases 2 e 9 e de seus inibidores teciduais nas lesões cutâneas das variantes poiquilodérmica e clássica da micose fungoide / A comparative analysis of the expression and activity of metalloproteinases 2 and 9 and their tissue inhibitors in cutaneous lesions of poikilodermatous and classic variants of mycosis fungoides

Micose fungoide poiquilodérmica (MFp) é uma variante clínica de micose fungoide (MF). É mais indolente e caracterizada pela presença da poiquilodermia. As metaloproteinases (MMP) e seus inibidores específicos TIMP (Tissue Inhibitors of Metaloproteinases) estão envolvidos na oncogênese. Especificamente as MMP2 e MMP9 e seus inibidores, TIMP-2 e TIMP-1, respectivamente, foram relacionados ao prognóstico em tumores. Poucos trabalhos estudaram MMP e nenhum estudou a ação dos TIMP na MF. Objetivos: avaliar a relação entre MMP2 e MMP9 e seus inibidores TIMP2 e TIMP1 e a agressividade da MF e descrever a casuística de micose fungoide poiquilodérmica no ambulatório de linfomas cutâneos da Divisão de Clínica Dermatológica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Métodos: análise retrospectiva de 54 casos de MFp, sendo 25 de MFp localizada 14 de MFp generalizada e 15 de MFp mista. Para análise das MMP e TIMP, os grupos de MFp foram comparados com 7 amostras de pele normal (PN), 10 casos de MF clássica inicial (MFi), 9 casos de MF tumoral não-transformada (MFT nt) e 10 de MF tumoral transformada (MFT t). Resultados: A proporção de mulheres: homens foi 2,44. MFp apresentou maior tempo entre os primeiros sintomas e o diagnóstico. MFpG apresentou maior prevalência de lesões do tipo pitiríase liquenoide crônica (PLC) (79%). Houve alta prevalência de MF hipocromiante (62%) no grupo MFp mista. A histologia da MFp apresentou características típicas de MF e, adicionalmente, atrofia, telangectasias e derrame pigmentar, específicos da forma poiquilodérmica. Na imuno-histoquímica predominou o fenótipo CD3+, CD4+, CD7-, CD8- em todos os grupos, e MFp apresentou significantemente menor predomínio do fenótipo CD8+ que o grupo MFi. O grupo MFpG apresentou baixa positividade para pesquisa de clonalidade T da pele (12,5%). A MMP2 esteve mais presente na epiderme em MFi e MFp relativamente a MFT. Na derme superficial, os grupos MFi e MFp...

Poikilodermatous mycosis fungoides (pMF) is a clinical variant of mycosis fungoides (MF). It is more indolent than classic MF and is characterized by the presence of poikiloderma. The matrix metalloproteinases (MMPs) and their specific inhibitors TIMP (Tissue Inhibitors of Metalloproteinases) are involved in oncogenesis. Specifically, MMP2 and MMP9 and their inhibitors, TIMP-2 and TIMP-1, respectively, have been related to prognosis in tumors. There are few studies on MMP and none on the role of TIMPs in MF. Objectives: To evaluate if there is a relationship between the presence and activity of MMP2 and MMP9 and their inhibitors TIMP2 and TIMP1, and the aggressiveness of MF. To describe a casuistic of poikilodermatous mycosis fungoides in an outpatient clinic in the Dermatological Division of Hospital das Clinicas of University of Sao Paulo Medical School. Methods: Retrospective analysis of 54 cases of pMF, this included 25 localized pMF (LpMF), 14 generalized pMF (GpMF) and 15 mixed pMF. For the analysis of MMPs and TIMPs, the pMF groups were compared with 7 normal skin samples (NS), 10 cases of initial classical MF (cMF), 9 cases of non-transformed tumor MF (nt MFT) and 10 transformed tumor MF (t MFT). Results: The proportion of women : men was 2.44. The pMFs groups showed a longer period of time from the first symptoms to the diagnosis than the cMF group. The GpMF group had a higher incidence of pityriasis lichenoides chronica-like lesions (PLC) (79%) than the other groups. There was a high incidence of hypopigmented MF (62%) in the mixed pMF group. Histology showed typical characteristics of MF and, additionally, atrophy, telangiectasia and pigmentary alterations compatible with pMF. At immunohistochemistry the cases were predominantly CD3+, CD4+, CD7-, CD8- phenotype in all groups, and the pMF groups had a significantly lower prevalence of CD8+ phenotype than the cMF group. The GPMF group showed low positivity for clonality of the T-cell...

Economic evaluation in the context of rare diseases: is it possible? / Evaluación económica en el contexto de enfermedades raras: ¿es posible? / Avaliação econômica no âmbito das doenças raras: isto é possível?

This study analyzes the available evidence on the adequacy of economic evaluation for decision-making on the incorporation or exclusion of technologies for rare diseases. The authors conducted a structured literature review in MEDLINE via PubMed, CRD, LILACS, SciELO, and Google Scholar (gray literature). Economic evaluation studies had their origins in Welfare Economics, in which individuals maximize their utilities based on allocative efficiency. There is no widely accepted criterion in the literature to weigh the expected utilities, in the sense of assigning more weight to individuals with greater health needs. Thus, economic evaluation studies do not usually weigh utilities asymmetrically (that is, everyone is treated equally, which in Brazil is also a Constitutional principle). Healthcare systems have ratified the use of economic evaluation as the main tool to assist decision-making. However, this approach does not rule out the use of other methodologies to complement cost-effectiveness studies, such as Person Trade-Off and Rule of Rescue.

El objetivo fue sistematizar las evidencias disponibles sobre la pertinencia de utilizar la evaluación económica para la incorporación/exclusión de tecnología en enfermedades raras. Se realizó una revisión sistemática de la literatura en MEDLINE vía PubMed, CRD, LILACS, SciELO y Google Académico (literatura gris). Los estudios de evaluación económica se originan de la Economía del Bienestar, en la que los individuos maximizan sus utilidades, basándose en la eficiencia de asignación. No existe un criterio ampliamente aceptado para examinar las utilidades, a fin de dar más peso a los individuos con mayores necesidades. Generalmente, los estudios no equilibran asimétricamente las utilidades, todas son consideradas iguales, lo que en Brasil es también un principio constitucional. Los sistemas de salud han ratificado el uso de la evaluación económica como la principal herramienta para ayudar en la toma de decisiones. Sin embargo, este abordaje no excluye el uso de otras metodologías complementarias a los estudios de coste-efectividad, como la técnica de compensación personal o la regla del rescate.

O objetivo deste estudo foi analisar as evidências disponíveis sobre a adequação do uso de avaliação econômica sobre incorporação/exclusão de tecnologias para doenças raras. Foi realizada uma revisão estruturada da literatura, nas bases MEDLINE, via PubMed, CRD, LILACS, SciELO e Google Acadêmico (literatura cinzenta). Os estudos de avaliação econômica têm origem na Economia do Bem-Estar, na qual os indivíduos maximizam suas utilidades, fundamentando-se na eficiência alocativa. Não há um critério amplamente aceito para ponderar as utilidades esperadas, no sentido de dar mais peso aos indivíduos com maiores necessidades em saúde. Geralmente não se ponderam assimetricamente as utilidades; todas são tratadas de forma igualitária, que, no caso brasileiro, também é um princípio constitucional. Os sistemas de saúde têm ratificado o uso de avaliação econômica como principal instrumento para auxiliar na tomada de decisão. No entanto, essa postura não exclui o uso de outras metodologias complementares aos estudos de custo-efetividade, como Person Trade-Off e regra de resgate.

Metaloproteinasas de la matriz en Odontología y sus consideraciones desde el campo de la química computacional / Matrix metalloproteinases and their considerations in Dentistry from the field of computational chemistry

Las metaloproteinasas de la matriz son una familia de proteasas zinc-dependientes encargadas de la remodelación de los componentes proteicos de la matriz extracelular de todos los tejidos, su actividad catalítica es controlada por inhibidores tisulares de metaloproteinasas de la matriz. En condiciones patológicas se pierde el equilibrio existente entre MMPs con respecto a la de estos inhibidores endógenos, este desequilibrio es evidente en enfermedades orales como la caries dental, gingivitis, periodontitis, entre otras, por lo tanto la posibilidad de lograr una inhibición selectiva de la actividad de estas enzimas con inhibidores sintéticos constituye un enfoque prometedor en el tratamiento de distintas enfermedades de la cavidad oral. Se presenta a continuación una revisión bibliográfica cuyo objetivo es analizar el papel que juegan las metaloproteinasas de la matriz en el desarrollo de patologías orales e identificar el aporte que ha hecho el análisis computacional de estas enzimas en el campo de la odontología. Para tal fin se llevó a cabo una búsqueda de la literatura disponible en bases de datos como Pubmed, Sience Direct, Ovid y Ebsco Host empleando palabras claves como: patologías orales, cáncer oral, adhesión dentinaria, metaloproteinasas de la matriz, inhibidor sintético de metaloproteinasas y modelado molecular. Se seleccionaron 35 artículos para orientar la presente revisión. Al terminar se pudo concluir que existe correlación positiva entre la desregulación de determinadas MMPs y la progresión de ciertas enfermedades orales, esto ha impulsado la identificación y el diseño insílico de inhibidores efectivos para estas proteínas, partiendo de análisis relación estructura-actividad y acoplamiento molecular computacional. Hasta la fecha se ha logrado demostrar que los inhibidores de MMPs más potentes presentan grupos hidroxamatos. Teniendo en cuenta lo anterior, el diseño de compuestos que bloqueen la actividad representa una estrategia quimiopreventiva racional encaminada a la inhibición de las MMPs(AU)

Matrix metalloproteinases are a family of zinc-dependent proteases responsible for the remodeling the protein components of extracellular matrix of all tissues; its catalytic activity is controlled by tissue inhibitors of matrix metalloproteinases. At pathological conditions the balance between MMPs regarding these endogenous inhibitors is lost, this imbalance is evident in oral diseases including dental caries, gingivitis, periodontitis, among others, hence the possibility of achieving selective inhibition of activity of these enzymes with synthetic inhibitors is a promising approach in the treatment of various diseases of the oral cavity. A literature review aimed at analyzing the role of matrix metalloproteinases in the development of oral diseases and identify the contribution made by the computational analysis of these enzymes in the field of dentistry is presented below. To this end a search of the literature available was conducted in databases such as Pubmed, Sience Direct, Ovid, and Ebsco Host using keywords like: oral pathology, oral cancer, dentin bonding, matrix metalloproteinases, synthetic inhibitor of metalloproteinases, and molecular modeling. 35 items were selected to guide this review. At the end it was concluded that there is positive correlation between deregulation of certain MMPs and progression of certain oral diseases, this has boosted in silico identifying and designing effective inhibitors for these proteins, based on structure-activity relationship analysis and molecular docking computational. To date it has successfully demonstrated that the most potent inhibitors of MMPs have hydroxamate groups. So far it has successfully demonstrated that the most potent inhibitors of MMPs have hydroxamate groups. Considering the above, the design of compounds that block the chemopreventive activity represents a rational strategy for the inhibition of MMPs(AU)

Análise da expressão das metaloproteinases e seus inibidores teciduais no músculo detrusor de pacientes com obstrução infravesical por hiperplasia prostática benigna / Expression of metalloproteinases and their tissue inhibitors in the detrusor muscle of patients with bladder outlet obstruction due to benign prostatic hyperplasia

Introdução: A obstrução infravesical (OIV) de longo prazo secundária a hiperplasia prostática benigna (HPB) pode causar alterações funcionais e morfológicas na bexiga. Um dos principais eventos consiste no aumento da deposição de colágeno e perda de complacência vesical, levando a alteração de armazenamento e esvaziamento urinário. O aumento da deposição de colágeno na matriz extracelular (MEC) da musculatura detrusora é a principal razão para a diminuição da complacência vesical. Na bexiga, assim como em outros órgãos, este fenômeno depende da atividade equilibrada de enzimas proteolíticas, incluindo as metaloproteinases (MMP) e os seus inibidores endógenos (inibidores teciduais de metaloproteinases-TIMPs). Como estes fenômenos são desconhecidos na bexiga obstruída, o objetivo deste estudo foi avaliar a expressão gênica de colágeno, MMPs e seus inibidores na bexiga de pacientes com obstrução infravesical. Material e Métodos: Foi realizada uma análise prospectiva e controlada de 43 pacientes com OIV devido a HPB, que foram submetidos à ressecção transuretral da próstata (RTUP) entre 2011 e 2012. Como grupo controle foram selecionados espécimes de músculo detrusor de 10 pacientes que foram submetidos a prostatectomia radical retropúbica devido adenocarcinoma de próstata. Todos estes pacientes tinham idade menor que 60 anos, tamanho de próstata menor que 30 gramas ao ultra-som e escore internacional de sintomas prostáticos (IPSS) menor que 7. Todos os pacientes foram submetidos a estudo urodinâmico pré e pós operatório (após 6 meses). A biópsia de fragmento de músculo da bexiga foi realizada ao final da RTUP e colocada em solução estabilizadora de RNA para quantificação da expressão de colágenos I e III, metaloproteinases de matriz 1, 2 e 9, e inibidores de MMPs (TIMP1, TIMP2 e RECK) na bexiga de pacientes com HPB. Os genes descritos foram avaliados através da técnica de reação em cadeia da polimerase quantitativa em tempo real (qRT-PCR)....

Introduction: Long-term Bladder outlet obstruction (BOO) secondary to Benign prostatic Hyperplasia (BPH) can cause functional and morphological abnormalities in the bladder, such as increased collagen deposition and loss of compliance, leading to urinary storage and voiding symptoms. A decrease in bladder compliance is known to be correlated with deterioration of renal function. Increased deposition of collagen in the extracellular matrix (ECM) is the primary reason for a decreased compliance. In the bladder, as in other organs, this phenomenon is dependent on the balanced activity of proteolytic enzymes, including matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). The imbalance between MMPs and TIMPs is a key regulator in ECM turnover. Since these mechanisms are unknown in the obstructed bladder, the objective of this study was to evaluate gene expression of collagen, MMPs and their inhibitors in patients with bladder outlet obstruction due to BPH. Material and Methods: We performed a prospective and controlled analysis of 43 patients with BOO due to BPH who underwent transurethral resection of the prostate (TURP) from 2011 to 2012. The control group was comprised of 10 bladder specimens from patients with < 60 years who underwent radical prostatectomy with an International Prostatic Symptom Score (IPSS) < 8 and prostate volume < 30 grams. All patients underwent urodynamic analysis pre and post operatively after 6 months. A biopsy of the bladder muscle was performed at the end of TURP for analysis of collagen, metalloproteinases and TIMPs gene expressions. For this purpose we used the quantitative real time polymerase chain reaction method (qRT-PCR)...

Genes responsible for vaginal extracellular matrix metabolism are modulated by women's reproductive cycle and menopause

Objectives To analyze the expression of genes involved in extracellular matrix (ECM) biogenesis and remodeling in vaginal tissue of women with clinically normal pelvic floor support (defined as controls) according to the phase of menstrual cycle and postmenopausal women with and without pelvic organ prolapse (POP). Materials and Methods This study examined the expression of matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs), and the Lysyl oxidase (LOX) family genes in the anterior vaginal wall of Caucasian women by real-time RT-PCR. Initially, mRNA expression was assessed in premenopausal controls in the secretory (group 1, n = 10) vs. proliferative (group 2, n = 8) phase of menstrual cycle. In addition, we compared premenopausal controls in the proliferative phase (group 2) vs. postmenopausal controls (group 3, n = 5). Finally, we analyzed postmenopausal controls (group 3) vs. postmenopausal women with advanced POP (group 4, n = 13). Results According to the phase of menstrual cycle, MMP1 was significantly reduced (p = 0.003), whereas the expression of TIMP1 and LOXL4 was significantly up-regulated during proliferative phase (both p < 0.01) when compared to the secretory phase in premenopausal control women. Regarding menopausal status/ageing, all MMPs were down-regulated, while TIMP3, TIMP4 and LOXL2 were significantly up-regulated in postmenopausal control women when compared to premenopausal controls (p = 0.005, p = 0.01 and p < 0.001, correspondingly). TIMP4 and LOXL2 mRNA levels were significantly decreased in postmenopausal POP patients compared to asymptomatic postmenopausal controls (p < 0.01 for both). Conclusions Our results indicate that ovarian cycle and age-related changes influence the expression of genes encoding proteins responsible for ECM metabolism in human vagina. Moreover, POP is associated with alteration in vaginal ECM components after menopause. .

The expression of a nitric oxide derivative, tissue inhibitors of metalloproteinase-3, and tissue inhibitors of metalloproteinase-4 in chronic periodontitis with type 2 diabetes mellitus

PURPOSE: The purpose of this study was to analyze the expression of inducible nitric oxide synthases (iNOS), tissue inhibitors of metalloproteinase (TIMP)-3, and TIMP-4 in the gingival tissues of periodontal patients with or without type 2 diabetes mellitus (DM). METHODS: Depending on the patient's systemic condition and clinical criteria of the gingiva, each gingival sample was classified into one of three groups. Sixteen clinically, systemically healthy patients (group 1), 16 periodontal patients (group 2), and 16 periodontal patients with DM (group 3) were included. Tissue samples in each group were collected, prepared, and analyzed by western blotting. Quantification of the relative amount of TIMP-3, TIMP-4, and iNOS was performed. RESULTS: The expression levels of iNOS and TIMP-3 both increased in group 1, group 2, and group 3 in increasing order, and were significantly higher in both group 2 and group 3 as compared to group 1 (P<0.05). The expression levels of TIMP-4 increased in the same order, but significantly increased in group 2 as compared to group 1, in group 3 as compared to group 1, and group 3 as compared to group 2 (P<0.05). CONCLUSIONS: This study demonstrated that iNOS, TIMP-3, and TIMP-4 might be involved in the progression of periodontal inflammation associated with type 2 DM. It is thought that further study of these factors can be applied practically for the diagnosis and control of periodontitis in diabetics.

Expression of P38 MAPK and MMP-2 mRNA in neonatal rats with hyperoxia-induced lung injury / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To observe P38 mitogen-activated protein kinase (P38 MAPK) and matrix metalloproteinase-2 (MMP-2) mRNA expression level changes in neonatal rats with hyperoxia-induced lung injury,and to investigate the influence of P38 MAPK activation on MMP-2 mRNA expression.</p><p><b>METHODS</b>Thirty-six Sprague-Dawley (SD) rats were randomly divided into three groups: air control, hyperoxia and SB203580-treated hyperoxia (n=12). The rats were sacrificed on the 3rd and 7th days and the lungs were removed. Hematoxylin-eosine staining was used to observe the pathological changes in lung tissues.</p><p><b>RESULTS</b>Compared with the air and SB203580-treated groups, levels of P38 MAPK and MMP-2 mRNA significantly increased in the hyperoxia group (P<0.01).</p><p><b>CONCLUSIONS</b>Expression of P38 MAPK increases in neonatal rats with hyperoxia-induced acute lung injury and this may play a role in control of the expression of MMP-2 mRNA.</p>

Expression and significance of MMP-26, TIMP-4 and MMP-9 in diffuse large B-cell lymphoma cells / 中国实验血液学杂志

The aim of this study was to investigate the expression of matrix metalloproteinase 26 (MMP-26), tissue inhibitor of metalloproteinase-4 (TIMP-4) and matrix metalloproteinase 9 (MMP-9) in patients with diffuse large B cell lymphoma (DLBCL) and their correlations with pathogenesis and development of DLBCL. A total of 95 specimens excised from DLBCL patients were prepared. Expression of MMP-26, TIMP-4 and MMP-9 were tested by SABC immunohistochemistry method and its correlation to clinicopathology indexes were analyzed. The results showed that as compared with reactive hyperplasia of lymph nodes, the high expression of MMP-26, TIMP-4 and MMP-9 were found in different types of DLBCL. The positive expression rate of MMP-26 was related to immune typing (P < 0.05). The expression level of MMP-26 in GCB was lower than that in non-GCB, and did not relate to clinical staging, age, sex, diseased region (P > 0.05). The positive expression rate of MMP-9 was related to clinical staging, the positive expression rate of MMP-9 proteins in patient at III and IV stage was obviously higher than that in patients at I and II stage, but did not relate to immune type, age, sex and diseased region of DLBCL (P > 0.05). The expression of TIMP-4 did not relate to immune type, clinical stage, age, sex, disease region (P > 0.05). The expression of MMP-26 in pathologic tissue of DLBCL did not relate to expression of TIMP-4, but positively related to expression of MMP-9 protein (r = 0.486, P < 0.05). It is concluded that MMP-26 and MMP-9 synergically express in DLBCL. MMP-26 may be involve in pathogenesis and invasiveness of DLBCL, the expression of MMP-26 relates to subtypes of DLBCL. The MMP-26 may serve as an indicator for typing of DLBCL and contributes to predict the invasion and metastasis of DLBCL and itself may become a potential target for therapy.