Integrins as attractive targets for cancer therapeutics

Integrins are transmembrane receptors that have been implicated in the biology of various human physiological and pathological processes. These molecules facilitate cell-extracellular matrix and cell-cell interactions, and they have been implicated in fibrosis, inflammation, thrombosis, and tumor metastasis. The role of integrins in tumor progression makes them promising targets for cancer treatment, and certain integrin antagonists, such as antibodies and synthetic peptides, have been effectively utilized in the clinic for cancer therapy. Here, we discuss the evidence and knowledge on the contribution of integrins to cancer biology. Furthermore, we summarize the clinical attempts targeting this family in anti-cancer therapy development.

Metalloproteinases and colorectal cancer. Correlation of gene expression and clinical-pathological parameters

Abstract Purpose: To analyze gene and protein expression of metalloproteinases 1, 2, 9, 11 and 16 and their correlation with clinicopathological variables in colorectal adenocarcinoma. Methods: A retrospective study of 114 patients with colorectal adenocarcinoma treated surgically in the period 2006 to 2008 in Hospital de Câncer de Barretos - Fundação Pio XII. The evaluation of gene expression was performed by RT-PCR, and protein by immunohistochemistry. The analysis of gene expression was classified as overexpressed genes and poorly expressed (fold change of approximately 2, p<0.05). The positivity of the markers in the immunohistochemical study was performed by semi-quantitative analysis. The tissue of TMA (Tissue Microarray) was done by two independent pathologists. Results: The gene expression validated by immuno - histochemical was MMP-1(p= 0.00 and 1.57 fold change) and MMP - 2 (p= 0.01 and - 1.84 to fold change) when correlated with the histological types mucinous and adenocarcinoma NOS, MMP9 (p=0.01 and fold change of 1.13) and MMP-16 (p=0.03 and 1.61 fold change) when compared with the histological types villous and adenocarcinoma NOS, MMP - 11 statistically significant in relation to male (p = 0.04 and 1.65 fold change). Conclusions: The MMPs 1, 2, 9, 11 and 16 gene and protein expression with statistical significance in at least one of the clinicopathological variables studied. Thus, we conclude that these MMPs have potential as a prognostic factor in colorectal adenocarcinoma.

EFEITO DOS AGENTES DE CROSS-LINKING NA DURABILIDADE DA INTERFACE ADESIVA / EFFECT OF CROSS-LINKING AGENTS ON THE DURABILITY OF THE ADHESIVE INTERFACE

As metaloproteinases (MMPs) são enzimas colagenolítcas endó- genas, capazes de degradar as fibrilas de colágeno presentes na dentina, gerando falhas da interface adesiva. Foram propostos agentes de cross-linking para diminuir essa degradação. O objetivo desta revisão de literatura foi analisar a ação de diferentes agentes de cross-linking sobre as MMPs. A seleção dos artigos foi realizada por meio de uma busca na base de dados PubMed/MEDLINE. A amostra final foi composta por 40 estudos publicados entre 2018 e 2010. Os estudos atuais apresentaram os agentes de cros-s-linking (cabordiimida, glutaraldeído, proantocianidina, riboflavina/ UV-A e quitosana) com vantagens como inespecificidade em relação aos tipos de MMPs, aumento da resistência da fibra colágena e possibilidade de bloquear o sítio de clivagem da enzima. Ob- servou-se que a cabordiimida, riboflavina/UV-A, o glutaraldeído, a proantocianidina e a quitosana apresentaram resultados positivos na diminuição da degradação da interface adesiva. A carbodiimida e riboflavina/UV-A não são citotóxicas, diferentemente do glutaraldeído. A proantocianidina, quando incorporada no adesivo, apesar de interferir na polimerização dos monômeros adesivos, pode ser efetiva quando utilizada incorporada ao condicionamen- to ácido. A quitosana é capaz de reforçar as fibrilas de colágeno. Assim, foi possível conhecer mais sobre a ação dos agentes de cross-linking disponíveis. No entanto, há necessidade de mais pesquisas sobre esses agentes.

Metalloproteases are endogenous collagenolytic enzymes, capable of degrading the collagen fibrils present in the dentin, producing adhesive interface failures. Cross-linking agents has been proposed to reduce this degradation. The aim of this literature review was to analyze the action of different cross-linking agents on MMPs. The search was conducted in the PubMed database. The final sample consisted of 40 studies published between 2018 and 2010. Current studies have shown cross-linking agents (cabordiimide, glutaraldehyde, proanthocyanidin, riboflavin / UV-A and chitosan) present some advantages as non- specificity to type of MMPs, collagen fiber's toughness development and prevent bonding to the cleavage site of the enzyme. For this reason, it is necessary to know the action of the available cross-linking agents. It was observed that Cabordiimide, riboflavin / UV-A, glutaraldehyde, proanthocyanidin and chitosan presented positive results in reducing degradation of the adhesive interface. Carbodiimide and riboflavin / UV-A are non-cytotoxic, unlike glutaraldehyde. Proanthocyanidin incorporated into the adhesive interferes with the polymerization of the adhesive monomers. Chitosan is able to reinforce collagen fibrils. Thus, it was possible to know more about the action of the available cross-linking agents. However, there is a need for more research on these agents.

Pro - inflammatory cytokines and metalloproteinase activation in polypropylene mesh implant in rat subcutaneous tissue

ABSTRACT Aims and Objectives: Polypropylene meshes have been increasingly adopted for correction of pelvic organ prolapse due to its lower recurrence rate when compared to surgeries without meshes. The study of the interaction of these materials with the host tissue may contribute to the development of materials with best biocompatibility and, consequently, less complication rates. Materials and Methods: The present study compares the inflammatory reaction of standard-weight (SW) and lightweight (LW) meshes (72 g/m216g/m2 respectively), implanted in the abdomen of 20 adult rats, which were euthanized in four or 30 days. Quantification of pro-inflammatory markers, IL-1 and TNF-α, and of metalloproteinases, MMP2 and MMP3, were carried out through immunohistochemistry with AxioVision® software. Results: There were no significant differences in the quantification of IL-1 and TNF-α in LW versus SW meshes. However, IL-1 quantification increased along time (30 days >4 days, p=0.0269). Also, MMP-2 quantification was similar to SW and LW and both presented a significant increase along time (30 days >4 days, p <0.0001). MMP-3 quantification also showed no difference between the SW and LW groups, but increased along time (30 days >4 days, p=0.02). Conclusions: Mesh's density did not influence the quantification of pro-inflammatory cytokines IL-1 and TNF-α and metalloproteinases 2 and 3. The increased expression of IL-1, MMP-2 and MMP-3 over time could represent a longstanding inflammatory response after PP mesh implantation. Possibly, the occurrence of adverse events following PP prosthetic implants can be influenced by other factors, not solely related to the amount of implanted material.

Proteases are Modulated by Fascin in Oral Cancer Invasion

BACKGROUND: Cancer invasion is a critical factor for survival and prognosis of patients with cancer. Identifying and targeting factors that influence cancer invasion are an important strategy to overcome cancer. In this study, we investigated the role of fascin known to be associated with cancer invasion. METHODS: Fascin depletion was performed with lentiviral short hairpin RNA against fascin mRNA and stable cell line (Fascin(dep)) was established. Matrigel-Transwell invasion and three-dimensional (3D) culture system were used to observe fascin depletion effects. In order to observe the changes of protease secretion by fascin depleted cancer cells, protease antibody array was performed. RESULTS: Fascin was highly expressed in invasive cancer cells. Fascin-depleted cells showed decreased cancer invasion in Matrigel-Transwell invasion and 3D culture system. In addition, inhibition of proteases secreation and decrease of intracellular proteases mRNA expression were observed in fascin deplete cells. CONCLUSIONS: These results indicates that fascin is closely involved in proteases activity and cancer invasion. Therefore, fascin is a strategically important factor for controlling cancer invasion.

Experimental Study on the Up-Regulation of NF-kappa B and MMP-9 mRNA Level in HUVECs Stimulated by Serum from Children with Coronary Artery Lesions of Kawasaki Disease / 现代检验医学杂志

Objective To investigate the relationship between nuclear factor kappa B(NF-κB) and matrix metalloproteinase-9 (MMP-9) mRNA in human umbilical vein endothelial cells(HUVECs) stimulated by the serum from children with coronary artery lesions of Kawasaki disease (KD).Methods HUVECs were cultured and were divided into 4 groups:normal serum group,general fever group,Non-CALs group and CALs group.Co-Immunoprecipitation (ChIP) was used to detect the relationship between NF-κB and MMP-9,and RT-PCR was used to detect the mRNA level of MMP-9.Results Compared with control groups,NF-κB p65 could bind the promoter of MMP 9 in HUVECs cultured with 10 ％ serum from KD patients with coronary artery lesions.The mRNA level of MMP 9 was also up-regulated.Conclusion NF-κB p65 can promote the transcription of MMP-9 in HUVECs induced by the serum from KD patients with coronary artery lesions.

Structural insights into leishmanolysins encoded on chromosome 10 of Leishmania (Viannia) braziliensis

BACKGROUND Leishmanolysins have been described as important parasite virulence factors because of their roles in the infection of promastigotes and resistance to host's defenses. Leishmania (Viannia) braziliensis contains several leishmanolysin genes in its genome, especially in chromosome 10. However, the functional impact of such diversity is not understood, but may be attributed partially to the lack of structural data for proteins from this parasite. OBJECTIVES This works aims to compare leishmanolysin sequences from L. (V.) braziliensis and to understand how the diversity impacts in their structural and dynamic features. METHODS Leishmanolysin sequences were retrieved from GeneDB. Subsequently, 3D models were built using comparative modeling methods and their dynamical behavior was studied using molecular dynamic simulations. FINDINGS We identified three subgroups of leishmanolysins according to sequence variations. These differences directly affect the electrostatic properties of leishmanolysins and the geometry of their active sites. We identified two levels of structural heterogeneity that might be related to the ability of promastigotes to interact with a broad range of substrates. MAIN CONCLUSION Altogether, the structural plasticity of leishmanolysins may constitute an important evolutionary adaptation rarely explored when considering the virulence of L. (V.) braziliensis parasites.

Advances in bacterial extracellular metalloproteases and their pathogenic roles / 中华微生物学和免疫学杂志

Bacterial extracellular metalloproteases ( BEMPs) are a large group of metal ion-contai-ning proteases. All BEMPs identified so far are endopeptidase or endoprotease. BEMPs can be classified into nine metalloprotease families based on the sequences and structures of enzymatic molecules. Double-valence zinc ion ( Zn2+) is necessarily required by catalytic centers of most BEMPs. The main function of BEMPs in non-pathogenic heterotrophic bacteria is to hydrolyze environmental proteins and polypeptides to provide vari-ous amino acids as nutrients. However, BEMPs of pathogenic bacteria, serving as important virulence fac-tors, help the pathogens invade into hosts and spread in hosts. In recent years, the roles and mechanism of BEMPs in bacterial pathogenesis have attracted great attention. Here, we make a brief review about the structures and types as well as the functions and pathogenic roles of BEMPs.

Effect of acupuncture plus thunder-fire moxibustion on MMP-3, TIMP-1 and TGF-β1 in rats with knee osteoarthritis / 针灸推拿医学（英文版）

Objective: To observe the effect of acupuncture plus thunder-fire moxibustion on the expressions of matrix metalloproteinase-3 (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and transforming growth factor-β1 (TGF-β1) in cartilage of knee osteoarthritis (KOA) rats, and to explore the mechanism of acupuncture plus thunder-fire moxibustion in the treatment of KOA. Methods:Thirty Sprague-Dawley (SD) rats were randomly divided into a blank control group, a model group and an acupuncture-moxibustion group by random digits table, 10 rats in each group. Rats in the model group and the acupuncture-moxibustion group were injected with papain in the right posterior knee joint to prepare the models. The levels of MMP-3 and TIMP-1 in rat synovium of each group were measured by enzyme-linked immunosorbent assay (ELISA) after 2 weeks of treatment. The level of TGF-β1 was determined by Motic B5 Micro-camera system. Results:The levels of MMP-3 and TIMP-1 in the cartilage of the model group were significantly higher than those in the blank control group (allP<0.01); the levels of MMP-3 and TIMP-1 in the acupuncture-moxibustion group were lower than those in the model group, and the between-group differences were statistically significant (all P<0.05). The levels of MMP-3 and TIMP-1 in the acupuncture-moxibustion group were higher than those in the blank control group, and the differences were statistically significant (all P<0.05). The level of TGF-β1 in cartilage tissues of the model group was significantly lower than that in the blank control group (P<0.01); the level of TGF-β1 in the acupuncture-moxibustion group was higher than that in the model group (P<0.05), but it was lower than that in the blank control group, and the between-group difference was statistically significant (P<0.05). Conclusion: Acupuncture plus thunder-fire moxibustion can effectively recover the abnormal expressions of MMP-3 and TIMP-1 in KOA model rats and somewhat up-regulate TGF-β1, which may be one of its mechanisms of acupuncture plus thunder-fire for KOA.

Effect of acupuncture plus thunder-fire moxibustion on MMP-3, TIMP-1 and TGF-β1 in rats with knee osteoarthritis / 针灸推拿医学（英文版）

Objective: To observe the effect of acupuncture plus thunder-fire moxibustion on the expressions of matrix metalloproteinase-3 (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and transforming growth factor-β1 (TGF-β1) in cartilage of knee osteoarthritis (KOA) rats, and to explore the mechanism of acupuncture plus thunder-fire moxibustion in the treatment of KOA. Methods:Thirty Sprague-Dawley (SD) rats were randomly divided into a blank control group, a model group and an acupuncture-moxibustion group by random digits table, 10 rats in each group. Rats in the model group and the acupuncture-moxibustion group were injected with papain in the right posterior knee joint to prepare the models. The levels of MMP-3 and TIMP-1 in rat synovium of each group were measured by enzyme-linked immunosorbent assay (ELISA) after 2 weeks of treatment. The level of TGF-β1 was determined by Motic B5 Micro-camera system. Results:The levels of MMP-3 and TIMP-1 in the cartilage of the model group were significantly higher than those in the blank control group (allP<0.01); the levels of MMP-3 and TIMP-1 in the acupuncture-moxibustion group were lower than those in the model group, and the between-group differences were statistically significant (all P<0.05). The levels of MMP-3 and TIMP-1 in the acupuncture-moxibustion group were higher than those in the blank control group, and the differences were statistically significant (all P<0.05). The level of TGF-β1 in cartilage tissues of the model group was significantly lower than that in the blank control group (P<0.01); the level of TGF-β1 in the acupuncture-moxibustion group was higher than that in the model group (P<0.05), but it was lower than that in the blank control group, and the between-group difference was statistically significant (P<0.05). Conclusion: Acupuncture plus thunder-fire moxibustion can effectively recover the abnormal expressions of MMP-3 and TIMP-1 in KOA model rats and somewhat up-regulate TGF-β1, which may be one of its mechanisms of acupuncture plus thunder-fire for KOA.

Prevalencia de los polimorfismos de nucleótido único ARG574PRO del GEN MMP-9Y ALA38VAL del gen MMP-11 en pacientes con cáncer de mama / Prevalence of the ARG574PRO single nucleotide polymorphisms of the MMP-9 and ALA38VAL GENE of the MMP-11 gene in patients with breast cancer

El cáncer de mama (CM) es uno de los más frecuentes en Argentina y primera causa de muerte por cáncer en mujeres. Las metaloproteasas son endopeptidasas que degradan la matriz extracelular, facilitando la invasión tumoral y las metástasis. Se observó la utilidad de la MMP-9 como un marcador diagnóstico, pronóstico y de seguimiento en pacientes con CM. La MMP-11 parece tener un efecto dual en cáncer, su aumento se asocia a un incremento de tumores primarios de mama, pero con una represión en el desarrollo de metástasis. En el trabajo se analizaron los polimorfismos de nucleótido único (SNPs) Arg574Pro del gen MMP-9 y Ala38Val del MMP-11, con relación a las metástasis de CM. Se tomaron muestras de sangre de pacientes con CM metastásico y no metastásico (controles), con receptores de progesterona+, estrógeno+ y HER2-neu+/-. Se extrajo ADN de 25 muestras y se diseñaron cebadores para amplificar la región que contenían los SNPs Arg574Pro y Ala38Val. Se estandarizó la PCR para los SNPs correspondientes, aclarando que el cebador izquierdo que amplifica Arg574Pro, hibrida sobre los polimorfismos rs146961494 y rs35691798. Se realizó el análisis de las enzimas de restricción, MbiI para Arg574Pro y AatII para Ala38Val. Se concluye que para MMP-9, el polimorfismo presenta el alelo C como el G sólo en el grupo metastásico. En cuanto al gen MMP-11, se encuentra en alta frecuencia la variante alélica T, la cual no corresponde al alelo ancestral, indicando que puede estar su función/expresión relacionada con el carcinoma mamario. Estos hallazgos son preliminares (AU)

Breast cancer (BC) is one of the most common in Argentina and the leading cause of cancer death in women. Metalloproteases are endopeptidases that degrade the extracellular matrix, facilitating tumor invasion and metastases. The utility of MMP-9 was observed as a diagnostic, prognostic and follow-up marker in BC patients. MMP-11 appears to have a dual effect on cancer. High levels are associated with an increase in primary breast tumors, but with repression in the development of metastases. Arg574Pro SNPs of the MMP-9 gene and Ala38Val of MMP-11 gene were analyzed in relation to BC metastases. Blood samples were taken from patients with BC metastatic and non-metastatic (controls), with progesterone+, estrogen+ and HER2-neu+/- receptors. DNA from 25 samples was drawn and primers were designed to amplify the region containing the SNPs Arg574Pro and Ala38Val. PCR was standardized for the corresponding SNPs, clarifying that the Arg574Pro amplified left primer hybridizes to polymorphisms rs146961494 and rs35691798. The restriction enzyme analysis was performed, MbiI for Arg574Pro and AatII for Ala38Val. It is concluded that for MMP-9, the polymorphism presents the C allele as the G only in the metastatic group. As for the MMP-11 gene, the allelic variant T is found in high frequency, which does not correspond to the ancestral allele, indicating that its function/expression may be related to mammary carcinoma. These findings are preliminary (AU)

STUDIES OF MOLECULAR CHANGES IN INTERVERTEBRAL DISC DEGENERATION IN ANIMAL MODEL

ABSTRACT Objective: To evaluate the structural and molecular changes in the extracellular matrix (ECM) during the process of intervertebral disc degeneration, using animal model. Methods: Wistar rats underwent intervertebral disc degeneration through 20-gauge needle puncture, and 360° rotation applied for 30 sec, representing the degenerated group, while control group was not submitted to this procedure. Histological parameters and expression of extracellular matrix molecules were evaluated in the 15th and 28th days after degenerative induction. Results: Fifteen days after the induction of intervertebral disc degeneration, significant changes were observed, such as reduction in the expression metalloprotease-9 (MMP9) and interleukins (IL-6 and IL-10). There was a significant increase in the expression of vascular endothelial growth factor (VEGF) and caspase-3. However, different alterations in the ECM were observed at 28 days, the level of collagen I, metalloprotease-2 (MMP2) and caspase-3 were enhanced. Furthermore, expression of heparanase isoforms (HPSE1 and HPSE2) mRNA were increased in the degenerative intervertebral disc. Conclusion: The different profiles of ECM molecules observed during the intervertebral disc degeneration suggest that molecular processes such as ECM remodeling, neovascularization, apoptosis and inflammation occur. Experimental Study.

Role of ADAMTS13 in diagnosis and pathogenesis of liver diseases / 临床肝胆病杂志

Recent studies have demonstrated that coagulation function and liver microcirculation disturbance are important in the development and progression of liver diseases. ADAMTS13, also known as von Willebrand factor-cleaving protease, is a metalloproteinase produced by hepatic stellate cells, with major functions to cleave the von Willebrand factor multimers produced by vascular endothelial cells, regulate the adhesive capacity of platelets, and influence the body′s coagulation function and microcirculation. The important role of ADAMTS13 in the pathophysiological processes of various severe liver diseases such as liver cirrhosis, severe alcoholic hepatitis, hepatic veno-occlusive disease after stem cell transplantation, and liver graft dysfunction is reviewed in this paper, and its association with the severity of liver diseases is clarified. Plasma ADAMTS13 is involved in the development and progression of various liver diseases, and measurement of its level and activity can help the diagnosis and differential diagnosis of liver diseases.

Multi-step purifications of botulinum neurotoxin A light chain and identification of its metalloproteases activity / 军事医学

Objective To obtain highly purified botulinum neurotoxin A light chain(BoNT-ALC) protein in E.coli by genetic engineering and multi-step purifications, and identify its metalloproteases activity.Methods The full-length of BoNT-ALC was cloned from BoNT A by PCR and inserted into plasmid pET-22b.Then pET-22b-ALC was transformed into E.coli BL21( DE3) strains and induced by IPTG.The protein was purified by Ni-NTA sepharose,anion exchange column and gel filtration.The enzymatic activity of the protein was identified by SNAP-25.Results and Conclusion A highly purified and homogeneous protein is obtained, which shows good enzymatic activity.

Efecto del alendronato sobre el perfil de citoquinas y metaloproteinasas 2 y 9 en un modelo múrido de artritis experimental / Alendronate effects on cytokines and metalloproteases 2 and 9 profiles in an experimental arthritis murine model

Resumen Introducción: La artritis es una de las artropatías más frecuentes, se caracteriza por el daño que produce en el cartílago articular y la resorción ósea subcondral. El diagnóstico temprano es de crucial importancia para instaurar una terapia preventiva, ya que, en ocasiones, la enfermedad es diagnosticada al presentarse lesiones óseas de difícil resolución. Objetivos: Caracterizar, en un modelo múrido de artritis experimental producida por adyuvante, el perfil de distintos biomarcadores articulares, interleuquinas (IL-4, IL-6 y TNF-a) y metaloproteasas (MMP-2 y MMP-9), que permitan seguir la evolución de la enfermedad y analizar sus diferencias, al aplicar el tratamiento con alendronato en forma preventiva o curativa. Materiales y métodos: El alendronato, en forma preventiva, se aplicó el día 0 y de manera curativa a los dos meses posadyuvante. Se realizó un puntaje de los síntomas clínicos; al sacrificio, se determinaron los marcadores articulares y se realizaron los estudios histopatológicos y radiográficos. Resultados: Lo más destacable fue que el grupo que recibió el alendronato, de manera preventiva, alcanzó un puntaje clínico normal de manera más temprana que el grupo control con adyuvante. Asimismo, los animales tratados con alendronato presentaron valores significativamente más bajos de metaloproteasas. Conclusiones: Nuestros resultados sugieren que, aparentemente, el alendronato disminuye la actividad de proteasas vinculadas a la fisiopatología de la enfermedad articular, lo cual podría resultar sumamente beneficioso para la terapéutica a instaurar.

Abstract Introduction: Arthritis is one of the most common arthropathies, characterized by cartilage damage associated with subchondral bone resorption. Early diagnosis is crucial for the prevention of subchondral bone lesions. Objectives: To use an experimental adjuvant arthritis rat model, to measure joint biomarkers, interleukins (IL-4, IL-6 and TNF-a), and metalloproteases (MMP-2 and MMP-9) to follow the progression of the disease and to analyze the possible changes in the different treatment groups, with preventive or curative alendronate. Materials and methods: Preventive alendronate was applied on day 0, and a curative regimen 2 months post-adjuvant. A clinical scale score was used for characterizing clinical symptoms, and, at sacrifice, joint biomarkers and histopathological and radiographic studies were determined. Results: The most notable result was that the group that received preventive alendronate reached a normal clinical score faster than control adjuvant group. All alendronate groups showed significantly lower MMPs levels. Conclusions: Alendronate apparently decreases proteases activity linked to the pathophysiology of joint disease, this could be extremely beneficial for the clinical outcome of arthritis.

Proteolytic activity in the adult and larval stages of the human roundworm parasite Angiostrongylus costaricensis

Angiostrongylus costaricensis is a nematode that causes abdominal angiostrongyliasis, a widespread human parasitism in Latin America. This study aimed to characterize the protease profiles of different developmental stages of this helminth. First-stage larvae (L1) were obtained from the faeces of infected Sigmodon hispidus rodents and third-stage larvae (L3) were collected from mollusks Biomphalaria glabrata previously infected with L1. Adult worms were recovered from rodent mesenteric arteries. Protein extraction was performed after repeated freeze-thaw cycles followed by maceration of the nematodes in 40 mM Tris base. Proteolysis of gelatin was observed by zymography and found only in the larval stages. In L3, the gelatinolytic activity was effectively inhibited by orthophenanthroline, indicating the involvement of metalloproteases. The mechanistic class of the gelatinases from L1 could not be precisely determined using traditional class-specific inhibitors. Adult worm extracts were able to hydrolyze haemoglobin in solution, although no activity was observed by zymography. This haemoglobinolytic activity was ascribed to aspartic proteases following its effective inhibition by pepstatin, which also inhibited the haemoglobinolytic activity of L1 and L3 extracts. The characterization of protease expression throughout the A. costaricensis life cycle may reveal key factors influencing the process of parasitic infection and thus foster our understanding of the disease pathogenesis.

Análise imunoistoquímica de metaloproteases nos cistos dentígeros, cistos radiculares e tumores odontogênicos ceratocísticos: revisão sistemática / Immunohistochemical analysis of metalloproteases in dentigerous cysts, radicular cysts and keratocystic odontogenic tumors: systematic review

Evidence suggests that metalloprotease expression may affect the biological behavior of odontogenic lesions. This study was conducted to review the literature about the role of metalloproteases in the development of odontogenic lesions. A search was carried out using one database, MEDLINE, via PubMed. Only articles written in English were included. Abstracts of all articles retrieved in the electronic search were evaluated for their relevance. Three articles met inclusion criteria. They analyzed the role of MMP-2, MMP-8 and MMP-13 in radicular cysts, dentigerous cysts and keratocystic odontogenic tumors, and of MMP-1, MMP-7 and MMP-27 in keratocystic odontogenic tumors. The immunostaining technique used for all studies was similar, differing only in type of staining used. Different immunoreactivity results were found in the studies. The pattern of metalloprotease expression in odontogenic lesions was different from the pattern found in other lesions. In the studies analyzed, there was a significant positive immunoreactivity for metalloproteases in odontogenic lesions, particularly in keratocystic odontogenic tumors, a finding that may explain KCOT aggressiveness.

Evidências sugerem que a expressão das metaloproteinases podem afetar o comportamento biológico das lesões odontogênicas. Esse estudo foi conduzido a fim de revisar a literatura sobre o papel das metaloproteinases no desenvolvimento das lesões odontogênicas. A pesquisa foi realizada utilizando a base de dados do MEDLINE, via PUBMED. Somente artigos escritos em língua inglesa foram aceitos. Os resumos de todos os artigos encontrados na busca foram avaliados de acordo com sua relevância. Três artigos preencheram os critérios de inclusão. Eles analisaram o papel da MMP-2, MMP-8 e MMP-13 nos cistos radiculares, cistos dentígeros e nos tumores odontogênicos ceratocísticos (TOC) e MMP-1, MMP-7 e MMP-27 no TOC. A técnica imunoistoquímica utilizada por todos os estudos foi similar, diferindo somente pelo tipo da coloração utilizada. Diferentes imunomarcações foram encontradas nos estudos. O padrão da expressão das metaloproteinases nas lesões odontogênicos variou entre as lesões. Nos estudos analisados, houve uma imunomarcação positiva, significante estatiticamente, das metaloproteinases nas lesões odontogênicas em especial nos TOCs, o que pode explicar a agressividade dessas lesões.

Role of a disintegrin and metalloprotease with thrombospondin type 1 motifs in aged rat myocardium after ischemic preconditioning / 中华老年医学杂志

Objective To investigate the effect of ischemic preconditioning (IPC) on the expression of a disintegrin and metalloprotease with thrombospondin type 1 motifs (ADAMTS-1), and to study whether the application of small interfering (si)RNA specifically targeting ADAMTS-1 would help to recover IPC protection in the aged heart. Methods The 32 young (4 months) and 32 aged(24 months) male Sprague-Dawley (SD) rats were assigned randomly to IPC group (n=20) and sham operated group (n= 12) respectively. Myocardial samples from the ischemic-reperfused region were harvested for detecting the ADAMTS-1 expression. In addition, the 110 aged SD rats were assignedrandomly to ADAMTS-1 siRNA group and control group (n=55, each). The effects of ADAMTS-1siRNA transfcction on the expression of ADAMTS-1 protein, myocardial infarction survival rate,heart function and myocardial infarction size after IPC were observed.Results Twenty-four hours after IPC, the ADAMTS-1 protein expression increased significantly in iscbemic-reperfused region both in young and aged rats (P＜0. 05), and the protein expression was higher in aged rats than in young rats (P＜0.05). In young-IPC group, the absorbency showed ADAMTS-1 protein expression at 0 hrs and 24 hrs after IPC were 0. 05±0.01 and 0.12±0.03 by immunohistochemical staining, and were 0.68±0. 16 and 1. 17±0.21 by Western blots respectively. In aged-IPC group, the absorbency showed ADAMTS-1 protein expression at 0 hrs and 24 hrs after IPC were 0.07±0. 03 and 0.21 ±0.04 by immunohistochemical staining, and were 0. 76±0. 21 and 1. 48±0. 17 by Western blots. In the aged rats, ADAMTS-1 siRNA transfection inhibited ADAMTS-1 protein expression (0. 66±0. 19and 0.78±0.21, by Western blots at 0 hrs and 24 hrs after IPC, P＞0.05), but didn't improve myocardial infarction survival rates [ADAMTS-1 siRNA group and sham operated group: 14.3% (5/35) vs. 17.1 %(6/35), P＞0.05], left ventricular fractional shortening [(14.0±3.2)% vs. (13.0±2.9)%, P＞0.05] and myocardial infarction size[(39.0±4.1)% vs. (38.0±5.3)%, P＞0.05].Conclusions ADAMTS-1 expression induced by IPC increases significantly in aged versus in young rats. ADAMTS-1 knockdown by siRNA inhibits ADAMTS-1 protein expression but cannot recover the age-associated loss of IPC protection.

Diagnostic value of a distintegrin and metalloproteases-8 in non-small cell lung cancer / 中国综合临床

Objective To study the diagnostic values of a distintegrin and metalloproteases-8 (ADAMS) in non-small cell lung cancer(NSCLC).Methods The serum protein level of ADAM8 was assayed by ELISA in 62 NSCLC patients,27 lung benign lesions and 32 healthy people.Results The serum levels of ADAM8 of NSCLC [(456.88±143.87)ng/L] were higher than those with lung benign lesions[ (271.63±74.20) ng/L] and normal controls(253.09±72.15 ng/L) (P<0.01), but there was no significant difference between lung benign lesions and normal controls (P0.05).No significant difference was found between adenocarcinoma and squamous cell carcinoma in serum ADAM8 level,the serum levels of ADAM8 in NSCLC with stages Ⅲ-Ⅳ [ (498.80 ± 151.80) ng/L] were higher than those with stages Ⅰ -Ⅱ[(385.80±95.85) ng/L] (P <0.01 ).The diagnostic sensitivity of detection of ADAM8 for NSCLC was 77.4% and the specificity was 90.6%.Conclusion The overexpression of ADAM8 in serum of NSCLC patients indicates that ADAM8 is related with occurrence and metastasis of NSCLC;De-tection of ADAM8 could assist the diagnosis for NSCLC.

Rationale for anti-inflammatory therapy in dry eye syndrome: [review] / Bases da terapia antiinflamatória em síndrome do olho seco: [revisão]

Dry eye is a multifactorial condition that results in a dysfunctional lacrimal functional unit. Evidence suggests that inflammation is involved in the pathogenesis of the disease. Changes in tear composition including increased cytokines, chemokines, metalloproteinases and the number of T cells in the conjunctiva are found in dry eye patients and in animal models. This inflammation is responsible in part for the irritation symptoms, ocular surface epithelial disease, and altered corneal epithelial barrier function in dry eye. There are several anti-inflammatory therapies for dry eye that target one or more of the inflammatory mediators/pathways that have been identified and are discussed in detail.

Olho seco é uma doença multifatorial que resulta em disfunção da unidade lacrimal glandular. Evidências sugerem que inflamação está involvida na patogênese da doença. Mudanças na composição das lágrimas, incluindo aumento de citocinas, quimiocinas, metaloproteinases e o número de células T na conjuntiva são encontrados em pacientes com olho seco e em modelos animais. Esta inflamação é responsável em parte pelos sintomas de irritação, doença epitelial de surperfície ocular e função epitelial de barreira alterada em olho seco. Existem várias terapias antiinflamatórias que se direcionam para um ou mais mediadores/vias que foram identificados e são discutidos em detalhe.