Analogues of the pan-selectin antagonist rivipansel (GMI-1070).

The selectin family consisting of E-, P- and L-selectin plays dominant roles in atherosclerosis, ischemia-reperfusion injury, inflammatory diseases, and metastatic spreading of some cancers. An early goal in selectin-targeted drug discovery campaigns was to identify ligands binding to all three selectins, so-called pan-selectin antagonists. The physiological epitope, tetrasaccharide sialyl Lewisx (sLex, 1) binds to all selectins, albeit with very different affinities. Whereas P- and L-selectin require additional interactions contributed by sulfate groups for high binding affinity, E-selectin can functionally bind sLex-modified glycolipids and glycoproteins. Rivipansel (3) marked the first pan-selectin antagonist, which simultaneously interacted with both the sLex and the sulfate binding site. The aim of this contribution was to improve the pan-selectin affinity of rivipansel (3) by leveraging a new class of sLex mimetics in combination with an optimized linker length to the sulfate bearing group. As a result, the pan-selectin antagonist 11b exhibits an approximatively 5-fold improved affinity for E-, as well as P-selectin.

Let's Get Rolling: Precise Control of Microfluidic Assay Conditions to Recapitulate Selectin-Mediated Rolling Interactions of the Leukocyte Adhesion Cascade.

The leukocyte adhesion cascade governs the recruitment of circulating immune cells from the vasculature to distal sites. The initial adhesive interactions between cell surface ligands displaying sialyl-LewisX (sLeX) and endothelial E- and P-selectins serve to slow the cells down enough to interact more closely with the surface, polarize, and exit into the tissues. Therefore, precise microfluidic assays are critical in modeling how well immune cells can interact and "roll" on selectins to slow down enough to complete further steps of the cascade. Here, we present a systematic protocol for selectin mediated rolling on recombinant surfaces and endothelial cell monolayers on polyacrylamide gels of varying stiffness. We also describe step-by-step the protocol for setting up and performing the experiment and how to analyze and present the data collected. This protocol serves to simplify and detail the procedure needed to investigate the initial selectin-mediated interactions of immune cells with the vasculature. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Preparing dishes for cell rolling experiments Basic Protocol 2: Fabrication of polyacrylamide gels for cell rolling experiments Alternate Protocol 1: Protein conjugation with N6 linker Alternate Protocol 2: HUVEC culturing for monolayers Basic Protocol 3: Conducting cell rolling experiments on polyacrylamide gels Basic Protocol 4: ImageJ analysis of cell rolling movies Basic Protocol 5: Quantification of Fc site density on a surface (e.g., for Fc chimeras).

Perioperative Treatment with Rivaroxaban and Dabigatran on Changes of Coagulation and Platelet Activation Biomarkers following Left Atrial Appendage Closure.

Insufficient data exist regarding the investigation of the impact of novel oral anticoagulants (NOACs) on coagulation activation biomarkers in the context of left atrial appendage closure (LAAC) and device-related thrombosis (DRT). The study was designed to investigate the changes and presence of coagulation activation biomarkers between different antithrombotic strategies following LAAC. A total of 120 nonvalvular atrial fibrillation patients intolerant of long-term anticoagulants, who underwent successful WATCHMAN closure implantation, were enrolled (rivaroxaban, n = 82; dabigatran, n = 38). Blood samples were obtained from left atrium (LA) and left atrial appendage (LAA) during the operation and fasting blood samples on the same day of LAAC and 45 days after discharge. The biochemical indicators, thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), von Willebrand factor (vWF), and CD40 ligand (CD40L), were measured by enzyme-linked immunosorbent assay. The primary endpoints of this study were the efficacy and safety characteristics of different antithrombotic strategies, including DRT incidence, stroke or transient ischemic attack, systemic embolism, and clinical major and nonmajor bleeding complications during the follow-up of 180 days. The results revealed that TAT, vWF, sP-selectin, and CD40L levels in vein were significantly reduced by 2.4% (p = 0.043), 5.0% (p < 0.001), 8.7% (p < 0.001), and 2.5% (p = 0.043) from their baseline levels after rivaroxaban treatment. Conversely, no significant changes were detected in the dabigatran group. Furthermore, the plasma levels of platelet activation biomarkers (CD40L and sP-selectin) in both LA and LAA groups were significantly lower after anticoagulation with rivaroxaban, as compared to dabigatran treatment (CD40L: 554.62 ± 155.54 vs. 445.02 ± 130.04 for LA p = 0.0013, 578.51 ± 156.28 vs. 480.13 ± 164.37 for LAA p = 0.0052; sP-selectin: 2849.07 ± 846.69 vs. 2225.54 ± 799.96 for LA p = 0.0105, 2915.52 ± 1402.40 vs. 2203.41 ± 1061.67 for LAA p = 0.0022). Notably, the present study suggests that rivaroxaban may be more effective in the prevention of DRT for patients undergoing LAAC.

Topology of molecular deformations induces triphasic catch bonding in selectin-ligand bonds.

Among the long-standing efforts to elucidate the physical mechanisms of protein-ligand catch bonding, particular attention has been directed at the family of selectin proteins. Selectins exhibit slip, catch-slip, and slip-catch-slip bonding, with minor structural modifications causing major changes in selectins' response to force. How can a single structural mechanism allow interconversion between these various behaviors? We present a unifying theory of selectin-ligand catch bonding, using a structurally motivated free energy landscape to show how the topology of force-induced deformations of the molecular system produces the full range of observed behaviors. We find that the pathway of bond rupture deforms in non-trivial ways, such that unbinding dynamics depend sensitively on force. This implies a severe breakdown of Bell's theory-a paradigmatic theory used widely in catch bond modeling-raising questions about the suitability of Bell's theory in modeling other catch bonds. Our approach can be applied broadly to other protein-ligand systems.

The pathophysiological role of circulating adhesion molecules in schizophrenia: A systematic review and meta-analysis.

BACKGROUND: Increasing evidence suggests an association between schizophrenia and atherosclerosis. We conducted a systematic review and meta-analysis of cell adhesion molecules, critically involved in early atherosclerosis, in schizophrenia. METHODS: We searched electronic databases from inception to 11 November 2023 for case-control studies assessing vascular cell, VCAM-1, intercellular, ICAM-1, platelet endothelial cell, PECAM-1, neural cell, NCAM, and Down syndrome cell, DSCAM, adhesion molecules, selectins (E-, L-, and P-selectin), integrins, and cadherins in patients with schizophrenia and healthy controls. Risk of bias and certainty of evidence were assessed using the JBI checklist and GRADE, respectively. RESULTS: In 19 eligible studies, there were non-significant between-group differences in the concentrations of cell adhesion molecules, barring higher P-selectin in patients with schizophrenia (standard mean difference, SMD = 2.05, 95 % CI 0.72 to 3.38, p = 0.003; I2 = 97.2 %, p<0.001; very low certainty of evidence). Limited or no information was available regarding PECAM-1, DSCAM, ESAM, integrins, and cadherins. In meta-regression and subgroup analysis, there were significant associations between the SMD of ICAM-1 and matrix used (plasma or serum) and pharmacological treatment of schizophrenia, and between the SMD of VCAM-1 and pharmacological treatment, but not with other study and patient characteristics. CONCLUSIONS: The results of our systematic review and meta-analysis do not support a significant role of immunoglobulin-like adhesion molecules, selectins, integrins, or cadherins in mediating the associations between schizophrenia, atherosclerosis, and cardiovascular disease. Further studies are warranted to investigate these associations in patients with different cardiovascular risk and the effects of antipsychotic treatments on cell adhesion molecules and surrogate markers of atherosclerosis (PROSPERO registration number: CRD42023463916).

Differential expression of adhesion molecules in sickle cell anemia and gut microbiome effect.

Sickle cell anemia (SCA) causes a long-standing vascular inflammation state, leading to endothelial dysfunction and chronic overexpression of several adhesion molecules, which contributes to acute and constant vaso-occlusive (VOC) episodes. It has been demonstrated that hydroxyurea (HU) can reduce VOC events, organ damage, blood transfusions, and even the adhesion properties to endothelial cells of SCA subjects. Due to VOC episodes, these patients are also more susceptible to recurrent bacterial translocation and dysbiosis. Given this, our study aimed to uncover the interplay between adhesion molecules, gut microbiome, and hydroxyurea in a population of Angolan SCA children. Serum and fecal samples were obtained before and after HU treatment in 35 children. After HU, four of these adhesion molecules were significantly reduced: sE-selectin (p = 0.002), ADAMTS13 (p = 0.023), sICAM-1 (p = 0.003), and sVCAM-1 (p = 0.018). A positive correlation was observed between the number of neutrophils and sICAM-1, platelets, and sP-selectin, and also between leukocytes, sICAM-1, and sVCAM-1. Most taxa showing a significant correlation mainly belonged to the Clostridiales order. Specifically, from the Clostridium genera, the groups g19, g21, and g34 were all negatively correlated with HbF levels; g19, g21, and g24 positively correlated with leukocytes; g19 positively with neutrophils and sVCAM-1; and g34 positively with E- and P-selectin. Serratia, an opportunistic pathogen, was positively correlated with sE-selectin and sICAM-1 levels. Additionally, a negative correlation was observed between sP-selectin and Bifidobacterium. Research studies in this area could improve our understanding and contribute to finding new prognostic biomarkers to guarantee precise SCA patient stratification and predict severe complications.

Isoquercetin for thromboinflammation in sickle cell disease: a randomized double-blind placebo-controlled trial.

ABSTRACT: Data from a small trial in patients with cancer suggest that isoquercetin (IQ) treatment lowered thrombosis biomarkers and prevented clinical thrombosis, but, to our knowledge, no studies of IQ have been conducted to target thromboinflammation in adults with sickle cell disease (SCD). We conducted a randomized, double-blind, placebo-controlled trial in adults with steady-state SCD (hemoglobin SS [HbSS], HbSß0thal, HbSß+thal, or HbSC). The primary outcome was the change in plasma soluble P-selectin (sP-selectin) after treatment compared with baseline, analyzed in the intention-to-treat population. Between November 2019 and July 2022, 46 patients (aged 40 ± 11 years, 56% female, 75% under hydroxyurea treatment) were randomized to receive IQ (n = 23) or placebo (n = 23). IQ was well tolerated and all the adverse events (AEs; n = 21) or serious AEs (n = 14) recorded were not attributable to the study drug. The mean posttreatment change for sP-selectin showed no significant difference between the treatment groups (IQ, 0.10 ± 6.53 vs placebo, 0.74 ± 4.54; P = .64). In patients treated with IQ, whole-blood coagulation (P = .03) and collagen-induced platelet aggregation (P = .03) were significantly reduced from the baseline. Inducible mononuclear cell tissue factor gene expression and plasma protein disulfide isomerase reductase activity were also significantly inhibited (P = .003 and P = .02, respectively). Short-term fixed-dose IQ in patients with SCD was safe with no off-target bleeding and was associated with changes from the baseline in the appropriate direction for several biomarkers of thromboinflammation. The trial was registered at www.clinicaltrials.gov as #NCT04514510.

Dilataciones quísticas congénitas de las vías biliares (primera parte). Vías biliares intrahepáticas / Congenital bile duct cystic dilatation (part 1). Intrahepatic bile ducts

RESUMEN La enfermedad de Caroli es una enfermedad infrecuente que requiere un alto índice de sospecha para su diagnóstico. Puede afectar un segmento hepático, un lóbulo o todo el hígado; suele generar episodios repetidos de colangitis. Existe una amplia gama de propuestas terapéuticas que oscilan desde el tratamiento médico hasta el trasplante de hígado. En este trabajo presentamos 3 casos, realizamos una revisión de la literatura y proponemos una ampliación de la clasificación de Alonso-Lej modificada por Todani que, a nuestra manera de ver, tiene implicaciones a la hora de seleccionar un tratamiento.

ABSTRACT Caroli's disease is a rare condition, and its diagnosis requires high level of suspicion. The disease may affect one segment, one lobe or the entire liver, and may result in repeated episodes of cholangitis. The disease can be managed using different therapeutic approaches ranging from medical treatment to liver transplantation. In this paper we report 3 cases with review of the literature and propose a modification of the classification by Alonso-Lej modified by Todani which we believe may be useful to guide treatment.

Etiología y perfil de resistencia antimicrobiana en pacientes con infección urinaria / Etiology and antimicrobial resistance profile in patients with urinary infection

Introducción: La infección de vías urinarias (IVU) es una de las enfermedades más prevalentes en la práctica clínica Objetivo: Identificar los principales agentes etiológicos y la frecuencia de resistencia a antibióticos por parte de microorganismos aislados por urocultivos en pa cientes con IVU en un hospital de primer nivel de atención. Materiales y Métodos: Estudio descriptivo de corte transversal, a partir de una muestra aleatoria de pacientes con IVU en La Virginia, Risaralda, entre el 1 de abril de 2014 a 31 de marzo de 2015. Se evaluaron las bacterias aisladas en la totalidad de urocultivos procesados y los resultados de los antibiogramas. Se establecieron frecuencias y proporciones. Para el análisis de datos, se utilizó SPSS Statistics 22. Se hizo análisis multivariado. Resultados: Se realizaron 1563 urocultivos en el periodo de estudio, de los cuales 329 (21,0%) mostraron crecimiento mayor a 100.000 UFC. Las frecuencias más altas de resistencia para E. coli se observaron para cefalotina (75,8%), ampicilina (72,6%) y trimetoprim/sulfametoxazol (55,3%). De 296 pacientes seleccionados aleatoriamente se halló que la cistitis era la IVU más frecuente (70,3%) y al 50,7% no se les prescribió ningún antimicrobiano. El uso de antiulcerosos se asoció con mayor probabilidad de uso inadecuado del antibiótico (OR:4,28; IC95%:1,070-17,153; p=0,04). Conclusiones: Existe una elevada resistencia bacteriana a los antibióticos de primera línea para el tratamiento de las IVUs, lo que sugiere la importancia de identi ficar los microorganismos y sus perfiles de sensibilidad a antimicrobianos para seleccionar con mejor criterio cual emplear.

Introduction: Urinary tract infection (UTI) is one of the most prevalent diseases in clinical practice. Objective: To identify the main etiologic agents and the frequency of antibiotic resistance by microorganisms isolated from urine culture and sensitivity in patients with IVU in a hospital primary care. Materials and Methods. Descriptive cross-sectional study, from a random sample of patients with UTI in La Virginia, Risaralda, from April 1, 2014 to March 31, 2015. Bacteria isolated from all processed urine cultures and the results of susceptibility were evaluated. Frequencies and proportions were established. For data analysis was used SPSS Statistics 22. Results: A total of 1563 urine cultures were performed in the study period, of which 329 (21.0%) showed further growth to 100,000 UFC. Higher frequencies of resis tance were observed for E. coli to cephalothin (75.8%), ampicillin (72.6%) and trimethoprim/sulfamethoxazole (55.3%). In the 296 randomized patients it was found that the most common UTI was cystitis (70.3%) and 50.7% were not prescribed any antimicrobial. The use of anti-ulcer is associated with increased probability of inappropriate use of antibiotics (OR:4.28; 95% CI:1.070-17.153; p=0.04). Conclusions: There is a high bacterial resistance to first-line antibiotics for treatment of UTIs, suggesting the importance of identifying microorganisms and their antimicrobial susceptibility profiles to select which use better approach.

The effect of mesenchymal stem cell use on intra-abdominal adhesions in a rat model

PURPOSE: Intra-abdominal adhesions (IAA) are among the most frequently seen pathologies in general surgery practice with an increased morbidity and mortality. In the present study, we investigated the effect of locally applied mesenchymal stem cells (MSCs) on IAA. METHODS: Twenty-four Wistar Albino rats were used in the study. The rats were divided into three groups including: Sham, control, and MSCs group. On day 0, cecum was reached under anesthesia in all groups, except the Sham group. Scraping with a sponge was performed until petechial bleeding occurred. The control group received no treatment. In the stem cell group, MSCs were applied topically immediately after surgery on adhesions. The rats were sacrificed on day 10 and colon tissues and blood samples were collected for macroscopic, histopathological, and biochemical analysis. RESULTS: In our study, E-selectin, P-selectin, TNF-α and IL-1 levels were statistically significantly lower in the MSC group than the control group, while the sham group has the lowest levels. In both the macroscopic and histopathological analyses (Zühlke's scale), the least amount of adhesion was observed in the Sham group. In addition, although there was less adhesion in the MSC group than the control group, the difference did not reach statistical significance. CONCLUSION: Topical MSC application immediately after surgery suppresses the inflammatory process. However it was found to be ineffective in histopathological and macroscopic examinations performed on the 10th day.

Alteraciones inmunológicas y de los valores de selectinas en pacientes hipertensos tratados según criterios actuales / Immunological alterations and selectin values in hypertensive patients treated according to current criteri

Fundamento y objetivo: Calcular la relación entre las selectinas P y E, y los cambios inmunológicos que se producen en la hipertensión esencial. Pacientes y método:Se incluyeron 261 pacientes con hipertensión esencial con y sin hipertrofia del ventrículo izquierdo (HVI), a los que se les determinó las concentraciones de selectinas y citocinas específicas. Resultados:Los valores de selectina-P y E estuvieron elevados respecto al grupo control (media [DE] de 75 [51] ng/mL frente a 45 [17] ng/mL, p<0,0001, y 47 [18] ng/mL frente a 38 [15] ng/mL, p=0,049), así como las concentraciones de citocinas (p<0,0001). Además, las selectinas se relacionaron significativamente con los cambios en marcadores inmunológicos. El análisis multivariado mostró que la citocina interleucina (IL) 1ra (p<0,0001) y selectina-P (p=0,013) fueron factores independientes de los valores de selectina-E. Para selectina-P, lo fueron IL-1ra (p=0,005), IL-8 (p<0,0001), y selectina-E (p=0,013). Por último, las concentraciones de selectinas no fueron diferentes entre pacientes con y sin hipertrofia ventricular. Conclusiones: La activación inmunológica influye en los valores de selectinas en pacientes asintomáticos con hipertensión esencial. La HVI no indujo cambios significativos (AU)

Background and objective: To calculate the relationsship of E and P selectins with immunological changes in essential hypertension.Patients and method: We included 261 patients with essential hypertension with or without left ventricular hypertrophy (LVH), in whom selectins and specific cytokines were quantified. Results:E-and P-selectins were increased in hypertension compared to controls [75(51) ng/mL versus 45(17) ng/mL, (p<0.0001) and 47(18) ng/mL versus 38(15) ng/mL, (p=0.049), respectively], as well as cytokine concentrations (p<0.0001). Furthermore, selectin values were significantly correlated with changes in immunological markers. The multivariate analysis showed that IL-1ra (p<0.0001) and P-selectin (p=0.013) were independent factors of E-selectin values. For P-selectin, IL-1ra (p=0.005), IL-8 (p<0.0001) and selectin-E (p=0.013) influenced on its concentration. Finally, selectin values were similar between patients with or without left ventricular hypertrophy. Conclusions: Immunological activation influenced on selectin concentrations in cardiologic asymptomatic patients with essential hypertension. LVH did not induce significant changes (AU)

Mecanismos que controlan la migración del linfocito T a la piel / Mechanisms that control T lymphocyte migration into the skin

La piel es un órgano complejo que cumple funciones de barrera física e inmunológica. La presencia de numerosos tipos celulares explica su participación en la inmunidad innata y adaptativa y su capacidad de iniciar una cascada de eventos con repercusión sistémica, a la vez que la hace órgano blanco de procesos patológicos sistémicos. Uno de los principales componentes del sistema inmunitario cutáneo son las células de Langerhans, especializadas en la captura y presentación de antígenos; ante estímulos como la captura de antígenos extraños o propios alterados, migran al ganglio linfático para presentar los antígenos a los linfocitos T. Una vez activados, los linfocitos T pueden migrar a la piel gracias a la expresión de CLA (Cutaneous Lymphocyte-associated Antigen), cuyo ligando, la E-Selectina, se expresa en los endotelios dérmicos. Este proceso de migración y alojamiento en la piel está controlado por quimiocinas, citocinas y moléculas de adhesión que se presentan en el texto.

Respuesta inflamatoria durante los procesos de isquemia: moléculas de adhesión e inmunomodulación / Inflammatory response during ischaemic processes: adhesion molecules and immunomodulation

Introducción. Tras la isquemia cerebral se produce la muerte necrótica de las células afectadas por la ausencia de oxígeno y glucosa, especialmente de las neuronas. Esta necrosis desencadena la activación del sistema inmune y el inicio de la respuesta inflamatoria. El sistema nervioso central cuenta con células inflamatorias innatas como la microglía y los macrófagos, que poseen una función importante en la recepción y propagación de señales inflamatorias. Desarrollo. La respuesta inflamatoria se caracteriza por la expresión de mediadores inflamatorios y la invasión de células inflamatorias circulantes. El paso de los leucocitos a través del endotelio implica dos etapas coordinadas en el tiempo: la adhesión y la subsiguiente migración transendotelial. Por ello, las moléculas de adhesión en leucocitos y células endoteliales, como son las selectinas, las sialomucinas, la superfamilia de las inmunoglobulinas y las integrinas, constituyen moléculas clave que contribuyen al daño cerebral. Sin embargo, dicha respuesta precisa eliminar los restos celulares tanto necróticos como apoptóticos para iniciar los posibles procesos de reparación y plasticidad cerebral. Por tanto, la respuesta inflamatoria es una respuesta coordinada, y tras la activación de la inflamación se desencadena también una respuesta inmunosupresora y antiinflamatoria. Conclusiones. La inflamación se ha asociado a un aumento en el daño cerebral en pacientes con infarto cerebral, aunque es necesaria para activar los mecanismos de reparación. Por ello resulta preciso un estricto control de la respuesta inflamatoria después del infarto cerebral para reducir el daño del tejido afectado sin la inhibición de los mecanismos de reparación (AU)

Introduction. After cerebral ischemia, necrotic cell death occurs specially for neurons, mainly due to the privation of oxygen and glucose. Cell necrosis triggers the activation of the immune system followed by an inflammatory response. This reaction is characterized by the activation of astrocytes and microglia together with the infiltration of peripheral immune cells. Development. Both, microglia and inflammatory cells, including circulating peripheral inflammatory cells, get activated and release a plethora of inflammatory mediators, cytokines, chemokines, etc. Such released factors induce the overexpression of adhesion molecules, increasing the blood brain barrier permeability, thus favoring even more inflammatory cell infiltration. In the end, this contributes to increase brain damage. Inflammatory response is nevertheless necessary in order to eliminate cellular debris from both apoptotic and necrotic cells. It seems to be also implicated in the initiation of certain mechanisms responsible for brain repair and plasticity. As a result, the inflammatory response is a coordinated effort. Activation of inflammation triggers an immunosuppressant and anti-inflammatory response. A high rate of infections in patients suffering from stroke, together with increased serum levels of anti-inflammatory molecules in these patients, support this statement. The anti-inflammatory response could be interpreted as the organism attempting to control the heightened inflammatory response that occurs after cerebral ischemia. On the other hand, following an ischemic event, there are several new cerebral epitopes that get exposed to the immune system, which would never have been exposed under normal physiological conditions. Conclusion. Therefore immunosuppression after an ischemic accident hinders the development of auto-immune responses (AU)

Bases moleculares de las interacciones leucocito-endotelio durante la respuesta inflamatoria / Molecular basis of leukocyte–endothelium interactions during the inflammatory response

El proceso de extravasación leucocitaria, un paso crucial de la respuesta inflamatoria, implica la migración de los leucocitos desde la corriente sanguínea hasta los tejidos diana donde ejercen su función efectora. La extravasación de los leucocitos está orquestada por la acción conjunta de receptores de adhesión celular y factores quimiotácticos, e implica cambios morfológicos drásticos tanto en leucocitos como en células endoteliales. De este modo, constituye un proceso activo para ambos tipos celulares que promueve la rápida y eficiente llegada de los leucocitos a los focos inflamatorios sin comprometer la integridad de la barrera endotelial. Este artículo revisa la extravasación leucocitaria, con especial hincapié en los hallazgos más recientes en este campo, tanto desde el punto de vista molecular como mecanístico. Incluye la descripción de nuevos pasos en la cascada de adhesión tales como el enlentecimiento del rodamiento, la locomoción intraluminal o la ruta alternativa de migración transcelular, así como el papel funcional de nuevos receptores de adhesión, la organización espaciotemporal de los receptores en la membrana plasmática y las rutas de señalización que controlan los diferentes estadios del proceso de extravasación (AU)

The process of leukocyte extravasation, a critical step in the inflammatory response, involves the migration of leukocytes from the bloodstream towards target tissues, where they exert their effector function. Leukocyte extravasation is orchestrated by the combined action of cellular adhesion receptors and chemotactic factors, and involves radical morphological changes in both leukocytes and endothelial cells. Thus, it constitutes an active process for both cell types and promotes the rapid and efficient influx of leukocytes to inflammatory foci without compromising the integrity of the endothelial barrier. This article provides a review of leukocyte extravasation from both molecular and mechanical points of view, with a particular emphasis on the most recent findings on the topic. It includes a description of newly revealed steps in the adhesion cascade, such as slow rolling motion, intraluminal crawling and alternative pathways for transcellular migration, and discusses the functional role of novel adhesion receptors, the spatiotemporal organization of receptors at the plasma membrane, and the signaling pathways that control different phases of the extravasation process. for transcellular migration, and discusses the functional role of novel adhesion receptors, the spatiotemporal organization of receptors at the plasma membrane and the signaling pathways that control different phases of the extravasation process (AU)

Câncer de mama e disfunção endotelial: [revisão] / Breast cancer and endothelial dysfunction: [review]

Entre as mulheres brasileiras a principal causa de mortalidade são as doenças cardiovasculares, seguida em freqüência pelo câncer, sendo o de mama o mais comum. É bastante conhecida a associação de câncer com eventos tromboembólicos, mas pouco estabelecida sua relação com os demais eventos cardiovasculares. Para estudar estes eventos desde suas alterações primordiais, como a lesão e disfunção endotelial e a formação da placa aterosclerótica, vários métodos têm sido utilizados. Dentre eles, a dosagem sérica de P e E-selectina e do fator de von Willebrand são relevantes devido à associação tanto com o risco cardiovascular quanto com o processo de progressão e formação de metástase do câncer de mama. Outro método de avaliação da função endotelial é a medida da dilatação da artéria braquial mediada por fluxo, que cada vez mais ganha popularidade devido à sua natureza não-invasiva e a comprovação de sua associação com a disfunção endotelial e risco de eventos cardiovasculares. Buscamos, através desta revisão, condensar o que houve de mais relevante nestes últimos anos sobre a associação de câncer, em especial o de mama, com lesão endotelial e risco cardiovascular.

The main cause of death among Brazilian women is cardiovascular disease followed by cancer with breast cancer as the most incident. The relationship between cancer and thrombosis is well known, although its association with other cardiovascular events is poorly understood. In order to study these events from the earliest findings such as endothelial injury and dysfunction and the evolving atherosclerotic plaque, many methods are currently being used. Among these methods, E- and P-selectin and the von Willebrand factor have been associated, either with cardiovascular risk or with breast cancer growth and metastasis. Brachial artery flow-mediated dilatation is a tool available that emerged in the last decade due to its noninvasive nature and its clear association with endothelial dysfunction and cardiovascular risk. The aim of this revision is to bring the newest and most relevant updates about the association of breast cancer, endothelial injury and cardiovascular risk.

Fucoidan: advances in the study of its anti-inflammatory and anti-oxidative effects / 药学学报

Fucoidan is a natural polysaccharide extracted from brown seaweeds, with a wide variety of biological features, especially the anti-inflammatory and anti-oxidative effects. Studies indicated that the anti-inflammatory effect of fucoidan related to its capacity to interact with the selectin or scavenger receptor on the cell membrane. Fucoidan can also inhibit the synthesis and release of reactive oxygen species (ROS), as well as promote its clearance, showing the anti-oxidative activity.

Evaluación de disfunción endotelial en pacientes con diabetes tipo 2 / Dysfunction endothelial evaluation in type 2 diabetes patients

El objetivo de este trabajo fue estudiar moléculas involucradas en la activación endotelial, tales como la molécula de adhesión sE-Selectina (sE-S) y el péptido vasoconstrictor Endotelina-1 (ET-1) en individuos diabéticos tipo 2 y su asociación con otros factores de riesgo cardiovascular. Se estudiaron 62 pacientes diabéticos que se compararon con un grupo control. Las concentraciones de sE-S y ET-1 fueron significativamente mayores en los diabéticos que en los controles (sE-S: 90,6±26,2 ng/mL vs. 49,5±9,2 ng/mL, p<0,00001; ET-1: 11,3±3,7 vs. 7,7±0,5 pg/mL, p<0,001, respectivamente). Estas moléculas, en pacientes con índice de masa corporal (IMC) normal y aumentado, mostraron diferencias significativas (sE-S: 75,5±22,4 vs. 97,1±32,9 ng/mL, p<0,05; ET-1: 8,4±2,4 vs. 14,1±4,9 pg/mL, p=0,001, respectivamente). No se encontraron diferencias entre individuos diabéticos normo e hipertensos, no fumadores y fumadores, ni normo e hipercolesterolémicos. El 81% de la población estudiada presentó un pobre control glucémico (HA1c>7%), siendo significativamente mayores los niveles de ET-1 en este grupo (p<0,01) no así para sE-S (p=0,74). Los resultados obtenidos muestran que los pacientes diabéticos presentan activación endotelial reflejada en los niveles elevados de sE-S y ET-1. El IMC aumentado y el pobre control glucémico incrementan la disfunción endotelial en estos pacientes.

The object of this work was to study molecules involved in endothelial activation, such as E-selectin (sE-S) and the vasoconstrictor peptide Endothelin-1 (ET-1) in Type 2 diabetes patients, and their relation with other cardiovascular risk factors. Sixty-two patients with diabetes were compared with matched controls. sE-S and ET-1 concentrations in diabetes patients were significantly elevated compared with controls (sE-S: 90.6±26.2 ng/mL vs 49.5±9.2 ng/mL, p<0.00001; ET-1: 11.3±3.7 vs 7.7±0.5 pg/mL, p<0.001, respectively). sE-S and ET-1 levels in diabetes patients with normal and increased body mass index showed significant differences (sE-S: 75.5±22.4 vs. 97.1±32.9 ng/mL, p<0.05; ET-1: 8.4±2.4 vs. 14.1±4.9 pg/mL, p=0.001 respectively). There were no significant differences in none of the molecules values between patients with or without hypertension, smokers or non-smokers, neither in diabetes patients with or without hypercholesterolemia. Eighty-one percent of the population with diabetes presented a poor glycemic control (HA1c>7%) and in these patients, ET-1 plasma levels were significantly increased (p<0.01), but not sE-S (p=0.74). These results show that obesity and a poor glycemic control increase the endothelial dysfunction in type 2 diabetes patients.

Moléculas de adesão e câncer oral: revisão de literatura / Adhesion molecules in oral cancer: review

O presente trabalho consiste em uma revisão de literatura onde se evidencia que as moléculas de adesão desempenham um importante papel nos processos fisiológicos celulares, através das interações célula-célula, célula-matriz extracelular. Sua expressão alterada pode estar associada aos diversos e complexos mecanismos envolvidos no comportamento biológico do câncer oral, podendo aumentar o potencial metastático de células tumorais.

This paper has reviewed the literature about adhesion molecules. It has showed the role of cell adhesion molecules on cellular physiology by cell-cell and cell-matrix interactions. Its altered expression can be related in many pathways involved in oral cancer biological behavior, being capable of improving the metastatic potential of neoplastic cells.

Moléculas de adhesión: importancia en la respuesta inmune e inflamatoria / Adhesion molecules: Importance in the immune and inflammatory response

Las moléculas de adhesión son receptores funcionales que se expresan en la membrana celular y participan activamente en múltiples fenómenos fisiológicos y patológicos, como son: la organización de las células animales durante el desarrollo embrionario mediante su diferenciación, migración y localización en órganos y tejidos; en los fenómenos de la hemostasia, como la agregación plaquetaria y la formación de trombos; en la reparación tisular y la cicatrización de las heridas; en la diseminación tumoral o metástasis, y desempeñan un papel fundamental en la migración y activación de los leucocitos en la inmunovigilancia, en el desarrollo de la respuesta inflamatoria y de los mecanismos que intervienen en la respuesta inmune celular. La característica fundamental de estos receptores es la capacidad de transducir señales al interior de la célula y modular cascadas de señales inducidas por diferentes factores de crecimiento. El conocimiento de la regulación de la expresión de estas, su estado de activación en la superficie celular, la distribución celular y tisular y sus posibles interacciones, son de crucial importancia en la comprensión de los mecanismos de acción involucrados en el funcionamiento de las células que participan en la defensa inmunológica, en la fisiopatogenia de diferentes enfermedades y en el desarrollo de nuevas estrategias terapéuticas, por lo que el estudio del comportamiento de estas moléculas en el curso de diferentes enfermedades, constituye una línea de trabajo de gran actualidad e interés en el campo de la inmunología y en la práctica médica(AU)

Sepsis: emerging role of nitric oxide and selectins

Sepse – um estado de infecção bacteriana sistêmica – frequentemente leva à falência múltipla de órgãos e associa-se a altos índices de mortalidade, apesar de progressos recentes no manejo de pacientes em unidades de terapia intensiva. Muitos dos efeitos maléficos associados à sepse são atribuídos a uma resposta inflamatória patologicamente ampliada que leva a recrutamento neutrofílico e ativação das moléculas de adesão do grupo das selectinas, durante as fases iniciais do processo . O óxido nítrico e sua diversas isoformas também foram implicados nas diversas manifestações vasculares da sepse como participantes diretos da toxicidade celular. Esta revisão descreve o papel das selectinas e do óxido nítrico em situações clínicas e experimentais de sepse, bem como os respectivos efeitos de processos terapêuticos de bloqueio.