Angiogenesis and Multiple Sclerosis Pathogenesis: A Glance at New Pharmaceutical Approaches

Multiple sclerosis is a chronic disease of the central nervous system characterized by demyelination and destruction of axons. The most common form of the disease is the relapsing-remitting multiple sclerosis in which episodic attacks with typical neurological symptoms are followed by episodes of partial or complete recovery. One of the underestimated factors that contribute to the pathogenesis of multiple sclerosis is excessive angiogenesis. Here, we review the role of angiogenesis in the onset and in the development of the disease, the molecular mechanisms underlying angiogenesis, the current therapeutic approaches, and the potential therapeutic strategies with a look at natural compounds as multi-target drugs with both neuroprotective and anti-angiogenic properties

Characterization of IgM, total IgG, igG1 and hcabs in colostra of llamas (Lama glama) by Elisa

Objetivos: determinar los niveles de IgM, IgG total y Anticuerpos de Cadena Pesada (HCAbs; por su sigla en inglés Heavy Chain Antibodies) (IgG2 e IgG3) en calostro de llamas y evaluar la concentración de HCAbs en relación a la IgG total y al isotipo convencional IgG1. Métodos: en este estudio se utilizaron 15 llamas preñadas, que fueron ordeñadas dentro de las primeras 24 horas post-parto. Se diseñaron ELISAs Sandwich para la cuantificación de IgM total, IgG total e IgG1. La concentración de HCAbs fue calculada mediante la diferencia entre IgG total e IgG1. (HCAbs =IgG total-IgG1). Resultados: los niveles encontrados fueron: IgM=17.02 mg/ml (DS=9.85) IgG total= 42.54 mg/ml (DS=27.79), IgG1=24.34 mg/ml (DS=13.96) y HCAbs (IgG total-IgG1)= 18.19 mg/ml (DS=15.49). Los resultados de IgG fueron consistentes en relación a lo descripto en otras especies con similar tipo de placentación. Los HCAbs representan el 43% de IgG calostral y la concentración de IgM presentó valores muy altos (dos y tres veces más elevados) que los descriptos en las especies con similar tipo de placentación.Fil: Caggiano, Nicolás. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Saccodossi, Natalia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "Profesor R. A. Margni"; ArgentinaFil: Gentile, Maria Teresa. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "Profesor R. A. Margni"; ArgentinaFil: Chiappe Barbará, María Angelina. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Leoni, Juliana. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "Profesor R. A. Margni"; ArgentinaFil: de Simone, Emilio Adrian. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "Profesor R. A. Margni"; Argentin

Valuation of asymmetric IgG antibodies in swine serum and placental extracts

Antibodies (AC) of the immune system play a role during gestation that has yet to be fully understood. The present investigation focused on the percentage of asymmetric AcIgG united to the lectin concanavalin A relative to total AcIgG, in blood serums and placental extracts of sows at different stages of gestation, utilizing the differential ELISA method. The 45 samples processed were of serum and homogenates of maternal (HoPM) and fetal (HoPF) placenta from sows at 30 d (n = 17), 65-70 d (n = 9), and 95–114 d (n = 6) d of gestation, and from 13 non-pregnant uteri (HoU). The difference between non-pregnant and pregnant sows in percentage (asymmetric AcIgG/total AcIG) in serum (38 ± 3 vs. 37 ± 2), was not significant, but there was a difference (P<0.01) between the two groups at 30 d and 95 d of gestation (32 ± 3 vs. 43 ± 3). As for percentages (asymmetric AcIgG/total AcIgG) in HoPM, the 65 gestation sows significantly surpassed all other groups and those at 95 d gestation were inferior to all other groups. High percentages (asymmetric AcIgG/total AcIgG) were found in HoPF throughout gestation 52 ± 5, 44 ± 3, and 47 ± 4 at 30, 65, and 95 d, respectively). It is suggested that these antibodies were of maternal origen and serve to protect the fetus from its mother’s immune system. We postulate that the presence of asymmetric AcIgG in serum and maternal and fetal placenta functions in regulation of the maternal immune response and is essential for a successful pregnancy

Interaction between audiology and genetics in the study of a family: the complexity of molecular diagnosis and genetic counseling

Hearing loss is a multifaceted condition with many etiologies, among which genetic mutation is. Therefore, it is important to connect audiological investigation to etiological diagnosis. AIM: this study aims to establish the audiological and genetic profiles of three non-syndromic children with sensorineural hearing loss. MATERIALS AND METHOD: three brothers aged 3, 5 and 16 were enrolled in this study. They were submitted to behavioral and electrophysiological hearing tests and molecular studies. RESULTS: the hearing tests showed moderate to moderately severe bilateral symmetric sensorineural hearing loss and an accentuated descending slope. Transient and Distortion Product Otoacoustic emissions were absent in the two younger children. ABR showed a bilateral moderately severe to severe sensorineural hearing loss. P300 showed bilateral normal latencies in the older brother. Molecular tests showed that the two younger children were heterozygote for mutation 35delG on gene GJB2. CONCLUSION: The combination of speech and hearing tests and genetic analysis allows for the etiologic diagnosis of seemingly similar hearing loss cases, which however display different genetic backgrounds. Molecular studies must be comprehensive enough to avoid precipitated diagnosis which may impair genetic counseling.A deficiência auditiva como déficit sensorial mais comum tem dentre suas diferentes etiologias as alterações genéticas. Assim, é importante que a investigação audiológica se associe à busca do diagnóstico etiológico. OBJETIVO: Relatar o perfil audiológico e genético de três irmãos portadores de deficiência auditiva neurossensorial não-sindrômica. MATERIAL E MÉTODO: Estudo de caso de três irmãos, do sexo masculino, com 3, 5 e 16 anos, respectivamente, submetidos à avaliação audiológica comportamental e eletrofisiológica, e estudo molecular. RESULTADOS: Os achados audiológicos mostraram: audiometria do tipo neurossensorial, bilateral, simétrica, de grau moderado a moderadamente severo e configuração descendente acentuada. EOAT e EOAPD ausentes nos dois irmãos mais novos. PEATE compatível com perda auditiva moderadamente severa a severa. Presença do P300 com latências dentro da normalidade bilateralmente no irmão mais velho. Os achados do exame molecular mostraram que as duas crianças mais novas eram heterozigotos para a mutação 35delG no gene GJB2 e o mais velho não apresentava essa mutação. CONCLUSÃO: A associação das avaliações fonoaudiológicas e genéticas permite o diagnóstico etiológico de perdas auditivas que à primeira vista são semelhantes, mas que não obedecem à mesma estrutura genética. Os estudos moleculares devem ser abrangentes, evitando diagnósticos precipitados que prejudiquem o aconselhamento genético.Instituto de Estudos Avançados da AudiçãoUniversidade Federal de São Paulo (UNIFESP)Instituto de Estudos da AudiçãoUniversidade Estadual de CampinasUniversidade Estadual de Campinas Departamento de Genética MédicaUSP Faculdade de Medicina Departamento de Fisioterapia, Fonoaudiologia e Terapia OcupacionalFAPESPUNIFESPSciEL

High-Resolution Conformational Analysis of RGDechi-Derived Peptides Based on a Combination of NMR Spectroscopy and MD Simulations

The crucial role of integrin in pathological processes such as tumor progression and metastasis formation has inspired intense efforts to design novel pharmaceutical agents modulating integrin functions in order to provide new tools for potential therapies. In the past decade, we have investigated the biological proprieties of the chimeric peptide RGDechi, containing a cyclic RGD motif linked to an echistatin C-terminal fragment, able to specifically recognize αvβ3 without cross reacting with αvβ5 and αIIbβ3 integrin. Additionally, we have demonstrated using two RGDechi-derived peptides, called RGDechi1-14 and ψRGDechi, that chemical modifications introduced in the C-terminal part of the peptide alter or abolish the binding to the αvβ3 integrin. Here, to shed light on the structural and dynamical determinants involved in the integrin recognition mechanism, we investigate the effects of the chemical modifications by exploring the conformational space sampled by RGDechi1-14 and ψRGDechi using an integrated natural-abundance NMR/MD approach. Our data demonstrate that the flexibility of the RGD-containing cycle is driven by the echistatin C-terminal region of the RGDechi peptide through a coupling mechanism between the N- and C-terminal regions

Ruta graveolens water extract (RGWE) ameliorates ischemic damage and improves neurological deficits in a rat model of transient focal brain ischemia

The limited therapeutic options for ischemic stroke treatment render necessary the identification of new strategies. In recent years, it has been shown that natural compounds may represent a valid therapeutic opportunity. Therefore, the present study aimed to evaluate the protective effect of Ruta graveolens water extract (RGWE) in an in vivo experimental model of brain ischemia

Interaction between audiology and genetics in the study of a family: the complexity of molecular diagnosis and genetic counseling

Hearing loss is a multifaceted condition with many etiologies, among which genetic mutation is. Therefore, it is important to connect audiological investigation to etiological diagnosis. AIM: this study aims to establish the audiological and genetic profiles of three non-syndromic children with sensorineural hearing loss. MATERIALS AND METHOD: three brothers aged 3, 5 and 16 were enrolled in this study. They were submitted to behavioral and electrophysiological hearing tests and molecular studies. RESULTS: the hearing tests showed moderate to moderately severe bilateral symmetric sensorineural hearing loss and an accentuated descending slope. Transient and Distortion Product Otoacoustic emissions were absent in the two younger children. ABR showed a bilateral moderately severe to severe sensorineural hearing loss. P300 showed bilateral normal latencies in the older brother. Molecular tests showed that the two younger children were heterozygote for mutation 35delG on gene GJB2. CONCLUSION: The combination of speech and hearing tests and genetic analysis allows for the etiologic diagnosis of seemingly similar hearing loss cases, which however display different genetic backgrounds. Molecular studies must be comprehensive enough to avoid precipitated diagnosis which may impair genetic counseling.A deficiência auditiva como déficit sensorial mais comum tem dentre suas diferentes etiologias as alterações genéticas. Assim, é importante que a investigação audiológica se associe à busca do diagnóstico etiológico. OBJETIVO: Relatar o perfil audiológico e genético de três irmãos portadores de deficiência auditiva neurossensorial não-sindrômica. MATERIAL E MÉTODO: Estudo de caso de três irmãos, do sexo masculino, com 3, 5 e 16 anos, respectivamente, submetidos à avaliação audiológica comportamental e eletrofisiológica, e estudo molecular. RESULTADOS: Os achados audiológicos mostraram: audiometria do tipo neurossensorial, bilateral, simétrica, de grau moderado a moderadamente severo e configuração descendente acentuada. EOAT e EOAPD ausentes nos dois irmãos mais novos. PEATE compatível com perda auditiva moderadamente severa a severa. Presença do P300 com latências dentro da normalidade bilateralmente no irmão mais velho. Os achados do exame molecular mostraram que as duas crianças mais novas eram heterozigotos para a mutação 35delG no gene GJB2 e o mais velho não apresentava essa mutação. CONCLUSÃO: A associação das avaliações fonoaudiológicas e genéticas permite o diagnóstico etiológico de perdas auditivas que à primeira vista são semelhantes, mas que não obedecem à mesma estrutura genética. Os estudos moleculares devem ser abrangentes, evitando diagnósticos precipitados que prejudiquem o aconselhamento genético.69870

Protection from angiotensin II–mediated vasculotoxic and hypertensive response in mice lacking PI3Kγ

Hypertension affects nearly 20% of the population in Western countries and strongly increases the risk for cardiovascular diseases. In the pathogenesis of hypertension, the vasoactive peptide of the renin-angiotensin system, angiotensin II and its G protein–coupled receptors (GPCRs), play a crucial role by eliciting reactive oxygen species (ROS) and mediating vessel contractility. Here we show that mice lacking the GPCR-activated phosphoinositide 3-kinase (PI3K)γ are protected from hypertension that is induced by administration of angiotensin II in vivo. PI3Kγ was found to play a role in angiotensin II–evoked smooth muscle contraction in two crucial, distinct signaling pathways. In response to angiotensin II, PI3Kγ was required for the activation of Rac and the subsequent triggering of ROS production. Conversely, PI3Kγ was necessary to activate protein kinase B/Akt, which, in turn, enhanced L-type Ca2+ channel–mediated extracellular Ca2+ entry. These data indicate that PI3Kγ is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3Kγ function might be exploited to improve therapeutic intervention on hypertension