JM-20, a Benzodiazepine-Dihydropyridine Hybrid Molecule, Inhibits the Formation of Alpha-Synuclein-Aggregated Species.

Studies showed that JM-20, a benzodiazepine-dihydropyridine hybrid molecule, protects against rotenone and 6-hydroxydopamine neurotoxicity. However, its protective effects against cytotoxicity induced by endogenous neurotoxins involved in Parkinson's disease (PD) pathogenesis have never been investigated. In this study, we evaluated the ability of JM-20 to inhibit alpha-synuclein (aSyn) aggregation. We also evaluated the interactions of JM-20 with aSyn by molecular docking and molecular dynamics and assessed the protective effect of JM-20 against aminochrome cytotoxicity. We demonstrated that JM-20 induced the formation of heterogeneous amyloid fibrils, which were innocuous to primary cultures of mesencephalic cells. Moreover, JM-20 reduced the average size of aSyn positive inclusions in H4 cells transfected with SynT wild-type and synphilin-1-V5, but not in HEK cells transfected with synphilin-1-GFP. In silico studies showed the interaction between JM-20 and the aSyn-binding site. Additionally, we showed that JM-20 protects SH-SY5Y cells against aminochrome cytotoxicity. These results reinforce the potential of JM-20 as a neuroprotective compound for PD and suggest aSyn as a molecular target for JM-20.

Agathisflavone as a Single Therapy or in Association With Mesenchymal Stem Cells Improves Tissue Repair in a Spinal Cord Injury Model in Rats.

Agathisflavone is a flavonoid with anti-neuroinflammatory and myelinogenic properties, being also capable to induce neurogenesis. This study evaluated the therapeutic effects of agathisflavone-both as a pharmacological therapy administered in vivo and as an in vitro pre-treatment aiming to enhance rat mesenchymal stem cells (r)MSCs properties-in a rat model of acute spinal cord injury (SCI). Adult male Wistar rats (n = 6/group) underwent acute SCI with an F-2 Fogarty catheter and after 4 h were treated daily with agathisflavone (10 mg/kg ip, for 7 days), or administered with a single i.v. dose of 1 × 106 rMSCs either unstimulated cells (control) or pretreated with agathisflavone (1 µM, every 2 days, for 21 days in vitro). Control rats (n = 6/group) were treated with a single dose methylprednisolone (MP, 60 mg/kg ip). BBB scale was used to evaluate the motor functions of the animals; after 7 days of treatment, the SCI area was analyzed after H&E staining, and RT-qPCR was performed to analyze the expression of neurotrophins and arginase. Treatment with agathisflavone alone or with of 21-day agathisflavone-treated rMSCs was able to protect the injured spinal cord tissue, being associated with increased expression of NGF, GDNF and arginase, and reduced macrophage infiltrate. In addition, treatment of animals with agathisflavone alone was able to protect injured spinal cord tissue and to increase expression of neurotrophins, modulating the inflammatory response. These results support a pro-regenerative effect of agathisflavone that holds developmental potential for clinical applications in the future.

Neuroimmunomodulatory Properties of Flavonoids and Derivates: A Potential Action as Adjuvants for the Treatment of Glioblastoma.

Glioblastomas (GBMs) are tumors that have a high ability to migrate, invade and proliferate in the healthy tissue, what greatly impairs their treatment. These characteristics are associated with the complex microenvironment, formed by the perivascular niche, which is also composed of several stromal cells including astrocytes, microglia, fibroblasts, pericytes and endothelial cells, supporting tumor progression. Further microglia and macrophages associated with GBMs infiltrate the tumor. These innate immune cells are meant to participate in tumor surveillance and eradication, but they become compromised by GBM cells and exploited in the process. In this review we discuss the context of the GBM microenvironment together with the actions of flavonoids, which have attracted scientific attention due to their pharmacological properties as possible anti-tumor agents. Flavonoids act on a variety of signaling pathways, counteracting the invasion process. Luteolin and rutin inhibit NFκB activation, reducing IL-6 production. Fisetin promotes tumor apoptosis, while inhibiting ADAM expression, reducing invasion. Naringenin reduces tumor invasion by down-regulating metalloproteinases expression. Apigenin and rutin induce apoptosis in C6 cells increasing TNFα, while decreasing IL-10 production, denoting a shift from the immunosuppressive Th2 to the Th1 profile. Overall, flavonoids should be further exploited for glioma therapy.

The Flavonoid Agathisflavone from Poincianella pyramidalis Prevents Aminochrome Neurotoxicity.

Flavonoids have been suggested to protect dopaminergic neurons in Parkinson's disease based on studies that used exogenous neurotoxins. In this study, we tested the protective ability of agathisflavone in SH-SY5Y cells exposed to the endogenous neurotoxin aminochrome. The ability of aminochrome to induce loss of lysosome acidity is an important mechanism of its neurotoxicity. We demonstrated that the flavonoid inhibited cellular death and lysosomal dysfunction induced by aminochrome. In addition, we demonstrated that the protective effect of agathisflavone was suppressed by antagonists of estrogen receptors (ERα and ERß). These results suggest lysosomal protection and estrogen signaling as mechanisms involved in agathisflavone neuroprotection in a Parkinson's disease study model.

Transcriptome Sequencing Reveals Wide Expression Reprogramming of Basal and Unknown Genes in Leptospira biflexa Biofilms.

The genus Leptospira is composed of pathogenic and saprophytic spirochetes. Pathogenic Leptospira is the etiological agent of leptospirosis, a globally spread neglected disease. A key ecological feature of some pathogenic species is their ability to survive both within and outside the host. For most leptospires, the ability to persist outside the host is associated with biofilm formation, a most important bacterial strategy to face and overcome hostile environmental conditions. The architecture and biochemistry of leptospiral biofilms are rather well understood; however, the genetic program underpinning biofilm formation remains mostly unknown. In this work, we used the saprophyte Leptospira biflexa as a model organism to assess over- and underrepresented transcripts during the biofilm state, using transcriptome sequencing (RNA-seq) technology. Our results showed that some basal biological processes like DNA replication and cell division are downregulated in the mature biofilm. Additionally, we identified significant expression reprogramming for genes involved in motility, sugar/lipid metabolism, and iron scavenging, as well as for outer membrane-encoding genes. A careful manual annotation process allowed us to assign molecular functions to many previously uncharacterized genes that are probably involved in biofilm metabolism. We also provided evidence for the presence of small regulatory RNAs in this species. Finally, coexpression networks were reconstructed to pinpoint functionally related gene clusters that may explain how biofilm maintenance is regulated. Beyond elucidating some genetic aspects of biofilm formation, this work reveals a number of pathways whose functional dissection may impact our understanding of leptospiral biology, in particular how these organisms adapt to environmental changes. IMPORTANCE In this work, we describe the first transcriptome based on RNA-seq technology focused on studying transcriptional changes associated with biofilm growth in a member of the genus Leptospira. As many pathogenic species of this genus can survive inside the host but also persist in environmental water, mostly forming biofilms, identifying the molecular basis of this capacity can impact the understanding of how leptospires are able to fulfill a complete life cycle that alternates between adaptation to the host and adaptation to hostile external environmental conditions. We identified several genes and regulatory networks that can be the kickoff for deepening understanding of the molecular mechanisms involving bacterial persistence via biofilm formation; understanding this is important for the future development of tools for controlling leptospirosis.

Violência sexual: Papel da Delegacia da Mulher e manejo médico / Sexual violence: The role of the Women's Police Station and the medical management

Os autores tecem comentários sobre a violência sexual contra a mulher, bem como as definiçöes pertinentes. É exaltada a importância da criaçäo da Delegacia para a Mulher e nela säo pesquisados os registros de estupro ocorridos em Porto Alegre-RS nos anos de 1999 e 2000. Säo abordados aspectos do exame ginecológico e do resguardo de provas médico-legais, bem como as medidas profiláticas referentes à gestaçäo, às doenças sexualmente transmissíveis e às seqüelas psico-sexuais. Ressalta-se a importância do seguimento dessas pacientes como importante elemento terapêutico. Os autores destacam que este atendimento holístico permitirá que a mulher violentada, recupere sua integridade física, social, psicológica e sexual mais rapidamente e com um mínimo cicatriz.

Alteraçöes do perfil das subfraçöes de lipoproteínas associadas à terapia de reposiçäo hormonal / Changes in the profile of lipoprotein subfractions associated with hormone replacement therapy

OBJECTIVE: To report the effects of 2 regimens of hormone replacement therapy during the postmenopausal period on the profile of the major lipoprotein subfractions (HDL, LDL, and VLDL). METHODS: We carried out a cohort study in 38 postmenopausal patients who were starting their hormone replacement therapy due to gynecological indications, for a period of 12 weeks. Analysis of lipoprotein subclasses was performed through nuclear magnetic resonance spectroscopy. RESULTS: Hormone replacement therapy cause an increase in the proportion of larger subfractions of VLDL and HDL (p=0.008 and 0.03, respectively) and in the proportion of larger particles of VLDL due to a 36 percent increase in the levels of larger particles (p=0.004), concomitantly with a 15 percent reduction in the levels of smaller particles (p=0.04). In regard to HDL, the increase occurred only a 17 percent increase in the levels of larger particles (p=0.002). No significant change occurred in the distribution pattern of LDL subfractions. CONCLUSION: The proportion of larger subfractions of VLDL and HDL increases after hormone replacement therapy. The increase in the proportion of larger particles of VLDL occurs due to an increase in the levels of the larger subclasses concomitantly with a reduction in the smaller particles. However, an increase in the proportion of larger particles of HDL occurs only due to an increase in the levels of the larger subfractions

Terapia de reposiçäo hormonal em pacientes tratadas por câncer de endométrio / Hormonal replacement therapy in patients treated for endometrial cancer

O adenocarcinoma de endométrio, por ser uma neoplasia estrogênio-dependente, vinha sendo considerado uma contra-indicação absoluta para o uso da terapia de reposição hormonal(TRH). Os autores realizam revisão bibliográfica e analisam os principais estudos que questionam este assunto e que apontam para a possibilidade de uso de TRH em pacientes com câncer de endométrio em casos selecionados, baseados em indicadores prognósticos e na autorização da paciente, conhecedora dos riscos/benefícios da mesma

Aspectos neuro-psicológicos do climatérios / Neuropsychological symptoms in menopause

É destacado o papel dos neuropeptídios, neurotransmissores cerebrais e dos hormônios sexuais na neuromodulaçäo dos sintomas psicológicos do climatério. É também enfatizada a influência sócio-cultural e a vivência pessoal e profissional sobre esses sintomas

Câncer de colo uterino: está surgindo mais precocemente? / Uterine cervix carcinoma: Is the disease starting at an earlier age?

Analisaram-se 758 casos de câncer de colo uterino ocorridos no Hospital da Santa Casa de Misericórdia e no Hospital Säo Lucas - Porto Alegre, RS. A detecçäo ocorreu dominantemente na fase invasora (82,2%) e apenas 15,8% na fase in situ. Comparando nossos achados com os de outro autor, publicados em 1973, verificamos que näo houve mudança significativa no sentido de detecçäo na fase inicial da moléstia (p < 0,05). A idade média das portadoras de carcinoma in situ foi de 38,98 ñ 10,43 anos, sendo a mais jovem com 21 anos e das com carcinoma invasor foi 47,7 ñ 12,9 anos, tendo a mais jovem 23. No total, 22,2% dos casos ocorreram abaixo de 35 anos. Comparando este estudo com o de outros trabalhos publicados em 1970 e 1981, encontramos diferença estatisticamente significativa, que nos levou `a hipótese de que o carcinoma de câncer uterino esteja ocorrendo mais precocemente

Estudo sobre comportamento sexual do jovem universitário de Porto Alegre (UFRGS e PUC/RS) / Study about sexually behaviour of university students of Porto Alegre (UFRGS) and PUC/RS

Realizou-se um questionário fechado entre jovens universitários, de 16 aos 22 anos, da Pontifícia Universidade Católica e da Universidade Federal do Rio Grande do Sul, com o objetivo de avaliar o comportamento sexual da juventude universitária de Porto Alegre. Obteve-se 682 inquéritos, compreendendo 58,2% do sexo feminino e 41,8% do sexo masculino. Foram levantados os índices de prevalência acerca dos aspectos que costumam ser mais importantes e necessários de se tornarem conhecidos. Encontrou-se a prática da masturbaçäo em 77,1%, relaçöes sexuais em 70,8% e a realizaçäo do aborto em 13,2%. Também discutiu-se a idade da primeira relaçäo sexual, o companheiro escolhido para iniciaçäo, o conhecimento dos pais a respeito das relaçöes pré-matrimoniais, o local preferido para as relaçöes, o conhecimento dos métodos anticoncepcionais, sua utilizaçäo, as informaçöes a respeito das doenças sexualmente transmissíveis, a homossexualidade, o sexo em grupo e a necessidade de afeto nas relaçöes sexuais