Temozolomide Resistance in Glioblastoma by NRF2: Protecting the Evil.

The transcription factor NRF2 is constitutively active in glioblastoma, a highly aggressive brain tumor subtype with poor prognosis. Temozolomide (TMZ) is the primary chemotherapeutic agent for this type of tumor treatment, but resistance to this drug is often observed. This review highlights the research that is demonstrating how NRF2 hyperactivation creates an environment that favors the survival of malignant cells and protects against oxidative stress and TMZ. Mechanistically, NRF2 increases drug detoxification, autophagy, DNA repair, and decreases drug accumulation and apoptotic signaling. Our review also presents potential strategies for targeting NRF2 as an adjuvant therapy to overcome TMZ chemoresistance in glioblastoma. Specific molecular pathways, including MAPKs, GSK3ß, ßTRCP, PI3K, AKT, and GBP, that modulate NRF2 expression leading to TMZ resistance are discussed, along with the importance of identifying NRF2 modulators to reverse TMZ resistance and develop new therapeutic targets. Despite the significant progress in understanding the role of NRF2 in GBM, there are still unanswered questions regarding its regulation and downstream effects. Future research should focus on elucidating the precise mechanisms by which NRF2 mediates resistance to TMZ, and identifying potential novel targets for therapeutic intervention.

Phenolic glycolipid-1 of Mycobacterium leprae is involved in human Schwann cell line ST8814 neurotoxic phenotype.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae infection in Schwann cells. Axonopathy is considered a hallmark of leprosy neuropathy and is associated with the irreversible motor and sensory loss seen in infected patients. Although M. leprae is recognized to provoke Schwann cell dedifferentiation, the mechanisms involved in the contribution of this phenomenon to neural damage remain unclear. In the present work, we used live M. leprae to infect the immortalized human Schwann cell line ST8814. The neurotoxicity of infected Schwann cell-conditioned medium (SCCM) was then evaluated in a human neuroblastoma cell lineage and mouse neurons. ST8814 Schwann cells exposed to M. leprae affected neuronal viability by deviating glial 14 C-labeled lactate, important fuel of neuronal central metabolism, to de novo lipid synthesis. The phenolic glycolipid-1 (PGL-1) is a specific M. leprae cell wall antigen proposed to mediate bacterial-Schwann cell interaction. Therefore, we assessed the role of the PGL-1 on Schwann cell phenotype by using transgenic M. bovis (BCG)-expressing the M. leprae PGL-1. We observed that BCG-PGL-1 was able to induce a phenotype similar to M. leprae, unlike the wild-type BCG strain. We next demonstrated that this Schwann cell neurotoxic phenotype, induced by M. leprae PGL-1, occurs through the protein kinase B (Akt) pathway. Interestingly, the pharmacological inhibition of Akt by triciribine significantly reduced free fatty acid content in the SCCM from M. leprae- and BCG-PGL-1-infected Schwann cells and, hence, preventing neuronal death. Overall, these findings provide novel evidence that both M. leprae and PGL-1, induce a toxic Schwann cell phenotype, by modifying the host lipid metabolism, resulting in profound implications for neuronal loss. We consider this metabolic rewiring a new molecular mechanism to be the basis of leprosy neuropathy.

A importância dos fatores associados a não adesão ao exame preventivo do câncer de colo uterino por mulheres brasileiras ­ revisão sistemática / The importance of factors associated with non-adherence to preventive screening for cervical cancer by Brazilian women ­ systematic review

Objetivo: O presente estudo busca avaliar a importância da adesão ao exame de Papanicolaou no diagnóstico do Papilomavírus humano, bem como relatar as dificuldades e os fatores da não realização do mesmo por mulheres brasileiras. Métodos: revisão sistemática da literatura mediante busca de artigos indexados nas plataformas eletrônicas de dados PubMed, BVS-Brasil e SciELO, entre os anos de 2008 a 2018. Resultados: No total foram encontrados 1.458 artigos nas bases de dados selecionadas, foram excluídos 1.411 artigos, os quais se enquadraram nos critérios de exclusão, e 38 duplicatas. Ao final do total de artigos analisados foram incluídos 10 para a realização da síntese quali-quantitativa. Considerações finais: A partir dos artigos analisados pode-se observar que as diferenças entre raça, classe econômica, nível de escolaridade e estado civil mostram-se como fatores determinantes quando comparamos a diferença na adesão e acesso do exame de Papanicolaou entre as mulheres brasileiras. Faz-se necessária a utilização de ações, campanhas e estratégias para a melhoria na realização do exame, enfatizando a sua importância.

Objective: The present study aims to evaluate the importance of the adhesion of the Pap smear technique to the diagnosis of the human papillomavirus, as well as to report the difficulties and factors of noncompletion by Brazilian women. Methods: systematic review of the literature by searching articles indexed in the electronic platforms of data PubMed, BVS-Brazil and Scielo, between the years of 2008 to 2018. Results: In total, 1,458 articles were found in the selected databases, 1,411 articles were excluded, as these were included in the exclusion criteria and 38 duplicates. At the end of the total of analyzed articles, 10 were included for the accomplishment of the qualitative-quantitative synthesis. Final considerations: From the analyzed articles, it can be observed that the differences between race, economic class, schooling level and marital status are determining factors when comparing the difference in the adhesion and access of the Pap test among Brazilian women. It is necessary to use actions, campaigns and strategies for improving the exam, emphasizing the importance of taking the exam.

Leishmanicidal effect of 1,3,4-thiadiazolium mesoionic salts on Leishmania amazonensis in vitro.

Leishmaniasis is a neglected broad clinical spectrum disease caused by protozoa of the genus Leishmania, which affect millions of people annually in the world and the treatment has severe side effects and resistant strains have been reported. Mesoionic salts are a subclass of the betaine group with extensive biological activity such as microbicide and anti-inflammatory In this work, we analyze the cytotoxic effects of mesoionic salts, 4-phenyl-5-(X-phenyl)-1,3,4-thiadiazolium-2-phenylamine chloride (X = 4 Cl; 3,4 diCl and 3,4 diF), on Leishmania amazonensis in vitro. Initially, Mesoionic salts toxicity were evaluated by XTT assay on L. amazonensis promastigotes. Our results show that the mesoionic salts MI-3,4 diCl, MI-4 Cl and MI-3,4 diF were toxic to the promastigote parasite with IC50 values of 14.3, 40.1 and 61.8 µM, respectively. The amastigote survival was evaluated in treated infected-macrophages, and the results demonstrate that MI-4 Cl (IC50 = 33 µM) and MI-3,4 diCl (IC50 = 43 µM) have a toxic effect against these forms. None of the mesoionic compounds tested present host cell toxicity up to the tested concentration of 100 µM. The selectivity index for MI-3,4 diCl and MI-4 Cl were 3.94 and 6.97, respectively. Nitric oxide (NO) production assayed by Griess reagent, in LPS-activated macrophages or not, in the presence of the salts showed that only the MI-3,4 diCl compound reduced NO levels. Lipid profile analysis of treated-promastigotes showed no alteration of neutral lipids. Evaluation of mitochondrial membrane potential (∆Ψm) showed that the MI-4Cl compound was able to reduce (∆Ψm) by 50%. Therefore, our results suggest that the chlorinated compounds are promising biomolecules, which cause inhibition of L.amazonensis promastigotes, amastigotes, leading to mitochondrial damage.

Índices utilizados para diagnóstico e plano de tratamento do ronco primário e da síndrome da apnéia obstrutiva do sono (SAOS) / Assessment of the knowledge of dentists in the face of care for severe cardiac patients in primary care

Os distúrbios do sono vem sendo cada dia mais estudados e evidenciados perante a medicina, sendo que muitos destes estão atrelados a fatores etiológicos ligados a diversas doenças sistêmicas, tais como, hipertensão arterial, problemas cardíacos e fator de risco para diabetes. Sendo assim, a utilização de Índices como o de Epworth, Berlim e Pittsburgh como auxiliadores anamnésicos, é de grande valia para um correto diagnóstico. Por meio deste, pudemos concluir que tais índices são de extrema importância por serem referências iniciais para a solicitação de exames mais complexos e de alto custo. Portanto, este trabalho tem por objetivo fazer uma revisão da literatura sobre a essência científica de tais índices, analisando a eficácia dos mesmos(AU)

Sleep wake disorders see being increasingly studied day and evidenced before the medicine, and many of these disorders are linked to etiological factors related to various systemic diseases such as, hypertension, heart disease and a risk factor for diabetes. Thus, the use of indices such as the Epworth, Berlin and Pittsburgh as amnesic helpers, is of great value to a correct diagnosis. Through this we can conclude that such indices are extremely important because they are initial references to the request for more complex tests and costly. Therefore, this study aims to review the literature on the scientific essence of such indices, analyzing effectiveness(AU)

Tratamento com aparelho intra-oral da síndrome obstrutiva do sono (SAHOS): relato de caso / Treatment with intra-oral appliance of obstructive sleep apnea syndrome (OSAS): case report

O objetivo deste trabalho foi analisar o tratamento com o uso de aparelhos intra- orais para a síndrome de apneia e hipopnéia obstrutiva do sono e relatar o caso de um paciente portador da síndrome em estágio moderado. O presente caso clínico trata-se de um paciente de 37 anos de idade, portador de síndrome de apneia e hipopneia obstrutiva do sono (SAHOS) moderada, diagnosticada por um exame de polissonografia, que se apresentou com os seguintes sintomas: sonolência e cansaço diurno, possuía apneias durante o sono, além de reportar que sofria de bruxismo e ronco, segundo ele, tudo referido por sua cônjuge. A modalidade de tratamento utilizada foi o aparelho intrabucal, do tipo protrusor mandibular, o qual é um tratamento não invasivo indicado a princípio nos casos de ronco primário e nessa síndrome de grau leve e moderado. O tratamento realizado foi eficaz na melhora da sintomatologia, desobstruindo a passagem de ar nas vias aéreas superiores, permitindo melhor ventilação do paciente e controlando os efeitos colaterais e secundários da síndrome. Os resultados da polissonografia com a utilização do aparelho intra-oral, foi alvo de discussão relatada neste trabalho(AU)

The objective of this study was to analyze the treatment with the use of intra-oral devices for sleep apnea-hypopnea syndrome Obstructive sleep and report the case of a patient with the syndrome in the moderate stage. The present case it is of a white, 37-year-old boy with an apnea-hypopnea syndrome moderate obstructive sleep, who presented with the following symptoms: sleepiness and daytime tiredness, had sleep apneas, and informed us that suffered from bruxism and snoring. The treatment modality used was the intraoral appliance, which is a non-invasive treatment used for this syndrome of mild to moderate. Final Thoughts: The treatment was effective in improving symptoms, clearing the air passage in the upper airway, allowing better ventilation of the patient and controlling side effects and secondary syndrome. However polissonografy results was object of discussion in the paper(AU)

Exames para o diagnóstico da síndrome da apnéia obstrutiva do sono: conhecimentos gerais para o cirurgião dentista que atua na área do sono / Investigations for the diagnosis of the syndrome obstructive sleep apnea: general knowledge for the dentist surgery that works in the sleep area

A Síndrome da Apneia e Hipopnéia Obstrutiva do Sono (SAHOS) foi descrita há quase três décadas na literatura, porém somente há pouco tempo tem conseguido o crescente interesse dos cirurgiões-dentistas; por isso foi feita esta revisão de literatura sobre a inter-relação entre a análise cefalométrica e os pacientes portadores desta patologia. Os estudos revisados mostram que existem diferenças significantes entre uma série de características da via aérea superior e das dimensões esqueléticas entre os pacientes com SAHOS e indivíduos normais. Foi observado que a análise cefalométrica tem sido utilizada como um importante meio auxiliar no diagnóstico e no planejamento do tratamento da Síndrome da Apneia e Hipopnéia Obstrutiva do Sono, associando um grande número de variáveis à prevalência desta síndrome. Esses conhecimentos básicos são de grande importância para o Cirurgião Dentista que atua na área da Odontologia do Sono(AU)

The Syndrome Obstructive Sleep Apnea (OSA) was described almost three decades ago in the literature, but only recently has stimulated a growing interest of dental surgeons; therefore was done this review of literature on the interrelationship between cephalometric analysis and patients with this pathology. The reviewed studies show that there are significant differences between a number of characteristics of the upper airway and skeletal dimensions between OSA patients and people in their normal stages. It was observed that the cephalometric analysis has been used as an important tool in the diagnosis and treatment planning Syndrome Obstructive Sleep Apnea, associating an extensive number of variables to the prevalence of this syndrome. This basic knowledge is of great importance for the Dental Surgeon who works in the area of Odontology Sleep(AU)

Isovitexin as marker and bioactive compound in the antinociceptive activity of the Brazilian crude drug extracts of Echinodorus scaber and E. grandiflorus

Abstract Echinodorus scaber Rataj and Echinodorus grandiflorus (Cham. & Schltdl.) Micheli, Alismataceae, are popularly used to relieve inflammatory complaints and as diuretic. A study on the antinociceptive effect and selected marker compounds in eleven extracts from different locations was undertaken and their antinociceptive effect was assessed. The fingerprints were compared by HPLC-DAD and the content of vitexin, isovitexin, isoorientin and vitexin-2-O-rhamnoside were determined. All samples presented antinociceptive activity reducing the writhes by 36.4-62.5% and 47.4-79.8% at 10 and 50 mg/kg, respectively; indomethacin (5 mg/kg) reduced writhes by 82.6-90.1%. The content of the flavonoids C-glycosides, however, presented a strong variation. Isovitexin and isoorientin were found in all the samples, with content ranging from traces to 14.70 µg/mg and 2.12-84.27 µg/mg extract, respectively, while vitexin-2-O-rhamnoside occurred in quantifiable amounts only in 3 out of 11 samples ranging from 5.43 to 33.13 µg/mg extract; vitexin was not detected at all or detected in trace amounts. According to the fingerprints, the samples could be arranged in four main groups. All eleven extracts showed antinociceptive activity. Isovitexin was the only flavonoid present in all samples and can be regarded, acting in synergy with the other compounds or not, as the responsible for the antinociceptive activity. Therefore, isovitexin is a good choice as chemical marker when the antinociceptive activity of E. scaber and E. grandiflorus is investigated.