Antimicrobial metabolites produced by endophytic fungi associated with the leaves of Vochysia divergens.

Investigation of the endophytic fungi Nigrospora sphaerica, Nigrospora oryzae, and Pseudofusicoccum stromaticum MeOH fractions isolated from the leaves of Vochysia divergens, a medicinal species from the Brazilian Pantanal, led to the identification of five compounds, namely a new compound (1E,8Z)-10,11-dihydroxy-5,5,8-trimethyl-4-oxocycloundeca-1,8-diene-1-carbaldehyde (1) and four known compounds: 5-methylmellein (2), sclerone (3), daldinone A (4), and lasiodiplodin (5). All compounds were identified using spectroscopic methods, and 1 was corroborated with mass spectrometry, while the known compounds were compared with data in the literature. The relative configuration of compound 1 was determined based on theoretical conformational studies as well as the J experimental values between the hydroxymethyne hydrogens. The antimicrobial activity of the compounds was evaluated. Promising results were obtained for compounds 2, 4, and 5 since they inhibited the bacterium Pseudomonas aeruginosa, an opportunistic pathogen, suggesting the potential of these microorganisms as a source of new antibacterial agents.

New perspectives in cancer immunotherapy: targeting IL-6 cytokine family.

Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) as they represent the main communication bridge between cancer cells, the tumor stroma, and the immune system. Interleukin (IL)-6 represents a keystone cytokine in the link between inflammation and cancer. Many cytokines from the IL-6 family, which includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1, have been shown to elicit tumor-promoting roles by modulating the TME, making them attractive therapeutic targets for cancer treatment.The development of immune checkpoint blockade (ICB) immunotherapies has radically changed the outcome of some cancers including melanoma, lung, and renal, although not without hurdles. However, ICB shows limited efficacy in other solid tumors. Recent reports support that chronic inflammation and IL-6 cytokine signaling are involved in resistance to immunotherapy. This review summarizes the available preclinical and clinical data regarding the implication of IL-6-related cytokines in regulating the immune TME and the response to ICB. Moreover, the potential clinical benefit of combining ICB with therapies targeting IL-6 cytokine members for cancer treatment is discussed.

Phenolic compounds and bioactive extract produced by endophytic fungus Coriolopsis rigida.

Coriolopsis rigida was isolated as an endophytic fungus from the medicinal plant Cochlospermum regium, and their production of secondary metabolites has not yet been investigated. Thus, the endophyte was cultivated on rice solid media to evaluate its ability to produce bioactive compounds and then the chloroform extract was obtained. Two phenolic compounds, tyrosol (1) and a new natural product p-hydroxyphenylacetamide (2), were isolated from the extract. The structures of the compounds were elucidated mainly by NMR. The extract showed potent antioxidant activity with an efficient concentration (EC50) value of 0.33 mg mL-1. Additionally, demonstrated allelopathic activity inhibited the seedling growth of Lactuca sativa L. and Raphanus sativus L. by 63% and 55%, respectively.

Risco de violência e qualidade de vida de pessoas idosas atendidas no ambiente hospitalar / Risk of violence and quality of life of hospitalized older adults / El riesgo de violencia y la calidad de vida de ancianos atendidos en ambiente hospitalario

Objetivo: analisar a associação entre o risco de violência e a qualidade de vida de pessoas idosas no ambiente hospitalar. Método: estudo quantitativo, transversal, multicêntrico, desenvolvido com 323 pacientes atendidos em dois hospitais universitários da Paraíba. Foram utilizados instrumentos de caracterização sociodemográfica, risco de violência e qualidade de vida. Os dados foram analisados por estatística descritiva e inferencial, mediante o teste de qui-quadrado de Pearson, correlação de Spearman e regressão logística múltipla. Resultados: o risco de violência foi prevalente em mulheres idosas e com baixa qualidade de vida. As pessoas idosas com baixa qualidade de vida apresentaram 5,24 (IC=3,04-9,05; p<0,001) maior probabilidade de apresentar risco de violência. Conclusão: foi identificada associação significativa sob o ponto de vista estatístico entre a qualidade de vida e o risco para a violência entre pessoas idosas.

Objective: to examine for association between risk of violence and quality of life of hospitalized older adults. Method: in this multicenter, quantitative, cross-sectional study, conducted with 323 patients attending two university hospitals in Paraíba State, surveyed sociodemographic, risk of violence, and quality of life characteristics. The questionnaire data were analyzed by descriptive and inferential statistics using the Pearson chi-squared test, Spearman correlation test, and multiple logistic regression. Results: risk of violence was prevalent in older women with poor quality of life. Older adults with poor quality of life scored 5.24 times higher risk of violence (CI=3.04-9.05; p<0.001). Conclusion: a significant association was found between quality of life and risk of violence in older adults.

Objetivo: analizar la asociación entre el riesgo de violencia y la calidad de vida de ancianos en el ambiente hospitalario. Método: estudio cuantitativo, transversal, multicéntrico, desarrollado junto a 323 pacientes atendidos en dos hospitales universitarios de Paraíba. Se utilizaron instrumentos de caracterización sociodemográfica, riesgo de violencia y calidad de vida. Los datos fueron analizados mediante estadística descriptiva e inferencial, utilizando la prueba de chi-cuadrado de Pearson, correlación de Spearman y regresión logística múltiple. Resultados: el riesgo de violencia fue prevalente en ancianas con baja calidad de vida. Los ancianos con baja calidad de vida fueron 5,24 (IC=3,04-9,05; p<0,001) más propensos a estar en riesgo de violencia. Conclusión: se identificó una asociación estadísticamente significativa entre la calidad de vida y el riesgo de violencia entre los ancianos.

Identification of natural cytochalasins as leads for neglected tropical diseases drug discovery.

Investigating the chemical diversity of natural products from tropical environments is an inspiring approach to developing new drug candidates for neglected tropical diseases (NTDs). In the present study, phenotypic screenings for antiprotozoal activity and a combination of computational and biological approaches enabled the identification and characterization of four cytochalasins, which are fungal metabolites from Brazilian biodiversity sources. Cytochalasins A-D exhibited IC50 values ranging from 2 to 20 µM against intracellular Trypanosoma cruzi and Leishmania infantum amastigotes, values comparable to those of the standard drugs benznidazole and miltefosine for Chagas disease and leishmaniasis, respectively. Furthermore, cytochalasins A-D reduced L. infantum infections by more than 80% in THP-1 cells, most likely due to the inhibition of phagocytosis by interactions with actin. Molecular modelling studies have provided useful insights into the mechanism of action of this class of compounds. Furthermore, cytochalasins A-D showed moderate cytotoxicity against normal cell lines (HFF-1, THP-1, and HepG2) and a good overall profile for oral bioavailability assessed in vitro. The results of this study support the use of natural products from Brazilian biodiversity sources to find potential drug candidates for two of the most important NTDs.

Endophytic fungus Phomopsis sp. as a source of 3-nitropropionic acid with larvicidal activity against Aedes aegypti (Linnaeus 1762, Diptera: Culicidae).

BACKGROUND: Aedes aegypti is the primary vector of viruses, such as Zika, chikungunya, yellow fever, and dengue. In this context, a biomonitored chemical study was conducted to evaluate the activity of the crude extract of the endophytic fungus Phomopsis sp. against the larvae of Aedes aegypti. METHODS: Crude extract, fractions, and isolated substances were evaluated in in-vitro assays against third-stage larvae of Aedes aegypti. RESULTS: We isolated 3-nitropropionic acid with an LC50 of 15.172 ppm and LC90 of 18.178 ppm after 24 hours of larval exposure. CONCLUSIONS: The results indicated that 3-nitropropionic acid exerted larvicidal activity.

Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment.

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.

Aromatic compounds from the endophytic fungus Asordaria conoidea and their allelochemical property using OSMAC strategy.

Endophytic fungi are biodiverse and alternative source of bioactive compounds, due their different abilities of genetic expression and alteration of biosynthetic pathway when submitted to different culture conditions. The metabolic profile of three different crude extracts (A, B and C), obtained from the endophytic fungus Asordaria conoidea, were evaluated by HPLC and 1H NMR. Antioxidant and allelochemical activity were also evaluated. OSMAC diversified the metabolic production, mainly in the solid culture, where the tyrosol, 4-hydroxybenzaldehyde, 2-phenylacetamide and vanillic acid were isolated. The structures of the compounds were elucidated mainly by NMR. Extracts had antioxidant potential, however, only Extract C showed allelochemical activity, as inhibition of 65.5% in growth. This study confirms the efficiency of the OSMAC platform in producing extracts of different properties and compounds. Herein the A. conoidea was isolated for the first time as an endophytic microorganism.

Endophytic fungus Phomopsis sp. as a source of 3-nitropropionic acid with larvicidal activity against Aedes aegypti (Linnaeus 1762, Diptera: Culicidae)

ABSTRACT Background: Aedes aegypti is the primary vector of viruses, such as Zika, chikungunya, yellow fever, and dengue. In this context, a biomonitored chemical study was conducted to evaluate the activity of the crude extract of the endophytic fungus Phomopsis sp. against the larvae of Aedes aegypti. Methods: Crude extract, fractions, and isolated substances were evaluated in in-vitro assays against third-stage larvae of Aedes aegypti. Results: We isolated 3-nitropropionic acid with an LC50 of 15.172 ppm and LC90 of 18.178 ppm after 24 hours of larval exposure. Conclusions: The results indicated that 3-nitropropionic acid exerted larvicidal activity.

Utilización de tromboprofilaxis en el período grávido - puerperal por Ginecólogos y Residentes de Ginecología del Uruguay

Resumen: Introducción: La enfermedad tromboembólica venosa en el período grávido - puerperal es una de las primeras causas de morbi-mortalidad materna. No existe un consenso acerca de las directivas para su abordaje, por lo que el objetivo de esta investigación fue conocer cómo se desempeñan los Ginecólogos y Residentes de Ginecología del Uruguay, con respecto a distintos factores de riesgo, la indicación de tromboprofilaxis y las herramientas disponibles. Metodología: Se realizó de julio a octubre del 2020, un estudio observacional, descriptivo, transversal donde se incluyeron a Ginecólogos y Residentes de Ginecología del Uruguay, mediante una encuesta electrónica anónima a través de la plataforma Survey Monkey. Resultados: Se obtuvo un n de 159 encuestados. El 57,3% refirió pensar sistemáticamente en factores de riesgo para enfermedad tromboembólica venosa. Las guías más utilizadas para la clasificación del riesgo e indicación de tromboprofilaxis fueron la American College of Obstestricians and Gynecologists con un 81,0% y la Royal College of Obstestricians and Gynaecologists con un 13,0%. La herramienta terapéutica con mayor disponibilidad es la heparina de bajo peso molecular y la menos utilizada es la compresión neumática intermitente. Conclusiones: Existen inconsistencias entre la clasificación de riesgo e indicación de tromboprofilaxis en diferentes situaciones clínicas. Existe un porcentaje no despreciable de profesiones que no piensan sistemáticamente en factores de riesgo para eventos tromboembólicos durante el período grávido - puerperal.

Abstract: Introduction: One of the main causes of maternal morbity and mortality in the pregnant - puerperal period is venous thromboembolic disease. There is no consensus on the guidelines to address this illness. The main objective of this research was to know how Gynecologists and Gynecology Residents of Uruguay perform, in reference to considering potential risk factors, indication for thromboprophylaxis and the tools available. Methodology: An observational, descriptive, cross-sectional study carried out from July to October 2020, including Gynecologists and Gynecology Residents of Uruguay, through an anonymous online survey using the Survey Monkey platform. Results: A final n of 159 respondents was obtained. 57.3% of which referred to think systematically about risk factors for venous thromboembolic disease. The most popular guidelines for risk classification and indication of thromboprophylaxis were the American College of Obstestricians and Gynaecologists with 81.0% and the Royal College of Obstestricians and Gynaecologists with 13.0%. The most chosen therapeutic tool was low molecular weight heparin, and the least preferred one was intermittent pneumatic compression. Conclusions: There are incoherences between the risk classification and the actual indication of thromboprophylaxis in different clinical situations. There´s still a non-negligible percentage of professionals that do not systematically consider risk factors for thromboembolic events during the pregnant-puerperal period.

Resumo: Introdução: A doença tromboembólica venosa no período gestação - puerpério é uma das principais causasde morbidadee mortalidade materna. Nãohá consenso sobre as diretrizes para o seu abordagem, por issoo objetivo desta pesquisa foi saber como encarao os ginecologistas e os residentes em ginecologia do Uruguai, no que dizrespeito à fatores de risco, indicação de tromboprofilaxia e as ferramentas disponíveis. Metodologia: Estudo observacional, descritivo e transveral realizado de julho a outubro de 2020, que incluiu ginecologistas e residentes em ginecologia do Uruguai. Um levantamento eletrônico anónimo foi desenvuelto através da plataforma SurveyMonkey. Resultados: Foram estudados 159 entrevistados. 57,3% relataram pensarsobre fatores de risco para doença tromboembólica venosa. As diretrizesmais utilizadas para classificação de risco e indicação de tromboprofilaxia foram o American College of Obstestricians and Gynecologists com 81,0% e o Royal College of Obstestricians and Gynaecologists com 13,0%. A ferramenta mais selecionada é heparina de baixo peso molecular e a menos utilizada é a compressão pneumática intermitente. Conclusões: Há inconsistências entre a classificação de risco e a indicação de tromboprofilaxia em diferentes situações clínicas. Ainda há um numero consideravel de profisionais que não pensam sistematicamente em fatores de risco para eventos tromboembólicos durante o período gravidez - puerperal.

The Role of the IL-6 Cytokine Family in Epithelial-Mesenchymal Plasticity in Cancer Progression.

Epithelial-mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression, EMP results in heterogeneous and dynamic populations of cells with mixed epithelial and mesenchymal characteristics, which are required for local invasion and metastatic dissemination. Cancer development is associated with an inflammatory microenvironment characterized by the accumulation of multiple immune cells and pro-inflammatory mediators, such as cytokines and chemokines. Cytokines from the interleukin 6 (IL-6) family play fundamental roles in mediating tumour-promoting inflammation within the tumour microenvironment, and have been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where some members often act as diagnostic or prognostic biomarkers. All IL-6 family members signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and are able to activate a wide array of signalling pathways and transcription factors. In general, IL-6 cytokines activate EMP processes, fostering the acquisition of mesenchymal features in cancer cells. However, this effect may be highly context dependent. This review will summarise all the relevant literature related to all members of the IL-6 family and EMP, although it is mainly focused on IL-6 and oncostatin M (OSM), the family members that have been more extensively studied.

First aid intervention with mothers/caregivers of children affected by the Zika virus in Brazil.

BACKGROUND: Children with microcephaly associated with the Zika virus are more likely to develop choking and apnea, so it is necessary that mothers of this population receive first aid training to cope with emergency situations that their children may experience. OBJECTIVE: To understand how an educational first aid intervention with mothers/caregivers of Brazilian children with congenital Zika virus syndrome impacts their management of seizures and choking. METHOD: A qualitative study conducted in a philanthropic institution with ten mothers/caregivers of children with congenital Zika virus syndrome. Data were collected between August and November 2018 through four focus groups with two meetings for intervention/educational workshops in first aid on situations of choking and seizure. After one month, two more meetings were held to evaluate the effectiveness of this action performed at home. The empirical material was submitted to Content Analysis, and discussed in the light of Paulo Freire's Pedagogy of Autonomy. RESULTS: The mothers/caregivers performed ineffective and harmful behaviors to the children in situations of choking and seizure before the intervention. Thus, the intervention empowered these caregivers through an exchange of experiences which began to present discernment, autonomy, resolving capacity and confidence to act in these experienced situations. They also became knowledge disseminators for family members and neighbors. CONCLUSION: The educational intervention can have satisfactory results in training mothers/caregivers in first aid, highlighting the importance of this initiative to reduce the morbidity and mortality of children who experience choking and seizures.

Spirocyclic lactams and curvulinic acid derivatives from the endophytic fungus Curvularia lunata and their antibacterial and antifungal activities.

Curvularia lunata, isolated from the capitula of Paepalanthus chiquitensis (Eriocaulaceae), was cultured in potato dextrose broth (PDB) medium. The ethyl acetate extract yielded two new spirocyclic γ-lactams (3 and 4), and five known compounds, namely: triticones E (1) and F (2), 5-O-methylcurvulinic acid (5), curvulinic acid (6) and curvulin (7). Their structures were elucidated by spectroscopic analysis and by the comparison with literature data. Besides, a computational study was used to elucidate the absolute configuration of the C - 3' in the compounds (3) and (4). The extract and the compounds (1 and 2), (6) and (7) were assayed against gram-positive and gram-negative bacteria and fluconazole-resistant yeast. The triticones (1) and (2) showed good antibacterial activity for Escherichia coli, with a minimum inhibitory concentration of 62.5 µg/mL.

Botryane terpenoids produced by Nemania bipapillata, an endophytic fungus isolated from red alga Asparagopsis taxiformis - Falkenbergia stage.

A chemical study of the EtOAc extract of Nemania bipapillata (AT-05), an endophytic fungus isolated from the marine red alga Asparagopsis taxiformis - Falkenbergia stage, led to the isolation of five new botryane sesquiterpenes, including the diastereomeric pair (+)-(2R,4S,5R,8S)-(1) and (+)-(2R,4R,5R,8S)-4-deacetyl-5-hydroxy-botryenalol (2), (+)-(2R,4S,5R,8R)-4-deacetyl-botryenalol (3), one pair of diastereomeric botryane norsesquiterpenes bearing an unprecedented degraded carbon skeleton, (+)-(2R,4R,8R)-(4) and (+)-(2R,4S,8S)-(5), which were named nemenonediol A and nemenonediol B, respectively, in addition to the known 4ß-acetoxy-9ß,10ß,15α-trihydroxyprobotrydial (6). Their structures were elucidated using 1D and 2D NMR, HRESIMS and comparison with literature data of similar known compounds. The absolute configurations of 2, 3 and 4 were deduced by comparison of experimental and calculated electronic circular dichroism (ECD) spectra, while those of 1 and 5 were assigned from vibrational circular dichroism (VCD) data. Compound 4 weakly inhibited acetylcholinesterase, whereas compound 1 inhibited both acetylcholinesterase and butyrylcholinesterase. Compounds 1, 3, 5 and 6 were tested against two carcinoma cell lines (MCF-7 and HCT-116), but showed no significant citotoxicity at tested concentrations (IC50 > 50 µM).

Improvement of bioactive metabolite production in microbial cultures-A systems approach by OSMAC and deconvolution-based 1 HNMR quantification.

Traditionally, the screening of metabolites in microbial matrices is performed by monocultures. Nonetheless, the absence of biotic and abiotic interactions generally observed in nature still limit the chemical diversity and leads to "poorer" chemical profiles. Nowadays, several methods have been developed to determine the conditions under which cryptic genes are activated, in an attempt to induce these silenced biosynthetic pathways. Among those, the one strain, many compounds (OSMAC) strategy has been applied to enhance metabolic production by a systematic variation of growth parameters. The complexity of the chemical profiles from OSMAC experiments has required increasingly robust and accurate techniques. In this sense, deconvolution-based 1 HNMR quantification have emerged as a promising methodology to decrease complexity and provide a comprehensive perspective for metabolomics studies. Our present work shows an integrated strategy for the increased production and rapid quantification of compounds from microbial sources. Specifically, an OSMAC design of experiments (DoE) was used to optimize the microbial production of bioactive fusaric acid, cytochalasin D and 3-nitropropionic acid, and Global Spectral Deconvolution (GSD)-based 1 HNMR quantification was carried out for their measurement. The results showed that OSMAC increased the production of the metabolites by up to 33% and that GSD was able to extract accurate NMR integrals even in heavily coalescence spectral regions. Moreover, GSD-1 HNMR quantification was reproducible for all species and exhibited validated results that were more selective and accurate than comparative methods. Overall, this strategy up-regulated important metabolites using a reduced number of experiments and provided fast analyte monitor directly in raw extracts.

New Benzaldehyde and Benzopyran Compounds from the Endophytic Fungus Paraphaeosphaeria sp. F03 and Their Antimicrobial and Cytotoxic Activities.

Three new benzaldehyde derivatives, sporulosaldeins A - C (1: -3: ), and 3 new benzopyran derivatives, sporulosaldeins D - F (4: -6: ), were discovered from an endophytic fungus, Paraphaeosphaeria sp. F03, which was isolated from Paepalanthus planifolius leaves. Compounds 1: -6: were elucidated by 1- and 2-dimensional nuclear magnetic resonance experiments and high-resolution mass spectrometry analysis. The absolute configuration of compound 5: was determined through the comparison of experimental and calculated electronic circular dichroism data. Compounds 1: -6: were found to exhibit antifungal activity with minimum inhibitory concentration (MIC) values of 7.8 - 250 µg/mL and racemic mixture of compound 6: exhibited weak cytotoxicity against MCF-7 and LM3 with IC50 values of 34.4 and 39.2 µM, respectively.

Aromatic compounds produced by endophytic fungi isolated from red alga Asparagopsis taxiformis - Falkenbergia stage.

Endophytic fungi were isolated from red alga Asparagopsis taxiformis - Falkenbergia stage, collected from the Brazilian coast, and were identified as Annulohypoxylon stygium (AT-03) and A. yungensis (AT-06) based on their macro/micromorphological and molecular features. Bioassay-guided fractionation of the EtOAc extract from laboratory cultures of both strains yielded known compounds pyrogallol from A. stygium, (3 R)-scytalone and (3 R,4 R)-4-hydroxy-scytalone from A. yungensis. Pyrogallol was active against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli strains. An inactive fraction from A. stygium afforded two additional compounds, (3 R,4 R)-3,4,5-trihydroxy-1-tetralone and tyrosol. Optically active compounds had their stereochemistry determined by circular dichroism (CD) spectroscopy.