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Dioclea violacea seed mannose-binding lectin (DvL) has attracted considerable attention because of its interesting biological activities, including antitumor, antioxidant, and anti-inflammatory activities. This study evaluated the cytotoxic effect of DvL on tumor and normal cells using the mitochondrial activity reduction (MTT) assay, the carcinogenic and anti-carcinogenic activity by the epithelial tumor test (ETT) in Drosophila melanogaster, and the anti-angiogenic effect by the chick embryo chorioallantoic membrane (CAM) assay. Data demonstrated that DvL promoted strong selective cytotoxicity against tumor cell lines, especially A549 and S180 cells, whereas normal cell lines were weakly affected. Furthermore, DvL did not promote carcinogenesis in D. melanogaster at any concentration tested, but modulated DXR-induced carcinogenesis at the highest concentrations tested. In the CAM and immunohistochemical assays, DvL inhibited sarcoma 180-induced angiogenesis and promoted the reduction of VEGF and TGF-ß levels at all concentrations tested. Therefore, our results demonstrated that DvL is a potent anticancer, anti-angiogenic, and selective cytotoxic agent for tumor cells, suggesting its potential application as a prototype molecule for the development of new drugs with chemoprotective and/or antitumor effects.
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Dioclea , Drosophila melanogaster , Neovascularização Patológica , Animais , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Humanos , Dioclea/química , Embrião de Galinha , Drosophila melanogaster/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Inibidores da Angiogênese/farmacologia , Membrana Corioalantoide/efeitos dos fármacos , Membrana Corioalantoide/irrigação sanguínea , Lectinas de Plantas/farmacologia , Células A549 , Linhagem Celular Tumoral , Camundongos , AngiogêneseRESUMO
BACKGROUND: Arboviral diseases are a group of infectious diseases caused by viruses transmitted by arthropods, mainly mosquitoes. These diseases, such as those caused by the dengue (DENV), Zika (ZIKV), chikungunya (CHIKV), and yellow fever (YFV) viruses, have a significant impact worldwide. In this context, entomological surveillance plays a crucial role in the control and prevention of arboviruses by providing essential information on the presence, distribution, and activity of vector mosquitoes. Based on entomological surveillance, transovarian transmission provides information regarding the maintenance and dissemination of arboviruses. The objective of this study was to detect these arboviruses in Goiânia, Goiás, and analyze the occurrence of transovarian transmission. METHODS: Aedes aegypti eggs were collected from different regions of Goiânia and cultivated under controlled laboratory conditions until the emergence of adult mosquitoes. Adult females were grouped into pools containing their heads and thoraxes. These pools were subsequently evaluated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) assay. RESULTS: A total of 157 pools (N=1570) were analyzed, with two pools testing positive for CHIKV and one pool testing positive for ZIKV, indicating that the offspring resulting from transovarian transmission are potentially infectious. CONCLUSIONS: In summary, the demonstration of the vertical transmission mechanisms of CHIKV and ZIKV in A. aegypti serves as an alert to health authorities, as these diseases are still underreported, and their primary urban vector has likely acquired this capacity, contributing to the dissemination of these infections.
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Aedes , Arbovírus , Febre de Chikungunya , Vírus Chikungunya , Dengue , Infecção por Zika virus , Zika virus , Animais , Feminino , Adulto , Humanos , Infecção por Zika virus/epidemiologia , Febre de Chikungunya/epidemiologia , Mosquitos Vetores , Vírus da Febre AmarelaRESUMO
Abstract Background: Arboviral diseases are a group of infectious diseases caused by viruses transmitted by arthropods, mainly mosquitoes. These diseases, such as those caused by the dengue (DENV), Zika (ZIKV), chikungunya (CHIKV), and yellow fever (YFV) viruses, have a significant impact worldwide. In this context, entomological surveillance plays a crucial role in the control and prevention of arboviruses by providing essential information on the presence, distribution, and activity of vector mosquitoes. Based on entomological surveillance, transovarian transmission provides information regarding the maintenance and dissemination of arboviruses. The objective of this study was to detect these arboviruses in Goiânia, Goiás, and analyze the occurrence of transovarian transmission. Methods: Aedes aegypti eggs were collected from different regions of Goiânia and cultivated under controlled laboratory conditions until the emergence of adult mosquitoes. Adult females were grouped into pools containing their heads and thoraxes. These pools were subsequently evaluated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) assay. Results: A total of 157 pools (N=1570) were analyzed, with two pools testing positive for CHIKV and one pool testing positive for ZIKV, indicating that the offspring resulting from transovarian transmission are potentially infectious. Conclusions: In summary, the demonstration of the vertical transmission mechanisms of CHIKV and ZIKV in A. aegypti serves as an alert to health authorities, as these diseases are still underreported, and their primary urban vector has likely acquired this capacity, contributing to the dissemination of these infections.
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The disposal of industrial effluents strongly influences low-order streams, which makes them fragile ecosystems that can be impacted by contamination. In central Brazil, the Extrema River spring targets the dumping of pharmaceutical products from the surrounding industries. So, this work aimed to investigate the presence of antibiotics in Extrema River spring samples and the isolation of Staphylococcus aureus, a potential multidrug-resistant bacteria, verifying the antimicrobial resistance profile of these isolates. Three campaigns were carried out in different locals (P1-P3) between October and December 2021, in the dry and rainy seasons. The high-performance liquid chromatography-tandem mass spectrometry (LCMS) approach indicated the presence of sulfamethoxazole (≥ 1 ng/L), metronidazole (< 0.5 ng/L), and chloramphenicol (< 5 ng/L) in the water samples in November (rainy season). S. aureus was isolated in P1 (n = 128), P2 (n = 168), and P3 (n = 36), with greater resistance to trimethoprim-sulfamethoxazole (90%), clindamycin (70%), and gentamicin (60%). The presence of antibiotics in the Extrema River spring may cause S. aureus antibiotic resistance development. The presence of antibiotics and the high percentage of isolated multidrug-resistant S. aureus in the Extrema River spring cause concern and indicate the clandestine dumping of effluents from nearby pharmaceutical industries. Since preserving the springs of low-order streams is important for the environment and public health, we encourage monitoring the wastewater from Extrema River's nearby pharmaceutical industries and preserving the spring of this river.
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Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Antibacterianos/farmacologia , Staphylococcus aureus , Brasil , Ecossistema , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade MicrobianaRESUMO
Inducing immunogenic cell death (ICD) during cancer therapy is a major challenge that might significantly improve patient survival. The purpose of this study was to develop a theranostic nanocarrier, capable both of conveying a cytotoxic thermal dose when mediating photothermal therapy (PTT) after its intravenous delivery, and of consequently inducing ICD, improving survival. The nanocarrier consists of red blood cell membranes (RBCm) embedding the near-infrared dye IR-780 (IR) and camouflaging Mn-ferrite nanoparticles (RBCm-IR-Mn). The RBCm-IR-Mn nanocarriers were characterized by size, morphology, surface charge, magnetic, photophysical, and photothermal properties. Their photothermal conversion efficiency was found to be size- and concentration-dependent. Late apoptosis was observed as the cell death mechanism for PTT. Calreticulin and HMGB1 protein levels increased for in vitro PTT with temperature around 55 °C (ablative regime) but not for 44 °C (hyperthermia), suggesting ICD elicitation under ablation. RBCm-IR-Mn were then intravenously administered in sarcoma S180-bearing Swiss mice, and in vivo ablative PTT was performed five days later. Tumor volumes were monitored for the subsequent 120 days. RBCm-IR-Mn-mediated PTT promoted tumor regression in 11/12 animals, with an overall survival rate of 85% (11/13). Our results demonstrate that the RBCm-IR-Mn nanocarriers are great candidates for PTT-induced cancer immunotherapy.
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Two lineages (BA.1 and BA.2) of the Omicron variant are the main ones responsible for the recent COVID-19 pandemic waves worldwide. Monitoring the prevalence and spread of these variants is important as the presence of mutations might lower the efficacy of vaccines and hinder the benefits of monoclonal antibody therapies. Although the need to screen these new lineages is emerging, genetic sequencing is scarce due to its high cost. Alternatively, we propose using reverse transcription loop-mediated isothermal amplification (RT-LAMP) to infer the prevalence of these lineages and aid in genomic surveillance in countries with limited genetic sequencing capacity. For this, we designed specific primers and tested them on a panel of 267 sequenced RNA genomes from different lineages. The test for BA.1 and its descendants showed 96.63% sensitivity, 100% specificity, and 98.85% accuracy, and the test for BA.2 and descendants showed 90.00% sensitivity, 98.85% specificity, and 98.52% accuracy. These results demonstrate the potential of RT-LAMP to be an alternative to help monitor variants, especially in countries with scarce resources.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Colorimetria , Pandemias , COVID-19/diagnóstico , Técnicas de Amplificação de Ácido NucleicoRESUMO
Despite the advance of vaccination worldwide, epidemic waves caused by more transmissible and immune evasive genetic variants of SARS-CoV-2 have sustained the ongoing pandemic of COVID-19. Monitoring such variants is expensive, as it usually relies on whole-genome sequencing methods. Therefore, it is necessary to develop alternatives that could help identify samples from specific variants. Reverse transcription loop-mediated isothermal amplification is a method that has been increasingly used for nucleic acid amplification, as it is cheaper and easier to perform when compared to other molecular techniques. As a proof of concept that can help distinguish variants, we present an RT-LAMP assay capable of detecting samples carrying a group of mutations that can be related to specific SARS-CoV-2 lineages, here demonstrated for the Variant of Concern Gamma. We tested 60 SARS-CoV-2 RNA samples extracted from swab samples and the reaction showed a sensitivity of 93.33%, a specificity of 88.89% and a kappa value of 0.822 for samples with a Ct ≤ 22.93. The RT-LAMP assay demonstrated to be useful to distinguish VOC Gamma and may be of particular interest as a screening approach for variants in countries with poor sequencing coverage.
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COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , COVID-19/epidemiologia , Colorimetria/métodos , Primers do DNA , Humanos , Técnicas de Diagnóstico Molecular/métodos , Mutação , Técnicas de Amplificação de Ácido Nucleico/métodos , RNA Viral/genética , SARS-CoV-2/genética , Sensibilidade e EspecificidadeRESUMO
TP53 gene mutation is the most common genetic alteration in human malignant tumors and is mainly responsible for Li-Fraumeni syndrome. Among the several cancers related to this syndrome, breast cancer (BC) is the most common. The TP53 p.R337H germline pathogenic variant is highly prevalent in Brazil's South and Southeast regions, accounting for 0.3% of the general population. We investigated the prevalence of TP53 germline pathogenic variants in a cohort of 83 BC patients from the Midwest Brazilian region. All patients met the clinical criteria for hereditary breast and ovarian cancer syndrome (HBOC) and were negative for BRCA1 and BRCA2 mutations. Moreover, 40 index patients fulfilled HBOC and the Li-Fraumeni-like (LFL) syndromes criteria. The samples were tested using next generation sequencing for TP53. Three patients harbored TP53 missense pathogenic variants (p.Arg248Gln, p.Arg337His, and p.Arg337Cys), confirmed by Sanger sequencing. One (1.2%) patient showed a large TP53 deletion (exons 2-11), which was also confirmed. The p.R337H variant was detected in only one patient. In conclusion, four (4.8%) early-onset breast cancer patients fulfilling the HBOC and LFL syndromes presented TP53 pathogenic variants, confirming the relevance of genetic tests in this group of patients. In contrast to other Brazilian regions, TP53 p.R337H variant appeared with low prevalence.
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Neoplasias da Mama , Síndrome de Li-Fraumeni , Neoplasias Ovarianas , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Síndrome de Li-Fraumeni/epidemiologia , Síndrome de Li-Fraumeni/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Síndrome , Proteína Supressora de Tumor p53/genéticaRESUMO
The Arboviral diseases are caused by arthropod-borne viruses, such as Mayaro virus (MAYV), the etiological agent of Mayaro fever. This disease has been drawing the attention of the public health authorities for the increased number of cases likely due to virus adaptation for survival to urban areas as well as infection and multiplication in other vectors insects. Therefore, this work aimed to identify the MAYV infecting Aedes aegypti mosquitoes in Goiânia, the capital of state of Goiás, Brazil. For the development of study, the larvae of A. aegypti were collected in Basic Health Units from different regions of Goiânia then the larvae were grown to adult mosquitoes in controlled laboratory conditions. The female mosquitoes were submitted to the procedure of head and body separation. The RNAs obtained from these samples were analyzed by real-time PCR for identification of arboviruses. We only detect the presence of MAVY in the mosquitoes, in this sense our findings suggest that A. aegypti harbor MAYV in different anatomical sites, and potentially the process of vertical transmission of MAYV can occur in this vector.
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Aedes , Alphavirus , Arbovírus , Zika virus , Alphavirus/genética , Animais , Brasil , Feminino , Mosquitos VetoresRESUMO
Azathioprine (AZA) is the main drug used in immunomodulatory therapy in post-transplant patients or with autoimmune diseases. However, no study has evaluated the AZA angiogenic response. Therefore, this study investigated the effects of AZA on the angiogenic process through macroscopic, histological, and immunohistochemical analyses in chick embryo chorioallantoic membrane (CAM). Our results showed potent anti-angiogenic activity of AZA at the higher concentrations tested in the CAM assay. The histological analysis of CAM confirmed this effect, since AZA induced a significant reduction in all parameters evaluated. In addition, immunohistochemical evaluation of CAM revealed that AZA decreased TGF-ß and VEGF levels, important cytokines involved in the angiogenic process. Therefore, the AZA anti-angiogenic effect identified in our study provides new information for the possible application of this drug in anticancer treatment.
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Inibidores da Angiogênese/farmacologia , Azatioprina/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Membrana Corioalantoide/irrigação sanguínea , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Vasos Sanguíneos/metabolismo , Embrião de Galinha , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
SARS-CoV-2 currently represents a serious global public health problem. Non-pharmaceutical intervention measures (NPIs) have been widely adopted, and the testing strategy since the beginning of the infection is the most effective tool for tracking, isolating, and minimizing transmission. The high operating costs and the need for sophisticated instrumentation related to gold standard diagnostic for COVID-19, Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR), have highlighted the urgency and importance of developing and applying new diagnostic techniques, especially in places with scarce resources. Thus, alternative molecular tests, such as Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP), based on isothermal amplification have been used to detect SARS-CoV-2 using different protocols. The potential for field application of RT-LAMP is due to the lower cost and time and not requiring high-cost instrumentation. Here, we evaluate the colorimetric RT-LAMP to detect SARS-CoV-2 in a hospital environment and correlate its performance with tests performed in a reference laboratory. The analysis performed at the hospital showed high sensitivity (88.89%), specificity (98.55%), accuracy (95.83%), and a Cohen's kappa of 0.895. However, we achieved 100% of agreement when comparing the RT-LAMP results with the gold standard (qRT-PCR) results for samples with Ct < 30 in the hospital-based test. In addition, a similar performance was found in the field compared to the reference laboratory, corroborating the proposal to apply the test directly at point-of-care.
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COVID-19 , SARS-CoV-2 , Colorimetria , Hospitais , Humanos , Técnicas de Diagnóstico Molecular , Técnicas de Amplificação de Ácido Nucleico , Sensibilidade e EspecificidadeRESUMO
Infection caused by the new coronavirus (SARS-CoV-2) has become a serious worldwide public health problem, and one of the most important strategies for its control is mass testing. Loop-mediated isothermal amplification (LAMP) has emerged as an important alternative to simplify the diagnostics of infectious diseases. In addition, an advantage of LAMP is that it allows for easy reading of the final result through visual detection. However, this step must be performed with caution to avoid contamination and false-positive results. LAMP performed on microfluidic platforms can minimize false-positive results, in addition to having potential for point-of-care applications. Here, we describe a polystyrene-toner (PS-T) centrifugal microfluidic device manually controlled by a fidget spinner for molecular diagnosis of COVID-19 by RT-LAMP, with integrated and automated colorimetric detection. The amplification was carried out in a microchamber with 5 µL capacity, and the reaction was thermally controlled with a thermoblock at 72 °C for 10 min. At the end of the incubation time, the detection of amplified RT-LAMP fragments was performed directly on the chip by automated visual detection. Our results demonstrate that it is possible to detect COVID-19 in reactions initiated with approximately 10-3 copies of SARS-CoV-2 RNA. Clinical samples were tested using our RT-LAMP protocol as well as by conventional RT-qPCR, demonstrating comparable performance to the CDC SARS-CoV-2 RT-qPCR assay. The methodology described in this study represents a simple, rapid, and accurate method for rapid molecular diagnostics of COVID-19 in a disposable microdevice, ideal for point-of-care testing (POCT) systems.
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Teste de Ácido Nucleico para COVID-19/métodos , Determinação de Ponto Final/métodos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , Poliestirenos , SARS-CoV-2/isolamento & purificação , Animais , COVID-19/diagnóstico , COVID-19/genética , Teste de Ácido Nucleico para COVID-19/instrumentação , Centrifugação/instrumentação , Centrifugação/métodos , Chlorocebus aethiops , Determinação de Ponto Final/instrumentação , Humanos , Técnicas de Diagnóstico Molecular/instrumentação , Técnicas de Amplificação de Ácido Nucleico/instrumentação , SARS-CoV-2/genética , Fatores de Tempo , Células VeroRESUMO
Ehrlich solid carcinoma (ESC) is one of the tumor models used in cancer research. Although it is widely used, it has no ultrasonographic descriptions. In this study, serial B-mode and Doppler ultrasonographic examinations were performed for 23 days for ESCs inoculated into 18 Swiss albino mice. The growth patterns were analyzed, and on the basis of their growth curve, the tumors were classified into two groups: fast growth (FG) and slow growth (SG). Ultrasonographic characteristics of the tumor's capsule, margins, echogenicity, echotexture, vascular index (VI), distribution of vascular flow, and Doppler indices such as the resistive index, pulsatility index, and peak systolic velocity (SV) were analyzed and compared between the two groups. A high VI and earlier blood flow were noted in the FG group (p<0.05). Additionally, SV was higher in the FG group than in the SG group (13.28 ± 0.38 cm/s vs. 8.43 ± 0.26 cm/s). In contrast, a change in echogenicity and flow distribution patterns were observed, especially in FG tumors. Therefore, ESC presented with few ultrasonographic differences between FG and SG tumors, especially vascularization during the initial stages of tumor growth.
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BACKGROUND: People living in poverty (PLP) are highly vulnerable to hepatitis B virus (HBV) infection. This study aimed to investigate the epidemiology of HBV infection in PLP in the metropolitan region of Goiânia, Goiás State, in the Central-West Region of Brazil. METHODS: A cross-sectional study was conducted from August to December 2016 in adults aged ≥12 years living in poverty. The following serological markers for HBV were investigated: hepatitis B surface antigen (HBsAg), antibody to HBV core antigen (total anti-HBc), IgM anti-HBc, and hepatitis B surface antibody (anti-HBs), which were detected by enzyme-linked immunosorbent assay (ELISA). Poisson regression analysis with robust variance was performed to verify the factors associated with HBV exposure. RESULTS: The study included 378 participants. The overall prevalence rate of HBV (any viral marker) was 9.8% (95% confidence interval [CI], 7.2-13.2). The prevalence rate of HBsAg in combination with total anti-HBc was 0.8% (95% CI, 0.3-2.4), total anti-HBc in combination with anti-HBs was 7.7% (95% CI, 5.4-10.9), and total anti-HBc alone was 1.3% (95% CI, 0.5-3.0) in the population. Furthermore, isolated positivity for anti-HBs was identified in only 25.4% (95% CI, 21.3-30.0) of the participants. Multiple regression analysis revealed that age (adjusted prevalence ratio [APR], 1.04; 95% CI, 1.01-1.07), female sex (APR, 2.18; 95% CI, 1.01-4.73), sexual intercourse under the influence of alcohol (APR, 2.49; 95% CI, 1.36-7.06), and exposure to Treponema pallidum (APR, 3.10; 95% CI, 1.36-7.06) were associated with HBV exposure. CONCLUSION: There was a high prevalence of HBV exposure in PLP in the Central-West Region of Brazil, indicating significant viral spread of the infection. Additionally, there was low serological evidence of immunisation against hepatitis B, indicating that a large proportion of the participants in this study are susceptible to the infection. The results support the need for public health policies that facilitate access to the existing healthcare services in hard-to-reach groups with special regard to immunisation programmes against hepatitis B.
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Hepatite B/epidemiologia , Pobreza/estatística & dados numéricos , Adulto , Fatores Etários , Biomarcadores , Brasil/epidemiologia , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Anticorpos Anti-Hepatite B , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/imunologia , Humanos , Masculino , Prevalência , Análise de Regressão , Testes Sorológicos , Fatores Sexuais , Comportamento Sexual , Infecções por Treponema/epidemiologia , Adulto JovemRESUMO
Anticancer potential of ruthenium complexes has been widely investigated, but safety evaluation studies are still scarce. Despite of ruthenium-based anticancer agents are known to cause fewer side effects compared to other metal-based drugs, these compounds are not fully free of toxicity, causing mainly nephrotoxicity. Based on the promising results from antitumor activity of the complexes [Ru(L-Met)(bipy)(dppb)]PF6 (RuMet) and [Ru(L-Trp)(bipy)(dppb)]PF6 (RuTrp), for the first time we investigated the toxicity profile of these complexes in rodent and zebrafish models. The acute oral toxicity was evaluated in Swiss mice. The mutagenic and genotoxic potential was determined by a combination of Micronucleus (MN) and Comet assay protocols, after exposure of Swiss mice to RuMet and RuTrp in therapeutic doses. Zebrafish embryos were exposed to these complexes, and their development observed up to 96 h post-fertilization. RuMet and RuTrp complexes showed low acute oral toxicity. Recorded behavioral changes were not recorded, nor were macroscopic morphological changes or structural modifications in the liver and kidneys. These complexes did not cause genetic toxicity, presenting a lack of micronuclei formation and low DNA damage induction in the cells from Swiss mice. In contradiction, cisplatin treatment exhibited high mutagenicity and genotoxicity. RuMet and RuTrp showed low toxicity in the embryo development of zebrafish. The RuMet and RuTrp complexes demonstrated low toxicity in the two study models, an interesting property in preclinical studies for novel anticancer agents.
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Antineoplásicos/toxicidade , Dano ao DNA/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Compostos de Rutênio/toxicidade , Administração Oral , Aminoácidos/química , Animais , Antineoplásicos/química , Cisplatino/toxicidade , Ensaio Cometa , Feminino , Masculino , Camundongos , Testes para Micronúcleos , Compostos de Rutênio/química , Testes de Toxicidade Aguda , Peixe-ZebraRESUMO
Background: The PPARG2 Pro12Ala (rs1801282) and IL6 -174G >C (rs1800795) have important function in body weight regulation and a potential role in obesity risk. We aimed to investigate the association between PPARG2 Pro12Ala and IL6 -174G >C variants and the genotypes interaction with body composition, metabolic markers, food consumption, and physical activity in severely obese patients. Methods: 150 severely obese patients (body mass index (BMI) ≥ 35 kg/m2) from Central Brazil were recruited. Body composition, metabolic parameters, physical activity, and dietary intake were measured. The genotype was determined by the qPCR TaqMan Assays System. Multiple linear regression and multiple logistic regression models were fitted adjusting for confounders. Results: Ala carriers of the Pro12Ala polymorphism had higher adiposity measures (BMI: p=0.031, and fat mass: p=0.049) and systolic blood pressure (p=0.026) compared to Pro homozygotes. We found no important associations between the -174G >C polymorphism and obesity phenotypes. When genotypes were combined, individuals with genotypes ProAla + AlaAla and GC + CC presented higher BMI (p=0.029) and higher polyunsaturated fatty acids (PUFAs) consumption (p=0.045) compared to the ones with genotypes ProPro and GG, and individuals carriers of the PPARG2 Ala allele only (genotype ProAla + AlaAla and GG) had higher fat mass and systolic and diastolic blood pressure compared to the ones with genotypes ProPro and GG. Conclusions: Severely obese individuals carrying the Ala allele of the PPARG2 Pro12Ala polymorphism had higher measures of adiposity and blood pressure, while no important associations were found for the IL6 -174G >C polymorphism.
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Pressão Sanguínea/genética , Índice de Massa Corporal , Obesidade Mórbida/genética , PPAR gama/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Distribuição da Gordura Corporal , Brasil/epidemiologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/fisiopatologiaRESUMO
Peritoneal carcinomatosis is considered as a potentially lethal clinical condition, and the therapeutic options are limited. The antitumor effectiveness of the [Ru(l-Met)(bipy)(dppb)]PF6(1) and the [Ru(l-Trp)(bipy)(dppb)]PF6(2) complexes were evaluated in the peritoneal carcinomatosis model, Ehrlich ascites carcinoma-bearing Swiss mice. This is the first study that evaluated the effect of Ru(II)/amino acid complexes for antitumor activity in vivo. Complexes 1 and 2 (2 and 6 mg kg-1) showed tumor growth inhibition ranging from moderate to high. The mean survival time of animal groups treated with complexes 1 and 2 was higher than in the negative and vehicle control groups. The induction of Ehrlich ascites carcinoma in mice led to alterations in hematological and biochemical parameters, and not the treatment with complexes 1 and 2. The treatment of Ehrlich ascites carcinoma-bearing mice with complexes 1 and 2 increased the number of Annexin V positive cells and cleaved caspase-3 levels and induced changes in the cell morphology and in the cell cycle phases by induction of sub-G1 and G0/G1 cell cycle arrest. In addition, these complexes reduce angiogenesis induced by Ehrlich ascites carcinoma cells in chick embryo chorioallantoic membrane model. The treatment with the LAT1 inhibitor decreased the sensitivity of the Ehrlich ascites carcinoma cells to complexes 1 and 2 in vitro-which suggests that the LAT1 could be related to the mechanism of action of amino acid/ruthenium(II) complexes, consequently decreasing the glucose uptake. Therefore, these complexes could be used to reduce tumor growth and increase mean survival time with less toxicity than cisplatin. Besides, these complexes induce apoptosis by combination of different mechanism of action.
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Antineoplásicos/farmacologia , Carcinoma de Ehrlich/patologia , Neoplasias Peritoneais/patologia , Compostos de Rutênio/farmacologia , Aminoácidos/farmacologia , Animais , Western Blotting , CamundongosRESUMO
Antimetastatic activities, low toxicity to normal cells and high selectivity for tumor cells make of the ruthenium complexes promising candidates in the search for develop new chemotherapeutic agents for the treatment of cancer. This study aimed to determine the cytotoxic, genotoxic and to elucidate the signaling pathway involved in the death cell process induced by cis-[RuCl(BzCN)(bipy)(dppb)]PF6(1) and cis-[RuCl(BzCN)(bipy)(dppe)]PF6(2) in Ehrlich ascites carcinoma (EAC) in vitro. Moreover, we report for the first time the anti-angiogenic potential on chick embryo chorioallantoic membrane (CAM) model. Peripheral blood mononuclear cells (PBMC) were isolated from healthy controls with an age range of 20-30 years and used to calculate the selectivity index (SI). The complex 2 (IC50 = 8.5 ± 0.4/SI = 6.3) showed high cytotoxic and selectivity index against EAC cells than complex 1 (IC50 = 14.9 ± 0.2/SI = 0.2) using the MTT assay. Complex 2 induced DNA damage on Ehrlich tumor cells at concentrations and time periods evalueted. In consequence, it was observed an increase of Tp53 gene expression, G0/G1-arrest cells, and increased levels of cleaved PARP protein. Beside that, the treatment of EAC with complex 2 led to an increase in Annexin V-positive cells and apoptosis induction by Caspase-7. Additionally, the complex 2 inhibited the angiogenesis caused by Ehrlich tumor cells in CAM model. This complex is active and selective for Ehrlich tumor cells, inducing DNA damage, cell cycle arrest and cell death by caspase-dependent apoptosis involving PARP activation (PARP1), and Tp53 induction.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Dano ao DNA/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto , Animais , Antineoplásicos/química , Carcinoma de Ehrlich/irrigação sanguínea , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Células Cultivadas , Embrião de Galinha , Galinhas , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/patologia , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Camundongos , Rutênio/química , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
Novel metal complexes have received great attention in the last decades due to their potential anticancer activity. Notably, ruthenium-based complexes have emerged as good alternative to the currently used platinum-based drugs for cancer therapy, providing less toxicity and side effects to patients. Glioblastoma is an aggressive and invasive type of brain tumor and despite of advances is the field of neurooncology there is no effective treatment until now. Therefore, we sought to investigate the potential antiproliferative activity of phosphine-ruthenium-based complexes on human glioblastoma cell lines. Due to its octahedral structure as opposed to the square-planar geometry of platinum(II) compounds, ruthenium(II) complexes exhibit different structure-function relationship probably acting through a different mechanism from that of cisplatin beyond their ability to bind DNA. To better improve the pharmacological activity of metal complexes we hypothesized that neutron activation of ruthenium in the complexes would allow to decrease the effective concentration of the compound needed to kill tumor cells. Herein we report on the effect of unmodified and neutron activated phosphine ruthenium II complexes on glioblastoma cell lines carrying wild-type and mutated p53 tumor suppressor gene. Induction of apoptosis/authophagy as well as generation of reactive oxygen species were determined. The phosphine ruthenium II complexes tested were highly active against glioblastoma cell lines inducing cell death both through apoptosis and autophagy in a p53 independent fashion. Neutron activation of ruthenium compounds rendered them more active than their original counterparts suggesting a new strategy to improve the antitumor activity of these compounds.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Neuroglia/efeitos dos fármacos , Nêutrons , Fosfinas/farmacologia , Compostos de Rutênio/farmacologia , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/efeitos da radiação , Expressão Gênica , Humanos , Mutação , Neuroglia/metabolismo , Neuroglia/patologia , Fosfinas/efeitos da radiação , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Compostos de Rutênio/efeitos da radiação , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
OBJECTIVE: To identify genetic counseling programs that do not encourage therapeutic abortion for individuals with hemoglobin disorders and/or for their relatives. METHOD: Systematic literature review of articles published from 2001 to 2012 that are located in the PubMed, LILACS, SciELO and SCOPUS databases using keywords in Portuguese, English and Spanish and that met the inclusion and exclusion criteria described on a standardized form. RESULTS: A total of 409 articles were located, but only eight (1.9%) were selected for analysis. CONCLUSION: Although seldom mentioned in the literature, educational/preventive programs targeting hemoglobinopathies are feasible and allow the affected individuals to acquire knowledge on the consequences of this condition and their odds of transmitting it.