RESUMEN
This study aimed to assess the ability of rosmarinic acid (RA) to prevent kidney stone formation in an ethylene glycol and ammonium chloride (EG/AC) model. There was an increase in diuresis in the normotensive (NTRs) and hypertensive rats (SHRs) treated with hydrochlorothiazide (HCTZ) and exposed to EG/AC, while RA restored urine volume in NTRs. The EG/AC groups exhibited lower urine pH and electrolyte imbalance; these parameters were not affected by any of the treatments. Both HCTZ+EG/AC and RA+EG/AC reduced calcium oxalate crystal formation in NTR and SHR urine. Kidney tissue analysis revealed alterations in oxidative stress and inflammation parameters in all EG/AC-receiving groups, with RA enhancing antioxidant defenses in SHRs. Additionally, crystals were found in the kidney histology of all EG/AC-exposed groups, with reduced Bowman's capsule areas in NTRs and SHRs. The NTR VEH+EG/AC group showed intense renal damage, while the others maintained their structures, where treatments with HCTZ and RA were fundamental for kidney protection in the NTRs. Docking analysis showed that RA exhibited good binding affinity with matrix metalloproteinase-9, phosphoethanolamine cytidylyltransferase, and human glycolate oxidase enzymes. The data disclosed herein underscore the importance of further research to understand the underlying mechanisms better and validate the potential of RA for clinical use.
RESUMEN
BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.
Asunto(s)
Paclitaxel , Enfermedades del Sistema Nervioso Periférico , Humanos , Ratones , Animales , Paclitaxel/toxicidad , PPAR gamma , Factor Neurotrófico Derivado del Encéfalo , Factor 2 Relacionado con NF-E2 , Enfermedades Neuroinflamatorias , Calidad de Vida , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & controlRESUMEN
RESUMO Introdução: Com a implementação do Sistema Único de Saúde (SUS) no Brasil, houve a reformulação do currículo médico sob uma perspectiva biopsicossocial. Para atender a essa demanda no âmbito acadêmico, o componente de humanidades médicas (HM) foi delineado para estimular reflexões interdisciplinares de cunho ético-humanista. A proposta é potencializada com o desenvolvimento de estratégias educacionais capazes de garantir a execução da disciplina no contexto das metodologias ativas. Nessa perspectiva, no ano de 2020, devido à pandemia da Covid-19, o formato tradicional de aulas presenciais necessitou de adaptação para o ensino remoto, o que suscitou a concepção e proposta de adoção de pôster criativo como recurso metodológico. Objetivo: Este estudo teve como objetivo analisar as possíveis contribuições da produção do pôster criativo para o aprendizado e processo de formação do médico, no contexto da disciplina de HM. Método: Trata-se de um estudo de abordagem qualitativa de viés exploratório-descritivo. A coleta foi realizada mediante entrevista individual semiestruturada, por meio virtual, no período de agosto a novembro de 2022. Após a transcrição, utilizou-se a análise de conteúdo temática desenvolvida por Bardin para auxiliar na análise dos relatos transcritos e na elaboração de unidades temáticas. A interpretação seguiu referenciais teóricos interdisciplinares do campo da saúde e componentes da disciplina de HM. Resultado: No total, 20 acadêmicos de uma universidade pública do estado do Pará compuseram a amostra deste estudo. A partir da organização e leitura das transcrições, emergiram as seguintes categorias: experiência no ensino presencial; experiência no ensino remoto; processo de elaboração do pôster; arte e humanidades médicas; contribuições da disciplina e do pôster. Conclusão: O uso da ferramenta pôster destaca o papel dos acadêmicos como protagonistas do seu aprendizado no recorte de HM. A maioria referiu o uso do pôster como elemento potencializador para a reflexão proposta pela disciplina, favorecido pela mediação da arte, em diversas modalidades de expressão. Houve a oportunidade de os acadêmicos exporem seus sentimentos e compreensões acerca de temáticas sensíveis à formação médica.
ABSTRACT Introduction: The implementation of the Unified Health System in Brazil led to a need to reformulate the medical curriculum from a biopsychosocial perspective. In the academic field, the Medical Humanities (MH) component has stimulated interdisciplinary reflections of an ethical-humanist nature. This exercise is streamlined with the development of educational strategies capable of guaranteeing the execution of the discipline in the context of active methodologies. From this perspective, in 2020, due to the COVID 19 pandemic, the traditional format of face-to-face classes was forced to be adapted for remote teaching, which led to the conception and proposal for adoption of posters as a methodological resource. Objective: To analyze the possible contributions of creative poster production to the physician's learning and training process, in the context of the medical humanities discipline. Method: A qualitative exploratory-descriptive approach. The data was collected through virtual, semi-structured, individual interviews, from August to November 2022. Following transcription of the interviews, thematic content analysis developed by Bardin (2011) was used to assist in the analysis of the transcribed reports and the development of thematic units. The interpretation followed interdisciplinary theoretical references in the field of health and components of the medical humanities discipline. Result: The study sample was composed of 20 academics from a public university in the state of Pará. From the organization and reading of the transcripts, the following thematic units emerged: experience in face-to-face teaching; experience in remote teaching; poster creation process; art and medical humanities; contributions from the discipline and the poster. Conclusion: The use of posters as a tool highlights the role of academics as protagonists of their own learning in the medical humanities field. The majority referred to the use of the poster as an element that enhanced the reflection proposed by the discipline, favored by the mediation of art, in different forms of expression. It offered an opportunity for academics to express their feelings and understandings about topics sensitive to medical training.
RESUMEN
To understand which type of hospital waste may contain the highest amount of antibiotic resistant microorganisms that could be released into the environment, the bacterial strains entering and leaving a hospital wastewater treatment plant (HWTP) were identified and tested for their antibiotic susceptibility. To achieve this goal, samples were collected from three separate sites, inlet and outlet wastewater positions, and sludge generated in a septic tank. After microbiological characterization according to APHA, AWWA, and WEF protocols, the relative susceptibility of the bacterial strains to various antibiotic agents was assessed according to the Clinical and Laboratory Standards Institute guidelines, to determine whether there were higher numbers of resistant bacterial strains in the inlet wastewater sample than in the outlet wastewater and sludge samples. The results showed more antibiotic resistant bacteria in the sludge than in the inlet wastewater, and that the Enterobacteriaceae family was the predominant species in the collected samples. The most antibiotic-resistant families were found to be Streptococcacea and non-Enterobacteriaceae. Some bacterial strains were resistant to all the tested antibiotics. We conclude that the studied HWTP can be considered a source of resistant bacterial strains. It is suggested that outlet water and sludge generated in HWTPs should be monitored, and that efficient treatment to eliminate all bacteria from the different types of hospital waste released into the environment is adopted.
Asunto(s)
Aguas del Alcantarillado , Aguas Residuales , Humanos , Aguas del Alcantarillado/microbiología , Bacterias , Antibacterianos/farmacología , HospitalesRESUMEN
OBJECTIVE: The aim of this study was to analyze the effect of the pharmacological treatment on the sleep patterns of children with attention deficit hyperactivity disorder (ADHD). DATA SOURCE: A high-sensitivity electronic search was performed in the following databases: Cochrane Library, MEDLINE via PubMed, LILACS via the Regional Health Portal (BVS), Embase, Scopus, CINAHL, and Web of Science, as recommended by the Cochrane Handbook, and which has undergone peer review according to the PRESS Guide. DATA SYNTHESIS: The studies contemplated the use of the drugs atomoxetine, guanfacine, methylphenidate, dasotraline, L-theanine, and lisdexamfetamine. They showed efficiency in reducing the symptoms of ADHD, although all, except atomoxetine, affected sleep quality, such as by reducing total rapid eye movement (REM), non-REM phase, slow-wave sleep time, and longer sleep-onset latency. CONCLUSIONS: The drugs used in the treatment of ADHD seem to have negative repercussions on the sleep quality of children, with the drug atomoxetine showing lesser effects on this variable.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Estimulantes del Sistema Nervioso Central , Metilfenidato , Niño , Humanos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Clorhidrato de Atomoxetina/uso terapéutico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Metilfenidato/uso terapéutico , SueñoRESUMEN
Abstract Objective: The aim of this study was to analyze the effect of the pharmacological treatment on the sleep patterns of children with attention deficit hyperactivity disorder (ADHD). Data source: A high-sensitivity electronic search was performed in the following databases: Cochrane Library, MEDLINE via PubMed, LILACS via the Regional Health Portal (BVS), Embase, Scopus, CINAHL, and Web of Science, as recommended by the Cochrane Handbook, and which has undergone peer review according to the PRESS Guide. Data synthesis: The studies contemplated the use of the drugs atomoxetine, guanfacine, methylphenidate, dasotraline, L-theanine, and lisdexamfetamine. They showed efficiency in reducing the symptoms of ADHD, although all, except atomoxetine, affected sleep quality, such as by reducing total rapid eye movement (REM), non-REM phase, slow-wave sleep time, and longer sleep-onset latency. Conclusions: The drugs used in the treatment of ADHD seem to have negative repercussions on the sleep quality of children, with the drug atomoxetine showing lesser effects on this variable.
RESUMO Objetivo: Analisar a interferência do tratamento farmacológico no padrão de sono das crianças com transtorno do déficit de atenção com hiperatividade (TDAH). Fontes de dados: Busca eletrônica de alta sensibilidade nas bases de dados Cochrane Library, Medical Literature Analysis and Retrieval System Online (MEDLINE) via United States National Library of Medicine (PubMed), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) via Biblioteca Virtual em Saúde (BVS), Embase, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL) e Web of Science, de acordo com o preconizado pelo Cochrane Handbook, de artigos que passaram pela revisão por pares segundo o Guia PRESS. Síntese dos dados: Os estudos que contemplaram o uso das drogas atomoxetina (ATX), guanfacina, metilfenidato (MPH), dasotralina, L-teanina e lisdexanfetamina mostraram eficiência na redução dos sintomas do TDAH, embora todos os medicamentos, exceto a atomoxetina, tenham afetado a qualidade do sono — reduzindo REM total, fase não REM, tempo de sono de ondas lentas e maior latência de início do sono. Conclusões: Os fármacos utilizados no tratamento do TDAH costumam cursar com repercussões negativas sobre a qualidade do sono de crianças, e o fármaco atomoxetina demonstrou menores efeitos sobre essa variável.
RESUMEN
This article seeks to characterize the bacterial profile of pediatric hospital wastewater samples collected at the outlet of a wastewater treatment plant, and to estimate their relative susceptibility to antimicrobial agents. A total of 64 strains were isolated in the wastewater samples, of which 49 were identified as belonging to different families: Enterobacteriaceae (e.g. Escherichia coli, Klebsiella sp., Citrobacter sp.) comprised 57.2% of the identified bacteria, non-Enterobacteriaceae (e.g. Aeromonas sp., Pseudomonas sp.) comprised 30.6%, and Streptococcaceae (e.g. Enterococcus sp.) comprised 12.2%. The tests of the susceptibility of the bacteria to the antimicrobial agents used in the hospital showed that 100% of the bacterial species found discharged in the hospital wastewater treatment system were resistant to one or more of the antimicrobial agents according to the criteria of the U.S. Clinical Laboratory Standards Institute/National Committee for Clinical Laboratory Standards. The antimicrobial agent tests showed that meropenem, norfloxacin, ciprofloxacin, levofloxacin, and cefepime were the most effective antimicrobials against bacteria of the Enterobacteriaceae family. For bacteria of the non-Enterobacteriaceae family, norfloxacin, ciprofloxacin, levofloxacin, and cefepime presented the most effective antimicrobial action, whereas for bacteria of the Streptococcaceae family, ampicillin, vancomycin, and gentamicin were the most effective antimicrobials. Hospital wastewater treatment plants could be considered as places of selection pressure for bacterial resistance because of the presence of antibiotic-resistant bacteria coming from sewers or created at the treatment plant.
RESUMEN
Urban afforestation can mitigate the effects of air pollution, but the suitability of plant species for this purpose needs to be determined according to pollution intensity and climate change. The goal of this study was to evaluate the sensitivity of different phytotoxicity endpoints using two native Brazilian plant species as models, Aroeira (Schinus terebinthifolius) and Cuvatã (Cupania vernalis). The sensitivity parameters evaluated could help in selecting the most air-pollution-tolerant plant species for use in urban afforestation programs. The two plant species were exposed, in a greenhouse, to the combustion gases of a diesel engine for 120 days, with daily intermittent gas exposure. Every 30 days, leaf injury (chlorosis and necrosis), biomass, and physiological/biochemical parameters (proteins, chlorophyll, and peroxidase enzyme activity) were evaluated for both plant species. For the two selected species, the endpoints studied can be ranked according to their sensitivity (or inversely the tolerance) to diesel oil combustion gases in the following order: peroxidase > biomass ≈ chlorophyll > protein > leaf injury. The endpoint responses of higher plants can be used to assess the suitability of particular plant species for use in urban afforestation areas with relatively intense vehicle traffic.
Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Alcaloides , Anacardiaceae , Contaminantes Atmosféricos/análisis , Alcaloides/farmacología , Anacardiaceae/metabolismo , Brasil , Clorofila/metabolismo , Gases/metabolismo , Peroxidasas/metabolismo , Plantas/metabolismo , SapindaceaeRESUMEN
Alzheimer's disease (AD) is the most prevalent form of dementia with a complex pathophysiology not fully elucidated but with limited pharmacological treatment. The Usnic acid (UA) is a lichen secondary metabolite found in two enantiomeric forms: (R)-(+)-UA or (S)-(-)-UA, with antioxidant and anti-inflammatory potential. Thus, given the role of neuroinflammation and oxidative injury in the AD, this study aimed to investigate experimentally the cognitive enhancing and anti-neuroinflammatory effects of UA enantiomers. First, the interactions of UA on acetylcholinesterase (AChE) was assessed by molecular docking and its inhibitory capability on AChE was assessed in vitro. In vivo trials investigated the effects of UA enantiomers in mice exposed to Aß1-42 peptide (400 pmol/mice) intracerebroventricularly (i.c.v.). For this, mice were treated orally during 24 days with (R)-(+)-UA or (S)-(-)-UA at 25, 50, or 100 mg/kg, vehicle, or donepezil (2 mg/kg). Animals were submitted to the novel object recognized, Morris water maze, and inhibitory-avoidance task to assess the cognitive deficits. Additionally, UA antioxidant capacity and neuroinflammatory biomarkers were measured at the cortex and hippocampus from mice. Our results indicated that UA enantiomers evoked complex-receptor interaction with AChE like galantamine in silico. Also, UA enantiomers improved the learning and memory of the animals and in parallel decreased the myeloperoxidase activity and the lipid hydroperoxides (LOOH) on the cortex and hippocampus and reduced the IL-1ß levels on the hippocampus. In summary, UA restored the cognitive deficits, as well as the signs of LOOH and neuroinflammation induced by Aß1-42 administration in mice.
Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/farmacología , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Benzofuranos/farmacología , Corteza Cerebral/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Nootrópicos/farmacología , Fragmentos de Péptidos/farmacología , Péptidos beta-Amiloides/administración & dosificación , Animales , Antiinflamatorios/administración & dosificación , Antioxidantes/administración & dosificación , Conducta Animal/efectos de los fármacos , Benzofuranos/administración & dosificación , Corteza Cerebral/inmunología , Modelos Animales de Enfermedad , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Inflamación/inducido químicamente , Inyecciones Intraventriculares , Interleucina-1beta/efectos de los fármacos , Ratones , Simulación del Acoplamiento Molecular , Nootrópicos/administración & dosificación , Fragmentos de Péptidos/administración & dosificaciónRESUMEN
This study sought to use concentration-time-response surfaces to show the effects of exposure to toxic (semi-)metals on peroxidase activity in higher plants as a function of exposure-concentration and exposure-time. Maize (Zea mays L.) seedlings (i.e., leaves and roots) were exposed to arsenic (as As3+) or aluminium (as Al3+) under hydroponic conditions, and their biomass and peroxidase enzyme responses were assessed at different concentration-time-exposures. The 3D ecotoxi-profile generated with these data showed two distinct regions: the first region is formed by exposures (i.e., points for time-concentration pairings) that were not statistically different from the results of the control points (i.e., zero toxicant concentration and all exposure-times), whereas the second region is formed by exposure pairings with results that were statistically different to those obtained from control pairings. Overall, the data show that enzyme activity increased over a shorter exposure-time when there was an increase in the exposure-concentration of the toxicant, which can be seen on a 3-D toxicity profile. We propose that quantitative relationship ratios from different assessed endpoints (e.g., biomass and enzyme activity) and enzymatic concentration-time-response surfaces could be helpful in the field of environmental-policy management.
Asunto(s)
Arsénico/toxicidad , Peroxidasa/metabolismo , Zea mays/fisiología , Aluminio/farmacología , Biomasa , Hidroponía , Oxidación-Reducción , Peroxidasas , Hojas de la Planta/metabolismo , Raíces de Plantas/metabolismo , Plantones/efectos de los fármacos , Tiempo , Zea mays/efectos de los fármacosRESUMEN
BACKGROUND: The aim of this study was to evaluate the cardiovascular effects of N-phenyl-itaconimide (Imide-1), N-4-methyl-phenyl-itaconimide (Imide-2), N-4-methoxy-phenyl-itaconimide (Imide-3) and N-4-chloro-phenyl-itaconimide (Imide-4), and investigate the mechanisms of action involved in the observed responses. METHODS: The relaxant effect was investigated in rat superior mesenteric arteries by using isometric tension measurements. Additionally, in isolated atria were evaluated the heart rate and force of cardiac contraction and in vivo experiments was evaluated blood pressure and heart rate. RESULTS: Cumulative administration of itaconimides (3 × 10-8 to 3 × 10-4 M) in pre-contracted mesenteric artery rings with phenylephrine, 1 µM, induced endothelium-independent vasorelaxation. The itaconimides showed similar maximum efficacies. Additionally, Imide-3 induced vasorelaxation in rings exposed to a depolarizing-tyrode solution containing 60 mM KCl or 20 mM KCl similar to the control, suggesting the non-participation of K+ channels. Imide-3 attenuated Ca2+ influx in a concentration-dependent manner. As well, imide-3 reduced CaCl2-induced contraction in nominally calcium-free medium, in the presence of cyclopiazonic acid (20 µM), phenylephrine (1 µM) and nifedipine (1 µM), indicating a reduction of Ca2+ influx by receptor-operated channels (ROC) and store-operated channels (SOC). The presence of SKF 96365 (10-5 M), SOC blocker, did not significantly alter the vasorelaxant effect induced by imide-3. Moreover, imide-3 induced a negative inotropic effect. In vivo studies, in non-anesthetized normotensive rats, imide-3 lowered blood pressure and induced bradycardia. CONCLUSIONS: These results suggest that itaconimides have concentration-dependent vascular effects and the vasorelaxation seems to be endothelium-independent. The vasodilatory effect induced by imide-3 may be due to a possible influence on the CaV and ROC. In addition, imide-3 is able to reduce force of cardiac contraction, blood pressure and promote bradycardia.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Imidas/farmacología , Arterias Mesentéricas/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Imidazoles/farmacología , Imidas/química , Masculino , Arterias Mesentéricas/fisiología , Contracción Muscular/fisiología , Nifedipino/farmacología , Técnicas de Cultivo de Órganos , Fenilefrina/farmacología , Ratas , Ratas Wistar , Vasodilatación/fisiologíaRESUMEN
Xanthones are a class of heterocyclic natural products that have been widely studied for their pharmacological potential. In fact, they have been serving as scaffolds for the design of derivatives focusing on drug development. One of the main study targets of xanthones is their anticancer activity. Several compounds belonging to this class have already demonstrated cytotoxic and antitumor effects, making it a promising group for further exploration. This review therefore focuses on recently published studies, emphasizing their natural and synthetic sources and describing the main mechanisms of action responsible for the anticancer effect of promising xanthones.
Asunto(s)
Productos Biológicos/química , Xantonas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Productos Biológicos/metabolismo , Productos Biológicos/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Plantas/química , Plantas/metabolismo , Xantonas/metabolismo , Xantonas/uso terapéuticoRESUMEN
In this article we compare the efficiency of different methods of rapid-response remediation of beach sand contaminated with microbiological and/or organic matter. Contaminated beach sands were treated in laboratory by different treatment methods (i.e., oxidation, UV-photoexposure, or thermal methods) and the efficiency of disinfection and breakdown of organic matter were evaluated. Contaminants in raw and treated beach sands were measured by membrane filtration method, and by chemical and biochemical oxygen demand, and chromatographic analysis. All the methods tested were efficient for disinfecting beach sand with microbiological contamination, except for the UV-photoexposure method, which showed only moderate disinfection potential. Chemical degradation efficiency of beach sand contaminated by crude petroleum was higher with Fenton and Photo-Fenton (associated with the use of surfactant and ultrasound) methods. Photo-Fenton method improvement can increase the efficiency of contaminated beach sand treatment, and can also help beach managers when selecting which method to adopt for remedial actions.
Asunto(s)
Playas/normas , Contaminación Ambiental/análisis , Restauración y Remediación Ambiental/métodos , Sedimentos Geológicos , Petróleo/análisis , Dióxido de Silicio , Brasil , Enterobacteriaceae/aislamiento & purificación , Monitoreo del Ambiente/métodos , Escherichia coli/aislamiento & purificación , Sedimentos Geológicos/química , Sedimentos Geológicos/microbiología , Modelos TeóricosRESUMEN
BACKGROUND: It was recently demonstrated that the phthalimide N-(4-methyl-phenyl)-4- methylphthalimide (MPMPH-1) has important effects against acute and chronic pain in mice, with a mechanism of action correlated to adenylyl cyclase inhibition. Furthermore, it was also demonstrated that phthalimide derivatives presented antiproliferative and anti-tumor effects. Considering the literature data, the present study evaluated the effects of MPMPH-1 on breast cancer bone metastasis and correlated painful symptom, and provided additional toxicological information about the compound and its possible metabolites. METHODS: In silico toxicological analysis was supported by in vitro and in vivo experiments to demonstrate the anti-tumor and anti-hypersensitivity effects of the compound. RESULTS: The data obtained with the in silico toxicological analysis demonstrated that MPMPH-1 has mutagenic potential, with a low to moderate level of confidence. The mutagenicity potential was in vivo confirmed by micronucleus assay. MPMPH-1 treatments in the breast cancer bone metastasis model were able to prevent the osteoclastic resorption of bone matrix. Regarding cartilage, degradation was considerably reduced within the zoledronic acid group, while in MPMPH-1, chondrocyte multiplication was observed in random areas, suggesting bone regeneration. Additionally, the repeated treatment of mice with MPMPH-1 (10 mg/kg, i.p.), once a day for up to 36 days, significantly reduces the hypersensitivity in animals with breast cancer bone metastasis. CONCLUSION: Together, the data herein obtained show that MPMPH-1 is relatively safe, and significantly control the cancer growth, allied to the reduction in bone reabsorption and stimulation of bone and cartilage regeneration. MPMPH-1 effects may be linked, at least in part, to the ability of the compound to interfere with adenylylcyclase pathway activation.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Mama/patología , Ftalimidas/uso terapéutico , Animales , Antineoplásicos/toxicidad , Neoplasias Óseas/secundario , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ftalimidas/toxicidadRESUMEN
Tricyclic compounds call the attention because of their pharmacological properties, and are considered a preferred platform for the development of drugs. Especially, in cancer treatment, these planar compounds are known for their ability to stack with DNA base pairs, acting as intercalators. In this sense, natural products (NPs) are a prodigal source of polycyclic compounds, comprising classes, such as carbolines, anthraquinones and xanthones. However, most of these compounds lack suitable physico-chemical properties, compatible to oral bioaviability. In this perspective, this paper aims to overview the role of tricyclic cores in the development of cytotoxic compounds, focusing on the leadlikeness estimation of the most prominent NP classes and their synthetic derivatives.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Compuestos Macrocíclicos/química , Fenómenos Químicos , HumanosRESUMEN
The purpose of this study was to validate the potential anti-hypersensitive activity of two chalcones, (2E)-1-(4-aminophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (ANCh) and N-{4-[(2E)-3-(4-nitrophenyl)prop-2-enoil]phenyl}acetamide (AcANCh), by different models of acute and persistent pain in mice, besides in silico analysis. Molecules computational investigation for prediction of Lipinki's and Veber's rules to determine solubility, % absorption, drug likeness and toxicity liabilities was performed. Male and female C57BL/6 mice (20-30â¯g, nâ¯=â¯6) were used. Firstly, mice were pre-treated with the compounds ANCh or AcANCh and then submitted to the models of acute hypersensitivity by the intraplantar injection of different phlogistic agents. The mechanical sensitivity was assessed using von Frey hairs (0.6â¯g). The obtained data shows that both compounds presented important inhibitory effects on mechanical hypersensitivity induced by carrageenan (with oral bioavailability). The anti-hypersensitive effect was also accompanied by the interference in leukocyte migration, interleukin-1ß (IL-1ß) and tumour necrosis factor (TNF) levels reduction and by the absence of unspecific effects. Added to the in vivo results, the in silico analysis presented none violation in Lipinski's or Veber's rules, good probability to cell membrane permeability and oral bioavailability, positive values of drug likeness and few risk of computational toxicity. ANCh partially reduced the hypersensitivity induced by IL-1ß and TNF, epinephrine and prostaglandin E2 (PGE2). AcANCh had similar effect, except for the absent of inhibition in PGE2-injected mice. Both compounds were capable of reducing the mechanical hypersensitivity presented in all persistent models of hypersensitivity (inflammatory pain, chronic nerve constriction and cancer pain), with emphasis for ANCh. These results suggest that both chalcones could represent good strategies for the control of acute and chronic pain, without important side effects. ANCh seems to involve cell migration and cytokines production as the main mechanism, together with interference in PGE2 neuronal sensitization pathway. In vivo and in silico analyses reinforce the potential characteristics of the compounds to become future drugs.
Asunto(s)
Chalconas/farmacología , Dolor Crónico/tratamiento farmacológico , Animales , Carragenina/fisiología , Dolor Crónico/inducido químicamente , Dolor Crónico/metabolismo , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Femenino , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The treatment of chronic pain remains a challenge for clinicians worldwide, independent of its pathogenesis. It motivates several studies attempting to discover strategies to treat the disease. The in silico analysis using molecular docking approach demonstrated that the phthalimide N-(4methyl-phenyl)-4-methylphthalimide (MPMPH-1) presented high affinity to adenylyl-cyclase enzyme (AC). It also prominently reduced the mechanical hypersensitivity of mice challenged by Forskolin, an AC activator. This effect lasted for up to 48h after Forskolin injection, presenting activity longer than MDL-12330A (AC inhibitor). MPMPH-1 was also effective in reducing the hypersensitivity induced by IL-1ß, bradykinin, prostaglandin E2 or epinephrine, chemical mediators that have, among others, AC as pivotal protein in their signalling cascade to induce mechanical-pain behaviour. The compound presented marked inhibition in inflammatory-pain models induced by carrageenan, lipopolysaccharide or complete Freund's adjuvant, including neutrophil migration inhibition. Furthermore, it also seems to act in both peripheral and pain central-control pathways, being also effective in reducing the persistent cancer-pain behaviour induced by melanoma cells in mice. MPMPH-1 could represent a promising pharmacological tool to treat acute and chronic painful diseases, with good bioavailability, local activity, and lack of locomotor-activity interference. Further studies are necessary to determine the exact mechanism of action but it seems to involve AC enzyme as possible target.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Dolor Crónico/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Ftalimidas/química , Ftalimidas/uso terapéutico , Dolor Agudo/inducido químicamente , Dolor Agudo/patología , Analgésicos/química , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Carragenina/toxicidad , Dolor Crónico/inducido químicamente , Dolor Crónico/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/patología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/patología , Masculino , Melanoma Experimental/complicaciones , Ratones , Simulación del Acoplamiento Molecular/métodos , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Neuralgia/patología , Dimensión del Dolor/métodos , Umbral del Dolor/fisiología , Ftalimidas/farmacologíaRESUMEN
Aim. To evaluate the osteogenic potential of chalcones using the rat critical size calvarial defect. Methods. The chalcones were synthesized from acetophenone following the Claisen-Schmidt aldol condensation method by varying the substituted benzaldehydes (3,4-Cl; 4-Cl; 4-CH3; 4-OCH3, H). The five chalcone molecules were evaluated in three concentrations (1 percent, 5 percent and 10 percent) in comparison to control and vehicle (Vaseline) groups. The results of the remaining wound areas were calculated statistically by the ANOVA method followed by the Student-Newman-Keuls test and the histological sections were analyzed qualitatively by light microscopy. Results. All molecules at 10 percent concentration showed significant bone closure compared to the control, vehicle and chalcone groups at 1 percent concentration (p<0.01). Active osteoblasts were observed on the repair surfaces in all groups treated with chalcones. Treatment with the C5 molecule at concentration of a 10 percent resulted in greater bone neoformation compared to the other molecules, with features of secondary bone observed. Conclusion. The chalcones evidenced a dose-dependent osteogenic potential and C5 was more effective in bone repair
Asunto(s)
Animales , Femenino , Ratas , Osteogénesis , Chalconas/síntesis química , Ratas WistarRESUMEN
There is scientific evidence that beach sands are a significant contributor to the pathogen load to which visitors are exposed. To develop beach quality guidelines all beach zones must be included in microbiological evaluations, but monitoring methods for beach sand quality are relatively longstanding, expensive, laborious and require moderate laboratory infrastructure. This paper aimed to evaluate the microorganism activity in different beach zones applying and comparing a classical method of membrane filtration (MF) with two colorimetric screening methods based on fluorescein (FDA) and tetrazolium (TTC) salt biotransformation to evaluate a new rapid and low-cost method for beach sand microbiological contamination assessments. The colorimetric results can help beach managers to evaluate rapidly and at low cost the microbiological quality of different beach zones in order to decide whether remedial actions need to be adopted to prevent exposure of the public to microbes due to beach sand and/or water contamination.
Asunto(s)
Playas/normas , Monitoreo del Ambiente/métodos , Dióxido de Silicio/análisis , Microbiología del AguaRESUMEN
Pyrazoline is an important 5-membered nitrogen heterocycle that has been extensively researched. Ten derivatives were synthesized and tested for antileukemic effects on 2 human acute leukemia cell lines, K562 and Jurkat. The most cytotoxic of these derivatives, compound 21, was chosen for investigation of cytotoxicity mechanisms. The results obtained with selectivity calculations revealed that compound 21 is more selective for acute leukemia (K562 and Jurkat cell lines) than for other tumor cell lines. Moreover, compound 21 was not cytotoxic to normal cell lines, indicating a potential use in clinical tests. Compound 21 caused a significant cell cycle arrest in the S-phase in Jurkat cells and increased the proportion of cells in the sub G0/G1 phase in both cell lines. Cells treated with compound 21 demonstrated morphological changes characteristic of apoptosis in the EB/AO assay, confirmed by externalization of phosphatidylserine by the annexin V - fluorescein isothiocyanate method and by DNA fragmentation. An investigation of cytotoxicity mechanisms suggests the involvement of an intrinsic apoptosis pathway due to mitochondrial damage and an increase in the ratio of mitochondrial Bax/Bcl2. Pyrazoline 21 obeyed Lipinski's "rule of five" for drug-likeness. Based on these preliminary results, the antileukemic activity of compound 21 makes it a potential anticancer agent.