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Abstract Autoimmune hepatitis (AIH) is an immune-mediated inflammatory disease that requires the integration of histological abnormalities, characteristic laboratory findings, autoantibody positivity, and exclusion of other liver diseases for diagnosis. The case of a 28-year-old female patient with a week-long history of generalized jaundice associated with diffuse and intermittent abdominal pain is presented. Liver tests revealed hepatocellular injury (R factor = 17.6) with severe transaminitis (aspartate aminotransferase [AST]: 1.502 IU/L, alanine aminotransferase [ALT]: 2.029 IU/L) and conjugated hyperbilirubinemia (total serum bilirubin: 10.9 mg/dL, direct bilirubin: 8.50 mg/dL). Serological tests for hepatotropic viruses were negative, as were autoantibodies for autoimmune hepatitis. Percutaneous liver biopsy revealed findings compatible with autoimmune hepatitis. The revised 1999 International Autoimmune Hepatitis Group (IAIHG) score was calculated pretreatment, resulting in a score of 16, thus diagnosing it as definitive severe AIH. The patient was treated with oral steroids, obtaining clinical and biochemical improvement, so she was discharged after seven days of hospitalization without incidents. Maintaining a high index of suspicion for AIH, despite the initial negativity of autoantibodies, and complementing the diagnostic approach with percutaneous liver biopsy allow the timely diagnosis and treatment of this group of patients, thus preventing progression to advanced cirrhosis and its complications.
Resumen La hepatitis autoinmune (HAI) es una enfermedad inflamatoria inmunomediada la cual requiere para su diagnóstico la integración de anomalías histológicas, hallazgos de laboratorio característicos, positividad de autoanticuerpos y exclusión de otras enfermedades hepáticas. Se presenta el caso de una paciente femenina de 28 años con un cuadro de ictericia generalizada de una semana de evolución asociado a dolor abdominal difuso e intermitente. Las pruebas hepáticas revelaron lesión hepatocelular (factor R= 17,6) con transaminasemia grave (aspartato-aminotransferasa [AST]: 1,502 UI/L, alanina-aminotransferasa [ALT]: 2,029 UI/L) e hiperbilirrubinemia conjugada (bilirrubina sérica total: 10,9 mg/dL, bilirrubina directa: 8,50 mg/dL). Las pruebas serológicas para virus hepatotropos fueron negativas, así como los autoanticuerpos para hepatitis autoinmune. La biopsia hepática percutánea reveló hallazgos compatibles de hepatitis autoinmune. Se calculó el puntaje revisado del Grupo Internacional de Hepatitis Autoinmune (IAIHG) de 1999 pretratamiento, en el que se obtuvo un puntaje de 16, por lo que se diagnosticó como HAI grave definitiva. La paciente fue manejada con esteroides orales y se obtuvo una mejoría clínica y bioquímica, por lo que fue egresada a los siete días de hospitalización, sin eventualidades. Mantener un alto índice de sospecha de HAI, a pesar de la negatividad inicial de los autoanticuerpos, y complementar el abordaje diagnóstico con biopsia hepática percutánea permite el diagnóstico y tratamiento oportuno de este grupo de pacientes, de modo que se previene la progresión a cirrosis avanzada y sus complicaciones.
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Chemotherapy currently available for leishmaniasis treatment has many adverse side effects and drug resistance. Therefore, the identification of new targets and the development of new drugs are urgently needed. Previously, we reported the synthesis of a N-(2-methoxyphenyl)-1-methyl-1H-benzimidazol-2-amine, named compound 8, with an IC50 value in the micromolar range against L. mexicana, it also inhibited 68.27% the activity of recombinant L. mexicana arginase. Herein, we report studies carried out to characterize the mechanism of action of compound 8, as well as its in vivo leishmanicidal activity. It was shown in our ultrastructural studies that compound 8 induces several changes, such as membrane blebbing, the presence of autophagosomes, membrane detachment and mitochondrial and kinetoplast disorganization, among others. Compound 8 triggers the production of ROS and parasite apoptosis. It reduced 71% of the parasite load of L. mexicana in an experimental model of cutaneous leishmaniasis in comparison with a control. Altogether, the data obtained suggest the potential use of compound 8 in the treatment of cutaneous leishmaniasis.
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Leishmania mexicana , Leishmaniose Cutânea , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Apoptose , Arginase , Benzimidazóis/farmacologia , AminasRESUMO
Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of α/ß-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound 5a, which incorporates an α-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC50 < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that 5a has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity.
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Antineoplásicos , Moduladores de Tubulina , Humanos , Moduladores de Tubulina/química , Estrutura Molecular , Relação Estrutura-Atividade , Nocodazol/farmacologia , Tubulina (Proteína)/metabolismo , Proliferação de Células , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , Polimerização , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Type 2 diabetes (T2D) is one of the most common diseases and the 8th leading cause of death worldwide. Individuals with T2D are at risk for several health complications that reduce their life expectancy and quality of life. Although several drugs for treating T2D are currently available, many of them have reported side effects ranging from mild to severe. In this work, we present the synthesis in a gram-scale as well as the in silico and in vitro activity of two semisynthetic glycyrrhetinic acid (GA) derivatives (namely FC-114 and FC-122) against Protein Tyrosine Phosphatase 1B (PTP1B) and α-glucosidase enzymes. Furthermore, the in vitro cytotoxicity assay on Human Foreskin fibroblast and the in vivo acute oral toxicity was also conducted. The anti-diabetic activity was determined in streptozotocin-induced diabetic rats after oral administration with FC-114 or FC-122. Results showed that both GA derivatives have potent PTP1B inhibitory activity being FC-122, a dual PTP1B/α-glucosidase inhibitor that could increase insulin sensitivity and reduce intestinal glucose absorption. Molecular docking, molecular dynamics, and enzymatic kinetics studies revealed the inhibition mechanism of FC-122 against α-glucosidase. Both GA derivatives were safe and showed better anti-diabetic activity in vivo than the reference drug acarbose. Moreover, FC-114 improves insulin levels while decreasing LDL and total cholesterol levels without decreasing HDL cholesterol.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ácido Glicirretínico , Humanos , Animais , Ratos , Diabetes Mellitus Experimental/tratamento farmacológico , Simulação de Acoplamento Molecular , Qualidade de Vida , alfa-Glucosidases , Ácido Glicirretínico/farmacologiaRESUMO
Resumen Rojo Villa, J.A., Rojo Villa, L.G., y Martínez Félix, J. (2021). Correlación entre el estado nutricional y nivel de actividad física en escolares del sur de Sonora, México. PENSAR EN MOVIMIENTO: Revista de Ciencias del Ejercicio y la Salud, 19(2), 1-14. La falta de actividad física y presencia de malnutrición son factores importantes que comprometen la salud de toda la población. El estudio tuvo como propósito determinar el grado de asociación entre el estado nutricional y el nivel de actividad física en escolares del sur del estado de Sonora, México. El estudio es de tipo cuantitativo, descriptivo y transversal. La muestra está conformada por 156 estudiantes de nivel primaria ambos sexos (mujeres 48.71% y hombres 51.28%), con rango de edad de 10 a 12 años (10.86 ± 1.56). Las variables evaluadas fueron: nivel de actividad física con el cuestionario PAQ-C, estado nutricional utilizando los percentiles e IMC/E con referencias de la OMS en el año 2007. Los principales resultados indican que el 3.20% de los escolares cuenta con bajo peso; por otra parte, el sobrepeso y obesidad en conjunto suman 19.86% y predomina el sexo masculino con mayor número de casos: el 23.76% cuenta con niveles moderados de actividad física; el sexo femenino cuenta con mayor presencia en los niveles bajos y muy bajos. Se encontró una correlación inversa significativa entre el estado nutricional y nivel de actividad física, tanto en el sexo femenino (r = -0.19; p = .003) como en el masculino (r = -0.55; p < .0001). En conclusión, la asociación entre malnutrición y bajos niveles de actividad física podrían ser considerados para establecer estrategias preventivas y de intervención.
Abstract Rojo Villa, J.A., Rojo Villa, L.G., & Martínez Félix, J. (2021). Correlation between nutritional status and level of physical activity in school children from southern Sonora, México. PENSAR EN MOVIMIENTO: Revista de Ciencias del Ejercicio y la Salud, 19(2), 1-14. The lack of physical activity and malnutrition are important factors that compromise the health of the entire population. The purpose of the study is to determine the degree of association between the nutritional status and the level of physical activity in school children in southern Sonora, Mexico. The study is quantitative, descriptive, and cross-sectional. The sample is comprised of elementary students of both sexes (female 48.71% and male 51.28%) with ages ranging between 10 and 12 years (10.86 ± 1.56). The evaluated variables included level of physical activity with the PAQ-C questionnaire and nutritional status using BMI/Age percentiles from WHO in 2007. Main results indicate that 3.20% of school children are underweight, while overweight and obesity combined add up to 19.86%, with males having the highest number of cases (23.76% with moderate levels of physical activity) and females having a greater presence at low and very low levels. A significant inverse correlation was found between nutritional status and level of physical activity in both females (r = -0.19; p = .003) and males (r = -0.55; p < .0001). In conclusion, the association between malnutrition and low levels of physical activity could be considered to establish preventive and intervention strategies.
Resumo Rojo Villa, J.A., Rojo Villa, L.G., & Martínez Félix, J. (2021). Correlação entre estado nutricional e nível de atividade física em estudantes do sul de Sonora, México. PENSAR EN MOVIMIENTO: Revista de Ciencias del Ejercicio y la Salud, 19(2), 1-14. A falta de atividade física e a presença de desnutrição são fatores importantes que comprometem a saúde de toda a população. O objetivo do estudo foi determinar o grau de associação entre o estado nutricional e o nível de atividade física em estudantes do estado de Sonora, no sul do México. O estudo é quantitativo, descritivo e transversal. A amostra é composta por 156 estudantes do ensino fundamental de ambos os sexos (mulheres 48,71% e homens 51,28%), com faixa etária de 10 a 12 anos (10,86 ± 1,56). As variáveis avaliadas foram: nível de atividade física com o questionário PAQ-C, estado nutricional por meio de percentis e IMC/E com referências da OMS em 2007. Os principais resultados indicam que 3,20% dos alunos estão abaixo do peso; por outro lado, o sobrepeso e a obesidade juntos somam 19,86% e o sexo masculino predomina com o maior número de casos: 23,76% apresentam níveis moderados de atividade física; o sexo feminino tem maior presença nos níveis: baixo e muito baixo. Foi encontrada uma correlação inversa significativa entre o estado nutricional e o nível de atividade física, tanto no sexo feminino (r = -0,19; p = 0,003) quanto no masculino (r = -0,55; p <0,0001). Em conclusão, a associação entre desnutrição e os baixos níveis de atividade física pode ser considerada para o estabelecimento de estratégias preventivas e de intervenção.
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Humanos , Masculino , Feminino , Criança , Exercício Físico , Estado Nutricional , Alimentação Escolar , MéxicoRESUMO
Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme's structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman's method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis.
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Giardia lamblia/efeitos dos fármacos , Giardíase/tratamento farmacológico , Hidrolases/metabolismo , Animais , Antiprotozoários/farmacologia , Simulação por Computador , Cisteína/química , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Giardia lamblia/patogenicidade , Giardíase/imunologia , Tiomalato Sódico de Ouro/farmacologia , Humanos , Hidrolases/efeitos dos fármacos , Hidrolases/ultraestrutura , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Rabeprazol , Tiamina/análogos & derivados , Tiamina/farmacologia , Trofozoítos/efeitos dos fármacosRESUMO
Cancer is the second leading cause of death, after cardiovascular diseases. Different strategies have been developed to treat cancer; however, chemotherapy with cytotoxic agents is still the most widely used treatment approach. Nevertheless, drug resistance to available chemotherapeutic agents is still a serious problem, and the development of new active compounds remains a constant need. Taking advantage of the molecular hybridization approach, in the present work we designed, synthesized, and tested the cytotoxic activity of two hybrid compounds and seven derivatives based on the structure of combretastatin A-4 and 2,3-diphenyl-2H-indazole. Practical modifications of reported synthetic protocols for 2-pheny-2H-indazole and 2,3-dipheny-2H-indazole derivatives under microwave irradiation were implemented. The cytotoxicity assays showed that our designed hybrid compounds possess strong activity, especially compound 5, which resulted even better than the reference drug cisplatin against HeLa and SK-LU-1 cells (IC50 of 0.16 and 6.63 µM, respectively), and it had similar potency to the reference drug imatinib against K562 cells. Additionally, in silico and in vitro studies strongly suggest tubulin as the molecular target for hybrid compound 5.
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In this work, optimized conditions for preparation of chitosan and hyaluronan polyelectrolyte complex are proposed. The objective was to produce new biomaterials being biocompatible and bioresorbable in the body as well as approaching the extracellular matrix (ECM) structure. These materials will be tested for chondrocyte development in tissue engineering and wound healing applications. Nanofibers made of the polyelectrolyte complex (PEC) were successfully manufactured by electrospinning, and casted films were used as a model for properties comparison. To our knowledge, it is the first time that stable chitosan/hyaluronan fibers are produced, which were observed to be long-lasting in buffer at pH~7.4. The role of thermal treatment at 120 °C for 4 h is examined to control the degree of swelling by crosslinking of the two polysaccharides by H-bonds and amide bonds formation. The properties of the materials are tested for different PEC compositions at different pH values, based on swelling and solubility degrees, diameters of nanofibers and mechanical performances. The influence of the solvent (acidic potential and composition) utilized to process biomaterials is also examined. Acid formic/water 50/50 v/v is observed to be the more appropriated solvent for the carried-out procedures.
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Microtubules are highly dynamic polymers composed of α- and ß-tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to ß-tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well-known tubulin-depolymerizing agents that have close binding sites in the ß-tubulin. In this study, we designed and synthesized a set of nine 2,4-diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC-3, HCT-15, MCF-7, MDA-MB-231, and SK-LU-1), a noncancerous one (COS-7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4 e and 4 i on tubulin organization and polymerization was analyzed on the SK-LU-1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4 i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non-N-substituted 2,4-diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization.
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Antineoplásicos/farmacologia , Desenho de Fármacos , Quinazolinas/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Polimerização/efeitos dos fármacos , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
BACKGROUND: Spontaneous bleedings occurring into joints (hemarthrosis) are the most common manifestations of hemophilia and causes severe joint damage ultimately resulting in joint disfunction known as hemophilic arthropathy. Among available therapeutic options for reducing recurrent hemarthrosis-associated damage, radiosynoviorthesis (RS) has proven effective in improving joint function. AIM: To assess the impact of RS with Yttrium(90) citrate (C-Y(90)) on frequency of hemarthroses and joint function in a group of pediatric patients. METHODS: Between November 1998 and February 2017, we evaluated 27 pediatric patients with mild, moderate or severe hemophilia with haemophilic arthropathy. Overall, RS was applied in 60 joints. Some patients received more than one single intra-articular injection with C-Y(90). RESULTS: During the follow-up, one patient showed joint bleeding 15 months after RS, one patient after 12 months and one patient after 45 days. The episodes of hemarthrosis were reduced and joint function significantly improved in all patients. CONCLUSION: RS with C-Y(90) is a simple and safe treatment for reducing the frequency of hemarthroses in patients with hemophilia. It decreases the use of factor VIII / IX and improves joint function.
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Hemartrose , Hemofilia A , Criança , Hemartrose/etiologia , Hemartrose/radioterapia , Hemofilia A/complicações , HumanosRESUMO
BACKGROUND: It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide. OBJETIVES: To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity. METHODS: CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis. FINDINGS CMC-20: showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole. MAIN CONCLUSIONS: The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.
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Albendazol/farmacologia , Antiprotozoários/farmacologia , Proteínas do Citoesqueleto/efeitos dos fármacos , Giardia lamblia/efeitos dos fármacos , Tiazóis/farmacologia , Albendazol/química , Animais , Antiprotozoários/química , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Camundongos , Nitrocompostos , Testes de Sensibilidade Parasitária , Tiazóis/química , Fatores de TempoRESUMO
Objective: To evaluate the time of ureteral ejection of intravenous sodium fluorescein in the assessment of ureteral patency in patients undergoing total laparoscopic hysterectomy (TLH). Material and Methods: Fifty-four women undergoing TLH were studied in a public teaching hospital in Culiacan, Sinaloa, Mexico. They underwent cystoscopic evaluation of ureteral patency after intravenous administration of 100 mg of sodium fluorescein. The present study analyzed the time elapsed in minutes from the intravenous administration of fluorescein to the outflow of stained urine by one or both ureteral meatus, the degree of urine staining, and the impact of body mass index (BMI) (BMI; normal, overweight, and obesity) on ejection time. Results: The overall average time elapsed to visualize the ejection of fluorescein through at least one ureteral meatus was 7.5 minutes [95% confidence interval (CI): 6.3-8.7]. There were no significant differences in the time of ureteral ejection of fluorescein taking BMI into account (p=0.579), with a mean time for normal BMI of 8.1 minutes (95% CI: 5.1-11.2), for overweight of 7.0 minutes (95% CI: 5.5-8.5), and for obesity of 7.8 minutes (95% CI: 5.3-10.3). Conclusion: Intravenously administered 10% sodium fluorescein dye is rapidly eliminated and strongly stains urine, which makes it useful for identifying ureteral patency during cystoscopy after TLH. Fluorescein excretion is not affected by patient BMI.
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BACKGROUND It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide. OBJETIVES To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity. METHODS CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis. FINDINGS CMC-20 showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole. MAIN CONCLUSIONS The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.
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Humanos , Animais , Camundongos , Tiazóis/farmacologia , Albendazol/farmacologia , Giardia lamblia/efeitos dos fármacos , Proteínas do Citoesqueleto/efeitos dos fármacos , Antiprotozoários/farmacologia , Tiazóis/química , Fatores de Tempo , Albendazol/química , Técnica Indireta de Fluorescência para Anticorpo , Testes de Sensibilidade Parasitária , Antiprotozoários/químicaRESUMO
BACKGROUND It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide. OBJETIVES To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity. METHODS CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis. FINDINGS CMC-20 showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole. MAIN CONCLUSIONS The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.
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Humanos , Animais , Camundongos , Tiazóis/farmacologia , Albendazol/farmacologia , Giardia lamblia/efeitos dos fármacos , Proteínas do Citoesqueleto/efeitos dos fármacos , Antiprotozoários/farmacologia , Tiazóis/química , Fatores de Tempo , Albendazol/química , Técnica Indireta de Fluorescência para Anticorpo , Testes de Sensibilidade Parasitária , Antiprotozoários/químicaRESUMO
RESUMEN Introducción: el estado funcional en las diferentes edades es el resultante de la interacción de los elementos biológicos, psicológicos y sociales, es probable que constituya el reflejo más fiel de la integridad del individuo a lo largo del proceso de envejecimiento. Objetivo: evaluar el estado funcional de adultos mayores pertenecientes al consultorio médico número cinco del Policlínico Universitario Hermanos Cruz, municipio Pinar del Río en el año 2017. Métodos: se realizó un estudio observacional, descriptivo y de corte transversal con un universo de 151 adultos mayores y una muestra aleatoria simple de 110 adultos mayores, que cumplieron con los criterios de inclusión. Se utilizaron métodos teóricos y empíricos. Para la recogida de la información se utilizaron las historias de salud familiar e individuales, también se aplicó un cuestionario con consentimiento aprobado, basado en la Escala Geriátrica de Evaluación Funcional, así como en el Índice de Actividades Básicas de la Vida Diaria, de Katz y la Escala de Actividades Instrumentadas de la Vida Diaria de Lawton-Brody. La información fue procesada y expuesta en tablas, se utilizó el porciento como medida de resumen. Resultados: predominó el grupo de edades de 60 a 64 años y del sexo femenino, prevaleció la familia extensa con un 70 %, la hipertensión arterial (73,6 %) resultó el antecedente patológico prevalente. Conclusiones: la evaluación funcional de los ancianos permitirá trazar estrategias encaminadas a mejorar la calidad de vida de este importante segmento poblacional.
ABSTRACT Introduction: the functional status at different ages is the result of the interaction of biological, psychological and social elements; it is probably the most accurate indicator of the wellbeing of the individual throughout the aging process. Objective: to assess the functional status of the older adults belonging to the No-5 Doctor's Office at Hermanos Cruz Polyclinic, Pinar del Río municipality in 2017. Methods: an observational, descriptive and cross-sectional study was conducted with a target group comprising 151 older adults and a simple random sample of 110 who met the inclusion criteria, applying theoretical and empirical methods. To collect the information, family and individual health histories were analyzed. A questionnaire was also applied, always considering the voluntary nature and acceptance of the people included in the research, based on the Geriatric Functional Assessment Scale (GFAS), as well as on the Katz Index of Basic Activities of Daily Life (BAODL) and the Lawton-Brody Scale of Instrumented Activities of Daily Life. Results: the age group from 60 to 64 years (28,1 %), and female gender (54,5 %) predominated, extended family pattern prevailed (70 %), hypertension prevailed (73,6 %) resulted in the prevailing pathological antecedent. Conclusions: functional assessment of older adults will allow establishing strategies to improve the quality of life of this important group of population.
RESUMO
Leishmanicidal drugs have many side effects, and drug resistance to all of them has been documented. Therefore, the development of new drugs and the identification of novel therapeutic targets are urgently needed. Leishmania mexicana trypanothione reductase (LmTR), a NADPH-dependent flavoprotein oxidoreductase important to thiol metabolism, is essential for parasite viability. Its absence in the mammalian host makes this enzyme an attractive target for the development of new anti-Leishmania drugs. Herein, a tridimensional model of LmTR was constructed and the molecular docking of 20 molecules from a ZINC database was performed. Five compounds (ZINC04684558, ZINC09642432, ZINC12151998, ZINC14970552, and ZINC11841871) were selected (docking scores -10.27 kcal/mol to -5.29 kcal/mol and structurally different) and evaluated against recombinant LmTR (rLmTR) and L. mexicana promastigote. Additionally, molecular dynamics simulation of LmTR-selected compound complexes was achieved. The five selected compounds inhibited rLmTR activity in the range of 32.9% to 40.1%. The binding of selected compounds to LmTR involving different hydrogen bonds with distinct residues of the molecule monomers A and B is described. Compound ZINC12151998 (docking score -10.27 kcal/mol) inhibited 32.9% the enzyme activity (100 µM) and showed the highest leishmanicidal activity (IC50 = 58 µM) of all the selected compounds. It was more active than glucantime, and although its half-maximal cytotoxicity concentration (CC50 = 53 µM) was higher than that of the other four compounds, it was less cytotoxic than amphotericin B. Therefore, compound ZINC12151998 provides a promising starting point for a hit-to-lead process in our search for new anti-Leishmania drugs that are more potent and less cytotoxic.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Leishmania mexicana/efeitos dos fármacos , Leishmania mexicana/enzimologia , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Sequência de Aminoácidos , Sítios de Ligação , Relação Dose-Resposta a Droga , Ligação de Hidrogênio , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Farmacocinética , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Gorham-Stout disease is a rare condition characterized by unifocal and massive type IV osteolysis (variant of idiopathic nonhereditary osteolytic disease) with a slow progression, which is self-limiting for some years. It is characterized by recurrent vascular tumors with disruption of the anatomical architecture and intraosseous proliferation of vascular channels that leads to the destruction and resorption of the bone matrix. The aim of this study is to present the clinical features of this disease, as well as the importance of prompt diagnosis and treatment, with a review of the reported cases. CASE REPORTS: We describe two cases of Gorham-Stout disease between 2013 and 2017 with surgical interventions, follow-up and results. Case one involves an 11-year-old male with involvement of the left iliac bone, with adequate evolution after a surgical procedure with a lyophilized cadaveric tricortical bone allograft. Case two involves a 6-year-old male with cervical spine C1-C3 repercussion; in the protocol for surgical treatment, he presented with signs of spinal cord compression and died. CONCLUSION: Diagnosis of Gorham-Stout disease is made by exclusion, and its clinical presentation varies widely, from spontaneous remission to a fatal outcome.
Assuntos
Osteólise Essencial/cirurgia , Transplante Ósseo/métodos , Vértebras Cervicais/diagnóstico por imagem , Criança , Evolução Fatal , Humanos , Ílio/diagnóstico por imagem , Masculino , Osteólise Essencial/complicações , Osteólise Essencial/diagnóstico por imagem , Radiografia/métodos , Articulação Sacroilíaca/diagnóstico por imagem , Compressão da Medula Espinal/etiologiaRESUMO
Crude oil (CO) is a super mixture of chemical compounds whose toxic effects are reported in fish species according to international guidelines. In the current study a proteomic analysis of oxidized proteins (ox) was performed on the brain and liver of Nile tilapia exposed to WAF obtained from relevant environmental loads (0.01, 0.1 and 1.0â¯g/L) of Maya CO. Results have shown that oxidation of specific proteins was a newly discovered organ-dependent process able to disrupt key functions in Nile tilapia. In control fish, enzymes involved on aerobic metabolism (liver aldehyde dehydrogenase and brain dihydrofolate reductase) and liver tryptophan--tRNA ligase were oxidized. In WAF-treated liver specimens, fructose-bisphosphate aldolase (FBA), ß-galactosidase (ß-GAL) and dipeptidyl peptidase 9 (DPP-9) were detected in oxidized form. oxDPP-9 could be favorable by reducing the risk associated with altered glucose metabolism, the opposite effects elicited by oxFBA and oxß-GAL. oxTrypsin showed a clear adverse effect by reducing probably the hepatocyte capacity to achieve proteolysis of oxidized proteins as well as for performing the proper digestive function. Additionally, enzyme implicated in purine metabolism adenosine (deaminase) was oxidized. Cerebral enzymes of mitochondrial respiratory chain complex (COX IV, COX5B), of glycosphingolipid biosynthesis (ß-N-acetylhexosaminidase), involved in catecholamines degradation (catechol O-methyltransferase), and microtubule cytoskeleton (stathmin) were oxidized in WAF-treated specimens. This response suggests, in the brain, an adverse scenario for the mitochondrial respiration process and for ATP provision as for ischemia/reoxygenation challenges. Proteomic analysis of oxidized proteins is a promising tool for monitoring environmental quality influenced by hydrocarbons dissolved in water.
Assuntos
Encéfalo/efeitos dos fármacos , Ciclídeos , Fígado/efeitos dos fármacos , Petróleo/toxicidade , Proteoma , Poluentes Químicos da Água/toxicidade , Animais , Encéfalo/metabolismo , Catalase/metabolismo , Catecolaminas/metabolismo , Monitoramento Ambiental , Glutationa Peroxidase/metabolismo , Glicoesfingolipídeos/metabolismo , Peroxidação de Lipídeos , Fígado/metabolismo , Microtúbulos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteólise , Espécies Reativas de Oxigênio/metabolismo , Estatmina/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Unilateral congenital pulmonary lymphangiectasia (CPL) is an extremely rare disease of the pulmo nary lymphatic vessels. OBJECTIVE: to present a case of CPL in a premature newborn. CLINICAL CASE: premature male newborn with severe respiratory failure at 2 hours of extrauterine life was treated with exogenous surfactant, catecholamines and high frequency oscillatory ventilation (HFOV). Chest computed tomography (CT) scan showed bullae and air trapping of the left lung; the histopathological study showed cystic dilation of the bronchoalveolar lymphatic channels. The diagnosis of secondary unilateral CPL was made. The clinical course up to 19 months of age was normal and the chest CT scan showed few emphysematous bullae. CONCLUSIONS: CPL must be one of the differential diagnoses in neonates with unexplained respiratory distress. The prognosis will depend on the type of CPL and lung involvement.
Assuntos
Doenças do Prematuro/diagnóstico , Pneumopatias/congênito , Linfangiectasia/congênito , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Pneumopatias/diagnóstico , Linfangiectasia/diagnóstico , MasculinoRESUMO
La linfangiectasia pulmonar congénita (LPC) unilateral es una enfermedad extremadamente rara de los vasos linfáticos pulmonares. OBJETIVO: presentar un caso de LPC en un recién nacido prematuro. CASO CLÍNICO: recién nacido masculino, prematuro, con insuficiencia respiratoria severa a las 2 horas de vida extrauterina, recibió tratamiento con surfactante exógeno, catecolaminas y ventilación de alta frecuencia oscilatoria (VAFO). La tomografía axial computarizada (TAC) de tórax reveló bulas y atrapamiento de aire de pulmón izquierdo, el estudio histopatológico describió dilatación quística de los canales linfáticos broncoalveolares. Se diagnosticó LPC unilateral secundaria. La evolución clínica hasta los 19 meses de edad fue normal y la TAC de tórax mostró escasas bulas enfisematosas. CONCLUSIONES: La LPC debe ser uno de los diagnósticos diferenciales en neonatos con dificultad respiratoria inexplicable. El pronóstico dependerá del tipo de LPC y de la afectación pulmonar.
Unilateral congenital pulmonary lymphangiectasia (CPL) is an extremely rare disease of the pulmo nary lymphatic vessels. OBJECTIVE: to present a case of CPL in a premature newborn. CLINICAL CASE: premature male newborn with severe respiratory failure at 2 hours of extrauterine life was treated with exogenous surfactant, catecholamines and high frequency oscillatory ventilation (HFOV). Chest computed tomography (CT) scan showed bullae and air trapping of the left lung; the histopathological study showed cystic dilation of the bronchoalveolar lymphatic channels. The diagnosis of secondary unilateral CPL was made. The clinical course up to 19 months of age was normal and the chest CT scan showed few emphysematous bullae. CONCLUSIONS: CPL must be one of the differential diagnoses in neonates with unexplained respiratory distress. The prognosis will depend on the type of CPL and lung involvement.