RESUMEN
The association of age at the onset of CRC and the prevalence of a KRAS G12C mutation is unclear. A retrospective, multicenter study evaluating metastatic CRC patients from January 2019 to July 2023, treated at the Oncoclinicas units and tested for tissue based KRAS/NRAS and BRAF mutations in a centralized genomics lab. A mismatch repair (MMR) status was retrieved from different labs and electronic medical records, as were patient demographics (age, gender) and tumor sidedness. The chi-square test was used to examine the association between clinical and molecular variables, with p value < 0.05 being statistically significant. A total of 858 cases were included. The median age was 63.7 years (range 22-95) and 17.4% were less than 50 years old at the diagnosis of metastatic CRC. Male patients represented 50.3% of the population. The sidedness distribution was as follows: left side 59.2%, right side 36.8% and not specified 4%. The prevalence of the KRAS mutation was 49.4% and the NRAS mutation was 3.9%. Among KRAS mutated tumors, the most common variants were G12V (27.6%) and G12D (23.5%), while KRAS G12C was less frequent (6.4%), which represented 3.1% of the overall population. The BRAF mutant cases were 7.3% and most commonly V600E. Only five (<1%) non-V600E mutations were detected. MSI-high or dMMR was present in 14 cases (1.6%). In the age-stratified analysis, left-sidedness (p < 0.001) and a KRAS G12C mutation (p = 0.046) were associated with a younger age (<50 years). In the sidedness-stratified analysis, a BRAF mutation (p = 0.001) and MSI-high/dMMR status (p = 0.009) were more common in right-sided tumors. Our data suggest that KRAS G12C mutations are more frequent in early-onset metastatic CRC. To the best of our knowledge, this is the largest cohort in the Latin American population with metastatic CRC reporting RAS, BRAF and MSI/MMR status.
RESUMEN
Peroxisome proliferator-activated receptor gamma (PPARγ) regulates multiple pathways involved in the pathogenesis of obesity and atherosclerosis. Here, we evaluated the therapeutic potential of GQ-177, a new thiazolidinedione, on diet-induced obesity and atherosclerosis. The intermolecular interaction between PPARγ and GQ-177 was examined by virtual docking and PPAR activation was determined by reporter gene assay identifying GQ-177 as a partial and selective PPARγ agonist. For the evaluation of biological activity of GQ-177, low-density lipoprotein receptor-deficient (LDLr(-/-)) C57/BL6 mice were fed either a high fat diabetogenic diet (diet-induced obesity), or a high fat atherogenic diet, and treated with vehicle, GQ-177 (20mg/kg/day), pioglitazone (20mg/kg/day, diet-induced obesity model) or rosiglitazone (15mg/kg/day, atherosclerosis model) for 28 days. In diet-induced obesity mice, GQ-177 improved insulin sensitivity and lipid profile, increased plasma adiponectin and GLUT4 mRNA in adipose tissue, without affecting body weight, food consumption, fat accumulation and bone density. Moreover, GQ-177 enhanced hepatic mRNA levels of proteins involved in lipid metabolism. In the atherosclerosis mice, GQ-177 inhibited atherosclerotic lesion progression, increased plasma HDL and mRNA levels of PPARγ and ATP-binding cassette A1 in atherosclerotic lesions. GQ-177 acts as a partial PPARγ agonist that improves obesity-associated insulin resistance and dyslipidemia with atheroprotective effects in LDLr(-/-) mice.
Asunto(s)
Aterosclerosis/metabolismo , Obesidad/metabolismo , PPAR gamma/agonistas , PPAR gamma/metabolismo , Receptores de LDL/genética , Sulfonas/farmacología , Tiazolidinedionas/farmacología , Adiponectina/genética , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Aorta Torácica/patología , Aterosclerosis/sangre , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/patología , Densidad Ósea , Línea Celular , HDL-Colesterol/sangre , Factores de Crecimiento de Fibroblastos/genética , Transportador de Glucosa de Tipo 4/genética , Humanos , Leptina/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Noqueados , Modelos Moleculares , Miocardio/metabolismo , Obesidad/sangre , Obesidad/tratamiento farmacológico , Obesidad/patología , Sulfonas/uso terapéutico , Tiazolidinedionas/uso terapéuticoRESUMEN
BACKGROUND: The aim of this study was to identify predictors of 30-day mortality in patients with malignant pleural effusion (MPE) who need pleural palliative procedures. METHODS: Data was prospectively collected from our database, between January 2013 and July 2014 on 86 patients with MPE and complete follow-up 30 days after the procedure. The sample was divided into two groups. The first group (G1) included patients who had died up to 30 days after the palliative procedure, and the second group (G2) included patients who survived for more than 30 days after the palliative procedure. The identification of prognostic factors occurred through univariate analysis using Fisher exact test for analysis of categorical variables and the t test for quantitative variables. Subsequently, all variables were used in the multivariate logistic regression analysis. The cutoff values for any significant continuous variables were determined by receiver operating characteristics analysis. RESULTS: There were 24 patients in G1 and 62 patients in G2. Univariate analysis of factors affecting postprocedural survival disclosed nine factors that were associated with significantly reduced postoperative survival. At the multivariate analysis, high levels of white blood cells, (p = .013), low levels of red blood cells (p < .0001) and protein in pleural fluid (p = .001), and primary lung and gastrointestinal sites (p = .0076) were identified as independent predictors of mortality. CONCLUSIONS: We identified four factors that are easily recognized in daily practice and can help select patients with low life expectancy. Therefore, invasive procedures and hospitalizations for this subgroup of patients can be prevented.
Asunto(s)
Neoplasias Gastrointestinales/complicaciones , Neoplasias Pulmonares/complicaciones , Cuidados Paliativos , Derrame Pleural Maligno/mortalidad , Derrame Pleural Maligno/terapia , Anciano , Catéteres de Permanencia , Drenaje , Índices de Eritrocitos , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Derrame Pleural Maligno/etiología , Pleurodesia , Pronóstico , Estudios Prospectivos , Proteínas/análisis , Factores de Riesgo , Tasa de Supervivencia , Talco/administración & dosificación , ToracocentesisRESUMEN
Jatropha elliptica is a shrub distributed throughout the north and west of Brazil and reputedly possesses a wide range of therapeutical properties. The roots of this plant possess molluscicidal activity and contain terpenoids, coumarin, lignoid, steroids and alkaloid. In the present study, we assessed the schistosomicidal, miracicidal and cercaricidal activities (against Schistosoma mansoni) and molluscicidal activities (against adults and egg masses of Biomphalaria glabrata) of the alkaloid diethyl 4-phenyl-2,6-dimethyl-3,5-pyridinedicarboxylate, isolated from the ethanol extract of the rhizome of J. elliptica, have been determined. The alkaloid was 100% lethal to adult schistosomes within 4 days at a concentration of 50 µg/mL. Alterations were observed in the schistosome tegument occasioned by treatment with the alkaloid, such as formation of vesicles and vacuolisation. The extent of tegumental damage of the worm was proportional to the time of incubation and to the concentration of compound. The alkaloid also exhibited a potent cercaricidal activity (LC100 = 2 µg/mL); it was totally ineffective against miracicidal forms of the parasite. Moreover, the alkaloid presented strong activity against adult snails (LC90 = 36.43 µg/mL) but was inactive against their egg masses. It is observed then the potential of this compound for the development of new therapies for the treatment of schistosomiasis.
Asunto(s)
Biomphalaria/efectos de los fármacos , Jatropha/química , Moluscocidas/farmacología , Extractos Vegetales/farmacología , Schistosoma mansoni/efectos de los fármacos , Esquistosomicidas/farmacología , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Animales , Brasil , Moluscocidas/aislamiento & purificación , Piridinas/aislamiento & purificación , Piridinas/farmacología , Rizoma/química , Esquistosomicidas/aislamiento & purificaciónRESUMEN
Noni is a fruit with potential medicinal use preventing elevated blood glucose levels in diabetes mellitus. Its effects have been attributed to an antioxidant property in several other diseases. However, the effects of noni-chronic supplementation on exercise performance in the presence of diabetes conditions are not known. Thirty-two male Wistar rats were used to verify the effects of chronic noni (Morinda citrifolia L) juice administration on glycemia, triglyceride levels, and its relation to physical performance. In addition, it was verified if chronic noni supplementation is safe for clinical use through kidney morphology analysis. In half of the rats, diabetes mellitus (DM) was induced with STZ. All rats were submitted to an incremental workload running test (IWT) until fatigued so that oxygen consumption and performance indexes (exercise time to fatigue and workload) could be analyzed before noni administration. Then, the control and DM groups received a placebo (saline solution) or noni juice (dilution 2:1) at a dose of 2 mL/kg once a day for 60 days. The result was four groups: control + placebo (CP), control + noni (CN), DM + placebo (DMP), and DM + noni (DMN). Our dose was based on in previous study by Nayak et al. (2011) that observed a significant reduction in glycemia with 2 ml/kg of the noni juice without any toxicity effect cited. Groups were then given a third IWT to verify the effect of the noni juice on exercise performance (exercise time to fatigue, workload, maximal oxygen consumption) and glycemia. Twenty-four hours after the third test, all animals were euthanized and blood and kidneys were removed for posterior analysis. The DM induction with STZ impaired the performance by 39%. Noni administration improved the time to fatigue and workload in DM rats beyond reducing hyperglycemia. These results could be associated with an improved energy efficiency promoted by noni ingestion, since the oxygen consumption was not different between the groups, although the exercise was longer in animals with noni ingestion. Our results provided evidence that chronic noni administration causes kidney damage since increased Bowman's space area in the control rats, suggesting glomerular hyperfiltration at the same magnitude as the non-treated DM group.In conclusion, chronic noni ingestion promoted glycemic control and improved the performance in DM rats but caused kidney toxicity.
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Parálisis/diagnóstico , Sífilis Congénita/diagnóstico , Sífilis Congénita/tratamiento farmacológico , Treponema pallidum/aislamiento & purificación , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Parálisis/tratamiento farmacológico , Parálisis/microbiología , Penicilinas/uso terapéutico , Medición de Riesgo , Resultado del TratamientoRESUMEN
The isolation of single monoclonal antibodies (mAbs) against a given antigen was only possible with the introduction of the hybridoma technology, which is based on the fusion of specific B lymphocytes with myeloma cells. Since then, several mAbs were described for therapeutic, diagnostic, and research purposes. Despite being an old technique with low complexity, hybridoma-based strategies have limitations that include the low efficiency on B lymphocyte-myeloma cell fusion step, and the need to use experimental animals. In face of that, several methods have been developed to improve mAb generation, ranging from changes in hybridoma technique to the advent of completely new technologies, such as the antibody phage display and the single B cell antibody ones. In this review, we discuss the hybridoma technology along with emerging mAb isolation approaches, taking into account their advantages and limitations. Finally, we explore the usefulness of the hybridoma technology nowadays.
RESUMEN
A 22-year-old Tennessee Walking Horse mare was presented to the Auburn University Large Animal Teaching Hospital with a 3-day history of lethargy, anorexia, and mild signs of colic. The mare had a several-month history of weight loss and refractory cough. Physical examination revealed an increased respiratory rate, and crackles and wheezes were heard on thoracic auscultation. Thoracic ultrasonographic examination showed disseminated, minor, bilateral comet tail-like lesions on the parietal pleural surfaces. Abdominal ultrasonographic examination was unremarkable. Trans-rectal palpation revealed a firm small colon impaction with concomitant diarrhea. Laboratory data were characterized by a very pronounced acute inflammatory leukogram with severe neutropenia and significant left shift, evidence of hepatocellular damage/necrosis, cholestasis, and possibly mixed metabolic alkalosis and acidosis. On cytologic evaluation of a peritoneal fluid sample, there were many large granular lymphocytes (LGL). Large numbers of LGL were also observed on cytologic examination of a subsequent transtracheal wash. The final cytologic interpretation was disseminated lymphoma with LGL morphology. Due to worsening of the clinical signs and poor prognosis, the mare was euthanized. On necropsy and in histopathologic examination, disseminated lymphoma with LGL morphology was noted in a mesenteric lymph node, lungs, liver, spleen, kidneys, and right dorsal colon. Lymphoma with LGL morphology is rarely diagnosed in the horse. This report provides unique cytologic findings of a case of disseminated lymphoma with LGL morphology in a horse, confirmed with histopathologic evaluation.
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Enfermedades de los Caballos/patología , Linfoma/patología , Animales , Líquido Ascítico/patología , Citodiagnóstico/veterinaria , Femenino , Caballos , Hígado/patología , Pulmón/patología , Ganglios Linfáticos/patología , Linfocitos/patología , Linfoma/veterinariaRESUMEN
Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that improve insulin-mediated glucose uptake and possess beneficial vasculoprotective actions. However, because undesirable side effects are associated with these drugs, novel TZDs are under development. In this study, we evaluated the biological activity of LYSO-7, a new indole-thiazolidine, on PPAR activation, inflammation and atherogenesis using a gene reporter assay, lipopolysaccharide (LPS)-activated RAW 264.7 cell culture, and a low-density lipoprotein receptor knockout (LDLr(-/-)) mouse model of atherosclerosis. LYSO-7 shows low cytotoxicity in RAW 264.7 cells and at 2.5µmol/L induces PPARα and PPARγ transactivation as well as inhibits LPS-induced nitrite production and the mRNA gene expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). In addition, treatment with LYSO-7 reduces the development of atherosclerosis in LDLr(-/-) mice, improves the lipid profile, blood glucose levels, and downregulates CD40 and CD40L expression without affecting the body weight of the animals. Altogether, our data show that LYSO-7 possesses anti-inflammatory properties and that treatment with this TZD attenuates atherosclerosis progression in LDLr(-/-) mice by modulating lipid metabolism and inflammation. Thus, LYSO-7 shows potential as a new drug candidate for the treatment of atherosclerosis.
Asunto(s)
Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Indoles/uso terapéutico , Receptores de LDL/deficiencia , Tiazolidinedionas/uso terapéutico , Tiazolidinas/uso terapéutico , Animales , Línea Celular , Indoles/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Activados del Proliferador del Peroxisoma/agonistas , Tiazolidinedionas/farmacología , Tiazolidinas/farmacologíaRESUMEN
The aim of this study was to report on a rare case of Garré's sclerosing osteomyelitis. The patient was a 54-year-old woman with a history of treatment for lupus using corticoids for 20 years, and for osteoporosis using alendronate for five years. She presented edema and developed a limitation of left knee movement one year earlier, with mild effusion and pain on metaphyseal palpation, but without fever. She was in a good general state, without local secretion. Images of her knee showed trabecular osteolysis of the distal metaphysis of the femur and a periosteal reaction in both proximal tibias and both distal femurs, compatible with chronic osteomyelitis of low virulence and slow progression. Magnetic resonance imaging showed T2 hypersignal in the femur and tibia. Curettage was performed on the left distal femur, with release of secretion, but this was negative on culturing. A biopsy showed chronic infection and inflammation, fibrosis, xanthogranulomatous reaction and foci of suppuration. Antibiotic therapy was administered for six months. The etiology was not clarified: bacterial infection was suspected, but culturing was generally negative. The chronic process was maintained by low-virulence infection or even after treatment. The differential diagnoses were fibrous dysplasia, syphilis, pustulosis palmoplantaris, rectocolitis, Crohn's disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) and Paget's disease. The unifocal diseases were osteoid osteoma, Ewing's disease, osteosarcoma and eosinophilic granuloma.
Relatar um caso raro de osteomielite esclerosante de Garrè. Paciente feminino, 54 anos, com história de tratamento de lúpus com corticoide havia 20 anos e osteoporose, em uso de alendronato havia cinco anos. Apresentava edema e limitação do joelho esquerdo havia um ano, derrame leve, dor à palpação metafisária, afebril, bom estado geral, sem secreção local. Imagens do joelho evidenciaram osteólise trabecular da metáfise distal do fêmur e reação periosteal nas duas tíbias proximais e nos dois fêmures distais, compatíveis com osteomielite crônica, de baixa virulência e progressão lenta. Hipersinal em T2 no fêmur e tíbia à ressonância. Curetagem do fêmur distal esquerdo, com saída de secreção, mas cultura negativa. Biópsia evidenciou infecção e inflamação crônica, fibrose, reação xantogranulomatosa e focos de supuração. Feita antibioticoterapia por seis meses. Etiologia não esclarecida, suspeita de infecção bacteriana, mas geralmente a cultura é negativa, processo crônico mantido por infecção de baixa virulência ou mesmo após o tratamento. Diagnósticos diferenciais: displasia fibrosa, sífilis, pustulose palmoplantar, retocolite, Crohn, Sapho (sinovite, acne, pustulose, hiperostose, osteíte) e Paget. Unifocais: osteoma osteoide, Ewing, osteossarcoma e granuloma eosinofílico.
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Enfermedades de los Caballos/patología , Osteosarcoma/veterinaria , Neoplasias de los Senos Paranasales/veterinaria , Animales , Eutanasia Animal , Resultado Fatal , Caballos , Masculino , Neoplasias Mandibulares/patología , Neoplasias Mandibulares/veterinaria , Osteosarcoma/patología , Neoplasias de los Senos Paranasales/patologíaRESUMEN
The aim of this study was to report on a rare case of Garré's sclerosing osteomyelitis. The patient was a 54-year-old woman with a history of treatment for lupus using corticoids for 20 years, and for osteoporosis using alendronate for five years. She presented edema and developed a limitation of left knee movement one year earlier, with mild effusion and pain on metaphyseal palpation, but without fever. She was in a good general state, without local secretion. Images of her knee showed trabecular osteolysis of the distal metaphysis of the femur and a periosteal reaction in both proximal tibias and both distal femurs, compatible with chronic osteomyelitis of low virulence and slow progression. Magnetic resonance imaging showed T2 hypersignal in the femur and tibia. Curettage was performed on the left distal femur, with release of secretion, but this was negative on culturing. A biopsy showed chronic infection and inflammation, fibrosis, xanthogranulomatous reaction and foci of suppuration. Antibiotic therapy was administered for six months. The etiology was not clarified: bacterial infection was suspected, but culturing was generally negative. The chronic process was maintained by low-virulence infection or even after treatment. The differential diagnoses were fibrous dysplasia, syphilis, pustulosis palmoplantaris, rectocolitis, Crohn's disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) and Paget's disease. The unifocal diseases were osteoid osteoma, Ewing's disease, osteosarcoma and eosinophilic granuloma...
Relatar um caso raro de osteomielite esclerosante de Garrè. Paciente feminino, 54 anos, com história de tratamento de lúpus com corticoide havia 20 anos e osteoporose, em uso de alendronato havia cinco anos. Apresentava edema e limitação do joelho esquerdo havia um ano, derrame leve, dor à palpação metafisária, afebril, bom estado geral, sem secreção local. Imagens do joelho evidenciaram osteólise trabecular da metáfise distal do fêmur e reação periosteal nas duas tíbias proximais e nos dois fêmures distais, compatíveis com osteomielite crônica, de baixa virulência e progressão lenta. Hipersinal em T2 no fêmur e tíbia à ressonância. Curetagem do fêmur distal esquerdo, com saída de secreção, mas cultura negativa. Biópsia evidenciou infecção e inflamação crônica, fibrose, reação xantogranulomatosa e focos de supuração. Feita antibioticoterapia por seis meses. Etiologia não esclarecida, suspeita de infecção bacteriana, mas geralmente a cultura é negativa, processo crônico mantido por infecção de baixa virulência ou mesmo após o tratamento. Diagnósticos diferenciais: displasia fibrosa, sífilis, pustulose palmoplantar, retocolite, Crohn, Sapho (sinovite, acne, pustulose, hiperostose, osteíte) e Paget. Unifocais: osteoma osteoide, Ewing, osteossarcoma e granuloma eosinofílico...
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Humanos , Femenino , Persona de Mediana Edad , Osteomielitis/cirugía , Osteomielitis/diagnóstico , Osteomielitis/terapiaRESUMEN
Tiazolidinadionas (TZDs) são agentes sensibilizadores de insulina que agem por ligação ao receptor gama ativado por proliferador de peroxissomos (PPARγ). Elas têm apresentado efeitos cardioprotetores em humanos e propriedades anti-aterogênicas em modelos animais. Estudos in vitro têm sugerido que esses efeitos anti-aterogênicos da ativação de PPARγ ocorrem por inibição da expressão de genes pro-inflamatórios e por aumentar o efluxo de colesterol via ativação dos receptores LXR-ABCA1. Entretanto, vários efeitos colaterais são associados ao tratamento com as TZDs, tornando necessária a pesquisa por novos compostos desta classe. Neste estudo, 14 novas tiazolidina-2,4- dionas, que são TZDs modificadas por bioisosterismo, foram avaliadas quanto à expressão de fatores aterogênicos e inflamatórios em linhagens de macrófagos J774 e RAW 264.7 e em camundongos com deleção genética para o receptor de LDL (LDLr-/-). Após a avaliação da citotoxicidade em macrófagos, foram eleitas cinco TZDs, denominadas de GQ-11, GQ-97, GQ-177, GQ-145 e LYSO-7. Três destas TZDs (GQ- 145, GQ-177 e LYSO-7) aumentaram significativamente a expressão de RNAm dos fatores de transcrição PPARγ1, PPARγ2 e do receptor CD36, assim como também aumentaram a expressão gênica de ABCA1 em 2.9, 3.5 e 6.7 vezes, respectivamente. Em adição, estas TZDs diminuíram a expressão gênica de iNOS, COX2, VCAM e IL-6 associado a redução na produção de nitritos, mas apenas a LYSO-7 reduziu significativamente a expressão desses genes quando comparada à rosiglitazona (RSG), além de diminuir a expressão da proteína-1 quimiotática para monócitos (MCP-1). No estudo experimental, os camundongos LDLr-/- machos foram alimentados com dieta hipercolesterolêmica por 16 semanas e quatro semanas antes da eutanásia receberam os derivados tiazolidínicos (20 mg/kg/dia) por gavagem. GQ-177 inibiu a progressão da placa aterosclerótica associada à aumento nas concentrações plasmáticas de HDL-C, com elevação na expressão de ABCA1, e redução da via inflamatória CD40-CD40L. LYSO-7 também mostrou inibição da aterogênese associada à redução das concentrações plasmáticas de colesterol total e triacilgliceróis, com diminuição na interação entre CD40-CD40L e expressão de citocinas inflamatórias. A GQ-145 não alterou os níveis plasmáticos dos lipídeos, mas aumentou a expressão de todos os genes pró-aterogênicos e pró-inflamatórios. Adicionalmente, as vias de ativação destas novas TZDs também foram estudadas por ensaio de luciferase, como gene repórter. A GQ-177 induziu ativação de PPARγ e ligação ao seu domínio, enquanto a LYSO-7 estimulou ativação de PPARα e PPARδ. Portanto, conclui-se que as novas TZDs, especialmente a GQ-177 e a LYSO-7, podem apresentar propriedades ateroprotetoras associadas ao transporte reverso de colesterol e aos efeitos antiinflamatórios, e poderiam ser uma alternativa promissora para o tratamento da aterosclerose. Porém, estudos complementares são requeridos para caracterizar as vias de sinalização intracelular, visto que as duas demonstraram ativar diferentes isotipos do fator de transcrição PPAR
Thiazolidinediones (TZDs) are insulin-sensitizing agents that act by binding to peroxisome proliferator-activated receptor-γ (PPARγ). They have been demonstrated to possess cardioprotective effects in humans and antiatherogenic properties in animal models. In vitro studies have also suggested that these antiatherogenic effects of PPARγ activation occur by inhibiting the inflammatory gene expression and by increasing cholesterol efflux via LXR-ABCA1 activation. However, several side effects are associated with TZDs treatment making necessary the search for new compounds. In this study, 14 new thiazolidine-2,4-diones, modified TZDs by bioisosterism, were tested for aterogenic and inflammtary factors in RAW 264.7 macrophages and in low-density lipoprotein receptor-deficient mice. After the citotoxicity evaluation in RAW 264.7 macrophages the TZDs named GQ-11, GQ-97, GQ-177, GQ-145 e LYSO-7 were selected for this study. Three of these TZDs (GQ-177, GQ-145 and LYSO-7) significantly increased the expression of PPARγ1, PPARγ2 and CD36 mRNA, and enhanced the expression of ABCA1 mRNA in 2.9, 3.5 and 6.7 fold, respectively. Moreover, they also significantly decreased the expression of iNOS, COX2, VCAM and IL-6 mRNA in relation to control, and these results are associated to reduction on nitrits concentration. In addition, LYSO-7 significantly reduced the expression of these genes when compared to rosiglitazone, and decreased expression of MCP1 mRNA. In the experimental study, male LDLr-/- mice were fed an atherogenic diet containing 0.5% cholesterol for 16 weeks, and 4 weeks before euthanasia they received TZDs (20mg/kg/ per day) by gavage. GQ-177 treatment inhibited progression of atherosclerotic plaque associated to increased plasma concentrations of HDL-C, with enhance of ABCA1 expression and reduction on CD40-CD40L interaction. LYSO-7 treatment also showed inhibition of the atherogenesis associated to decreased plasma concentrations of total cholesterol and TAG, with reduction on CD40-CD40L pathway and inflammatory cytokines expression.GQ-145 did not alter the lipid plasma levels and increased the expression of all pro-atherogenic and pro-inflammatory genes. Furthermore, the activation of PPARs has also been studied, by luciferase assay as reporter gene. GQ-177 induced activation of PPARγ, whereas LYSO-7 stimulated activation of PPARα and PPARß/δ. Altogether, our data suggest that the new TZDs derivatives, specially GQ- 177 and LYSO-7, may have atheroprotective properties associated with the reverse cholesterol transport and anti-inflammatory effects, and could be a promising alternative for the treatment of atherosclerosis. However, further studies are warranted in order to characterize the pathways of intracellular signaling since both have demonstrated to activate different isotypes of PPAR
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Animales , Masculino , Ratones , Aterosclerosis/patología , Luciferasas/farmacología , Muerte Celular , Supervivencia Celular , Receptores X del Hígado/análisis , Receptores Activados del Proliferador del Peroxisoma , PPAR gammaRESUMEN
Objetivo. Analisar os fatores de risco e os de proteção relativos a doenças crônicas não transmissíveis na cidade de Goiânia, capital de Goiás. Método. Foram analisadas informações provenientes do sistema de vigilância de fatores de risco e os de proteção referentes a doenças crônicas não transmissíveis por inquérito telefônico ? Vigitel ? em 2009. A amostra foi composta de 2.011 entrevistas, e as frequências das doenças crônicas foram apresentadas em relação à população geral e por sexo, com intervalos de confiança de 95%. Resultados. O estudo mostrou diferenças na prevalência de fatores de risco e fatores de proteção afetosa doenças crônicas não transmissíveis entre sexos. As diferenças estatisticamente significativas entre os sexos foram: para os homens, ex-fumantes, fumo passivo no trabalho, consumo de carne com excesso de gordura, inatividade física, consumo de bebidas alcoólicas e como fator de proteção o consumo de feijão; para as mulheres foram significativos apenas fatores de proteção como consumo regular de frutas, legumes e verduras, consumo recomendado de frutas, legumes e verduras e proteção contra raios ultravioleta. Conclusões. Essas informações devem redirecionar a implementação das políticas públicas com foco no modode viver mais saudável e nas escolhas individuais mais adequadas da população adulta na cidade de Goiânia.
Objective. To estimate the prevalence of protective factors and risk factors for the most important chronic nontransmissiblediseases in Goiania, State Capital of Goias. Method. The data were that collected in 2009 through Vigitel, an ongoing population-based telephone inquiry surveillance system, implemented in all Brazilian State capitals since 2006. In 2009, over 2,011 interviews were completed over the phone with a random sample of individuals living in Goiania.Results. These analyses showed differences in the prevalence of determinants of chronic diseases by demographic characteristics such as gender. The statistically significant diference between gender were: for men, former smokers, passive smoking at work, intake of meat with excessive fat, sedentariness, alcoholic beverages intake, andas a protection factor beans intake; for women only protective factors were significant as regular fruit and vegetable intake, the recommended fruit and vegetable intake and protection against ultraviolet rays.Conclusion. The Vigitel system was implemented to monitor changes in the prevalence of determinants of chronic diseases over time to inform public health workers and decision makers to adjust existing programs andpolicies according to the changing profile of consumers. The ultimate goal is to improve the health conditions of the population in Goiania.