RESUMEN
Aim: We examined whether ADIPOQ (rs266729 and rs1501299) and NOS3 (rs3918226 and rs1799983) SNPs or the haplotypes formed by them, affect blood pressure (BP) control in 196 patients with adherence to antihypertensive therapy grouped into controlled (BP <140/90 mmHg) and uncontrolled (BP ≥140/90 mmHg) hypertension. Materials & methods: The average of the three most recent BP measurements was retrieved from the patients' electronic medical records. Adherence to antihypertensive therapy was evaluated using the Morisky-Green test. Haplotype frequencies were estimated using Haplo.stats. Multiple logistic/linear regression analyses were adjusted for the covariates ethnicity, dyslipidemia, obesity, cardiovascular disease and uric acid. Results: ADIPOQ rs266729 genotypes CG (additive model) and CG+GG (dominant model) were associated with uncontrolled hypertension and CG was associated with higher systolic BP and mean arterial pressure (p < 0.05). ADIPOQ haplotypes 'GT' and 'GG' were associated with uncontrolled hypertension and 'GT' was associated with higher diastolic BP and mean arterial pressure (p < 0.05). Conclusion: ADIPOQ SNPs and haplotypes affect BP control in hypertensive patients undergoing treatment.
Asunto(s)
Antihipertensivos , Hipertensión , Humanos , Presión Sanguínea/genética , Antihipertensivos/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Haplotipos/genética , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Adiponectina/genética , Adiponectina/farmacología , Óxido Nítrico Sintasa de Tipo III/genéticaRESUMEN
The new severe acute respiratory syndrome coronavirus (SARS-CoV-2) recently emerged as a worrying pandemic, with many confirmed cases and deaths globally. Therefore, there is a clear need for identifying effective therapeutic options and a review of secondary metabolites related to Brazilian herbal medicines was performed as a strategy for the discovery of new antiviral agents. To confirm this potential, an in silico screening of the identified compounds identified was also evaluated. The review was performed by the PubMed database and the selected natural compounds were subjected to in silico analysis such as QSAR, molecular docking and ADMET. 497 secondary metabolites were identified from 23 species. The in silico assays indicated 19 potential anti-SARS-CoV-2 compounds, being triterpenes and phenolic compounds. The indicated compounds showed a high affinity with proteins considered as the main molecular targets against SARS-CoV-2 and parameters indicated low toxicity. In addition to Brazilian medicinal plants, these compounds can be found in other species and they can be a base for the synthesis of other anti-COVID-19 drugs. Therefore, this review is important to conduct researches that address the emerging need for drugs in COVID-19 treatment.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Preparaciones de Plantas , Plantas Medicinales , SARS-CoV-2/efectos de los fármacos , Antivirales/farmacología , Humanos , Simulación del Acoplamiento Molecular , Fitoquímicos/farmacología , Preparaciones de Plantas/farmacología , Plantas Medicinales/químicaRESUMEN
Silibinin, a natural compound extracted from milk thistle, has demonstrated antitumor properties in urinary bladder cancer cells; however, the role of TP53 gene in these effects is unclear. In order to better understand the molecular and antiproliferative mechanisms of this compound, urinary bladder cancer cells with different TP53 gene status, RT4 (low-grade tumor, wild TP53 gene), 5637 (high-grade tumor, Grade 2, mutated TP53 gene), and T24 (high-grade tumor, Grade 3, mutated TP53 gene) were treated with several concentrations of silibinin (1, 5, 10, 50, 100, and 150 µM). Cytotoxicity, prooxidant effect, morphological changes, cell migration, cell cycle progression, global methylation profile, and relative expression of HOXB3, c-MYC, PLK1, SMAD4, SRC, HAT, HDAC, and RASSF1A genes were evaluated. The silibinin presented cytotoxic and prooxidant effects in the three cell lines. In mutated TP53 cells, significant interference in cell migration and cell cycle arrest at the G2/M phase was observed. Additionally, silibinin induced global DNA hypomethylation in the highest grade tumor cells. For wild-type TP53 cells, a sub-G1 apoptotic population was present. Furthermore, there was modulation of gene expression responsible for cell growth (SMAD and c-MYC), migration (SRC), cell cycle kinetics (PLK1), angiogenesis (HOXB3), and of genes associated with epigenetic events such as DNA acetylation (HAT) and deacetylation (HDAC). In conclusion, the silibinin inhibited the urinary bladder tumor cell proliferation independently of TP53 status; however, cell cycle effects, gene expression changes, and alteration of cell migration are dependent on TP53 status. © 2020 Wiley Periodicals, Inc.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Proliferación Celular/efectos de los fármacos , Silibina/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteína p53 Supresora de Tumor/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaAsunto(s)
Compuestos de Bencidrilo/toxicidad , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Genisteína/toxicidad , Indoles/toxicidad , Glándulas Mamarias Animales/efectos de los fármacos , Fenoles/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Anticarcinógenos/toxicidad , Compuestos de Bencidrilo/administración & dosificación , Estrógenos no Esteroides/toxicidad , Femenino , Genisteína/administración & dosificación , Indoles/administración & dosificación , Glándulas Mamarias Animales/crecimiento & desarrollo , Glándulas Mamarias Animales/patología , Fenoles/administración & dosificación , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/patología , Distribución Aleatoria , Ratas Sprague-DawleyRESUMEN
Bladder cancer is a common malignancy worldwide. Despite the increased use of cisplatin-based combination therapy, the outcomes for patients with advanced disease remain poor. Recently, altered activation of the PI3K/ Akt/mTOR pathway has been associated with reduced patient survival and advanced stage of bladder cancer, making its upstream or downstream components attractive targets for therapeutic intervention. In the present study, we showed that treatment with DTCM-glutaramide, a piperidine that targets PDK1, results in reduced proliferation, diminished cell migration and G1 arrest in 5637 and T24 bladder carcinoma cells. Conversely, no apoptosis, necrosis or autophagy were detected after treatment, suggesting that reduced cell numbers in vitro are a result of diminished proliferation rather than cell death. Furthermore previous exposure to 10 µg/ml DTCM- glutarimide sensitized both cell lines to ionizing radiation. Although more studies are needed to corroborate our findings, our results indicate that PDK1 may be useful as a therapeutic target to prevent progression and abnormal tissue dissemination of urothelial carcinomas.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citostáticos/farmacología , Piperidonas/farmacología , Tolerancia a Radiación/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Apoptosis/efectos de la radiación , Autofagia/efectos de los fármacos , Autofagia/efectos de la radiación , Western Blotting , Caspasas/metabolismo , Adhesión Celular/efectos de los fármacos , Adhesión Celular/efectos de la radiación , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Ensayo de Unidades Formadoras de Colonias , Rayos gamma , Humanos , Necrosis , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
BACKGROUND: Atherosclerotic coronary artery disease (CAD) is a multifactorial process that appears to be caused by the interaction of environmental risk factors with multiple predisposing genes. It is nowadays accepted that increased levels of DNA damage induced by xenobiotics play an important role in the early phases of atherogenesis. Therefore, in this study, we focus on determining whether genetic variations in xenobiotic-metabolizing [glutathione-S-transferase theta 1 (GSTT1), glutathione-S-transferase mu 1 (GSTM1), cytochrome P450 IIEI (CYP2E1)] and DNA repair [X-ray cross-complementing group 1 (XRCC1)] genes might be associated with increased risk for CAD. METHODS: A case-control study was conducted with 400 individuals who underwent subjected to coronary angiography. A total of 299 were patients diagnosed with effective coronary atherosclerosis (case group; >20% obstructive lesion), and 101 (control group) were individuals diagnosed as negative for CAD (<20% obstructive lesions). The polymorphism identifications for GSTM1 and GSTT1, and for CYP2E1 and XRCC1 genes were performed by polymerase chain reaction (PCR) amplification and by PCR-RFLP, respectively. RESULTS AND CONCLUSIONS: The XRCC1 homozygous wild-type genotype Arg/Arg for codon 399 was statistically less pronounced in the case subjects (21.4%) than in controls (38.5%); individuals with the variant XRCC1 genotype had a 2.3-fold increased risk for coronary atherosclerosis than individuals with the wild-type genotype (OR=2.3, 95% CI=1.13-4.69). Conversely, no association between GSTM1, GSTT1, and CYP2E1gene polymorphisms and coronary atherosclerosis was detected. The results provide evidence of the role of DNA damage and repair in cardiovascular disease.
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Enfermedad de la Arteria Coronaria/genética , Reparación del ADN/genética , Polimorfismo Genético , Anciano , Alelos , Sustitución de Aminoácidos , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/metabolismo , Citocromo P-450 CYP2E1/genética , Daño del ADN , Proteínas de Unión al ADN/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Humanos , Masculino , Persona de Mediana Edad , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
Bladder carcinoma is one of the most common tumors in the world and despite the therapy currently available most of the patients relapse. Better understanding of the factors involved in disease pathogenesis would provide insights for the development of more effective strategies in treatment. Recently, differential miRNA expression profiles in bladder urothelial carcinomas identified miR-100 down-regulation and miR-708 up-regulation among the most common alterations, although the possible influence of these miRNAs in the control of basic mechanisms in bladder tumors has not been addressed. In this context, the present study aimed to evaluate the in vitro effects of miR-100 forced expression and miR-708 inhibition in the bladder carcinoma cell line 5637. Our results showed that overexpression of miR-100 significantly inhibited growth when compared to controls at both times tested (72 and 96 hours, p<0.01) with a maximum effect at 72 hours reducing proliferation in 29.6 %. Conversely, no effects on cell growth were observed after inhibition of miR-708. MiR-100 also reduced colony formation capacity of 5637 cells by 24.4%. No alterations in cell cycle progression or apoptosis induction were observed. The effects of miR-100 on growth and clonogenicity capacity in 5637 cells evince a possible role of this miRNA in bladder carcinoma pathogenesis. Further studies are necessary to corroborate our findings and examine the potential use of this microRNA in future therapeutic interventions.
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MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Apoptosis/genética , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Transfección , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Urinary bladder cancer is the fourth most common malignancy in the Western world. Transitional cell carcinoma (TCC) is the most common subtype, accounting for about 90% of all bladder cancers. The TP53 gene plays an essential role in the regulation of the cell cycle and apoptosis and therefore contributes to cellular transformation and malignancy; however, little is known about the differential gene expression patterns in human tumors that present with the wild-type or mutated TP53 gene. Therefore, because gene profiling can provide new insights into the molecular biology of bladder cancer, the present study aimed to compare the molecular profiles of bladder cancer cell lines with different TP53 alleles, including the wild type (RT4) and two mutants (5637, with mutations in codons 280 and 72; and T24, a TP53 allele encoding an in-frame deletion of tyrosine 126). Unsupervised hierarchical clustering and gene networks were constructed based on data generated by cDNA microarrays using mRNA from the three cell lines. Differentially expressed genes related to the cell cycle, cell division, cell death, and cell proliferation were observed in the three cell lines. However, the cDNA microarray data did not cluster cell lines based on their TP53 allele. The gene profiles of the RT4 cells were more similar to those of T24 than to those of the 5637 cells. While the deregulation of both the cell cycle and the apoptotic pathways was particularly related to TCC, these alterations were not associated with the TP53 status.
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Apoptosis/genética , Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica , Transducción de Señal/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Teorema de Bayes , Línea Celular Tumoral , Análisis por Conglomerados , ADN Complementario/genética , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/genética , Genes Relacionados con las Neoplasias/genética , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
OBJECTIVE: Formocresol, paramonochlorophenol, or calcium hydroxide have been widely used in dental practice to eradicate bacteria and consequently to produce root canal disinfection. Taking into consideration strong evidence for a relationship between DNA damage and carcinogenesis, the purpose of the present study was to evaluate the genotoxic effects of antimicrobial endodontic compounds in human peripheral lymphocytes by single-cell gel (comet) assay. This technique detects DNA strand breaks in individual cells. STUDY DESIGN: A total of 10 microL of the tested substance solution (formocreso1, paramonochlorofeno1, and calcium hydroxide at 100-microg/mL concentration) was added to human peripheral lymphocytes from 10 volunteers for 1 hour at 37 degrees C. The negative control group was treated with vehicle control (PBS) for 1 hour at 37 degrees C, as well. For the positive control group, lymphocytes were exposed to hydrogen peroxide at 100 microM during 5 minutes on ice. RESULTS: No DNA breakage was detected after a treatment of peripheral lymphocytes by formocresol, paramonochlorophenol, or calcium hydroxide at 100 microg/mL. CONCLUSIONS: In summary, our results indicate that exposure to formocresol, paramonochlorophenol, or calcium hydroxide may not be a factor that increases the level of DNA lesions in human peripheral lymphocytes as detected by single-cell gel (comet) assay.
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Antiinfecciosos Locales/toxicidad , Daño del ADN , Linfocitos/efectos de los fármacos , Irrigantes del Conducto Radicular/toxicidad , Adulto , Hidróxido de Calcio/toxicidad , Células Cultivadas , Clorofenoles/toxicidad , Ensayo Cometa , Femenino , Formocresoles/toxicidad , Humanos , MasculinoRESUMEN
OBJECTIVE: Taking into consideration that DNA damage plays an important role in carcinogenesis, the purpose of this study was to evaluate whether regular and white mineral trioxide aggregate (MTA) are able to induce genetic damage in primary human cells. STUDY DESIGN: Human peripheral lymphocytes obtained from 10 healthy volunteers were exposed to 2 presentation forms of MTA at final concentrations ranging from 1 to 1000 microg/mL for 1 hour at 37 degrees C. The negative control group was treated with vehicle control (phosphate buffer solution, PBS) for 1 hour at 37 degrees C and the positive control group was treated with hydrogen peroxide (at 100 microM) for 5 minutes on ice. Results were analyzed by the Friedman nonparametric test. RESULTS: The results pointed out that either regular or white MTA in all concentrations tested did not induce DNA breakage in human peripheral lymphocytes as depicted by the mean tail moment. CONCLUSION: In summary, our results indicate that exposure to MTA may not be a factor that increases the level of DNA lesions in human peripheral lymphocytes as detected by single cell gel (comet) assay.