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Métodos Terapéuticos y Terapias MTCI
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1.
Oxid Med Cell Longev ; 2021: 5544600, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34691356

RESUMEN

Supplemental oxygen administration is frequently used in premature infants and adults with pulmonary insufficiency. NADPH quinone oxidoreductase (NQO1) protects cells from oxidative injury by decreasing reactive oxygen species (ROS). In this investigation, we tested the hypothesis that overexpression of NQO1 in BEAS-2B cells will mitigate cell injury and oxidative DNA damage caused by hyperoxia and that A-1221C single nucleotide polymorphism (SNP) in the NQO1 promoter would display altered susceptibility to hyperoxia-mediated toxicity. Using stable transfected BEAS-2B cells, we demonstrated that hyperoxia decreased cell viability in control cells (Ctr), but this effect was differentially mitigated in cells overexpressing NQO1 under the regulation of the CMV viral promoter, the wild-type NQO1 promoter (NQO1-NQO1), or the NQO1 promoter carrying the SNP. Interestingly, hyperoxia decreased the formation of bulky oxidative DNA adducts or 8-hydroxy-2'-deoxyguanosine (8-OHdG) in Ctr cells. qPCR studies showed that mRNA levels of CYP1A1 and NQO1 were inversely related to DNA adduct formation, suggesting the protective role of these enzymes against oxidative DNA injury. In SiRNA experiments entailing the NQO1-NQO1 promoter, hyperoxia caused decreased cell viability, and this effect was potentiated in cells treated with CYP1A1 siRNA. We also found that hyperoxia caused a marked induction of DNA repair genes DDB2 and XPC in Ctr cells, supporting the idea that hyperoxia in part caused attenuation of bulky oxidative DNA lesions by enhancing nucleotide excision repair (NER) pathways. In summary, our data support a protective role for human NQO1 against oxygen-mediated toxicity and oxidative DNA lesions in human pulmonary cells, and protection against toxicity was partially lost in SNP cells. Moreover, we also demonstrate a novel protective role for CYP1A1 in the attenuation of oxidative cells and DNA injury. Future studies on the mechanisms of attenuation of oxidative injury by NQO1 should help in developing novel approaches for the prevention/treatment of ARDS in humans.


Asunto(s)
Pulmón/metabolismo , Pulmón/fisiopatología , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Estrés Oxidativo , Humanos , Pulmón/patología
2.
PLoS One ; 6(10): e26589, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22066002

RESUMEN

Many carcinogenic polycyclic aromatic hydrocarbons (PAHs) and their metabolites can bind covalently to DNA. Carcinogen-DNA adducts may lead to mutations in critical genes, eventually leading to cancer. In this study we report that fish oil (FO) blocks the formation of DNA adducts by detoxification of PAHs. B6C3F1 male mice were fed a FO or corn oil (CO) diet for 30 days. The animals were then treated with seven carcinogenic PAHs including benzo(a)pyrene (BaP) with one of two doses via a single intraperitoneal injection. Animals were terminated at 1, 3, or 7 d after treatment. The levels of DNA adducts were analyzed by the (32)P-postlabeling assay. Our results showed that the levels of total hepatic DNA adducts were significantly decreased in FO groups compared to CO groups with an exception of low PAH dose at 3 d (P = 0.067). Total adduct levels in the high dose PAH groups were 41.36±6.48 (Mean±SEM) and 78.72±8.03 in 10(9) nucleotides (P = 0.011), respectively, for the FO and CO groups at 7 d. Animals treated with the low dose (2.5 fold lower) PAHs displayed similar trends. Total adduct levels were 12.21±2.33 in the FO group and 24.07±1.99 in the CO group, P = 0.008. BPDE-dG adduct values at 7 d after treatment of high dose PAHs were 32.34±1.94 (CO group) and 21.82±3.37 (FO group) in 10(9) nucleotides with P value being 0.035. Low dose groups showed similar trends for BPDE-dG adduct in the two diet groups. FO significantly enhanced gene expression of Cyp1a1 in both the high and low dose PAH groups. Gstt1 at low dose of PAHs showed high levels in FO compared to CO groups with P values being 0.014. Histological observations indicated that FO played a hepatoprotective role during the early stages. Our results suggest that FO has a potential to be developed as a cancer chemopreventive agent.


Asunto(s)
Carcinógenos/metabolismo , Aductos de ADN/metabolismo , Grasas Insaturadas en la Dieta/farmacología , Aceites de Pescado/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hidrocarburos Policíclicos Aromáticos/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Dieta , Ácidos Grasos/análisis , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/patología , Masculino , Fase I de la Desintoxicación Metabólica/genética , Fase II de la Desintoxicación Metabólica/genética , Ratones
3.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 27(8): 745-8, 2007 Aug.
Artículo en Chino | MEDLINE | ID: mdl-17879544

RESUMEN

OBJECTIVE: To observe the efficacy and safety of zhongfu hypotension capsule (ZHC) in treating hypertension of yin-deficiency with sthenic-yang syndrome type. METHODS: Adopting the stratified, block randomized, double-blinded, double-dummy, positive parallel controlled, multi-centered clinical trial method, the tested group was treated by orally taken 3 capsules of ZHC (0.5 g/capsule) twice a day, and the control group was treated by orally taken Lotensin Tablet 1 tablet (10 mg/tab.) once a day. And all received the adiaphorous drug with the dosage-form mimic to that used in the tested group. The therapeutic course was 4 weeks for both groups. RESULTS: The markedly effective rate and the total effective rate in reducing blood pressure was 58.65% and 79.81% respectively in the tested group, and 60.51% and 78.34% respectively in the control group; while the markedly effective rate and the total effective rate for alleviating TCM syndrome was 21.15% and 78.85% in the tested group, and 25.48% and 86.62% in the control group respectively. Comparisons between the two groups showed insignificant difference (P > 0.05). CONCLUSION: ZHC has good efficacy and is safety in treating hypertension.


Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Hipertensión/tratamiento farmacológico , Fitoterapia , Deficiencia Yin/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Benzazepinas/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Síndrome , Comprimidos , Deficiencia Yin/patología
4.
Cancer Epidemiol Biomarkers Prev ; 14(5): 1230-5, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15894677

RESUMEN

I-compounds are bulky covalent DNA modifications that are derived from metabolic intermediates of nutrients. Some I-compounds may play protective roles against cancer, aging, and degenerative diseases. Many carcinogens and tumor promoters significantly reduce I-compound levels gradually during carcinogenesis. Colon cancer is the second leading cause of cancer death in the United States, whereas cancer of the small intestine is relatively rare. Here we have studied levels of I-compounds in DNA of colon and duodenum of male Sprague-Dawley rats treated with azoxymethane. The effects of dietary lipids (fish oil or corn oil) on colon and duodenal DNA I-compounds were also investigated. Rats fed a diet containing fish oil or corn oil were treated with 15 mg/kg azoxymethane. Animals were terminated 0, 6, 9, 12, or 24 hours after injection. I-compound levels were analyzed by the nuclease P1-enhanced (32)P-postlabeling assay. Rats treated with azoxymethane displayed lower levels of I-compounds in colon DNA compared with control groups (0 hour). However, I-compound levels in duodenal DNA were not diminished after azoxymethane treatment. Animals fed a fish oil diet showed higher levels of I-compounds in colonic DNA compared with corn oil groups (mean adduct levels for fish and corn oil groups were 13.35 and 10.69 in 10(9) nucleotides, respectively, P = 0.034). Taken together, these results support claims that fish oil, which contains a high level of omega-3 polyunsaturated fatty acids, may have potent chemopreventive effects on carcinogen-induced colon cancer. The fact that duodenal I-compounds were not diminished by azoxymethane treatment may have been due to the existence of tissue-specific factors protecting against carcinogenesis. In conclusion, our observations show that endogenous DNA adducts may serve not only as sensitive biomarkers in carcinogenesis and cancer prevention studies, but are also helpful to further our understanding of the chemopreventive properties of omega-3 fatty acids and mechanisms of carcinogenesis.


Asunto(s)
Azoximetano/metabolismo , Carcinógenos/metabolismo , Neoplasias del Colon/genética , Neoplasias del Colon/prevención & control , Aceite de Maíz/farmacología , Aductos de ADN/farmacología , Daño del ADN/efectos de los fármacos , Neoplasias Duodenales/genética , Neoplasias Duodenales/prevención & control , Aceites de Pescado/farmacología , Análisis de Varianza , Animales , Azoximetano/administración & dosificación , Biomarcadores , Carcinógenos/administración & dosificación , Neoplasias del Colon/metabolismo , Neoplasias Duodenales/metabolismo , Masculino , Modelos Animales , Nucleótidos , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Endonucleasas Específicas del ADN y ARN con un Solo Filamento
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