RESUMEN
BACKGROUND: Oxidative stress has been implicated in the pathogenesis of chronic kidney disease (CKD), prompting the exploration of antioxidants as a potential therapeutic avenue for mitigating disease progression. This study aims to investigate the beneficial impact of Tempol on the progression of CKD in a rat model utilizing oxidized albumin as a biomarker. METHODS: After four weeks of treatment, metabolic parameters, including body weight, left ventricle residual weight, kidney weight, urine volume, and water and food intake, were measured. Systolic blood pressure, urinary protein, oxidized albumin level, serum creatinine (Scr), blood urea nitrogen (BUN), 8-OHdG, TGF-ß1, and micro-albumin were also assessed. Renal fibrosis was evaluated through histological and biochemical assays. P65-NF-κB was quantified using an immunofluorescence test, while Smad3, P65-NF-κB, and Collagen I were measured using western blot. TNF-α, IL-6, MCP-1, TGF-ß1, Smad3, and P65-NF-κB were analyzed by RT-qPCR. RESULTS: Rats in the high-salt diet group exhibited impaired renal function, characterized by elevated levels of blood urea nitrogen, serum creatinine, 8-OHdG, urine albumin, and tubulointerstitial damage, along with reduced body weight. However, these effects were significantly ameliorated by Tempol administration. In the high-salt diet group, blood pressure, urinary protein, and oxidized albumin levels were notably higher compared to the normal diet group, but Tempol administration in the treatment group reversed these effects. Rats in the high-salt diet group also displayed increased levels of proinflammatory factors (TNF-α, IL-6, MCP1) and profibrotic factors (NF-κB activation, Collagen I), elevated expression of NADPH oxidation-related subunits (P65), and activation of the TGF-ß1/Smad3 signaling pathway. Tempol treatment inhibited NF-κB-mediated inflammation and TGF-ß1/Smad3-induced renal fibrosis signaling pathway activation. CONCLUSION: These findings suggest that Tempol may hold therapeutic potential for preventing and treating rats undergoing 5/6 nephrectomy. Further research is warranted to elucidate the mechanisms underlying Tempol's protective effects and its potential clinical applications. Besides, there is a discernible positive relationship between oxidized albumin and other biomarkers, such as 8-OHG, urinary protein levels, mALB, Scr, BUN, and TGF-ß1 in a High-salt diet combined with 5/6 nephrectomy rat model. These findings suggest the potential utility of oxidized albumin as a sensitive indicator for oxidative stress assessment.
Asunto(s)
Óxidos N-Cíclicos , Insuficiencia Renal Crónica , Marcadores de Spin , Factor de Crecimiento Transformador beta1 , Animales , Ratas , Albúminas/química , Albúminas/metabolismo , Peso Corporal , Colágeno/metabolismo , Creatinina , Dieta , Fibrosis , Inflamación/tratamiento farmacológico , Interleucina-6/metabolismo , Nefrectomía , FN-kappa B/metabolismo , Estrés Oxidativo , Insuficiencia Renal Crónica/tratamiento farmacológico , Cloruro de Sodio/efectos adversos , Cloruro de Sodio/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Biomarcadores , Sodio en la Dieta/efectos adversosRESUMEN
Statins, known as HMG-CoA reductase (HMGCR) inhibitors, have primarily been utilized for metabolic and angiographic medical applications because of their cholesterol-lowering effects. Similar to other drugs, statins may also induce a series of potential side effects. Statins inhibit the HMGCR (rate-limiting enzyme) activity in early stages of mevalonate pathway and then indirectly affect a number of intermediate products, including non-sterol isoprenoids (coenzyme Q10, dolichol etc.), which can result in impaired functions of body organs. Recently, scores of studies have uncovered additional functional mechanisms of statins in other diseases, such as diabetes mellitus, nervous system diseases, coronary heart disease, inflammation and cancers. This review aims to summarize the positive and adverse mechanisms of statin therapy. Statin care should be taken in the treatment of many diseases including cancers. Since the underlying mechanisms are not fully elucidated, future studies should spend more time and efforts on basic research to explore the mechanisms of statins.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Enfermedad Coronaria/tratamiento farmacológico , Diabetes Mellitus/inducido químicamente , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inflamación/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológicoRESUMEN
Accumulating evidence has shown that long noncoding RNAs (lncRNAs) play significant roles in the development and progression of many types of cancer including colorectal cancer. RP11400N13.3 is a novel lncRNA discovered recently and its biological function and underlying mechanism in colorectal cancer remain elusive. This study aimed to reveal the relationship between RP11400N13.3 and colorectal cancer. Our results demonstrated that the expression of RP11400N13.3 was significantly upregulated in both colorectal cancer tissues and cell lines as compared to normal adjacent tissues and normal colonic epithelial cells by RTqPCR, respectively. Upregulation of RP11400N13.3 was found to be correlated with a poor overall survival rate. Functional studies revealed that RP11400N13.3 facilitated the proliferation, migration, invasion and tumor growth of colorectal cancer cells while inhibiting the apoptosis of cancer cells in vitro and in vivo. We also observed that RP11400N13.3 serves as a sponge for miR47223p, and that P2Y receptor family member 8 (P2RY8) was predicted to be a target of miR47223p by bioinformatics analysis. Western blot assay indicated that the expression of P2RY8 was negatively or positively regulated by miR47223p or RP11400N13.3. In addition, rescue experiments revealed that RP11400N13.3 promoted proliferation, migration and invasion by directly regulating the expression of miR47223p and P2RY8. In conclusion, our results revealed that RP11400N13.3 promoted colorectal cancer progression via modulating the miR47223p/P2RY8 axis, thus suggesting RP11400N13.3 as a potential therapeutic target for the treatment of colorectal cancer.
Asunto(s)
Neoplasias Colorrectales/metabolismo , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Receptores Purinérgicos P2Y/metabolismo , Animales , Apoptosis/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Femenino , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Persona de Mediana Edad , Pronóstico , ARN Largo no Codificante/genética , Receptores Purinérgicos P2Y/genética , Tasa de SupervivenciaRESUMEN
The aim of this study was to investigate the relationship among left ventricular (LV) concentric hypertrophy, endocardial remodeling, and myocardial deformation in type-2 diabetes mellitus (T2DM). Fifty-three T2DM patients with normotension and 36 healthy controls underwent cardiovascular magnetic resonance imaging to assess for LV concentric hypertrophy (LV myocardial mass index, LVMMi; LVMMi-to-LV end-diastolic volume index ratio, MVR), endocardial remodeling (fractal dimension of trabeculations, FD), and myocardial deformation (global longitudinal, radial and circumferential strain, systolic and diastolic strain rate). When compared with healthy controls, T2DM was associated with LV concentric hypertrophy (LVMMi: T2DM, 52.7 ± 8.9 g/m2; controls, 48.7 ± 8.4 g/m2, p = 0.032; MVR: T2DM, 0.88 ± 0.19 g/mL; controls, 0.77 ± 0.16 g/mL, p = 0.007), endocardial remodeling (max. apical FD: T2DM, 1.265 ± 0.056; controls, 1.233 ± 0.055, p = 0.008; mean apical FD: T2DM, 1.198 ± 0.043; controls, 1.176 ± 0.043, p = 0.020), and subtle diastolic dysfunction (peak longitudinal diastolic strain rate, PDSRL: T2DM, 1.1 ± 0.2/s; controls, 1.2 ± 0.3/s, p = 0.031). In the stepwise multivariable regression model, the MVR was an independent determinant of the maximum apical FD (standardized ß, sß = 0.525, p < 0.001) and mean apical FD (sß = 0.568, p < 0.001). The mean apical FD was an independent determinant of the PDSRL (p = 0.004). LV concentric hypertrophy is an independent determinant of endocardial remodeling, a process that may contribute to subtle LV diastolic dysfunction in T2DM patients.