RESUMEN

Arsenic is a naturally occurring element present in food, soil and water and human exposure is associated with increased cancer risk. Arsenic inhibits DNA repair at low, non-cytotoxic concentrations and amplifies the mutagenic and carcinogenic impact of other DNA-damaging agents, such as ultraviolet radiation (UVR). Arsenic exposure leads to oxidation of zinc coordinating cysteine residues, zinc loss and decreased activity of the DNA repair protein poly(ADP)ribose polymerase (PARP)-1. Because arsenic stimulates NADPH oxidase (NOX) activity leading to generation of reactive oxygen species (ROS), the goal of this study was to investigate the role of NOX in arsenic-induced inhibition of PARP activity and retention of DNA damage. NOX involvement in the arsenic response was assessed in vitro and in vivo. Keratinocytes were treated with or without arsenite, solar-simulated UVR, NOX inhibitors and/or isoform specific NOX siRNA. Knockdown or inhibition of NOX decreased arsenite-induced ROS, PARP-1 oxidation and DNA damage retention, while restoring arsenite inhibition of PARP-1 activity. The NOX2 isoform was determined to be the major contributor to arsenite-induced ROS generation and DNA damage retention. In vivo DNA damage was measured by immunohistochemical staining and analysis of dorsal epidermis sections from C57BI/6 and p91phox knockout (NOX2-/-) mice. There was no significant difference in solar-simulated UVR DNA damage as detected by percent PH2AX positive cells within NOX2-/- mice versus control. In contrast, arsenite-dependent retention of UVR-induced DNA damage was markedly reduced. Altogether, the in vitro and in vivo findings indicate that NOX is involved in arsenic enhancement of UVR-induced DNA damage.

Asunto(s)

Arsénico/toxicidad , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , NADPH Oxidasa 2/metabolismo , Rayos Ultravioleta , Animales , Línea Celular , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Ratones , Ratones Noqueados , NADPH Oxidasa 1/genética , NADPH Oxidasa 1/metabolismo , NADPH Oxidasa 2/genética , Especies Reactivas de Oxígeno

RESUMEN

Skeletal fluorosis is a chronically metabolic bone disease with extensive hyperostosis osteosclerosis caused by long time exposure to fluoride. Skeletal fluorosis brings about a series of abnormal changes of the extremity, such as joint pain, joint stiffness, bone deformity, etc. Differentiation and maturation of osteoblasts were regulated by osteoclasts via Sema4D/Plexin-B1 signaling pathway. Furthermore, the differentiation and maturation of osteoclasts are conducted by osteoblasts via RANKL/RANK/OPG pathway. Both of these processes form a feedback circuit which is a key link in skeletal fluorosis. In this study, an osteoblast-osteoclast co-culture model in vitro was developed to illustrate the mechanism of skeletal fluorosis. With the increase of fluoride concentration, the expression level of Sema4D was decreased and TGF-β1 was increased continuously. OPG/RANKL mRNA level, however, increased gradually. On the basis of that, the inhibition of Sema4D/Plexin-B1/RhoA/ROCK signaling pathway caused by fluoride promoted the level of TGF-β1 and activated the proliferation of osteoblasts. In addition, osteroprotegerin (OPG) secreted by osteoblasts was up-regulated by fluoride. The competitive combination of OPG and RANKL was strengthened and the combination of RANKL and RANK was hindered. And then the differentiation and maturation of osteoclasts were inhibited, and bone absorption was weakened, leading to skeletal fluorosis.

Asunto(s)

Animales , Ratas , Antígenos CD , Genética , Metabolismo , Proliferación Celular , Retroalimentación Fisiológica , Feto , Fluoruros , Farmacología , Proteínas Activadoras de GTPasa , Genética , Metabolismo , Regulación del Desarrollo de la Expresión Génica , Osteoblastos , Metabolismo , Patología , Osteoclastos , Metabolismo , Patología , Osteogénesis , Genética , Osteoprotegerina , Genética , Metabolismo , Ligando RANK , Genética , Metabolismo , ARN Mensajero , Genética , Metabolismo , Receptor Activador del Factor Nuclear kappa-B , Genética , Metabolismo , Receptores de Superficie Celular , Genética , Metabolismo , Semaforinas , Genética , Metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Genética , Metabolismo , Quinasas Asociadas a rho , Genética , Metabolismo , Proteína de Unión al GTP rhoA , Genética , Metabolismo

RESUMEN

<p><b>OBJECTIVE</b>To investigate the relationship between human beta2-Adrenergic Receptor (ADRB2) gene C659G polymorphism and essential hypertension in Xinjiang Kazakans.</p><p><b>METHODS</b>Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) methods were used to detect the C659G polymorphism of ADRB2 gene in 435 Kazakans including 273 hypertensives (EH) and 162 normotensives (NT) and genotype frequencies between EH and NT were analyzed.</p><p><b>RESULTS</b>The genotype frequencies (CC, CG, GG) of the C659G allele were 85.75%, 13.79%, 0.64% respectively and the C659 and G659 allele frequencies were 7.36%, 92.64% in this cohort. The ADRB2 genotype distribution and the allele frequencies of C659 and G659 were significantly higher in EH than those in NT (all P < 0.05). The G allele is a risk factor contributed to hypertension (OR 12.37). After adjustment for age and BMI, the systolic and diastolic blood pressure levels were significant higher in CG + GG genotype group compared with CC genotype group (P < 0.05).</p><p><b>CONCLUSION</b>There was significant association between the C659G polymorphism of ADRB2 gene and essential hypertension in Xinjiang Kazakans suggesting a role of ADRB2 gene C659G polymorphism in the development of hypertension in Xinjiang Kazakans.</p>

Asunto(s)

Humanos , Estudios de Casos y Controles , Frecuencia de los Genes , Hipertensión , Polimorfismo Genético , Receptores Adrenérgicos

RESUMEN

<p><b>OBJECTIVE</b>To observe the effects of Tongxinluo Supermicro Powder on the nuclear factor-kappaB (NF-kappaB), inter-cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in aorta of rabbits fed with high-lipid diet.</p><p><b>METHODS</b>Healthy male New Zealand rabbits were randomly divided into 4 groups (n = 8 each): control group, model group, atorvastatin group (3 mg x kg(-1) x d(-1) per gavage), and Tongxinluo group (0.31 g x kg(-1) x d(-1) per gavage). At the end of 6 weeks, the expression of NF-kappaB, ICAM-1 and VCAM-1 were observed by immunochemistry methods, Western blotting and reverse transcription polymerase chain reaction (RT-PCR).</p><p><b>RESULT</b>The nuclear translocation of NF-kappaB in aortic endothelial cells and the gene expressions of NF-kappaB, ICAM-1 and VCAM-1 at protein and mRNA levels of the model group was significantly increased compared that in the control group (all P < 0.05), these effects could be significantly attenuated by atorvastatin and Tongxinluo Supermicro Powder (P < 0.01 vs. model group).</p><p><b>CONCLUSIONS</b>Similar as atorvastatin, Tongxinluo Supermicro Powder could relieve the process of atherosclerosis by decreasing the nuclear translocation of NF-kappaB and reducing the expression of ICAM-1, VCAM-1 in this model.</p>

Asunto(s)

Animales , Masculino , Conejos , Alimentación Animal , Aorta , Metabolismo , Grasas de la Dieta , Medicamentos Herbarios Chinos , Farmacología , Molécula 1 de Adhesión Intercelular , Metabolismo , FN-kappa B , Metabolismo , Molécula 1 de Adhesión Celular Vascular , Metabolismo

RESUMEN

<p><b>OBJECTIVE</b>To study the effect and mechanism of Kangxianling (KXL, a Chinese compound recipe) in treating adriamycin (ADR) induced renal fibrosis rats.</p><p><b>METHODS</b>Forty-five male SD rats were randomly divided into 4 groups, the normal group (n = 7), the sham operative group (n = 8), the model group (n = 15), and the treatment group (n = 15). Model of renal interstitial fibrosis was established in rats by unilateral nephrectomy and intravenous injection of ADR twice at a 30-day interval, and the rats in the treatment group treated with KXL once a day for 72 days. Body weight, serum creatinine (SCr), blood urea nitrogen (BUN) levels and endogenous creatinine clearance rate (CCr) of animals were analyzed at the end of the 4th and the 8th week after operation. Rats were sacrificed after 72 days of treatment and their kidney obtained for pathological examination with HE and PASM staining. And protein expression levels of transforming growth factor beta (TGF-beta) receptor I (TbetaR I), TGF-beta receptor II (TbetaR II), Smad2 and Smad7 were determined by Western blotting.</p><p><b>RESULTS</b>Levels of SCr and BUN in animals of the model group were significantly higher and CCr lower than those in the normal group (P < 0.05). Pathological examination of kidney in the model group showed thickened glomerular/tubular basement membrane with segmental sclerosis and hyaline degeneration; atrophy of the renal tubule around the sclerotic glomeruli and part of them disappeared; hypertrophy of partial glomeruli with surrounding severe dilated tubules; obvious glomeruli centering phenomena; severe tubular epithelial cell degeneration, necrosis with protein cast; fibrous tissue proliferation and large amount of inflammatory cell interstitial infiltration. The protein expression of TbetaR I and Smad2 in kidney tissue of the model group were significantly up-regulated, while that of TbetaR II and Smad7 unchanged. After KXL intervention, level of BUN lowered, SCr tended to normal and the endogenous SCr was raised to some degree. The renal pathological status in the treatment group was significantly improved and with markedly lowering of TbetaR I and Smad2 protein expression.</p><p><b>CONCLUSION</b>KXL could inhibit the protein expression of TbetaR I and Smad2 in kidney tissue, so as to alleviate the renal fibrosis induced by adriamycin and improve the renal function.</p>

Asunto(s)

Animales , Masculino , Ratas , Doxorrubicina , Medicamentos Herbarios Chinos , Usos Terapéuticos , Fibrosis , Riñón , Metabolismo , Patología , Enfermedades Renales , Quimioterapia , Metabolismo , Nefrectomía , Fitoterapia , Distribución Aleatoria , Ratas Sprague-Dawley , Proteína Smad2 , Proteína smad7

RESUMEN

<p><b>OBJECTIVE</b>To investigate the chronic efficacy of low-dose hydrochlorothiazide (HCTZ) in patients with mild-to-moderate hypertension.</p><p><b>METHODS</b>After a 2-weeks placebo run-in period, 232 patients with mild or moderate hypertension were recruited and received HCTZ (12.5 mg once daily) therapy for one year. Patient compliance and blood pressure were monitored and serum BUN, Cr, glucose, electrolytes, and lipids were measured before, 6 weeks and 1 year after treatment.</p><p><b>RESULTS</b>(1) Reduction of SBP, DBP and MAP were more significantly at 1 year [(10.45 +/- 17.28) mm Hg, (8.45 +/- 11.06) mm Hg, (9.12 +/- 10.88) mm Hg] than that at 6 weeks post therapy [(6.01 +/- 16.05) mm Hg, (2.90 +/- 10.33) mm Hg, (3.94 +/- 10.68) mm Hg, all P < 0.05]. Blood pressure were reduced to normal in 35.1% patients at 1 year and in 20.3% patients at 6 weeks (P < 0.05). (2) No patient developed diabetes mellitus or hypokalemia during therapy while the serum uric acid at 1 year post therapy was significantly higher than that at before therapy (P < 0.05).</p><p><b>CONCLUSION</b>The study indicates that low dose HCTZ is an effective and safe antihypertensive agent for patients with mild-to-moderate hypertension and uric acid changes during therapy need to be monitored.</p>

Asunto(s)

Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antihipertensivos , Presión Sanguínea , Hidroclorotiazida , Hipertensión , Quimioterapia , Resultado del Tratamiento

RESUMEN

<p><b>OBJECTIVE</b>To determine whether the blood pressure (BP) response to hydrochlorothiazide (HCTZ) was associated with the angiotensin converting-enzyme (ACE) I/D and aldosterone synthase (CYP11B2)-344T/C polymorphisms.</p><p><b>METHODS</b>The BP response to HCTZ 12.5 mg once daily for 6 weeks was assessed in 829 subjects with mild or moderate essential hypertension, and compared across the ACE and CYP11B2 genotypes.</p><p><b>RESULTS</b>Of the 829 enrolled subjects, 785 completed the study. The systolic BP response differed according to the ACE (DD 9.4 +/- 15.7 mm Hg, ID 4.8 +/- 16.3 mm Hg, and II 5.1 +/- 14.8 mm Hg, P < 0.01), but not the CYP11B2 genotype (P > 0.05). Subjects with the combination of ACE DD and CYP11B2 CC genotypes tended to have a more pronounced systolic BP reduction than the other genotypic combinations of these 2 genes. Multiple linear regression analyses showed that the ACE DD genotype and serum aldosterone concentration at baseline were associated with the systolic BP reduction after treatment. None of the genetic associations with changes in diastolic BP or mean arterial pressure reached statistical significance (P > 0.05).</p><p><b>CONCLUSIONS</b>The present study suggested that the ACE DD genotype was associated with the systolic BP response to HCTZ, and that the subjects with the combination of ACE DD and CYP11B2 CC genotypes might have a better BP response to HCTZ than the other genotypic combinations of these 2 genes.</p>

Asunto(s)

Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Citocromo P-450 CYP11B2 , Genética , Hidroclorotiazida , Usos Terapéuticos , Hipertensión , Quimioterapia , Genética , Peptidil-Dipeptidasa A , Genética , Polimorfismo de Nucleótido Simple , Inhibidores de los Simportadores del Cloruro de Sodio , Usos Terapéuticos