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11.
Delivery of a hammerhead ribozyme specifically down-regulates the production of fibrillin-1 by cultured dermal fibroblasts 总被引:4,自引:1,他引:4
Kilpatrick MW; Phylactou LA; Godfrey M; Wu CH; Wu GY; Tsipouras P 《Human molecular genetics》1996,5(12):1939-1944
The hammerhead ribozyme is a small catalytic RNA molecule. Potential
hammerhead ribozymes that possess a catalytic domain and flanking sequence
complementary to a target mRNA can cleave in trans at a putative cleavage
site within the target molecule. We have investigated the potential of
hammerhead ribozymes to down-regulate the product of the fibrillin-1 gene
(FBN1). Fibrillin is a 347 kDa glycoprotein that is a major constituent of
the elastin-associated microfibrils. Mutations in the FBN1 gene are
responsible for Marfan syndrome (MFS), a common systemic disorder of the
connective tissue. Many FBN1 mutations responsible for MFS appear to act in
a dominant-negative fashion, raising the possibility that reduction of the
amount of product from the mutant FBN1 allele might be a valid therapeutic
approach for MFS. A trans-acting hammerhead ribozyme (FBN1-RZ1) targeted to
the 5' end of the human FBN1 mRNA has been designed and synthesized, and
shown to cleave its target efficiently in vitro. FBN1-RZ1 cleavage is
magnesium dependent and efficient at both 37 and 50 degrees C. Delivery of
the FBN1-RZ1 ribozyme into cultured dermal fibroblasts, by receptor-
mediated endocytosis of a ribozyme-transferrin-polylysine complex,
specifically reduces both cellular FBN1 mRNA and the deposition of
fibrillin in the extracellular matrix. These results suggest that the use
of hammerhead ribozymes is a valid approach to the study of fibrillin gene
expression and possibly to the development of a therapeutic approach to
MFS.
相似文献
12.
13.
Colbert LH Lanza E Ballard-Barbash R Slattery ML Tangrea JA Caan B Paskett ED Iber F Kikendall W Lance P Shike M Schoen RE Daston C Schatzkin A;Polyp Prevention Trial Study Group 《Cancer causes & control : CCC》2002,13(5):445-453
Objective: To examine prospectively the association between physical activity and adenomatous polyp recurrence. Methods: Information on past year total physical activity was collected annually through an interview-administered questionnaire from the 1905 men and women enrolled in a randomized dietary intervention study, the Polyp Prevention Trial. Multiple logistic regression analysis was used to examine the association between physical activity and polyp recurrence in up to three years of follow-up from baseline colonoscopy. Results: There were no significant associations between moderate, vigorous, or total physical activity at the start of the trial and overall polyp recurrence in either men or women. Participants who reported consistent vigorous activity throughout the trial period had no significantly reduced risk of polyp recurrence compared to those who reported consistent sedentary activity (OR = 0.8, CI = 0.5–1.1). Consistent vigorous activity was also not significantly associated with either advanced or multiple polyps, nor with polyp recurrence at any specific anatomical location in the large bowel. Conclusions: These prospective data suggest that recent physical activity is not associated with polyp recurrence in a three-year period. 相似文献
14.
A DNA endonuclease, isolated from the nuclei of normal human and xeroderma
pigmentosum complementation group A (XPA) cells, which recognizes
predominately pyrimidine dimers, was examined for the mechanism by which it
locates sites of damage on UVC-irradiated DNA. In reaction mixtures with
low ionic strengths (i.e. lacking KCl), the normal and XPA endonuclease
locate sites of UV damage on both naked and reconstituted nucleosomal DNA
by different mechanisms. On both of these substrates, the normal
endonuclease acts by a processive mechanism, meaning that it binds
non-specifically to DNA and scans the DNA for sites of damage, whereas the
XPA endonuclease acts by a distributive one, meaning that it randomly
locates sites of damage on DNA. However, while both the normal and XPA
endonucleases can incise UVC irradiated naked DNA, they differ in ability
to incise damaged nucleosomal DNA. The normal endonuclease showed increased
activity on UVC treated nucleosomal DNA compared with naked DNA, whereas
the XPA endonuclease showed decreased activity on the damaged nucleosomal
substrate. Since a processive mechanism of action is sensitive to the ionic
strength of the micro-environment, the KCl concentration of the reaction
was increased. At 70 mM KCI, the normal endonuclease switched to a
distributive mechanism of action and its ability to incise damaged
nucleosomal DNA also decreased. These studies show that there is a
correlation between the ability of these endonucleases to act by a
processive mechanism and their ability to incise damaged nucleosomal DNA;
the normal endonuclease, which acts processively, can incise damaged
nucleosomal DNA, whereas the XPA endonuclease, which acts distributively,
is defective in ability to incise this substrate.
相似文献
15.
Epidemiological evidence indicates that aflatoxin B1 (AFB1) intake is
associated with an increased risk of hepatocellular carcinoma (HCC). The
hepatocarcinogenesis is initiated by covalent binding of AFB1 to cellular
DNA. To determine whether nutritional factors and hormonal status may
influence the binding of AFB1 to hepatic DNA, a cross- sectional study was
performed on a total of 42 male asymptomatic hepatitis B surface antigen
(HBsAg) carriers and 43 male non-carriers in a cohort study on the
multistage development of HCC in Taiwan. The major AFB1-DNA adduct in vivo,
AFB1-N7-guanine, was measured by high- performance liquid chromatography in
urine. Urinary AFB1-N7-guanine was detectable in 40% of the subjects. HBsAg
carriers had a higher detection rate of urinary AFB1-DNA adducts than
non-carriers and the difference was statistically significant after
multivariate adjustment. After taking into account the total AFB1 urinary
metabolite level, chronic HBsAg carrier status, and other potential
confounders, plasma levels of cholesterol, alpha-tocopherol, and alpha- and
beta-carotene were positively associated with the detection rate of the
AFB1-DNA adducts in a dose-dependent manner, whereas plasma lycopene level
was inversely related to the presence of the adducts in urine. The
association of urinary AFB1-DNA adducts with the plasma levels of
cholesterol, alpha-tocopherol, lycopene, and alpha- and beta-carotene was
observed at both low and high exposure levels of AFB1. There was a
synergistic interaction of plasma alpha-tocopherol with alpha- and beta-
carotene on the adduct levels. No association with the adducts was found
for plasma levels of retinol and testosterone. This study demonstrated
different associations of antioxidant vitamins with AFB1- DNA adduct
formation. The data consistent with our previous finding in cultured
woodchuck hepatocytes that alpha-tocopherol and beta-carotene enhanced
AFB1-DNA adduct formation suggest that prospective investigation of the
relationship between plasma micronutrients and risk of AFB1-related HCC is
warranted.
相似文献
16.
LO Larsson MW Bentzon K Berg Kelly L Mellander B-E Skoogh I-L Strannegård A Lind 《Acta paediatrica (Oslo, Norway : 1992)》1994,83(10):1091-1094
We studied 3592 Swedish schoolchildren, 8 or 9 years old, examined for palpable submandibular, cervical and supraclavicular lymph nodes. All children were skin tested with 2 TU PPD RT23 and with 0.1 μ g of Mycobacterium avium sensitin or 0.1 μ g of M. scrofulaceum sensitin. A total of 991 children had palpable lymph nodes in any of the three locations. Among them, 811 had lymph nodes in one location, 162 in two locations and 18 in three. In 312 children, the lymph nodes were ± 5 mm in size in any location. The most common location was submandibular. Boys had a significantly higher prevalence of palpable lymph nodes than girls. There was also seasonal variation. Children infected by atypical mycobacteria (sensitin reaction ±6 mm) did not have a higher prevalence of palpable lymph nodes than those not infected. 相似文献
17.
18.
Slattery ML Murtaugh MA Sweeney C Ma KN Potter JD Caan BJ Samowitz W 《Nutrition and cancer》2005,51(2):155-161
Peroxisome proliferator-activated receptor-gamma (PPARgamma) has been hypothesized as being involved in colorectal cancer given its role in adipocyte development and insulin resistance. In this study we evaluated the association between the Pro12Ala (P12A) PPARgamma polymorphism and body mass index (BMI), waist-to-hip ratio (WHR), physical activity level, and energy intake and risk of colorectal cancer using data from a population-based, case-control study of colon cancer (1,577 cases and 1,971 controls) and rectal cancer (794 cases and 1,001 controls). We further evaluated how the P12A PPARgamma polymorphism is associated with obesity and fat pattern in the control population. The odd ratio for PPARgamma PA or AA genotype relative to the PP genotype for colon cancer was 0.9 (95% confidence interval, CI=0.8-1.0) and for rectal cancer was 1.2 (95% CI=1.0-1.5) adjusting for race, age, and sex. P12A PPARgamma did not significantly interact with BMI, WHR, energy intake, and energy expenditure to alter risk of colon or rectal cancer. Furthermore, the P12A PPARgamma polymorphism was not associated with obesity or WHR in the control population; it did not interact with energy intake or energy expenditure to alter risk of obesity or large WHR. These data do not support the hypothesis that the P12A PPARgamma polymorphism is associated with colon or rectal cancer through regulation of energy balance. 相似文献
19.
Bobak M Pikhart H Kubinova R Malyutina S Pajak A Sebakova H Topor-Madry R Nikitin Y Caan W Marmot M 《Occupational and environmental medicine》2005,62(8):546-550
Background: Psychosocial factors at work are thought to influence health partly through health behaviours. Aims: To examine the association between effort-reward imbalance and job control and several alcohol related measures in three eastern European populations. Methods: A cross-sectional study was conducted in Novosibirsk (Russia), Krakow (Poland), and Karvina (Czech Republic). The participants completed a questionnaire that included effort-reward at work, job control, and a number of sociodemographic variables. Annual alcohol intake, annual number of drinking sessions, the mean dose of alcohol per drinking session, and binge drinking (⩾80 g of ethanol in one session at least once a week) were based on graduated frequencies in the questionnaire. Data were also available on problem drinking (⩾2 positive answers on CAGE questionnaire) and negative social consequences of drinking. All male participants in full employment (n = 694) were included in the present analyses. Results: After controlling for age and centre, all indices of alcohol consumption and problem drinking were associated with the effort-reward ratio. Adjustment for material deprivation did not change the results but adjustment for depressive symptoms reduced the estimated effects. Job control was not associated with any of the alcohol related outcomes. Conclusions: The imbalance of effort-reward at work is associated with increased alcohol intake and problem drinking. The association appears to be partly mediated by depressive symptoms, which might be either an antecedent or a consequence of men''s drinking behaviour. 相似文献
20.
Newman VA Thomson CA Rock CL Flatt SW Kealey S Bardwell WA Caan BJ Pierce JP;Women's Healthy Eating Living 《Journal of the American Dietetic Association》2005,105(3):382-91; quiz 488