Dietary flavonoids, quercetin, luteolin and genistein, reduce oxidative DNA damage and lipid peroxidation and quench free radicals

Several dietary flavonoids such as quercetin, luteolin and genistein have been suggested to have cancer chemopreventive effects, although the mechanisms are not fully understood. In the present study, the effects of these flavonoids as antioxidants were investigated in the following systems: (1) production of hydrogen peroxide (H2O2) and superoxide anion (O2*-), (2) lipid peroxidation induced by FeCl2 in rat liver, and (3) formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) induced by either UV or Fenton reaction in calf thymus DNA. The results showed that quercetin and luteolin were equally potent in scavenging H2O2, with genistein having a moderate effect. Quercetin and luteolin had a potent inhibitory effect on O2*- generation by xanthine/xanthine oxidase while genistein had a moderate effect. Quercetin and luteolin were potent in inhibiting lipid peroxidation induced by FeCl2 in rat liver while genistein had a very weak inhibitory effect. All the test compounds had a potent quenching effect on 8-OHdG formation induced by UV light irradiation, with the order of effects being genistein > luteolin > quercetin. Of the test compounds, luteolin exhibited the most potent quenching effect on Fenton-induced 8-OHdG formation. The scavenging of oxygen free radicals, the inhibitory effect on lipid peroxidation and the quenching effect on 8-OHdG formation by quercetin, luteolin and genistein may, at least in part, be responsible for their anticarcinogenic effects.     

Antitumor activity and pharmacokinetics following oral administration of natural product DNA topoisomerase I inhibitors 10-hydroxycamptothecin and camptothecin in SCID mice bearing human breast cancer xenografts

The DNA topoisomerase I inhibitors, 10-hydroxycamptothecin (HCPT) and camptothecin (CPT), are indole alkaloids isolated from the Chinese tree, Camptotheca acuminata. They have been shown to have a wide spectrum of anticancer activity both in vitro and in vivo. However, their use has been limited due to their water-insolubility. The purpose of the present study was 2-fold, to determine the in vitro and in vivo activity of HCPT and CPT against human breast cancer and to determine the pharmacokinetics of the two drugs to better understand how they can best be used therapeutically. The bl vitro inhibitory effect on tumor growth was observed with breast cancer cell line MDA-MB-468. The in vivo antitumor effects were then determined using severe combined immunodeficient (SCID) mice bearing MDA-MB-468 xenografts. The tumor-bearing mice were orally administered HCPT (1, 3, 6, 9 mg/kg/day, 5 days per week) or CPT (1, 3, 6 mg/kg/day, 5 days per week) for 3 weeks. Growth of the MDA-MB-468 cells was inhibited by HCPT and CPT in vitro and in vivo in a dose-dependent manner. Complete regression of the tumor xenografts, determined by tumor measurement and microscopic examination, occurred in the groups of animals treated with doses of HCPT or CPT of 3 mg/kg/day or more. In general, HCPT was more effective and less toxic than CPT. To determine the potential mechanisms for the pharmacologic differences, the comparative pharmacokinetics of HCPT and CPT were determined in tumor-bearing SCID mice following i.v. or oral administration of H-3-HCPT or H-3-CPT. Parent drugs and their metabolites in plasma, urine, feces, and various tissues were quantified by a recently developed reversed-phase HPLC method. Significant absorption of both HCPT and CPT was observed after oral administration, with CPT having a higher bioavailability. HCPT and CPT were distributed widely into various tissues including the tumor, enterohepatic system, kidneys, and bone marrow. These studies indicate that HCPT and CPT are of potential use in treatment of breast cancer, providing the basis for the design of future human trials with these anticancer drugs.     

职业人群不健康行为生活方式与高尿酸血症的关系及高血压、血脂异常的效应修饰作用

目的 探索不健康行为生活方式与高尿酸血症的关系,以及高血压、血脂异常的效应修饰作用,为预防高尿酸血症提供理论依据。方法 采用横断面调查研究设计,基于2021年10-12月来自四川省、贵州省28个地级市和重庆市33个区（县）中国铁路成都局集团有限公司的西南职业人群队列基线数据,通过问卷调查、体格测量及实验室生化检测收集研究对象的人口学特征、行为生活方式、慢性非传染性疾病患病情况。不健康行为生活方式得分根据吸烟、饮酒、膳食模式、体力活动和低体重/超重状况进行评分,分值越高不健康行为生活方式越多。采用多因素logistic回归模型分析不健康行为生活方式评分、吸烟状况、饮酒状况等与高尿酸血症的关系,采用分层分析探索高血压等疾病对不健康行为生活方式与高尿酸血症之间关系的修饰效应。结果 共纳入11 748名研究对象,高尿酸血症患病率为34.4%。多因素logistic回归分析显示,现在吸/既往吸烟、现在饮/既往饮酒及BMI异常是高尿酸血症患病的危险因素,不健康行为生活方式对高尿酸血症患病风险呈现累积效应,随着得分的升高,高尿酸血症患病风险升高,OR值由1.64（95%CI：1.34~2.00）上升至2.89（95%CI：2.39~3.50）。分层分析结果显示,在高血压及血脂异常人群中,不健康行为生活方式对高尿酸血症患病风险影响更大。结论 多种不健康行为生活方式的共存会升高高尿酸血症患病风险,这一效应在高血压、血脂异常人群中更明显。及时纠正不健康行为生活方式,并控制高血压和血脂异常,降低患高尿酸血症的风险。     

综合治疗对脑梗塞相关危险因素的影响

目的　探讨综合治疗对脑梗塞复发的相关危险因素的影响。方法　随机选择85 例脑梗塞伴各类危险因素患者在综合治疗前后,对他们进行血压、空腹血糖、胆固醇、甘油三酯及血液流变学等8 项指标的测定。结果　经过1 ～3 年临床观察随访,有50 % 以上高血糖、高血脂、高粘滞血症患者检验指标趋于正常,94 .3 % 的高血压得到控制与稳定,经t 检验,血液流变学4 项P 值< 0 .05 ,差异有显著意义,高血压、空腹血糖、胆固醇、甘油三酯的P 值< 0 .01 ,差异有非常显著意义。结论　综合治疗对控制相关危险因素,预防脑梗塞复发有重要临床意义     

中国地鼠情绪唤醒水平评定量表的制定

为建立一套适合于中国地鼠情绪唤醒水平观测的评定方法,并验证其可靠性,在Ａｄｅｒ 情绪唤醒评定方法基础上进行修订,对中国地鼠进行试测,建立情绪唤醒水平划界分。结果显示总分以５ 分为界,能区分高／ 低情绪唤醒水平的中国地鼠;条目与量表总分呈中高度相关（ ｒ ＝ ０ ．３２６８ ～０ ．７３４７） ,量表总分重测信度良好（ ｒ ＝ ０ ．５８７４ ～０ ．６１０５） ,评定者评分一致性高,符合率达９５－２ ％     

Prevalence and anatomic characteristics of infarct-like lesions on MR images of middle-aged adults: the atherosclerosis risk in communities study.

BACKGROUND AND PURPOSE: MR imaging has revealed putative evidence of subclinical cerebrovascular disease (CVD) as reflected by white matter signal changes and infarct-like lesions (ILLs). Nonetheless, the prevalence of this condition in the general population has been defined only to a limited extent. We herein report the prevalence and anatomic characteristics of ILLs seen on cranial MR images obtained as part of a population-based study of cardiovascular disease in middle-aged adults. These results are contrasted to those of previous similar studies, particularly those of an elderly population in the Cardiovascular Health Study (CHS). METHODS: This Atherosclerosis Risk in Communities (ARIC) cohort consists of a probability sample of community-living persons who were 55 to 72 years old at the time of MR examination. MR imaging of 1890 participants was performed at two ARIC field centers, based on a common protocol. MR studies were evaluated by trained readers at the MR Reading Center using original digital data displayed on a high-resolution workstation. The measures of lesion size, anatomic location, and signal intensity were collected. The definition for an ILL was a non-mass, hyperintense region with an arterial vascular distribution on spin-density and T2-weighted images. RESULTS: Two hundred ninety participants had ILLs, for an overall prevalence of 15.3%. Eighty-two percent of participants with ILLs had lesions that were 3 mm or larger in maximal dimension, although 87% of these lesions were 20 mm or smaller in maximal dimension. The prevalence of ILLs increased with age, from 7.9% in the 55- to 59-year-old age group to 22.9% in the 65- to 72-year-old age group (P < .001). Lesion prevalence was greater in black (20.7%) than in white persons (10.2% [P < .0001]), but did not differ significantly between male and female participants. The basal ganglia and thalamic region was the most commonly affected anatomic site, accounting for 78.9% of the lesions. CONCLUSION: Considering that the prevalence of self-reported stroke or transient ischemic attack in ARIC participants is 1.5%, these results suggest that there is significantly more subclinical than clinical CVD in the general population. Furthermore, the prevalence of this subclinical disease increases with age, and is greater in black persons. ILLs are dominated by "lacunae" in the basal ganglia and thalamus. These results are, in general, similar to those of a comparable study of elderly participants in the CHS, except for a 60% lower prevalence of ILLs in this younger population.     

Social interactions of high school students with mental retardation and their general education peers

The informal social interaction behavior that is typical of a high school lunchroom in which general and special education students are physically included was described. Using systematic observation and social comparison methods, we compared the performance of two groups of students (12 general education students and 12 students with mental retardation). Both similarities and differences were found in the interactions of students with mental retardation and their general education peers with respect to social behaviors, conversational topics, and context within which interactions occurred. However, despite being in proximity, students with mental retardation rarely interacted with any of approximately 500 general education students present in the lunchroom. Implications are discussed for increasing social interaction among high school students.     

Effect of dietary inducer dimethylfumarate on glutathione in cultured human retinal pigment epithelial cells.

PURPOSE: To determine the effect of dimethylfumarate (DMF), an inducer of glutathione (GSH)-dependent detoxification, on intracellular GSH levels in cultured human retinal pigment epithelium (hRPE) cells, its mechanism of action, and its effect on hRPE cells subjected to oxidative injury. METHODS: Established hRPE cell lines were treated with DMF and assayed by high-pressure liquid chromatography for intracellular and extracellular GSH levels. Quantification of gamma-glutamylcysteine synthetase (GLCL) was determined through northern and western blot analyses, and activity was measured. Effects of pretreatment with DMF on GSH redox status of hRPE cells was determined. Sensitivity of hRPE cells to oxidative stress was determined using tert-butylhydroperoxide as the oxidative agent. RESULTS: Dimethylfumarate caused a transient decrease followed by a significant increase in intracellular GSH. Glutathione increased maximally at 24 hours with 100 to 200 microM DMF. The initial decrease could be accounted for by the formation of a DMF-GSH conjugate. Dimethylfumarate treatment increased the steady state mRNA expression of the regulatory subunit of GLCL, but no increase was seen for the catalytic subunit. However, protein levels were increased for both, and the catalytic activity of GLCL was also increased. Whereas the initial decrease in GSH made hRPE cells more susceptible to oxidative damage, pretreatment with DMF under conditions that increased intracellular GSH protected hRPE cells against oxidative damage. CONCLUSIONS: These results suggest a means by which the antioxidant capability of hRPE may be augmented without direct antioxidant supplementation. Specifically, a dietary compound that conjugates with GSH can induce GSH synthesis, increase GSH concentration, and improve protection by GSH-dependent detoxification pathways in hRPE. However, the early depletion of GSH before stimulated synthesis necessitates caution in prevention strategies using dietary inducers.     

Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study

OBJECTIVE: To develop protocols to photograph and evaluate retinal vascular abnormalities in the Atherosclerosis Risk in Communities (ARIC) Study; to test reproducibility of the grading system; and to explore the relationship of these microvascular changes with blood pressure. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Among 4 examination centers, 11,114 participants (48-73 years of age) at their third triennial examination, after excluding persons with diabetes from this analysis. METHODS: One eye of each participant was photographed by technicians with nonmydriatic fundus cameras. Reading center graders evaluated focal arteriolar narrowing, arteriovenous (AV) nicking, and retinopathy by examining slides on a light box and measured diameters of all vessels in a zone surrounding the optic disc on enhanced digitized images. To gauge generalized narrowing, vessel diameters were combined into central arteriolar and venular equivalents with formulas adjusting for branching, and the ratio of equivalents (A/V ratio) was calculated. MAIN OUTCOME MEASURES: Retinal vascular abnormalities, mean arteriolar blood pressure (MABP). RESULTS: Among 11,114 participants, photographs were obtained of 99%, with quality sufficient to perform retinal evaluations in 81%. In the 9040 subjects with usable photographs, A/V ratio (lower values indicate generalized arteriolar narrowing) ranged from 0.57 to 1.22 (median = 0.84, interquartile range = 0.10), focal arteriolar narrowing was found in 7%, AV nicking in 6%, and retinopathy in 4%. Because of attrition of subjects and limitation of methods, prevalence of abnormality was likely underestimated. Controlling for gender, race, age, and smoking status, these retinal changes were associated with higher blood pressure. For every 10-mmHg increase in MABP, A/V ratio decreased by 0.02 unit (P < 0.0001), focal arteriolar narrowing had an odds ratio (OR) of 2.00 (95% confidence interval [CI] = 1.87-2.14), AV nicking had an OR of 1.25 (95% CI = 1.16-1.34), and retinopathy had an OR of 1.25 (95% CI = 1.15-1.37). For any degree of generalized narrowing, individuals with focal narrowing had MABP approximately 8 mmHg higher than those without (P < 0.0001). Masked replicate assessment of a sample found the following reproducibility: for A/V ratio, correlation coefficient = 0.79 and median absolute difference = 0.03; for focal arteriolar narrowing, kappa = 0.45; for AV nicking, kappa = 0.61; and for retinopathy, kappa = 0.89. CONCLUSION: Protocols have been developed for nonmydriatic fundus photography and for evaluation of retinal vascular abnormalities. Several microvascular changes were significantly associated with higher blood pressure; follow-up will show whether these are predictive of later cerebrovascular or cardiovascular disease independently of other known risk factors.