Hexavalent chromium-induced DNA damage and repair mechanisms

Hexavalent chromium is a commonly used industrial metal that has been shown to induce lung cancer in workers having long term exposure. In the particulate form, Cr(VI) dissolves slowly in vivo, leading to an extended exposure of lung cells. Hexavalent chromium is taken into the cell and rapidly reduced to Cr(V), Cr(IV), Cr(III), and reactive oxygen species. Cells treated with Cr(VI) are subject to several types of DNA damage resulting from this reduction, including base modification, single-strand breaks, double-strand breaks, Cr-DNA adducts, DNA-Cr-DNA adducts, and protein-Cr-DNA adducts. These types of damage, if left unrepaired or are misrepaired, can lead to growth arrest, cytotoxicity, and apoptosis, as well as mutations leading to neoplastic transformation and ultimately tumorigenesis. Here we review the current literature on Cr-induced DNA damage and its repair.     

DNA repair mechanisms in eukaryotes: Special focus in Entamoeba histolytica and related protozoan parasites

Eukaryotic cell viability highly relies on genome stability and DNA integrity maintenance. The cellular response to DNA damage mainly consists of six biological conserved pathways known as homologous recombination repair (HRR), non-homologous end-joining (NHEJ), base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), and methyltransferase repair that operate in a concerted way to minimize genetic information loss due to a DNA lesion. Particularly, protozoan parasites survival depends on DNA repair mechanisms that constantly supervise chromosomes to correct damaged nucleotides generated by cytotoxic agents, host immune pressure or cellular processes. Here we reviewed the current knowledge about DNA repair mechanisms in the most relevant human protozoan pathogens. Additionally, we described the recent advances to understand DNA repair mechanisms in Entamoeba histolytica with special emphasis in the use of genomic approaches based on bioinformatic analysis of parasite genome sequence and microarrays technology.     

Activation mechanisms, biological role and inhibitors of metalloproteases in the extracellular matrix

Prometalloproteinases are activated by serine proteases, MMP-3, leucocytic elastase, furin, furin-like proteases and by membrane-type metalloproteinases as well. They form complexes with some proMMPs and thus they modify their activation.     

Cytogenetic markers, DNA single-strand breaks, urinary metabolites, and DNA repair rates in styrene-exposed lamination workers

The effect of occupational exposure to styrene on frequencies of chromosomal aberrations and binucleated cells with micronuclei and on single-strand break levels in peripheral blood lymphocytes was studied in 86 reinforced plastic workers and 42 control individuals (including 16 maintenance workers with intermittent, low-dose exposure). In these individuals, the irradiation-specific DNA repair rates and the repair rates of 8-oxoguanines were investigated. We assessed the exposure by measuring the concentrations of styrene in air and in blood and of mandelic acid, phenylglyoxylic acid, 4-vinyl phenol conjugates and regioisomeric phenyl hydroxyethyl mercapturic acids in urine. All these parameters correlated with one another. No clear relationship was found between the styrene exposure and the frequencies of chromosomal aberrations. Binucleated cells with micronuclei were moderately related to the parameters of styrene exposure. We found a negative correlation between all exposure parameters and single-strand breaks. The positive correlation between exposure parameters and DNA repair rates suggests that particular DNA repair pathways may be induced by styrene exposure.     

Nonalcoholic fatty liver disease: emerging mechanisms and consequences

PURPOSE OF REVIEW: One of the critical complications of obesity and diabetes is nonalcoholic fatty liver disease, a disorder of triacylglycerol accumulation in the liver that has potential to develop into end stage liver failure. In this review, the recent progress in understanding the role of hepatic triacylglycerol synthesis in the development of nonalcoholic fatty liver disease is discussed. RECENT FINDINGS: It has become apparent that the development of hepatic steatosis is a complex, multifactorial process. Although the molecular pathways underlying its development have been described, there are no established therapies for nonalcoholic fatty liver disease. Recently, however, DGAT1 and DGAT2, the enzymes responsible for the final step in triacylglycerol synthesis, have been characterized as playing a vital role in hepatic triacylglycerol metabolism. Cellular and murine models in which diacylglycerol acyltransferase expression is altered suggest that these enzymes may play a role in the development hepatic steatosis, are feasible targets in the treatment of nonalcoholic fatty liver disease, but also function as lipotoxic buffers. SUMMARY: Hepatic steatosis remains the watershed event in the progression of nonalcoholic fatty liver disease. The diacylglycerol acyltransferases are emerging as important mediators of hepatic triacylglycerol accumulation. Therefore, these enzymes are attractive targets in the development of therapies to prevent liver triacylglycerol accumulation and the consequences of nonalcoholic fatty liver disease.     

修复基因XRCC1、XPD和XRCC3多态性与苯致DNA损伤修复能力关系的研究

目的探讨XRCC1、XPD、XRCC3基因多态性与苯致DNA损伤修复能力的关系。方法以确诊并已脱离苯作业的80名慢性苯中毒患者作为病例组,以同期接苯的62名苯作业工人为对照组,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)分析技术,检测XRCC1 C26304T(Arg194Trp)、G27466A(Arg280His)、G28152A(Arg399Gln)、G36189A(Gln632Gln)和XPD C22541A(Arg156Arg)、C23591T(Asp312Asn)、A35931C(Lys751Gln)以及XRCC3 C18067T(Thr241Met)位点的多态性,采用细胞阻滞微核试验和碱性彗星试验分别从细胞水平和分子水平检测DNA修复能力。结果携带XPD35931 AC+CC变异基因型的个体、携带XPCC318067C/T变异基因型的个体均比携带相应野生基因型个体的苯致DNA损伤修复能力强。结论     

Mercury in seafood: mechanisms of accumulation and consequences for consumer health

Mercury is a largely uncontrollable heavy metal contaminant in that it is globally ubiquitous, and environmentally persistent. The element has the potential for global mobilization following liberation from environmental stores, which can occur as a consequence of either anthropogenic activities or natural processes. Furthermore, organic forms like methylmercury accumulate in biological tissues with an exceptionally long biological half-life, facilitating the magnification of this toxin along trophic food chains. Bioaccumulation is particularly evident in aquatic environments, in which long-lived piscivorous fishes and marine mammals are reported with a mercury burden one-million times that of the surrounding water body, typically attaining mercury burdens exceeding 1 microg g(-1). Mercury levels in other seafood, however, are typically reported in the range of 0.1 to 0.2 microg g(-1) and usually less then 0.5 microg g(-1). The primary source of human exposure to environmental mercury is through seafood consumption. The dangers associated with the consumption of large amounts of methylmercury accumulated in seafood are well recognized from past poisoning incidents, in which fish with mercury burdens in the range of 9 to 24 microg g(-1) were consumed. Nevertheless, the toxicological consequence of chronic low-level mercury exposure from habitual seafood consumption is an area of contention. This review discusses the mechanisms of mercury accumulation and distribution in fish tissues and the toxicological consequences of mercury exposure from seafood consumption with regard to international safety guidelines.     

Effects of age and dietary restriction on oxidative DNA damage, antioxidant protection and DNA repair in rats

Summary Background Experimentally imposed dietary restriction is known to extend the lifespan of rodents, perhaps by slowing the accumulation of oxidative damage that is thought to be one of the causes of aging. Aim of the study We examined the effects of restricted total food intake, and protein and calorie restriction, on DNA oxidation and related biomarkers in rats. Methods From 1 to 17 months, rats in group 1 received normal diet ad libitum. Group 2 received 70% of the quantity consumed by the first group. Group 3 had the same quantity as group 2, but with a reduction in protein (from 18% to 10% of the diet by weight), and group 4 were further restricted with a 30% decrease in calories. Lymphocytes were isolated from blood samples taken every two months. DNA breaks, oxidised pyrimidines, resistance to H₂O₂–induced damage, and strand break repair were measured with the comet assay. Organs were isolated from rats killed at 17 months, with 1 month–old rats for comparison; DNA oxidation and antioxidant enzyme activities were measured. Results DNA breaks in lymphocytes increased from 1 to 3 months but thereafter declined with age, except in ad libitum fed rats. Oxidised pyrimidines did not change significantly. Resistance to H₂O₂–induced damage was least at 3 months, and increased with age. Repair of DNA strand breaks was efficient at all ages. Diet had little effect on these endpoints. Diet had no influence on 8–oxo–7.8–dihydroguanine levels in DNA from liver, testis and brain of 17 monthold rats. Combining data from all four groups, the levels in brain and liver were significantly higher at 17 months compared with 1 month. Antioxidant enzyme activities tended to increase between 1 and 17 months; effects of diet were not so consistent. Conclusions While DNA damage shows a modest increase with age in some organs, antioxidant status and DNA strand break repair do not decline with age. Restricted diets (including protein and calorie restriction) have no effect on any of these markers of genetic stability.     

Postprandial hyperglycemia on vascular endothelial function: mechanisms and consequences

Vascular endothelial dysfunction precedes atherosclerosis and contributes to cardiovascular disease (CVD), which accounts for one-third of all deaths in the United States. Chronic hyperglycemia, such as that associated with diabetes, is well known to impair vascular function. However, recent evidence demonstrates that acute or postprandial hyperglycemia (PPH) not only exacerbates vascular endothelial dysfunction in individuals with chronic hyperglycemia but also transiently impairs vascular function in healthy individuals. Postprandial hyperglycemia has been shown to better predict future CVD mortality compared with fasting glucose in both diabetic and normoglycemic individuals. Compelling evidence exists suggesting that PPH-mediated insults to the vascular endothelium contribute to CVD, especially in pathophysiologic conditions whereby vascular recovery is compromised. Although the mechanisms by which PPH induces vascular dysfunction is not fully understood, oxidative stress–mediated disruptions in nitric oxide homeostasis are implicated as key events leading to vascular dysfunction associated with PPH. This review aims to highlight the findings of clinical studies using functional indices of vascular function to demonstrate that PPH impairs vascular function. We will also discuss the evidence showing the central involvement of oxidative stress in dysregulating nitric oxide homeostasis and contributing to PPH-mediated vascular endothelial dysfunction. Lastly, this review will identify areas of knowledge that remain limited and will provide recommendations for future investigation to more fully define PPH as an important risk factor for CVD.     

DNA损伤修复与肿瘤的放射敏感性

放射治疗在恶性肿瘤的治疗中具有重要地位,如何提高肿瘤的放射敏感性是临床和基础研究工作的一大主题。放射线可引起细胞DNA不同形式的损伤,而DNA损伤后的修复过程会导致肿瘤细胞放射敏感性下降,甚至出现放射性抵抗。多年来人们对这一问题开展了大量研究,本文就DNA损伤修复机制及其对恶性肿瘤放疗敏感性的影响的研究进展做一综述。     

The problem of infertility in high fertility populations: Meanings,consequences and coping mechanisms in two Nigerian communities

This paper examines how socio-economic contexts shape local meanings of infertility, how the prevalence of infertility affects these meanings, and how the above affect community responses, life experiences and infertility treatment-seeking behaviors in two African communities. The paper is based on interdisciplinary research conducted among the Ijo and the Yakurr people of southern Nigeria that included a survey of approximately 100 infertile women and a matching sample of 100 fertile women, as well as in-depth ethnographic interviews with infertile and fertile women in two communities: Amakiri in Delta State and Lopon in Cross River State.     

Production and repair of DNA damage in mammalian cells

Cellular genomes are continually subjected to endogenous and environmentally induced structural alterations. Our environment contains a multitude of substances that are carcinogenic and which, in many cases, are thought to act via direct damage to DNA. In order to better understand the consequences of DNA damage in cell killing and carcinogenesis, it will be important to: (a) develop new and sensitive techniques for the identification of specific types of DNA lesions; (b) examine what influence the function or activity of a DNA sequence has on the distribution of DNA damage within that DNA sequence and on its repair efficiency; (c) examine what influence the cell cycle has on the efficiency of DNA repair.     

健康人群吸烟、DNA损伤与DNA修复基因多态研究

DNA修复基因在防止机体受致癌剂作用过程中起重要作用,但尚不清楚特定的遗传变异对修复表现型和癌症风险的影响。通过测定308位属于欧洲发展规划组织(EPIC)的意大利人的DNA加合物水平及调查3种DNA损伤修复基因的多态性:XRCCl—Arg399Gln(外显子10)。XRCC3-Thr241Met(外显子7)和XPD—Lys751Gln(外显子23)。通过用DNA-32P一末端标记阵列测DNA加合物水平。用PCR—RFLP测其基因型。XRCC3-241Met基因型与较高的DNA加合物水平显著相关,而XRCCl-399Gln型和XPD-751Gln型仅在从不吸烟者中才与较高的DNA加合物水平相关。XRCC3-241Met纯合子平均DNA加合物水平为11.44±1.48(±SE),Thr/Met杂合子为7.69±0.88,而Thr/Thr纯合子为6.94±1.11(F=3.026,P=0.042)。从不吸烟者XRCCl-399Gln纯合子DNA加合物水平平均为15.60±5.42,与Gln/Arg杂合子的6.16±0.97和Arg,Arg纯合子的6.78±1.10相比(F=5.237,P=0.007)。调整几种混杂因素后观察到XPD-751Gln相比从不吸烟的XPD-751Lys纯合子其比值比有显著性(OR=3.81,95％CI:1.02~14.16)且DNA加合物水平高于平均值。表明所有已分析的多态可导致不同的DNA修复,并提示需进一步探讨存在于基因多态、吸烟和其他风险因素间的交互作用。     

Vitamin A and clefting: putative biological mechanisms

Nutritional factors such as vitamin intake contribute to the etiology of cleft palate. Vitamin A is a regulator of embryonic development. Excess vitamin A can cause congenital malformations such as spina bifida and cleft palate. Therefore, preventive nutritional strategies are required. This review identifies putative biological mechanisms underlying the association between maternal vitamin A intake and cleft palate. Excessive vitamin A may disturb all three stages of palatogenesis: 1) during shelf outgrowth, it may decrease cell proliferation and thus prevent tissue development; 2) it may prevent shelf elevation by affecting extracellular matrix composition and hydration; and 3) during shelf fusion, it may affect epithelial differentiation and apoptosis, which precludes the formation of a continuous palate. In general, high doses of vitamin A affect palatogenesis through interference with cell proliferation and growth factors such as transforming growth factor β and platelet-derived growth factor. The effects of lower doses of vitamin A need to be investigated in greater depth in order to improve public health recommendations.     

DNA repair phenotype and dietary antioxidant supplementation

Phytochemicals may protect cellular DNA by direct antioxidant effect or modulation of the DNA repair activity. We investigated the repair activity towards oxidised DNA in human mononuclear blood cells (MNBC) in two placebo-controlled antioxidant intervention studies as follows: (1) well-nourished subjects who ingested 600 g fruits and vegetables, or tablets containing the equivalent amount of vitamins and minerals, for 24 d; (2) poorly nourished male smokers who ingested 500 mg vitamin C/d as slow- or plain-release formulations together with 182 mg vitamin E/d for 4 weeks. The mean baseline levels of DNA repair incisions were 65.2 (95 % CI 60.4, 70.0) and 86.1 (95 % CI 76.2, 99.9) among the male smokers and well-nourished subjects, respectively. The male smokers also had high baseline levels of oxidised guanines in MNBC. After supplementation, only the male smokers supplemented with slow-release vitamin C tablets had increased DNA repair activity (27 (95 % CI 12, 41) % higher incision activity). These subjects also benefited from the supplementation by reduced levels of oxidised guanines in MNBC. In conclusion, nutritional status, DNA repair activity and DNA damage are linked, and beneficial effects of antioxidants might only be observed among poorly nourished subjects with high levels of oxidised DNA damage and low repair activity.     

Experimental analysis of biological effects of microwaves: their systemic, ultrastructural and neuronal mechanisms

For 200 hours the cats were exposed to microwaves of 2375 mHz, the energy current density being 500 mWt/cm2. 6 diversions of the electrocorticogram and multi-cellular activity were registered by coal electrodes. After the exposure an electro-microscopic study of the lateral hypothalamic brain field was carried out. Under the radiation effect synchronization of slow bioelectric activity over the range of 6-10 to 12-16 took place. The analysis of the conditional probability matrix of series generation of action potential in the studied structures demonstrated their functional separation according to multi-cellular activity parameters in proportion to exposure growth. Damage of axodendritic synapses which provided morphologic links between brain structures was considered its morphologic substrate.