Genetic toxicity assessment using liver cell models: past,present, and future

ABSTRACT

Genotoxic compounds may be detoxified to non-genotoxic metabolites while many pro-carcinogens require metabolic activation to exert their genotoxicity in vivo. Standard genotoxicity assays were developed and utilized for risk assessment for over 40 years. Most of these assays are conducted in metabolically incompetent rodent or human cell lines. Deficient in normal metabolism and relying on exogenous metabolic activation systems, the current in vitro genotoxicity assays often have yielded high false positive rates, which trigger unnecessary and costly in vivo studies. Metabolically active cells such as hepatocytes have been recognized as a promising cell model in predicting genotoxicity of carcinogens in vivo. In recent years, significant advances in tissue culture and biological technologies provided new opportunities for using hepatocytes in genetic toxicology. This review encompasses published studies (both in vitro and in vivo) using hepatocytes for genotoxicity assessment. Findings from both standard and newly developed genotoxicity assays are summarized. Various liver cell models used for genotoxicity assessment are described, including the potential application of advanced liver cell models such as 3D spheroids, organoids, and engineered hepatocytes. An integrated strategy, that includes the use of human-based cells with enhanced biological relevance and throughput, and applying the quantitative analysis of data, may provide an approach for future genotoxicity risk assessment.     

Functional mechanism underlying cyclooxygenase-2 expression in rat small intestine following administration of indomethacin: Relation to intestinal hypermotility

Background and Aim:  We recently reported that cyclooxygenase (COX)-2 is upregulated in the rat small intestine after administration of indomethacin, and this may be the key to non-steroidal anti-inflammatory drug (NSAID)-induced intestinal damage. The present study investigated the mechanism for COX-2 expression induced in the rat small intestine by indomethacin, in relation with ulcerogenic processes.
Methods:  Animals were given indomethacin or SC-560 p.o., and the intestinal mucosa was examined 24 h later.
Results:  Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility, bacterial invasion and inducible nitric oxide synthase (iNOS) activity, as well as the expression of COX-2 mRNA in the mucosa. Although SC-560 did not cause any damage, this agent caused intestinal hypermotility, the bacterial invasion and the upregulation of COX-2 expression. The mucosal PGE₂ content was decreased by SC-560 at 3 h but recovered 12 h later, and this recovery of PGE₂ was attenuated by both atropine and ampicillin, in addition to rofecoxib. The intestinal hypermotility response to indomethacin was prevented by both 16,16-dimethyl PGE₂ and atropine, but not ampicillin. Yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 and iNOS activity in the intestinal mucosa following indomethacin treatment, resulting in the prevention of intestinal lesions.
Conclusion:  These results suggest that COX-2 expression in the intestinal mucosa following the administration of indomethacin is associated with intestinal hypermotility and bacterial invasion. The intestinal hypermotility caused by COX-1 inhibition may be a key to COX-2 expression after administration of NSAIDs and their intestinal ulcerogenic properties.     

职业性萘暴露工人的健康监护结果评价

目的：讨论萘对人体的慢性毒效应和亚临床客观检测指标。方法：对河南省萘暴露工人（环境接触萘浓度平均为８．２５～２６．４３ｍｇ／ｍ３）进行了健康监护和医学动态观察。结果：发现长期萘暴露工人的白细胞、血小板减少及眼晶体混浊检出率显著高于对照组（Ｐ＜０．００１）；血清ＳＯＤ同功酶、ＧＳＨ－ＰＸ活性显著低于对照组，而ＬＰＯ水平、神经元特异性烯醇化酶（ＮＳＥ）活性水平以及外周血染色体畸变和微核阳性检出率均显著高于对照组（Ｐ＜０．００１）。神经行为功能检查结果，主要为消极情绪增加，记忆力下降等。事件相关电位Ｐ３００峰潜伏期比对照组显著延长，与对照组差异显著（Ｐ＜０．０５）。结论：慢性低浓度萘暴露对工人主要损害部位（靶器官）有皮肤，眼、血液和神经组织等。ＮＣＴＢ、ＮＳＥ、Ｐ３００三项可作为早期神经受损的客观指标。     

小儿内伤头痛辨治

74例小儿慢性头痛经辨证治疗,显效80.95%,好转16.67%,无效2.38%。痰浊头痛二陈汤或半夏白术天麻汤加减;肾虚头痛,杞菊地黄汤加减;淤血头痛,补阳还五汤;气血虚头痛八珍汤加减。指出了小儿内伤头痛的病因病机,并指出脑电图,脑阻抗血流图、CT、甲皱微循环可做为此病的诊断及疗效指标。     

透明质酸钠玻璃体腔内充填在严重开放性眼球损伤治疗中的应用

目的 研究透明质酸钠玻璃体腔内充填对严重开放性眼球损伤预后的影响。方法 在严重开放性眼球损伤一期手术缝合后玻璃体腔内充填透明质酸钠至眼压Tn。结果 用透明质酸钠在玻璃体腔内充填，眼球萎缩的发生率（6．67％）明显低于用BSS液充填的发生率（70．58％）。结论 透明质酸钠玻璃体腔内充填在严重开放性眼球损伤治疗中的应用对眼球外形维持和视功能恢复有重要作用。     

甲状腺机能亢进危象：附14例临床分析

本文报道14例甲亢危象,其发病率为4.5％,其发病与感染、劳累、情绪激动及同位素治疗有关。指出同位素治疗甲亢初期应服用抗甲状腺药物,讨论了淡漠型危象的有关问题。     

Focal vulnerability of developing brain: CT studies on disproportionally dilated lateral ventricles

Summary Cranial computed tomography (CT) of 108 cases with dilated lateral ventricles was reviewed to elucidate the relationship between focal vulnerability of developing brain and disproportional dilatation of lateral ventricles. CT findings of 108 cases with symmetrical dilatation of lateral ventricles were classified into three types by morphometry of lateral ventricles: anterior horn predominant type (31 cases), diffuse type (36 cases), posterior horn predominant type (41 cases). Posterior horn predominant type has a tendency to occur in congenital anomalies and premature brain damage, and anterior horn predominant type in infantile brain damage. This disproportional dilatation of anterior or posterior horns suggests a vulnerability of periventricular structure in developing brain.     

The aging process and potential interventions to extend life expectancy

Aging is commonly defined as the accumulation of diverse deleterious changes occurring in cells and tissues with advancing age that are responsible for the increased risk of disease and death. The major theories of aging are all specific of a particular cause of aging, providing useful and important insights for the understanding of age-related physiological changes. However, a global view of them is needed when debating of a process which is still obscure in some of its aspects. In this context, the search for a single cause of aging has recently been replaced by the view of aging as an extremely complex, multifactorial process. Therefore, the different theories of aging should not be considered as mutually exclusive, but complementary of others in the explanation of some or all the features of the normal aging process. To date, no convincing evidence showing the administration of existing “anti-aging” remedies can slow aging or increase longevity in humans is available. Nevertheless, several studies on animal models have shown that aging rates and life expectancy can be modified. The present review provides an overlook of the most commonly accepted theories of aging, providing current evidence of those interventions aimed at modifying the aging process.     

加减下瘀血汤对低密度及氧化型低密度脂蛋白诱导小鼠肾足细胞血管内皮生长因子分泌的干预作用

目的：观察脂质低密度（LDL）及氧化型低密度脂蛋白（OX-LDL）对体外培养小鼠足细胞分泌血管内皮生长因子（VEGF）的影响及加减下瘀血汤的保护作用.方法：观察不同浓度下LDL和OX-LDL对小鼠肾足细胞分泌VEGF的影响,再用不同浓度加减下瘀血汤含药血清进行干预,分别用RT-PCR及ELISA检测足细胞分泌VEGF的变化.结果：LDL和OX-LDL可使肾足细胞分泌VEGF明显增高,且有浓度依赖性.中药加减下瘀血汤含药血清的干预可以明显抑制脂质诱导肾足细胞VEGF的高表达.结论：LDL和OX-LDL可以通过促进足细胞分泌VEGF增加而加重脂质肾毒性,而中药加减下瘀血汤可能通过抑制脂质诱导足细胞分泌过多VEGF,从而保护足细胞的脂质损伤.