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.     

Nicotine-induced dopamine plasticity: a gateway to neurotransmitter replacement?

Nicotine,the principal neuroactive component of tobacco,acts on the reward systems of smokers,inducing addiction.Experimental evidence indicates that nicotine-induced addiction alters the activity of dopaminergic neurons within reward-processing brain centers.The effect of developmental nicotine exposure on neuroplasticity of identified reward neurocircuitry in the adult is finally emerging and begins to be understood at the molecular,cellular,and behavioral level(Romoli et al.,2019).     

Gentamicin-induced diffuse renal tubular dysfunction.

Sir, Aminoglycoside-induced renal tubular dysfunction could be dividedinto Fanconi-like syndrome (FS) and Bartter-like syndrome (BS)[1]. The risk factors and mechanisms of tubular dysfunctionare little known. Here, we report a case of gentamicin-inducedFS, BS and distal renal tubular acidosis (RTA) and propose thepossible involvement of mitochondria. Case. A 66-year-old Chinese male was admitted because ofpneumonia.     

Evaluation of mandibular block using a standardized method.

The purpose of this prospective randomized study was to investigate the manifestations and efficiency of mandibular block (MB) using a standardized method. In this study, 123 patients requiring MB were randomly assigned to receive MB using a repeated measures design. Mandibular block was administered in each patient by using 2.1 mL of 2% lidocaine with 1:100 000 epinephrine for the inferior alveolar nerve, lingual nerve, and/or buccal nerve. Clinical parameters including the electric pulp test and test for soft tissue sensation using a sharp dental explorer were assessed on both the operated side and contralateral side before and 5, 10, and 15 minutes after injection, and at the end of surgical procedure. Results of the test of the contralateral tooth served as the control group. No response to the electric pulp test at a maximum output (80 readings) was used as the criterion for pulpal anesthesia. Results obtained with electric pulp test and sharp explorer test were not significantly different during various intervals on the contralateral side, indicating the reliability of this standardized method for assessing MB. The MB technique achieved a high rate of subjective numbness (100%) according to the perception of the patients of overall numbness and lip numbness. Overall anesthetic success rates of pulpal anesthesia were 5.7% for the central incisor, 38.2% for the canine, 55.3% for the first premolar, and 90.2% for the first molar. No significant difference was found in the efficiency of anesthesia related to sex or age of the patients. A slower onset of pulpal anesthesia after MB was found for the anterior teeth than for the posterior teeth. This study suggests that the use of a standardized method might produce a clearer and more comprehensive evaluation of the efficiency and manifestations of MB.     

“搓滚舒筋”练功疗法

“搓滚舒筋”练功疗法,是一种以竹筒为简易器械的脚底搓滚练功治疗“筋挛缩”症的方法。最早文献见于马王堆汉墓出土的帛书《五十二病方》,起码有两干多年的渊源。骨伤科常用之,内、外诸科亦有用之。这一传统疗法,筒、便、廉、验,值得弘扬。     

近红外光谱仪监测窒息新生儿听觉刺激诱发时的脑氧合代谢及脑血流变化

目的了解窒息新生儿在听觉刺激诱发脑神经活动时的脑氧合代谢和脑血流量的改变。 方法1998~2003年北京中日友好医院儿科选择窒息新生儿34例为窒息组，健康新生儿40名为对照组。使用近红外光谱仪，观察听觉刺激试验诱发的脑氧合血红蛋白\[Hb O2\]、还原血红蛋白\[Hb H\]和总血红蛋白\[Hb tot\]浓度的变化，并比较两组脑氧合代谢和脑血流量的改变。根据\[Hb O2\]、\[Hb H\]和\[Hb tot\]不同的变化，将氧合代谢曲线分为A(\[Hb O2\]、\[Hb H\]和\[Hb tot\]均增加)； B(\[Hb O2\]和\[Hb tot\]增加,\[Hb H\]降低)；C(\[Hb O2\]和\[Hb tot\]降低,\[Hb H\]增加)3种曲线类型。 结果窒息组中25例(25/34、73.5%)显示C型变化，对照组中28例(28/40、70.0%)显示A型变化，两组中A、C两型例数比较差异显著(P<0.05)。两组\[Hb O2\]和\[Hb tot\]数值变化幅度比较差异显著(P<0.05)。 结论窒息新生儿听觉刺激诱发相应皮层的神经活动时，显示局部脑血流量下降、氧合代谢降低，重度窒息儿更明显。     

“黄风湿”系列疗法——火针封闭治疗痛风石的疗效观察

痛风是一种由嘌呤代谢紊乱所致的疾病,日久不愈、反复发作则逐渐形成痛风石沉积。常规治疗对痛风石效果不明显。黄再军医院采用火针封闭疗法治疗痛风石36例,经临床观察治愈率为69.4%,显效率为25.0%,有效率为5.6%,总有效率达100%。