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首页> 外文期刊>Anaesthesia: Journal of the Association of Anaesthetists of Great Britain and Ireland >Quality and safety in healthcare revisited: A challenge to anaesthetists
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Quality and safety in healthcare revisited: A challenge to anaesthetists

机译：再谈医疗保健的质量和安全：麻醉师的挑战

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Dithiocarbamates (DTC), a sulfhydryl group containing compounds, are extensively used by humans that include metam and thiram due to their pesticide properties, and disulfiram (DSF) as an alcohol deterrent. We screened these DTC in an osteoblast viability assay. DSF exhibited the highest cytotoxicity (IC50 488nM). Loss in osteoblast viability and proliferation was due to induction of apoptosis via G1 arrest. DSF treatment to osteoblasts reduced glutathione (GSH) levels and exogenous addition of GSH prevented DSF-induced reactive oxygen species generation and osteoblast apoptosis. DSF also inhibited osteoblast differentiation in vitro and in vivo, and the effect was associated with inhibition of aldehyde dehydrogenase (ALDH) activity. Out of various ALDH isozymes, osteoblasts expressed only ALDH2 and DSF downregulated its transcript as well as activity. Alda-1, a specific activator of ALDH2, stimulated osteoblast differentiation. Subcutaneous injection of DSF over the calvarium of new born rats reduced the differentiation phenotype of calvarial osteoblasts but increased the mRNA levels of Runx-2 and osteocalcin. DSF treatment at a human-equivalent dose of 30 mg/kg p.o. to adult Sprague Dawley rats caused trabecular osteopenia and suppressed the formation of mineralized nodule by bone marrow stromal cells. Moreover, DSF diminished bone regeneration at the fracture site. In growing rats, DSF diminished growth plate height, primary and secondary spongiosa, mineralized osteoid and trabecular strength. Substantial decreased bone formation was also observed in the cortical site of these rats. We conclude that DSF has a strong osteopenia inducing effect by impairing osteoblast survival and differentiation due to the inhibition of ALDH2 function.
机译：二硫代氨基甲酸酯（DTC）是一种含巯基的化合物，由于其杀虫剂的特性，已广泛用于包括metam和thiram的人类，以及作为抗醇剂的disulfiram（DSF）。我们在成骨细胞活力测定中筛选了这些DTC。 DSF表现出最高的细胞毒性（IC50 488nM）。成骨细胞活力和增殖的丧失是由于通过G1阻滞诱导凋亡。 DSF处理成骨细胞可降低谷胱甘肽（GSH）水平，外源添加GSH可防止DSF诱导的活性氧生成和成骨细胞凋亡。 DSF还可以在体外和体内抑制成骨细胞的分化，其作用与抑制醛脱氢酶（ALDH）活性有关。在各种ALDH同工酶中，成骨细胞仅表达ALDH2，而DSF则下调其转录本和活性。 Alda-1是ALDH2的特异性激活剂，可刺激成骨细胞分化。在新生大鼠的颅骨上皮下注射DSF降低了颅骨成骨细胞的分化表型，但增加了Runx-2和骨钙素的mRNA水平。以人等效剂量30 mg / kg p.o进行DSF治疗。对成年的Sprague Dawley大鼠造成小梁性骨质减少，并抑制了骨髓基质细胞矿化结节的形成。此外，DSF减少了骨折部位的骨再生。在成年大鼠中，DSF降低了生长板高度，原发性和继发性海绵体，矿化的类骨质和小梁强度。在这些大鼠的皮质部位也观察到大量的骨形成减少。我们得出结论，由于抑制ALDH2功能，DSF通过损害成骨细胞存活和分化而具有很强的骨质减少症诱导作用。

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