苯磷硫胺在慢性糖尿病并发症中的预防作用。
Preventive effects of benfotiamine in chronic diabetic complications.
机构信息
Department of Pathology, The University of Western Ontario, London, ON, Canada.
出版信息
J Diabetes Investig. 2011 Apr 7;2(2):123-31. doi: 10.1111/j.2040-1124.2010.00077.x.
UNLABELLED
Aims/Introduction: In diabetes, increased oxidative stress as a result of damage to the electron transport chain can lead to tissue injury through upregulation of multiple vasoactive factors and extracellular matrix proteins. Benfotiamine, a lipid soluble thiamine derivative, through reducing mitochondrial superoxide production, blocks multiple pathways leading to tissue damage in hyperglycemia. We investigated if treatment with benfotiamine can prevent diabetes-induced production of vasoactive factors and extracellular matrix proteins, and whether such effects are tissue-specific. We also examined whether effects of benfotiamine are mediated through a nuclear mechanism.
MATERIALS AND METHODS
Retinal, renal and cardiac tissues from the streptozotocin-induced diabetic rats were examined after 4 months of follow up. mRNA levels were quantified using real-time RT-PCR. Protein levels were quantified using western blot and ELISA. Cellular expressions of 8-Hydroxy-2'-deoxyguanosine, a marker of nuclear DNA damage and Phospho-H2AX were also examined.
RESULTS
Diabetic animals showed hyperglycemia, glucosuria, increased urinary albumin/creatine ratio and loss of bodyweight. In the kidneys, heart and retina, diabetes caused increased production of endothelin-1, transforming growth factor-β1, vascular endothelial growth factor and augmented extracellular matrix proteins (collagen, fibronectin [FN] and its splice variant extradomain B containing FN), along with evidence of structural alterations, characteristic of diabetes-induced tissue damage. Such changes were prevented by benfotiamine. Furthermore, benfotiamine prevented diabetes-induced oxidative DNA damage and upregulation of p300, a histone acetylator and a transcription coactivator.
CONCLUSIONS
Data from the present study suggest that benfotiamine is effective in preventing tissue damage in diabetes and at the transcriptional level such effects are mediated through prevention of p300 upregulation. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00077.x, 2010).
目的/引言：在糖尿病中，由于电子传递链受损导致的氧化应激增加，可通过上调多种血管活性因子和细胞外基质蛋白导致组织损伤。苯磷硫胺是一种脂溶性硫胺衍生物，通过减少线粒体超氧化物的产生，阻断高血糖导致组织损伤的多个途径。我们研究了苯磷硫胺治疗是否可以预防糖尿病引起的血管活性因子和细胞外基质蛋白的产生，以及这种作用是否具有组织特异性。我们还检查了苯磷硫胺的作用是否通过核机制介导。
材料和方法
用链脲佐菌素诱导糖尿病大鼠 4 个月后，检测视网膜、肾脏和心脏组织。采用实时 RT-PCR 定量检测 mRNA 水平，用 Western blot 和 ELISA 定量检测蛋白水平。还检测了细胞核 DNA 损伤标志物 8-羟基-2'-脱氧鸟苷和磷酸化组蛋白 H2AX 的细胞表达。
结果
糖尿病动物表现为高血糖、糖尿、尿白蛋白/肌酐比值升高和体重减轻。在肾脏、心脏和视网膜中，糖尿病引起内皮素-1、转化生长因子-β1、血管内皮生长因子的产生增加，并增加细胞外基质蛋白（胶原、纤维连接蛋白[FN]及其包含外显子 B 的剪接变体），同时出现结构改变，这是糖尿病引起的组织损伤的特征。这些变化可被苯磷硫胺预防。此外，苯磷硫胺可预防糖尿病引起的氧化 DNA 损伤和 p300 的上调，p300 是一种组蛋白乙酰转移酶和转录共激活因子。
结论
本研究数据表明，苯磷硫胺可有效预防糖尿病引起的组织损伤，在转录水平上，这种作用是通过预防 p300 上调介导的。
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