Vijayalakshmi Bodiga, Sesikeran Boindala, Udaykumar Putcha, Kalyanasundaram Subramaniam, Raghunath Manchala
Department of Pathology, National Institute of Nutrition, Indian Council of Medical Research, Jamai Osmania, Hyderabad-500007, Andhra Pradesh, India.
World J Gastroenterol. 2006 Feb 21;12(7):1078-85. doi: 10.3748/wjg.v12.i7.1078.
To investigate if cisplatin alters vitamin status and if VR modulates cisplatin induced intestinal apoptosis and oxidative stress in Wistar/NIN (WNIN) male rats.
Weanling, WNIN male rats (n = 12 per group) received adlibitum for 17 wk: control diet (20% protein) or the same with 50% vitamin restriction. They were then sub-divided into two groups of six rats each and administered cisplatin (2.61 mg/kg bodyweight) once a week for three wk or PBS (vehicle control). Intestinal epithelial cell (IEC) apoptosis was monitored by morphometry, Annexin-V binding, M30 cytodeath assay and DNA fragmentation. Structural and functional integrity of the villus were assessed by villus height/crypt depth ratio and activities of alkaline phosphatase, lys, ala-dipeptidyl amino-peptidase, respectively. To assess the probable mechanism(s) of altered apoptosis, oxidative stress parameters, caspase-3 activity, and expression of Bcl-2 and Bax were determined.
Cisplatin per se decreased plasma vitamin levels and they were the lowest in VR animals treated with cisplatin. As expected VR increased only villus apoptosis, whereas cisplatin increased stem cell apoptosis in the crypt. However, cisplatin treatment of VR rats increased apoptosis both in villus and crypt regions and was associated with higher levels of TBARS, protein carbonyls and caspase-3 activity, but lower GSH concentrations. VR induced decrease in Bcl-2 expression was further lowered by cisplatin. Bax expression, unaffected by VR was increased on cisplatin treatment. Mucosal functional integrity was severely compromised in cisplatin treated VR-rats.
Low intake of vitamins increases the sensitivity of rats to cisplatin and promotes intestinal epithelial cell apoptosis.
研究顺铂是否会改变维生素状态，以及维生素限制（VR）是否会调节顺铂诱导的Wistar/NIN（WNIN）雄性大鼠肠道细胞凋亡和氧化应激。
断乳的WNIN雄性大鼠（每组n = 12）自由进食17周：对照组饮食（20%蛋白质）或相同饮食但维生素限制50%。然后将它们分为两组，每组6只大鼠，每周一次给予顺铂（2.61 mg/kg体重），共3周，或给予PBS（溶剂对照）。通过形态学、膜联蛋白-V结合、M30细胞死亡检测和DNA片段化监测肠道上皮细胞（IEC）凋亡。分别通过绒毛高度/隐窝深度比以及碱性磷酸酶、赖氨酰、丙氨酰二肽基氨基肽酶的活性评估绒毛的结构和功能完整性。为了评估细胞凋亡改变的可能机制，测定氧化应激参数、半胱天冬酶-3活性以及Bcl-2和Bax的表达。
顺铂本身会降低血浆维生素水平，在接受顺铂治疗的维生素限制动物中维生素水平最低。如预期的那样，维生素限制仅增加绒毛细胞凋亡，而顺铂增加隐窝中的干细胞凋亡。然而，对维生素限制大鼠进行顺铂治疗会增加绒毛和隐窝区域的细胞凋亡，并与较高水平的硫代巴比妥酸反应物、蛋白质羰基和半胱天冬酶-3活性相关，但谷胱甘肽浓度较低。维生素限制诱导的Bcl-2表达降低在顺铂治疗后进一步降低。不受维生素限制影响的Bax表达在顺铂治疗后增加。在接受顺铂治疗的维生素限制大鼠中，黏膜功能完整性严重受损。
低维生素摄入量会增加大鼠对顺铂的敏感性，并促进肠道上皮细胞凋亡。
