ω-3多不饱和脂肪酸对荷瘤大鼠的作用
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摘要
研究背景:恶性肿瘤是现代医学的顽症,而肿瘤引起的机体消耗状态是它的重要特征之一,也是引起晚期肿瘤病人死亡的主要原因之一。蛋白质的丢失在肿瘤引起的机体消耗中至关重要,因为它不仅是机体的营养物质,更参与到机体的各项重要生命活动中。近年来国外的研究发现,ω-3 PUFA对肿瘤的生长有一定的抑制作用,并能部分改善肿瘤引起的机体消耗,但是国内相关研究不多,在静脉应用ω-3 PUFA方面尤为少见。
目的:通过建立肠外营养肿瘤大鼠模型,比较含ω-3 PUFA及ω-6 PUFA的不同肠外营养支持对大鼠肿瘤及机体消耗状态的影响,为临床治疗提供参考依据。
方法:将40只SPF级SD大鼠随机分成4组(正常大鼠组、肿瘤大鼠组、ω-3 PUFA组、ω-6 PUFA组),每组10只。对后三组大鼠腹腔接种walker 256肉瘤,建立肿瘤动物模型,再对需进行肠外营养干预的两组大鼠实施颈静脉置管手术,术后分别给予含ω-3 PUFA或ω-6 PUFA的脂肪乳剂,维持10天后处死各组大鼠,采集血液、肌肉标本。测定血清IL-6、TNF-α及白蛋白浓度,使用Western Blot方法测定肌肉Atrogin-1基因的蛋白表达量,并比较各组大鼠间的营养状况。
结果:ω-3 PUFA组的去腹水体重重于肿瘤大鼠组(186.10±8.43 g vs 174.80±8.61 g;P=0.022),与ω-6 PUFA组比较无统计学差异(186.10±8.43 g vs 178.00±9.92 g;P=0.094),ω-6 PUFA组与肿瘤大鼠组之间的去腹水体重无统计学差异(P=0.501)。ω-3PUFA组的体重丢失少于肿瘤大鼠组(-21.30±2.95 g vs-26.80±1.03 g;P=0.009),与ω-6PUFA组比较无统计学差异(-21.30±2.95 g vs-24.7±3.97 g;P=0.094),ω-6 PUFA组与肿瘤大鼠组之间的体重丢失无统计学差异(P=0.295)。ω-3 PUFA组腹水量与肿瘤大鼠组比较无统计学差异(43.40±2.76 g vs 44.1±2.18 g;P=0.470),但少于ω-6 PUFA组(43.40±2.76 g vs 45.70±2.45 g;P=0.022),ω-6 PUFA组与肿瘤大鼠组之间的腹水量无统计学差异(P=0.104)。ω-3 PUFA组的血清白蛋白浓度与ω-6 PUFA组比较无统计学差异(27.07+1.40g/L vs 26.17±3.44 g/L;P=0.453)。ω-3 PUFA组的血清IL-6浓度与肿瘤大鼠组比较无统计学差异(56.70±41.79 PG/ml vs 71.63±39.50 PG/ml:P=0.501),但明显低于ω-6 PUFA组(71.63±39.50 PG/ml vs 141.72±98.32 PG/ml:P=0.002),而ω-6 PUFA组的血清IL-6浓度则高于肿瘤大鼠组(P=0.010)。同样,(ω-3PUFA组的血清TNF-α浓度与肿瘤大鼠组比较无统计学差异(131.67±22.10 PG/ml vs141.27±19.37 PG/ml;P=0.441),但低于ω-6 PUFA组(131.67±22.10 PG/ml vs167.26±37.98 PG/ml;P=0.007),而ω-6 PUFA组的血清TNF-α浓度则高于肿瘤大鼠组(P=0.042)。ω-3 PUFA组Atrogin-1蛋白质的表达低于ω-6 PUFA组。
结论:1.相比ω-6 PUFA,运用ω-3 PUFA可以通过抑制NF-κB激活,降低荷瘤大鼠血清IL-6、TNF-α浓度。2.相比ω-6 PUFA,运用ω-3 PUFA存在改善荷瘤大鼠体重,减轻荷瘤大鼠体重丢失的趋势。3.运用ω-3 PUFA可使荷瘤大鼠的Atrogin-1基因蛋白质表达减少,提示它可能存在着某些机制影响泛素-蛋白水解系统,从而改善机体的骨骼肌蛋白的消耗。
Background:malignant tumor is an obstinate illness of modern medicine,and the body consumption caused by cancer is one of its pathognomonic features,and also is the main reason which leads patients' death.Protein loss is most important in cancer induced body consumption,because proteins are not only nutritive material,but also play an important role in many vital movements.Recent years,many researches show thatω-3 PUFA could inhibit tumor growth and improve cancer induced body consumption.There is few internal researches aboutω-3 PUFA therapy tumor,especially by the per-vein way.
Objective:This research administer tumor rats with omega-3 PUFA or omega-6 PUFA emulsion per-jugular vein to identify the effect of using omega-3 PUFA in oncotherapy.
Methods:We randomly divide 40 SPF SD Rats into 4 groups at 10 of each-group,named normal group,tumor group,ω-3 PUFA group andω-6 PUFA group.Inoculate the last three groups with walker 256 sarcoma cell to set an animal model.After 4 days we administerω-3 PUFA group andω-6 PUFA group with corresponding fat emulsion,keep on 10 days. At the end of the 14 day experiment stage,we kill all 40 rats,gather blood and muscle.We determine the concentration of IL-6,TNF-αand albumin in serum.And determine the Atrogin-1 gene protein expression by Western Blot.During the 14 day experiment stage we weight these rats on alternate day.Than compare the different effect of this tow fat emulsion.
Results:the weight without ascitic fluid ofω-3 PUFA group is heavier than tumor group (186.10±3:8.43g vs 174.80±8.61g;P=0.022),and is no statistical difference withω-6 PUFA group(186.10±8.43g vs 178.00±9.92g;P=0.094).There is no statistical difference between tumor group andω-6 PUFA group's weight without ascitic fluid(P=0.501).The weight loss ofω-3 PUFA group is less than tumor group(-21.30±2.95g vs -26.80±1.03g;P=0.009), and is no statistical difference withω-6 PUFA group(-21.30±2.95g vs -24.7±3.97g; P=0.094).There is no statistical difference between tumor group andω-6 PUFA group's weight loss(P=0.295).The ascitic fluid ofω-3 PUFA group and tumor group is no statistical difference(43.40±2.76g vs 44.10±2.18g;P=0.470),and it is same toω-6 PUFA group and tumor group's ascitic fluid(45.70±2.45g vs 44.10±2.18g;P=0.104).But the ascitic fluid ofω-3 PUFA group is less thanω-6 PUFA group(P= 0.022).The albumin ofω-3 PUFA group is higher thanω-6 PUFA group,but it's not statically significant (27.07±1.40 g/L vs 26.17±3.44 g/L;P= 0.453).The serum IL-6 concentration ofω-3 PUFA group is lower thanω-6 PUFA group(56.70±41.79PG/ml vs 141.72±98.32PG/ml; P=0.002),and is no statistical difference with tumor group(56.70±41.79PG/ml vs 71.63±39.50PG/ml;P=0.501).Butω-6 PUFA group's serum IL-6 concentration is higher than tumor group(P=0.010).The serum TNF-αconcentration ofω-3 PUFA group is lower thanω-6 PUFA group(131.67±22.10PG/ml vs 167.26±37.98PG/ml;P=0.007),and no statistical difference with tumor group(131.67±22.10PG/ml vs 141.27±19.37PG/ml; P=0.441).Butω-6 PUFA group's serum TNF-αconcentration is higher than tumor group (P=0.042).The Atrogin-1 gene protein expression ofω-3 PUFA group is lower thanω-6 PUFA group.
Conclusions:1.comparing toω-6 PUFA,ω-3 PUFA can reduce the serum concentration of IL-6 and TNF-αin tumor rats by inhibit the NF-κB active-pathway.2.comparing toω-6 PUFA,ω-3 PUFA can increase the des- ascitic-fluid-weight and improve the weight loss of tumor rats.3.ω-3 PUFA can down regulate the protein expression of Atrogin-1 gene in tumor rats' muscle,to hint there may be existing some possible mechanism influence the ubiquitinproteasome system,thus improve the body protein wasting.
目的:通过建立肠外营养肿瘤大鼠模型,比较含ω-3 PUFA及ω-6 PUFA的不同肠外营养支持对大鼠肿瘤及机体消耗状态的影响,为临床治疗提供参考依据。
方法:将40只SPF级SD大鼠随机分成4组(正常大鼠组、肿瘤大鼠组、ω-3 PUFA组、ω-6 PUFA组),每组10只。对后三组大鼠腹腔接种walker 256肉瘤,建立肿瘤动物模型,再对需进行肠外营养干预的两组大鼠实施颈静脉置管手术,术后分别给予含ω-3 PUFA或ω-6 PUFA的脂肪乳剂,维持10天后处死各组大鼠,采集血液、肌肉标本。测定血清IL-6、TNF-α及白蛋白浓度,使用Western Blot方法测定肌肉Atrogin-1基因的蛋白表达量,并比较各组大鼠间的营养状况。
结果:ω-3 PUFA组的去腹水体重重于肿瘤大鼠组(186.10±8.43 g vs 174.80±8.61 g;P=0.022),与ω-6 PUFA组比较无统计学差异(186.10±8.43 g vs 178.00±9.92 g;P=0.094),ω-6 PUFA组与肿瘤大鼠组之间的去腹水体重无统计学差异(P=0.501)。ω-3PUFA组的体重丢失少于肿瘤大鼠组(-21.30±2.95 g vs-26.80±1.03 g;P=0.009),与ω-6PUFA组比较无统计学差异(-21.30±2.95 g vs-24.7±3.97 g;P=0.094),ω-6 PUFA组与肿瘤大鼠组之间的体重丢失无统计学差异(P=0.295)。ω-3 PUFA组腹水量与肿瘤大鼠组比较无统计学差异(43.40±2.76 g vs 44.1±2.18 g;P=0.470),但少于ω-6 PUFA组(43.40±2.76 g vs 45.70±2.45 g;P=0.022),ω-6 PUFA组与肿瘤大鼠组之间的腹水量无统计学差异(P=0.104)。ω-3 PUFA组的血清白蛋白浓度与ω-6 PUFA组比较无统计学差异(27.07+1.40g/L vs 26.17±3.44 g/L;P=0.453)。ω-3 PUFA组的血清IL-6浓度与肿瘤大鼠组比较无统计学差异(56.70±41.79 PG/ml vs 71.63±39.50 PG/ml:P=0.501),但明显低于ω-6 PUFA组(71.63±39.50 PG/ml vs 141.72±98.32 PG/ml:P=0.002),而ω-6 PUFA组的血清IL-6浓度则高于肿瘤大鼠组(P=0.010)。同样,(ω-3PUFA组的血清TNF-α浓度与肿瘤大鼠组比较无统计学差异(131.67±22.10 PG/ml vs141.27±19.37 PG/ml;P=0.441),但低于ω-6 PUFA组(131.67±22.10 PG/ml vs167.26±37.98 PG/ml;P=0.007),而ω-6 PUFA组的血清TNF-α浓度则高于肿瘤大鼠组(P=0.042)。ω-3 PUFA组Atrogin-1蛋白质的表达低于ω-6 PUFA组。
结论:1.相比ω-6 PUFA,运用ω-3 PUFA可以通过抑制NF-κB激活,降低荷瘤大鼠血清IL-6、TNF-α浓度。2.相比ω-6 PUFA,运用ω-3 PUFA存在改善荷瘤大鼠体重,减轻荷瘤大鼠体重丢失的趋势。3.运用ω-3 PUFA可使荷瘤大鼠的Atrogin-1基因蛋白质表达减少,提示它可能存在着某些机制影响泛素-蛋白水解系统,从而改善机体的骨骼肌蛋白的消耗。
Background:malignant tumor is an obstinate illness of modern medicine,and the body consumption caused by cancer is one of its pathognomonic features,and also is the main reason which leads patients' death.Protein loss is most important in cancer induced body consumption,because proteins are not only nutritive material,but also play an important role in many vital movements.Recent years,many researches show thatω-3 PUFA could inhibit tumor growth and improve cancer induced body consumption.There is few internal researches aboutω-3 PUFA therapy tumor,especially by the per-vein way.
Objective:This research administer tumor rats with omega-3 PUFA or omega-6 PUFA emulsion per-jugular vein to identify the effect of using omega-3 PUFA in oncotherapy.
Methods:We randomly divide 40 SPF SD Rats into 4 groups at 10 of each-group,named normal group,tumor group,ω-3 PUFA group andω-6 PUFA group.Inoculate the last three groups with walker 256 sarcoma cell to set an animal model.After 4 days we administerω-3 PUFA group andω-6 PUFA group with corresponding fat emulsion,keep on 10 days. At the end of the 14 day experiment stage,we kill all 40 rats,gather blood and muscle.We determine the concentration of IL-6,TNF-αand albumin in serum.And determine the Atrogin-1 gene protein expression by Western Blot.During the 14 day experiment stage we weight these rats on alternate day.Than compare the different effect of this tow fat emulsion.
Results:the weight without ascitic fluid ofω-3 PUFA group is heavier than tumor group (186.10±3:8.43g vs 174.80±8.61g;P=0.022),and is no statistical difference withω-6 PUFA group(186.10±8.43g vs 178.00±9.92g;P=0.094).There is no statistical difference between tumor group andω-6 PUFA group's weight without ascitic fluid(P=0.501).The weight loss ofω-3 PUFA group is less than tumor group(-21.30±2.95g vs -26.80±1.03g;P=0.009), and is no statistical difference withω-6 PUFA group(-21.30±2.95g vs -24.7±3.97g; P=0.094).There is no statistical difference between tumor group andω-6 PUFA group's weight loss(P=0.295).The ascitic fluid ofω-3 PUFA group and tumor group is no statistical difference(43.40±2.76g vs 44.10±2.18g;P=0.470),and it is same toω-6 PUFA group and tumor group's ascitic fluid(45.70±2.45g vs 44.10±2.18g;P=0.104).But the ascitic fluid ofω-3 PUFA group is less thanω-6 PUFA group(P= 0.022).The albumin ofω-3 PUFA group is higher thanω-6 PUFA group,but it's not statically significant (27.07±1.40 g/L vs 26.17±3.44 g/L;P= 0.453).The serum IL-6 concentration ofω-3 PUFA group is lower thanω-6 PUFA group(56.70±41.79PG/ml vs 141.72±98.32PG/ml; P=0.002),and is no statistical difference with tumor group(56.70±41.79PG/ml vs 71.63±39.50PG/ml;P=0.501).Butω-6 PUFA group's serum IL-6 concentration is higher than tumor group(P=0.010).The serum TNF-αconcentration ofω-3 PUFA group is lower thanω-6 PUFA group(131.67±22.10PG/ml vs 167.26±37.98PG/ml;P=0.007),and no statistical difference with tumor group(131.67±22.10PG/ml vs 141.27±19.37PG/ml; P=0.441).Butω-6 PUFA group's serum TNF-αconcentration is higher than tumor group (P=0.042).The Atrogin-1 gene protein expression ofω-3 PUFA group is lower thanω-6 PUFA group.
Conclusions:1.comparing toω-6 PUFA,ω-3 PUFA can reduce the serum concentration of IL-6 and TNF-αin tumor rats by inhibit the NF-κB active-pathway.2.comparing toω-6 PUFA,ω-3 PUFA can increase the des- ascitic-fluid-weight and improve the weight loss of tumor rats.3.ω-3 PUFA can down regulate the protein expression of Atrogin-1 gene in tumor rats' muscle,to hint there may be existing some possible mechanism influence the ubiquitinproteasome system,thus improve the body protein wasting.
引文
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14. Crawford M, Galli C, Visioli F, Renaud S, Simopoulos AP, Spector AA. Role of plant-derived omega-3 fatty acids in human nutrition. Ann Nutr Metab 2000;44:263-265.
15. Hamid R. , Singh J. , Reddy B. S. & Cohen, L. A. (1999) Inhibition by dietary menhaden oil of cyclooxygenase-1 and -2 in N-nitrosomethylurea-induced rat mammary tumors. Int. J. Oncol. 14: 523 - 528.
16. Obata T. , Nagakura T. , Masaki T. , Maekawa K. & Yamashita K. (1999) Eicosapentaenoic acid inhibits prostaglandin D2 generation by inhibiting cyclo-oxygenase-2 in cultured human mast cells. Clin. Exp. Allergy 29: 1129-1135.
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19. Yang, P., Felix, E., Madden, T., Chan, D. & Newman, R. A. Relative formation of PGE2 and PGE3 by eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in human lung cancer cells. Proc. Am. Assoc. Cancer Res. 2002; 43: number 1533 (abs.).
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24. 7Babcock, T., Helton, W. S. & Espat, N. J. Eicosapentaenoic acid (EPA): an anti inflammatory ω-3 fat with potential clinical applications. Nutrition 2000; 16: 1116-1118.
25. Weihua, Z., Makela, S., Andersson, L. C., Salmi, S., Saji, S., Webster, J. I., Jensen, E. V., Nilsson, S., Warner, M. & Gustafsson, J.-A. A role for estrogen receptor β in the regulation of growth of the ventral prostate. Proc. Natl. Acad. Sci. U.S.A. 2001; 98:6330 - 6335.
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27. Choi YS, Goto S, Ikeda I, Sugano M. Effect of dietary n-3 polyunsaturated fatty acids on cholesterol synthesis and degradation in rats of different ages. Lipids 1989;24:45 - 50.
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