锁阳多糖延缓衰老的作用及端粒酶调控机制研究
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摘要
目的:本文研究锁阳抗衰老作用的主要有效部位,对活性成分锁阳多糖(Cynomorium songaricum polysaccharides,CSP)从形态学、自由基、免疫等多个角度研究其抗衰老作用及端粒、端粒酶调控机制。实验通过比较锁阳不同溶液提取物对D-半乳糖致衰小鼠的抗氧化、抗衰老作用,探讨锁阳抗衰老的有效部位和有效提取部位的主要有效成分;研究CSP提取精制工艺,为工业化生产提供依据;研究CSP对衰老模型小鼠免疫功能的影响和对端粒酶活性的影响;CSP对衰老模型小鼠血液及脑组织细胞染色体末端端粒长度和小鼠骨髓及睾丸组织端粒酶逆转录酶(telomerase reverse transcriptase,TERT)mRNA表达的影响,观察其抗衰老免疫机制及端粒酶机制,为锁阳多糖的保健作用和药用价值的开发和利用提供依据。
方法:制备锁阳水、无水乙醇、乙酸乙酯提取物混悬液,应用HPLC法,苯酚-硫酸法测定不同提取物中所含的主要活性成分儿茶素、熊果酸和多糖。建立小鼠衰老模型,以锁阳的不同提取液连续给药56 d,取血并测定其过氧化氢酶(CAT)、总抗氧化能力(TAOC)、谷胱甘肽过氧化物酶(GSH-PX)三项指标。
昆明小鼠腹腔注射D-半乳糖500 mg·kg~(-1)·d~(-1)制作衰老模型,CSP低(20mg·kg~(-1))、中(40 mg·kg~(-1))、高(80 mg·kg~(-1))CSP治疗,连续56天后,测定脾脏、胸腺脏器系数,应用MTT法测定骨髓细胞增殖数,通过体内淋巴细胞转化率和腹腔巨噬细胞吞噬率观察非特异性免疫功能。应用Elisa法测定睾丸组织端粒酶的活性。
昆明小鼠D-半乳糖制作衰老模型,动物分成正常组、模型组、CSP低、中、高剂量、黄芪多糖(40 mg·kg~(-1))各组,连续灌胃给药56 d后,应用荧光实时定量PCR方法测定各组小鼠血细胞及脑组织端粒的相对长度,应用荧光实时定量RT-PCR法测定骨髓及睾丸组织TERT mRNA的表达。
结果:锁阳水提物主要含多糖类成分,含65.64%,不含熊果酸,儿茶素含量也极低,为0.026%。衡量CSP的多糖得率和纯度,选择水提醇沉法提取锁阳多糖,精制后CSP得率为1.24%,多糖含量93.2%,平均分子质量1.29×10~5。
锁阳不同提取物均具有一定的抗氧化、抗衰老能力,其中水、醇提物作用最显著。锁阳水提物的CAT、GSH-PX、TAOC三个抗氧化指标同模型组相比均有统计学差异,接近正常组水平。醇提物CAT、GSH-PX明显高于模型组,对TAOC影响不明显。酯提物只能提高GSH-PX,对另外两个指标影响很小。
较高剂量的CSP能够提高衰老小鼠免疫功能。CSP高、中、低剂量骨髓细胞增殖数分别为(0.44±0.09);(0.43±0.08);(0.39±0.10),各组同衰老组(0.32±0.11)相比均有明显差异(P＜0.0 5)。高剂量CSP能够显著提高衰老小鼠体内淋巴细胞转化率(P＜0.01)和腹腔巨噬细胞吞噬率(P＜0.05)。中、高剂量CSP组小鼠睾丸组织端粒酶阳性率明显增加。
高、中剂量CSP组血细胞相对端粒长度T/S ratio分别为(1.64±0.36),(1.33±0.28),同衰老组(1.01±0.13)相比,有极显著性差异(P＜0.01),脑组织高、中、低剂量CSP组分别为(3.34±0.58),(2.30±0.75),(1.55±0.58),同衰老组(1.04±0.33)相比,有极显著性差异(P＜0.01)。
骨髓中相对TERT/GAPDH基因表达各给药组均值均高于衰老模型组,但只有CSP高剂量组(1.0129±0.0106)显著高于衰老模型组(1.0000±0.0021)(P＜0.05)。在睾丸中低(1.0004±0.0002)、中(1.0006±0.0003)、高剂量CSP(1.0009±0.0007)和黄芪多糖对照组(1.0005±0.0006)相对TERT/GAPDH基因表达均显著高于衰老模型组(1.0000±0.0003)(P＜0.05)。
结论:CSP可以提高衰老小鼠免疫功能,并可以通过促进TERT的转录过程,提高端粒酶活性,抑制染色体末端端粒长度的缩短,从而起到延缓组织细胞的衰老进程的作用。
论文从衰老的自由基、免疫、端粒三大机制入手,多个角度研究其抗衰老的作用及机制,为锁阳的推广应用和锁阳多糖的研发和应用提供了基础,也为中药锁阳及CSP的养生保健、提高老年人生活质量提供了依据。论文将分子生物学理论和技术应用于传统补肾中药的抗衰老研究,为补肾中药的研究提供了一个新的思路。
Objective:Cynomorium songaricum polysaccharides(CSP) are the main components of Cynomorium songaricum Rupr.(CSR).The anti-senescence effects of CSP and the regulation mechanism of telomerase were studied.
Effects of anti-oxidation and anti-aging of different extractions of CSR were compared to explore which components were the most effective.The effects of CSP on immune function and the activity of telomerase,as well as the telomere length in blood and brain tissues and the expression of telomerase reverse transcriptase(TERT) mRNA in bone marrow and testis of the D-galactose-induced aging mice were studied.
Methods:D-gal-induced aging mice were fed by gavages on the extractions by water,ethanol,and ethyl acetate of CSR respectively. After 8 weeks,the activities of CAT,TAOC,and GSH-PX in blood were determined.
Kunming mice were intraperitoneal injected D-galactose(500 mg·kg~(-1)·d~(-1))to make the aging models,and different dosages of CSP were given by gavages for 56 days.Spleen coefficient and thymus coefficient were determined.MTT method was used to detect the proliferated number of the bone marrow cells.Lymphocyte transformation rate and peritoneal macrophage phagocytic rate in vivo were tested.The activity of telomerase in the testis of the mile mice were detected by Elisa method.
Kunming mice were intraperitoneal injected D-galactose to make the aging models,and different dosages of CSP(20,40,80 mg·kg~(-1)) were given by garages for 56 days.The average length of telomere was determined by real-time fluorescence quantitative PCR.The expression of TERT mRNA was determined by real-time fluorescence quantitative RT-PCR.
Results:The water and ethanol extraction of CSR had significantly abilities of anti-oxidation and anti-aging process.Compared with the aging group,activities of CAT,TAOC,and GSH-PX in aging mice fed on water extraction of CSR increased significantly.CSP water extraction contained 65.64%polysaccharide. Refined CSP with the content of 93.2%,the average molecule weight of which was 1.29×10~5。
CSP could increase immune function of the aging mice.Low, middle and high dosages of CSP could cause a significant increase of the proliferated number of the bone marrow cells in the aged mice (P＜0.01).High dosages of CSP could significantly increase the lymphocyte transformation rate(P＜0.01) and the peritoneal macrophage phagocytic rate(P＜0.05).High and middle dosages of CSP could significantly increase the activity of telomerase.
Relative T/S ratio of group high and middle dosages of CSP in blood were(1.64±0.36),(1.33±0.28),respectively,higher than the group of senescence(1.01±0.13)(P＜0.01).Values of the group of high, middle,and low dosages of CSP in brain tissues were(3.34±0.58), (2.30±0.75),(1.55±0.58),significantly higher than the group of senescence(1.04±0.33)(P＜0.01).
The mean of the Relative TERT/ GAPDH ratio in bone marrow of all of the polysaccharides groups were higher than that of the senescence model group.But,only the high dosage CSP(1.0129±0.0106) was significantly higher than the senescence model group(1.0000±0.0021) (P＜0.05).Values of the group of high,middle,and low dosages of CSP in testis were(1.0004±0.0002),(1.0006±0.0003),(1.0009±0.0007), significantly higher than the group of senescence(1.04±0.33) (P＜0.05).
Conclusion:CSP can exert the anti-aging effects by promoting the process of transcription,prolonging the telomere length,and increasing the activity of senescence mice.The research on mechanism of telomerase regulate the effect of CSP of anti-senescence will provide some evidence for CSP to applying in the clinical to prolong life-span.
方法:制备锁阳水、无水乙醇、乙酸乙酯提取物混悬液,应用HPLC法,苯酚-硫酸法测定不同提取物中所含的主要活性成分儿茶素、熊果酸和多糖。建立小鼠衰老模型,以锁阳的不同提取液连续给药56 d,取血并测定其过氧化氢酶(CAT)、总抗氧化能力(TAOC)、谷胱甘肽过氧化物酶(GSH-PX)三项指标。
昆明小鼠腹腔注射D-半乳糖500 mg·kg~(-1)·d~(-1)制作衰老模型,CSP低(20mg·kg~(-1))、中(40 mg·kg~(-1))、高(80 mg·kg~(-1))CSP治疗,连续56天后,测定脾脏、胸腺脏器系数,应用MTT法测定骨髓细胞增殖数,通过体内淋巴细胞转化率和腹腔巨噬细胞吞噬率观察非特异性免疫功能。应用Elisa法测定睾丸组织端粒酶的活性。
昆明小鼠D-半乳糖制作衰老模型,动物分成正常组、模型组、CSP低、中、高剂量、黄芪多糖(40 mg·kg~(-1))各组,连续灌胃给药56 d后,应用荧光实时定量PCR方法测定各组小鼠血细胞及脑组织端粒的相对长度,应用荧光实时定量RT-PCR法测定骨髓及睾丸组织TERT mRNA的表达。
结果:锁阳水提物主要含多糖类成分,含65.64%,不含熊果酸,儿茶素含量也极低,为0.026%。衡量CSP的多糖得率和纯度,选择水提醇沉法提取锁阳多糖,精制后CSP得率为1.24%,多糖含量93.2%,平均分子质量1.29×10~5。
锁阳不同提取物均具有一定的抗氧化、抗衰老能力,其中水、醇提物作用最显著。锁阳水提物的CAT、GSH-PX、TAOC三个抗氧化指标同模型组相比均有统计学差异,接近正常组水平。醇提物CAT、GSH-PX明显高于模型组,对TAOC影响不明显。酯提物只能提高GSH-PX,对另外两个指标影响很小。
较高剂量的CSP能够提高衰老小鼠免疫功能。CSP高、中、低剂量骨髓细胞增殖数分别为(0.44±0.09);(0.43±0.08);(0.39±0.10),各组同衰老组(0.32±0.11)相比均有明显差异(P＜0.0 5)。高剂量CSP能够显著提高衰老小鼠体内淋巴细胞转化率(P＜0.01)和腹腔巨噬细胞吞噬率(P＜0.05)。中、高剂量CSP组小鼠睾丸组织端粒酶阳性率明显增加。
高、中剂量CSP组血细胞相对端粒长度T/S ratio分别为(1.64±0.36),(1.33±0.28),同衰老组(1.01±0.13)相比,有极显著性差异(P＜0.01),脑组织高、中、低剂量CSP组分别为(3.34±0.58),(2.30±0.75),(1.55±0.58),同衰老组(1.04±0.33)相比,有极显著性差异(P＜0.01)。
骨髓中相对TERT/GAPDH基因表达各给药组均值均高于衰老模型组,但只有CSP高剂量组(1.0129±0.0106)显著高于衰老模型组(1.0000±0.0021)(P＜0.05)。在睾丸中低(1.0004±0.0002)、中(1.0006±0.0003)、高剂量CSP(1.0009±0.0007)和黄芪多糖对照组(1.0005±0.0006)相对TERT/GAPDH基因表达均显著高于衰老模型组(1.0000±0.0003)(P＜0.05)。
结论:CSP可以提高衰老小鼠免疫功能,并可以通过促进TERT的转录过程,提高端粒酶活性,抑制染色体末端端粒长度的缩短,从而起到延缓组织细胞的衰老进程的作用。
论文从衰老的自由基、免疫、端粒三大机制入手,多个角度研究其抗衰老的作用及机制,为锁阳的推广应用和锁阳多糖的研发和应用提供了基础,也为中药锁阳及CSP的养生保健、提高老年人生活质量提供了依据。论文将分子生物学理论和技术应用于传统补肾中药的抗衰老研究,为补肾中药的研究提供了一个新的思路。
Objective:Cynomorium songaricum polysaccharides(CSP) are the main components of Cynomorium songaricum Rupr.(CSR).The anti-senescence effects of CSP and the regulation mechanism of telomerase were studied.
Effects of anti-oxidation and anti-aging of different extractions of CSR were compared to explore which components were the most effective.The effects of CSP on immune function and the activity of telomerase,as well as the telomere length in blood and brain tissues and the expression of telomerase reverse transcriptase(TERT) mRNA in bone marrow and testis of the D-galactose-induced aging mice were studied.
Methods:D-gal-induced aging mice were fed by gavages on the extractions by water,ethanol,and ethyl acetate of CSR respectively. After 8 weeks,the activities of CAT,TAOC,and GSH-PX in blood were determined.
Kunming mice were intraperitoneal injected D-galactose(500 mg·kg~(-1)·d~(-1))to make the aging models,and different dosages of CSP were given by gavages for 56 days.Spleen coefficient and thymus coefficient were determined.MTT method was used to detect the proliferated number of the bone marrow cells.Lymphocyte transformation rate and peritoneal macrophage phagocytic rate in vivo were tested.The activity of telomerase in the testis of the mile mice were detected by Elisa method.
Kunming mice were intraperitoneal injected D-galactose to make the aging models,and different dosages of CSP(20,40,80 mg·kg~(-1)) were given by garages for 56 days.The average length of telomere was determined by real-time fluorescence quantitative PCR.The expression of TERT mRNA was determined by real-time fluorescence quantitative RT-PCR.
Results:The water and ethanol extraction of CSR had significantly abilities of anti-oxidation and anti-aging process.Compared with the aging group,activities of CAT,TAOC,and GSH-PX in aging mice fed on water extraction of CSR increased significantly.CSP water extraction contained 65.64%polysaccharide. Refined CSP with the content of 93.2%,the average molecule weight of which was 1.29×10~5。
CSP could increase immune function of the aging mice.Low, middle and high dosages of CSP could cause a significant increase of the proliferated number of the bone marrow cells in the aged mice (P＜0.01).High dosages of CSP could significantly increase the lymphocyte transformation rate(P＜0.01) and the peritoneal macrophage phagocytic rate(P＜0.05).High and middle dosages of CSP could significantly increase the activity of telomerase.
Relative T/S ratio of group high and middle dosages of CSP in blood were(1.64±0.36),(1.33±0.28),respectively,higher than the group of senescence(1.01±0.13)(P＜0.01).Values of the group of high, middle,and low dosages of CSP in brain tissues were(3.34±0.58), (2.30±0.75),(1.55±0.58),significantly higher than the group of senescence(1.04±0.33)(P＜0.01).
The mean of the Relative TERT/ GAPDH ratio in bone marrow of all of the polysaccharides groups were higher than that of the senescence model group.But,only the high dosage CSP(1.0129±0.0106) was significantly higher than the senescence model group(1.0000±0.0021) (P＜0.05).Values of the group of high,middle,and low dosages of CSP in testis were(1.0004±0.0002),(1.0006±0.0003),(1.0009±0.0007), significantly higher than the group of senescence(1.04±0.33) (P＜0.05).
Conclusion:CSP can exert the anti-aging effects by promoting the process of transcription,prolonging the telomere length,and increasing the activity of senescence mice.The research on mechanism of telomerase regulate the effect of CSP of anti-senescence will provide some evidence for CSP to applying in the clinical to prolong life-span.
引文
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