红景天苷干预细胞衰老的分子机制及其防治骨质疏松活性的研究
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摘要
红景天(Rhodiola)为景天科红景天属多年生草本或亚灌木植物,是珍稀药用植物之一,被誉为“高原人参”。大量实验研究和临床观察表明,红景天具有多种药理活性,包括增加机体免疫力、刺激神经系统、抗应激反应、抗疲劳、抗缺氧等,具有典型的“适应原样”作用。红景天苷是红景天的主要活性成分之一。本实验室先前的研究表明红景天苷能有效延长果蝇寿命,有效下调D-半乳糖诱导的衰老小鼠体内晚期糖基化产物(AGE)水平,并显著改善小鼠的神经系统和免疫系统,展现出良好的抗衰老效应。本研究中,我们采用氧化应激诱导的早熟性衰老模型、复制性衰老及DNA损伤诱导的细胞衰老模型,从细胞和分子水平进一步探讨了红景天苷干预衰老的效应机制。
衰老的自由基学说是一个经典的衰老理论,研究表明红景天苷是一个抗氧化剂,但其抗氧化活性与其干预衰老的作用尚缺乏直接的实验依据。我们首先应用亚致死量的H202作用于年轻的2BS细胞(PD28)建立早熟性细胞衰老模型,同时采用红景天苷进行干预,结果表明红景天苷能显著逆转H202诱导的衰老样改变,包括细胞形态、SA-β-Gal染色阳性率、G1期阻滞以及衰老相关蛋白p53、p21和p16等的表达上调。红景天苷的这种保护作用具有一定的剂量依赖性,在5μM剂量下效果最佳。在该模型中,红景天苷的抗氧化活性也得到了证实,该化合物能显著下调模型细胞内ROS含量,5μM剂量下与2mM的NAC效果相当,同时下调MDA含量,对总SOD活力及蛋白表达也有一定的上调作用。与此同时,采用复制衰老性细胞衰老模型发现,红景天苷能显著延迟2BS细胞的复制性衰老,延长2BS细胞代龄8PD左右,对衰老表型的影响与其在H202模型中的相似。进一步的实验表明,在上述两个模型中采用NAC对比研究发现,红景天苷降调节p53、p21部分依赖于ROS水平的下降,尚有ROS非依赖机制。这可能的原因是红景天苷能直接调节DNA损伤修复的相关分子表达进而改变由此诱导的衰老样表型。为此,我们采用一种具有强烈DNA断裂活性的烯二炔类抗肿瘤抗生素——力达霉素(0.1nM)作用于年轻2BS细胞,在分子水平上,红景天苷能显著减少LDM诱导的DNA损伤程度——γ-H2AX水平,并且依然能逆转LDM引起的p53、p21表达上调；同时,对力达霉素诱导年轻2BS细胞产生的衰老样表型也有一定的逆转作用。此外,我们发现红景天苷能显著促进2BS细胞内线粒体的增殖,这可能是红景天苷发挥延缓衰老作用的新机制,并且其效果与相同剂量的白藜芦醇相当,但其机制可能不同于白藜芦醇,SIRT1抑制剂并不能抑制红景天苷的促线粒体增殖效应。这些研究表明红景天苷具有良好的延缓衰老的效应,该效应一方面与其抗氧化活性相关,一方面也与直接调节DNA损伤修复相关。
此外,骨质疏松是一种常见的与增龄密切相关的代谢性骨病,通过改善骨质代谢、增强成骨细胞的作用,最终达到恢复患者骨量水平为目的的治疗方案日益受到人们的重视。骨形态形成因子2(bmp2)基因的表达对于成骨细胞活性及其分化有着关键作用。我们通过一种以bmp2为靶点的新型抗骨质疏松药物筛选模型发现,红景天苷能有效上调小鼠颅骨细胞MC3T3-E1中BMP2的表达效应,表明该化合物可能具有一定的促骨形成能力。为证实红景天苷的这一效应,我们首先采用大鼠成骨细胞(ROB)和人成骨样细胞MG63研究了红景天苷对成骨细胞的影响,测定了红景天苷对成骨细胞增殖以及成骨性标志物碱性磷酸酶(ALP)和胶原合成的影响；进而采用雌性大鼠去势模型,观察了红景天苷对绝经后骨质疏松症模型的作用。体外研究表明,红景天苷作用于ROB细胞后,能显著促进成骨性的骨形成：MTT试验表明红景天苷促进细胞增殖达30%左右,ALP活性测定表明经红景天苷作用后其活性上调30%,3H-脯氨酸掺入试验表明红景天苷作用成骨细胞后其胶原合成增加1倍左右。在MG63细胞中我们观察到了相似的结果。此外,real-time RTPCR检测发现,MG63细胞内bmp2的mRNA表达水平在1μM和5μM的红景天苷作用48h后上调接近1倍；Western blot结果表明红景天苷能剂量依赖和时间依赖地上调ROB和MG63细胞中的BMP2蛋白表达水平。体内实验结果表明红景天苷能剂量依赖地抑制去势大鼠的骨量减少,与阳性药物雷洛昔芬效果相当,但对于破骨细胞的活性则无显著的抑制作用,间接地说明了红景天苷增加骨量不是依赖于抑制骨吸收而是促进成骨性的骨形成。这些结果显示了该化合物具有良好的防治骨质疏松的应用前景。
综上所述,本研究结果表明,红景天苷在细胞水平上具有显著的延缓衰老的作用,这一方面得益于红景天苷的抗氧化作用,能有效减少ROS引起的损伤,另一方面红景天苷本身可能具有促进DNA损伤修复的功能,从而抑制p53-p21衰老相关信号通路的活化。并且,红景天苷具有显著的促线粒体增殖的效应,这可能是其发挥延缓衰老作用的新机制。另外,红景天苷具有显著的上调bmp2的作用,能促进成骨性的骨生成,具有良好的抗骨质疏松病的应用前景。
Rhodiola rosea L, also known as "goden root", is a popular plant in traditional medicine in China and is reputable for improving depression, enhancing work performance, eliminating fatigue and treating symptoms of asthenia subsequent to intense physical and psychological stress. Due to these therapeutic properties, R. rosea L is considered to be one of the most active adaptogenic drugs. Salidroside and other salidroside-like compounds are considered to be most critical plant constitutes needed for the multiple therapeutic benefits of R. rosea L. Our previous study has shown that salidroside is able to extend the life span of drosophila and protect mouse against aging induced by D-galactose, showing considerable anti-aging effect. However, direct demonstration regarding the role of salidroside in anti-aging process in vitro and relevant molecular mechanisms is still deficient.
In this study, we first selected the H2O2-induced premature senescence model in human fetal lung diploid fibroblasts (2BS cells) to investigate whether salidroside directly protects the cells against aging in vitro and to illustrate the associated molecular mechanisms. We found that salidroside considerably reverses the senescence-like phenotypes in the oxidant challenged model, which include morphological alterations, G1 phase arrest, positive SA-β-gal staining, as well as increase of senescence-associated molecules expression such as p53, p21 and p16. The protection occurs in a tightly dose-dependent manner, with 5μM offering best efficacy under most cases. The proposed antioxidant property of the compound was confirmed in this cellular system, evidenced by ROS scavenging, MDA decreasing as well as T-SOD increasing activity, and thus at least partially is accountable for the protection of the compound against cellular premature senescence. Meanwhile, similar protection of salidroside against replicative senescence model was observed as well and it was able to increase cumulative population doublings (CPDs) of 2BS by at least 8 PDs by the supplementation to the medium from early PD. Interestingly, the regulation of corresponding molecular markers by salidroside involves ROS-independent mechanisms when compared with NAC in above two models. One possibility for such phenomena could be that salidroside may directly regulate ROS-irrelevant DNA damage system that initiates the associated molecular changes resulting in senescence-like phenotypes. To confirm this, we used Lidamycin, a potent radiomimetic anti-tumor antibiotic and senescence inducer to induce DNA damaging response in 2BS cells and test the regulation of salidroside accordingly. Similarly, we observed the protection of salidroside against DNA damage response as evidenced by down-regulation of p53 protein and y-H2AX foci after Lidamycin exposure. As anticipated, the senescence-like phenotypes in young 2BS induced by Lidamycin are also partly reversed by the salidroside. Moreover, stimulation of mitochondria biogenesis is found to be another novel property of the compound. Notably, the stimulatory effect of salidroside on mitochondrial proliferation is comparable to that of resveratrol in late PD 2BS cells, while the mode of action for this compound may be different from that of resveratrol. These findings present salidroside as an attractive and bio-safe agent with the potential to retard aging process and more importantly, may attenuate age-related diseases in humans.
In another part of work, we studied the protective role of salidroside against osteoporosis. Many observations clearly indicate the high potency of BMP2 as an inducer of osteogenesis which contributes to be a novel therapeutic target for diseases associated with bone loss, especially in menopausal and postmenopausal women. A considerable up-regulation of bmp2 expression by salidroside is observed in a high-throughput screening model in which a firefly luciferase reporter gene driven by the mouse bmp2 promoter has been transfected to clonal murine calvarial MC3T3-E1 cells, which indicates the possible stimulatory effect on bone formation of this compound. To confirm this effect, rat osteoblasts (ROB) and human osteoblast-like MG63 cells as well as an ovariectomized-osteoporosis (OVX-OP) rat model were used. Results in ROB indicate that salidroside increases the osteoblast viability, the alkaline phosphatase (ALP) activity and bone collagen synthesis by about 1.3,1.3 and 1.9 fold, respectively. Similar results were also observed in MG63 cells. Besides, the BMP2 expression at both mRNA and protein level is significantly elevated in response to salidroside in ROB and MG63 cells detected by real-time PCR as well as western blot analysis, repectively. Furthermore, our in vivo data demonstrates that salidroside significantly reverses the bone loss in ovariectomized rats, which is comparable to that of raloxifene, a clinical drug for prevention and therapy in menopausal and postmenopausal women. Interestingly, salidroside is observed to mildly inhibit the activity of osteoclasts at lower doses rather than higher doses, which was different from that of raloxifene. This finding indicates indirectly that salidroside elevated the bone mass in ovariectomized rats mainly due to its stimulatory effect on bone formation rather than the inhibition of bone resorption. In conclusion, salidroside is a potent BMP2 activator that stimulates bone formation and thus could be a potential anti-osteoporosis drug.
Taken together, our work provide evidences supporting that salidroside, an active component of R. rosea L. extracts that has been generally recognized as bio-safe, exerts protective effects against cellular senescence in replicative and stess-induced models. The main mode of action for the anti-aging regulation of salidroside involves both ROS-dependent and ROS-independent mechanisms. The stimulatory effect of salidroside on mitochondria biogenesis, and on BMP2 expression as well, may be novel mechanisms for its benefit in delaying aging as well as age-related diseases such as osteoporosis.
衰老的自由基学说是一个经典的衰老理论,研究表明红景天苷是一个抗氧化剂,但其抗氧化活性与其干预衰老的作用尚缺乏直接的实验依据。我们首先应用亚致死量的H202作用于年轻的2BS细胞(PD28)建立早熟性细胞衰老模型,同时采用红景天苷进行干预,结果表明红景天苷能显著逆转H202诱导的衰老样改变,包括细胞形态、SA-β-Gal染色阳性率、G1期阻滞以及衰老相关蛋白p53、p21和p16等的表达上调。红景天苷的这种保护作用具有一定的剂量依赖性,在5μM剂量下效果最佳。在该模型中,红景天苷的抗氧化活性也得到了证实,该化合物能显著下调模型细胞内ROS含量,5μM剂量下与2mM的NAC效果相当,同时下调MDA含量,对总SOD活力及蛋白表达也有一定的上调作用。与此同时,采用复制衰老性细胞衰老模型发现,红景天苷能显著延迟2BS细胞的复制性衰老,延长2BS细胞代龄8PD左右,对衰老表型的影响与其在H202模型中的相似。进一步的实验表明,在上述两个模型中采用NAC对比研究发现,红景天苷降调节p53、p21部分依赖于ROS水平的下降,尚有ROS非依赖机制。这可能的原因是红景天苷能直接调节DNA损伤修复的相关分子表达进而改变由此诱导的衰老样表型。为此,我们采用一种具有强烈DNA断裂活性的烯二炔类抗肿瘤抗生素——力达霉素(0.1nM)作用于年轻2BS细胞,在分子水平上,红景天苷能显著减少LDM诱导的DNA损伤程度——γ-H2AX水平,并且依然能逆转LDM引起的p53、p21表达上调；同时,对力达霉素诱导年轻2BS细胞产生的衰老样表型也有一定的逆转作用。此外,我们发现红景天苷能显著促进2BS细胞内线粒体的增殖,这可能是红景天苷发挥延缓衰老作用的新机制,并且其效果与相同剂量的白藜芦醇相当,但其机制可能不同于白藜芦醇,SIRT1抑制剂并不能抑制红景天苷的促线粒体增殖效应。这些研究表明红景天苷具有良好的延缓衰老的效应,该效应一方面与其抗氧化活性相关,一方面也与直接调节DNA损伤修复相关。
此外,骨质疏松是一种常见的与增龄密切相关的代谢性骨病,通过改善骨质代谢、增强成骨细胞的作用,最终达到恢复患者骨量水平为目的的治疗方案日益受到人们的重视。骨形态形成因子2(bmp2)基因的表达对于成骨细胞活性及其分化有着关键作用。我们通过一种以bmp2为靶点的新型抗骨质疏松药物筛选模型发现,红景天苷能有效上调小鼠颅骨细胞MC3T3-E1中BMP2的表达效应,表明该化合物可能具有一定的促骨形成能力。为证实红景天苷的这一效应,我们首先采用大鼠成骨细胞(ROB)和人成骨样细胞MG63研究了红景天苷对成骨细胞的影响,测定了红景天苷对成骨细胞增殖以及成骨性标志物碱性磷酸酶(ALP)和胶原合成的影响；进而采用雌性大鼠去势模型,观察了红景天苷对绝经后骨质疏松症模型的作用。体外研究表明,红景天苷作用于ROB细胞后,能显著促进成骨性的骨形成：MTT试验表明红景天苷促进细胞增殖达30%左右,ALP活性测定表明经红景天苷作用后其活性上调30%,3H-脯氨酸掺入试验表明红景天苷作用成骨细胞后其胶原合成增加1倍左右。在MG63细胞中我们观察到了相似的结果。此外,real-time RTPCR检测发现,MG63细胞内bmp2的mRNA表达水平在1μM和5μM的红景天苷作用48h后上调接近1倍；Western blot结果表明红景天苷能剂量依赖和时间依赖地上调ROB和MG63细胞中的BMP2蛋白表达水平。体内实验结果表明红景天苷能剂量依赖地抑制去势大鼠的骨量减少,与阳性药物雷洛昔芬效果相当,但对于破骨细胞的活性则无显著的抑制作用,间接地说明了红景天苷增加骨量不是依赖于抑制骨吸收而是促进成骨性的骨形成。这些结果显示了该化合物具有良好的防治骨质疏松的应用前景。
综上所述,本研究结果表明,红景天苷在细胞水平上具有显著的延缓衰老的作用,这一方面得益于红景天苷的抗氧化作用,能有效减少ROS引起的损伤,另一方面红景天苷本身可能具有促进DNA损伤修复的功能,从而抑制p53-p21衰老相关信号通路的活化。并且,红景天苷具有显著的促线粒体增殖的效应,这可能是其发挥延缓衰老作用的新机制。另外,红景天苷具有显著的上调bmp2的作用,能促进成骨性的骨生成,具有良好的抗骨质疏松病的应用前景。
Rhodiola rosea L, also known as "goden root", is a popular plant in traditional medicine in China and is reputable for improving depression, enhancing work performance, eliminating fatigue and treating symptoms of asthenia subsequent to intense physical and psychological stress. Due to these therapeutic properties, R. rosea L is considered to be one of the most active adaptogenic drugs. Salidroside and other salidroside-like compounds are considered to be most critical plant constitutes needed for the multiple therapeutic benefits of R. rosea L. Our previous study has shown that salidroside is able to extend the life span of drosophila and protect mouse against aging induced by D-galactose, showing considerable anti-aging effect. However, direct demonstration regarding the role of salidroside in anti-aging process in vitro and relevant molecular mechanisms is still deficient.
In this study, we first selected the H2O2-induced premature senescence model in human fetal lung diploid fibroblasts (2BS cells) to investigate whether salidroside directly protects the cells against aging in vitro and to illustrate the associated molecular mechanisms. We found that salidroside considerably reverses the senescence-like phenotypes in the oxidant challenged model, which include morphological alterations, G1 phase arrest, positive SA-β-gal staining, as well as increase of senescence-associated molecules expression such as p53, p21 and p16. The protection occurs in a tightly dose-dependent manner, with 5μM offering best efficacy under most cases. The proposed antioxidant property of the compound was confirmed in this cellular system, evidenced by ROS scavenging, MDA decreasing as well as T-SOD increasing activity, and thus at least partially is accountable for the protection of the compound against cellular premature senescence. Meanwhile, similar protection of salidroside against replicative senescence model was observed as well and it was able to increase cumulative population doublings (CPDs) of 2BS by at least 8 PDs by the supplementation to the medium from early PD. Interestingly, the regulation of corresponding molecular markers by salidroside involves ROS-independent mechanisms when compared with NAC in above two models. One possibility for such phenomena could be that salidroside may directly regulate ROS-irrelevant DNA damage system that initiates the associated molecular changes resulting in senescence-like phenotypes. To confirm this, we used Lidamycin, a potent radiomimetic anti-tumor antibiotic and senescence inducer to induce DNA damaging response in 2BS cells and test the regulation of salidroside accordingly. Similarly, we observed the protection of salidroside against DNA damage response as evidenced by down-regulation of p53 protein and y-H2AX foci after Lidamycin exposure. As anticipated, the senescence-like phenotypes in young 2BS induced by Lidamycin are also partly reversed by the salidroside. Moreover, stimulation of mitochondria biogenesis is found to be another novel property of the compound. Notably, the stimulatory effect of salidroside on mitochondrial proliferation is comparable to that of resveratrol in late PD 2BS cells, while the mode of action for this compound may be different from that of resveratrol. These findings present salidroside as an attractive and bio-safe agent with the potential to retard aging process and more importantly, may attenuate age-related diseases in humans.
In another part of work, we studied the protective role of salidroside against osteoporosis. Many observations clearly indicate the high potency of BMP2 as an inducer of osteogenesis which contributes to be a novel therapeutic target for diseases associated with bone loss, especially in menopausal and postmenopausal women. A considerable up-regulation of bmp2 expression by salidroside is observed in a high-throughput screening model in which a firefly luciferase reporter gene driven by the mouse bmp2 promoter has been transfected to clonal murine calvarial MC3T3-E1 cells, which indicates the possible stimulatory effect on bone formation of this compound. To confirm this effect, rat osteoblasts (ROB) and human osteoblast-like MG63 cells as well as an ovariectomized-osteoporosis (OVX-OP) rat model were used. Results in ROB indicate that salidroside increases the osteoblast viability, the alkaline phosphatase (ALP) activity and bone collagen synthesis by about 1.3,1.3 and 1.9 fold, respectively. Similar results were also observed in MG63 cells. Besides, the BMP2 expression at both mRNA and protein level is significantly elevated in response to salidroside in ROB and MG63 cells detected by real-time PCR as well as western blot analysis, repectively. Furthermore, our in vivo data demonstrates that salidroside significantly reverses the bone loss in ovariectomized rats, which is comparable to that of raloxifene, a clinical drug for prevention and therapy in menopausal and postmenopausal women. Interestingly, salidroside is observed to mildly inhibit the activity of osteoclasts at lower doses rather than higher doses, which was different from that of raloxifene. This finding indicates indirectly that salidroside elevated the bone mass in ovariectomized rats mainly due to its stimulatory effect on bone formation rather than the inhibition of bone resorption. In conclusion, salidroside is a potent BMP2 activator that stimulates bone formation and thus could be a potential anti-osteoporosis drug.
Taken together, our work provide evidences supporting that salidroside, an active component of R. rosea L. extracts that has been generally recognized as bio-safe, exerts protective effects against cellular senescence in replicative and stess-induced models. The main mode of action for the anti-aging regulation of salidroside involves both ROS-dependent and ROS-independent mechanisms. The stimulatory effect of salidroside on mitochondria biogenesis, and on BMP2 expression as well, may be novel mechanisms for its benefit in delaying aging as well as age-related diseases such as osteoporosis.
引文
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