Research Progress on Osteogenic Differentiation of Apical Papilla Stem Cells
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摘要: 根尖牙乳头干细胞（stem cells from apical papilla，SCAP）具有很强的多系分化潜能，其中成骨分化可以应用于骨组织再生，为口腔颌骨缺损治疗提供新思路。成骨分化是个复杂的网络调控过程，诸如各种细胞因子、表观遗传物质、各种信号分子和信号通路等内源性物质均可产生不同程度的影响。这些因素相互作用可以促进SCAP的增殖、迁移和成骨分化，但其在SCAP成骨分化的不同进程中的具体机制和内在联系各不相同。对近年来有关促进SCAP成骨分化的各种因素及其可能的调控机制研究文献进行综述，以期为其进一步的应用研究提供新信息。Abstract: Stem cells from apical papilla （SCAP） have a strong multi-line differentiation potential, in which osteogenic differentiation can be applied to bone tissue regeneration, providing a new idea for the treatment of oral jaw defects. Osteogenic differentiation is a complex network regulation process, and endogenous substances such as various cytokines, epigenetic material, various signaling molecules and signaling pathways can have different degrees of influence. The interaction of these factors can promote the proliferation, migration and osteogenic differentiation of SCAP, but the specific mechanisms and internal links in different processes of osteogenic differentiation of SCAP are different. In this paper, the factors that promote osteogenic differentiation of SCAP and their possible regulatory mechanisms were reviewed to provide new information for further application research.
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三七（Panax notoginseng （Burk.） F. H. chen ex C. H.），又名参三七、田七等，为五加科多年生草本植物，是我国名贵中药材。三七中主要有效成分包括：三七多糖，三七皂苷、黄酮类、氨基酸、挥发油等[1]。据现有研究发现三七多糖具有调节免疫功能[2]、抗炎[3]、降血糖[4]、降血脂[5]、抗氧化[6]、抗衰老[7]等药理作用，刘平平等[8]发现从三七发酵液提取的三七多糖对DPPH自由基、羟自由基等具有一定清除作用。现已有研究表明，天然多糖如：银耳多糖、山药多糖、灵芝多糖等具有良好的吸湿保湿性能，在日化产品中具有良好的应用前景[9]，而三七多糖是否具有吸湿、保湿的生物活性尚未见报道。
三七药渣是三七在工业中提取三七总皂苷后的废渣[10]，其中三七多糖、三七素等成分仍具有药用价值却不能得到有效利用。本课题组前期采用水提醇沉法，从工业三七药渣中提取三七粗多糖，通过DEAE Sepharose Fast Flow成功分离出中性多糖和酸性多糖，已证实三七药渣中提取的三七多糖具有多种生理活性[11-12]，且具有良好的安全性[13]。本文拟在前期研究基础上，首次考察从药渣中提取的三七粗多糖及纯化后各组分是否具有吸湿、保湿及体外抗氧化活性，为三七多糖用于日化产品、保健食品、药品研发奠定基础。
1. 材料与方法
1.1 样品与试剂
三七药渣（云南三七科技提供）；D-无水葡萄糖对照品、D-半乳糖醛酸对照品、DPPH、ABTS（上海源叶生物）；甘油、抗坏血酸（VC）、七水合硫酸亚铁（广东光华科技）；海藻酸钠（上海易恩）；DEAE Sepharose Fast Flow填料（美国GE Healthcare）；透析袋（合肥白鲨生物科技）；其余试剂均为国产分析级纯。
1.2 仪器与设备
BSA224S万分之一分析天平（德国Sartorius公司）；DK-98- II水浴锅（天津市泰斯特）；RE-52AA旋转蒸发仪（上海亚荣）；H1850高速离心机（湖南湘仪）；SCIENTZ-10ND 冷冻干燥机（宁波新芝）；玻璃干燥器（四川蜀玻集团）；岛津UV-1900紫外-分光光度计（日本岛津）；Bio-rad MODEL 680酶标仪（美国Bio-rad 公司）。
1.3 实验方法
1.3.1 三七多糖的提取、纯化及含量测定
采用水提醇沉法从工业三七药渣中提取CPPN，取干燥三七药渣1000 g，加入10倍量超纯水，沸水浴提取6 h，过滤；滤渣加入8倍量超纯水，沸水浴提取6 h，过滤；滤渣继续加入6倍量超纯水，沸水浴提取6 h，过滤。合并3次滤液，8000 r/min离心5 min，取上清液，80℃减压浓缩，至原体积的1/10后，加入滤液3倍体积的无水乙醇，放4 ℃下醇沉过夜。8000 r/min离心5 min，弃去上清液，收集沉淀。分别用无水乙醇、乙醚洗涤沉淀三次后加入适量超纯水复溶，冷冻干燥，即得CPPN。采用DEAE Sepharose Fast Flow阴离子交换填料对CPPN进行纯化，取CPPN 600 mg，溶于20 mL超纯水中，8000 r/min离心10 min去除不溶物，经0.45 μm微孔滤膜过滤后上样，以超纯水、0.1、0.2、0.3 M NaCl溶液对其进行梯度洗脱，收集洗脱液，5 mL/管。硫酸蒽酮法跟踪检测，绘制洗脱曲线其中管数为横坐标，吸光度值为纵坐标。依据洗脱曲线，合并各组分，80℃减压浓缩至原体积1/10，超纯水透析36 h（MwCO 14000Da），每4 h换一次水。透析结束后，真空冷冻干燥，分离得到的各组分依次命名为NPPN、APPNⅠ、APPNⅡ、APPNⅢ。采用硫酸蒽酮法，测定三七多糖中性糖含量，间羟基联苯法测定三七多糖糖醛酸含量[14]。
1.3.2 吸湿/保湿能力考察
参照蔡婉静等[15]在研究中采用的方法，以常用的保湿剂甘油和海藻酸钠对照，考察CPPN、NPPN、APPNⅠ、APPNⅡ、APPNⅢ的吸湿和保湿能力。（1）吸湿性。准确称取CPPN、NPPN、APPNⅠ、APPNⅡ、APPNⅢ、甘油和海藻酸钠各0.5 g于称量瓶中，平行3份，将其放入置有饱和碳酸钾溶液（RH43%）和饱和硫酸铵溶液（RH81%）的干燥器内，室温下放置，并在4、8、12、24、36 h分别称量样品放置前重量（W0）和放置后的重量（W1），吸湿能力按照公式（1）计算：
$$ {\text{吸湿性}}(\%)=({\rm{W}}_0-{\rm{W}}_1)\times100/{\rm{W}}_0 $$ (1) （2）保湿性。准确称取CPPN、NPPN、APPNⅠ、APPNⅡ、APPNⅢ、甘油和海藻酸钠各0.5 g于称量瓶中，平行3份，并分别加入3倍样品质量的超纯水，转动称量瓶直至样品将水分完全吸收。将称量瓶放入装有干燥完全的硅胶的干燥室内，于室温下放置，并在4、8、12、24、36 h分别称量样品放置前重量（H0）和放置后的重量（H1）。保湿能力按照公式（2）计算:
$$ {\text{保湿性}}(\%)={\rm{H}}_1 \times100/{\rm{H}}_0 $$ (2) 1.3.3 抗氧化能力测定
（1） DPPH自由基清除能力。将维生素C和三七多糖各待测组分用蒸馏水配置成0.25、0.5、1.0、2.0、4.0、8.0 mg/mL浓度的样液测定时，在96孔板中加入2×10-4 mol/L的DPPH乙醇溶液100 μL，然后加入100 μL待测液，摇匀后，在室温，黑暗处放置30 min，并测定517 nm处的吸光度值At，用乙醇代替DPPH溶液测定本底吸光度值Ar，用超纯水代替样品溶液测得参比溶液吸光度A0[16]。采用Vc作为阳性对照，同一测定设计3个平行，清除率按公式（3）计算:
$$ {\rm{DPPH}}{\text{自由基清除率}}(\%)=[1-({\rm{A}}_{\rm{t}}-{\rm{A}}_{\rm{r}})/{\rm{A}}_0]\times100 $$ (3) （2） ABTS+自由基清除能力。将5 mL的7 mmol/L ABTS和88 μL的140 mmol/L K2S2O8混合，常温避光条件下静置过夜（12 h），形成ABTS+自由基储备液。使用前用无水乙醇稀释成在734 nm波长下的吸光度为0.7±0.02工作液[17]。测定时，在96孔板中加入ABTS+工作液100 μL和100 μL待测液，振荡混匀，10 min后测定反应液在734 nm处的吸光值At，用乙醇代替ABTS+工作液测定本底吸光度值Ar，用超纯水代替样品溶液测得参比溶液吸光度A0。采用Vc作为阳性对照，同一测定设计3个平行，清除率由公式（4）计算：
$$ {\rm{ABTS}}^+{\text{自由基清除率}}(\%)=[1-({\rm{A}}_{\rm{t}}-{\rm{A}}_{\rm{r}})/{\rm{A}}_0]\times100 $$ (4) （3） 羟基自由基清除能力。配置2.25 mmol/LFeSO4水溶液、9 mmol/L水杨酸乙醇溶液，分别取50 μL加入96孔板，取50 μL待测液加入，再加入50 μL 8.80 mmol/L H2O2溶液，37 ℃反应30 min，测定510 nm处吸光度At。用超纯水代替H2O2测得对应待测溶液的本底吸光度值Ar，用超纯水代替待测液测得参比溶液吸光度A0[18]。采用Vc作为阳性对照，同一测定设计3个平行，清除率由公式（5）计算：
$$ {\text{羟基自由基清除率}}(\%)=[1-({\rm{A}}_{\rm{t}}-{\rm{A}}_{\rm{r}})/{\rm{A}}_0]\times 100 $$ (5) 2. 结果
2.1 三七多糖的提取、纯化及含量测定
1 000 g三七药渣采用经水提醇沉法，共提取到34.97g CPPN，得率为3.49 %。采用DEAE Sepharose Fast Flow对CPPN进行纯化，以超纯水、0.1、0.2、0.3 M NaCl溶液洗脱，共得到4个洗脱峰（洗脱曲线见图1），得率分别为27.68%、11.89%、15.41%、21.04%，对CPPN、NPPN、APPNⅠ、APPNⅡ、APPNⅢ的含量测定结果如表1所示。
图 1 DEAE Sepharose Fast Flow洗脱曲线Figure 1. Elution curve with DEAE Sepharose Fast Flow表 1 三七多糖的含量测定结果（%）Table 1. Determined the contents of Panax notoginseng polysaccharide（%）样品 中性糖含量 糖醛酸含量 总糖含量 CPPN 32.4 36.25 68.65 NPPN 73.33 - 73.33 APPNⅠ 48.33 27.5 75.83 APPNⅡ 21.67 57.92 79.59 APPNⅢ 13.75 79.58 93.33 注：总糖含量 = 中性糖含量 + 糖醛酸含量。 2.2 三七多糖的吸湿性
在RH43%环境中，水分的含量随时间的变化结果如图2所示，三七多糖及各组分的吸湿率均逐渐上升，吸湿率大小依次为甘油>APPNⅢ>海藻酸钠>CPPN>APPNⅡ>APPNⅠ>NPPN，36 h时，吸湿率分别为37.21%、25.50%、23.55%、19.10%、18.43%、16.99%、13.20%。从图3可以看出，在高湿度（RH81%）环境中，在0～12 h，CPPN、APPNⅠ、APPNⅡ、APPNⅢ的吸湿率上升较快，12 h～36 h变化缓慢，36 h时，吸湿率大小为甘油>APPNⅢ>海藻酸钠>APPNⅡ>APPNⅠ>CPPN>NPPN，吸湿率大小依次为83.57%、42.58%、39.76%、30.81%、27.80%、24.59%、20.80%。由两图对比显示，APPNⅢ在高湿度和低湿度下都具有良好的吸湿性，其吸湿性高于海藻酸钠。
图 2 三七多糖在RH43%环境中的吸湿率变化情况Figure 2. Relationship between moisture retention rate and time
图 3 三七多糖在RH81%环境中的吸湿率变化情况Figure 3. Relationship between moisture retention rate and time2.3 三七多糖的保湿性
保湿性考察实验结果如图4，在干燥硅胶环境中，CPPN、NPPN、APPNⅠ、APPNⅡ、APPNⅢ、甘油和海藻酸钠保湿率均持续下降，保湿率大小依次为APPNⅢ>海藻酸钠>CPPN>APPNⅡ>甘油>APPNⅠ>NPPN，在36 h时，保湿率分别为45.64%、40.35%、38.40%、36.15%、35.38%、34.35%、33.59%。
图 4 三七多糖在干硅胶环境中的保湿率变化情况Figure 4. Relationship between moisture retention rate and time2.4 三七多糖对DPPH的清除能力
由图5可知，CPPN、APPNⅠ、APPNⅡ、APPNⅢ对DPPH均具有较好的清除能力，且呈明显的量效关系，当多糖浓度为8 mg/mL时，CPPN对DPPH自由基的清除效果最好，达58.36%，而NPPN、APPNⅠ、APPNⅡ、APPNⅢ的清除率分别为12.90%、50.66%、37.26%、47.71%。抗氧化活性顺序为CPPN>APPNⅠ>APPNⅢ>APPNⅡ>NPPN。艾于杰等[18]发现纯化后的茶多糖清除DPPH清除能力纯化前强于纯化后，推测粗多糖对DPPH的清除作用可能为各组分结合后协同作用。本研究中三七粗多糖清除效果最好，推测其原因为七粗多糖中各组分协同发挥抗氧化作用。
图 5 三七多糖对DPPH的清除能力Figure 5. Scavening rate of DPPH of Panax notoginseng polysaccharide2.5 三七多糖对ABTS+的清除能力
ABTS 可被活性氧氧化，生成蓝绿色的ABTS+自由基，在734 nm 处有特征吸收，当抗氧化剂存在时，自由基被抗氧化剂清除时，蓝绿色会逐渐褪色或消失[19]。三七多糖及纯化后各组分对ABTS+的清除效果图6所示，随着多糖浓度的增大，其清除ABTS+自由基的效果也不断增强。当多糖浓度为8 mg/mL时，CPPN、NPPN、APPNⅠ、APPNⅡ、APPNⅢ的清除率分别为95.91%、36.41%、87.37%、68.34%、83.34%，抗氧化活性顺序为CPPN>APPNⅠ>APPNⅢ>APPNⅡ>NPPN。三七粗多糖对ABTS+自由基的清除效果最好，分离纯化得到的4个组分中，APPNⅠ的清除效果较强，NPPN的清除能力较弱。有研究表明，多糖对ABTS+自由基的清除能力与DPPH自由基的清除能力具有一致性[20]，本研究中CPPN、NPPN、APPNⅠ、APPNⅡ、APPNⅢ对ABTS+的清除能力与对DPPH自由基清除能力趋势一致。
图 6 三七多糖对ABTS+的清除能力Figure 6. Scavening rate of ABTS+ of Panax notoginseng polysaccharide2.6 三七多糖对羟基自由基的清除能力
羟基自由基是机体内攻击性最强的活性氧，多糖是具有多羟基的醛或多羟基的酮，该结构上带有还原性的半缩醛羟基，使自由基被还原，从而阻止自由基进行连锁反应[21]。由图7可知，各浓度的VC对羟自由基的清除率最高，不同浓度的CPPN及纯化后各组分对羟自由基均具有一定的清除作用，随多糖浓度的升高，对羟自由基的清除能力也不断升高，当CPPN浓度为8 mg/mL，CPPN的清除能力为98.95%，与VC接近。同一浓度下，抗氧化活性顺序为CPPN>APPNⅢ>APPNⅡ>APPNⅠ>NPPN。
3. 讨论
本文采用水提醇沉法成功从三七药渣中提取出三七多糖，并经过DEAE Sepharose Fast Flow对其纯化，成功分离出NPPN、APPNⅠ、APPNⅡ、APPNⅢ，并对CPPN、NPPN、APPNⅠ、APPNⅡ、APPNⅢ的吸湿和保湿性能首次初步探究，发现APPNⅢ的吸湿性能优于海藻酸钠，其保湿性能也优于海藻酸钠及常用保湿剂甘油，表明APPNⅢ是一种优良的保湿剂。
自由基，是生物体新陈代谢的正常产物，在正常的生理状态下，人体内自由基的产生处于动态平衡中，受体内各种内源性抗氧化网络的严格调控。当机体平衡一旦被打破，体内自由基过多时，自由基会引发氧化应激损伤，诱导各种疾病的发生和发展，如炎症、肿瘤等疾病。现有研究表明，诸多植物多糖具有抗氧化活性，如：枸杞多糖[22]、茯苓多糖[23]。多糖的抗氧化活性常与多糖分子量、糖基组成、糖苷键类型、高级结构等相关[18]。三七多糖体外抗氧化活性研究显示：三七粗多糖与分离纯化后的各组分比较，其对三种自由基的清除效果最佳，抗氧化能力最强，推测三七粗多糖中各组分多糖的抗氧化性有协同作用；纯化后的三种酸性多糖的抗氧化活性均强于中性多糖，说明三七多糖的抗氧化性与其酸性基团密切相关。综上，通对三七多糖具有吸湿、保湿性能及体外抗氧化活性，表明三七多糖具有应用于日化行业、保健食品、药品的潜力，为工业三七药渣的综合利用提供了新思路，有利于三七资源的综合利用。
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