纳米壳聚糖的制备及降脂活性研究
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摘要
壳聚糖是一种具有降脂活性的天然阳离子多糖，在国内外已得到广泛关注和研究。但是，实际应用中，壳聚糖使用剂量较高的情况下才能达到较好的降脂效果，因此有必要对壳聚糖进行改性提高其降脂活性。已有研究表明，壳聚糖的降脂作用与胃肠道中对脂类物质的结合以及其自身的消化吸收状况有关，增大其比表面积，加速其在胃液中的溶解可能有助于提高其降脂活性。本课题采用超微粉碎法制备纳米壳聚糖，在此基础上，比较了纳米壳聚糖和普通壳聚糖的降脂活性，探讨了纳米壳聚糖的降脂机制，并进一步研究了纳米壳聚糖的分子量与降脂活性之间的关系。本研究对壳聚糖功能性食品的开发具有重要的理论学术意义和实际应用价值。
采用干法球磨和湿法珠磨两种超微粉碎方法制备纳米壳聚糖。以分子量为537.8kDa和59.2kDa的两种壳聚糖为原料，考察了壳聚糖粉碎过程中平均粒径的变化，并研究了粉碎前后壳聚糖结构和理化性质的变化。结果显示，干法球磨时，两种壳聚糖分别处理10h和8h后平均粒径降到纳米范围内，处理12h后平均粒径分别降至368.4nm和337.2nm；湿法珠磨时，两种壳聚糖分别处理2.5h和1h后平均粒径降至纳米范围内，处理5h后平均粒径分别降至543.8nm和290.6nm。两种粉碎处理后，壳聚糖的分子量均下降，但脱乙酰度和化学结构的变化并不明显。粉碎引起了壳聚糖结晶结构和一些理化性质的改变。干法球磨处理后，壳聚糖的结晶度下降，堆积密度上升，粉体流动性下降，亮度略有下降，黄色加重。湿法珠磨处理后，壳聚糖的持水力明显提高，色泽也明显改善。
利用体外实验研究了纳米壳聚糖的降脂活性及机制。通过检测溶解时体系pH值的变化考察了干法球磨和湿法珠磨制得的纳米壳聚糖在模拟胃液中的溶解速度，在模拟胃肠道环境中通过控制胃液消化时间研究了它们体外脂质结合能力与溶解速度的关联性，并以普通壳聚糖作对照比较。结果显示，两种纳米壳聚糖在模拟胃液中溶解时体系pH值上升速度明显快于普通壳聚糖，说明两种纳米壳聚糖的溶解速度均快于普通壳聚糖。在模拟胃肠道环境下，两种纳米壳聚糖对油脂和胆酸盐的结合能力均明显强于普通壳聚糖。模拟胃液消化时间由0.5h逐渐增加至4h时，普通壳聚糖对两种脂质的结合量逐渐增加，而两种纳米壳聚糖的脂质结合量变化不大，表明这两种纳米壳聚糖对脂质较强的结合能力与它们较快的溶解速度有关。
用高脂饮食建立高脂大鼠模型，比较了干法球磨和湿法珠磨制得的纳米壳聚糖和普通壳聚糖在大鼠体内的降脂活性，结合此前体外实验结果分析了纳米壳聚糖的降脂机制。结果表明，两种纳米壳聚糖的降脂活性均明显强于普通壳聚糖，而且这两种纳米壳聚糖降脂活性差距并不明显。相比普通壳聚糖饲料组，干法球磨制得的纳米壳聚糖使大鼠血清甘油三酯(TG)、总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)含量下降了13.6%、13.0%和28.1%，肝脏TG和TC下降了18.2%和17.1%，湿法球磨制得的纳米壳聚糖使大鼠血清TG、TC和LDL-C含量下降了18.2%、17.4%和32.7%，肝脏TG和TC含量降低了21.0%和18.0%，同时两种纳米壳聚糖均降低了大鼠的体重增加值、Lee’s指数、肝脏指数、体脂含量，并减轻了大鼠的脂肪肝症状。相比普通壳聚糖饲料组，两种纳米壳聚糖使大鼠粪便中脂肪含量分别提高了26.7%和31.4%，胆固醇含量提高了27.9%和29.8%，同时也提高了大鼠肝脏和血清中脂蛋白脂酶(LPL)和肝脂酶(HL)活性，结合体外实验和动物实验的结果分析可知，纳米壳聚糖相比普通壳聚糖降脂活性提高的原因在于，纳米壳聚糖在胃肠道环境中可通过快速溶解结合更多的脂类物质，从而增加粪便中的脂类排泄量，更好地减少机体对食物中脂质的吸收，此外，对脂质代谢关键脂酶活性更好的调节能力进一步增强了降脂活性。
通过比较不同分子量纳米壳聚糖在大鼠体内的降脂活性，探讨了纳米壳聚糖的分子量与降脂活性之间的关系。结果表明，纳米壳聚糖的降脂活性与其分子量大小存在一定的联系，分子量由315.2kDa下降至37.2kDa时，纳米壳聚糖的降脂活性基本呈现出一种先下降后上升而后又下降的趋势，分子量为98.6kDa和51.4kDa的纳米壳聚糖降脂活性最强。随分子量的下降，纳米壳聚糖抑制外源脂质吸收的能力逐渐减弱，但低分子量纳米壳聚糖(37.2~98.6kDa)调节大鼠血清和肝脏中LPL和HL活性的能力相对较强，表明分子量为98.6kDa和51.4kDa的纳米壳聚糖较高的降脂活性可能与它们对脂质代谢关键脂酶的较强的调节能力有关。
本文通过干法球磨和湿法珠磨制备了纳米壳聚糖，证实了两法制得的纳米壳聚糖相比普通壳聚糖具有更强的降脂活性，发现了纳米壳聚糖可更明显地提高大鼠脂质排泄量和脂质代谢关键脂酶活性，确定了具有较好降脂活性纳米壳聚糖的分子量。
Chitosan, a kind of natural cationic polysaccharides with hypolipidemic activity, hasattracted considerable attention and research. However, during the application, the betterhypolipidemic effect of chitosan is always related to high usage dose, and it is necessary tomodify chitosan to improve its hypolipidemic activity. Some study has shown that thehypolipidemic function of chitosan is related to its binding action to lipids and its digestionand absorption characteristics, so the increase in specific surface might enhance thehypolipidemic activity of chitosan by accelerating its dissolution in gastric juice. Thisresearch employed ultrafine milling to prepare nanosized chitosan, compared thehypolipidemic activity of nanosized chitosan and ordinary chitosan, analyzed thehypolipidemic mechanism of nanosized chitosan, and investigated the relationship betweenthe molecular weight of nanosized chitosan and its hypolipidemic activitiy. This study was oftheoretical significance and of great practical significance in exploiting chitosan as functionalproducts.
The dry ball milling and wet media milling were used to prepare nanosized chitosan. Withhigh and low molecular weights of chitosan (538.7kDa and59.2kDa) used as millingmaterals, the change in mean diameter of chitosan was studied during the milling process, andthe change of its structure and physicochemical properties after milling were also studied. Ourresults showed that the two chitosan samples can be milled to nanometre range after10h and8h of this milling, and their particle sizes were reduced to368.4nm and337.2nm after12hof milling. These two chitosan samples can be milled to nanometre range after2.5h and1hof wet media milling, and their particle sizes were reduced to543.8nm and290.6nm after5h of this milling. Both the two milling resulted in the decrease in molecular weight of chitosan,but did not significantly change its deacetylation degree (DD) and chemical structure. Thesetwo milling aroused some change in crystalline sturcture and physicochemical properties.After dry ball milling, the crystalline degree of chitosan was decreased, bulk density wasincreased, fluidity was decreased, brightness was slightly decreased, and yellowness wasincreased. After wet media milling, the water holding capacity of chitosan was greatlyincreased, and the color of chitosan were greatly improved.
The hypolipidemic activity and mechnanism of nanosized chitosan was studied by invitro experiment. By using ordinary chitosan as control, the dissolution speed of nanosizedchitosan prepared by dry ball milling and wet media milling in simulated gastric juice wereevaluated by determining the pH change, and the correlation between the dissolution speed ofnanosized chitosan and their lipid-binding capacities were studied by controlling the digestivetime in simulated gastric juice. The results showed that the pH of gastric juice dissolving nanosized chitosan prepared by these two methods rose fater than that of ordinary chitosan,indicating that the dissolution speed of the two nanosized chitosan were higher than that ofordinary chitosan. Under simulated gastrointestinal environment, the oil and bile salt-bindingcapacities of the two nanosized chitosan were higher than those of ordinary chitosan. As thedigestive time in simulated gastric juice was gradually increased from0.5h to4h, the bindingcapacities of ordinary chitosan to these two lipids gradually increased, but the lipids-bindingcapacities of the two nanosized chitosan were kept nearly unchanged, indicating that thebetter lipids-binding capacities of nanosized chitosan was attributed to their higher dissolutionspeeds in simulated gastric juice.
The hypolipidemic activity of nanosized chitosan prepared by dry ball milling and wetmedia milling were compared to ordinary chitosan in rats fed high-fat diets, and thehypolipidemic mechanism of nanosized chitosan were discussed by the combined analyzationof the results of animal experiment and in vitro experiment. The results showed that thehypolipidemic activities of the two nanosized chitosan prepared by dry ball milling and mediamilling were better than that of ordinary chitosan, and there was no great difference betweenthese two nanosized chitosan. Compared with rats fed ordinary chitosan, nanosized chitosanprepared by ball milling decreased the serum TG, TC and LDL-C of rats by13.6%、13.0%and28.1%, and decreased the liver TG and TC by18.2%and17.1%, nanosized chitosan preparedby media milling decreased the serum TG, TC and LDL-C of rats by18.2%、17.4%and32.7%,and decreased the liver TG and TC by21.0%and18.0%, and these two nanosized chitosandecreased body weight gain, Lee’s index, liver index and body fat weight of rats, and relivedits fatty liver symptom. Compared with ordinary chitosan group, the two nanosized chitosangroups increased fecal fat content by26.7%and31.4%，and fecal cholesterol content by27.9%and29.8%, and also increased the activities of serum and liver lipoprotein lipase (LPL)and hepatic lipase (HL). As suggested by the results of in vitro experiment and animalexperiment, the reason for the better nanosized chitosan relative to ordinary chitosan might bethat the faster dissolution speed of nanosized chitosan make it easier to bind more lipids ingastrointestinal tract, which decreased the lipid absoprtion by increasing the lipid contents infeces, and the better stimulating ability of nanosized chitosan on lipid metabolism-related keylipase further increased its hypolipidemic activity.
The hypolipidemic activities of nanosized chitosan with different molecular weightswere compared in rats to study the relationship between its hypolipidemic activity andmolecular weight. The results indicated that the hypolipidemic activity of nanosized chitosanwas related to its molecular weight, and as molecular weight of nanosized chitosan decreasedfrom315.2kDa to37.2kDa, its hypolipidemic activity first decreased, then increased andfinally again decreased, and two nanosized chitosan with molecular weights of98.6and51.4kDa exhibited the most effective hypolipidemic activity. As the molecular weight of nanosized chitosan decreased, the ability of nanosized chitosan on inhibiting exogenous lipidabsorption decreased, but the stimulating ability of low molecular weights (37.2~98.6kDa) ofnanosized chitosan on the serum and liver LPL and HL of rats was relatively high. Theseresults indicated that the effectiveness of nanosized chitosan with molecular weights of98.6and51.4kDa in hypolipidemci activites might be partly attributed to their high stimulatingability on lipid metabolism-related key lipase.
In this study, the nanosized chitosan were prepared by dry ball milling and wet mediamilling, and the superior hypolipidemic activity of the two nanosized chitosan relative toordinary chitosan was demonstrated by animal experiment. It was found that compared withordinary chitosan, nanosized chitosan increased the lipid content in feces and lipidmetabolism-related key lipase of rats. Besides, the molecule weight of nanosized chitosanpossessing the effective hypolipidemic activity was ascertained.
采用干法球磨和湿法珠磨两种超微粉碎方法制备纳米壳聚糖。以分子量为537.8kDa和59.2kDa的两种壳聚糖为原料，考察了壳聚糖粉碎过程中平均粒径的变化，并研究了粉碎前后壳聚糖结构和理化性质的变化。结果显示，干法球磨时，两种壳聚糖分别处理10h和8h后平均粒径降到纳米范围内，处理12h后平均粒径分别降至368.4nm和337.2nm；湿法珠磨时，两种壳聚糖分别处理2.5h和1h后平均粒径降至纳米范围内，处理5h后平均粒径分别降至543.8nm和290.6nm。两种粉碎处理后，壳聚糖的分子量均下降，但脱乙酰度和化学结构的变化并不明显。粉碎引起了壳聚糖结晶结构和一些理化性质的改变。干法球磨处理后，壳聚糖的结晶度下降，堆积密度上升，粉体流动性下降，亮度略有下降，黄色加重。湿法珠磨处理后，壳聚糖的持水力明显提高，色泽也明显改善。
利用体外实验研究了纳米壳聚糖的降脂活性及机制。通过检测溶解时体系pH值的变化考察了干法球磨和湿法珠磨制得的纳米壳聚糖在模拟胃液中的溶解速度，在模拟胃肠道环境中通过控制胃液消化时间研究了它们体外脂质结合能力与溶解速度的关联性，并以普通壳聚糖作对照比较。结果显示，两种纳米壳聚糖在模拟胃液中溶解时体系pH值上升速度明显快于普通壳聚糖，说明两种纳米壳聚糖的溶解速度均快于普通壳聚糖。在模拟胃肠道环境下，两种纳米壳聚糖对油脂和胆酸盐的结合能力均明显强于普通壳聚糖。模拟胃液消化时间由0.5h逐渐增加至4h时，普通壳聚糖对两种脂质的结合量逐渐增加，而两种纳米壳聚糖的脂质结合量变化不大，表明这两种纳米壳聚糖对脂质较强的结合能力与它们较快的溶解速度有关。
用高脂饮食建立高脂大鼠模型，比较了干法球磨和湿法珠磨制得的纳米壳聚糖和普通壳聚糖在大鼠体内的降脂活性，结合此前体外实验结果分析了纳米壳聚糖的降脂机制。结果表明，两种纳米壳聚糖的降脂活性均明显强于普通壳聚糖，而且这两种纳米壳聚糖降脂活性差距并不明显。相比普通壳聚糖饲料组，干法球磨制得的纳米壳聚糖使大鼠血清甘油三酯(TG)、总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)含量下降了13.6%、13.0%和28.1%，肝脏TG和TC下降了18.2%和17.1%，湿法球磨制得的纳米壳聚糖使大鼠血清TG、TC和LDL-C含量下降了18.2%、17.4%和32.7%，肝脏TG和TC含量降低了21.0%和18.0%，同时两种纳米壳聚糖均降低了大鼠的体重增加值、Lee’s指数、肝脏指数、体脂含量，并减轻了大鼠的脂肪肝症状。相比普通壳聚糖饲料组，两种纳米壳聚糖使大鼠粪便中脂肪含量分别提高了26.7%和31.4%，胆固醇含量提高了27.9%和29.8%，同时也提高了大鼠肝脏和血清中脂蛋白脂酶(LPL)和肝脂酶(HL)活性，结合体外实验和动物实验的结果分析可知，纳米壳聚糖相比普通壳聚糖降脂活性提高的原因在于，纳米壳聚糖在胃肠道环境中可通过快速溶解结合更多的脂类物质，从而增加粪便中的脂类排泄量，更好地减少机体对食物中脂质的吸收，此外，对脂质代谢关键脂酶活性更好的调节能力进一步增强了降脂活性。
通过比较不同分子量纳米壳聚糖在大鼠体内的降脂活性，探讨了纳米壳聚糖的分子量与降脂活性之间的关系。结果表明，纳米壳聚糖的降脂活性与其分子量大小存在一定的联系，分子量由315.2kDa下降至37.2kDa时，纳米壳聚糖的降脂活性基本呈现出一种先下降后上升而后又下降的趋势，分子量为98.6kDa和51.4kDa的纳米壳聚糖降脂活性最强。随分子量的下降，纳米壳聚糖抑制外源脂质吸收的能力逐渐减弱，但低分子量纳米壳聚糖(37.2~98.6kDa)调节大鼠血清和肝脏中LPL和HL活性的能力相对较强，表明分子量为98.6kDa和51.4kDa的纳米壳聚糖较高的降脂活性可能与它们对脂质代谢关键脂酶的较强的调节能力有关。
本文通过干法球磨和湿法珠磨制备了纳米壳聚糖，证实了两法制得的纳米壳聚糖相比普通壳聚糖具有更强的降脂活性，发现了纳米壳聚糖可更明显地提高大鼠脂质排泄量和脂质代谢关键脂酶活性，确定了具有较好降脂活性纳米壳聚糖的分子量。
Chitosan, a kind of natural cationic polysaccharides with hypolipidemic activity, hasattracted considerable attention and research. However, during the application, the betterhypolipidemic effect of chitosan is always related to high usage dose, and it is necessary tomodify chitosan to improve its hypolipidemic activity. Some study has shown that thehypolipidemic function of chitosan is related to its binding action to lipids and its digestionand absorption characteristics, so the increase in specific surface might enhance thehypolipidemic activity of chitosan by accelerating its dissolution in gastric juice. Thisresearch employed ultrafine milling to prepare nanosized chitosan, compared thehypolipidemic activity of nanosized chitosan and ordinary chitosan, analyzed thehypolipidemic mechanism of nanosized chitosan, and investigated the relationship betweenthe molecular weight of nanosized chitosan and its hypolipidemic activitiy. This study was oftheoretical significance and of great practical significance in exploiting chitosan as functionalproducts.
The dry ball milling and wet media milling were used to prepare nanosized chitosan. Withhigh and low molecular weights of chitosan (538.7kDa and59.2kDa) used as millingmaterals, the change in mean diameter of chitosan was studied during the milling process, andthe change of its structure and physicochemical properties after milling were also studied. Ourresults showed that the two chitosan samples can be milled to nanometre range after10h and8h of this milling, and their particle sizes were reduced to368.4nm and337.2nm after12hof milling. These two chitosan samples can be milled to nanometre range after2.5h and1hof wet media milling, and their particle sizes were reduced to543.8nm and290.6nm after5h of this milling. Both the two milling resulted in the decrease in molecular weight of chitosan,but did not significantly change its deacetylation degree (DD) and chemical structure. Thesetwo milling aroused some change in crystalline sturcture and physicochemical properties.After dry ball milling, the crystalline degree of chitosan was decreased, bulk density wasincreased, fluidity was decreased, brightness was slightly decreased, and yellowness wasincreased. After wet media milling, the water holding capacity of chitosan was greatlyincreased, and the color of chitosan were greatly improved.
The hypolipidemic activity and mechnanism of nanosized chitosan was studied by invitro experiment. By using ordinary chitosan as control, the dissolution speed of nanosizedchitosan prepared by dry ball milling and wet media milling in simulated gastric juice wereevaluated by determining the pH change, and the correlation between the dissolution speed ofnanosized chitosan and their lipid-binding capacities were studied by controlling the digestivetime in simulated gastric juice. The results showed that the pH of gastric juice dissolving nanosized chitosan prepared by these two methods rose fater than that of ordinary chitosan,indicating that the dissolution speed of the two nanosized chitosan were higher than that ofordinary chitosan. Under simulated gastrointestinal environment, the oil and bile salt-bindingcapacities of the two nanosized chitosan were higher than those of ordinary chitosan. As thedigestive time in simulated gastric juice was gradually increased from0.5h to4h, the bindingcapacities of ordinary chitosan to these two lipids gradually increased, but the lipids-bindingcapacities of the two nanosized chitosan were kept nearly unchanged, indicating that thebetter lipids-binding capacities of nanosized chitosan was attributed to their higher dissolutionspeeds in simulated gastric juice.
The hypolipidemic activity of nanosized chitosan prepared by dry ball milling and wetmedia milling were compared to ordinary chitosan in rats fed high-fat diets, and thehypolipidemic mechanism of nanosized chitosan were discussed by the combined analyzationof the results of animal experiment and in vitro experiment. The results showed that thehypolipidemic activities of the two nanosized chitosan prepared by dry ball milling and mediamilling were better than that of ordinary chitosan, and there was no great difference betweenthese two nanosized chitosan. Compared with rats fed ordinary chitosan, nanosized chitosanprepared by ball milling decreased the serum TG, TC and LDL-C of rats by13.6%、13.0%and28.1%, and decreased the liver TG and TC by18.2%and17.1%, nanosized chitosan preparedby media milling decreased the serum TG, TC and LDL-C of rats by18.2%、17.4%and32.7%,and decreased the liver TG and TC by21.0%and18.0%, and these two nanosized chitosandecreased body weight gain, Lee’s index, liver index and body fat weight of rats, and relivedits fatty liver symptom. Compared with ordinary chitosan group, the two nanosized chitosangroups increased fecal fat content by26.7%and31.4%，and fecal cholesterol content by27.9%and29.8%, and also increased the activities of serum and liver lipoprotein lipase (LPL)and hepatic lipase (HL). As suggested by the results of in vitro experiment and animalexperiment, the reason for the better nanosized chitosan relative to ordinary chitosan might bethat the faster dissolution speed of nanosized chitosan make it easier to bind more lipids ingastrointestinal tract, which decreased the lipid absoprtion by increasing the lipid contents infeces, and the better stimulating ability of nanosized chitosan on lipid metabolism-related keylipase further increased its hypolipidemic activity.
The hypolipidemic activities of nanosized chitosan with different molecular weightswere compared in rats to study the relationship between its hypolipidemic activity andmolecular weight. The results indicated that the hypolipidemic activity of nanosized chitosanwas related to its molecular weight, and as molecular weight of nanosized chitosan decreasedfrom315.2kDa to37.2kDa, its hypolipidemic activity first decreased, then increased andfinally again decreased, and two nanosized chitosan with molecular weights of98.6and51.4kDa exhibited the most effective hypolipidemic activity. As the molecular weight of nanosized chitosan decreased, the ability of nanosized chitosan on inhibiting exogenous lipidabsorption decreased, but the stimulating ability of low molecular weights (37.2~98.6kDa) ofnanosized chitosan on the serum and liver LPL and HL of rats was relatively high. Theseresults indicated that the effectiveness of nanosized chitosan with molecular weights of98.6and51.4kDa in hypolipidemci activites might be partly attributed to their high stimulatingability on lipid metabolism-related key lipase.
In this study, the nanosized chitosan were prepared by dry ball milling and wet mediamilling, and the superior hypolipidemic activity of the two nanosized chitosan relative toordinary chitosan was demonstrated by animal experiment. It was found that compared withordinary chitosan, nanosized chitosan increased the lipid content in feces and lipidmetabolism-related key lipase of rats. Besides, the molecule weight of nanosized chitosanpossessing the effective hypolipidemic activity was ascertained.
引文
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