螺旋藻活性肽的纯化、鉴定及降压、护肝机制研究
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摘要
本课题通过多种酶对钝顶螺旋藻进行酶解,采用超滤、凝胶过滤色谱、反相高效液相色谱等手段,纯化获取血管紧张素转化酶(ACE)抑制肽,经质谱分析和氨基酸测序进行鉴定,对其抑制类型和体外稳定性进行了研究,并以原发性高血压大鼠(SHR)为模型采用Real-Time PCR和酶联免疫吸附测定法进行了体内降压作用和调控机制研究。此外,本课题分别基于ICR小鼠和Wistar大鼠,研究了膳食性螺旋藻及其酶解液对D-氨基半乳糖(D-GalN)或对乙酰氨基酚(APAP)所致肝损害的保护作用和调控机制。
结果表明:分子量范围为0到3000 D的酶解液的ACE抑制活性为最高,该部分分子量的碱性蛋白酶和木瓜蛋白酶酶解液通过纯化获得2种高活性的ACE抑制肽,经鉴定分别为异亮氨酸-谷氨酰胺-脯氨酸(Ile-Gln-Pro,IQP)和缬氨酸-谷氨酸-脯氨酸(Val-Glu-Pro,VEP),IC_(50)值分别为5.77±0.09μmol/L和27.36±0.14μmol/L。两种ACE抑制肽经测定均为非竞争性抑制剂,Ki值分别为7.61±0.16μmol/L和23.59±0.54μmol/L,在主要胃肠蛋白酶的消化下能保持良好的抑制活性。
SHR大鼠试验表明,Ile-Gln-Pro和Val-Glu-Pro的单次口服最低有效降压剂量分别为2.5 mg/kg和5 mg/kg,降压效果与其对RAS系统主要成分的调控作用有关。与正对照Captopril相比,Ile-Gln-Pro和Val-Glu-Pro表现出比体外活性要强的体内活性,并且维持最大降压效果的时间更长。
此外,对ICR小鼠和Wistar大鼠体内试验研究表明,膳食性螺旋藻及其酶解液能够有效地抑制D-GalN或APAP引起的急性肝损害,并且其护肝作用与之对肝脂质过氧化、致炎细胞因子IL-18和肝局部RAS系统的调控作用有关。
本课题首次从螺旋藻中纯化获得高活性的ACE抑制肽,关于螺旋藻在动物体内降压、护肝效果以及对IL-18和肝局部RAS系统的表达调控研究填补了相关空白,成果表明螺旋藻在防治高血压和肝损害的医药和功能食品方面具有广阔的前景。
The present study was performed to isolate and purify angiotensin converting enzyme (ACE) inhibitory peptides from enzymatic digests of Spirulina platensis by ultra-filtration, gel filtration chromatography and reverse-phase high-performance liquid chromatography. The purified peptides were identified by mass spectrometry and amino acid sequencing, and were determined for the inhibition pattern and the stability in vitro. The in vivo antihypertensive effects and regulation mechanism on the renin-angiotensin system (RAS) were also investigated in spontaneous hypertensive rats (SHR) by methods of Real-Time PCR and Enzyme-linked immunosorbent assay. Furthermore, the hepatoprotective effects and the regulation mechanism of dietary Spirulina platensis and its enzymatic digests against D-galactosamine (D-GalN) or acetaminophen (APAP) induced hepatitis were investigated in ICR mice and Wistar rats.
The results indicated that the enzymatic digests ranging in 0 - 3,000 D had the highest ACE inhibitory activity. Two potent ACE inhibitory peptides with IC_(50) values of 5.77±0.09μmol/L and 27.36±0.14μmol/L were obtained from the Alcalase and papain digests, and were identified as Ile-Gln-Pro and Val-Glu-Pro, respectively. Both of the peptides were determined as non-competitive inhibitors with K_i values of 7.61±0.16μmol/L and 23.59±0.54μmol/L respectively, and kept their inhibitory activities well after incubation with main gastrointestinal proteases.
In vivo experiments in SHRs indicated that the least effective doses of Ile-Gln-Pro and Val-Glu-Pro were 2.5 mg/kg body weight (BW) and 5 mg/kg BW respectively, and the antihypertensive effects were accompanied with their regulation on major components in the RAS. Compared with Captopril, both of the peptides exhibited more potent activities in vivo than in vitro, and maintained the best antihypertensive effects longer.
Furthermore, dietary Spirulina platensis and its enzymatic digests could effectively suppress the acute liver injuries induced by D-GalN or APAP in ICR mice and Wistar rats, and the hepatoprotective effects were accompanied with their regulation on lipid peroxidation in the liver as well as expressions of the proinflammatory cytokine IL-18 and the hepatic RAS components.
The present work purified potent ACE inhibitory peptides from Spirulina platensis for the first time, and innovatively investigated the antihypertensive and hepatoprotective effects of Spirulina platensis and the regulation on expressions of IL-18 and the RAS components. The results suggested Spirulina platensis would be of great prospects as an ingredient of functional foods or medicines in treatment of hypertension and liver injuries.
结果表明:分子量范围为0到3000 D的酶解液的ACE抑制活性为最高,该部分分子量的碱性蛋白酶和木瓜蛋白酶酶解液通过纯化获得2种高活性的ACE抑制肽,经鉴定分别为异亮氨酸-谷氨酰胺-脯氨酸(Ile-Gln-Pro,IQP)和缬氨酸-谷氨酸-脯氨酸(Val-Glu-Pro,VEP),IC_(50)值分别为5.77±0.09μmol/L和27.36±0.14μmol/L。两种ACE抑制肽经测定均为非竞争性抑制剂,Ki值分别为7.61±0.16μmol/L和23.59±0.54μmol/L,在主要胃肠蛋白酶的消化下能保持良好的抑制活性。
SHR大鼠试验表明,Ile-Gln-Pro和Val-Glu-Pro的单次口服最低有效降压剂量分别为2.5 mg/kg和5 mg/kg,降压效果与其对RAS系统主要成分的调控作用有关。与正对照Captopril相比,Ile-Gln-Pro和Val-Glu-Pro表现出比体外活性要强的体内活性,并且维持最大降压效果的时间更长。
此外,对ICR小鼠和Wistar大鼠体内试验研究表明,膳食性螺旋藻及其酶解液能够有效地抑制D-GalN或APAP引起的急性肝损害,并且其护肝作用与之对肝脂质过氧化、致炎细胞因子IL-18和肝局部RAS系统的调控作用有关。
本课题首次从螺旋藻中纯化获得高活性的ACE抑制肽,关于螺旋藻在动物体内降压、护肝效果以及对IL-18和肝局部RAS系统的表达调控研究填补了相关空白,成果表明螺旋藻在防治高血压和肝损害的医药和功能食品方面具有广阔的前景。
The present study was performed to isolate and purify angiotensin converting enzyme (ACE) inhibitory peptides from enzymatic digests of Spirulina platensis by ultra-filtration, gel filtration chromatography and reverse-phase high-performance liquid chromatography. The purified peptides were identified by mass spectrometry and amino acid sequencing, and were determined for the inhibition pattern and the stability in vitro. The in vivo antihypertensive effects and regulation mechanism on the renin-angiotensin system (RAS) were also investigated in spontaneous hypertensive rats (SHR) by methods of Real-Time PCR and Enzyme-linked immunosorbent assay. Furthermore, the hepatoprotective effects and the regulation mechanism of dietary Spirulina platensis and its enzymatic digests against D-galactosamine (D-GalN) or acetaminophen (APAP) induced hepatitis were investigated in ICR mice and Wistar rats.
The results indicated that the enzymatic digests ranging in 0 - 3,000 D had the highest ACE inhibitory activity. Two potent ACE inhibitory peptides with IC_(50) values of 5.77±0.09μmol/L and 27.36±0.14μmol/L were obtained from the Alcalase and papain digests, and were identified as Ile-Gln-Pro and Val-Glu-Pro, respectively. Both of the peptides were determined as non-competitive inhibitors with K_i values of 7.61±0.16μmol/L and 23.59±0.54μmol/L respectively, and kept their inhibitory activities well after incubation with main gastrointestinal proteases.
In vivo experiments in SHRs indicated that the least effective doses of Ile-Gln-Pro and Val-Glu-Pro were 2.5 mg/kg body weight (BW) and 5 mg/kg BW respectively, and the antihypertensive effects were accompanied with their regulation on major components in the RAS. Compared with Captopril, both of the peptides exhibited more potent activities in vivo than in vitro, and maintained the best antihypertensive effects longer.
Furthermore, dietary Spirulina platensis and its enzymatic digests could effectively suppress the acute liver injuries induced by D-GalN or APAP in ICR mice and Wistar rats, and the hepatoprotective effects were accompanied with their regulation on lipid peroxidation in the liver as well as expressions of the proinflammatory cytokine IL-18 and the hepatic RAS components.
The present work purified potent ACE inhibitory peptides from Spirulina platensis for the first time, and innovatively investigated the antihypertensive and hepatoprotective effects of Spirulina platensis and the regulation on expressions of IL-18 and the RAS components. The results suggested Spirulina platensis would be of great prospects as an ingredient of functional foods or medicines in treatment of hypertension and liver injuries.
引文
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