Lactobacillus paracasei subsp. paracasei NTU 101 發酵產物對改善腦血管疾病之研究

鄭孟純

doi:10.6342/NTU201700388

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Lactobacillus paracasei subsp. paracasei NTU 101 发酵产物对改善脑血管疾病之研究

Study on the Lactobacillus paracasei subsp. paracasei NTU 101-fermented products for improvement in cerebrovascular diseases

郑孟纯 , 博士　　导师：潘子明　　共同指导教授：陈俊任

繁体中文 DOI： 10.6342/NTU201700388

脑血管疾病；氧气与葡萄糖剥夺； NTU 101 ；发酵产物； glyceryl 1,3-dipalmitate ； cerebrovascular diseases ； oxygen-glucose deprivation ； NTU 101 ； fermented product ； glyceryl 1,3-dipalmitate

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摘要 │ 参考文献 (226) │ 国际计量

摘要〈TOP〉

脑血管疾病为一种严重的神经性疾病，亦为导致死亡与成年人长期残疾的主要原因。脑血管疾病发生期间，氧气和葡萄糖供应不足造成细胞损伤与大量自由基产生，最终导致神经细胞死亡及造成智力减退，由脑血管疾病引起之认知障碍及失智症统称为血管性失智症。近年来研究指出萃取自蔬果与饮品中之天然化合物，藉由抗氧化、抗发炎及抑制微胶细胞活化等机制达到神经保护之效果。本研究室先前研究结果显示，Lactobacillus paracasei subsp. paracasei NTU 101 (NTU 101) 发酵产物可改善数种与氧化压力及/或发炎反应相关之疾病，亦能降低脑血管疾病之危险因子如：高血压、粥状动脉硬化、高血脂及肥胖。推论 NTU 101 发酵产物应具抗氧化及抗发炎等生理活性，故具预防及治疗脑血管疾病之潜力。首先，以菌数、pH 值与乳酸变化作为指标，初步筛选出适合 NTU 101 发酵之基质为 25% 牛奶添加 5% 葡萄糖 (25% SM + 5% Glc)。25% SM + 5% Glc 发酵液之乙醇萃取物，於浓度 1 mg/mL 下，可预防由氧气与葡萄糖剥夺及再灌注 (oxygen glucose deprivation-reoxygenation, OGD/R) 所造成之细胞死亡，与 OGD/R 相比，显着回复细胞存活率达 42% (p < 0.05，回复率公式:(样品组细胞存活率- OGD/R 组细胞存活率)/OGD/R 组细胞存活率 × 100%)。进一步探讨 25% SM + 5% Glc 中具神经保护之生物活性物质，25% SM + 5% Glc 之 NTU 101 发酵液乙醇萃取物中的区分物 2-7-4 (F-2-7-4) 於浓度 10 μg/mL 下与 OGD/R 相比显着增加细胞存活率达 40% (p < 0.05)。F-2-7-4 由超高效液相层析串联质谱仪 (ultra-performance liquid chromatography-mass spectrometry) 得其伪离子峰为 m/z 551.5033 ([M-H2O+H]+)，利用核磁共振 (nuclear magnetic resonance) 仪监定其分子式为 C35H68O5、分子量为 568 之化合物 glyceryl 1,3-dipalmitate (GD)。动物试验以含有 GD 之 25% SM + 5% Glc 之 NTU 101 发酵液乙醇萃取物 (NTU101F) 来评估其对於醋酸去氧皮质酮与盐溶液 (deoxycorticosterone acetate and salt solution, DOCA-S) 高血压诱导血管性失智症之改善效果，实验结果显示，NTU101F (11、22 或 110 mg/kg) 可改善弓动脉弹性蛋白排列散乱及增加内皮型一氧化氮合成酶 (endothelial nitric oxide synthase) 表现量，促使一氧化氮生成，达到血管舒张之效果，亦可降低脑部水分滞留及脑组织中基质金属蛋白酶 9 (matrix metalloproteinases-9)、氧化压力及发炎之情形，进而改善学习记忆之能力。以上结果显示，NTU101F 可透过抗氧化及抗发炎机制，预防血管性失智症之效果，具有潜力应用於脑血管疾病。进一步利用人类神经纤维瘤母细胞 (SH-SY5Y) 探讨 GD 之神经保护机制，GD 可减缓 OGD/R 引起胞内活性氧 (reactive oxygen species) 之生成，提升细胞核中过氧化体增生剂活化接受器 γ (peroxisome proliferator-activated receptor gamma) 与核因子-红血球之 2 相关因子-2 (nuclear factor erythroid 2-related factor 2, Nrf2) 之蛋白表现量，进而促使 Nrf2 下游抗氧化酵素-第一型血红素氧化酶 (heme oxygenase-1, HO-1) 之表现，因而提升神经细胞抗氧化之能力，进而降低氧化压力所造成之损伤。GD 可抑制核因子活化 B 细胞 κ 轻链增强子 (nuclear factor kappa-light-chain-enhancer of activated B cells) 之表现量，降低发炎反应。亦可藉由提升钙离子通道蛋白 (plasma membrane Ca2+ ATPase) 之表现量，调控细胞内钙离子之含量，达到减缓神经细胞损伤之效果。我们的研究结果显示 GD 具预防或治疗缺血性脑损伤及神经退行性疾病之潜力。由反应曲面法所得之最适 GD 生成条件为牛奶浓度 25.53%、葡萄糖浓度 44.32 g/L 及培养温度 39.52oC，於此最适培养条件下，可生成 71.51 ng/g 之GD。以葡萄糖与牛奶为替代培养基可降低生产成本，提升其应用於商业之可行性。

并列摘要〈TOP〉

Cerebrovascular disease is a common and serious neurological disease, which is the leading cause of death and long-term disability in adults. During the development of cerebrovascular disease, glucose and oxygen deficiencies induce subcellular damage and produce large amounts of free radicals, finally leading to neuronal death and intelligence deterioration. Cerebrovascular disease causes cognitive impairment and vascular dementia. Recent studies have focused on the potential preventative effects of natural fruit and vegetable extracts and beverages against certain age-related neurological disorders. The underlying mechanisms include antioxidation, anti-inflammation, and inhibition of microglia activation. Therefore, natural products are attracting increasing attention in the field of drug discovery. Our research group found that the fermentation metabolites of Lactobacillus paracasei subsp. paracasei NTU 101 (NTU 101) have antioxidant and anti-inflammation effects. In addition, they reduce the risk factors of cerebrovascular diseases such as hypertension, atherosclerosis, hyperlipidemia, and obesity. NTU 101-fermented metabolites have the potential to prevent and treat cerebrovascular diseases. The addition of 5% glucose to a 25% milk solution (25% SM + 5% Glc) exerted a significant effect not only on the number of bacterial cells but also on their acid-producing ability. A more statistically significant increase in cell viability was observed in the group treated with the 1 mg/mL ethanol NTU 101 extract-fermented 25% SM + 5% Glc (NTU101F) than was observed in the control oxygen-glucose deprivation-reoxygenation (OGD/R) pre-treatment groups (42%, p < 0.05, recovery rate: (cell viability of sample-treatment group - cell viability of OGD/R group)/cell viability of OGD/R group × 100%). Therefore, we investigated the neuroprotective compounds in the NTU101F. At a concentration of 10 μg/mL, fraction 2-7-4 (F-2-7-4) significantly enhanced cell viability by 40% (p < 0.05). The molecular formula of F-2-7-4 was identified as glyceryl 1,3-dipalmitate (GD, C35H68O5) using nuclear magnetic resonance and ultra-performance liquid chromatography-mass spectrometry (m/z 551.5033, [M-H2O+H]+). The hypertension-induced vascular dementia rats were orally administered the GD-containing-NTU101F (11, 22, or 110 mg/kg), which improved the elastin arrangement and upregulated the expression of endothelial nitric oxide (NO) synthase (eNOS). The upregulated eNOS stimulated NO synthesis and, thereby, improved hypertension. NTU101F also improved the learning and memory ability, and decreased brain edema, matrix metalloproteinase (MMP)-9 and oxidative activity, and inflammation in the hippocampus. Our results indicate that NTU101F effectively inhibited oxidative stress- and inflammation-related mechanisms in the brain, thus providing neuroprotection and preventing hypertension-associated loss of cognitive abilities. Therefore, we further investigated the neuroprotective effect of GD in human neuroblastoma SH-SY5Y cells. GD ameliorated OGD/R-induced apoptosis by elevating the expression of nuclear peroxisome proliferator-activated receptor gamma and nuclear factor erythroid 2-related factor 2 (Nrf2) proteins and its downstream heme oxygenase-1, which attenuated reactive oxygen species generation. Pre-treatment with GD reduced the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, which attenuated the induction of pro-inflammatory mediators. GD also increased the plasma membrane Ca2+ adenosine triphosphatase (ATPase, PMCA) level and, thereby, reduced the levels of cytosolic Ca2+, which also correlated with the reduced cell death. Our findings indicate the potential of the therapeutic application of GD in the prevention and treatment of cerebral ischemic and neurodegenerative diseases. The response surface plot predicted a maximum GD concentration (71.51 ng/g) at an incubation temperature of 39.52°C using the substrate containing 25.53% milk and 44.32 g/L glucose. The milk powder and glucose were used as an alternative medium which could decrease the production cost, with the potential prospects for application.

参考文献 ( 226 ) 〈TOP〉

Aderem, A., Underhill, D.M. 1999. Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17: 593-623.
连结：
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