鸡腿蘑（Coprinus comatus）防治糖尿病生物活性物质结构鉴定及液体发酵的研究
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摘要
鸡腿蘑(Coprinus comatus)，被联合国粮农组织(FAO)和世界卫生组织(WHO)确定为具“天然、营养、保健”三种功能为一体的16种珍稀食用菌之一。现代研究表明，鸡腿蘑具有降低血糖、防止肝损伤、抗肿瘤、提高机体免疫力等功效。本课题以抑制糖尿病非酶糖基化反应为筛选指标，首次对鸡腿蘑发酵液中的抗糖尿病活性成份分进行分离纯化，并以此展开结构分析、生理活性及发酵优化等相关的研究。具体结果如下：
1、通过AB-8大孔树脂吸附分离与检测表明，鸡腿蘑发酵液中在抑制非酶糖基化反应方面具有高活性的物质是非多糖和非蛋白类物质。对AB-8大孔树脂吸附20％乙醇洗脱组分进行常压C18反相柱分离，获得了一种具有高抑制非酶糖基化活性的物质，将其命名为Comatin。其在2mg／mL浓度下的抑制率达到95.86％，在0.5mg／mL浓度下抑制率达到60.53％。
2、在常压分离的基础上，通过中压C18反相柱对Comatin进行纯化，获得色谱纯的Comatin。通过核磁共振、质谱、红外、紫外测定，推定Comatin为4，5-二羟基-2-甲氧基苯甲醛(4，5-Dihydroxy-2-Methoxy-Benzaldehyde，4，5-DHMB)，为首次从鸡腿蘑中分离获得，进一步有力的证明了鸡腿蘑防治糖尿病的作用。经过量子化学计算4，5-DHMB具有稳定的结构。
3、建立了HPLC检测鸡腿蘑发酵液中4，5-DHMB的方法，实验表明，鸡腿蘑发酵液采用乙酸乙酯预处理对HPLC的测定具有良好的效果。本文所建立的测定方法，在样品浓度为1.23～123μg·mL~(-1)范围内线性关系良好；在3.8，19.1，114.8μg·mL~(-1)浓度水平上，其日内和日间精度分别为1.5～5.6％，2.5～4.6％；准确度为97.9～110.2％；在4.90，9.80，58.8μ·mL~(-1)。3个添加水平范围内，回收率为93.8～96.6％，相对标准偏差为3.3～8.5％。该方法能够在20min内完成一次分析，具有快速、准确、可靠的特点。
4、体外试验表明，4，5-DHMB对非酶糖基化抑制作用的半抑制浓度IC_(50)为0.39mg／mL。根据实验结果分析，4，5-DHMB可能与蛋白质某一位点结合，且这种结合是在己二醛与牛血清白蛋白结合之后，同时4，5-DHMB与其结合后改变了非酶糖基化反应产物的结构，表现其荧光消失。根据经过量子化学计算结果以及与相关文献的对比分析，4，5-DHMB对非酶糖基化的抑制并不是在于影响蛋白质中的氨基与糖的醛基的结合，而更有可能是对Amadori产物之后反应过程产生重要的影响，或者是对希夫碱重排产生影响，这与实验结果所推导的结论相吻合。同时，4，5-DHMB在体外还具有抑制α-葡萄糖苷酶作用，其对α-葡萄糖苷酶抑制作用的半抑制浓度IC_(50)为2.96mg／mL，且是一种非竞争性抑制剂，K_m=3.5×10~(-4)mol／L，Dixon曲线表明，K_i值为1.35mg／mL。
5、口服糖耐量试验表明，4，5-DHMB显著降低口服葡萄糖后2～3 h血糖的水平，说明4，5-DHMB具有降血糖的作用；预防性动物试验表明，4，5-DHMB具有较好的预防小鼠由四氧嘧啶诱导糖尿病的作用。
6、糖尿病小鼠动物试验表明，4，5-DHMB降低了四氧嘧啶诱导的1型糖尿病小鼠的血糖水平：降低了体内果糖胺水平，说明抑制了体内非酶糖基化反应；降低了小鼠三磷酸甘油酯和胆固醇水平，糖尿病小鼠糖脂代谢得到改善，减轻了糖脂毒性。在一定程度上延缓了胰岛β细胞功能衰竭，从而形成良性循环。
7、以4，5-DHMB为目的产物，对鸡腿蘑液体发酵及发酵条件进行了优化，Plackett-Burman实验表明，影响4，5-DHMB产量和鸡腿蘑生物量的主要因素不尽相同，且相同因素的正负效应作用也不一致，这表明4，5-DHMB形成与鸡腿蘑菌丝体的生长处于不偶联的状态。通过全因子中心组合实验设计对发酵培养基进行了优化，获得以4，5-DHMB为目的产物的鸡腿蘑最优发酵培养基为：玉米粉15.40g／L，麸皮13.01g／L、KH_2PO_4 4.02g／L、MgSO_4·7H_2O 1.87g／L，葡萄糖5 g／L，在此条件下4，5-DHMB产量达到最大值：674.49μg·mL~(-1)。通过Box-Behnken实验设计对发酵条件进行了优化，获得以4，5-DHMB为目的产物的鸡腿蘑最优发酵条件为：发酵温度26.84℃，发酵时间99.57h，起始pH 6.30，装液量173.93mL／500mL，在此条件下4，5-DHMB产量达到最大值：894.01μg·mL~(-1)。
8、7L发酵罐规模的发酵实验表明在鸡腿蘑液体发酵过程中，4，5-DHMB的合成与鸡腿蘑菌体的形态有着较为密切的联系；搅拌速度对4，5-DHMB产量的影响主要是由于搅拌所形成的剪切力对鸡腿蘑菌体形态的影响，在较低的搅拌转速下有利于鸡腿蘑产生4，5-DHMB。通风量或溶氧水平对4，5-DHMB产量的影响要远大于对鸡腿蘑生长速度和生物量的影响。在鸡腿蘑发酵过程中，发酵液pH变化较小，说明不产生或极少产生有机酸，同时也不产生类似于灵芝酸类的萜类物质。
9、研究表明，较优的7L发酵罐鸡腿蘑发酵条件为：装液系数60％，发酵温度27℃，发酵起始pH 6.30，接种量7.5％，搅拌转速为75rpm，起始通风量0.6vvm，发酵到88～96h时降通风量降低到0.4vvm，发酵时间112～120h，4，5-DHMB产量达到最大值830.41μg·mL~(-1)。
Coprinus comatus, a precious macro-fungus, has been designated as natural, nutritious and healthy food by the Food and Agriculture Organization (FAO) and the World Health Organization (WHO). It has recently acquired interests due to its attractive potential application in pharmaceutical industries. It was reported that the immunomodulation activites, such as antihyperg-lycemia, liver injury recovering, immunomodulating, antitumor and hypolipidemic, have been observed in C. comatus. In this dissertation, with inhibition of non-enzymatic glycation reaction as the main index, the separation, purification, structure analysis and high efficiency production process of an antidiabetic substance from C. comatus fermentation broth were investigated in detail. The main results were described as follows:
1. In this study, a substance which gained from C. comatus fermentation broth with macropopous resin, has been proved that could inhibit the non-enzymatic glycation (NEG) reaction. And this substance was identified to be neither polysaccharide not protein. Comatin, which has high inhibition percentage on the NEG reaction, was obtained from the fermentation broth, which absorbed by macropopous resin and then separated with normal pressure C18 reversed-phase chromatography. It was observed that 95.86% and 60.53% inhibition percentage of comatin at the dose of 2mg/mL, and 0.5mg/mL, respectively. Comatin was further purified through medium pressure C18 RP chromatography to gain chromatographic grade sample.
2. Based on the spectral data of NMR, MS, infrared and ultraviolet, comatin was identified as 4,5-Dihydroxy-2-Methoxy-Benzaldehyde (4,5-DHMB). The quantum chemistry calculation showed that 4, 5-DHMB has the stable structure. As we best knowledge, this is first report that 4,5-Dihydroxy-2-Methoxy-Benzaldehyde obtained from C. comatus.
3. A high performance liquid chromatographic procedure was developed to determine the content of 4, 5-DHMB in C. comatus fermentation broth, and has proved to be validated. Chromatographic separation is performed on a C18 column (150mm×2.1mm i.d., 5μm particle).The mobile phase is composed of methanol-water (30:70, v/v) to 100% methanol in 20 min for gradient elution at a flow rate of 0.3mL/min. The method has good liner in the range of 1.23～123μg·mL~(-1) with R2=0.999. Intra- and inter-day precision ranged from 1.5 to 5.6% and 2.5 to 4.6%, respectively. The recovery was within 93.8%-96.6%. The assay procedure is simple, quickly, precise, and assure the continuous research for Coprinus comatus submerged culture and 4, 5-DHMB.
4. In vitro experiment showed that the IC50 of 4,5-DHMB on inhibition the non-enzymatic glycation reaction was 0.39mg/mL, and also found that 4,5-DHMB could combine with Amadori products to change their structure and finally attenuate their fluorescence intensity. Furthermore, the quantum chemistry calculation showed that the possible mechanism of 4, 5-DHMB inhibition non-enzymatic glycation lie in its influence on the reaction after Amadori reaction or the process of shift base rearrangement. The IC50 of 4, 5-DHMB on inhibiting the a-glycosidase was 2.96, and it has been proved to be a non-competitive inhibitor. The values of Km and Ki were 3.5x 104mol/L and 1.35 mg/mL, respectively.
5. The blood glucose levels were significantly elevated above initial blood glucose levels in response to the glucose challenge. There was a significant improvement in glucose tolerance of about 21 and 10.3% at 1 h peak value in 4, 5-DHMB mice. The maximum fall in fasting blood glucose (FBG) was after 1 h and maintained up to 2 h during fasting. It therefore appeared that 4, 5-DHMB was effective on FBG and healthy mice.
6. In vitro experiment demonstrated that: 1) 4, 5-DHMB could protect diabetic mice which induced by alloxan; 2) 4, 5-DHMB could remarkedly decreased the level of fasting blood glucose, plasma fructosamine, triglyceride, cholesterol in 1 type diabetic mice and attenuated the injured degree of 13 cell in pancreatic islet.
7. The results of Plackett-Burrnan suggested that the conditions for 4, 5-DHMB accumulation and mycelia growth were different. In order to achieve a high concentration, high yield and high productivity of 4,5-DHMB, a response surface methodology (RSM) was developed to optimize the nutritional and environmental conditions of 4,5-DHMB production. Firstly, the medium composition were optimized utilizing CCD design and the optimum medium composition were corn powder 15.40 g/L, wheat bran 13.01 g/L, KH_2PO_4 4.02 g/L, MgSO4·7H_2O 1.87 g/L, glucose 5 g/L. With the optimum medium, 674.49 μg/mL 4,5-DHMB was achieved. The optimum environmental conditions for 4,5-DHMB production were described as follows: Temperature 26.84"C, fermentation time 99.57h, initial pH 6.30, volume of medium 173.93 mL/500 mL. 894.01μg/mL 4, 5-DHMB was production under the optimized conditions.
8. Fermentations were carried out in a 7 i fermentor (71, Bioflo 101, NBS, USA) with 4 1 fermentation medium. It was found that the broth state play key role on the 4,5-DHMB production. A low agitation speed was facilitated the secretion of 4,5-DHMB from C. comatus, This may be due to the fact that shearing force severely change the state of mycelia in fermentation broth. Litter influence was observed aeration and dissolved oxygen on the mycelia growth and the biomass accumulation, but aeration and dissolved oxygen play important role on 4, 5-DHMB synthesis. On another hand, a little organic acid was detected in the C. comatus fermentation broth.
9. The optimized fermentation conditions for the 7 1 fermentor were determined: 4 1 fermentation medium, temperature 27℃, initiate pH 6.30, inoculum concentration 7.5%, agitation speed 75rpm, initiate aeration 0.6wm and lowered to 0.4wm after 88～6h, fermentation time112～120h. A highest 4,5-DHMB concentration (830.41μg/mL) was achieved by combinational consideration of the optimum nutritional and environmental conditions in 7 1 fermentor.
1、通过AB-8大孔树脂吸附分离与检测表明，鸡腿蘑发酵液中在抑制非酶糖基化反应方面具有高活性的物质是非多糖和非蛋白类物质。对AB-8大孔树脂吸附20％乙醇洗脱组分进行常压C18反相柱分离，获得了一种具有高抑制非酶糖基化活性的物质，将其命名为Comatin。其在2mg／mL浓度下的抑制率达到95.86％，在0.5mg／mL浓度下抑制率达到60.53％。
2、在常压分离的基础上，通过中压C18反相柱对Comatin进行纯化，获得色谱纯的Comatin。通过核磁共振、质谱、红外、紫外测定，推定Comatin为4，5-二羟基-2-甲氧基苯甲醛(4，5-Dihydroxy-2-Methoxy-Benzaldehyde，4，5-DHMB)，为首次从鸡腿蘑中分离获得，进一步有力的证明了鸡腿蘑防治糖尿病的作用。经过量子化学计算4，5-DHMB具有稳定的结构。
3、建立了HPLC检测鸡腿蘑发酵液中4，5-DHMB的方法，实验表明，鸡腿蘑发酵液采用乙酸乙酯预处理对HPLC的测定具有良好的效果。本文所建立的测定方法，在样品浓度为1.23～123μg·mL~(-1)范围内线性关系良好；在3.8，19.1，114.8μg·mL~(-1)浓度水平上，其日内和日间精度分别为1.5～5.6％，2.5～4.6％；准确度为97.9～110.2％；在4.90，9.80，58.8μ·mL~(-1)。3个添加水平范围内，回收率为93.8～96.6％，相对标准偏差为3.3～8.5％。该方法能够在20min内完成一次分析，具有快速、准确、可靠的特点。
4、体外试验表明，4，5-DHMB对非酶糖基化抑制作用的半抑制浓度IC_(50)为0.39mg／mL。根据实验结果分析，4，5-DHMB可能与蛋白质某一位点结合，且这种结合是在己二醛与牛血清白蛋白结合之后，同时4，5-DHMB与其结合后改变了非酶糖基化反应产物的结构，表现其荧光消失。根据经过量子化学计算结果以及与相关文献的对比分析，4，5-DHMB对非酶糖基化的抑制并不是在于影响蛋白质中的氨基与糖的醛基的结合，而更有可能是对Amadori产物之后反应过程产生重要的影响，或者是对希夫碱重排产生影响，这与实验结果所推导的结论相吻合。同时，4，5-DHMB在体外还具有抑制α-葡萄糖苷酶作用，其对α-葡萄糖苷酶抑制作用的半抑制浓度IC_(50)为2.96mg／mL，且是一种非竞争性抑制剂，K_m=3.5×10~(-4)mol／L，Dixon曲线表明，K_i值为1.35mg／mL。
5、口服糖耐量试验表明，4，5-DHMB显著降低口服葡萄糖后2～3 h血糖的水平，说明4，5-DHMB具有降血糖的作用；预防性动物试验表明，4，5-DHMB具有较好的预防小鼠由四氧嘧啶诱导糖尿病的作用。
6、糖尿病小鼠动物试验表明，4，5-DHMB降低了四氧嘧啶诱导的1型糖尿病小鼠的血糖水平：降低了体内果糖胺水平，说明抑制了体内非酶糖基化反应；降低了小鼠三磷酸甘油酯和胆固醇水平，糖尿病小鼠糖脂代谢得到改善，减轻了糖脂毒性。在一定程度上延缓了胰岛β细胞功能衰竭，从而形成良性循环。
7、以4，5-DHMB为目的产物，对鸡腿蘑液体发酵及发酵条件进行了优化，Plackett-Burman实验表明，影响4，5-DHMB产量和鸡腿蘑生物量的主要因素不尽相同，且相同因素的正负效应作用也不一致，这表明4，5-DHMB形成与鸡腿蘑菌丝体的生长处于不偶联的状态。通过全因子中心组合实验设计对发酵培养基进行了优化，获得以4，5-DHMB为目的产物的鸡腿蘑最优发酵培养基为：玉米粉15.40g／L，麸皮13.01g／L、KH_2PO_4 4.02g／L、MgSO_4·7H_2O 1.87g／L，葡萄糖5 g／L，在此条件下4，5-DHMB产量达到最大值：674.49μg·mL~(-1)。通过Box-Behnken实验设计对发酵条件进行了优化，获得以4，5-DHMB为目的产物的鸡腿蘑最优发酵条件为：发酵温度26.84℃，发酵时间99.57h，起始pH 6.30，装液量173.93mL／500mL，在此条件下4，5-DHMB产量达到最大值：894.01μg·mL~(-1)。
8、7L发酵罐规模的发酵实验表明在鸡腿蘑液体发酵过程中，4，5-DHMB的合成与鸡腿蘑菌体的形态有着较为密切的联系；搅拌速度对4，5-DHMB产量的影响主要是由于搅拌所形成的剪切力对鸡腿蘑菌体形态的影响，在较低的搅拌转速下有利于鸡腿蘑产生4，5-DHMB。通风量或溶氧水平对4，5-DHMB产量的影响要远大于对鸡腿蘑生长速度和生物量的影响。在鸡腿蘑发酵过程中，发酵液pH变化较小，说明不产生或极少产生有机酸，同时也不产生类似于灵芝酸类的萜类物质。
9、研究表明，较优的7L发酵罐鸡腿蘑发酵条件为：装液系数60％，发酵温度27℃，发酵起始pH 6.30，接种量7.5％，搅拌转速为75rpm，起始通风量0.6vvm，发酵到88～96h时降通风量降低到0.4vvm，发酵时间112～120h，4，5-DHMB产量达到最大值830.41μg·mL~(-1)。
Coprinus comatus, a precious macro-fungus, has been designated as natural, nutritious and healthy food by the Food and Agriculture Organization (FAO) and the World Health Organization (WHO). It has recently acquired interests due to its attractive potential application in pharmaceutical industries. It was reported that the immunomodulation activites, such as antihyperg-lycemia, liver injury recovering, immunomodulating, antitumor and hypolipidemic, have been observed in C. comatus. In this dissertation, with inhibition of non-enzymatic glycation reaction as the main index, the separation, purification, structure analysis and high efficiency production process of an antidiabetic substance from C. comatus fermentation broth were investigated in detail. The main results were described as follows:
1. In this study, a substance which gained from C. comatus fermentation broth with macropopous resin, has been proved that could inhibit the non-enzymatic glycation (NEG) reaction. And this substance was identified to be neither polysaccharide not protein. Comatin, which has high inhibition percentage on the NEG reaction, was obtained from the fermentation broth, which absorbed by macropopous resin and then separated with normal pressure C18 reversed-phase chromatography. It was observed that 95.86% and 60.53% inhibition percentage of comatin at the dose of 2mg/mL, and 0.5mg/mL, respectively. Comatin was further purified through medium pressure C18 RP chromatography to gain chromatographic grade sample.
2. Based on the spectral data of NMR, MS, infrared and ultraviolet, comatin was identified as 4,5-Dihydroxy-2-Methoxy-Benzaldehyde (4,5-DHMB). The quantum chemistry calculation showed that 4, 5-DHMB has the stable structure. As we best knowledge, this is first report that 4,5-Dihydroxy-2-Methoxy-Benzaldehyde obtained from C. comatus.
3. A high performance liquid chromatographic procedure was developed to determine the content of 4, 5-DHMB in C. comatus fermentation broth, and has proved to be validated. Chromatographic separation is performed on a C18 column (150mm×2.1mm i.d., 5μm particle).The mobile phase is composed of methanol-water (30:70, v/v) to 100% methanol in 20 min for gradient elution at a flow rate of 0.3mL/min. The method has good liner in the range of 1.23～123μg·mL~(-1) with R2=0.999. Intra- and inter-day precision ranged from 1.5 to 5.6% and 2.5 to 4.6%, respectively. The recovery was within 93.8%-96.6%. The assay procedure is simple, quickly, precise, and assure the continuous research for Coprinus comatus submerged culture and 4, 5-DHMB.
4. In vitro experiment showed that the IC50 of 4,5-DHMB on inhibition the non-enzymatic glycation reaction was 0.39mg/mL, and also found that 4,5-DHMB could combine with Amadori products to change their structure and finally attenuate their fluorescence intensity. Furthermore, the quantum chemistry calculation showed that the possible mechanism of 4, 5-DHMB inhibition non-enzymatic glycation lie in its influence on the reaction after Amadori reaction or the process of shift base rearrangement. The IC50 of 4, 5-DHMB on inhibiting the a-glycosidase was 2.96, and it has been proved to be a non-competitive inhibitor. The values of Km and Ki were 3.5x 104mol/L and 1.35 mg/mL, respectively.
5. The blood glucose levels were significantly elevated above initial blood glucose levels in response to the glucose challenge. There was a significant improvement in glucose tolerance of about 21 and 10.3% at 1 h peak value in 4, 5-DHMB mice. The maximum fall in fasting blood glucose (FBG) was after 1 h and maintained up to 2 h during fasting. It therefore appeared that 4, 5-DHMB was effective on FBG and healthy mice.
6. In vitro experiment demonstrated that: 1) 4, 5-DHMB could protect diabetic mice which induced by alloxan; 2) 4, 5-DHMB could remarkedly decreased the level of fasting blood glucose, plasma fructosamine, triglyceride, cholesterol in 1 type diabetic mice and attenuated the injured degree of 13 cell in pancreatic islet.
7. The results of Plackett-Burrnan suggested that the conditions for 4, 5-DHMB accumulation and mycelia growth were different. In order to achieve a high concentration, high yield and high productivity of 4,5-DHMB, a response surface methodology (RSM) was developed to optimize the nutritional and environmental conditions of 4,5-DHMB production. Firstly, the medium composition were optimized utilizing CCD design and the optimum medium composition were corn powder 15.40 g/L, wheat bran 13.01 g/L, KH_2PO_4 4.02 g/L, MgSO4·7H_2O 1.87 g/L, glucose 5 g/L. With the optimum medium, 674.49 μg/mL 4,5-DHMB was achieved. The optimum environmental conditions for 4,5-DHMB production were described as follows: Temperature 26.84"C, fermentation time 99.57h, initial pH 6.30, volume of medium 173.93 mL/500 mL. 894.01μg/mL 4, 5-DHMB was production under the optimized conditions.
8. Fermentations were carried out in a 7 i fermentor (71, Bioflo 101, NBS, USA) with 4 1 fermentation medium. It was found that the broth state play key role on the 4,5-DHMB production. A low agitation speed was facilitated the secretion of 4,5-DHMB from C. comatus, This may be due to the fact that shearing force severely change the state of mycelia in fermentation broth. Litter influence was observed aeration and dissolved oxygen on the mycelia growth and the biomass accumulation, but aeration and dissolved oxygen play important role on 4, 5-DHMB synthesis. On another hand, a little organic acid was detected in the C. comatus fermentation broth.
9. The optimized fermentation conditions for the 7 1 fermentor were determined: 4 1 fermentation medium, temperature 27℃, initiate pH 6.30, inoculum concentration 7.5%, agitation speed 75rpm, initiate aeration 0.6wm and lowered to 0.4wm after 88～6h, fermentation time112～120h. A highest 4,5-DHMB concentration (830.41μg/mL) was achieved by combinational consideration of the optimum nutritional and environmental conditions in 7 1 fermentor.
引文
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