蛹虫草提取物对高尿酸血症大鼠的降尿酸作用及机制

doi:10.13560/j.cnki.biotech.bull.1985.2024-0379

生物技术通报 ›› 2024, Vol. 40 ›› Issue (11): 34-46.doi: 10.13560/j.cnki.biotech.bull.1985.2024-0379

• 菌物功效及作用机制专题（专题主编：王迪教授） • 上一篇下一篇

蛹虫草提取物对高尿酸血症大鼠的降尿酸作用及机制

熊心怡¹^,²(), 刘利平², 冯杰², 张劲松², 李德顺², 刘朋²(), 刘艳芳²()

1.上海海洋大学食品学院，上海 201306
2.上海市农业科学院食用菌研究所农业农村部南方食用菌资源利用重点实验室国家食用菌工程技术研究中心，上海 201403

收稿日期:2024-04-21 出版日期:2024-11-26 发布日期:2024-12-19
通讯作者: 刘朋，女，博士，助理研究员，研究方向：食用菌功能活性物质；E-mail: liupeng@saas.sh.cn；
刘艳芳，女，博士，研究员，研究方向：食用菌功能成分研究；E-mail: aliu-1980@163.com
作者简介:熊心怡，女，硕士研究生，研究方向：食用菌营养评价与功能；E-mail: xxinyi1030@163.com
基金资助:
国家现代农业产业技术体系项目(CARS-20);上海市农业科学院卓越团队建设计划(2022A-03)

Effect and Mechanism of Cordyceps militaris Extract on Lowering Uric Acid in Hyperuricemia Rats

XIONG Xin-yi¹^,²(), LIU Li-ping², FENG Jie², ZHANG Jin-song², LI De-shun², LIU Peng²(), LIU Yan-fang²()

1. College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306
2. Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences; Key Laboratory of Edible Fungi Resources and Utilization（South）, Ministry of Agriculture and Rural Affairs, P. R. China; National Engineering Research Center of Edible Fungi, Shanghai 201403

Received:2024-04-21 Published:2024-11-26 Online:2024-12-19

摘要/Abstract

摘要：

【目的】 探究蛹虫草（Cordyceps militaris）提取物对高尿酸血症模型大鼠的降尿酸（uric acid，UA）作用及其机制。【方法】 测定蛹虫草提取物总糖、还原糖、多糖、蛋白质和多酚物质含量，基于灌胃氧嗪酸钾联合酵母膏饲养建立高尿酸血症大鼠模型，通过对大鼠的血清UA水平、肾功能、氧化应激和炎症以及肠道微生物组成变化等测定以评价蛹虫草提取物对高尿酸血症大鼠的影响作用及其机制。【结果】 蛹虫草提取物含有35.86%多糖、27.05%蛋白质及0.21%的酚类物质。动物实验结果表明，蛹虫草提取物降低高尿酸血症大鼠血清的UA水平，其中0.5 g/(kg·d)的蛹虫草提取物效果最佳，可使UA水平从281.62 μmol/L降至93.27 μmol/L，抑制率为66.88%，同时可抑制高尿酸血症大鼠肾脏组织的氧化应激和炎症反应。分子机制研究表明，蛹虫草提取物可以下调高尿酸血症大鼠肾脏组织中尿酸盐阴离子转运蛋白（uric acid transporter 1，URAT1）、葡萄糖转运蛋白9（glucose transporter 9，GLUT9）的表达水平；上调有机阴离子转运蛋白1（organic anion transporter 1，OAT1）和三磷酸腺苷结合盒转运蛋白G2（ATP binding cassette subfamily G member 2，ABCG2）的表达水平。蛹虫草提取物能显著抑制肝脏组织中的黄嘌呤氧化酶活力。此外，蛹虫草提取物能够提升高尿酸血症大鼠肠道微生物的多样性，维持其肠道微生态平衡。【结论】 蛹虫草提取物具有良好的抗高尿酸血症的作用，可能与调节尿酸转运蛋白表达水平和抑制黄嘌呤氧化酶活力等有关。

关键词: 高尿酸血症, 蛹虫草, 水提物, 尿酸转运蛋白, 肠道微生物

Abstract:

【Objective】 To investigate the effect and the corresponding mechanism of Cordyceps militaris（C. militaris）extract on lowering uric acid by hyperuricemia model rats. 【Method】 The contents of total sugars, reducing sugars, polysaccharides, proteins and polyphenols in C. militaris extract were determined. The rat model of hyperuricemia was established based on feeding of potassium oxonate combined with yeast paste. The serum uric acid level, renal function, oxidative stress and inflammation of rats and the changes of intestinal microbial composition were measured to evaluate the effect of C. militaris extract on hyperuricemia rats and its mechanism. 【Result】 The C. militaris extract contained 35.86% polysaccharides, 27.05% proteins, and 0.21% polyphenols. Animal experiments demonstrated that C. militaris extract significantly reduced the serum uric acid levels in hyperuricemia rats. The most effective dose was found to be 0.5 g/(kg·d), leading to a reduction in uric acid levels from 281.62 μmol/L to 93.27 μmol/L, with an inhibition rate of 66.88%. It also inhibited the oxidative stress and inflammation in renal tissue of hyperuricemia rats. Molecular mechanism studies showed that C. militaris extract down-regulated uric acid transporter1（URAT1）and glucose transporter 9（GLUT9）, up-regulated the expressions of organic anion transporter 1（OAT1）and ATP binding cassette subfamily G member 2（ABCG2）in renal tissues of hyperuricemia rats. Concurrently, C. militaris extract significantly inhibited the xanthine oxidase activity in liver tissues. In addition, C. militaris extract enhanced the diversity of intestinal microbiota and maintained the balance of intestinal microecology in hyperuricemia rats. 【Conclusion】 C. militaris extract demonstrated a good anti-hyperuricemia effect, which might be related to regulating the expression of uric acid transporter and inhibiting the activity of xanthine oxidase.

Key words: hyperuricemia, Cordyceps militaris, water extract, uric acid transporters, gut microbiota

熊心怡, 刘利平, 冯杰, 张劲松, 李德顺, 刘朋, 刘艳芳. 蛹虫草提取物对高尿酸血症大鼠的降尿酸作用及机制[J]. 生物技术通报, 2024, 40(11): 34-46.

XIONG Xin-yi, LIU Li-ping, FENG Jie, ZHANG Jin-song, LI De-shun, LIU Peng, LIU Yan-fang. Effect and Mechanism of Cordyceps militaris Extract on Lowering Uric Acid in Hyperuricemia Rats[J]. Biotechnology Bulletin, 2024, 40(11): 34-46.

图/表 11

表1 用于RT-qPCR目的基因的引物

Table 1 Primers for RT-qPCR target genes

基因Gene	引物序列Primer sequence（5'-3'）
URAT1	F: GCTACCAGAATCGGCACGCT
URAT1	R: CACCGGGAAGTCCACAATCC
GLUT9	F: GAGATGCTCATTGTGGGACG
GLUT9	R: GTGCTACTTCGTCCTCGGT
ABCG2	F: GTAGGTCGGTGTGCGAGTCA
ABCG2	R: AACCAGTTGTGGGCTCATCC
OAT1	F: GGCACCTTGATTGGCTATGT
OAT1	R: CCACAGCATGGAGAGACAGA
TNF-α	F: GCGTGTTCATCCGTTCTCTACC
TNF-α	R: TACTTCAGCGTCTCGTGTGTTTCT
IL-6	F: AGTTGCCTTCTTGGGACTGATGT
IL-6	R: GGTCTGTTGTGGGTGGTATCCTC
β-actin	F: GCAGGAGTACGATGAGTCCG
β-actin	R: ACGCAGCTCAGTAACAGTCC

表2 蛹虫草提取物的氨基酸和核苷类成分分析

Table 2 Analysis of amino acids and nucleosides components in C. militaris extract

氨基酸成分 Amino acid component	含量 Content/%	氨基酸成分 Amino acid component	含量 Content/%	核苷类成分 Nucleosides component	含量 Content/%
L-组氨酸	0.16	L-脯氨酸	0.41	胞嘧啶	0.01
L-精氨酸	0.94	L-鸟氨酸	2.31	胞苷	0.03
L-天冬酰胺	0.25	D-2-氨基丁酸	0.02	鸟嘌呤	0.02
L-谷氨酰胺	0.01	L-赖氨酸	1.08	腺嘌呤	0.03
L-丝氨酸	0.59	L-酪氨酸	0.34	尿苷	0.41
L-甘氨酸	0.14	L-甲硫氨酸	0.09	胸腺嘧啶	0.04
L-天冬氨酸	0.68	L-缬氨酸	0.64	肌苷	0.06
L-瓜氨酸	0.02	L-异亮氨酸	0.34	鸟苷	0.21
L-谷氨酸	1.92	L-亮氨酸	0.65	胸苷	0.02
L-苏氨酸	0.76	L-苯丙氨酸	0.28	腺苷	0.34
L-丙氨酸	1.57	L-色氨酸	0.10	虫草素	0.83
γ-氨基丁酸	0.25			N⁶-（2-羟乙基）腺苷	0.54

图1 蛹虫草提取物的红外光谱

Fig. 1 FT-IR spectrum of C. militaris extract

图2 蛹虫草提取物对高尿酸血症大鼠肾功能损伤的影响 A：血清尿酸水平；B：血清尿素氮浓度；C：血清肌酐浓度；D：肾脏胶原容积率；E：肾脏HE染色切片；F：肾脏Masson染色切片。与CTL组相比，###：P<0.001；与MC组相比，**：P<0.01，***：P<0.001。比例尺：100 μm

Fig. 2 Effects of C. militaris extract on renal function and renal pathological injury in hyperuricemia rats A: Serum uric acid level; B: serum urea nitrogen concentration; C: serum creatinine concentration; D: renal fibrotic area; E: HE staining of kidney; F: masson staining of kidney. Compared with CTL group, ###: P<0.001；compared with MC group, **: P<0.01, ***: P<0.001. Scale bar: 100 μm

图3 蛹虫草提取物对高尿酸血症大鼠肾脏氧化应激的影响 A：肾脏中GSH含量；B：肾脏中MDA含量；C：肾脏T-AOC。与CTL组相比，#：P<0.05；与MC组相比，**：P<0.01，***：P<0.001

Fig. 3 Effects of C. militaris extract on renal oxidative stress in hyperuricemia rats A: Renal GSH content; B: renal MDA content; C: renal T-AOC. Compared with CTL group, #: P<0.05；compared with MC group, **: P<0.01, ***: P<0.001

图4 蛹虫草提取物对高尿酸血症大鼠肾脏炎症的影响 A：肾脏CD68免疫组化切片；B：肾脏NLRP3的免疫组化切片；C：肾脏IL-1β免疫组化切片；D：CD68阳性表达率；E：IL-6 mRNA相对表达水平；F：TNF-α mRNA相对表达水平；G：NLRP3阳性表达率；H：IL-1β阳性表达率。与CTL组相比，###：P<0.001；与MC组相比，**：P<0.01，***：P<0.001，比例尺：100 μm

Fig. 4 Effects of C. militaris extract on renal inflammation in hyperuricemia rats A: IHC staining of CD68; B: IHC staining of NLRP3; C: IHC staining of IL-1β; D: positive area of CD68; E: relative mRNA levels of IL-6; F: relative mRNA levels of TNF-α; G: positive area of NLRP3; H: positive area of IL-1β. Compared with CTL group, ###: P<0.001；compared with MC group, **: P<0.01, ***: P<0.001. Scale bar: 100 μm

图5 蛹虫草提取物对高尿酸血症大鼠肾脏尿酸转运蛋白的影响 A：肾脏URAT1的免疫组化切片；B：肾脏OAT1免疫组化切片；C：URAT1阳性表达率；D：URAT1mRNA的表达水平；E：GLUT9 mRNA的表达水平；F：OAT1阳性表达率；G：OAT1 mRNA的表达水平；H：ABCG2 mRNA的表达水平。与CTL组相比，###：P<0.001；与MC组相比，**：P<0.01，***：P<0.001，比例尺：100 μm

Fig. 5 Effects of C. militaris extract on renal uric acid transporter in hyperuricemia rats A: IHC staining of URAT1; B: IHC staining of OAT1; C: positive area of URAT1; D: relative mRNA levels of URAT1; E: relative mRNA levels of GLUT9; F: positive area of OAT1; G: relative mRNA levels of OAT1; H: relative mRNA levels of ABCG2. Compared with CTL group, ###: P<0.001；compared with MC group, **: P<0.01, ***: P<0.001. Scale bar: 100 μm

图6 蛹虫草提取物对高尿酸血症大鼠XOD活性和肝脏病理学损伤的影响 A：肝脏XOD活力；B：肝脏HE染色切片。与CTL组相比，###：P<0.001；与MC组相比，*：P<0.05，**：P<0.01，***：P<0.001，比例尺：100 μm

Fig. 6 Effects of C. militaris extract on XOD activity and liver pathological injury in hyperuricemia rats A: XOD activity in kidney; B: HE staining of kidney. Compared with CTL group, ###: P<0.001；compared with MC group, *: P<0.05, **: P<0.01, ***: P<0.001. Scale bar: 100 μm

图7 高尿酸血症大鼠肠道微生物PCA分析图（A）和LEfSe多级物种层级树图（B）

Fig. 7 PCA analysis（A）and LEfSe multilevel species-level tree（B）of gut microbiota in hyperuricemia rats

图8 蛹虫草提取物对高尿酸血症大鼠关键肠道微生物相对丰度的影响

Fig. 8 Effects of C. militaris extract on the relative abundances of key gut microbiota in rats with hyperuricemia

图9 差异OTUs与生化指标的相关性分析

Fig. 9 Correlation analysis of differential OTUs and biochemical indexes

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蛹虫草提取物对高尿酸血症大鼠的降尿酸作用及机制

Effect and Mechanism of Cordyceps militaris Extract on Lowering Uric Acid in Hyperuricemia Rats

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