丹皮酚对大脑中动脉缺血模型小鼠行为功能障碍的改善作用研究

doi:10.12114/j.issn.1007-9572.2022.0346

中国全科医学 ›› 2023, Vol. 26 ›› Issue (27): 3441-3449.DOI: 10.12114/j.issn.1007-9572.2022.0346

丹皮酚对大脑中动脉缺血模型小鼠行为功能障碍的改善作用研究

陈茜¹, 骆建宇², 邝枣园²^,^*(), 许沁²^,^*()

1．510006　广东省广州市，广州中医药大学基础医学院
2．510006　广东省广州市，广州中医药大学针灸康复临床医学院

收稿日期:2022-03-06 修回日期:2022-11-11 出版日期:2023-09-20 发布日期:2023-01-12
通讯作者: 邝枣园, 许沁
作者贡献：许沁提出研究思路，确定模型的选择；陈茜负责小鼠模型制作、负责各种实验、对样本进行采集、收集相关数据、进行统计学分析和绘制图表，负责论文起草最终版本修订，对论文负责；骆建宇负责行为学实验，负责行为学数据的采集和统计学分析；邝枣园设计研究方案，研究命题的提出、设计。
基金资助:
国家自然科学基金资助项目(81903836); 广东省中医药局局科研项目(20201086)

Effect of Paeonol on Improving Behavioral Dysfunction in a Mouse Model of Middle Cerebral Artery Occlusion

CHEN Xi¹, LUO Jianyu², KUANG Zaoyuan²^,^*(), XU Qin²^,^*()

1. School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
2. Acupuncture & Rehabilitation Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

Received:2022-03-06 Revised:2022-11-11 Published:2023-09-20 Online:2023-01-12
Contact: KUANG Zaoyuan, XU Qin

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摘要/Abstract

摘要： 背景中风是严重危害人体健康的心脑血管系统疾病之一，具有高患病率、高致残率和高致死率的特征。牡丹皮是毛茛科植物牡丹干燥根皮，具有清热凉血、活血化瘀之功效。丹皮酚是牡丹皮的主要活性成分，已有研究证实在缺糖缺氧条件下，丹皮酚对神经元有一定保护作用。目的观察丹皮酚对大脑中动脉缺血（MCAO）模型小鼠的干预效果，探究丹皮酚溶液灌胃在治疗中风行为功能障碍的神经生物学机制。方法本研究时间为2019年12月—2021年12月。缺血性中风模型的建立与评价：将20只SPF级雄性C57BL/6小鼠，采用随机数字表法分成假手术组（n=10）、模型组（MCAO组，n=10），采用线栓法制成小鼠MCAO模型，造模24 h后，通过Longa评分评价各组小鼠神经功能受损情况；激光散斑血流成像系统监测各组小鼠在MCAO术后大脑血流改变状况；对MCAO术后的小鼠进行TTC染色，在病理上观察小鼠大脑的损伤情况。探究丹皮酚对MCAO小鼠的行为功能保护作用：将50只SPF级、雄性C57BL/6小鼠进行随机分组：假手术组（n=10）、模型+玉米油组（n=20）、模型+丹皮酚组（n=20）。造模后24 h，验证模型稳定后，模型+丹皮酚组用丹皮酚玉米油溶液灌胃，给药浓度为100 mg·kg-1· d-1，其余组灌服等量玉米油。在造模28 d后，统计三组小鼠的存活情况，绘制生存曲线；使用Longa评分判断小鼠神经功能恢复情况；尼氏染色法检测小鼠大脑梗死面积；行为学测试小鼠在造模前及造模后7、14、21、28 d 5个时间点的运动感觉功能改变。探究丹皮酚对MCAO小鼠行为功能改善的机制：随机将30只SPF级、雄性C57BL/6小鼠分成假手术组（n=6）、模型+玉米油组（n=12）、模型+丹皮酚组（n=12）。造模后24 h，验证模型稳定后，药物组用丹皮酚玉米油溶液灌胃，给药浓度为100 mg·kg-1·d-1，其余组灌服等量玉米油。造模后2 d，用Western blotting法测定小鼠大脑纹状体白介素1β（IL-1β）蛋白表达情况，探究急性期内丹皮酚是否能降低大脑炎性反应；造模后14 d，采用免疫荧光法检测小鼠大脑半暗带离子钙结合衔接分子1（IBA1）、胶质纤维酸性蛋白（GFAP）的表达。结果模型+玉米油组小鼠干预28 d的生存率为66.47%，丹皮酚组小鼠生存率为81.43%。Log-rank检验结果显示，三组小鼠干预28 d的生存曲线比较，差异有统计学意义（χ2=1.436，P<0.05）。造模28 d后，模型+丹皮酚组Longa评分低于模型+玉米油组（P<0.05）。三组小鼠造模后14 d脑组织中IBA1、GFAP表达水平比较，差异有统计学意义（P<0.05）；模型+玉米油组、模型+丹皮酚组小鼠造模后14 d脑组织中IBA1、GFAP表达水平高于假手术组（P<0.05）；模型+丹皮酚组小鼠造模后14 d脑组织中IBA1、GFAP表达水平低于模型+玉米油组（P<0.05）。模型+玉米油组小鼠造模后2 d纹状体IL-1β蛋白表达水平高于假手术组（P<0.05）；模型+丹皮酚组小鼠造模后2 d纹状体IL-1β蛋白表达水平低于模型+玉米油组（P<0.05）。结论丹皮酚可控制MCAO模型中小鼠在急性阶段的发症反应，减少了小鼠急性脑梗死面积，延长了小鼠生存期、改善了其运动感觉功能。

关键词: 脑缺血, 大脑中动脉缺血, 丹皮酚, 离子钙结合衔接分子1, 胶质纤维酸性蛋白, 白介素1β, 功能障碍

Abstract:

Background

Stroke is a cardiovascular disease that seriously endangers human health, which is characterized by high prevalence, disability and mortality rates. Peony bark is the dried root bark of peony in the buttercup family, which has the effect of clearing heat and cooling blood, activating blood circulation and resolving blood stasis. Paeonol (PAE) is the main active ingredient of peony bark, has been confirmed to have neuroprotective effect under hypoglycemia and hypoxia conditions.

Objective

To observe the effect and neurobiological mechanism of gastric administration of paeonol solution on improving behavioral dysfunction caused by middle cerebral artery occlusion (MCAO) , a kind of stroke, in a mouse model.

Methods

The study was conducted from December 2019 to December 2021. Twenty SPF male C57BL/6 mice were randomized into SHAM group (n=10) and model group (MCAO group, n=10) . The MCAO model was formed by intraluminal suture method. After 24 hours of modeling, the neurological function of each group was evaluated by Longa Score. Laser Speckle Contrast Imaging was used to monitor the changes of cerebral blood flow after MCAO. TTC staining was used in the pathological examination of cerebral infarction in MCAO mice. For investigating the protective effect of PAE on behavioural dysfunction of MCAO mice, 50 SPF male C57BL/6 mice were randomly grouped into SHAM group (n=10) , model+corn oil group (n=20) , and model+PAE group (n=20) . After the verification of model stability at 24 hours following the modeling, the model+PAE group received intragastric administration of PAE and corn oil solution in a concentration of 100 mg·kg^-1· d^-1, and the other two groups were gavaged with equal amounts of corn oil. Then on the 28th day after of modelling, survival curve was plotted to assess the survival status of mice in the three groups; the neurological recovery of mice was determined using the Longa Score; the area of cerebral infarction was examined by Nissl staining. The behavioural changes in motor sensory function were tested at five time points: the day before modeling, and 7, 14, 21 and 28 days after modelling. For exploring the mechanism of PAE improving behavioural dysfunction in MCAO mice, 30 SPF male C57BL/6 mice were randomly divided into SHAM group (n=6) , model+corn oil group (n=12) and model+PAE group (n=12) . After verifying the model stability at 24 hours following the modeling, the model+PAE group received intragastric administration of PAE and corn oil solution in a concentration of 100 mg·kg^-1· d^-1, and the other two groups were gavaged with an equal amount of corn oil. The expression of interleukin 1β (IL-1β) protein in the striatum of mouse brain was measured by Western blotting on the second day after modelling to investigate whether PAE could reduce the inflammatory response in the brain during the acute period. The expression of ionized calcium-binding adapter molecule 1 (IBA1) and glial fibrillary acidic protein (GFAP) in the penumbra was measured by immunofluorescence on the 14th day after modelling.

Results

The 28-day survival rate was 66.47% for the model+corn oil group, and 81.43% for model+PAE group. Log-rank test showed that the 28-day survival curve significantly differed across SHAM group, model+corn oil group, and model+PAE group (χ²=1.436, P<0.05) The Longa Score was lower in model+PAE group than in model+corn oil group on the 28th day after modelling (P<0.05) . The differences in the expression levels of IBA1 and GFAP in brain tissues of the three groups were statistically significant (P<0.05) . Specifically, the expression levels of IBA1 and GFAP in brain tissues in SHAM group were lower than those of the other two groups (P<0.05) . The expression levels of IBA1 and GFAP in brain tissues in model+PAE group were lower than those in model+corn oil group (P<0.05) . On the second day after modelling, model+corn oil group had higher expression level of IL-1β in striatum than both SHAM group and model+PAE group (P<0.05) .

Conclusion

PAE could control the inflammatory response in the acute stage, reduce the area of acute cerebral infarction, prolong the survival time and improve the motor sensory function in the mouse model of MCAO.

Key words: Brain Ischemia, Middle cerebral artery occlusion, Paeonol, Ionized calcium binding adapter molecule 1, Glial fibrillary acidic protein, Interleukin 1β, Dysfunction

陈茜,骆建宇,邝枣园,等. 丹皮酚对大脑中动脉缺血模型小鼠行为功能障碍的改善作用研究[J]. 中国全科医学, 2023, 26(27): 3441-3449. DOI: 10.12114/j.issn.1007-9572.2022.0346.
CHEN Xi,LUO Jianyu,KUANG Zaoyuan, et al. Effect of Paeonol on Improving Behavioral Dysfunction in a Mouse Model of Middle Cerebral Artery Occlusion[J]. Chinese General Practice, 2023, 26(27): 3441-3449. DOI: 10.12114/j.issn.1007-9572.2022.0346.

图/表 15

表1 神经功能缺损评价标准（Longa评分）

Table 1 Scoring criteria for neurological deficits using the Longa Score

动物表现	评分（分）
无神经功能缺损症状，两前肢均显示正常力量，可伸直	0
不能完全伸展患侧前爪	1
向患侧转圈，但在休息时保持正常姿势	2
行走时靠患侧倾斜	3
无自发行走，意识水平低	4
死亡	5

图1 小鼠神经功能缺损示意图

Figure 1 Schematic diagram of neurological defects in mice

图2 两组小鼠造模后24 h激光散斑成像脑血流灌注量示例图注：MCAO=大脑中动脉缺血；左侧蓝色为梗死灶。

Figure 2 Example of cerebral blood flow perfusion in two groups of mice 24 hours after modeling by laser speckle imaging

图3 MCAO模型小鼠造模后24 h TTC染色图注：圆圈表示梗死部位。

Figure 3 TTC staining of the location and area of cerebral infarction in the mouse model of MCAO at 24 hours after modeling

图4 三组小鼠干预28 d的生存曲线比较注：假手术组10只，模型+玉米油组、模型+丹皮酚组各20只。

Figure 4 Comparison of 28-day survival curves among three groups of mice

表2 三组小鼠造模28 d的Longa评分比较〔M（P25，P75），分〕

Table 2 Comparison of the Longa Score of three groups of mice on the 28th day after modeling

组别	只数	Longa评分
假手术组	10	0^a
模型+玉米油组	9	1.0（0.5，1.5）
模型+丹皮酚组	9	0（0，1.0）^a
H值		15.73
P值		<0.01

表3 三组小鼠造模后28 d健侧大脑面积/患侧大脑面积系数比较（±s）

Table 3 Comparison of the ratio of healthy brain area to affected brain area in three groups of mice on the 28th day after modeling

组别	只数	健侧大脑面积/患侧大脑面积系数
假手术组	5	0.99±0.01
模型+玉米油组	5	1.96±0.27^a
模型+丹皮酚组	5	1.59±0.13^ab
F值		39.46
P值		<0.01

图5 各组小鼠患侧大脑面积与健侧大脑的比较

Figure 5 Comparison of brain area of affected side and healthy side in each group of mice

表4 三组小鼠各时间点走格子测试踩空率比较（±s，%）

Table 4 Comparison of rate of committing foot-faults in the grid-walking test in three groups of mice at five time points

组别	只数	基线	造模后7 d	造模后14 d	造模后21 d	造模后28 d
假手术组	9	1.40±0.84	1.70±0.82	1.24±0.92	1.70±0.82	1.30±0.95
模型+玉米油组	10	1.44±1.01	11.48±5.04^a	10.17±5.90^a	9.59±3.82^a	5.78±4.68^a
模型+丹皮酚组	10	1.11±0.60	5.33±1.23^ab	5.49±4.04^ab	3.56±2.55^b	2.69±1.55^b
F值		F_交互=7.122，F_组间=19.960，F_时间=33.970
P值		P_交互<0.01，P_组间<0.01，P_时间<0.01

表5 三组小鼠在各时间点爬杯试验拖爪率（±s，%）

Table 5 Dragging rates in three groups at five time points in the cup climbing test

组别	只数	基线	造模后7 d	造模后14 d	造模后21 d	造模后28 d
假手术组	9	4.00±5.16	5.00±5.27	2.00±4.22	3.00±4.83	4.00±6.99
模型+玉米油组	10	3.33±5.00	65.56±20.68^a	45.56±18.11^a	45.56±18.11^a	38.89±17.63^a
模型+丹皮酚组	10	3.33±5.00	43.33±14.14^ab	28.89±11.67^ab	27.78±13.94^ab	21.11±10.54^ab
F值		F_交互=3.486，F_组间=17.310，F_时间=9.099
P值		P_交互<0.01，P_组间<0.01，P_时间<0.01

表6 三组小鼠在各时间点粘纸测试中感觉粘纸时间（±s，s）

Table 6 The time-to-contact of mice in three groups at five time points in the adhesive removal test

组别	只数	基线	造模后7 d	造模后14 d	造模后21 d	造模后28 d
假手术组	9	2.47±0.95	3.51±1.66	4.14±2.42	2.87±1.87	2.24±0.66
模型+玉米油组	10	3.53±1.04	16.56±13.12^a	13.47±6.99^a	11.51±8.13^a	7.86±7.33^a
模型+丹皮酚组	10	4.19±2.39	8.99±5.58^ab	4.19±1.82^b	1.88±0.63^b	2.72±0.95
F值		F_交互=12.890，F_组间=45.020，F_时间=66.680
P值		P_交互<0.01，P_组间<0.01，P_时间<0.01

表7 三组小鼠造模后14 d脑组织中IBA1、GFAP表达水平比较（±s）

Table 7 Comparison of IBA1 protein expression levels in penumbra of three groups of mice on the 14th day after modeling

组别	只数	IBA1	GFAP
假手术组	3	18.13±4.95	10.73±4.78
模型+玉米油组	5	50.56±11.88^a	51.32±13.63^a
模型+丹皮酚组	5	36.16±2.99^ab	36.52±4.51^ab
F值		16.14	19.39
P值		<0.01	<0.01

图6 三组小鼠造模后14 d脑半暗带IBA1、GFAP蛋白表达注：IBA1=离子钙结合衔接分子1，GFAP=胶质纤维酸性蛋白，DAPI=4'，6-二脒基-2-苯基吲哚；荧光例图比例尺为20 μm；使用荧光二抗594（红色）标记IBA1，荧光二抗488（绿色）标记GFAP，DAPI标记细胞核。

Figure 6 Levels of IBA1 and GFAP protein expression in penumbra of three groups of mice on the 14th day after modeling

表8 三组小鼠造模后2 d纹状体IL-1β蛋白表达水平比较（±s）

Table 8 Comparison of IL-1β protein expression levels in striatum of mice in three groups on the second after modeling

组别	只数	IL-1β
假手术组	3	1.03±0.05^a
模型+玉米油组	6	1.75±0.13
模型+丹皮酚组	6	1.26±0.29^a
F值		13.51
P值		<0.01

图7 三组小鼠造模后2 d纹状体IL-1β蛋白表达电泳图注：IL-1β=白介素1β。

Figure 7 The expression level of IL-1β protein in striatum of mice in three groups on the second after modeling

参考文献 17

[1]	DE GRAAF J A, VAN MIERLO M L, POST M W M, et al. Long-term restrictions in participation in stroke survivors under and over 70 years of age[J]. Disabil Rehabil，2018，40(6):637-645. DOI：10.1080/09638288.2016.1271466.
[2]	ZHAO B, SHI Q J, ZHANG Z Z, et al. Protective effects of paeonol on subacute/chronic brain injury during cerebral ischemia in rats[J]. Exp Ther Med，2018，15(4):3836-3846. DOI：10.3892/etm.2018.5893.
[3]	HE L X, TONG X Y, ZENG J, et al. Paeonol suppresses neuroinflammatory responses in LPS-activated microglia cells[J]. Inflammation，2016，39(6):1904-1917. DOI：10.1007/s10753-016-0426-z.
[4]	宋宁宁，武继彪，魏欣冰，等. 丹皮酚减轻大鼠海马神经元缺糖缺氧损伤及抑制NMDA受体激活[J]. 药学学报，2009，44(11):1228-1232. DOI：10.16438/j.0513-4870.2009.11.015.
[5]	LONGA E Z, WEINSTEIN P R, CARLSON S, et al. Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke，1989，20(1):84-91. DOI：10.1161/01.str.20.1.84.
[6]	PAUL J S, LUFT A R, YEW E, et al. Imaging the development of an ischemic core following photochemically induced cortical infarction in rats using Laser Speckle Contrast Analysis （LASCA）[J]. Neuroimage，2006，29(1):38-45. DOI：10.1016/j.neuroimage.2005.07.019.
[7]	PU H J, SHI Y J, ZHANG L L, et al. Protease-independent action of tissue plasminogen activator in brain plasticity and neurological recovery after ischemic stroke[J]. Proc Natl Acad Sci USA，2019，116(18):9115-9124. DOI：10.1073/pnas.1821979116.
[8]	SHI Y, JIANG X, ZHANG L, et al. Endothelium-targeted over expression of heat shock protein 27 ameliorates blood-brain barrier disruption after ischemic brain injury[J]. Proc Natl Acad Sci USA，2017，114(7):E1243-1252. DOI：10.1073/pnas.1621174114.
[9]	BOUET V, BOULOUARD M, TOUTAIN J, et al. The adhesive removal test：a sensitive method to assess sensorimotor deficits in mice[J]. Nat Protoc，2009，4(10):1560-1564. DOI：10.1038/nprot.2009.125.
[10]	OLSEN T S, SKRIVER E B, HERNING M. Cause of cerebral infarction in the carotid territory. Its relation to the size and the location of the infarct and to the underlying vascular lesion[J]. Stroke，1985，16(3):459-466. DOI：10.1161/01.str.16.3.459.
[11]	ASTRUP J, SIESJÖ B K, SYMON L. Thresholds in cerebral ischemia - the ischemic penumbra[J]. Stroke，1981，12(6):723-725. DOI：10.1161/01.str.12.6.723.
[12]	SOMMER C J. Ischemic stroke：experimental models and reality[J]. Acta Neuropathol，2017，133(2):245-261. DOI：10.1007/s00401-017-1667-0.
[13]	SAVITZ S I, COX C S Jr. Concise review：cell therapies for stroke and traumatic brain injury：targeting microglia[J]. Stem Cells，2016，34(3):537-542. DOI：10.1002/stem.2253.
[14]	MORIOKA T, KALEHUA A N, STREIT W J. The microglial reaction in the rat dorsal Hippocampus following transient forebrain ischemia[J]. J Cereb Blood Flow Metab，1991，11(6):966-973. DOI：10.1038/jcbfm.1991.162.
[15]	KOBAYASHI A, TANIZAKI Y, KIMURA A, et al. AG490，a Jak2 inhibitor，suppressed the progression of murine ovarian cancer[J]. Eur J Pharmacol，2015，766:63-75. DOI：10.1016/j.ejphar.2015.09.039.
[16]	ZHAO S C, WANG C, XU H, et al. Age-related differences in interferon regulatory factor-4 and-5 signaling in ischemic brains of mice[J]. Acta Pharmacol Sin，2017，38(11):1425-1434. DOI：10.1038/aps.2017.122.
[17]	WANG F J, ZHU M M, JIANG N, et al. Paeonol ameliorates lipopolysaccharides-induced acute lung injury by regulating TLR4/MyD88/NF-κB signaling pathway[J]. Pharmazie，2019，74(2):101-106. DOI：10.1691/ph.2019.8860.

丹皮酚对大脑中动脉缺血模型小鼠行为功能障碍的改善作用研究

Effect of Paeonol on Improving Behavioral Dysfunction in a Mouse Model of Middle Cerebral Artery Occlusion

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