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1.
目的 研究6,7-二乙酰黄芩素对硫代乙酰胺致大鼠急性肝性脑病模型的防治作用及机制。方法 Wistar雄性大鼠60只,随机分为对照组、模型组、乳果糖(阳性药,6 g/kg)组和6,7-二乙酰黄芩素低、中、高剂量(6.25、12.50、25.00 mg/kg)组,每天ig给药1次,连续给药7 d。第5天给药结束后,除对照组外,采用硫代乙酰胺(300 mg/kg)连续ip 2 d建立大鼠肝性脑病模型。观察大鼠状态,考察大鼠肝性脑病评分与死亡率;测定各组大鼠血氨、结肠pH值、血清天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、碱性磷酸酶(ALP)、总胆红素(TBIL)水平;采用苏木素-伊红(HE)染色法观察大鼠肝组织病理学变化;采用ELISA试剂盒法检测大鼠脑组织中γ-氨基丁酸(GABA)、谷氨酸(Glu)、血浆中的5-羟色胺(5-HT)、去甲肾上腺素(NE)的含量;采用Western Blotting试验测定脑组织中GABA-α1蛋白的表达。结果 造模48 h后,与模型组比较,6,7-二乙酰黄芩素高剂量组大鼠体质量显著升高(P<0.05),肝性脑病评分显著降低(P<0.05);各剂量组死亡率均降低;中、高剂量组血清ALT、AST、ALP和TBIL水平均显著降低(P<0.05);低、中、高剂量组血氨水平显著降低(P<0.05、0.01);中、高剂量组结肠pH显著降低(P<0.05、0.01);中、高剂量组大鼠肝脏组织病理学损伤明显改善;各剂量组脑组织中GABA水平显著降低(P<0.01);中、高剂量组血浆中5-HT水平显著降低(P<0.01);高剂量组血浆中NE水平显著降低(P<0.01);高剂量组脑组织中Glu含量显著增加(P<0.01);高剂量脑组织中GABA-α1蛋白表达显著降低(P<0.05)。结论 6,7-二乙酰黄芩素对肝脏具有保护作用,对急性肝性脑病具有防治作用,其机制可能与降低血氨、降低结肠pH、调节神经递质水平、抑制相关神经递质受体的表达有关。  相似文献   
2.
目的研究鲜天麻对睡眠干扰(sleep interruption,SI)诱导的小鼠学习记忆障碍的改善作用。方法 HPLC法测定鲜天麻中天麻素、对羟基苯甲醇的含量,苯酚硫酸法测定多糖的含量。60只ICR雄鼠随机分为对照组、睡眠干扰模型组、阳性药(莫达非尼)组和鲜天麻低(3 g/kg)、高(9 g/kg)剂量组。睡眠干扰造模14 d后,依次进行自主活动、新物体识别、水迷宫和避暗等动物行为学检测实验,并测定小鼠血清和海马组织超氧化物歧化酶(SOD)、丙二醛(MDA)水平及海马组织乙酰胆碱(Ach)、谷氨酸(Glu)和去甲肾上腺素(NE)水平。结果自主活动实验中,各组小鼠运动功能无显著性差异。与对照组比较,模型组小鼠在新物体识别实验中的相对辨别指数(DI)显著性下降,水迷宫寻台潜伏期明显延长,避暗实验错误次数增加、入暗潜伏期缩短;血清和海马组织MDA水平升高,海马组织的SOD水平降低;海马组织Ach、Glu和NE水平均显著降低。与模型组比较,莫达非尼和鲜天麻各剂量能不同程度增加小鼠新物体识别DI,提高新物体辨别能力;增强空间学习获得和保持能力,缩短水迷宫潜伏期;减少避暗错误次数、延长避暗潜伏期;提高血清和海马组织中SOD、Ach、Glu和NE水平,降低MDA水平。结论鲜天麻能改善睡眠干扰引起的学习记忆障碍,改善氧化应激和神经递质水平,是一种有潜力的改善学习记忆中药。  相似文献   
3.
目的 探讨女珍颗粒联合佐匹克隆片治疗更年期失眠症的临床疗效。方法 选取2016年3月—2018年10月在内蒙古自治区精神卫生中心进行治疗的82例更年期失眠患者为研究对象,根据用药的差别分为观察组(41例)和对照组(41例)。对照组给予佐匹克隆片,7.5 mg/次,1次/d,睡前服用;观察组在对照组基础上口服女珍颗粒,6 g/次,3次/d。两组均治疗4周后进行效果对比。结果 经治疗,对照组有效率为82.92%,显著低于治疗组95.12%(P<0.05)。经治疗,两组患者匹兹堡睡眠质量指数量表(PSQI)评分降低;多导睡眠监测(PSG)中入睡时间、觉醒时间降低,总睡眠时间增加,睡眠效率提高;睡眠结构中I期时间缩短,II、III期及快速动眼期时间延长(P<0.05),且观察组睡眠情况显著优于对照组(P<0.05)。经治疗,两组患者血清中神经递质去甲肾上腺素(NE)、5-羟色胺(5-HT)、多巴胺(DA)水平显著升高(P<0.05),且观察组神经递质水平显著高于对照组(P<0.05)。经治疗,两组焦虑自评量表评分(SAS)、抑郁自评量表评分(SDS)、SCL-90、Hamilton抑郁量表(HAMD)评分均显著降低(P<0.05),且观察组上述评分显著低于对照组(P<0.05)。结论 女珍颗粒联合佐匹克隆片治疗更年期失眠症效果良好,可有效减轻失眠症状,改善患者负面情绪,提高患者生活质量,有着良好临床应用价值。  相似文献   
4.
目的:以芒针透刺督脉组穴配合隔姜灸对脑卒中后睡眠障碍患者进行干预治疗,观察患者睡眠改善情况及血清5-羟色胺(5-HT)、去甲肾上腺素(NA)和乙酰胆碱(Ach)水平变化,并分析其机制。方法:将同期收治的76例脑卒中后睡眠障碍患者采用随机数字表法分为观察组与对照组各38例。两组均给予脑卒中后常规西医康复治疗,在此基础上对照组辅以传统针灸治疗,观察组采用芒针透刺督脉组穴配合隔姜灸治疗,均连续治疗8周。治疗前后分别测定两组匹兹堡睡眠质量指数(PSQI)、睡眠状况自评量表(SSRS)、美国国立卫生研究院卒中量表(NIHSS)评分,据以计算睡眠障碍治疗总有效率;检测两组血清5-HT、NA和Ach水平,并观察有无不良反应。结果:两组治疗后PSQI、SSRS、NIHSS评分均较治疗前明显降低(P<0.05),且观察组治疗后各评分均明显低于对照组(P<0.05);观察组和对照组睡眠障碍治疗总有效率分别为92.11%、76.38%,两组比较差异有统计学意义(P<0.05);两组治疗后血清5-HT、NA、Ach水平均较治疗前明显提高(P<0.05),且观察组治疗后各指标均明显高于对照组(P<0.05);两组在治疗期间均未发生明显不良反应。结论:芒针透刺督脉组穴配合隔姜灸治疗脑卒中后睡眠障碍安全有效,可明显改善患者预后,机制可能与上调神经递质水平有关。  相似文献   
5.
6.
AimsChronic stress plays an important role in promoting the progression and migration of cancers. However, little is known of any direct impact on tumor progression related to the regulation of emotion‐related circuitry. The aim of this study was to explore the neural‐circuit mechanisms underlying stress‐induced progression of cancers and the impact of emotion‐related regulation of circuitry on tumor growth.MethodsOptogenetic manipulation was applied to unpredictable chronic mild stress (UCMS)–treated mice bearing breast tumor cell. The stress‐related hormones, tumor‐related cytokines, the tyrosine hydroxylase (TH)–positive neurons and their fibers, dopamine receptor–positive cells, and anxiety level were measured using ELISA, immunohistochemical staining, fluorescence in situ hybridization, and behavioral test, respectively.ResultsBy investigating breast cancer mouse models with a chronic mild stress model, optogenetic stimulation, and behavioral analysis, we show that chronic stress induced anxiety‐like behavior in mice and increased serum concentration of norepinephrine and corticosterone, hormones closely related to stress and anxiety. Optogenetic activation of VTA TH terminals in the mPFC rescued anxiety‐like behavior induced by chronic stress. Chronic stress resulted in marked progression of breast tumors, and repetitive optogenetic activation of VTA TH terminals in the mPFC significantly attenuated stress‐induced progression of breast cancers and reduced serum concentration of norepinephrine and corticosterone. Furthermore, there was a positive correlation between serum norepinephrine or corticosterone concentration and tumor size.ConclusionsThese findings indicate a positive role of an emotion regulation circuit on the progression of breast cancer and reveal a link between stress, emotion regulation, and the progression of breast cancers. Our findings provide new insights pertinent to therapeutic interventions in the treatment of breast cancers.  相似文献   
7.
高耀  王鹏  许腾  武文泽  向欢  韩雨梅  田俊生  秦雪梅 《中草药》2021,52(5):1360-1368
目的通过对多种生物样本中内源性代谢物特征进行综合分析,阐释逍遥散抗抑郁的作用机制。方法对慢性不可预知温和刺激(chronic unpredicted mild stress,CUMS)抑郁大鼠模型的血液、尿液、海马、肝脏、盲肠、粪便和临床患者的血浆、尿液等生物样本中逍遥散具有显著调节作用的差异代谢物进行代谢特征综合分析,归纳总结逍遥散在不同生物样本中调节的关键差异代谢物和代谢通路。结果逍遥散在不同生物样本中调节的相同差异代谢物有34个,其中11个变化趋势一致,涉及的关键代谢通路为能量代谢和神经递质通路等。结论逍遥散能够通过调节体内代谢平衡所在的代谢通路发挥抗抑郁作用,为系统挖掘逍遥散抗抑郁代谢机制提供依据。  相似文献   
8.
Fast excitatory synaptic transmission in the central nervous system relies on the AMPA-type glutamate receptor (AMPAR). This receptor incorporates a nonselective cation channel, which is opened by the binding of glutamate. Although the open pore structure has recently became available from cryo-electron microscopy (Cryo-EM), the molecular mechanisms governing cation permeability in AMPA receptors are not understood. Here, we combined microsecond molecular dynamic (MD) simulations on a putative open-state structure of GluA2 with electrophysiology on cloned channels to elucidate ion permeation mechanisms. Na+, K+, and Cs+ permeated at physiological rates, consistent with a structure that represents a true open state. A single major ion binding site for Na+ and K+ in the pore represents the simplest selectivity filter (SF) structure for any tetrameric cation channel of known structure. The minimal SF comprised only Q586 and Q587, and other residues on the cytoplasmic side formed a water-filled cavity with a cone shape that lacked major interactions with ions. We observed that Cl readily enters the upper pore, explaining anion permeation in the RNA-edited (Q586R) form of GluA2. A permissive architecture of the SF accommodated different alkali metals in distinct solvation states to allow rapid, nonselective cation permeation and copermeation by water. Simulations suggested Cs+ uses two equally populated ion binding sites in the filter, and we confirmed with electrophysiology of GluA2 that Cs+ is slightly more permeant than Na+, consistent with serial binding sites preferentially driving selectivity.

Glutamate receptor ion channels are found at synapses throughout the vertebrate nervous system, where they convert submillisecond glutamate signals into cation currents. Advances in structural biology have provided molecular scale maps of their ion pores, permitting comparison with a burgeoning menagerie of structures from related ion channels. It has been comparatively difficult to obtain candidate open pore structures of glutamate receptors, with the notable exceptions being from single-particle cryo-electron microscopy (Cryo-EM) of complexes between GluA2 and Stargazin (1, 2), the prototypical transmembrane AMPA receptor regulatory protein (TARP). However, it is unclear from simple inspection of these structures whether 1) the ion pore is conductive or 2) it is open to its fullest extent or to the highest conductance level. One structure has the unedited form of GluA2 (Q), that is, GluA2 lacking the common RNA editing of the Q586 residue to Arginine (3), while the other structure is of the edited form (Q586R), which should have a low conductance (4). Previous electrophysiological work suggests that the radius of the narrowest part of the AMPA channel [either with or without Stargazin (5, 6)] is 4 Å, and neither the upper gate nor the selectivity filter (SF) are this wide in either candidate open structure. However, these estimates are based on the geometric mean radius of large, elongated cations. A substantial body of electrophysiological work provides good benchmarks for how permeation should proceed in an open AMPA receptor pore. For example, canonical measurements of reversal potentials show that alkali earth cations from sodium (Na+) up to cesium (Cs+) should permeate GluA1 (7) and GluA2 (Q) (8) approximately equally well and that the single channel conductance of the full level of GluA2 (Q) should be considerable [∼30 pS (9)].Most computational work on ion permeation through channels has been focused on simple, selective potassium (K+) channels like KcsA (1012), being the first reported crystal structures of ion channels (13). Thanks to their minimal sequences, these channels demand little computational overhead. Their key structural features are two membrane-spanning helices and a reentrant loop forming a narrow SF for permeant ions. This core motif defines a superfamily of tetrameric and pseudotetrameric channels that encompass selective, semiselective, and nonselective cation conductances. In common with many eukaryotic channels, the AMPA-type glutamate receptor (AMPAR) has a pore domain whose gating state is controlled by substantially larger domains outside the membrane (amino terminal domain [ATD] and ligand-binding domain [LBD], Fig. 1A), which account for about 75% of the protein mass. The large size presents a challenge for conventional molecular dynamic (MD) simulations, with the AMPA receptor being about six-times bigger than KcsA.Open in a separate windowFig. 1.AMPA receptor and the simulation setup. (A) The activated open state of the AMPA receptor from Cryo-EM [PDB ID: 5WEO (1)] with Stargazin molecules removed. The receptor is composed of ATD, LBD, and TMD. (B) The TMD and linkers to the LBD layer were included the MD simulations. The sites where the linkers were truncated and physically restrained (see Methods) are marked with red balls. Two out of the four subunits are shown. (C) The SF region of the AMPA receptor pore, with key residues labeled. Again, only two diagonally opposed subunits are drawn. (D) The computational electrophysiology setup was composed of two tetrameric AMPA channels, each embedded in a separate POPC lipid bilayer, solvated with water molecules and ions. A small cation imbalance between the two compartments α and β was maintained during the simulations. The resulting gradient gave a transmembrane potential to drive ion permeation.It remains to be seen to what extent key features of ion permeation elucidated in prokaryotic channels (selectivity, discrete sites, desolvated ions, and block by divalent ions) are widely applicable in channels with more substantial architectures. Recent experimental and MD work on nonselective prokaryotic channels like NaK and NaK-CNG as well as a mutant of the human hERG1 channel suggests that ion permeation in these channels differs substantially from classical K+-selective ion permeation (1417). The SF of nonselective cation channels is much more flexible, with fewer ion binding sites leading to distinct conduction mechanisms and hydration states for Na+ and K+ when passing through the filter. In the AMPA receptor, in one activated open Cryo-EM structure of GluA2 (1), density for a presumptive hydrated sodium ion was observed adjacent to the unedited Q586 residue. In the structure of RNA-edited GluA2 (Q586R) with Stargazin (2), ions were absent. The closed state structure of a GluA1/A2 heteromer featured strong density of unknown identity adjacent to C589 (18). Whether the paucity and heterogeneity of resolved ions is due to a lack of order in the filter region, the lack of detail in the coulomb potential density, or a true deficit of ions remains unclear. However, observations in these AMPA receptor structures are in marked contrast to the Cryo-EM structures of several other nonselective cation channels, such as hyperpolarization-activated cyclic nucleotide-gated (HCN) (19) and cyclic nucleotide-gated (CNG) channels (20), where two or three bound ions were visible. Further context comes from canonical K+-selective channels, which feature up to four ions in a row (21), and crystal structures of Ca2+-selective transient receptor potential (TRP) channels where two Ca2+ ions were readily resolved (22).Here, we used MD-based computational electrophysiology to examine ion permeation through the mammalian AMPA receptor ion channel. We determined that the published structure is stably open, suitably detailed for MD simulations, and most likely represents a native fully open state. We identified a minimal SF consisting of a single major ion binding site that does not fully dehydrate ions. In simulations, Cs+ co-opted a secondary binding site. Consistent with multiple sites promoting ion selectivity, electrophysiology of AMPARs in human embryonic kidney (HEK293) cells showed that Cs+ is slightly more permeant than Na+.  相似文献   
9.
刘新锋  潘家华  沈艳 《中草药》2019,50(4):931-935
目的观察自拟枣仁安神方联合艾司西酞普兰治疗冠心病(CHD)伴焦虑症患者的效果,以及对血清相关神经递质的影响,探讨自拟枣仁安神方的作用机制。方法选取驻马店市中心医院2016年4月—2018年3月期间收治的120例CHD伴焦虑症患者,随机分为对照组和治疗组,每组各60例。两组均给予CHD常规治疗方案,包括阿司匹林肠溶片、琥珀酸美托洛尔片、单硝酸异山梨酯、阿托伐他汀。对照组同时给予艾司西酞普兰,治疗组在对照组的基础上联合自拟枣仁安神方治疗,4周为1个疗程,连续3个疗程。在治疗前后对患者进行汉密尔顿焦虑量表(HAMA)评分、中医证候评分和心绞痛评分,评价CHD和焦虑症疗效,并检测血清5-羟色胺(5-HT)、髓过氧化物酶(MPO)、去甲肾上腺素(NE)和血浆神经肽(NPY)水平。结果治疗后,治疗组CHD和焦虑症有效率分别为91.67%、93.33%,高于对照组的78.33%、80.00%,差异显著(P0.05);治疗组HAMA评分、中医证候评分和心绞痛评分均低于对照组(P0.05);治疗组患者血清5-HT、NE、NPY水平高于对照组,MPO水平低于对照组(P0.05)。结论自拟枣仁安神方联合艾司西酞普兰治疗CHD伴焦虑症,能够改善患者CHD和焦虑症症状,提高疗效,通过调节5-HT、NE、NPY和MPO水平来发挥治疗作用。  相似文献   
10.
[目的] 分析帕金森病(PD)伴情绪障碍患者的证素分布特征,初步探究PD伴情绪障碍患者的脑内神经递质特征。[方法] 选择2016年1—12月就诊于本院脑病科门诊的41例PD患者,按照情绪障碍诊断标准分为PD伴情绪障碍组与PD非情绪障碍组,对纳入患者进行一般情况、中医四诊信息、汉密尔顿抑郁量表、汉密尔顿焦虑量表的测评,并对其中可配合脑电超慢涨落分析的27例PD患者进行神经递质检测。[结果] PD伴情绪障碍组心神、气滞出现频次明显高于PD非情绪障碍组,差异具有统计学意义(P<0.05);PD伴情绪障碍组心神、心、肝、热、气滞、阳亢、阴虚的分值明显高于PD非情绪障碍组,两组间差异具有统计学意义(P<0.05)。PD伴情绪障碍组与PD非情绪障碍组相比,谷氨酸(GLU)的测定值较高,5-羟色胺(5-HT)、乙酰胆碱(ACH)的测定值较低,两组间差异具有统计学意义(P<0.05)。[结论] PD伴情绪障碍患者可在治疗帕金森病的基础上佐以养心安神,理气通滞之品。GLU的升高,5-HT、ACH的降低可能为PD患者发生情绪障碍的神经生化基础。  相似文献   
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