Oxytocin decreases colonic motility of cold water stressed rats via oxytocin receptors

AIM: To investigate whether cold water intake into the stomach affects colonic motility and the involvement of the oxytocin-oxytocin receptor pathway in rats.METHODS: Female Sprague Dawley rats were used and some of them were ovariectomized. The rats were subjected to gastric instillation with cold(0-4℃, cold group) or room temperature(20-25℃, control group) saline for 14 consecutive days. Colon transit was determined with a bead inserted into the colon. Colonic longitudinal muscle strips were prepared to investigate the response to oxytocin in vitro. Plasma concentration of oxytocin was detected by ELISA. Oxytocin receptorexpression was investigated by Western blot analysis. Immunohistochemistry was used to locate oxytocin receptors.RESULTS: Colon transit was slower in the cold group than in the control group(P < 0.05). Colonic smooth muscle contractile response to oxytocin decreased, and the inhibitory effect of oxytocin on muscle contractility was enhanced by cold water intake(0.69 ± 0.08 vs 0.88 ± 0.16, P < 0.05). Atosiban and tetrodotoxin inhibited the effect of oxytocin on colonic motility. Oxytocin receptors were located in the myenteric plexus, and their expression was up-regulated in the cold group(P < 0.05). Cold water intake increased blood concentration of oxytocin, but this effect was attenuated in ovariectomized rats(286.99 ± 83.72 pg/mL vs 100.56 ± 92.71 pg/mL, P < 0.05). However, in ovariectomized rats, estradiol treatment increased blood oxytocin, and the response of colonic muscle strips to oxytocin was attenuated.CONCLUSION: Cold water intake inhibits colonic motility partially through oxytocin-oxytocin receptor signaling in the myenteric nervous system pathway, which is estrogen dependent.

Variations in the oxytocin receptor gene and prosocial behavior:moderating effects of situational factors

Humans are the most prosocial primate species and they often exhibit high levels of prosocial behavior toward genetically unrelated individuals.Traditional evolutionary theories are not sufficient to explain the individual differences and mechanisms related to prosociality.In this study,we focused on the gene–situation interaction in prosocial behaviors,and the patterns of genotype variance related to cooperation and comforting in different situations.We explored the interaction between the oxytocin receptor(OXTR)gene and situations,and the genotype variance under low and high prosociality situations between outgroup and ingroup recipients in a sample of 422 Chinese males.Prosociality was tested by measuring the prosocial tendencies,and prosocial behaviors were tested in cooperation and comforting tasks.OXTR single nucleotide polymorphisms(SNPs)were genotyped using polymerase chain reaction–restriction fragment length polymorphism analysis.The results suggested that the relationship between OXTR SNPs(specifically rs13316193,rs1042778 and rs237887)and prosocial behavior varied across different situations,and that the associations were moderated by the recipient’s identity and the prosocial cost.Our findings indicate the action of a moderating mechanism between the OXTR gene and prosocial behaviors according to situational factors.

Estrogen and oxytocin involvement in social preference in male mice:a study using a novel long-term social preference paradigm with aromatase,estrogen receptor-αand estrogen receptor-β,oxytocin,and oxytocin receptor knockout male mice

Certain aspects of social behavior help animals make adaptive decisions during encounters with other animals.When mice choose to approach another conspecific,the motivation and preference behind the interaction is not well understood.Estrogen and oxytocin are known to influence a wide array of social behaviors,including social motivation and social preference.The present study investigated the effects of estrogen and oxytocin on social preference using aromatase(ArKO),estrogen receptor(ER)α(αERKO),ERβ(βERKO),oxytocin(OTKO),oxytocin receptor(OTRKO)knockout and their respective wild-type(WT)male mice.Mice were presented with gonadally-intact versus castrated male(IC),intact male versus ovariectomized female(IF),or intact male versus empty cage(IE)stimuli sets for 5 days.ArWT showed no preference for either stimuli in IC and IF and intact male preference in IE,but ArKO mice preferred a castrated male or an ovariectomized female,or had no preference for either stimulus in IC,IF and IE stimuli sets,respectively,suggesting reduced intact male preference.αandβWT mice preferred a castrated male,showed no preference,and preferred an intact male in IC,IF and IE,respectively.αERKO mice displayed similar modified social preference patterns as ArKO,whereas the social preference ofβERKO mice remained similar toβWT.OTWT preferred a castrated male whereas OTKO,OTRWT and OTRKO mice failed to show any preference in IC and none showed preference for either stimuli in IF.Collectively,these findings suggest that estrogen regulates social preference in male mice and that impaired social preference in oxytocin-deficient mice may be due to severe deficits in social recognition.

柴胡皂苷A抗抑郁的靶点识别及作用研究

中药柴胡具有改善抑郁患者临床治疗效果的作用,柴胡皂苷A(saikosaponin A,SSA)是柴胡主要药效成分,本研究以SSA为研究对象,利用慢性不可预知性温和应激(chronic unpredictable mild stress,CUMS)模型小鼠悬尾(tail suspension test,TST)和强迫游泳实验(forced swimming test,FST)明确SSA的抗抑郁作用。利用计算机分子对接技术分析并验证SSA的作用靶点,并利用细胞热转移测定实验(cellular thermal shift assay,CETSA)和药物亲和力靶稳定性实验(drug affinity responsive target stability,DARTS)验证SSA的靶标;采用Western blotting等技术研究SSA的抗抑郁作用机制。CUMS模型TST和FST结果表明,与模型组相比,SSA能够显著缩短小鼠的不动时间,表明SSA具有显著的抗抑郁作用。计算机分子对接证明了SSA与催产素受体(oxytocin receptor,OXTR)结合效果较好,表明SSA抗抑郁的作用靶点可能是OXTR。CETSA结果表明在一系列温度梯度处理下,SSA能够明显延缓OXTR的热变性;DARTS实验结果表明,在一系列酶浓度梯度处理下,SSA能够显著降低OXTR对蛋白质水解的敏感性,表明SSA抗抑郁的作用靶点是OXTR。此外,SSA对OXTR下游的ERK通路没有激活作用。本研究表明SSA发挥抗抑郁作用的靶点可能为OXTR,为抑郁症等精神疾病的临床研究治疗和新药开发提供必要的理论与参考依据。

Localization of the hydrogen sulfide and oxytocin systems at the depth of the sulci in a porcine model of acute subdural hematoma

In the porcine model discussed in this review,the acute subdural hematoma was induced by subdural injection of autologous blood over the left parietal cortex,which led to a transient elevation of the intracerebral pressure,measured by bilateral neuromonitoring.The hematoma-induced brain injury was associated with albumin extravasation,oxidative stress,reactive astrogliosis and microglial activation in the ipsilateral hemisphere.Further proteins and injury markers were validated to be used for immunohistochemistry of porcine brain tissue.The cerebral expression patterns of oxytocin,oxytocin receptor,cystathionine-γ-lyase and cystathionine-β-synthase were particularly interesting:these four proteins all co-localized at the base of the sulci,where pressure-induced brain injury elicits maximum stress.In this context,the pig is a very relevant translational model in contrast to the rodent brain.The structure of the porcine brain is very similar to the human:the presence of gyri and sulci(gyrencephalic brain),white matter to grey matter proportion and tentorium cerebelli.Thus,pressure-induced injury in the porcine brain,unlike in the rodent brain,is reflective of the human pathophysiology.

Oxytocin in rat nucleus raphe magnus influences pain modulation

The main function of Nucleus raphe magnus (NRM) is mostly pain mediation. Our previous study has demonstrated that oxytocin (OXT) regulates antinociception through the central nervous system rather than the peripheral organs, and pain stimulation increases OXT concentration in the NRM. The experiment was designed to investigate OXT in the rat NRM effect on pain modulation. The results showed that 1) pain stimulation increased OXT concentration in NRM perfusion liquid;2) Intra-NRM microinjection of OXT increased the pain threshold in a dose-dependent manner, whereas intra-NRM microinjection of OXT receptor antagonist, desGly-NH2, d(CH2)5[D-Tyr2, Thr-sup-4]OVT decreased the pain threshold;3) NRM pre-treatment with OXT receptor antagonist completely attenuated the pain threshold increase induced by intra-NRM administration of OXT. The data suggested that OXT in NRM was involved in antinociception via OXT receptors.

催产素受体在山羊结状神经节的分布

为研究山羊结状神经节(Nodose ganglion,NG)的神经细胞内是否具备接受催产素(Oxytocin,OT)调节的条件。选取成年山羊结状神经节,采用免疫组化SP法检测催产素受体(Oxytocin receptor,OTR)在结状神经节内各种结构上的分布特点,用Image-pro plus 6.0分析结状神经节神经细胞和非神经细胞结构的催产素受体表达差异性。结果表明,结状神经节内OTR免疫阳性产物分布广泛,神经细胞、过路神经纤维、血管内皮细胞、支持细胞和雪旺细胞均有不同程度的着色。神经细胞胞核和支持细胞着色最深,为棕褐色,OTR分布强阳性。大部分神经细胞胞质着色为黄褐色,OTR分布中等阳性,这部分神经细胞胞质约占神经细胞总数的78%。血管内皮细胞、细胞膜,以及一小部分神经细胞胞质着色较浅,为淡黄色,OTR分布弱阳性。神经细胞胞核的核仁呈圆形,着色极浅或不着色,OTR分布阴性。图像分析表明神经细胞胞体的相对表达量与其他非神经结构差异极显著。OTR免疫阳性产物在山羊NG中广泛表达,且主要分布在NG内脏感觉神经细胞内,提示催产素有可能作用于NG内脏感觉神经细胞,从而通过内脏反射弧传入神经纤维影响内脏器官活动,而NG可能成为OT对内脏器官进行内分泌调节和通过自主神经对内脏器官进行神经调节两者相互协调作用的节点。

缩宫素受体和平滑肌动蛋白在子宫肌层及子宫瘢痕组织中的表达

目的探究缩宫素受体(OTR)和平滑肌动蛋白(SMA)在子宫肌层和瘢痕组织中的表达情况。方法选择2020年1月至2021年12月在嘉兴市妇幼保健院行剖宫产手术生产的产妇60例,使用缩宫素前,分别取非高龄初产妇及高龄初产妇子宫切口上缘肌层组织、经产妇子宫瘢痕组织样本,均为20例,行常规病理检验,并采用免疫组化法检测OTR和SMA的表达情况。结果非高龄初产妇子宫肌层组织OTR表达水平高于高龄初产妇子宫肌层组织和经产妇子宫瘢痕组织,差异均有统计学意义(均P<0.05);高龄初产妇子宫肌层组织OTR表达水平与经产妇子宫瘢痕组织比较,差异无统计学意义(P>0.05);非高龄初产妇子宫肌层、高龄初产妇子宫肌层的SMA表达水平高于经产妇子宫瘢痕组织,差异均有统计学意义(均P<0.05)。结论子宫瘢痕和高龄对OTR和SMA表达有影响,高龄导致子宫肌层OTR表达下降,瘢痕导致OTR和SMA表达均下降。

催产素及其受体调节骨代谢研究

催产素(oxytocin, OT)除具有调节分娩和母乳分泌的作用外,外周性OT和催产素受体(oxytocin receptor, OTR),非中枢性,对骨骼也有直接的调节作用。骨髓间充质干细胞、成骨细胞(osteoblast, OB)、破骨细胞(osteoclast, OC)、骨细胞、软骨细胞、脂肪细胞均表达OT及OTR。OB在雌激素的刺激下,合成OT,并成为骨形成的旁分泌-自分泌调节剂。在雌激素的介导之下,OT/OTR与OB形成前馈环路。骨保护素(osteoclastogenesis inhibitory factor, OPG)/核因子κB受体活化因子配体(receptor activator of nuclear factor-κB ligand, RANKL)信号通路是OT及OTR发挥抗骨质疏松(osteoporosis, OP)作用的关键通路。OT通过上调骨形成蛋白,下调骨吸收标志物水平,进而提高骨髓间充质干细胞活性,促进其向OB方向而非脂肪细胞方向分化。OT通过促进OTR易位到OB的细胞核中,诱导OB的矿化。OT通过触发胞浆内Ca^(2+)释放和一氧化氮的合成,调节OB中OPG/RANKL的比例,对破骨细胞具有双向的调节作用。此外,OT同样能够提高骨细胞和软骨细胞的活性,并在提高骨量,改善骨显微结构方面具有重要的作用。基于OT和OTR具有抗OP的良好作用,本文对近年来OT及OTR调节骨代谢的研究进行综述,以期为其临床应用与研究提供参考。

缩宫素在中枢神经系统疾病中的研究进展

缩宫素是一种肽类激素,由垂体后叶分泌,经下丘脑的室旁核和视上核合成。缩宫素具有促进妊娠子宫平滑肌收缩和乳腺肌上皮收缩(排乳)的功能。近年来,缩宫素与脑内缩宫素受体结合产生的生理作用在中枢神经系统疾病领域受到广泛关注。该文回顾并总结缩宫素在中枢神经系统疾病中的研究进展及缩宫素类似物的应用,以期为缩宫素临床应用及新药研究开发提供参考。

催产素受体配体及其中枢和外周功能研究进展

催产素(oxytocin,OT)是一个含有9个氨基酸残基的环状神经肽,除了传统的缩宫和泌乳作用外,近年来,OT在中枢神经系统及其它外周器官的新功能也受到广泛关注,如改善精神分裂症、自闭症和焦虑症等精神心理症状。OT通过与其受体(oxytocin receptor,OTR)结合而发挥生理作用,目前研究人员以OT信号系统作为药物靶标,通过开发新型OTR配体(即激动剂和拮抗剂)来预防和改善相应症状。该文从OTR药理学角度对其激动剂和拮抗剂及其生物学功能的最新研究进展进行了综述。

缩宫素受体在子宫腺肌症肌层平滑肌组织中的表达及与痛经的关系

目的探讨子宫腺肌症(adenomyosis,AM)患者子宫肌层平滑肌组织中缩宫素受体(oxytocin receptor,OTR)的表达水平与痛经程度的关联性。方法收集2013年9月-2014年8月在本院妇科因AM行全子宫切除手术的腺肌症患者50例为腺肌症组,同期因子宫肌瘤行全子宫切除的患者20例为对照组。应用免疫组化染色法(S-P法)检测20例正常子宫肌层、50例子宫腺肌症肌层平滑肌组织中的OTR表达情况。采用光学显微镜及Image Plus Pro 6.0图像分析系统测定OTR水平,并对其差异进行分析。结果 AM组子宫肌层平滑肌组织中OTR的表达高于对照组(62 370±34 758 vs 16 082±11 125,P<0.01),且表达强度随着痛经程度的加重而增加,差异均有统计学意义。结论 OTR在AM患者子宫肌层平滑肌组织中的表达与痛经程度呈正相关,推测患者痛经形式可能为宫缩痛,表明宫缩强度的增加参与了AM疼痛的发病机制。

影响选择性剖宫产产后出血量的相关因素分析

探讨选择性剖宫产产后出血量与缩宫素受体及宫颈评分等的相关性。方法选择因社会因素进行剖宫产病例100例,记录基本资料,进行宫颈评分,计算术中及术后24 h出血量,并采集子宫肌层组织标本,进行缩宫素受体含量分析。结果观察的11个因素中,与产后出血直接相关的因素有宫颈评分、新生儿体重以及缩宫素受体含量,与产后出血间接相关的因素有孕妇体重、孕妇体重指数及胎先露的高低。结论选择适当手术时机,控制孕妇及新生儿体重,降低剖宫产率等对降低产后出血具有重要意义。

催产素及受体基因与社会适应行为

作为一种在哺乳动物分娩和泌乳中起神经调节作用的激素,催产素(oxytocin,OT)在人类的母婴关系和社会关系中也发挥着重要作用。研究发现催产素及其受体基因与人类的社会适应行为关系密切。催产素会影响亲子依恋和父母教养行为,也能促进人际信任及慷慨行为;同时,不同催产素受体(oxytocinreceptor,OXTR)基因型的个体,在亲子关系和一些亲社会行为方面都表现出了差异。来自于激素和基因水平的研究提示我们,催产素及其受体基因可能是通过促进社会识别、调节共情以及降低恐惧、减缓焦虑来影响人类一系列的社会适应行为。未来的研究应考虑结合分子遗传学和神经科学的研究方法,从基因-激素-行为三个层面系统的研究催产素影响社会行为的分子过程和认知神经过程。

分娩过程中使用缩宫素对产后出血的影响

目前,产后出血仍是孕产妇死亡的主要原因之一,研究证实分娩过程中使用缩宫素增加了产后出血的发生风险,尤其是在缩宫素使用时间过长、浓度过高或未积极管理第三产程时。缩宫素受体的脱敏反应是其主要病理生理学机制,临床上表现为后续缩宫素诱导的子宫收缩反应性降低,进而引起宫缩乏力和产后出血。综述使用缩宫素与产后出血的相关性研究进展,帮助临床医生建立合理的缩宫素管理方案,减少宫缩乏力性产后出血的发生。

缩宫素与前列腺素对人子宫平滑肌细胞缩宫素受体表达的影响

目的研究缩宫素(OT)、前列腺素干预对原代培养的子宫平滑肌细胞缩宫素受体(OTR)表达的影响。方法分别用OT、前列腺素E2(PGE2)、前列腺素F2alpha(PGF2alpha)干预原代人子宫平滑肌细,检测细胞匀浆中的OTR mRNA、蛋白的表达。结果OT干预前后OTR的表达无显著改变。PGE2、PGF2alpha干预组较未干预组OTR的表达明显增加。PGE2与PGF2alpha共干预组较未干预组及PGE2、PGF2alpha单独干预组OTR的表达明显增加。结论OT不能增加人子宫平滑肌细胞上OTR的表达,PGE2、PGF2alpha可增加人子宫平滑肌细胞中OTR的表达,且有协同作用。

EGFR、WT-1、CD10和OTR在子宫内膜间质肉瘤中表达研究

目的:研究表皮生长因子受体(Epidermal growth factor receptor,EGFR)、Wilm’s肿瘤基因-1(the Wilm’stumor gene-1,WT-1)、CD10和催产素受体(Oxytocin receptors,OTR)在子宫内膜间质肉瘤(Endometrial stromal sarcoma,ESS)表达情况,为鉴别诊断提供一定的依据。方法:采用免疫组化SP法检测40例子宫内膜间质肉瘤(包括35例低度恶性子宫内膜间质肉瘤和5例未分化子宫内膜肉瘤),15例子宫富于细胞平滑肌瘤和10例子宫平滑肌肉瘤中的EGFR、WT-1、CD10和OTR的表达。结果:免疫组织化学结果显示:子宫内膜间质肉瘤EGFR、WT-1、CD10和OTR的阳性率分别为67.5%(27/40)、52.5%(21/40)、82.5%(33/40)、和7.25%(3/40)。子宫富于细胞平滑肌瘤EGFR、WT-1、CD10和OTR的阳性率分别为80.0%(12/15)、46.7%(7/15)、13.3%(2/15)和100%(15/15)。子宫平滑肌肉瘤EGFR、WT-1、CD10和OTR的阳性率分别为70.0%(7/10)、50.0%(5/10)、0(0/10)和100%(10/10)。EGFR在27例子宫内膜间质肉瘤、12例富于细胞平滑肌瘤和7例平滑肌肉瘤中表达。21例低度恶性子宫内膜间质肉瘤、7例富于细胞平滑肌瘤和5例平滑肌肉瘤中表达WT-1,但是在5例未分化子宫内膜肉瘤中未有表达。7例ESS没有表达CD10,其中4例是未分化子宫内膜肉瘤。富于细胞平滑肌瘤有2例表达CD10。CD10在ESS、子宫富于细胞平滑肌瘤和子宫平滑肌肉瘤中的表达差异有统计学意义(P<0.05)。在3例伴有平滑肌分化的子宫内膜间质肉瘤中有OTR局灶表达,全部15例富于细胞平滑滑肌瘤都弥散性表达OTR,10例平滑肌肉瘤中有8例高度表达OTR和2例弱表达OTR。结论:EGFR和WT-1在子宫内膜间质肉瘤、子宫富于细胞平滑肌瘤和子宫平滑肌肉瘤均有较高的表达,CD10和OTR在鉴别子宫内膜间质肉瘤和子宫平滑肌肿瘤方面特异性较EGFR和WT-1高,可作为鉴别子宫内膜间质肉瘤和子宫平滑肌肿瘤的辅助标记物。

催产素及其受体与哺乳动物的生殖

催产素 (OT)是一种 9肽激素 ,主要由哺乳动物下丘脑产生 ,以神经内分泌、旁分泌或自分泌形式 ,在哺乳动物生殖过程中发挥重要作用。催产素受体 (OTR)是与G 蛋白相耦联的膜蛋白 ,通过激活磷脂酶C发挥其生理作用。OT在交配、分娩、哺乳时由神经垂体 (垂体后叶 )脉冲式释放 ,促进子宫平滑肌和乳腺肌上皮细胞收缩 ,利于精子运行、胎儿娩出和射出乳汁 ;OT在中枢神经系统中参与调节母性行为 ;在性腺中促进某些物种的黄体形成。OT与PGF2α共同作用使有蹄动物黄体退化。以上过程都依赖于OT和OTR基因的时空特异性表达 ,多种激素参与它们的表达调控。但OT的生理作用有时也可被其它途径所替代。

催产素受体在雌性山羊颈动脉体的分布

研究催产素受体(OTR)在雌性山羊颈动脉体(CB)中是否存在及其分布特点,为催产素(OT)是否对CB起调节作用提供形态学基础。用免疫组织化学SP法对雌性山羊的CB进行OTR免疫组织化学染色,观察CB中OTR的分布特点。结果显示,在雌性山羊CB的实质细胞群和间质组织中均有不同程度的OTR阳性反应产物存在。OTR强阳性产物分布在Ⅰ型细胞、Ⅱ型细胞的细胞质和细胞膜,在Ⅰ型细胞的细胞核呈弱阳性表达,在Ⅱ型细胞的细胞核呈强阳性表达。在间质组织中,血管内皮细胞和神经纤维中有中等阳性反应产物存在,并且实质细胞群和间质组织的OTR相对表达量差异性极显著(P<0.01)。结果表明,OTR主要分布于CB的实质细胞群中,CB具备接受OT调控的条件。因此,催产素可以通过激活CB中的OTR来影响CB的功能活动。

痛经康口服液对痛经大鼠子宫组织中催产素受体及加压素受体mRNA的表达的影响

目的观察痛经康口服液(延胡索、当归、川芎、香附等)抗痛经作用及相关机制。方法大鼠股部皮下注射己烯雌酚,1次/d,连续11 d,其中第1天及第11天注射量为0.8 mg/只,第2天至第10天注射量为0.4 mg/只。于最后1次给药40 min后,所有大鼠按4 U/kg体质量腹腔注射缩宫素致大鼠扭体反应。采血,处死,取子宫组织采用RT-PCR方法检测大鼠子宫组织催产素受体(OTR)及加压素受体(VPR)mRNA的表达情况。结果痛经康低、中、高剂量组出现扭体反应的动物数量均较模型对照组少。田七痛经胶囊组、痛经康中、高剂量组出现扭体反应潜伏期较模型对照组延长,30 min扭体反应次数较模型对照组减少,其中痛经康中剂量组与模型对照组比较扭体反应潜伏期明显延长(P<0.01),但扭体反应次数无统计学差异。痛经康低、中、高剂量组可不同程度降低痛经大鼠子宫催产素及加压素受体mRNA表达,与模型组比较差异显著(P<0.01,P<0.05)。结论痛经康口服液具有明显的抗痛经作用,机制可能与下调痛经大鼠子宫催产素及加压素受体表达有关。