Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit

Rationale The ionotropic NMDA glutamate receptor is composed of NR1 and NR2 (NR2A-D) subunits. While there is compelling evidence that NMDA receptors modulate behavioral effects of ethanol, there is little understanding of how the subunit composition of the NMDA receptor mediates these effects.Objectives In the current study, we assessed the relative roles of NMDA subunits via phenotypic assessment of ethanol-related behaviors in NR2A knockout (KO) mice.Results Results demonstrated that NR2A KO and heterozygous mice failed to show evidence of ethanol-induced conditioned place preference. As compared to wild-type (WT) controls, KO mice showed impaired motor coordination at baseline and, in some instances, following ethanol treatment on the accelerating rotarod, balance beam, and wire-hang tests. By contrast, open field locomotor-stimulant, sedative/hypnotic, and hypothermic responses to ethanol were not different between genotypes, nor was voluntary ethanol consumption and preference in a two-bottle choice paradigm. Blood ethanol concentrations were lower in KO than WT mice following intraperitoneal ethanol injection.Conclusions Results suggest that the loss of NR2A subunit-containing NMDA receptors impairs the ability to form or express learned reward-related responses to ethanol and causes deficits in motor coordination. However, the loss of NR2A does not alter other measures of acute ethanol intoxication or ethanol consumption, possibly implicating other NMDA subunits in these effects. These data provide novel insight into the role of NMDA receptors in modulating the behavioral effects of ethanol.Research supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program.     

逍遥散对慢性应激损伤大鼠NR受体亚型表达的影响

目的:本研究用逍遥散和糖皮质激素受体(GR)阻滞剂干预慢性应激损伤大鼠,观察其海马区NR受体亚型表达情况。方法:以逍遥散(5.265g/kg)和GR受体阻滞剂RU-38486(12.5g/kg)为干预药物,应用慢性不可预知应激对大鼠进行为期3周的造模,在造模的同时给予实验药物,3周后停止刺激,于第22天处死大鼠取材。采用荧光免疫组织化学法,测定各组大鼠海马区NR表达。结果:GR受体阻滞剂RU-38486与中药复方逍遥散可显著下调慢性应激损伤大鼠海马区NR阳性表达。结论:逍遥散可以通过促进慢性应激损伤大鼠海马区NR表达下调,从而达到部分恢复慢性应激大鼠下丘脑—垂体—肾上腺(HPA)轴负反馈功能的作用,起到缓解诸应激症状的疗效。     

Advances in understanding the molecular basis of the first steps in color vision

Serving as one of our primary environmental inputs, vision is the most sophisticated sensory system in humans. Here, we present recent findings derived from energetics, genetics and physiology that provide a more advanced understanding of color perception in mammals. Energetics of cis–trans isomerization of 11-cis-retinal accounts for color perception in the narrow region of the electromagnetic spectrum and how human eyes can absorb light in the near infrared (IR) range. Structural homology models of visual pigments reveal complex interactions of the protein moieties with the light sensitive chromophore 11-cis-retinal and that certain color blinding mutations impair secondary structural elements of these G protein-coupled receptors (GPCRs). Finally, we identify unsolved critical aspects of color tuning that require future investigation.     

益胃饮含药血清对胃癌细胞MFC增殖凋亡及NR4A3/HGF表达的影响

目的:探讨不同浓度益胃饮对体外培养的胃癌细胞MFC的增殖、凋亡及NR4A3蛋白表达的影响。方法:MFC细胞经不同浓度益胃饮含药血清处理后,采用MTT法检测药物对肿瘤细胞的抑制作用,显微镜观察细胞形态学改变;采用流式细胞仪及Annexin V/PI染色的方法检测益胃饮含药血清对MFC胃癌细胞周期及凋亡的影响,并以RT-PCR芯片技术(Mouse TumorM etastasis PCR Array)分析该方对胃癌细胞MFC肿瘤相关基因表达的影响;结果:益胃饮含药血清浓度在4%~12%时,对肿瘤细胞的生长有抑制作用,且呈时间剂量依赖性。流式细胞仪分析结果显示,细胞凋亡百分率随着药物浓度的增加和作用时间的延长而增加,而RT-PCR芯片技术分析结果显示NR4A3表达则随之增强而HGF显著下调。结论:益胃饮含药血清对人胃癌细胞MFC增殖有抑制作用,并能诱导细胞凋亡,其作用机制可能是益胃饮通过促进Nr4 a3表达,下调HGF而达到的。     

Mechanisms responsible for the effect of median nerve electrical stimulation on traumatic brain injury-induced coma：orexin-A-mediated N-methyl-D-aspartate receptor subunit NR1 upregulation

Electrical stimulation of the median nerve is a noninvasive technique that facilitates awakening from coma. In rats with traumatic brain inju-ry-induced coma, median nerve stimulation markedly enhances prefrontal cortex expression of orexin-A and its receptor, orexin receptor 1. To further understand the mechanism underlying wakefulness mediated by electrical stimulation of the median nerve, we evaluated its effects on the expression of the N-methyl-D-aspartate receptor subunit NR1 in the prefrontal cortex in rat models of traumatic brain injury-in-duced coma, using immunohistochemistry and western blot assays. In rats with traumatic brain injury, NR1 expression increased with time after injury. Rats that underwent electrical stimulation of the median nerve (30 Hz, 0.5 ms, 1.0 mA for 15 minutes) showed elevated NR1 expression and greater recovery of consciousness than those without stimulation. These effects were reduced by intracerebroventric-ular injection of the orexin receptor 1 antagonist SB334867. Our results indicate that electrical stimulation of the median nerve promotes recovery from traumatic brain injury-induced coma by increasing prefrontal cortex NR1 expressionvia an orexin-A-mediated pathway.     

Probabilistic cumulative risk assessment of anti-androgenic pesticides in food

In this paper, we present a cumulative risk assessment of three anti-androgenic pesticides (vinclozolin, procymidone and prochloraz) using the relative potency factor (RPF) approach and an integrated probabilistic risk assessment (IPRA) model. RPFs for each substance were estimated for three reproductive endpoints (ano-genital distance, and weights of the seminal vesicles and the musculus levator ani/bulbocavernosus) in male rat foetuses exposed in utero. The cumulative dietary intake was estimated based on consumption data and residue data from the Netherlands. The IPRA model combines variability in both exposure and sensitivity between individuals into a distribution of individual margins of exposures (IMoEs) and IMoEs of 1 or less indicate a possible concern.     

Tongqiao Huoxue Decoction ameliorates traumatic brain injury-induced gastrointestinal dysfunction by regulating CD36/15-LO/NR4A1 signaling,which fails when CD36 and CX3CR1 are deficient

Aims

Gastrointestinal (GI) dysfunction, as a common peripheral-organ complication after traumatic brain injury (TBI), is primarily characterized by gut inflammation and damage to the intestinal mucosal barrier (IMB). Previous studies have confirmed that TongQiao HuoXue Decoction (TQHXD) has strong anti-inflammatory properties and protects against gut injury. However, few have reported on the therapeutic effects of TQHXD in a TBI-induced GI dysfunction model. We aimed to explore the effects of TQHXD on TBI-induced GI dysfunction and the underlying mechanism thereof.

Methods

We assessed the protective effects and possible mechanism of TQHXD in treating TBI-induced GI dysfunction via gene engineering, histological staining, immunofluorescence (IF), 16S ribosomal ribonucleic acid (rRNA) sequencing, real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), Western blot (WB), and flow cytometry (FCM).

Results

TQHXD administration ameliorated TBI-induced GI dysfunction by modulating the abundance and structure of bacteria; reconstructing the destroyed epithelial and chemical barriers of the IMB; and improving M1/M2 macrophage, T-regulatory cell (Treg)/T helper 1 cell (Th₁), as well as Th₁₇/Treg ratios to preserve homeostasis of the intestinal immune barrier. Notably, Cluster of Differentiation 36 (CD36)/15-lipoxygenase (15-LO)/nuclear receptor subfamily 4 group A member 1 (NR4A1) signaling was markedly stimulated in colonic tissue of TQHXD-treated mice. However, insufficiency of both CD36 and (C-X3-C motif) chemokine receptor 1 (CX3CR1) worsened GI dysfunction induced by TBI, which could not be rescued by TQHXD.

Conclusion

TQHXD exerted therapeutic effects on TBI-induced GI dysfunction by regulating the intestinal biological, chemical, epithelial, and immune barriers of the IMB, and this effect resulted from the stimulation of CD36/NR4A1/15-LO signaling; however, it could not do so when CX3CR1 and CD36 were deficient. TQHXD might therefore be a potential drug candidate for treating TBI-induced GI dysfunction.