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Causal association between insulin sensitivity index and Alzheimer's disease. 胰岛素敏感性指数与阿尔茨海默病之间的因果关系。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-31 DOI: 10.1111/jnc.16254
Fang Xu, Shiyang Wu, Shan Gao, Xuan Li, Chen Huang, Yan Chen, Ping Zhu, Guiyou Liu

Evidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post-prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome-wide significant (p < 5E-08, primary analyses) and 61 suggestive (p < 1E-05, secondary analyses) ISI genetic variants from large-scale genome-wide association studies (GWAS; N = 53 657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (N = 63 926) and FinnGen_G6_AD_WIDE (N = 412 181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave-one-out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta-analysis to combine MR estimates from two non-overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR = 0.79, 95% CI: 0.68-0.92, p = 0.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR = 0.89, 95% CI: 0.82-0.96, p = 0.003). Heterogeneity, horizontal pleiotropy test, and leave-one-out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (p > 0.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR-associated T2D and AD.

观察性研究和孟德尔随机化(MR)研究的证据表明,胰岛素抵抗(IR)与阿尔茨海默病(AD)有关。然而,不同的胰岛素抵抗指标对阿尔茨海默病的因果效应仍不一致。在此,我们旨在评估餐后胰岛素敏感性指数(ISI)与阿尔茨海默病风险之间的因果关系。我们首先进行了主要和次要的单变量 MR 分析。我们选择了 8 个独立的全基因组显著性(P 0.05)。我们提供的遗传学证据表明,ISI的增加与AD风险的降低有显著的因果关系,而AD风险的降低是由T2D介导的。这些发现可为针对与 IR 相关的 T2D 和 AD 的预防策略提供依据。
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引用次数: 0
Circulating medium- and long-chain acylcarnitines are associated with plasma P-tau181 in cognitively normal older adults. 认知能力正常的老年人体内循环的中链和长链酰基肉碱与血浆 P-tau181 相关。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1111/jnc.16244
Tahmida Sharmin, Pratishtha Chatterjee, James D Doecke, Nicholas J Ashton, Kevin Huynh, Steve Pedrini, Hamid R Sohrabi, Benjamin Heng, Shaun Eslick, Henrik Zetterberg, Kaj Blennow, Manohar Garg, Ralph N Martins

Alzheimer's disease (AD) pathogenesis involves dysregulation in diverse biochemical processes. Nevertheless, plasma tau phosphorylated at threonine 181 (P-tau181), a recognised AD biomarker, has been described to reflect early-stage cortical amyloid-β (Aβ) deposition in cognitively normal (CN) adults. Therefore, identifying changes in plasma metabolites associated with plasma P-tau181 at the pre-clinical stage may provide insights into underlying biochemical mechanisms to better understand initial AD pathogenesis. In the current study, plasma P-tau181, quantified via single molecule array (Simoa) technology, and plasma metabolites, quantified via targeted-mass spectrometry, were investigated for associations in CN older adults and upon stratification by positron emission tomography (PET)-Aβ load. In addition, the P-tau181-linked metabolites were evaluated for cognitive performance and neuroimaging markers of AD and the potential to distinguish between CN Aβ- and CN Aβ+ individuals. Significant positive associations of medium- and long-chain acylcarnitines (ACs) were observed with P-tau181 in the entire cohort, CN Aβ- and CN Aβ+, suggesting a link between initial Aβ pathology and fatty acid oxidation-mediated energy metabolism pathways. However, in CN Aβ-, additional linear associations of P-tau181 were observed with muscle metabolism and nitric oxide homeostasis-associated metabolites. Upon investigating the P-tau181-linked metabolites for cognitive performance, significant inverse correlations of the verbal and visual episodic memory and the global composite score were noted in CN Aβ+ with medium- and long-chain ACs, suggesting prognostic value of ACs accompanying weaker cognitive performance. While investigating neuroimaging markers, ACs had positive associations with PET-Aβ load and inverse associations with hippocampal volume in CN Aβ+, indicating connections of ACs with initial AD pathogenesis. Furthermore, based on receiver operating characteristics analysis, the associated ACs potentially classified PET-Aβ status in older adults. Therefore, plasma P-tau181-linked circulating ACs may serve as potential prognostic markers for initial AD pathogenesis in CN older adults. However, further cross-sectional and longitudinal research in highly characterised AD cohorts is needed to validate current findings.

阿尔茨海默病(AD)的发病机制涉及多种生化过程的失调。然而,血浆中苏氨酸181磷酸化的tau(P-tau181)是公认的阿尔茨海默病生物标志物,据描述可反映认知能力正常(CN)成年人皮质淀粉样蛋白-β(Aβ)沉积的早期阶段。因此,在临床前阶段确定与血浆P-tau181相关的血浆代谢物的变化可能有助于深入了解潜在的生化机制,从而更好地理解AD的初期发病机制。在目前的研究中,通过单分子阵列(Simoa)技术量化的血浆P-tau181和通过靶向质谱技术量化的血浆代谢物被用于研究中老年人的相关性,并根据正电子发射断层扫描(PET)-Aβ负荷进行分层。此外,还评估了与 P-tau181 相关联的代谢物与认知能力和注意力缺失症神经影像学标志物的关系,以及区分 CN Aβ- 和 CN Aβ+ 人群的潜力。在整个队列、CN Aβ-和CN Aβ+人群中,观察到中链和长链酰基肉碱(AC)与P-tau181呈显著正相关,这表明最初的Aβ病理学与脂肪酸氧化介导的能量代谢途径之间存在联系。然而,在 CN Aβ- 中,还观察到 P-tau181 与肌肉代谢和一氧化氮稳态相关代谢物的线性关系。在研究 P-tau181 相关代谢物与认知能力的关系时,发现在中链和长链 AC 的 CN Aβ+ 中,言语和视觉外显记忆与总体综合评分呈显著的反向相关性,这表明伴随认知能力减弱的 AC 具有预后价值。在研究神经影像标记物时,ACs 与 PET-Aβ 负荷呈正相关,与 CN Aβ+ 的海马体积呈反相关,表明 ACs 与最初的 AD 发病机制有关。此外,根据接收器操作特性分析,相关的AC可对老年人的PET-Aβ状态进行分类。因此,血浆中与 P-tau181 链接的循环 ACs 可作为 CN 老年人初期 AD 发病的潜在预后标志物。不过,还需要在高度特征化的AD队列中开展进一步的横断面和纵向研究,以验证目前的发现。
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引用次数: 0
o1 and Gαo1/Gαo2 deletion differentially affect hippocampal mossy fiber tract anatomy and neuronal morphogenesis. Gαo1和Gαo1/Gαo2缺失会对海马苔藓纤维束解剖结构和神经元形态发生产生不同影响。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1111/jnc.16248
Markus Höltje, Anton Wolkowicz, Irene Brunk, Jens Baron, Gudrun Ahnert-Hilger

The heterotrimeric G-protein αo subunit is ubiquitously expressed in the CNS as two splice variants Gαo1 and Gαo2, regulating various brain functions. Here, we investigated the effect of single Gαo1, Gαo2, and double Gαo1/2 knockout on the postnatal development of the murine mossy fiber tract, a central pathway of the hippocampal connectivity circuit. The size of the hippocampal synaptic termination fields covered by mossy fiber boutons together with various fiber length parameters of the tract was analyzed by immunohistochemical staining of the vesicular Zinc transporter 3 (ZnT3) or Synaptoporin at postnatal days 2, 4, 8, 12, 16, and in the adult. Ultimately, Gαo1 knockout resulted in a reduced developmental growth of synaptic mossy fiber terminal fields by 37% in the adult Stratum lucidum and by 30% in the total mossy fiber tract size. Other morphological parameters such as projection length of the infrapyramidal bundle of the tract were increased (+52% in Gαo1 -/- mice). In contrast, Gαo2 knockout had no effects on the mossy fiber tract. Moreover, by using primary heterozygous and homozygous Gαo1 knockout hippocampal cultures, we detected a strongly pronounced reduction in axon and dendrite length (-50% and -38%, respectively) as well as axon and dendrite arborization complexity (-75% and -72% branch nodes, respectively) in the homozygous knockout. Deletion of both splice variants Gαo1 and Gαo2 partially rescued the in vivo and completely reconstituted the in vitro effects, indicating an opposing functional relevance of the two Gαo splice variants for neuronal development and synaptic connectivity.

异三聚体G蛋白αo亚基在中枢神经系统中以两种剪接变体Gαo1和Gαo2的形式普遍表达,调控着大脑的各种功能。在这里,我们研究了单Gαo1、Gαo2和双Gαo1/2敲除对小鼠苔藓纤维束(海马连接回路的中心通路)出生后发育的影响。在小鼠出生后第2、4、8、12、16天和成年后,通过对囊泡锌转运体3(ZnT3)或突触素进行免疫组化染色,分析了苔藓纤维束覆盖的海马突触终止区的大小以及苔藓纤维束的各种纤维长度参数。最终,Gαo1基因敲除导致突触苔藓纤维末端场的发育生长在成年后的透明层中减少了37%,苔藓纤维束的总大小减少了30%。其他形态学参数,如束下锥体束的投射长度也有所增加(Gαo1 -/-小鼠的投射长度增加了52%)。相比之下,Gαo2基因敲除对苔藓纤维束没有影响。此外,通过使用原代杂合和同源Gαo1基因敲除的海马培养物,我们检测到同源基因敲除小鼠的轴突和树突长度(分别为-50%和-38%)以及轴突和树突分枝复杂性(分别为-75%和-72%的分枝结点)均明显下降。删除两个剪接变体 Gαo1 和 Gαo2 部分挽救了体内效应,并完全恢复了体外效应,这表明两个 Gαo 剪接变体对神经元发育和突触连接具有相反的功能相关性。
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引用次数: 0
Cross-species translational paradigms for assessing positive valence system as defined by the RDoC matrix. 根据 RDoC 矩阵的定义,评估正价系统的跨物种转化范式。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1111/jnc.16243
Tyler D Dexter, Benjamin Z Roberts, Samantha M Ayoub, Michael Noback, Samuel A Barnes, Jared W Young

Functions associated with processing reward-related information are fundamental drivers of motivation, learning, and goal-directed behavior. Such functions have been classified as the positive valence system under the Research Domain and Criteria (RDoC) criteria and are negatively impacted across a range of psychiatric disorders and mental illnesses. The positive valence system is composed of three comprehensive categories containing related but dissociable functions that are organized into either Reward Responsiveness, Reward Learning, or Reward Valuation. The presence of overlapping behavioral dysfunction across diagnostic mental disorders is in-part what motivated the RDoC initiative, which emphasized that the study of mental illness focus on investigating relevant behavior and cognitive functions and their underlying mechanisms, rather than separating efforts on diagnostic categories (i.e., transdiagnostic). Moreover, the RDoC approach is well-suited for preclinical neuroscience research, as the rise in genetic toolboxes and associated neurotechnologies enables researchers to probe specific cellular targets with high specificity. Thus, there is an opportunity to dissect whether behaviors and cognitive functions are supported by shared or distinct neural mechanisms. For preclinical research to effectively inform our understandings of human behavior however, the cognitive and behavioral paradigms should have predictive, neurobiological, and pharmacological predictive validity to the human test. Touchscreen-based testing systems provide a further advantage for this endeavor enabling tasks to be presented to animals using the same media and task design as in humans. Here, we outline the primary categories of the positive valence system and review the work that has been done cross-species to investigate the neurobiology and neurochemistry underlying reward-related functioning. Additionally, we provide clinical tasks outlined by RDoC, along with validity and/or need for further validation for analogous rodent paradigms with a focus on implementing the touchscreen-based cognitive testing systems.

与处理奖励相关信息有关的功能是动机、学习和目标导向行为的基本驱动力。根据《研究领域与标准》(RDoC)标准,这些功能被归类为正价系统,并在一系列精神障碍和心理疾病中受到负面影响。正价系统由三个综合类别组成,包含相关但可分离的功能,分别归类为奖赏反应、奖赏学习或奖赏评价。RDoC倡议强调,精神疾病研究的重点是调查相关的行为和认知功能及其内在机制,而不是将诊断类别分开(即跨诊断)。此外,RDoC 方法非常适合临床前神经科学研究,因为基因工具箱和相关神经技术的兴起使研究人员能够以高度特异性探查特定的细胞靶标。因此,有机会剖析行为和认知功能是由共同的神经机制支持还是由不同的神经机制支持。不过,要使临床前研究能有效地帮助我们理解人类行为,认知和行为范例应该对人类测试具有预测性、神经生物学和药理学预测有效性。基于触摸屏的测试系统为这项工作提供了进一步的优势,它可以使用与人类相同的媒介和任务设计向动物展示任务。在此,我们概述了积极情绪系统的主要类别,并回顾了跨物种研究奖励相关功能的神经生物学和神经化学的工作。此外,我们还提供了 RDoC 概述的临床任务,以及类似啮齿类动物范例的有效性和/或进一步验证的必要性,重点是实施基于触摸屏的认知测试系统。
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引用次数: 0
Hypertension is associated with the reduction in epidermal small fibres independently of sural nerve inflammation in type 2 diabetic subjects. 高血压与 2 型糖尿病患者表皮小纤维的减少有关,而与硬神经炎症无关。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-25 DOI: 10.1111/jnc.16235
Zhenchao Wang, Hanae Kushibiki, Takefusa Tarusawa, Sho Osonoi, Saori Ogasawara, Chinatsu Miura, Takanori Sasaki, Masaki Ryuzaki, Soroku Yagihashi, Hiroki Mizukami

Diabetic polyneuropathy (DPN) is a multifactorial disease associated not only with hyperglycaemia but also with circulatory disturbances such as hypertension. A close interaction between the immune system and hypertension is known. It remains unclear whether the inflammatory response is associated with hypertension in the pathology of human DPN. Autopsied patients were evaluated: 7 non-diabetic patients (nDM), 11 non-diabetic patients with hypertension (nDMHT), 6 patients with diabetes (DM) and 9 patients with hypertension and diabetes (DMHT). Intraepidermal nerve fibre density (IENFD) was examined by immunofluorescent staining. Dissected sural nerve (SNs) were morphometrically quantified. Dermal and endoneurial macrophage infiltration was evaluated by double immunostaining using anti-CD68 and anti-CD206 antibodies. IENFD was significantly decreased in DM compared to nDM (p < 0.05) and was further decreased in DMHT (p < 0.05). Myelinated nerve fibre density (MNFD) in the SN was significantly decreased in DM compared with nDM (p < 0.05) and further decreased in DMHT (p < 0.01 vs. DM). The infiltration of CD206-/CD68+ proinflammatory macrophages in the SN was significantly increased in DM compared to nDM (p < 0.05), whilst the number of CD206+/CD68+ anti-inflammatory macrophages was decreased in DM (p < 0.05). Hypertension had no impact on macrophage infiltration. The ratio of CD206- and CD206+ macrophage was negatively correlated with MNFD (r = 0.42, p < 0.05) but not IENFD (r = 0.30, p = 0.09). Dermal CD206+ macrophage infiltration was similar amongst all groups. Diabetes complicated by hypertension significantly increased the total diffusion barrier thickness (p < 0.01 vs. DM). Total diffusion barrier thickness was inversely correlated with both IENFD (r = -0.59, p < 0.01) and MNFD (r =-0.62, p < 0.01). Our results suggest that vascular factors and inflammation might be synergistically involved in pathological changes in human diabetic patients through different mechanisms.

糖尿病多发性神经病(DPN)是一种多因素疾病,不仅与高血糖有关,还与高血压等循环障碍有关。众所周知,免疫系统与高血压之间存在密切的相互作用。在人类 DPN 的病理过程中,炎症反应是否与高血压有关仍不清楚。对尸检患者进行了评估:其中包括 7 名非糖尿病患者(nDM)、11 名患有高血压的非糖尿病患者(nDMHT)、6 名糖尿病患者(DM)和 9 名患有高血压和糖尿病的患者(DMHT)。采用免疫荧光染色法检测表皮内神经纤维密度(IENFD)。对解剖的鞍神经(SN)进行形态计量。使用抗-CD68和抗-CD206抗体进行双重免疫染色,评估真皮和内皮巨噬细胞浸润情况。与 nDM 相比,DM 的 IENFD 明显降低(p -/CD68+促炎巨噬细胞在 SN 中的浸润在 DM 中明显增加,与 nDM 相比,p +/CD68+抗炎巨噬细胞在 DM 中减少(p - 和 CD206+ 巨噬细胞与 MNFD 呈负相关(r = 0.42,p + 巨噬细胞浸润在所有组中相似)。糖尿病并发高血压明显增加了总弥散屏障厚度(p
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引用次数: 0
Effect of the glucagon-like peptide-1 receptor agonists on diabetic peripheral neuropathy: A meta-analysis. 胰高血糖素样肽-1 受体激动剂对糖尿病周围神经病变的影响:荟萃分析。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-25 DOI: 10.1111/jnc.16242
Shujin Fan, Yue Qiu, Jing Liu, Tianxin Zhu, Chuan Wang, Dan Liu, Li Yan, Meng Ren

Previous researches found that glucagon-like peptide 1 receptor agonists (GLP-1RA) offer benefits beyond their anti-diabetic properties, including weight loss and cardiovascular disease prevention. However, the effects of GLP-1RA on diabetic peripheral neuropathy (DPN) remain unclear. This meta-analysis aims to assess the potential benefits of GLP-1RA treatment in DPN patients by evaluating peripheral neural function. Following the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a meta-analysis of the clinical trials investigating the impact of GLP-1RA treatment on peripheral neural function in patients with DPN. Outcomes were measured using electrophysiological tests, including nerve conduction velocity (NCV) and action potential amplitude. Our meta-analysis included six studies with 271 participants. Following GLP-1RA treatment, NCV significantly improved compared to the control group (MD 1.74; 95% CI 1.16 to 2.33; p < 0.001) and before treatment (MD 2.16; 95% CI 1.04 to 3.27; p < 0.001). Despite the improvement in NCV, blood glucose levels did not change significantly (MD -0.20 95% CI -0.87 to 0.46, p = 0.55) indicating that GLP-1RA enhances NCV through mechanisms other than glucose lowering. Nonetheless, as a result of the limited population studied, further research is needed to strengthen the reliability of these findings.

以往的研究发现,胰高血糖素样肽 1 受体激动剂(GLP-1RA)除了具有抗糖尿病的特性外,还具有减肥和预防心血管疾病的功效。然而,GLP-1RA 对糖尿病周围神经病变(DPN)的影响仍不清楚。本荟萃分析旨在通过评估外周神经功能,评估 GLP-1RA 治疗对 DPN 患者的潜在益处。根据 Cochrane 协作组织和系统综述和荟萃分析首选报告项目 (PRISMA) 指南,我们对研究 GLP-1RA 治疗对 DPN 患者外周神经功能影响的临床试验进行了荟萃分析。结果通过电生理测试(包括神经传导速度(NCV)和动作电位振幅)进行测量。我们的荟萃分析包括六项研究,共有 271 名参与者。与对照组相比,GLP-1RA 治疗后神经传导速度明显改善(MD 1.74; 95% CI 1.16 to 2.33; p
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引用次数: 0
Dispensable regulation of brain development and myelination by the immune-related protein Serpina3n. 免疫相关蛋白Serpina3n对大脑发育和髓鞘化的不可或缺的调节作用
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-25 DOI: 10.1111/jnc.16250
Meina Zhu, Yan Wang, Joohyun Park, Annlin Titus, Fuzheng Guo

Serine protease inhibitor clade A member 3n (Serpina3n) or its human orthologue SERPINA3 is a secretory immune-related molecule produced primarily in the liver and brain under homeostatic conditions and up-regulated in response to system inflammation. Yet, it remains elusive regarding its cellular identity and physiological significance in the development of the postnatal brain. Here, we reported that oligodendroglial lineage cells are the major cell population expressing Serpina3n protein in the postnatal murine CNS. Using loss-of-function genetic tools, we found that Serpina3n conditional knockout (cKO) from Olig2-expressing cells does not significantly affect cognitive and motor functions in mice. Serpina3n depletion does not appear to interfere with oligodendrocyte differentiation and developmental myelination nor affects the population of other glial cells and neurons in vivo. Interestingly, Serpina3n is significantly up-regulated in response to oxidative stress and its deficiency alleviates oxidative injury and diminishes cell senescence of oligodendrocytes in vitro. Together, our data suggest that the immune-related molecule Serpina3n plays a minor role in neural cell development under homeostasis, yet it primes oligodendrocytes for CNS insults and regulates oligodendrocyte health under injured conditions. Our findings raise the interest in pursuing its functional significance in the CNS under disease/injury conditions.

丝氨酸蛋白酶抑制剂 A 族成员 3n(Serpina3n)或其人类直向同源物 SERPINA3 是一种分泌性免疫相关分子,主要在肝脏和大脑的平衡状态下产生,并在系统炎症反应时上调。然而,它在出生后大脑发育过程中的细胞特性和生理意义仍然难以确定。在这里,我们报告了少突胶质细胞系细胞是小鼠出生后中枢神经系统中表达Serpina3n蛋白的主要细胞群。利用功能缺失遗传工具,我们发现从Olig2表达细胞中条件性敲除(cKO)Serpina3n不会对小鼠的认知和运动功能产生显著影响。Serpina3n的缺失似乎不会干扰少突胶质细胞的分化和发育髓鞘化,也不会影响体内其他胶质细胞和神经元的数量。有趣的是,Serpina3n 在应对氧化应激时会显著上调,其缺乏会减轻氧化损伤,并减少体外少突胶质细胞的细胞衰老。总之,我们的数据表明,免疫相关分子Serpina3n在平衡状态下的神经细胞发育过程中发挥着微不足道的作用,但它能为少突胶质细胞应对中枢神经系统损伤做好准备,并在损伤条件下调节少突胶质细胞的健康。我们的研究结果提高了人们对其在中枢神经系统疾病/损伤条件下功能意义的兴趣。
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引用次数: 0
Zinc signaling controls astrocyte-dependent synapse modulation via the PAF receptor pathway. 锌信号通过 PAF 受体途径控制星形胶质细胞依赖性突触调节。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-25 DOI: 10.1111/jnc.16252
Janelle E Stanton, Sakshi Hans, Ioannis Zabetakis, Andreas M Grabrucker

Astrocytes are important regulators of neuronal development and activity. Their activation plays a key role in the response to many central nervous system (CNS) pathologies. However, reactive astrocytes are a double-edged sword as their chronic or excessive activation may negatively impact CNS physiology, for example, via abnormal modulation of synaptogenesis and synapse function. Accordingly, astrocyte activation has been linked to neurodegenerative and neurodevelopmental disorders. Therefore, the attenuation of astrocyte activation may be an important approach for preventing and treating these disorders. Since zinc deficiency has been consistently linked to increased pro-inflammatory signaling, we aimed to identify cellular zinc-dependent signaling pathways that may lead to astrocyte activation using techniques such as immunocytochemistry and protein biochemistry to detect astrocyte GFAP expression, fluorescent imaging to detect oxidative stress levels in activated astrocytes, cytokine profiling, and analysis of primary neurons subjected to astrocyte secretomes. Our results reveal a so far not well-described pathway in astrocytes, the platelet activation factor receptor (PAFR) pathway, as a critical zinc-dependent signaling pathway that is sufficient to control astrocyte reactivity. Low zinc levels activate PAFR signaling-driven crosstalk between astrocytes and neurons, which alters excitatory synapse formation during development in a PAFR-dependent manner. We conclude that zinc is a crucial signaling ion involved in astrocyte activation and an important dietary factor that controls astrocytic pro-inflammatory processes. Thus, targeting zinc homeostasis may be an important approach in several neuroinflammatory conditions.

星形胶质细胞是神经元发育和活动的重要调节器。星形胶质细胞的活化在应对许多中枢神经系统(CNS)病症中起着关键作用。然而,反应性星形胶质细胞是一把双刃剑,因为它们的长期或过度激活可能会对中枢神经系统的生理学产生负面影响,例如通过对突触生成和突触功能的异常调节。因此,星形胶质细胞的激活与神经退行性疾病和神经发育障碍有关。因此,抑制星形胶质细胞的活化可能是预防和治疗这些疾病的重要方法。由于锌缺乏一直与促炎症信号传导增加有关,我们旨在利用免疫细胞化学和蛋白质生物化学检测星形胶质细胞 GFAP 表达、荧光成像检测活化星形胶质细胞中的氧化应激水平、细胞因子谱分析以及星形胶质细胞分泌物对原代神经元的分析等技术,确定可能导致星形胶质细胞活化的细胞锌依赖信号传导途径。我们的研究结果揭示了星形胶质细胞中一个迄今为止尚未被充分描述的通路--血小板活化因子受体(PAFR)通路,它是一个关键的锌依赖信号通路,足以控制星形胶质细胞的反应性。低锌水平会激活 PAFR 信号驱动的星形胶质细胞与神经元之间的串扰,从而以 PAFR 依赖性的方式改变发育过程中兴奋性突触的形成。我们的结论是,锌是参与星形胶质细胞活化的关键信号离子,也是控制星形胶质细胞促炎过程的重要饮食因子。因此,针对锌的平衡可能是治疗多种神经炎症的重要方法。
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引用次数: 0
Association of serum lipidomic profiles with risk of intracranial aneurysm: A Mendelian randomization study. 血清脂质体特征与颅内动脉瘤风险的关系:孟德尔随机研究
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-25 DOI: 10.1111/jnc.16247
Mingqin Zhang, Dongyi Yang, Jiabin Wang, Dan Wang, Jin Xu, Yibo Wang

A two-sample Mendelian randomization (MR) analysis was utilized to assess the causal relationship between lipidomic profiles and the risk of intracranial aneurysms (IAs). Genetic variants related to lipidomic profiles (227 components) and IA [IA, aneurysmal subarachnoid hemorrhage (aSAH) only, unruptured IA (uIA) only] were obtained from published genome-wide association studies (GWASs) or the IEU Open GWAS project and used as instrumental variables for MR analysis. The inverse-variance weighted method was used in the primary analyses to derive causality estimates and was expressed as odds ratio (OR) with 95% confidence interval (CI). Of these 227 lipidomic profiles, only genetically predicted high levels of cholesterol to total lipids ratio in very small very-low-density lipoproteins (VLDL) [OR = 0.629 (95% CI, 0.504-0.786)], cholesteryl esters to total lipids ratio in very small VLDL [OR = 0.637 (95% CI, 0.509-0.797)], ratio of docosahexaenoic acid to total fatty acids [OR = 0.691 (95% CI, 0.582-0.820)], and ratio of polyunsaturated fatty acids to monounsaturated fatty acids [OR = 0.630 (95% CI, 0.522-0.760)] reduced the risk of aSAH, whereas genetically predicted high ratio of monounsaturated fatty acids to total fatty acids [OR = 1.471 (95% CI, 1.215-1.781)] increased the risk of aSAH. Moreover, genetically predicted high levels of cholesterol to total lipids ratio in very small VLDL [OR = 0.657 (95% CI, 0.542-0.798)], cholesteryl esters to total lipids ratio in very small VLDL [OR = 0.663 (95% CI, 0.548-0.803)], free cholesterol to total lipids ratio in small VLDL [OR = 0.682 (95% CI, 0.560-0.832)], phospholipids to total lipids ratio in small VLDL [OR = 0.674 (95% CI, 0.548-0.830)], and ratio of polyunsaturated fatty acids to monounsaturated fatty acids [OR = 0.678 (95% CI, 0.569-0.808)] reduced the risk of IA. The results of multivariable MR demonstrated that these causal associations persisted after adjusting for systolic blood pressure and cigarettes smoked per day. The effect of serum lipids on IA and aSAH may be mainly caused by subclasses of lipids such as VLDL.

采用双样本孟德尔随机化(MR)分析法评估脂质体特征与颅内动脉瘤(IAs)风险之间的因果关系。从已发表的全基因组关联研究(GWAS)或IEU开放式GWAS项目中获得了与脂质组特征(227个成分)和IA[仅动脉瘤性蛛网膜下腔出血(aSAH),仅未破裂的IA(uIA)]相关的遗传变异,并将其作为MR分析的工具变量。主要分析采用逆方差加权法得出因果关系估计值,并以带 95% 置信区间 (CI) 的比值比 (OR) 表示。在这 227 项脂质组学特征中,只有基因预测的高水平胆固醇与极小极低密度脂蛋白(VLDL)中总脂质的比率[OR = 0.629 (95% CI, 0.504-0.786)], 胆固醇酯与极小极低密度脂蛋白中总脂质的比率[OR = 0.637 (95% CI, 0.509-0.797)], 二十二碳六烯酸与总脂肪酸的比率[OR = 0.691(95% CI,0.582-0.820)]和多不饱和脂肪酸与单不饱和脂肪酸之比[OR = 0.630(95% CI,0.522-0.760)]可降低罹患 aSAH 的风险,而基因预测的单不饱和脂肪酸与总脂肪酸之比偏高[OR = 1.471(95% CI,1.215-1.781)]则会增加罹患 aSAH 的风险。此外,遗传预测的高水平胆固醇与极小 VLDL 中总脂类的比率[OR = 0.657 (95% CI, 0.542-0.798)], 胆固醇酯与极小 VLDL 中总脂类的比率[OR = 0.663 (95% CI, 0.548-0.803)], 游离胆固醇与极小 VLDL 中总脂类的比率[OR = 0.682(95% CI,0.560-0.832)]、小 VLDL 中磷脂与总脂的比率[OR = 0.674(95% CI,0.548-0.830)]和多不饱和脂肪酸与单不饱和脂肪酸的比率[OR = 0.678(95% CI,0.569-0.808)]降低了 IA 的风险。多变量磁共振结果表明,在调整收缩压和每日吸烟量后,这些因果关系依然存在。血清脂质对IA和aSAH的影响可能主要是由VLDL等亚类脂质引起的。
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引用次数: 0
Sex- and age-dependent impacts of nicotine and ethanol binge drinking on the brain: Insights from preclinical research. 尼古丁和乙醇暴饮对大脑的影响与性别和年龄有关:临床前研究的启示。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-24 DOI: 10.1111/jnc.16249
Stella J Farias Cardozo, Andrew J Lawrence, Roberta Goncalves Anversa

Electronic cigarette use among adolescents is a growing concern, not only due to the high incidence of co-use with other substances, such as alcohol, but also due to the fact brain is still maturing during this period. Combined exposure to alcohol and nicotine leads to plastic adaptation of crucial circuits in the brain, which can contribute to the development of addiction. It is well established that nicotine exposure can facilitate alcohol binge drinking, and vice-versa, in a sex-, age- and exposure-dependent manner. Nonetheless, the central mechanisms underlying the synergistic relationship between these two substances and the emergence of differential behavioural traits dependent on these factors remain underexplored. Preclinical studies continue to provide valuable insights into such mechanisms. Here, we discuss recent preclinical findings that report behavioural changes characteristic of addiction following nicotine consumption, primarily in models of vaping and alcohol use; and insights into the neural mechanisms impacted by intake of these two substances, with a focus on the adolescent brain.

青少年使用电子香烟的问题日益受到关注,这不仅是因为青少年与酒精等其他物质同时使用电子香烟的比例很高,还因为在这一时期大脑仍在发育成熟。同时接触酒精和尼古丁会导致大脑关键回路的可塑性适应,从而导致成瘾的产生。众所周知,尼古丁接触会促进酒精暴饮,反之亦然,这与性别、年龄和接触方式有关。然而,这两种物质之间的协同关系以及依赖于这些因素而出现的不同行为特征的核心机制仍未得到充分探索。临床前研究继续为这些机制提供有价值的见解。在此,我们将讨论最近的临床前研究结果,这些结果报告了尼古丁摄入后成瘾所特有的行为变化,主要是在吸食和使用酒精的模型中;以及对摄入这两种物质所影响的神经机制的见解,重点是青少年大脑。
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引用次数: 0
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Journal of Neurochemistry
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