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The Identification of Potential Anti-Depression/Anxiety Drug Targets by Stress-Induced Rat Brain Regional Proteome and Network Analyses 通过应激诱导的大鼠脑区域蛋白质组和网络分析确定潜在的抗抑郁/焦虑药物靶点
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1007/s11064-024-04220-x
Nan Liu, Jiaxin Tu, Faping Yi, Xiong Zhang, Xianhui Zhong, Lili Wang, Liang Xie, Jian Zhou

Depression and anxiety disorders are prevalent stress-related neuropsychiatric disorders and involve multiple molecular changes and dysfunctions across various brain regions. However, the specific and shared pathophysiological mechanisms occurring in these regions remain unclear. Previous research used a rat model of chronic mild stress (CMS) to segregate and identify depression-susceptible, anxiety-susceptible, and insusceptible groups; then the proteomes of six distinct brain regions (the hippocampus, prefrontal cortex, hypothalamus, pituitary, olfactory bulb, and striatum) were separately and quantitatively analyzed. To gain a comprehensive and systematic understanding of the molecular abnormalities, this study aimed to investigate and compare differential proteomics data from the six regions. Differentially expressed proteins (DEPs) were identified in between specific regions and across all regions and subjected to a series of bioinformatics analyses. Regional comparisons showed that stress-induced proteomic changes and corresponding gene ontology and pathway enrichments were largely distinct, attributable to differences in cell populations, protein compositions, and brain functions of these areas. Additionally, a notable degree of overlap in the significantly enriched terms was identified, potentially suggesting strong connections in the enrichment across different regions. Furthermore, intra-regional and inter-regional protein–protein interaction networks and drug-target-DEP networks were constructed. Integrated analysis of the three association networks in the six regions, along with the DisGeNET database, identified ten DEPs as potential targets for anti-depression/anxiety drugs. Collectively, these findings revealed commonalities and differences across different brain regions at the protein level induced by CMS, and identified several novel protein targets for the development of new therapeutics for depression and anxiety.

Graphical Abstract

抑郁症和焦虑症是普遍存在的与压力有关的神经精神疾病,涉及多个脑区的多种分子变化和功能障碍。然而,发生在这些区域的特定和共同的病理生理机制仍不清楚。之前的研究利用慢性轻度应激(CMS)大鼠模型来分离和识别抑郁易感组、焦虑易感组和不易感组,然后分别对六个不同脑区(海马、前额叶皮层、下丘脑、垂体、嗅球和纹状体)的蛋白质组进行定量分析。为了全面系统地了解分子异常,本研究旨在调查和比较六个区域的差异蛋白质组学数据。研究人员对特定区域之间和所有区域之间的差异表达蛋白(DEPs)进行了鉴定,并进行了一系列生物信息学分析。区域比较显示,应激诱导的蛋白质组变化以及相应的基因本体论和通路富集在很大程度上是不同的,这归因于这些区域的细胞群、蛋白质组成和大脑功能的差异。此外,在显著富集的术语中还发现了明显的重叠,这可能表明不同区域的富集存在密切联系。此外,还构建了区域内和区域间蛋白质-蛋白质相互作用网络以及药物-靶点-DEP网络。通过对六个区域的三个关联网络以及 DisGeNET 数据库进行综合分析,确定了十个 DEPs 作为抗抑郁/焦虑药物的潜在靶点。总之,这些发现揭示了不同脑区在 CMS 诱导的蛋白质水平上的共性和差异,并为开发治疗抑郁症和焦虑症的新疗法确定了几个新的蛋白质靶点。
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引用次数: 0
Neuroprotective Effects Exerted by a Combination of Selected Lactic Acid Bacteria in a Mouse Parkinsonism Model under Levodopa-Benserazide Treatment 精选乳酸菌组合在左旋多巴-苄丝肼治疗下的小鼠帕金森病模型中发挥的神经保护作用
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1007/s11064-024-04217-6
Daiana Pérez Visñuk, Jean Guy LeBlanc, Alejandra de Moreno de LeBlanc

Alterations of the microbiota-gut-brain axis has been associated with intestinal and neuronal inflammation in Parkinson’s disease (PD). The aim of this work was to study some mechanisms associated with the neuroprotective effect of a combination (MIX) of lactic acid bacteria (LAB) composed by Lactiplantibacillus plantarum CRL2130 (riboflavin overproducing strain), Streptococcus thermophilus CRL808 (folate producer strain), and CRL807 (immunomodulatory strain) in cell cultures and in a chronic model of parkinsonism induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in aged mice, and under levodopa-benserazide treatment. In vitro, N2a differentiated neurons were exposed to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and treated with intracellular bacterial extracts or with conditioned media from BV-2 cells exposed to the bacterial extracts. In vivo, motor skills, tyrosine hydrolase (TH) in brain and cytokine concentrations in serum and in brain were evaluated. The study of the faecal microbiota and the histology of the small intestine was also performed. The results showed that the neuroprotective effect associated with LAB MIX administration did not interfere with levodopa-benserazide treatment. This effect could be associated with the antioxidant and immunomodulatory potential of the LAB selected in the MIX, and was associated with the significant improvement in the motor tests and a higher number of TH + cells in the brain. In addition, LAB MIX administration was associated with modulation of the immune response. LAB administration decreased intestinal damage with an increase in the villus length /crypt depth ratio. Finally, the administration of the LAB MIX in combination with levodopa-benserazide treatment was able to partially revert the intestinal dysbiosis observed in the model, showing greater similarity to the profiles of healthy controls, and highlighting the increase in the Lactobacillaceae family. Different mechanisms of action would be related to the protective effect of the selected LAB combination which has the potential to be evaluated as an adjuvant for conventional PD therapies.

微生物群-肠-脑轴的改变与帕金森病(PD)的肠道和神经元炎症有关。这项工作的目的是研究由植物乳杆菌(Lactiplantibacillus plantarum)CRL2130(核黄素过量产生菌株)、嗜热链球菌(Streptococcus thermophilus)CRL804(核黄素过量产生菌株)和嗜酸链球菌(Streptococcus thermophilus)组成的乳酸菌(LAB)组合(MIX)的神经保护作用的一些相关机制、在细胞培养中,以及在用 1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的老年小鼠帕金森病慢性模型和左旋多巴-苄丝肼治疗中,N2a 分化出了叶酸菌株 CRL2130 和 CRL807(免疫调节菌株)。在体外,将 N2a 分化神经元暴露于神经毒素 1-甲基-4-苯基吡啶(MPP+),并用细胞内细菌提取物或暴露于细菌提取物的 BV-2 细胞的条件培养基进行处理。在体内,对运动技能、大脑中的酪氨酸水解酶(TH)以及血清和大脑中的细胞因子浓度进行了评估。此外,还对粪便微生物群和小肠组织学进行了研究。结果表明,服用 LAB MIX 所产生的神经保护作用不会干扰左旋多巴-苄丝肼治疗。这种效果可能与 MIX 中所选 LAB 的抗氧化和免疫调节潜力有关,也与运动测试的显著改善和大脑中 TH + 细胞数量的增加有关。此外,服用 LAB MIX 还能调节免疫反应。服用 LAB 可减少肠道损伤,增加绒毛长度/绒毛深度比。最后,在左旋多巴-苄丝肼治疗的同时服用 LAB MIX 能够部分恢复在模型中观察到的肠道菌群失调,显示出与健康对照组更相似的特征,并突出了乳酸杆菌家族的增加。不同的作用机制可能与所选 LAB 组合的保护作用有关,该组合有可能被评估为传统帕金森病疗法的辅助疗法。
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引用次数: 0
Correction: Arne Schousboe: in Memoriam (1944–2024) 更正:阿尔内-舒斯博:悼念(1944-2024 年)
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1007/s11064-024-04215-8
Henry Sershen
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引用次数: 0
Dexmedetomidine Promotes NREM Sleep by Depressing Oxytocin Neurons in the Paraventricular Nucleus in Mice 右美托咪定通过抑制小鼠脑室旁核中的催产素神经元促进 NREM 睡眠
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-30 DOI: 10.1007/s11064-024-04221-w
Ying Zhang, Jiaxin Li, Yan Li, Wei Wang, Daming Wang, Junli Ding, Licheng Wang, Juan Cheng

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist with sedative effects on sleep homeostasis. Oxytocin-expressing (OXT) neurons in the paraventricular nucleus (PVN) of the hypothalamus (PVNOXT) regulate sexual reproduction, drinking, sleep-wakefulness, and other instinctive behaviors. To investigate the effect of DEX on the activity and signal transmission of PVNOXT in regulating the sleep-wakefulness cycle. Here, we employed OXT-cre mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in PVNOXT neurons. Combining chemogenetic methods with electroencephalogram (EEG) /electromyogram (EMG) recordings, we found that cannula injection of DEX in PVN significantly increased the duration of non-rapid eye movement (NREM) sleep in mice. Furthermore, the chemogenetic activation of PVNOXT neurons using i.p. injection of clozapine N-oxide (CNO) after cannula injection of DEX to PVN led to a substantial increase in wakefulness. Electrophysiological results showed that DEX decreased the frequency of action potential (AP) and the spontaneous excitatory postsynaptic current (sEPSC) of PVNOXT neurons through α2-adrenoceptors. Therefore, these results identify that DEX promotes sleep and maintains sleep homeostasis by inhibiting PVNOXT neurons through the α2-adrenoceptor.

右美托咪定(DEX)是一种高选择性α2肾上腺素受体激动剂,对睡眠平衡具有镇静作用。下丘脑室旁核(PVN)中表达催产素(OXT)的神经元(PVNOXT)调节性繁殖、饮酒、睡眠觉醒和其他本能行为。为了研究DEX对PVNOXT调节睡眠-觉醒周期的活性和信号传递的影响。在这里,我们利用OXT-cre小鼠在PVNOXT神经元中选择性地靶向和表达基于DREADD的化学遗传工具hM3D(Gq)。结合化学遗传学方法和脑电图(EEG)/肌电图(EMG)记录,我们发现在PVN中插管注射DEX能显著延长小鼠非快速眼动(NREM)睡眠的持续时间。此外,在PVN插管注射DEX后,使用氯氮平N-氧化物(CNO)对PVNOXT神经元进行化学激活,可使小鼠的觉醒时间大幅增加。电生理结果显示,DEX通过α2-肾上腺素受体降低了PVNOXT神经元的动作电位(AP)频率和突触后自发兴奋电流(sEPSC)。因此,这些结果表明,DEX通过α2-肾上腺素受体抑制PVNOXT神经元,从而促进睡眠和维持睡眠平衡。
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引用次数: 0
Epigenetic Mechanisms of Aluminum-Induced Neurotoxicity and Alzheimer’s Disease: A Focus on Non-Coding RNAs 铝诱导神经毒性和阿尔茨海默病的表观遗传学机制:聚焦非编码 RNA。
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-27 DOI: 10.1007/s11064-024-04214-9
Michael Aschner, Anatoly V. Skalny, Abel Santamaria, Joao B. T. Rocha, Borhan Mansouri, Yousef Tizabi, Roberto Madeddu, Rongzu Lu, Eunsook Lee, Alexey A. Tinkov

Aluminum (Al) is known to induce neurotoxic effects, potentially contributing to Alzheimer’s disease (AD) pathogenesis. Recent studies suggest that epigenetic modification may contribute to Al neurotoxicity, although the mechanisms are still debatable. Therefore, the objective of the present study was to summarize existing data on the involvement of epigenetic mechanisms in Al-induced neurotoxicity, especially AD-type pathology. Existing data demonstrate that Al exposure induces disruption in DNA methylation, histone modifications, and non-coding RNA expression in brains. Alterations in DNA methylation following Al exposure were shown to be mediated by changes in expression and activity of DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs). Al exposure was shown to reduce histone acetylation by up-regulating expression of histone deacetylases (HDACs) and impair histone methylation, ultimately contributing to down-regulation of brain-derived neurotrophic factor (BDNF) expression and activation of nuclear factor κB (NF-κB) signaling. Neurotoxic effects of Al exposure were also associated with aberrant expression of non-coding RNAs, especially microRNAs (miR). Al-induced patterns of miR expression were involved in development of AD-type pathology by increasing amyloid β (Aβ) production through up-regulation of Aβ precursor protein (APP) and β secretase (BACE1) expression (down-regulation of miR-29a/b, miR-101, miR-124, and Let-7c expression), increasing in neuroinflammation through NF-κB signaling (up-regulation of miR-9, miR-125b, miR-128, and 146a), as well as modulating other signaling pathways. Furthermore, reduced global DNA methylation, altered histone modification, and aberrant miRNA expression were associated with cognitive decline in Al-exposed subjects. However, further studies are required to evaluate the contribution of epigenetic mechanisms to Al-induced neurotoxicity and/or AD development.

众所周知,铝(Al)具有神经毒性作用,可能导致阿尔茨海默病(AD)的发病。最近的研究表明,表观遗传修饰可能有助于铝的神经毒性,但其机制仍有待商榷。因此,本研究旨在总结表观遗传机制参与铝诱导的神经毒性,尤其是 AD 型病理学的现有数据。现有数据表明,铝暴露会诱导大脑中DNA甲基化、组蛋白修饰和非编码RNA表达的破坏。研究表明,暴露于铝后DNA甲基化的改变是由DNA甲基转移酶(DNMTs)和十-十一转位蛋白(TETs)的表达和活性变化介导的。研究表明,接触铝会通过上调组蛋白去乙酰化酶(HDACs)的表达来减少组蛋白乙酰化,并损害组蛋白甲基化,最终导致脑源性神经营养因子(BDNF)表达下调和核因子κB(NF-κB)信号的激活。铝暴露的神经毒性效应还与非编码 RNA,特别是微 RNA(miR)的异常表达有关。铝诱导的 miR 表达模式通过上调 Aβ 前体蛋白(APP)和 β 分泌酶(BACE1)的表达(下调 miR-29a/b、miR-101、miR-124 和 Let-7c 的表达),通过 NF-κB 信号转导增加神经炎症(上调 miR-9、miR-125b、miR-128 和 146a),以及调节其他信号通路。此外,全局 DNA 甲基化的减少、组蛋白修饰的改变和 miRNA 表达的异常与暴露于铝的受试者认知能力的下降有关。然而,要评估表观遗传机制对铝诱导的神经毒性和/或注意力缺失症发展的贡献,还需要进一步的研究。
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引用次数: 0
Targeting Adipokines: A Promising Therapeutic Strategy for Epilepsy 靶向脂肪因子:治疗癫痫病的前景广阔的策略
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1007/s11064-024-04219-4
Iqraa Shaikh, Lokesh Kumar Bhatt

Epilepsy affects 65 million people globally and causes neurobehavioral, cognitive, and psychological defects. Although research on the disease is progressing and a wide range of treatments are available, approximately 30% of people have refractory epilepsy that cannot be managed with conventional medications. This underlines the importance of further understanding the condition and exploring cutting-edge targets for treatment. Adipokines are peptides secreted by adipocyte’s white adipose tissue, involved in controlling food intake and metabolism. Their regulatory functions in the central nervous system (CNS) are multifaceted and identified in several physiology and pathologies. Adipokines play a role in oxidative stress and neuroinflammation which are associated with brain degeneration and connected neurological diseases. This review aims to highlight the potential impacts of leptin, adiponectin, apelin, vaspin, visfatin, and chimerin in the pathogenesis of epilepsy.

癫痫影响着全球 6500 万人,并导致神经行为、认知和心理缺陷。尽管对这种疾病的研究正在取得进展,并有多种治疗方法可供选择,但仍有约 30% 的人患有难治性癫痫,无法用常规药物治疗。这凸显了进一步了解这种疾病并探索前沿治疗目标的重要性。脂肪因子是脂肪细胞白色脂肪组织分泌的多肽,参与控制食物摄入和新陈代谢。它们在中枢神经系统(CNS)中的调控功能是多方面的,并在多种生理和病理现象中被发现。脂肪因子在氧化应激和神经炎症中发挥作用,而氧化应激和神经炎症与大脑退化和相关神经疾病有关。本综述旨在强调瘦素、脂肪连素、apelin、vaspin、visfatin 和 chimerin 在癫痫发病机制中的潜在影响。
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引用次数: 0
4,5-Dimethoxycanthin-6-one Inhibits Glioblastoma Stem Cell and Tumor Growth by Inhibiting TSPAN1 Interaction with TM4SF1 4,5-二甲氧基黄嘌呤-6-酮通过抑制 TSPAN1 与 TM4SF1 的相互作用抑制胶质母细胞瘤干细胞和肿瘤生长
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1007/s11064-024-04211-y
Wei Li, Li-jian Yang, Yuan-yuan Xiong, Zeng-shi Li, Xi Li, Yi Wen

Glioblastoma stem cells (GSCs) have been implicated in the self-renewal and treatment resistance of glioblastoma (GBM). Our previous study found that 4,5-dimethoxycanthin-6-one has the potential to inhibit GBM cell proliferation. This current study aims to elucidate the molecular mechanism underlying the effects of 4,5-dimethoxycanthin-6-one in GBM development. The effect of 4,5-dimethoxycanthin-6-one on GSC formation and differentiation was explored in human GBM cell lines U251 and U87. Subsequently, 4,5-dimethoxycanthin-6-one binding to tetraspanin 1 (TSPAN1) / transmembrane 4 L six family member 1 (TM4SF1) was analyzed by molecular simulation docking. Co-immunoprecipitation (Co-IP) and immunofluorescence (IF) were used to assess the interactions between TSPAN1 and TM4SF1 in GSCs. Cell proliferation was detected by cell counting kit-8 (CCK-8) and colony formation assay. To evaluate cell migration, invasion and apoptosis, we employed wound healing assay, transwell and flow cytometry, respectively. Furthermore, subcutaneous xenograft tumor models in nude mice were constructed to evaluate the impact of 4,5-dimethoxycanthin-6-one on GSCs in vivo by examining tumor growth and histological characteristics. 4,5-Dimethoxycanthin-6-one inhibited GSC formation and promoted stem cell differentiation in a concentration-dependent manner. Molecular docking models of 4,5-dimethoxycanthin-6-one with TM4SF1 and TSPAN1 were constructed. Then, the interaction between TSPAN1 and TM4SF1 in GSC was clarified. Moreover, 4,5-dimethoxycanthin-6-one significantly inhibited the expressions of TM4SF1 and TSPAN1 in vitro and in vivo. Overexpression of TSPAN1 partially reversed the inhibitory effects of 4,5-dimethoxycanthin-6-one on GSC formation, proliferation, migration and invasion. 4,5-Dimethoxycanthin-6-one inhibited GBM progression by inhibiting TSPAN1/TM4SF1 axis. 4,5-Dimethoxycanthin-6-one might be a novel and effective drug for the treatment of GBM.

胶质母细胞瘤干细胞(GSCs)与胶质母细胞瘤(GBM)的自我更新和耐药性有关。我们之前的研究发现,4,5-二甲氧基黄嘌呤-6-酮具有抑制 GBM 细胞增殖的潜力。本研究旨在阐明 4,5-二甲氧基黄嘌呤-6-酮在 GBM 生长过程中的分子机制。研究人员在人类 GBM 细胞系 U251 和 U87 中探讨了 4,5-二甲氧基黄嘌呤-6-酮对 GSC 形成和分化的影响。随后,通过分子模拟对接分析了4,5-二甲氧基黄嘌呤-6-酮与四跨蛋白1(TSPAN1)/跨膜4 L六家族成员1(TM4SF1)的结合。共免疫沉淀(Co-IP)和免疫荧光(IF)用于评估 TSPAN1 和 TM4SF1 在 GSCs 中的相互作用。通过细胞计数试剂盒-8(CCK-8)和集落形成试验检测细胞增殖。为了评估细胞迁移、侵袭和凋亡,我们分别采用了伤口愈合试验、透孔法和流式细胞术。此外,我们还构建了裸鼠皮下异种移植肿瘤模型,通过检测肿瘤生长和组织学特征来评估 4,5-二甲氧基黄嘌呤-6-酮对体内 GSCs 的影响。4,5-二甲氧基黄嘌呤-6-酮以浓度依赖的方式抑制了GSC的形成并促进了干细胞的分化。研究人员构建了4,5-二甲氧基黄嘌呤-6-酮与TM4SF1和TSPAN1的分子对接模型。然后,阐明了TSPAN1和TM4SF1在GSC中的相互作用。此外,4,5-二甲氧基黄嘌呤-6-酮能显著抑制TM4SF1和TSPAN1在体外和体内的表达。过量表达TSPAN1可部分逆转4,5-二甲氧基黄嘌呤-6-酮对GSC形成、增殖、迁移和侵袭的抑制作用。4,5-二甲氧基黄嘌呤-6-酮通过抑制 TSPAN1/TM4SF1 轴来抑制 GBM 的进展。4,5-二甲氧基黄嘌呤-6-酮可能是一种治疗GBM的新型有效药物。
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引用次数: 0
LINC00894 Regulates Cerebral Ischemia/Reperfusion Injury by Stabilizing EIF5 and Facilitating ATF4-Mediated Induction of FGF21 and ACOD1 Expression LINC00894 通过稳定 EIF5 和促进 ATF4 介导的 FGF21 和 ACOD1 表达调控脑缺血再灌注损伤
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1007/s11064-024-04213-w
Yifei Chen, Hengxiang Cui, Zhuanzhuan Han, Lei Xu, Lin Wang, Yuefei Zhang, Lijun Liu

The non-coding RNA LINC00894 modulates tumor proliferation and drug resistance. However, its role in brain is still unclear. Using RNA-pull down combined with mass spectrometry and RNA binding protein immunoprecipitation, EIF5 was identified to interact with LINC00894. Furthermore, LINC00894 knockdown decreased EIF5 protein expression, whereas LINC00894 overexpression increased EIF5 protein expression in SH-SY5Y and BE(2)-M17 (M17) neuroblastoma cells. Additionally, LINC00894 affected the ubiquitination modification of EIF5. Adeno-associated virus (AAV) mediated LINC00894 overexpression in the brain inhibited the expression of activated Caspase-3, while increased EIF5 protein level in rats and mice subjected to transient middle cerebral artery occlusion reperfusion (MCAO/R). Meanwhile, LINC00894 knockdown increased the number of apoptotic cells and expression of activated Caspase-3, and its overexpression decreased them in the oxygen–glucose deprivation and reoxygenation (OGD/R) in vitro models. Further, LINC00894 was revealed to regulated ATF4 protein expression in condition of OGD/R and normoxia. LINC00894 knockdown also decreased the expression of glutamate-cysteine ligase catalytic subunit (GCLC) and ATF4, downregulated glutathione (GSH), and the ratio of GSH to oxidized GSH (GSH: GSSG) in vitro. By using RNA-seq combined with qRT-PCR and immunoblot, we identified that fibroblast growth factor 21 (FGF21) and aconitate decarboxylase 1 (ACOD1), as the ATF4 target genes were regulated by LINC00894 in the MCAO/R model. Finally, we revealed that ATF4 transcriptionally regulated FGF21 and ACOD1 expression; ectopic overexpression of FGF21 or ACOD1 in LINC00894 knockdown cells decreased activated Caspase-3 expression in the OGD/R model. Our results demonstrated that LINC00894 regulated cerebral ischemia injury by stabilizing EIF5 and facilitating EIF5-ATF4-dependent induction of FGF21 and ACOD1.

非编码 RNA LINC00894 可调节肿瘤增殖和耐药性。然而,它在大脑中的作用仍不清楚。利用 RNA 拉低结合质谱法和 RNA 结合蛋白免疫沉淀法,确定了 EIF5 与 LINC00894 的相互作用。此外,在SH-SY5Y和BE(2)-M17(M17)神经母细胞瘤细胞中,LINC00894敲除会降低EIF5蛋白的表达,而LINC00894过表达则会增加EIF5蛋白的表达。此外,LINC00894 还影响了 EIF5 的泛素化修饰。腺相关病毒(AAV)介导的LINC00894过表达抑制了活化Caspase-3的表达,同时提高了一过性大脑中动脉闭塞再灌注(MCAO/R)大鼠和小鼠的EIF5蛋白水平。同时,在氧-葡萄糖剥夺和再氧合(OGD/R)体外模型中,LINC00894敲除会增加凋亡细胞的数量和活化Caspase-3的表达,而过表达则会降低它们。此外,LINC00894 还能调节 ATF4 蛋白在 OGD/R 和常氧条件下的表达。LINC00894 基因敲除还降低了谷氨酸-半胱氨酸连接酶催化亚基(GCLC)和 ATF4 的表达,下调了谷胱甘肽(GSH)以及体外 GSH 与氧化 GSH 的比率(GSH:GSSG)。通过RNA-seq结合qRT-PCR和免疫印迹,我们发现成纤维细胞生长因子21(FGF21)和醋酸脱羧酶1(ACOD1)作为ATF4靶基因在MCAO/R模型中受到LINC00894的调控。最后,我们发现 ATF4 可转录调控 FGF21 和 ACOD1 的表达;在 OGD/R 模型中,在 LINC00894 敲除的细胞中异位过表达 FGF21 或 ACOD1 可降低活化的 Caspase-3 的表达。我们的研究结果表明,LINC00894通过稳定EIF5和促进EIF5-ATF4依赖性诱导FGF21和ACOD1来调节脑缺血损伤。
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引用次数: 0
NMN Synbiotics: A Multifaceted Therapeutic Approach for Alzheimer’s Disease NMN 合成生物素:阿尔茨海默病的多元治疗方法。
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-22 DOI: 10.1007/s11064-024-04210-z
Caifeng Li, Xiaodong Zhao, Huilian Xu, Xiaoyong Liu, Yan He, Jinsong Gu

With the aging global population, Alzheimer’s disease (AD) has become a significant social and economic burden, necessitating the development of novel therapeutic strategies. This study investigates the therapeutic potential of nicotinamide mononucleotide (NMN) synbiotics, a combination of NMN, Lactiplantibacillus plantarum CGMCC 1.16089, and lactulose, in mitigating AD pathology. APP/PS1 mice were supplemented with NMN synbiotics and compared against control groups. The effects on amyloid-β (Aβ) deposition, intestinal histopathology, tight junction proteins, inflammatory cytokines, and reactive oxygen species (ROS) levels were assessed. NMN synbiotics intervention significantly reduced Aβ deposition in the cerebral cortex and hippocampus by 67% and 60%, respectively. It also ameliorated histopathological changes in the colon, reducing crypt depth and restoring goblet cell numbers. The expression of tight junction proteins Claudin-1 and ZO-1 was significantly upregulated, enhancing intestinal barrier integrity. Furthermore, NMN synbiotics decreased the expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α, and reduced ROS levels, indicative of attenuated oxidative stress. The reduction in Aβ deposition, enhancement of intestinal barrier function, decrease in neuroinflammation, and alleviation of oxidative stress suggest that NMN synbiotics present a promising therapeutic intervention for AD by modulating multiple pathological pathways. Further research is required to elucidate the precise mechanisms, particularly the role of the NLRP3 inflammasome pathway, which may offer a novel target for AD treatment.

随着全球人口的老龄化,阿尔茨海默病(AD)已成为一项重大的社会和经济负担,因此有必要开发新型治疗策略。本研究探讨了烟酰胺单核苷酸(NMN)合生元(NMN、植物乳杆菌 CGMCC 1.16089 和乳糖的组合)在减轻阿兹海默症病理变化方面的治疗潜力。给 APP/PS1 小鼠补充 NMN 合生素,并与对照组进行比较。评估了对淀粉样蛋白-β(Aβ)沉积、肠道组织病理学、紧密连接蛋白、炎症细胞因子和活性氧(ROS)水平的影响。NMN 合成益生菌的干预显著减少了大脑皮层和海马中的 Aβ 沉积,降幅分别为 67% 和 60%。它还改善了结肠的组织病理学变化,降低了隐窝深度并恢复了鹅口疮细胞的数量。紧密连接蛋白 Claudin-1 和 ZO-1 的表达显著上调,增强了肠道屏障的完整性。此外,NMN 合生素还降低了促炎细胞因子 IL-1β、IL-6 和 TNF-α 的表达,并降低了 ROS 水平,表明氧化应激有所减轻。Aβ 沉积的减少、肠道屏障功能的增强、神经炎症的减少以及氧化应激的减轻表明,NMN 合生素通过调节多种病理途径,是一种很有前景的治疗 AD 的干预措施。要阐明其确切机制,特别是 NLRP3 炎症小体通路的作用,还需要进一步的研究。
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引用次数: 0
Epidermal Neural Crest Stem Cell Conditioned Medium Enhances Spinal Cord Injury Recovery via PI3K/AKT-Mediated Neuronal Apoptosis Suppression 表皮神经干细胞条件培养基通过抑制 PI3K/AKT 介导的神经元凋亡促进脊髓损伤的恢复
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-18 DOI: 10.1007/s11064-024-04207-8
Ziqian Ma, Tao Liu, Liang Liu, Yilun Pei, Tianyi Wang, Zhijie Wang, Yun Guan, Xinwei Zhang, Yan Zhang, Xueming Chen

This study aimed to assess the impact of conditioned medium from epidermal neural crest stem cells (EPI-NCSCs-CM) on functional recovery following spinal cord injury (SCI), while also exploring the involvement of the PI3K-AKT signaling pathway in regulating neuronal apoptosis. EPI-NCSCs were isolated from 10-day-old Sprague-Dawley rats and cultured for 48 h to obtain EPI-NCSC-CM. SHSY-5Y cells were subjected with H2O2 treatment to induce apoptosis. Cell viability and survival rates were evaluated using the CCK-8 assay and calcein-AM/PI staining. SCI contusion model was established in adult Sprague-Dawley rats to assess functional recovery, utilizing the Basso, Beattie and Bresnahan (BBB) scoring system, inclined test, and footprint observation. Neurological restoration after SCI was analyzed through electrophysiological recordings. Histological analysis included hematoxylin and eosin (H&E) staining and Nissl staining to evaluate tissue organization. Apoptosis and oxidative stress levels were assessed using TUNEL staining and ROS detection methods. Additionally, western blotting was performed to examine the expression of apoptotic markers and proteins related to the PI3K/AKT signaling pathway. EPI-NCSC-CM significantly facilitated functional and histological recovery in SCI rats by inhibiting neuronal apoptosis through modulation of the PI3K/AKT pathway. Administration of EPI-NCSCs-CM alleviated H2O2-induced neurotoxicity in SHSY-5Y cells in vitro. The use of LY294002, a PI3K inhibitor, underscored the crucial role of the PI3K/AKT signaling pathway in regulating neuronal apoptosis. This study contributes to the ongoing exploration of molecular pathways involved in spinal cord injury (SCI) repair, focusing on the therapeutic potential of EPI-NCSC-CM. The research findings indicate that EPI-NCSC-CM exerts a neuroprotective effect by suppressing neuronal apoptosis through activation of the PI3K/AKT pathway in SCI rats. These results highlight the promising role of EPI-NCSC-CM as a potential treatment strategy for SCI, emphasizing the significance of the PI3K/AKT pathway in mediating its beneficial effects.

Graphical Abstract

本研究旨在评估表皮神经嵴干细胞条件培养基(EPI-NCSCs-CM)对脊髓损伤(SCI)后功能恢复的影响,同时探索PI3K-AKT信号通路在调节神经细胞凋亡中的参与。从10天大的Sprague-Dawley大鼠体内分离出EPI-NCSCs,培养48小时后获得EPI-NCSC-CM。用 H2O2 处理 SHSY-5Y 细胞以诱导细胞凋亡。细胞活力和存活率通过 CCK-8 检测法和钙黄绿素-AM/PI 染色法进行评估。利用 Basso、Beattie 和 Bresnahan(BBB)评分系统、倾斜试验和足迹观察,在成年 Sprague-Dawley 大鼠中建立了 SCI 挫伤模型,以评估功能恢复情况。通过电生理记录分析 SCI 后的神经恢复情况。组织学分析包括苏木精和伊红(H&E)染色以及尼氏染色,以评估组织结构。采用TUNEL染色和ROS检测方法评估细胞凋亡和氧化应激水平。此外,还进行了Western印迹以检测凋亡标志物和与PI3K/AKT信号通路相关的蛋白质的表达。通过调节PI3K/AKT通路抑制神经细胞凋亡,EPI-NCSC-CM明显促进了SCI大鼠的功能和组织学恢复。服用 EPI-NCSCs-CM 可减轻 H2O2- 诱导的 SHSY-5Y 细胞体外神经毒性。PI3K抑制剂LY294002的使用强调了PI3K/AKT信号通路在调节神经细胞凋亡中的关键作用。这项研究有助于不断探索脊髓损伤(SCI)修复的分子通路,重点是 EPI-NCSC-CM 的治疗潜力。研究结果表明,EPI-NCSC-CM通过激活PI3K/AKT通路抑制SCI大鼠神经细胞凋亡,从而发挥神经保护作用。这些结果凸显了 EPI-NCSC-CM 作为一种潜在的 SCI 治疗策略的前景,强调了 PI3K/AKT 通路在介导其有益作用方面的重要性。
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Neurochemical Research
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