Neurochemistry international最新文献_第4页

Characterizing stroke-related cellular changes in the surviving neurons of mouse ischemic stroke 小鼠缺血性中风存活神经元中与中风相关的细胞变化特征。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-11-11 DOI: 10.1016/j.neuint.2025.106086

Takeshi Ikegami , Tsutomu Sasaki , Takashi Shimbo , Tomomi Kitayama , Yukari Yamamoto , Yuya Ouchi , Sho Yamazaki , Shintaro Sugiyama , Kumiko Nishiyama , Yasufumi Gon , Shuhei Okazaki , Kenichi Todo , Shigenobu Matsumura , Katsuto Tamai , Hideki Mochizuki

Rapid restoration of cerebral blood flow through endovascular therapy is crucial for minimizing neuronal injury in ischemic stroke. This study characterized cellular and molecular alterations during the acute and subacute phases of distal middle cerebral artery occlusion (dMCAO) in mice using single-nucleus (snRNA-seq) and single-cell (scRNA-seq) RNA sequencing. C57BL/6 mice were assigned to control, sham, dMCAO 3-day, and dMCAO 14-day groups. snRNA-seq identified diverse cell populations, including neurons (glutamatergic and GABAergic), fibroblast-like cells, astrocytes, oligodendrocytes, microglia, endothelial cells, and pericytes. Microglia shifted from homeostatic (Siglech, P2ry12) to acute-phase (Lgals1, Top2a, Mki67) and disease-associated states, consistent with previous evidence confirming that our dataset captured stroke-related dynamics. snRNA-seq enabled efficient recovery and analysis of neurons, revealing stroke-induced cell state changes.; notably, glutamatergic neurons declined on day 3, while endothelial cells increased. Gene ontology analysis indicated neuronal death, autophagy, and cAMP biosynthesis pathways. Elevated Syngap1, Ikbkb, and Rock1 expression across glutamatergic subclusters suggested roles in cell death–related mechanisms and vulnerability to ischemic injury. Dissociation of SynGAP1 from PSD-95 after ischemia may enhance ERK1/2 phosphorylation, whereas ischemic preconditioning suppresses this dissociation and prevents ERK1/2 overactivation. Immunohistochemistry confirmed Syngap1 and cAMP response element-binding (CREB) pathway activation at 3 and 14 days post-ischemia, aligning with sequencing results. Suppressing CREB with pAAV-A-CREB reduced neuronal survival, underscoring its role in autophagy and neuroprotection. These findings provide mechanistic insight into stroke-induced molecular alterations and identify autophagy and cAMP pathways within the penumbra as promising therapeutic targets.

通过血管内治疗快速恢复脑血流是减少缺血性脑卒中神经元损伤的关键。本研究通过单核（snRNA-seq）和单细胞（scRNA-seq） RNA测序，表征了小鼠远端大脑中动脉闭塞（dMCAO）急性和亚急性期的细胞和分子变化。将C57BL/6小鼠分为对照组、假手术组、dMCAO 3 d组和dMCAO 14 d组。snRNA-seq鉴定了不同的细胞群，包括神经元（谷氨酸能和gaba能）、成纤维细胞样细胞、星形胶质细胞、少突胶质细胞、小胶质细胞、内皮细胞和周细胞。小胶质细胞从稳态（Siglech, P2ry12）转变为急性期（Lgals1, Top2a, Mki67）和疾病相关状态，这与先前的证据一致，证实了我们的数据集捕获了卒中相关的动态。snRNA-seq能够有效地恢复和分析神经元，揭示中风诱导的细胞状态变化。值得注意的是，第3天谷氨酸能神经元减少，内皮细胞增加。基因本体论分析提示神经元死亡、自噬和cAMP生物合成途径。谷氨酸能亚群中Syngap1、Ikbkb和Rock1表达的升高表明其在细胞死亡相关机制和缺血性损伤易感性中起作用。缺血后PSD-95的SynGAP1解离可增强ERK1/2磷酸化，而缺血预处理可抑制这种解离并防止ERK1/2过度激活。免疫组织化学证实Syngap1和cAMP反应元件结合（CREB）通路在缺血后3和14天激活，与测序结果一致。用pAAV-A-CREB抑制CREB可降低神经元存活，强调其在自噬和神经保护中的作用。这些发现为中风诱导的分子改变提供了机制，并确定了半暗带内的自噬和cAMP途径是有希望的治疗靶点。

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引用次数: 0

Striatal injection of aminochrome in Wistar rats induces early-stage behavioral changes of Parkinson's disease and dopaminergic degeneration in the caudal and medial regions of the nigra pars compacta 纹状体注射氨基色素诱导Wistar大鼠帕金森病早期行为改变及紧黑部尾部和内侧区域多巴胺能变性。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-11-06 DOI: 10.1016/j.neuint.2025.106083

Jéssica Teles-Souza , Juciele Valeria Ribeiro de Oliveira , Fillipe Mendes de Araújo , Flávia Santos Sanches , Lívia Bacelar de Jesus , Suzane Lopes de Souza , Amanda Dias Pinheiro Santos Brito , Camilla Melo Oliveira Leite , Gabriel de Jesus Ferrolho , Emiliano Fernandez-Villalba , Deise Souza Vilas Bôas , Rejane Conceição Santana , Silvia Lima Costa , Maria Trinidad Herrero , Victor Diogenes Amaral Silva

Most preclinical Parkinson's disease (PD) models use neurotoxic agents to cause rapid dopaminergic neuron degeneration, mimicking the late stage of PD. That creates a gap in understanding early-stage pathophysiology, critical for neuroprotective therapies and early diagnosis. To replicate the prodromal stage of PD, it is pivotal that preclinical study models promote a slow and selective death of dopaminergic neurons, triggering degenerative processes and early symptoms. In this context, we investigated behavioral and neuronal changes using a model of unilateral aminochrome injection (6 nmol/6 μL) in the striatum of adult male Wistar rats (CEUA-ICS, Protocol 3006070223), focusing on subtle changes representative of the early stages of PD. On the fourteenth day after the stereotaxic injection, we observed behavioral impairments marked by a reduction of frequency of entries, time spent and distance traveled in the central quadrants in the open field test, reduction of frequency of rearing and grooming in the open field, as well as an increase in the rate of motor asymmetry in the cylinder test. In addition, we observed a decrease in the transition of animals through the elevated plus maze, with a reduction in the number of entries into the open arm. Immunohistochemical analyses indicated that aminochrome induces cytotoxicity for tyrosine hydroxylase-positive (TH⁺) cells and induces astrogliosis and microgliosis. Our findings show that striatal injection of aminochrome induces a reduction in the density of TH⁺ fibers in the striatum, a slight reduction in the number of dopaminergic neurons in the caudal and medial regions of the nigra pars compacta (SNpc), and subtle motor deficits typical of an early stage of PD. Here, we provided evidence that aminochrome can induce a rodent model of the prodromal stages of PD.

大多数临床前帕金森病（PD）模型使用神经毒性药物引起快速多巴胺能神经元变性，模拟帕金森病的晚期。这在理解早期病理生理学方面造成了空白，而早期病理生理学对神经保护疗法和早期诊断至关重要。为了复制PD的前驱阶段，关键是临床前研究模型促进多巴胺能神经元缓慢和选择性死亡，引发退行性过程和早期症状。在这种情况下，我们使用单侧氨基色素注射（6 nmol/6μ l）的模型研究成年雄性Wistar大鼠纹状体的行为和神经元变化（CEUA-ICS，协议3006070223），重点关注具有代表性的PD早期的细微变化。在立体定向注射后的第14天，我们观察到大鼠的行为障碍，表现为在开放场地测试中进入中央象限的次数、时间和距离减少，在开放场地饲养和梳理的频率减少，以及在圆柱体测试中运动不对称率增加。此外，我们观察到动物通过高架+迷宫的过渡减少，进入张开手臂的次数减少。免疫组化分析表明，氨基色素对酪氨酸羟酶阳性（TH+）细胞具有细胞毒性，可诱导星形胶质细胞和小胶质细胞增生。我们的研究结果表明，纹状体注射氨基色素导致纹状体中TH+纤维密度降低，紧黑部（SNpc）尾侧和内侧区域多巴胺能神经元数量轻微减少，以及PD早期典型的轻微运动障碍。在这里，我们提供了证据，证明氨基色素可以诱导PD前驱期的啮齿动物模型。

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引用次数: 0

Functional impact of CYFIP2 RNA editing on actin regulation, axon growth, and spinogenesis CYFIP2 RNA编辑对肌动蛋白调控、轴突生长和脊柱发生的功能影响。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-11-05 DOI: 10.1016/j.neuint.2025.106084

Luca La Via , Elona Ndoj , Matteo Bertoli , Veronica Mutti , Giulia Carini , Alice Filippini , Federica Bono , Chiara Fiorentini , Giovanni Ribaudo , Alessandra Gianoncelli , Giuseppe Borsani , Isabella Russo , Alessandro Barbon

Cytoplasmic FMRP-interacting protein 2 (CYFIP2) is a component of the wave regulatory complex (WRC), one of the most important players in regulating cellular actin dynamics. Interestingly, the CYFIP2 transcript undergoes RNA editing, an epitranscriptomic modification catalyzed by ADAR enzymes, which leads to adenosine (A) to inosine (I) deamination. CYFIP2 editing in the coding sequence results in a K/E substitution at amino acid 320. The functional meaning of this regulation is still unknown. In this study, we aimed to investigate the potential implications of CYFIP2 RNA editing related to actin dynamics during cell differentiation, axon development and synaptogenesis in neural cells. We generated SH-SY5Y neuroblastoma cell lines in which the CYFIP2 gene has been functionally inactivated via CRISPR-Cas9 technology. CYFIP2 KO cells exhibited profound actin filament disorganization and loss of the ability to differentiate into a neuron-like phenotype. The overexpression of both the unedited (K) and edited (E) CYFIP2 isoforms restored normal abilities. Finally, we used primary neuronal cultures in which endogenous CYFIP2 was knocked down via short hairpin RNA (shRNA) technology and CYFIP2 editing variants were overexpressed.

While CYFIP2-KD cells presented a decrease in axon development and spine frequency, CYFIP2-E variants increased the number of axon branches, total axon length and dendritic spine frequency compared with both CYFIP2-KD cells and CYFIP-K variants. Overall, our work reveals for the first time the functional significance of the CYFIP2 K/E RNA editing process in regulating the spread of neuronal axons during the initial stages of in vitro development and spinogenesis.

胞质fmrp相互作用蛋白2 （CYFIP2）是波浪调节复合体（WRC）的一个组成部分，是调节细胞肌动蛋白动力学的最重要的参与者之一。有趣的是，CYFIP2转录本经历RNA编辑，这是一种由ADAR酶催化的表转录组修饰，导致腺苷(A)脱胺为肌苷(I)。在编码序列中编辑CYFIP2导致在氨基酸320处K/E替换。这一规定的功能意义尚不清楚。在这项研究中，我们旨在研究CYFIP2 RNA编辑在神经细胞分化、轴突发育和突触发生过程中与肌动蛋白动力学相关的潜在影响。我们通过CRISPR-Cas9技术获得了CYFIP2基因功能失活的SH-SY5Y神经母细胞瘤细胞系。CYFIP2 KO细胞表现出严重的肌动蛋白丝紊乱和向神经元样表型分化的能力丧失。未编辑的(K)和编辑的(E) CYFIP2亚型的过表达恢复了正常的能力。最后，我们使用了原代神经元培养物，其中内源性CYFIP2通过短发夹RNA （shRNA）技术被敲除，CYFIP2编辑变体被过表达。虽然CYFIP2-KD细胞的轴突发育和脊柱频率减少，但与CYFIP2-KD细胞和cyfip2 - k变异体相比，CYFIP2-E变异体的轴突分支数量、轴突总长度和树突脊柱频率增加。总的来说，我们的工作首次揭示了CYFIP2 K/E RNA编辑过程在体外发育和脊柱发生的初始阶段调节神经元轴突扩散的功能意义。

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引用次数: 0

Oral administration of arginine suppresses Aβ pathology in animal models of Alzheimer's disease 口服精氨酸抑制阿尔茨海默病动物模型中的Aβ病理

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-10-30 DOI: 10.1016/j.neuint.2025.106082

Kanako Fujii , Toshihide Takeuchi , Yuzo Fujino , Noriko Tanaka , Nao Fujino , Akiko Takeda , Eiko N. Minakawa , Yoshitaka Nagai

Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain. In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an App^NL-G-F knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated App^NL-G-F knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes. These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.

近年来，针对淀粉样蛋白β (Aβ)的抗体治疗阿尔茨海默病（AD）已被开发出来，但其临床疗效仍然有限，且成本高、不良反应等问题也被提出。因此，迫切需要建立一种安全且具有成本效益的治疗方法来抑制Aβ聚集或防止其在大脑中的积累。在这项研究中，我们报道了精氨酸，一种临床批准的安全的化学伴侣，在体外和体内抑制a β聚集。我们使用体外实验证明精氨酸以浓度依赖的方式抑制a β42肽的聚集形成。在表达北极突变E22G的a β42肽的AD果蝇模型中，口服精氨酸剂量依赖性地减少了a β42的积累，并恢复了a β42介导的毒性。在AppNL-G-F敲入的人类APP家族突变小鼠模型中，口服精氨酸抑制了Aβ斑块沉积，降低了大脑中不溶性Aβ42的水平。精氨酸处理的AppNL-G-F敲入小鼠也显示出行为异常的改善和神经炎症相关细胞因子基因的表达降低。这些结果表明，在AD动物模型中，口服精氨酸不仅可以减少Aβ沉积，还可以改善Aβ介导的神经系统表型。这些研究结果确定精氨酸是一种安全且具有成本效益的抑制a β聚集的候选药物，并强调了其重新定位的潜力，可用于AD治疗的快速临床转化。精氨酸还可能广泛应用于由蛋白质错误折叠和聚集引起的神经退行性疾病。

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引用次数: 0

Food restriction and amphetamine exposure synergistically enhance accumbal dopamine D1 receptor-mediated locomotor activity 食物限制和安非他明暴露协同增强伏隔多巴胺D1受体介导的运动活动。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-10-27 DOI: 10.1016/j.neuint.2025.106081

Seohyeon Lee , Hyung Shin Yoon , Jeong-Hoon Kim

Natural rewards such as food and drugs of abuse share the mesolimbic dopamine system, including the nucleus accumbens (NAcc), as a common neural pathway that influences appetite and addictive behavior. Ghrelin, an orexigenic hormone, acts synergistically with mesolimbic dopamine in this process. In the present study, we examined the effects of food restriction (FR) on plasma ghrelin levels and amphetamine (AMPH)-induced locomotor activity. Chronic FR (cFR) significantly enhanced AMPH-induced locomotor activity compared to normal feeding and acute FR (aFR), which was associated with increased plasma ghrelin and dopamine D1 receptor (D1R) expression levels in the NAcc. These effects were inhibited by either systemic or NAcc-specific administration of D1R or ghrelin receptor antagonists. Furthermore, rats under the aFR condition showed enhanced locomotor activity in response to intra-accumbal microinjection of the D1R agonist when pre-exposed to AMPH, whereas rats in the cFR condition showed these effects regardless of pre-exposures to either AMPH or saline. These results demonstrate that FR conditions interact with drugs of abuse via the accumbal ghrelin and D1R systems, thereby contributing to the expression of addictive behaviors. Notably, these findings suggest that dietary status should be considered during addiction treatment.

自然奖励，如食物和药物滥用共享中脑边缘多巴胺系统，包括伏隔核（NAcc），作为一个共同的神经通路，影响食欲和成瘾行为。胃饥饿素是一种促氧激素，在这一过程中与中脑边缘多巴胺协同作用。在本研究中，我们研究了食物限制（FR）对血浆胃饥饿素水平和安非他明（AMPH）诱导的运动活动的影响。与正常喂养和急性FR （aFR）相比，慢性FR （cFR）显著增强了amph诱导的运动活性，这与NAcc血浆胃饥饿素和多巴胺D1受体（D1R）表达水平升高有关。这些作用可被D1R或胃饥饿素受体拮抗剂的全身或nac特异性施用所抑制。此外，aFR条件下的大鼠在预先暴露于AMPH时，对伏隔区内微量注射D1R激动剂的运动活动表现出增强的反应，而cFR条件下的大鼠无论预先暴露于AMPH还是生理盐水都表现出这些作用。这些结果表明FR条件通过伏隔胃饥饿素和D1R系统与药物滥用相互作用，从而促进成瘾行为的表达。值得注意的是，这些发现表明在成瘾治疗期间应考虑饮食状况。

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引用次数: 0

The epigenetic mechanism of sleep disorders related cognitive impairment 睡眠障碍相关认知障碍的表观遗传机制

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-10-25 DOI: 10.1016/j.neuint.2025.106079

Meimei Guo , Yuhan Liu , Jiabin Zhou , Yu Lei

Sleep deprivation is a prevalent social problem affecting millions worldwide and can induce epigenetic alterations in the brain, impacting neuronal synaptic plasticity and cognitive function. The epigenetic alteration in clock genes significantly contribute to impaired learning and memory, though the precise mechanisms remain elusive. This review examines the prevalence of sleep loss and its impact on the cognitive function and circadian clock genes. We then discuss the intricate relationship between circadian clock genes and epigenetic alterations, and how these epigenetic changes may serve as potential targets for treating sleep disorders and memory impairment. Moving forward, further exploration of the cognitive impairment caused by sleep deprivation via epigenetic mechanism is essential to deepen our understanding of this complex interplay.

睡眠剥夺是一个普遍存在的社会问题，影响着全世界数百万人，它会诱发大脑的表观遗传改变，影响神经元突触的可塑性和认知功能。时钟基因的表观遗传改变显著地促进了学习和记忆的受损，尽管精确的机制仍然难以捉摸。本文综述了睡眠缺失的普遍性及其对认知功能和生物钟基因的影响。然后，我们讨论了生物钟基因和表观遗传改变之间的复杂关系，以及这些表观遗传改变如何作为治疗睡眠障碍和记忆障碍的潜在靶点。展望未来，通过表观遗传机制进一步探索睡眠剥夺引起的认知障碍对于加深我们对这种复杂相互作用的理解至关重要。

引用次数: 0

LC-MS/MS techniques for the analysis of steroid panel in human cerebrospinal fluid LC-MS/MS技术分析人脑脊液中类固醇成分。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-10-23 DOI: 10.1016/j.neuint.2025.106080

Tereza Skodova , Jana Vitku , Ondrej Bradac , Petr Skalicky , Adela Bubenikova , Radmila Kanceva , Lucie Kolatorova

The metabolic processes within the brain are reflected in the cerebrospinal fluid (CSF). It is in close contact with the nervous system, which is both target and source of multiple steroids. The aim of our study was to develop and validate robust, sensitive LC-MS/MS methods with and without derivatization step for the analysis of unconjugated steroids from all major steroid classes in CSF. The validation of the method without derivatization was performed for ten C19- steroids (dehydroepiandrosterone (DHEA), 7α-hydroxyDHEA, 7β-hydroxyDHEA, 7-ketoDHEA, testosterone, epitestosterone, dihydrotestosterone, 11-hydroxytestosterone, 11-ketotestosterone and androstenedione), ten C21- steroids (cortisol, 11-deoxycortisol, 21-deoxycortisol, cortisone, corticosterone, 11-deoxycorticosterone, pregnenolone, progesterone, 17-hydroxyprogesterone, aldosterone) and three C18- steroids (estrone, estradiol, estriol). The method with derivatization is validated for determination of eleven C19- steroids (testosterone, 11-ketodihydrotestosterone, 11-hydroxytestosterone, DHEA, 7α-hydroxyDHEA, 7β-hydroxyDHEA, 7-ketoDHEA, androstenedione, androsterone, epiandrosterone, 7β-hydroxyepiandrosterone) and six C21- steroids (cortisol, cortisone, corticosterone, pregnenolone, 17-hydroxypregnenolone, progesterone) in CSF. The method without derivatization is applicable for the determination of the majority of steroids in CSF, except for pregnenolone, 17-hydroxypregnenolone and DHEA, for which the derivatization method provides better sensitivity. When analyzing CSF samples of normal pressure hydrocephalus (NPH) patients, 11-ketodihydrotestosterone, epitestosterone, androsterone, epiandrosterone, 7β-hydroxyepiandrosterone, 7-ketoDHEA and 21-deoxycortisol were found to be below the LLOQ, suggesting that their presence is very limited. 17-hydroxypregnenolone, and 11-deoxycortisol were quantified for the first time, their CSF levels in NPH subjects are presented. We also observed significantly increased CSF levels of testosterone and 17-hydroxyprogesterone in men compared to women, both with NPH.

脑内的代谢过程反映在脑脊液（CSF）中。它与神经系统密切接触，是多种类固醇的靶点和来源。本研究的目的是开发和验证可靠、敏感的LC-MS/MS方法，用于分析脑脊液中所有主要类固醇类的非共轭类固醇。对10种C19-甾体（脱氢表雄酮（DHEA）、7α-羟基DHEA、7-羟基DHEA、7-酮DHEA、睾酮、表雄酮、二氢睾酮、11-羟基睾酮、11-酮睾酮和雄烯二酮）、10种C21-甾体（皮质醇、11-脱氧皮质醇、21-脱氧皮质醇、可的松、皮质酮、11-脱氧皮质酮、孕烯醇酮、孕酮、17-羟孕酮、醛固酮）和3种C18-甾体(雌酮、雌二醇、雌三醇)。验证了衍生化法测定脑脊液中11种C19-甾体（睾酮、11-酮二氢睾酮、11-羟基睾酮、DHEA、7α-羟基DHEA、7β-羟基DHEA、雄烯二酮、雄酮、表雄酮、7β-羟基雄酮）和6种C21-甾体（皮质醇、可的松、皮质酮、孕烯醇酮、17-羟基孕烯醇酮、孕酮）的含量。除孕烯醇酮、17-羟基孕烯醇酮和脱氢表雄酮外，不衍生化法适用于脑脊液中大部分类固醇的测定，衍生化法对这些类固醇的灵敏度更高。在分析常压脑积水（NPH）患者脑脊液样本时，发现11-酮二氢睾酮、表甾酮、雄酮、表雄酮、7- β-羟基雄酮、7-酮脱氢表雄酮和21-脱氧皮质醇低于LLOQ，表明它们的存在非常有限。首次定量测定了17-羟基孕烯醇酮和11-脱氧皮质醇，并给出了它们在NPH受试者脑脊液中的水平。我们还观察到，与NPH患者相比，男性脑脊液中睾酮和17-羟孕酮水平显著升高。

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引用次数: 0

Astrocytic HIF-1α/VEGF induces endothelial PI3K/Akt activation to accelerate post-ischemic angiogenesis upon LCN2 inhibition 星形胶质细胞HIF-1α/VEGF诱导内皮细胞PI3K/Akt激活，在LCN2抑制下加速缺血后血管生成。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-10-14 DOI: 10.1016/j.neuint.2025.106078

Ning Tian , Xiaoxia Li , Yanlin Jiang , Jungang Deng , Hao Wang , Bing Guo , Meiling Chen , Rujia Liao

Therapeutic angiogenesis represents a pivotal yet underexplored avenue for functional recovery following cerebral ischemia. Although lipocalin-2 (LCN2) participates in neuropathological processes, its cell-type-specific regulation of post-ischemic vascular remodeling remains unknown. Here, we demonstrate that CRISPR/Cas9-mediated C8D1A astrocyte-like cells-specific LCN2 knockout significantly enhances vascular network formation in endothelial co-cultures under oxygen-glucose deprivation/reperfusion (OGD/R). Clinically, elevated LCN2 (GDS4521 dataset) correlates with poor stroke prognosis. Functional analyses revealed that AAV-shRNA-mediated LCN2 knockdown in photothrombotic stroke mice reduced infarct volume, attenuated peri-infarct neuronal loss, increased peri-infarct vascular density, and improved neurobehavioral outcomes at 7 days post-ischemia. Mechanistically, transcriptomic profiling identified hypoxia-inducible factor 1α (HIF-1α) as the master regulator of ischemia-induced angiogenesis. Molecular docking confirmed LCN2-HIF1α interaction. Furthermore, LCN2 ablation unleashes a HIF-1α/VEGF signaling cascade in C8D1A astrocyte-like cells, which activates endothelial phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) via paracrine mechanisms to drive functional revascularization. These findings not only redefine ischemic pathophysiology but also pioneers LCN2 inhibition as a translational strategy to overcome the limitations of current pro-angiogenic therapies in cerebrovascular disease.

治疗性血管生成是脑缺血后功能恢复的关键但尚未充分探索的途径。尽管脂载素-2 （LCN2）参与神经病理过程，但其对缺血后血管重构的细胞类型特异性调控尚不清楚。在这里，我们证明了CRISPR/ cas9介导的C8D1A星形细胞样细胞特异性LCN2敲除显著增强了氧糖剥夺/再灌注（OGD/R）下内皮共培养血管网络的形成。临床上，升高的LCN2 （GDS4521数据集）与卒中预后不良相关。功能分析显示，在光血栓性卒中小鼠中，aav - shrna介导的LCN2敲低减少了梗死体积，减轻了梗死周围神经元的损失，增加了梗死周围血管密度，并在缺血后7天改善了神经行为结果。在机制上，转录组学分析发现缺氧诱导因子1α (HIF-1α)是缺血诱导血管生成的主要调节因子。分子对接证实LCN2-HIF1α相互作用。此外，LCN2消融在C8D1A星形细胞样细胞中释放HIF-1α/VEGF信号级联，通过旁分泌机制激活内皮磷脂酰肌醇-3激酶/蛋白激酶B (PI3K/Akt)，驱动功能性血运重建。这些发现不仅重新定义了缺血病理生理学，而且开创了LCN2抑制作为一种翻译策略来克服当前脑血管疾病促血管生成治疗的局限性。

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引用次数: 0

Psychotropic and neurodegenerative drugs modulate platelet activity via the PAF pathway 精神药物和神经退行性药物通过PAF途径调节血小板活性。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-10-13 DOI: 10.1016/j.neuint.2025.106073

Savvato Kosidou , Zisis Zannas , Anna Ofrydopoulou , Dimitra A. Lambropoulou , Alexandros Tsoupras

Mild psychiatric conditions such as anxiety and depression, as well as severe disorders like schizophrenia and neurodegenerative diseases, are increasingly recognized as systemic inflammatory conditions. Platelets possess both hemostatic and immunomodulatory roles in these situations, with sharing key molecular pathways with the central nervous system, offering thus a valuable peripheral model for evaluating psychotropic drug effects. Platelet-activating factor (PAF), a potent thrombo-inflammatory mediator, has emerged as a potential link between the two systems, yet its involvement in drug responses remains understudied. This study systematically investigates the effects of psychotropic drugs (i.e. antidepressants, antipsychotics and anxiolytics), and neuroprotective (anti-Alzheimer's/Anti-Parkinson's) drugs on platelet aggregation, focusing on PAF-pathway in comparison to a control platelet agonist, ADP. Using ex vivo light transmission aggregometry, we determined IC₅₀ values for each drug and analyzed the impact of selected drug combinations, in which the NSAID diclofenac was also included. Results revealed that most of the compounds assessed inhibited more effectively the PAF-induced aggregation of platelets compared to their effect on the ADP-pathway, with perphenazine showing the greatest anti-PAF potency. Several drug combinations, notably those including alprazolam and diclofenac, demonstrated significant synergistic effects. These findings suggest that commonly prescribed psychotropic drugs and medications for neurodegenerative disorders can influence platelet activity, mostly through the PAF-pathway, and that their interactions with NSAIDs may amplify their efficacy. Nevertheless, some drugs and their combinations induced lysis of platelets at much higher concentrations than their IC50 values, which stems safety concerns for their use.

焦虑和抑郁等轻度精神疾病，以及精神分裂症和神经退行性疾病等严重疾病，越来越多地被认为是全身性炎症。在这些情况下，血小板具有止血和免疫调节作用，与中枢神经系统共享关键的分子通路，因此为评估精神药物的作用提供了有价值的外周模型。血小板活化因子（PAF）是一种有效的血栓炎症介质，已成为这两个系统之间的潜在联系，但其在药物反应中的作用仍未得到充分研究。本研究系统地研究了精神药物（如抗抑郁药、抗精神病药和抗焦虑药）和神经保护药物（抗阿尔茨海默病/抗帕金森病）对血小板聚集的影响，重点研究了paf途径与对照血小板激动剂ADP的比较。使用体外光透射聚合法，我们确定了每种药物的IC50值，并分析了所选药物组合的影响，其中也包括非甾体抗炎药双氯芬酸。结果显示，与对adp通路的影响相比，大多数被评估的化合物更有效地抑制paf诱导的血小板聚集，其中奋乃嗪显示出最大的抗paf效力。几种药物组合，特别是阿普唑仑和双氯芬酸，显示出显著的协同效应。这些发现表明，常用的精神药物和神经退行性疾病药物可以影响血小板活性，主要是通过paf途径，并且它们与非甾体抗炎药的相互作用可能会增强其疗效。然而，一些药物及其组合在比IC50值高得多的浓度下诱导血小板溶解，这引起了对其使用安全性的担忧。

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引用次数: 0

Neuronal FSTL4 negatively regulates BDNF-mediated neuron-glioma interaction 神经元FSTL4负调控bdnf介导的神经元-胶质瘤相互作用。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-10-11 DOI: 10.1016/j.neuint.2025.106072

Yan Sun , Mi Xiao , Xunhui Wang , Yanchun Xu , Anbin Chen , Bin Li , Baohui Feng , Bangbao Tao

Gliomas exploit various molecular pathways to promote their survival, proliferation, and invasion. Recent studies reveal the complex neuron-glioma interaction and BDNF plays a major role in this interaction. However, it's unclear whether and how the BDNF-mediated cross-talk between neurons and gliomas is regulated. FSTL4 is reported to negatively regulate BDNF maturation. Here, we hypothesized that neuronal FSTL4 may negatively regulate BDNF-mediated neuron-glioma cross-talk. By using a combination of approaches like chemogenetic activation of primary neurons and CRISPR knockout/activation of endogenous FSTL4, we show that activated primary neurons support the proliferation of co-cultured glioma cells and neuronal BDNF secretion mediates this neuron-glioma interaction via activating TrkB in glioma cells. In addition, this process is negatively regulated by neuronal FSTL4 as its CRISPR KO in primary neurons further supports the proliferation of co-cultured glioma cells. Importantly, CRISPR activation of endogenous FSTL4 expression in primary neurons results in impaired ability to support co-cultured glioma cells, highlighting the therapeutic potential of activating endogenous FSTL4 for glioma treatment. Taken together, our study shows that the FSTL4/BDNF/TrkB axis plays an essential role in fine-tuning the neuron-glioma interaction and targeting this interplay with CRISPR tools may help to develop novel therapeutic strategies.

胶质瘤利用多种分子途径促进其生存、增殖和侵袭。近年来的研究揭示了复杂的神经-胶质瘤相互作用，而BDNF在这种相互作用中起着重要作用。然而，神经元和胶质瘤之间的bdnf介导的串扰是否以及如何被调节尚不清楚。据报道，FSTL4负调控BDNF成熟。在这里，我们假设神经元FSTL4可能负调控bdnf介导的神经元-胶质瘤串扰。通过化学发生激活原代神经元和CRISPR敲除/激活内源性FSTL4等方法，我们发现激活的原代神经元支持共培养胶质瘤细胞的增殖，神经元BDNF分泌通过激活胶质瘤细胞中的TrkB介导这种神经元与胶质瘤的相互作用。此外，这一过程受到神经元FSTL4的负调控，因为其在原代神经元中的CRISPR KO进一步支持共培养胶质瘤细胞的增殖。重要的是，CRISPR激活原代神经元中内源性FSTL4表达会导致支持共培养胶质瘤细胞的能力受损，这突出了激活内源性FSTL4治疗胶质瘤的治疗潜力。综上所述，我们的研究表明FSTL4/BDNF/TrkB轴在微调神经元-胶质瘤相互作用中起着至关重要的作用，用CRISPR工具靶向这种相互作用可能有助于开发新的治疗策略。

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引用次数: 0