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Inhibiting the activation of enteric glial cells alleviates intestinal inflammation and comorbid anxiety- and depressive-like behaviors in the ulcerative colitis mice 抑制肠胶质细胞的活化可减轻溃疡性结肠炎小鼠的肠道炎症以及合并的焦虑和抑郁样行为。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-07 DOI: 10.1016/j.neuint.2024.105789
Yan Li , Yan Wang , Qian Sun , Meng-Ying Li , Jia-Zhou Xu , Yun-Qing Li , Hua Zhang

Ulcerative colitis (UC) is a common inflammatory bowel disease with a complex origin in clinical settings. It is frequently accompanied by negative emotional responses, including anxiety and depression. Enteric glial cells (EGCs) are important components of the gut-brain axis and are involved in the development of the enteric nervous system (ENS), intestinal neuroimmune, and regulation of intestinal motor functions. Since there is limited research encompassing the regulatory function of EGCs in anxiety- and depression-like behaviors induced by UC, this study aims to reveal their regulatory role in such behaviors and associated intestinal inflammation. This study applied morphological, molecular biological, and behavioral methods to observe the morphological and functional changes of EGCs in UC mice. The results indicated a significant activation of EGCs in the ENS of dextran sodium sulfate -induced UC mice. This activation was evidenced by morphological alterations, such as elongation or terminal swelling of processes. Besides EGCs activation, UC mice exhibited significantly elevated expression levels of pro-inflammatory cytokines in the peripheral blood, accompanied by anxiety- and depression-like behaviors. The inhibition of EGCs activity within the ENS can ameliorate the anxiety- and depression-like behaviors caused by UC. Our data suggest that UC and its resulting behaviors may be related to the activation of EGCs within the ENS. Moreover, the modulation of intestinal inflammation through inhibition of EGCs activation emerges as a promising clinical approach for alleviating UC-induced anxiety- and depression-like behaviors.

溃疡性结肠炎(UC)是一种常见的炎症性肠病,在临床上病因复杂。它经常伴有负面情绪反应,包括焦虑和抑郁。肠胶质细胞(EGCs)是肠道-大脑轴的重要组成部分,参与肠道神经系统(ENS)的发育、肠道神经免疫和肠道运动功能的调节。由于有关EGCs在UC诱导的焦虑和抑郁样行为中的调节功能的研究有限,本研究旨在揭示EGCs在此类行为和相关肠道炎症中的调节作用。本研究采用形态学、分子生物学和行为学方法观察了EGCs在UC小鼠体内的形态和功能变化。结果表明,右旋糖酐硫酸钠诱导的UC小鼠的ENS中的EGCs被明显激活。这种活化表现为形态学上的改变,如过程的伸长或末端肿胀。除EGCs活化外,UC小鼠外周血中促炎细胞因子的表达水平也明显升高,并伴有焦虑和抑郁样行为。抑制 ENS 中 EGCs 的活性可以改善 UC 引起的焦虑和抑郁行为。我们的数据表明,UC 及其导致的行为可能与 ENS 中 EGCs 的激活有关。此外,通过抑制EGCs的活化来调节肠道炎症是一种很有前景的临床方法,可用于缓解UC引起的焦虑和抑郁样行为。
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引用次数: 0
Pharmacological inhibition of cGAS ameliorates postoperative cognitive dysfunction by suppressing caspase-3/GSDME-dependent pyroptosis 抑制 cGAS 的药理作用可通过抑制 caspase-3/GSDME 依赖性裂解来改善术后认知功能障碍
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-04 DOI: 10.1016/j.neuint.2024.105788
Xueshan Bu , Ping Gong , Lei Zhang , Wenqin Song , Jiabao Hou , Qingwen Li , Wei Wang , Zhongyuan Xia

Neuroinflammation is a major driver of postoperative cognitive dysfunction (POCD). The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS–STING) signaling is a prominent alarming device for aberrant double-stranded DNA (dsDNA) that has emerged as a key mediator of neuroinflammation in cognitive-related diseases. However, the role of the cGAS–STING pathway in the pathogenesis of POCD remains unclear. A POCD model was developed in male C57BL/6J mice by laparotomy under isoflurane (Iso) anesthesia. The cGAS inhibitor RU.521 and caspase-3 agonist Raptinal were delivered by intraperitoneal administration. BV2 cells were exposed to Iso and lipopolysaccharide (LPS) in the absence or presence of RU.521, and then cocultured with HT22 cells in the absence or presence of Raptinal. Cognitive function was assessed using the Morris water maze test and novel object recognition test. Immunofluorescence assays were used to observe the colocalization of dsDNA and cGAS. The downstream proteins and pro-inflammatory cytokines were detected using the Western blot and enzyme-linked immunosorbent assay (ELISA). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to assess the degree of cell death in the hippocampus following anesthesia/surgery treatment. Isoflurane/laparotomy and Iso + LPS significantly augmented the levels of cGAS in the hippocampus and BV2 cells, accompanied by mislocalized dsDNA accumulation in the cytoplasm. RU.521 alleviated cognitive impairment, diminished the levels of 2′3′-cGAMP, cGAS, STING, phosphorylated NF-κB p65 and NF-κB-pertinent pro-inflammatory cytokines (TNFα and IL-6), and repressed pyroptosis-associated elements containing cleaved caspase-3, N-GSDME, IL-1β and IL-18. These phenotypes could be rescued by Raptinal in vivo and in vitro. These findings suggest that pharmacological inhibition of cGAS mitigates neuroinflammatory burden of POCD by dampening caspase-3/GSDME-dependent pyroptosis, providing a potential therapeutic strategy for POCD.

神经炎症是术后认知功能障碍(POCD)的主要驱动因素。环GMP-AMP合成酶-干扰素基因刺激器(cGAS-STING)信号传导是异常双链DNA(dsDNA)的显著报警装置,已成为认知相关疾病中神经炎症的关键介质。然而,cGAS-STING通路在POCD发病机制中的作用仍不清楚。研究人员在异氟醚(Iso)麻醉下对雄性 C57BL/6J 小鼠进行开腹手术,建立了 POCD 模型。腹腔注射 cGAS 抑制剂 RU.521 和 caspase-3 激动剂 Raptinal。在无RU.521或有RU.521的情况下,将BV2细胞暴露于Iso和脂多糖(LPS),然后在无Raptinal或有Raptinal的情况下与HT22细胞共培养。认知功能通过莫里斯水迷宫测试和新物体识别测试进行评估。免疫荧光试验用于观察dsDNA和cGAS的共定位。使用 Western 印迹和酶联免疫吸附试验(ELISA)检测下游蛋白和促炎细胞因子。末端脱氧核苷酸转移酶dUTP缺口标记(TUNEL)染色用于评估麻醉/手术治疗后海马细胞的死亡程度。异氟醚/扁桃体切除术和异体+LPS显著增加了海马和BV2细胞中cGAS的水平,并伴随着胞质中dsDNA的错位聚集。RU.521 可减轻认知障碍,降低 2′3′-cGAMP、cGAS、STING、磷酸化 NF-κB p65 和 NF-κB 相关促炎细胞因子(TNFα 和 IL-6)的水平,并抑制含有裂解的 caspase-3、N-GSDME、IL-1β 和 IL-18 的嗜热相关元素。这些表型在体内和体外均可被雷普替尼尔所挽救。这些研究结果表明,药理抑制cGAS可以通过抑制依赖于caspase-3/GSDME的热凋亡减轻POCD的神经炎症负担,为POCD提供了一种潜在的治疗策略。
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引用次数: 0
Red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain through stimulating the expressions of TNF-α and IL-1β 红核 mGluR1 和 mGluR5 通过刺激 TNF-α 和 IL-1β 的表达促进神经病理性疼痛的发展
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-04 DOI: 10.1016/j.neuint.2024.105786
Xue Tian , Wen-Tao Wang , Miao-Miao Zhang , Qing-Qing Yang , Ya-Li Xu , Ji-Bo Wu , Xin-Xin Xie , Jun-Yang Wang , Jing-Yuan Wang

Our previous study has identified that glutamate in the red nucleus (RN) facilitates the development of neuropathic pain through metabotropic glutamate receptors (mGluR). Here, we further explored the actions and possible molecular mechanisms of red nucleus mGluR Ⅰ (mGluR1 and mGluR5) in the development of neuropathic pain induced by spared nerve injury (SNI). Our data indicated that both mGluR1 and mGluR5 were constitutively expressed in the RN of normal rats. Two weeks after SNI, the expressions of mGluR1 and mGluR5 were significantly boosted in the RN contralateral to the nerve injury. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN contralateral to the nerve injury at 2 weeks post-SNI significantly ameliorated SNI-induced neuropathic pain. However, unilateral administration of mGluRⅠ agonist DHPG to the RN of normal rats provoked a significant mechanical allodynia, this effect could be blocked by LY367385 or MTEP. Further studies indicated that the expressions of TNF-α and IL-1β in the RN were also elevated at 2 weeks post-SNI. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN at 2 weeks post-SNI significantly inhibited the elevations of TNF-α and IL-1β. However, administration of mGluR Ⅰ agonist DHPG to the RN of normal rats significantly enhanced the expressions of TNF-α and IL-1β, these effects were blocked by LY367385 or MTEP. These results suggest that activation of red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain by stimulating the expressions of TNF-α and IL-1β. mGluR Ⅰ maybe potential targets for drug development and clinical treatment of neuropathic pain.

我们之前的研究发现,红核(RN)中的谷氨酸通过代谢型谷氨酸受体(mGluR)促进神经病理性疼痛的发生。在此,我们进一步探讨了红核 mGluR Ⅰ(mGluR1 和 mGluR5)在幸免神经损伤(SNI)诱导的神经病理性疼痛发生过程中的作用和可能的分子机制。我们的数据表明,mGluR1 和 mGluR5 在正常大鼠的 RN 中均呈组成型表达。SNI两周后,mGluR1和mGluR5在神经损伤对侧RN中的表达明显增加。在 SNI 两周后,向神经损伤对侧 RN 施用 mGluR1 拮抗剂 LY367385 或 mGluR5 拮抗剂 MTEP 可明显改善 SNI 引起的神经病理性疼痛。然而,对正常大鼠的 RN 单侧施用 mGluRⅠ 激动剂 DHPG 会引起明显的机械异感,LY367385 或 MTEP 可阻断这种效应。进一步的研究表明,SNI 后 2 周时,RN 中 TNF-α 和 IL-1β 的表达也升高。在 SNI 后 2 周给 RN 注射 mGluR1 拮抗剂 LY367385 或 mGluR5 拮抗剂 MTEP 可显著抑制 TNF-α 和 IL-1β 的升高。然而,给正常大鼠的 RN 施用 mGluR Ⅰ 激动剂 DHPG 会显著增强 TNF-α 和 IL-1β 的表达,LY367385 或 MTEP 可阻断这些效应。这些结果表明,激活红核 mGluR1 和 mGluR5 可刺激 TNF-α 和 IL-1β 的表达,从而促进神经病理性疼痛的发生。
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引用次数: 0
Novel psychoplastogen DM506 reduces cue-induced heroin-seeking and inhibits tonic GABA currents in the Prelimbic Cortex 新型精神生长因子DM506可减少线索诱导的海洛因觅食行为,并抑制前边缘皮层的强直性GABA电流。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-03 DOI: 10.1016/j.neuint.2024.105785
Kassandra Looschen , Shailesh Narayan Khatri , Malabika Maulik , Colin Salisbury , Alaina F. Carman , Katilyn Corriveau , Colton Smith , Dina Manetti , Maria Novella Romanelli , Hugo R. Arias , Cassandra D. Gipson , Swarup Mitra

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch-clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABAA receptor α and δ subunits at AD14 in heroin and saline self-administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex.

阿片类药物使用障碍是一个重大的公共卫生危机,表现为持续的觅药行为和高复发率。现有的治疗方法大多依赖于使用小分子药物靶向阿片受体,但无法持续缓解症状。精神兴奋药是一类新型的非阿片类药物,可对神经元的可塑性产生快速而持续的影响,从而产生治疗效果。Ibogalogs是伊博格生物碱的合成衍生物,没有致幻或不良副作用。在本研究中,我们考察了 DM506(一种新型伊博格罗碱,没有任何心脏毒性或致幻作用)对海洛因自我给药后线索诱导的寻求行为的治疗潜力。单次全身给药剂量为40毫克/千克时,DM506能显著降低雌雄大鼠在海洛因自我给药后戒断第1天(AD1)的线索诱导寻求行为。在AD14时再次检测线索诱导的寻求时,我们发现接受DM506的雄性大鼠继续显示出线索诱导的寻求减少,而雌性大鼠则没有观察到这种效应。由于有证据表明迷幻药会影响内侧前额叶皮层(PrL)的强直性GABA电流,以及阿片类和精神原介导的神经适应,这是其功能效应的基础,因此我们对急性应用或慢性孵育DM506的未服药大鼠的PrL切片进行了贴片钳记录。qPCR分析没有发现在AD14时,海洛因和生理盐水自我给药动物的GABAA受体α和δ亚基的mRNA水平有任何差异。总之,我们的数据表明,DM506 可减轻线索诱导的海洛因寻求,并抑制前边缘皮层的强直 GABA 电流。
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引用次数: 0
IL-17A enhances the inflammatory response of glaucoma through Act1/TRAF6/NF-κB pathway IL-17A 通过 Act1/TRAF6/NF-κB 通路增强青光眼的炎症反应
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 DOI: 10.1016/j.neuint.2024.105787
Yunfan Zheng , Zhenni Mou , Sisi Tan, Xiaochen Wang, Jingchang Yuan, Hong Li

Objectives

To investigate the possible roles of Interleukin 17A (IL-17A) and IL-17A neutralizing antibodies (IL-17Ab) in glaucoma and the potential mechanisms.

Methods

The two glaucoma animal models, chronic ocular hypertension (COH) and N-methyl-D-aspartate (NMDA)-induced retinal ganglion cell (RGC) damage, were established and treated with intravitreal injection of IL-17A or IL-17Ab. Intraocular pressure (IOP) was measured by a rebound tonometer. The retina and RGC injury were evaluated by HE staining, TUNLE assay and Brn3a immunofluorescence staining. The frequency of IL-17A+CD4+T cells in peripheral blood was detected by flow cytometry. The expression of glial fibrillary acidic protein (GFAP) was detected by immunofluorescence staining, Western Blot and qPCR in retina. The RNA and protein expression of Act1/TRAF6/NF-κB were detected by Western Blot and qPCR in retina.

Results

The expression of IL-17A increased in glaucoma models. After intravitreal injection of IL-17A, in the retina, the number of RGCs decreased, the apoptosis of RGCs increased, the Müller cell gliosis was more obvious. In addition, peripheral inflammation aggravated. Whereas the intravitreal injection of IL-17Ab alleviated the relevant manifestations and peripheral inflammation, reduced the gliosis of Müller cells. In the COH model, IOP increased after the injection of IL-17A, while the intravitreal injection of IL-17Ab led to a decrease in IOP. Furthermore, IL-17A promotes the apoptosis of RGCs by binding to IL-17A receptor, activating Act1/TRAF6/NF-κB pathways.

Conclusion

IL-17A plays a role in and aggravates RGC damage in glaucoma. IL-17Ab can neutralize the pro-inflammatory effect of IL-17A and have a protective function in glaucoma. These findings reveal the importance of IL-17A in the pathogenesis of glaucoma, which will shed light on a novel direction for the prevention and treatment of glaucoma, and also provide a reference for further research on other retinal diseases.

目的 研究白细胞介素17A(IL-17A)和IL-17A中和抗体(IL-17Ab)在青光眼中的可能作用及其潜在机制。方法 建立了两种青光眼动物模型,即慢性眼压过高(COH)和N-甲基-D-天冬氨酸(NMDA)诱导的视网膜神经节细胞(RGC)损伤,并用IL-17A或IL-17Ab进行玻璃体内注射治疗。用回弹式眼压计测量眼压(IOP)。视网膜和RGC损伤通过HE染色、TUNLE检测和Brn3a免疫荧光染色进行评估。流式细胞术检测了外周血中IL-17A+CD4+T细胞的频率。通过免疫荧光染色、Western Blot 和 qPCR 检测视网膜中神经胶质纤维酸性蛋白(GFAP)的表达。通过 Western Blot 和 qPCR 检测视网膜中 Act1/TRAF6/NF-κB 的 RNA 和蛋白表达。静脉注射IL-17A后,视网膜中RGC数量减少,RGC凋亡增加,Müller细胞胶质病变更加明显。此外,外周炎症加剧。而玻璃体内注射IL-17Ab可减轻相关表现和外周炎症,减轻Müller细胞的胶质增生。在 COH 模型中,注射 IL-17A 后眼压升高,而玻璃体内注射 IL-17Ab 则使眼压降低。此外,IL-17A通过与IL-17A受体结合,激活Act1/TRAF6/NF-κB通路,促进RGC的凋亡。IL-17Ab能中和IL-17A的促炎作用,对青光眼有保护作用。这些发现揭示了IL-17A在青光眼发病机制中的重要作用,为青光眼的预防和治疗指明了新的方向,也为其他视网膜疾病的进一步研究提供了参考。
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引用次数: 0
Molecular mechanisms of the ambroxol action in Gaucher disease and GBA1 mutation-associated Parkinson disease 氨溴索作用于戈谢病和GBA1突变相关帕金森病的分子机制
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-24 DOI: 10.1016/j.neuint.2024.105774
Zuzanna Cyske, Lidia Gaffke, Estera Rintz, Karolina Wiśniewska, Grzegorz Węgrzyn, Karolina Pierzynowska

Glucocerebrosidase (GCase), encoded by the GBA1 gene, is one of the lysosomal enzymes responsible for hydrolyzing the glycosphingolipids. Deficiency in GCase activity (in patients with two defective alleles of GBA1) leads to glucosylceramide storage in lysosomes which in turn results in the development of the Gaucher diseases, a lysosomal storage disorder, while a heterozygous state may be correlated with the GBA1 mutation-associated Parkinson disease. One of the proposed forms of therapy for these two conditions is the use of pharmacological chaperones which work by facilitating the achievement of the correct conformation of abnormally folded enzymes. Several compounds with chaperone activities against GCase have already been tested, one of which turned out to be ambroxol. Studies conducted on the action of this compound have indeed indicated its effectiveness in increasing GCase levels and activity. However, some data have begun to question its activity as a chaperone against certain GCase variants. Then, a number of articles appeared pointing to other mechanisms of action of ambroxol, which may also contribute to the improvement of patients' condition. This paper summarizes the biological mechanisms of action of ambroxol in Gaucher disease and GBA1 mutation-associated Parkinson disease, focused on its activity as a chaperone, modulator of ERAD pathways, inducer of autophagy, and pain reliever in cellular and animal models as well as in patients. The effects of these activities on the reduction of disease markers and symptoms in patients are also discussed. Consideration of all the properties of ambroxol can help in the appropriate choice of therapy and the determination of the effective drug dose.

由 GBA1 基因编码的葡糖脑苷脂酶(GCase)是一种溶酶体酶,负责水解糖磷脂。GCase 活性缺陷(GBA1 的两个等位基因缺陷患者)会导致葡萄糖甘油酰胺在溶酶体中储存,进而导致溶酶体储存障碍性疾病戈谢病的发生,而杂合状态可能与 GBA1 基因突变相关的帕金森病有关。针对这两种疾病提出的治疗方法之一是使用药理伴侣,其作用是促进折叠异常的酶获得正确的构象。已经测试了几种对 GCase 具有伴侣活性的化合物,其中一种是氨溴索。对这种化合物的作用进行的研究确实表明,它能有效提高 GCase 的水平和活性。然而,一些数据开始质疑它作为伴侣剂对某些 GCase 变体的活性。随后,一些文章指出了氨溴索的其他作用机制,这些机制也可能有助于改善患者的病情。本文总结了氨溴索在戈谢病和GBA1突变相关帕金森病中的生物学作用机制,重点介绍了氨溴索在细胞和动物模型以及患者体内作为伴侣、ERAD通路调节剂、自噬诱导剂和止痛剂的活性。此外,还讨论了这些活性对减少疾病标志物和患者症状的影响。考虑氨溴索的所有特性有助于选择适当的疗法和确定有效的药物剂量。
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引用次数: 0
Ferroptosis: A new strategy for targeting Alzheimer’s disease 铁突变:针对阿尔茨海默病的新策略
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-23 DOI: 10.1016/j.neuint.2024.105773
Rong Rong Qiang , Yang Xiang , Lei Zhang , Xin Yue Bai , Die Zhang , Yang Jing Li , Yan Ling Yang , Xiao Long Liu

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a complex pathogenesis, which involves the formation of amyloid plaques and neurofibrillary tangles. Many recent studies have revealed a close association between ferroptosis and the pathogenesis of AD. Factors such as ferroptosis-associated iron overload, lipid peroxidation, disturbances in redox homeostasis, and accumulation of reactive oxygen species have been found to contribute to the pathological progression of AD. In this review, we explore the mechanisms underlying ferroptosis, describe the link between ferroptosis and AD, and examine the reported efficacy of ferroptosis inhibitors in treating AD. Finally, we discuss the potential challenges to ferroptosis inhibitors use in the clinic, enabling their faster use in clinical treatment.

阿尔茨海默病(AD)是一种神经退行性疾病,发病机制复杂,包括淀粉样蛋白斑块和神经纤维缠结的形成。最近的许多研究表明,铁蛋白沉积与阿兹海默症的发病机制密切相关。研究发现,与铁变态反应相关的铁超载、脂质过氧化、氧化还原平衡紊乱和活性氧积累等因素导致了AD的病理进展。在这篇综述中,我们探讨了铁蛋白沉积的内在机制,描述了铁蛋白沉积与 AD 之间的联系,并研究了铁蛋白沉积抑制剂治疗 AD 的疗效。最后,我们讨论了在临床中使用铁蛋白沉积抑制剂可能面临的挑战,以便更快地将其用于临床治疗。
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引用次数: 0
Nicotinic acid attenuates amyloid β1-42-induced mitochondrial dysfunction and inhibits the mitochondrial pathway of apoptosis in differentiated SH-SY5Y cells 烟酸可减轻淀粉样β1-42诱导的线粒体功能障碍,并抑制分化的SH-SY5Y细胞线粒体凋亡途径。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-22 DOI: 10.1016/j.neuint.2024.105772
Anna Litwiniuk , Małgorzata Kalisz , Anita Domańska , Magdalena Chmielowska , Lidia Martyńska , Agnieszka Baranowska-Bik , Wojciech Bik

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive memory loss and behavioral disorders. The excessive accumulation of amyloid β (Aβ) and the formation of neurofibrillary tangles (NFTs) damage synaptic connections and the death of neurons. However, the underlying mechanisms of pathogenesis of AD remain unclear. Growing evidence indicates that impaired mitochondrial function may play a crucial role in the development of AD. In the current study, we investigated whether nicotinic acid (NA) could protect against amyloid β1-42-induced cytotoxicity in differentiated SH-SY5Y cells. Our results revealed the neuroprotective effects of NA on the differentiated SH-SY5Y cells treated with Aβ1-42. In detail, the 1-h pre-incubation with NA increased cell viability and lowered LDH levels. NA pre-incubation abolished Aβ1-42 treatment-associated alterations of mRNA levels of synaptic genes and enhanced the relative β3 Tubulin fluorescence intensity. NA eliminated the Aβ1-42-induced mitochondrial dysfunction by increasing the potential of mitochondrial membranes and maintaining a balance between the fusion and fission of mitochondria. Moreover, Aβ1-42 decreased mRNA levels of anti-apoptotic bcl2 and increased mRNA levels of pro-apoptotic: bim, bak, cytochrome c, and caspase 9. At the same time, the NA pre-treatment reduced Aβ1-42-dependent apoptotic death of differentiated SH-SY5Y cells.

The above data suggest that NA presents a protective activity against Aβ1-42-induced cytotoxicity in differentiated SH-SY5Y cells by inhibiting the mitochondrial pathway of apoptosis and restoring the proper function of mitochondria.

阿尔茨海默病(AD)是一种慢性神经退行性疾病,以进行性记忆丧失和行为障碍为特征。淀粉样β(Aβ)的过度积累和神经纤维缠结(NFT)的形成会破坏突触连接,导致神经元死亡。然而,注意力缺失症的发病机制仍不清楚。越来越多的证据表明,线粒体功能受损可能在AD的发病过程中起着至关重要的作用。在本研究中,我们探讨了烟酸(NA)能否保护分化的SH-SY5Y细胞免受淀粉样β1-42诱导的细胞毒性。我们的研究结果表明,NA对经Aβ1-42处理的分化SH-SY5Y细胞具有神经保护作用。具体而言,与 NA 预孵育一小时可提高细胞活力并降低 LDH 水平。NA预孵育可消除Aβ1-42处理相关的突触基因mRNA水平的改变,并增强β3 Tubulin荧光的相对强度。NA通过提高线粒体膜的电位和维持线粒体融合与分裂之间的平衡,消除了Aβ1-42诱导的线粒体功能障碍。此外,Aβ1-42 还降低了抗凋亡的 bcl2 的 mRNA 水平,提高了促凋亡的 bim、bak、细胞色素 c 和 caspase 9 的 mRNA 水平。同时,NA 预处理可减少 Aβ1-42 依赖性分化的 SH-SY5Y 细胞凋亡。上述数据表明,NA通过抑制线粒体凋亡途径和恢复线粒体的正常功能,对Aβ1-42诱导的分化SH-SY5Y细胞的细胞毒性具有保护作用。
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引用次数: 0
Focus on brain-lung crosstalk: Preventing or treating the pathological vicious circle between the brain and the lung 关注脑肺串扰:预防或治疗脑肺之间的病理恶性循环。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-18 DOI: 10.1016/j.neuint.2024.105768
Xiaoqiu Li , Jie Deng , Yu Long , Yin Ma , Yuanyuan Wu , Yue Hu , Xiaofang He , Shuang Yu , Dan Li , Nan Li , Fei He

Recently, there has been increasing attention to bidirectional information exchange between the brain and lungs. Typical physiological data is communicated by channels like the circulation and sympathetic nervous system. However, communication between the brain and lungs can also occur in pathological conditions. Studies have shown that severe traumatic brain injury (TBI), cerebral hemorrhage, subarachnoid hemorrhage (SAH), and other brain diseases can lead to lung damage. Conversely, severe lung diseases such as acute respiratory distress syndrome (ARDS), pneumonia, and respiratory failure can exacerbate neuroinflammatory responses, aggravate brain damage, deteriorate neurological function, and result in poor prognosis. A brain or lung injury can have adverse effects on another organ through various pathways, including inflammation, immunity, oxidative stress, neurosecretory factors, microbiome and oxygen. Researchers have increasingly concentrated on possible links between the brain and lungs. However, there has been little attention given to how the interaction between the brain and lungs affects the development of brain or lung disorders, which can lead to clinical states that are susceptible to alterations and can directly affect treatment results. This review described the relationships between the brain and lung in both physiological and pathological conditions, detailing the various pathways of communication such as neurological, inflammatory, immunological, endocrine, and microbiological pathways. Meanwhile, this review provides a comprehensive summary of both pharmacological and non-pharmacological interventions for diseases related to the brain and lungs. It aims to support clinical endeavors in preventing and treating such ailments and serve as a reference for the development of relevant medications.

最近,人们越来越关注大脑和肺部之间的双向信息交流。典型的生理数据通过血液循环和交感神经系统等渠道进行交流。然而,在病理情况下,大脑和肺之间也会发生交流。研究表明,严重的脑外伤(TBI)、脑出血、蛛网膜下腔出血(SAH)和其他脑部疾病会导致肺部损伤。相反,急性呼吸窘迫综合征(ARDS)、肺炎和呼吸衰竭等严重肺部疾病会加剧神经炎症反应,加重脑损伤,恶化神经功能,导致预后不良。脑损伤或肺损伤可通过炎症、免疫、氧化应激、神经分泌因子、微生物组和氧等各种途径对另一个器官产生不良影响。研究人员越来越关注大脑和肺之间可能存在的联系。然而,人们很少关注脑与肺之间的相互作用如何影响脑部或肺部疾病的发展,这可能导致临床状态容易发生改变,并直接影响治疗效果。本综述描述了生理和病理状态下脑与肺之间的关系,详细介绍了神经、炎症、免疫、内分泌和微生物等各种交流途径。同时,本综述全面总结了针对脑肺相关疾病的药物和非药物干预措施。其目的是为预防和治疗此类疾病的临床工作提供支持,并为相关药物的开发提供参考。
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引用次数: 0
Intracerebroventricular infusion of secretoneurin inhibits neuronal NLRP3-Apoptosis pathway and preserves learning and memory after cerebral ischemia 脑室内灌注 Secretoneurin 可抑制神经元 NLRP3-Apoptosis 通路并保护脑缺血后的学习和记忆。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-16 DOI: 10.1016/j.neuint.2024.105770
Caihong Gu , Xiuwen Kang , Xiaobing Chen , Yan Sun , Xiaomin Li

Transient global cerebral ischemia (GCI) results in delayed neuronal death, primarily apoptosis, in the hippocampal CA1 subregion, which leads to severe cognitive deficits. While therapeutic hypothermia is an approved treatment for patients following cardiac arrest, it is associated with various adverse effects. Secretoneurin (SN) is an evolutionarily conserved neuropeptide generated in the brain, adrenal medulla and other endocrine tissues. In this study, SN was infused into the rat brain by intracerebroventricular injection 1 day after GCI, and we demonstrated that SN could significantly preserve spatial learning and memory in the Barnes maze tasks examined on days 14–17 after GCI. To further investigate underlying pathways involved, we demonstrated that, on day 5 after GCI, SN could significantly inhibit GCI-induced expression levels of Apoptosis Inducing Factor (AIF) and cleaved-PARP1, as well as neuronal apoptosis and synaptic loss in the hippocampal CA1 region. Additionally, SN could attenuate GCI-induced activation of both caspase-1 and caspase-3, and the levels of pro-inflammatory cytokines IL-1β and IL-18 in the CA1 region. Mechanically, we observed that treatment with SN effectively inhibited NLRP3 protein elevation and the bindings of NLRP3-ASC and ASC-caspase-1 in hippocampal neurons after GCI. In summary, our data indicate that SN could effectively attenuate NLRP3 inflammasome formation, as well as the activation of caspase-1 and -3, the production of pro-inflammatory cytokines, and ultimately the neuronal apoptotic loss induced by GCI. Potential neuronal pyroptosis, or caspase-1-dependent cell death, could also be involved in ischemic neuronal death, which needs further investigation.

短暂性全脑缺血(GCI)会导致海马 CA1 亚区神经元延迟死亡,主要是细胞凋亡,从而导致严重的认知障碍。虽然治疗性低温是一种获准用于心脏骤停患者的治疗方法,但它与各种不良反应有关。分泌神经肽(SN)是一种进化保守的神经肽,产生于大脑、肾上腺髓质和其他内分泌组织。在本研究中,我们在大鼠GCI后1天通过脑室内注射将SN注入大鼠大脑,结果表明SN能显著保护大鼠在GCI后第14至17天进行的巴恩斯迷宫任务中的空间学习和记忆。为了进一步研究其中的潜在途径,我们证实,在 GCI 后的第 5 天,SN 可以显著抑制 GCI 诱导的凋亡诱导因子(AIF)和裂解-PARP1 的表达水平,以及海马 CA1 区的神经元凋亡和突触丢失。此外,SN还能减轻GCI诱导的caspase-1和caspase-3的激活,以及CA1区促炎细胞因子IL-1β和IL-18的水平。在机制上,我们观察到 SN 能有效抑制 GCI 后海马神经元中 NLRP3 蛋白的升高以及 NLRP3-ASC 和 ASC-caspase-1 的结合。总之,我们的数据表明,SN 能有效抑制 NLRP3 炎性体的形成,以及 Caspase-1 和 -3 的激活、促炎性细胞因子的产生,并最终抑制 GCI 诱导的神经元凋亡。潜在的神经元热凋亡或依赖于 caspase-1 的细胞死亡也可能参与缺血性神经元死亡,这还需要进一步研究。
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引用次数: 0
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Neurochemistry international
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