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Shh regulates M2 microglial polarization and fibrotic scar formation after ischemic stroke Shh 可调节缺血性中风后 M2 小胶质细胞的极化和纤维化瘢痕的形成。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-20 DOI: 10.1016/j.neuint.2024.105862

Background

Fibrotic scar formation is a critical pathological change impacting tissue reconstruction and functional recovery after ischemic stroke. The regulatory mechanisms behind fibrotic scarring in the central nervous system (CNS) remain largely unknown. While macrophages are known to play a role in fibrotic scar formation in peripheral tissues, the involvement of microglia, the resident immune cells of the CNS, in CNS fibrosis requires further exploration. The Sonic Hedgehog (Shh) signaling pathway, pivotal in embryonic development and tissue regeneration, is also crucial in modulating fibrosis in peripheral tissues. However, the impact and regulatory mechanisms of Shh on fibrotic scar formation post-ischemic stroke have not been thoroughly investigated.

Methods

This study explores whether Shh can regulate fibrotic scar formation post-ischemic stroke and its underlying mechanisms through in vivo and in vitro manipulation of Shh expression.

Results

Our results showed that Shh expression was upregulated in the serum of acute ischemic stroke patients, as well as in the serum, CSF, and ischemic regions of MCAO/R mice. Moreover, the upregulation of Shh expression was positively correlated with fibrotic scar formation and M2 microglial polarization. Shh knockdown inhibited fibrotic scar formation and M2 microglial polarization while aggravating neurological deficits in MCAO/R mice. In vitro, adenoviral knockdown or Smoothened Agonist (SAG) activation of Shh expression in BV2 cells following OGD/R regulated their polarization and influenced the expression of TGFβ1 and PDGFA, subsequently affecting fibroblast activation.

Conclusion

These results suggest that Shh regulates M2 microglial polarization and fibrotic scar formation after cerebral ischemia.
背景:纤维化瘢痕的形成是影响缺血性中风后组织重建和功能恢复的关键病理变化。中枢神经系统(CNS)纤维化瘢痕背后的调控机制在很大程度上仍不为人所知。虽然已知巨噬细胞在外周组织的纤维化瘢痕形成中发挥作用,但中枢神经系统的常驻免疫细胞小胶质细胞参与中枢神经系统纤维化的情况还需要进一步探索。音速刺猬(Shh)信号通路在胚胎发育和组织再生中起着关键作用,在调节外周组织纤维化方面也至关重要。然而,Shh 对缺血性脑卒中后纤维化瘢痕形成的影响和调控机制尚未得到深入研究:方法:本研究通过在体内和体外操纵 Shh 的表达,探讨 Shh 能否调控缺血性脑卒中后纤维化瘢痕的形成及其内在机制:结果:我们的研究结果表明,急性缺血性脑卒中患者的血清以及 MCAO/R 小鼠的血清、脑脊液和缺血区域中 Shh 表达上调。此外,Shh表达的上调与纤维化瘢痕形成和M2小胶质细胞极化呈正相关。敲除Shh可抑制纤维化瘢痕形成和M2小胶质细胞极化,同时加重MCAO/R小鼠的神经功能缺损。在体外,腺病毒敲除或平滑激动剂(SAG)激活OGD/R后BV2细胞中的Shh表达,可调节其极化,并影响TGFβ1和PDGFA的表达,进而影响成纤维细胞的活化:这些结果表明,Shh 可调控脑缺血后 M2 小胶质细胞的极化和纤维化瘢痕的形成。
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引用次数: 0
GABA, epigallocatechin gallate, tea, and the gut-brain axis GABA、表没食子儿茶素没食子酸酯、茶和肠脑轴。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1016/j.neuint.2024.105860
Our investigations on GABA-enriched tea and the reduction of stress in a student cohort have shown that more than just GABA may be involved. The effects of other constituents that are changed in the enrichment process are likely to be important. We have concentrated on GABA as well as the major tea flavonoid, epigallocatechin gallate. While this flavonoid is known to get to the brain on oral administration, it is far from clear that GABA does the same. GABA may act primarily on the gut and influence brain function via the gut-brain axis and the gut microbiome. In addition, there may be a microbiome in the brain that has a role. The situation is complex and not clearly understood. Mixtures of bioactive compounds are always difficult to investigate, but even the precise mechanisms of how pure oral GABA acts as a neuro-nutraceutical is unclear.
我们对富含 GABA 的茶叶和减轻学生压力的研究表明,这可能不仅仅与 GABA 有关。在富集过程中发生变化的其他成分的影响可能也很重要。我们重点研究了 GABA 以及主要的茶黄酮类化合物--表没食子儿茶素没食子酸酯。众所周知,这种类黄酮经口服可进入大脑,但 GABA 是否也能进入大脑还不清楚。GABA 可能主要作用于肠道,并通过肠脑轴和肠道微生物群影响大脑功能。此外,大脑中的微生物群也可能发挥作用。情况错综复杂,尚不清楚。生物活性化合物的混合物总是难以研究,但即使是纯口服 GABA 如何作为神经营养素发挥作用的确切机制也不清楚。
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引用次数: 0
Carotenoids modulate antioxidant pathways in In vitro models of Parkinson's disease: A comprehensive scoping review 类胡萝卜素调节帕金森病体外模型中的抗氧化途径:综合范围综述
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.1016/j.neuint.2024.105857

Parkinson's disease (PD) is the second most common neurodegenerative disease, and it has affected the living quality of elderly people significantly. PD is characterised by the accumulation of α-Synuclein and progressive loss of dopaminergic neurons at the substantia nigra pars compacta. In the pathogenesis of Parkinson's disease, α-Synuclein, oxidative stress, and electron transport chain (ETC) are the three main factors that contribute to the production of reactive oxygen species (ROS). Currently, there is no commercial disease-modifying agent available for PD; the first-line treatment, Levodopa (l-DOPA), could only relieve the symptoms of PD, with many side effects. Carotenoids, which encompass red, orange, and yellow pigments found in nature and contribute to the colouration of plants, have been associated with various health benefits, including anti-cancer and neuroprotective effects due to their antioxidant properties. This scoping review delves into the impact and underlying mechanisms of carotenoids on cell-based models of neurodegenerative diseases.

帕金森病(Parkinson's disease,PD)是第二大常见的神经退行性疾病,严重影响了老年人的生活质量。帕金森病的特征是α-突触核蛋白的积累和黑质部位多巴胺能神经元的逐渐丧失。在帕金森病的发病机制中,α-突触核蛋白、氧化应激和电子传递链(ETC)是导致活性氧(ROS)产生的三个主要因素。目前,尚无针对帕金森氏症的商品化疾病修饰药物;一线治疗药物左旋多巴(l-DOPA)只能缓解帕金森氏症的症状,且副作用较大。类胡萝卜素包括自然界中的红色、橙色和黄色色素,是植物着色的主要成分。类胡萝卜素具有多种健康益处,包括因其抗氧化特性而具有的抗癌和神经保护作用。本范围综述将深入探讨类胡萝卜素对神经退行性疾病细胞模型的影响及其内在机制。
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引用次数: 0
Corrigendum to “HPOB, an HDAC6 inhibitor, attenuates corticosterone-induced injury in rat adrenal pheochromocytoma PC12 cells by inhibiting mitochondrial GR translocation and the intrinsic apoptosis pathway’[Neurochemistry International 99 (2016) 239–251] HPOB,一种HDAC6抑制剂,通过抑制线粒体GR转位和内在凋亡途径减轻皮质酮诱导的大鼠肾上腺嗜铬细胞瘤PC12细胞损伤'[Neurohemistry International 99 (2016) 239-251]的更正。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-14 DOI: 10.1016/j.neuint.2024.105856
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引用次数: 0
Soy lysolecithin prevents hypertension and cognitive impairment induced in mice by high salt intake by inhibiting intestinal inflammation 大豆卵磷脂通过抑制肠道炎症预防高盐摄入诱发的小鼠高血压和认知障碍
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.neuint.2024.105858

High salt (HS) intake induces hypertension and cognitive impairment. Preventive strategies include against dietary supplements. Soybean lecithin is a widely used phospholipid supplement. Lysolecithin is important in cell signaling, digestion, and absorption. This study aimed to investigate the effects of lysophosphatidylcholine containing >70% of the total phospholipids (LPC70), on hypertension and cognitive impairment induced in mice by HS intake. Mice were provided with HS solution (2% NaCl in drinking water) with or without LPC70 for 12 weeks. Blood pressure, cognitive function, and inflammatory response of intestine were determined. Hypertension and impaired object recognition memory induced by HS intake were implicated with increased inducible nitric oxide synthase in the small intestine and tau hyperphosphorylation in the prefrontal cortex. LPC70 treatment prevented cognitive impairment by suppressing inducible nitric oxide synthase and tau hyperphosphorylation. LPC70 may be valuable as a functional food component in preventing HS-induced cognitive impairment.

高盐(HS)摄入会诱发高血压和认知障碍。预防策略包括反对膳食补充剂。大豆卵磷脂是一种广泛使用的磷脂补充剂。卵磷脂在细胞信号传导、消化和吸收方面具有重要作用。本研究旨在探讨含磷脂总量 70% 的溶血磷脂酰胆碱(LPC70)对摄入 HS 引起的小鼠高血压和认知障碍的影响。向小鼠提供含或不含 LPC70 的 HS 溶液(饮用水中含 2% NaCl),持续 12 周。对小鼠的血压、认知功能和肠道炎症反应进行了测定。摄入 HS 引起的高血压和物体识别记忆受损与小肠中诱导型一氧化氮合酶增加和前额叶皮层中 tau 过度磷酸化有关。LPC70 治疗可抑制诱导型一氧化氮合酶和 tau 过度磷酸化,从而防止认知障碍。LPC70作为一种功能性食品成分,在预防HS诱导的认知障碍方面可能具有重要价值。
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引用次数: 0
A critical appraisal of geroprotective activities of flavonoids in terms of their bio-accessibility and polypharmacology 从生物可及性和多药理角度对黄酮类化合物的老年保护活性进行严格评估
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1016/j.neuint.2024.105859

Flavonoids, a commonly consumed natural product, elicit health-benefits such as antioxidant, anti-inflammatory, antiviral, anti-allergic, hepatoprotective, anti-carcinogenic and neuroprotective activities. Several studies have reported the beneficial role of flavonoids in improving memory, learning, and cognition in clinical settings. Their mechanism of action is mediated through the modulation of multiple signalling cascades. This polypharmacology makes them an attractive natural scaffold for designing and developing new effective therapeutics for complex neurological disorders like Alzheimer's disease and Parkinson's disease. Flavonoids are shown to inhibit crucial targets related to neurodegenerative disorders (NDDs), including acetylcholinesterase, butyrylcholinesterase, β-secretase, γ-secretase, α-synuclein, Aβ protein aggregation and neurofibrillary tangles formation. Conserved neuro-signalling pathways related to neurotransmitter biogenesis and inactivation, ease of genetic manipulation and tractability, cost-effectiveness, and their short lifespan make Caenorhabditis elegans one of the most frequently used models in neuroscience research and high-throughput drug screening for neurodegenerative disorders. Here, we critically appraise the neuroprotective activities of different flavonoids based on clinical trials and epidemiological data. This review provides critical insights into the absorption, metabolism, and tissue distribution of various classes of flavonoids, as well as detailed mechanisms of the observed neuroprotective activities at the molecular level, to rationalize the clinical data. We further extend the review to critically evaluate the scope of flavonoids in the disease management of neurodegenerative disorders and review the suitability of C. elegans as a model organism to study the neuroprotective efficacy of flavonoids and natural products.

类黄酮是一种常见的天然产品,具有抗氧化、抗炎、抗病毒、抗过敏、保肝、抗癌和保护神经等保健作用。一些研究报告称,类黄酮在临床环境中对改善记忆、学习和认知能力有益。黄酮类化合物的作用机制是通过调节多种信号级联介导的。这种多药理作用使黄酮类化合物成为一种极具吸引力的天然支架,可用于设计和开发治疗阿尔茨海默病和帕金森病等复杂神经系统疾病的新型有效疗法。黄酮类化合物可抑制与神经退行性疾病(NDDs)有关的关键靶点,包括乙酰胆碱酯酶、丁酰胆碱酯酶、β-分泌酶、γ-分泌酶、α-突触核蛋白、Aβ 蛋白聚集和神经纤维缠结的形成。与神经递质的生物发生和失活相关的神经信号通路的保守性、遗传操作的简易性和可操作性、成本效益以及短暂的寿命使 elegans 成为神经科学研究和神经退行性疾病高通量药物筛选中最常用的模型之一。在此,我们根据临床试验和流行病学数据对不同黄酮类化合物的神经保护活性进行了批判性评估。这篇综述对各类类黄酮的吸收、代谢和组织分布,以及在分子水平上观察到的神经保护活性的详细机制提供了重要的见解,从而使临床数据合理化。我们进一步扩展了综述范围,对黄酮类化合物在神经退行性疾病治疗中的应用范围进行了批判性评估,并回顾了将秀丽隐杆线虫作为模型生物来研究黄酮类化合物和天然产品的神经保护功效的适宜性。
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引用次数: 0
Activity-based anorexia (ABA) model: Effects on brain neuroinflammation, redox balance and neuroplasticity during the acute phase 基于活动的厌食症(ABA)模型:对急性期大脑神经炎症、氧化还原平衡和神经可塑性的影响。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-06 DOI: 10.1016/j.neuint.2024.105842

Several evidences suggest that immuno-inflammatory responses are involved in the pathogenesis of anorexia nervosa (AN). Herein we investigate the possible alteration of key mediators of inflammation, redox balance, and neuroplasticity in the brain of rats showing an anorexic-like phenotype. We modeled AN in adolescent female rats using the activity-based anorexia (ABA) paradigm and measured gene expression levels of targets of interest in the prefrontal cortex (PFC) and dorsal hippocampus (DH). We observed reduced mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α, the inflammasome NLRP3, and the microglial marker CD11b in both PFC and DH of ABA animals. Conversely, the mRNA of IL-6, which acts as both a pro-inflammatory and anti-inflammatory cytokine, was increased. Moreover, we observed an overall upregulation of different antioxidant enzymes in PFC, while their profile was not affected or opposite in the DH, with the exception of MT1α. Interestingly, ABA animals showed elevated levels of the neuroplasticity marker BDNF in both PFC and DH. Our data indicate that ABA induction is associated with anatomical-specific cerebral alteration of mediators of neuroinflammation, oxidative balance and neuroplasticity. Although more research should be conducted, these results add important information about the role of these systems in the complex AN etiopathogenesis.

一些证据表明,免疫炎症反应与神经性厌食症(AN)的发病机制有关。在此,我们研究了表现出厌食症样表型的大鼠大脑中炎症、氧化还原平衡和神经可塑性的关键介质可能发生的变化。我们使用基于活动的厌食症(ABA)范式模拟了青春期雌性大鼠的厌食症,并测量了前额叶皮层(PFC)和背侧海马(DH)中相关靶点的基因表达水平。我们观察到,在 ABA 动物的前额叶皮层和海马背侧,促炎细胞因子 IL-1β 和 TNF-α、炎性组 NLRP3 以及小胶质细胞标志物 CD11b 的 mRNA 水平均有所降低。相反,同时作为促炎和抗炎细胞因子的 IL-6 的 mRNA 则有所增加。此外,我们还观察到 PFC 中不同抗氧化酶的整体上调,而在 DH 中,除了 MT1α 外,其他抗氧化酶没有受到影响,或者相反。有趣的是,ABA动物在PFC和DH中都显示出神经可塑性标志物BDNF水平的升高。我们的数据表明,ABA诱导与大脑解剖特异性神经炎症介质、氧化平衡和神经可塑性的改变有关。尽管还需要进行更多的研究,但这些结果为这些系统在复杂的AN发病机制中的作用提供了重要信息。
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引用次数: 0
Traditionally used edible medicinal plants protect against rotenone induced toxicity in SH-SY5Y cells-a prospect for the development of herbal nutraceuticals 传统食用药用植物可防止鱼藤酮诱导的 SH-SY5Y 细胞毒性--中草药保健品的开发前景广阔。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-06 DOI: 10.1016/j.neuint.2024.105855

Plants are good sources of pharmacologically active compounds. The present study aimed to examine the neuroprotective potentials of the methanol extracts of Salix tetrasperma Roxb. leaf (STME) and Plantago asiatica L. (PAME), two edibles medicinal plants of Manipur, India against neurotoxicity induced by rotenone in SH-SY5Y cells. Free radical quenching activities were evaluated by ABTS and DPPH assays. The cytotoxicity of rotenone and the neuronal survival were assessed by MTT assay and MAP2 expression analysis. DCF-DA, Rhodamine 123 (Rh-123), and DAPI measured the intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), and apoptotic nuclei, respectively. Superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities were also assessed. LC-QTOF-MS analysis was performed for the identification of the compounds present in STME and PAME. The study showed that both the plant extracts (STME and PAME) showed antioxidant and neuroprotective capabilities in rotenone-induced neurotoxicity by preventing oxidative stress through the reduction of intracellular ROS levels and reversing the activities of GPx, SOD, and CAT caused by rotenone. Further, both plants prevented apoptotic cell death by normalizing the steady state of MMP and protecting nuclear DNA condensation. LC-QTOF-MS analysis shows the presence of known neuroprotective compounds like uridine and gabapentin in STME and PAME respectively. The two plants might be an important source of natural antioxidants and nutraceuticals with neuroprotective abilities. This could be investigated further to formulate herbal nutraceuticals for the treatment of neurodegenerative disease like Parkinson's disease.

植物是药理活性化合物的良好来源。本研究旨在研究印度曼尼普尔的两种食用药用植物 Salix tetrasperma Roxb. 叶(STME)和 Plantago asiatica L. (PAME)的甲醇提取物对 SH-SY5Y 细胞由鱼藤酮诱导的神经毒性的保护潜力。通过 ABTS 和 DPPH 试验评估了自由基淬灭活性。通过 MTT 试验和 MAP2 表达分析评估了鱼藤酮的细胞毒性和神经元存活率。DCF-DA、罗丹明123(Rh-123)和DAPI分别测量细胞内活性氧(ROS)水平、线粒体膜电位(MMP)和凋亡核。此外,还评估了超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GPx)和过氧化氢酶(CAT)的活性。对 STME 和 PAME 中的化合物进行了 LC-QTOF-MS 分析鉴定。研究表明,两种植物提取物(STME 和 PAME)在鱼藤酮诱导的神经毒性中都表现出抗氧化和神经保护能力,它们通过降低细胞内 ROS 水平来防止氧化应激,并逆转鱼藤酮引起的 GPx、SOD 和 CAT 活性。此外,这两种植物还能通过使 MMP 的稳态正常化和保护核 DNA 凝聚来防止细胞凋亡。LC-QTOF-MS 分析表明,STME 和 PAME 中分别含有尿苷和加巴喷丁等已知的神经保护化合物。这两种植物可能是具有神经保护能力的天然抗氧化剂和营养保健品的重要来源。可以进一步研究这两种植物,以配制治疗帕金森病等神经退行性疾病的草药保健品。
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引用次数: 0
Generation and characterization of cortical organoids from iPSC-derived dental pulp stem cells using traditional and innovative approaches 利用传统和创新方法从 iPSC 衍生的牙髓干细胞中生成皮质类器官并确定其特征。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1016/j.neuint.2024.105854

Cortical organoids derived from human induced pluripotent stem cells (hiPSCs) represent a powerful in vitro experimental system to investigate human brain development and disease, often inaccessible to direct experimentation. However, despite steady progress in organoid technology, several limitations remain, including high cost and variability, use of hiPSCs derived from tissues harvested invasively, unexplored three-dimensional (3D) structural features and neuronal connectivity. Here, using a cost-effective and reproducible protocol as well as conventional two-dimensional (2D) immunostaining, we show that cortical organoids generated from hiPSCs obtained by reprogramming stem cells from human exfoliated deciduous teeth (SHED) recapitulate key aspects of human corticogenesis, such as polarized organization of neural progenitor zones with the presence of outer radial glial stem cells, and differentiation of superficial- and deep-layer cortical neurons and glial cells. We also show that 3D bioprinting and magnetic resonance imaging of intact cortical organoids are alternative and complementary approaches to unravel critical features of the 3D architecture of organoids. Finally, extracellular electrical recordings in whole organoids showed functional neuronal networks. Together, our findings suggest that SHED-derived cortical organoids constitute an attractive model of human neurodevelopment, and support the notion that a combination of 2D and 3D techniques to analyze organoid structure and function may help improve this promising technology.

源自人类诱导多能干细胞(hiPSCs)的皮质类器官是研究人类大脑发育和疾病的强大体外实验系统,通常无法直接进行实验。然而,尽管类器官技术取得了稳步进展,但仍存在一些局限性,包括成本高、可变性大、使用的hiPSCs来源于有创采集的组织、三维(3D)结构特征和神经元连接性有待探索。在这里,我们使用一种具有成本效益和可重复性的方案以及传统的二维(2D)免疫染色法,表明通过对人类脱落牙齿(SHED)干细胞进行重编程而获得的hiPSCs所生成的皮质类器官再现了人类皮质生成的关键方面,如神经祖细胞区的极化组织与外侧放射状胶质干细胞的存在,以及浅层和深层皮质神经元和胶质细胞的分化。我们还表明,三维生物打印和完整皮层有机体的磁共振成像是揭示有机体三维结构关键特征的替代和互补方法。最后,对整个有机体的细胞外电记录显示了功能性神经元网络。总之,我们的研究结果表明,SHED衍生的大脑皮层有机体是人类神经发育的一个极具吸引力的模型,并支持结合二维和三维技术来分析有机体结构和功能可能有助于改进这一前景广阔的技术的观点。
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引用次数: 0
Deciphering the molecular landscape of the FAM72 gene family: Implications for stem cell biology and cancer 解密 FAM72 基因家族的分子景观:对干细胞生物学和癌症的影响
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.1016/j.neuint.2024.105853

Family with sequence similarity 72 (FAM72) is a protein-coding gene family located on chromosome 1 in humans, uniquely featuring four paralogs: FAM72A, FAM72B, FAM72C, and FAM72D. While FAM72's presence as a gene pair with the SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2) is intriguing, its functional roles, particularly in neural stem cells, remain incompletely understood. This review explores the distinct characteristics of FAM72, shedding light on its expression patterns, potential roles in cell cycle regulation, stem cell renewal and implications in neurogenesis and tumorigenesis.

序列相似性家族 72(FAM72)是位于人类 1 号染色体上的一个蛋白质编码基因家族,有四个独特的旁系亲属:FAM72A、FAM72B、FAM72C 和 FAM72D。虽然 FAM72 与 SLIT-ROBO Rho GTPase-activating protein 2(SRGAP2)是一对基因,但其功能作用,尤其是在神经干细胞中的功能作用,仍不完全清楚。这篇综述探讨了FAM72的独特特征,揭示了它的表达模式、在细胞周期调控、干细胞更新中的潜在作用以及在神经发生和肿瘤发生中的影响。
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引用次数: 0
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Neurochemistry international
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