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Unveiling a novel memory center in human brain: neurochemical identification of the nucleus incertus, a key pontine locus implicated in stress and neuropathology. 揭示人脑中的新型记忆中心:神经化学鉴定与压力和神经病理学有关的关键脑桥部位--incertus 核。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-16 DOI: 10.1186/s40659-024-00523-z
Camila de Ávila, Anna Gugula, Aleksandra Trenk, Anthony J Intorcia, Crystal Suazo, Jennifer Nolz, Julie Plamondon, Divyanshi Khatri, Lauren Tallant, Alexandre Caron, Anna Blasiak, Geidy E Serrano, Thomas G Beach, Andrew L Gundlach, Diego F Mastroeni

Background: The nucleus incertus (NI) was originally described by Streeter in 1903, as a midline region in the floor of the fourth ventricle of the human brain with an 'unknown' function. More than a century later, the neuroanatomy of the NI has been described in lower vertebrates, but not in humans. Therefore, we examined the neurochemical anatomy of the human NI using markers, including the neuropeptide, relaxin-3 (RLN3), and began to explore the distribution of the NI-related RLN3 innervation of the hippocampus.

Methods: Histochemical staining of serial, coronal sections of control human postmortem pons was conducted to reveal the presence of the NI by detection of immunoreactivity (IR) for the neuronal markers, microtubule-associated protein-2 (MAP2), glutamic acid dehydrogenase (GAD)-65/67 and corticotrophin-releasing hormone receptor 1 (CRHR1), and RLN3, which is highly expressed in NI neurons in diverse species. RLN3 and vesicular GABA transporter 1 (vGAT1) mRNA were detected by fluorescent in situ hybridization. Pons sections containing the NI from an AD case were immunostained for phosphorylated-tau, to explore potential relevance to neurodegenerative diseases. Lastly, sections of the human hippocampus were stained to detect RLN3-IR and somatostatin (SST)-IR.

Results: In the dorsal, anterior-medial region of the human pons, neurons containing RLN3- and MAP2-IR, and RLN3/vGAT1 mRNA-positive neurons were observed in an anatomical pattern consistent with that of the NI in other species. GAD65/67- and CRHR1-immunopositive neurons were also detected within this area. Furthermore, RLN3- and AT8-IR were co-localized within NI neurons of an AD subject. Lastly, RLN3-IR was detected in neurons within the CA1, CA2, CA3 and DG areas of the hippocampus, in the absence of RLN3 mRNA. In the DG, RLN3- and SST-IR were co-localized in a small population of neurons.

Conclusions: Aspects of the anatomy of the human NI are shared across species, including a population of stress-responsive, RLN3-expressing neurons and a RLN3 innervation of the hippocampus. Accumulation of phosphorylated-tau in the NI suggests its possible involvement in AD pathology. Further characterization of the neurochemistry of the human NI will increase our understanding of its functional role in health and disease.

背景:无脑核(NI)最初由 Streeter 于 1903 年描述,是人脑第四脑室底部的一个中线区域,其功能 "未知"。一个多世纪后,NI 的神经解剖学在低等脊椎动物中得到了描述,但在人类中却没有。因此,我们使用包括神经肽松弛素-3(RLN3)在内的标记物研究了人类 NI 的神经化学解剖,并开始探索与 NI 相关的 RLN3 神经支配在海马中的分布。方法:通过检测神经元标记物微管相关蛋白-2(MAP2)、谷氨酸脱氢酶(GAD)-65/67、促肾上腺皮质激素释放激素受体 1(CRHR1)和 RLN3 的免疫反应性(IR)来揭示 NI 的存在。荧光原位杂交法检测了 RLN3 和囊泡 GABA 转运体 1 (vGAT1) mRNA。免疫染色法检测磷酸化-tau,以探索与神经退行性疾病的潜在相关性。最后,对人类海马的切片进行染色,以检测RLN3-IR和体生长抑素(SST)-IR:结果:在人类脑桥的背侧、前内侧区域,观察到含有RLN3-IR和MAP2-IR的神经元,以及RLN3/vGAT1 mRNA阳性神经元,其解剖模式与其他物种的NI一致。在这一区域还检测到了 GAD65/67- 和 CRHR1- 免疫阳性神经元。此外,RLN3- 和 AT8-IR 在一名 AD 受试者的 NI 神经元内共定位。最后,在海马CA1、CA2、CA3和DG区域的神经元中检测到了RLN3-IR,但没有RLN3 mRNA。在DG区,RLN3-和SST-IR共同定位在一小部分神经元中:结论:人类 NI 的解剖结构在物种间具有共通性,其中包括应激反应型 RLN3 表达神经元群和海马的 RLN3 神经支配。NI中磷酸化-tau的积累表明它可能与AD病理有关。对人类 NI 神经化学特性的进一步研究将加深我们对其在健康和疾病中的功能作用的了解。
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引用次数: 0
Chrysin-loaded PEGylated liposomes protect against alloxan-induced diabetic neuropathy in rats: the interplay between endoplasmic reticulum stress and autophagy. 含蛹虫草素的聚乙二醇脂质体对阿脲诱导的大鼠糖尿病神经病变有保护作用:内质网应激和自噬之间的相互作用
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-09 DOI: 10.1186/s40659-024-00521-1
Mahran Mohamed Abd El-Emam, Amany Behairy, Mahmoud Mostafa, Tarek Khamis, Noura M S Osman, Amira Ebrahim Alsemeh, Mohamed Fouad Mansour

Background: Diabetic neuropathy (DN) is recognized as a significant complication arising from diabetes mellitus (DM). Pathogenesis of DN is accelerated by endoplasmic reticulum (ER) stress, which inhibits autophagy and contributes to disease progression. Autophagy is a highly conserved mechanism crucial in mitigating cell death induced by ER stress. Chrysin, a naturally occurring flavonoid, can be found abundantly in honey, propolis, and various plant extracts. Despite possessing advantageous attributes such as being an antioxidant, anti-allergic, anti-inflammatory, anti-fibrotic, and anticancer agent, chrysin exhibits limited bioavailability. The current study aimed to produce a more bioavailable form of chrysin and discover how administering chrysin could alter the neuropathy induced by Alloxan in male rats.

Methods: Chrysin was formulated using PEGylated liposomes to boost its bioavailability and formulation. Chrysin PEGylated liposomes (Chr-PLs) were characterized for particle size diameter, zeta potential, polydispersity index, transmission electron microscopy, and in vitro drug release. Rats were divided into four groups: control, Alloxan, metformin, and Chr-PLs. In order to determine Chr- PLs' antidiabetic activity and, by extension, its capacity to ameliorate DN, several experiments were carried out. These included measuring acetylcholinesterase, fasting blood glucose, insulin, genes dependent on autophagy or stress in the endoplasmic reticulum, and histopathological analysis.

Results: According to the results, the prepared Chr-PLs exhibited an average particle size of approximately 134 nm. They displayed even distribution of particle sizes. The maximum entrapment efficiency of 90.48 ± 7.75% was achieved. Chr-PLs effectively decreased blood glucose levels by 67.7% and elevated serum acetylcholinesterase levels by 40% compared to diabetic rats. Additionally, Chr-PLs suppressed the expression of ER stress-related genes (ATF-6, CHOP, XBP-1, BiP, JNK, PI3K, Akt, and mTOR by 33%, 39.5%, 32.2%, 44.4%, 40.4%, 39.2%, 39%, and 35.9%, respectively). They also upregulated the miR-301a-5p expression levels by 513% and downregulated miR-301a-5p expression levels by 65%. They also boosted the expression of autophagic markers (AMPK, ULK1, Beclin 1, and LC3-II by 90.3%, 181%, 109%, and 78%, respectively) in the sciatic nerve. The histopathological analysis also showed that Chr-PLs inhibited sciatic nerve degeneration.

Conclusion: The findings suggest that Chr-PLs may be helpful in the protection against DN via regulation of ER stress and autophagy.

背景:糖尿病神经病变(DN)被认为是糖尿病(DM)引起的一种重要并发症。糖尿病神经病变的发病机制因内质网(ER)应激而加速,ER应激会抑制自噬并导致疾病进展。自噬是一种高度保守的机制,对减轻ER应激诱导的细胞死亡至关重要。蛹虫草素是一种天然黄酮类化合物,大量存在于蜂蜜、蜂胶和各种植物提取物中。尽管菊黄素具有抗氧化、抗过敏、抗炎、抗纤维化和抗癌等优点,但其生物利用度有限。目前的研究旨在生产一种生物利用度更高的菊黄素,并探索服用菊黄素如何改变阿脲诱导的雄性大鼠神经病变:方法:使用 PEG 化脂质体配制金丝桃素,以提高其生物利用度和配方。对蛹素 PEG 化脂质体(Chr-PLs)的粒径、ZETA 电位、多分散指数、透射电子显微镜和体外药物释放进行了表征。大鼠被分为四组:对照组、阿洛欣组、二甲双胍组和 Chr-PLs 组。为了确定 Chr-PLs 的抗糖尿病活性,并进而确定其改善 DN 的能力,进行了多项实验。这些实验包括测量乙酰胆碱酯酶、空腹血糖、胰岛素、依赖于自噬或内质网压力的基因以及组织病理学分析:结果表明,制备的 Chr-PLs 平均粒径约为 134 nm。它们的粒径分布均匀。最大夹带效率为 90.48 ± 7.75%。与糖尿病大鼠相比,Chr-PLs 能有效降低 67.7% 的血糖水平,提高 40% 的血清乙酰胆碱酯酶水平。此外,Chr-PLs 还抑制了 ER 应激相关基因的表达(ATF-6、CHOP、XBP-1、BiP、JNK、PI3K、Akt 和 mTOR 的表达分别为 33%、39.5%、32.2%、44.4%、40.4%、39.2%、39% 和 35.9%)。它们还将 miR-301a-5p 的表达水平上调了 513%,将 miR-301a-5p 的表达水平下调了 65%。它们还提高了坐骨神经中自噬标记物(AMPK、ULK1、Beclin 1 和 LC3-II)的表达,分别提高了 90.3%、181%、109% 和 78%。组织病理学分析也表明,Chr-PLs 可抑制坐骨神经变性:结论:研究结果表明,Chr-PLs可通过调节ER应激和自噬作用来预防DN。
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引用次数: 0
Lead and calcium crosstalk tempted acrosome damage and hyperpolarization of spermatozoa: signaling and ultra-structural evidences. 铅和钙的串扰诱导了顶体损伤和精子的超极化:信号和超结构证据。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-05 DOI: 10.1186/s40659-024-00517-x
Rajkumar Singh Yadav, Bhawna Kushawaha, Rahul Dhariya, Dilip Kumar Swain, Brijesh Yadav, Mukul Anand, Priyambada Kumari, Pradeep Kumar Rai, Dipty Singh, Sarvajeet Yadav, Satish Kumar Garg

Background: Exposure of humans and animals to heavy metals is increasing day-by-day; thus, lead even today remains of significant public health concern. According to CDC, blood lead reference value (BLRV) ranges from 3.5 µg/dl to 5 μg/dl in adults. Recently, almost 2.6% decline in male fertility per year has been reported but the cause is not well established. Lead (Pb2+) affects the size of testis, semen quality, and secretory functions of prostate. But the molecular mechanism(s) of lead toxicity in sperm cells is not clear. Thus, present study was undertaken to evaluate the adverse effects of lead acetate at environmentally relevant exposure levels (0.5, 5, 10 and 20 ppm) on functional and molecular dynamics of spermatozoa of bucks following in vitro exposure for 15 min and 3 h.

Results: Lead significantly decreased motility, viable count, and motion kinematic patterns of spermatozoa like curvilinear velocity, straight-line velocity, average path velocity, beat cross frequency and maximum amplitude of head lateral displacement even at 5 ppm concentration. Pb2+ modulated intracellular cAMP and Ca2+ levels in sperm cells through L-type calcium channels and induced spontaneous or premature acrosome reaction (AR) by increasing tyrosine phosphorylation of sperm proteins and downregulated mitochondrial transmembrane potential. Lead significantly increased DNA damage and apoptosis as well. Electron microscopy studies revealed Pb2+ -induced deleterious effects on plasma membrane of head and acrosome including collapsed cristae in mitochondria.

Conclusions: Pb2+ not only mimics Ca2+ but also affects cellular targets involved in generation of cAMP, mitochondrial transmembrane potential, and ionic exchange. Lead seems to interact with Ca2+ channels because of charge similarity and probably enters the sperm cell through these channels and results in hyperpolarization. Our findings also indicate lead-induced TP and intracellular Ca2+ release in spermatozoa which in turn may be responsible for premature acrosome exocytosis which is essential feature of capacitation for fertilization. Thus, lead seems to reduce the fertilizing capacity of spermatozoa even at 0.5 ppm concentrations.

背景:人类和动物接触重金属的机会与日俱增,因此,即使在今天,铅仍然是公众健康的重大问题。根据美国疾病预防控制中心(CDC)的数据,成人血铅参考值(BLRV)为 3.5 µg/dl 至 5 μg/dl。最近有报道称,男性生育能力每年下降近 2.6%,但原因尚未明确。铅(Pb2+)会影响睾丸大小、精液质量和前列腺的分泌功能。但铅对精子细胞毒性的分子机制尚不清楚。因此,本研究评估了环境相关暴露水平(0.5、5、10 和 20 ppm)的醋酸铅在体外暴露 15 分钟和 3 小时后对雄鹿精子功能和分子动力学的不利影响:结果:铅明显降低了精子的运动能力、存活率和运动模式,如曲线速度、直线速度、平均路径速度、搏动交叉频率和头部横向位移的最大振幅,即使在百万分之 5 的浓度下也是如此。铅通过 L 型钙通道调节精子细胞内的 cAMP 和 Ca2+ 水平,并通过增加精子蛋白质的酪氨酸磷酸化和下调线粒体跨膜电位诱导自发或过早顶体反应(AR)。铅还会明显增加 DNA 损伤和细胞凋亡。电子显微镜研究显示,铅对精子头部和顶体的质膜产生有害影响,包括线粒体嵴的塌陷:结论:Pb2+不仅能模拟 Ca2+,还能影响细胞中参与产生 cAMP、线粒体跨膜电位和离子交换的靶点。由于电荷的相似性,铅似乎与 Ca2+ 通道相互作用,可能通过这些通道进入精子细胞并导致超极化。我们的研究结果还表明,铅诱导精子的 TP 和细胞内 Ca2+ 释放,这反过来又可能导致顶体过早外渗,而顶体外渗是获能受精的基本特征。因此,即使在 0.5 ppm 的浓度下,铅似乎也会降低精子的受精能力。
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引用次数: 0
Retraction Note: Tridax procumbens flavonoids promote osteoblast differentiation and bone formation. 撤稿说明:蒲公英黄酮类化合物可促进成骨细胞分化和骨形成。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-06-24 DOI: 10.1186/s40659-024-00525-x
Md Abdullah Al Mamun, Mohammad Jakir Hosen, Kamrul Islam, Amina Khatun, M Masihul Alam, Md Abdul Alim Al-Bari
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引用次数: 0
Molecular hydrogen promotes retinal vascular regeneration and attenuates neovascularization and neuroglial dysfunction in oxygen-induced retinopathy mice. 分子氢促进氧诱导视网膜病变小鼠的视网膜血管再生,并减轻新生血管和神经胶质细胞功能障碍。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-06-24 DOI: 10.1186/s40659-024-00515-z
Yatu Guo, Jiahui Qin, Ruiqiang Sun, Peng Hao, Zhixin Jiang, Yuchuan Wang, Zhiqi Gao, Huan Zhang, Keliang Xie, Wei Zhang
<p><strong>Background: </strong>Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H<sub>2</sub>) is widely considered as a useful neuroprotective and antioxidative therapeutic method for hypoxic-ischemic disease without toxic effects. However, whether H<sub>2</sub> provides physiological angiogenesis promotion, neovascularization suppression and glial protection in the progression of ROP is largely unknown.This study aims to investigate the effects of H<sub>2</sub> on retinal angiogenesis, neovascularization and neuroglial dysfunction in the retinas of oxygen-induced retinopathy (OIR) mice.</p><p><strong>Methods: </strong>In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H<sub>2</sub>) inhalation were administered. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. To count the number of neovascularization endothelial nuclei, routine HE staining of retinal sections was conducted. Immunohistochemistry was performed using DyLight 594 labeled GSL I-isolectin B4 (IB4), as well as primary antibodies against proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), and Iba-1. Western blots were used to measure the expression of NF-E2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), Notch1, Dll4, and HIF-1α. Additionally, the expression of target genes such as NQO1, HO-1, Notch1, Hey1, Hey2, and Dll4 was measured. Human umbilical vein endothelial cells (HUVECs) treated with H<sub>2</sub> under hypoxia were used as an in vitro model. RT-PCR was used to evaluate the mRNA expression of Nrf2, Notch/Dll4, and the target genes. The expression of reactive oxygen species (ROS) was observed using immunofluorescence staining.</p><p><strong>Results: </strong>Our results indicate that 3-4% H<sub>2</sub> does not disturb retinal physiological angiogenesis, but ameliorates vaso-obliteration and neovascularization in OIR mice. Moreover, H<sub>2</sub> prevents the decreased density and reverses the morphologic and functional changes in retinal astrocytes caused by oxygen-induced injury. In addition, H<sub>2</sub> inhalation reduces microglial activation, especially in the area of neovascularization in OIR mice. H<sub>2</sub> plays a protective role in vascular regeneration by promoting Nrf2 activation and suppressing the Dll4-induced Notch signaling pathway in vivo. Also, H<sub>2</sub> promotes the proliferation of HUVECs under hypoxia by negatively regulating the Dll4/Notch pathway and reducing ROS levels through Nrf2 pathway aligning with our findings in vivo.Moreove
背景:早产儿视网膜病变(ROP早产儿视网膜病变(ROP)是一种发生在早产儿视网膜上的增生性视网膜血管疾病,是导致儿童失明的主要原因。目前,抗血管内皮生长因子(VEGF)和视网膜光凝是治疗早产儿视网膜病变的主流方法,但它们会产生各种并发症。氢气(H2)被广泛认为是一种有效的神经保护和抗氧化治疗方法,可治疗缺氧缺血性疾病,且无毒副作用。本研究旨在探讨氢气对氧致视网膜病变(OIR)小鼠视网膜血管生成、新生血管形成和神经胶质功能障碍的影响:在这项研究中,将7天大的野生型(WT)或Nrf2缺陷型(Nrf2-/-)小鼠暴露于75%的氧气中5天,然后放回正常空气条件下。在不同阶段吸入氢气(H2)。对血管阻塞、新生血管和血管渗漏进行分析和比较。为了计算新生血管内皮细胞核的数量,对视网膜切片进行了常规 HE 染色。使用 DyLight 594 标记的 GSL I-isolectin B4(IB4)以及增殖细胞核抗原(PCNA)、神经胶质纤维酸性蛋白(GFAP)和 Iba-1 的一抗进行免疫组化。Western 印迹用于测量 NF-E2 相关因子 2 (Nrf2)、血管内皮生长因子 (VEGF)、Notch1、Dll4 和 HIF-1α 的表达。此外,还测量了 NQO1、HO-1、Notch1、Hey1、Hey2 和 Dll4 等靶基因的表达。以缺氧条件下用 H2 处理的人脐静脉内皮细胞(HUVECs)为体外模型。采用 RT-PCR 技术评估 Nrf2、Notch/Dll4 和靶基因的 mRNA 表达。使用免疫荧光染色法观察活性氧(ROS)的表达:结果:我们的研究结果表明,3-4% 的 H2 不会干扰视网膜生理性血管生成,但会改善 OIR 小鼠的血管闭塞和新生血管形成。此外,H2 还能防止氧损伤引起的视网膜星形胶质细胞密度下降,并逆转其形态和功能变化。此外,吸入 H2 还能减少小胶质细胞的活化,尤其是在 OIR 小鼠的新生血管区域。H2 在体内通过促进 Nrf2 激活和抑制 Dll4 诱导的 Notch 信号通路,对血管再生起到保护作用。此外,视网膜氧传感机制(HIF-1α/VEGF)也参与了氢介导的视网膜血管再通和新生血管抑制:总之,我们的研究结果表明,氢气可能是一种治疗 POR 的有效药物,它对人类 ROP 的有益作用可能涉及 Nrf2-Notch 轴和 HIF-1α/VEGF 通路的激活。
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引用次数: 0
Exercise reduces physical alterations in a rat model of fetal alcohol spectrum disorders. 运动可减少胎儿酒精中毒谱系障碍大鼠模型的身体改变。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-06-22 DOI: 10.1186/s40659-024-00520-2
Ronald Vargas-Foitzick, Bayron García-Ordenes, Donovan Iratchet, Angie Acuña, Spencer Alcayaga, Cristian Fernández, Karla Toledo, Marianela Rodríguez, Carolina Naranjo, René Bustamante, Paola A Haeger

Background: Prenatal alcohol exposure (PAE) has serious physical consequences for children such as behavioral disabilities, growth disorders, neuromuscular problems, impaired motor coordination, and decreased muscle tone. However, it is not known whether loss of muscle strength occurs, and which interventions will effectively mitigate physical PAE impairments. We aimed to investigate whether physical alteration persists during adolescence and whether exercise is an effective intervention.

Results: Using paradigms to evaluate different physical qualities, we described that early adolescent PAE animals have significant alterations in agility and strength, without alterations in balance and coordination compared to CTRL animals. We evaluated the effectiveness of 3 different exercise protocols for 4 weeks: Enrichment environment (EE), Endurance exercise (EEX), and Resistance exercise (REX). The enriched environment significantly improved the strength in the PAE group but not in the CTRL group whose strength parameters were maintained even during exercise. Resistance exercise showed the greatest benefits in gaining strength, and endurance exercise did not.

Conclusion: PAE induced a significant decrease in strength compared to CTRL in PND21. Resistance exercise is the most effective to reverse the effects of PAE on muscular strength. Our data suggests that individualized, scheduled, and supervised training of resistance is more beneficial than endurance or enriched environment exercise for adolescents FASD.

背景:产前酒精暴露(PAE)会对儿童的身体造成严重后果,如行为障碍、生长障碍、神经肌肉问题、运动协调能力受损和肌肉张力下降。然而,目前尚不清楚肌肉力量是否会丧失,也不知道哪些干预措施能有效减轻 PAE 对身体造成的损害。我们的目的是调查体能改变是否会在青春期持续存在,以及运动是否是一种有效的干预措施:结果:通过使用范式评估不同的身体素质,我们发现青春期早期 PAE 动物与 CTRL 动物相比,在灵活性和力量方面有显著改变,而在平衡和协调方面没有改变。我们评估了 3 种不同运动方案的效果,为期 4 周:充实环境(EE)、耐力锻炼(EEX)和阻力锻炼(REX)。充实环境明显改善了 PAE 组的力量,但 CTRL 组的力量参数在运动过程中仍能保持不变。阻力运动对增强力量的益处最大,而耐力运动则不然:结论:与 CTRL 相比,PAE 会导致 PND21 的力量显著下降。阻力运动对逆转 PAE 对肌肉力量的影响最为有效。我们的数据表明,对 FASD 青少年而言,个性化、有计划和有监督的阻力训练比耐力锻炼或丰富环境锻炼更有益。
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引用次数: 0
Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice. 蛋白酪氨酸磷酸酶受体δ PTPRD的缺失会增加成年小鼠大脑皮层神经元的数量、损害突触功能并诱发类似自闭症的行为。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-06-18 DOI: 10.1186/s40659-024-00522-0
Bastián I Cortés, Rodrigo C Meza, Carlos Ancatén-González, Nicolás M Ardiles, María-Ignacia Aránguiz, Hideaki Tomita, David R Kaplan, Francisca Cornejo, Alexia Nunez-Parra, Pablo R Moya, Andrés E Chávez, Gonzalo I Cancino

Background: The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown.

Results: Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety.

Conclusions: These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.

背景:大脑皮层负责许多高级认知功能。大脑皮层发育过程中的干扰会对大脑功能产生长期影响,并与脑部疾病的病因有关。我们之前发现,蛋白酪氨酸磷酸酶受体δ Ptprd 是大脑皮层发育的关键,它与几种人类神经发育障碍有遗传关联。Ptprd 的表达缺失会过度激活神经前体细胞中的促神经再生受体 TrkB 和 PDGFRβ,从而诱发胚胎和新生小鼠兴奋性神经元的异常增加。然而,这些改变是否会对成年期产生长期影响仍是未知数:结果:在这里,我们发现在 Ptprd+/- 或 Ptprd-/- 小鼠中,兴奋性神经元的发育增加会持续到成年,从而影响内侧前额叶皮层的兴奋性突触功能。同样,Ptprd 的杂合性或同源性也会诱导抑制性皮质 GABA 能神经元的增加,并损害抑制性突触传递。最后,Ptprd+/- 或 Ptprd-/- 小鼠表现出类似自闭症的行为,但没有学习和记忆障碍或焦虑:这些结果表明,Ptprd 的缺失会对大脑皮层神经元数量和突触功能产生长期影响,并可能对类似 ASD 的行为产生异常影响。
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引用次数: 0
Inhibition of astroglial hemichannels prevents synaptic transmission decline during spreading depression. 抑制星形胶质细胞半通道可防止扩散抑制过程中的突触传递衰退。
IF 6.7 2区 生物学 Q1 BIOLOGY Pub Date : 2024-06-12 DOI: 10.1186/s40659-024-00519-9
Juan E Tichauer, Matías Lira, Waldo Cerpa, Juan A Orellana, Juan C Sáez, Maximiliano Rovegno

Background: Spreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is repetitive and produces a metabolic overload that increases secondary damage. However, the mechanisms associated with the initiation and propagation of SD are unknown. Multiple lines of evidence indicate that persistent and uncontrolled opening of hemichannels could participate in the pathogenesis and progression of several neurological disorders including acute brain injuries. Here, we explored the contribution of astroglial hemichannels composed of connexin-43 (Cx43) or pannexin-1 (Panx1) to SD evoked by high-K+ stimulation in brain slices.

Results: Focal high-K+ stimulation rapidly evoked a wave of SD linked to increased activity of the Cx43 and Panx1 hemichannels in the brain cortex, as measured by light transmittance and dye uptake analysis, respectively. The activation of these channels occurs mainly in astrocytes but also in neurons. More importantly, the inhibition of both the Cx43 and Panx1 hemichannels completely prevented high K+-induced SD in the brain cortex. Electrophysiological recordings also revealed that Cx43 and Panx1 hemichannels critically contribute to the SD-induced decrease in synaptic transmission in the brain cortex and hippocampus.

Conclusions: Targeting Cx43 and Panx1 hemichannels could serve as a new therapeutic strategy to prevent the initiation and propagation of SD in several acute brain injuries.

背景:扩散抑制(SD)是一种有趣的现象,其特征是影响神经元和神经胶质细胞的大规模缓慢脑去极化。这种现象具有重复性,会产生新陈代谢超载,从而增加继发性损伤。然而,SD 的启动和传播机制尚不清楚。多种证据表明,半通道持续、不受控制的开放可能参与了包括急性脑损伤在内的多种神经系统疾病的发病和进展。在此,我们探讨了由 connexin-43 (Cx43) 或 pannexin-1 (Panx1) 组成的星形胶质细胞半通道对高 K+刺激诱发脑片 SD 的贡献:结果:局灶性高K+刺激可迅速诱发SD波,这与大脑皮层中Cx43和Panx1半通道活性的增加有关,这分别是通过透光率和染料吸收分析测定的。这些通道的激活主要发生在星形胶质细胞中,但也发生在神经元中。更重要的是,抑制 Cx43 和 Panx1 半通道可完全阻止高 K+诱导的大脑皮层 SD。电生理记录还显示,Cx43和Panx1半通道对SD诱导的大脑皮层和海马突触传递的减少起着关键作用:结论:靶向 Cx43 和 Panx1 半通道可作为一种新的治疗策略,在多种急性脑损伤中预防 SD 的发生和传播。
{"title":"Inhibition of astroglial hemichannels prevents synaptic transmission decline during spreading depression.","authors":"Juan E Tichauer, Matías Lira, Waldo Cerpa, Juan A Orellana, Juan C Sáez, Maximiliano Rovegno","doi":"10.1186/s40659-024-00519-9","DOIUrl":"10.1186/s40659-024-00519-9","url":null,"abstract":"<p><strong>Background: </strong>Spreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is repetitive and produces a metabolic overload that increases secondary damage. However, the mechanisms associated with the initiation and propagation of SD are unknown. Multiple lines of evidence indicate that persistent and uncontrolled opening of hemichannels could participate in the pathogenesis and progression of several neurological disorders including acute brain injuries. Here, we explored the contribution of astroglial hemichannels composed of connexin-43 (Cx43) or pannexin-1 (Panx1) to SD evoked by high-K<sup>+</sup> stimulation in brain slices.</p><p><strong>Results: </strong>Focal high-K<sup>+</sup> stimulation rapidly evoked a wave of SD linked to increased activity of the Cx43 and Panx1 hemichannels in the brain cortex, as measured by light transmittance and dye uptake analysis, respectively. The activation of these channels occurs mainly in astrocytes but also in neurons. More importantly, the inhibition of both the Cx43 and Panx1 hemichannels completely prevented high K<sup>+</sup>-induced SD in the brain cortex. Electrophysiological recordings also revealed that Cx43 and Panx1 hemichannels critically contribute to the SD-induced decrease in synaptic transmission in the brain cortex and hippocampus.</p><p><strong>Conclusions: </strong>Targeting Cx43 and Panx1 hemichannels could serve as a new therapeutic strategy to prevent the initiation and propagation of SD in several acute brain injuries.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"57 1","pages":"39"},"PeriodicalIF":6.7,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction: Conformational characterization of the mammalian-expressed SARS-CoV-2 recombinant receptor binding domain, a COVID-19 vaccine. 更正:哺乳动物表达的 SARS-CoV-2 重组受体结合域(COVID-19 疫苗)的构象特征。
IF 6.7 2区 生物学 Q1 BIOLOGY Pub Date : 2024-06-01 DOI: 10.1186/s40659-024-00514-0
Leina Moro-Pérez, Tammy Boggiano-Ayo, Sum Lai Lozada-Chang, Olga Lidia Fernández-Saiz, Beatriz Perez-Masson, Kathya Rashida de la Luz, Jose Alberto Gómez-Pérez
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引用次数: 0
The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration. 线粒体激素作用在骨和软骨退行性病变的发生和治疗方面的最新研究成果。
IF 6.7 2区 生物学 Q1 BIOLOGY Pub Date : 2024-06-01 DOI: 10.1186/s40659-024-00494-1
Wacili Da, Quan Chen, Bin Shen

It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.

人们普遍认为,衰老、线粒体功能障碍和细胞表型异常与骨和软骨的退化密切相关。因此,全面了解线粒体功能的调控模式及其内在机制,有望缓解骨关节炎、椎间盘退化和骨质疏松症的进展。线粒体荷尔蒙发生(又称线粒体激素发生)是一种细胞适应性应激反应机制,线粒体通过产生活性氧(ROS)、协调未折叠蛋白反应(UPRmt)、诱导线粒体衍生肽(MDP)、激发线粒体动态变化和激活线粒体吞噬来恢复平衡和增强抵抗刺激的能力,所有这些都是由低剂量的应激物引起的。不同性质、强度和持续时间的刺激源会引起不同程度的线粒体应激反应,随后激活一种或多种信号通路,启动有丝分裂。本综述特别关注与有丝分裂相关的效应分子和调控网络,同时还仔细研究了线粒体功能障碍通过氧化应激损伤导致骨和软骨退化的现有机制。此外,它还强调了机械刺激、间歇性饮食限制、缺氧预处理和低剂量有毒化合物引发有丝分裂的潜力,从而缓解骨和软骨退化。
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引用次数: 0
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