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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 Agricultural and Biological Sciences 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 Agricultural and Biological Sciences 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 Agricultural and Biological Sciences 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。
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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 Agricultural and Biological Sciences 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 Agricultural and Biological Sciences 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
The crucial role of HFM1 in regulating FUS ubiquitination and localization for oocyte meiosis prophase I progression in mice. HFM1 在小鼠卵母细胞减数分裂前期 I 进展过程中调节 FUS 泛素化和定位的关键作用。
IF 6.7 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-05-31 DOI: 10.1186/s40659-024-00518-w
Chenyi Zhong, Huiyuan Wang, Xiong Yuan, Yuheng He, Jing Cong, Rui Yang, Wenjie Ma, Li Gao, Chao Gao, Yugui Cui, Jie Wu, Rongrong Tan, Danhua Pu

Background: Helicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency (POI). However, the underlying molecular mechanism has not been clearly elucidated. The aim of this study was to investigate the function of HFM1 in the first meiotic prophase of mouse oocytes.

Results: The results suggested that the deficiency of HFM1 resulting in increased apoptosis and depletion of oocytes in mice, while the oocytes were arrested in the pachytene stage of the first meiotic prophase. In addition, impaired DNA double-strand break repair and disrupted synapsis were observed in the absence of HFM1. Further investigation revealed that knockout of HFM1 promoted ubiquitination and degradation of FUS protein mediated by FBXW11. Additionally, the depletion of HFM1 altered the intranuclear localization of FUS and regulated meiotic- and oocyte development-related genes in oocytes by modulating the expression of BRCA1.

Conclusions: These findings elaborated that the critical role of HFM1 in orchestrating the regulation of DNA double-strand break repair and synapsis to ensure meiosis procession and primordial follicle formation. This study provided insights into the pathogenesis of POI and highlighted the importance of HFM1 in maintaining proper meiotic function in mouse oocytes.

背景:减数分裂螺旋酶 1(HFM1)是一种在生殖细胞中表达的推定 DNA 螺旋酶,据报道与卵巢早衰(POI)密切相关。然而,其潜在的分子机制尚未明确阐明。本研究旨在探讨HFM1在小鼠卵母细胞减数第一次分裂前期的功能:结果:结果表明,HFM1的缺乏导致小鼠卵母细胞凋亡和耗竭增加,同时卵母细胞停滞在减数第一次分裂前期的pachytene阶段。此外,在 HFM1 缺失的情况下,还观察到 DNA 双链断裂修复受损和突触中断。进一步研究发现,HFM1的敲除促进了FUS蛋白在FBXW11介导下的泛素化和降解。此外,HFM1的缺失改变了FUS的核内定位,并通过调节BRCA1的表达调控卵母细胞中减数分裂和卵母细胞发育相关基因:这些发现阐明了HFM1在协调DNA双链断裂修复和突触调控中的关键作用,从而确保减数分裂过程和原始卵泡的形成。这项研究揭示了 POI 的发病机制,并强调了 HFM1 在维持小鼠卵母细胞正常减数分裂功能方面的重要性。
{"title":"The crucial role of HFM1 in regulating FUS ubiquitination and localization for oocyte meiosis prophase I progression in mice.","authors":"Chenyi Zhong, Huiyuan Wang, Xiong Yuan, Yuheng He, Jing Cong, Rui Yang, Wenjie Ma, Li Gao, Chao Gao, Yugui Cui, Jie Wu, Rongrong Tan, Danhua Pu","doi":"10.1186/s40659-024-00518-w","DOIUrl":"10.1186/s40659-024-00518-w","url":null,"abstract":"<p><strong>Background: </strong>Helicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency (POI). However, the underlying molecular mechanism has not been clearly elucidated. The aim of this study was to investigate the function of HFM1 in the first meiotic prophase of mouse oocytes.</p><p><strong>Results: </strong>The results suggested that the deficiency of HFM1 resulting in increased apoptosis and depletion of oocytes in mice, while the oocytes were arrested in the pachytene stage of the first meiotic prophase. In addition, impaired DNA double-strand break repair and disrupted synapsis were observed in the absence of HFM1. Further investigation revealed that knockout of HFM1 promoted ubiquitination and degradation of FUS protein mediated by FBXW11. Additionally, the depletion of HFM1 altered the intranuclear localization of FUS and regulated meiotic- and oocyte development-related genes in oocytes by modulating the expression of BRCA1.</p><p><strong>Conclusions: </strong>These findings elaborated that the critical role of HFM1 in orchestrating the regulation of DNA double-strand break repair and synapsis to ensure meiosis procession and primordial follicle formation. This study provided insights into the pathogenesis of POI and highlighted the importance of HFM1 in maintaining proper meiotic function in mouse oocytes.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11140966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141185835","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
Distinct properties of putative trophoblast stem cells established from somatic cell nuclear-transferred pig blastocysts. 从体细胞核移植猪囊胚建立的假定滋养层干细胞的不同特性
IF 6.7 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-05-30 DOI: 10.1186/s40659-024-00516-y
Eunhye Kim, Lian Cai, Hyerin Choi, Mirae Kim, Sang-Hwan Hyun

Background: Genetically modified pigs are considered ideal models for studying human diseases and potential sources for xenotransplantation research. However, the somatic cell nuclear transfer (SCNT) technique utilized to generate these cloned pig models has low efficiency, and fetal development is limited due to placental abnormalities.

Results: In this study, we unprecedentedly established putative porcine trophoblast stem cells (TSCs) using SCNT and in vitro-fertilized (IVF) blastocysts through the activation of Wing-less/Integrated (Wnt) and epidermal growth factor (EGF) pathways, inhibition of transforming growth factor-β (TGFβ) and Rho-associated protein kinase (ROCK) pathways, and supplementation with ascorbic acid. We also compared the transcripts of putative TSCs originating from SCNT and IVF embryos and their differentiated lineages. A total of 19 porcine TSCs exhibiting typical characteristics were established from SCNT and IVF blastocysts (TSCsNT and TSCsIVF). Compared with the TSCsIVF, TSCsNT showed distinct expression patterns suggesting unique TSCsNT characteristics, including decreased mRNA expression of genes related to apposition, steroid hormone biosynthesis, angiopoiesis, and RNA stability.

Conclusion: This study provides valuable information and a powerful model for studying the abnormal development and dysfunction of trophoblasts and placentas in cloned pigs.

背景:转基因猪被认为是研究人类疾病的理想模型,也是异种移植研究的潜在来源。然而,用于产生这些克隆猪模型的体细胞核移植(SCNT)技术效率较低,胎儿发育因胎盘异常而受到限制:在这项研究中,我们通过激活无翼/整合(Wnt)和表皮生长因子(EGF)通路、抑制转化生长因子-β(TGFβ)和Rho相关蛋白激酶(ROCK)通路以及补充抗坏血酸,利用SCNT和体外受精(IVF)囊胚史无前例地建立了猪滋养层干细胞(TSCs)。我们还比较了来源于SCNT和IVF胚胎的假定TSCs及其分化系的转录本。从 SCNT 和 IVF 胚泡中共建立了 19 个具有典型特征的猪 TSCs(TSCsNT 和 TSCsIVF)。与 TSCsIVF 相比,TSCsNT 显示出不同的表达模式,表明 TSCsNT 具有独特的特征,包括与贴壁、类固醇激素生物合成、血管生成和 RNA 稳定性相关的基因 mRNA 表达减少:这项研究为研究克隆猪滋养细胞和胎盘的异常发育和功能障碍提供了宝贵的信息和强大的模型。
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引用次数: 0
Electroacupuncture attenuates neuropathic pain via suppressing BIP-IRE-1α-mediated endoplasmic reticulum stress in the anterior cingulate cortex 电针通过抑制前扣带回皮层 BIP-IRE-1α 介导的内质网应激减轻神经性疼痛
IF 6.7 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-05-29 DOI: 10.1186/s40659-024-00511-3
Lin-Wei Ma, Yu-Fan Liu, Hui Zhang, Chang-Jun Huang, Ang Li, Xin-Zhe Qu, Jia-Piao Lin, Yan Yang, Yong-Xing Yao
Studies have suggested that endoplasmic reticulum stress (ERS) is involved in neurological dysfunction and that electroacupuncture (EA) attenuates neuropathic pain (NP) via undefined pathways. However, the role of ERS in the anterior cingulate cortex (ACC) in NP and the effect of EA on ERS in the ACC have not yet been investigated. In this study, an NP model was established by chronic constriction injury (CCI) of the left sciatic nerve in rats, and mechanical and cold tests were used to evaluate behavioral hyperalgesia. The protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that glucose-regulated protein 78 (BIP) and inositol-requiring enzyme 1α (IRE-1α) were co-localized in neurons in the ACC. After CCI, BIP, IRE-1α, and phosphorylation of IRE-1α were upregulated in the ACC. Intra-ACC administration of 4-PBA and Kira-6 attenuated pain hypersensitivity and downregulated phosphorylation of IRE-1α, while intraperitoneal injection of 4-PBA attenuated hyperalgesia and inhibited the activation of P38 and JNK in ACC. In contrast, ERS activation by intraperitoneal injection of tunicamycin induced behavioral hyperalgesia in naive rats. Furthermore, EA attenuated pain hypersensitivity and inhibited the CCI-induced overexpression of BIP and pIRE-1α. Taken together, these results demonstrate that EA attenuates NP by suppressing BIP- and IRE-1α-mediated ERS in the ACC. Our study presents novel evidence that ERS in the ACC is implicated in the development of NP and provides insights into the molecular mechanisms involved in the analgesic effect of EA.
研究表明,内质网应激(ERS)与神经功能紊乱有关,电针(EA)通过未确定的途径减轻神经性疼痛(NP)。然而,前扣带回皮层(ACC)中的ERS在NP中的作用以及EA对ACC中ERS的影响尚未得到研究。本研究通过对大鼠左侧坐骨神经的慢性收缩损伤(CCI)建立了NP模型,并使用机械试验和冷试验来评估行为性过痛。采用 Western 印迹法和免疫荧光法评估了蛋白质的表达和分布。结果显示,葡萄糖调节蛋白78(BIP)和肌醇需要酶1α(IRE-1α)共同定位在ACC的神经元中。CCI 后,ACC 中的 BIP、IRE-1α 和 IRE-1α 磷酸化均上调。在ACC内注射4-PBA和Kira-6可减轻痛觉过敏并下调IRE-1α的磷酸化,而腹腔注射4-PBA可减轻痛觉过敏并抑制P38和JNK在ACC中的激活。与此相反,腹腔注射曲卡霉素激活 ERS 会诱发天真大鼠的行为性过痛。此外,EA还能减轻痛觉过敏,抑制CCI诱导的BIP和pIRE-1α过表达。综上所述,这些结果表明 EA 通过抑制 BIP 和 IRE-1α 介导的 ACC ERS 来减轻 NP。我们的研究提供了新的证据,证明 ACC 中的 ERS 与 NP 的发生有关,并为 EA 镇痛作用的分子机制提供了新的见解。
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引用次数: 0
The hepatoprotective effect of 4-phenyltetrahydroquinolines on carbon tetrachloride induced hepatotoxicity in rats through autophagy inhibition. 4-苯基四氢喹啉通过抑制自噬对四氯化碳诱导的大鼠肝中毒的保肝作用
IF 6.7 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-05-27 DOI: 10.1186/s40659-024-00510-4
Mohamed Hussein Abdelgalil, Reem H Elhammamy, Hanan M Ragab, Eman Sheta, Ahmed Wahid

Background: The liver serves as a metabolic hub within the human body, playing a crucial role in various essential functions, such as detoxification, nutrient metabolism, and hormone regulation. Therefore, protecting the liver against endogenous and exogenous insults has become a primary focus in medical research. Consequently, the potential hepatoprotective properties of multiple 4-phenyltetrahydroquinolines inspired us to thoroughly study the influence of four specially designed and synthesized derivatives on carbon tetrachloride (CCl4)-induced liver injury in rats.

Methods and results: Seventy-seven Wistar albino male rats weighing 140 ± 18 g were divided into eleven groups to investigate both the toxicity profile and the hepatoprotective potential of 4-phenyltetrahydroquinolines. An in-vivo hepatotoxicity model was conducted using CCl4 (1 ml/kg body weight, a 1:1 v/v mixture with corn oil, i.p.) every 72 h for 14 days. The concurrent treatment of rats with our newly synthesized compounds (each at a dose of 25 mg/kg body weight, suspended in 0.5% CMC, p.o.) every 24 h effectively lowered transaminases, preserved liver tissue integrity, and mitigated oxidative stress and inflammation. Moreover, the histopathological examination of liver tissues revealed a significant reduction in liver fibrosis, which was further supported by the immunohistochemical analysis of α-SMA. Additionally, the expression of the apoptotic genes BAX and BCL2 was monitored using real-time PCR, which showed a significant decrease in liver apoptosis. Further investigations unveiled the ability of the compounds to significantly decrease the expression of autophagy-related proteins, Beclin-1 and LC3B, consequently inhibiting autophagy. Finally, our computer-assisted simulation dockingonfirmed the obtained experimental activities.

Conclusion: Our findings suggest that derivatives of 4-phenyltetrahydroquinoline demonstrate hepatoprotective properties in CCl4-induced liver damage and fibrosis in rats. The potential mechanism of action may be due to the inhibition of autophagy in liver cells.

背景:肝脏是人体内的代谢枢纽,在解毒、营养代谢和激素调节等各种基本功能中发挥着至关重要的作用。因此,保护肝脏免受内源性和外源性损伤已成为医学研究的首要重点。因此,多种 4-苯基四氢喹啉的潜在保肝特性激发了我们深入研究四种专门设计合成的衍生物对四氯化碳(CCl4)诱导的大鼠肝损伤的影响:将体重为 140 ± 18 克的 77 只 Wistar 白化雄性大鼠分为 11 组,研究 4-苯基四氢喹啉的毒性概况和保肝潜力。使用四氯化碳(1 毫升/千克体重,1:1 v/v 与玉米油的混合物,静脉注射)进行体内肝毒性模型试验,每 72 小时一次,连续 14 天。同时,每 24 小时用我们新合成的化合物(每种剂量为 25 毫克/千克体重,悬浮于 0.5% CMC 中,口服)治疗大鼠,可有效降低转氨酶,保护肝组织完整性,减轻氧化应激和炎症反应。此外,肝组织病理学检查显示,肝纤维化显著减少,α-SMA 的免疫组化分析进一步证实了这一点。此外,利用实时 PCR 监测了凋亡基因 BAX 和 BCL2 的表达,结果显示肝脏凋亡明显减少。进一步的研究发现,这些化合物能够显著降低自噬相关蛋白 Beclin-1 和 LC3B 的表达,从而抑制自噬。最后,我们的计算机辅助模拟对接证实了所获得的实验活性:我们的研究结果表明,4-苯基四氢喹啉衍生物对 CCl4 诱导的大鼠肝损伤和肝纤维化具有保肝作用。潜在的作用机制可能是由于抑制了肝细胞的自噬作用。
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引用次数: 0
Effect of Cannabis sativa L. extracts, phytocannabinoids and their acetylated derivates on the SHSY-5Y neuroblastoma cells' viability and caspases 3/7 activation. 大麻提取物、植物大麻素及其乙酰化衍生物对 SHSY-5Y 神经母细胞瘤细胞活力和 Caspases 3/7 活化的影响。
IF 6.7 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-05-27 DOI: 10.1186/s40659-024-00506-0
Elizabeth Tapia-Tapia, Pablo Aránguiz, Rodrigo Diaz, Luis Espinoza, Caroline R Weinstein-Oppenheimer, Mauricio Cuellar

Background: There is a need for novel treatments for neuroblastoma, despite the emergence of new biological and immune treatments, since refractory pediatric neuroblastoma is still a medical challenge. Phyto cannabinoids and their hemisynthetic derivatives have shown evidence supporting their anticancer potential. The aim of this research was to examine Phytocannabinoids or hemisynthetic cannabinoids, which reduce the SHSY-5Y, neuroblastoma cell line's viability.

Methods: Hexane and acetyl acetate extracts were produced starting with Cannabis sativa L. as raw material, then, 9-tetrahidrocannabinol, its acid counterpart and CBN were isolated. In addition, acetylated derivatives of THC and CBN were synthesized. The identification and purity of the chemicals was determined by High Performance Liquid Chromatography and 1H y 13C Magnetic Nuclear Resonance. Then, the capacity to affect the viability of SHSY-5Y, a neuroblastoma cell line, was examined using the resazurin method. Finally, to gain insight into the mechanism of action of the extracts, phytocannabinoids and acetylated derivatives on the examined cells, a caspase 3/7 determination was performed on cells exposed to these compounds.

Results: The structure and purity of the isolated compounds was demonstrated. The extracts, the phytocannabinoids and their acetylated counterparts inhibited the viability of the SHSY 5Y cells, being CBN the most potent of all the tested molecules with an inhibitory concentration of 50 percent of 9.5 µM.

Conclusion: Each of the evaluated molecules exhibited the capacity to activate caspases 3/7, indicating that at least in part, the cytotoxicity of the tested phytocannabinoids and their hemi-synthetic derivatives is mediated by apoptosis.

背景:尽管出现了新的生物和免疫疗法,但由于难治性小儿神经母细胞瘤仍然是一个医学难题,因此需要对神经母细胞瘤进行新型治疗。植物大麻素及其半合成衍生物已显示出支持其抗癌潜力的证据。本研究的目的是研究植物大麻素或半合成大麻素,它们能降低 SHSY-5Y 神经母细胞瘤细胞系的活力。方法:首先以大麻为原料生产正己烷和乙酰乙酸提取物,然后分离出 9-四氢大麻酚、其酸性对应物和 CBN。此外,还合成了四氢大麻酚和 CBN 的乙酰化衍生物。化学物质的鉴定和纯度是通过高效液相色谱法和 1H y 13C 磁核共振法测定的。然后,使用雷沙祖林法检测了其影响 SHSY-5Y (一种神经母细胞瘤细胞系)活力的能力。最后,为了深入了解萃取物、植物大麻素和乙酰化衍生物对受检细胞的作用机制,对暴露于这些化合物的细胞进行了caspase 3/7测定:结果:分离出的化合物的结构和纯度得到了证实。提取物、植物大麻素及其乙酰化对应物抑制了 SHSY 5Y 细胞的活力,其中 CBN 的抑制浓度为 9.5 µM,是所有测试分子中最强的:结论:所评估的每种分子都具有激活 Caspases 3/7 的能力,这表明所测试的植物大麻素及其半合成衍生物的细胞毒性至少有一部分是由细胞凋亡介导的。
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