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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
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 BIOLOGY 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。
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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 BIOLOGY 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 BIOLOGY 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 BIOLOGY 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。
{"title":"The hepatoprotective effect of 4-phenyltetrahydroquinolines on carbon tetrachloride induced hepatotoxicity in rats through autophagy inhibition.","authors":"Mohamed Hussein Abdelgalil, Reem H Elhammamy, Hanan M Ragab, Eman Sheta, Ahmed Wahid","doi":"10.1186/s40659-024-00510-4","DOIUrl":"10.1186/s40659-024-00510-4","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods and results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":"57 1","pages":"32"},"PeriodicalIF":6.7,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11129499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154037","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
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 BIOLOGY 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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引用次数: 0
Connexin channels and hemichannels are modulated differently by charge reversal at residues forming the intracellular pocket. 形成细胞内袋的残基上的电荷反转对连接蛋白通道和半通道的调节作用不同。
IF 6.7 2区 生物学 Q1 BIOLOGY Pub Date : 2024-05-23 DOI: 10.1186/s40659-024-00501-5
Felipe Villanelo, Peter J Minogue, Jaime Maripillán, Mauricio Reyna-Jeldes, Joaquin Jensen-Flores, Isaac E García, Eric C Beyer, Tomás Pérez-Acle, Viviana M Berthoud, Agustín D Martínez

Background: Members of the β-subfamily of connexins contain an intracellular pocket surrounded by amino acid residues from the four transmembrane helices. The presence of this pocket has not previously been investigated in members of the α-, γ-, δ-, and ε-subfamilies. We studied connexin50 (Cx50) as a representative of the α-subfamily, because its structure has been determined and mutations of Cx50 are among the most common genetic causes of congenital cataracts.

Methods: To investigate the presence and function of the intracellular pocket in Cx50 we used molecular dynamics simulation, site-directed mutagenesis, gap junction tracer intercellular transfer, and hemichannel activity detected by electrophysiology and by permeation of charged molecules.

Results: Employing molecular dynamics, we determined the presence of the intracellular pocket in Cx50 hemichannels and identified the amino acids participating in its formation. We utilized site-directed mutagenesis to alter a salt-bridge interaction that supports the intracellular pocket and occurs between two residues highly conserved in the connexin family, R33 and E162. Substitution of opposite charges at either position decreased formation of gap junctional plaques and cell-cell communication and modestly reduced hemichannel currents. Simultaneous charge reversal at these positions produced plaque-forming non-functional gap junction channels with highly active hemichannels.

Conclusions: These results show that interactions within the intracellular pocket influence both gap junction channel and hemichannel functions. Disruption of these interactions may be responsible for diseases associated with mutations at these positions.

背景:连接蛋白β亚家族成员含有一个由四个跨膜螺旋的氨基酸残基包围的胞内袋。此前还没有人研究过 α-、γ-、δ- 和 ε 亚家族成员是否存在这个口袋。我们研究了作为α-亚家族代表的连接蛋白50(Cx50),因为它的结构已经确定,而且Cx50的突变是先天性白内障最常见的遗传原因之一:为了研究 Cx50 细胞内口袋的存在和功能,我们使用了分子动力学模拟、定点突变、缝隙连接示踪剂细胞间转移以及通过电生理学和带电分子渗透检测的半通道活性:利用分子动力学,我们确定了 Cx50 半通道细胞内口袋的存在,并确定了参与其形成的氨基酸。我们利用定点突变改变了支持胞内袋的盐桥相互作用,这种作用发生在附件蛋白家族中高度保守的两个残基 R33 和 E162 之间。在这两个位置替换相反的电荷会减少缝隙连接斑块的形成和细胞间的通讯,并适度降低半通道电流。在这些位置上同时进行电荷反转会产生形成斑块的无功能缝隙连接通道和高活性半通道:这些结果表明,细胞内袋的相互作用会影响缝隙连接通道和半通道的功能。这些相互作用的破坏可能是导致与这些位置的突变相关的疾病的原因。
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引用次数: 0
IDH1 mutation produces R-2-hydroxyglutarate (R-2HG) and induces mir-182-5p expression to regulate cell cycle and tumor formation in glioma. IDH1 突变会产生 R-2-hydroxyglutarate (R-2HG),并诱导 mir-182-5p 的表达,从而调节胶质瘤的细胞周期和肿瘤形成。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-05-17 DOI: 10.1186/s40659-024-00512-2
Haiting Zhao, Li Meng, Peng Du, Xinbin Liao, Xin Mo, Mengqi Gong, Jiaxin Chen, Yiwei Liao

Background: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), are present in most gliomas. IDH1 mutation is an important prognostic marker in glioma. However, its regulatory mechanism in glioma remains incompletely understood.

Results: miR-182-5p expression was increased within IDH1-mutant glioma specimens according to TCGA, CGGA, and online dataset GSE119740, as well as collected clinical samples. (R)-2-hydroxyglutarate ((R)-2HG) treatment up-regulated the expression of miR-182-5p, enhanced glioma cell proliferation, and suppressed apoptosis; miR-182-5p inhibition partially eliminated the oncogenic effects of R-2HG upon glioma cells. By direct binding to Cyclin Dependent Kinase Inhibitor 2 C (CDKN2C) 3'UTR, miR-182-5p inhibited CDKN2C expression. Regarding cellular functions, CDKN2C knockdown promoted R-2HG-treated glioma cell viability, suppressed apoptosis, and relieved cell cycle arrest. Furthermore, CDKN2C knockdown partially attenuated the effects of miR-182-5p inhibition on cell phenotypes. Moreover, CDKN2C knockdown exerted opposite effects on cell cycle check point and apoptosis markers to those of miR-182-5p inhibition; also, CDKN2C knockdown partially attenuated the functions of miR-182-5p inhibition in cell cycle check point and apoptosis markers. The engineered CS-NPs (antagomir-182-5p) effectively encapsulated and delivered antagomir-182-5p, enhancing anti-tumor efficacy in vivo, indicating the therapeutic potential of CS-NPs(antagomir-182-5p) in targeting the miR-182-5p/CDKN2C axis against R-2HG-driven oncogenesis in mice models.

Conclusions: These insights highlight the potential of CS-NPs(antagomir-182-5p) to target the miR-182-5p/CDKN2C axis, offering a promising therapeutic avenue against R-2HG's oncogenic influence to glioma.

背景:大多数胶质瘤都存在异柠檬酸脱氢酶 1 和 2(IDH1 和 IDH2)突变。IDH1 突变是胶质瘤预后的重要标志。结果发现:根据 TCGA、CGGA 和在线数据集 GSE119740,以及收集的临床样本,IDH1 突变的胶质瘤标本中 miR-182-5p 表达增加。(R)-2-羟基戊二酸((R)-2HG)处理上调了 miR-182-5p 的表达,增强了胶质瘤细胞的增殖,抑制了细胞凋亡;抑制 miR-182-5p 可部分消除 R-2HG 对胶质瘤细胞的致癌作用。通过与细胞周期蛋白依赖性激酶抑制剂 2 C(CDKN2C)3'UTR 直接结合,miR-182-5p 抑制了 CDKN2C 的表达。在细胞功能方面,CDKN2C的敲除促进了R-2HG处理的胶质瘤细胞的活力,抑制了细胞凋亡,并缓解了细胞周期的停滞。此外,CDKN2C的敲除部分减弱了miR-182-5p抑制对细胞表型的影响。此外,CDKN2C敲除对细胞周期检查点和细胞凋亡标志物的影响与miR-182-5p抑制相反;CDKN2C敲除还部分削弱了miR-182-5p抑制对细胞周期检查点和细胞凋亡标志物的影响。工程化的CS-NPs(antagomir-182-5p)能有效封装和递送antagomir-182-5p,提高体内抗肿瘤疗效,表明CS-NPs(antagomir-182-5p)在靶向miR-182-5p/CDKN2C轴对抗R-2HG驱动的小鼠肿瘤发生方面具有治疗潜力:这些发现凸显了CS-NPs(antagomir-182-5p)靶向miR-182-5p/CDKN2C轴的潜力,为对抗R-2HG对胶质瘤的致癌影响提供了一条前景广阔的治疗途径。
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引用次数: 0
Therapeutic potential of oleic acid supplementation in myotonic dystrophy muscle cell models. 在肌营养不良症肌肉细胞模型中补充油酸的治疗潜力。
IF 6.7 2区 生物学 Q1 BIOLOGY Pub Date : 2024-05-17 DOI: 10.1186/s40659-024-00496-z
Nerea Moreno, Maria Sabater-Arcis, Teresa Sevilla, Manuel Perez Alonso, Jessica Ohana, Ariadna Bargiela, Ruben Artero

Background: We recently reported that upregulation of Musashi 2 (MSI2) protein in the rare neuromuscular disease myotonic dystrophy type 1 contributes to the hyperactivation of the muscle catabolic processes autophagy and UPS through a reduction in miR-7 levels. Because oleic acid (OA) is a known allosteric regulator of MSI2 activity in the biogenesis of miR-7, here we sought to evaluate endogenous levels of this fatty acid and its therapeutic potential in rescuing cell differentiation phenotypes in vitro. In this work, four muscle cell lines derived from DM1 patients were treated with OA for 24 h, and autophagy and muscle differentiation parameters were analyzed.

Results: We demonstrate a reduction of OA levels in different cell models of the disease. OA supplementation rescued disease-related phenotypes such as fusion index, myotube diameter, and repressed autophagy. This involved inhibiting MSI2 regulation of direct molecular target miR-7 since OA isoschizomer, elaidic acid (EA) could not cause the same rescues. Reduction of OA levels seems to stem from impaired biogenesis since levels of the enzyme stearoyl-CoA desaturase 1 (SCD1), responsible for converting stearic acid to oleic acid, are decreased in DM1 and correlate with OA amounts.

Conclusions: For the first time in DM1, we describe a fatty acid metabolism impairment that originated, at least in part, from a decrease in SCD1. Because OA allosterically inhibits MSI2 binding to molecular targets, reduced OA levels synergize with the overexpression of MSI2 and contribute to the MSI2 > miR-7 > autophagy axis that we proposed to explain the muscle atrophy phenotype.

背景:我们最近报告说,在罕见的神经肌肉疾病肌营养不良症1型中,Musashi 2(MSI2)蛋白的上调通过降低miR-7的水平导致肌肉分解代谢过程自噬和UPS的过度激活。由于油酸(OA)是miR-7生物生成过程中MSI2活性的已知异构调节剂,我们在此试图评估这种脂肪酸的内源性水平及其在体外挽救细胞分化表型方面的治疗潜力。在这项工作中,我们用OA处理了来自DM1患者的四种肌肉细胞系24小时,并分析了自噬和肌肉分化参数:结果:我们发现在不同的疾病细胞模型中,OA的水平都有所下降。结果:我们发现,在不同的疾病细胞模型中,OA水平都有所下降,补充OA后,疾病相关表型(如融合指数、肌管直径)得到改善,自噬功能受到抑制。这涉及抑制MSI2对直接分子靶标miR-7的调控,因为OA异构体麦饭石酸(EA)不能产生同样的挽救效果。OA水平的降低似乎源于生物生成受损,因为在DM1中,负责将硬脂酸转化为油酸的硬脂酰-CoA脱饱和酶1(SCD1)的水平降低,并与OA数量相关:我们首次在 DM1 中描述了脂肪酸代谢障碍,这种障碍至少部分源于 SCD1 的减少。由于OA会异位抑制MSI2与分子靶标的结合,因此OA水平的降低会与MSI2的过度表达产生协同作用,并促成MSI2 > miR-7 > 自噬轴,我们提出了这一轴来解释肌肉萎缩表型。
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