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Selective disruption of synaptic NMDA receptors of the hippocampal trisynaptic circuit in Aβ pathology. 在 Aβ 病理学中选择性破坏海马三突触回路的突触 NMDA 受体
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-08-22 DOI: 10.1186/s40659-024-00537-7
Rocio Alfaro-Ruiz, Alejandro Martín-Belmonte, Carolina Aguado, Ana Esther Moreno-Martínez, Yugo Fukazawa, Rafael Luján

Synaptic dysfunction is an early feature in Alzheimer's disease (AD) pathogenesis and a major morphological correlate of memory deficits. Given the main synaptic location of N-methyl-D-aspartate receptors (NMDARs), their dysregulation has been implicated in these pathological effects. Here, to detect possible alterations in the expression and synaptic localisation of the GluN1 subunit in the brain of amyloidogenic APP/PS1 mice, we employed histoblot and SDS-digested freeze-fracture replica labelling (SDS-FRL) techniques. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus in a layer-dependent manner, in the cortex and the caudate putamen of APP/PS1 transgenic mice at 12 months of age but was unaltered at 1 and 6 months. Using quantitative SDS-FRL, we unravelled the molecular organisation of GluN1 in seven excitatory synapse populations at a high spatial resolution in the CA1 and CA3 fields and the DG of the hippocampus in 12-month-old APP/PS1 mice. In the CA1 field, the labelling density for GluN1 in the excitatory synapses established on spines and interneurons, was significantly reduced in APP/PS1 mice compared to age-matched wild-type mice in the stratum lacunosum-moleculare but unaltered in the stratum radiatum. In the CA3 field, synaptic GluN1 was reduced in mossy fibre-CA3 pyramidal cell synapses but unaltered in the A/C-CA3 pyramidal cell synapses. In the DG, the density of GluN1 in granule cell-perforant pathway synapses was reduced in APP/PS1 mice. Altogether, our findings provide evidence of specific alterations of synaptic GluN1 in the trisynaptic circuit of the hippocampus in Aβ pathology. This differential vulnerability in the disruption of NMDARs may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit and cognitive impairment characteristic of APP/PS1 mice.

突触功能障碍是阿尔茨海默病(AD)发病机制的早期特征,也是记忆缺陷的主要形态学相关因素。鉴于 N-甲基-D-天冬氨酸受体(NMDARs)主要位于突触部位,它们的失调被认为与这些病理效应有关。在此,为了检测淀粉样蛋白致病 APP/PS1 小鼠大脑中 GluN1 亚基的表达和突触定位的可能变化,我们采用了组织印迹和 SDS 消化冷冻-断裂复制标记(SDS-FRL)技术。组织印迹显示,APP/PS1 转基因小鼠在 12 个月大时,GluN1 在海马、皮层和尾状核的表达明显减少,但在 1 个月和 6 个月大时没有变化。利用定量 SDS-FRL,我们在 12 个月大的 APP/PS1 小鼠的 CA1 和 CA3 区域以及海马 DG 中以高空间分辨率揭示了七个兴奋性突触群中 GluN1 的分子组织。在CA1区域,与年龄匹配的野生型小鼠相比,APP/PS1小鼠建立在棘突和中间神经元上的兴奋性突触的GluN1标记密度在裂隙-痣层显著降低,但在放射层没有变化。在CA3区域,苔藓纤维-CA3锥体细胞突触的GluN1减少,但A/C-CA3锥体细胞突触的GluN1没有变化。在DG中,APP/PS1小鼠颗粒细胞-穿孔通路突触的GluN1密度降低。总之,我们的研究结果提供了证据,证明在Aβ病理学中,海马三突触回路中的突触GluN1发生了特异性改变。这种对 NMDARs 破坏的不同脆弱性可能与导致海马回路异常网络活动和 APP/PS1 小鼠特有的认知障碍的机制有关。
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引用次数: 0
Placental growth factor mediates pathological uterine angiogenesis by activating the NFAT5-SGK1 signaling axis in the endometrium: implications for preeclampsia development. 胎盘生长因子通过激活子宫内膜中的 NFAT5-SGK1 信号轴介导病理性子宫血管生成:对子痫前期发展的影响。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-08-17 DOI: 10.1186/s40659-024-00526-w
Janet P Raja Xavier, Toshiyuki Okumura, Melina Apweiler, Nirzari A Chacko, Yogesh Singh, Sara Y Brucker, Satoru Takeda, Florian Lang, Madhuri S Salker

After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.

月经后,子宫螺旋动脉通过血管生成得到修复。这一过程由子宫内膜基质细胞(EnSCs)和内皮细胞之间的旁分泌通讯严格调控。这些过程中的任何分子畸变都可能导致妊娠并发症,包括流产或子痫前期(PE)。已知胎盘生长因子(PlGF)是导致病理性血管生成的一个因素,但对其机制仍知之甚少。在这项研究中,我们探讨了 PlGF 是否会通过破坏 EnSCs 和内皮旁分泌通讯来促进病理性子宫血管生成。我们观察到,PlGF 在 EnSCs 中介导了独立于补体的活化 T 细胞核因子 5(NFAT5)的激活。NFAT5激活了下游靶标,包括SGK1、HIF-1α和VEGF-A。使用质谱法和酶联免疫吸附法对来自 EnSCs 的 PlGF - 条件培养基(CM)进行深入鉴定后发现,VEGF-A 含量较低,而细胞外基质组织相关蛋白含量丰富。PlGF-CM 中的分泌因子通过下调 Notch-VEGF 信号,阻碍了内皮细胞(HUVECs)的正常血管生成线索。有趣的是,PlGF-CM 未能支持人胎盘(BeWo)细胞侵入 HUVEC 单层。抑制 EnSCs 中的 SGK1 可改善 HUVECs 的血管生成效应并促进 BeWo 的侵袭,这揭示了 SGK1 是调节 PlGF 介导的抗血管生成信号的关键中间体。综上所述,子宫内膜中紊乱的 PlGF-NFAT5-SGK1 信号传导可通过负向调节 EnSCs-内皮串联导致子宫微环境中血管质量低下,从而促进病理性子宫血管生成。综上所述,这种信号转导可能会影响滋养细胞的正常侵入,从而影响胎盘的形成,并可能与 PE 等并发症的风险增加有关。
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引用次数: 0
Dissecting reactive astrocyte responses: lineage tracing and morphology-based clustering. 剖析反应性星形胶质细胞的反应:系谱追踪和基于形态学的聚类。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-08-14 DOI: 10.1186/s40659-024-00532-y
Lina M Delgado-García, Ana C Ojalvo-Sanz, Thabatta K E Nakamura, Eduardo Martín-López, Marimelia Porcionatto, Laura Lopez-Mascaraque

Brain damage triggers diverse cellular and molecular events, with astrocytes playing a crucial role in activating local neuroprotective and reparative signaling within damaged neuronal circuits. Here, we investigated reactive astrocytes using a multidimensional approach to categorize their responses into different subtypes based on morphology. This approach utilized the StarTrack lineage tracer, single-cell imaging reconstruction and multivariate data analysis. Our findings identified three profiles of reactive astrocyte responses, categorized by their effects on cell size- and shape- related morphological parameters: "moderate", "strong," and "very strong". We also examined the heterogeneity of astrocyte reactivity, focusing on spatial and clonal distribution. Our research revealed a notable enrichment of protoplasmic and fibrous astrocytes within the "strong" and "very strong" response subtypes. Overall, our study contributes to a better understanding of astrocyte heterogeneity in response to an injury. By characterizing the diverse reactive responses among astrocyte subpopulations, we provide insights that could guide future research aimed at identifying novel therapeutic targets to mitigate brain damage and promote neural repair.

脑损伤会引发多种细胞和分子事件,其中星形胶质细胞在激活受损神经元回路中的局部神经保护和修复信号方面起着至关重要的作用。在这里,我们采用一种多维方法对反应性星形胶质细胞进行了研究,根据形态学将它们的反应分为不同的亚型。这种方法利用了 StarTrack 行系示踪、单细胞成像重建和多变量数据分析。我们的研究结果确定了反应性星形胶质细胞反应的三种类型,根据它们对细胞大小和形状相关形态参数的影响进行分类:"中等"、"强 "和 "非常强"。我们还研究了星形胶质细胞反应的异质性,重点是空间和克隆分布。我们的研究发现,在 "强 "和 "极强 "反应亚型中,原生质和纤维状星形胶质细胞明显增多。总之,我们的研究有助于更好地理解星形胶质细胞对损伤的异质性反应。通过描述星形胶质细胞亚群之间的不同反应性反应,我们提出了一些见解,这些见解可以指导未来的研究,从而确定新的治疗靶点,减轻脑损伤并促进神经修复。
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引用次数: 0
Neuronal repair after spinal cord injury by in vivo astrocyte reprogramming mediated by the overexpression of NeuroD1 and Neurogenin-2 通过过表达 NeuroD1 和 Neurogenin-2 介导的体内星形胶质细胞重编程修复脊髓损伤后的神经元
IF 6.7 2区 生物学 Q1 BIOLOGY Pub Date : 2024-08-12 DOI: 10.1186/s40659-024-00534-w
Zuliyaer Talifu, Chunjia Zhang, Xin Xu, Yunzhu Pan, Han Ke, Zehui Li, Wubo Liu, Huayong Du, Xiaoxin Wang, Feng Gao, Degang Yang, Yingli Jing, Yan Yu, Liangjie Du, Jianjun Li
As a common disabling disease, irreversible neuronal death due to spinal cord injury (SCI) is the root cause of functional impairment; however, the capacity for neuronal regeneration in the developing spinal cord tissue is limited. Therefore, there is an urgent need to investigate how defective neurons can be replenished and functionally integrated by neural regeneration; the reprogramming of intrinsic cells into functional neurons may represent an ideal solution. A mouse model of transection SCI was prepared by forceps clamping, and an adeno-associated virus (AAV) carrying the transcription factors NeuroD1 and Neurogenin-2(Ngn2) was injected in situ into the spinal cord to specifically overexpress these transcription factors in astrocytes close to the injury site. 5-bromo-2´-deoxyuridine (BrdU) was subsequently injected intraperitoneally to continuously track cell regeneration, neuroblasts and immature neurons marker expression, neuronal regeneration, and glial scar regeneration. In addition, immunoprotein blotting was used to measure the levels of transforming growth factor-β (TGF-β) pathway-related protein expression. We also evaluated motor function, sensory function, and the integrity of the blood-spinal cord barrier(BSCB). The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord was achieved by specific AAV vectors. This intervention led to a significant increase in cell regeneration and the proportion of cells with neuroblasts and immature neurons cell properties at the injury site(p < 0.0001). Immunofluorescence staining identified astrocytes with neuroblasts and immature neurons cell properties at the site of injury while neuronal marker-specific staining revealed an increased number of mature astrocytes at the injury site. Behavioral assessments showed that the intervention did not improve The BMS (Basso mouse scale) score (p = 0.0726) and gait (p > 0.05), although the treated mice had more sensory sensitivity and greater voluntary motor ability in open field than the non-intervention mice. We observed significant repair of the BSCB at the center of the injury site (p < 0.0001) and a significant improvement in glial scar proliferation. Electrophysiological assessments revealed a significant improvement in spinal nerve conduction (p < 0.0001) while immunostaining revealed that the levels of TGF-β protein at the site of injury in the intervention group were lower than control group (p = 0.0034); in addition, P70 s6 and PP2A related to the TGF-β pathway showed ascending trend (p = 0.0036, p = 0.0152 respectively). The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord after spinal cord injury can reprogram astrocytes into neurons and significantly enhance cell regeneration at the injury site. The reprogramming of astrocytes can lead to tissue repair, thus improving the reduced threshold and increasing voluntary movements. This strategy can also improve the integrity of the blood-spinal cord barrier and enhance nerve con
作为一种常见的致残性疾病,脊髓损伤(SCI)导致的不可逆神经元死亡是功能障碍的根本原因;然而,发育中的脊髓组织的神经元再生能力有限。因此,迫切需要研究如何通过神经再生来补充有缺陷的神经元并实现功能整合;将固有细胞重编程为功能神经元可能是一个理想的解决方案。通过钳夹法制备了小鼠横断性脊髓损伤(SCI)模型,并将携带转录因子NeuroD1和Neurogenin-2(Ngn2)的腺相关病毒(AAV)原位注射到脊髓中,以特异性地在损伤部位附近的星形胶质细胞中过表达这些转录因子。随后腹腔注射 5-溴-2´-脱氧尿苷(BrdU)以持续跟踪细胞再生、神经母细胞和未成熟神经元标记表达、神经元再生和胶质疤痕再生。此外,我们还使用免疫蛋白印迹法测量了转化生长因子-β(TGF-β)通路相关蛋白的表达水平。我们还评估了运动功能、感觉功能和血脊髓屏障(BSCB)的完整性。脊髓中NeuroD1和Ngn2的原位过表达是通过特异性AAV载体实现的。与未干预小鼠相比,干预小鼠的感觉灵敏度更高,野外自主运动能力更强。我们观察到损伤部位中心的 BSCB 有明显修复(p < 0.0001),胶质疤痕增生也有明显改善。免疫染色显示,干预组损伤部位的 TGF-β 蛋白水平低于对照组(p = 0.0034);此外,与 TGF-β 通路相关的 P70 s6 和 PP2A 呈上升趋势(分别为 p = 0.0036 和 p = 0.0152)。在脊髓损伤后的脊髓中原位过表达 NeuroD1 和 Ngn2 可将星形胶质细胞重编程为神经元,并显著促进损伤部位的细胞再生。星形胶质细胞的重编程可导致组织修复,从而改善降低的阈值并增加自主运动。这一策略还能改善血脊髓屏障的完整性,增强神经传导功能。然而,单纯的星形胶质细胞重编程并不能显著改善下肢的跨步功能。
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引用次数: 0
PvMYB60 gene, a candidate for drought tolerance improvement in common bean in a climate change context. PvMYB60 基因是在气候变化背景下提高普通豆类耐旱性的候选基因。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-08-10 DOI: 10.1186/s40659-024-00528-8
Vera Martínez-Barradas, Massimo Galbiati, Francisco Barco-Rubio, Dario Paolo, Carmen Espinoza, Eleonora Cominelli, Patricio Arce-Johnson

Background: Common bean (Phaseolus vulgaris) is one of the main nutritional resources in the world, and a low environmental impact source of protein. However, the majority of its cultivation areas are affected by drought and this scenario is only expected to worsen with climate change. Stomatal closure is one of the most important plant responses to drought and the MYB60 transcription factor is among the key elements regulating stomatal aperture. If targeting and mutating the MYB60 gene of common bean would be a valuable strategy to establish more drought-tolerant beans was therefore investigated.

Results: The MYB60 gene of common bean, with orthology to the Arabidopsis AtMYB60 gene, was found to have conserved regions with MYB60 typical motifs and architecture. Stomata-specific expression of PvMYB60 was further confirmed by q-RT PCR on organs containing stomata, and stomata-enriched leaf fractions. Further, function of PvMYB60 in promoting stomata aperture was confirmed by complementing the defective phenotype of a previously described Arabidopsis myb60-1 mutant.

Conclusions: Our study finally points PvMYB60 as a potential target for obtaining more drought-tolerant common beans in the present context of climate change which would further greatly contribute to food security particularly in drought-prone countries.

背景:蚕豆(Phaseolus vulgaris)是世界上主要的营养资源之一,也是对环境影响较小的蛋白质来源。然而,其大部分种植区都受到干旱的影响,而且这种情况预计只会随着气候变化而恶化。气孔关闭是植物对干旱最重要的反应之一,而 MYB60 转录因子是调节气孔开度的关键因素之一。因此,我们研究了靶向突变蚕豆的 MYB60 基因是否是建立更耐旱蚕豆的一种有价值的策略:结果:研究发现,蚕豆的 MYB60 基因与拟南芥的 AtMYB60 基因具有同源关系,其保守区域具有 MYB60 基因的典型基序和结构。通过对含有气孔的器官和气孔丰富的叶片部分进行 q-RT PCR,进一步证实了 PvMYB60 的气孔特异性表达。此外,通过补充先前描述的拟南芥 myb60-1 突变体的缺陷表型,证实了 PvMYB60 在促进气孔开度方面的功能:我们的研究最终指出,在当前气候变化的背景下,PvMYB60 是获得更耐旱普通豆类的潜在靶标,这将进一步极大地促进粮食安全,尤其是易受干旱影响国家的粮食安全。
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引用次数: 0
Enhancing adipose tissue functionality in obesity: senotherapeutics, autophagy and cellular senescence as a target. 增强肥胖症中脂肪组织的功能:以衰老治疗、自噬和细胞衰老为目标。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-08-08 DOI: 10.1186/s40659-024-00531-z
Consuelo Arias, Javiera Álvarez-Indo, Mariana Cifuentes, Eugenia Morselli, Bredford Kerr, Patricia V Burgos

Obesity, a global health crisis, disrupts multiple systemic processes, contributing to a cascade of metabolic dysfunctions by promoting the pathological expansion of visceral adipose tissue (VAT). This expansion is characterized by impaired differentiation of pre-adipocytes and an increase in senescent cells, leading to a pro-inflammatory state and exacerbated oxidative stress. Particularly, the senescence-associated secretory phenotype (SASP) and adipose tissue hypoxia further impair cellular function, promoting chronic disease development. This review delves into the potential of autophagy modulation and the therapeutic application of senolytics and senomorphics as novel strategies to mitigate adipose tissue senescence. By exploring the intricate mechanisms underlying adipocyte dysfunction and the emerging role of natural compounds in senescence modulation, we underscore the promising horizon of senotherapeutics in restoring adipose health. This approach not only offers a pathway to combat the metabolic complications of obesity, but also opens new avenues for enhancing life quality and managing the global burden of obesity-related conditions. Our analysis aims to bridge the gap between current scientific progress and clinical application, offering new perspectives on preventing and treating obesity-induced adipose dysfunction.

肥胖症是一场全球性健康危机,它扰乱了多个系统过程,通过促进内脏脂肪组织(VAT)的病理扩张,导致一连串的代谢功能障碍。这种扩张的特点是前脂肪细胞分化受损,衰老细胞增加,导致炎症状态和氧化应激加剧。尤其是衰老相关分泌表型(SASP)和脂肪组织缺氧会进一步损害细胞功能,促进慢性疾病的发展。这篇综述深入探讨了自噬调节的潜力,以及作为缓解脂肪组织衰老新策略的衰老素和衰老形态素的治疗应用。通过探索脂肪细胞功能障碍的复杂机制以及天然化合物在衰老调节中的新兴作用,我们强调了衰老治疗剂在恢复脂肪健康方面前景广阔。这种方法不仅提供了一种对抗肥胖代谢并发症的途径,还为提高生活质量和管理肥胖相关疾病的全球负担开辟了新的途径。我们的分析旨在弥合当前科学进展与临床应用之间的差距,为预防和治疗肥胖引起的脂肪功能障碍提供新的视角。
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引用次数: 0
Effects of a supplemented diet containing 7 probiotic strains (Honeybeeotic) on honeybee physiology and immune response: analysis of hemolymph cytology, phenoloxidase activity, and gut microbiome. 含有 7 种益生菌株的补充食物(Honeybeeotic)对蜜蜂生理和免疫反应的影响:血淋巴细胞学、酚氧化酶活性和肠道微生物组分析。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-08-07 DOI: 10.1186/s40659-024-00533-x
Patrizia Robino, Livio Galosi, Alessandro Bellato, Silvia Vincenzetti, Elena Gonella, Ilario Ferrocino, Evelina Serri, Lucia Biagini, Alessandra Roncarati, Patrizia Nebbia, Chiara Menzio, Giacomo Rossi

Background: In this study, a probiotic mixture (Honeybeeotic) consisting of seven bacterial strains isolated from a unique population of honeybees (Apis mellifera ligustica) was used. That honeybee population was located in the Roti Abbey locality of the Marche Region in Italy, an area isolated from human activities, and genetic contamination from other honeybee populations. The aim was to investigate the effects of this probiotic mixture on the innate immunity and intestinal microbiome of healthy common honeybees in two hives of the same apiary. Hive A received a diet of 50% glucose syrup, while hive B received the same syrup supplemented with the probiotics, both administered daily for 1 month. To determine whether the probiotic altered the immune response, phenoloxidase activity and hemolymph cellular subtype count were investigated. Additionally, metagenomic approaches were used to analyze the effects on gut microbiota composition and function, considering the critical role the gut microbiota plays in modulating host physiology.

Results: The results revealed differences in hemocyte populations between the two hives, as hive A exhibited higher counts of oenocytoids and granulocytes. These findings indicated that the dietary supplementation with the probiotic mixture was safe and well-tolerated. Furthermore, phenoloxidase activity significantly decreased in hive B (1.75 ± 0.19 U/mg) compared to hive A (3.62 ± 0.44 U/mg, p < 0.005), suggesting an improved state of well-being in the honeybees, as they did not require activation of immune defense mechanisms. Regarding the microbiome composition, the probiotic modulated the gut microbiota in hive B compared to the control, retaining core microbiota components while causing both positive and negative variations. Notably, several genes, particularly KEGG genes involved in amino acid metabolism, carbohydrate metabolism, and branched-chain amino acid (BCAA) transport, were more abundant in the probiotic-fed group, suggesting an effective nutritional supplement for the host.

Conclusions: This study advocated that feeding with this probiotic mixture induces beneficial immunological effects and promoted a balanced gut microbiota with enhanced metabolic activities related to digestion. The use of highly selected probiotics was shown to contribute to the overall well-being of the honeybees, improving their immune response and gut health.

研究背景在这项研究中,使用了一种益生菌混合物(蜜蜂益生菌),该混合物由从蜜蜂(Apis mellifera ligustica)独特种群中分离出来的七种细菌菌株组成。该蜜蜂种群位于意大利马尔凯大区的罗蒂阿贝地区,该地区与人类活动和其他蜜蜂种群的遗传污染隔绝。目的是研究这种益生菌混合物对同一养蜂场两个蜂巢中健康普通蜜蜂的先天免疫和肠道微生物组的影响。蜂巢 A 的食物是 50%的葡萄糖浆,而蜂巢 B 的食物也是同样的葡萄糖浆,并添加了益生菌,每天给药,持续 1 个月。为了确定益生菌是否改变了免疫反应,对酚氧化酶活性和血淋巴细胞亚型计数进行了调查。此外,考虑到肠道微生物群在调节宿主生理方面的关键作用,还采用了元基因组学方法来分析对肠道微生物群组成和功能的影响:结果表明,两个蜂巢的血细胞数量存在差异,A 蜂巢的卵母细胞和粒细胞数量更高。这些结果表明,膳食中补充益生菌混合物是安全的,而且耐受性良好。此外,与蜂巢 A(3.62 ± 0.44 U/mg, p)相比,蜂巢 B 的酚氧化酶活性(1.75 ± 0.19 U/mg )明显降低:这项研究表明,饲喂这种益生菌混合物可诱导有益的免疫效应,促进肠道微生物群的平衡,增强与消化有关的代谢活动。研究表明,使用精选的益生菌有助于蜜蜂的整体健康,改善其免疫反应和肠道健康。
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引用次数: 0
Uncovering the role of the subcommissural organ in early brain development through transcriptomic analysis 通过转录组分析揭示亚组织器官在早期大脑发育中的作用
IF 6.7 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-27 DOI: 10.1186/s40659-024-00524-y
Maryori González, Felipe Maurelia, Jaime Aguayo, Roberto Amigo, Rodrigo Arrué, José Leonardo Gutiérrez, Marcela Torrejón, Carlos Farkas, Teresa Caprile
The significant role of embryonic cerebrospinal fluid (eCSF) in the initial stages of brain development has been thoroughly studied. This fluid contains crucial molecules for proper brain development such as members of the Wnt and FGF families, apolipoproteins, and retinol binding protein. Nevertheless, the source of these molecules remains uncertain since they are present before the formation of the choroid plexus, which is conventionally known as the primary producer of cerebrospinal fluid. The subcommissural organ (SCO) is a highly conserved gland located in the diencephalon and is one of the earliest differentiating brain structures. The SCO secretes molecules into the eCSF, prior to the differentiation of the choroid plexus, playing a pivotal role in the homeostasis and dynamics of this fluid. One of the key molecules secreted by the SCO is SCO-spondin, a protein involved in maintenance of the normal ventricle size, straight spinal axis, neurogenesis, and axonal guidance. Furthermore, SCO secretes transthyretin and basic fibroblast growth factor 2, while other identified molecules in the eCSF could potentially be secreted by the SCO. Additionally, various transcription factors have been identified in the SCO. However, the precise mechanisms involved in the early SCO development are not fully understood. To uncover key molecular players and signaling pathways involved in the role of the SCO during brain development, we conducted a transcriptomic analysis comparing the embryonic chick SCO at HH23 and HH30 stages (4 and 7 days respectively). Additionally, a public transcriptomic data from HH30 entire chick brain was used to compare expression levels between SCO and whole brain transcriptome. These analyses revealed that, at both stages, the SCO differentially expresses several members of bone morphogenic proteins, Wnt and fibroblast growth factors families, diverse proteins involved in axonal guidance, neurogenic and differentiative molecules, cell receptors and transcription factors. The secretory pathway is particularly upregulated at stage HH30 while the proliferative pathway is increased at stage HH23. The results suggest that the SCO has the capacity to secrete several morphogenic molecules to the eCSF prior to the development of other structures, such as the choroid plexus.
胚胎脑脊液(eCSF)在大脑发育初始阶段的重要作用已得到深入研究。脑脊液中含有大脑正常发育所需的重要分子,如 Wnt 和 FGF 家族成员、脂蛋白和视黄醇结合蛋白。然而,这些分子的来源仍不确定,因为它们在脉络丛形成之前就已存在,而脉络丛通常被认为是脑脊液的主要产生者。硬脑膜下器官(SCO)是位于间脑中的一个高度保守的腺体,是最早分化的大脑结构之一。在脉络丛分化之前,SCO 向脑脊液中分泌分子,对脑脊液的平衡和动态起着关键作用。SCO分泌的关键分子之一是SCO-spondin,这是一种参与维持正常脑室大小、直脊柱轴、神经发生和轴突导向的蛋白质。此外,SCO 还能分泌转甲状腺素和碱性成纤维细胞生长因子 2,而电子脑脊液中已确定的其他分子也可能由 SCO 分泌。此外,在 SCO 中还发现了各种转录因子。然而,SCO 早期发育的确切机制尚未完全明了。为了揭示 SCO 在大脑发育过程中发挥作用的关键分子和信号通路,我们对胚胎小鸡 SCO 在 HH23 和 HH30 阶段(分别为 4 天和 7 天)进行了转录组分析。此外,我们还使用了来自 HH30 整个小鸡大脑的公开转录组数据来比较 SCO 和整个大脑转录组的表达水平。这些分析表明,在这两个阶段,SCO都不同程度地表达了骨形态发生蛋白、Wnt和成纤维细胞生长因子家族的多个成员、参与轴突导向的多种蛋白、神经原和分化分子、细胞受体和转录因子。分泌途径尤其在 HH30 阶段上调,而增殖途径则在 HH23 阶段增加。结果表明,在脉络丛等其他结构发育之前,SCO有能力向eCSF分泌多种形态发生分子。
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引用次数: 0
A preclinical mice model of multiple sclerosis based on the toxin-induced double-site demyelination of callosal and cerebellar fibers. 基于毒素诱导的胼胝体和小脑纤维双部位脱髓鞘的多发性硬化症临床前小鼠模型。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-22 DOI: 10.1186/s40659-024-00529-7
Sebastián Vejar, Ignacio S Pizarro, Raúl Pulgar-Sepúlveda, Sinay C Vicencio, Andrés Polit, Cristian A Amador, Rodrigo Del Rio, Rodrigo Varas, Juan A Orellana, Fernando C Ortiz

Background: Multiple sclerosis (MS) is an irreversible progressive CNS pathology characterized by the loss of myelin (i.e. demyelination). The lack of myelin is followed by a progressive neurodegeneration triggering symptoms as diverse as fatigue, motor, locomotor and sensory impairments and/or bladder, cardiac and respiratory dysfunction. Even though there are more than fourteen approved treatments for reducing MS progression, there are still no cure for the disease. Thus, MS research is a very active field and therefore we count with different experimental animal models for studying mechanisms of demyelination and myelin repair, however, we still lack a preclinical MS model assembling demyelination mechanisms with relevant clinical-like signs.

Results: Here, by inducing the simultaneous demyelination of both callosal and cerebellar white matter fibers by the double-site injection of lysolecithin (LPC), we were able to reproduce CNS demyelination, astrocyte recruitment and increases levels of proinflammatory cytokines levels along with motor, locomotor and urinary impairment, as well as cardiac and respiratory dysfunction, in the same animal model. Single site LPC-injections either in corpus callosum or cerebellum only, fails in to reproduce such a complete range of MS-like signs.

Conclusion: We here report that the double-site LPC injections treatment evoke a complex MS-like mice model. We hope that this experimental approach will help to deepen our knowledge about the mechanisms of demyelinated diseases such as MS.

背景:多发性硬化症(MS)是一种以髓鞘脱失(即脱髓鞘)为特征的不可逆的进行性中枢神经系统病变。髓鞘缺失后,神经逐渐变性,引发疲劳、运动、运动和感觉障碍和/或膀胱、心脏和呼吸功能障碍等多种症状。尽管目前有超过 14 种已获批准的治疗方法可减轻多发性硬化症的进展,但仍无法治愈该疾病。因此,多发性硬化症的研究是一个非常活跃的领域,我们利用不同的实验动物模型来研究脱髓鞘和髓鞘修复的机制,但我们仍然缺乏一个将脱髓鞘机制与相关临床症状相结合的临床前多发性硬化症模型:结果:在这里,通过双部位注射溶血卵磷脂(LPC)诱导胼胝体和小脑白质纤维同时脱髓鞘,我们能够在同一动物模型中再现中枢神经系统脱髓鞘、星形胶质细胞募集和促炎细胞因子水平升高,以及运动、运动和排尿障碍,以及心脏和呼吸功能障碍。而仅在胼胝体或小脑注射单部位 LPC,则无法再现如此全面的 MS 样征:我们在此报告,双部位 LPC 注射治疗可诱发复杂的多发性硬化症样小鼠模型。我们希望这种实验方法有助于加深我们对多发性硬化症等脱髓鞘疾病机制的认识。
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引用次数: 0
Renoprotective effect of a novel combination of 6-gingerol and metformin in high-fat diet/streptozotocin-induced diabetic nephropathy in rats via targeting miRNA-146a, miRNA-223, TLR4/TRAF6/NLRP3 inflammasome pathway and HIF-1α. 通过靶向 miRNA-146a、miRNA-223、TLR4/TRAF6/NLRP3 炎性体通路和 HIF-1α ,6-姜酚和二甲双胍的新型组合对高脂饮食/链脲佐菌素诱导的大鼠糖尿病肾病具有肾保护作用
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-20 DOI: 10.1186/s40659-024-00527-9
Merna G Aboismaiel, Mohamed N Amin, Laila A Eissa

Background: MiRNA-146a and miRNA-223 are key epigenetic regulators of toll-like receptor 4 (TLR4)/tumor necrosis factor-receptor-associated factor 6 (TRAF6)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway, which is involved in diabetic nephropathy (DN) pathogenesis. The currently available oral anti-diabetic treatments have been insufficient to halt DN development and progression. Therefore, this work aimed to assess the renoprotective effect of the natural compound 6-gingerol (GR) either alone or in combination with metformin (MET) in high-fat diet/streptozotocin-induced DN in rats. The proposed molecular mechanisms were also investigated.

Methods: Oral gavage of 6-gingerol (100 mg/kg) and metformin (300 mg/kg) were administered to rats daily for eight weeks. MiRNA-146a, miRNA-223, TLR4, TRAF6, nuclear factor-kappa B (NF-κB) (p65), NLRP3, caspase-1, and hypoxia-inducible factor-1 alpha (HIF-1α) mRNA expressions were measured using real-time PCR. ELISA was used to measure TLR4, TRAF6, NLRP3, caspase-1, tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1β) renal tissue levels. Renal tissue histopathology and immunohistochemical examination of fibronectin and NF-κB (p65) were performed.

Results: 6-Gingerol treatment significantly reduced kidney tissue damage and fibrosis. 6-Gingerol up-regulated miRNA-146a and miRNA-223 and reduced TLR4, TRAF6, NF-κB (p65), NLRP3, caspase-1, TNF-α, IL-1β, HIF-1α and fibronectin renal expressions. 6-Gingerol improved lipid profile and renal functions, attenuated renal hypertrophy, increased reduced glutathione, and decreased blood glucose and malondialdehyde levels. 6-Gingerol and metformin combination showed superior renoprotective effects than either alone.

Conclusion: 6-Gingerol demonstrated a key protective role in DN by induction of miRNA-146a and miRNA-223 expression and inhibition of TLR4/TRAF6/NLRP3 inflammasome signaling. 6-Gingerol, a safe, affordable, and abundant natural compound, holds promise for use as an adjuvant therapy with metformin in diabetic patients to attenuate renal damage and stop the progression of DN.

背景:miRNA-146a和miRNA-223是toll样受体4(TLR4)/肿瘤坏死因子受体相关因子6(TRAF6)/NOD样受体家族含吡啶域3(NLRP3)炎性小体通路的关键表观遗传调节因子,而该通路参与了糖尿病肾病(DN)的发病机制。目前可用的口服抗糖尿病疗法不足以阻止 DN 的发生和发展。因此,本研究旨在评估天然化合物 6-姜酚(GR)单独或与二甲双胍(MET)联用对高脂饮食/链脲佐菌素诱导的大鼠 DN 的肾保护作用。此外,还对拟议的分子机制进行了研究:方法:每天给大鼠灌胃 6-姜酚(100 毫克/千克)和二甲双胍(300 毫克/千克),连续八周。采用实时 PCR 法检测 MiRNA-146a、miRNA-223、TLR4、TRAF6、核因子-kappa B(NF-κB)(p65)、NLRP3、caspase-1 和缺氧诱导因子-1 α(HIF-1α)mRNA 的表达。用酶联免疫吸附法测定 TLR4、TRAF6、NLRP3、caspase-1、肿瘤坏死因子-α(TNF-α)和白细胞介素-1-β(IL-1β)的肾组织水平。对肾组织进行组织病理学检查,并对纤维连接蛋白和 NF-κB (p65) 进行免疫组化检查:结果:6-姜酚治疗能明显减轻肾组织损伤和纤维化。6-姜酚上调了 miRNA-146a 和 miRNA-223,降低了 TLR4、TRAF6、NF-κB (p65)、NLRP3、caspase-1、TNF-α、IL-1β、HIF-1α 和纤维连接蛋白的肾脏表达。6 姜酚改善了血脂状况和肾功能,减轻了肾肥大,增加了还原型谷胱甘肽,降低了血糖和丙二醛水平。结论:6-姜酚通过诱导 miRNA-146a 和 miRNA-223 的表达以及抑制 TLR4/TRAF6/NLRP3 炎性体信号转导,对 DN 起着关键的保护作用。6-姜酚是一种安全、经济、丰富的天然化合物,有望与二甲双胍一起作为糖尿病患者的辅助疗法,以减轻肾损伤并阻止 DN 的进展。
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