Biochimica et biophysica acta. Molecular basis of disease最新文献_第4页

Phosphorylation of BRCA1 at serine 1387 plays a critical role in cathepsin S-mediated radiation resistance via BRCA1 degradation and BCL2 stabilization BRCA1 在丝氨酸 1387 处的磷酸化在 cathepsin S 通过 BRCA1 降解和 BCL2 稳定介导的抗辐射中起着关键作用。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-09-25 DOI: 10.1016/j.bbadis.2024.167523

There is evidence that BRCA1, particularly cytoplasmic BRCA1, plays a significant role in initiating apoptosis through various mechanisms. Maintaining the stability of BRCA1 in cancer cells may be a promising therapeutic strategy for breast cancer, especially in cases of triple-negative breast cancer (TNBC) lacking appropriate therapeutic targets. Previously, it was reported that cathepsin S (CTSS) interacts with the BRCT domain of BRCA1, leading to ubiquitin-mediated degradation. We further investigated the critical role of BRCA1 phosphorylation at Ser1387, which is mediated by ionizing radiation (IR)-induced activation of ATM. This phosphorylation event was identified as a key factor in CTSS-mediated ubiquitin degradation of BRCA1. The functional inhibition of CTSS, using small molecules or a knockdown system, sensitized TNBC cells when exposed to IR by restoring the stability of cytoplasmic BRCA1. The increase in cytoplasmic BRCA1 led to the degradation of anti-apoptotic BCL2, which was responsible for the radiosensitization effect observed with CTSS inhibition. These results suggest that inhibiting CTSS may be an effective strategy for radiosensitization in TNBC cells through BCL2 degradation that is mediated by inhibition of CTSS-induced BRCA1 degradation.

有证据表明，BRCA1，尤其是细胞质 BRCA1，通过各种机制在启动细胞凋亡方面发挥着重要作用。维持 BRCA1 在癌细胞中的稳定性可能是一种很有前景的乳腺癌治疗策略，尤其是在缺乏适当治疗靶点的三阴性乳腺癌（TNBC）病例中。此前有报道称，螯合蛋白酶 S（CTSS）与 BRCA1 的 BRCT 结构域相互作用，导致泛素介导的降解。我们进一步研究了 BRCA1 在 Ser1387 处磷酸化的关键作用，该作用由电离辐射（IR）诱导的 ATM 激活介导。这一磷酸化事件被确定为 CTSS 介导的 BRCA1 泛素降解的关键因素。利用小分子或基因敲除系统对 CTSS 进行功能性抑制，可恢复细胞质 BRCA1 的稳定性，从而使 TNBC 细胞在暴露于 IR 时变得敏感。细胞质 BRCA1 的增加导致了抗凋亡 BCL2 的降解，而这正是 CTSS 抑制所产生的放射增敏效应的原因。这些结果表明，抑制CTSS可能是通过抑制CTSS诱导的BRCA1降解介导的BCL2降解实现TNBC细胞放射增敏的有效策略。

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引用次数: 0

Aberrant TCF21 upregulation in adenomyosis impairs endometrial decidualization by increasing PDE4C expression 子宫腺肌病中 TCF21 的异常上调会通过增加 PDE4C 的表达而损害子宫内膜的蜕膜化。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-09-25 DOI: 10.1016/j.bbadis.2024.167526

Background

Impaired decidualization is a major cause of infertility in patients with adenomyosis (AM). However, the effect of transcription factor 21 (TCF21) on AM and the underlying mechanism of associated-impaired decidualization remain unclear. The aim of this study was to investigate the expression of TCF21 in endometrial tissues of AM patients and the specific mechanisms by which it impairs the decidualization of human endometrial stromal cells (HESCs), with a view to improving the reproductive outcome of AM infertile patients.

Methods

We compared gene expressions via transcriptomics between the control and AM-associated recurrent implantation failure (RIF) groups. qRT-PCR, western blot, and IHC were performed to confirm the expression and location of TCF21 in the endometrium. Furthermore, we confirmed that high expression of TCF21 impairs decidualization by qRT-PCR, immunofluorescence, and western blot. RNA-seq following overexpression of TCF21 in HESCs was conducted to identify TCF21-related molecular changes during in vitro decidualization. Then we performed ChIP-seq/qPCR and dual-luciferase reporter assay to explore the exact interaction between TCF21 and PDE4C. The related downstream mechanisms were further proved using IHC, qRT-PCR, western blot, and ELISA.

Results

According to the RNA-seq analysis, TCF21 expression was remarkably higher in the endometrium of the AM-related RIF group compared to the control group. We confirmed the same results using samples from patients with AM and controls. TCF21 overexpression in HESCs impaired decidualization through suppression of decidual markers and cytoskeleton alterations. The mechanistic analysis revealed that TCF21 inhibited intracellular cAMP levels by directly increasing PDE4C expression and suppressing FOXO1 expression.

Conclusions

TCF21 compromises decidualization in patients with AM via the PDE4C/cAMP-FOXO1 axis, which offers valuable insights on the pathology of decidualization-related infertility and indicates a potential treatment to improve endometrial receptivity in AM.

背景：蜕膜化受损是子宫腺肌症（AM）患者不孕的主要原因。然而，转录因子21（TCF21）对AM的影响以及相关蜕膜化受损的潜在机制仍不清楚。本研究的目的是调查TCF21在AM患者子宫内膜组织中的表达，以及其损害人子宫内膜基质细胞（HESCs）蜕膜化的具体机制，以期改善AM不孕患者的生殖结局：方法：我们通过转录组学比较了对照组和AM相关的复发性着床失败（RIF）组的基因表达。此外，我们还通过qRT-PCR、免疫荧光和Western印迹证实了TCF21的高表达会影响蜕膜化。在HESCs中过表达TCF21后，我们进行了RNA-seq分析，以确定体外蜕膜过程中与TCF21相关的分子变化。然后，我们进行了ChIP-seq/qPCR和双荧光素酶报告实验，以探索TCF21与PDE4C之间的确切相互作用。结果显示：RNA-seq分析显示，TCF21与PDE4C之间存在相互作用，并通过IHC、qRT-PCR、Western blot和ELISA等方法进一步证实了相关的下游机制：结果：RNA-seq分析显示，与对照组相比，AM相关RIF组子宫内膜中TCF21的表达明显升高。我们使用 AM 患者和对照组的样本证实了同样的结果。通过抑制蜕膜标志物和细胞骨架的改变，TCF21在HESCs中的过表达损害了蜕膜化。机理分析表明，TCF21通过直接增加PDE4C的表达和抑制FOXO1的表达来抑制细胞内cAMP水平：结论：TCF21通过PDE4C/cAMP-FOXO1轴损害AM患者的蜕膜化，这为蜕膜化相关不孕症的病理学提供了有价值的见解，并指出了改善AM患者子宫内膜接受性的潜在治疗方法。

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引用次数: 0

miR4352b a cross-species modulator of SOSTDC1, targets dual pathway to regulate bone health and fracture healing miR4352b 是 SOSTDC1 的跨物种调制剂，以调节骨骼健康和骨折愈合的双重途径为目标。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-09-24 DOI: 10.1016/j.bbadis.2024.167514

Mutations in SOST can lead to various monogenic bone diseases. Its paralog, SOSTDC1, shares 55 % protein sequence homology and belongs to the BMP antagonist class. Sostdc1−/− mice exhibit distinct effects on cortical and trabecular bone. Genetic polymorphisms in SOSTDC1 impacting peak bone mass makes SOSTDC1 gene, a candidate for influencing BMD variation in humans. SOSTDC1 is upregulated in bone loss conditions, altering BMP-responsive genes and signaling modulators, suggesting its dual BMP/Wnt antagonist role may enhance both pathways. Overexpression of SOSTDC1 confirmed its role as an osteogenic antagonist. Glycine max (Soy)-derived miR4352b, identified for cross-kingdom applications, precisely targets SOSTDC1, a key regulator of bone. SOSTDC1 competitively binds to BMP2 receptor, BMPR1A. Gma-miR4352b suppresses SOSTDC1 expression, enhancing osteogenesis and countering SOSTDC1's inhibition of osteogenic potential. Modeling estrogen deficiency to mimic elevated SOSTDC1 levels, we observed an inverse correlation with SOSTDC1 expression, while serum BMP2 and PINP levels increased following gma-miR4352b supplementation. In fracture healing, SOSTDC1's crucial role becomes evident in conditions of delayed fracture healing. As healing progresses, SOSTDC1 expression decreases. Gma-miR4352b, compared to scrambled miRNA, remarkably promotes callus formation, achieving 68 % healing by day 10, surpassing the scrambled group at 44 %. By the day 13, the treatment group exhibits advanced healing, challenging to find the callus, while the scrambled group maintains a healing rate similar to day10. The accelerated healing in the treatment group underscores the importance of SOSTDC1 in influencing early fracture healing, potentially through the activation of both BMP2 and Wnt signaling pathways.

SOST 基因突变可导致各种单基因骨病。它的同系物 SOSTDC1 蛋白序列同源性为 55%，属于 BMP 拮抗剂类。Sostdc1-/- 小鼠对皮质骨和骨小梁有不同的影响。影响峰值骨量的 SOSTDC1 基因多态性使 SOSTDC1 基因成为影响人类 BMD 变化的候选基因。在骨质流失的情况下，SOSTDC1 会上调，改变 BMP 响应基因和信号调节器，这表明其 BMP/Wnt 双重拮抗剂作用可能会增强这两种途径。过表达 SOSTDC1 证实了其作为成骨拮抗剂的作用。Glycine max（大豆）衍生的 miR4352b 被鉴定为跨领域应用，可精确靶向骨骼的关键调节因子 SOSTDC1。SOSTDC1 与 BMP2 受体 BMPR1A 竞争性结合。Gma-miR4352b 可抑制 SOSTDC1 的表达，从而促进成骨并对抗 SOSTDC1 对成骨潜能的抑制。通过模拟雌激素缺乏导致的 SOSTDC1 水平升高，我们观察到 SOSTDC1 的表达与血清 BMP2 和 PINP 水平呈反相关，而补充 gma-miR4352b 后，血清 BMP2 和 PINP 水平升高。在骨折愈合过程中，SOSTDC1 的关键作用在骨折延迟愈合的情况下显而易见。随着愈合的进展，SOSTDC1 的表达会减少。与加扰 miRNA 相比，Gma-miR4352b 能显著促进胼胝体的形成，到第 10 天，胼胝体愈合率达到 68%，超过加扰组的 44%。到第 13 天，治疗组的愈合速度加快，很难找到胼胝，而加扰组的愈合速度与第 10 天相似。治疗组的加速愈合强调了 SOSTDC1 在影响骨折早期愈合方面的重要性，它可能是通过激活 BMP2 和 Wnt 信号通路来实现的。

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引用次数: 0

Monocyte and macrophage profiles in patients with inherited long-chain fatty acid oxidation disorders 遗传性长链脂肪酸氧化紊乱患者的单核细胞和巨噬细胞概况。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-09-20 DOI: 10.1016/j.bbadis.2024.167524

Patients with inherited disorders of the long-chain fatty acid oxidation (lcFAO) machinery present with a heterogeneous profile of disease manifestations and aggravation of symptoms is often triggered by inflammatory activation. Monocytes and macrophages are innate immune cells that play a major role in the onset and resolution of inflammation. These cells undergo metabolic rewiring upon activation including the regulation of the FAO rate. The rewiring of FAO and the effect of lcFAO disorders (lcFAOD) on human monocyte and macrophage phenotype and function remain largely unknown. Here, we performed extensive phenotyping of circulating monocytes and analyzed plasma cytokine levels in 11 lcFAOD patients and 11 matched control subjects. In patients with lcFAOD, we observed induced plasma levels of the inflammatory cytokines IL-1β and IL-6, and enhanced CD206 and CD62L surface marker expression in circulating monocyte subsets. To mimic the most common lcFAOD very-long-chain acyl-CoA dehydrogenase disorder (VLCADD), we used siRNA-mediated knockdown of the ACADVL gene (encoding VLCAD) in macrophages derived from healthy volunteers. Hereby, we found that siVLCAD affected IL-4-induced alternative macrophage activation while leaving LPS responses and cellular metabolism intact. In the same line, monocyte-derived macrophages from lcFAOD patients had elevated levels of the IL-4-induced alternative macrophage markers CD206 and CD200R. Still, they did not show major metabolic defects or changes in the LPS-induced inflammatory response. Our results indicate that monocytes and macrophages from lcFAOD patients present no major inflammatory or metabolic differences and show that IL-4-induced surface markers are intertwined with lcFAO in human macrophages.

长链脂肪酸氧化（lcFAO）机制遗传性疾病患者的疾病表现各不相同，炎症激活往往会引发症状加重。单核细胞和巨噬细胞是先天性免疫细胞，在炎症的发生和消退过程中发挥着重要作用。这些细胞在激活后会进行新陈代谢的重新布线，包括调节 FAO 的速率。FAO 的重新布线以及 lcFAO 紊乱（lcFAOD）对人类单核细胞和巨噬细胞表型和功能的影响在很大程度上仍是未知的。在这里，我们对 11 名 lcFAOD 患者和 11 名匹配的对照组受试者的循环单核细胞进行了广泛的表型分析，并对血浆细胞因子水平进行了分析。在 lcFAOD 患者中，我们观察到血浆中的炎性细胞因子 IL-1β 和 IL-6 水平升高，循环单核细胞亚群的 CD206 和 CD62L 表面标志物表达增强。为了模拟最常见的 lcFAOD 极长链酰基-CoA 脱氢酶紊乱症（VLCADD），我们使用 siRNA 介导敲除健康志愿者巨噬细胞中的 ACADVL 基因（编码 VLCAD）。因此，我们发现 siVLCAD 会影响 IL-4 诱导的巨噬细胞替代活化，而 LPS 反应和细胞代谢则保持不变。同样，lcFAOD 患者单核细胞衍生的巨噬细胞中，IL-4 诱导的替代性巨噬细胞标记物 CD206 和 CD200R 水平升高。不过，它们并没有表现出重大的代谢缺陷或 LPS 诱导的炎症反应的变化。我们的研究结果表明，lcFAOD 患者的单核细胞和巨噬细胞在炎症或新陈代谢方面没有重大差异，并表明 IL-4 诱导的表面标志物与人类巨噬细胞中的 lcFAO 相互交织。

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引用次数: 0

ARL11 knockdown alleviates spinal cord injury by inhibiting neuroinflammation and M1 activation of microglia in mice 敲除 ARL11 可抑制小鼠的神经炎症和小胶质细胞的 M1 激活，从而减轻脊髓损伤。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-09-20 DOI: 10.1016/j.bbadis.2024.167522

Spinal cord injury (SCI) is a severe central nervous system injury and microglia are major participants in neuroinflammation after injury. ADP-ribosylation factor-like GTPase 11 (ARL11) is a GTP-binding protein. Whether ARL11 is involved in the SCI progression is unknown. In the impactor-induced moderate SCI mouse model, ARL11 protein and mRNA expression were significantly increased in the injury site. LPS (100 ng/mL) and IFN-γ (20 ng/mL) were incubated with BV2 cells (immortalized mouse microglial cell line) to drive them into an M1-like phenotype. ARL11 up-regulation was also observed in activated microglia in SCI mice and LPS and IFN-γ treated BV2 cells. Basso Mouse Scale scores and inclined plate test revealed that ARL11 deletion promoted motor function recovery in SCI mice. Pathological examination showed ARL11 knockdown reduced spinal cord tissue damage, increased neuron numbers, and inhibited neuronal apoptosis in SCI mice. ARL11 knockdown notably inhibited IL-1β and IL-6 production in vivo and in vitro. Furthermore, ARL11 deletion significantly inhibited iNOS protein and mRNA expression in vivo and in vitro, and COX-2 expression in vivo. Mechanism studies revealed that ARL11 silencing decreased phosphorylated ERK1/2 protein expression. Additionally, ELF1 knockdown significantly inhibited ARL11 protein and mRNA expression in vitro. ELF1 acted as a transcription activator in regulating ARL11 expression by binding to the promoter. In conclusion, ARL11 knockdown protects neurons by inhibiting M1 microglia-induced neuroinflammation, thereby promoting motor functional recovery in SCI mice. This may occur in part under the regulation of ELF1. Our study provides a new molecular target for SCI treatment.

脊髓损伤（SCI）是一种严重的中枢神经系统损伤，小胶质细胞是损伤后神经炎症的主要参与者。ADP-ribosylation factor-like GTPase 11（ARL11）是一种 GTP 结合蛋白。ARL11 是否参与了 SCI 的进展尚不清楚。在撞击器诱导的中度 SCI 小鼠模型中，损伤部位的 ARL11 蛋白和 mRNA 表达明显增加。LPS（100 ng/mL）和IFN-γ（20 ng/mL）与BV2细胞（永生化小鼠小胶质细胞系）孵育，使其进入M1样表型。在 SCI 小鼠活化的小胶质细胞以及经 LPS 和 IFN-γ 处理的 BV2 细胞中也观察到 ARL11 上调。巴索小鼠量表评分和斜板试验显示，ARL11缺失促进了SCI小鼠运动功能的恢复。病理学检查显示，ARL11敲除可减少SCI小鼠脊髓组织损伤、增加神经元数量并抑制神经元凋亡。ARL11 基因敲除明显抑制了体内和体外 IL-1β 和 IL-6 的产生。此外，ARL11 基因缺失还能显著抑制体内和体外 iNOS 蛋白和 mRNA 的表达，以及体内 COX-2 的表达。机理研究显示，沉默 ARL11 可降低磷酸化 ERK1/2 蛋白的表达。此外，ELF1基因敲除可显著抑制体外ARL11蛋白和mRNA的表达。ELF1通过与启动子结合，在调节ARL11表达过程中起到转录激活剂的作用。总之，ARL11敲除可抑制M1小胶质细胞诱导的神经炎症，从而保护神经元，促进SCI小鼠的运动功能恢复。这可能部分是在 ELF1 的调控下发生的。我们的研究为治疗 SCI 提供了一个新的分子靶点。

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引用次数: 0

Pathophysiological significance of the p.E31G variant in RAC1 responsible for a neurodevelopmental disorder with microcephaly 导致小头畸形神经发育障碍的 RAC1 p.E31G 变异的病理生理学意义。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-09-20 DOI: 10.1016/j.bbadis.2024.167520

RAC1 encodes a Rho family small GTPase that regulates actin cytoskeletal reorganization and intracellular signaling pathways. Pathogenic RAC1 variants lead to a neurodevelopmental disorder with diverse phenotypic manifestations, including abnormalities in brain size and facial dysmorphism. However, the underlying pathophysiological mechanisms have yet to be elucidated. Here, we present the case of a school-aged male who exhibited global developmental delay, intellectual disability, and acquired microcephaly. Through whole exome sequencing, we identified a novel de novo variant in RAC1, (NM_006908.5): c.92 A > G,p.(E31G). We then examined the pathophysiological significance of the p.E31G variant by focusing on brain development. Biochemical analyses revealed that the recombinant RAC1-E31G had no discernible impact on the intrinsic GDP/GTP exchange activity. However, it exhibited a slight inhibitory effect on GTP hydrolysis. Conversely, it demonstrated a typical response to both a guanine-nucleotide exchange factor and a GTPase-activating protein. In transient expression analyses using COS7 cells, RAC1-E31G exhibited minimal interaction with the downstream effector PAK1, even in its GTP-bound state. Additionally, overexpression of RAC1-E31G was observed to exert a weak inhibitory effect on the differentiation of primary cultured hippocampal neurons. Moreover, in vivo studies employing in utero electroporation revealed that acute expression of RAC1-E31G resulted in impairments in axonal elongation and dendritic arborization in the young adult stage. These findings suggest that the p.E31G variant functions as a dominant-negative version in the PAK1-mediated signaling pathway and is responsible for the clinical features observed in the patient under investigation, namely microcephaly and intellectual disability.

RAC1 编码一种 Rho 家族小 GTP 酶，可调节肌动蛋白细胞骨架重组和细胞内信号通路。致病性 RAC1 变体会导致神经发育障碍，具有多种表型表现，包括脑部大小异常和面部畸形。然而，其潜在的病理生理机制仍有待阐明。在此，我们介绍了一例表现出全面发育迟缓、智力障碍和获得性小头畸形的学龄男性病例。通过全外显子组测序，我们发现了 RAC1 的一个新变异 (NM_006908.5)：c.92 A > G,p.(E31G)。然后，我们以大脑发育为重点，研究了 p.E31G 变异的病理生理学意义。生化分析表明，重组 RAC1-E31G 对内在 GDP/GTP 交换活性没有明显影响。不过，它对 GTP 水解有轻微的抑制作用。相反，它对鸟嘌呤核苷酸交换因子和 GTP 酶激活蛋白都表现出典型的反应。在使用 COS7 细胞进行的瞬时表达分析中，RAC1-E31G 与下游效应物 PAK1 的相互作用微乎其微，即使在 GTP 结合状态下也是如此。此外，还观察到过表达 RAC1-E31G 对原代培养的海马神经元的分化有微弱的抑制作用。此外，采用子宫内电穿孔法进行的体内研究显示，急性表达 RAC1-E31G 会导致幼年期轴突伸长和树突轴化受损。这些研究结果表明，p.E31G变异体在PAK1介导的信号通路中起显性阴性作用，是导致所研究患者出现小头畸形和智力障碍等临床特征的原因。

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引用次数: 0

Role of Elavl-like RNA-binding protein in retinal development and signal transduction. Elavl 样 RNA 结合蛋白在视网膜发育和信号转导中的作用

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-09-20 DOI: 10.1016/j.bbadis.2024.167518

RNA-binding proteins (RBPs) play central roles in post-transcriptional gene regulation. However, the function of RBP in retinal progenitor cell differentiation and synaptic signal transmission are largely unexplored. Previously we have shown that Elavl2 regulates amacrine cell (AC) differentiation during retinogenesis, by directly binding to Nr4a2 and Barhl2. Elavl2 is expressed in early neuronal progenitors to mature neurons, and Elavl4 expression begins slightly later, during cortical neuron development as a paralog. Here, Retinal-specific Elavl2 and Elavl4 double knockout mice were made to further explore the role of Elavl2 and Elavl4 in retinal development and signal transduction. We disclose that Elavl4 binds to Satb1 to regulate Neurod1, then promoting retinal progenitor and amacrine cells differentiation. We were also surprised to find that Elavl2 interacted with GABA_B receptors at the RNA and protein levels. In conclusion, Elavl2 and Elavl4 regulate amacrine cells differentiation through different pathways, leading to decreased scotopic vision. Our findings reveal the roles of Elavl2 and Elavl4 in retinal amacrine cells differentiation in modulating visual functions.

RNA 结合蛋白（RBPs）在转录后基因调控中发挥着核心作用。然而，RBP 在视网膜祖细胞分化和突触信号传递中的功能在很大程度上尚未被探索。此前，我们已经证明，Elavl2 通过直接与 Nr4a2 和 Barhl2 结合，在视网膜发生过程中调控羊膜细胞（AC）的分化。Elavl2 在从早期神经元祖细胞到成熟神经元的过程中都有表达，而 Elavl4 的表达开始稍晚，在皮质神经元发育过程中作为旁系亲属开始表达。为了进一步探讨Elavl2和Elavl4在视网膜发育和信号转导中的作用，我们制作了视网膜特异性Elavl2和Elavl4双基因敲除小鼠。我们发现，Elavl4与Satb1结合，调控Neurod1，进而促进视网膜祖细胞和视母细胞的分化。我们还惊奇地发现，Elavl2与GABAB受体在RNA和蛋白质水平上存在相互作用。总之，Elavl2和Elavl4通过不同途径调控视网膜神经元细胞的分化，导致视力下降。我们的研究结果揭示了Elavl2和Elavl4在视网膜杏仁核细胞分化中调节视觉功能的作用。

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引用次数: 0

Postnatally overfed mice display cardiac function alteration following myocardial infarction 产后喂养过度的小鼠在心肌梗死后会出现心脏功能改变

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-09-18 DOI: 10.1016/j.bbadis.2024.167516

Background

Cardiovascular (CV) pathologies remain a leading cause of death worldwide, often associated with common comorbidities such as overweight, obesity, type 2 diabetes or hypertension. An innovative mouse model of metabolic syndrome induced by postnatal overfeeding (PNOF) through litter size reduction after birth was developed experimentally. This study aimed to evaluate the impact of PNOF on cardiac remodelling and the development of heart failure following myocardial infarction.

Methods

C57BL/6 male mice were raised in litter adjusted to 9 or 3 pups for normally-fed (NF) control and PNOF group respectively. After weaning, all mice had free access to standard diet and water. At 4 months, mice were subjected to myocardial infarction (MI). Echocardiographic follows-up were performed up to 6-months post-surgery and biomolecular analyses were carried-out after heart collection.

Findings

At 4 months, PNOF mice exhibited a significant increase in body weight, along with a basal reduction in left ventricular ejection fraction (LVEF) and an increase in left ventricular end-systolic area (LVESA), compared to NF mice. Following MI, PNOF mice demonstrated a significant decrease in stroke volume and an increased heart rate compared to their respective initial values, as well as a notable reduction in cardiac output 4-months after MI. After 6-months, left ventricle and lung masses, fibrosis staining, and mRNA expression were all similar in the NF-MI and PNOF-MI groups.

Interpretation

After MI, PNOF mice display signs of cardiac function worsening as evidenced by a decrease in cardiac output, which could indicate an early sign of heart failure decompensation.

背景心血管（CV）疾病仍然是全球死亡的主要原因，通常与超重、肥胖、2 型糖尿病或高血压等常见合并症有关。通过实验开发了一种创新的小鼠代谢综合征模型，该模型由产后过度喂养（PNOF）通过减少出生后的窝产仔数诱发。本研究旨在评估PNOF对心肌梗死后心脏重塑和心力衰竭发展的影响。方法C57BL/6雄性小鼠在正常喂养（NF）对照组和PNOF组分别以9只或3只幼鼠的窝仔数进行饲养。断奶后，所有小鼠均可自由摄入标准饮食和水。4 个月时，小鼠发生心肌梗死（MI）。研究结果与 NF 组小鼠相比，PNOF 组小鼠在 4 个月时体重显著增加，左心室射血分数（LVEF）基本降低，左心室收缩末期面积（LVESA）增加。与各自的初始值相比，PNOF 小鼠在心肌梗死后的搏出量显著减少，心率增加，心肌梗死 4 个月后的心输出量也明显减少。6个月后，NF-MI组和PNOF-MI组的左心室和肺部肿块、纤维化染色和mRNA表达均相似。

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引用次数: 0

Molecular mechanisms of mitochondrial stress responses 线粒体应激反应的分子机制

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-09-16 DOI: 10.1016/j.bbadis.2024.167370

引用次数: 0

Mitochondrial rheostat that predisposes to cancer 易患癌症的线粒体流变器

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-09-16 DOI: 10.1016/j.bbadis.2024.167361

引用次数: 0