Biochimica et biophysica acta. Molecular cell research最新文献_第3页

CISD2 counteracts the inhibition of ER-mitochondrial calcium transfer by anti-apoptotic BCL-2 CISD2 可抵消抗凋亡 BCL-2 对 ER 线粒体钙传递的抑制。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-10-04 DOI: 10.1016/j.bbamcr.2024.119857

Jens Loncke , Ian de Ridder , Justin Kale , Larry Wagner , Allen Kaasik , Jan B. Parys , Martijn Kerkhofs , David W. Andrews , David Yule , Tim Vervliet , Geert Bultynck

CISD2, a 2Fe2S cluster domain-containing protein, is implicated in Wolfram syndrome type 2, longevity and cancer. CISD2 is part of a ternary complex with IP₃ receptors (IP₃Rs) and anti-apoptotic BCL-2 proteins and enhances BCL-2's anti-autophagic function. Here, we examined how CISD2 impacted the function of BCL-2 in apoptosis and in controlling IP₃R-mediated Ca²⁺ signaling. Using purified proteins, we found a direct interaction between the cytosolic region of CISD2 and BCL-2's BH4 domain with a submicromolar affinity. At the functional level, the cytosolic region of CISD2, as a purified protein, did not affect the ability of BCL-2 to inhibit BAX-pore formation. In a cellular context, loss of CISD2 did not impede the suppression of apoptosis by BCL-2. Also, in Ca²⁺-signaling assays, absence of CISD2 did not affect the inhibition of IP₃R-mediated Ca²⁺ release by BCL-2. Combined, these experiments indicate that CISD2 is not essential for BCL-2 function in apoptosis and cytosolic Ca²⁺ signaling. Instead, CISD2 overexpression enhanced BCL-2-mediated suppression of cytosolic IP₃R-mediated Ca²⁺ release. However, consistent with the presence of CISD2 and BCL-2 at mitochondria-associated ER membranes (MAMs), the most striking effect was observed at the level of ER-mitochondrial Ca²⁺ transfer. While BCL-2 overexpression inhibited ER-mitochondrial Ca²⁺ transfer, overexpression of CISD2 together with BCL-2 abrogated the effect of BCL-2. The underlying mechanism is linked to ER-mitochondrial contact sites, since BCL-2 reduced ER-mitochondrial contact sites while co-expression of CISD2 together with BCL-2 abolished this effect. These findings reveal a unique interplay between BCL-2 and CISD2 at Ca²⁺-signaling nanodomains between ER and mitochondria.

CISD2是一种含2Fe2S簇结构域的蛋白质，与沃尔夫拉姆综合征2型、长寿和癌症有关。CISD2是IP3受体（IP3Rs）和抗凋亡BCL-2蛋白三元复合物的一部分，能增强BCL-2的抗自噬功能。在此，我们研究了 CISD2 如何影响 BCL-2 在细胞凋亡和控制 IP3R 介导的 Ca2+ 信号转导中的功能。通过纯化蛋白，我们发现 CISD2 的胞浆区与 BCL-2 的 BH4 结构域之间存在直接相互作用，亲和力达到亚摩尔级。在功能层面上，CISD2的胞浆区作为一种纯化蛋白，并不影响BCL-2抑制BAX孔形成的能力。在细胞环境中，CISD2的缺失并不妨碍BCL-2抑制细胞凋亡。此外，在 Ca2+ 信号传导实验中，CISD2 的缺失并不影响 BCL-2 对 IP3R 介导的 Ca2+ 释放的抑制作用。这些实验综合表明，CISD2 对于 BCL-2 在细胞凋亡和细胞膜 Ca2+ 信号转导中的功能并不是必不可少的。相反，CISD2 的过表达增强了 BCL-2 介导的对细胞膜 IP3R 介导的 Ca2+ 释放的抑制。然而，与 CISD2 和 BCL-2 存在于线粒体相关的 ER 膜（MAMs）一致，在 ER - 线粒体 Ca2+ 转移水平观察到了最显著的影响。BCL-2的过表达抑制了ER-线粒体Ca2+的转移，而CISD2与BCL-2一起过表达则削弱了BCL-2的作用。其潜在机制与ER-线粒体接触位点有关，因为BCL-2减少了ER-线粒体接触位点，而CISD2与BCL-2共同表达则消除了这种效应。这些发现揭示了 BCL-2 和 CISD2 在 ER 和线粒体之间的 Ca2+ 信号纳米域的独特相互作用。

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引用次数: 0

Effects of high-fat diet on folic acid-induced kidney injury in mice 高脂饮食对叶酸诱导的小鼠肾损伤的影响

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-09-30 DOI: 10.1016/j.bbamcr.2024.119856

Doyeon Kim , Minjung Son , Sugyeong Ha , Jeongwon Kim , Mi-Jeong Kim , Jian Yoo , Byeong Moo Kim , Hae Young Chung , Haeseung Lee , Donghwan Kim , Sangok Kim , Ki Wung Chung

Obesity is recognized as a significant contributor to the onset of kidney disease. However, the key processes involved in the development of kidney disease in obese individuals are not well understood. Here, we investigated the effects of high-fat diet (HFD)-induced obesity on folic acid (FA)-induced kidney injury in mice. Mice were fed an HFD for 12 weeks to induce obesity, followed by an additional intraperitoneal injection of FA. The results showed that mice fed HFD developed higher levels of kidney damage than those in the chow group. In contrast, mice exposed to both HFD and FA showed less fibrosis and inflammatory responses compared to the FA only treated group. Furthermore, the HFD with FA group exhibited elevated lipid accumulation in the kidney and reduced expression of mitochondrial proteins compared to the FA-treated group. Under in vitro experimental conditions, we found that lipid accumulation induced by oleic acid treatment reduced inflammatory and fibrotic responses in both renal tubules and fibroblasts. Finally, RNA sequencing analysis revealed that the inflammasome and pyroptosis signaling pathways were significantly increased in the HFD group with FA injection. In summary, these findings suggest that obesity increases renal injury due to a lack of appropriate inflammatory, fibrotic, and metabolic responses and the activation of the inflammasome and pyroptosis signaling pathways.

肥胖被认为是导致肾病发病的一个重要因素。然而，肥胖者肾脏疾病发生的关键过程尚不十分清楚。在此，我们研究了高脂饮食（HFD）诱导的肥胖对叶酸（FA）诱导的小鼠肾损伤的影响。给小鼠喂食高脂饮食 12 周以诱导肥胖，然后再腹腔注射叶酸。结果显示，喂食高纤维食物的小鼠比饲料组的小鼠出现更严重的肾损伤。相比之下，同时摄入 HFD 和 FA 的小鼠与只摄入 FA 的组相比，纤维化和炎症反应较轻。此外，与 FA 处理组相比，HFD 和 FA 组的肾脏脂质积累增加，线粒体蛋白表达减少。在体外实验条件下，我们发现油酸处理诱导的脂质积累减轻了肾小管和成纤维细胞的炎症和纤维化反应。最后，RNA 测序分析表明，注射 FA 的高脂血症组中，炎性体和裂解酶信号通路显著增加。总之，这些研究结果表明，由于缺乏适当的炎症、纤维化和新陈代谢反应以及炎性体和裂解酶信号通路的激活，肥胖会加重肾损伤。

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引用次数: 0

NLRX1 attenuates endoplasmic reticulum stress via STING in cardiac hypertrophy NLRX1 通过 STING 减轻心肌肥厚中的内质网应激反应

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-09-30 DOI: 10.1016/j.bbamcr.2024.119852

Keying Mi , Xiaoyan Wang , Chao Ma , Yinghua Tan , Gang Zhao , Xinran Cao , Haitao Yuan

Endoplasmic reticulum stress-induced cell apoptosis is a pivotal mechanism underlying the progression of cardiac hypertrophy. NLRX1, a member of the NOD-like receptor family, modulates various cellular processes, including STING, NF-κB, MAPK pathways, reactive oxygen species production, essential metabolic pathways, autophagy and cell death. Emerging evidence suggests that NLRX1 may offer protection against diverse cardiac diseases. However, the impacts and mechanisms of NLRX1 on endoplasmic reticulum stress in cardiac hypertrophy remains largely unexplored. In our study, we observed that the NLRX1 and phosphorylated STING (p-STING) were highly expressed in both hypertrophic mouse heart and cellular model of cardiac hypertrophy. Whereas over-expression of NLRX1 mitigated the expression levels of p-STING, as well as the endoplasmic reticulum stress markers, including transcription activating factor 4 (ATF4), C/EBP homologous protein (CHOP) and the ratios of phosphorylated PERK to PERK, phosphorylated IRE1 to IRE1 and phosphorylated eIF2α to eIF2α in an Angiotensin II (Ang II)-induced cellular model of cardiac hypertrophy. Importantly, the protective effects of NLRX1 were attenuated upon pretreatment with the STING agonist, DMXAA. Our findings provide the evidence that NLRX1 attenuates the PERK-eIF2α-ATF4-CHOP axis of endoplasmic reticulum stress response via inhibition of p-STING in Ang II-treated cardiomyocytes, thereby ameliorating the development of cardiac hypertrophy.

内质网应激诱导的细胞凋亡是心肌肥厚进展的关键机制。NLRX1 是 NOD 样受体家族的成员，它能调节各种细胞过程，包括 STING、NF-κB、MAPK 途径、活性氧生成、基本代谢途径、自噬和细胞死亡。新的证据表明，NLRX1 可预防多种心脏疾病。然而，NLRX1 对心脏肥大中内质网应激的影响和机制在很大程度上仍未得到探索。在我们的研究中，我们观察到 NLRX1 和磷酸化 STING（p-STING）在肥厚小鼠心脏和心脏肥厚细胞模型中均高表达。而在血管紧张素 II（Ang II）诱导的心脏肥大细胞模型中，过度表达 NLRX1 可减轻 p-STING 的表达水平，以及内质网应激标志物，包括转录激活因子 4（ATF4）、C/EBP 同源蛋白（CHOP）和磷酸化 PERK 与 PERK、磷酸化 IRE1 与 IRE1 和磷酸化 eIF2α 与 eIF2α 的比率。重要的是，在 STING 激动剂 DMXAA 的预处理下，NLRX1 的保护作用减弱。我们的研究结果提供了证据，证明 NLRX1 通过抑制 Ang II 处理的心肌细胞中的 p-STING 来减弱内质网应激反应的 PERK-eIF2α-ATF4-CHOP 轴，从而改善心脏肥大的发展。

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引用次数: 0

AGR2 knockdown induces ER stress and mitochondria fission to facilitate pancreatic cancer cell death AGR2 基因敲除可诱导ER应激和线粒体分裂，从而促进胰腺癌细胞死亡。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-09-30 DOI: 10.1016/j.bbamcr.2024.119854

Philip Salu , Daniel Tuvin , Katie M. Reindl

Anterior gradient 2 (AGR2) is often overexpressed in many human cancers, including pancreatic ductal adenocarcinoma (PDAC). Elevated AGR2 expression is known to play a critical role in tumor development, progression, and metastasis and positively correlates with poor patient survival. However, the relationship between AGR2 expression and tumor growth is not fully understood. Our study aims to investigate the impact of AGR2 knockdown on the survival of two pancreatic cancer cell lines, HPAF–II and PANC–1, that exhibit high AGR2 expression. This study revealed that the knockdown of AGR2 expression through an inducible shRNA-mediated approach reduced the proliferative ability and colony-forming potential of PDAC cells compared to scramble controls. Significantly, knocking down AGR2 led to the inhibition of multiple protein biosynthesis pathways and induced ER stress through unfolded protein response (UPR) activation. AGR2 knockdown induced ER stress and increased mitochondrial fission, while mitochondrial fusion remained unaffected. Ultimately, apoptotic cell death was heightened in AGR2 knockdown PDAC cells compared to the controls. Overall, these data reveal a new axis involving AGR2-ER stress-associated mitochondrial fission that could be targeted to improve PDAC patient outcomes.

前梯度 2（AGR2）经常在包括胰腺导管腺癌（PDAC）在内的许多人类癌症中过度表达。众所周知，AGR2 的高表达在肿瘤发生、发展和转移过程中起着至关重要的作用，并与患者生存率低呈正相关。然而，AGR2 表达与肿瘤生长之间的关系尚未完全明了。我们的研究旨在探讨 AGR2 基因敲除对两种高表达 AGR2 的胰腺癌细胞系 HPAF-II 和 PANC-1 生存的影响。研究发现，通过诱导性 shRNA 介导的方法敲除 AGR2 表达，与混杂对照组相比，可降低 PDAC 细胞的增殖能力和集落形成潜能。值得注意的是，敲除 AGR2 会抑制多种蛋白质的生物合成途径，并通过激活未折叠蛋白反应（UPR）诱导 ER 应激。敲除 AGR2 会诱发 ER 应激并增加线粒体裂变，而线粒体融合则不受影响。最终，与对照组相比，AGR2 基因敲除的 PDAC 细胞凋亡增加。总之，这些数据揭示了一个涉及 AGR2-ER应激相关线粒体裂变的新轴，可以针对该轴改善PDAC患者的预后。

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引用次数: 0

An artificial peptide inhibits autophagy through calcineurin-TFEB pathway 人工肽通过钙神经蛋白-TFEB途径抑制自噬。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-09-30 DOI: 10.1016/j.bbamcr.2024.119853

Yumeng Yang , Yanan Li , Hanxiao Shang , Yueyang Liu , Wenying Li , Limin Chen , Na Cheng , Yuchen Zhang , Nan Zhang , Yanxia Yin , Li Tong , Zhimei Li , Jingyu Yang , Jing Luo

We previously reported that a bioactive peptide (pep3) can potently inhibit the enzyme activity of purified calcineurin (CN). In this paper, we further demonstrate that transfected pep3 can strongly inhibit CN enzyme activity in HEK293 cells. Transcription factor EB (TFEB) plays an important role in the autophagy-lysosome pathway (ALP) as one of the substrates of CN, so we study the effect of pep3 on the CN-TFEB-ALP pathway. Pep3 can significantly inhibit the mRNA levels of the TFEB downstream genes and the expression of the autophagy-associated proteins, and autophagy flux in HEK293 cells. We also validated the inhibitory effect of pep3 on autophagy in mice. These findings may provide a new idea for discovering more CN inhibitors and autophagy inhibitory drugs.

我们以前曾报道过一种生物活性肽（pep3）能有效抑制纯化的钙调磷酸酶（CN）的酶活性。在本文中，我们进一步证明了转染的 pep3 能强烈抑制 HEK293 细胞中 CN 的酶活性。转录因子 EB（TFEB）作为 CN 的底物之一，在自噬-溶酶体通路（ALP）中发挥着重要作用，因此我们研究了 pep3 对 CN-TFEB-ALP 通路的影响。Pep3能明显抑制TFEB下游基因的mRNA水平、自噬相关蛋白的表达以及HEK293细胞的自噬通量。我们还在小鼠体内验证了 pep3 对自噬的抑制作用。这些发现为发现更多的CN抑制剂和自噬抑制药物提供了新思路。

引用次数: 0

TRIM40 interacts with ROCK1 directly and inhibits colorectal cancer cell proliferation through the c-Myc/p21 axis TRIM40 与 ROCK1 直接相互作用，通过 c-Myc/p21 轴抑制结直肠癌细胞增殖。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-09-30 DOI: 10.1016/j.bbamcr.2024.119855

Fangyu Hu , Lingling Zhao , Junyu Wang , Xiaoying Li , Zixuan Xue , Yimeng Ma , Minghui Zheng , Chenglin Chen , Meiting Tong , Xiaohuan Guo , Hongyan Li , Honglei Jin , Qipeng Xie , Xiaodong Zhang , Chuanshu Huang , Haishan Huang

Background

Colorectal cancer (CRC) is the most common malignancy of the digestive tract, and to date, morbidity and mortality rates remain high. While existing therapeutic methods have achieved certain effective outcomes, there are still many problems in treating this disease. Therefore, it is still urgent to constantly find new therapeutic targets in CRC that could lead to new therapeutics.

Methods

Immunohistochemistry, Real-time PCR and Western Blot were employed to measure mRNA and protein levels of the target protein, respectively. The proliferation ability of CRC cells was evaluated using ATP assay, Soft agar assay, and nude mouse subcutaneous tumorigenesis assay. Protein Degradation Assay was conducted to determine protein degradation rate, while Ubiquitination assay was used to assess the ubiquitination modification level of target proteins. Immunoprecipitation assay was used to study protein interactions, and pull-down assay was employed to investigate direct interactions between proteins.

Results

TRIM40 was significantly down-regulated in CRC tissues, with its expression levels positively correlating with disease prognosis. Using both in vitro and in vivo approaches, it was demonstrated that TRIM40 could significantly inhibit the proliferation of CRC cells. Molecular mechanism studies showed that TRIM40 directly binds to and ubiquitinates ROCK1 protein, accelerating its degradation and subsequently reducing the stability of c-Myc protein. This cascade of events results in the release of transcriptional inhibition of p21 by c-Myc, leading to increased p21 expression and G0/G1 phase arrest in CRC cells.

Conclusion

This research suggests that TRIM40 could be a valuable therapeutic target for the treatment of CRC.

背景：大肠癌（CRC）是消化道最常见的恶性肿瘤，迄今为止，发病率和死亡率仍然居高不下。虽然现有的治疗方法取得了一定的疗效，但在治疗该疾病方面仍存在许多问题。因此，不断寻找 CRC 的新治疗靶点，从而开发出新的治疗方法，仍是当务之急：方法：采用免疫组化、Real-time PCR和Western Blot技术分别检测靶蛋白的mRNA和蛋白水平。采用 ATP 试验、软琼脂试验和裸鼠皮下肿瘤发生试验评估 CRC 细胞的增殖能力。蛋白质降解试验用于测定蛋白质的降解率，泛素化试验用于评估目标蛋白质的泛素化修饰水平。免疫沉淀试验用于研究蛋白质之间的相互作用，而牵引试验则用于研究蛋白质之间的直接相互作用：结果：TRIM40在CRC组织中明显下调，其表达水平与疾病预后呈正相关。体外和体内研究表明，TRIM40能明显抑制CRC细胞的增殖。分子机制研究表明，TRIM40 可直接与 ROCK1 蛋白结合并泛素化，加速其降解，进而降低 c-Myc 蛋白的稳定性。这一系列事件导致c-Myc释放对p21的转录抑制，导致p21表达增加，CRC细胞G0/G1期停滞：这项研究表明，TRIM40 可能是治疗 CRC 的一个有价值的治疗靶点。

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引用次数: 0

Mitochondrial dynamics and sex-specific responses in the developing rat hippocampus: Effect of perinatal asphyxia and mesenchymal stem cell Secretome treatment 发育中大鼠海马的线粒体动态和性别特异性反应：围产期窒息和间充质干细胞Secretome处理的影响

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-09-25 DOI: 10.1016/j.bbamcr.2024.119851

M. Zamorano-Cataldo , I. Vega-Vásquez , C. García-Navarrete , J. Toledo , D. Bustamante , F. Ezquer , F.A. Urra , N. Farfán-Troncoso , M. Herrera-Marschitz , P. Morales

Aims

Perinatal asphyxia is one of the major causes of neonatal death at birth. Survivors can progress but often suffer from long-term sequelae. We aim to determine the effects of perinatal asphyxia on mitochondrial dynamics and whether mesenchymal stem cell secretome (MSC-S) treatment can alleviate the deleterious effects.

Materials and methods

Animals were subjected to 21 min of asphyxia at the time of delivery. MSC-S or vehicle was intranasally administered 2 h post-delivery. Mitochondrial mass (D-loop, qPCR), mitochondrial dynamics proteins (Drp1, Fis1 and OPA1, Western blot), mitochondrial dynamics (TOMM20, Immunofluorescence), as well as mitochondrial membrane potential (ΔΨ_m) (Safranin O) were evaluated at P1 and P7 in the hippocampus.

Key findings

Perinatal asphyxia increased levels of mitochondrial dynamics proteins Drp1 and S-OPA1 at P1 and Fis1 at P7. Mitochondrial density and mass were decreased at P1. Perinatal asphyxia induced sex-specific differences, with increased L-OPA1 in females at P7 and increased mitochondria circularity. In males, asphyxia-exposed animals exhibited a reduced ΔΨ_m at P7. MSC-S treatment normalised levels of mitochondrial dynamics proteins involved in fission.

Significance

This study provides novel insights into the effects of perinatal asphyxia on mitochondrial dynamics in the developing brain and on the therapeutic opportunities provided by mesenchymal stem cell secretome treatment. It also highlights on the relevance of considering sex as a biological variable in perinatal brain injury and therapy development. These findings contribute to the development of targeted, personalised therapies for infants affected by perinatal asphyxia.

目的：围产期窒息是新生儿出生时死亡的主要原因之一。存活者可以继续发育，但往往会留下长期后遗症。我们旨在确定围产期窒息对线粒体动力学的影响，以及间充质干细胞分泌物（MSC-S）治疗是否能减轻其有害影响：动物在分娩时窒息21分钟。材料与方法：动物在分娩时窒息 21 分钟，分娩后 2 小时鼻内注射间充质干细胞-S 或药物。在海马P1和P7时评估线粒体质量（D-loop，qPCR）、线粒体动力学蛋白（Drp1、Fis1和OPA1，Western印迹）、线粒体动力学（TOMM20，免疫荧光）以及线粒体膜电位（ΔΨm）（Safranin O）：主要研究结果：围产期窒息会增加线粒体动力学蛋白 Drp1 和 S-OPA1 的水平（P1）和 Fis1 的水平（P7）。线粒体密度和质量在P1时下降。围产期窒息引起了性别差异，雌性在P7时L-OPA1增加，线粒体循环性增加。在雄性动物中，窒息暴露的动物在P7时表现出ΔΨm减少。MSC-S处理可使参与裂变的线粒体动力学蛋白水平恢复正常：这项研究为围产期窒息对发育中大脑线粒体动力学的影响以及间充质干细胞分泌组治疗提供了新的见解。研究还强调了将性别视为围产期脑损伤和治疗发展中的一个生物变量的相关性。这些发现有助于为受围产期窒息影响的婴儿开发有针对性的个性化疗法。

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引用次数: 0

Microbial chaperonin 60 inhibits osteoclast differentiation by interfering with RANK/RANKL binding and overexpression of lipocalin2 微生物伴侣素 60 可通过干扰 RANK/RANKL 结合和脂钙蛋白 2 的过表达来抑制破骨细胞分化。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-09-19 DOI: 10.1016/j.bbamcr.2024.119850

Joo-Young Cho , Hee-Eun Woo , Jiah Yeom , Mirae An , Seongho Ma , Dong Joon Yim , Sang-Hun Kim , Young-Hee Lim

Osteoclasts play a crucial role in bone destruction in rheumatoid arthritis (RA). This study aimed to investigate the inhibitory effects of chaperonin 60 (CPN60), identified in the surface proteins of Propionibacterium freudenreichii MJ2, on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation, and elucidate the underlying mechanisms. Treatment with CPN60 inhibited RANKL-induced osteoclast differentiation by decreasing the expression of osteoclast differentiation-related genes and proteins. CPN60 interfered with the binding of RANKL to RANK, as elucidated using surface plasmon resonance (SPR) and immunofluorescence. In silico molecular docking analysis further supported the interference of CPN60 with the binding of RANKL and RANK. CPN60 suppressed the expression of molecules linked to the calcium-dependent pathway in RANKL-induced osteoclast differentiation at both mRNA and protein levels. Microarray analysis showed elevated expression of lipocalin 2 (Lcn2), which was closely linked to the inhibition of osteoclast differentiation in CPN60-treated RAW 264.7 cells. Inhibition of Lcn2 decreased the inhibitory effect of CPN60 on osteoclast differentiation, indicating that increased expression of Lcn2 by CPN60 contributes to the inhibition of osteoclastogenesis. In addition, CPN60 treatment alleviated arthritis symptoms in collagen-induced arthritis mice by reducing the generation of collagen-specific antibodies and inhibiting osteoclast differentiation. In conclusion, CPN60 of P. freudenreichii MJ2 interfered with RANKL–RANK binding, reduced the expression of genes and proteins related to osteoclast differentiation and upregulated Lcn2 expression, thereby inhibiting RANKL-induced osteoclast differentiation, which might contribute to ameliorate collagen-induced arthritis.

破骨细胞在类风湿性关节炎（RA）的骨质破坏中起着至关重要的作用。本研究的目的是研究在丙酸芽孢杆菌 MJ2 表面蛋白中发现的合子素 60（CPN60）对核因子卡巴-B 配体受体激活剂（RANKL）诱导的破骨细胞分化的抑制作用，并阐明其潜在机制。CPN60 通过降低破骨细胞分化相关基因和蛋白的表达，抑制了 RANKL 诱导的破骨细胞分化。CPN60 干扰了 RANKL 与 RANK 的结合，这一点通过表面等离子体共振（SPR）和免疫荧光得到了阐明。硅学分子对接分析进一步证实了 CPN60 对 RANKL 和 RANK 结合的干扰作用。CPN60 在 mRNA 和蛋白质水平上抑制了 RANKL 诱导的破骨细胞分化过程中与钙依赖途径相关的分子的表达。微阵列分析显示，在 CPN60 处理的 RAW 264.7 细胞中，脂钙蛋白 2（Lcn2）的表达升高，这与破骨细胞分化的抑制密切相关。抑制 Lcn2 会降低 CPN60 对破骨细胞分化的抑制作用，这表明 CPN60 增加 Lcn2 的表达有助于抑制破骨细胞的生成。此外，通过减少胶原特异性抗体的产生和抑制破骨细胞的分化，CPN60 治疗可减轻胶原诱导的关节炎小鼠的关节炎症状。总之，P. freudenreichii MJ2的CPN60干扰了RANKL-RANK的结合，降低了破骨细胞分化相关基因和蛋白的表达，并上调了Lcn2的表达，从而抑制了RANKL诱导的破骨细胞分化，这可能有助于改善胶原蛋白诱导的关节炎。

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引用次数: 0

Cdc25A phosphatase is activated and mediates neuronal cell death by PUMA via pRb/E2F1 pathway in a model of Parkinson's disease 在帕金森病模型中，PUMA 通过 pRb/E2F1 通路激活 Cdc25A 磷酸酶并介导神经细胞死亡。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-09-19 DOI: 10.1016/j.bbamcr.2024.119848

Anoy Kumar Das, Subhas C. Biswas

Parkinson's disease (PD) is a predominant movement disorder caused mainly due to selective loss of the dopaminergic neurons in the substantia nigra pars compacta of the mid brain. There is currently no cure for PD barring treatments to manage symptoms. The reasons might be due to lack of precise understanding of molecular mechanisms leading to neurodegeneration. Aberrant cell cycle activation has been implicated in neuronal death pathways of various neurodegenerative diseases including PD. This study investigates the role of cell cycle regulator Cell division cycle 25A (Cdc25A) in a PD-relevant neuron death model induced by 6-OHDA treatment. We find Cdc25A is rapidly elevated, activated and is playing a key role in neuron death by regulating Rb phosphorylation and E2F1 activity. Knockdown of Cdc25A via shRNA downregulates the levels of pro-apoptotic PUMA, an E2F1 target and cleaved Caspase-3 levels, suggesting Cdc25A may regulate neuronal apoptosis through these effectors. Our work sheds light on the intricate signaling networks involved in neurodegeneration and highlights Cdc25A as a potential therapeutic target for mitigating aberrant cell cycle re-entry underlying PD pathogenesis. These novel insights into molecular mechanisms provide a foundation for future development of neuroprotective strategies to slow or prevent progression of this debilitating disease.

帕金森病（Parkinson's disease，简称 PD）是一种主要的运动障碍疾病，主要是由于中脑黑质旁的多巴胺能神经元选择性丧失所致。目前，除控制症状的治疗方法外，帕金森病尚无根治方法。究其原因，可能是对导致神经变性的分子机制缺乏准确的认识。细胞周期激活异常与包括帕金森病在内的多种神经退行性疾病的神经元死亡途径有关。本研究探讨了细胞周期调节因子细胞分裂周期 25A（Cdc25A）在 6-OHDA 治疗诱导的帕金森病相关神经元死亡模型中的作用。我们发现 Cdc25A 快速升高、激活，并通过调节 Rb 磷酸化和 E2F1 活性在神经元死亡中发挥关键作用。通过 shRNA 敲除 Cdc25A 可下调促凋亡 E2F1 靶点 PUMA 的水平和 Caspase-3 的裂解水平，这表明 Cdc25A 可通过这些效应因子调控神经元凋亡。我们的研究揭示了神经退行性变所涉及的错综复杂的信号网络，并强调了 Cdc25A 是缓解作为帕金森病发病基础的细胞周期重入异常的潜在治疗靶点。这些对分子机制的新见解为未来开发神经保护策略以减缓或预防这种使人衰弱的疾病的进展奠定了基础。

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引用次数: 0

Insights into eukaryotic translation initiation factor 5A: Its role and mechanisms in protein synthesis 真核生物翻译起始因子 5A：在蛋白质合成中的作用和机制。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-09-19 DOI: 10.1016/j.bbamcr.2024.119849

Keying Guo, Jie Zhou

The protein synthesis within eukaryotic cells is a complex process involving various translation factors. Among these factors, eukaryotic translation initiation factor 5 A (eIF5A) emerges as a crucial translation factor with high evolutionary conservation. eIF5A is unique as it is the only protein in eukaryotic cells containing the hypusine modification. Initially presumed to be a translation initiation factor, eIF5A was subsequently discovered to act mainly during the translation elongation phase. Notably, eIF5A facilitates the translation of peptide sequences containing polyproline stretches and exerts a universal regulatory effect on the elongation and termination phases of protein synthesis. Additionally, eIF5A indirectly affects various physiological processes within the cell by modulating the translation of specific proteins. This review provides a comprehensive overview of the structure, physiological functions, various post-translational modifications of eIF5A, and its association with various human diseases. The comparison between eIF5A and its bacterial homolog, EF-P, extends the discussion to the evolutionary conservation of eIF5A. This highlights its significance across different domains of life.

真核细胞内的蛋白质合成是一个涉及各种翻译因子的复杂过程。在这些因子中，真核翻译起始因子 5A（eIF5A）是一个具有高度进化保护性的关键翻译因子。eIF5A 的独特之处在于它是真核细胞中唯一含有次碱基修饰的蛋白质。eIF5A 最初被认为是一种翻译起始因子，后来发现它主要在翻译延伸阶段发挥作用。值得注意的是，eIF5A 能促进含有多脯氨酸段的肽序列的翻译，并对蛋白质合成的延伸和终止阶段产生普遍的调节作用。此外，eIF5A 还通过调节特定蛋白质的翻译间接影响细胞内的各种生理过程。本综述全面概述了 eIF5A 的结构、生理功能、各种翻译后修饰及其与各种人类疾病的关联。eIF5A 与细菌同源物 EF-P 的比较将讨论扩展到 eIF5A 的进化保护。这凸显了它在不同生命领域的重要性。

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