Biochimica et biophysica acta. Molecular basis of disease最新文献

Mitochondrial respiratory complex II is altered in renal carcinoma 肾癌的线粒体呼吸复合体 II 发生了改变。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-31 DOI: 10.1016/j.bbadis.2024.167556

Background

Renal cell carcinoma (RCC) is a disease typified by anomalies in cell metabolism. The function of mitochondria, including subunits of mitochondrial respiratory complex II (CII), in particular SDHB, are often affected. Here we investigated the state and function of CII in RCC patients.

Methods

We evaluated tumour tissue as well as the adjacent healthy kidney tissue of 78 patients with RCC of different histotypes, focusing on their mitochondrial function. As clear cell RCC (ccRCC) is by far the most frequent histotype of RCC, we focused on these patients, which were grouped based on the pathological WHO/ISUP grading system to low- and high-grade patients, indicative of prognosis. We also evaluated mitochondrial function in organoids derived from tumour tissue of 7 patients.

Results

ccRCC tumours were characterized by mutated von Hippel-Lindau gene and high expression of carbonic anhydrase IX. We found low levels of mitochondrial DNA, protein and function, together with CII function in ccRCC tumour tissue, but not in other RCC types and non-tumour tissues. Mitochondrial content increased in high-grade tumours, while the function of CII remained low. Tumour organoids from ccRCC patients recapitulated molecular characteristics of RCC tissue.

Conclusions

Our findings suggest that the state of CII, epitomized by its assembly and SDHB levels, deteriorates with the progressive severity of ccRCC. These observations hold the potential for stratification of patients with worse prognosis and may guide the exploration of targeted therapeutic interventions.

背景：肾细胞癌（RCC）是一种以细胞代谢异常为特征的疾病。线粒体的功能，包括线粒体呼吸复合体 II（CII）亚基，尤其是 SDHB，经常受到影响。在此，我们研究了 RCC 患者体内 CII 的状态和功能：方法：我们对 78 名不同组织类型的 RCC 患者的肿瘤组织和邻近的健康肾脏组织进行了评估，重点研究了它们的线粒体功能。由于透明细胞 RCC（ccRCC）是迄今为止最常见的 RCC 组织类型，因此我们重点研究了这些患者，并根据病理 WHO/ISUP 分级系统将其分为低分级和高级别患者，以反映预后情况。结果：ccRCC肿瘤的特点是von Hippel-Lindau基因突变和碳酸酐酶IX的高表达。我们在 ccRCC 肿瘤组织中发现线粒体 DNA、蛋白质和功能以及 CII 功能水平较低，而在其他 RCC 类型和非肿瘤组织中则没有发现。高级别肿瘤中线粒体含量增加，而CII的功能仍然很低。ccRCC患者的肿瘤组织细胞再现了RCC组织的分子特征：我们的研究结果表明，随着ccRCC病情的逐渐严重，CII的状态（以其组装和SDHB水平为缩影）会恶化。这些观察结果有望对预后较差的患者进行分层，并为探索有针对性的治疗干预措施提供指导。

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引用次数: 0

BCAR1 facilitates the survival of lung adenocarcinoma cells by augmenting the unfolded protein response, autophagy, and the formation of vasculogenic mimicry BCAR1 通过增强未折叠蛋白反应、自噬和血管生成模拟的形成来促进肺腺癌细胞的存活。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-31 DOI: 10.1016/j.bbadis.2024.167558

Background

Our objective was to elucidate the pivotal roles of BCAR1 in unfolded protein response (UPR), autophagy and vasculogenic mimicry (VM) formation, processes that essential for the metastasis of lung adenocarcinoma (LUAD) cells.

Methods

The morphological assessment of endoplasmic reticulum (ER) status and autolysosomes in H1975 and H1299 LUAD cells following BCAR1 knockout (KO) was conducted using transmission electron microscope. The expression of markers and cellular functions related to the UPR, autophagy, and VM formation were examined in LUAD cells tissues. Additionally, proteomic analysis of LUAD cells was performed via mass spectrometry, and the pertinent signaling pathways were analyzed using bioinformatics tools.

Results

BCAR1-KO inhibited autophagy and UPR induced triggered starvation in LUAD cells. Cleaved-ATF6a-mediated UPR and subsequent autophagy, enhanced by BCAR1, were confirmed using the UPR stimulator and blocker. High BCAR1 expression, along with elevated UPR and autophagy, predicts poor prognosis in LUAD patients. BCAR1-KO reduced tube formation and VM markers expressions in LUAD cells. Additionally, BCAR1 expression positively correlated with VM formation in BALB/c-nu mice xenografts and LUAD patient tissues.

Conclusion

BCAR1 promotes LUAD metastasis by enhancing cancer cell survival in nutrient-poor environments through ATF6-mediated UPR activation and autophagy. As BCAR1 induces VM formation, metastatic lesions eventually colonize. Thus, BCAR1 is a promising anti-metastasis target.

背景：我们的目的是阐明BCAR1在未折叠蛋白反应（UPR）、自噬和血管生成模拟（VM）形成过程中的关键作用，这些过程对肺腺癌（LUAD）细胞的转移至关重要：方法：利用透射电子显微镜对 BCAR1 基因敲除（KO）后的 H1975 和 H1299 LUAD 细胞的内质网（ER）状态和自溶体进行形态学评估。研究还检测了LUAD细胞组织中与UPR、自噬和VM形成相关的标记物表达和细胞功能。此外，还通过质谱对LUAD细胞进行了蛋白质组学分析，并使用生物信息学工具分析了相关信号通路：结果：BCAR1-KO抑制了LUAD细胞的自噬和UPR诱导的饥饿。利用UPR刺激剂和阻断剂证实了BCAR1介导的Cleaved-ATF6a UPR和随后的自噬。BCAR1的高表达以及UPR和自噬的升高可预测LUAD患者的不良预后。BCAR1-KO 可减少 LUAD 细胞中的管形成和 VM 标记表达。此外，BCAR1的表达与BALB/c-nu小鼠异种移植和LUAD患者组织中VM的形成呈正相关：结论：BCAR1通过ATF6介导的UPR激活和自噬，提高了癌细胞在营养不良环境中的存活率，从而促进了LUAD的转移。由于 BCAR1 能诱导 VM 形成，转移病灶最终会定植。因此，BCAR1 是一个很有前景的抗转移靶点。

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引用次数: 0

EZH2 contributes to sepsis-induced acute lung injury through regulating macrophage polarization EZH2通过调节巨噬细胞的极化对脓毒症诱发的急性肺损伤起作用

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-28 DOI: 10.1016/j.bbadis.2024.167554

Background

Zeste enhancer homolog 2 (EZH2) is a pivotal regulator of gene dynamics implicated in the progression of sepsis-induced acute lung injury (SALI). EZH2 regulates aberrant inflammatory and immune responses in macrophages via unconventional biochemical interactions. However, the mechanisms driving atypical behavior of EZH2 during sepsis remain elusive, and therapeutic strategies targeting EZH2 are currently underutilized.

Purpose

This study aimed to investigate how EZH2 regulates macrophage polarization through the AKT pathway to improve SALI and to explore therapeutic drugs targeting EZH2.

Methods

We used Western blotting, hematoxylin-eosin stainin, immunofluorescence, flow cytometry, qRT-PCR, RNA sequencing, and chromatin immunoprecipitation sequencing methods to investigate regulation of macrophage immune response by EZH2 and explored its specific mechanism. These methods were also used to examine the protective effects of MS177 against SALI.

Results

Specific deletion of EZH2 in macrophages reduced the level of AKTIP, downregulated the M1 macrophage markers CD86 and cytotoxic T cell marker CD8+, upregulated the M2 macrophage marker CD206 and regulatory T cell marker FOXP3+, decreased the levels of pro-inflammatory cytokines IL-6, TNF-α, and IL-β, and increased the level of anti-inflammatory cytokine IL-10. This ultimately improved lung injury and mortality in SALI mice. EZH2 promoted the M1 polarization of macrophages by activating AKT2 via direct binding to the promoter region of AKTIP in a SALI mouse model. Furthermore, MS177 alleviated SALI by degrading EZH2 both in vitro and in vivo.

Conclusion

EZH2 regulates macrophage polarization via the AKTIP-AKT2 pathway. Our findings suggest that MS177 is a promising therapeutic agent for EZH2-dependent SALI.

背景：Zeste 增强子同源物 2（EZH2）是基因动态的关键调节因子，与脓毒症诱发的急性肺损伤（SALI）的进展有关。EZH2 通过非常规的生化相互作用调节巨噬细胞的异常炎症和免疫反应。目的：本研究旨在探讨 EZH2 如何通过 AKT 通路调控巨噬细胞极化以改善 SALI，并探索针对 EZH2 的治疗药物：我们采用Western印迹、苏木精-伊红染色、免疫荧光、流式细胞术、qRT-PCR、RNA测序和染色质免疫沉淀测序等方法研究了EZH2对巨噬细胞免疫应答的调控，并探讨了其具体机制。这些方法还被用于研究MS177对SALI的保护作用：结果：EZH2在巨噬细胞中的特异性缺失降低了AKTIP的水平，下调了M1巨噬细胞标志物CD86和细胞毒性T细胞标志物CD8+，上调了M2巨噬细胞标志物CD206和调节性T细胞标志物FOXP3+，降低了促炎细胞因子IL-6、TNF-α和IL-β的水平，提高了抗炎细胞因子IL-10的水平。这最终改善了 SALI 小鼠的肺损伤和死亡率。在 SALI 小鼠模型中，EZH2 通过直接结合 AKTIP 的启动子区域激活 AKT2，从而促进巨噬细胞的 M1 极化。此外，MS177通过在体外和体内降解EZH2减轻了SALI：结论：EZH2通过AKTIP-AKT2途径调节巨噬细胞的极化。我们的研究结果表明，MS177是一种治疗EZH2依赖性SALI的有效药物。

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引用次数: 0

TMEM106B knockdown exhibits a neuroprotective effect in Parkinson's disease models via regulating autophagy-lysosome pathway 通过调节自噬-溶酶体通路，敲除 TMEM106B 可在帕金森病模型中发挥神经保护作用

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-28 DOI: 10.1016/j.bbadis.2024.167553

Background

TMEM106B, a lysosomal transmembrane protein, has been reported to be associated with Parkinson's disease (PD). However, the precise physiopathologic mechanism of TMEM106B in PD remains unclear.

Objective

This study aimed to explore the influence of TMEM106B on the autophagy-lysosome pathway (ALP) in PD.

Methods

55 patients with PD and 40 healthy controls were enrolled. RT-qPCR and ELISA were employed to assess the levels of TMEM106B. In vitro and in vivo models of PD, Lentivirus-shTMEM106B and AAV-shTMEM106B were used to knockdown the expression of TMEM106B. Behavioral experiments, western blot, immunofluorescence, and immunohistochemistry were used to detect the effect of TMEM106B on the ALP process.

Results

We found that the levels of TMEM106B were increased in the PD patients and PD models. TMEM106B knockdown markedly improved the motor deficits and tyrosine hydroxylase (TH) expression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. TMEM106B knockdown promoted α-syn clearance by regulating the ALP process in MPP⁺-induced SH-SY5Y cells and MPTP-treated mice. Further studies revealed that TMEM106B knockdown might activate ALP through activating AMPK-mTOR-TFEB axis. Furthermore, TMEM106B may play a vital role in the ALP by mediating the expression of TDP43. Conclusions: Taken together, our study suggests that TMEM106B knockdown mediates the ALP pathway, leading to a decrease in α-syn, providing a new direction and perspective for the regulation of autophagy in PD.

背景据报道，溶酶体跨膜蛋白TMEM106B与帕金森病（PD）有关。本研究旨在探讨 TMEM106B 对帕金森病自噬-溶酶体途径（ALP）的影响。采用 RT-qPCR 和 ELISA 方法评估 TMEM106B 的水平。在体外和体内PD模型中，使用慢病毒-shTMEM106B和AAV-shTMEM106B敲除TMEM106B的表达。结果我们发现，TMEM106B在PD患者和PD模型中的水平均升高。TMEM106B的敲除明显改善了1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）缺失小鼠的运动障碍和酪氨酸羟化酶（TH）的表达。在MPP+诱导的SH-SY5Y细胞和MPTP处理的小鼠中，TMEM106B敲除可通过调节ALP过程促进α-syn的清除。进一步研究发现，TMEM106B敲除可能通过激活AMPK-mTOR-TFEB轴来激活ALP。此外，TMEM106B 可能通过介导 TDP43 的表达在 ALP 中发挥重要作用。结论综上所述，我们的研究表明，TMEM106B敲除可介导ALP通路，导致α-syn的减少，这为自噬在帕金森病中的调控提供了一个新的方向和视角。

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引用次数: 0

The relevance of the heme oxygenase system in alleviating diabetes-related hormonal and metabolic disorders 血红素加氧酶系统在缓解糖尿病相关激素和代谢紊乱方面的作用

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-25 DOI: 10.1016/j.bbadis.2024.167552

Heme oxygenase (HO) is an enzyme that catalyzes heme degradation. HO dysfunction is linked to various pathological conditions, including diabetes. Results of animal studies indicate that HO expression and activity are downregulated in experimentally induced diabetes. This is associated with severe hormonal and metabolic disturbances. However, these pathological changes have been shown to be reversed by therapy with HO activators. In animals with experimentally induced diabetes, HO was upregulated by genetic manipulation or by pharmacological activators such as hemin and cobalt protoporphyrin. Induction of HO alleviated elevated blood glucose levels and improved insulin action, among other effects. This effect resulted from beneficial changes in the main insulin-sensitive tissues, i.e., the skeletal muscle, the liver, and the adipose tissue. The action of HO activators was due to positive alterations in pivotal signaling molecules and regulatory enzymes. Furthermore, diabetes-related oxidative and inflammatory stress was reduced due to HO induction. HO upregulation was effective in various animal models of type 1 and type 2 diabetes. These data suggest the possibility of testing HO activators as a potential tool for alleviating hormonal and metabolic disorders in people with diabetes.

血红素加氧酶（HO）是一种催化血红素降解的酶。HO 功能障碍与包括糖尿病在内的多种病理情况有关。动物研究结果表明，在实验诱导的糖尿病中，HO 的表达和活性都会下调。这与严重的激素和代谢紊乱有关。然而，使用 HO 激活剂治疗后，这些病理变化被逆转。在实验性糖尿病动物中，通过基因操作或药物激活剂（如hemin和原卟啉钴）可上调HO。诱导 HO 可缓解血糖水平升高，改善胰岛素作用等效果。这种效应来自主要胰岛素敏感组织（即骨骼肌、肝脏和脂肪组织）的有益变化。HO 激活剂的作用是由于关键信号分子和调节酶发生了积极变化。此外，由于HO的诱导作用，与糖尿病相关的氧化应激和炎症应激得以减轻。HO上调对各种1型和2型糖尿病动物模型都有效。这些数据表明，有可能将HO激活剂作为缓解糖尿病患者荷尔蒙和新陈代谢紊乱的潜在工具进行测试。

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引用次数: 0

Thioredoxin-1 protein interactions in neuronal survival and neurodegeneration 硫氧还蛋白-1 蛋白在神经元存活和神经退行性变中的相互作用

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-23 DOI: 10.1016/j.bbadis.2024.167548

Neuronal cell death remains the principal pathophysiologic hallmark of neurodegenerative diseases and the main challenge for treatment strategies. Thioredoxin1 (Trx1) is a major cytoplasmic thiol oxidoreductase protein involved in redox signaling, hence a crucial player in maintaining neuronal health. Trx1 levels are notably reduced in neurodegenerative diseases including Alzheimer's and Parkinson's diseases, however, the impact of this decrease on neuronal physiology remains largely unexplored. This is mainly due to the nature of Trx1 redox regulatory role which is afforded by a rapid electron transfer to its oxidized protein substrates. During this reaction, Trx1 forms a transient bond with the oxidized disulfide bond in the substrate. This is a highly fast reaction which makes the identification of Trx1 substrates a technically challenging task. In this project, we utilized a transgenic mouse model expressing a Flag-tagged mutant form of Trx1 that can form stable disulfide bonds with its substrates, hence allowing identification of the Trx1 target proteins. Autophagy is a vital housekeeping process in neurons that is critical for degradation of damaged proteins under oxidative stress conditions and is interrupted in neurodegenerative diseases. Given Trx1's suggested involvement in autophagy, we aimed to identify potential Trx1 substrates following pharmacologic induction of autophagy in primary cortical neurons. Treatment with rapamycin, an autophagy inducer, significantly reduced neurite outgrowth and caused cytoskeletal alterations. Using immunoprecipitation and mass spectrometry, we have identified 77 Trx1 target proteins associated with a wide range of cellular functions including cytoskeletal organization and neurodegenerative diseases. Focusing on neuronal cytoskeleton organization, we identified a novel interaction between Trx1 and RhoB which was confirmed in genetic models of Trx1 downregulation in primary neuronal cultures and HT22 mouse immortalized hippocampal neurons. The applicability of these findings was also tested against the publicly available proteomic data from Alzheimer's patients. Our study uncovers a novel role for Trx1 in regulating neuronal cytoskeleton organization and provides a mechanistic explanation for its multifaceted role in the physiology and pathology of the nervous system, offering new insights into the molecular mechanisms underlying neurodegeneration.

神经细胞死亡仍然是神经退行性疾病的主要特征，也是治疗策略面临的主要挑战。硫氧还蛋白1（Trx1）是一种主要的细胞质硫醇氧化还原酶蛋白，参与氧化还原信号转导，因此是维持神经元健康的关键因素。在包括阿尔茨海默氏症和帕金森氏症在内的神经退行性疾病中，Trx1 的水平明显下降，然而，这种下降对神经元生理学的影响在很大程度上仍未得到探讨。这主要是由于 Trx1 的氧化还原调节作用是通过其氧化蛋白质底物的快速电子转移来实现的。在这一反应过程中，Trx1 与底物中的氧化二硫键形成瞬时结合。这种反应速度极快，因此鉴定 Trx1 底物是一项极具技术挑战性的任务。在本项目中，我们利用转基因小鼠模型表达了一种能与底物形成稳定二硫键的 Flag 标记突变型 Trx1，从而鉴定出了 Trx1 的靶蛋白。自噬是神经元中一个重要的内务过程，在氧化应激条件下对降解受损蛋白质至关重要，在神经退行性疾病中会被中断。鉴于 Trx1 被认为参与了自噬，我们的目的是在原代皮质神经元中通过药物诱导自噬后鉴定潜在的 Trx1 底物。雷帕霉素是一种自噬诱导剂，它能显著减少神经元的生长并引起细胞骨架的改变。通过免疫沉淀和质谱分析，我们发现了 77 个与细胞骨架组织和神经退行性疾病等多种细胞功能相关的 Trx1 靶蛋白。以神经细胞骨架组织为重点，我们发现了 Trx1 和 RhoB 之间的新型相互作用，这种相互作用在原代神经元培养物和 HT22 小鼠永生海马神经元中 Trx1 下调的遗传模型中得到了证实。这些发现的适用性还通过公开的阿尔茨海默病患者蛋白质组数据进行了检验。我们的研究发现了 Trx1 在调节神经元细胞骨架组织中的新作用，并从机理上解释了它在神经系统生理和病理中的多方面作用，为神经退行性变的分子机制提供了新的见解。

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引用次数: 0

Hyperglycaemia induces diet-dependent defects of the left-right axis by lowering intracellular pH 高血糖通过降低细胞内 pH 值诱发饮食依赖性左右轴缺陷。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-21 DOI: 10.1016/j.bbadis.2024.167550

Pregestational diabetes is a risk factor for congenital anomalies, including heterotaxy syndrome, a rare birth defect characterized by the abnormal arrangement of organs relative to the left-right (L-R) body axis. To provide insight into the underlying mechanism by which diabetes induces heterotaxy, we here analyzed the L-R axis of mouse embryos of diabetic dams. Various Pitx2 expression patterns indicative of disruption of L-R axis formation were apparent in such embryos. Expression of Nodal at the node, which triggers a Nodal-Pitx2 expression cascade in lateral plate mesoderm, showed marked regression associated with L-R axis malformation. This regression was similar to that apparent in Wnt3a^−/− embryos, and canonical Wnt signalling was indeed found to be downregulated in embryos of diabetic dams. RNA sequencing revealed dysregulation of glycolysis in embryos of diabetic dams, and high glucose lowered intracellular pH in the primitive streak, leading to the suppression of Wnt signalling and the regression of Nodal expression. Of note, maternal vitamin A intake increased the incidence of L-R axis defects in embryos of diabetic dams, with dysregulation of retinoic acid metabolism being apparent in these embryos and in Wnt3a^−/− embryos. Our results shed light on the mechanisms underlying embryopathies associated with maternal diabetes and suggest the importance of diet for prevention of heterotaxy.

妊娠糖尿病是先天性畸形的一个风险因素，包括异轴综合征，这是一种罕见的先天缺陷，其特征是器官相对于身体左-右（L-R）轴的异常排列。为了深入了解糖尿病诱导异轴的内在机制，我们在此分析了糖尿病母鼠胚胎的 L-R 轴。在这些胚胎中，各种表明 L-R 轴形成中断的 Pitx2 表达模式显而易见。节点处的 Nodal 表达会触发侧板中胚层中的 Nodal-Pitx2 表达级联，这种表达的明显衰退与 L-R 轴畸形有关。这种退行与 Wnt3a-/- 胚胎中的退行相似，而且在糖尿病母体的胚胎中确实发现典型的 Wnt 信号下调。RNA 测序显示，糖尿病母鼠胚胎中糖酵解失调，高糖降低了原始条纹细胞内的 pH 值，导致 Wnt 信号受抑制和 Nodal 表达减弱。值得注意的是，母体维生素 A 的摄入增加了糖尿病母体胚胎 L-R 轴缺陷的发生率，这些胚胎和 Wnt3a-/- 胚胎的视黄酸代谢明显失调。我们的研究结果揭示了与母体糖尿病相关的胚胎病理机制，并提示了饮食对预防异位症的重要性。

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引用次数: 0

Increased NPM1 inhibit ferroptosis and aggravate renal fibrosis via Nrf2 pathway in chronic kidney disease 慢性肾脏病患者体内 NPM1 的增加会通过 Nrf2 途径抑制铁蛋白沉积并加重肾脏纤维化。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-20 DOI: 10.1016/j.bbadis.2024.167551

Recent findings underscore the significance of ferroptosis, an innovative iron-dependent mode of cell death, in the etiology and progression of chronic kidney disease (CKD). Nucleophosmin 1 (NPM1), a nucleolar protein, contributes to fibrogenesis and modulates cellular functions and mortality. Initial investigations utilized bioinformatics techniques to pinpoint genes with altered expression in CKD and to forecast the potential links between NPM1, ferroptosis, and renal fibrosis. Increased NPM1 expression was verified in the renal tissues of CKD patients. Experimental models of renal fibrosis in both animals and cells were then used for further study. The suppression of NPM1 led to an augmentation in iron metabolism and lipid peroxidation processes integral to ferroptosis, contributing to the mitigation of renal fibrosis. In contrast, an elevation in NPM1 expression had the opposite effect. This modulation may be interconnected with the nuclear factor erythroid 2–related factor 2 pathway. Moreover, the application of the ferroptosis inhibitor, Fer-1, not only obstructed ferroptosis but also diminished NPM1 expression, which, in turn, contributed to the alleviation of renal fibrosis. Thus, our findings suggest that in CKD the NPM1 level increased and led to decreased ferroptosis and aggravated renal fibrosis via an Nrf2 pathway. Ferroptosis inhibitor can alleviate renal fibrosis.

最近的研究结果表明，慢性肾脏病（CKD）的病因和进展中存在一种创新的铁依赖性细胞死亡模式--铁变态反应（ferroptosis）。Nucleophosmin 1（NPM1）是一种核仁蛋白，它有助于纤维形成并调节细胞功能和死亡率。最初的研究利用生物信息学技术确定了 CKD 中表达改变的基因，并预测了 NPM1、铁变态反应和肾脏纤维化之间的潜在联系。NPM1 在慢性肾功能衰竭患者肾组织中的表达增加已得到证实。然后利用动物和细胞肾纤维化实验模型进行了进一步研究。抑制 NPM1 会导致铁代谢和脂质过氧化过程的增强，从而减轻肾脏纤维化。相反，NPM1 表达的增加则产生了相反的效果。这种调节可能与核因子红细胞 2 相关因子 2 途径相互关联。此外，应用铁突变抑制剂 Fer-1 不仅能阻碍铁突变，还能减少 NPM1 的表达，这反过来又有助于减轻肾脏纤维化。因此，我们的研究结果表明，在慢性肾脏病患者中，NPM1水平升高，并通过Nrf2途径导致铁蛋白沉积减少和肾纤维化加重。铁蛋白沉积抑制剂可缓解肾脏纤维化。

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引用次数: 0

Mitostasis in age-associated neurodegeneration 与年龄相关的神经变性中的有丝分裂。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-20 DOI: 10.1016/j.bbadis.2024.167547

Mitochondria are essential organelles that play crucial roles in various metabolic and signalling pathways. Proper neuronal function is highly dependent on the health of these organelles. Of note, the intricate structure of neurons poses a critical challenge for the transport and distribution of mitochondria to specific energy-intensive domains, such as synapses and dendritic appendages. When faced with chronic metabolic challenges and bioenergetic deficits, neurons undergo degeneration. Unsurprisingly, disruption of mitostasis, the process of maintaining cellular mitochondrial content and function within physiological limits, has been implicated in the pathogenesis of several age-associated neurodegenerative disorders. Indeed, compromised integrity and metabolic activity of mitochondria is a principal hallmark of neurodegeneration. In this review, we survey recent findings elucidating the role of impaired mitochondrial homeostasis and metabolism in the onset and progression of age-related neurodegenerative disorders. We also discuss the importance of neuronal mitostasis, with an emphasis on the major mitochondrial homeostatic and metabolic pathways that contribute to the proper functioning of neurons. A comprehensive delineation of these pathways is crucial for the development of early diagnostic and intervention approaches against neurodegeneration.

线粒体是重要的细胞器，在各种代谢和信号通路中发挥着关键作用。神经元的正常功能高度依赖于这些细胞器的健康。值得注意的是，神经元错综复杂的结构对线粒体向特定能量密集区（如突触和树突附属物）的运输和分布提出了严峻挑战。当面临长期代谢挑战和生物能不足时，神经元会发生退化。有丝分裂稳态是将细胞线粒体的含量和功能维持在生理限度内的过程，它与几种与年龄相关的神经退行性疾病的发病机制有关，这一点不足为奇。事实上，线粒体的完整性和代谢活性受到损害是神经退行性疾病的主要标志。在这篇综述中，我们回顾了最近的研究成果，这些成果阐明了线粒体平衡和代谢受损在与年龄相关的神经退行性疾病的发生和发展中的作用。我们还讨论了神经元有丝分裂的重要性，重点是有助于神经元正常功能的主要线粒体平衡和代谢途径。全面描述这些途径对于开发早期诊断和干预神经退行性疾病的方法至关重要。

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引用次数: 0

Conditional Pten inactivation in pituitary results in sex-specific prolactinoma formation 垂体中的条件性 Pten 失活导致催乳素瘤的形成具有性别特异性。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-18 DOI: 10.1016/j.bbadis.2024.167543

Pituitary tumors, including prolactinomas, present significant clinical challenges that require a deeper understanding of their molecular roots for improved diagnostics and therapies. Here, we investigate the role of the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K) pathway in pituitary tumorigenesis using a mouse model. Conditional knockout of Pten in all pituitary cell lineages resulted in prolactinoma formation exclusively in female mice, demonstrating the critical role of PTEN in pituitary homeostasis. While Pten inactivation induced Akt activation in all pituitary cells, only prolactin-producing cells exhibited tumorigenic changes, suggesting specific cell-type effects. Histological and molecular analyses of prolactinomas revealed similarities with human pituitary tumors, such as decreased vascularization and cell adhesion proteins and increased accumulation of cell cycle proteins. Notably, prolactinomas displayed diminished levels of phosphorylated extracellular signal-regulated kinase (ERK), implicating downregulation of ERK in tumorigenesis. Finally, we analyzed PTEN/PI3K activation in a collection of human pituitary tumors. Overall, our study delineates the intricate interplay between the PTEN and ERK signaling pathways, providing insights into sex-specific mechanisms of pituitary tumorigenesis and potential therapeutic strategies for prolactinomas.

垂体瘤（包括泌乳素瘤）给临床带来了巨大挑战，需要深入了解其分子根源，以改进诊断和治疗。在这里，我们利用小鼠模型研究了磷酸酶和天丝同源物（PTEN）/磷酸肌醇3-激酶（PI3K）通路在垂体肿瘤发生中的作用。在所有垂体细胞系中条件性敲除Pten会导致雌性小鼠泌乳素瘤的形成，这证明了PTEN在垂体稳态中的关键作用。虽然 Pten 失活会诱导所有垂体细胞中的 Akt 激活，但只有产生泌乳素的细胞才会出现致瘤变化，这表明存在特定的细胞类型效应。泌乳素瘤的组织学和分子分析显示了与人类垂体瘤的相似之处，如血管化和细胞粘附蛋白减少以及细胞周期蛋白积累增加。值得注意的是，泌乳素瘤的细胞外信号调节激酶（ERK）磷酸化水平降低，表明ERK下调与肿瘤发生有关。最后，我们分析了一系列人类垂体瘤中 PTEN/PI3K 的激活情况。总之，我们的研究描述了 PTEN 和 ERK 信号通路之间错综复杂的相互作用，为垂体肿瘤发生的性别特异性机制和泌乳素瘤的潜在治疗策略提供了见解。

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