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

DOCK2 deficiency alleviates neuroinflammation and affords neuroprotection after spinal cord injury 脊髓损伤后，缺乏 DOCK2 可减轻神经炎症并提供神经保护。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-01 DOI: 10.1016/j.bbamcr.2024.119882

Haocong Zhang, Liangbi Xiang, Hong Yuan, Hailong Yu

Neuroinflammation-caused secondary injury is a key event after spinal cord injury (SCI). Dedicator of cytokinesis 2 (DOCK2) belonging to DOCK-A subfamily has a vital role in microglia polarization and neuroinflammation via mediating Rac activation. However, the role of DOCK2 in SCI is unclear. In the present study, SCI model in mice was established by an impactor at thoracic T10 level. DOCK2 expression was significantly increased in the spinal cord after SCI. After knocking down DOCK2 using a lentivirus-mediated method, SCI mice exhibited improved motor function recovery, as revealed by increased Basso Mouse Scale (BMS) score, angle of incline, and relatively coordinated footprint, and decreased damaged area in the spinal cord. DOCK2 deficiency reduced neuronal apoptosis in the spinal cord after injury. Besides, deficiency of DOCK2 suppressed neuroinflammation after SCI, demonstrated by the reduction in pro-inflammatory mediators including IFN-γ, IL-1β and IL-6 and the increase in IL-4, IL-10 and IL-13, anti-inflammatory factors. The CD86, iNOS and COX-2 were down-regulated in the spinal cord, whereas CD206, Arg-1 and TGF-β were up-regulated by DOCK2 deficiency. Rac activation was prevented by DOCK2 deficiency following SCI. In vitro experiments were conducted for further verification. Treatment of BV-2 microglia with lentivirus-mediated DOCK2 inhibited IFN-γ/LPS-induced pro-inflammatory microglia polarization but increased IL-4-induced anti-inflammatory microglia, through inhibiting Rac activation. In brief, our data reveal that DOCK2 deficiency improves functional recovery in mice after SCI, which is related to Rac activation.

神经炎症引起的继发性损伤是脊髓损伤（SCI）后的一个关键事件。属于 DOCK-A 亚家族的细胞因子 2（DOCK2）通过介导 Rac 激活，在小胶质细胞极化和神经炎症中发挥着重要作用。然而，DOCK2 在 SCI 中的作用尚不清楚。在本研究中，小鼠胸部 T10 水平的撞击器建立了 SCI 模型。SCI 后脊髓中 DOCK2 的表达明显增加。用慢病毒介导的方法敲除 DOCK2 后，SCI 小鼠的运动功能恢复得到改善，表现为巴索小鼠量表（BMS）评分、倾斜角度和相对协调的足印增加，脊髓受损面积减少。缺乏 DOCK2 可减少损伤后脊髓中神经元的凋亡。此外，DOCK2的缺乏还抑制了脊髓损伤后的神经炎症，表现为促炎介质（包括IFN-γ、IL-1β和IL-6）的减少和抗炎因子IL-4、IL-10和IL-13的增加。脊髓中的 CD86、iNOS 和 COX-2 下调，而 CD206、Arg-1 和 TGF-β 则因 DOCK2 缺乏而上调。脊髓损伤后，缺乏 DOCK2 可阻止 Rac 激活。为了进一步验证，我们进行了体外实验。用慢病毒介导的 DOCK2 处理 BV-2 小胶质细胞可抑制 IFN-γ/LPS 诱导的促炎性小胶质细胞极化，但通过抑制 Rac 激活，可增加 IL-4 诱导的抗炎性小胶质细胞。简而言之，我们的数据揭示了 DOCK2 缺乏能改善 SCI 后小鼠的功能恢复，这与 Rac 激活有关。

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引用次数: 0

Hypoxia enhances IL-8 signaling through inhibiting miR-128-3p expression in glioblastomas 缺氧通过抑制miR-128-3p在胶质母细胞瘤中的表达来增强IL-8信号。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-01 DOI: 10.1016/j.bbamcr.2024.119885

Kuo-Hao Ho , Shao-Yuan Hsu , Peng-Hsu Chen , Chia-Hsiung Cheng , Ann-Jeng Liu , Ming-Hsien Chien , Ku-Chung Chen

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor known for its hypoxic microenvironment. Understanding the dysregulated mechanisms in hypoxic GBM is crucial for its effective treatment. Through data mining of The Cancer Genome Atlas (TCGA) with hypoxia enrichment scores and in vitro experiments, miR-128-3p was negatively correlated with hypoxia signaling and the epithelial-mesenchymal transition (EMT). Additionally, lower miR-128-3p levels existed in hypoxic GBM, leading to desensitizing temozolomide (TMZ)'s efficacy, a first-line therapeutic drug for GBM. Overexpressing miR-128-3p enhanced both the in vitro and in vivo sensitivity of hypoxic gliomas to TMZ treatment. Mechanistically, HIF-1α suppressed miR-128-3p expression in hypoxic GBM. Through establishing miR-128-3p-mediated transcriptomic profiles and data mining, interleukin (IL)-8 was selected. IL-8 respectively showed positive and negative correlations with hypoxia and miR-128-3p, and was associated with poor TMZ therapeutic results in GBM. Elevated miR-128-3p, which targets both the 3′-untranslated region (UTR) and 5′UTR of IL-8, resulted in suppression of IL-8 expression. Moreover, IL-8 was validated to be involved in HIF-1α/miR-128-3p-regulated TMZ sensitivity and the EMT in hypoxic GBM cells. Collectively, the HIF-1α/miR-128-3p/IL-8 signaling pathway plays a critical role in promoting the progression of hypoxic GBM. Targeting this signaling pathway holds promise as a potential therapeutic strategy.

多形性胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，以其缺氧微环境而闻名。了解缺氧GBM的失调机制对其有效治疗至关重要。通过对癌症基因组图谱（TCGA）的数据挖掘和缺氧富集评分以及体外实验，miR-128-3p与缺氧信号传导和上皮-间质转化（EMT）呈负相关。此外，低氧GBM中存在较低的miR-128-3p水平，导致替莫唑胺（TMZ）的疗效脱敏，这是GBM的一线治疗药物。过表达miR-128-3p增强了缺氧胶质瘤对TMZ治疗的体外和体内敏感性。在机制上，HIF-1α抑制miR-128-3p在缺氧GBM中的表达。通过建立mir -128-3p介导的转录组谱和数据挖掘，选择白细胞介素(IL)-8。IL-8分别与缺氧和miR-128-3p呈正相关和负相关，并与TMZ治疗GBM效果差有关。miR-128-3p同时靶向IL-8的3'-非翻译区（UTR）和5'UTR，升高导致IL-8表达抑制。此外，IL-8被证实参与了缺氧GBM细胞中HIF-1α/ mir -128-3p调节的TMZ敏感性和EMT。总之，HIF-1α/miR-128-3p/IL-8信号通路在促进缺氧GBM的进展中起关键作用。靶向这一信号通路有望成为一种潜在的治疗策略。

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引用次数: 0

Functional analysis of yak alveolar type II epithelial cells at high and low altitudes based on single-cell sequencing 基于单细胞测序的高、低海拔牦牛肺泡II型上皮细胞功能分析。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-01 DOI: 10.1016/j.bbamcr.2024.119889

Jingyi Li , Nating Huang , Xun Zhang , Huizhen Wang , Jiarui Chen , Qing Wei

The adaptation of lung cells to high-altitude environments represents a notable gap in our understanding of how animals cope with hypoxic conditions. Alveolar epithelial cells type II (AEC II) are crucial for lung development and repair. However, their, specific role in the adaptation of yaks to high-altitude environments remains unclear. In this study, we aimed to address this gap by investigating the differential responses of AEC II in yaks at high and low altitudes (4000 m and 2600 m, respectively). We used the 10 × scRNA-seq technology to construct a comprehensive cell atlas of yak lung tissue, and identified 15 distinct cell classes. AEC II in high-altitude yaks revealed increased immunomodulatory, adhesive, and metabolic activities, which are crucial for maintaining lung tissue stability and energy supply under hypoxic conditions. Furthermore, alveolar epithelial progenitor cells within AEC II can differentiate into both Alveolar epithelial cell type I (AEC I) and AEC II. SHIP1 and other factors are promoters of AEC I transdifferentiation, whereas SFTPC and others promote AEC II transdifferentiation. This study provides new insights into the evolutionary adaptation of lung cells in plateau animals by elucidating the molecular mechanisms underlying AEC II adaptation to high-altitude environments.

肺细胞对高海拔环境的适应代表了我们对动物如何应对缺氧条件的理解中的一个显着差距。肺泡上皮细胞II型（AEC II）对肺的发育和修复至关重要。然而，它们在牦牛适应高海拔环境中的具体作用尚不清楚。在这项研究中，我们旨在通过研究高海拔和低海拔（分别为4000 m和2600 m）牦牛对AEC II的不同反应来解决这一差距。我们利用10 × scRNA-seq技术构建了牦牛肺组织完整的细胞图谱，鉴定出15个不同的细胞类别。高原牦牛AEC II表现出免疫调节、黏附和代谢活性的增强，这对维持低氧条件下肺组织的稳定和能量供应至关重要。此外，AEC II内的肺泡上皮祖细胞可以分化为I型肺泡上皮细胞（AEC I）和AEC II型。SHIP1等因子是AEC I转分化的促进因子，而SFTPC等因子是AEC II转分化的促进因子。本研究通过阐明AEC II型肺细胞适应高海拔环境的分子机制，为高原动物肺细胞的进化适应提供了新的见解。

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引用次数: 0

Unraveling the role of the P2X7 receptor in cancer radioresistance: Molecular insights and therapeutic implications

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-29 DOI: 10.1016/j.bbamcr.2025.119910

Seyedeh Nasibeh Mousavikia , Maryam M. Matin , Mohammad Taghi Bahreyni Tossi , Hosein Azimian

The P2X7 receptor, a key player in purinergic signaling, is a crucial factor in modulating the response of cancer cells to radiotherapy. The aim of this study was to elucidate the molecular mechanisms by which P2X7 receptor activation contributes to radioresistance in different cancer types. P2X7 receptor signaling influences cellular processes such as DNA damage repair and inflammatory responses, thereby improving tumor survival after radiation exposure. Activation of the P2X7 receptor leads to changes in the tumor microenvironment and promotes an adaptive response that enables cancer cells to resist therapeutic interventions. Therefore, targeting the P2X7 receptor could represent a new therapeutic strategy against cancer. By linking molecular insights with therapeutic implications, this research highlights the P2X7 receptor as a promising target for overcoming radioresistance in cancer therapy and paves the way for novel combination approaches that could significantly improve patient outcomes.

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引用次数: 0

SLC26A9 promotes the initiation and progression of breast cancer by activating the PI3K/AKT signaling pathway

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-27 DOI: 10.1016/j.bbamcr.2025.119912

Zhiyuan Ma , Hu Wang , Zhengxing Zhou , Chengli Lu , Minglin Zhang , Renmin Mu , Chengmin Zhang , Zhiqiang Yi , Zilin Deng , Yingying Zhao , Jiaxing Zhu , Guorong Wen , Hai Jin , Jiaxing An , Biguang Tuo , Peng Yuan , Xuemei Liu , Taolang Li

SLC26A9 is a member of the Slc26a family of multifunctional anion transporters that function as Cl⁻ channels in the stomach. We reported for the first time that SLC26A9 is involved in gastric tumorigenesis. However, the role of SLC26A9 in breast cancer has not yet been investigated. We first demonstrated that the upregulation of SLC26A9 is associated with the clinicopathological progression and poor prognosis of patients with breast cancer and is positively correlated with HER2 amplification. SLC26A9 alters the proliferation, migration, and invasion potential of breast cancer cells by regulating the PI3K/AKT signaling pathway. SLC26A9 acts as an oncogene in the development of breast cancer. These findings provide valuable insights for the development of future diagnostic and therapeutic strategies for BC.

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引用次数: 0

Inhibition of hydrogen peroxide-induced senescence markers by yeast-derived vacuoles in human lung fibroblasts

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-27 DOI: 10.1016/j.bbamcr.2025.119907

Su-Min Lee , Eunsu Seo , Yang-Hoon Kim , Jiho Min

Senescence significantly contributes to aging in various tissues, influenced by factors such as lysosomal alkalinization, which disrupts autophagic flux and accumulates toxic substances. This disruption leads to oxidative stress, increased lysosomal permeability, cellular senescence, and apoptosis. Similar to mammalian lysosomes, S. cerevisiae-derived vacuoles degrade macromolecules using hydrolytic enzymes and mitigate these aging effects. Our study assessed the anti-aging potential of yeast vacuoles in human lung fibroblasts treated with hydrogen peroxide (H₂O₂). Pretreatment with vacuoles at concentrations of 1, 5, and 10 μg/ml decreased SA-β-gal-positive cell counts, reduced mRNA levels of senescence markers (p21 and p53), and senescence-associated secretory phenotype (SASP) factors (IL-6 and TNF-α) compared to controls treated with H₂O₂ alone. Additionally, these vacuoles significantly diminished intracellular reactive oxygen species (ROS) levels, indicating their potential as effective lung anti-senescence agents. This study suggests that yeast vacuoles could be used as a preventive measure against changes associated with lung aging.

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引用次数: 0

H2S inhibition of xanthine dehydrogenase to xanthine oxidase conversion reduces uric acid levels and improves myoblast functions

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-27 DOI: 10.1016/j.bbamcr.2025.119909

Joshua MacNeil , Yuehong Wang , Guangdong Yang

Hydrogen sulfide (H₂S) is an important gasotransmitter that regulates a wide range of pathophysiological processes. Higher uric acid levels are associated with an increased risk of metabolic diseases. The causal mechanism linking H₂S signalling and uric acid metabolism in skeletal muscles has not yet been elucidated. This study aimed to explore the intertwined metabolisms of H₂S and uric acid as well as their integrated roles in controlling myoblast cell functions. It was first found that purine overload increased uric acid levels, promoted oxidative stress, mitochondrial damage, and apoptosis in cultured mouse myoblasts, which could be reversed by the exogenously application of H₂S at physiologically relevant concentration. In addition, H₂S significantly inhibited the expressions of inflammatory genes (encoding IL2, IL4, and TNFα) but had no effect on oxidative stress, mitochondrial damage and cell death induced by excessive uric acid. Mechanistically, H₂S inhibited xanthine oxidoreductase (XOR) activity by blocking the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO), thus reducing uric acid levels and improving myoblast functions. In addition, purine and uric acid attenuated the expression of cystathionine gamma-lyase (CSE, an H₂S-generating enzyme) and suppressed endogenous H₂S production. Blood uric acid levels and skeletal muscle XOR activity were significantly higher in CSE knockout mice than in wild-type mice. This study revealed a mutual interaction between H₂S signalling and uric acid metabolism in the regulation myoblast functions. Thus, the CSE/H₂S system may be a target for the prevention of hyperuricemia-related metabolic syndromes.

{"title":"H2S inhibition of xanthine dehydrogenase to xanthine oxidase conversion reduces uric acid levels and improves myoblast functions","authors":"Joshua MacNeil , Yuehong Wang , Guangdong Yang","doi":"10.1016/j.bbamcr.2025.119909","DOIUrl":"10.1016/j.bbamcr.2025.119909","url":null,"abstract":"<div><div>Hydrogen sulfide (H<sub>2</sub>S) is an important gasotransmitter that regulates a wide range of pathophysiological processes. Higher uric acid levels are associated with an increased risk of metabolic diseases. The causal mechanism linking H<sub>2</sub>S signalling and uric acid metabolism in skeletal muscles has not yet been elucidated. This study aimed to explore the intertwined metabolisms of H<sub>2</sub>S and uric acid as well as their integrated roles in controlling myoblast cell functions. It was first found that purine overload increased uric acid levels, promoted oxidative stress, mitochondrial damage, and apoptosis in cultured mouse myoblasts, which could be reversed by the exogenously application of H<sub>2</sub>S at physiologically relevant concentration. In addition, H<sub>2</sub>S significantly inhibited the expressions of inflammatory genes (encoding IL2, IL4, and TNFα) but had no effect on oxidative stress, mitochondrial damage and cell death induced by excessive uric acid. Mechanistically, H<sub>2</sub>S inhibited xanthine oxidoreductase (XOR) activity by blocking the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO), thus reducing uric acid levels and improving myoblast functions. In addition, purine and uric acid attenuated the expression of cystathionine gamma-lyase (CSE, an H<sub>2</sub>S-generating enzyme) and suppressed endogenous H<sub>2</sub>S production. Blood uric acid levels and skeletal muscle XOR activity were significantly higher in CSE knockout mice than in wild-type mice. This study revealed a mutual interaction between H<sub>2</sub>S signalling and uric acid metabolism in the regulation myoblast functions. Thus, the CSE/H<sub>2</sub>S system may be a target for the prevention of hyperuricemia-related metabolic syndromes.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119909"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MARCH5 ameliorates aortic valve calcification via RACGAP1-DRP1 associated mitochondrial quality control

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-27 DOI: 10.1016/j.bbamcr.2025.119911

Jialiang Zhang , Yaoyu Zhang , Wenhua Lei , Jing Zhou , Yanjiani Xu , Zhou Hao , Yanbiao Liao , Fangyang Huang , Mao Chen

Background

Mitochondrial E3 ubiquitin ligase (MARCH5) as an important regulator in maintaining mitochondrial function. Our aims were to investigate the role and mechanism of MARCH5 in aortic valve calcification.

Methods

Human aortic valves, both calcified and non-calcified, were analyzed for MARCH5 expression using western blotting. Mitochondrial fragmentation was evaluated using transmission electron microscope. Osteogenic differentiation of human aortic valvular interstitial cells (HVICs) was induced with osteoblastic medium (OM), confirmed by western blotting and Alizarin red staining. Mitochondrial morphology and oxidative phosphorylation were assessed using MitoTracker and Seahorse, respectively. MARCH5-knockdown and ApoE-knockout mice fed high-fat diet were used to study aortic valve calcification.

Results

The mitochondrial quality control was impaired in calcified valves, and the level of MARCH5 protein was also decreased in calcified valves. Inhibition of MARCH5 impaired mitochondrial quality control, increased mitochondrial stress and accelerates osteogenic transformation in OM treated HVICs. While, overexpression MARCH5 has the opposite effects. Co-immunoprecipitation, mass spectrometry and molecular docking found MARCH5 interacted Rac GTPase-activating protein 1 (RACGAP1) and promoted its ubiquitination, leading to impaired mitochondrial quality control. Inhibiting RACGAP1 reversed osteogenic transformation induced by MARCH5 silencing in OM treated HVICs. Silencing dynamin-related protein 1 (DRP1) under RACGAP1 inhibition had no additional benefit. In vivo, deficiency of MARCH5 promoted aortic valve calcification, while inhibition RACGAP1 reversed aortic valve calcification in MARCH5 deficiency mice.

Conclusion

Downregulation of MARCH5 promotes RACGAP1 ubiquitination, activating DRP1 and impairing mitochondrial quality control, which contributes to aortic valve calcification. This identifies a potential therapeutic target for aortic valve calcification.

{"title":"MARCH5 ameliorates aortic valve calcification via RACGAP1-DRP1 associated mitochondrial quality control","authors":"Jialiang Zhang , Yaoyu Zhang , Wenhua Lei , Jing Zhou , Yanjiani Xu , Zhou Hao , Yanbiao Liao , Fangyang Huang , Mao Chen","doi":"10.1016/j.bbamcr.2025.119911","DOIUrl":"10.1016/j.bbamcr.2025.119911","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial E3 ubiquitin ligase (MARCH5) as an important regulator in maintaining mitochondrial function. Our aims were to investigate the role and mechanism of MARCH5 in aortic valve calcification.</div></div><div><h3>Methods</h3><div>Human aortic valves, both calcified and non-calcified, were analyzed for MARCH5 expression using western blotting. Mitochondrial fragmentation was evaluated using transmission electron microscope. Osteogenic differentiation of human aortic valvular interstitial cells (HVICs) was induced with osteoblastic medium (OM), confirmed by western blotting and Alizarin red staining. Mitochondrial morphology and oxidative phosphorylation were assessed using MitoTracker and Seahorse, respectively. MARCH5-knockdown and ApoE-knockout mice fed high-fat diet were used to study aortic valve calcification.</div></div><div><h3>Results</h3><div>The mitochondrial quality control was impaired in calcified valves, and the level of MARCH5 protein was also decreased in calcified valves. Inhibition of MARCH5 impaired mitochondrial quality control, increased mitochondrial stress and accelerates osteogenic transformation in OM treated HVICs. While, overexpression MARCH5 has the opposite effects. Co-immunoprecipitation, mass spectrometry and molecular docking found MARCH5 interacted Rac GTPase-activating protein 1 (RACGAP1) and promoted its ubiquitination, leading to impaired mitochondrial quality control. Inhibiting RACGAP1 reversed osteogenic transformation induced by MARCH5 silencing in OM treated HVICs. Silencing dynamin-related protein 1 (DRP1) under RACGAP1 inhibition had no additional benefit. In vivo, deficiency of MARCH5 promoted aortic valve calcification, while inhibition RACGAP1 reversed aortic valve calcification in MARCH5 deficiency mice.</div></div><div><h3>Conclusion</h3><div>Downregulation of MARCH5 promotes RACGAP1 ubiquitination, activating DRP1 and impairing mitochondrial quality control, which contributes to aortic valve calcification. This identifies a potential therapeutic target for aortic valve calcification.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119911"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Serum starvation induces cytosolic DNA trafficking via exosome and autophagy-lysosome pathway in microglia

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-27 DOI: 10.1016/j.bbamcr.2025.119905

Liyan Zhou, Zilong Wu, Xiaoqing Yi, Dongxue Xie, Jufen Wang, Wenhe Wu

The imbalance of microglial homeostasis is highly associated with age-related neurological diseases, where cytosolic endogenous DNA is also likely to be found. As the main medium for storing biological information, endogenous DNA could be localized to cellular compartments normally free of DNA when cells are stimulated. However, the intracellular trafficking of endogenous DNA remains unidentified. In this study, we demonstrated that nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), as the components of endogenous DNA, undergo different intracellular trafficking under conditions of microglial homeostasis imbalance induced by serum starvation. Upon detecting various components of endogenous DNA in the cytoplasmic and extracellular microglia, we found that cytosolic nDNA primarily exists in a free form and undergoes degradation through the autophagy-lysosome pathway. In contrast, cytosolic mtDNA predominantly exists in a membrane-wrapped form and is trafficked through both exosome and autophagy-lysosome pathways, with the exosome pathway serving as the primary one. When the autophagy-lysosome pathway was inhibited, there was an increase in exosomes. More importantly, the inhibition of the autophagy-lysosome pathway resulted in enhanced trafficking of mtDNA through the exosome pathway. These findings unveiled the crosstalk between these two pathways in the trafficking of microglial cytosolic DNA and thus provide new insights into intervening in age-related neurological diseases.

{"title":"Serum starvation induces cytosolic DNA trafficking via exosome and autophagy-lysosome pathway in microglia","authors":"Liyan Zhou, Zilong Wu, Xiaoqing Yi, Dongxue Xie, Jufen Wang, Wenhe Wu","doi":"10.1016/j.bbamcr.2025.119905","DOIUrl":"10.1016/j.bbamcr.2025.119905","url":null,"abstract":"<div><div>The imbalance of microglial homeostasis is highly associated with age-related neurological diseases, where cytosolic endogenous DNA is also likely to be found. As the main medium for storing biological information, endogenous DNA could be localized to cellular compartments normally free of DNA when cells are stimulated. However, the intracellular trafficking of endogenous DNA remains unidentified. In this study, we demonstrated that nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), as the components of endogenous DNA, undergo different intracellular trafficking under conditions of microglial homeostasis imbalance induced by serum starvation. Upon detecting various components of endogenous DNA in the cytoplasmic and extracellular microglia, we found that cytosolic nDNA primarily exists in a free form and undergoes degradation through the autophagy-lysosome pathway. In contrast, cytosolic mtDNA predominantly exists in a membrane-wrapped form and is trafficked through both exosome and autophagy-lysosome pathways, with the exosome pathway serving as the primary one. When the autophagy-lysosome pathway was inhibited, there was an increase in exosomes. More importantly, the inhibition of the autophagy-lysosome pathway resulted in enhanced trafficking of mtDNA through the exosome pathway. These findings unveiled the crosstalk between these two pathways in the trafficking of microglial cytosolic DNA and thus provide new insights into intervening in age-related neurological diseases.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119905"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The key vulnerabilities and therapeutic opportunities in the USP7-p53/MDM2 axis in cancer

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-27 DOI: 10.1016/j.bbamcr.2025.119908

Gouranga Saha , Mrinal K. Ghosh

The MDM2/MDMX-p53 circuitry is essential for controlling the development, apoptosis, immune response, angiogenesis, senescence, cell cycle progression, and proliferation of cancer cells. Research has demonstrated that USP7 exerts strong control over p53, MDM2, and MDMX stability, with multiple mediator proteins influencing the USP7-p53-MDM2/MDMX axis to modify p53 expression level and function. In cases where p53 is of the wild type (Wt-p53) in tumors, inhibiting USP7 promotes the degradation of MDM2/MDMX, leading to the activation of p53 signaling. This, in turn, results in cell cycle arrest and apoptosis. Hence, targeting USP7 presents a promising avenue for cancer therapy. Targeting USP7 in tumors that harbor mutant p53 (Mut-p53) is unlikely and remains largely unexplored due to the existence of numerous USP7 targets that function independently of p53. Considering that Mut-p53 exhibits resistance to degradation by MDM2 and other E3 ligases and also shares the same signaling pathways as Wt-p53, it is reasonable to suggest that USP7 may play a role in stabilizing Mut-p53. However, there is still much to be done in this area. If the hypothesis is correct, USP7 may be a potent target in cancers containing both Wt-p53 and Mut-p53.

{"title":"The key vulnerabilities and therapeutic opportunities in the USP7-p53/MDM2 axis in cancer","authors":"Gouranga Saha , Mrinal K. Ghosh","doi":"10.1016/j.bbamcr.2025.119908","DOIUrl":"10.1016/j.bbamcr.2025.119908","url":null,"abstract":"<div><div>The MDM2/MDMX-p53 circuitry is essential for controlling the development, apoptosis, immune response, angiogenesis, senescence, cell cycle progression, and proliferation of cancer cells. Research has demonstrated that USP7 exerts strong control over p53, MDM2, and MDMX stability, with multiple mediator proteins influencing the USP7-p53-MDM2/MDMX axis to modify p53 expression level and function. In cases where p53 is of the wild type (Wt-p53) in tumors, inhibiting USP7 promotes the degradation of MDM2/MDMX, leading to the activation of p53 signaling. This, in turn, results in cell cycle arrest and apoptosis. Hence, targeting USP7 presents a promising avenue for cancer therapy. Targeting USP7 in tumors that harbor mutant p53 (Mut-p53) is unlikely and remains largely unexplored due to the existence of numerous USP7 targets that function independently of p53. Considering that Mut-p53 exhibits resistance to degradation by MDM2 and other E3 ligases and also shares the same signaling pathways as Wt-p53, it is reasonable to suggest that USP7 may play a role in stabilizing Mut-p53. However, there is still much to be done in this area. If the hypothesis is correct, USP7 may be a potent target in cancers containing both Wt-p53 and Mut-p53.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119908"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0