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

{"title":"TMCO1 promotes ferroptosis and ECM deposition in glaucomatous trabecular meshwork via ERK1/2 signaling","authors":"Yang Zhang ,&nbsp;Ruiqi Han ,&nbsp;Shushu Xu ,&nbsp;Bingqiao Shen ,&nbsp;Huan Yu ,&nbsp;Junjue Chen ,&nbsp;Huiping Yao ,&nbsp;Shouyue Huang ,&nbsp;Yisheng Zhong","doi":"10.1016/j.bbadis.2024.167530","DOIUrl":"10.1016/j.bbadis.2024.167530","url":null,"abstract":"<div><div>Glaucoma, a leading cause of global blindness, is marked by irreversible retinal ganglion cells (RGCs) loss, elevated intraocular pressure (IOP), and extracellular matrix (ECM) deposition in the trabecular meshwork (TM). Transmembrane and coiled-coil domain protein 1 (TMCO1), implicated in calcium regulation, has potential links to primary open-angle glaucoma (POAG). Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, is also observed in glaucoma. This study investigates the role of TMCO1 in POAG, focusing on its involvement in TM ECM deposition via ferroptosis induction and ERK1/2 phosphorylation inhibition.</div><div>In both in vivo and in vitro models, we demonstrated that dexamethasone (DEX) stimulation upregulates TMCO1, leading to increased ECM deposition and ferroptosis in human trabecular meshwork cells (HTMCs). Furthermore, treatment with ferrostatin-1 (Fer-1), a ferroptosis inhibitor, significantly reduced ECM deposition and ferroptosis in HTMCs. These findings establish TMCO1 as a critical regulator of ferroptosis and ECM deposition through the ERK/MAPK pathway, positioning it as a promising therapeutic target for glaucoma.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167530"},"PeriodicalIF":4.2,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334279","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}

{"title":"Impaired hippocampal plasticity associated with loss of recycling endosomal SLC9A6/NHE6 is ameliorated by the TrkB agonist 7,8-dihydroxyflavone","authors":"Andy Y.L. Gao ,&nbsp;Yanis Inglebert ,&nbsp;Roy Shi ,&nbsp;Alina Ilie ,&nbsp;Jelena Popic ,&nbsp;Jamie Mustian ,&nbsp;Nahum Sonenberg ,&nbsp;John Orlowski ,&nbsp;R. Anne McKinney","doi":"10.1016/j.bbadis.2024.167529","DOIUrl":"10.1016/j.bbadis.2024.167529","url":null,"abstract":"<div><div>Proper maintenance of intracellular vesicular pH is essential for cargo trafficking during synaptic function and plasticity. Mutations in the <em>SLC9A6</em> gene encoding the recycling endosomal pH regulator (Na⁺, K⁺)/H⁺ exchanger isoform 6 (NHE6) are causal for Christianson syndrome (CS), a severe form of X-linked intellectual disability. NHE6 expression is also downregulated in other neurodevelopmental and neurodegenerative disorders, such as autism spectrum disorder and Alzheimer's disease, suggesting its dysfunction could contribute more broadly to the pathophysiology of other neurological conditions. To understand how ablation of NHE6 function leads to severe learning impairments, we assessed synaptic structure, function, and cellular mechanisms of learning in a novel line of <em>Nhe6</em> knockout (KO) mice expressing a plasma membrane-tethered green fluorescent protein within hippocampal neurons. We uncovered significant reductions in dendritic spine<del>s</del> density, AMPA receptor (AMPAR) expression, and AMPAR-mediated neurotransmission in CA1 pyramidal neurons. The neurons also failed to undergo functional and structural enhancement during long-term potentiation (LTP). Significantly, the selective TrkB agonist 7,8-dihydroxyflavone restored spine density as well as functional and structural LTP in KO neurons. TrkB activation thus may act as a potential clinical intervention to ameliorate cognitive deficits in CS and other neurodegenerative disorders.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167529"},"PeriodicalIF":4.2,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SENP1 prevents high fat diet-induced non-alcoholic fatty liver diseases by regulating mitochondrial dynamics","authors":"Wenjing Zeng,&nbsp;Li Wang,&nbsp;Chaowen Wang,&nbsp;Xiaowei Xiong,&nbsp;Qianqian Huang,&nbsp;Sheng Chen,&nbsp;Chen Liu,&nbsp;Wentao Liu,&nbsp;Yuan Wang,&nbsp;Qiren Huang","doi":"10.1016/j.bbadis.2024.167527","DOIUrl":"10.1016/j.bbadis.2024.167527","url":null,"abstract":"<div><div>Mitochondrial dynamics plays a crucial role in the occurrence and development of non-alcoholic fatty liver diseases (NAFLD). SENP1, a SUMO-specific protease, catalyzes protein de-SUMOylation and involves in various physiological and pathological processes. However, the exact role of SENP1 in NAFLD remains unclear. Therefore, we investigated the regulatory role of SENP1 in mitochondrial dynamics during the progression of NAFLD. In the study, the NAFLD <em>in vivo</em> model induced by high fat diet (HFD) and <em>in vitro</em> model induced by free fatty acids (FFA) were established to investigate the role and underlying mechanism of SENP1 through detecting mitochondrial morphology and dynamics. Our results showed that the down-regulation of SENP1 expression and the mitochondrial dynamics dysregulation occurred in the NAFLD, evidenced as mitochondrial fragmentation, up-regulation of p-Drp1 ser616 and down-regulation of MFN2, OPA1. However, over-expression of SENP1 significantly alleviated the NAFLD, rectified the mitochondrial dynamics disorder, reduced Cyt-c release and ROS levels induced by FFA or HFD; moreover, the over-expression of SENP1 also reduced the SUMOylation levels of Drp1 and prevented the Drp1 translocation to mitochondria. Our findings suggest that the possible mechanisms of SENP1 were through rectifying the mitochondrial dynamics disorder, reducing Cyt-c release and ROS-mediated oxidative stress. The findings would provide a novel target for the prevention and treatment of NALFD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167527"},"PeriodicalIF":4.2,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334278","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}

{"title":"Unraveling the pathogenesis of viral-induced pulmonary arterial hypertension: Possible new therapeutic avenues with mesenchymal stromal cells and their derivatives.","authors":"Sebastián Castillo-Galán ,&nbsp;Valentina Parra ,&nbsp;Jimena Cuenca","doi":"10.1016/j.bbadis.2024.167519","DOIUrl":"10.1016/j.bbadis.2024.167519","url":null,"abstract":"<div><div>Pulmonary hypertension (PH) is a severe condition characterized by elevated pressure in the pulmonary artery, where metabolic and mitochondrial dysfunction may contribute to its progression. Within the PH spectrum, pulmonary arterial hypertension (PAH) stands out with its primary pulmonary vasculopathy. PAH's prevalence varies from 0.4 to 1.4 per 100,000 individuals and is associated with diverse conditions, including viral infections such as HIV. Notably, recent observations highlight an increased occurrence of PAH among COVID-19 patients, even in the absence of pre-existing cardiopulmonary disorders. While current treatments offer partial relief, there's a pressing need for innovative therapeutic strategies, among which mesenchymal stromal cells (MSCs) and their derivatives hold promise. This review critically evaluates recent investigations into viral-induced PAH, encompassing pathogens like human immunodeficiency virus, herpesvirus, Cytomegalovirus, Hepatitis B and C viruses, SARS-CoV-2, and Human endogenous retrovirus K (HERKV), with a specific emphasis on mitochondrial dysfunction. Furthermore, we explore the underlying rationale driving novel therapeutic modalities, including MSCs, extracellular vesicles, and mitochondrial interventions, within the framework of PAH management.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167519"},"PeriodicalIF":4.2,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334280","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}

{"title":"PRR promotes hypertensive renal injury by activating Wnt/β-catenin signaling and inflammation infiltration in mice","authors":"Mengjiao Lin ,&nbsp;Dedong Wang ,&nbsp;Yanlan Chen ,&nbsp;Gewenhan Chen ,&nbsp;Yanni Zhou ,&nbsp;Juanjuan Ou ,&nbsp;Liangxiang Xiao","doi":"10.1016/j.bbadis.2024.167517","DOIUrl":"10.1016/j.bbadis.2024.167517","url":null,"abstract":"<div><div>Hypertension stands out as a substantial independent risk factor in the progression of chronic kidney disease; however, the exact pathological mechanisms remain elusive. Our preliminary studies find that Wnt/β-catenin control renin-angiotensin system (RAS) expression, thus playing an important role in the pathogenesis of hypertension and renal fibrosis. As an integral component of the RAS, the (pro)renin receptor (PRR) plays a crucial role in the activation of the RAS and hypertension. Recent studies suggest a reciprocal relationship between PRR and Wnt/β-catenin signaling, potentially contributing to hypertensive renal fibrosis development. To assess the role of PRR in mediating hypertensive nephropathy, we manipulated this signaling by over expression of PRR ligand or blockade of PRR by siPRR. In vivo, PRR induction promoted hypertension, proteinuria, renal fibrosis, inflammatory response and β-catenin activation in Ang II induced hypertension mice. Conversely, blockade of PRR inhibited Ang II mediated hypertension, renal fibrosis and inflammation. In vitro, PRR over expression renal tubular cells exacerbated the Ang II induced fibrotic response and inflammation. Moreover, PRR was upregulated in hypertensive nephropathy patients, and correlated with renal function and renal fibrosis. These results indicate that PRR interact with Wnt/β-catenin signaling promote the progression of hypertensive nephropathy. PRR could be served as a biomarker for the diagnosis and treatment of hypertensive renal fibrosis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167517"},"PeriodicalIF":4.2,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323920","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}

{"title":"Phosphorylation of BRCA1 at serine 1387 plays a critical role in cathepsin S-mediated radiation resistance via BRCA1 degradation and BCL2 stabilization","authors":"Gil-Im Mun ,&nbsp;Eun Choi ,&nbsp;Hee Jin ,&nbsp;Seul-Ki Choi ,&nbsp;Hanhee Lee ,&nbsp;Seoyoung Kim ,&nbsp;Junghyun Kim ,&nbsp;Chaerin Kang ,&nbsp;Hye Lim Oh ,&nbsp;Hae-June Lee ,&nbsp;Dae-Ro Ahn ,&nbsp;Yun-Sil Lee","doi":"10.1016/j.bbadis.2024.167523","DOIUrl":"10.1016/j.bbadis.2024.167523","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167523"},"PeriodicalIF":4.2,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant TCF21 upregulation in adenomyosis impairs endometrial decidualization by increasing PDE4C expression","authors":"Ruoer Yu ,&nbsp;Chenxuan Wei ,&nbsp;Guojing Li,&nbsp;Jing Ouyang,&nbsp;Na Liu,&nbsp;Nihao Gu,&nbsp;Yu Lin,&nbsp;Hong Xu","doi":"10.1016/j.bbadis.2024.167526","DOIUrl":"10.1016/j.bbadis.2024.167526","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167526"},"PeriodicalIF":4.2,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR4352b a cross-species modulator of SOSTDC1, targets dual pathway to regulate bone health and fracture healing","authors":"Divya Rai ,&nbsp;Anirban Sardar ,&nbsp;Anuj Raj ,&nbsp;Bhaskar Maji ,&nbsp;Shikha Verma ,&nbsp;Ashish Kumar Tripathi ,&nbsp;Sanchita Gupta ,&nbsp;Ashish Sharma ,&nbsp;Yogeshwar Vikram Dhar ,&nbsp;Ritu Trivedi","doi":"10.1016/j.bbadis.2024.167514","DOIUrl":"10.1016/j.bbadis.2024.167514","url":null,"abstract":"<div><div>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. <em>Glycine</em> 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.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167514"},"PeriodicalIF":4.2,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334276","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}

{"title":"PU.1 regulates osteoarthritis progression via CSF1R in synovial cells","authors":"Tingting Wang ,&nbsp;Jiakai Wang ,&nbsp;Tao Sun ,&nbsp;Rong Zhang ,&nbsp;Yishuo Li ,&nbsp;Tianyu Hu","doi":"10.1016/j.bbadis.2024.167525","DOIUrl":"10.1016/j.bbadis.2024.167525","url":null,"abstract":"<div><div>This study elucidates the molecular mechanisms driving osteoarthritis (OA) by focusing on the transcription factor PU.1's role in synovial cells, specifically macrophages and fibroblast-like synoviocytes (FLS). Analyzing OA-related synovial gene expression from the GEO database highlighted immune regulation pathways in OA. Using protein-protein interaction and the JASPAR database, we pinpointed essential genes in OA development. Synovial tissues from OA patients and controls revealed pronounced PU.1 and its target CSF1R presence. In a surgically induced OA mouse model with PU.1 and CSF1R knockdown, ChIP assays confirmed PU.1's binding to the CSF1R promoter. Dual luciferase reporter assays and immunohistochemistry validated PU.1's regulatory impact on CSF1R transcription. Combined analysis of microarrays GSE55235 and GSE206848 showed heightened PU.1 expression in OA, associated with immune regulation in macrophages. In vitro findings aligned with in vivo results, emphasizing PU.1's influence on macrophage polarization and FLS-induced inflammation. PU.1's direct activation of CSF1R transcription underpins its key role in OA progression. This research offers insights into OA's molecular basis, suggesting potential therapeutic targets.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167525"},"PeriodicalIF":4.2,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142309354","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}

{"title":"ARL11 knockdown alleviates spinal cord injury by inhibiting neuroinflammation and M1 activation of microglia in mice","authors":"Haocong Zhang,&nbsp;Liangbi Xiang,&nbsp;Hong Yuan,&nbsp;Hailong Yu","doi":"10.1016/j.bbadis.2024.167522","DOIUrl":"10.1016/j.bbadis.2024.167522","url":null,"abstract":"<div><div>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 <em>in vivo</em> and <em>in vitro.</em> Furthermore, ARL11 deletion significantly inhibited iNOS protein and mRNA expression <em>in vivo</em> and <em>in vitro,</em> and COX-2 expression <em>in vivo</em>. Mechanism studies revealed that ARL11 silencing decreased phosphorylated ERK1/2 protein expression. Additionally, ELF1 knockdown significantly inhibited ARL11 protein and mRNA expression <em>in vitro</em>. 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.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167522"},"PeriodicalIF":4.2,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142303286","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}