International immunopharmacology最新文献

{"title":"Endplate chondrocyte-derived exosomal miR-128-3p mitigates intervertebral disc degeneration by targeting TRAF6 via the miR-128-3p/TRAF6 axis to suppress pyroptosis.","authors":"Qiuwei Li, Ruocheng Guo, Zuomeng Wu, Chenhao Zhao, Xuewu Chen, Hong Wang, Cailiang Shen","doi":"10.1016/j.intimp.2024.113620","DOIUrl":"https://doi.org/10.1016/j.intimp.2024.113620","url":null,"abstract":"<p><p>Intervertebral disc degeneration (IVDD) is a leading cause of chronic back pain and significantly impacts quality of life. The pathogenesis of IVDD is largely driven by inflammation, pyroptosis, and extracellular matrix (ECM) degradation, which current therapies fail to adequately address. In this study, we explore the therapeutic potential of exosomes derived from endplate chondrocytes (EPCs), with a particular focus on the microRNA miR-128-3p. Our findings reveal that exosomes isolated from third-generation EPCs, enriched with miR-128-3p, exhibit potent anti-inflammatory and anti-pyroptotic effects in lipopolysaccharide-treated nucleus pulposus cells, which are key contributors to IVDD pathology. Specifically, we demonstrate that miR-128-3p delivered via EPC-derived exosomes directly targets TRAF6, effectively suppressing activation of the NF-κB signaling pathway, which is known to play a pivotal role in inflammation and ECM breakdown, leading to a marked reduction in pro-inflammatory cytokine release and mitigation of ECM degradation. Importantly, third-generation EPC exosomes, with higher levels of miR-128-3p, showed superior efficacy compared to fifth-generation EPCs, underscoring the critical role of miR-128-3p in mediating these protective effects. Our research highlights the promise of EPC-derived exosomes, particularly those rich in miR-128-3p, as a novel, cell-free therapeutic approach for IVDD. Unlike current treatments that focus primarily on symptom management, our approach targets key molecular pathways underlying IVDD progression, including inflammation, pyroptosis, and ECM degradation. By elucidating the miR-128-3p/TRAF6 axis, this study provides a foundation for the development of targeted, biologically based interventions aimed at halting or even reversing IVDD, thereby offering hope for more effective and lasting therapeutic options.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"143 Pt 3","pages":"113620"},"PeriodicalIF":4.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoliensinine suppresses chondrocytes pyroptosis against osteoarthritis via the MAPK/NF-κB signaling pathway","authors":"Zhengze Zhang ,&nbsp;Jizhi Ma ,&nbsp;Yanzi Yi ,&nbsp;Shuai Wang ,&nbsp;Yuewen He ,&nbsp;Yurui Liu ,&nbsp;Kai Meng ,&nbsp;Yong Wang ,&nbsp;Wuhua Ma","doi":"10.1016/j.intimp.2024.113589","DOIUrl":"10.1016/j.intimp.2024.113589","url":null,"abstract":"<div><h3>Background</h3><div>Isoliensinine is an active compound derived from Nelumbo nucifera which has long been used for its anti-inflammatory properties. However, the mechanism of Isoliensinine in the treatment of osteoarthritis is poorly known.</div></div><div><h3>Purpose</h3><div>The present study aims to investigate whether Isoliensinine could alleviate osteoarthritis by regulating MAPK/NF-κB signaling pathway-mediated pyroptosis.</div></div><div><h3>Methods</h3><div>Network pharmacology and KEGG enrichment analysis were used to identify the therapeutic targets of Isoliensinine for OA. Molecular docking was used to confirm the binding ability of Isoliensinine and related proteins. <em>In vitro</em>, chondrocytes were stimulated with IL-1β to construct an inflammatory model and treated with Isoliensinine. The viability of the cells was assessed using the CCK-8 kit. The apoptosis rate of cells was measured using Annexin V-FITC/PI assay. And assessed the levels of ROS, lipid-ROS, and mitochondrial membrane potential. Corresponding assay kits were utilized to measure the levels of MDA and SOD. Subsequently, the anabolic and catabolic markers in chondrocytes, alongside inflammatory targets were measured by RT-PCR and Western blot. The expression level of pyroptosis and MAPK/NF-κB signaling pathway-related targets was examined. Furthermore, we constructed a rat osteoarthritis model using ACLT surgery. We then assessed the progression of osteoarthritis by Micro-CT, H&amp;E staining, S&amp;F staining and immunohistochemistry.</div></div><div><h3>Results</h3><div>Enrichment analysis showed that Isoliensinine treatment of osteoarthritis may be through the MAPK/NF-κB pathway, and molecular docking showed that Isoliensinine and MAPK/NF-κB pathway proteins had a good binding ability. Data showed that Isoliensinine could reduce ECM degradation and inflammation, and inhibit IL-1β-induced apoptosis. It also mitigated ROS and LPO activation, regulated mitochondrial dysfunction, and reduced intracellular oxidative stress levels. Furthermore, Western blot showed that Isoliensinine also inhibited the activation of the MAPK/NF-κB pathway, thereby inhibiting the pyroptosis of chondrocytes. <em>In vivo</em>, Micro-CT, H&amp;E staining and S&amp;F staining results showed that Isoliensinine could effectively improve joint damage caused by osteoarthritis. And IHC analyses indicated NLRP3, MMP3 protein expression were significantly diminished and Collagen II expression was increased in the Isoliensinine treatment groups.</div></div><div><h3>Conclusion</h3><div>In conclusion, our study suggested that Isoliensinine mitigates ECM degradation, oxidative stress, chondrocytes apoptosis, and pyroptosis through the inhibition of the MAPK and NF-κB pathways, thereby delaying the progression of osteoarthritis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"143 ","pages":"Article 113589"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting NFE2L2/GPX4 signaling pathway: Therapeutic potential of arsenic sulfide-induced ferroptosis in combating rhabdomyosarcoma","authors":"Yu Cai ,&nbsp;Shumin Lu ,&nbsp;Chuanying Zhu ,&nbsp;Ting Kang,&nbsp;Zhiyi Liu,&nbsp;Ruizhe Huang,&nbsp;Yawei Zhao,&nbsp;Siyu Chen","doi":"10.1016/j.intimp.2024.113614","DOIUrl":"10.1016/j.intimp.2024.113614","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"143 ","pages":"Article 113614"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation unleashed: The role of pyroptosis in chronic liver diseases.","authors":"Lujian Zhu, Hongjie Tong, Chao Ren, Kun Chen, Shengnan Luo, Qin Wang, Maodong Guo, Yichen Xu, Minli Hu, Jinyong Fang, Jinxian Xu, Peifei Shi","doi":"10.1016/j.intimp.2024.113006","DOIUrl":"10.1016/j.intimp.2024.113006","url":null,"abstract":"<p><p>Pyroptosis, a newly identified form of programmed cell death intertwined with inflammatory responses, is facilitated by the Gasdermin family's pore-forming activity, leading to cell lysis and the release of pro-inflammatory cytokines. This process is a double-edged sword in innate immunity, offering protection against pathogens while risking excessive inflammation and tissue damage when dysregulated. Specifically, pyroptosis operates through two distinct signaling pathways, namely the Caspase-1 pathway and the Caspase-4/5/11 pathway. In the context of chronic liver diseases like fibrosis and cirrhosis, inflammation emerges as a central contributing factor to their pathogenesis. The identification of inflammation is characterized by the activation of innate immune cells and the secretion of pro-inflammatory cytokines such as IL-1α, IL-1β, and TNF-α. This review explores the interrelationship between pyroptosis and the inflammasome, a protein complex located in liver cells that recognizes danger signals and initiates Caspase-1 activation, resulting in the secretion of IL-1β and IL-18. The article delves into the influence of the inflammasome and pyroptosis on various liver disorders, with a specific focus on their molecular and pathophysiological mechanisms. Additionally, the potential therapeutic implications of targeting pyroptosis for liver diseases are highlighted for future consideration.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"141 ","pages":"113006"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of m6A modification in cardiovascular disease: A systematic review and integrative analysis","authors":"Xu-Man Feng ,&nbsp;Yu Zhang ,&nbsp;Ning Chen ,&nbsp;Lin-Lin Ma ,&nbsp;Miao Gong ,&nbsp;Yu-Xiang Yan","doi":"10.1016/j.intimp.2024.113603","DOIUrl":"10.1016/j.intimp.2024.113603","url":null,"abstract":"<div><h3>Background and aims</h3><div>This study focused on the recent advancements in understanding the association between N6-methyladenosine (m⁶A) modification and cardiovascular disease (CVD).</div></div><div><h3>Methods</h3><div>The potential mechanisms of m⁶A related to CVD were summarized by literature review. Associations between m⁶A levels and CVD were explored across 8 electronic databases: PubMed, Embase, Web of Science, Cochrane Library, Sinomed, Wan Fang, CNKI, and Vip. Standard mean difference (SMD) and 95 % confidence interval (95 % CI) were calculated to assess the total effect in integrated analysis.</div></div><div><h3>Results</h3><div>The systematic review summarized previous studies on the association between m⁶A modification and CVD, highlighting the potential role of m⁶A in CVD progression. A total of 11 studies were included for integrative analysis. The mean m⁶A levels were significantly higher in CVD than those in normal controls (SMD = 1.86, 95 % CI: 0.16–3.56, <em>P</em> &lt; 0.01).</div></div><div><h3>Conclusions</h3><div>This systematic review provided new targets for early detection and treatment for CVD. And the integrated analysis showed that increased level of m⁶A was associated with CVD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"143 ","pages":"Article 113603"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence of the “hit and run” characteristics of Cerebroprotein Hydrolysate-I in the treatment of neonatal HIE based on pharmacokinetic and pharmacological studies","authors":"Tingting Zhang ,&nbsp;Ye Liu ,&nbsp;Guangji Wang ,&nbsp;Zhongbo Wang ,&nbsp;Xin Fan ,&nbsp;Yun Shen ,&nbsp;Wei Liu ,&nbsp;Dianzhui Zhang ,&nbsp;Laipeng He ,&nbsp;Lin Xie ,&nbsp;Tengjie Yu ,&nbsp;Yan Liang","doi":"10.1016/j.intimp.2024.113580","DOIUrl":"10.1016/j.intimp.2024.113580","url":null,"abstract":"<div><div>Hypoxic ischemic encephalopathy (HIE) is the leading cause of neonatal mortality and disability, but its treatment options are very limited and there is an urgent need to further improve treatment outcomes. The present study aims to reveal the therapeutic effects, action pattern, and potential mechanisms of Cerebroprotein hydrolysate-I (CH-I), a mixture of hydrolyzed peptides and amino acids, for the management of HIE. To simulate the complex pathogenesis of HIE more accurately, we innovatively constructed a “triple hit” neonatal HIE rat model. The efficacy of CH-1 was examined in this model, and it was found that CH-I treatment not only significantly improved the behavior and small molecule metabolism disorders of neonatal HIE rats, but also reduced intracerebral neuronal apoptosis, neuroinflammation, and oxidative stress levels. In addition, the neuroprotective effect of CH-I was also confirmed in the hypoxic oligodendrocyte precursor cell model. We innovatively found that CH-I could reverse myelin damage induced by HIE modeling via activating the Wnt/β-catenin signaling pathway. More importantly, a robust quantitative analysis assay for the main peptides in CH-I was developed based on LC-MS/MS system combining Skyline software. Then the pharmacokinetics of the main peptides was studied based on ‘relative exposure approach’ combining ‘mixed calibration curves’ strategy. The transient exposure of peptides <em>in vivo</em> indicated that CH-I should exert neuroprotective effects through the “hit and run” pattern.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"143 ","pages":"Article 113580"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTRP13 attenuates atherosclerosis by inhibiting endothelial cell ferroptosis via activating GCH1","authors":"Jie Du ,&nbsp;Xinxin Zhu ,&nbsp;Youqi Zhang ,&nbsp;Xingtao Huang ,&nbsp;Xuedong Wang ,&nbsp;Fan Yang ,&nbsp;Hongyuan Xia ,&nbsp;Jingbo Hou","doi":"10.1016/j.intimp.2024.113617","DOIUrl":"10.1016/j.intimp.2024.113617","url":null,"abstract":"<div><div>C1q/TNF-related protein 13 (CTRP13) is a secreted adipokine that has been shown to play an important role in a variety of cardiovascular diseases. However, the effect of CTRP13 on ferroptosis of endothelial cells and its underlying mechanism remain unclear. In the present study, we analyzed the effects of CTRP13 on endothelial dysfunction in high-lipid-induced ApoE^−/− mice and ox-LDL-induced mouse aortic endothelial cells (MAECs). In vivo experiment: Male ApoE^−/− mice fed high fat were given C1ql3 gene overexpression adeno-associated virus. The atherosclerotic plaque size, lipid content, collagen fiber proportion and iron deposition level were measured. In vitro, CTRP13 combined with ox-LDL was used to pretreat MAECs to detect cell survival rate, lipid peroxidation, iron ion deposition and mitochondrial level. In this study, CTRP13 was found to inhibit ferroptosis of endothelial cells, demonstrated by up-regulated the expression of ferroptosis protective protein glutathione Peroxidase 4 (GPX4), and decreased the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) protein. Mechanistically, gtp cyclohydrolase 1(GCH1) silencing or tetrahydrobiopterin (BH4) inhibiting may counteract the protective effect of CTRP13 on ox-LDL-induced ferroptosis of endothelial cells, which is characterized by decreased cell activity, mitochondrial damage, increased iron ion deposition and lipid peroxidation, decreased GPX4 expression, and increased ACSL4 expression. This study demonstrated for the first time that CTRP13 can improve mitochondrial oxidative stress, inhibit ferroptosis of endothelial cells and improve endothelial cell dysfunction by activating the GCH1/BH4 signaling pathway, thereby inhibiting the progression of atherosclerosis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"143 ","pages":"Article 113617"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nintedanib attenuates NLRP3 inflammasome-driven liver fibrosis by targeting Src signaling","authors":"Ye-Ting Wu ,&nbsp;Qi-Zhe Li ,&nbsp;Yi-Qi Wu ,&nbsp;Mao Mu ,&nbsp;Huan Wu ,&nbsp;Hai-Ying Tian ,&nbsp;Xue-Ke Zhao","doi":"10.1016/j.intimp.2024.113630","DOIUrl":"10.1016/j.intimp.2024.113630","url":null,"abstract":"<div><div>Liver injury induces an inflammatory response that activates hepatic stellate cells, which is the initial factor of liver fibrosis. Nintedanib, a multi-targeted tyrosine kinase inhibitor targeting the Src signalling pathway, has been approved for the treatment of idiopathic pulmonary fibrosis. However, it is still not known whether nintedanib ameliorates liver fibrosis by inhibiting inflammasome activation. Here, a carbon tetrachloride (CCl₄)-induced liver fibrosis model was used to assess the anti-fibrotic efficacy of nintedanib <em>in vivo</em>. Lipopolysaccharide and ATP were used to activate nucleotide oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in LX-2 cells, and the efficacy of nintedanib on NLRP3 inflammasome activation was evaluated. Moreover, we used Src-overexpressing and Src-downregulating lentiviruses to transfect LX-2 cells to explore the targets of nintedanib. Nintedanib attenuated inflammation and extracellular matrix accumulation in CCl₄-induced fibrotic livers and reduced the expression of NLRP3, fibrotic makers, and the phosphorylation of Src, epidermal growth factor receptor (EGFR), AKT, ERK1/2 in LX-2 cells. Furthermore, nintedanib thwarted NLRP3 inflammasome activation by suppressing the phosphorylation of Src and its downstream signalling pathway and reducing reactive oxygen species production. Our study indicates that nintedanib effectively suppresses NLRP3 inflammasome activation and has the potential for the treatment of liver fibrosis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"143 ","pages":"Article 113630"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ro 90-7501 suppresses colon cancer progression by inducing immunogenic cell death and promoting RIG-1-mediated autophagy","authors":"Xuening Zhao,&nbsp;Zhenshuai Zhang,&nbsp;Jian Wang,&nbsp;Shasha Feng,&nbsp;Li Jiang,&nbsp;Lu Chen,&nbsp;Kaijian Lei,&nbsp;Tianxiao Wang","doi":"10.1016/j.intimp.2024.113631","DOIUrl":"10.1016/j.intimp.2024.113631","url":null,"abstract":"<div><div>Colon cancer is one of the leading causes of cancer-related mortality worldwide. Current treatments, including surgery, chemotherapy, and radiation therapy, often have limited efficacy due to tumor heterogeneity and resistance mechanisms. Therefore, there is a critical need for novel therapeutic strategies that can enhance the immune response against colon cancer cells while promoting their efficient clearance. In this study, we investigated the anti-tumor effects of Ro 90-7501, a specific small molecule, in colon cancer cell lines (HCT8 and SW480) and in vivo models. MTS, EdU, Scratch Wound and Transwell assays were performed to detect the cell proliferation and metastasis. Additionally, flow cytometry and immunofluorescence staining were used to analyze changes in apoptosis and necrosis. Furthermore, we examined its ability to induce immunogenic cell death (ICD) and promote retinoic acid-inducible gene I (RIG-I)-mediated autophagy. The expression levels of key molecules involved in ICD and autophagy were assessed using Western blot analysis, immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). Our findings demonstrated that Ro 90-7501 significantly suppressed colon cancer cell proliferation and metastasis, inducing apoptosis and necrosis. Mechanistically, Ro 90-7501 triggered ICD by upregulating the exposure of calreticulin (CRT) on the cell surface and increasing the release of high mobility group box 1 (HMGB1) and extracellular ATP levels. Concurrently, it promoted RIG-I-mediated autophagy via the MAVS-TRAF6 signaling axis, evidenced by increased expression of autophagy-related genes, such as microtubule-associated protein 1 light chain 3 (LC3) and Beclin 1 proteins, coupled with a reduction in P62 protein. Additionally, Ro 90-7501 treatment activated the RIG-I-MAVS-TRAF6 signaling axis in colon cancer cells. Furthermore, Ro 90-7501 enhanced the secretion of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα), thereby activating the immune response. In conclusion, Ro 90-7501 exhibits potent anti-tumor activity against colon cancer by inducing ICD and promoting RIG-I-mediated autophagy. These results suggest that Ro 90-7501 may serve as a promising therapeutic candidate for colon cancer treatment by enhancing both intrinsic cellular processes and adaptive immune responses. Further studies are warranted to elucidate the detailed mechanisms underlying these effects and to evaluate its therapeutic potential in clinical settings.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"143 ","pages":"Article 113631"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitoxantrone attenuates lipopolysaccharide-induced acute lung injury via inhibition of NEDD8 activating enzyme","authors":"Haiying Liu ,&nbsp;Yuqi Liu ,&nbsp;Xiaoxi Lin ,&nbsp;Jianhui Fan ,&nbsp;Zhao Huang ,&nbsp;Ao Li","doi":"10.1016/j.intimp.2024.113605","DOIUrl":"10.1016/j.intimp.2024.113605","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Lipopolysaccharide (LPS) triggers the activation of nuclear factor kappa B (NF-κB) by interacting with Toll-like receptor 4 (TLR4), leading to the production of various proinflammatory enzymes and cytokines that are crucial in the development of acute lung injury (ALI). Mitoxantrone (MTX) has been demonstrated to mitigate the inflammatory response caused by LPS; however, its precise function in the context of ALI is not fully comprehended.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This study aimed to investigate the inhibitory effects and underlying mechanisms of MTX against LPS-induced ALI.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;ALI was induced in C57BL/6 mice &lt;em&gt;via&lt;/em&gt; a single intratracheal administration of LPS (5 mg/kg), followed by an intraperitoneal injection of MTX to evaluate its therapeutic potential. The effects of MTX on lung injury and the progression of inflammation in ALI mice were assessed using a comprehensive range of techniques, including hematoxylin-eosin (H&amp;E) staining, immunohistochemistry (IHC), myeloperoxidase activity measurement, cell enumeration in bronchoalveolar lavage fluid (BALF), Western blotting, and enzyme-linked immunosorbent assay (ELISA). Additionally, IHC, Western blotting, and co-immunoprecipitation were used to elucidate the specific signaling pathways and molecular mechanisms by which MTX exerted its anti-inflammatory effects in ALI mice. Surface plasmon resonance (SPR) and molecular docking were used to examine the target to which MTX binds directly to reduce inflammation. We also established a lung epithelial cell injury model using LPS-treated A549 cells. The polyubiquitination of IκBα and TRAF6 in LPS-induced A549 cells was detected through Western blotting following immunoprecipitation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In mice with LPS-induced ALI, MTX exhibits anti-inflammatory effects by ameliorating histopathological abnormalities caused by LPS, reducing inflammatory cell infiltration, and decreasing the production of proinflammatory enzymes and cytokines. It has been observed that MTX directly binds to the NEDD8 activating enzyme (NAE), thereby inhibiting the transfer of NEDD8 to the substrates UBC12, Cul1, and Cul5. Consequently, the polyubiquitination of IκBα and TRAF6 is disrupted, leading to the suppression of TAK1 activation by TRAF6. This suppression of TAK1 activity hindered the phosphorylation of IKK and MAPK. By stabilizing IκBα through dephosphorylation &lt;em&gt;via&lt;/em&gt; IKK inhibition and preventing polyubiquitination, NF-κB activation is reduced. This cascade of events ultimately leads to a reduction in the production of proinflammatory enzymes and cytokines, effectively mitigating the inflammatory response in ALI. In A549 cells, MTX reduces the LPS-induced K48-linked polyubiquitination of IκBα and K63-linked polyubiquitination of TRAF6. This process can be reversed by the overexpression of NEDD8. Additionally, treatment with MG-132, a proteasome inhibitor, ","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"143 ","pages":"Article 113605"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}