Mediators of Inflammation最新文献

{"title":"Predictive Value of IL-6 and Lymphocyte Subsets for Death in Children With Influenza-Associated Encephalopathy A Retrospective Study.","authors":"Ruiyang Sun, Xue Zhang, Jiapu Hou, Wanyu Jia, Peng Li, Daobin Wang, Shuqin Fu, Chunlan Song","doi":"10.1155/mi/5564727","DOIUrl":"https://doi.org/10.1155/mi/5564727","url":null,"abstract":"<p><p><b>Objective:</b> This study aims to investigate the predictive value of interleukin-6 (IL-6) and lymphocyte subsets for death in children with influenza-associated encephalopathy (IAE). <b>Patients:</b> This study included 76 children with IAE who were divided into a death group and a survival group. The differences in the levels of IL-6 and lymphocyte subsets between the two groups were analyzed, and the predictive value of these two parameters was compared by receiver operating characteristic (ROC) curve analysis. <b>Results:</b> The level of IL-6 and the percentage of natural killer (NK) cells in the death group were higher than those in the survival group (<i>p</i>  < 0.05). The percentage of CD4⁺ T cells and CD4⁺/CD8⁺ levels in the death group were lower than those in the survival group. ROC curves were used for analysis, and the area under the curves (AUCs) of IL-6, the percentage of CD4⁺ T cells, the percentage of CD4⁺/CD8⁺, and the percentage of NK cells were 0.812, 0.810, 0.740, and 0.706, respectively. The AUC of the combination of these four metrics was 0.870. There was a little difference in the efficacy of the four clinical indicators, and the predictive efficacy of the combined test was higher than that of the single test. <b>Conclusion:</b> The IL-6 concentration, percentage of CD4⁺ T cells, percentage of NK cells, and CD4⁺/CD8⁺ have predictive value for death in children with IAE, and the combination of these four metrics has improved the predictive value.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"5564727"},"PeriodicalIF":4.4,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11611401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Expression Profiles and Clinical Significance of Mixed Lineage Kinases in Glioma.","authors":"Jin Huang, Yuankun Liu, Gaosong Wang, Yuning Chen, Yifan Shen, Jiahao Zhang, Wei Ji, Junfei Shao","doi":"10.1155/2024/5521016","DOIUrl":"10.1155/2024/5521016","url":null,"abstract":"<p><p>Mixed lineage kinases (MLKs), comprising seven members: MLK1-4, dual leucine zipper kinase (DLK), leucine zipper kinase (LZK), and sterile alpha motif and leucine zipper containing kinase (ZAK), belong to the mitogen-activated protein kinase kinase kinase (MAP3K) family. These kinases are implicated in the progression of numerous cancers by activating mitogen-activated protein kinase (MAPK) cascades or functioning as ser/thr and tyr kinases. However, their specific roles in glioma remain elusive. In the present study, we utilized bioinformatics approaches to investigate the expression patterns of MLKs in low-grade gliomas (LGG) and glioblastoma multiforme (GBM). Additionally, we analyzed their clinical significance and delved into the potential mechanisms underlying MLK activity as well as their association with tumor-immune infiltrating cells (TIICs) in glioma. Furthermore, we conducted in vitro studies to elucidate the functional roles of MLK1-2 in glioma. Our findings revealed that the expressions of MLK1-2 were conspicuously downregulated in GBM and positively correlated with patients' overall survival. Conversely, ZAK exhibited an opposing trend. Notably, our newly devised risk score model exhibited superior performance in predicting patient prognoses. Moreover, we analyzed the potential mechanisms of MLK activity and its interplay with tumor immune infiltration. Last, we validated the antitumor effect of MLK1-2 at the in vitro level. In summary, our study sheds new insights into the roles of MLKs in glioma, particularly MLK1-2, and their potential as therapeutic targets.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"5521016"},"PeriodicalIF":4.4,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11604285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"rTMS and TENS Relieve Neuropathic Pain in CCI Model Rats by Modulating Central Nervous System TRPV1 and Neuroinflammation.","authors":"Zhangyu Xu, Quanzhen Zhong, Fei Xing, Yuanliang Zhu, Yue Hu, Maomao Huang, Mouwang Zhou, Jianxiong Wang","doi":"10.1155/mi/8500317","DOIUrl":"https://doi.org/10.1155/mi/8500317","url":null,"abstract":"<p><p><b>Background:</b> Repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex (PFC) and transcutaneous electrical nerve stimulation (TENS) have both been demonstrated as effective at alleviating neuropathic pain (NP). However, the comparative efficacy of these two neuromodulation techniques and the specific neural mechanisms underlying their effects remain unclear. <b>Objective:</b> This study aims to compare the efficacy of rTMS in the PFC and TENS in mitigating peripheral NP and to investigate the impact of rTMS on neuroinflammation. <b>Methods:</b> Eighteen adult male Sprague-Dawley rats were randomly divided into three groups: NP (chronic constriction injury [CCI] group, <i>n</i> = 6), rTMS (<i>n</i> = 6), and TENS (<i>n</i> = 6). rTMS was applied to the PFC, while TENS was applied to the right hind limb of the rats 1 week postoperatively. This treatment regimen was administered once daily, 5 days a week, for 4 consecutive weeks. The paw withdrawal mechanical threshold (PWMT) was measured to assess the pain-alleviating effects of rTMS and TENS. We further conducted enzyme-linked immunosorbent assays (ELISAs) to measure the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) in the PFC and L4-L6 spinal cord to evaluate their impact on neuroinflammation. Additionally, we examined transient receptor potential vanilloid type 1 (TRPV1) expression in the PFC and the L4‒L6 spinal cord using western blotting and real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to explore the potential mechanisms involved. Hematoxylin and eosin (H&E) staining of the sciatic nerve was further performed to observe pathological changes. <b>Results:</b> Compared to the CCI group, both the rTMS and TENS groups exhibited a significant increase in PWMT, with the rTMS group demonstrating a notably greater PWMT than the TENS group. Furthermore, rTMS treatment triggered a significant decrease in IL-1β, IL-6, and TNF-α levels in the PFC and spinal cord, while TENS only decreased IL-1β expression in these regions. In both treatment groups, TRPV1 expression was significantly lower in the spinal cord, while H&E staining indicated improved pathological manifestations in the sciatic nerve. <b>Conclusion:</b> Both rTMS and TENS effectively ameliorated CCI-induced NP, with rTMS of the PFC showing superior performance. Both treatments reduced TRPV1 expression and suppressed neuroinflammation in the spinal cord, indicating that this may be one of the mechanisms through which they exert their therapeutic effects.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"8500317"},"PeriodicalIF":4.4,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11606689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Secretion of Inflammatory Cytokines Triggered by TLR2 Through Calcium-Dependent and Calcium-Independent Pathways in Keratinocytes.","authors":"Eun-Ok Kim, Dain Park, In Jin Ha, Se-Eun Bae, Min Young Lee, Miyong Yun, Kyuseok Kim","doi":"10.1155/mi/8892514","DOIUrl":"10.1155/mi/8892514","url":null,"abstract":"<p><p>Keratinocytes can be activated by <i>Cutibacterium acnes</i>, leading to the production of proinflammatory cytokines via toll-like receptors (TLRs) 2 and 4. Although several studies have investigated keratinocytes, the mechanism of calcium-mediated activation remains unclear. Herein, we investigated whether calcium influx via TLR2 and TLR4 stimulation was involved in cytokine secretion by keratinocytes in HaCaT cells. Although TLR2 stimulation by peptidoglycan (PGN) increased intracellular calcium influx, TLR4 stimulation by lipopolysaccharide (LPS) did not increase it, as analyzed using flow cytometry with the calcium indicator Fluo-3. However, activation by either TLR2 or TLR4 ligands upregulated the intracellular calcium influx in THP-1 monocytes. Additionally, the expression of major proinflammatory cytokines and chemokines, such as interleukin (IL)-6, IL-8, IL-1<i>α</i>, granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein-1 (MCP-1), was significantly increased by TLR2 in HaCaT cells. Moreover, treatment with the intracellular calcium chelator, BAPTA-AM, disrupted PGN-mediated induction of IL-6, IL-8, and MCP-1 production. Real-time quantitative polymerase chain reaction (PCR) and western blotting revealed that TLR2 stimulation induced expression of the epidermal differentiation marker keratin 1. In conclusion, TLR2-induced intracellular calcium influx plays a pivotal role in the secretion of proinflammatory cytokines, such as IL-6 and MCP-1, in keratinocytes. Moreover, the continuous influx of calcium via TLR2 activation leads to keratinization. In vitro studies using HaCaT cells provide basic research on the effect of TLR2-induced calcium on <i>C. acnes</i>-mediated inflammation in keratinocytes. These studies are limited in their ability to clinically predict what happens in human keratinocytes. Clinical studies on patients with acne, including three-dimensional (3D) cultures of primary keratinocytes, are required to develop new diagnostic markers for determining the severity of acne vulgaris.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"8892514"},"PeriodicalIF":4.4,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11588404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sublingual Immunotherapy Decreased the Serum Levels of Interleukin-36<i>γ</i> in Allergic Rhinitis.","authors":"Xiaowei Qin, Chunrui Wang, Jueqi Li, Xiaopeng Zhang, Tianhong Zhang","doi":"10.1155/2024/9692031","DOIUrl":"10.1155/2024/9692031","url":null,"abstract":"<p><p><b>Background:</b> Allergy immunotherapy (AIT), a treatment approach for allergic rhinitis (AR), is recognized for its potential to modify the disease course beyond mere symptom relief. Interleukin-36<i>γ</i> (IL-36<i>γ</i>), a key player in immune responses, has been implicated in promoting eosinophilic inflammation in AR by activating eosinophils. We aimed to investigate the effect of IL-36<i>γ</i> on group II lymphoid cell (ILC2) in AR patients who underwent sublingual immunotherapy (SLIT). <b>Methods:</b> Twenty-four AR patients were enrolled and administered with SLIT. Serum proteins of IL-36<i>γ</i>, interleukin-5 (IL-5), and interleukin-13 (IL-13) during SLIT were quantitatively assessed using enzyme-linked immunosorbent assay (ELISA). The proportion of ILC2 was determined by flow cytometry. Sorted ILC2s were stimulated by IL-36<i>γ</i> and ILC2 cell differentiation, and type II cytokines expression were examined. <b>Results:</b> SLIT treatment decreased the serum protein levels of IL-36<i>γ</i>, IL-5, IL-13, and the proportion of ILC2 significantly. IL-36<i>γ</i> suppressed the proliferation of ILC2 by inhibiting the levels of ILC2 transcription factor. IL-36<i>γ</i> also inhibited IL-5 and IL-13 expression from ILC2. <b>Conclusion:</b> The changes of IL-36<i>γ</i> during SLIT were related to the inhibited function of ILC2, implying that IL-36<i>γ</i> may be used as a new biomarker for monitoring the efficacy of SLIT in AR.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"9692031"},"PeriodicalIF":4.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Ca²⁺/PI3K/Akt/eNOS/NO Pathway in Astragaloside IV-Induced Inhibition of Endothelial Inflammation Triggered by Angiotensin II.","authors":"Shiyu Zhang, Shijie Li, Shiyang Xie, Lin Cui, Yuan Gao, Youping Wang","doi":"10.1155/2024/3193950","DOIUrl":"https://doi.org/10.1155/2024/3193950","url":null,"abstract":"<p><p>Inflammation induced by angiotensin II (Ang II) is a key event in the progression of numerous cardiovascular diseases. Astragaloside IV (AS-IV), a glycoside extracted from <i>Astragalus membranaceus Bunge</i>, has been shown to inhibit Ang II-induced inflammatory responses in vivo. However, the mechanisms underlying the beneficial effects are still unclear. This study investigated whether AS-IV attenuates endothelial inflammation induced by Ang II via the activation of endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) pathway. Human umbilical vein endothelial cells (HUVECs) were cultured in the presence of AS-IV with or without the specific inhibitor of NOS or Ca²⁺- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent cascade prior to Ang II exposure. Incubation of HUVECs with AS-IV enhanced NO production and eNOS^ser1177 phosphorylation. These responses were abrogated by the inhibition of NOS or Ca²⁺- and PI3K/Akt-dependent pathway. In addition, preincubation of HUVECs with AS-IV inhibited Ang II-induced cytokine and chemokine production, adhesion molecule expression, monocyte adhesion, and nuclear factor kappa B (NF-κB) activation as evidenced by the attenuation of inhibitor of kappa B alpha phosphorylation and subsequent NF-κB DNA binding. These effects of AS-IV were abolished by the suppression of NOS or Ca²⁺- and PI3K/Akt-dependent cascade. Our findings indicate that AS-IV attenuates inflammatory responses triggered by Ang II possibly via the activation of Ca²⁺/PI3K/Akt/eNOS/NO pathway in endothelial cells.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"3193950"},"PeriodicalIF":4.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ITGA1 Promotes Glioma Cell Proliferation and Affects Immune Cell Infiltration in Low-Grade Glioma.","authors":"Yanhong Ren, Jianchang Xu, Zhengkui Zhang, Rutong Yu","doi":"10.1155/2024/6147483","DOIUrl":"10.1155/2024/6147483","url":null,"abstract":"<p><p><b>Background:</b> Low-grade glioma (LGG) is a commonly occurring type of central nervous system cancer. Integrin α1 (ITGA1), a family member of integrins, is implied in the malignant development of cancers, but the fundamental role of ITGA1 has not been illustrated yet in glioma. This study aimed to evaluate the prognostic value of ITGA1. <b>Methods:</b> Correlations between ITGA1 and relevant clinical features were analyzed in the LGG datasets based on Chinese Glioma Genome Atlas (CGGA) and Tumor Genome Atlas (TCGA). Glioma clinical samples and glioma cell lines were identified at the level of mRNA and protein level by Western blot. Cox regression were developed to assess the involvement of ITGA1 expression in predicting survival in LGG patients. Application of GSEA enrichment analysis to reveal ITGA1-mediated biological functions in LGG. Using TIMER 2.0 to analyze correlations between immune cell infiltration. In addition, ITGA1 high expression was analyzed for correlation with immune checkpoint-related genes and cumulative survival time. <b>Results:</b> ITGA1 was significantly more expressed in LGG than in normal samples. Cox regression indicated that ITGA1 was a risk factor independently for prognosis in LGG patients. GSEA enrichment analysis indicated that ITGA1 was engaged in several immunomodulatory processes. ITGA1 expression was shown to be highly correlated with the immune score, stromal score, and estimate score in LGG. ITGA1 was significantly related to the immune checkpoint-associated gene expression. In vivo experiments showed that overexpression of ITGA1 promoted glioma cell invasion. <b>Conclusion:</b> High ITGA1 expression is correlated with immune infiltration of the low-grade tumor, leading to poor prognoses in LGG patients.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"6147483"},"PeriodicalIF":4.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The AMPK-mTOR Pathway Is Inhibited by Chaihu Shugan Powder, Which Relieves Nonalcoholic Steatohepatitis by Suppressing Autophagic Ferroptosis.","authors":"Zheng Liang, Dajin Pi, Jianwei Zhen, Haizhen Yan, Chuiyang Zheng, July Liang Chen, Wen Fan, Qingliang Song, Jinyue Pan, Dongdong Liu, Maoxing Pan, Qinhe Yang, Yupei Zhang","doi":"10.1155/2024/4777789","DOIUrl":"10.1155/2024/4777789","url":null,"abstract":"<p><p>Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), which is distinguished by the accumulation of fat in the liver, damage to liver cells, and inflammation. Chaihu Shugan powder (CSP), a renowned traditional Chinese medicine (TCM) blend extensively utilized in China to address liver disease, has demonstrated its efficacy in reducing lipid buildup and effectively combating inflammation. Hence, the primary objective of this research is to examine the impacts and possible mechanisms of CSP on NASH through assessments of liver histopathology, lipidomic analysis, and gene expression. To induce a mouse model of NASH, we employed a diet which deficient in methionine and choline, known as methionine-choline deficient (MCD) diet. Initially, we examined the impact of administering CSP to NASH mice by assessing the levels of serum and liver indicators. We found that CSP was able to reduce lipid buildup and inflammation in mice. In addition, a total of 1009 genes exhibited enrichment in both the autophagy and ferroptosis pathways. The liver protein levels of Adenosine monophosphate-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR)-mediated autophagy and ferroptosis markers, such as p-AMPK<i>α</i>/AMPK<i>α</i>, p-mTOR/mTOR, Beclin-1, microtubule associated protein 1 light chain 3 gamma (LC3), p62 (sequestosome 1 [SQSTM1/p62]), Kelch-like ECH-associated protein 1 (KEAP1), nuclear factor erythroid 2-related factor 2 (Nrf-2), ferritin heavy chain 1 (FTH1), and glutathione peroxidase 4 (GPX4), were restored by CSP. Furthermore, our findings indicated that the suppression of autophagy had a repressive impact on the occurrence of ferroptosis in the mouse model, indicating that autophagy activation likely plays a role in mediating ferroptosis in NASH.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"4777789"},"PeriodicalIF":4.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Involvement of TANK-Binding Kinase 1 in the MyD88-Dependent NF-<i>κ</i>B Pathway Through Syk.","authors":"Han Gyung Kim, Ji Hye Kim, Tao Yu, Jae Youl Cho","doi":"10.1155/2024/8634515","DOIUrl":"10.1155/2024/8634515","url":null,"abstract":"<p><p>Inflammation is a vital immune defense mechanism regulated by Toll-like receptors (TLRs) and the nuclear factor-kappa B (NF-<i>κ</i>B) pathway. TANK-binding kinase 1 (TBK1) is central to immunity and inflammation and influences antiviral responses and cellular processes. However, the precise role of TBK1 in modulating the NF-<i>κ</i>B pathway through interactions with other proteins, such as spleen tyrosine kinase (Syk), remains poorly understood. As dysregulation of TBK1 and NF-<i>κ</i>B can lead to a variety of diseases, they are important therapeutic targets. In this work, inflammatory processes involving the TBK1-Syk-NF-<i>κ</i>B pathway were elucidated using lipopolysaccharide (LPS)-induced macrophages; human embryonic kidney 293 (HEK293) cells overexpressing MyD88, TBK1, and Syk proteins and their mutants; and real-time polymerase chain reaction (PCR), immunoblotting analyses, and kinase assays. TBK1 was activated in LPS-, poly I:C-, and Pam3CSK-stimulated macrophages. Transcript levels of <i>TNF</i>, <i>NOS2</i>, and <i>IL1B</i> were increased in cells overexpressing TBK1 but not in cells overexpressing TBK1 K38A. The transcription of <i>TNF</i>, <i>NOS2</i>, and <i>IL1B</i> and NF-<i>κ</i>B luciferase activity were inhibited by silencing TBK1 in LPS-stimulated RAW264.7 cells and MyD88-transfected HEK293 cells. Syk was the key mediator of the TBK1-dependent NF-<i>κ</i>B pathway and bound directly to the coiled coil domain of TBK1, which was necessary to activate Syk and the Syk-p85 pathway. This research advances the understanding of the role of TBK1 in NF-<i>κ</i>B signaling, emphasizing Syk as a key mediator. The interaction between TBK1 and Syk has potential for precise immune modulation that can be applied to treat immune-related disorders.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"8634515"},"PeriodicalIF":4.4,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy Improves Inflammatory Response in Sepsis Accompanied by Changes in Gut Microbiota.","authors":"La Wang, WenJia Wang, GuiTong Jiang, ZunLi Ke, RuiXi Luo, WeiYi Tian","doi":"10.1155/2024/9550301","DOIUrl":"10.1155/2024/9550301","url":null,"abstract":"<p><p><b>Background:</b> Sepsis is defined as a life-threatening disease. Autophagy and the microbiome are increasingly connected with sepsis. The aim of this study was to investigate the protective effect of autophagy and the possible mechanisms. <b>Methods:</b> The septic rat model was established by cecal ligation perforation (CLP). Rapamycin (Rap), 3-methyladenine (3-MA), and chloroquine (CQ) were administered to interfere autophagy. Western blot (WB) was used to detect the expression of key proteins in autophagy. Hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assays (ELISAs) were used to identify the effect of autophagy on various organs. 16S ribosomal RNA gene sequencing was used to analyze the changes of the gut microbiota. <b>Results:</b> Rap significantly upregulated the expression of key autophagy proteins, and 3-MA reduced the relative expression compared to the CLP group. The autophagic flux showed a corresponding trend. Interestingly, the autophagy inducer significantly decreased the mortality and the lipopolysaccharide (LPS) level in serum compared with the CLP group. Autophagy activation significantly improves the inflammatory response in sepsis. Histopathological sections showed that CLP destroyed the tight junctions between ileal epithelial cells, while autophagy induction reversed the damage. The sequencing results showed that autophagy activation increased the alpha diversity and alterted the composition and structure of gut microbiota. The abundance of Proteobacteria was markedly decreased in the Rap group, whereas Bacteroidetes was notably increased compared with the CLP group. Additionally, the protective effect of autophagy further changed the biomarkers in the microbial community. The top 35 functions in each sample were analyzed to obtain 18 genes including RNA synthesis, ATP binding and transport, chromosome assignment, osmotic polysaccharide transport, transcytosis, and methylation. <b>Conclusion:</b> Autophagy is able to improve inflammation and may directly or indirectly regulate the microbiota of septic rats. Autophagy may be an important target for future clinical interventions in the treatment of sepsis.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"9550301"},"PeriodicalIF":4.4,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142503545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}