Pub Date : 2024-08-01Epub Date: 2024-02-15DOI: 10.1007/s10753-024-01971-1
Jia Liu, Sheng-Xiao Zhang, Rong Zhao, Shan Song, He-Yi Zhang, Cai-Hong Wang, Xiao-Feng Li
The purpose of this research was to characterize the microbiota of patients with psoriatic arthritis (PsA) and to compare the relationship between the microbiota and peripheral lymphocyte subsets and cytokines. We collected stool samples from 13 PsA patients and 26 sex- and age-matched healthy controls (HCs) and researched the gut microbiota by sequencing the V3-V4 variable region of the bacterial 16S rRNA gene with the Illumina Miseq PE300 system. Flow cytometry was used to assess the peripheral lymphocyte subsets in these participants. Record measures of disease activity such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Alpha and beta diversity were assessed using results from QIIME2. Panel demonstrated the average relative abundance of the different genera in PsA and HCs. Correlation between clinical parameters and the relative abundance of the genus in samples was assessed by the Pearson correlation analysis using R (version 4.0.1). Compared with HC, the abundance of gut microbiota (Chao 1 and ACE) decreased in patients with PsA, and the diversity of bacteria (Shannon and Simpson indices) also decreased in PsA (Fig. 1a). β Diversity analysis indicated differences in microbial communities between PsA and HC (Fig. 1b, r = 0.039, p = 0.264, ANOSIM). Furthermore, 18 bacterial groups were significantly different at the genus level in PsA compared to HCs (p < 0.05) (Fig. 2).In the phylum and genus, lymphocyte subsets and cytokines are associated with the microbiota. The gut microbiota of patients with PsA differs from HC, which was closely related to lymphocyte subsets.
{"title":"Dysbiosis of the Gut Microbiota in Patients with Psoriatic Arthritis is Closely Related to Lymphocyte Subsets and Cytokines.","authors":"Jia Liu, Sheng-Xiao Zhang, Rong Zhao, Shan Song, He-Yi Zhang, Cai-Hong Wang, Xiao-Feng Li","doi":"10.1007/s10753-024-01971-1","DOIUrl":"10.1007/s10753-024-01971-1","url":null,"abstract":"<p><p>The purpose of this research was to characterize the microbiota of patients with psoriatic arthritis (PsA) and to compare the relationship between the microbiota and peripheral lymphocyte subsets and cytokines. We collected stool samples from 13 PsA patients and 26 sex- and age-matched healthy controls (HCs) and researched the gut microbiota by sequencing the V3-V4 variable region of the bacterial 16S rRNA gene with the Illumina Miseq PE300 system. Flow cytometry was used to assess the peripheral lymphocyte subsets in these participants. Record measures of disease activity such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Alpha and beta diversity were assessed using results from QIIME2. Panel demonstrated the average relative abundance of the different genera in PsA and HCs. Correlation between clinical parameters and the relative abundance of the genus in samples was assessed by the Pearson correlation analysis using R (version 4.0.1). Compared with HC, the abundance of gut microbiota (Chao 1 and ACE) decreased in patients with PsA, and the diversity of bacteria (Shannon and Simpson indices) also decreased in PsA (Fig. 1a). β Diversity analysis indicated differences in microbial communities between PsA and HC (Fig. 1b, r = 0.039, p = 0.264, ANOSIM). Furthermore, 18 bacterial groups were significantly different at the genus level in PsA compared to HCs (p < 0.05) (Fig. 2).In the phylum and genus, lymphocyte subsets and cytokines are associated with the microbiota. The gut microbiota of patients with PsA differs from HC, which was closely related to lymphocyte subsets.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139735150","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}
Pub Date : 2024-08-01Epub Date: 2024-02-20DOI: 10.1007/s10753-024-01988-6
Chunguang Yan, Jing Chen, Botao Wang, Jingya Wang, Ming Luo, Jingru Tong, Xuanli Xu, Qi Zhang, Ximo Wang
The role of programmed death ligand 1 (PD-L1) has been extensively investigated in adaptive immune system. However, increasing data show that innate immune responses are also affected by the immune checkpoint molecule. It has been demonstrated that regulation of PD-L1 signaling in macrophages may be a potential therapeutic method for acute respiratory distress syndrome (ARDS). However, the PD-L1 expression pattern in local macrophages and whole lung tissues remains mysterious, hindering optimization of the potential treatment program. Therefore, we aim to determine the PD-L1 expression pattern during ARDS. Our findings show that PD-L1 levels are markedly increased in lipopolysaccharide (LPS)-stimulated lung tissues, which might be attributable to an increase in the gene expression by immune cells, including macrophages and neutrophils. In vitro experiments are performed to explore the mechanism involved in LPS-induced PD-L1 production. We find that PD-L1 generation is controlled by transcription factors early growth response 1 (Egr-1) and CCAAT/enhancer binding protein delta (C/EBPδ). Strikingly, PD-L1 production is enhanced by phosphoinositide-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway via up-regulation of Egr-1 and C/EBPδ expressions. Additionally, we observe that expressions of Egr-1 and C/EBPδ mutually reinforce each other. Moreover, we observe that PD-L1 is protective for ARDS due to its regulatory role in macrophage-associated inflammatory response. In summary, during LPS-induced ARDS, PD-L1 expression, which is beneficial for the disease, is increased via the PI3K-AKT1-Egr-1/C/EBPδ signaling pathway, providing theoretical basis for application of methods controlling PD-L1 signaling in macrophages for ARDS treatment in clinic.
{"title":"PD-L1 Expression Is Increased in LPS-Induced Acute Respiratory Distress Syndrome by PI3K-AKT-Egr-1/C/EBPδ Signaling Pathway.","authors":"Chunguang Yan, Jing Chen, Botao Wang, Jingya Wang, Ming Luo, Jingru Tong, Xuanli Xu, Qi Zhang, Ximo Wang","doi":"10.1007/s10753-024-01988-6","DOIUrl":"10.1007/s10753-024-01988-6","url":null,"abstract":"<p><p>The role of programmed death ligand 1 (PD-L1) has been extensively investigated in adaptive immune system. However, increasing data show that innate immune responses are also affected by the immune checkpoint molecule. It has been demonstrated that regulation of PD-L1 signaling in macrophages may be a potential therapeutic method for acute respiratory distress syndrome (ARDS). However, the PD-L1 expression pattern in local macrophages and whole lung tissues remains mysterious, hindering optimization of the potential treatment program. Therefore, we aim to determine the PD-L1 expression pattern during ARDS. Our findings show that PD-L1 levels are markedly increased in lipopolysaccharide (LPS)-stimulated lung tissues, which might be attributable to an increase in the gene expression by immune cells, including macrophages and neutrophils. In vitro experiments are performed to explore the mechanism involved in LPS-induced PD-L1 production. We find that PD-L1 generation is controlled by transcription factors early growth response 1 (Egr-1) and CCAAT/enhancer binding protein delta (C/EBPδ). Strikingly, PD-L1 production is enhanced by phosphoinositide-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway via up-regulation of Egr-1 and C/EBPδ expressions. Additionally, we observe that expressions of Egr-1 and C/EBPδ mutually reinforce each other. Moreover, we observe that PD-L1 is protective for ARDS due to its regulatory role in macrophage-associated inflammatory response. In summary, during LPS-induced ARDS, PD-L1 expression, which is beneficial for the disease, is increased via the PI3K-AKT1-Egr-1/C/EBPδ signaling pathway, providing theoretical basis for application of methods controlling PD-L1 signaling in macrophages for ARDS treatment in clinic.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905582","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}
We explored the sex difference in lung ischemia-reperfusion injury (LIRI) and the role and mechanism of estrogen (E2) and angiotensin II (Ang II) in LIRI. We established a model of LIRI in mice. E2, Ang II, E2 inhibitor (fulvestrant), and angiotensin II receptor blocker (losartan) were grouped for treatment. The lung wet/dry weight ratio, natural killer (NK) cells (by flow cytometry), neutrophils (by flow cytometry), expression of key proteins (by Western blot, immunohistochemistry, ELISA, and immunofluorescence), and expression of related protein mRNA (by qPCR) were detected. The ultrastructure of the alveolar epithelial cells was observed by transmission electron microscopy. We found that E2 and Ang II played an important role in the progression of LIRI. The two signaling pathways showed obvious antagonism, and E2 regulates LIRI in the different sexes by downregulating Ang II, leading to a better prognosis. E2 and losartan reduced the inflammatory cell infiltration in lung tissue and key inflammatory factors in serum while fulvestrant and Ang II had the opposite effect. The protective effect of E2 was related with AKT, p38, COX2, and HIF-1α.
我们探讨了肺缺血再灌注损伤(LIRI)的性别差异以及雌激素(E2)和血管紧张素II(Ang II)在LIRI中的作用和机制。我们建立了小鼠 LIRI 模型。将 E2、Ang II、E2 抑制剂(氟维司群)和血管紧张素 II 受体阻滞剂(洛沙坦)分组进行治疗。检测了肺干湿重量比、自然杀伤(NK)细胞(通过流式细胞术)、中性粒细胞(通过流式细胞术)、关键蛋白的表达(通过 Western 印迹、免疫组织化学、ELISA 和免疫荧光)以及相关蛋白 mRNA 的表达(通过 qPCR)。透射电子显微镜观察了肺泡上皮细胞的超微结构。我们发现,E2 和 Ang II 在 LIRI 的进展过程中起着重要作用。这两种信号通路表现出明显的拮抗作用,E2通过下调Ang II调节不同性别的LIRI,从而导致更好的预后。E2和洛沙坦能减少肺组织中的炎症细胞浸润和血清中的关键炎症因子,而氟维司群和Ang II的作用恰恰相反。E2的保护作用与AKT、p38、COX2和HIF-1α有关。
{"title":"High Dose of Estrogen Protects the Lungs from Ischemia-Reperfusion Injury by Downregulating the Angiotensin II Signaling Pathway.","authors":"Peng Dai, Jutong He, Yanhong Wei, Ming Xu, Jinping Zhao, Xuefeng Zhou, Hexiao Tang","doi":"10.1007/s10753-024-01973-z","DOIUrl":"10.1007/s10753-024-01973-z","url":null,"abstract":"<p><p>We explored the sex difference in lung ischemia-reperfusion injury (LIRI) and the role and mechanism of estrogen (E2) and angiotensin II (Ang II) in LIRI. We established a model of LIRI in mice. E2, Ang II, E2 inhibitor (fulvestrant), and angiotensin II receptor blocker (losartan) were grouped for treatment. The lung wet/dry weight ratio, natural killer (NK) cells (by flow cytometry), neutrophils (by flow cytometry), expression of key proteins (by Western blot, immunohistochemistry, ELISA, and immunofluorescence), and expression of related protein mRNA (by qPCR) were detected. The ultrastructure of the alveolar epithelial cells was observed by transmission electron microscopy. We found that E2 and Ang II played an important role in the progression of LIRI. The two signaling pathways showed obvious antagonism, and E2 regulates LIRI in the different sexes by downregulating Ang II, leading to a better prognosis. E2 and losartan reduced the inflammatory cell infiltration in lung tissue and key inflammatory factors in serum while fulvestrant and Ang II had the opposite effect. The protective effect of E2 was related with AKT, p38, COX2, and HIF-1α.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930995","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}
Pub Date : 2024-08-01Epub Date: 2024-05-31DOI: 10.1007/s10753-024-01990-y
Yun-Han Yang, Fang Yan, Peng-Shuang Shi, Liu-Chan Yang, De-Jun Cui
In this study, we investigated the role of hypoxia in the development of chronic inflammatory bowel disease (IBD), focusing on its impact on the HIF-1α signaling pathway through the upregulation of lipocalin 2 (LCN2). Using a murine model of colitis induced by sodium dextran sulfate (DSS) under hypoxic conditions, transcriptome sequencing revealed LCN2 as a key gene involved in hypoxia-mediated exacerbation of colitis. Bioinformatics analysis highlighted the involvement of crucial pathways, including HIF-1α and glycolysis, in the inflammatory process. Immune infiltration analysis demonstrated the polarization of M1 macrophages in response to hypoxic stimulation. In vitro studies using RAW264.7 cells further elucidated the exacerbation of inflammation and its impact on M1 macrophage polarization under hypoxic conditions. LCN2 knockout cells reversed hypoxia-induced inflammatory responses, and the HIF-1α pathway activator dimethyloxaloylglycine (DMOG) confirmed LCN2's role in mediating inflammation via the HIF-1α-induced glycolysis pathway. In a DSS-induced colitis mouse model, oral administration of LCN2-silencing lentivirus and DMOG under hypoxic conditions validated the exacerbation of colitis. Evaluation of colonic tissues revealed altered macrophage polarization, increased levels of inflammatory factors, and activation of the HIF-1α and glycolysis pathways. In conclusion, our findings suggest that hypoxia exacerbates colitis by modulating the HIF-1α pathway through LCN2, influencing M1 macrophage polarization in glycolysis. This study contributes to a better understanding of the mechanisms underlying IBD, providing potential therapeutic targets for intervention.
{"title":"HIF-1α Pathway Orchestration by LCN2: A Key Player in Hypoxia-Mediated Colitis Exacerbation.","authors":"Yun-Han Yang, Fang Yan, Peng-Shuang Shi, Liu-Chan Yang, De-Jun Cui","doi":"10.1007/s10753-024-01990-y","DOIUrl":"10.1007/s10753-024-01990-y","url":null,"abstract":"<p><p>In this study, we investigated the role of hypoxia in the development of chronic inflammatory bowel disease (IBD), focusing on its impact on the HIF-1α signaling pathway through the upregulation of lipocalin 2 (LCN2). Using a murine model of colitis induced by sodium dextran sulfate (DSS) under hypoxic conditions, transcriptome sequencing revealed LCN2 as a key gene involved in hypoxia-mediated exacerbation of colitis. Bioinformatics analysis highlighted the involvement of crucial pathways, including HIF-1α and glycolysis, in the inflammatory process. Immune infiltration analysis demonstrated the polarization of M1 macrophages in response to hypoxic stimulation. In vitro studies using RAW264.7 cells further elucidated the exacerbation of inflammation and its impact on M1 macrophage polarization under hypoxic conditions. LCN2 knockout cells reversed hypoxia-induced inflammatory responses, and the HIF-1α pathway activator dimethyloxaloylglycine (DMOG) confirmed LCN2's role in mediating inflammation via the HIF-1α-induced glycolysis pathway. In a DSS-induced colitis mouse model, oral administration of LCN2-silencing lentivirus and DMOG under hypoxic conditions validated the exacerbation of colitis. Evaluation of colonic tissues revealed altered macrophage polarization, increased levels of inflammatory factors, and activation of the HIF-1α and glycolysis pathways. In conclusion, our findings suggest that hypoxia exacerbates colitis by modulating the HIF-1α pathway through LCN2, influencing M1 macrophage polarization in glycolysis. This study contributes to a better understanding of the mechanisms underlying IBD, providing potential therapeutic targets for intervention.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179369","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}
Pub Date : 2024-08-01DOI: 10.1007/s10753-024-02115-1
Canbin Dong, Jui-Ming Lin, Yilun Wang, Junhao Zhu, Lanmei Lin, Jinhua Xu, Juan Du
This study aims to explore the common pathogenic mechanisms of psoriasis and atopic dermatitis, two T-cell-mediated autoimmune diseases. Utilizing single-cell transcriptomic sequencing data, we revealed that Treg cells primarily express TIGIT in both psoriasis and atopic dermatitis, and identified a subset of macrophages that highly express SGK1. These cells can interact with T cells via the NECTIN2-TIGIT signaling pathway, inhibiting the differentiation of T cells into a pro-inflammatory phenotype, thereby uncovering a common immunoregulatory mechanism in both diseases. Furthermore, we discovered that inhibition of SGK1 exacerbates the inflammatory response in disease models of both conditions. These findings not only provide a new perspective for a common therapeutic strategy for psoriasis and atopic dermatitis but also highlight the importance of considering these molecular interactions in future treatments. Validation of these observations through further qPCR, immunofluorescence, and animal studies has identified potential new targets for the treatment of psoriasis and atopic dermatitis.
本研究旨在探索银屑病和特应性皮炎这两种T细胞介导的自身免疫性疾病的共同致病机制。利用单细胞转录组测序数据,我们发现在银屑病和特应性皮炎中,Treg细胞主要表达TIGIT,并发现了高表达SGK1的巨噬细胞亚群。这些细胞可通过 NECTIN2-TIGIT 信号通路与 T 细胞相互作用,抑制 T 细胞分化为促炎表型,从而揭示了这两种疾病的共同免疫调节机制。此外,我们还发现,在这两种疾病的疾病模型中,抑制 SGK1 会加剧炎症反应。这些发现不仅为银屑病和特应性皮炎的共同治疗策略提供了新的视角,而且突出了在未来治疗中考虑这些分子相互作用的重要性。通过进一步的 qPCR、免疫荧光和动物实验验证这些观察结果,发现了治疗银屑病和特应性皮炎的潜在新靶点。
{"title":"Exploring the Common Pathogenic Mechanisms of Psoriasis and Atopic Dermatitis: The Interaction between SGK1 and TIGIT Signaling Pathways.","authors":"Canbin Dong, Jui-Ming Lin, Yilun Wang, Junhao Zhu, Lanmei Lin, Jinhua Xu, Juan Du","doi":"10.1007/s10753-024-02115-1","DOIUrl":"https://doi.org/10.1007/s10753-024-02115-1","url":null,"abstract":"<p><p>This study aims to explore the common pathogenic mechanisms of psoriasis and atopic dermatitis, two T-cell-mediated autoimmune diseases. Utilizing single-cell transcriptomic sequencing data, we revealed that Treg cells primarily express TIGIT in both psoriasis and atopic dermatitis, and identified a subset of macrophages that highly express SGK1. These cells can interact with T cells via the NECTIN2-TIGIT signaling pathway, inhibiting the differentiation of T cells into a pro-inflammatory phenotype, thereby uncovering a common immunoregulatory mechanism in both diseases. Furthermore, we discovered that inhibition of SGK1 exacerbates the inflammatory response in disease models of both conditions. These findings not only provide a new perspective for a common therapeutic strategy for psoriasis and atopic dermatitis but also highlight the importance of considering these molecular interactions in future treatments. Validation of these observations through further qPCR, immunofluorescence, and animal studies has identified potential new targets for the treatment of psoriasis and atopic dermatitis.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859598","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}
Pub Date : 2024-08-01Epub Date: 2024-02-24DOI: 10.1007/s10753-024-01981-z
Tangtian Chen, Qiumin Xie, Bin Tan, Qin Yi, Han Xiang, Rui Wang, Qin Zhou, Bolin He, Jie Tian, Jing Zhu, Hao Xu
Mitochondrial dysfunction is considered one of the major pathogenic mechanisms of sepsis-induced cardiomyopathy (SIC). Pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of mitochondrial metabolism, is essential for maintaining mitochondrial function. However, its specific role in SIC remains unclear. To investigate this, we established an in vitro model of septic cardiomyopathy using lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Our study revealed a significant increase in PDK4 expression in LPS-treated H9C2 cardiomyocytes. Inhibiting PDK4 with dichloroacetic acid (DCA) improved cell survival, reduced intracellular lipid accumulation and calcium overload, and restored mitochondrial structure and respiratory capacity while decreasing lactate accumulation. Similarly, Oxamate, a lactate dehydrogenase inhibitor, exhibited similar effects to DCA in LPS-treated H9C2 cardiomyocytes. To further validate whether PDK4 causes cardiomyocyte and mitochondrial damage in SIC by promoting lactate production, we upregulated PDK4 expression using PDK4-overexpressing lentivirus in H9C2 cardiomyocytes. This resulted in elevated lactate levels, impaired mitochondrial structure, and reduced mitochondrial respiratory capacity. However, inhibiting lactate production reversed the mitochondrial dysfunction caused by PDK4 upregulation. In conclusion, our study highlights the pathogenic role of PDK4 in LPS-induced cardiomyocyte and mitochondrial damage by promoting lactate production. Therefore, targeting PDK4 and its downstream product lactate may serve as promising therapeutic approaches for treating SIC.
{"title":"Inhibition of Pyruvate Dehydrogenase Kinase 4 Protects Cardiomyocytes from lipopolysaccharide-Induced Mitochondrial Damage by Reducing Lactate Accumulation.","authors":"Tangtian Chen, Qiumin Xie, Bin Tan, Qin Yi, Han Xiang, Rui Wang, Qin Zhou, Bolin He, Jie Tian, Jing Zhu, Hao Xu","doi":"10.1007/s10753-024-01981-z","DOIUrl":"10.1007/s10753-024-01981-z","url":null,"abstract":"<p><p>Mitochondrial dysfunction is considered one of the major pathogenic mechanisms of sepsis-induced cardiomyopathy (SIC). Pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of mitochondrial metabolism, is essential for maintaining mitochondrial function. However, its specific role in SIC remains unclear. To investigate this, we established an in vitro model of septic cardiomyopathy using lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Our study revealed a significant increase in PDK4 expression in LPS-treated H9C2 cardiomyocytes. Inhibiting PDK4 with dichloroacetic acid (DCA) improved cell survival, reduced intracellular lipid accumulation and calcium overload, and restored mitochondrial structure and respiratory capacity while decreasing lactate accumulation. Similarly, Oxamate, a lactate dehydrogenase inhibitor, exhibited similar effects to DCA in LPS-treated H9C2 cardiomyocytes. To further validate whether PDK4 causes cardiomyocyte and mitochondrial damage in SIC by promoting lactate production, we upregulated PDK4 expression using PDK4-overexpressing lentivirus in H9C2 cardiomyocytes. This resulted in elevated lactate levels, impaired mitochondrial structure, and reduced mitochondrial respiratory capacity. However, inhibiting lactate production reversed the mitochondrial dysfunction caused by PDK4 upregulation. In conclusion, our study highlights the pathogenic role of PDK4 in LPS-induced cardiomyocyte and mitochondrial damage by promoting lactate production. Therefore, targeting PDK4 and its downstream product lactate may serve as promising therapeutic approaches for treating SIC.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139944124","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}
Pub Date : 2024-08-01Epub Date: 2024-01-18DOI: 10.1007/s10753-024-01970-2
Shanshan Lin, Jiayu Yan, Wenjian Wang, Lianxiang Luo
Sepsis-induced acute respiratory distress syndrome (ARDS) poses a grave danger to life, resulting from sepsis-induced multi-organ failure. Although ferroptosis, a form of iron-dependent lipid peroxidative cell death, has been associated with sepsis-induced ARDS, the specific mechanisms are not fully understood. In this study, we utilized WGCNA, PPI, friends analysis, and six machine learning techniques (Lasso, SVM, RFB, XGBoost, AdaBoost, and LightGBM) to pinpoint STAT3 as a potential diagnostic marker. A significant increase in monocyte and neutrophil levels was observed in patients with sepsis-induced ARDS, as revealed by immune infiltration analyses, when compared to controls. Moreover, there was a positive correlation between STAT3 expression and the level of infiltration. Single-cell analysis uncovered a notable disparity in B-cell expression between sepsis and sepsis-induced ARDS. Furthermore, in vitro experiments using LPS-treated human bronchial epithelial cells (BEAS-2B) and THP1 cells demonstrated a significant increase in STAT3 phosphorylation expression. Additionally, the inhibition of STAT3 phosphorylation by Stattic effectively prevented LPS-induced ferroptosis in both BEAS-2B and THP1 cells. This indicates that the activation of STAT3 phosphorylation promotes ferroptosis in human bronchial epithelial cells in response to LPS. In summary, this research has discovered and confirmed STAT3 as a potential biomarker for the diagnosis and treatment of sepsis-induced ARDS.
{"title":"STAT3-Mediated Ferroptosis is Involved in Sepsis-Associated Acute Respiratory Distress Syndrome.","authors":"Shanshan Lin, Jiayu Yan, Wenjian Wang, Lianxiang Luo","doi":"10.1007/s10753-024-01970-2","DOIUrl":"10.1007/s10753-024-01970-2","url":null,"abstract":"<p><p>Sepsis-induced acute respiratory distress syndrome (ARDS) poses a grave danger to life, resulting from sepsis-induced multi-organ failure. Although ferroptosis, a form of iron-dependent lipid peroxidative cell death, has been associated with sepsis-induced ARDS, the specific mechanisms are not fully understood. In this study, we utilized WGCNA, PPI, friends analysis, and six machine learning techniques (Lasso, SVM, RFB, XGBoost, AdaBoost, and LightGBM) to pinpoint STAT3 as a potential diagnostic marker. A significant increase in monocyte and neutrophil levels was observed in patients with sepsis-induced ARDS, as revealed by immune infiltration analyses, when compared to controls. Moreover, there was a positive correlation between STAT3 expression and the level of infiltration. Single-cell analysis uncovered a notable disparity in B-cell expression between sepsis and sepsis-induced ARDS. Furthermore, in vitro experiments using LPS-treated human bronchial epithelial cells (BEAS-2B) and THP1 cells demonstrated a significant increase in STAT3 phosphorylation expression. Additionally, the inhibition of STAT3 phosphorylation by Stattic effectively prevented LPS-induced ferroptosis in both BEAS-2B and THP1 cells. This indicates that the activation of STAT3 phosphorylation promotes ferroptosis in human bronchial epithelial cells in response to LPS. In summary, this research has discovered and confirmed STAT3 as a potential biomarker for the diagnosis and treatment of sepsis-induced ARDS.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139484438","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}
Endothelial dysfunction is associated with the development of hypertension. We hypothesize that inflammatory and normal endothelial exosomes play their roles by mediating endothelial function, and they induce endothelial angiogenesis through different signaling pathways. Endothelial cell-derived exosomes were isolated from the human umbilical vein endothelial cells (HUVECs) treated with (TExo) or without (CExo) tumor necrosis factor (TNF)-α. We monitored dermal microcirculation profiles in spontaneously hypertensive rats (SHRs) and WKY rats using a laser Doppler imager and a laser Doppler perfusion and temperature monitor. Tube formation, levels of angiogenesis-related proteins in HUVEC-conditioned media, and reactive oxygen species (ROS) levels were assessed following TNF-α, CExo, or TExo treatments. Western blot analysis was conducted to examine signaling proteins associated with inflammation and ROS. The results showed increased blood perfusion and the mean amplitude of endothelial oscillator in SHRs following CExo administration. TNF-α, CExo, and TExo treatments promoted endothelial tube formation and elevated levels of angiogenic factors and ROS. TExo significantly increased phosphorylation levels of STAT3, p38, and level of NF-κB, while decreasing phosphorylation levels of JNK and Erk (P < 0.01 or P < 0.05). CExo significantly increased STAT3 phosphorylation and reduced JNK and Erk phosphorylation (all P < 0.01). In conclusion, TNF-α and TExo induce inflammatory and pathological angiogenesis via the NF-κB pathway, while CExo exhibits a physiologically pro-angiogenic effect on endothelial cells. Increased ROS, interplaying with inflammatory signals, contribute to exosome-mediated alterations of endothelial function, thereby playing a role in the development of hypertension.
{"title":"Characteristics of Inflammatory and Normal Endothelial Exosomes on Endothelial Function and the Development of Hypertension.","authors":"Bingwei Li, Qiuju Zhang, Rui Yang, Yuhong He, Honggang Zhang","doi":"10.1007/s10753-024-01967-x","DOIUrl":"10.1007/s10753-024-01967-x","url":null,"abstract":"<p><p>Endothelial dysfunction is associated with the development of hypertension. We hypothesize that inflammatory and normal endothelial exosomes play their roles by mediating endothelial function, and they induce endothelial angiogenesis through different signaling pathways. Endothelial cell-derived exosomes were isolated from the human umbilical vein endothelial cells (HUVECs) treated with (T<sub>Exo</sub>) or without (C<sub>Exo</sub>) tumor necrosis factor (TNF)-α. We monitored dermal microcirculation profiles in spontaneously hypertensive rats (SHRs) and WKY rats using a laser Doppler imager and a laser Doppler perfusion and temperature monitor. Tube formation, levels of angiogenesis-related proteins in HUVEC-conditioned media, and reactive oxygen species (ROS) levels were assessed following TNF-α, C<sub>Exo</sub>, or T<sub>Exo</sub> treatments. Western blot analysis was conducted to examine signaling proteins associated with inflammation and ROS. The results showed increased blood perfusion and the mean amplitude of endothelial oscillator in SHRs following C<sub>Exo</sub> administration. TNF-α, C<sub>Exo</sub>, and T<sub>Exo</sub> treatments promoted endothelial tube formation and elevated levels of angiogenic factors and ROS. T<sub>Exo</sub> significantly increased phosphorylation levels of STAT3, p38, and level of NF-κB, while decreasing phosphorylation levels of JNK and Erk (P < 0.01 or P < 0.05). C<sub>Exo</sub> significantly increased STAT3 phosphorylation and reduced JNK and Erk phosphorylation (all P < 0.01). In conclusion, TNF-α and T<sub>Exo</sub> induce inflammatory and pathological angiogenesis via the NF-κB pathway, while C<sub>Exo</sub> exhibits a physiologically pro-angiogenic effect on endothelial cells. Increased ROS, interplaying with inflammatory signals, contribute to exosome-mediated alterations of endothelial function, thereby playing a role in the development of hypertension.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139491197","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}
Auraptene (AUT) is widely known to possess both antioxidant and anti-inflammatory properties. This study attempted to evaluate the protective effects of AUT in dextran sodium sulfate (DSS)-induced colitis in mice and to determine the underlying molecular mechanisms. Our results suggest that AUT substantially minimizes the severity and worsening of DSS-induced colitis in mice, indicated by the lengthening of the colon, lower disease activity index, reduced oxidation levels, and attenuated inflammatory factors. Molecular studies revealed that AUT reduces the nuclear translocation of nuclear factor-κB (NF-κB), thereby inhibiting the expression of inflammatory factors. Additionally, AUT promotes the diversity of the intestinal flora in mice with colitis by increasing the number of beneficial bacteria such as Lactobacillaceae and lowering the number of harmful bacteria. In conclusion, AUT mitigates DSS-induced colitis by maintaining the integrity of the intestinal barrier and modulating the levels of the intestinal microbial species.
众所周知,金合欢烯(AUT)具有抗氧化和抗炎特性。本研究试图评估 AUT 对右旋糖酐硫酸钠(DSS)诱导的小鼠结肠炎的保护作用,并确定其潜在的分子机制。我们的研究结果表明,AUT 大大降低了右旋糖酐硫酸钠诱导的小鼠结肠炎的严重程度和恶化程度,表现为结肠延长、疾病活动指数降低、氧化水平降低和炎症因子减弱。分子研究显示,AUT 可减少核因子-κB(NF-κB)的核转位,从而抑制炎症因子的表达。此外,AUT 还能增加乳酸菌等有益菌的数量,降低有害菌的数量,从而促进结肠炎小鼠肠道菌群的多样性。总之,AUT 可通过维持肠道屏障的完整性和调节肠道微生物种类的水平来缓解 DSS 引发的结肠炎。
{"title":"Auraptene Mitigates Colitis Induced by Dextran Sulfate Sodium in Mice by Regulating Specific Intestinal Flora and Repairing the Intestinal Barrier.","authors":"Tong Chen, Naizhong Jin, Qi Zhang, Zhongming Li, Qiutao Wang, Xuedong Fang","doi":"10.1007/s10753-023-01965-5","DOIUrl":"10.1007/s10753-023-01965-5","url":null,"abstract":"<p><p>Auraptene (AUT) is widely known to possess both antioxidant and anti-inflammatory properties. This study attempted to evaluate the protective effects of AUT in dextran sodium sulfate (DSS)-induced colitis in mice and to determine the underlying molecular mechanisms. Our results suggest that AUT substantially minimizes the severity and worsening of DSS-induced colitis in mice, indicated by the lengthening of the colon, lower disease activity index, reduced oxidation levels, and attenuated inflammatory factors. Molecular studies revealed that AUT reduces the nuclear translocation of nuclear factor-κB (NF-κB), thereby inhibiting the expression of inflammatory factors. Additionally, AUT promotes the diversity of the intestinal flora in mice with colitis by increasing the number of beneficial bacteria such as Lactobacillaceae and lowering the number of harmful bacteria. In conclusion, AUT mitigates DSS-induced colitis by maintaining the integrity of the intestinal barrier and modulating the levels of the intestinal microbial species.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139485613","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}