InflammationPub Date : 2025-08-01Epub Date: 2025-01-22DOI: 10.1007/s10753-024-02223-y
Jie Chen, Wei-Jian Zhang, Xiao-Yu Liu, Tian-Peng Hu, Nan Gao, Zhong-Hao Li, Yu Wang, Guo-Qiang Zhang
{"title":"KW-2449 Ameliorates Cardiac Dysfunction in a Rat Model of Sepsis-Induced Cardiomyopathy.","authors":"Jie Chen, Wei-Jian Zhang, Xiao-Yu Liu, Tian-Peng Hu, Nan Gao, Zhong-Hao Li, Yu Wang, Guo-Qiang Zhang","doi":"10.1007/s10753-024-02223-y","DOIUrl":"10.1007/s10753-024-02223-y","url":null,"abstract":"<p><p>KW-2449 is a novel multitargeted kinase inhibitor that has been reported to alleviate chronic inflammation and altered immunity during the treatment of autoimmune diseases. The aim of the study was to investigate the effect of KW-2449 on sepsis-induced cardiomyopathy (SIC). A rat model of moderate SIC was induced using the cecal ligation and puncture (CLP) method. KW-2449 was administered to rats at 10 mg/kg for 3 consecutive days by intraperitoneal injection. At 24 hours after CLP, echocardiography, electrocardiogram, and hemodynamic analyses were performed. Blood and cardiac tissues were collected for further analysis. RNA sequencing (RNA-seq) analyses were used to identify the key genes affected by KW-2449 treatment during SIC. KW-2449 improved the liver dysfunction in septic rats. KW-2449 significantly improved left ventricular (LV) systolic function and hemodynamics compared to the CLP group. KW-2449 suppressed the systemic inflammatory response, decreased myocardial inflammation and cell apoptosis in the CLP rats. RNA-seq analyses indicated that there were a total of 2256 differentially expressed genes in the CLP group compared to the Control group, among which 63 genes were down-regulated and 59 genes were up-regulated by KW-2449. Specifically, Pparα was identified as a key target gene of KW-2449 in the treatment of SIC by RNA-seq analysis.KW-2449 also significantly upregulated the protein expression of Pparα in the LV tissue of septic rats. KW-2449 reduced systemic inflammation, cardiac inflammation, and improved cardiac dysfunction in the CLP-induced SIC rat model. The underlying mechanism of the cardio-protective role of KW-2449 in the CLP-induced SIC might be related to Pparα.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"2732-2744"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023252","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":"Inhibiting NLRP3 Inflammasome Activation to Alleviate Retinal Inflammation and Protect the Optic Nerve of OPTN(E50K)Mice.","authors":"Shujing Wang, Rong Xiao, Yanfei Lu, Yanfeng Zhang, Shiqi Zhang, Xinna Liu, Huiping Yuan","doi":"10.1007/s10753-024-02178-0","DOIUrl":"10.1007/s10753-024-02178-0","url":null,"abstract":"<p><p>OPTN (E50K) mutation is one of the significant pathogenic mutations in normal tension glaucoma (NTG). The molecular mechanism of NTG optic nerve injury is complex and diverse; its key mechanism is still unclear. The NLR family pyrin domain containing (NLRP3) inflammasome plays an essential role in the occurrence and development of inflammation. There is no report on whether NLRP3 inflammasome activation plays a crucial role in NTG optic nerve injury. Here, we explored the role of retinal inflammatory cascade reaction triggered by NLRP3 inflammasome activation in OPTN (E50K) mutated NTG optic nerve injury. This research may provide innovative strategies for effectively treating NTG optic nerve injury caused by OPTN (E50K) mutation. The R28 cell was constructed by AAV2 transfection, named GFP-R28, WT-R28, and E50K-R28 groups. Western blot, qPCR, and immunofluorescence were performed to measure the expression levels of the neurotrophic factors, the senescence indicators, the NLRP3-related indicators, the expression of the glial cell markers, and the inflammatory cytokines. Further, observe the changes in the above indicators in the WT-R28 and E50K-R28 groups after treatment with MCC950. Next, we compared the expression of neurotrophic factors and senescence indicators, NLRP3-related indicators, glial cell markers, and inflammatory factors between young and old WT and OPTN (E50K) mice. We examined the visual function of mice on days 1, 4 and 7. Furthermore, we observed the retinal morphology and the expression of neurotrophic factors and senescence indicators, NLRP3-related indicators, glial cell markers, and inflammatory factors between all groups were measured. We found that OPTN (E50K) mutations lead to NLRP3 inflammasome activation. The OPTN (E50K) mutant groups showed an inflammatory cascade, including glial cell activation and release of proinflammatory factors, leading to retinal structural and functional impairment in mice.MCC950 effectively inhibited the activation of the NLRP3 inflammasome and alleviated the retinal inflammatory cascade caused by the OPTN (E50K) mutation, ultimately improving visual function and retinal damage in mice. OPTN (E50K) mutation induces the activation of the NLRP3 inflammasome, which leads to a retinal inflammatory cascade. MCC950 can inhibit the activation of the NLRP3 inflammasome and retinal inflammatory cascade, improving visual function in OPTN (E50K) mutation mice.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"2105-2121"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12336093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692975","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":"Rhaponticin Alleviates Collagen-induced Arthritis by Inhibiting NLRP3/GSDMD-mediated Neutrophil Extracellular Traps.","authors":"Jingjing Zhang, Xinyue Xie, Qinhao Shen, Chenchen Yuan, Guotao Lu, Weiming Xiao, Weijuan Gong, Xiaoyan Fu, Xuebing Feng","doi":"10.1007/s10753-024-02228-7","DOIUrl":"10.1007/s10753-024-02228-7","url":null,"abstract":"<p><p>Neutrophil extracellular traps (NETs) play an important role in the inflammatory response and progressive joint destruction in rheumatoid arthritis (RA). Rhaponticin (Rha) is a stilbene glycoside compound with antioxidant and anti-inflammatory effects. This study aimed to investigate the therapeutic potential of Rha in RA, with a specific focus on its effects on NETs and on the underlying mechanisms of Rha. NETs formation induced by phorbol 12-myristate 13-acetate (PMA) and a collagen-induced arthritis (CIA) mouse model were implemented to evaluate the pharmacological effects of Rha in vitro and in vivo. The potential mechanism of Rha in improving RA was screened and verified using the SuperPred and DisGeNET databases. Disulfiram (a GSDMD inhibitor) and S100a8<sup>cre</sup> GSDMD<sup>fl/fl</sup> mice were used to confirm whether GSDMD is key to the role of Rha. The findings demonstrate that Rha significantly inhibited reactive oxygen species and NETs production in PMA-activated neutrophils. In vivo, Rha treatment significantly relieved joint symptoms in CIA mice and NETs production. Mechanistically, Rha reduced NETs production via inhibition of NLRP3/GSDMD activation. Neutrophil-specific GSDMD depletion eliminated the effects of Rha on NETs production in vitro. Disulfiram eliminated the effects of Rha on the inhibition of NETs production and alleviated joint inflammation in mice in vivo and in vitro. Overall, our results indicated that Rha exerts a protective effect against CIA by inhibiting NETs production through the NLRP3/GSDMD pathway. The results of this study provide new strategies for treating RA.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"2756-2771"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12336096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894106","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":"Cellular Senescence Contributes to Colonic Barrier Integrity Impairment Induced by Toxoplasma gondii Infection.","authors":"Yingting Huang, Yumeng Zhou, Zhicheng He, Jiayi Yang, Jianqi Gu, Bingqian Cui, Siyu Li, Heng Deng, Wendi Zhao, Xiaoying Yang, Fenfen Sun, Cheng He, Wei Pan","doi":"10.1007/s10753-024-02213-0","DOIUrl":"10.1007/s10753-024-02213-0","url":null,"abstract":"<p><p>Toxoplasma gondii (T. gondii) induces gut barrier integrity impairment, which is crucial to the establishment of long-term infection in hosts. Cellular senescence is an imperative event that drives disease progression. Several studies have indicated that T. gondii induces oxidative stress and cell cycle blockade in the tissues of hosts, suggesting cellular senescence induced by the parasite. Here, we explored whether cell senescence is involved in T. gondii-mediated colonic barrier integrity damage in mice. C57BL/6J mice were infected with 10 cysts of T. gondii. Senolytic therapy (dasatinib and quercetin, DQ, a combination therapy for reducing senescent cells) was given by oral gavage 4 weeks post-infection. Alcian blue staining, immunofluorescence, western blot, quantitative PCR (qPCR), and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate the thickness of the colonic mucus layer, the expression profiles of genes and proteins related to tight junction function and cellular senescence in the colonic tissues, and the levels of serum lipopolysaccharides (LPS), respectively. T. gondii-infected mice exhibited deteriorated secreted mucus, shortened length, decreased expression of zonula occludens-1 (ZO-1) and occludin in the colon, accompanied by elevated levels of serum LPS. Moreover, the infection upregulated cell senescence-related markers (p16<sup>INK4A</sup>, p21<sup>CIP1</sup>) while inhibiting Lamin B1 expression. In addition, the expression levels of senescence-associated secretory phenotypes (SASPs), including IL-1β, TNF-α, IL-6, MMP9 and CXCL10, were upregulated post-infection. Notably, reducing cell senescence with DQ administration, significantly ameliorated the colonic pathological alterations induced by T. gondii infection. This study uncovers for the first time that cellular senescence contributes to the colonic barrier integrity damage induced by chronic T. gondii infection. Importantly, we provide evidence that senolytic therapy exerts a therapeutic effect on the intestinal pathological lesions.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"2600-2612"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12336079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004698","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}
InflammationPub Date : 2025-08-01Epub Date: 2024-10-22DOI: 10.1007/s10753-024-02168-2
Hancheng Zhou, Jiaxin Huang, Zixin Fan, Wen Sun, Yan Xu, Lu Li
{"title":"Quorum Sensing Molecule Autoinducer-2 Promotes Macrophage Classical Polarization and Exacerbates Periodontal Inflammation Via Nf-Κb Signalling.","authors":"Hancheng Zhou, Jiaxin Huang, Zixin Fan, Wen Sun, Yan Xu, Lu Li","doi":"10.1007/s10753-024-02168-2","DOIUrl":"10.1007/s10753-024-02168-2","url":null,"abstract":"<p><strong>Background: </strong>The role of quorum sensing signaling in the immunoinflammatory response during the development of periodontitis is not yet known. This study aimed to explore the effect of Autoinducer-2, a quorum sensing signaling molecule, on macrophage phenotypic remodeling in the immune microenvironment of periodontitis, to further elucidate its mechanism and to discover inhibitors against periodontitis.</p><p><strong>Methods: </strong>Bioluminescence experiments and periodontitis model were used to demonstrate the association between periodontitis progression with AI-2. Next, AI-2 challenged macrophage was introduced to transcriptomic sequence and the immune profile was characterized in combination with flow cytometry, qPCR, and immunofluorescence. Activation of NF-κB signalling by AI-2 was confirmed by fluorescence co-localization and immunoblotting. Finally, morphological methods such as Micro-CT and HE, TRAP staining and immunological methods such as immunohistochemistry/fluorescence staining were used to assess the mechanisms by which AI-2 regulates periodontitis progression.</p><p><strong>Results: </strong>AI-2 level was positively correlated with the progression of periodontitis stages and was significantly higher in periodontitis stage III and IV patients. AI-2 promotes macrophage classical polarization and facilitates the secretion of inflammatory factors in vitro, which is dependent on the activation of the NF-κB signaling pathway. AI-2 promotes alveolar bone resorption, but D-ribose acts as a quorum sensing inhibitor to alleviate macrophage classical polarization and attenuates alveolar bone resorption and inflammatory responses in periodontitis mice.</p><p><strong>Conclusions: </strong>Our study demonstrates that AI-2 promoted classical polarization of macrophage and exacerbated periodontal inflammation which could be reversed by D-ribose.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"1974-1986"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464287","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}
InflammationPub Date : 2025-08-01Epub Date: 2024-12-10DOI: 10.1007/s10753-024-02203-2
Ya Li, Deng Pan, Huifeng Liu, Wenya Xie, Xiaoyong Li, Xin Mu, Li Chen, Min Yang, Xianliang Wang, Xianxiao Li, Jianhui Li, Bianhong Zhang, Fangxia Guan, Faisal Aziz, Jingyu Cao, Xiangzhan Zhu
{"title":"REGγ-mediated Barrier Disruption and NF-κB Activation Aggravates Intestinal Inflammation in Necrotizing Enterocolitis.","authors":"Ya Li, Deng Pan, Huifeng Liu, Wenya Xie, Xiaoyong Li, Xin Mu, Li Chen, Min Yang, Xianliang Wang, Xianxiao Li, Jianhui Li, Bianhong Zhang, Fangxia Guan, Faisal Aziz, Jingyu Cao, Xiangzhan Zhu","doi":"10.1007/s10753-024-02203-2","DOIUrl":"10.1007/s10753-024-02203-2","url":null,"abstract":"<p><p>Necrotizing enterocolitis (NEC) stands as the most prevalent and severe gastrointestinal ailment affecting premature newborns, particularly those with extremely low birth weights. Intestinal barrier dysfunction emerges as a crucial factor in NEC's pathogenesis. REGγ predominantly manifests in the intestinal epithelium and has shown to regulate experimental colitis. However, the potential correlation between REGγ and NEC remains ambiguous. This study reveals that REGγ is notably overexpressed in both human and murine NEC samples. REGγ-deficient mice displayed improvements in intestinal mucosal inflammation and reduced NEC severity. Additionally, REGγ deficiency notably lowered the expression of phosphorylated transcription factor p65 and inflammatory factors in intestinal epithelial cells of NEC-afflicted mice. REGγ exacerbates the local inflammation by triggering the degradation of IκBɛ, a negative regulator of NFκB. Clinically, REGγ and p65 expression levels exhibit a positive correlation in NEC specimens. Moreover, pre-treatment of mice with a p65 inhibitor effectively suppressed the expression of inflammatory mediators and alleviated REGγ-mediated NEC development. These findings underscore that abnormal upregulation of REGγ triggers NEC development by enhancing NF-κB activity and exacerbating epithelial barrier dysfunction. Thus, novel therapeutic approaches targeting REGγ inhibition may offer enhanced treatment for NEC.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"2476-2493"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800611","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":"Exosomal miR-146a-5p Derived from HSCs Accelerates Sepsis-induced Liver Injury by Suppressing KLF-4.","authors":"Ziyi Sheng, Hua Song, Xianzhi Gao, Bian Shu, Yu You, Zuojin Liu","doi":"10.1007/s10753-024-02172-6","DOIUrl":"10.1007/s10753-024-02172-6","url":null,"abstract":"<p><p>This study aimed to investigate whether and how lipopolysaccharide (LPS) activated hepatic stellate cells (HSCs) regulate macrophage activity and to explore the impact of microRNAs (miRNAs) in exosomes from HSCs on this process. Mice subjected to LPS or cecal ligation and puncture (CLP) were used to explore sepsis-induced liver injury. Liver injury was evaluated using HE staining, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured. LPS-Exo or N-LPS-Exo from HSCs were added to hepatic macrophages, and iNOS, IL-1β, and TNF-α expression was detected via Western blotting. miRNA microarray analysis and PCR were used to evaluate differentially expressed miRNAs between LPS-Exo and N-LPS-Exo. Target genes were screened using the TargetScan database and verified with luciferase assays and WB. Inflammation and macrophage activity were observed in vivo using HE and CD86 staining in mice injected with PKH67-labeled LPS-Exo or N-LPS-Exo. Sepsis-related liver injury activates hepatic stellate cells, which regulate macrophage activity through exosomes. Specifically, exosomal miR-146a-5p secreted by hepatic stellate cells targets KLF-4, regulating the macrophage inflammatory response through the JNK signaling pathway. Exosomes containing miRNA-146a-5p released from HSCs following LPS treatment may increase macrophage sensitivity to LPS and trigger an inflammatory response. Exosomal miR-146a-5p derived from HSCs accelerates sepsis-induced liver injury by suppressing KLF-4 expression.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"2022-2035"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716286","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}
InflammationPub Date : 2025-08-01Epub Date: 2024-11-29DOI: 10.1007/s10753-024-02177-1
Qibing Wu, Yixi Niu, Hanmo Li, Yaping Pan, Chen Li
{"title":"Comprehensive Analysis of Sialylation-Related Gene Profiles and Their Impact on the Immune Microenvironment in Periodontitis.","authors":"Qibing Wu, Yixi Niu, Hanmo Li, Yaping Pan, Chen Li","doi":"10.1007/s10753-024-02177-1","DOIUrl":"10.1007/s10753-024-02177-1","url":null,"abstract":"<p><p>Periodontitis is a chronic inflammatory disease strongly influenced by host's immune response. Aberrant sialylation on cell surface plays a key role in inflammation and immunity. This study aims to identify sialylation-related genes associated with periodontitis and explore their impact on periodontal immune microenvironment. Differential expression analysis and machine learning were employed to determine core sialylation-related genes after datasets were retrieved and integrated. A diagnostic model incorporating these genes was constructed, following the immune cell infiltration analysis. Consensus clustering and weighted gene co-expression network analysis stratified periodontitis patients into subgroups and identified associated module genes. Single-cell sequencing data was further utilized to investigate the impact of sialylation on the periodontal immune microenvironment with pseudo-time series analysis and cell communication analysis. Periodontitis had a higher sialylation score with six key sialylation genes (CHST2, SELP, ST6GAL1, ST3GAL1, NEU1, FCN1) identified. The multi-gene diagnostic model demonstrated high accuracy and efficacy. Significant associations were observed between the key genes and immune cell populations, such as monocytes and B cells, in the periodontal immune microenvironment. Clustering analysis revealed two distinct sialylation-related subgroups with differential immune profiles. Single-cell data showed a significantly higher expression of sialylation-related genes in monocytes, which was found to significantly impact their developmental processes as well as their intercellular communication with B cells. The six identified sialylation-related genes hold potential as periodontitis biomarkers. High sialylation expression can impact the differentiation and cell-cell communication of monocytes. Sialylation-related genes are closely associated with alterations in the periodontal immune microenvironment.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"2087-2104"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750707","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":"Evaluating the Anti-inflammatory Potential of JN-KI3: The Therapeutic Role of PI3Kγ-Selective Inhibitors in Asthma Treatment.","authors":"Lei Jia, Mengyun Ma, Wendian Xiong, Jingyu Zhu, Yanfei Cai, Yun Chen, Jian Jin, Mingzhu Gao","doi":"10.1007/s10753-024-02180-6","DOIUrl":"10.1007/s10753-024-02180-6","url":null,"abstract":"<p><p>Asthma is a chronic airway inflammatory disease of the airways characterized by the involvement of numerous inflammatory cells and factors. Therefore, targeting airway inflammation is one of the crucial strategies for developing novel drugs in the treatment of asthma. Phosphoinositide 3-kinase gamma (PI3Kγ) has been demonstrated to have a significant impact on inflammation and immune responses, thus emerging as a promising therapeutic target for airway inflammatory disease, including asthma. There are few studies reporting on the therapeutic effects of PI3Kγ-selective inhibitors in asthma disease. In this study, we investigated the anti-inflammatory and therapeutic effects of PI3Kγ-selective inhibitor JN-KI3 for treating asthma by utilizing both in vivo and in vitro approaches, thereby proving that PI3Kγ-selective inhibitors could be valuable in the treatment of asthma. In RAW264.7 macrophages, JN-KI3 effectively suppressed C5a-induced Akt phosphorylation in a concentration-dependent manner, with no discernible toxicity observed in RAW264.7 cells. Furthermore, JN-KI3 can inhibit the PI3K/Akt signaling pathway in lipopolysaccharide-induced RAW264.7 cells, leading to the suppression of transcription and expression of the classical inflammatory cytokines in a concentration-dependent manner. Finally, an ovalbumin-induced murine asthma model was constructed to evaluate the initial therapeutic effect of JN-KI3 for treating asthma. Oral administration of JN-KI3 inhibited the infiltration of inflammatory cells and the expression of T-helper type 2 cytokines in bronchoalveolar lavage fluid, which was associated with the suppression of the PI3K signaling pathway. Lung tissue and immunohistochemical studies demonstrated that JN-KI3 inhibited the accumulation of inflammatory cells around the bronchus and blood vessels, as well as the secretion of mucus and excessive deposition of collagen around the airway. In addition, it reduced the infiltration of white blood cells into the lungs. In summary, JN-KI3 shows promise as a candidate for the treatment of asthma. Our study also suggests that the inhibitory effects of PI3Kγ on inflammation could offer an additional therapeutic strategy for pulmonary inflammatory diseases.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"2137-2151"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948222","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}
InflammationPub Date : 2025-08-01Epub Date: 2024-12-27DOI: 10.1007/s10753-024-02202-3
Xiujuan Zhao, Minghui Xia, Zhengxin Peng, Qiuyang Du, Yang Liu, Yu Xia, Panjing Lv, Xiao Zhang, Shijie Yuan, Xiaorong Xie, Jing Wang, Shuguo Sun, Xiang-Ping Yang, Ran He
{"title":"TFEB Phase Separation Mediates the Amelioration Effect of Intermittent Fasting on Inflammatory Colitis.","authors":"Xiujuan Zhao, Minghui Xia, Zhengxin Peng, Qiuyang Du, Yang Liu, Yu Xia, Panjing Lv, Xiao Zhang, Shijie Yuan, Xiaorong Xie, Jing Wang, Shuguo Sun, Xiang-Ping Yang, Ran He","doi":"10.1007/s10753-024-02202-3","DOIUrl":"10.1007/s10753-024-02202-3","url":null,"abstract":"<p><p>Intermittent fasting (IF) has been shown to ameliorate inflammation including DSS-induced colitis. It is well known that autophagy can limit inflammation and TFEB is a master transcriptional factor that regulates the processes of autophagy. However, whether TFEB is involved in the regulation of IF-mediated amelioration of inflammation and its mechanism remained unclear. In this study, we found that IF ameliorated DSS-induced colitis and induced TFEB. Nutrition deprivation induced TFEB puncta formation, which processes the characteristics of liquid-liquid phase separation (LLPS) showed by fluorescence recovery after photobleaching (FRAP) assay and 1,6-hexanediol treatment. We found the 24-33 amino acids of Coiled-Coil (CC) domain located in N terminus is essential for TFEB phase separation. Deletion of 24-33 amino acids within the CC domain inhibited TFEB-mediated target gene expression. In addition, we found transcription co-activators, EP300 and MED1, co-localized with TFEB condensate to formed a transcriptional hub that promotes the efficient expression of target genes. More importantly, TFEB inhibitor with ability to suppress TFEB puncta formation abolished the IF-mediated amelioration of DSS colitis. Together, these findings revealed a critical role of TFEB phase separation in the regulation of its transcriptional activity and anti-inflammatory functions induced by IF.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":"2458-2475"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894215","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}