International immunopharmacology最新文献

{"title":"PINK1 affects mitochondrial oxidative phosphorylation by regulating MFN2 to alleviate diabetic kidney disease","authors":"Xiaoyan Pei,&nbsp;Jie Liu,&nbsp;Yu Wei,&nbsp;Yanhui Zhu,&nbsp;Yu Li,&nbsp;Qiong Wang,&nbsp;Langen Zhuang,&nbsp;Guoxi Jin","doi":"10.1016/j.intimp.2025.114786","DOIUrl":"10.1016/j.intimp.2025.114786","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic kidney disease (DKD) is widely recognized as a prevalent and major microvascular complication of diabetes mellitus. Mitofusin 2 (MFN2) has been closely linked to the development of diabetes mellitus, yet its precise role in the pathogenesis of DKD remains uncertain. The objective of our current research was to explore the role of MFN2 in the advanced DKD and its underlying molecular pathway. This research was to examine the involvement and molecular pathways of MFN2 in the advancement of DKD.</div></div><div><h3>Methods</h3><div>In this study, MFN2 was manipulated in high glucose (HG)-treated HK2 cells to investigate its impact on cell proliferation, apoptosis, and mitochondrial oxidative phosphorylation. Models of MFN2 overexpression or silencing were established in db/db mice as a diabetes model. The alterations in kidney morphology, renal fibrosis severity, macrophage polarization, and related inflammatory factors (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]) were evaluated. Furthermore, HK2 cells were co-cultivated with M1-type macrophages to examine the impact of MFN2 expression on macrophage polarization. Subsequently, we delved deeper into the upstream mechanisms utilizing the STRING database.</div></div><div><h3>Results</h3><div>Our study identified that MFN2 expression was downregulated in HG-treated HK-2 cells. The overexpression of MFN2 resulted in increased HK2 cell proliferation, improved degree of oxidative phosphorylation, and reduced apoptosis. In db/db mice, MFN2 overexpression exerted a protective effect on DKD-induced nephropathy and fibrosis. Notably, MFN2 overexpression influenced macrophage polarization and modulated expression of related inflammatory factors by promoting mitochondrial oxidative phosphorylation. Additionally, STRING database prediction revealed that PTEN-induced kinase 1 (PINK1) regulated MFN2 expression, which was consistent with MFN2 changes in DKD, and this regulation was associated with DKD progression.</div></div><div><h3>Conclusion</h3><div>The role of MFN2 in maintaining mitochondrial function in DKD may be regulated by PINK1 and provides a new potential therapeutic target for DKD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"157 ","pages":"Article 114786"},"PeriodicalIF":4.8,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900242","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":"Regulatory roles of noncanonical inflammasomes in kidney diseases","authors":"Young-Su Yi","doi":"10.1016/j.intimp.2025.114787","DOIUrl":"10.1016/j.intimp.2025.114787","url":null,"abstract":"<div><div>Inflammation is a body's immune defense against infection and injury. The inflammatory response has two main phases: the priming and triggering phases. The triggering phase involves the activation of inflammasomes, cytoplasmic platforms for initiating inflammation, and Inflammasomes are classified into two categories: canonical and noncanonical. Kidney disease, or renal disease, refers to damage or illness affecting the kidneys, leading to a progressive decline in their function. Although the roles of canonical inflammasomes in kidney diseases are well-documented, recent research highlights novel roles of noncanonical inflammasomes in managing various inflammatory conditions. In particular, emerging studies emphasize the regulatory functions of noncanonical inflammasomes in a range of kidney diseases. This review explores recent discoveries regarding the regulatory functions of noncanonical inflammasomes, including human caspase-4/5 and murine caspase-11, in the progression of kidney diseases. It also examines the potential of targeting these inflammasomes as a novel therapeutic approach.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"157 ","pages":"Article 114787"},"PeriodicalIF":4.8,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900261","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":"Disrupting the immune homeostasis: the emerging role of macrophage ferroptosis in autoimmune diseases","authors":"Tianfu Liu ,&nbsp;Yichen Huang ,&nbsp;Yizhe Wang ,&nbsp;Haili Shen","doi":"10.1016/j.intimp.2025.114745","DOIUrl":"10.1016/j.intimp.2025.114745","url":null,"abstract":"<div><div>Autoimmune diseases are a class of chronic disorders characterized by the aberrant activation of the immune system, where macrophages play a central role in regulating immune responses during disease onset and progression. Ferroptosis, a form of iron-dependent programmed cell death, has recently attracted significant interest due to its involvement in various pathological conditions. In macrophages, ferroptosis not only compromises cell viability but also disrupts immune homeostasis by promoting pro-inflammatory responses and suppressing anti-inflammatory pathways, thereby intensifying inflammation and exacerbating disease severity. While substantial progress has been made in elucidating macrophage ferroptosis in atherosclerosis and oncology, its precise mechanistic role in autoimmune diseases remains largely unexplored. This review systematically summarizes the molecular mechanisms of macrophage ferroptosis and its regulatory effects on immune homeostasis, with particular emphasis on its role in autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), and systemic sclerosis (SSc). Furthermore, we discuss potential therapeutic targets related to macrophage ferroptosis in these conditions. By integrating current knowledge, this review aims to provide a theoretical framework and novel perspectives for developing innovative therapeutic strategies targeting autoimmune diseases.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"157 ","pages":"Article 114745"},"PeriodicalIF":4.8,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900262","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":"Ex vivo pembrolizumab pharmacology for personalized PD-1 inhibitor therapy reveals a critical gap between receptor occupancy and T cell functionality","authors":"Judith D.J. Verdonk ,&nbsp;Berber Piet ,&nbsp;Rob ter Heine ,&nbsp;Michel M. van den Heuvel ,&nbsp;Ruben L. Smeets ,&nbsp;Hans J.P.M. Koenen","doi":"10.1016/j.intimp.2025.114754","DOIUrl":"10.1016/j.intimp.2025.114754","url":null,"abstract":"<div><h3>Purpose</h3><div>Targeting the programmed death (ligand)-1 (PD-1/PD-L1) axis with immune checkpoint inhibitors (ICIs), like pembrolizumab, has improved cancer survival. Unfortunately, the optimal dose remains unknown and less than 50 % of patients respond. Understanding PD-1 receptor pharmacology and developing early-response biomarkers are crucial to personalize therapy. We hypothesize that characterizing individual pre-treatment variability in immune responses to pembrolizumab will enhance PD-1 receptor pharmacology insights and improve treatment response prediction. Hence, this study evaluates the performance of a newly developed <em>ex vivo</em> immunopharmacological bioassay under healthy and pathological states.</div></div><div><h3>Methods</h3><div>Peripheral blood mononuclear cells from healthy individuals and non-small cell lung cancer (NSCLC) patients were stimulated <em>in vitro</em> in the presence of pembrolizumab. PD-1 expression, interleukin-2 (IL-2) secretion, T cell differentiation, expression of activation markers and phosphorylation of T cell signalling molecules were analysed.</div></div><div><h3>Results</h3><div>In healthy individuals, receptor saturation occurred at &gt;0.025 μg/mL pembrolizumab. Yet IL-2 production still increased significantly beyond this concentration. NSCLC patients showed significantly higher PD-1 expression and IL-2 production than healthy individuals. Nevertheless, pembrolizumab induced IL-2 production similarly in both cohorts. In NSCLC patients, pembrolizumab inhibited differentiation towards CD4 central memory T cells. Remarkably, phosphorylation of proximal phospho-markers in response to pembrolizumab varied between NSCLC patients, potentially discriminating responders from non-responders.</div></div><div><h3>Conclusions</h3><div>We highlight the importance of evaluating T cell functionality alongside PD-1 receptor occupancy. We identified PD-1-induced modulation of phosphorylation of proximal signalling molecules as potential predictors for ICI treatment response in NSCLC. We recommend further development of this immunopharmacological bioassay for personalization of ICI treatment.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"157 ","pages":"Article 114754"},"PeriodicalIF":4.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900260","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":"NSMCE2 promotes the occurrence and development of HCC by regulating the SUMOylation of PPARα","authors":"Yukai Chen ,&nbsp;Shishi Zou ,&nbsp;Le Xu ,&nbsp;Jiayu Chen ,&nbsp;Ling Wang ,&nbsp;Yang Shen ,&nbsp;Yangtao Xu ,&nbsp;Yuxin Wei ,&nbsp;Ximing Xu","doi":"10.1016/j.intimp.2025.114762","DOIUrl":"10.1016/j.intimp.2025.114762","url":null,"abstract":"<div><h3>Background</h3><div>Primary liver cancer is a malignant tumor of the digestive system and ranks as the sixth most commonly diagnosed cancer globally. It has also risen to become the third leading cause of cancer-related deaths globally, following lung and colorectal cancers. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancer, approximately 75 to 85 %. Several studies suggest that NSMCE2 contributes to cancer through its SUMO E3 ligase activity, yet its specific role in HCC remains poorly understood.</div></div><div><h3>Methods</h3><div>We gathered data from various databases and obtained 10 pairs of tissue samples from HCC patients to detect the NSMCE2 expression levels. Additionally, we conducted both in vivo and in vitro experiments to confirm the impact of NSMCE2 on the development and progression of HCC. We further analyzed the potential mechanism of NSMCE2 regulation on HCC by bioinformatics, and detected the specific mechanism of NSMCE2 regulating PPARα by co-immunoprecipitation.</div></div><div><h3>Results</h3><div>Our study shows that NSMCE2 is an important tumor promoter in HCC and acts through the PPARα-CYP7A1 axis. Specifically, NSMCE2 affects the occurrence and progression of HCC by SUMOylating PPARα, reducing its ubiquitination degradation, and activating the PPARα-CYP7A1 axis.</div></div><div><h3>Conclusions</h3><div>Our study uncovered the role of NSMCE2 in the development and progression of HCC, providing new insights into the pathogenesis and potential therapeutic strategies of HCC.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"157 ","pages":"Article 114762"},"PeriodicalIF":4.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900258","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":"Protective potential of nodakenin in high-fat diet-mediated colitis-associated cancer: Inhibition of STAT3 activation and Wnt/β-catenin pathway, and gut microbiota modulation","authors":"Kyung-Sook Chung ,&nbsp;So-Won Heo ,&nbsp;Jung-Hun Lee ,&nbsp;Hee-Soo Han ,&nbsp;Gi-Hui Kim ,&nbsp;Ye-Rin Kim ,&nbsp;Min-Su Kim ,&nbsp;Ju-Eun Hong ,&nbsp;Ki-Jong Rhee ,&nbsp;Kyung-Tae Lee","doi":"10.1016/j.intimp.2025.114734","DOIUrl":"10.1016/j.intimp.2025.114734","url":null,"abstract":"<div><div>A high-fat diet (HFD) exerts complex effects on the risk of colitis-associated cancer (CAC). Nodakenin, a key phytochemical isolated from the dried roots of <em>Angelicae gigas</em> Nakai (Umbelliferae), possesses anti-inflammatory and anti-adipogenic properties and shows potential as a therapeutic agent for colorectal cancer (CRC). In this study, we investigated the protective effects and underlying molecular mechanisms of nodakenin in an animal model of CRC induced by HFD, azoxymethane (AOM), and dextran sodium sulfate (DSS). Oral administration of nodakenin significantly alleviated clinical symptoms, such as recovery of weight, spleen weight, and colon length, and suppressed tumor progression in the colonic tissues of HFD/AOM/DSS-induced CRC mice. Nodakenin inhibited the activation of STAT3-related inflammatory mediators and downregulated proteins involved in the Wnt/β-catenin signaling pathway. These effects contributed to the disruption of epithelial-mesenchymal transition (EMT) and the restoration of tight junction integrity within the colonic tissue. Furthermore, nodakenin treatment improved the composition of the gut microbiota, leading to observable species-level differences. Network analysis revealed significant correlations between clinical parameters, inflammatory markers, EMT and apoptotic factors, and the composition of the gut microbiota. Specifically, negative correlations were observed between spleen weight and <em>Alistipes</em>, as well as between MCP-1 and <em>Clostridium</em>_g21. Positive correlations with spleen weight were observed with species belonging to <em>Anaerotruncus</em>, <em>Emergencia</em>, and <em>Parvibacter</em>. <em>Bacteroidaceae_uc</em> and <em>Bacteroides</em> correlated positively with MCP-1, <em>Streptococcus</em> correlated positively with PUMA, and <em>Harryflintia, Odoribacteraceae_uc</em>, and <em>Roseburia</em> correlated positively with cleaved caspase-3. Overall, our findings suggested that nodakenin effectively alleviates HFD/AOM/DSS-induced CRC by targeting inflammatory pathways (STAT3 and Wnt/β-catenin), suppressing EMT, and restoring gut microbiota balance. These multiple mechanisms underscore its potential as a promising agent for the prevention and treatment of colitis-associated colorectal cancer.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"157 ","pages":"Article 114734"},"PeriodicalIF":4.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895354","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":"Wogonin potentiates the irradiation effect on hepatocellular carcinoma by activating the Hippo-Yes-associated protein/transcriptional co-activator with PDZ-binding motif pathway","authors":"Xiao Xu ,&nbsp;Yan Cheng ,&nbsp;Zeyu Yang ,&nbsp;Yong Yin ,&nbsp;Yonghong Qian ,&nbsp;Haiyu Yang ,&nbsp;Shusheng Zhu ,&nbsp;Hu Tian ,&nbsp;Yanshuang Zhuang ,&nbsp;Shimin Zhu ,&nbsp;Pingjin Yang ,&nbsp;Songbing Qin ,&nbsp;Weigan Shen","doi":"10.1016/j.intimp.2025.114740","DOIUrl":"10.1016/j.intimp.2025.114740","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate whether wogonin increases the radiosensitivity of hepatocellular carcinoma (HCC) cells by activating Hippo-Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling.</div></div><div><h3>Methods</h3><div>HCC cells were treated with irradiation and wogonin; their proliferation and apoptosis were evaluated. Xenograft models were established to assess the radio-synergistic effects of wogonin; we evaluated whether wogonin influences the efficacy of radiotherapy in HCC cells by activating Hippo-YAP/TAZ signaling.</div></div><div><h3>Results</h3><div>Fifty micromolar wogonin enhanced the radiosensitivity of HCC cells; 4-Gy X-rays promoted apoptosis in HCC cells. Wogonin pretreatment significantly increased radiosensitivity. In xenograft models, tumor weight and volume in the 100 mg/kg wogonin plus irradiation group were significantly reduced; pYAP and pTAZ levels were downregulated in HCC cells treated with radiotherapy. Following treatment with 4-Gy X-rays and 100 μM wogonin, the relative pYAP/total YAP and pTAZ/total TAZ ratios increased. We identified the possible target genes of YAP/TAZ: <em>AXL</em>, <em>CCN1</em>, and <em>CCN2</em>. WB results revealed the upregulation of AXL, CCN1, and CCN2 in the irradiation group. However, in the group receiving irradiation and wogonin, the protein expression levels of AXL, CCN1, and CCN2 were downregulated. XMU-MP-1 inhibited pYAP and pTAZ expression in the combination treatment group, thereby promoting AXL, CCN1, and CCN2 expression. The proliferative ability of HCC cells in the wogonin plus irradiation group was partially recovered following treatment with XMU-MP-1. Apoptosis in HCC cells was reversed after pretreatment with 2 μM XMU-MP-1 in the wogonin plus irradiation group.</div></div><div><h3>Conclusion</h3><div>Wogonin may modulate Hippo-YAP/TAZ signaling and enhance the radiosensitivity of HCCs.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"157 ","pages":"Article 114740"},"PeriodicalIF":4.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895355","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":"Apigenin prevents hypertensive vascular remodeling by regulating the TP53 pathway","authors":"Jie Gao ,&nbsp;Ding Wang ,&nbsp;Xiaotong Zhang ,&nbsp;Guojun Yang ,&nbsp;Dongmei Xi ,&nbsp;Xuqing Qin ,&nbsp;Yanming Wang ,&nbsp;Yu Jin ,&nbsp;Yanli Guo ,&nbsp;Xinzhi Li ,&nbsp;Ketao Ma","doi":"10.1016/j.intimp.2025.114706","DOIUrl":"10.1016/j.intimp.2025.114706","url":null,"abstract":"<div><div>Vascular remodeling is a critical independent risk factor contributing to the increased incidence of cardiovascular events in hypertensive patients. Apigenin plays a pivotal role in hypertension protection. However, its impact on hypertension-induced vascular remodeling remains underexplored. This study investigates the protective effects and underlying mechanisms of apigenin on vascular remodeling in hypertension. In vivo experiments demonstrated that apigenin attenuated aortic remodeling in spontaneously hypertensive rats (SHRs). Treatment with apigenin resulted in a reduction in the mid-membrane thickness, vessel wall diameter, and wall-to-lumen ratio in the vascular cross-sections of SHRs. In vitro, angiotensin II (Ang II)-induced vascular smooth muscle cell (VSMC) proliferation and migration were inhibited by apigenin. Western blot analysis revealed that apigenin downregulated the expression of Ang II-induced proliferating cell nuclear antigen (PCNA), matrix metalloproteinase-9 (MMP9), and matrix metalloproteinase-2 (MMP2). Furthermore, apigenin induced cell cycle arrest at the G0/G1 phase by activating tumor protein p53 (TP53) in VSMCs. Network pharmacology and molecular docking identified TP53 as the key target through which apigenin mitigates hypertension-induced vascular remodeling. The TP53 inhibitor Pifithrin-α (PFT-α) reversed the inhibitory effects of apigenin on Ang II-induced VSMC proliferation and migration. In conclusion, apigenin mitigates hypertension-induced vascular remodeling, potentially by upregulating the TP53 pathway.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"157 ","pages":"Article 114706"},"PeriodicalIF":4.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895350","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":"Temporin-GHa derived peptide shows inhibitory efficacy against Cutibacterium acnes and alleviates inflammatory reactions in acne vulgaris","authors":"Ting Zhao ,&nbsp;Yanmei Zha ,&nbsp;Shangjun Jiang ,&nbsp;Rong Wang ,&nbsp;Yanting Song ,&nbsp;Lushuang Li ,&nbsp;Junchen Lyu ,&nbsp;Wenting Hu ,&nbsp;Daqi Zhang ,&nbsp;Shuang Wu ,&nbsp;Yingxia Zhang","doi":"10.1016/j.intimp.2025.114756","DOIUrl":"10.1016/j.intimp.2025.114756","url":null,"abstract":"<div><div>Acne vulgaris is a widespread chronic inflammatory skin disease that is mainly caused by <em>Cutibacterium acnes</em> infection and subsequent inflammation. Temporin-GHaR4G7R (GHaR4G7R) was derived from Temporin-GHa of frog <em>Hylarana guentheri</em>. Its antibacterial performance against <em>C. acnes</em> and potential mechanism against acne vulgaris <em>in vitro</em> and <em>in vivo</em> were evaluated. <em>In vitro</em> tests demonstrated that GHaR4G7R displayed potent bactericidal effects against <em>C. acnes</em>, with both the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 3.1 μM. It exerted antibacterial effect by disrupting the bacterial membranes, accompanied by low propensity for developing drug resistance. GHaR4G7R significantly inhibited the formation of early biofilms and eliminated established biofilms of <em>C. acnes</em> by decreasing exopolysaccharide synthesis. Meanwhile, GHaR4G7R demonstrated an anti-inflammatory effect on HaCaT cells challenged with heat-inactivated <em>C. acnes</em> by significantly down-regulating the expression of TLR2/NF-κB/MAPK pathway-associated proteins by qRT-PCR, immunofluorescence, and Western blot assays. As expected, GHaR4G7R significantly decreased the bacterial colonization in rat ear model induced by <em>C. acnes</em>, and relieved the auricular swelling and inflammatory cell infiltration through inhibiting the TLR2/NF-κB/MAPK signaling pathway, leading to down-regulation of the inflammatory cytokine expression and alleviation of the skin inflammation <em>in vivo</em>. The research indicates that GHaR4G7R might be a potential alternative for developing novel strategies for treating acne vulgaris.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"157 ","pages":"Article 114756"},"PeriodicalIF":4.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895353","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":"TCN1 as an inflammatory regulator in psoriasis: Activation of the NF-κB pathway and potential therapeutic target","authors":"Jian Huang ,&nbsp;Huanhuan Yu ,&nbsp;Xiuqing Yuan ,&nbsp;Yuanqiu Zhong ,&nbsp;Xinhui Li ,&nbsp;Yongfeng Chen","doi":"10.1016/j.intimp.2025.114784","DOIUrl":"10.1016/j.intimp.2025.114784","url":null,"abstract":"<div><h3>Objective</h3><div>This study investigates how TCN1 regulates inflammation and the cell cycle in psoriasis, focusing on the NF-κB pathway through in vitro experiments and bioinformatics analyses.</div></div><div><h3>Methods</h3><div>DEGs were identified by analyzing transcriptome data from four datasets comparing psoriatic lesions and normal skin (GSE34248, <span><span>GSE30999</span><svg><path></path></svg></span>, <span><span>GSE14905</span><svg><path></path></svg></span>, and <span><span>GSE13355</span><svg><path></path></svg></span>). Validation of TCN1 expression following biologic treatment was conducted using <span><span>GSE201827</span><svg><path></path></svg></span>, <span><span>GSE51440</span><svg><path></path></svg></span>, and <span><span>GSE117239</span><svg><path></path></svg></span>. GO and GSEA were performed to explore biological pathways.</div><div>The expression levels of TCN1 in psoriatic lesions and healthy skin were assessed by qPCR and immunohistochemistry (IHC). In vitro, HaCaT keratinocytes were stimulated with TNF-α and IL-17 A, and TCN1 expression was modulated through siRNA-mediated knockdown and plasmid-mediated overexpression. Subsequent changes in TCN1 and key inflammatory cytokines were evaluated by qPCR and Western blotting (WB). Furthermore, immunofluorescence assays were performed to visualize the subcellular localization of TCN1 and the nuclear translocation of phosphorylated p65 (p-p65) in HaCaT cells. Cell cycle progression was assessed using BrdU-PI flow cytometry.</div></div><div><h3>Results</h3><div>TCN1 was upregulated in psoriatic lesions, and its expression levels were positively correlated with the PASI score. Following biologic treatment, TCN1 expression was reduced. TCN1 overexpression was associated with activation of the NF-κB signaling pathway, accompanied by increased synthesis of psoriasis-related inflammatory mediators, as well as an elevated proportion of cells in the S phase of the cell cycle.</div></div><div><h3>Conclusions</h3><div>TCN1 is essential in modulating inflammation and the cell cycle in psoriasis, implying its value as both a biomarker for diagnosis and a candidate for therapeutic intervention.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"157 ","pages":"Article 114784"},"PeriodicalIF":4.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900259","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}