Journal of Inflammation Research最新文献

{"title":"The EZH2 Inhibitor GSK126 Alleviates Thromboinflammation in Deep Vein Thrombosis by Suppressing TLR4 Signaling via H3K27me3 Modulation.","authors":"Rudan Zhou, Ji Luo, Hongyu Zheng","doi":"10.2147/JIR.S551388","DOIUrl":"10.2147/JIR.S551388","url":null,"abstract":"<p><strong>Background: </strong>Deep vein thrombosis (DVT) is characterized by abnormal clot formation, often accompanied by endothelial dysfunction and inflammation. Among various inflammatory mediators, extracellular histone H3-acting as a damage-associated molecular pattern (DAMP)-has been implicated in DVT pathogenesis by activating Toll-like receptor 4 (TLR4). Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, regulates gene expression via H3K27me3. Because TLR4 transcription may be epigenetically modulated, this study aimed to evaluate whether GSK126, an EZH2 inhibitor, mitigates DVT by modulating H3K27me3 and suppressing TLR4 signaling.</p><p><strong>Methods: </strong>To evaluate whether GSK126 attenuates histone H3-exacerbated thromboinflammation in vivo, we employed a stenosis-induced DVT mouse model combined with exogenous histone H3 injection. <i>Tlr4</i>-deficient (<i>Tlr4</i> ^-/^-) mice were used to assess the role of TLR4 signaling in thrombus formation and inflammation. GSK126 was administered intraperitoneally, and thrombus burden along with inflammatory gene expression were quantified. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with lipopolysaccharide (LPS) and treated with GSK126, either alone or in combination with the TLR4-specific inhibitor TAK-242. <i>TLR4</i> mRNA and protein levels, as well as downstream inflammatory signaling, were analyzed using qPCR and Western blotting.</p><p><strong>Results: </strong>GSK126 significantly reduced thrombus burden, TLR4 expression, and inflammatory mediators in vivo. In endothelial cells, GSK126 decreased TLR4 and phosphorylated IκBα levels, which was consistently accompanied by reduced H3K27me3 levels. Co-treatment with TAK-242 enhanced these effects. These findings suggest that GSK126 alleviates TLR4-mediated inflammation, likely through its modulation of histone methylation, specifically H3K27me3.</p><p><strong>Conclusion: </strong>Our results support a role for TLR4 signaling in DVT pathogenesis and suggest that EZH2 inhibition with GSK126 may represent a novel therapeutic approach to thromboinflammation by modulating H3K27me3 and suppressing TLR4-driven inflammatory pathways.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"13519-13534"},"PeriodicalIF":4.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12499598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244631","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":"Isolated Central Nervous System FHL3 in an Asian Pediatric Patient: A Case Report and Literature Review.","authors":"Zhanwei Zhang, Haolin Duan, Ciliu Zhang, Fang He, Fei Yin, Lifen Yang, Jing Peng","doi":"10.2147/JIR.S543598","DOIUrl":"10.2147/JIR.S543598","url":null,"abstract":"<p><p>Familial hemophagocytic lymphohistiocytosis (FHL) is a genetic inflammatory response syndrome involving many organs. Central nervous system (CNS)-isolated FHL is a rare, neuroinflammatory condition. Here, we report a case of CNS-isolated FHL3. Brain magnetic resonance imaging (MRI) showed CNS lesions mimicking chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids and multiple sclerosis. Whole-exome sequencing (WES) demonstrated likely pathogenic, parentally inherited homozygous variants of <i>UNC13D</i> (c.2588G>A, p.G863D). Neuropathological examination of a brain biopsy specimen revealed lymphocyte infiltration. Reduced levels of CD107a were also observed. CNS-isolated FHL was final diagnosis. The patient's clinical and radiological condition improved after allogeneic hematopoietic stem cell transplantation (HSCT). A study of five isolated CNS FHL3 cases (onset: 7-31 years; three females, one male, and one unknown) identified the hotspot variants c.2588G>A and c.2346_2349del. Possible triggers include the Epstein-Barr virus and herpes simplex virus. Common CNS symptoms included headache, seizures, diplopia, and ataxia (3/5 each). MRI revealed multifocal cerebral/brainstem/spinal cord lesions. Cerebrospinal fluid revealed nonspecific inflammation. Biopsies revealed T-cell predominant lymphocytic infiltration (3/3). Reduced CD107a expression was observed in four patients. Two developed systemic hemophagocytic lymphohistiocytosis (HLH). Steroids (5/5) and intravenous immunoglobulin (4/5) were the primary treatments and HSCT (4/4) achieved good outcomes. One died of HLH. To date, homozygous variants of <i>UNC13D</i> (c.2588G>A, p.G863D) have not been reported in CNS-isolated FHL. Symptoms and brain MRI of CNS-isolated FHL simulate some neuroinflammatory diseases; however, WES and functional analysis may be useful for distinguishing between them. HSCT might be an effective therapeutic strategy.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"13625-13633"},"PeriodicalIF":4.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251503","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":"Prognostic Value of SIRI in Sepsis: A Retrospective Study and Machine Learning-Based Model Development.","authors":"Yilin Zhu, Zhiyang Wang, Shifeng Li, Xin Xiao, Yujie Liu, Jiachen He, Fang Huang, Jun Wang","doi":"10.2147/JIR.S536139","DOIUrl":"10.2147/JIR.S536139","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;In recent years, the Systemic Inflammation Response Index (SIRI) has demonstrated unique advantages in evaluating sepsis prognosis. This study aims to investigate the predictive value of SIRI for 28-day outcomes in sepsis patients, and develop and validate a prognostic model for 28-day mortality.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The demographic characteristics, disease severity, laboratory tests, treatments, and outcome measures were recorded from the adult sepsis patients. The restricted cubic splines and the ROC curve analysis were employed to evaluate the relationship and predictive capability of SIRI. Next, SIRI was categorized into tertiles, and univariate and multivariate Cox regression analyses were performed to assess its association with prognosis, supplemented by Kaplan-Meier (K-M) curves, and compare mortality differences. Patients from the First Affiliated Hospital of Soochow University were randomly allocated into training and internal validation sets at a 3:1 ratio, using the Boruta algorithm and LASSO regression and a prognostic model was constructed via logistic regression, while patients from the First People's Hospital of Zhangjiagang City served as the external validation set. Then, the predictive performance, accuracy, and clinical utility of the model were validated using the ROC curve, Hosmer-Lemeshow test, calibration curve, and decision curve analysis (DCA).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The 380 patients from the First Affiliated Hospital of Soochow University and 240 patients from the First People's Hospital of Zhangjiagang City were enrolled for the present study. The restricted cubic spline analysis revealed a nonlinear increasing trend in mortality risk with rising SIRI levels. The ROC curve analysis demonstrated that SIRI has superior predictive capability than the APACHE II and SOFA scores. When SIRI was categorized into tertiles, both the univariate and multivariate Cox regression analyses identified SIRI as significantly associated to 28-day prognosis (&lt;i&gt;p&lt;/i&gt;&lt;0.001). The K-M curves further confirmed that higher SIRI levels correlated to lower 28-day survival rates (&lt;i&gt;p&lt;/i&gt;&lt;0.001). In the training set, the Boruta algorithm combined with LASSO regression selected six independent risk factors: blood urea nitrogen (BUN), age, phosphorus (P), lactate (Lac), mechanical ventilation (MV), and SIRI. These were incorporated into the predictive model through logistic regression analysis. The ROC curve analysis revealed that the model exhibited good predictive performance across the training set (AUC: 0.851), internal validation set (AUC: 0.908), and external validation set (AUC: 0.792). The calibration of the model was verified using the Hosmer-Lemeshow test and calibration curve, while DCA was performed to confirm its clinical utility.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;SIRI is significantly correlated to the 28-day prognosis in sepsis patients, and has excellent predictive value for short","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"13609-13623"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238540","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":"Mechanistic Insights into Qin Bi Yin for Psoriasis Treatment Using Network Pharmacology, Experimental Validation, and Molecular Docking.","authors":"Shouxu Zhang, Yue Du, Haomin Zhang, Xingwu Duan, Lingling Li","doi":"10.2147/JIR.S544019","DOIUrl":"10.2147/JIR.S544019","url":null,"abstract":"<p><strong>Objective: </strong>In this study, we investigated the potential mechanism of action of Qing Bi Yin (QBY) in psoriasis treatment via regulation of the sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptor 1 (S1PR1) pathway and Th17 cell differentiation.</p><p><strong>Methods: </strong>Network pharmacology was used to identify potential targets and elucidate the potential mechanisms of QBY in psoriasis. The predicted mechanisms were validated with in vitro Th17 cell differentiation assays using isolated mouse splenic CD4+ T cells. Molecular docking was performed to evaluate the binding affinities between active compounds and key target proteins.</p><p><strong>Results: </strong>We identified 262 overlapping QBY psoriasis target genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed significant associations with the sphingolipid signaling pathway, Th17 cell differentiation, and IL-17 signaling pathway. Network algorithms were used to identify 10 key active compounds and five hub genes. QBY treatment suppresses S1P synthesis and <i>S1pr1</i> expression in Th17-polarized cells. QBY inhibited Th17 cell proliferation and differentiation, reduced inflammatory cytokine secretion by Th17 cells via the S1P/S1PR1 pathway, and modulated STAT3 and SMAD2 phosphorylation. Molecular docking showed strong binding affinities between active compounds (glabridin, luteolin, licoflavone A, and isobutyrylshikonin) from QBY and key targets (STAT3, SMAD2, SPHK1, and RORγt) in Th17 cells.</p><p><strong>Conclusion: </strong>QBY ameliorates psoriatic inflammation by regulating Th17 cell differentiation via the S1P/S1PR1 signaling pathway. These findings underscore the clinical translational potential of QBY and its active constituent glabridin.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"13535-13554"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244563","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":"The Ubiquitin-Proteasome System: A Key Regulatory Hub in Myocarditis Leading to Dilated Cardiomyopathy.","authors":"Xiang Yin, Dongfei Wang, Jialan Lyu, Jie Ding, Zhicheng Pan, Kai Wang, Xiaogang Guo","doi":"10.2147/JIR.S541274","DOIUrl":"10.2147/JIR.S541274","url":null,"abstract":"<p><p>The ubiquitin-proteasome system (UPS), a key regulator of protein quality control essential for maintaining normal biological processes, also plays a vital role in cardiomyopathy. Myocarditis, a myocardial inflammatory disease characterized by chronic inflammation and immune activation, can progress to secondary dilated cardiomyopathy (DCM). Inflammatory DCM is further defined by structural and functional myocardial dysfunction and immune system dysregulation. Given its role in modulating the immune system, the UPS is critical to this transition from myocarditis to DCM. This review focuses primarily on viral myocarditis, summarizing findings on the UPS's role in inflammation and its contribution to the progression to DCM in both animal models and human studies. We delve into the intricate involvement of the UPS in various processes, including virus replication, host protein degradation, pattern recognition receptor (PRR) signaling, and both innate and adaptive immunity. The molecular mechanisms underlying their context-dependent regulatory duality-wherein individual UPS components exert opposing inhibitory or activating effects across the progression from viral myocarditis to DCM-are elucidated and discussed. Targeting the UPS to ameliorate inflammation offers a potential therapeutic strategy for myocarditis and secondary DCM.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"13555-13574"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238784","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":"Sirp-α Antibody Inhibits Renal Cell Carcinoma Progression via Akt1/Akt2 Modulation in Tumor-Associated Macrophages.","authors":"Junfeng Hao, Naiquan Liu, Xin Huang, Hanlei Zhou, Hanrong Li, Yizhou Zhang, Bing Yu, Ziqian Bi, Xinyuan Song, Shunan Li, Keyu Chen, Ning Li, Chao Zhu, Jiahe Wang","doi":"10.2147/JIR.S530775","DOIUrl":"10.2147/JIR.S530775","url":null,"abstract":"<p><strong>Introduction and aim: </strong>Immunotherapies targeting tumor-associated macrophages (TAM) to improve antitumor immunity, are promising treatment strategies for many types of cancer. The signal-regulatory protein-α (Sirp-α)/CD47 axis is a key innate immune checkpoint target important in regulating phagocytosis in macrophages. We aimed to determine whether a Sirp-α monoclonal antibody (mAb) could prevent renal cell carcinoma (RCC) progression by acting on macrophages and modifying their phenotype.</p><p><strong>Methods: </strong>We explored the gene expression signature of macrophages in the RCC microenvironment by analyzing transcriptome data of blood monocytes from patients with RCC vs healthy donors, and macrophages vs non-immune cells in RCC from public databases. We characterized the prevailing macrophage polarization phenotypes and the different ratios of Akt1 and Akt2 in RCC according to cell surface markers and expression profiles, prior to examining the effect of Sirp-α mAb on the M2 macrophage polarization in an in vitro co-culture model of RCC cells with macrophages. The co-culture model included human RCC cell lines and induced M2 macrophages, including a subset that had been transfected to overexpress phosphoinositide 3-kinase (PI3K).</p><p><strong>Results and conclusion: </strong>Treatment of RCC with Sirp-α mAb counteracted the enhanced migration and invasion of RCC as measured in wound healing and transwell assays and in vivo model. Collectively, our data showed that the different ratio of Akt1 and Akt2 of the PI3K/Akt pathway is involved in the RCC-induced M2 polarization of macrophages and that a new mechanism that the Sirp-α mAb inhibited M2 macrophage polarization by regulating components of the PI3K/Akt pathway. Elucidating the mechanism by which Sirp-α mAb inhibits the development of RCC allows us to provide a new theoretical basis for the study of the mAb in RCC immunotherapy.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"13575-13592"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238757","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":"Purinergic Receptors in Dendritic Cells.","authors":"Miaomiao Wang, Xiaoxiao Zhao, Shuai Hou, Zhongbo Wu, Hai-Yan Yin","doi":"10.2147/JIR.S549102","DOIUrl":"10.2147/JIR.S549102","url":null,"abstract":"<p><p>Dendritic cells (DCs) are regarded as highly effective antigen-presenting cells (APCs) and play a crucial role in immunomodulation. A growing body of research focuses on extracellular purines and their purinergic receptors in DCs. In this review, we provide an overview of the expression and function of purinergic receptors (P1 and P2) in DCs. To date, four P1 receptors (A1, A2A, A2B, A3), five P2X receptors (P2X1, P2X4, P2X5, P2X6, P2X7) and eight P2Y receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, P2Y14) have been reported to be expressed in DCs, with expression levels varying according to DC developmental stages (immature vs mature) and subsets. Functionally, P1 receptors are preferentially activated by adenosine(ADO) generated via ectonucleotidases, promoting the release of cytokines such as IL-10 and IL-23, and enhancing the activation, migration, and antigen presentation of DCs. In contrast, extracellular ATP-activated P2 receptors increase the secretion of pro-inflammatory cytokines including TNF-α, IL-1β, IL-18, and IL-12, while simultaneously inhibiting DC migration and antigen presentation efficiency. Therefore, only under the conditions that immune cells express the relevant receptors and ectonucleotidases dynamically regulate the ATP/ADO ratio can a mutually restrictive Yin-Yang relationship between P1 and P2 receptors be established, thereby safeguarding systemic immune homeostasis.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"13423-13432"},"PeriodicalIF":4.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232670","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":"The Association Between Markers of Lipid Homeostasis, Inflammation, and Atherosclerosis Index in Patients with Type 2 Diabetes and Coronary Heart Disease Stratified by Glycemic Control: A Cross-Sectional Study.","authors":"Ping Yang, Tian Dai, Bo Liu, Jun Yin, Xiaoli Li, Wenxin Zai, Hong Zhuang","doi":"10.2147/JIR.S550135","DOIUrl":"10.2147/JIR.S550135","url":null,"abstract":"<p><strong>Objective: </strong>This cross-sectional study investigates the relationship between systemic markers of lipid homeostasis, inflammation, and atherosclerosis index (AI) in patients with both type 2 diabetes and coronary heart disease (CHD), stratified by their glycemic control status.</p><p><strong>Methods: </strong>A total of 120 patients with type 2 diabetes and CHD were included and stratified into a Good Glycemic Control group (GGC, HbA1c<7%, n=72) and a Poor Glycemic Control group (PGC, HbA1c≥7%, n=48). AI was assessed using brachial-ankle pulse wave velocity (baPWV), and coronary stenosis was evaluated angiographically. Blood lipids, glucose metabolism indicators (Fasting Plasma Glucose [FPG], Fasting Insulin [FINS], HOMA-IR), and serum inflammatory markers (TNF-α, IL-1β, hs-CRP) were quantified. Pearson correlation and logistic regression analyses were used to assess associations and identify risk factors for AI.</p><p><strong>Results: </strong>The PGC group exhibited significantly higher AI and coronary stenosis scores, a more atherogenic lipid profile (higher TC, TG, LDL-C; lower HDL-C), and elevated HOMA-IR and inflammatory markers compared to the GGC group (all P<0.05). Baseline characteristics and medication use were similar, except for higher insulin use in the PGC group. Pearson analysis revealed that AI was positively correlated with hs-CRP, TG, coronary stenosis scores, and HOMA-IR (all P<0.05). Logistic regression identified hs-CRP, TG, coronary stenosis score, and HOMA-IR as independent risk factors for increased AI.</p><p><strong>Conclusion: </strong>In patients with type 2 diabetes and CHD, poor glycemic control is strongly associated with increased arterial stiffness, dyslipidemia, systemic inflammation, and insulin resistance. These findings highlight the critical, intertwined roles of these pathways in atherosclerosis and underscore the necessity of a multifactorial approach to cardiovascular risk management in this high-risk population.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"13453-13463"},"PeriodicalIF":4.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232649","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":"MRPL35 Attenuates Neonatal Parenteral Nutrition-Associated Cholestasis by Modulating the ROS/JNK/NF-κB Pathway.","authors":"Xiaodong Sun, Leilei Shen, Ruixue Zheng, Min Tao, Sheng Chen","doi":"10.2147/JIR.S528466","DOIUrl":"10.2147/JIR.S528466","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to elucidate the role of the MRPL35/ROS/JNK/NF-κB signaling pathway in the pathogenesis of neonatal parenteral nutrition-associated cholestasis (PNAC) to identify underlying mechanisms and potential therapeutic targets.</p><p><strong>Methods: </strong>The study employed both human and animal models. Neonates receiving parenteral nutrition for at least 2 weeks were divided into PNAC (n=10) and control groups (n=13). A PNAC model was established in male Sprague-Dawley rats (parenteral nutrition for 14 days, n=6/group), with interventions including adenovirus-mediated MRPL35 overexpression and N-acetylcysteine (NAC) treatment. Inflammatory markers, oxidative stress indicators, and signaling pathway activation were assessed using ELISA, immunohistochemistry, qRT-PCR, and Western blotting.</p><p><strong>Results: </strong>Clinically, neonates with PNAC exhibited elevated serum levels of AST, DBil, TBA, TNF-α, and IL-1β, along with reduced levels of anti-inflammatory cytokines (IL-4, IL-10), increased ROS, and higher apoptosis in peripheral blood mononuclear cells (PBMCs). MRPL35 expression was significantly downregulated and JNK and NF-κB pathways were activated. In the animal model, PNAC rats showed severe liver injury, elevated TNF-α, IL-1β and ROS in hepatocytes, and higher hepatocyte apoptosis; the expression of <i>MRPL35</i> mRNA was significantly downregulated. Overexpression of MRPL35 reduced JNK/NF-κB activation, inflammatory cytokines, oxidative stress and liver injury, effects that were enhanced by co-treatment with N-acetylcysteine (NAC).</p><p><strong>Conclusion: </strong>The MRPL35/ROS/JNK/NF-κB signaling pathway plays a critical role in the pathogenesis of PNAC. Targeting MRPL35 is expected to alleviate liver injury by blocking mitochondrial ROS signaling, offering a novel precision treatment model targeting the mitochondrial-inflammation axis for PNAC.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"13489-13502"},"PeriodicalIF":4.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232662","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":"Bromodomain and Extraterminal Protein Inhibition: A Novel Therapeutic Strategy in Arthritis.","authors":"Weibei Sheng, Jin Zhao, Fei Yu, Deli Wang, Hui Zeng, Peng Liu","doi":"10.2147/JIR.S535057","DOIUrl":"10.2147/JIR.S535057","url":null,"abstract":"<p><p>Arthritis is an inflammatory condition that affects the joints and surrounding tissues, triggered by factors such as inflammation, infection, degeneration, and trauma. The major forms of arthritis include osteoarthritis (OA), rheumatoid arthritis (RA), and gouty arthritis (GA). Its pathogenesis primarily involves synovial inflammation, cartilage degradation, and subchondral bone remodeling, with pro-inflammatory cytokines, collagenases, and other mediators playing central roles in disease onset and progression. The bromodomain and extraterminal (BET) protein family-a subclass of the larger bromodomain protein superfamily-comprises BRD2, BRD3, BRD4, and BRDT. The regulatory functions of BET proteins in inflammation highlight their considerable potential for mitigating arthritis-related pathology. This review provides a comprehensive overview of recent research on the role of BET proteins in OA, RA, and GA, aiming to deepen our understanding of the protective mechanisms of BET inhibitors, underscore their potential as therapeutic targets, and emphasize their relevance in the development of novel treatment strategies.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"13503-13517"},"PeriodicalIF":4.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232714","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}