Journal of Advanced Research最新文献

{"title":"Macrophage exosomes mediate palmitic acid-induced metainflammation by transferring miR-3064-5p to target IκBα and activate NF-κB signaling","authors":"Huiyu Luo ,&nbsp;Jiexian Wang ,&nbsp;Fengjuan Lin ,&nbsp;Yuguo Liu ,&nbsp;Xinglong Wu ,&nbsp;Gan Li ,&nbsp;Chuhong Su ,&nbsp;Junbin Chen ,&nbsp;Fei Xiong ,&nbsp;Jiaqi Mo ,&nbsp;Zhongdaixi Zheng ,&nbsp;Xiangyi Zheng ,&nbsp;Qing Li ,&nbsp;Longying Zha","doi":"10.1016/j.jare.2024.06.024","DOIUrl":"10.1016/j.jare.2024.06.024","url":null,"abstract":"<div><h3>Introduction</h3><div>High palmitic acid (PA) levels trigger metainflammation, facilitating the onset and progression of chronic metabolic diseases. Recently, exosomes were identified as new inflammation mediators. However, the mechanism by which macrophage exosomes mediate PA-induced inflammation remains unclear.</div></div><div><h3>Objectives</h3><div>To explore how PA induces metainflammation through macrophage exosomes.</div></div><div><h3>Methods</h3><div>Exosomes secreted by RAW264.7 mouse macrophages stimulated with PA (Exos^PA) or not (Exos) were prepared by ultracentrifugation. The differential miRNAs between Exos^PA and Exos were identified by high-throughput sequencing, and their targeted mRNAs and proteins were bioinformatically analyzed and verified by qPCR and western blot. Mouse macrophages and metabolic cells (AML-12 hepatocytes, C2C12 myocytes or 3T3-L1 adipocytes) were treated with Exos^PA or Exos. The verified miRNAs and its targeted molecules related to inflammation were analyzed in recipient cells. Furthers, exosomes were prepared from primary peritoneal macrophages isolated from AIN93G diet-fed (Control PM-Exos) or HPD-fed (PA PM-Exos) mice. Control or PA PM-Exos were then tail vein injected (30 μg) into mice (n = 10), once a week for 2 weeks. The verified miRNA and its targets in blood, blood exosomes, and metabolic tissues were detected. Finally, measured the levels of miRNA, inflammatory factors, and fatty acids in the blood of 20 obese/overweight individuals and 20 healthy individuals.</div></div><div><h3>Results</h3><div>Exo^PA activate NF-κB signaling and enhance inflammatory enzyme/cytokine production in macrophages and metabolic cells. Exo^PA enrich miR-3064-5p and target to inhibit IκBα as verified by exosome inhibitors and miR-3064-5p mimics and inhibitors. HPD elevates exosomal miR-3064-5p, macrophage exosomal miR-3064-5p, and inflammatory cytokine levels in mice circulation. PA PM-Exos from HPD-fed mice triggered inflammation in the circulation and metabolic tissues/organs of chow diet-fed mice. Overweight/obese individuals exhibit increased levels of circulating palmitoleic acid, exosomal miR-3064-5p, and high-sensitivity C-reactive proteins.</div></div><div><h3>Conclusions</h3><div>Macrophage exosomes transferring miR-3064-5p to target IκBα and activate NF-κB signaling in metabolic cells is a mechanism of PA-induced metainflammation.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"71 ","pages":"Pages 501-519"},"PeriodicalIF":11.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive single-cell analysis deciphered the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury","authors":"Juan Li,&nbsp;Mengjuan Xuan,&nbsp;Li Yang,&nbsp;Yingru Liu,&nbsp;Na Lou,&nbsp;Leiya Fu,&nbsp;Qingmiao Shi,&nbsp;Chen Xue","doi":"10.1016/j.jare.2025.02.018","DOIUrl":"10.1016/j.jare.2025.02.018","url":null,"abstract":"<div><h3>Introduction</h3><div>Sepsis-related acute liver injury involves complex immune dysfunctions. Epoxyeicosatrienoic acids (EETs), bioactive molecules derived from arachidonic acid (AA) via cytochrome P450 (CYP450) and rapidly hydrolyzed by soluble epoxide hydrolase (sEH), possess anti-inflammatory properties. Nevertheless, the impact of the sEH inhibitor TPPU on sepsis-related acute liver injury remains uncertain.</div></div><div><h3>Objectives</h3><div>This study utilized comprehensive single-cell analysis to investigate the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury.</div></div><div><h3>Methods</h3><div>Hepatic bulk RNA sequencing and proteomics analyses were employed to investigate the mechanisms underlying sepsis-related acute liver injury induced by cecal ligation and puncture in mice. Cytometry by time-of-flight and single-cell RNA sequencing were conducted to thoroughly examine the immunoregulatory role of TPPU at single-cell resolution.</div></div><div><h3>Results</h3><div>Downregulation of AA metabolism and the CYP450 pathway was observed during sepsis-related acute liver injury, and TPPU treatment reduced inflammatory cytokine production and mitigated sepsis-related hepatic inflammatory injury. Comprehensive single-cell analysis revealed that TPPU promotes the expansion of anti-inflammatory CD206⁺CD73⁺ M2-like macrophages and PDL1^-CD39^-CCR2⁺ neutrophils, reprogramming liver neutrophils to an anti-inflammatory CAMP⁺NGP⁺CD177⁺ phenotype. Additionally, TPPU inhibits the CCL6-CCR1 signaling mediated by M2-like macrophages and CAMP⁺NGP⁺CD177⁺ neutrophils, altering intercellular communication within the septic liver immune microenvironment.</div></div><div><h3>Conclusion</h3><div>This study demonstrated TPPU’s protective efficacy against sepsis-related acute liver injury, underscoring its vital role in modulating liver macrophages and neutrophils and enhancing prospects for personalized immunomodulatory therapy.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"71 ","pages":"Pages 457-470"},"PeriodicalIF":11.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design of a targeted dual drug delivery system for boosting the efficacy of photoimmunotherapy against melanoma proliferation and metastasis","authors":"Yi Chen ,&nbsp;Shan Xu ,&nbsp;Shuang Ren ,&nbsp;Jiyuan Zhang ,&nbsp;Jinzhuan Xu ,&nbsp;Yuxuan Song ,&nbsp;Jianqing Peng ,&nbsp;Shuai Zhang ,&nbsp;Qianming Du ,&nbsp;Yan Chen","doi":"10.1016/j.jare.2024.05.017","DOIUrl":"10.1016/j.jare.2024.05.017","url":null,"abstract":"<div><h3>Introduction</h3><div>The combination of a photosensitizer and indoleamine-2,3 dioxygenase (IDO) inhibitor provides a promising photoimmunotherapy (PIT) strategy for melanoma treatment. A dual drug delivery system offers a potential approach for optimizing the inhibitory effects of PIT on melanoma proliferation and metastasis.</div></div><div><h3>Objective</h3><div>To develop a dual drug delivery system based on PIT and to study its efficacy in inhibiting melanoma proliferation and metastasis.</div></div><div><h3>Methods</h3><div>We constructed a multifunctional nano-porphyrin material (P18-APBA-HA) using the photosensitizer-purpurin 18 (P18), hyaluronic acid (HA), and 4-(aminomethyl) phenylboronic acid (APBA). The resulting P18-APBA-HA was inserted into a phospholipid membrane and the IDO inhibitor epacadostat (EPA) was loaded into the internal phase to prepare a dual drug delivery system (LipEPAP18-APBA-HA). Moreover, we also investigated its physicochemical properties, targeting, anti-tumor immunity, and anti-tumor proliferation and metastasis effects.</div></div><div><h3>Results</h3><div>The designed system utilized the pH sensitivity of borate ester to realize an enhanced-targeting strategy to facilitate the drug distribution in tumor lesions and efficient receptor-mediated cellular endocytosis. The intracellular release of EPA from LipEPAP18-APBA-HA was triggered by thermal radiation, thereby inhibiting IDO activity in the tumor microenvironment, and promoting activation of the immune response. Intravenous administration of LipEPAP18-APBA-HA effectively induced anti-tumor immunity by promoting dendritic cell maturation, cytotoxic T cell activation, and regulatory T cell suppression, and regulating cytokine secretion, to inhibit the proliferation of melanoma and lung metastasis.</div></div><div><h3>Conclusion</h3><div>The proposed nano-drug delivery system holds promise as offers a promising strategy to enhance the inhibitory effects of the combination of EPA and P18 on melanoma proliferation and metastasis.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"71 ","pages":"Pages 533-550"},"PeriodicalIF":11.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141072483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippo-YAP/TAZ-ROS signaling axis regulates metaflammation induced by SelenoM deficiency in high-fat diet-derived obesity","authors":"Jingzeng Cai ,&nbsp;Jiaqiang Huang ,&nbsp;Di Li ,&nbsp;Xintong Zhang ,&nbsp;Bendong Shi ,&nbsp;Qiaohan Liu ,&nbsp;Cheng Fang ,&nbsp;Shiwen Xu ,&nbsp;Ziwei Zhang","doi":"10.1016/j.jare.2024.06.005","DOIUrl":"10.1016/j.jare.2024.06.005","url":null,"abstract":"<div><h3>Introduction</h3><div>Metabolic inflammation (metaflammation) in obesity is primarily initiated by proinflammatory macrophage infiltration into adipose tissue. SelenoM contributes to the modulation of antioxidative stress and inflammation in multiple pathological processes; however, its roles in metaflammation and the proinflammatory macrophage (M1)-like state in adipose tissue have not been determined.</div></div><div><h3>Objectives</h3><div>We hypothesize that SelenoM could effectively regulate metaflammation via the Hippo-YAP/TAZ-ROS signaling axis in obesity derived from a high-fat diet.</div></div><div><h3>Methods</h3><div>Morphological changes in adipose tissue were examined by hematoxylin-eosin (H&amp;E) staining and fluorescence microscopy. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to evaluate the impact of SelenoM deficiency on blood glucose levels. RNA-Seq analysis, LC-MS analysis, Mass spectrometry analysis and western blotting were performed to detect the levels of genes and proteins related to glycolipid metabolism in adipose tissue.</div></div><div><h3>Results</h3><div>Herein, we evaluated the inflammatory features and metabolic microenvironment of mice with SelenoM-deficient adipose tissues by multi-omics analyses. The deletion of SelenoM resulted in glycolipid metabolic disturbances and insulin resistance, thereby accelerating weight gain, adiposity, and hyperglycemia. Mice lacking SelenoM in white adipocytes developed severe adipocyte hypertrophy via impaired lipolysis. SelenoM deficiency aggravated the generation of ROS by reducing equivalents (NADPH and glutathione) in adipocytes, thereby promoting inflammatory cytokine production and the M1-proinflammatory reaction, which was related to a change in nuclear factor kappa-B (NF-κB) levels in macrophages. Mechanistically, SelenoM deficiency promoted metaflammation via Hippo-YAP/TAZ-ROS-mediated transcriptional regulation by targeting large tumor suppressor 2 (LATS2). Moreover, supplementation with N-acetyl cysteine (NAC) to reduce excessive oxidative stress partially rescued adipocyte inflammatory responses and macrophage M1 activation.</div></div><div><h3>Conclusion</h3><div>Our data indicate that SelenoM ameliorates metaflammation mainly via the Hippo-YAP/TAZ-ROS signaling axis in obesity. The identification of SelenoM as a key regulator of metaflammation presents opportunities for the development of novel therapeutic interventions targeting adipose tissue dysfunction in obesity.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"71 ","pages":"Pages 603-620"},"PeriodicalIF":11.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141328247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statistical agnostic regression: A machine learning method to validate regression models","authors":"J.M. Gorriz, J. Ramirez, F. Segovia, C. Jimenez-Mesa, F.J. Martinez-Murcia, J. Suckling","doi":"10.1016/j.jare.2025.04.026","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.026","url":null,"abstract":"&lt;h3&gt;&lt;strong&gt;Introduction:&lt;/strong&gt;&lt;/h3&gt;Regression analysis is a central topic in statistical modeling, aimed at estimating the relationships between a dependent variable, commonly referred to as the response variable, and one or more independent variables, i.e., explanatory variables. Linear regression is by far the most popular method for performing this task in various fields of research, such as data integration and predictive modeling when combining information from multiple sources.&lt;h3&gt;&lt;strong&gt;Objectives:&lt;/strong&gt;&lt;/h3&gt;Classical methods for solving linear regression problems, such as Ordinary Least Squares (OLS), Ridge, or Lasso regressions, often form the foundation for more advanced machine learning (ML) techniques, which have been successfully applied, though without a formal definition of statistical significance. At most, permutation or analyses based on empirical measures (e.g., residuals or accuracy) have been conducted, leveraging the greater sensitivity of ML estimations for detection.&lt;h3&gt;&lt;strong&gt;Methods:&lt;/strong&gt;&lt;/h3&gt;In this paper, we introduce Statistical Agnostic Regression (SAR) for evaluating the statistical significance of ML-based linear regression models. This is achieved by analyzing concentration inequalities of the actual risk (expected loss) and considering the worst-case scenario. To this end, we define a threshold that ensures there is sufficient evidence, with a probability of at least &lt;span&gt;&lt;span style=\"\"&gt;&lt;/span&gt;&lt;span data-mathml='&lt;math xmlns=\"http://www.w3.org/1998/Math/MathML\"&gt;&lt;mrow is=\"true\"&gt;&lt;mn is=\"true\"&gt;1&lt;/mn&gt;&lt;mo linebreak=\"badbreak\" is=\"true\"&gt;-&lt;/mo&gt;&lt;mi is=\"true\"&gt;&amp;#x3B7;&lt;/mi&gt;&lt;/mrow&gt;&lt;/math&gt;' role=\"presentation\" style=\"font-size: 90%; display: inline-block; position: relative;\" tabindex=\"0\"&gt;&lt;svg aria-hidden=\"true\" focusable=\"false\" height=\"2.432ex\" role=\"img\" style=\"vertical-align: -0.697ex;\" viewbox=\"0 -747.2 2226.9 1047.3\" width=\"5.172ex\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"&gt;&lt;g fill=\"currentColor\" stroke=\"currentColor\" stroke-width=\"0\" transform=\"matrix(1 0 0 -1 0 0)\"&gt;&lt;g is=\"true\"&gt;&lt;g is=\"true\"&gt;&lt;use xlink:href=\"#MJMAIN-31\"&gt;&lt;/use&gt;&lt;/g&gt;&lt;g is=\"true\" transform=\"translate(722,0)\"&gt;&lt;use xlink:href=\"#MJMAIN-2212\"&gt;&lt;/use&gt;&lt;/g&gt;&lt;g is=\"true\" transform=\"translate(1723,0)\"&gt;&lt;use xlink:href=\"#MJMATHI-3B7\"&gt;&lt;/use&gt;&lt;/g&gt;&lt;/g&gt;&lt;/g&gt;&lt;/svg&gt;&lt;span role=\"presentation\"&gt;&lt;math xmlns=\"http://www.w3.org/1998/Math/MathML\"&gt;&lt;mrow is=\"true\"&gt;&lt;mn is=\"true\"&gt;1&lt;/mn&gt;&lt;mo is=\"true\" linebreak=\"badbreak\"&gt;-&lt;/mo&gt;&lt;mi is=\"true\"&gt;η&lt;/mi&gt;&lt;/mrow&gt;&lt;/math&gt;&lt;/span&gt;&lt;/span&gt;&lt;script type=\"math/mml\"&gt;&lt;math&gt;&lt;mrow is=\"true\"&gt;&lt;mn is=\"true\"&gt;1&lt;/mn&gt;&lt;mo linebreak=\"badbreak\" is=\"true\"&gt;-&lt;/mo&gt;&lt;mi is=\"true\"&gt;η&lt;/mi&gt;&lt;/mrow&gt;&lt;/math&gt;&lt;/script&gt;&lt;/span&gt;, to conclude the existence of a linear relationship in the population between the explanatory (feature) and the response (label) variables.&lt;h3&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt;&lt;/h3&gt;Simulations demonstrate that the proposed agnostic (non-parametric) test can perform an analysis of variance com","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"89 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and phenotypic associations of frailty with cardiovascular indicators and behavioral characteristics","authors":"Yihan Chen ,&nbsp;Siying Lin ,&nbsp;Shuangyu Yang ,&nbsp;Mengling Qi ,&nbsp;Yu Ren ,&nbsp;Chong Tian ,&nbsp;Shitian Wang ,&nbsp;Yuedong Yang ,&nbsp;Jianzhao Gao ,&nbsp;Huiying Zhao","doi":"10.1016/j.jare.2024.06.012","DOIUrl":"10.1016/j.jare.2024.06.012","url":null,"abstract":"<div><h3>Introduction</h3><div>Frailty Index (FI) is a common measure of frailty, which has been advocated as a routine clinical test by many guidelines. The genetic and phenotypic relationships of FI with cardiovascular indicators (CIs) and behavioral characteristics (BCs) are unclear, which has hampered ability to monitor FI using easily collected data.</div></div><div><h3>Objectives</h3><div>This study is designed to investigate the genetic and phenotypic associations of frailty with CIs and BCs, and further to construct a model to predict FI.</div></div><div><h3>Method</h3><div>Genetic relationships of FI with 288 CIs and 90 BCs were assessed by the cross-trait LD score regression (LDSC) and Mendelian randomization (MR). The phenotypic data of these CIs and BCs were integrated with a machine-learning model to predict FI of individuals in UK-biobank. The relationships of the predicted FI with risks of type 2 diabetes (T2D) and neurodegenerative diseases were tested by the Kaplan-Meier estimator and Cox proportional hazards model<em>.</em></div></div><div><h3>Results</h3><div>MR revealed putative causal effects of seven CIs and eight BCs on FI. These CIs and BCs were integrated to establish a model for predicting FI. The predicted FI is significantly correlated with the observed FI (Pearson correlation coefficient = 0.660, P-value = 4.96 × 10^-62). The prediction model indicated “usual walking pace” contributes the most to prediction. Patients who were predicted with high FI are in significantly higher risk of T2D (HR = 2.635, <em>P</em> &lt; 2 × 10^-16) and neurodegenerative diseases (HR = 2.307, <em>P</em> = 1.62 × 10^-3) than other patients.</div></div><div><h3>Conclusion</h3><div>This study supports associations of FI with CIs and BCs from genetic and phenotypic perspectives. The model that is developed by integrating easily collected CIs and BCs data in predicting FI has the potential to monitor disease risk.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"71 ","pages":"Pages 263-277"},"PeriodicalIF":11.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141307691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tailoring obeticholic acid activity by iridium(III) complex conjugation to develop a farnesoid X receptor probe","authors":"Dou Niu ,&nbsp;Xiaolei Wu ,&nbsp;Yuxin Zhang ,&nbsp;Xueliang Wang ,&nbsp;Daniel Shiu-Hin Chan ,&nbsp;Shaozhen Jing ,&nbsp;Chun-Yuen Wong ,&nbsp;Wanhe Wang ,&nbsp;Chung-Hang Leung","doi":"10.1016/j.jare.2024.10.028","DOIUrl":"10.1016/j.jare.2024.10.028","url":null,"abstract":"<div><h3>Introduction</h3><div>The farnesoid X receptor (FXR) is a crucial regulator in the intestine, maintaining bile acid homeostasis. Inhibiting intestinal FXR shows promise in managing inflammatory bowel and liver diseases by reducing bile acid accumulation. Additionally, changes in FXR expression could serve as a potential biomarker for intestinal diseases. Therefore, developing an imaging probe for FXR holds significant potential for the early detection, simultaneous treatment, and monitoring of FXR-related diseases.</div></div><div><h3>Objectives</h3><div>The study aimed to develop a bioimaging probe for FXR by conjugating obeticholic acid (OCA), an FXR agonist, to an iridium(III) complex, and to investigate its application for targeting FXR in intestinal cells.</div></div><div><h3>Methods</h3><div>OCA was conjugated to an iridium(III) complex to generate the novel complex <strong>1</strong>. The effect of complex <strong>1</strong> on FXR activity, nuclear translocation, and downstream targets was investigated in intestinal epithelial cells using various biochemical and cellular assays. Additionally, the photophysical properties of complex <strong>1</strong> were assessed for FXR imaging.</div></div><div><h3>Results</h3><div>Complex <strong>1</strong> retained the desirable photophysical properties for monitoring FXR in intestinal cells while reversing OCA’s activity from agonistic to antagonistic. It disrupted FXR-RXR heterodimerization, inhibited FXR nuclear translocation, and downregulated downstream targets responsible for bile acid absorption, transport, and metabolism in intestinal epithelial cells.</div></div><div><h3>Conclusion</h3><div>The study successfully developed an imaging probe and modulator of FXR by conjugating OCA to an iridium(III) complex. Complex <strong>1</strong> retained the favorable photophysical properties of the iridium(III) complex, while reversing OCA’s activity from agonistic to antagonistic. The findings highlight the exciting application of using metals to tailor the activity of nuclear receptor modulators in living systems.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"71 ","pages":"Pages 307-316"},"PeriodicalIF":11.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Exopolysaccharide from the yeast Papiliotrema terrestris PT22AV for skin wound healing” [J. Adv. Res. 46 (2023) 61–74]","authors":"Masoud Hamidi ,&nbsp;Oseweuba Valentine Okoro ,&nbsp;Giuseppe Ianiri ,&nbsp;Hafez Jafari ,&nbsp;Khodabakhsh Rashidi ,&nbsp;Saeed Ghasemi ,&nbsp;Raffaello Castoria ,&nbsp;Davide Palmieri ,&nbsp;Cédric Delattre ,&nbsp;Guillaume Pierre ,&nbsp;Mahta Mirzaei ,&nbsp;Lei Nie ,&nbsp;Hadi Samadian ,&nbsp;Armin Shavandi","doi":"10.1016/j.jare.2025.02.038","DOIUrl":"10.1016/j.jare.2025.02.038","url":null,"abstract":"","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"71 ","pages":"Page 621"},"PeriodicalIF":11.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen receptor β activation alleviates inflammatory bowel disease by suppressing NLRP3-dependent IL-1β production in macrophages via downregulation of intracellular calcium level","authors":"Yanrong Zhu ,&nbsp;Yilei Guo ,&nbsp;Pengxiang Guo ,&nbsp;Jing Zhang ,&nbsp;Yue He ,&nbsp;Yufeng Xia ,&nbsp;Zhifeng Wei ,&nbsp;Yue Dai","doi":"10.1016/j.jare.2024.06.004","DOIUrl":"10.1016/j.jare.2024.06.004","url":null,"abstract":"<div><h3>Introduction</h3><div>Although several estrogen receptor β (ERβ) agonists have been reported to alleviate IBD, the pivotal mechanism remains obscure.</div></div><div><h3>Objectives</h3><div>To examine the effects and mechanisms of ERβ activation on cytokine/chemokine networks in colitis mice.</div></div><div><h3>Methods</h3><div>Dextran sulfate sodium salt (DSS) and trinitro-benzene-sulfonic acid (TNBS) were used to induce mouse colitis model. Multiple molecular biological methods were employed to evaluate the severity of mouse colitis and the level of cytokine and/or chemokine.</div></div><div><h3>Results</h3><div>Bioinformatics analysis, ELISA and immunofluorescence results showed that the targeted cytokines and/or chemokines associated with ERβ expression and activation is IL-1β, and the anti-colitis effect of ERβ activation was significantly attenuated by the overexpression of AAV9-IL-1β. Immunofluorescence analysis indicated that ERβ activation led to most evident downregulation of IL-1β expression in colonic macrophages as compared to monocytes and neutrophils. Given the pivotal roles of NLRP3, NLRC4, and AIM2 inflammasome activation in the production of IL-1β, we examined the influence of ERβ activation on inflammasome activity. ELISA and WB results showed that ERβ activation selectively blocked the NLRP3 inflammasome assembly-mediated IL-1β secretion. The calcium-sensing receptor (CaSR) and calcium signaling play crucial roles in the assembly of the NLRP3 inflammasome. WB and immunofluorescence results showed that ERβ activation reduced intracellular CaSR expression and calcium signaling in colonic macrophages. Combination with CaSR overexpression plasmid reversed the suppressive effect of ERβ activation on NLRP3 inflammasome assembly, and counteracting the downregulation of IL-1β secretion.</div></div><div><h3>Conclusion</h3><div>Our research uncovers that the anti-colitis effect of ERβ activation is accomplished through the reduction of IL-1β levels in colonic tissue, achieved by specifically decreasing CaSR expression in macrophages to lower intracellular calcium levels and inhibit NLRP3 inflammasome assembly-mediated IL-1β production.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"71 ","pages":"Pages 571-584"},"PeriodicalIF":11.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141285691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyroptosis: A spoiler of peaceful coexistence between cells in degenerative bone and joint diseases","authors":"Zhichao Li ,&nbsp;Wenxiang Cheng ,&nbsp;Kuanhui Gao ,&nbsp;Songlin Liang ,&nbsp;Liqing Ke ,&nbsp;Mengjie Wang ,&nbsp;Jilin Fan ,&nbsp;Dandan Li ,&nbsp;Peng Zhang ,&nbsp;Zhanwang Xu ,&nbsp;Nianhu Li","doi":"10.1016/j.jare.2024.06.010","DOIUrl":"10.1016/j.jare.2024.06.010","url":null,"abstract":"<div><h3>Background</h3><div>As people age, degenerative bone and joint diseases (DBJDs) become more prevalent. When middle-aged and elderly people are diagnosed with one or more disorders such as osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IVDD), it often signals the onset of prolonged pain and reduced functionality. Chronic inflammation has been identified as the underlying cause of various degenerative diseases, including DBJDs. Recently, excessive activation of pyroptosis, a form of programed cell death (PCD) mediated by inflammasomes, has emerged as a primary driver of harmful chronic inflammation. Consequently, pyroptosis has become a potential target for preventing and treating DBJDs.</div></div><div><h3>Aim of Review</h3><div>This review explored the physiological and pathological roles of the pyroptosis pathway in bone and joint development and its relation to DBJDs. Meanwhile, it elaborated the molecular mechanisms of pyroptosis within individual cell types in the bone marrow and joints, as well as the interplay among different cell types in the context of DBJDs. Furthermore, this review presented the latest compelling evidence supporting the idea of regulating the pyroptosis pathway for DBJDs treatment, and discussed the potential, limitations, and challenges of various therapeutic strategies involving pyroptosis regulation.</div></div><div><h3>Key Scientific Concepts of Review</h3><div>In summary, an interesting identity for the unregulated pyroptosis pathway in the context of DBJDs was proposed in this review, which was undertaken as a spoiler of peaceful coexistence between cells in a degenerative environment. Over the extended course of DBJDs, pyroptosis pathway perpetuated its activity through crosstalk among pyroptosis cascades in different cell types, thus exacerbating the inflammatory environment throughout the entire bone marrow and joint degeneration environment. Correspondingly, pyroptosis regulation therapy emerged as a promising option for clinical treatment of DBJDs.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"71 ","pages":"Pages 227-262"},"PeriodicalIF":11.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141322196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}