European Journal of Clinical Investigation最新文献

{"title":"The role of CEACAMs in neutrophil function.","authors":"Keith M Skubitz","doi":"10.1111/eci.14349","DOIUrl":"https://doi.org/10.1111/eci.14349","url":null,"abstract":"<p><strong>Background: </strong>In addition to the long-known antibacterial actions of neutrophils, neutrophils are recognized to have a variety of other effects and are functionally diverse. Neutrophils can either stimulate or inhibit B cells and T cells, regulate NK development and activity, augment or direct the resolution of inflammation, act as myeloid-derived suppressor cells, modulate tumour growth and metastasis and trigger autoimmune diseases. CEACAMs 1, 3, 6 and 8 are expressed on human neutrophils.</p><p><strong>Methods: </strong>A literature review was performed on the role of CEACAMs in neutrophil function.</p><p><strong>Results: </strong>CEACAMs 1, 6 and 8 can be upregulated from intracellular stores, while CEACAM3, an opsonin-independent phagocytic receptor, is constitutively expressed. CEACAM1 has an intracellular ITIM motif and an ITSM motif, and CEACAM3 has an ITAM-like motif; CEACAMs 6 and 8 are glycosylphosphatidylinositol-linked. CEACAM8 can also be released in a soluble form. These CEACAMs can interact with multiple other host CEACAMs as well as other molecules on bacteria, fungi and host cells, both transmitting and receiving signals. Known CEACAM-binding pathogens bind the CFG face of the N domain which is also important in CEACAM-CEACAM binding, although the ABDE face also appears to be involved in higher-order oligomers.</p><p><strong>Conclusions: </strong>Understanding the exact role of each individual CEACAM in human neutrophils is complicated by the fact that the neutrophil CEACAMs can interact with multiple ligands. The data demonstrates some of the many roles of CEACAMs in neutrophil function and the extensive role of the neutrophil in human biology beyond its classical role as a short-lived phagocyte.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 Suppl 2 ","pages":"e14349"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reciprocity between the regulation of the expression and functions of CEACAM.","authors":"Sonia M Najjar, M Paula Macedo","doi":"10.1111/eci.14362","DOIUrl":"https://doi.org/10.1111/eci.14362","url":null,"abstract":"","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 Suppl 2 ","pages":"e14362"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CEACAM1 in vascular homeostasis and inflammation.","authors":"Lisa Götz, Uwe Rueckschloss, Süleyman Ergün, Florian Kleefeldt","doi":"10.1111/eci.14345","DOIUrl":"https://doi.org/10.1111/eci.14345","url":null,"abstract":"<p><strong>Introduction: </strong>The glycoprotein Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1), also known as CD66a, is a member of the immunoglobulin superfamily. It is expressed in a variety of tissues including epithelial, immune, as well as endothelial cells, and is crucial to diverse physiological and pathological mechanisms. This review aims to provide a comprehensive understanding of CEACAM1's multifaceted roles in vascular biology and inflammatory processes.</p><p><strong>Methods: </strong>Directed literature research was conducted using databases, such as PubMed, and relevant studies were categorized based on the physiological effects of CEACAM1.</p><p><strong>Results: </strong>CEACAM1 plays a pivotal role in vascular homeostasis, particularly influencing the formation, maturation, and aging of blood vessels, as well as the endothelial barrier function. It supports endothelium-dependent vasodilation and nitric oxide formation, thus promoting vascular integrity and regulating blood pressure. Additionally, CEACAM1 is of emerging importance to vascular inflammation and its potential clinical consequences.</p><p><strong>Conclusion: </strong>CEACAM1 is a crucial regulator of vascular homeostasis and inflammation with significant implications for cardiovascular health. Despite the lack of understanding of tissue-specific modulation and isoform-dependent mechanisms, CEACAM1 could be a promising therapeutic target for the prevention of cardiovascular disease in the future.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 Suppl 2 ","pages":"e14345"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into circulating CEACAM1 in insulin clearance and disease progression: Evidence from the Portuguese PREVADIAB2 study.","authors":"Rita S Patarrão, Maria João Meneses, Hilda E Ghadieh, Laura Herrera, Sérgio Duarte, Rogério T Ribeiro, João F Raposo, Verena Schmitt, Bernhard B Singer, Amalia Gastaldelli, Carlos Penha-Gonçalves, Sonia M Najjar, M Paula Macedo","doi":"10.1111/eci.14344","DOIUrl":"https://doi.org/10.1111/eci.14344","url":null,"abstract":"<p><strong>Background: </strong>Type 2 diabetes (T2DM) and obesity are characterized by altered insulin metabolism and action. Reduced hepatic insulin clearance is increasingly recognized as a key contributor to hyperinsulinemia and insulin resistance. CEACAM1 promotes hepatic insulin clearance, and its loss in hepatocytes is associated with reduced insulin clearance in mice and men. This study examines whether CEACAM1 circulating levels reflect compromised insulin metabolism and resistance in the PREVADIAB2 cohort.</p><p><strong>Methods: </strong>A total of 1019 individuals from the PREVADIAB2 cohort were evaluated for diabetes by 75 g-OGTT and classified according to WHO 2019 criteria. CEACAM1 circulating levels were measured by ELISA, and insulin metabolism parameters were calculated. Hierarchical clustering of insulin metabolic indices and CEACAM1 levels was performed. Statistical significance was assessed using Kruskal-Wallis and Wilcoxon-Mann-Whitney tests.</p><p><strong>Results: </strong>BMI, insulin resistance (HOMA-IR), and hepatic steatosis progressively increased with disease severity. Insulin secretion rose and its clearance declined in parallel to circulating CEACAM1 levels in prediabetes and T2DM, indicating compensatory hyperinsulinemia. Hierarchical metabolic clustering identified four clusters with distinct patterns and further showed that insulin clearance positively correlated with circulating CEACAM1, especially in individuals with normoglycemia, lower obesity and hepatic steatosis. This suggests that circulating CEACAM1 can reflect the status of hepatic insulin clearance.</p><p><strong>Conclusions: </strong>This study demonstrates a progressive increase in insulin resistance and hyperinsulinemia in parallel to elevated BMI and hepatic steatosis prevalence, accompanied by declining circulating CEACAM1 levels. Cluster analysis further linked reduced insulin clearance to lower circulating CEACAM1 levels, suggesting its potential usefulness as a biomarker for metabolic disease progression.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 Suppl 2 ","pages":"e14344"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism and function of CEACAM1 splice isoforms.","authors":"Kenneth J Dery, Sonia M Najjar, Nicole Beauchemin, John E Shively, Jerzy W Kupiec-Weglinski","doi":"10.1111/eci.14350","DOIUrl":"https://doi.org/10.1111/eci.14350","url":null,"abstract":"<p><strong>Background: </strong>Alternative splicing is a fundamental mechanism in the post-transcriptional regulation of genes. The multifunctional transmembrane glycoprotein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) undergoes extensive alternative splicing to allow for tunable functions in cell signalling, adhesion and modulation of immune and metabolic responses. Splice isoforms that differ in their ectodomain and short or long cytoplasmic tail (CEACAM1-S/CEACAM1-L) have distinct functional roles. The mechanisms that regulate CEACAM1 RNA splicing remain elusive.</p><p><strong>Methods: </strong>This narrative review summarizes the current knowledge of the mechanism and function of CEACAM1 splice isoforms. Historical perspectives address the biological significance of the glycosylated Ig domains, the variable exon 7, and phosphorylation events that dictate its signal transduction pathways. The use of small antisense molecules to target mis-spliced variable exon 7 is discussed.</p><p><strong>Results: </strong>The Ig variable-like N domain mediates cell adhesion and immune checkpoint inhibitory functions. Gly and Tyr residues in the transmembrane (TM) domain are essential for dimerization. Calmodulin, Calcium/Calmodulin-dependent protein kinase II delta (CamK2D), Actin and Annexin A2 are binding partners of CEACAM1-S. Homology studies of the muCEACAM1-S and huCEACAM1-S TM predict differences in their signal transduction pathways. Hypoxia-inducible factor 1-α (HIF-1-α) induces alternative splicing to produce CEACAM1-S under limited oxygen conditions. Antisense small molecules directed to exon 7 may correct faulty expression of the short and long cytoplasmic tail splicing isoforms.</p><p><strong>Conclusion: </strong>More pre-clinical and clinical studies are needed to elucidate the precise mechanisms by which CEACAM1 RNA splicing may be exploited to develop targeted interventions towards novel therapeutic strategies.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 Suppl 2 ","pages":"e14350"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of lipid storage and inflammation in the liver by CEACAM1.","authors":"Sonia M Najjar, John E Shively","doi":"10.1111/eci.14338","DOIUrl":"https://doi.org/10.1111/eci.14338","url":null,"abstract":"<p><p>This review focuses on a special aspect of hepatic lipid storage and inflammation that occurs during nutritional excess in obesity. Mounting evidence supports that prolonged excess fatty acid (FA) uptake in the liver is strongly associated with hepatic lipid storage and inflammation and that the two processes are closely linked by a homeostatic mechanism. There is also strong evidence that bacterial lipids may enter the gut by a common mechanism with lipid absorption and that there is a set point to determine when their uptake triggers an inflammatory response in the liver. In fact, the progression from high uptake of FAs in the liver resulting in Metabolic dysfunction-associated steatotic liver disease (MASLD) to the development of the more serious Metabolic dysfunction-associated steatohepatitis (MASH) depends on the degree of inflammation and its progression from an acute to a chronic state. Thus, MASLD/MASH implicates both excess fatty acids and progressive inflammation in the aetiology of liver disease. We start the discussion by introduction of CD36, a major player in FA and lipopolysaccharide (LPS) uptake in the duodenum, liver and adipose tissue. We will then introduce CEACAM1, a major player in the regulation of hepatic de novo lipogenesis and the inflammatory response in the liver, and its dual association with CD36 in enterocytes and hepatocytes. We conclude that CEACAM1 and CD36 together regulate lipid droplet formation and inflammation in the liver.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 Suppl 2 ","pages":"e14338"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural aspects of CEACAM1 interactions.","authors":"Amit K Gandhi, Yu-Hwa Huang, Zhen-Yu J Sun, Walter M Kim, Yasuyuki Kondo, Thomas Hanley, Nicole Beauchemin, Richard S Blumberg","doi":"10.1111/eci.14357","DOIUrl":"10.1111/eci.14357","url":null,"abstract":"<p><p>Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a membrane protein that plays an important role in a variety of immune and non-immune functions. Such functions are regulated by its activity as a homophilic ligand but also through its ability to interact as a heterophilic ligand with various host proteins. These include CEACAM5, T cell immunoglobulin-mucin like protein-3 (TIM-3) and, potentially, protein death protein 1 (PD-1). Furthermore, CEACAM1 is targeted by various pathogens to allow them to invade a host and bypass an effective immune response. Clinically, CEACAM1 plays an important role in infectious diseases, autoimmunity and cancer. In this review, we describe the structural basis for CEACAM1 interactions as a homophilic and heterophilic ligand. We discuss the regulation of its monomeric, dimeric and oligomeric states in cis and trans binding as well as the consequences for eliciting downstream signalling activities. Furthermore, we explore the potential role of avidity in determining CEACAM1's activities.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":" ","pages":"e14357"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The emerging role of Fusobacteria in carcinogenesis.","authors":"Raisha J Gibbs, Adam C Chambers, Darryl J Hill","doi":"10.1111/eci.14353","DOIUrl":"https://doi.org/10.1111/eci.14353","url":null,"abstract":"<p><p>The Fusobacterium genus comprises Gram-negative, obligate anaerobic bacteria that typically reside in the periodontium of the oral cavity, gastrointestinal tract, and female genital tract. The association of Fusobacterial spp. with colorectal tumours is widely accepted, with further evidence that this pathogen may also be implicated in the development of other malignancies. Fusobacterial spp. influence malignant cell behaviours and the tumour microenvironment in various ways, which can be related to the multiple surface adhesins expressed. These adhesins include Fap2 (fibroblast-activated protein 2), CpbF (CEACAM binding protein of Fusobacteria), FadA (Fusobacterium adhesin A) and FomA (Fusobacterial outer membrane protein A). This review outlines the influence of Fusobacteria in promoting cancer initiation and progression, impacts of therapeutic outcomes and discusses potential therapeutic interventions where appropriate.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 Suppl 2 ","pages":"e14353"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between insulin-associated gene polymorphisms and new-onset diabetes mellitus in statin-treated patients.","authors":"Minju Park, Jung Sun Kim, Yoon-A Park, Da Hoon Lee, Seo-A Choi, Yoonkyung Chang, Tae-Jin Song, Hye Sun Gwak, Jeong Yee","doi":"10.1111/eci.14366","DOIUrl":"https://doi.org/10.1111/eci.14366","url":null,"abstract":"<p><strong>Background: </strong>While statins are effective at managing lipid levels, there is growing evidence for new-onset diabetes mellitus (NODM). The insulin signalling pathway (ISP) inhibited by statins is one of the potential mechanisms; however, most studies have been limited to in vitro settings. Therefore, this study aimed to identify the genetic associations within the ISP-related genes and NODM.</p><p><strong>Methods: </strong>We performed a retrospective analysis of samples collected prospectively from February 2021 to May 2021. Among ISP-related genes, we selected 11 candidate genes (IGF1, IGF2, IGF1R, INSR, IRS1, IRS2, PIK3CA, PIK3CB, PIK3R1, AKT1 and AKT2). An additional analysis was conducted comparing patients with DM prior to statin therapy and controls to determine whether the single nucleotide polymorphisms (SNPs) are specific to statin.</p><p><strong>Results: </strong>A total of 602 patients were analysed, including 71 (11.8%) with statin-induced NODM. After adjustment, IGF1R rs2715439, INSR rs1799817, INSR rs2059807 and PIK3R1 rs3730089 were found to be independently associated with NODM. In an additional analysis, all SNPs that demonstrated an association with statin-induced NODM lost their significance in patients with DM prior to statin therapy.</p><p><strong>Conclusion: </strong>This study revealed the ISP-related genetic effects, specifically involving genes such as INSR, IGF1R and PIK3R1, in the development of statin-induced NODM. Our findings suggest a potential mechanism of statin-induced NODM related to ISP-related genetic variants.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":" ","pages":"e14366"},"PeriodicalIF":4.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating Fetuin-A concentrations in rheumatic diseases: a systematic review and meta-analysis.","authors":"Biagio Di Lorenzo, Stefano Zoroddu, Arduino A Mangoni, Panagiotis Paliogiannis, Gian Luca Erre, Ciriaco Carru, Angelo Zinellu","doi":"10.1111/eci.14365","DOIUrl":"https://doi.org/10.1111/eci.14365","url":null,"abstract":"<p><strong>Background: </strong>Rheumatic diseases (RDs) include a broad group of disabling conditions with different phenotypes, from autoimmune to autoinflammatory, degenerative, metabolic or mixed manifestations. With the continuous efforts to identify therapeutic targets for new biologic drugs to treat overt clinical manifestations, research is also focusing on the discovery of new biomarkers to diagnose and manage early disease stages. In this context, we conducted a systematic review and meta-analysis of Fetuin-A (FtA), a glycoprotein synthesized by the liver that participates in several biological processes and has been proposed as a biomarker for several disorders, including rheumatoid arthritis.</p><p><strong>Methods: </strong>A systematic search in PubMed, Scopus and Web of Science, from inception to the 24th of August 2024, led to the identification of 13 manuscripts from 219 records; six additional studies were identified through reference hand-search, for a total of 19 studies.</p><p><strong>Results: </strong>There was a significant decrease in FtA concentrations in RD patients (standardized mean difference, SMD = -.91; 95% CI -1.43 to -.39, p = .001), with no substantial contribution from any individual study nor publication bias. The effect size was significantly associated with erythrocyte sedimentation rate, various lipid fractions, geographical area of study conduction, study design and specific type of RD.</p><p><strong>Conclusion: </strong>In conclusion, our study identified significant reductions in FtA concentrations in RD patients versus healthy controls. These alterations were significantly associated with specific study and patient characteristics. Further research is required to identify the exact pathophysiological mechanisms underlying these alterations and the possible utility of measuring FtA for the diagnosis and management of RDs.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":" ","pages":"e14365"},"PeriodicalIF":4.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}