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Targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) with specific antibody offers long-term benefits for cancer immunotherapy but can cause severe adverse effects in the heart. This study aimed to investigate the role of anti-CTLA-4 antibody in pressure overload-induced cardiac remodeling and dysfunction. Transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and heart failure in mice. Two weeks after the TAC treatment, mice received anti-CTLA-4 antibody injection twice a week at a dose of 10 mg/kg body weight. The administration of anti-CTLA-4 antibody exacerbated TAC-induced decline in cardiac function, intensifying myocardial hypertrophy and fibrosis. Further investigation revealed that anti-CTLA-4 antibody significantly elevated systemic inflammatory factors levels and facilitated the differentiation of T helper 17 (Th17) cells in the peripheral blood of TAC-treated mice. Importantly, anti-CTLA-4 mediated differentiation of Th17 cells and hypertrophic phenotype in TAC mice were dramatically alleviated by the inhibition of interleukin-17A (IL-17A) by an anti-IL-17A antibody. Furthermore, the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti-CTLA-4-mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti-CTLA-4 antibody exacerbates pressure overload-induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL-17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors-induced cardiotoxicity.
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Antígeno CTLA-4 , Insuficiencia Cardíaca , Ratones Endogámicos C57BL , Células Th17 , Animales , Células Th17/inmunología , Células Th17/metabolismo , Ratones , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/antagonistas & inhibidores , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Masculino , Interleucina-17/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Diferenciación Celular , Cardiomegalia/metabolismo , Cardiomegalia/patología , Cardiomegalia/etiologíaRESUMEN
P2Y11 is a G protein-coupled ATP receptor that activates IL-1 receptor (IL-1R) in a cyclic AMP dependent manner. In human macrophages, P2Y11/IL-1R crosstalk with CCL20 as a prime target is controlled by phosphodiesterase 4 (PDE4), which mediates breakdown of cyclic AMP. Here, we used gene expression analysis to identify activation of CXCR4 and CXCR7 as a hallmark of P2Y11 signaling. We found that PDE4 inhibition with rolipram boosts P2Y11/IL-1R-induced upregulation of CXCR7 expression and CCL20 production in an epidermal growth factor receptor dependent manner. Using an astrocytoma cell line, naturally expressing CXCR7 but lacking CXCR4, P2Y11/IL-1R activation effectively induced and CXCR7 agonist TC14012 enhanced CCL20 production even in the absence of PDE4 inhibition. Moreover, CXCR7 depletion by RNA interference suppressed CCL20 production. In macrophages, the simultaneous activation of P2Y11 and CXCR7 by their respective agonists was sufficient to induce CCL20 production with no need of PDE4 inhibition, as CXCR7 activation increased its own and eliminated CXCR4 expression. Finally, analysis of multiple CCL chemokines in the macrophage secretome revealed that CXCR4 inactivation and CXCR7 activation selectively enhanced P2Y11/IL-1R-mediated secretion of CCL20. Altogether, our data establish CXCR7 as an integral component of the P2Y11/IL-1R-initiated signaling cascade and CXCR4-associated PDE4 as a regulatory checkpoint.
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Receptores CXCR4 , Transducción de Señal , Humanos , Línea Celular , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/farmacología , AMP Cíclico/metabolismo , Macrófagos/metabolismo , Receptores CXCR4/genética , Receptores Purinérgicos/metabolismoRESUMEN
Next to its classical role in MHC II-mediated antigen presentation, CD74 was identified as a high-affinity receptor for macrophage migration inhibitory factor (MIF), a pleiotropic cytokine and major determinant of various acute and chronic inflammatory conditions, cardiovascular diseases and cancer. Recent evidence suggests that CD74 is expressed in T cells, but the functional relevance of this observation is poorly understood. Here, we characterized the regulation of CD74 expression and that of the MIF chemokine receptors during activation of human CD4+ T cells and studied links to MIF-induced T-cell migration, function, and COVID-19 disease stage. MIF receptor profiling of resting primary human CD4+ T cells via flow cytometry revealed high surface expression of CXCR4, while CD74, CXCR2 and ACKR3/CXCR7 were not measurably expressed. However, CD4+ T cells constitutively expressed CD74 intracellularly, which upon T-cell activation was significantly upregulated, post-translationally modified by chondroitin sulfate and could be detected on the cell surface, as determined by flow cytometry, Western blot, immunohistochemistry, and re-analysis of available RNA-sequencing and proteomic data sets. Applying 3D-matrix-based live cell-imaging and receptor pathway-specific inhibitors, we determined a causal involvement of CD74 and CXCR4 in MIF-induced CD4+ T-cell migration. Mechanistically, proximity ligation assay visualized CD74/CXCR4 heterocomplexes on activated CD4+ T cells, which were significantly diminished after MIF treatment, pointing towards a MIF-mediated internalization process. Lastly, in a cohort of 30 COVID-19 patients, CD74 surface expression was found to be significantly upregulated on CD4+ and CD8+ T cells in patients with severe compared to patients with only mild disease course. Together, our study characterizes the MIF receptor network in the course of T-cell activation and reveals CD74 as a novel functional MIF receptor and MHC II-independent activation marker of primary human CD4+ T cells.
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Antígenos de Diferenciación de Linfocitos B , Linfocitos T CD4-Positivos , COVID-19 , Antígenos de Histocompatibilidad Clase II , Oxidorreductasas Intramoleculares , Activación de Linfocitos , Factores Inhibidores de la Migración de Macrófagos , SARS-CoV-2 , Humanos , Antígenos de Diferenciación de Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Antígenos de Histocompatibilidad Clase II/inmunología , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Factores Inhibidores de la Migración de Macrófagos/genética , Activación de Linfocitos/inmunología , SARS-CoV-2/metabolismo , SARS-CoV-2/inmunología , COVID-19/inmunología , COVID-19/metabolismo , COVID-19/patología , Oxidorreductasas Intramoleculares/metabolismo , Oxidorreductasas Intramoleculares/genética , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Movimiento Celular , Masculino , Femenino , Persona de Mediana Edad , Receptores InmunológicosRESUMEN
Inflammation is the body's defense response to exogenous or endogenous stimuli, involving complex regulatory mechanisms. Discovering anti-inflammatory drugs with both effectiveness and long-term use safety is still the direction of researchers' efforts. The inflammatory pathway was initially identified to be involved in tumor metastasis and HIV infection. However, research in recent years has proved that the CXC chemokine receptor type 4 (CXCR4)/CXC motif chemokine ligand 12 (CXCL12) axis plays a critical role in the upstream of the inflammatory pathway due to its chemotaxis to inflammatory cells. Blocking the chemotaxis of inflammatory cells by CXCL12 at the inflammatory site may block and alleviate the inflammatory response. Therefore, developing CXCR4 antagonists has become a novel strategy for anti-inflammatory therapy. This review aimed to systematically summarize and analyze the mechanisms of action of the CXCR4/CXCL12 axis in more than 20 inflammatory diseases, highlighting its crucial role in inflammation. Additionally, the anti-inflammatory activities of CXCR4 antagonists were discussed. The findings might help generate new perspectives for developing anti-inflammatory drugs targeting the CXCR4/CXCL12 axis.
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Infecciones por VIH , Receptores CXCR4 , Humanos , Infecciones por VIH/tratamiento farmacológico , Quimiocina CXCL12 , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Descubrimiento de DrogasRESUMEN
C-X-C motif chemokine ligand 14 (CXCL14) is expressed in the airway epithelial cells of patients with asthma. However, the mechanisms of CXCL14 secretion and its effects on asthma pathogenesis remain unclear. Here, we investigated the role of CXCL14 in allergic airway inflammation and its effects on eosinophil infiltration. Our findings showed that Alternaria alternata, a major environmental allergen, stimulated CXCL14 secretion from airway epithelial cells via reactive oxygen species (ROS) generated in mitochondrial oxidative phosphorylation (OXPHOS) complexes, especially in OXPHOS complex II. In vivo, in a mouse model of allergic airway inflammation, intranasal administration of anti-CXCL14 antibody suppressed eosinophil and dendritic cell infiltration into the airways and goblet cell hyperplasia. In vitro, in human eosinophil-like cells, CXCL14 promoted cell migration through C-X-C chemokine receptor type 4 (CXCR4) binding. Eosinophil CXCR4 expression was upregulated by Alternaria stimulation via ROS production. These findings suggest that the crosstalk between Alternaria-stimulated airway epithelial CXCL14 secretion and eosinophil CXCR4 upregulation plays an important role in eosinophil infiltration into the lungs during allergic airway inflammation. In summary, this study demonstrates that CXCL14 could be a therapeutic target for allergic airway inflammation.
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The prevalence of chronic kidney disease (CKD) is highly increasing. Renal fibrosis is a common pathological feature in various CKD. Previous studies showed tubular cell senescence is highly involved in the pathogenesis of renal fibrosis. However, the inducers of tubular senescence and the underlying mechanisms have not been fully investigated. C-X-C motif chemokine receptor 4 (CXCR4), a G-protein-coupled seven-span transmembrane receptor, increases renal fibrosis and plays an important role in tubular cell injury. Whereas, whether CXCR4 could induce tubular cell senescence and the detailed mechanisms have not studied yet. In this study, we adopted adriamycin nephropathy and 5/6 nephrectomy models, and cultured tubular cell line. Overexpression or knockdown of CXCR4 was obtained by injection of related plasmids. We identified CXCR4 increased in injury tubular cells. CXCR4 was expressed predominantly in renal tubular epithelial cells and co-localized with adipose differentiation-related protein (ADRP) as well as the senescence-related protein P16INK4A . Furthermore, we found overexpression of CXCR4 greatly induced the activation of ß-catenin, while knockdown of CXCR4 inhibited it. We also found that CXCR4 inhibited fatty acid oxidation and triggered lipid deposition in tubular cells. To inhibit ß-catenin by ICG-001, an inhibitor of ß-catenin, could significantly block CXCR4-suppressed fatty acid oxidation. Taken together, our results indicate that CXCR4 is a key mediator in tubular cell senescence and renal fibrosis. CXCR4 promotes tubular cell senescence and renal fibrosis by inducing ß-catenin and inhibiting fatty acid metabolism. Our findings provide a new theory for tubular cell injury in renal fibrosis.
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Riñón , Receptores CXCR4 , Insuficiencia Renal Crónica , beta Catenina , beta Catenina/metabolismo , Senescencia Celular , Células Epiteliales/metabolismo , Ácidos Grasos/metabolismo , Fibrosis , Riñón/patología , Insuficiencia Renal Crónica/patología , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Animales , RatonesRESUMEN
Brucella species are Gram-negative intracellular bacterial pathogens that cause the worldwide zoonotic disease brucellosis. Brucella can infect many mammals, including humans and domestic and wild animals. Brucella manipulates various host cellular processes to invade and multiply in professional and non-professional phagocytic cells. However, the host targets and their modulation by Brucella to facilitate the infection process remain obscure. Here, we report that the host ubiquitin-specific protease, USP8, negatively regulates the invasion of Brucella into macrophages through the plasma membrane receptor, CXCR4. Upon silencing or chemical inhibition of USP8, the membrane localization of the CXCR4 receptor was enriched, which augmented the invasion of Brucella into macrophages. Activation of USP8 through chemical inhibition of 14-3-3 protein affected the invasion of Brucella into macrophages. Brucella suppressed the expression of Usp8 at its early stage of infection in the infected macrophages. Furthermore, we found that only live Brucella could negatively regulate the expression of Usp8, suggesting the role of secreted effector protein of Brucella in modulating the gene expression. Subsequent studies revealed that the Brucella effector protein, TIR-domain containing protein from Brucella, TcpB, plays a significant role in downregulating the expression of Usp8 by targeting the cyclic-AMP response element-binding protein pathway. Treatment of mice with USP8 inhibitor resulted in enhanced survival of B. melitensis, whereas mice treated with CXCR4 or 14-3-3 antagonists showed a diminished bacterial load. Our experimental data demonstrate a novel role of Usp8 in the host defense against microbial intrusion. The present study provides insights into the microbial subversion of host defenses, and this information may ultimately help to develop novel therapeutic interventions for infectious diseases.
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Brucella melitensis , Brucella , Brucelosis , Animales , Humanos , Ratones , Proteasas Ubiquitina-Específicas/metabolismo , Macrófagos/microbiología , Brucelosis/microbiología , Proteínas Bacterianas/genética , Mamíferos , Endopeptidasas/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismoRESUMEN
Osteosarcoma, recognized for its aggressiveness and resistance to chemotherapy, notably doxorubicin, poses significant treatment challenges. This comprehensive study investigated the CXCR4-CARM1-YAP signaling axis and its pivotal function in controlling aerobic glycolysis, which plays a crucial role in doxorubicin resistance. Detailed analysis of Dox-resistant 143b/MG63-DoxR cells has uncovered the overexpression of CXCR4. Utilizing a combination of molecular biology techniques including gene silencing, aerobic glycolysis assays such as Seahorse experiments, RNA sequencing, and immunofluorescence staining. The study provides insight into the mechanistic pathways involved. Results demonstrated that disrupting CXCR4 expression sensitizes cells to doxorubicin-induced apoptosis and alters glycolytic activity. Further RNA sequencing revealed that CARM1 modulated this effect through its influence on glycolysis, with immunofluorescence of clinical samples confirming the overexpression of CXCR4 and CARM1 in drug-resistant tumors. Chromatin immunoprecipitation studies further highlighted the role of CARM1, showing it to be regulated by methylation at the H3R17 site, which in turn affected YAP expression. Crucially, in vivo experiments illustrated that CARM1 overexpression could counteract the tumor growth suppression that resulted from CXCR4 inhibition. These insights revealed the intricate mechanisms at play in osteosarcoma resistance to doxorubicin and pointed toward potential new therapeutic strategies that could target this metabolic and signaling network to overcome drug resistance and improve patient outcomes.
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This research provides a glimmer of hope that the knockout of HCP5 leads to a therapy response to considerably prolong the life of patients with OC. RT-PCR evaluated the expression of lncRNA HCP5 in the ovarian cancer OVCAR-3 cell line. CRISPR knockout cell lines validated by western blot. Small genomic deletions at the targeted locus were induced. CCK-8 colony formation assays were used to analyze the effect of HCP5 knockout on the proliferation capacity of OVCAR-3 cells. Transwell migration and invasion assayed. Furthermore, the Sphere-formation assay isolated the most aggressive population of cancer stem cells. Bioinformatic analysis showed a significant correlation between lncRNA HCP5 up-regulation and OVCAR-3 cell proliferation. The ChIP technique assesses specific sites of interaction between transcription factors and DNA. Real-time PCR assays explored the relationship between HCP5, Hsa-miR-9-5p, CXCR4, CDH1, caspase-3, p53, bcl2 and survivin. PCR carried out amplification of the 448-bp band for sgRNA1 and sgRNA2 after the use of particular primers for HCP5. the number of breast cancer cells that moved to the bottom chamber reduced considerably after transfection with PX461-sgRNA1/2 vectors compared to the Blank control groups (P < 0.05). MTT assay designated growth curves that showed the rate of OVCAR-3 growth was significantly repressed (***P < 0.001) when compared with control OVCAR-3 cells after HCP5 knockdown. Also, the survival results of W.T cells in 24, 48 and 72 h showed 92%, 87% and 85%, respectively. This is while the cells of the CRISPR/Cas9 group in which LncRNA HCP5 was knocked out had 42% (*P < 0.05), 23%(**P < 0.01) and 14% (**P < 0.01) survival, respectively. The expression levels of caspase-3, Hsa-miR-9-5p, P53 genes in the HCP5 deletion of CRISPR/Cas9 group significantly increased than the W.T. control group; the deletion group showed a considerable reduction in HCP5 expression compared to the blank control group (3.6-fold, p < 0.01). Whereas BCL2, SURVIVIN, CXCR4, CDH1 genes expression markedly increased than in HCP5 knockout cells (5.8-fold, p < 0.05). These results indicate that CRISPR/Cas9-mediated HCP5 disruption on OVCAR-3 cell lines promotes anti-tumor biomarkers, suppressing ovarian cancer progression. Consistent with these results, HCP5 is one of the most critical lnc for the efficient proliferation and migration of OVCAR-3 cell lines.
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MicroARNs , Neoplasias Ováricas , ARN Largo no Codificante , Humanos , Femenino , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Survivin/genética , Survivin/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Apoptosis/genética , Línea Celular Tumoral , Regulación hacia Arriba , MicroARNs/genética , Proliferación Celular/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Regulación Neoplásica de la Expresión GénicaRESUMEN
Warts, hypogammaglobulinaemia, infections and myelokathexis syndrome (WHIMS) is a rare combined primary immunodeficiency caused by the gain of function of the CXCR4 chemokine receptor. We present the prevalence of cancer in WHIMS patients based on data from the French Severe Chronic Neutropenia Registry and an exhaustive literature review. The median follow-up of the 14 WHIMS 'patients was 28.5 years. A central review and viral evaluation of pathological samples were organized, and we conducted a thorough literature review to identify all reports of WHIMS cases. Six French patients were diagnosed with cancer at a median age of 37.6 years. The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%). We observed two human papillomavirus (HPV)-induced vulvar carcinomas, three lymphomas (two Epstein-Barr virus [EBV]-related) and one basal cell carcinoma. Among the 155 WHIMS cases from the literature, 22 cancers were reported in 16 patients, with an overall cancer 40-year risk of 23% (95% CI: 13%-39%). Malignancies included EBV-associated lymphoproliferative disorders and HPV-positive genital and anal cancers as in the French cohort. Worldwide, nine cases of malignancy were associated with HPV and four with EBV. Immunocompromised WHIMS patients appear to be particularly susceptible to developing early malignancy, mainly HPV-induced carcinomas, followed by EBV-related lymphomas.
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Agammaglobulinemia , Carcinoma , Infecciones por Virus de Epstein-Barr , Linfoma , Infecciones por Papillomavirus , Enfermedades de Inmunodeficiencia Primaria , Verrugas , Humanos , Adulto , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/epidemiología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4 , Verrugas/complicaciones , Verrugas/epidemiología , Verrugas/diagnóstico , Síndrome , Receptores CXCR4RESUMEN
BACKGROUND: Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking. METHODS: To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF. RESULTS: Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells. CONCLUSIONS: DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.
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Antiinflamatorios no Esteroideos , Enfermedades Autoinmunes , Dimetilfumarato , Inmunosupresores , Retina , Uveítis , Dimetilfumarato/administración & dosificación , Dimetilfumarato/farmacología , Uveítis/genética , Uveítis/inmunología , Uveítis/terapia , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Análisis de Expresión Génica de una Sola Célula , Modelos Animales de Enfermedad , Animales , Ratones , Femenino , Ratones Endogámicos C57BL , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/genética , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Transcripción Genética , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Atlas como Asunto , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Retina/efectos de los fármacos , Retina/inmunología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunologíaRESUMEN
Chemokine receptor 4 (CXCR4) plays a vital role in immunoregulation during hepatitis B virus (HBV) infection. This study aimed to screen single-nucleotide polymorphisms (SNPs) of CXCR4 for predicting pegylated interferon-alpha (PegIFNα) therapy response in chronic hepatitis B (CHB) patients. This retrospective cohort study enrolled a total of 945 CHB patients in two cohorts (Cohort 1, n = 238; Cohort 2, n = 707), and all the patients were hepatitis B e antigen (HBeAg)-positive and treated with PegIFNα for 48 weeks and followed up for 24 weeks. Twenty-two tag SNPs were selected in CXCR4 and its flanking region. A polygenic score (PGS) was utilized to evaluate the cumulative effect of multiple SNPs. The relationships between CXCR4 SNPs and PGS and PegIFNα treatment response were explored in the two cohorts. Among the 22 candidate SNPs of CXCR4, rs28367495 (T > C) was significantly linked to PegIFNα treatment response in both cohorts. In patients with more number of rs28367495 C allele, a higher rate of combined response (CR, defined as HBeAg seroconversion and HBV DNA level < 3.3 log10 IU/mL; P = 1.51 × 10-4), a lower mean hepatitis B surface antigen (HBsAg) level (P = 4.76 × 10-4), and a higher mean HBsAg decline (P = 3.88 × 10-4) at Week 72 were achieved. Moreover, a PGS integrating CXCR4_rs28367495 and five previously reported SNPs was strongly correlated with CR (P = 1.26 × 10-13), HBsAg level (P = 4.90 × 10-4), and HBsAg decline (P = 0.005) in all the patients of the two cohorts. CXCR4_rs28367495 is a promising indicator for predicting the responsiveness to PegIFNα treatment for HBeAg-positive CHB patients. The new PGS may further improve the prediction performance.
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Hepatitis B Crónica , Hepatitis B , Humanos , Antivirales/uso terapéutico , Antivirales/farmacología , ADN Viral , Hepatitis B/tratamiento farmacológico , Antígenos e de la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Interferón-alfa/farmacología , Polietilenglicoles/uso terapéutico , Polietilenglicoles/farmacología , Receptores CXCR4/genética , Proteínas Recombinantes , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Autoimmune uveitis (AU) is a severe disorder causing poor vision and blindness. However, the cellular dynamics and pathogenic mechanisms underlying retinal injury in uveitis remain unclear. In this study, single-cell RNA sequencing of the retina and cervical draining lymph nodes in experimental autoimmune uveitis mice was conducted to identify the cellular spatiotemporal dynamics and upregulation of the glycolysis-related gene LDHA. Suppression of LDHA can rescue the imbalance of T effector (Teff) cells/T regulator (Treg) cells under inflammation via downregulation of the glycolysis-PI3K signaling circuit and inhibition of the migration of CXCR4+ Teff cells towards retinal tissue. Furthermore, LDHA and CXCR4 are upregulated in the peripheral blood mononuclear cells of Vogt-Koyanagi-Harada patients. The LDHA inhibitor suppresses CD4+ T cell proliferation in humans. Therefore, our data indicate that the autoimmune environment of uveitis regulates Teff cell accumulation in the retina via glycolysis-associated LDHA. Modulation of this target may provide a novel therapeutic strategy for treating AU.
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Enfermedades Autoinmunes , Uveítis , Animales , Humanos , Ratones , Leucocitos Mononucleares , Fosfatidilinositol 3-Quinasas , Retina , Linfocitos T ReguladoresRESUMEN
Melanoma is a particularly aggressive type of skin cancer that can spread to distant organs, resulting in poor patient outcomes. C-X-C motif chemokine ligand 12 (CXCL12) interacts to the C-X-C chemokine receptor type 4 (CXCR4). This connection between CXCR4 and its companion ligand CXCL12 is important in melanoma metastasis and progression, encouraging cell proliferation, invasion, and survival via downstream signaling pathways. Furthermore, CXCR4 is implicated in the interaction between melanoma cells and the tumor microenvironment, which promotes malignant cell migration and immune evasion. Given the importance of the CXCR4/CXCL12 axis in melanoma, addressing this axis has the potential to prevent metastasis and improve patient outcomes. We present an overview of the CXCR4/CXCL12 axis in cancer progression and explain its role in the melanoma microenvironment in this paper. Furthermore, we investigate CXCR4's predictive usefulness as a possible biomarker for monitoring melanoma progression. Finally, we discuss the most recent research and clinical trials on CXCR4 inhibitors, emphasizing their efficacy and limits. We hope to improve the quality of life for melanoma patients by better understanding the role of CXCR4 and investigating novel therapeutic options.
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Quimiocina CXCL12 , Melanoma , Receptores CXCR4 , Transducción de Señal , Microambiente Tumoral , Humanos , Receptores CXCR4/metabolismo , Melanoma/metabolismo , Melanoma/patología , Quimiocina CXCL12/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Animales , Progresión de la EnfermedadRESUMEN
PURPOSE: Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2, a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC). METHODS: Public database was first interrogated to reveal the correlation between CAFs' scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18F-FDG, [18F]AlF-NOTA-FAPI-04, and [68Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen. RESULTS: CAFs' scores negatively correlated with the survival of TNBC patients (p < 0.05). The expression of CXCR4 and FAP was both significantly higher in tumors than in normal tissues. The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18F-FDG and [18F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12. CONCLUSION: The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.
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Quimiocina CXCL12 , Receptores CXCR4 , Neoplasias de la Mama Triple Negativas , Receptores CXCR4/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/radioterapia , Animales , Ratones , Quimiocina CXCL12/metabolismo , Humanos , Línea Celular Tumoral , Femenino , Ciclamas/farmacología , Ciclamas/uso terapéutico , Lutecio , Bencilaminas/farmacología , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Radiofármacos/uso terapéutico , Radiofármacos/farmacología , Endopeptidasas , Proliferación Celular/efectos de los fármacos , Gelatinasas/metabolismo , Proteínas de la Membrana/metabolismo , Serina Endopeptidasas/metabolismoRESUMEN
OBJECTIVE: To determine whether WJ-MSCs pretreated with VPA would enhance their migration to improve functional recovery of renal IRI in rats. METHODS: 150 Sprague-Dawley rats were distributed into 5 groups; Sham, IRI, WJ-MSC, VPA, and WJ-MSCs + VPA. 10 rats were sacrificed after 3, 5, and 7 days. Role of WJ-MSCs pretreated with VPA was evaluated by assessment of renal function, antioxidant enzymes together with renal histopathological and immunohistopathological analyses and finally by molecular studies. RESULTS: WJ-MSCs and VPA significantly improved renal function and increased antioxidants compared to IRI group. Regarding gene expression, WJ-MSCs and VPA decreased BAX and TGF-ß1, up-regulated Akt, PI3K, BCL2, SDF1α, and CXCR4 related to IRI. Additionally, WJ-MSCs pretreated with VPA improved the measured parameters more than either treatment alone. CONCLUSION: WJ-MSCs isolated from the umbilical cord and pretreated with VPA defended the kidney against IRI by more easily homing to the site of injury.
RESUMEN
Chemokines and chemokine receptors are indispensable to play a key role in the development of malignant tumors. As one of the most widely expressed chemokine receptors, chemokine (C-X-C motif) receptor 4 (CXCR4) has been a popular research focus. In most tumors, CXCR4 expression is significantly upregulated. Moreover, integrated nuclide diagnosis and therapy targeting CXCR4 show great potential. [68Ga]Ga-pentixafor, a radioligand targeting CXCR4, exhibits a strong affinity for CXCR4 both in vivo and in vitro. However, [177Lu]Lu-pentixather, the therapeutic companion of [68Ga]Ga-pentixafor, requires significant refinement to mitigate its pronounced hepatic biodistribution. The objective of this study was to synthesize theranostic molecular tracers with superior CXCR4 targeting functions. The Daudi cell line, which highly expressed CXCR4, and the MM.1S cell line, which weakly expressed CXCR4, were used in this study. Based on the pharmacophore cyclo (-d-Tyr-n-me-d-Orn-l-Arg-L-2-NAL-Gly-) (CPCR4) of pentixafor, six tracers were synthesized: [124I]I-1 ([124I]I-CPCR4), [99mTc]Tc-2 ([99mTc]Tc-HYNIC-CPCR4), [124I]I-3 ([124I]I-pentixafor), [18F]AlF-4 ([18F]AlF-NETA-CPCR4), [99mTc]Tc-5 ([99mTc]Tc-MAG3-CPCR4) and [124I]I-6 ([124I]I-pentixafor-Ga) and their radiochemical purities were all higher than 95%. After positron emission tomography (PET)/single-photon emission computed tomography (SPECT) imaging, the [124I]I-6 group exhibited the best target-nontarget ratio. At the same time, comparing the [68Ga]Ga-pentixafor group with the [124I]I-6 group, we found that the [124I]I-6 group had a better target-nontarget ratio and lower uptake in nontarget organs. Therefore, compound 6 was selected for therapeutic radionuclide (131I) labeling, and the tumor-bearing animal models were treated with [131I]I-6. The volume of the tumor site was significantly reduced in the treatment group compared with the control group, and no significant side effects were found. [124I]I-6 and [131I]I-6 showed excellent affinity for targeting CXCR4, and they showed great potential for the integrated diagnosis and treatment of tumors with high CXCR4 expression.
Asunto(s)
Complejos de Coordinación , Receptores CXCR4 , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Animales , Humanos , Ratones , Línea Celular Tumoral , Distribución Tisular , Radiofármacos/farmacocinética , Radiofármacos/farmacología , Radiofármacos/química , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Radioisótopos de Galio , Ratones Desnudos , Nanomedicina Teranóstica/métodos , FemeninoRESUMEN
BACKGROUND: Intravenous injection of adipose-derived stem cells (ADSCs) can improve the urinary function of stress urinary incontinence (SUI) model rats and C-X-C chemokine receptor type 4 (CXCR4)-positive ADSCs are found in urethral tissues. The CXCR4 ligand stromal cell-derived factor-1 (SDF-1) is highly expressed in urinary incontinence model rats. In this study, we investigated the involvement of the SDF-1/CXCR4 axis in the homing of ADSCs. METHODS: ADSCs were isolated from rats and purified. The levels of CXCR4 and CXCR7 were determined by western blot analysis and immunofluorescence assays following stimulation with SDF-1. Hypoxia conditioning was performed to treat the cells in vitro, following which the messenger RNA (mRNA) and protein level of SDF-1, CXCR4, and CXCR7 were estimated. RESULTS: We found that CXCR4 and CXCR7 were expressed in ADSCs at passage zero (P0), P1, and P3, and the expression of both increased after SDF-1 stimulation. The level of expression of the mRNAs and proteins of SDF-1, CXCR4, and CXCR7 in ADSCs was higher after hypoxic conditioning. We then knocked down CXCR4 or CXCR7 using small interfering RNAs and found that the mRNA levels of CXCR4 and CXCR7 were considerably downregulated in the si-CXCR4/7-transfected cells. We also found that the SDF-1/CXCR4 axis was required for the migration of ADSCs. The phosphorylation levels of Janus kinase (JAK), protein kinase B (AKT), and extracellular regulated protein kinase significantly increased in SDF-1-stimulated ADSCs. However, the migration of ADSCs was suppressed when the corresponding specific inhibitors were used to block JAK and AKT signaling or silence CXCR4, whereas no significant change was observed in the migratory ability of ADSCs when the ERK pathway was blocked or CXCR7 was silenced. CONCLUSIONS: The SDF-1/CXCR4 axis is involved in the migration of ADSCs and may play a role in the migrate of ADSCs in SUI.
RESUMEN
This study focuses on the design and synthesis of two novel coordination polymers (CPs), named 1 and 2, with excellent fluorescent properties. Their structures were characterized by X-ray single-crystal diffraction, revealing that both materials exhibit promising fluorescence performance, indicating their potential as fluorescent detection tools. Additionally, 1 was chosen to be combined with chitosan (CS), resulting in the successful fabrication of a biodegradable and non-toxic efficient drug carrier, termed CS-1@Cisplatin. This carrier possesses a large surface area and good solubility, enabling sustained drug release to target cells. Given that CXC motif chemokine receptor type 4 (CXCR4) is a key marker gene highly expressed in Rhabdomyosarcoma (RMS) cells and tissues, RMS was chosen as the biological model for testing. The results demonstrated that CS-1@Cisplatin effectively inhibited the invasiveness of RMS cells by significantly suppressing CXCR4 expression. Therefore, the system shows great potential for applications in RMS treatment, biometrics, and drug delivery, particularly in its unique advantage of targeting RMS by inhibiting the key marker gene CXCR4.
RESUMEN
AIM: WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome is a rare combined primary immunodeficiency disease caused by gain-of-function (GOF) mutations in the chemokine receptor CXCR4 and includes severe neutropenia as a common feature. Neutropenia is a known risk factor for periodontitis; however, a detailed periodontal evaluation of a WHIM syndrome cohort is lacking. This study aimed to establish the evidence base for the periodontal status of patients with WHIM syndrome. MATERIALS AND METHODS: Twenty-two adult WHIM syndrome patients and 22 age- and gender-matched healthy volunteers (HVs) were evaluated through a comprehensive medical and periodontal examination. A mouse model of WHIM syndrome was assessed for susceptibility to naturally progressing or inducible periodontitis. RESULTS: Fourteen patients with WHIM syndrome (63.6%) and one HV (4.5%) were diagnosed with Stage III/IV periodontitis. No WHIM patient presented with the early onset, dramatic clinical phenotypes typically associated with genetic forms of neutropenia. Age, but not the specific CXCR4 mutation or absolute neutrophil count, was associated with periodontitis severity in the WHIM cohort. Mice with a Cxcr4 GOF mutation did not exhibit increased alveolar bone loss in spontaneous or ligature-induced periodontitis. CONCLUSIONS: Overall, WHIM syndrome patients presented with an increased severity of periodontitis despite past and ongoing neutrophil mobilization treatments. GOF mutations in CXCR4 may be a risk factor for periodontitis in humans.