CXC Ligand Research Articles

LncRNA MALAT1 silencing represses CXCL12-induced proliferation, invasion, and homing behavior in multiple myeloma by inhibiting CXCR4

ABSTRACT Background: Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified in multiple myeloma (MM); its influence on the homing behavior in MM cells is unclear. This study elucidates the impact and mechanism by which MALAT1 affects the homing behavior in MM cells. Methods: Bone marrow was obtained from patients with MM. MALAT1 and C-X-C motif chemokine receptor 4 (CXCR4) expression in cluster of differentiation 138-purified (CD138) plasma cells were detected by qRT-PCR and Western blotting. MALAT1, CXCR4, and C-X-C motif chemokine ligand 12 (CXCL12) influences on MM cell viability, proliferation, and invasion was monitored by CCK-8, 5-Ethynyl-2'-deoxyuridine, and Transwell assays. qRT-PCR, Western blotting, and ELISA were utilized to detect homing effect-related proteins in MM cells, including intercellular adhesion molecule 1 (ICAM-1) and very late antigen-4 (VLA-4). Results: MALAT1 and CXCR4 were overexpressed in CD138-purified plasma cells from bone marrow of MM patients, associating with bone damage. MALAT1 upregulated CXCR4 in MM cells. MALAT1 overexpression enhanced MM cell viability, proliferation, and invasion, whereas CXCR4 silencing reversed them. CXCR4 silencing attenuated MALAT1 induction on ICAM-1 and VLA-4 expression in MM cells. CXCL12 upregulation intensified MM cell proliferation and invasion and ICAM-1 and VLA-4 expression in MM cells. MALAT1 silencing counteracted the impact of CXCL12. Conclusion: MALAT1 silencing may repress CXCL12 induction on MM cell proliferation, invasion, and homing behavior by inhibiting CXCR4. MALAT1 may be a promising target for MM treatment.

CXCL12/CXCR4 pathway as a novel therapeutic target for RNF213-associated pulmonary arterial hypertension

Genetic backgrounds of patients with pulmonary arterial hypertension (PAH) were not fully investigated. A variant of c.14429G > A (p.Arg4810Lys) in the ring finger protein 213 gene (RNF213) was recently identified as a risk allele for poor treatment response and poor clinical prognosis in patients with PAH. However, the molecular mechanisms of the RNF213 p.Arg4810Lys variant in development of PAH are unknown. We investigated the underlying molecular mechanisms of RNF213-associated vasculopathy using an in vivo mouse model. RNF213+/p.Arg4828Lys mice, harboring the heterozygous RNF213 p.Arg4828Lys variant corresponding to the p.Arg4810Lys variant in humans, were created using the CRISPR-Cas9 system to recapitulate the genetic status of PAH patients. RNF213+/p.Arg4828Lys mice had a significant elevation of the right ventricular systolic pressure, hypertrophy of the right ventricle, and increased thickness of the pulmonary arterial medial wall compared with wild-type mice after 3 months of exposure to a hypoxic environment. C-X-C motif chemokine ligand 12 (CXCL12), a C-X-C chemokine receptor type 4 (CXCR4) ligand, was significantly elevated in the lungs of RNF213+/p.Arg4828Lys mice, and PAH was ameliorated by the administration of a CXCR4 antagonist. CXCL12-CXCR4 is an angiogenic chemokine axis, and immunohistochemistry demonstrated an increase in CXCR4 in vimentin-positive spindle-shaped cells in adventitia and interstitial lesions in RNF213+/p.Arg4828Lys mice and lung specimens from severe PAH patients with the RNF213 p.Arg4810Lys variant. We confirmed a cause-and-effect relationship between the RNF213 p.Arg4810Lys variant and PAH via the CXCL12-CXCR4 pathway. The findings in this study suggest that targeting this pathway might be a novel therapeutic strategy for RNF213-associated vasculopathy.

Transcriptomic Analysis of THP-1 Cells Exposed by Monosodium Urate Reveals Key Genes Involved in Gout.

Gout is a common inflammatory arthritis, which is mainly caused by the deposition of monosodium urate (MSU) in tissues. Transcriptomics was used to explore the pathogenesis and treatment of gout in our work. The objective of the study was to analyze and validate potential therapeutic targets and biomarkers in THP-1 cells that were exposed to MSU. THP-1 cells were exposed to MSU. The inflammatory effect was characterized, and RNA-Seq analysis was then carried out. The differential genes obtained by RNA-Seq were analyzed with gene expression omnibus (GEO) series 160170 (GSE160170) gout-related clinical samples in the GEO database and gout-related genes in the GeneCards database. From the three analysis approaches, the genes with significant differences were verified by the differential genes' transcription levels. The interaction relationship of long non-coding RNA (lncRNA) was proposed by ceRNA network analysis. MSU significantly promoted the release of IL-1β and IL-18 in THP-1 cells, which aggravated their inflammatory effect. Through RNA-Seq, 698 differential genes were obtained, including 606 differential mRNA and 92 differential `LncRNA. Cross-analysis of the RNA-Seq differential genes, the GSE160170 differential genes, and the gout-related genes in GeneCards revealed a total of 17 genes coexisting in the tripartite data. Furthermore, seven differential genes-C-X-C motif chemokine ligand 8 (CXCL8), C-X-C motif chemokine ligand 2 (CXCL2), tumor necrosis factor (TNF), C-C motif chemokine ligand 3 (CCL3), suppressor of cytokine signaling 3 (SOCS3), oncostatin M (OSM), and MIR22 host gene (MIR22HG)-were verified as key genes that analyzed the weight of genes in pathways, the enrichment of inflammationrelated pathways, and protein-protein interaction (PPI) nodes combined with the expression of genes in RNA-Seq and GSE160170. It is suggested that MIR22HG may regulate OSM and SOCS3 through microRNA 4271 (miR-4271), OSM, and SOCS3m; CCL3 through microRNA 149-3p (miR-149-3p); and CXCL2 through microRNA 4652-3p (miR-4652-3p). The potential of CXCL8, CXCL2, TNF, CCL3, SOCS3, and OSM as gout biomarkers and MIR22HG as a therapeutic target for gout are proposed, which provide new insights into the mechanisms of gout biomarkers and therapeutic methods.

Icariin ameliorates Coxsackievirus B3-induced viral myocarditis by modulating the S100 calcium binding protein A6/β-catenin/c-Myc signaling pathway

BackgroundCoxsackievirus B3 (CVB3) is a leading cause of viral myocarditis and is currently lacking specific pharmacological treatments, highlighting the critical need for therapeutic development. Icariin (ICA), a prenylated flavonol glycoside, was previously found to exhibit several pharmacological effects, but its potential to combat CVB3 remains uninvestigated. PurposeThis study aimed to elucidate the anti-CVB3 efficacy of ICA and elucidate its molecular mechanisms. MethodsCVB3-infected HeLa cells, H9C2 cells and neonate rat ventricular cardiomyocytes (NRVCs) were selected as in vitro models, and were treated with ICA at 1 and 10 μM. Additionally, BALB/c mice that were infected with CVB3 via intraperitoneal injection were chosen as in vivo model and were treated with ICA or ribavirin over 3 days. The effect of ICA against CVB3 was determined by Cell Counting Kit-8 (CCK-8) assay, western blot, real-time fluorescence quantitative PCR (RT–qPCR), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) and flow cytometry. ResultsIn this study, it was found that ICA is capable of reducing CVB3 viral load both in vitro and in vivo. Mechanistic studies suggested that ICA prevents cardiomyocyte apoptosis by attenuating the S100 calcium binding protein A6 (S100A6)/β-catenin/c-Myc signaling pathway. Additionally, ICA inhibits the secretion of proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β) and CXC motif chemokine ligand 2 (CXCL2) in heart tissue, thereby mitigating CVB3-induced myocarditis. Moreover, ICA also regulates the immune response of CD4+ T, CD8+ T and Treg cells by changing the cells numbers in spleen tissue. Lastly, ICA can reduce the load of other enteroviruses (such as CVA6, CVA16 and EV71) in rhabdomyosarcoma (RD) cells as well. ConclusionOur findings indicate that ICA provides significant protection against CVB3 infection by modulating the S100A6/β-catenin/c-Myc signaling pathway, suggesting its potential use as a novel drug against CVB3 infection in clinical application.

Biomarkers of rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis

BackgroundInterstitial Lung Disease (ILD) represents the most common extra-articular manifestation of Rheumatoid Arthritis (RA) and is a major cause of mortality. This study aims to identify and evaluate biomarkers associated with Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD).MethodsWe searched PubMed, Cochrane Library, EMBASE, and Web of Science databases for studies related to biomarkers of RA-ILD up until October 7, 2023. The Newcastle-Ottawa Scale (NOS) and standards recommended by the Agency for Healthcare Research and Quality (AHRQ) were used for quality assessment, and meta-analysis was conducted using Stata18.0 software.ResultsA total of 98 articles were assessed for quality, 48 of which were included in the meta-analysis. 83 studies were of high quality, and 15 were of moderate quality. The meta-analysis showed significant differences in biomarkers such as C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), Anti-Cyclic Citrullinated Peptide (anti-CCP) antibody, Rheumatoid Factor (RF), Krebs von den Lungen-6 (KL-6), Surfactant Protein D (SP-D), Carcinoembryonic Antigen (CEA), Carbohydrate Antigen 19-9 (CA19-9), Matrix Metalloproteinase-7 (MMP-7), C-X-C Motif Chemokine Ligand 10 (CXCL-10), and Neutrophil-to-Lymphocyte Ratio (NLR) between RA-ILD patients and RA patients. However, Platelet-to-Lymphocyte Ratio [Platelet-to-Lymphocyte Ratio (PLR)], Cancer Antigen 125 [Cancer Antigen 125 (CA-125)], and Cancer Antigen 153 [Cancer Antigen 153 (CA-153)] did not show significant differences between the two groups. KL-6, MMP-7, and Human Epididymis Protein 4 (HE4) are negatively correlated with lung function, and KL-6 is associated with the prognosis of RA-ILD.ConclusionsBiomarkers hold promising clinical value for prediction, diagnosis, severity assessment, and prognosis evaluation in RA-ILD. However, these findings need to be validated through multicenter, large-sample, prospective cohort studies.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42023448372.

Goat Milk Protein-Derived ACE Inhibitory Peptide SLPQ Exerts Hypertension Alleviation Effects Partially by Regulating the Inflammatory Stress of Endothelial Cells

Hypertension has always posed a severe threat to people’s health. Food-derived angiotensin-converting enzyme (ACE)-inhibitory peptides have the potential to both prevent and treat hypertension. In the current investigation, two ACE-inhibitory peptides (SLPQ and PYVRYL) from goat milk were studied for their endothelial effects using EA.hy926 cells. PYVRYL outperformed SLPQ, yet neither impacted cell survival below 200 μg/mL. Investigation of SLPQ’s impact on EA.hy926 cell expression revealed 114 differentially expressed genes, with 65 downregulated and 49 upregulated. The genes were enriched in cytokine interactions, coagulation cascades, Hippo signaling, and ECM–receptor interaction. Decreased c-x-c motif chemokine ligand 2 (CXCL2), integrin subunit beta 2 (ITGB2), and fbj murine osteosarcoma viral oncogene homologue (FOS) expression and increased secreted phosphoprotein 1 (SPP1) expression may protect endothelial cells from inflammation. Our findings suggest that beyond ACE inhibition, SLPQ aids blood pressure control by influencing endothelial function, paving the way for its use as an antihypertensive food ingredient.

Preventing postsurgical colorectal cancer relapse: A hemostatic hydrogel loaded with METTL3 inhibitor for CAR-NK cell therapy

Colorectal cancer (CRC) recurrence post-surgery remains a major challenge. While Chimeric Antigen Receptor (CAR)-engineered natural killer (NK) cells hold immense therapeutic potential, their intratumoral infiltration ability remains limited, hampering efficacy. Building upon prior research suggesting that chemokines like C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10) recruit CAR-NK cells, we hypothesized that tumor cell m6A methylation, regulated by Methyltransferase-like 3 (METTL3), influences chemokine secretion. This study aims to elucidate the underlying mechanisms and improve METTL3 inhibition efficiency. We designed an adhesive hemostasis hydrogel loaded with STM2457, a METTL3 inhibitor, aimed at sustained release in the acidic tumor microenvironment. In vitro, the hydrogel promoted CAR-NK cell recruitment and tumor killing via sustained METTL3 inhibition. The hydrogel's Schiff base bonds further enabled intestinal adhesion and hemostasis in an incomplete tumor resection model of CRC. Combining the hydrogel with CAR-NK cell therapy significantly reduced CRC recurrence in vivo. Overall, our study reveals the crucial role of METTL3 in CRC recurrence and proposes a promising, multimodal strategy using STM2457-loaded hydrogel and CAR-NK cells for enhanced therapeutic efficacy.

Acute and chronic impact of interleukin-33 stimulation on chemokines and growth factors in human cord blood-derived mast cells.

Mast cells (MCs) are multifaceted immune cells that are capable of recognizing and responding to various stimuli by releasing an array of cytokines. We aimed to use human cord blood-derived mast cells (hCBMCs) as a model to evaluate different conditions under which chemokines and growth factors are expressed and secreted as mediators upon stimulation with the alarmin interleukin-33 (IL-33). hCBMCs were stimulated with 10 ng/mL or 20 ng/mL of recombinant human IL-33 (rhIL-33) for 6 h (acute) or 24 h (chronic). The mRNA expression of chemokines and growth factors was analyzed using microarrays, and the mediators released in the supernatant were evaluated using a multiplex assay. The mRNA expression levels of C-C chemokine ligands (CCL) CCL1, CCL5, granulocyte macrophage colony-stimulating factor (GM-CSF), and macrophage inflammatory protein (MIP)-4/CCL18 were upregulated under all conditions. In contrast, C-X-C motif chemokine ligand (CXCL) CXCL8 and CCL24 levels increased only under acute (6 h) and prolonged (24 h) conditions, respectively. Moreover, high levels of CXCL8, MIP-1α, and MIP-1β were secreted during acute inflammation, whereas the release of GM-CSF and CXCL9 proteins increased under all four conditions. This study highlights the sentinel role of MCs in mounting a specific immune response against a pathogenic-like stimulus in a timely and dose-dependent manner and is relevant for improving inflammatory treatment options.

Tumor-associated macrophages/C-X-C motif chemokine ligand 1 promotes breast cancer autophagy-mediated chemoresistance via IGF1R/STAT3/HMGB1 signaling

Autophagy-mediated chemoresistance is the core mechanism for therapeutic failure and poor prognosis in breast cancer. Breast cancer chemotherapy resistance is believed to be influenced by tumor-associated macrophages (TAMs), by which C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant cytokine secreted. Yet, its role in mediating autophagy-related chemoresistance is still unknown. This study aimed to explore the molecular mechanisms by which TAMs/CXCL1 induced autophagy-mediated chemoresistance in breast cancer. It was found that TAMs/CXCL1 promoted chemoresistance of breast cancer cells through autophagy activation in vitro, and CXCL1 silence could enhance the chemosensitivity of paclitaxel-resistant breast cancer cells via autophagy inhibition. A high-throughput quantitative PCR chip and subsequent target validation showed that CXCL1 induced autophagy-mediated chemoresistance by inhibiting VHL-mediated IGF1R ubiquitination. The elevated IGF1R then promoted STAT3/HMGB1 signaling to facilitate autophagy. Additionally, TAMs/CXCL1 silence improved paclitaxel chemosensitivity by suppressing autophagy in breast cancer mice xenografts, and clinical studies further linked CXCL1 to IGF1R/HMGB1 signaling, as well as shorter free survival of recurrence. Taken together, these results not only uncover the crucial role of TAMs/CXCL1 signaling in mediating breast cancer chemoresistance through enhancing autophagy, but also shed novel light on the molecular mechanism of IGF1R/STAT3/HMGB1 pathway in regulating autophagy and its impact on cancer prognosis.

Identification and Verification of Key Genes in Colorectal Cancer Liver Metastases Through Analysis of Single-Cell Sequencing Data and TCGA Data.

Colorectal cancer (CRC) is highly prevalent worldwide, with more patients experiencing colorectal cancer liver metastases (CRLM). This study aimed to identify key genes in CRLM through single-cell sequencing data reanalysis and experimental validation. The study analyzed single-cell RNA-sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for gene functional enrichment analysis. The Cancer Genome Atlas (TCGA) data enabled bulk-RNA expression and survival prognosis analysis. Real-time polymerase chain reaction (qPCR) detected mRNA expression, whereas Western blot determined protein levels. Cell function experiments assessed SPARC's impact on CRC cell behavior. Cluster analysis showed 23 classes among 17 CRLM samples, representing six cell types. A GO and KEGG analysis identified interleukin-1 beta (IL1B), CD2 molecule (CD2), and C-X-C motif chemokine ligand 8 (CXCL8) as significant prognostic factors in CRC. Secreted protein acidic and cysteine rich (SPARC) was one of the top differentially expressed genes (DEGs) in tissue stem cells, confirmed in primary and metastatic lesions. Metastatic lesions showed higher expression of SPARC and CRC stem cell marker leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), which was significantly correlated positively with LGR5 expression. Knockdown of SPARC reduced CRC cell sphere- and colony-formation, invasion, and migration abilities. Overexpression of SPARC significantly increased the malignancy of CRC cells. Several key genes were identified in the process of CRLM. In CRLM samples and those corresponding to CRC stem cells, SPARC was significantly upregulated. In the therapy of CRLM, SPARC might be a potential target.

CXCR3-CXCL11 Signaling Restricts Angiogenesis and Promotes Pericyte Recruitment.

Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces; yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor CXCR3 (CXC motif chemokine receptor 3) and one of its ligands, CXCL11 (CXC motif chemokine ligand 11)-that delimits EC angiogenic potential and promotes pericyte recruitment to ECs during development. We investigated the role of CXCR3 on vascular development using both 2- and 3-dimensional in vitro assays, to study EC-pericyte interactions and EC behavioral responses to blood flow. Additionally, genetic mutants and pharmacological modulators were used in zebra fish in vivo to study the impacts of CXCR3 loss and gain of function on vascular development. In vitro modeling of EC-pericyte interactions demonstrates that suppression of EC-specific CXCR3 signaling leads to loss of pericyte association with EC tubes. In vivo, phenotypic defects are particularly noted in the cranial vasculature, where we see a loss of pericyte association with ECs and expansion of the vasculature in zebra fish treated with the Cxcr3 inhibitor AMG487 or in homozygous cxcr3.1/3.2/3.3 triple mutants. We also demonstrate that CXCR3-deficient ECs are more elongated, move more slowly, and have impaired EC-EC junctions compared with their control counterparts. Our results suggest that CXCR3 signaling in ECs helps promote vascular stabilization events during development by preventing EC overgrowth and promoting pericyte recruitment.

Bioinformatics analysis identifies WNK1 gene as a potential biomarker for cholangiocarcinoma diagnosis and immune infiltration

BackgroundCholangiocarcinoma (CHOL) is a malignant epithelial carcinoma of the digestive system with poor prognosis and high mortality. WNK lysine deficient protein kinase 1 (WNK1) is known to be associated with tumorigenesis in various cancers. However, the relationship between WNK1 and CHOL development, as well as the potential mechanisms involved, remains poorly understood. MethodsMicroarray datasets of CHOL (GSE22633 and GSE32879) were retrieved from the Gene Expression Omnibus (GEO) database. Functional enrichment and immunoinfiltration analyses were performed for genes co-expressed with WNK1. GraphPad Prism 9 was utilized for statistical data analysis and the construction of receiver operating characteristic (ROC) curves. The impact of WNK1 on the CHOL tumor microenvironment was analyzed using Tumor Immune Estimation Resource (TIMER), Venn diagrams, STRING, and TISIDB database for information on WNK1-related chemokines and chemokine receptors. Protein-protein interaction (PPI) networks were used to predict transcription factors and microRNAs interacting with WNK1 and the associated hub genes. ResultsDifferential expression of WNK1 was observed between CHOL and normal samples, suggesting its diagnostic value. Functional analysis showed that WNK1 and its associated genes were primarily enriched in pathways such as leukocyte transendothelial migration and chemokine signaling. Neutrophils were the only type of infiltrating immune cells associated with WNK1 in the CHOL tumor microenvironment (TME). VEGFA and ALB were identified as hub genes, and X-C motif chemokine receptor 1 (XCR1) and C-X-C motif chemokine ligand 5 (CXCL5) were identified as core chemokines and chemokine receptors related to WNK1 and neutrophil infiltration in CHOL. ConclusionsBased on network analysis and the summary of previous studies, it was proposed that CHOL tumor cells secrete CXCL5, leading to neutrophil recruitment to the tumor microenvironment. Vascular endothelial growth factor A (VEGFA) released by the infiltrating neutrophils is suggested to promote overexpression of WNK1 by tumor cells, activating the VEGFA downstream pathway to promote angiogenesis and tumor progression.

Clarithromycin Modulates Neutrophilic Inflammation Induced by Prevotella intermedia in Human Airway Epithelial Cells.

Objectives: In the present study, we aimed to clarify the mechanisms by which periodontal pathogens, particularly Prevotella intermedia, induce severe neutrophilic inflammation. In addition, we aimed to test the efficacy of macrolides, which has not been resolved in the neutrophilic inflammation induced by P. intermedia. Methods: NCl-H292 human airway epithelial cells were pre-incubated with clarithromycin for 2 h before incubation with P. intermedia supernatants. Then, C-X-C motif chemokine ligand 8 (CXCL8) transcription and interleukin (IL)-8 production were measured. To elucidate the signaling pathway, mitogen-activated protein kinase inhibitors were added to the cell culture, and the cells were subjected to Western blotting. Results:P. intermedia supernatants promoted CXCL8 transcription and IL-8 production, and the reactions were significantly suppressed by clarithromycin pretreatment. Only trametinib, the selective mitogen-activated extracellular signal-regulated kinase inhibitor, downregulated CXCL8 transcription and IL-8 production. Furthermore, Western blotting revealed that stimulation with P. intermedia supernatants specifically induces extracellular signal-regulated kinases (ERK) 1/2 phosphorylation, which is suppressed by clarithromycin pretreatment. Notably, the interference analysis revealed that ERK3 might be dispensable for IL-8 production under the stimulation of P. intermedia supernatants. Conclusions: Our results provide new insight into the mechanism underlying P. intermedia-induced production of IL-8 from human airway epithelial cells. Furthermore, macrolides might have therapeutic potential in regulating periodontal pathogen-induced neutrophilic inflammation in the lungs.

Involvement of Intestinal Epithelium Aryl Hydrocarbon Receptor Expression and 3, 3'-Diindolylmethane in Colonic Tertiary Lymphoid Tissue Formation.

Tertiary lymphoid tissues (TLTs) are adaptive immune structures that develop during chronic inflammation and may worsen or lessen disease outcomes in a context-specific manner. Immune cell activity governing TLT formation in the intestines is dependent on immune cell aryl hydrocarbon receptor (AhR) activation. Homeostatic immune cell activity in the intestines is further dependent on ligand activation of AhR in intestinal epithelial cells (IECs), yet whether AhR activation and signaling in IECs influences the formation of TLTs in the presence of dietary AhR ligands is not known. To this end, we used IEC-specific AhR deletion coupled with a mouse model of dextran sodium sulfate (DSS)-induced colitis to understand how dietary AhR ligand 3, 3'-diindolylmethane (DIM) influenced TLT formation. DIM consumption increased the size of TLTs and decreased T-cell aggregation to TLT sites in an IEC-specific manner. In DSS-exposed female mice, DIM consumption increased the expression of genes implicated in TLT formation (Interleukin-22, Il-22; CXC motif chemokine ligand 13, CXCL13) in an IEC AhR-specific manner. Conversely, in female mice without DSS exposure, DIM significantly reduced the expression of Il-22 or CXCL13 in iAhRKO mice, but this effect was not observed in WT animals. Our findings suggest that DIM affects the immunological landscape of TLT formation during DSS-induced colitis in a manner contingent on AhR expression in IECs and biological sex. Further investigations into specific immune cell activity, IEC-specific AhR signaling pathways, and dietary AhR ligand-mediated effects on TLT formation are warranted.

The Effect of C-X-C Motif Chemokine Ligand 12 in Colorectal Cancer Associated with Chemoresistance and Radioresistance as Well as Stemness.

We aimed to explore the role of C-X-C motif chemokine ligand 12 (CXCL12) and cytokinecytokine receptor interaction signaling pathway in the radiotherapy and chemotherapy resistance as well as cell stemness in colorectal cancer (CRC). Bioinformatics analysis was used to identify the differentially expressed mRNAs and signal pathways closely related to differentially expressed mRNAs have also been analyzed in March 2022 at the Jinhua Central Hospital, China. Then, the expression of CXCL12 was detected by qRT-PCR in colorectal cancer cells and testing the effects of transfecting CXCL12 into different CRC-derived cell lines. The effects of CXCL12 on cell proliferation were evaluated by chemosensitivity assay and radiation sensitivity assay. Bioinformatics analysis of DEGs found a total of 2429 differentially expressed genes, THBS3 and CXCL12 genes are two abnormally highly expressed genes in the CRC. KEGG analysis showed the correlative signaling pathway, cytokine-cytokine receptor interaction, which is related to cell stemness. Furthermore, the expression of CXCL12 in CRC cells was detected and an increasing trend was obtained in CRC cells. In addition, the chemosensitivity and radiotherapy tolerance were elevated after transfected with CXCL12. CXCL12 could be a potential promote biomarkers in CRC and also promote the chemosensitivity and radiotherapy tolerance.

Signaling pathways and targeted therapy for rosacea.

Rosacea is a chronic skin inflammatory disease with a global prevalence ranging from 1% to 20%. It is characterized by facial erythema, telangiectasia, papules, pustules, and ocular manifestations. Its pathogenesis involves a complex interplay of genetic, environmental, immune, microbial, and neurovascular factors. Recent studies have advanced our understanding of its molecular basis, focusing on toll-like receptor (TLR) 2 pathways, LL37 expression, mammalian target of rapamycin (mTOR) activation, interleukin (IL)-17 signaling, transient receptor potential vanilloid (TRPV) functions, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. LL37-associated signaling pathways, particularly involving TLR2 and mTORC1, are critical in the pathogenesis of rosacea. LL37 interacts with signaling molecules such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), nuclear factor kappa B (NF-κB), inflammasomes, C-X-C motif chemokine ligand 8 (CXCL8), mas-related G-protein-coupled receptor X2 (MRGPRX2)-TRPV4, and vascular endothelial growth factor (VEGF). This interaction activates macrophages, neutrophils, mast cells, and vascular endothelial cells, leading to cytokine release including tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β, C motif chemokine ligand (CCL) 5, CXCL9, and CXCL10. These processes contribute to immune response modulation, inflammation, and angiogenesis in rosacea pathophysiology. The IL-17 signaling pathway also plays a crucial role in rosacea, affecting angiogenesis and the production of inflammatory cytokines. In addition, recent insights into the JAK/STAT pathways have revealed their integral role in inflammatory and angiogenic mechanisms associated with rosacea. Rosacea treatment currently focuses on symptom management, with emerging insights into these molecular pathways providing more targeted and effective therapies. Biological agents targeting specific cytokines, IL-17 inhibitors, JAK inhibitors, and VEGF antagonists are promising for future rosacea therapy, aiming for enhanced efficacy and fewer side effects. This review provides a comprehensive overview of the current knowledge regarding signaling pathways in rosacea and potential targeted therapeutic strategies.

CD8 positive T-cells decrease neurogenesis and induce anxiety-like behaviour following hepatitis B vaccination.

Mounting evidence indicates the involvement of peripheral immunity in the regulation of brain function, influencing aspects such as neuronal development, emotion, and cognitive abilities. Previous studies from our laboratory have revealed that neonatal hepatitis B vaccination can downregulate hippocampal neurogenesis, synaptic plasticity and spatial learning memory. In the current post-epidemic era characterized by universal vaccination, understanding the impact of acquired immunity on neuronal function and neuropsychiatric disorders, along with exploring potential underlying mechanisms, becomes imperative. We employed hepatitis B vaccine-induced CD3 positive T cells in immunodeficient mice to investigate the key mechanisms through which T cell subsets modulate hippocampal neurogenesis and anxiety-like behaviours. Our data revealed that mice receiving hepatitis B vaccine-induced T cells exhibited heightened anxiety and decreased hippocampal cell proliferation compared to those receiving phosphate-buffered saline-T cells or wild-type mice. Importantly, these changes were predominantly mediated by infiltrated CD8+ T cells into the brain, rather than CD4+ T cells. Transcriptome profiling of CD8+ T cells unveiled that C-X-C motif chemokine receptor 6 positive (CXCR6+) CD8+ T cells were recruited into the brain through microglial and astrocyte-derived C-X-C motif chemokine ligand 16 (CXCL16). This recruitment process impaired neurogenesis and induced anxiety-like behaviour via tumour necrosis factor-α-dependent mechanisms. Our findings highlight the role of glial cell derived CXCL16 in mediating the recruitment of CXCR6+CD8+ T cell subsets into the brain. This mechanism represents a potential avenue for modulating hippocampal neurogenesis and emotion-related behaviours after hepatitis B vaccination.

SKAP1 Expression in Cancer Cells Enhances Colon Tumor Growth and Impairs Cytotoxic Immunity by Promoting Neutrophil Extracellular Trap Formation via the NFATc1/CXCL8 Axis.

The mechanisms underlying the development and progression of colon cancer are not fully understood. Herein, Src kinase associated phosphoprotein 1 (SKAP1), an immune cell adaptor, is identified as a novel colon cancer-related gene. SKAP1 expression is significantly increased in colon cancer cells. High SKAP1 levels are independently predictive of poor survival in patients with colon cancer. Notably, SKAP1 expression in colon cancer cells exerted a significant tumor-promoting effect in vivo rather than in vitro. Screening of tumor-infiltrating immune cells revealed the involvement of neutrophils in SKAP1-induced colon tumor promotion. Enhanced formation of neutrophil extracellular traps (NETs) is found to be a key downstream event that contributed to the pro-tumor role of SKAP1. In colon cancer cells, SKAP1 increased the expression of C-X-C motif chemokine ligand 8 (CXCL8) via nuclear factor of activated T cells c1 (NFATc1). The blockade of CXCL8 or NFATc1 largely attenuated neutrophil infiltration, NET formation, and tumor promotion induced by SKAP1. Furthermore, inhibiting SKAP1-induced NET significantly enhanced the antitumor efficiency of adoptive natural killer cell therapy in colon tumor models. In conclusion, SKAP1 significantly promotes colon cancer growth via the cancer cell/neutrophil NFATc1/CXCL8/NET axis, suggesting that SKAP1 is a potential target for colon cancer therapy.

The Role of Chemokines in Obesity and Exercise-Induced Weight Loss.

Obesity is a global health crisis that is closely interrelated to many chronic diseases, such as cardiovascular disease and diabetes. This review provides an in-depth analysis of specific chemokines involved in the development of obesity, including C-C motif chemokine ligand 2 (CCL2), CCL3, CCL5, CCL7, C-X-C motif chemokine ligand 8 (CXCL8), CXCL9, CXCL10, CXCL14, and XCL1 (lymphotactin). These chemokines exacerbate the symptoms of obesity by either promoting the inflammatory response or by influencing metabolic pathways and recruiting immune cells. Additionally, the research highlights the positive effect of exercise on modulating chemokine expression in the obese state. Notably, it explores the potential effects of both aerobic exercises and combined aerobic and resistance training in lowering levels of inflammatory mediators, reducing insulin resistance, and improving metabolic health. These findings suggest new strategies for obesity intervention through the modulation of chemokine levels by exercise, providing fresh perspectives and directions for the treatment of obesity and future research.

Urinary CXCL-10, a prognostic biomarker for kidney graft injuries: a systematic review and meta-analysis

The challenges of long-term graft survival and the side effects of current immunosuppressive therapies in kidney transplantation highlight the need for improved drugs with fewer adverse effects. Biomarkers play a crucial role in quickly detecting post-transplant complications, with new biomarkers showing promise for ongoing monitoring of disease and potentially reducing the need for unnecessary invasive biopsies. The chemokines such as C-X-C motif chemokine ligand 10 (CXCL10), are particularly promising protein biomarkers for acute renal rejection, with urine samples being a desirable source for biomarkers. The aim of this review is to analyze the literature on the potential role of urinary CXCL10 protein in predicting kidney graft injuries. The results of this study demonstrate that evaluating urinary CXCL10 levels is more successful in identifying post-transplant injuries compared to assessing the CXCL10/Cr ratio.