Search Results (35)

Chemokine (CXC motif) ligand 8 (CXCL8) is a pro-inflammatory chemokine binding to CXC motif receptors 1/2 (CXCR1/2). Patients with temporal lobe epilepsy (TLE) exhibit increased serum CXCL8 levels. CXC motif ligand 1 (CXCL1), a murine ortholog of CXCL8, has been implicated in seizure generation and neuronal loss. This study evaluated the antiepileptogenic and antiseizure effects of reparixin in amygdaloid kindling rat model of TLE. Reparixin was administered during the kindling period for 14 days, and seizures were induced twice daily via electrical stimulation. To assess the antiseizure effects, reparixin was administered to fully kindled animals, and stimulations were performed 24 and 48 h later. Levetiracetam, a broad-spectrum antiseizure drug, was administered intraperitoneally (i.p.) as positive control 1 h before each stimulation. Reparixin delayed secondary seizure generalization during kindling. Reparixin reduced seizure severity and after-discharge duration in fully kindled animals at 24 h from treatment initiation. CXCR1/2 and protein kinase B pathway proteins exhibited no significant changes; reparixin reduced the phospho-extracellular signal-regulated kinase (pERK)/ERK ratio in the cortex and hippocampus. CXCL1 expression was significantly decreased in the cortex. Reparixin exhibited antiepileptogenic and partial antiseizure effects by modulating the CXCL1–CXCR1/2 axis and reducing ERK signaling. Already in clinical trials on respiratory diseases, reparixin could be repurposed for epilepsy therapy. Full article

Metastasis presents significant challenges in ovarian cancer treatment. Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) facilitate metastasis through epithelial-mesenchymal transition, yet the molecular underlying mechanisms are not fully understood. Here, we identified that tripartite motif-containing 46 (TRIM46) is significantly upregulated in ovarian cancer cells treated with a conditioned medium derived from macrophages stimulated by ovarian cancer cells (OC-MQs). Furthermore, TRIM46 was highly expressed in late-stage ovarian cancer patients and was associated with poor prognosis. Silencing of TRIM46 suppressed cancer cell invasion stimulated by OC-MQ and mesenchymal marker expression without affecting cell viability. Gene set enrichment analysis showed that the Wnt/β-catenin pathway is enriched in the high-TRIM46 expression group. Importantly, the inhibition of TRIM46-mediated β-catenin nuclear translocation and ovarian cancer cell invasion was reversed by CHIR99021, a Wnt/β-catenin activator. Additionally, C-X-C motif chemokine ligand 8 (CXCL8) was identified as being highly expressed in peritoneal MQs from the ascites of ovarian cancer patients and was positively correlated with C-X-C chemokine receptor 1/2 (CXCR1/2) expression in tumor cells. Notably, pre-treatment with reparixin, a CXCR1/2 inhibitor, blocked OC-MQ-induced TRIM46 expression and cell invasion. These results suggest that CXCL8 derived from TAMs promotes human ovarian cancer cell invasion via the Wnt/β-catenin pathway by upregulating TRIM46. Full article

Neuroinflammation is involved in various neurological and neurodegenerative disorders in which the activation of microglia is one of the key factors. In this study, we examined the anti-inflammatory effects of the flavonoids nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone) and eriodictyol (3′,4′,5,7-tetraxydroxyflavanone) on human microglia cell line activation stimulated by either lipopolysaccharide (LPS), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length Spike protein (FL-Spike), or the mycotoxin ochratoxin A (OTA). Human microglia were preincubated with the flavonoids (10, 50, and 100 µM) for 2 h, following which, they were stimulated for 24 h. The inflammatory mediators interleukin-1 beta (IL-1β), chemokine (C-X-C motif) ligand 8 (CXCL8), IL-6, and matrix metalloproteinase-9 (MMP-9) were quantified in the cell culture supernatant by enzyme-linked immunosorbent assay (ELISA). Both nobiletin and eriodictyol significantly inhibited the LPS, FL-Spike, and OTA-stimulated release of IL-1β, CXCL8, IL-6, and MMP-9 at 50 and 100 µM, while, in most cases, nobiletin was also effective at 10 µM, with the most pronounced reductions at 100 µM. These findings suggest that both nobiletin and eriodictyol are potent inhibitors of the pathogen-stimulated microglial release of inflammatory mediators, highlighting their potential for therapeutic application in neuroinflammatory diseases, such as long COVID. Full article

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. Full article

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. Full article

In Sjögren’s disease (SjD), the salivary glandular epithelial cells can induce the chemotaxis of B cells by secreting B-cell chemokines such as C-X-C motif chemokine ligand 13 (CXCL13). Syndecan-1 (SDC-1) is a major transmembrane heparan sulfate proteoglycan (HSPG) predominantly expressed on epithelial cells that binds to and regulates heparan sulfate (HS)-binding molecules, including chemokines. We aimed to determine whether SDC-1 plays a role in the pathogenesis of SjD by acting on the binding of HS to B-cell chemokines. To assess changes in glandular inflammation and SDC-1 concentrations in the submandibular gland (SMG) and blood, female NOD/ShiLtJ and sex- and age-matched C57BL/10 mice were used. In the SMG of NOD/ShiLtJ mice, inflammatory responses were identified at 8 weeks of age, but increased SDC-1 concentrations in the SMG and blood were observed at 6 weeks of age, when inflammation had not yet started. As the inflammation of the SMG worsened, the SDC-1 concentrations in the SMG and blood increased. The expression of the CXCL13 and its receptor C-X-C chemokine receptor type 5 (CXCR5) began to increase in the SMG at 6 weeks of age and continued until 12 weeks of age. Immunofluorescence staining in SMG tissue and normal murine mammary gland cells confirmed the co-localization of SDC-1 and CXCL13, and SDC-1 formed a complex with CXCL13 in an immunoprecipitation assay. Furthermore, NOD/ShiLtJ mice were treated with 5 mg/kg HS intraperitoneally thrice per week for 6–10 weeks of age, and the therapeutic effects in the SMG were assessed at the end of 10 weeks of age. NOD/ShiLtJ mice treated with HS showed attenuated salivary gland inflammation with reduced B-cell infiltration, germinal center formation and CXCR5 expression. These findings suggest that SDC-1 plays a pivotal role in the pathogenesis of SjD by binding to CXCL13 through the HS chain. Full article

This case-control study investigated single nucleotide polymorphism (SNP) genotypes (CXC motif chemokine ligand 8 (CXCL8): rs2227306 and rs2227307 and tumor necrosis factor (TNF): rs1800629) in 85 patients with pain-related temporomandibular disorders (TMDp) and 85 controls to explore their associations with TMDp presence, pain intensity (low/high), and the presence of chronic arthralgia/myalgia. TMDp was diagnosed using a validated protocol, and polymorphisms were genotyped from buccal mucosa swabs using TaqMan assays. High pain intensity individuals had an increased risk for carrying minor allele “G” (rs2227307) and “T” (rs2227306) compared to controls (76% vs. 55.3%, p = 0.012; 72% vs. 54.1%, p = 0.030, respectively). Carriers of the minor allele “G” (rs2227307) were more prevalent in TMDp patients with arthralgia compared to controls (70.30% vs. 55.30%, p = 0.037). According to logistic regression, the most important predictors for high pain intensity were minor allele “G” of rs2227307 (OR 2.435, 95% CI 1.123–5.282), increasing age (OR 1.038, 95% CI 1.002–1.075), and female sex (OR 4.592, 95% CI 1.289–16.361). The explored gene polymorphisms were not significant risk factors for TMDp presence. These findings highlight the importance of genetic variations, particularly rs2227307, in understanding the diverse clinical manifestations of temporomandibular disorders. Full article

Scutellarein is a key active constituent present in many plants, especially in Scutellaria baicalensis Georgi and Erigeron breviscapus (vant.) Hand-Mazz which possesses both anti-inflammatory and anti-oxidative activities. It also is the metabolite of scutellarin, with the ability to relieve LPS-induced acute lung injury (ALI), strongly suggesting that scutellarein could suppress respiratory inflammation. The present study aimed to investigate the effects of scutellarein on lung inflammation by using LPS-activated BEAS-2B cells (a human bronchial epithelial cell line) and LPS-induced ALI mice. The results showed that scutellarein could reduce intracellular reactive oxygen species (ROS) accumulation through inhibiting the activation of NADPH oxidases, markedly downregulating the transcription and translation of pro-inflammatory cytokines, including interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand (CXCL) 8 in LPS-activated BEAS-2B cells. The mechanism study revealed that it suppressed the phosphorylation and degradation of IκBα, consequently hindering the translocation of p65 from the cytoplasm to the nucleus and its subsequent binding to DNA, thereby decreasing NF-κB-regulated gene transcription. Notably, scutellarein had no impact on the activation of AP-1 signaling. In LPS-induced ALI mice, scutellarein significantly decreased IL-6, CCL2, and tumor necrosis factor-α (TNF-α) levels in the bronchoalveolar lavage fluid, attenuated lung injury, and inhibited neutrophil infiltration. Our findings suggest that scutellarein may be a beneficial agent for the treatment of infectious pneumonia by virtue of its anti-oxidative and anti-inflammatory activities. Full article

In patients with autoimmune disorders such as rheumatoid arthritis (RA), delayed wound healing is often observed. Timely and effective wound healing is a crucial determinant of a patient’s quality of life, and novel materials for skin wound repair, such as bioactive peptides, are continuously being studied and developed. One such bioactive peptide, AESIS-1, has been studied for its well-established anti-rheumatoid arthritis properties. In this study, we attempted to use the anti-RA material AESIS-1 as a therapeutic wound-healing agent based on disease-modifying antirheumatic drugs (DMARDs), which can help restore prompt wound healing. The efficacy of AESIS-1 in wound healing was assessed using a full-thickness excision model in diabetic mice; this is a well-established model for studying chronic wound repair. Initial observations revealed that mice treated with AESIS-1 exhibited significantly advanced wound repair compared with the control group. In vitro studies revealed that AESIS-1 increased the migration activity of human dermal fibroblasts (HDFs) without affecting proliferative activity. Moreover, increased HDF cell migration is mediated by upregulating chemokine receptor expression, such as that of CXC chemokine receptor 2 (CXCR2). The upregulation of CXCR2 through AESIS-1 treatment enhanced the chemotactic reactivity to CXCR2 ligands, including CXC motif ligand 8 (CXCL8). AESIS-1 directly activates the ERK and p38 mitogen-activated protein kinase (MAPK) signaling cascades, which regulate the migration and expression of CXCR2 in fibroblasts. Our results suggest that the AESIS-1 peptide is a strong wound-healing substance that increases the movement of fibroblasts and the expression of CXCR2 by turning on the ERK and p38 MAPK signaling cascades. Full article

Alternative polyadenylation (APA), including APA that occurs only in the 3′ UTR (3′ UTR-APA), is an important post-transcriptional regulatory mechanism that leads to distinct 3′ UTRs for some genes, increasing the complexity of the transcriptome. The post-transcriptional events regulating the expression of bovine, the C-X-C motif chemokine ligand 14 (CXCL14) gene, remains largely unknown. Here, we find that the bovine CXCL14 gene produces two different lengths of mRNA isoforms due to 3′ UTR-APA, and the short and long 3′ UTR is 126 bp and 1155 bp, respectively. We found that the expression level of the short isoform was significantly higher than that of the long isoform by luciferase assays and overexpression of different CXCL14 3′ UTR-APA isoforms. Moreover, using luciferase assay and site-directed mutagenesis experiments, the results showed that the long CXCL14 3′ UTR-APA isoform is downregulated by miR-17-5p, miR-150, and miR-217. However, because the short isoform lacks the true target of miR-17-5p, miR-150, and miR-217 in its 3′ UTR and thus escapes the inhibitory effect of these microRNAs, its expression level is significantly higher than that of the long isoform. Finally, we demonstrate that the short CXCL14 3′ UTR-APA isoform promotes preadipocyte proliferation by cell counting kit 8 (CCK8) assays. Collectively, our results show that the CXCL14 gene is post-transcriptionally regulated through APA and microRNAs. Full article

Pancreatic cancer (PC) has one of the lowest survival rates among all major types of cancer. Consequently, it is one of the leading causes of mortality worldwide. Serum biomarkers historically correlate well with the early prognosis of post-surgical complications of PC. However, attempts to identify an effective biomarker panel for the successful prognosis of PC were almost non-existent in the current literature. The current study investigated the roles of various serum biomarkers including carbohydrate antigen 19-9 (CA19-9), chemokine (C-X-C motif) ligand 8 (CXCL-8), procalcitonin (PCT), and other relevant clinical data for identifying PC progression, classified into sepsis, recurrence, and other post-surgical complications, among PC patients. The most relevant biochemical and clinical markers for PC prognosis were identified using a random-forest-powered feature elimination method. Using this informative biomarker panel, the selected machine-learning (ML) classification models demonstrated highly accurate results for classifying PC patients into three complication groups on independent test data. The superiority of the combined biomarker panel (Max AUC-ROC = 100%) was further established over using CA19-9 features exclusively (Max AUC-ROC = 75%) for the task of classifying PC progression. This novel study demonstrates the effectiveness of the combined biomarker panel in successfully diagnosing PC progression and other relevant complications among Egyptian PC survivors. Full article

CXCL14 (C-X-C motif chemokine ligand 14) is an important chemokine involved in infection and immunity and plays an important role in a variety of immune-related diseases. The 446 bp cDNA sequence of the CXCL14 gene in yaks was obtained. Additionally, the prokaryotic expression vector of the CXCL14 protein with a molecular weight of 27 kDa was successfully constructed and expressed. The proliferation activities and migration abilities of spleen macrophages were significantly inhibited after treatment with the CXCL14 protein at different concentrations (1, 10 and 20 μg/mL) (p < 0.05). Furthermore, the expressions of pro-inflammatory cytokines interleukin 1 beta (IL-1β), interleukin 6 (IL6), interleukin 8 (IL8) and interferon-α (TNF-α) were significantly increased (p < 0.05), but the expression of anti-inflammatory factor interleukin 10 (IL10) was significantly decreased (p < 0.05). The contents of inflammatory factors in the supernatant of cells were detected using ELISA, and it was also found that the contents of TNF-α, IL6 and cytochrome c oxidase subunit II (COX2) were significantly increased under different CXCL14 protein concentrations (p < 0.05). Finally, the exogenous addition of CXCL14 inhibited the activity, clonal formation and migration of hepatoma cells (HepG2). Additionally, after HepG2 cells were treated with 20 μg/mL CXCL14 protein for 12 h, 24 h and 36 h, the expression levels of BCL2 homologous antagonist/killer (BAK) and the BCL2-associated X apoptosis regulator (BAX) were increased to varying degrees, while the expression levels of hypoxia-inducible factor 1 subunit alpha (HIF1A), the mechanistic target of rapamycin kinase (mTOR) and cyclin-dependent kinase 1 (CDK1) genes decreased compared to the control group. In conclusion, the CXCL14 protein can inhibit the proliferation and migration of HepG2 cells by inducing the expression of macrophage pro-inflammatory factors and activating apoptosis-related genes to exert innate immunity. These results are helpful to further study the function of the CXCL14 protein and provide research data for the innate immune mechanism of yaks under harsh plateau environments. Full article

Stroke is the second most common cause of cognitive impairment and dementia. Vascular dementia (VaD), a cognitive impairment following a stroke, is common and significantly impacts the quality of life. We recently demonstrated via gut microbe transplant studies that the gut microbe-dependent trimethylamine-N-oxide (TMAO) pathway impacts stroke severity, both infarct size and long-term cognitive outcomes. However, the molecular mechanisms that underly the role of the microbiome in VaD have not been explored in depth. To address this issue, we performed a comprehensive RNA-sequencing analysis to identify differentially expressed (DE) genes in the ischemic cerebral cortex of mouse brains at pre-stroke and post-stroke day 1 and day 3. A total of 4016, 3752 and 7861 DE genes were identified at pre-stroke and post-stroke day 1 and day 3, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated pathways of neurodegeneration in multiple diseases, chemokine signaling, calcium signaling, and IL-17 signaling as the key enriched pathways. Inflammatory response genes interleukin-1 beta (Il-1β), chemokines (C–X–C motif chemokine ligand 10 (Cxcl10), chemokine ligand 2 (Ccl2)), and immune system genes (S100 calcium binding protein 8 (S100a8), lipocalin-2 (Lcn2)) were among the most significantly upregulated genes. Hypocretin neuropeptide precursor (Hcrt), a neuropeptide, and transcription factors such as neuronal PAS domain protein 4 (Npas4), GATA binding protein 3 (Gata3), and paired box 7 (Pax7) were among the most significantly downregulated genes. In conclusion, our results indicate that higher plasma TMAO levels induce differential mRNA expression profiles in the ischemic brain tissue in our pre-clinical stroke model, and the predicted pathways provide the molecular basis for regulating the TMAO-enhanced neuroinflammatory response in the brain. Full article

Endometriotic lesions are able to infiltrate surrounding tissue. This is made possible partly by an altered local and systemic immune response that helps achieve neoangiogenesis, cell proliferation and immune escape. Deep-infiltrating endometriosis (DIE) differs from other subtypes through the invasion of its lesions over 5 mm into affected tissue. Despite the invasive nature of these lesions and the wider range of symptoms they can trigger, DIE is described as a stable disease. This elicits the need for a better understanding of the underlying pathogenesis. We used the “Proseek^® Multiplex Inflammation I Panel” in order to simultaneously detect 92 inflammatory proteins in plasma and peritoneal fluid (PF) of controls and patients with endometriosis, as well as in particular patients with DIE, in order to gain a better insight into the systemically and locally involved immune response. Extracellular newly identified receptor for advanced gycation end-products binding protein (EN-RAGE), C-C motif Chemokine ligand 23 (CCL23), Eukaryotic translation initiation factor 4—binding protein 1 (4E-BP1) and human glial cell-line derived neurotrophic factor (hGDNF) were significantly increased in plasma of endometriosis patients compared to controls, whereas Hepatocyte Growth factor (HGF) and TNF-related apoptosis inducing ligand (TRAIL) were decreased. In PF of endometriosis patients, we found Interleukin 18 (IL-18) to be decreased, yet Interleukin 8 (IL-8) and Interleukin 6 (IL-6) to be increased. TNF-related activation-induced cytokine (TRANCE) and C-C motif Chemokine ligand 11 (CCL11) were significantly decreased in plasma, whereas C-C motif Chemokine ligand 23 (CCL23), Stem Cell Factor (SCF) and C-X-C motif chemokine 5 (CXCL5) were significantly increased in PF of patients with DIE compared to endometriosis patients without DIE. Although DIE lesions are characterized by increased angiogenetic and pro-inflammatory properties, our current study seems to support the theory that the systemic immune system does not play a major role in the pathogenesis of these lesions. Full article

The role of the gastric mucosal microbiome in Helicobacter pylori-negative gastric cancer (GC) remains unclear. Therefore, we aimed to characterize the microbial alterations and host inflammatory cytokine responses in H. pylori-negative GC. Gastric mucosal samples were obtained from 137 H. pylori-negative patients with GC (n = 45) and controls (chronic gastritis or intestinal metaplasia, n = 92). We performed 16S rRNA gene sequencing (n = 67), a quantitative reverse transcription-polymerase chain reaction to determine the relative mRNA expression levels of TNF (tumor necrosis factor), IL1B (interleukin 1 beta), IL6 (interleukin 6), CXCL8 (C-X-C motif chemokine ligand 8), IL10 (interleukin 10), IL17A (interleukin 17A), TGFB1 (transforming growth factor beta 1) (n = 113), and the correlation analysis between sequencing and expression data (n = 47). Gastric mucosal microbiota in patients with GC showed reduced diversity and a significantly different composition compared to that of the controls. Lacticaseibacillus was significantly enriched, while Haemophilus and Campylobacter were depleted in the cancer group compared to the control group. These taxa could distinguish the two groups in a random forest algorithm. Moreover, the combined relative abundance of these taxa, a GC microbiome index, significantly correlated with gastric mucosal IL1B expression, which was elevated in the cancer group. Overall, altered gastric mucosal microbiota was found to be associated with increased mucosal IL1B expression in H. pylori-negative GC. Full article