CXCL10 Levels Research Articles

Targeting CXCL8 signaling sensitizes HNSCC to anlotinib by reducing tumor-associated macrophage-derived CLU

BackgroundAlthough nutrition-starvation therapy for malignancies such as HNSCC is highly desirable, the clinical outcomes remain disappointing. Understanding the spatial heterogeneity of glucose deficiency can reveal the molecular mechanisms regulating cancer metabolism and identify therapeutic targets to improve effective nutrient-starvation therapies.MethodsMultiple omics data from RNA-seq, proteomics and spatial transcriptome analyses of HNSCC samples were integrated to analyze the spatial heterogeneity of glucose deficiency. In vivo and in vitro CXCL8 and CLU expression levels in tumor cells were determined using qPCR, immunohistochemistry and ELISA. The ability of CLU from TAMs to respond to tumor-derived CXCL8 was assessed using RNA sequencing, siRNA silencing, immunofluorescence and CCK-8 assays. A mouse subcutaneous xenograft model was used to assess the outcomes of nutrition-starvation therapy combined with blockade of CXCL8 signaling.ResultsA set of genes that was significantly upregulated in HNSCC under conditions of glucose deficiency was identified using integrating multiple omics data analyses. The upregulated gene set was used to determine the glucose-deficient area according to transcriptome data of HNSCC, and CXCL8 was one of the most highly upregulated genes. The levels of both CXCL8 mRNA and its protein IL-8 in cancer cells under conditions of glucose deficiency were increased in an NF-κB-dependent manner. Supplementary IL-8 stimulated TAMs to synthesize CLU, and CLU counteracted oxidative stress in HNSCC cells under conditions of glucose deficiency. Moreover, pharmacological blockade of CXCL8 signaling (reparixin) sensitized HNSCC cells to nutrient-starvation therapy (anlotinib) in two xenograft models.ConclusionOur results provide novel evidence of a feedback loop between cancer cells and TAMs in glucose-deficient regions. HNSCC-derived CXCL8 favors endogenous antioxidative processes and confers therapeutic resistance to nutrient-starvation therapies in HNSCC.Graphical

Elevated Cerebrospinal Fluid CXCL13 Is a Helpful Marker for the Early Diagnosis of Neuroborreliosis in Children.

Lyme neuroborreliosis (LNB) is an early systemic manifestation of Lyme disease in children, but standard diagnostic measures have constraints that limit early LNB diagnosis. Elevated cerebrospinal fluid (CSF) concentrations of the chemokine CXCL13 are considered a useful marker for early LNB diagnosis in adults, however, few studies have evaluated their diagnostic value in children. In this retrospective analysis, stored CSF samples of 232 hospitalized pediatric patients tested for LNB with standard serological methods were re-analyzed for CXCL13. CXCL13 levels were compared in children classified as definite, possible or no LNB patients according to European Federation of Neurological Societies guidelines. Specificity and sensitivity of CSF CXCL13 were determined for the diagnosis of early LNB, using previously published cutoff levels for pediatric patients. CSF CXCL13 levels differed significantly between 25 patients with definite LNB (all >7.8 pg/mL; range: 37.9->500 pg/mL) and 174 patients without LNB [160 (92%) <7.8 pg/mL; 13 (7%) with a range of 7.8-59.3 pg/mL; 1 (1%) with >500 pg/mL and Ureaplasma parvum CNS infection]. Using a cutoff of 55 pg/mL, CSF CXCL13 resulted in a specificity of 98.9% (95% CI: 97.4-100) and sensitivity of 92.0% (95% CI: 81.4-100). This study confirms the high sensitivity and specificity of CSF CXCL13 for the diagnosis of pediatric LNB using a cutoff value of 55 pg/mL. The use of CSF CXCL13 as an additional diagnostic measure in children with suspected LNB could improve diagnostic specificity and thereby reduce unnecessary antibiotic treatment, especially in the early phases of the disease.

A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types

Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene “MANAscore” algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL.

Caffeine intake during gestation and lactation causes long-term behavioral impairments in heterogenic mice offspring in a sex-dependent manner.

Growing evidence has indicated a potential association between maternal consumption of caffeine and impaired cognition and behavior in rodent offspring. However, potential sex differences, as well as caffeine-related effects in subsequent generations are still poorly investigated. We aimed to investigate the impact of pre-and/or neonatal exposition to caffeine on the neurodevelopment of male and female mice offspring. Adult female Swiss mice were randomly divided into four experimental groups, which received, via gavage, water or caffeine (120mg/day). Control/control (CC) received water during pregnancy and lactation; treated/control (TC): received caffeine during pregnancy and water during lactation; control/treated (CT): received water during pregnancy and caffeine during lactation; treated/treated (TT): received caffeine during pregnancy and lactation. Dams were euthanized at gestational day 17.5 and fetal brains were collected. Adult mice of F1 and F2 generations were submitted to behavioral analysis and their pre-frontal cortex and hippocampi were dissected to measure the levels of BDNF and CX3CL1. Caffeine induced reduction of CX3CL1 levels in female fetuses compared with controls. Maternal intake of caffeine was associated with anxiety- and compulsive-like behavior in both F1 and F2 female mice offspring. Interestingly, only F2 female mice exhibited caffeine-induced impairment of work memory. Hippocampal levels of CX3CL1 and BDNF were decreased in female F1TT and F2TT groups; while among males exposed to caffeine, only F1 offspring had reduced hippocampal CX3CL1 levels. Our results suggest that both pre- and neonatal exposition to caffeine lead to long-term behavioral and neurochemical impairments in a sex-dependent manner, adversely affecting the subsequent female generation.

Transcriptomic analysis of key genes and signaling pathways in sepsis-associated intestinal mucosal barrier damage

ObjectivesThe aim is to analyze differentially expressed genes (DEGs) in mice with sepsis-related intestinal mucosal barrier damage and to explore the diagnostic and protective mechanisms of this condition at the transcriptome level. MethodsSmall intestinal tissues from healthy male C57BL/6J mice subjected to Cecal ligation and puncture (CLP) and sham operation were collected. High-throughput sequencing was performed using the paired-end sequencing mode of the Illumina HiSeq platform. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted on the differentially expressed genes (DEGs). A protein–protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified with Cytoscape. These hub genes were then validated using quantitative real-time polymerase chain reaction (RT-qPCR). ResultsA total of 239 DEGs were identified, with 49 upregulated and 130 downregulated genes. KEGG enrichment analysis showed that these DEGs were primarily involved in cytokine-cytokine receptor interaction, Th1 and Th2 cell differentiation, viral protein interactions with cytokines and their receptors, and the IL-17 signaling pathway. The top 10 hub genes were selected using the cytoHubba plugin. Experimental validation confirmed that the expression levels of TBX21, CSF3, IL-6, CXCR3, and CXCL9 matched the sequencing results. ConclusionTBX21, CSF3, IL-6,CXCR3, and CXCL9 may be potential biological markers for the diagnosis and treatment the sepsis-associated intestinal mucosal barrier.

HBV and HBsAg strongly reshape the phenotype, function, and metabolism of DCs according to patients' clinical stage.

Hepatitis B is a liver infection caused by HBV. Infected individuals who fail to control the viral infection develop chronic hepatitis B and are at risk of developing life-threatening liver diseases, such as cirrhosis or liver cancer. Dendritic cells (DCs) play important roles in the immune response against HBV but are functionally impaired in patients with chronic hepatitis B. The underlying mechanisms involved in HBV-induced DC dysfunctions remain to be elucidated. We explored DC modulations by HBV and HBsAg by exposing blood-derived cDC1s, cDC2s, and plasmacytoid DCs from healthy donors to HBV or HBsAg and stimulating them with toll-like receptor ligand. Their phenotypic and functional features, as well as their metabolic profile, were analyzed through multiparametric flow cytometry and multiplex assays and further explored on patients' samples. We found that HBV deeply reshaped the DC secretome in response to toll-like receptor ligand. Strikingly, we observed that HBV-exposed DCs secrete high levels of CX3CL1 (fractalkine), a chemokine responsible for attracting antiviral effectors to the site of infection. HBsAg exposure favored DC activation while drastically altering TRAIL expression in response to toll-like receptor ligand and increasing the secretion of cytokines/chemokines involved in immune tolerance. HBsAg further dampened the metabolism of DC subsets while driving metabolic switches. Notably, the relevance of the CX3CL1/CX3CR1 axis, TGF-β, and metabolic disturbances was demonstrated within intrahepatic DC subsets in patients according to disease stage. Our work brings new insights into the immunomodulation induced by HBV on DCs, which contribute to impaired antiviral responses and progression toward chronicity.

The Role of Long Non-coding RNA (NKILA and LINC00993) as Tumour Biomarkers in Breast Cancer

Background: Long non-coding RNAs (NKILA and LINC00993) are downregulated in breast cancer (BC) and can have potential use as a novel tumor biomarker. The Aim of the work is to investigate the LncRNAs (NKILA and LINC00993) and cytokines (NF-κB and CXCL-1) as potential biomarkers in BC. Methods: This Cross-sectional study included sixty-four pairs of surgically resected human breast cancer tissues and adjacent breast tissues. Expressions of LncRNAs (NKILA, LINC00993) and (NF-κB, CXCL1) cytokines were detected using real-time quantitative polymerase chain reaction (qPCR) analysis, Results: There was a significant decrease in LncRNAs (NKILA, LINC00993) levels in tumor tissue compared to normal tissue (P&lt;0.001). Also, there was a significant increase in NF-κB and CXCL1 levels in tumor tissue compared to normal tissue (P&lt;0.001). ROC curve analysis indicated that the LncRNAs (NKILA, LINC00993) expression levels could be considered a promising marker for the diagnosis of breast cancer patients with a sensitivity (90.6%, 92.2% respectively). Also, cytokines (NF-κB and CXCL-1) expression levels could be considered a promising marker for the diagnosis of breast cancer patients with a sensitivity and specificity of 87.5%, and 89.1% respectively). Conclusion: These findings suggest that LncRNAs (NKILA, LINC00993) and cytokines (NF-κB and CXCL-1) can be used as novel biomarkers for breast cancer.

Comparative Assessment of Acute Pulmonary Effects Induced by Heat-Not-Burn Tobacco Aerosol Inhalation in a Murine Model

Tobacco smoking remains a major global health concern, causing preventable deaths and economic strain. Although new tobacco products such as heat-not-burn (HnB) are safer alternatives to traditional cigarettes, research on their associated risks remains limited. This study aimed to investigate the effects of HnB smoke exposure on the lungs compared to those of traditional cigarettes and the combined use of HnB and cigarettes using experiments with a mouse model. We quantitatively analyzed changes in the levels of 92 blood plasma proteins using the proximity extension assay method and observed significant changes in their levels in mice exposed to different smoke conditions; specifically, the levels of certain proteins, including Ccl20, Cxcl1, and Pdgfb, increased in the HnB smoke-exposed group, suggesting activation of nicotine pathways. Comparative analysis with traditional cigarette smoke-exposed mice further highlighted similarities and differences in their protein expression profiles. This study contributes to an improved understanding of the biological mechanisms underlying the harmful effects of alternative nicotine delivery systems and identifies potential biomarkers associated with the harmful effects of HnB smoke exposure. However, the precise impact of nicotine on the immune system may be influenced by various factors, necessitating further research.

P1193 Cross-Disease Analysis Unveils CXCL6 as a Shared Immune Mediator in Ulcerative Colitis and Periodontitis: Novel Insights from Bioinformatics

Abstract Background Emerging evidence underscores a pathological bidirectional relationship between ulcerative colitis (UC) and periodontitis (PD) through the oral-gut axis, highlighting a complex interplay with significant implications for patient health. However, the shared molecular features underlying this interaction have yet to be explored. Methods In this study, we initially established a potential link between periodontitis and ulcerative colitis based on Mendelian randomization. Following this, we analyzed gene expression profiles from the Gene Expression Omnibus (GEO) for both UC and PD, identifying overlapping genes between UC-differentially expressed genes (DEGs) and PD-DEGs. Results Functional enrichment analysis revealed associations with various immune pathways, underscoring the immunological relevance of these genes. Intersection with immune-related genes (IRGs) yielded 25 candidate genes, among which CXCL6 emerged as a central hub gene identified through three machine learning methods: LASSO, RF, and SVM-RFE. Subgroup analysis based on CXCL6 expression demonstrated that the CXCL6-high group exhibited increased immune cell infiltration and enhanced immune function. Moreover, our investigation of CXCL6 in relation to biological therapies in UC patients indicated a reduction in CXCL6 levels following treatment, suggesting potential benefits of biological therapies. Finally, we validated the expression of CXCL6 in a rat model of dual diseases. Conclusion In summary, CXCL6 is identified as a diagnostic biomarker and potential therapeutic target for UC combined with PD, warranting further investigation into its clinical significance and associated mechanisms.

P0198 Comparative Transcriptomic Analysis of Tonsil-derived and Adipose-derived Mesenchymal Stem Cells: Proliferation, Migration, and Anti-inflammatory Potential in Murine Colitis Model

Abstract Background Tonsil-derived mesenchymal stem cells (TMSCs) have emerged as a promising alternative to traditional MSCs due to their rapid proliferation and accessibility. This study explores the unique transcriptomic and cellular properties of TMSCs compared with adipose-derived MSCs (AMSCs). Methods TMSCs and AMSCs were cultured under identical conditions in low-glucose DMEM with 10% FBS. Proliferation was evaluated via CCK-8 assays, and migration potential was assessed using scratch assays. Transcriptomic differences were analyzed using RNA sequencing, with key findings validated by qPCR. Results TMSCs displayed distinct morphological features compared to AMSCs, with TMSCs showing a spindle shape, while AMSCs appeared more irregular and rounded shape. In terms of proliferation, TMSCs demonstrated a significantly higher proliferation rate by day 7 (245.3% of control vs. 134.4% of control, p &amp;lt; 0.001). However, there was no significant difference in migration capacity between TMSCs and AMSCs over a 24-hour period (50.8 ± 8.2 vs. 53.8 ± 9.8, p = 0.537). RNA sequencing analysis revealed notable differences in gene expression, with TMSCs showing enrichment in pathways related to extracellular matrix, cell adhesion, and immune response, particularly with upregulation of the MAPK signaling pathway compared with AMSCs. For anti-inflammatory cytokines, IL-33, FOXF1, and HGF were upregulated in TMSCs relative to AMSCs. In relation to proliferation and migration, CCL2, CXCL12, and STC1 levels were also higher in TMSCs. Additionally, TMSCs exhibited increased expression of RAB27B, suggesting a greater potential for exosome release. In a DSS-induced acute colitis model, both TMSCs and AMSCs alleviated colitis symptoms with significant improvements in colon length (p &amp;lt; 0.05). Real-time PCR analysis of mouse colonic tissue also demonstrated a reduction in pro-inflammatory cytokines, such as IL-1β, with TMSCs showing a more pronounced reduction. Conclusion This study demonstrates that TMSCs possess unique characteristics, including a higher proliferation rate and distinct gene expression profiles compared to AMSCs. While both MSC types exhibited similar anti-inflammatory effects in murine colitis model, the enhanced anti-inflammatory potential and increased exosome release capacity of TMSCs, combined with their easy availability, highlight their promise for clinical application.

The role of IFN-γ/CXCL10 axis in Mycoplasma pneumonia infection

Mycoplasma pneumoniae caused lower respiratory tract infection in children and can exacerbate these infections through the production of various inflammatory factors, with chemokines playing a key role. However, the pathogenesis of this infection is complicated and thus has not been thoroughly studied. We clarified that cytokine expression levels were analyzed in both peripheral blood and bronchoalveolar lavage fluid (BALF), and in vitro assays were conducted using THP-1 macrophages. We discovered that, compared to control children, M. pneumoniae pneumonia (MPP) patients expressed significantly higher levels of CXCL10 both in the peripheral blood and BALF. Moreover, numbers of macrophages, predominantly with a M1 phenotype, were significantly increased in BALFs of children of MPP. In vitro, coculture with IFN-γ or activated CD4+ Th1 cells significantly promoted CXCL10 expressions in THP-1 derived macrophages, which was largely reversed by siRNA-mediated down regulation of STAT1. In addition, IFN-γ-stimulated macrophages greatly promoted the trans-migration of Th1 cells. our data show that Th1 cells-derived IFN-γ augments CXCL10 production in macrophages via the JAK-STAT1 pathway, which subsequently recruits more immune cells like Th1 cells into the infection sites, thereby constituting a positive feedback loop and aggravating the type I inflammatory responses in MPP patients.

Circulating chemokine levels and receptor polymorphisms have potential as biomarkers for fibrosis stages in patients with chronic hepatitis C infection.

Chemokines and their receptors, which regulate lymphoid organ development and immune cell trafficking, are integral to the mechanisms underlying viral control, hepatic inflammation, and liver damage in chronic hepatitis C (CHC) infection. This study explores the potential relationship between serum chemokine levels/polymorphisms and hepatitis C infection in affected individuals, with a particular focus on their utility as biomarkers across different stages of fibrosis. Serum levels of the chemokines CXCL11, CXCL12, and CXCL16 were measured in patients with mild/moderate and advanced fibrosis due to CHC, as well as in healthy controls, using the ELISA method. The CXCL12 rs1801157 and CXCL16 rs2277680 polymorphisms were analyzed in blood samples from patients and healthy controls through RT-qPCR. Serum levels of CXCL11, CXCL12, and CXCL16 were significantly elevated in patients with advanced fibrosis compared to healthy controls. Furthermore, CXCL11 levels were markedly higher in patients with advanced fibrosis than in those with mild/moderate fibrosis. The frequency of the CXCL12 rs1801157 AA genotype was significantly higher in the advanced fibrosis group compared to the healthy control group. Similarly, the CXCL16 rs2277680 GA genotype was significantly more prevalent in the advanced fibrosis group than in the mild/moderate fibrosis group. The current study highlights that, in addition to the potential association between chemokine levels/polymorphisms and an increased risk of disease complications and pathological progression in CHC infection, serum CXCL11 levels and the CXCL16 rs2277680 allel polymorphism may be important factors in determining the fibrosis stage of hepatitis C infection.

Betulinic acid mitigates lipopolysaccharide-induced intestinal injury of weaned piglets through modulation of the mitochondrial quality control.

Intestinal injury of weaned piglets often leads to reduced immunity, diarrhea and growth retardation, resulting in significant economic losses to agriculture. Betulinic acid (BA) is a natural plant-derived active ingredient with multiple pharmacological activities including immune modulation and anti-inflammatory. This study was aimed to investigate the potential mechanism that BA as a feed additive mitigated lipopolysaccharide (LPS)-induced intestinal injury in piglets. The results indicated that BA pretreatment improved the morphology and structure of the intestine, enhanced intestinal mucosal barrier function, and activated the PPAR signaling pathway to reduce the mRNA levels of intestinal CD40 and CXCL13. Meanwhile, BA pretreatment improved the LPS-induced disruption of intestinal microbiota by increasing the abundance of the Firmicutes and decreasing the abundance of the Bacteroidota and Proteobacteria. Furthermore, BA pretreatment activated the AMPK/SIRT1/PGC-1α signaling pathway to enhance mitochondrial biogenesis, restored a balance to mitochondrial dynamics, and modulated the PINK1/Parkin, BNIP3 and FUNDC1 signaling pathways to activate mitophagy, thereby alleviating LPS-induced intestinal injury. Overall, the present study elucidated that dietary supplementation with BA could alleviate LPS-induced intestinal injury in weaned piglets by regulating mitochondrial quality control, which provided a novel approach for alleviating intestinal stress in weaned piglets.

Cellular Senescence Contributes to Colonic Barrier Integrity Impairment Induced by Toxoplasma gondii Infection.

Toxoplasma gondii (T. gondii) induces gut barrier integrity impairment, which is crucial to the establishment of long-term infection in hosts. Cellular senescence is an imperative event that drives disease progression. Several studies have indicated that T. gondii induces oxidative stress and cell cycle blockade in the tissues of hosts, suggesting cellular senescence induced by the parasite. Here, we explored whether cell senescence is involved in T. gondii-mediated colonic barrier integrity damage in mice. C57BL/6J mice were infected with 10 cysts of T. gondii. Senolytic therapy (dasatinib and quercetin, DQ, a combination therapy for reducing senescent cells) was given by oral gavage 4weeks post-infection. Alcian blue staining, immunofluorescence, western blot, quantitative PCR (qPCR), and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate the thickness of the colonic mucus layer, the expression profiles of genes and proteins related to tight junction function and cellular senescence in the colonic tissues, and the levels of serum lipopolysaccharides (LPS), respectively. T. gondii-infected mice exhibited deteriorated secreted mucus, shortened length, decreased expression of zonula occludens-1 (ZO-1) and occludin in the colon, accompanied by elevated levels of serum LPS. Moreover, the infection upregulated cell senescence-related markers (p16INK4A, p21CIP1) while inhibiting Lamin B1 expression. In addition, the expression levels of senescence-associated secretory phenotypes (SASPs), including IL-1β, TNF-α, IL-6, MMP9 and CXCL10, were upregulated post-infection. Notably, reducing cell senescence with DQ administration, significantly ameliorated the colonic pathological alterations induced by T. gondii infection. This study uncovers for the first time that cellular senescence contributes to the colonic barrier integrity damage induced by chronic T. gondii infection. Importantly, we provide evidence that senolytic therapy exerts a therapeutic effect on the intestinal pathological lesions.

Elevated CXCL1 triggers dopaminergic neuronal loss in the substantia nigra of C57BL/6J mice: Evaluation of a novel Parkinsonian mouse model.

Substantial evidence points to the early onset of peripheral inflammation in the development of Parkinson's disease (PD), supporting the "body-first" hypothesis. However, there remains a notable absence of PD-specific animal models induced by inflammatory cytokines. This study introduces a novel mouse model of PD driven by the proinflammatory cytokine CXCL1, identified in our previous research. The involvement of CXCL1 in PD pathogenesis was validated using subacute and chronic MPTP-induced mouse models. Based on these findings, 2-month-old C57BL/6J mice were intravenously administered CXCL1 (20 ng/kg/day) for 2 weeks (5 days per week), successfully replicating motor deficits and pathological alterations in the substantia nigra observed in the chronic MPTP model. These results demonstrate the potential of CXCL1-induced inflammation as a mechanism for PD modeling. The model revealed activation of the PPAR signaling pathway in CXCL1-mediated neuronal damage by CXCL1. Linoleic acid, a PPAR-γ activator, significantly mitigated MPTP- and CXCL1-induced toxicity and reduced serum CXCL1 levels. In addition, the CXCL1-injected mouse model shortened the timeline for developing chronic PD mouse model to 2 weeks, offering an efficient platform for studying inflammation-driven processes in PD. The findings provide critical insights into the inflammatory mechanisms underlying PD and identify promising therapeutic targets for intervention.

Constructing the Well Regenerated Decellularized Adipose Tissue Using External Volume Expansion Device.

External volume expansion (EVE) devices has been demonstrated to enhance the survival of fat grafts. Decellularized adipose tissue (DAT) serves as a promising scaffold for adipose regeneration; however, the effectiveness of adipose regeneration in DAT remains limited, and the underlying mechanisms of its regeneration require further investigation. This study explores the potential of EVE technology to enhance DAT-mediated adipogenesis by facilitating cellular recruitment and establishing a microenvironment conducive to adipose tissue regeneration. DAT was injected into the dorsal area of rats, followed by daily treatment with an EVE suction device for 10 hours per day over 14 days. Control groups underwent transplantation without suction. After the treatment period, tissue samples were collected and analyzed. This included volume measurement, H&E staining, immunofluorescence staining for CD34, CD90, CD68, CD31, and perilipin, electron microscopy for microscopic analysis, and ELISA analysis for IL1, TNFα, CCL2, and CXCL12. Fourteen days post-transplantation, the volume of DAT significantly increased in the EVE group compared to the control group. Histological H&E staining revealed a higher peripheral region in the EVE group. Electron microscopy examination showed that EVE suction led to increased porosity in the DAT material, with a greater number of cells adhering to the material. Immunofluorescence staining for CD34/CD90 adipose-derived stem cells also showed a significant increase in the EVE group. The presence of CD68-positive macrophages increased after EVE suction. Evaluation of vascularization using CD31 staining showed a higher level of vascularization in the EVE group compared to the control group. ELISA analysis of IL-1, TNF-α, CCL2, and CXCL12 levels demonstrated that the EVE group effectively increased the levels of adipogenic factors within the DAT. EVE enhances DAT-mediated adipogenesis by promoting stem cell recruitment, macrophage activation, and adipogenesis-related cytokine expression, ultimately improving the regeneration of functional adipose tissue. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

CXCL13 levels in cerebrospinal fluid in relapsing-remitting multiple sclerosis: The role of Borrelia in neuroinfections.

This study was compared the Borrelia antibodies and chemokine ligand 13 (CXCL13) levels in cerebrospinal fluid (CSF) samples from cases diagnosed with relapsing-remitting multiple sclerosis (RRMS), radiologically isolated syndrome (RIS), and pseudotumour cerebri (PTC). A total of 43 CSF samples were collected from patients diagnosed with RRMS, RIS and PTC. We prospectively investigated Borrelia IgG and IgM antibodies in the CSF samples of the cases by enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) method, and CXCL13 levels by ELISA. Data were statistically analysed using the the Spearman rank correlation test. Five antigens (protein 19, 20, 21, 58, and outer surface protein C (OspC)) were positive due to confirmation of the positive samples for Borrelia antibodies by the WB method. There were no significant differences in CSF CXCL13 levels between the three groups. The CXCL13 level was found to be statistically higher in the demyelinating group compared to the PTC group (p=0.001). The Borrelia antibodies were found positive in CSF samples of RRMS patients. The coexistence of high CXCL13 (may be a potential biomarker) suggests that LNB may also play a role in the etiopathogenesis of RRMS. In addition, the positive detection of OspC and p58 WB bands in most cases suggests that these protein bands can be used as in the differential diagnosis of neurodegenerative diseases and Lyme disease.

Imbalanced VWF-ADAMTS13 axis contributes to the detrimental impact of a preceding respiratory tract infection on stroke.

Respiratory tract infections (RTIs) caused by bacteria or viruses are associated with stroke severity. Recent studies have revealed an imbalance in the von Willebrand factor (VWF)-ADAMTS13 axis in patients with RTIs, including COVID-19. We examined whether this imbalance contributes to RTI-mediated stroke severity. Wild-type (WT), Vwf -/-, or Adamts13-/- mice with respective littermate controls (Vwf +/+, or Adamts13+/+) were infected intranasally with sublethal doses of S. aureus (on days 0, 2, and 5) or mouse-adapted SARS-CoV-2 (on day 0) and subjected to transient (30 or 45 min) cerebral ischemia followed by reperfusion. In S. aureus-infected mice, infarct volumes were assessed on day 2 and functional outcomes on weeks 1 and 4 post-reperfusion. In SARS-CoV-2-infected mice, infarct volumes and functional outcomes (Bederson score) were assessed on day 1 post-reperfusion. We demonstrated that S. aureus or SARS-CoV-2 RTI was accompanied by an imbalance in the VWF-ADAMTS13 axis and an increase in plasma levels of IL-6, CXCL1, and MCP-1, which was associated with larger infarcts and worse functional outcomes (P<0.05 vs. mock-infection). S. aureus- or SARS-CoV-2-infected Vwf -/- mice exhibited reduced infarcts and improved functional outcomes, while infected Adamts13-/- mice displayed greater stroke severity (P<0.05 vs. control). In the models of RTI preceding stroke, VWF contributes to stroke severity, while ADAMTS13 is protective.

CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection.

Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells. CXCL12 levels were negatively correlated with LDN numbers in longitudinal analyses of patient blood samples. CXCL12 blockade in SARS-CoV-2-infected mice increased blood/lung neutrophil numbers thereby accelerating disease progression without changing lung virus titers. The exaggerated mortality caused by CXCL12 blockade can be reversed by neutrophil depletion. In addition, blocking interactions between SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) reduced CXCL12 levels, suggesting a signal transduction from virus-mediated ACE2 ligation to increased CXCL12 secretion. Collectively, these results demonstrate a previously unappreciated role of CXCL12 in diminishing neutrophilia, including low density neutrophilia, and its deleterious effects in SARS-CoV-2 infections. The results also support the involvement of SARS-CoV-2-endothelial cell interactions in viral pathogenesis.

CXCL5 as a biomarker for early diagnosis and prognosis of sepsis: A comprehensive clinical evaluation.

Sepsis, a critical condition caused by a dysregulated host response to infection, has high morbidity and mortality rates. Timely diagnosis and treatment are vital for improving patient outcomes. This study explores the potential role of CXCL5 in the diagnosis, severity assessment, and prognosis of sepsis. We included 147 sepsis patients, 50 patients with systemic inflammatory response syndrome (SIRS) and 120 healthy controls. Serum CXCL5 levels, inflammation scores (APACHE II, SOFA), and other laboratory indicators were recorded. Univariate and multivariate logistic regression analyses were conducted to assess the relationship between CXCL5 and sepsis diagnosis, severity, and prognosis. A prognostic nomogram was constructed and evaluated using receiver operator characteristic curves, calibration curves, and clinical decision curves. Serum CXCL5 levels in sepsis patients were significantly higher than those in patients with SIRS and healthy controls. CXCL5 was identified as a risk factor for sepsis diagnosis. CXCL5 levels were significantly elevated in patients with septic shock (P=0.04) and in deceased patients compared to survivors (P<0.001). The prognostic model, incorporating CXCL5, lactate, APACHE II scores, C-reactive protein levels, and respiratory rate, demonstrated high predictive accuracy with an area under the curve of 0.873. Calibration and decision curve analyses demonstrated the model's good predictive performance and potential clinical value. Serum CXCL5 concentration is a promising biomarker for enhancing the diagnostic accuracy and prognostic evaluation of sepsis. The constructed multivariate prediction model offers new insights into sepsis prognosis, but its direct application in clinical practice requires further validation.