Chemokine Activity Research Articles

Neuronal cathepsin S increases neuroinflammation and causes cognitive decline via CX3CL1-CX3CR1 axis and JAK2-STAT3 pathway in aging and Alzheimer's disease.

Aging is an intricate process involving interactions among multiple factors, which is one of the main risks for chronic diseases, including Alzheimer's disease (AD). As a member of cysteine protease, cathepsin S (CTSS) has been implicated in inflammation across various diseases. Here, we investigated the role of neuronal CTSS in aging and AD started by examining CTSS expression in hippocampus neurons of aging mice and identified a significant increase, which was negatively correlated with recognition abilities. Concurrently, we observed an elevation of CTSS concentration in the serum of elderly people. Transcriptome and fluorescence-activated cell sorting (FACS) results revealed that CTSS overexpression in neurons aggravated brain inflammatory milieu with microglia activation to M1 pro-inflammatory phenotype, activation of chemokine C-X3-C-motif ligand 1 (CX3CL1)-chemokine C-X3-C-motif receptor 1 (CX3CR1) axis and janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway. As CX3CL1 is secreted by neurons and acts on the CX3CR1 in microglia, our results revealed for the first time the role of neuron CTSS in neuron-microglia "crosstalk." Besides, we observed elevated CTSS expression in multiple brain regions of AD patients, including the hippocampus. Utilizing CTSS selective inhibitor, LY3000328, rescued AD-related pathological features in APP/PS1 mice. We further noticed that neuronal CTSS overexpression increased cathepsin B (CTSB) activity, but decreased cathepsin L (CTSL) activity in microglia. Overall, we provide evidence that CTSS can be used as an aging biomarker and plays regulatory roles through modulating neuroinflammation and recognition in aging and AD process.

ROLE OF CASPASE-1/CASPASE-11-HMGB1-RAGE/TLR4 SIGNALING IN THE EXACERBATION OF EXTRAPULMONARY SEPSIS INDUCED LUNG INJURY BY MECHANICAL VENTILATION.

Mechanical ventilation (MV) is a clinically important measure for respiratory support in critically ill patients. Although moderate tidal volume MV does not cause lung injury, it can further exacerbate lung injury in pathological state such as sepsis. This pathological process is known as the 'two-hit' theory, whereby an initial lung injury (e.g., infection, trauma, or sepsis) triggers an inflammatory response that activates immune cells, presenting the lung tissue in a fragile state and rendering it more susceptible to subsequent injury. The second hit occurs when mechanical ventilation is applied to lung tissue in a fragile state, and it is noteworthy that this mechanical ventilation is harmless to healthy lung tissue, further aggravating pre-existing lung injury through unknown mechanisms. This interaction between initial injury and subsequent mechanical ventilation develops a malignant cycle significantly exacerbating lung injury and severely hampering patient prognosis. The two-hit theory is critical to understanding the complicated mechanisms of ventilator-associated lung injury and facilitates the subsequent development of targeted therapeutic strategies. CLP mice model was used to mimic clinical sepsis patients. After 12 hours the mice were mechanical ventilated for 2-6 hours. MV by itself didn't lead to HMGB1 release, but significantly strengthened HMGB1 in plasma and cytoplasm of lung tissue in septic mice. Plasma and lung tissue activation of cytokines and chemokines, MAPK signaling pathway, neutrophil recruitment, and ALI were progressively decreased in LysM HMGB1-/- (Hmgb1 deletion in myeloid cells) and iHMGB1-/- mice (inducible HMGB1-/- mouse strain where the Hmgb1 gene was globally deleted after tamoxifen treatment). Compared with C57BL/6 mice, although EC-HMGB1-/- (Hmgb1 deletion in endothelial cells) mice didn't have lower levels of inflammation, neutrophil recruitment and lung injury were reduced. Compared with LysM HMGB1-/- mice, EC-HMGB1-/- mice had higher levels of inflammation but significantly lower neutrophil recruitment and lung injury. Overall, iHMGB1-/- mice had the lowest levels of all the above indicators. The level of inflammation, neutrophil recruitment and the degree of lung injury were decreased in RAGE-/- mice, and even the above indices were further decreased in TLR4/RAGE-/- mice. Levels of inflammation and neutrophil recruitment were decreased in Caspase-11-/- and Caspase-1/11-/- mice, but no statistical difference between these two gene knockout mice. These data show for the first time that the Caspase-1/Caspase-11-HMGB1-TLR4/RAGE signaling pathway plays a key role in mice model of sepsis induced lung injury exacerbated by MV. Different species of HMGB1 knockout mice have different lung protective mechanisms in the 'two hits' model, and location is the key to function. Specifically, LysM HMGB1-/- mice due to the deletion of HMGB1 in myeloid cells resulted in a pulmonary protective mechanism that was associated with a downregulation of the inflammatory response. EC HMGB1-/- mice are deficient in HMGB1 owing to endothelial cells, resulting in a distinct pulmonary protective mechanism independent of the inflammatory response and more relevant to the improvement of alveolar-capillary permeability. iHMGB1-/- mice, which are systemically HMGB1-deficient, share both of these lung-protective mechanisms.

Exploring shared mechanisms between ulcerative colitis and psoriasis and predicting therapeutic natural compounds through bioinformatics and molecular docking

IntroductionPrevious studies have suggested a potential correlation between psoriasis (PS) and ulcerative colitis (UC). However, studies exploring the shared mechanisms of both diseases remain limited. Current treatments primarily involve using immunosuppressive drugs, which can lead to potential side effects and drug resistance. Traditional Chinese medicine has demonstrated favorable efficacy in treating UC and PS with fewer side effects. This study aims to elucidate the shared biological mechanisms underlying UC and PS and to predict natural compounds effective for treating both disorders. MethodWe collected and validated differentially expressed genes associated with UC and PS from the Gene Expression Omnibus database. A protein-protein interaction network was constructed using the STRING database, aiding in identifying core targets. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were utilized to analyze the functions and genomic enrichment of the identified core targets. The CIBERSORT method was employed to assess the correlation of core targets with immune cells. Compounds with potential therapeutic values were selected from the Coremine and TCMSP databases, and their therapeutic efficacy was predicted via molecular docking. ResultsIn UC and PS, 20 common core targets were identified, with matrix metalloproteinase 9 (MMP9), matrix metalloproteinase 1 (MMP1), cluster of differentiation 274 (CD274), C-X-C motif chemokine ligand 10 (CXCL10), and topoisomerase II alpha (TOP2A) emerging as the most relevant targets shared between both conditions. Elevated levels of macrophages and dendritic cells were observed in UC and PS, with CXCL10 exhibiting the closest association with macrophages. UC and PS shared common signaling pathways, including IL-17, TNF, and chemokine signaling pathways, among others. Molecular docking revealed that quercetin, baicalen, irisolidone, rutaecarpine, epigallocatechin-3-gallate, and others held potential as natural compounds for treating both disorders. ConclusionMMP9, MMP1, and CXCL10, central mediators in the inflammatory pathways of UC and PS, establish a shared mechanism by triggering cytokine and chemokine activation, leading to tissue damage and positioning them as promising therapeutic targets for both conditions. Compounds such as quercetin, luteolin, irisolidone, rutaecarpine, and so on may be key drugs for treating both conditions. These findings suggest the potential advancement of therapeutic strategies and the enhancement of patient care by exploring shared mechanisms and predicting promising natural compounds for treating UC and PS.

Duodenal transcriptomics demonstrates signatures of tissue inflammation and immune cell infiltration in children with environmental enteric dysfunction across global centers

BackgroundEnvironmental enteric dysfunction (EED) is an inflammatory condition of the small intestine that is prevalent in children residing in low- and middle-income countries. EED is accompanied by profound histopathologic changes in the small bowel, loss of absorptive capacity, increased intestinal permeability, increased microbial translocation, and nutrient loss. ObjectivesWe sought to identify dysregulated genes and pathways that might underlie pediatric EED. MethodsRNA-sequencing libraries were generated from endoscopically obtained duodenal tissue from undernourished children with EED from 3 prospective cohorts of children with EED. The EED transcriptome was defined in comparison to North American children without EED. Weighted gene coexpression network analysis (WGCNA) was tested for gene modules associated with EED and its histologic features. ResultsThe 1784 upregulated genes in EED were highly enriched for immune and inflammatory processes, including IL-17 and JAK-STAT signaling, and cytokine–cytokine receptor interactions. The 1388 downregulated genes included genes corresponding to xenobiotic metabolism, detoxification, and antioxidant capacities. A gene coexpression module enriched for antimicrobial responses and chemokine activity was significantly associated with villous blunting, goblet cell depletion, and overall histologic severity of EED. ConclusionsThe transcriptome signatures of EED include specific innate and adaptive immune responses that are consistently elevated across study centers, coupled with reduced detoxification and antioxidant capacities. These data may have implications for targeted interventions to improve EED outcomes.

New perspectives on chemokines in hepatocellular carcinoma therapy: a critical pathway for natural products regulation of the tumor microenvironment.

Hepatocellular carcinoma (HCC) is one of the most common primary neoplasms of the liver and one of the most common solid tumors in the world. Its global incidence is increasing and it has become the third leading cause of cancer-related deaths. There is growing evidence that chemokines play an important role in the tumor microenvironment, regulating the migration and localization of immune cells in tissues and are critical for the function of the immune system. This review comprehensively analyses the expression and activity of chemokines in the TME of HCC and describes their interrelationship with hepatocarcinogenesis and progression. Special attention is given to the role of chemokine-chemokine receptors in the regulation of immune cell accumulation in the TME. Therapeutic strategies targeting tumor-promoting chemokines or the induction/release of beneficial chemokines are reviewed, highlighting the potential value of natural products in modulating chemokines and their receptors in the treatment of HCC. The in-depth discussion in this paper provides a theoretical basis for the treatment of HCC. It is an important reference for new drug development and clinical research.

Chemokines Kill Bacteria by Binding Anionic Phospholipids without Triggering Antimicrobial Resistance.

Classically, chemokines coordinate leukocyte trafficking during immune responses; however, many chemokines have also been reported to possess direct antibacterial activity in vitro. Yet, the bacterial killing mechanism of chemokines and the biochemical properties that define which members of the chemokine superfamily are antimicrobial remain poorly understood. Here we report that the antimicrobial activity of chemokines is defined by their ability to bind phosphatidylglycerol and cardiolipin, two anionic phospholipids commonly found in the bacterial plasma membrane. We show that only chemokines able to bind these two phospholipids kill Escherichia coli and Staphylococcus aureus and that they exert rapid bacteriostatic and bactericidal effects against E. coli with a higher potency than the antimicrobial peptide beta-defensin 3. Furthermore, our data support that bacterial membrane cardiolipin facilitates the antimicrobial action of chemokines. Both biochemical and genetic interference with the chemokine-cardiolipin interaction impaired microbial growth arrest, bacterial killing, and membrane disruption by chemokines. Moreover, unlike conventional antibiotics, E. coli failed to develop resistance when placed under increasing antimicrobial chemokine pressure in vitro. Thus, we have identified cardiolipin and phosphatidylglycerol as novel binding partners for chemokines responsible for chemokine antimicrobial action. Our results provide proof of principle for developing chemokines as novel antibiotics resistant to bacterial antimicrobial resistance mechanisms.

Bioinformatics analysis of potential pathogenesis and risk genes of neuroinflammation-promoted brain injury in intracerebral hemorrhage

IntroductionSpontaneous (non-traumatic) intracerebral hemorrhage (ICH) is one of the major causes of global death. The purpose of our bioinformatics analysis was to detect viable pathophysiological targets and small-molecule drug candidates and to identify the precise secondary mechanisms of brain injury in ICH. Material and methodsThe GSE24265 dataset, consisting of data from four perihematomal brain tissues and seven contralateral brain tissues, was downloaded from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (DEGs) in ICH. Online analysis tool GEO2R and Drug Susceptibility Assessment Module within the ACBI Bioinformation tool was used for data differential expression analysis. TargetScan, miRDB, and RNA22 were used to investigate the miRNAs regulating the DEGs. The functional annotation of DEGs was performed using Gene Ontology (GO) resources, and the cell signaling pathway analysis of DEGs was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG). DAVID is used to perform GO function enrichment analysis and KEGG pathway analysis of candidate target genes. Enrichment analysis was performed for delving the molecular mechanism of DEGs, and protein–protein interaction (PPI) networks and microRNA (miRNA)-messenger RNA (mRNA) networks were used to reveal the hub nodes and the related interaction relationships. Hub genes and miRNA-mRNA interaction of PPI network were identified by STRING version 12.0 online software and Cytoscape. Next, the DEGs were analyzed using the L1000CDS2 database to identify small-molecule compounds with potential therapeutic effects. ResultsA total of 325 upregulated genes and 103 downregulated genes associated with ICH were identified. The biological functions of DEGs associated with ICH are mainly involved in the inflammatory response, chemokine activity, and immune response. The KEGG analysis identified several pathways significantly associated with ICH, including but not limited to cytokine-cytokine receptor interaction and MAPK signaling pathway. A PPI network consisting of 188 nodes and 563 edges was constructed using STRING, and 27 hub genes were identified with Cytoscape software. The miRNA-mRNA network with high connectivity contained key 27 mRNAs (from C-C motif chemokine ligand 5 (CCL5), C-C motif chemokine ligand 8 (CCL8), …., to dishevelled-associated activator of morphogenesis 1 (DAAM1), and FRAT regulator of WNT signaling pathway 1 (FRAT1)) and 135 candidate miRNAs. These genes and miRNAs are closely related to secondary brain injury induced by ICH. In addition, a L1000CDS2 analysis of six small-molecule compounds revealed their therapeutic potential. ConclusionsOur study explores the pathogenesis of brain tissue injury promoted by neuroinflammation in ICH and extends the clinical utility of its key genes. At the same time, we constructed a miRNA-mRNA network which may play crucial roles in the pathogenesis of ICH. In addition, we obtained six small molecule compounds that will have anti-inflammatory effects on ICH, including Geldanamycin, Dasatinib, BMS-345541, Saracatinib, and Afatinib.

Poxvirus Immune Evasion

Poxviruses have evolved a wide array of mechanisms to evade the immune response, and we provide an overview of the different immunomodulatory strategies. Poxviruses prevent the recognition of viral DNA that triggers the immune responses and inhibit signaling pathways within the infected cell. A unique feature of poxviruses is the production of secreted proteins that mimic cytokines and cytokine receptors, acting as decoy receptors to neutralize the activity of cytokines and chemokines. The capacity of these proteins to evade cellular immune responses by inhibiting cytokine activation is complemented by poxviruses’ strategies to block natural killer cells and cytotoxic T cells, often through interfering with antigen presentation pathways. Mechanisms that target complement activation are also encoded by poxviruses. Virus-encoded proteins that target immune molecules and pathways play a major role in immune modulation, and their contribution to viral pathogenesis, facilitating virus replication or preventing immunopathology, is discussed.

CD56-mediated activation of human natural killer cells is triggered by Aspergillus fumigatus galactosaminogalactan.

Invasive aspergillosis causes significant morbidity and mortality in immunocompromised patients. Natural killer (NK) cells are pivotal for antifungal defense. Thus far, CD56 is the only known pathogen recognition receptor on NK cells triggering potent antifungal activity against Aspergillus fumigatus. However, the underlying cellular mechanisms and the fungal ligand of CD56 have remained unknown. Using purified cell wall components, biochemical treatments, and ger mutants with altered cell wall composition, we herein found that CD56 interacts with the A. fumigatus cell wall carbohydrate galactosaminogalactan (GAG). This interaction induced NK-cell activation, degranulation, and secretion of immune-enhancing chemokines and cytotoxic effectors. Supernatants from GAG-stimulated NK cells elicited antifungal activity and enhanced antifungal effector responses of polymorphonuclear cells. In conclusion, we identified A. fumigatus GAG as a ligand of CD56 on human primary NK cells, stimulating potent antifungal effector responses and activating other immune cells.

Tumor-Derived Exosomal miR-143-3p Induces Macrophage M2 Polarization to Cause Radiation Resistance in Locally Advanced Esophageal Squamous Cell Carcinoma.

We aimed to determine whether monitoring tumor-derived exosomal microRNAs (miRNAs) could be used to assess radiotherapeutic sensitivity in patients with locally advanced esophageal squamous cell carcinoma (ESCC). RNA sequencing was employed to conduct a comparative analysis of miRNA expression levels during radiotherapy, focusing on identifying miRNAs associated with progression. Electron microscopy confirmed the existence of exosomes, and co-cultivation assays and immunofluorescence validated their capacity to infiltrate macrophages. To determine the mechanism by which exosomal miR-143-3p regulates the interplay between ESCC cells and M2 macrophages, ESCC cell-derived exosomes were co-cultured with macrophages. Serum miR-143-3p and miR-223-3p were elevated during radiotherapy, suggesting resistance to radiation and an unfavorable prognosis for ESCC. Increased levels of both miRNAs independently predicted shorter progression-free survival (p = 0.015). We developed a diagnostic model for ESCC using serum microRNAs, resulting in an area under the curve of 0.751. Radiotherapy enhanced the release of miR-143-3p from ESCC cell-derived exosomes. Immune cell infiltration analysis at the Cancer Genome Atlas (TCGA) database revealed that ESCC cell-derived miR-143-3p triggered M2 macrophage polarization. Mechanistically, miR-143-3p upregulation affected chemokine activity and cytokine signaling pathways. Furthermore, ESCC cell exosomal miR-143-3p could be transferred to macrophages, thereby promoting their polarization. Serum miR-143-3p and miR-223-3p could represent diagnostic and prognostic markers for patients with ESCC undergoing radiotherapy. Unfavorable prognosis could be linked to the increased levels of ESCC cell-derived exosomal miR-143-3p, which might promote tumor progression by interacting with macrophages.

Exploring shared molecular signatures and regulatory mechanisms in nonalcoholic steatohepatitis and inflammatory bowel disease using integrative bioinformatics analysis.

The co-existence of inflammatory bowel disease (IBD) and non-alcoholic steatohepatitis (NASH) has raised interest in identifying shared molecular mechanisms and potential therapeutic targets. However, the relationship between these two diseases remains unclear and effective medical treatments are still lacking. Through the bioinformatics analysis in this study, 116 shared differentially expressed genes (SDEGs) were identified between IBD and NASH datasets. GO and KEGG pathway analyses revealed significant involvement of SDEGs in apoptotic processes, cell death, defense response, cytokine and chemokine activity, and signaling pathways. Furthermore, weighted gene co-expression network analysis (WGCNA) identified five shared signature genes associated specifically with IBD and NASH, they were CXCL9, GIMAP2, ADAMTS5, GRAP, and PRF1. These five genes represented potential diagnostic biomarkers for distinguishing patients with diseases from healthy individuals by using two classifier algorithms and were positively related to autophagy, ferroptosis, angiogenesis, and immune checkpoint factors in the two diseases. Additionally, single-cell analysis of IBD and NASH samples highlighted the expression of regulatory genes in various immune cell subtypes, emphasizing their significance in disease pathogenesis. Our work elucidated the shared signature genes and regulatory mechanisms of IBD and NASH, which could provide new potential therapies for patients with IBD and NASH.

Identification and validation of core genes associated with intracranial aneurysms through bioinformatics analysis and Mendelian randomization

Intracranial aneurysms (IAs) often go undetected until rupture, leading to significant morbidity and mortality. Identifying biomarkers for early detection of IAs is crucial. The current study attempted to identify core genes linked with IAs and determine their relevance through Mendelian randomization. Limma helped identify differentially expressed genes between IAs and control superficial temporal artery samples. WGCNA was utilized to find IA-related modules and associated genes, which were further evaluated using KEGG and GO analyses to ascertain their potential roles. Five highly associated genes were screened with the CytoHubba plugin of Cytoscape software. ROC curves assessed the diagnostic efficacy of these genes. A two-sample Mendelian randomization evaluated the causal relationship between the core gene PTRPC and IAs, along with its correlation with immune infiltration. WGCNA and differential expression analysis depicted 584 related genes involved in cellular metabolism and chemokine activity. PTPRC was among the top highly associated genes identified through Cytoscape. It showed significant diagnostic value for IAs. Moreover, mendelian randomization depicted that PTPRC in CD4+ T cells is related to IA risk, with an OR of 0.63538 (95 % CI = 0.41636–0.96959, p = 0.03545). No reverse causal relationship was observed between PTPRC and IAs, with an OR of 0.99947 (95 % CI = 0.99719–1.00176, p = 0.65022). Additionally, immune cell infiltration results indicated a positive correlation between PTPRC in IAs with neutrophils and unactivated dendritic cells and a negative association with regulatory T cells (Tregs). PTPRC was identified as a core gene linked with IAs, providing evidence for IA diagnosis and studying molecular mechanisms.

Atypical chemokine receptors in the immune system.

Leukocyte migration is a fundamental component of innate and adaptive immune responses as it governs the recruitment and localization of these motile cells, which is crucial for immune cell priming, effector functions, memory responses and immune regulation. This complex cellular trafficking system is controlled to a large extent via highly regulated production of secreted chemokines and the restricted expression of their membrane-tethered G-protein-coupled receptors. The activity of chemokines and their receptors is also regulated by a subfamily of molecules known as atypical chemokine receptors (ACKRs), which are chemokine receptor-like molecules that do not couple to the classical signalling pathways that promote cell migration in response to chemokine ligation. There has been a great deal of progress in understanding the biology of these receptors and their functions in the immune system in the past decade. Here, we describe the contribution of the various ACKRs to innate and adaptive immune responses, focussing specifically on recent progress. This includes recent findings that have defined the role for ACKRs in sculpting extracellular chemokine gradients, findings that broaden the spectrum of chemokine ligands recognized by these receptors, candidate new additions to ACKR family, and our increasing understanding of the role of these receptors in shaping the migration of innate and adaptive immune cells.

Revealing biomarkers and major pathways between SARS-CoV-2 and SARS-like viruses using transcriptomics analysis

SARS-CoV-2 is the causative agent of Coronavirus Disease 2019 (COVID-19). It is common for patients with COVID-19 to present with fatigue, fever, cough, loss of taste and smell, headache, and other clinical manifestations. Several studies have proved that the transmission pathogenicity, genetic patterns of SARS and SARS-CoV-2 are very similar. In this study, we attempted to investigate the transcriptional signature of SARS-CoV-2 infection, with SARS virus. Differentially expressed genes (DEG) were identified through analyzing three datasets (GSE147507, GSE17400, and GSE150316). After identification the common DEG between each dataset were applied for pathways as well as gene ontology analysis to comprehend their compatibility. These common DEGs were also employed to generate the protein-protein interaction network, gene regulatory network, and gene co-expression network. The networks illustrated, how genes are regulated by various transcription factors and miRNAs. Overexpression's of many genes are linked to comorbid disorders, malignant cell growth, inflammatory cytokine, and chemokine activation. Finally, some drugs were predicted based on these highly expressed genes, which may have a significant impact on reducing the burden of these diseases in the future.

Assessing Bioprinted Functionalized Grafts for Biological Tendon Augmentation In Vitro.

Tendinopathy, characterized by inflammatory and degenerative changes, presents challenges in sports and medicine. In addressing the limitations of conservative management, this study focuses on developing tendon grafts using extrusion bioprinting with platelet-rich plasma (PRP)-infused hydrogels loaded with tendon cells. The objective is to understand paracrine interactions initiated by bioprinted tendon grafts in either inflamed or non-inflamed host tissues. PRP was utilized to functionalize methacrylate gelatin (GelMA), incorporating tendon cells for graft bioprinting. Bioinformatic analyses of overexpressed proteins, predictive of functional enrichment, revealed insights into PRP graft behavior in both non-inflamed and inflamed environments. PRP grafts activated inflammatory pathways, including Interleukin 17 (IL-17), neuroinflammation, Interleukin 33 (IL-33), and chemokine signaling. Interleukin 1 beta (IL-1b) in the graft environment triggered p38 mitogen-activated protein kinase (MAPK) signaling, nuclear factor kappa light chain enhancer of activated B cells (NF-kB) canonical pathway, and Vascular Endothelial Growth Factor (VEGF) signaling. Biological enrichment attributed to PRP grafts included cell chemotaxis, collagen turnover, cell migration, and angiogenesis. Acellular PRP grafts differed from nude grafts in promoting vessel length, vessel area, and junction density. Angiogenesis in cellular grafts was enhanced with newly synthesized Interleukin 8 (IL-8) in cooperation with IL-1b. In conclusion, paracrine signaling from PRP grafts, mediated by chemokine activities, influences cell migration, inflammation, and angiogenic status in host tissues. Under inflammatory conditions, newly synthesized IL-8 regulates vascularization in collaboration with PRP.

Obesity-related inflammatory protein signature in cardiovascular clinical outcomes: results from the Gutenberg Health Study.

The objective of this study was to investigate whether an obesity-related inflammatory protein signature (OIPS) is associated with adverse cardiovascular events. The Olink Target 96 Inflammation panel was performed in 6662 participants from the population-based Gutenberg Health Study (GHS). The OIPS was selected by a logistic regression model, and its association with cardiovascular outcomes was evaluated by Cox regression analysis. The GHS-derived OIPS was externally validated in the MyoVasc study. The identified OIPS entailed 21 proteins involved in chemokine activity, tumor necrosis factor (TNF) receptor binding, and growth factor receptor binding. The signature revealed a novel positive association of axis inhibition protein 1 with obesity. The OIPS was associated with increased risk of all-cause and cardiac deaths, major adverse cardiovascular events, and incident coronary artery disease, independent of clinical covariates and established risk instruments. A BMI-stratified analysis confirmed the association of OIPS with increased death in those with obesity and overweight and with increased risk for coronary artery disease in those with obesity. The association of OIPS with increased risk of all-cause and cardiac deaths was validated in the MyoVasc cohort. The OIPS showed a significant association with adverse clinical outcomes, particularly in those with overweight and obesity, and represents a promising tool for identifying patients at higher risk for worse cardiovascular outcomes.

Galectin-8-like isoform X1 mediates antibacterial, antiviral, and antioxidant responses in red-lip mullet (Planiliza haematocheilus) through positive modulation of pro-inflammatory cytokine, chemokine, and enzymatic antioxidant activity

Galectin 8 belongs to the tandem repeat subclass of the galectin superfamily. It possesses two homologous carbohydrate recognition domains linked by a short peptide and preferentially binds to β-galactoside-containing glycol-conjugates in a calcium-independent manner. This study identified Galectin-8-like isoform X1 (PhGal8X1) from red-lip mullet (Planiliza haematocheilus) and investigated its role in regulating fish immunity. The open reading frame of PhGal8X1 was 918bp, encoding a soluble protein of 305 amino acids. The protein had a theoretical isoelectric (pI) point of 7.7 and an estimated molecular weight of 34.078 kDa. PhGal8X1 was expressed in various tissues of the fish, with prominent levels in the brain, stomach, and intestine. PhGal8X1 expression was significantly (p < 0.05) induced in the blood and spleen upon challenge with different immune stimuli, including polyinosinic:polycytidylic acid, lipopolysaccharide, and Lactococcus garvieae. The recombinant PhGal8X1 protein demonstrated agglutination activity towards various bacterial pathogens at a minimum effective concentration of 50 μg/mL or 100 μg/mL. Subcellular localization observations revealed that PhGal8X1 was primarily localized in the cytoplasm. PhGal8X1 overexpression in fathead minnow cells significantly (p < 0.05) inhibited viral hemorrhagic septicemia virus (VHSV) replication. The expression levels of four proinflammatory cytokines and two chemokines were significantly (p < 0.05) upregulated in PhGal8X1 overexpressing cells in response to VHSV infection. Furthermore, overexpression of PhGal8X1 exhibited protective effects against oxidative stress induced by H2O2 through the upregulation of antioxidant enzymes. Taken together, these findings provide compelling evidence that PhGal8X1 plays a crucial role in enhancing innate immunity and promoting cell survival through effective regulation of antibacterial, antiviral, and antioxidant defense mechanisms in red-lip mullet.

Immunomodulatory effects of hydatid antigens on mesenchymal stem cells: gene expression alterations and functional consequences.

Cystic echinococcosis, caused by the larval stage of Echinococcus granulosus, remains a global health challenge. Mesenchymal stem cells (MSCs) are renowned for their regenerative and immunomodulatory properties. Given the parasite's mode of establishment, we postulate that MSCs likely play a pivotal role in the interaction between the parasite and the host. This study aims to explore the response of MSCs to antigens derived from Echinococcus granulosus, the etiological agent of hydatid disease, with the hypothesis that exposure to these antigens may alter MSC function and impact the host's immune response to the parasite. MSCs were isolated from mouse bone marrow and co-cultured with ESPs, HCF, or pLL antigens. We conducted high-throughput sequencing to examine changes in the MSCs' mRNA expression profile. Additionally, cell cycle, migration, and secretory functions were assessed using various assays, including CCK8, flow cytometry, real-time PCR, Western blot, and ELISA. Our analysis revealed that hydatid antigens significantly modulate the mRNA expression of genes related to cytokine and chemokine activity, impacting MSC proliferation, migration, and cytokine secretion. Specifically, there was a downregulation of chemokines (MCP-1, CXCL1) and pro-inflammatory cytokines (IL-6, NOS2/NO), alongside an upregulation of anti-inflammatory mediators (COX2/PGE2). Furthermore, all antigens reduced MSC migration, and significant alterations in cellular metabolism-related pathways were observed. Hydatid disease antigens induce a distinct immunomodulatory response in MSCs, characterized by a shift towards an anti-inflammatory phenotype and reduced cell migration. These changes may contribute to the parasite's ability to evade host defenses and persist within the host, highlighting the complex interplay between MSCs and hydatid disease antigens. This study provides valuable insights into the pathophysiology of hydatid disease and may inform the development of novel therapeutic strategies.

The association between glucose 6-phosphate dehydrogenase (G6PD) deficiency and attention deficit/hyperactivity disorder (ADHD)

IntroductionGlucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic enzymopathy that impacts 4.9% of the population, with greater prevalence among Mediterranean, East Asian, and African populations. G6PD deficiency results in levels of nicotinamide-adenine dinucleotide phosphate (NADPH) and glutathione (GSH) that are insufficient for maintaining the balance of oxidation-reduction in the body. This results in elevated production of reactive oxygen species (ROS), oxidative stress on proteins and lipids, damage to DNA, and potential activation of chemokine and cytokine pathways by astrocytes and microglia. We propose that these direct and indirect effects of G6PD deficiency are associated with development of ADHD.ObjectivesThis study investigated the association between G6PD deficiency and Attention Deficit/Hyperactivity Disorder (ADHD).MethodsThe study involved 7,473 G6PD-deficient patients and 29,892 matched case-controls (selected at a 1:4 ratio) from a cohort of 1,031,354 within the Leumit Health Services database. Clinical characteristics were analyzed using Fisher’s Exact Tests for categorical variables and Mann-Whitney U tests for continuous variables.ResultsThe average age of patients was 29.2 ± 22.3 years, with 68.7% being male. The mean follow-up duration was 14.3 ± 6.2 years. Individuals with G6PD deficiency showed a significant 16% higher risk of being diagnosed with ADHD (Odds Ratio (OR) = 1.16 [95% CI, 1.08-1.25], p &lt; 0.001) on follow up. Furthermore, G6PD deficiency was associated with a 30% greater likelihood of seeking care from adult neurologists (OR = 1.30 [95% CI, 1.22-1.38], p &lt; 0.001) and a 12% higher probability of consulting adult psychiatrists (OR = 1.12 [95% CI, 1.01-1.24], p = 0.048). The use of stimulant medications among G6PD deficient individuals was 17% higher for methylphenidate class drugs (OR = 1.17 [95% CI, 1.08, 1.27], p &lt; 0.001), and use of amphetamines elevated by 16% (OR = 1.16 [95% CI, 1.03, 1.37], p = 0.047).ConclusionsThis study establishes a significant association between G6PD deficiency and an increased risk of ADHD diagnoses. These findings suggest potential opportunities for the development of culturally sensitive interventions.Disclosure of InterestB. Krone Consultant of: HIPPO T&amp;C, Signant Health, J. Newcorn: None Declared, I. Manor: None Declared, E. Merzon: None Declared

CC Chemokine Family Members' Modulation as a Novel Approach for Treating Central Nervous System and Peripheral Nervous System Injury-A Review of Clinical and Experimental Findings.

Despite significant progress in modern medicine and pharmacology, damage to the nervous system with various etiologies still poses a challenge to doctors and scientists. Injuries lead to neuroimmunological changes in the central nervous system (CNS), which may result in both secondary damage and the development of tactile and thermal hypersensitivity. In our review, based on the analysis of many experimental and clinical studies, we indicate that the mechanisms occurring both at the level of the brain after direct damage and at the level of the spinal cord after peripheral nerve damage have a common immunological basis. This suggests that there are opportunities for similar pharmacological therapeutic interventions in the damage of various etiologies. Experimental data indicate that after CNS/PNS damage, the levels of 16 among the 28 CC-family chemokines, i.e., CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL17, CCL19, CCL20, CCL21, and CCL22, increase in the brain and/or spinal cord and have strong proinflammatory and/or pronociceptive effects. According to the available literature data, further investigation is still needed for understanding the role of the remaining chemokines, especially six of them which were found in humans but not in mice/rats, i.e., CCL13, CCL14, CCL15, CCL16, CCL18, and CCL23. Over the past several years, the results of studies in which available pharmacological tools were used indicated that blocking individual receptors, e.g., CCR1 (J113863 and BX513), CCR2 (RS504393, CCX872, INCB3344, and AZ889), CCR3 (SB328437), CCR4 (C021 and AZD-2098), and CCR5 (maraviroc, AZD-5672, and TAK-220), has beneficial effects after damage to both the CNS and PNS. Recently, experimental data have proved that blockades exerted by double antagonists CCR1/3 (UCB 35625) and CCR2/5 (cenicriviroc) have very good anti-inflammatory and antinociceptive effects. In addition, both single (J113863, RS504393, SB328437, C021, and maraviroc) and dual (cenicriviroc) chemokine receptor antagonists enhanced the analgesic effect of opioid drugs. This review will display the evidence that a multidirectional strategy based on the modulation of neuronal-glial-immune interactions can significantly improve the health of patients after CNS and PNS damage by changing the activity of chemokines belonging to the CC family. Moreover, in the case of pain, the combined administration of such antagonists with opioid drugs could reduce therapeutic doses and minimize the risk of complications.