Neutrophil extracellular traps (NETs) contribute to host defense by trapping pathogens. However, excessive or dysregulated NET formation is implicated in the pathogenesis of various conditions, including thrombosis, autoimmune diseases, and cancer. Despite their clinical significance, the specific intracellular signaling pathways underlying NET formation in response to proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), remain incompletely defined. Thus, in the present study, we aimed to elucidate the mechanisms underlying TNF-α-induced NET formation in human neutrophil-like differentiated HL-60 (dHL-60) cells. TNF-α induced rapid, non-lytic NET formation in dHL-60 cells without compromising cell viability. Mechanistically, TNF-α activated a signaling cascade involving c-Raf, MEK1/2, and p38 mitogen-activated protein kinase (MAPK). This signaling cascade regulated the sequential caspase activation, with caspase-2 acting upstream of caspase-1 cleavage to promote NET formation. Collectively, these findings suggest that TNF-α induces non-lytic NET formation via a defined c-Raf-MEK1/2-p38 MAPK-caspase pathway and a distinct caspase hierarchy. This mechanism offers a valuable experimental model for studying NET-mediated pathologies in proinflammatory environments.
Melanoma differentiation-associated protein 5 (MDA5), encoded by IFIH1, is a cytosolic double-stranded RNA (dsRNA) sensor. Mutation of IFIH1 resulting in MDA5 deficiency causes immune dysfunction and predisposition to specific respiratory viral pathogens due to the inability of innate immune system to detect viral dsRNA. Additionally, gene variants in IFIH1 have been linked to autoimmunity, including type 1 diabetes. To understand structure-function, we integrate structural biology and signaling principles to explain how MDA5 architecture governs interactions with dsRNA and type 1 interferon (T1-IFN) outputs. MDA5 binds dsRNA via its helicase core and C-terminal domain, uses ATP-dependent conformational cycling to assemble filaments, and exposes N-terminal CARDs that nucleate mitochondrial antiviral signaling protein polymerization, activating TBK1/IKKε-IRF and NF-κB programs that amplify T1-IFN production and inflammatory gene expression. Risk-associated IFIH1 alleles are predicted to increase T1-IFN production/activation thresholds, whereas rare loss-of-function variants attenuate T1-IFN outputs and confer protection. Finally, we outline therapeutic entry points that preserve antiviral defense while constraining chronic T1-IFN signaling to restrain MHC class I expression, chemokine production, and autoreactive T-cell recruitment. Targeting downstream pathways with small molecule inhibitors may delay early autoimmunity and target tissue functions in genetically defined subgroups.
This study explores the relationship between genetic factors, immune response, and clinical characteristics in patients with post-COVID-19. A total of 190 participants with mild to moderate symptoms were recruited from Siriraj Hospital. Cytokine single-nucleotide polymorphisms (SNPs) (IL1β: rs1143643; IL4: rs2243250, rs2243290; IFNγ: rs2069727, rs2430561; IL17A: rs2275913, rs3819025; TGFβ1: rs1800469) were genotyped using rhAmp™ SNP Genotyping. Participants were stratified by neutralizing antibody (Nab) and anti-receptor-binding domain immunoglobulin G (anti-RBD IgG) levels. Patients with high Nab levels had significantly higher HbA1c compared with those with low Nab levels (5.98 ± 1.21% vs. 5.66 ± 0.79%, P = 0.03). The TC genotype of TGFβ1 rs1800469 was associated with a lower frequency of patients in both the high Nab group (TT vs. TC: odds ratio [OR] = 0.445, P = 0.019) and in the high anti-RBD IgG group (TT vs. TC: OR = 0.472, P = 0.032). Similarly, the TA genotype of IFNγ rs2430561 was associated with a reduced frequency of patients in the high anti-RBD IgG group (TT vs. TA: OR = 0.245, P = 0.025). One month postinfection, Nab and low-density lipoprotein levels were reduced in patients with TC of rs1800469 (P = 0.028 and P = 0.018, respectively). A moderate positive correlation was observed between baseline Nab levels and HbA1c at 3 months in patients with the AA genotype of rs2430561 (r = 0.213, P = 0.035). These findings may suggest a possible link between genetic variants, glucose levels, and antibody responses in patients with post-COVID-19, providing insights into long-term management strategies.
Tumor necrosis factor-alpha (TNF-α), a crucial proinflammatory cytokine, is involved in immune regulation and in the pathogenesis of a variety of chronic inflammatory and autoimmune diseases. TNF-α signaling dysregulation is linked to chronic inflammatory diseases, multiorgan dysfunction, and tissue destruction through activation of TNF receptor 1 (TNFR1)-mediated inflammatory, apoptotic, and necroptotic pathways, while TNF receptor 2 (TNFR2) stimulation promotes immune regulation and tissue repair. Understanding these divergent signaling mechanisms is crucial for augmenting therapeutic interventions. The present review summarizes the molecular structure of TNF-α, compares TNFR1 and TNFR2 signaling cascades, and describes the cytokine’s role in diseases such as rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, multiple sclerosis, diabetes mellitus, atherosclerosis, heart failure, systemic lupus erythematosus, and cancer. We further evaluate clinically approved TNF inhibitors and emergent investigational agents, prominent advances in receptor-selective modulation, and small-molecule TNF suppression. Overall, this review emphasizes the therapeutic potential of selectively targeting TNF-α signaling while preserving essential immunoregulatory functions, offering insights that may support next-generation drug development.
Tonsils are among the largest lymphoid tissues within the Waldeyer's ring. They generate lymphocytes that facilitate immune responses and play essential protective roles in host defense. When tonsillar crypts are exposed to specific bacterial or viral infections, persistent allergic stimuli, or immune dysregulation, an inflammatory cascade may be triggered, increasing the risk of chronic tonsillitis (CT). CT is a common otolaryngological condition characterized by recurrent episodes of inflammation or a single prolonged episode (>3 months), and it typically presents with repeated acute pharyngalgia, fever, cough, tonsillar swelling and suppuration, itching of the throat, and dryness. The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways, first described by Darnell and Stark in the early 1990s, are highly conserved transmembrane signal transduction mechanisms. They act as central hubs for cytokine-mediated signaling and enable communication between cells and their external environment. Many cytokines exert their biological effects through this pathway. This review elaborates on the activation mechanism of the IL-6-JAK2-STAT3 signaling pathway, summarizes the major drug classes targeting this pathway, highlights the clinical significance in CT, and addresses the current knowledge gaps in the field.
This investigation examined whether initially elevated serum cytokine concentrations associate with a lower serum 25-hydroxyvitamin D (25(OH)D) increase shortly after initiating supplemental vitamin D. This secondary analysis combined data from separate randomized, double-blind, placebo-controlled studies consisting of reportedly healthy adults and individuals with knee osteoarthritis who received supplemental vitamin D. Subjects were separated into 2 groups based on serum IL-6 concentrations at baseline (Bsl; prior to supplemental vitamin D): (1) non-elevated IL-6 (<2.5 pg/mL; n = 22) or (2) elevated IL-6 (≥2.5 pg/mL; n = 11). Reportedly healthy adults and knee osteoarthritis subjects with elevated IL-6 were matched (1:2) to those with non-elevated IL-6. Matching was based on condition (healthy adults and knee osteoarthritis), age (±3.0 y), sex, body mass index (±3.0 kg/m2), and dose of supplemental vitamin D (cholecalciferol, 4,000 or 8,000 IU/d). Serum cytokine concentrations at Bsl and serum 25(OH)D concentrations at Bsl and following 7 and 28-d of daily vitamin D supplementation are reported here. Serum IL-6 and other cytokines (GM-CSF, IL-10, IL-13, IL-1β, IL-2, IL-4, IL-5, IL-7, IL-8, and TNF-α) were significantly increased in the elevated compared to the non-elevated IL-6 group at Bsl (all P < 0.05). Serum 25(OH)D concentrations at Bsl, 7-d, and 28-d were not significantly different between IL-6 groups. The increase in serum 25(OH)D from Bsl to 7-d (7-dΔ) was significantly lower in the elevated compared to the non-elevated IL-6 group (P < 0.05). The 7-dΔ in serum 25(OH)D displayed modest inverse associations with Bsl serum 25(OH)D (β = -0.46, P < 0.01) and IL-6 (β = -0.43, P < 0.01). However, the 28-dΔ in serum 25(OH)D was inversely associated with Bsl serum 25(OH)D (β = -0.57, P = 0.01) but not with Bsl serum IL-6 (β = 0.10, P = 0.31). We conclude that the serum 25(OH)D response to supplemental vitamin D is temporarily blunted with elevated baseline circulating IL-6 and other cytokines, but this response diminished as supplementation continued.
Interest in identifying biomarkers that reflect spine condition and support therapy monitoring has grown. Since low-grade inflammation and comorbidities can complicate treatment, they should be considered in research. Vaspin (SERPINA12) has been linked to low back pain (LBP) severity and disability, highlighting its potential as a biomarker connecting LBP and adipose tissue inflammation. The study aimed to assess the effect of traction therapy on serum vaspin levels and compare responses between women with obesity and normal BMI. A secondary aim was to explore associations between vaspin, LBP severity, disability scores, and selected inflammatory markers. It is a prospective clinical trial. Women aged 34-50 years with chronic LBP were divided into two groups: those with normal BMI and those with obesity. Both groups underwent 20 30-min sessions of lumbar traction therapy. At baseline and after therapy, LBP intensity, the Oswestry Disability Index (ODI), and the Roland-Morris Disability Questionnaire (RMDQ) were assessed, and blood samples were collected for analysis of vaspin, RANTES, interleukin (IL)-2, IL-17A, IL-4, and IL-10. After completing the traction therapy, there was a significant decrease in LBP, ODI, and RMDQ and an increase in the circulating levels of IL-10, regardless of BMI. However, vaspin concentration increased significantly only in women with normal BMI. Post-therapy, vaspin negatively correlated with ODI. IL-4 and IL-17A levels also correlated with vaspin, positively in women with normal BMI and negatively in those with obesity. Obesity-related inflammation may alter the biochemical response to traction therapy. Increases in vaspin concentration were found exclusively in women with normal BMI, indicating a possible BMI-dependent association between circulating vaspin concentrations and response to therapy.Registration: The study was registered at ClinicalTrials.gov with the ID number NCT04507074.
Multiple sclerosis (MS) is a central nervous system (CNS) disease with autoimmune inflammation, demyelination, and neurodegeneration. Untreated MS patients exhibit subnormal activation of the p-Ser-STAT1 transcription factor in peripheral blood mononuclear cells (PBMCs), causing weak interferon (IFN) signaling and low expression of some IFN-stimulated genes (ISGs). IFN-β therapy reduces MS exacerbations, delays progression, and largely corrects abnormal gene expression in PBMC. We hypothesize that long-term IFN-β therapy improves weak IFN responses and regulates MS immunity through a priming effect and induction of a more IFN-responsive state. The duration and strength of IFN-stimulated gene expression during prolonged therapy and their diminution after discontinuation are unknown. Using paired comparisons of 1- and 7-month PEG-IFN-β-treated MS patients' PBMCs, we investigated short- and long-term responses to in vivo IFN-β. Prolonged therapy created a new IFN setpoint with elevated expression of antiviral, immune, anti-inflammatory, and neuroprotective ISG while decreasing inflammatory and metabolic gene expression, often doubling their half-life. Genes that inhibit IFN-β signaling also showed long-term induction, reflecting a regulatory state that prevents overactivation. Strong IFN responses during long-term therapy of MS reflect a shift from subnormal IFN signaling and dysregulated immune control to a more responsive state that persists for months.
Human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infants, older adults, and immunocompromised individuals. A hallmark of RSV pathogenesis is early innate immune evasion by the nonstructural proteins NS1 and NS2. NS2 is a multifunctional interferon (IFN) antagonist that dampens both IFNβ induction and type I IFN responsiveness by targeting multiple nodes of the RIG-I/IFN signaling axis. Because NS2-mediated inhibition is often partial and context dependent, quantifying its effects in conventional cell-based assays is challenging. Here, we report the generation and characterization of a stable, virus-free reporter system in human A549 cells to measure NS2-dependent inhibition of dsRNA-driven IFNB induction. The platform combines stable NS2 expression with genomic integration of a dual cassette encoding a non-targeting short hairpin RNA that constitutively activates IRF-3 to induce a luciferase reporter under IFNB promoter control. This configuration yields a sensitive, reproducible luminescence readout of IFNB promoter activity in controlled, infection-free conditions, enabling robust quantification of NS2 antagonism with reduced variability. The scalable luminescence-based format supports early-stage discovery and prioritization of inhibitors that counteract NS2 function, and the modular design is adaptable to other viral antagonists, pathways, and cell types for standardized comparative studies.
Colorectal cancer (CRC) is a multifactorial malignancy characterized by complex interactions between oncogenic signaling networks and noncoding RNA regulators. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and microRNA-145 (miR-145) have been recognized as reliable diagnostic biomarkers for cancer. This study evaluates their biochemical interaction, along with their connection to the nuclear factor kappa beta (NF-κβ)/transforming growth factor-beta (TGF-β) signaling pathway and crosstalk with vascular endothelial growth factor (VEGF) and apoptotic markers in CRC. Serum samples were collected from 120 participants, including 90 CRC patients exhibiting a range of tumor grades and anatomical sites, in addition to 30 healthy controls. The expression levels of NF-κB and apoptotic markers were quantified using standardized immunoassays, while the relative expression levels of MALAT1, miR-145, TGF-β, and VEGF were assessed using real-time polymerase chain reaction. Integrative analysis of CRC samples reveals that MALAT1 overexpression correlates with downregulation of miR-145, increased NF-κβ, elevated levels of TGF-β and VEGF, and alterations in apoptotic proteins. Moreover, receiver operating characteristic analysis revealed excellent discriminative power for MALAT1 and miR-145 in distinguishing patients with CRC from healthy controls. These findings suggest that the MALAT1/miR-145 axis serves as a central biochemical node linking inflammatory and fibrotic signaling pathways and apoptotic protein expression in colorectal carcinogenesis. Targeting this regulatory network may offer novel therapeutic opportunities to suppress NF-κβ/TGF-β-driven tumor progression and improve CRC outcomes.
Objectives: Lipopolysaccharide (LPS) from oral Gram-negative bacteria induces inflammatory responses involving the chemokine CXCL1. Although CXCL1 is known to mediate inflammation, its role in disease processes remains incompletely understood. This study aimed to investigate the biological function of CXCL1, evaluate shRNAs as inhibitors, and determine whether CXCL1 suppression is associated with reduced LPS-induced cytokine production.Materials and Methods: Human CXCL1 cDNA was cloned into recombinant plasmid DNA and transfected into THP-1 monocyte-like cells. CXCL1-regulated cytokines, including tumor necrosis factor alpha (TNF-α) and IL-1β, were quantified by enzyme-linked immunosorbent assay (ELISA) following treatment with pharmacologic and molecular inhibitors. Multiple CXCL1-targeting shRNAs were designed, synthesized, and tested. The specificity of CXCL1 shRNA-mediated inhibition of LPS-induced proteins was analyzed using ELISA and a hybrid method analysis.Results: Treatment with a Janus kinase inhibitor or CXCL1 shRNA#2 significantly suppressed CXCL1 expression, resulting in reduced production of TNF-α and other pro-inflammatory cytokines, suggesting a regulatory role for CXCL1. CXCL1 shRNA#2 also markedly inhibited LPS-induced chemokines, kinases, transcription factors, and apoptotic genes, demonstrating broad anti-inflammatory effects.Conclusions: CXCL1 appears to play a regulatory role in LPS-dependent inflammatory pathways, and its suppression by shRNA or pharmacologic inhibitors effectively reduces cytokine production. These findings provide insight into CXCL1-associated mechanisms while highlighting the need for further mechanistic studies to elucidate the precise signaling pathways involved and may inform the development of potential therapeutic strategies for inflammatory diseases.
Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, and inflammation and immune dysregulation contribute to its pathogenesis. Interleukin (IL)17A's role has been demonstrated in PTC. Genetic variants in IL17A may affect susceptibility and progression; however, their impact in the Chinese population remains insufficiently understood. This hospital-based case-control study included 272 patients with PTC and 250 age/sex-matched controls. Four IL17A single-nucleotide polymorphisms-rs2275913, rs3748067, rs8193036, and rs3819024-were genotyped using TaqMan assays. IL17A plasma levels were measured by ELISA. Allele, genotype, and haplotype distribution among controls and patients, and IL17 variant associations with IL17A levels were analyzed using GraphPad Prism. The rs2275913 AA genotype and minor allele showed a higher frequency in patients with PTC compared to controls, indicating an increased risk of PTC (AA: odds ratio [OR] = 1.88, 95% confidence intervals [CI] = 1.17-2.95, P = 0.01; A: OR = 1.44, 95% CI = 1.12-1.84, P = 0.003). Patients with PTC had higher plasma IL17A levels than controls (P < 0.0001). IL17A genotypes, particularly rs2275913 AA, were associated with higher plasma IL17A concentrations. Genetic polymorphisms in IL17A (rs2275913) and elevated plasma IL17A levels correlate with PTC susceptibility in the Chinese cohort. These findings suggest IL17A's potential as a biomarker for risk stratification and highlight inflammatory pathways in PTC pathogenesis.
Osteoarthritis is a degenerative joint disease characterized by synovial inflammation and cartilage destruction. This study aimed to investigate the function of RAB5A in regulating human fibroblast-like synoviocytes (HFLS) and its subsequent impact on chondrocyte degeneration. Differential expression and pathway analyses were performed according to the Gene Expression Omnibus (GEO) dataset. HFLS were stimulated with IL-1β, and RAB5A was knocked down via transfection. Inflammatory signaling, cytokine expression, and extracellular vesicles (EVs) secretion were assessed. Isolated EVs were characterized by nanoparticle tracking analysis, transmission electron microscopy, and Western blotting. The functional effects of HFLS-derived EVs on chondrocyte inflammation, extracellular matrix metabolism, apoptosis, and viability were evaluated. Bioinformatics analysis identified RAB5A as a key gene linked to the endocytosis pathway. In IL-1β-stimulated HFLS, RAB5A expression was upregulated. RAB5A knockdown reduced the activation of p38 and NF-κB pathways and suppressed pro-inflammatory factors and matrix degradation mediators. Furthermore, RAB5A deficiency impaired EV secretion and altered their cargo. Crucially, while EVs from control HFLS promoted chondrocyte catabolism, inflammation, and apoptosis, EVs from RAB5A-knockdown HFLS mitigated these degenerative phenotypes. Our findings demonstrate that RAB5A, by modulating the biogenesis and composition of HFLS-derived EVs, plays a critical role in driving chondrocyte degeneration, highlighting its importance as a key molecular regulator in osteoarthritis.
This research study aimed to investigate the response of patients infected with the hepatitis C virus (HCV) toward direct-acting antivirals (DAAs) therapy. The research included a cohort of HCV-infected patients from different regions of Pakistan. Experimental studies were performed for the detailed analysis of virological response recorded at specific time intervals during the whole course of treatment. Sustained virological response (SVR) was explicitly defined as undetectable HCV RNA at 12 weeks post-completion of therapy (SVR12), ensuring alignment with international clinical standards. The standard genotypes analyzed for the selected interleukin (IL) variants were: IL-4 rs2243250 (C/C, C/T, T/T), IL-17 rs612242 (A/A, A/G, G/G), and IL-22 rs2064501 (A/A, A/G, G/G). The genetic profiling of these variants highlighted the significant role of cytokines in modulating the patient's immune response. The research also focused on the association between single-nucleotide polymorphisms (SNPs) of IL genes and categorization based on the outcomes of treatment by sequencing analysis. Our study found that the IL-4 rs2243250 SNP was predominantly heterozygous as CT in 52% SVR and 37% relapse patients. The IL-17 rs612242 SNP was mainly identified as AG in 54% SVR and 39% relapse patients, and the IL-22 rs2064501 SNP was prevalent in 32% relapse and 49% SVR patients as AG genotype. A homozygous genotype T/T was also analyzed for polymorphism rs2243250 in a relatively small percentage (16%) of non-responders. These research findings showed that C/T, C/C, and A/G genotypes were dominant in patients who cleared the infection after treatment. It confirmed the influence of single-nucleotide polymorphisms on the success rate of DAAs therapy, determined by observing the baseline characteristics and genetic factors of selected patients after comparing with healthy controls. Due to the limited genotyping of healthy controls (n = 4), comparative results involving the control group were interpreted with caution.
Primary hemophagocytic lymphohistiocytosis (pHLH) and macrophage activation syndrome (MAS) are the 2 fatal hyperinflammatory disorders sharing similar clinical features and underlying pathogenic mechanisms. The present study aimed to assess the cytokine profiles in these children and to ascertain whether specific cytokines correlate with specific laboratory parameters. We enrolled 10 pHLH and 10 MAS patients. Serum levels of cytokines, including IL-6, IL-8, IL-10, IFN-gamma, IL-1 beta, IL-18, and TNF-alpha, were measured in each patient and compared with age-matched controls. IL-18 and IL-10 were the 2 cytokines that were most significantly elevated in pHLH (P value < 0.001 and P value = 0.0011, respectively), while IL-8 was considerably lower than controls (P value = 0.0054). In MAS patients, IL-18 (P value = <0.002), IL-10 (P value = 0.0030), and IL-6 (P value = 0.028) were the 3 most significantly elevated cytokines. Specific cytokines were found to correlate significantly with ferritin, triglycerides, fibrinogen, platelet count, hemoglobin, absolute neutrophil count, and absolute monocyte count. Overall, IL-18 and IL-10 are the most consistently elevated cytokines in both pHLH and MAS, while IL-6 is uniquely elevated in MAS. Cytokines not only play a role in the HLH pathophysiology but may also serve as disease biomarkers.
The adhesion of monocytes to vascular endothelial cells constitutes a fundamental early process in atherogenesis. Fibroblast growth factor-18 (FGF-18), known to signal through the fibroblast growth factor receptor 1 (FGFR1), has emerging roles in maintaining vascular homeostasis, but its precise function in endothelial inflammation remains unclear. The protective role of recombinant human FGF-18 (rhFGF-18) against oxidized low-density lipoprotein (ox-LDL)-induced endothelial injury and its mechanism were investigated. We found that ox-LDL downregulated phospho-FGFR1 in human aortic vascular endothelial cells (HAVECs) dose- and time-dependently. rhFGF-18 treatment markedly suppressed ox-LDL-induced upregulation of the scavenger receptor LOX-1 and key pro-inflammatory factors (TNF-α, MCP-1, COX-2, and PGE2). Subsequently, rhFGF-18 reduced the expression of adhesion molecules VCAM-1 and ICAM-1, thereby decreasing THP-1 monocyte adhesion to HAVECs. Mechanistic investigations revealed that rhFGF-18 inhibits ox-LDL-induced phosphorylation and nuclear translocation of the transcriptional regulator TRIM28. Importantly, TRIM28 overexpression reversed the anti-inflammatory and anti-adhesive benefits of rhFGF-18. Collectively, this study identifies the FGF-18/TRIM28 axis as a crucial mechanism alleviating endothelial inflammation and monocyte adhesion, highlighting its potential as a therapeutic target for atherosclerosis.
Endothelial cell injury and dysfunction are among the main causes of sepsis-associated acute lung injury (ALI); however, the underlying mechanism through which endothelial activation coordinates the adhesion and migration of immune cells remains elusive. Bioinformatics analysis revealed that the hub gene (C-X-C motif chemokine ligand 10 [CXCL10]) was predicted to be involved in both endothelial activation and syndecan 4 (SDC4) binding capacity. In both the LPS- and tumor necrosis factor-alpha -induced sepsis models, the expression level and biological function of the hub gene were confirmed by means of quantitative PCR and immunofluorescence staining. With the knockdown of SDC4 and the HS mutation technique, loss-of-function experiments and downstream pathway experiments following modulation of the hub gene's expression were conducted to elucidate the underlying molecular mechanism. Through the overlap of GSE5883 and the glycosaminoglycan-binding DB, seven genes were discovered to be involved in the biological processes of SDC binding and cytokine-cytokine receptor interactions, including those involving CXCL10. Compared with that in the normal state, the expression of CXCL10 in the ALI state markedly increased during the acute phase of inflammation, and the SDC4 mRNA level greatly increased. Mechanistically, CXCL10 induces a proinflammatory response with the help of SDC4 as a coreceptor, leading to CXCR3/NF-κB pathway activation and VCAM1 overexpression. This proinflammatory phenotype was further enhanced by knockdown of SDC4. By mutating the heparan sulfate (HS) chain of SDC4, the severity of inflammation was exacerbated, and the recruitment of immune cells was also enhanced. In summary, endothelial-derived SDC4 acts as a negative mediator to ameliorate ALI through modulation of the CXCR3 pathway with the help of HS chains.
Sphingomyelins and their metabolites can influence levels of proinflammatory cytokines, which in turn can impact the progression of polycystic ovary syndrome (PCOS). However, no research has clearly elucidated the mediating role of proinflammatory cytokines in this process. To delineate the causal relationship of sphingomyelins and their metabolites with PCOS and the mediating role of proinflammatory cytokines. Two-sample Mendelian randomization (MR) analysis was conducted to investigate causation between sphingomyelins and their metabolites with PCOS. A two-step MR analysis was used to examine the mediating role of proinflammatory cytokines. Random-effects inverse variance weighting was primarily used, and the reliability of results was assessed via sensitivity analysis. Four types of sphingomyelins and their metabolites showed potential association with PCOS. Glycosyl-N-stearoyl-sphingosine (d18:1/18:0) levels were positively correlated with PCOS, while sphingomyelin (d18:1/24:1, d18:2/24:0), sphingomyelin (d38:1), and ceramide (d42:2) levels were negatively correlated with PCOS. Proinflammatory cytokines, such as eotaxin, interleukin-20 receptor subunit alpha, and TNF-related apoptosis-inducing ligand (TRAIL) levels, showed a positive correlation with PCOS. TRAIL played a 6.58% potential mediating role in causation between sphingomyelin (d38:1) levels and PCOS. This study provided new evidence of a causal relationship of sphingomyelins and their metabolites with PCOS and elucidated that the proinflammatory cytokine TRAIL may play a certain mediating role in this process. These findings contributed to a better understanding of PCOS pathogenesis.
