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Introduction: Plasminogen activator inhibitor-1 (PAI-1) is linked to thrombosis and endothelial dysfunction in severe COVID-19. The +43 G>A PAI-1 and 4G/5G promoter polymorphism can influence PAI-1 expression. The 4G5G PAI-1 promoter gene polymorphism constitutes the 4G4G, 4G5G, and 5G5G genotypes. However, the impact of PAI-1 polymorphisms on disease severity or endothelial dysfunction remains unclear. Methods: Clinical data, sera, and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients were studied. Results: Comorbidities and clinical biomarkers did not correlate with genotypes in either polymorphism. However, differences between fibrinolytic factors and interleukin-1ß (IL-1ß) were identified in genotypes of the 4G/5G but not the 43 G>A PAI polymorphism. Patients with the 4G4G genotype of the 4G/5G polymorphism showed high circulating PAI-1, mainly complexed with plasminogen activators, and low IL-1ß and plasmin levels, indicating suppressed fibrinolysis. NFκB was upregulated in PBMCs of COVID-19 patients with the 4G4G genotype. Discussion: Mechanistically, IL-1ß enhanced PAI-1 expression in 4G4G endothelial cells, preventing the generation of plasmin and cleavage products like angiostatin, soluble uPAR, and VCAM1. We identified inflammation-induced endothelial dysfunction coupled with fibrinolytic system overactivation as a risk factor for patients with the 5G5G genotype.
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COVID-19 , Inhibidor 1 de Activador Plasminogénico , Regiones Promotoras Genéticas , SARS-CoV-2 , Humanos , Inhibidor 1 de Activador Plasminogénico/genética , COVID-19/genética , COVID-19/sangre , Masculino , Regiones Promotoras Genéticas/genética , Femenino , Persona de Mediana Edad , SARS-CoV-2/fisiología , Anciano , Índice de Severidad de la Enfermedad , Leucocitos Mononucleares/metabolismo , Polimorfismo de Nucleótido Simple , Interleucina-1beta/genética , Genotipo , AdultoRESUMEN
BACKGROUND: NOD-like receptor protein 3 (NLRP3) inflammasome activation is indispensable for atherogenesis. Mitophagy has emerged as a potential strategy to counteract NLRP3 inflammasome activation triggered by impaired mitochondria. Our previous research has indicated that dihydromyricetin, a natural flavonoid, can mitigate NLRP3-mediated endothelial inflammation, suggesting its potential to treat atherosclerosis. However, the precise underlying mechanisms remain elusive. This study sought to investigate whether dihydromyricetin modulates endothelial mitophagy and inhibits NLRP3 inflammasome activation to alleviate atherogenesis, along with the specific mechanisms involved. METHODS: Apolipoprotein E-deficient mice on a high-fat diet were administered daily oral gavages of dihydromyricetin for 14 weeks. Blood samples were procured to determine the serum lipid profiles and quantify proinflammatory cytokine concentrations. Aortas were harvested to evaluate atherosclerotic plaque formation and NLRP3 inflammasome activation. Concurrently, in human umbilical vein endothelial cells, Western blotting, flow cytometry, and quantitative real-time PCR were employed to elucidate the mechanistic role of mitophagy in the modulation of NLRP3 inflammasome activation by dihydromyricetin. RESULTS: Dihydromyricetin administration significantly attenuated NLRP3 inflammasome activation and vascular inflammation in mice on a high-fat diet, thereby exerting a pronounced inhibitory effect on atherogenesis. Both in vivo and in vitro, dihydromyricetin treatment markedly enhanced mitophagy. This enhancement in mitophagy ameliorated the mitochondrial damage instigated by saturated fatty acids, thereby inhibiting the activation and nuclear translocation of NF-κB. Consequently, concomitant reductions in the transcript levels of NLRP3 and interleukin-1ß (IL-1ß), alongside decreased activation of NLRP3 inflammasome and IL-1ß secretion, were discerned. Notably, the inhibitory effects of dihydromyricetin on the activation of NF-κB and subsequently the NLRP3 inflammasome were determined to be, at least in part, contingent upon its capacity to promote mitophagy. CONCLUSION: This study suggested that dihydromyricetin may function as a modulator to promote mitophagy, which in turn mitigates NF-κB activity and subsequent NLRP3 inflammasome activation, thereby conferring protection against atherosclerosis.
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Aterosclerosis , Dieta Alta en Grasa , Flavonoles , Células Endoteliales de la Vena Umbilical Humana , Inflamasomas , Mitofagia , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Mitofagia/efectos de los fármacos , Animales , Flavonoles/farmacología , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Aterosclerosis/patología , Aterosclerosis/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Ratones , Humanos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones Endogámicos C57BL , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismoRESUMEN
Age-related macular degeneration (AMD) is a major global health problem as it is the leading cause of irreversible loss of central vision in the aging population. Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective but do not respond optimally in all patients. This study investigates the genetic factors associated with susceptibility to AMD and response to treatment, focusing on key polymorphisms in the ARMS2 (rs10490924), IL1B1 (rs1143623), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), VEGFA (rs3024997), ARMS2, IL1B1, TNFRSF1B, TNFRSF1A, and VEGFA serum levels in AMD development and treatment efficacy. This study examined the associations of specific genetic polymorphisms and serum protein levels with exudative and early AMD and the response to anti-VEGF treatment. The AA genotype of VEGFA (rs3024997) was significantly associated with a 20-fold reduction in the odds of exudative AMD compared to the GG + GA genotypes. Conversely, the TT genotype of ARMS2 (rs10490924) was linked to a 4.2-fold increase in the odds of exudative AMD compared to GG + GT genotypes. In females, each T allele of ARMS2 increased the odds by 2.3-fold, while in males, the TT genotype was associated with a 5-fold increase. Lower serum IL1B levels were observed in the exudative AMD group compared to the controls. Early AMD patients had higher serum TNFRSF1B levels than controls, particularly those with the GG genotype of TNFRSF1B rs1061622. Exudative AMD patients with the CC genotype of TNFRSF1A rs4149576 had lower serum TNFRSF1A levels compared to the controls. Visual acuity (VA) analysis showed that non-responders had better baseline VA than responders but experienced decreased VA after treatment, whereas responders showed improvement. Central retinal thickness (CRT) reduced significantly in responders after treatment and was lower in responders compared to non-responders after treatment. The T allele of TNFRSF1B rs1061622 was associated with a better response to anti-VEGF treatment under both dominant and additive genetic models. These findings highlight significant genetic and biochemical markers associated with AMD and treatment response. This study found that the VEGFA rs3024997 AA genotype reduces the odds of exudative AMD, while the ARMS2 rs10490924 TT genotype increases it. Lower serum IL1B levels and variations in TNFRSF1B and TNFRSF1A levels were linked to AMD. The TNFRSF1B rs1061622 T allele was associated with better anti-VEGF treatment response. These markers could potentially guide risk assessment and personalized treatment for AMD.
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Interleucina-1beta , Degeneración Macular , Polimorfismo de Nucleótido Simple , Receptores Tipo I de Factores de Necrosis Tumoral , Factor A de Crecimiento Endotelial Vascular , Humanos , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/sangre , Masculino , Femenino , Degeneración Macular/genética , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/sangre , Degeneración Macular/patología , Anciano , Interleucina-1beta/genética , Interleucina-1beta/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Anciano de 80 o más Años , Predisposición Genética a la Enfermedad , Persona de Mediana Edad , Genotipo , Alelos , Proteínas , Receptores Tipo II del Factor de Necrosis TumoralRESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an age-related disease severely affecting life quality with its prevalence rising as the population ages, yet there is still no effective treatment available. Cell therapy has emerged as a promising option for IPF, however, the absence of mature and stable animal models for IPF immunodeficiency hampers preclinical evaluations of human cell therapies, primarily due to rapid immune clearance of administered cells. This study aims to establish a reliable pulmonary fibrosis (PF) model in immunodeficient mice that supports autologous cell therapy and to investigate underlying mechanism. METHODS: We utilized thirty 5-week-old male NOD/SCID mice, categorizing them into three age groups: 12weeks, 32 weeks and 43 weeks, with 6 mice euthanized randomly from each cohort for lung tissue analysis. We assessed fibrosis using HE staining, Masson's trichrome staining, α-SMA immunohistochemistry and hydroxyproline content measurement. Further, ß-galactosidase staining and gene expression analysis of MMP9, TGF-ß1, TNF-α, IL-1ß, IL-6, IL-8, SOD1, SOD2, NRF2, SIRT1, and SIRT3 were performed. ELISA was employed to quantify protein levels of TNF-α, TGF-ß1, and IL-8. RESULTS: When comparing lung tissues from 32-week-old and 43-week-old mice to those from 12-week-old mice, we noted a marked increase in inflammatory infiltration, fibrosis severity, and hydroxyproline content, alongside elevated expression levels of α-SMA and MMP9. Notably, the degree of fibrosis intensified with age. Additionally, ß-galactosidase staining became more pronounced in older mice. Quantitative PCR analyses revealed age-related, increases in the expression of senescence markers (GLB1, P16, P21), and proinflammatory genes (TGF-ß1, TNF-α, IL-1ß, IL-6, and IL-8). Conversely, the expression of anti-oxidative stress-related genes (SOD1, SOD2, NRF2, SIRT1, and SIRT3) declined, showing statistically significant differences (*P < 0.05, **P < 0.01, ***P < 0.001). ELISA results corroborated these findings, indicating a progressive rise in the protein levels of TGF-ß1, TNF-α, and IL-8 as the mice aged. CONCLUSIONS: The findings suggest that NOD/SCID mice aged 32 weeks and 43 weeks effectively model pulmonary fibrosis in an elderly context, with the disease pathogenesis likely driven by age-associated inflammation and oxidative stress.
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Envejecimiento , Modelos Animales de Enfermedad , Ratones Endogámicos NOD , Ratones SCID , Sirtuina 1 , Animales , Ratones , Masculino , Sirtuina 1/metabolismo , Sirtuina 1/genética , Pulmón/patología , Pulmón/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/metabolismo , Interleucina-8/metabolismo , Interleucina-8/genética , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/genética , Sirtuina 3/genética , Sirtuina 3/metabolismo , Hidroxiprolina/metabolismo , Interleucina-6/metabolismo , Interleucina-6/genética , Actinas/metabolismo , Actinas/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/metabolismoRESUMEN
OBJECTIVES: This study aims to explore the mechanisms of dual regulation of osteoarthritis (OA) progression by the involvement of estrogen receptor (ER) in autophagy and inflammation. MATERIALS AND METHODS: Bioinformatics methods were used to explore the relationship among associated genes. Western blot assays were used to detect related protein expression of OA in C28I2 and induced OA cellular model. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis were used to detect OA related gene expression in C28I2 and induced OA cellular model. Co-immunoprecipitation (CO-IP) analysis were used to verify the direct interaction between ER and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). RESULTS: The C28I2 cellular model of OA was induced by interleukin-1ß (IL-1ß). The small interfering ribonucleic acid (SiRNA)-mediated knockdown of autophagy-related 16 like 1 (ATG16L1) in C28I2 decreased the expression of MAP1LC3B (LC3B) and NLRP3. Besides, ER-beta (ERß) agonist changed the gene expression of NLRP3 and ATG16L1. Moreover, CO-IP analysis indicated the direct interaction between ER and NLRP3. CONCLUSION: Our study results revealed that ATG16L1, NLRP3, and IL-1ß interacted closely and ERß was involved in OA process by affecting autophagy and inflammatory activation.
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Proteínas Relacionadas con la Autofagia , Receptor beta de Estrógeno , Proteína con Dominio Pirina 3 de la Familia NLR , Osteoartritis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/genética , Humanos , Receptor beta de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Autofagia , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/genética , Línea CelularRESUMEN
This study aimed to investigate the structural characteristics and intracellular mechanisms of polysaccharides (MP-PE-I) purified from a crabapple (Malus prunifolia) enzymatic hydrolysate (MP-PE). Activity-guided fractionation revealed that MP-PE-I was the active moiety and significantly reduced the production and gene expression of pro-inflammatory factors in interleukin (IL)-1ß-treated intestinal epithelial cells (Caco-2). Moreover, MP-PE-I downregulated the phosphorylation and nuclear localization of proteins involved in the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways, as evidenced by immunoblotting and immunofluorescence analysis. In antagonistic studies with specific inhibitors of the MAPK and NF-κB pathways, IL-6 inhibition was significantly regulated by p38; IL-8 by IκBα, JNK, and p38; and monocyte chemoattractant protein-1 (MCP-1) by JNK, p38, and ERK. Additionally, MP-PE-I significantly decreased the mRNA and protein expression of IL-1 receptor type 1. Chemical and structural characteristic analyses showed that MP-PE-I is a polysaccharide rich in rhamnogalacturonan (RG)-I and plays a crucial role in intestinal immunomodulation. To our knowledge, this is the first study to demonstrate the intestinal immunomodulatory activity, intracellular mechanisms, and structural characteristics of RG-I-rich polysaccharides isolated from crabapples.
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Interleucina-1beta , Pectinas , Polisacáridos , Pectinas/farmacología , Pectinas/química , Pectinas/aislamiento & purificación , Humanos , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Polisacáridos/farmacología , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Células CACO-2 , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , FN-kappa B/metabolismo , Hidrólisis , Proteínas Quinasas Activadas por Mitógenos/metabolismoRESUMEN
This study aimed to investigate the effects of corn gluten-derived soluble epoxide hydrolase (sEH) inhibitory peptides on nonalcoholic fatty liver fibrosis induced by a high-fat diet and carbon tetrachloride in mice. Mice treated with corn peptides at doses of 500 or 1000 mg/kg/d for 4 weeks exhibited reduced sEH activity in serum and liver, enhanced lipid metabolism, and decreased lipid accumulation and oxidative stress. Corn peptides effectively downregulated the mRNA levels of Pro-IL-1ß, Pro-IL-18, NOD-like receptor protein 3 (NLRP3), ASC, Pro-caspase-1, Caspase-1, and GSDMD in the liver. This hepatoprotective effect of corn peptides by inhibiting NLRP3 inflammasome activation was further validated in H2O2-induced HepG2 cells. Moreover, corn peptides restored the composition of the gut microbiota and promoted short-chain fatty acid production. This study provides evidence that corn-derived sEH inhibitory peptides have hepatoprotective activity against nonalcoholic fatty liver fibrosis by suppressing NLRP3 inflammasome activation and modulating gut microbiota.
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Microbioma Gastrointestinal , Inflamasomas , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Enfermedad del Hígado Graso no Alcohólico , Péptidos , Zea mays , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inmunología , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Inflamasomas/metabolismo , Inflamasomas/genética , Masculino , Humanos , Zea mays/química , Péptidos/farmacología , Péptidos/administración & dosificación , Hígado/metabolismo , Hígado/efectos de los fármacos , Bacterias/clasificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Células Hep G2 , Epóxido Hidrolasas/genética , Epóxido Hidrolasas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismoRESUMEN
Neutrophil infiltration plays a key role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). However, pertinent mechanisms remain poorly elucidated. Here, we obtained the data from gene expression omnibus (GEO) and gene set enrichment analysis (GSEA) to identify and validate neutrophil-associated hub genes in CRSwNP. We found that four neutrophil-associated hub genes, namely ICAM1, IL-1ß, TYROBP, and BCL2A1, were markedly upregulated and positively correlated with neutrophil infiltration levels in patients with CRSwNP. Subsequently, this was confirmed by real-time quantitative PCR. In conclusion, we identified the role of neutrophil infiltration in the pathophysiology of CRSwNP, which may be the potential targets for the diagnosis and treatment of CRSwNP.
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Pólipos Nasales , Neutrófilos , Rinitis , Sinusitis , Pólipos Nasales/genética , Humanos , Sinusitis/genética , Rinitis/genética , Neutrófilos/metabolismo , Enfermedad Crónica , Interleucina-1beta/genética , Molécula 1 de Adhesión Intercelular/genética , Infiltración Neutrófila/genética , Masculino , Femenino , Perfilación de la Expresión Génica , RinosinusitisRESUMEN
OBJECTIVE: Forgerini et al. investigated the role of seven genetic variants in the risk of upper gastrointestinal bleeding as an adverse drug reaction. In 289 participants (50 cases and 189 controls), the presence of seven variants in the IL-1ß, IL-1RN, and TNF-α genes was not associated with susceptibility to acetylsalicylic acid-induced upper gastrointestinal bleeding. The use of acetylsalicylic acid, even in low doses, may be associated with the onset of upper gastrointestinal bleeding as an idiosyncratic response. Considering the role of the genetic background in inter-individual responses to pharmacotherapy, we aimed to investigate the role of seven variants in the TNF-α, IL-ß, and IL-1RN genes in association with the risk of upper gastrointestinal bleeding in users of low-dose acetylsalicylic acid for the prevention of cardiovascular events. METHODS: A case-control study was conducted in a Brazilian hospital complex. The Case Group comprised patients diagnosed with upper gastrointestinal bleeding who were administered a low dose of acetylsalicylic acid (n=50). Two Control Groups were recruited: 1) low-dose acetylsalicylic acid users without gastrointestinal complaints and under the supervision of a cardiologist (n=50) and 2) healthy controls (n=189). Sociodemographic, clinical, pharmacotherapeutic, and lifestyle data were recorded through face-to-face interviews. Genomic DNA from all participants was genotyped for rs16944 and rs1143634 (IL-ß gene), rs4251961 (IL-1RN gene), and rs1799964, rs1799724, rs361525, and rs1800629 (TNF-α gene). RESULTS: No significant difference was noted in the genotypic frequencies of TNF-α, IL-ß, and IL-1RN variants between the Case and Control Groups of low-dose acetylsalicylic acid users (p>0.05). The frequency of rs1800629 genotypes (TNF-α gene) differed significantly between the Case Group and healthy controls (p=0.003). None of the evaluated variants were associated with a risk of upper gastrointestinal bleeding. CONCLUSION: This study aimed to explore pharmacogenomics biomarkers in low-dose acetylsalicylic acid users. Our data suggest that the presence of IL-1ß, IL-1RN, and TNF-α variants was not associated with an increased risk of upper gastrointestinal bleeding.
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Aspirina , Hemorragia Gastrointestinal , Proteína Antagonista del Receptor de Interleucina 1 , Interleucina-1beta , Factor de Necrosis Tumoral alfa , Humanos , Masculino , Estudios de Casos y Controles , Femenino , Aspirina/efectos adversos , Factor de Necrosis Tumoral alfa/genética , Interleucina-1beta/genética , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/genética , Persona de Mediana Edad , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/efectos adversos , Anciano , Factores de Riesgo , Genotipo , Predisposición Genética a la Enfermedad/genética , Adulto , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: There are only a few recognized drug targets for cerebral small vessel disease (CSVD). Though inflammation is increasingly implicated in the development of CSVD, it remains unclear whether immunomodulation could become a therapeutic target. Accordingly, the Mendelian randomization (MR) method was used to assess the genetically proxied impacts of IL6 receptor (IL6R) inhibitor, IL1ß inhibitor, Tumor necrosis factor (TNF) inhibitor and ß-tubulin inhibitor on CSVD through. METHODS: Single nucleotide polymorphisms (SNPs) near the IL6R, IL1ß, TNFRSF1A and ß-tubulin genes were identified as genetic proxies for immunomodulatory drugs. These SNPs exhibited significant associations with serum C-reactive protein (CRP) levels in a large European genome-wide association study. The causal effects of immunomodulatory drugs on CSVD manifestations and the mediation influence of 731 peripheral blood immune phenotypes linking these drugs to CSVD manifestations were examined using a two-sample two-step MR approach. RESULTS: A total of 9, 18, 4 and 1 SNP were identified to proxy the effects of IL1ß inhibitor, IL6R inhibitor, TNF inhibitor and ß-tubulin inhibitor, respectively. MR analysis showed a significant causal relationship between IL1ß inhibition and reduced volume of periventricular white matter hyperintensity (PWMH). IL6R inhibition was associated with a reduced risk of small vessel stroke, decreased axial diffusivity and mean diffusivity. Genetically proxied TNF inhibition may decrease the occurrence of cerebral microbleeds (CMBs) and severe enlarged perivascular spaces located at white matter (WM-EPVS). It could also protect WM integrity, as evidenced by the reduced volumes of PWMH and deep white matter hyperintensity (DWMH). Various peripheral blood immune phenotypes exhibited significant associations with immunomodulatory drugs. Notably, the median fluorescence intensity (MFI) of CD45 on CD8br cells partially mediated the effects of IL1ß inhibitor on PWMH volume. Indirect effects of TNF inhibition on PWMH and DWMH volume through the MFI of CD127 on CD28- CD8br cells were observed. The effects of TNF inhibition on the occurrence of any CMBs were partially mediated by the MFI of CD45 on natural killer T cells, and the effects of TNF inhibition on the occurrence of lobar CMBs were partially mediated by the MFI of HLA DR on CD33- HLA DR+ cells. Furthermore, the MFI of HLA DR on CD33- HLA DR+ cells partially mediated the effects of TNF inhibition on WM-EPVS. CONCLUSIONS: IL1ß inhibitor, IL6R inhibitor and TNF inhibitor were associated with lower burden of CSVD while the activation of certain immune cells such as Tregs and myeloid cells partially mediated their protective effects.
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Enfermedades de los Pequeños Vasos Cerebrales , Estudio de Asociación del Genoma Completo , Interleucina-1beta , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Humanos , Interleucina-1beta/genética , Agentes Inmunomoduladores/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , Tubulina (Proteína)/genéticaRESUMEN
STAT3 gain-of-function syndrome, characterized by early-onset autoimmunity and primary immune regulatory disorder, remains poorly understood in terms of its immunological mechanisms. We employed whole-genome sequencing of familial trios to elucidate the pivotal role of de novo mutations in genetic diseases. We identified 37 high-risk pathogenic loci affecting 23 genes, including a novel STAT3 c.508G>A mutation. We also observed significant down-regulation of pathogenic genes in affected individuals, potentially associated with inflammatory responses regulated by PTPN14 via miR378c. These findings enhance our understanding of the pathogenesis of STAT3 gain-of-function syndrome and suggest potential therapeutic strategies. Notably, combined JAK inhibitors and IL-6R antagonists may offer promising treatment avenues for mitigating the severity of STAT3 gain-of-function syndrome.
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Mutación con Ganancia de Función , Inflamación , Interleucina-1beta , Factor de Transcripción STAT3 , Humanos , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Niño , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Femenino , Inflamación/genética , Preescolar , MicroARNs/genéticaRESUMEN
The study evaluated the regenerative responses of the lacrimal functional unit (LFU) after lacrimal gland (LG) ablation. The LG of Wistar rats was submitted to G1) partial LG ablation, G2) partial ablation and transplantation of an allogeneic LG, or G3) total LG ablation, (n = 7-10/group). The eye wipe test, slit lamp image, tear flow, and histology were evaluated. RT-PCR analyzed inflammatory and proliferation mediators. The findings were compared to naïve controls after 1 and 2 months (M1 and M2). G3 presented increased corneal sensitivity, and the 3 groups showed corneal neovascularization. Histology revealed changes in the LG and corneal inflammation. In the LG, there was an increase in MMP-9 mRNA of G1 and G2 at M1 and M2, in RUNX-1 at M1 and M2 in G1, in RUNX-3 mRNA at M1 in G1, and at M2 in G2. TNF-α mRNA rose in the corneas of G1 and G2 at M2. There was an increase in the IL-1ß mRNA in the trigeminal ganglion of G1 at M1. Without changes in tear flow or evidence of LG regeneration, LG ablation and grafting are unreliable models for dry eye or LG repair in rats. The surgical manipulation extended inflammation to the LFU.
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Síndromes de Ojo Seco , Inflamación , Aparato Lagrimal , Ratas Wistar , Regeneración , Animales , Aparato Lagrimal/metabolismo , Aparato Lagrimal/patología , Aparato Lagrimal/cirugía , Síndromes de Ojo Seco/metabolismo , Síndromes de Ojo Seco/etiología , Síndromes de Ojo Seco/patología , Ratas , Inflamación/patología , Inflamación/metabolismo , Masculino , Córnea/metabolismo , Córnea/patología , Lágrimas/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Modelos Animales de EnfermedadRESUMEN
OBJECTIVE: To investigate the changes and clinical significance of NOD like receptor protein 3 (NLRP3) inflammasomes and related factors in patients with spinal fractures complicated with acute spinal cord injury (SCI). METHODS: Eighty-six spinal fracture patients complicated with acute SCI admitted to hospital from June 2019 to March 2022 were selected as SCI group, There were 48 males and 38 females, with an average age of (43.48±6.58) years old. And 100 healthy volunteers who underwent physical examination during the same time were selected as control group, including 56 males patients and 44 females patients, with an average age of (45.13±6.43) years old. Peripheral blood mononuclear cell (PBMC) were collected, and the mRNA expressions of NLRP3 and Caspase-1 were detected. Serum was collected and the levels of interleukin (IL)- 1ß, IL-18 were detected. According to Frankel's grade, the SCI group was divided into complete injury patients and incomplete injury patients, and according to the Japanese Orthopedic Society (JOA) grade, the SCI group was divided into good prognosis group and poor prognosis group. The difference of NLRP3, Caspase-1, IL-1ß, IL-18 among groups were compared, the influencing factors for poor prognosis in SCI patients was analyzed by Logistic regression. RESULTS: The mRNA expression levels of NLRP3 (1.41±0.33) and Caspase-1 (1.44±0.35) in PBMC and the levels of IL-1ß(45.34±13.22) pg·ml-1, IL-18(40.95±8.77) pg·ml-1 in serum of SCI group were higher than those of the control group[(1.00±0.19), (1.00±0.16), (16.58±4.24) pg·ml-1, (12.57±3.68) pg·ml-1] (P<0.05). The mRNA expression levels of NLRP3(1.63±0.34) and Caspase-1 (1.67±0.27) in PBMC and the levels of IL-1ß(51.09±11.10) pg·ml-1, IL-18 (47.65±7.93) pg·ml-1 in serum of patients with complete injury in the SCI group were higher than those of patients with incomplete injury [(1.31±0.27), (1.34±0.33), (42.85±13.36) pg·ml-1, (38.05±7.48) pg·ml-1](P<0.05). The mRNA expression levels of NLRP3 (1.66±0.31) and Caspase-1 (1.72±0.31)in PBMC and the levels of IL-1ß(51.21±11.31) pg·ml-1, IL-18 (45.70±7.25) pg·ml-1 in serum, the proportion of complete injury(21 patients), and the proportion of spinal cord edema or bleeding of patients(15 patients) with poor prognosis in the SCI group were higher than those of patients with good prognosis[(1.28±0.26), (1.37±0.36), (42.79±13.25) pg·ml-1ã(38.90±8.63) pg·ml-1, 5ã20 cases](P<0.05). Complete injury and the mRNA expression of NLRP3 in PBMC were the influencing factors for poor prognosis in the SCI group (P<0.05). CONCLUSION: The activation of NLRP3 inflammasomes in patients with spinal fractures complicated with acute SCI is associated with worsening injury and poor prognosis, and NLRP3 expression can serve as a marker for evaluating prognosis.
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Caspasa 1 , Inflamasomas , Interleucina-18 , Interleucina-1beta , Proteína con Dominio Pirina 3 de la Familia NLR , Traumatismos de la Médula Espinal , Fracturas de la Columna Vertebral , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Masculino , Femenino , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/sangre , Adulto , Persona de Mediana Edad , Interleucina-18/sangre , Interleucina-1beta/sangre , Interleucina-1beta/genética , Caspasa 1/sangre , Fracturas de la Columna Vertebral/sangre , Fracturas de la Columna Vertebral/complicaciones , Leucocitos Mononucleares/metabolismo , Pronóstico , Relevancia ClínicaRESUMEN
A growing number of patients presenting severe combined immunodeficiencies attributed to monoallelic RAC2 variants have been identified. The expression of the RHO GTPase RAC2 is restricted to the hematopoietic lineage. RAC2 variants have been described to cause immunodeficiencies associated with high frequency of infection, leukopenia, and autoinflammatory features. Here, we show that specific RAC2 activating mutations induce the NLRP3 inflammasome activation leading to the secretion of IL-1ß and IL-18 from macrophages. This activation depends on the activation state of the RAC2 variant and is mediated by the downstream kinase PAK1. Inhibiting the RAC2-PAK1-NLRP3 inflammasome pathway might be considered as a potential treatment for these patients.
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Mutación con Ganancia de Función , Inflamasomas , Interleucina-1beta , Macrófagos , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína RCA2 de Unión a GTP , Quinasas p21 Activadas , Proteínas de Unión al GTP rac , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Inflamasomas/inmunología , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Proteínas de Unión al GTP rac/genética , Proteínas de Unión al GTP rac/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Animales , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismo , Ratones , Interleucina-18/genética , Interleucina-18/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVES: Gestational hypertension (GH1) is one of the most common pregnancy-related complications, however, there is still insufficient knowledge about its development and molecular changes. The aim of our study was to examine the expression of miR-17, miR-29a and miR-181a, as well as TNF-α, IL-1ß, IL-6 and IL-17 in women with GH and to investigate possible correlations between these parameters. STUDY DESIGN: The study included 64 pregnant women, placed either in the control or the GH group. Quantitative real-time PCR (qPCR2) was used to determine expression levels of microRNAs and cytokines' mRNAs. MAIN OUTCOME MEASURES: Expression levels of miRNAs (miR-17, miR-29a and miR-181a) and proinflammatory cytokines mRNAs (TNF-α, IL-1ß, IL-6 and IL-17) in women with gestational hypertension were compared to the control group (healthy pregnant women). RESULTS: No significant changes in microRNAs expression level were found between compared groups. TNF-α was significantly upregulated in the GH group compared to controls. Expression levels of other investigated cytokines did not differ between examined groups. ROC curve analysis indicated that TNF-α does not show sufficient ability to discriminate between CG and GH patients. TNF-α was significantly positively correlated with IL-1ß and IL-17 and negatively correlated with miR-181a. CONCLUSIONS: Our results point to the involvement of proinflamatory cytokines in gestational hypertension. Although increased expression of TNF-α was found in the GH group, this cytokine did not show sufficient ability to discriminate between GH and healthy pregnancies.
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Citocinas , Hipertensión Inducida en el Embarazo , MicroARNs , ARN Mensajero , Humanos , Femenino , Embarazo , Hipertensión Inducida en el Embarazo/genética , MicroARNs/genética , Adulto , Citocinas/genética , ARN Mensajero/metabolismo , Estudios de Casos y Controles , Factor de Necrosis Tumoral alfa , Interleucina-1beta/genética , Interleucina-6/genéticaRESUMEN
This study evaluated the probiotic properties, safety profile, and antioxidative and immune system-enhancing effects of Enterococcus faecium strains isolated from human infant feces. E. faecium KU22001, E. faecium KU22002, and E. faecium KU22005 exhibited potential probiotic properties; however, to eliminate concerns about toxin production and antibiotic resistance, the E. faecium strains were heat-treated prior to experimental usage. E. faecium KU22001 showed the highest antioxidant activity and lowest reactive oxygen species production among the three strains. The immune system-enhancing effects of heat-killed E. faecium strains were evaluated using a nitric oxide assay. E. faecium KU22001 induced an increase in the mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, and proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in RAW 264.7 cells. Furthermore, E. faecium KU22001 activated the mitogen-activated protein kinase pathway, which was a key regulator of the immune system. These results demonstrate the potential use of E. faecium KU22001 as a multifunctional food material.
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Antioxidantes , Citocinas , Enterococcus faecium , Heces , Probióticos , Probióticos/farmacología , Ratones , Animales , Células RAW 264.7 , Humanos , Antioxidantes/metabolismo , Citocinas/metabolismo , Heces/microbiología , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Calor , Interleucina-6/metabolismo , Interleucina-6/genética , Factores Inmunológicos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Interleucina-1beta/metabolismo , Interleucina-1beta/genéticaRESUMEN
Cottonseed meal (CSM) and cottonseed protein concentrate (CPC) serve as protein alternatives to fish meal and soybean meal in the feed industry. However, the presence of gossypol residue in CSM and CPC can potentially trigger severe intestinal inflammation, thereby restricting the widespread utilization of these two protein sources. Probiotics are widely used to prevent or alleviate intestinal inflammation, but their efficacy in protecting fish against gossypol-induced enteritis remains uncertain. Here, the protective effect of Pediococcus pentosaceus, a strain isolated from the gut of Nile tilapia (Oreochromis niloticus), was evaluated. Three diets, control diet (CON), gossypol diet (GOS) and GOS supplemented with P. pentosaceus YC diet (GP), were used to feed Nile tilapia for 10 weeks. After the feeding trial, P. pentosaceus YC reduced the activity of myeloperoxidase (MPO) in the proximal intestine (PI) and distal intestine (DI). Following a 7-day exposure to Aeromonas hydrophila, the addition of P. pentosaceus YC was found to increase the survival rate of the fish. P. pentosaceus YC significantly inhibited the oxidative stress caused by gossypol, which was evidenced by lower reactive oxygen species (ROS) and malondialdehyde (MDA), as well as higher activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in PI and DI. Addition of P. pentosaceus YC significantly inhibited enteritis, with the lower expression of pro-inflammatory cytokines (il-1ß, il-6, il-8) and higher expression of anti-inflammatory cytokines tgf-ß. RNA-seq analysis indicated that P. pentosaceus YC supplementation significantly inhibited nlrc3 and promoted nf-κb expression in PI and DI, and the siRNA interference experiment in vivo demonstrated that intestinal inflammation was mediated by NLRC3/NF-κB/IL-1ß signaling pathway. Fecal bacteria transplantation experiment demonstrated that gut microbiota mediated the protective effect of P. pentosaceus YC. These findings offer valuable insights into the application of P. pentosaceus YC for alleviating gossypol-induced intestinal inflammation in fish.
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Alimentación Animal , Cíclidos , Enfermedades de los Peces , Gosipol , Pediococcus pentosaceus , Probióticos , Transducción de Señal , Animales , Cíclidos/inmunología , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/inducido químicamente , Enfermedades de los Peces/prevención & control , Probióticos/farmacología , Probióticos/administración & dosificación , Alimentación Animal/análisis , Transducción de Señal/efectos de los fármacos , Gosipol/administración & dosificación , Gosipol/farmacología , Dieta/veterinaria , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Aeromonas hydrophila/fisiología , FN-kappa B/metabolismo , FN-kappa B/genética , Microbioma Gastrointestinal/efectos de los fármacos , Intestinos/efectos de los fármacos , Intestinos/inmunología , Inflamación/veterinaria , Inflamación/inducido químicamente , Inflamación/inmunología , Infecciones por Bacterias Gramnegativas/veterinaria , Infecciones por Bacterias Gramnegativas/inmunología , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Proteínas de Peces/inmunología , Enteritis/veterinaria , Enteritis/prevención & control , Enteritis/inducido químicamente , Enteritis/inmunología , Enteritis/microbiologíaRESUMEN
Whole-genome sequencing was used to identify a dominant inherited NLRP12 c.1382dup mutation in refractory familial Crohn's disease (CD) patients. Additionally, we observed a T insertion at position 1382 in the third exon of NLRP12, leading to a frameshift mutation. Isolation of peripheral blood from mutation carriers and subsequent experiments demonstrated increased interleukin (IL)-1ß in CD patients with the NLRP12 c.1382dup mutation. However, the mechanisms by which the NLRP12 c.1382dup mutation mediates IL-1ß remain unclear. Our research findings reveal a close correlation between elevated p-ERK levels and increased expression of NLRP3 and IL-1ß in the presence of the NLRP12 c.1382dup mutation. Further experiments demonstrate that inhibiting p-ERK with PD98059 effectively reduces the production of NLRP3 and IL-1ß. This discovery provides new insights into the pathogenesis of CD, highlighting the significant role of the ERK/NLRP3/IL-1ß pathway in the progression of CD. Not only does this offer novel therapeutic targets for treating CD, but it also lays the groundwork for the development of treatment strategies targeting this pathway.
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Enfermedad de Crohn , Interleucina-1beta , Proteína con Dominio Pirina 3 de la Familia NLR , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Humanos , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Masculino , Femenino , Adulto , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Sistema de Señalización de MAP Quinasas , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Transducción de Señal , Persona de Mediana EdadRESUMEN
Objective To explore the regulatory mechanism of interleukin-33 (IL-33) on the inflammatory response in asthmatic mice. Methods Using 10 µg/mL of lipopolysaccharide (LPS) to establish a cellular inflammation model of mouse bone marrow mesenchymal stem cells (BMMSCs), the cells were divided into three groups: small interfering RNA of IL-33(si-IL-33) group, IL-33 overexpression (IL-33-OE) group, and model group, based on the transfection status of si-IL-33 plasmid and IL-33-OE plasmid. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect mRNA expression of IL-33, nucleotide binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), IL-1ß and IL-6. Fluo-3 AM was used to measure calcium ion content, and JC-1 mitochondrial membrane potential detection kit was performed to detect mitochondrial membrane potential changes. An asthma mouse model was established by intraperitoneal injection of sensitizers and activators. According to different treatment plans, the asthmatic mice were divided into si-IL-33 group, IL-33-OE group and model group, with 5 mice in each group. ELISA was used to detect the levels of IL-1ß, IL-6 and NLRP3 in mouse serum, while HE staining and Masson staining were performed to assess lung tissue lesions. Results Compared with the model group, the mRNA expression levels of IL-33, NLRP3, IL-1ß and IL-6 in the si-IL-33 group were all reduced, while those in the IL-33-OE group were increased. The calcium ion fluorescence was decreased in BMMSCs, while it was increased in the IL-33-OE group. In the si-IL-33 group, JC-1 existed in a polymer form in mitochondria, showing bright red fluorescence and weak green fluorescence, indicating stable mitochondria and normal mitochondrial function. After treating with IL-33-OE plasmid to reduce the mitochondrial membrane potentia, JC-1 cannot exist in polymer form within the mitochondrial matrix. At this point, the red fluorescence intensity inside the mitochondria decreases significantly, while the green fluorescence in the cytoplasm increases significantly. The levels of IL-1ß, IL-6, and NLRP3 in the serum of mice in the si-IL-33 group were significantly lower, while those in the IL-33-OE group were significantly higher. In the si-IL-33 group, almost no inflammatory cell infiltration was observed, indicating a relief of inflammation and normal epithelial cell morphology. Additionally, the fibrotic portion of the lung tissue in the si-IL-33 group tended to be normal. The total wall area of bronchus (WAt)/basement membrane perimeter (Pbm) and wall area of bronchial smooth muscle (WAm)/Pbm were reduced in the si-IL-33 group compared with the model group, while they were increased in the IL-33-OE group. Conclusion Knockdown of IL-33 inhibits the inflammatory response in asthmatic mice by downregulating the expression of NLRP3, IL-1ß and IL-6.
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Asma , Interleucina-33 , Ratones Endogámicos BALB C , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Interleucina-33/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Asma/genética , Asma/inmunología , Asma/metabolismo , Asma/terapia , Ratones , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Inflamación/genética , Inflamación/metabolismo , Femenino , Potencial de la Membrana Mitocondrial , Interleucina-6/genética , Interleucina-6/metabolismo , Técnicas de Silenciamiento del Gen , Células Madre Mesenquimatosas/metabolismoRESUMEN
The prevalence of Metabolic-associated fatty liver disease (MAFLD) has been steadily increasing worldwide, paralleling the global epidemic of obesity and diabetes. It is estimated that approximately one-quarter of the global population is affected by MAFLD. Despite its high prevalence, MAFLD often goes undiagnosed due to the lack of specific symptoms in its early stages. However, as the disease progresses, it can lead to more severe liver-related complications such as fibrosis, cirrhosis, and hepatocellular carcinoma. Therefore, we aimed to investigate the expression levels of the nucleotide-binding oligomerization domain, leucine-rich repeat (LRR)-containing proteins (NLR) family pyrin domain-containing protein 3 [NLRP3] inflammasome pathway components, NLRP3 and interleukin 1ß (IL-1ß) genes in patients with MAFLD with various degrees of steatosis and fibrosis. Participants were classified into two equal groups; MAFLD group: consisted of 120 patients with different degrees of hepatic fibrosis and steatosis based on fibro scan results. The non-MAFLD group was comprised of 107 participants. Molecular analysis of pyrin domain-containing protein 3 and IL-1ß relative gene expressions was performed in the blood of all participants, using Real-time quantitative polymerase chain reaction (RT-qPCR). Patients with post-MAFLD hepatic fibrosis had significantly higher relative gene expression levels of IL-1ß and NLRP3; with IL-1ß > 1.1 had AUC of 0.919, sensitivity of 88.33, specificity of 96.26, PPV of 96.4, and NPV of 88 and 92.3 accuracy (p value < 0.001). NLRP3 > 1.33 had a sensitivity of 97.5, specificity of 99.07, PPV of 99.2, NPV of 97.2, and 98.3 accuracy with an AUC of 0.991 (p value < 0.001) as predictors of post-MAFLD hepatic fibrosis.. A significant increase in the mean relative gene expression levels of both IL-1ß and NLRP3 found in patients with early fibrosis (F0-F1-2); 31.97 ± 11.8 and 6.76 ± 2.18, respectively; compared with patients with advanced hepatic fibrosis stages (F2-F3); 2.62 ± 3.71 and 4.27 ± 2.99 (p < 0.001 each). The present study provides novel evidence for the possible involvement of IL-1ß and NLRP3 inflammasome in metabolic-associated fatty liver disease pathogenesis and could be valid markers for the early detection of post-MAFLD hepatic fibrosis.