RESUMO

This study aimed to investigate the impact of different types of nasal inflammation on the regulation of entry-associated genes of respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus 229E (HCoV-229E), and influenza virus, in the nasal epithelium. Subjects were classified into three groups: control, eosinophilic chronic rhinosinusitis (ECRS), and noneosinophilic CRS (NECRS) groups. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), alanyl aminopeptidase (ANPEP), dipeptidyl peptidase 4 (DPP4), and beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1), and beta-galactoside alpha-2,3-sialyltransferase 4 (ST3GAL4) were selected as key entry-associated genes for SARS-CoV-2, HCoV-229E, MERS-CoV, and influenza, respectively, and were evaluated. Brushing samples obtained from each group and human nasal epithelial cells cultured using an air-liquid interface system were treated for 7 days with typical inflammatory cytokines and analyzed using real-time polymerase chain reaction. Western blot analysis and confocal microscopy were performed. The entry-associated genes showed distinct regulation patterns in response to each interleukin-4 (IL-4), interleukin-13 (IL-13), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Specifically, ACE2 significantly decreased in type 2 cytokines (IL-4 and IL-13), while TMPRSS2 significantly decreased in type 1 cytokines (TNF-α and IFN-γ). ANPEP significantly decreased in both types of cytokines. Remarkably, DPP4 significantly increased in type 2 cytokines and decreased in type 1 cytokines. Moreover, ST6GAL1 and ST3GAL4 significantly increased in type 2 cytokines and decreased in type 1 cytokines, particularly IFN-γ. These findings were supported by western blot analysis and confocal imaging results, especially for ACE2 and DPP4. The findings regarding differential regulation suggest that patients with ECRS, primarily mediated by type 2 inflammation, may have lower susceptibility to SARS-CoV-2 and HCoV-229E infections but higher susceptibility to MERS-CoV and influenza infections.

Assuntos

Citocinas , Mucosa Nasal , Internalização do Vírus , Humanos , Citocinas/genética , Citocinas/metabolismo , Mucosa Nasal/virologia , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Sinusite/virologia , Sinusite/genética , Sinusite/imunologia , SARS-CoV-2/imunologia , Rinite/virologia , Rinite/genética , Rinite/imunologia , Regulação da Expressão Gênica , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , COVID-19/imunologia , COVID-19/virologia , Coronavirus Humano 229E/genética , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia

RESUMO

In the context of the development of intervertebral disc degeneration (IDD), inflammatory mediators play a pivotal role. Nevertheless, due to the influence of the inflammatory microenvironment, the causal relationship between specific inflammatory mediators and the development of IDD remains uncertain. The understanding of the causal relationship between inflammatory mediators and IDD is of great importance in preventing and delaying disc degeneration in the future. We utilized genetic data concerning systemic circulating inflammatory regulators obtained from a Genome-Wide Association Study (GWAS) analyzing 41 serum cytokines in a cohort of 8293 individuals from Finland. The genetic data for IDD were derived from the most recent GWAS summary statistics conducted within the FinnGen consortium, encompassing 37,636 IDD cases and 270,964 controls. Our analysis employed bidirectional 2-sample Mendelian randomization (MR) techniques, which included several MR methods such as MR Egger, weighted median, inverse variance weighted, weighted mode, and simple mode. Additionally, the MR-PRESSO method was employed to identify horizontal pleiotropy, heterogeneity was quantified using the Cochran Q statistic, and MR-Egger intercept analysis was performed to assess pleiotropy. We established causal relationships between 3 specific inflammatory factors and IDD. Elevated levels of MIP-1ß (OR = 0.956, 95% CI: -0.08 to -0.006; P = .02) and IFN-G (OR = 0.915, 95% CI: -0.16 to -0.02; P = .01) expression were associated with a reduced risk of IDD. Conversely, genetic susceptibility to IDD was linked to a decrease in IL-13 levels (OR = 0.967, 95% CI: -0.063 to -0.004; P = .03). In this study, we have identified inflammatory factors that exhibit a causal relationship with the onset and progression of IDD, as supported by genetic predictions.

Assuntos

Estudo de Associação Genômica Ampla , Degeneração do Disco Intervertebral , Análise da Randomização Mendeliana , Humanos , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/epidemiologia , Degeneração do Disco Intervertebral/sangue , Masculino , Feminino , Finlândia/epidemiologia , Citocinas/sangue , Citocinas/genética , Polimorfismo de Nucleotídeo Único , Pessoa de Meia-Idade , Mediadores da Inflamação/sangue , Inflamação/genética , Inflamação/sangue , Predisposição Genética para Doença

RESUMO

Inflammation may be related to structural changes in the cerebral cortex. We aimed to explore whether cytokines mediate the link between these changes and primary headache. The summary statistics of genome-wide association study (GWAS) related to migraine and its subtypes, cluster headache were derived from the FinnGen Release 10 database, and tension-type headache data was from the GWAS Catalog. Ninety-one cytokines were obtained from genome-wide pQTL mapping data. GWAS data on cortical surface area (SA) and thickness (TH) came from the ENIGMA Consortium. The methods of Mendelian randomization (MR) analysis included the inverse-variance-weighted (IVW), MR-Egger, and weighted median. Migraine reduces the SA of paracentral[ß = -1.3645, OR = 0.2555, 95%CI (0.0660, 0.9898)] by fibroblast growth factor-23(FGF-23), with an intermediate ratio (IR) of 38.13%. Migraine may reduce the TH of superior parietal[ß = -0.0029, OR = 0.9971, 95%CI (0.9943, 0.9999)] by interleukin (IL)-15RA, with an absolute IR of 11.11%. Migraine without aura may reduce the TH of rostral anterior cingulate[ß = -0.0005, OR = 0.9995, 95%CI (0.9991, 0.9999)] by IL-18R1, with an IR of 11.63%. FGF23 and IL-15RA are associated with reduced SA or TH in migraine, while IL-18R1 is associated with increased TH in migraine without aura.

Assuntos

Córtex Cerebral , Citocinas , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Córtex Cerebral/patologia , Córtex Cerebral/diagnóstico por imagem , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/patologia

RESUMO

Neutrophil extracellular traps (NETs), crucial in immune defense mechanisms, are renowned for their propensity to expel decondensed chromatin embedded with inflammatory proteins. Our comprehension of NETs in pathogen clearance, immune regulation and disease pathogenesis, has grown significantly in recent years. NETs are not only pivotal in the context of infections but also exhibit significant involvement in sterile inflammation. Evidence suggests that excessive accumulation of NETs can result in vessel occlusion, tissue damage, and prolonged inflammatory responses, thereby contributing to the progression and exacerbation of various pathological states. Nevertheless, NETs exhibit dual functionalities in certain pathological contexts. While NETs may act as autoantigens, aggregated NET complexes can function as inflammatory mediators by degrading proinflammatory cytokines and chemokines. The delineation of molecules and signaling pathways governing NET formation aids in refining our appreciation of NETs' role in immune homeostasis, inflammation, autoimmune diseases, metabolic dysregulation, and cancer. In this comprehensive review, we delve into the multifaceted roles of NETs in both homeostasis and disease, whilst discussing their potential as therapeutic targets. Our aim is to enhance the understanding of the intricate functions of NETs across the spectrum from physiology to pathology.

Assuntos

Doenças Autoimunes , Armadilhas Extracelulares , Homeostase , Inflamação , Neutrófilos , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/genética , Humanos , Homeostase/imunologia , Inflamação/imunologia , Inflamação/patologia , Inflamação/genética , Neutrófilos/imunologia , Neutrófilos/patologia , Neutrófilos/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/genética , Citocinas/imunologia , Citocinas/metabolismo , Citocinas/genética , Transdução de Sinais/imunologia , Animais

RESUMO

BACKGROUND: Osteoarthritis (OA) and rheumatoid arthritis (RA) are often difficult to distinguish in the early stage of the disease. The purpose of this study was to explore the similarities and differences between the two diseases through Mendelian randomization (MR) and transcriptome analysis. METHODS: We first performed a correlation analysis of phenotypic data from genome-wide association studies (GWAS) of OA and RA. Then, we performed functional and pathway enrichment of differentially expressed genes in OA, RA, and normal patients. The infiltration of immune cells in arthritis was analyzed according to gene expression. Finally, MR analysis was performed with inflammatory cytokines and immune cells as exposures and arthritis as the outcome. The same and different key cytokines and immune cells were obtained by the two analysis methods. RESULTS: GWAS indicated that there was a genetic correlation between OA and RA. The common function of OA and RA is enriched in their response to cytokines, while the difference is enriched in lymphocyte activation. T cells are the main immune cells that differentiate between OA and RA. MR analysis further revealed that OA is associated with more protective cytokines, and most of the cytokines in RA are pathogenic. In addition, CCR7 on naive CD4 + T cell was positively correlated with OA. SSC-A on CD4 + T cell was negatively correlated with RA, while HLA DR on CD33- HLA DR + was positively correlated with RA. CONCLUSION: Our study demonstrated the similarities and differences of immune inflammation between OA and RA, allowing us to better understand these two diseases.

Assuntos

Artrite Reumatoide , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Osteoartrite , Humanos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Osteoartrite/genética , Citocinas/metabolismo , Citocinas/genética , Fenótipo , Transcriptoma/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética

RESUMO

Protozoan parasite Neospora caninum causes abortion in infected cattle while others remain asymptomatic. Host immunity plays a critical role in the outcome of bovine neosporosis. Despite extensive research, there is a critical gap in therapeutic and preventive measures, and no effective vaccines are available. Both beef and dairy cattle can suffer from N. caninum-induced abortions, but cumulative evidence suggests a breed susceptibility being higher in dairy compared with beef breeds. It has been established that the response to N. caninum infection primarily involves a cell-mediated immune response (CMIR) regulated by T-helper type 1 (Th1) cells and specific cytokines. The delayed-type hypersensitivity (DTH) skin test has been used to measure the ability of livestock to generate CMIR, in the context of breeding for disease resistance and as a method for diagnosis of several diseases. In this study, we evaluated the immune response triggered by an N. caninum-induced DTH skin test between Holstein - a dairy breed intensively selected- and Argentinean Creole heifers - a beef breed with minimal genetic selection- to assess differences in CMIR following experimental N. caninum infection. The immune response, measured through skinfold thickness and histological and immune molecular analysis, revealed variations between the breeds. Our study found an increased CMIR in Argentinean Creole heifers compared to Holstein heifers. Differential gene expression of key cytokines was observed at the DTH skin test site. Argentinean Creole heifers exhibited elevated IFN-γ, IL-12, IL-10, and IL-4, while Holstein heifers only showed higher expression of IL-17. This finding could underscore genetic diversity in response to neosporosis, which could be used in breeding cattle strategies for disease resistance in cattle populations.

Assuntos

Doenças dos Bovinos , Coccidiose , Imunidade Celular , Neospora , Animais , Bovinos , Neospora/imunologia , Coccidiose/veterinária , Coccidiose/imunologia , Coccidiose/parasitologia , Feminino , Doenças dos Bovinos/imunologia , Doenças dos Bovinos/parasitologia , Doenças dos Bovinos/genética , Citocinas/genética , Citocinas/imunologia , Hipersensibilidade Tardia/imunologia , Hipersensibilidade Tardia/veterinária

RESUMO

Oxymatrine (OMT) as a quinazine alkaloid extracted from matrine has been shown to exhibit anti-inflammatory and anti-tumour effects. However, the protective mechanism of OMT on NSAID-associated small bowel mucosal injury remains unreported. We found that OMT could improve the clinical symptoms and pathological inflammation scoring, reduce the secretion of proinflammatory cytokines IL-1ß, IL-6 and TNF-α and cell apoptosis, promote cell proliferation and protect intestinal mucosal barrier as compared with the Diclofenac Sodium (DS) group. Further RNA-seq and KEGG analysis uncovered that the differentially expressed genes between DS and control groups were mainly enriched in immune regulation, of which MIP-1γ and its receptor CCR1 expression were validated to be repressed by OMTH. MAPK/NF-κB as the MIP-1 upstream signalling was also inactivated by OMT treatment. In this study, OMT regulated gut microbiota. Venn diagrams visualized and identified 1163 shared OTUs between DS group and OMTH group. The results showed that the α diversity index in the DS group was lower than that in the OMTH group, indicating that the complexity of the flora was reduced in the intestinal inflammatory state. ß diversity mainly includes Principal Component Analysis (PCA) and Principal Co-ordinates Analysis (PCoA). The differences between groups can be observed through PCA. The more similar the composition of the flora, the closer the samples are. We found that the difference was smaller in the DS group than in the OMTH group. The results of PcoA showed that the sample similarity between OMTH groups was the highest. Moreover, gut microbiota analysis unveiled that the abundances of Ruminococcus 1, Oscillibacter and Prevotellaceae at the genus level as well as Lactobacillus SP-L-Yj at the species level were increased in OMTH group as compared with the DS group but the abundance of Allobaculum, Ruminococceos-UCG-005, Ruminococceos-NK4A214 and Clostridium associated with DS-induced small bowel mucosal injury could be decreased by OMTH. MIP-1α and CCR1 were upregulated in human small bowel injury samples as compared with the normal ileal mucosa tissues. In conclusion, our findings demonstrated that OMT could alleviate NSAID-associated small bowel mucosal injury by inhibiting MIP-1γ/CCR1 signalling and regulating gut microbiota.

Assuntos

Alcaloides , Anti-Inflamatórios não Esteroides , Microbioma Gastrointestinal , Mucosa Intestinal , Quinolizinas , Receptores CCR1 , Transdução de Sinais , Quinolizinas/farmacologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Alcaloides/farmacologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Animais , Masculino , Receptores CCR1/metabolismo , Receptores CCR1/genética , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/microbiologia , Intestino Delgado/metabolismo , Diclofenaco/efeitos adversos , Apoptose/efeitos dos fármacos , Humanos , Citocinas/metabolismo , Citocinas/genética , Matrinas

RESUMO

BACKGROUND: The genetic association between urticaria and mental disorders and whether inflammatory cytokines mediate this process remains unclear. MATERIALS AND METHODS: A Mendelian randomization (MR) approaches to elucidate the causal relationship between urticaria and mental disorders and to validate the mediation of inflammatory cytokines. Genome-wide association study (GWAS) databases used were obtained from Psychiatric Genomics Cooperation (PGC), GWAS Catalog, and FinnGen Consortium. Our study was conducted using inverse variance weighted (IVW) and Bayesian weighted MR (BWMR) methods for joint analysis. RESULTS: The MR results showed that urticaria increased the risk of attention deficit hyperactivity disorder (ADHD) (odds ratio [OR] = $ = $ 1.088, 95% confidence interval [CI]: 1.026-1.154, p = $ = $ 0.0051); cholinergic urticaria increased the risk of bipolar disorder (BD) (OR = $ = $ 1.012, 95% CI: 1.001-1.022, p = $ = $ 0.0274); dermatographic urticaria increased the risk of ADHD (OR = $ = $ 1.057, 95% CI: 1.005-1.112, p = $ = $ 0.0323); idiopathic urticaria increased the risk of schizophrenia (SCZ) (OR = $ = $ 1.057, 95% CI: 1.005-1.112, p = $ = $ 0.0323); other unspecified urticaria increased the risk of ADHD (OR = $ = $ 1.085, 95% CI: 1.023-1.151, p = $ = $ 0.0063). We found that eight inflammatory cytokines were negatively associated with mental disorders and seven inflammatory cytokines were positively associated with mental disorders. Finally, our results suggested that inflammatory cytokines do not act as mediators between urticaria and mental disorders. CONCLUSIONS: Our study reveals a causal relationship between urticaria and the increased risk of mental disorders. We suggest that the treatment of urticaria could incorporate psychiatric interventions and mental health assessment of patients.

Assuntos

Transtorno do Deficit de Atenção com Hiperatividade , Citocinas , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos Mentais , Urticária , Humanos , Citocinas/genética , Urticária/genética , Transtornos Mentais/genética , Transtornos Mentais/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Predisposição Genética para Doença/genética , Transtorno Bipolar/genética , Polimorfismo de Nucleotídeo Único

RESUMO

The role of astroglial and microglial cells in the pathogenesis of epilepsy is currently under active investigation. It has been proposed that the activity of these cells may be regulated by the agonists of peroxisome proliferator-activated nuclear receptors (PPARs). This study investigated the effects of a seven-day treatment with the PPAR ß/δ agonist GW0742 (Fitorine, 5 mg/kg/day) on the behavior and gene expression of the astroglial and microglial proteins involved in the regulation of epileptogenesis in the rat brain within a lithium-pilocarpine model of temporal lobe epilepsy (TLE). TLE resulted in decreased social and increased locomotor activity in the rats, increased expression of astro- and microglial activation marker genes (Gfap, Aif1), pro- and anti-inflammatory cytokine genes (Tnfa, Il1b, Il1rn), and altered expression of other microglial (Nlrp3, Arg1) and astroglial (Lcn2, S100a10) genes in the dorsal hippocampus and cerebral cortex. GW0742 attenuated, but did not completely block, some of these impairments. Specifically, the treatment affected Gfap gene expression in the dorsal hippocampus and Aif1 gene expression in the cortex. The GW0742 injections attenuated the TLE-specific enhancement of Nlrp3 and Il1rn gene expression in the cortex. These results suggest that GW0742 may affect the expression of some genes involved in the regulation of epileptogenesis.

Assuntos

Astrócitos , Modelos Animais de Doenças , Epilepsia do Lobo Temporal , Microglia , PPAR delta , PPAR beta , Tiazóis , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Ratos , PPAR delta/agonistas , PPAR delta/genética , PPAR delta/metabolismo , Masculino , Tiazóis/farmacologia , Tiazóis/uso terapêutico , PPAR beta/agonistas , PPAR beta/genética , PPAR beta/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Pilocarpina/farmacologia , Citocinas/metabolismo , Citocinas/genética , Fenóis , Compostos de Sulfidrila

RESUMO

MicroRNAs (miRNAs) play important roles in the regulation of cellular function and fate via post-transcriptional regulation of gene expression. Although several miRNAs are associated with physiological processes and kidney diseases, not much is known about changes in miRNAs in aging kidneys. We previously demonstrated that sodium hydrogen exchanger 1 (NHERF1) expression regulates cellular responses to cisplatin, age-dependent salt-sensitive hypertension, and sodium-phosphate cotransporter trafficking. However, the mechanisms driving these regulatory effects of NHERF1 on cellular processes are unknown. Here, we hypothesize that dysregulation of miRNA-mediated gene regulatory networks that induce fibrosis and cytokines may depend on NHERF1 expression. To address this hypothesis, we compared miRNA expression in kidneys from both male and female old (12-18-month-old) and young (4-7-month-old) wild-type (WT) and NHERF1 knockout (NHERF1-/-) mice. Our results identified that miRNAs significantly decreased in NHERF1-/- mice included miR-669m, miR-590-3p, miR-153, miR-673-3p, and miR-127. Only miR-702 significantly decreased in aged WT mice, while miR-678 decreased in both WT and NHERF1-/- old versus young mice. miR-153 was shown to downregulate transcription factors NFATc2 and NFATc3 which regulate the transcription of several cytokines. Immunohistochemistry and western blotting revealed a significant increase in nuclear NFATc2 and NFATc3 in old NHERF1-/- mice compared to old WT mice. Our data further show that expression of the cytokines IL-1ß, IL-6, IL-17A, MCP1, and TNF-α significantly increased in the old NHERF1-/- mice compared to the WT mice. We conclude that loss of NHERF1 expression induces cytokine expression in the kidney through interactive regulation between miR-153 and NFATc2/NFATc3 expression.

Assuntos

Envelhecimento , Rim , MicroRNAs , Fosfoproteínas , Trocadores de Sódio-Hidrogênio , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Trocadores de Sódio-Hidrogênio/genética , Trocadores de Sódio-Hidrogênio/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Camundongos , Rim/metabolismo , Masculino , Feminino , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Camundongos Knockout , Regulação da Expressão Gênica , Citocinas/metabolismo , Citocinas/genética , Camundongos Endogâmicos C57BL

RESUMO

BACKGROUND: Sarcopenic obesity, which is associated with a poorer prognosis than that of sarcopenia alone, may be positively affected by soy isoflavones, known inhibitors of muscle atrophy. Herein, we hypothesize that these compounds may prevent sarcopenic obesity by upregulating the gut metabolites with anti-inflammatory effects. METHODS: To explore the effects of soy isoflavones on sarcopenic obesity and its mechanisms, we employed both in vivo and in vitro experiments. Mice were fed a high-fat, high-sucrose diet with or without soy isoflavone supplementation. Additionally, the mouse C2C12 myotube cells were treated with palmitic acid and daidzein in vitro. RESULTS: The isoflavone considerably reduced muscle atrophy and the expression of the muscle atrophy genes in the treated group compared to the control group (Fbxo32, p = 0.0012; Trim63, p < 0.0001; Foxo1, p < 0.0001; Tnfa, p = 0.1343). Elevated levels of daidzein were found in the muscles and feces of the experimental group compared to the control group (feces, p = 0.0122; muscle, p = 0.0020). The real-time PCR results demonstrated that the daidzein decreased the expression of the palmitate-induced inflammation and muscle atrophy genes in the C2C12 myotube cells (Tnfa, p = 0.0201; Il6, p = 0.0008; Fbxo32, p < 0.0001; Hdac4, p = 0.0002; Trim63, p = 0.0114; Foxo1, p < 0.0001). Additionally, it reduced the palmitate-induced protein expression related to the muscle atrophy in the C2C12 myotube cells (Foxo1, p = 0.0078; MuRF1, p = 0.0119). CONCLUSIONS: The daidzein suppressed inflammatory cytokine- and muscle atrophy-related gene expression in the C2C12 myotubes, thereby inhibiting muscle atrophy.

Assuntos

Citocinas , Isoflavonas , Atrofia Muscular , Isoflavonas/farmacologia , Animais , Camundongos , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Masculino , Citocinas/metabolismo , Citocinas/genética , Linhagem Celular , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Sarcopenia/prevenção & controle , Sarcopenia/metabolismo , Sarcopenia/tratamento farmacológico , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Glycine max/química , Modelos Animais de Doenças , Ácido Palmítico/farmacologia

RESUMO

Immune responses of the epithelia of the upper respiratory tract are likely crucial in early inhibition of the viral replication and finally clearance of SARS-CoV-2. We aimed to compare the expression profiles of antimicrobial peptides/proteins (AMPs) and related cytokines observed in the nasopharynx of SARS-CoV-2-infected patients and non-infected controls and to assess the associations between these parameters and COVID-19 patients' outcomes. We included 45 subjects who had tested positive for SARS-CoV-2 and 22 control subjects who had tested negative for SARS-CoV-2. Biomaterial for SARS-CoV-2 detection, as well as gene and protein expression studies, was obtained from all subjects using nasopharyngeal swabs which were performed a maximum of 7 days before inclusion in the study. Univariable and multivariable statistics were performed. When compared to the controls, the mRNA expression levels of human ß-defensin 1 (hBD-1), LL-37, and trappin-2 were significantly higher in specimens of nasopharyngeal swabs from COVID-19 patients. Protein expression of hBD-1 was also increased in the COVID-19 group. mRNA expression levels of interferon-É£ (IFN-É£), tumor necrosis factor- ɑ (TNF-ɑ), and interleukin-6 (IL-6) measured in SARS-CoV-2-infected patients were significantly higher than those observed in the controls, which could also be confirmed in the protein levels of IFN-É£ and IL-6. A significant correlation between mRNA and protein levels could be observed only for IL-6. Univariable analysis revealed that low IFN-É£ mRNA levels were associated with severe/fatal outcomes. The occurrence of COVID-19 pneumonia was significantly associated with lower expression levels of IL-6 mRNA, IFN-É£ mRNA, and TNF-ɑ mRNA. Concerning the severe/fatal outcomes, the multivariable logistic regression model revealed that none of the aforementioned parameters remained significant in the model. However, the logistic regression model revealed that higher TNF-ɑ mRNA expression was a significant independent predictor of absence of pneumonia [odds ratio: 0.35 (95% CI 0.14 to 0.88, p = 0.024)]. In conclusion, nasopharyngeal expression of AMPs (hBD-1, LL-37, and trappin-2) and cytokines (IL-6, IFN-É£, and TNF-ɑ) is upregulated in response to early SARS-CoV-2 infection, indicating that these AMPs and cytokines play a role in the local host defense against the virus. Upregulated nasopharyngeal TNF-ɑ mRNA expression during the early phase of SARS-CoV-2 infection was a significant independent predictor of the absence of COVID-19 pneumonia. Hence, high TNF-ɑ mRNA expression in the nasopharynx appears to be a protective factor for lung complications in COVID-19 patients.

Assuntos

Peptídeos Antimicrobianos , COVID-19 , Citocinas , Nasofaringe , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/virologia , COVID-19/metabolismo , Nasofaringe/virologia , Nasofaringe/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Citocinas/metabolismo , Citocinas/genética , Adulto , Peptídeos Antimicrobianos/genética , Peptídeos Antimicrobianos/metabolismo , Idoso

RESUMO

BACKGROUND: Anisakis spp. are zoonotic nematodes causing mild to severe acute and chronic gastrointestinal infections. Chronic anisakiasis can lead to erosive mucosal ulcers, granulomas and inflammation, potential tumorigenic triggers. How Anisakis exerts its pathogenic potential through extracellular vesicles (EVs) and whether third-stage infective larvae may favor a tumorigenic microenvironment remain unclear. METHODS: Here, we investigated the parasite's tumorigenic and immunomodulatory capabilities using comparative transcriptomics, qRT-PCR and protein analysis with multiplex ELISA on human intestinal organoids exposed to Anisakis EVs. Moreover, EVs were characterized in terms of shape, size and concentration using classic TEM, SEM and NTA analyses and advanced interferometric NTA. RESULTS: Anisakis EVs showed classic shape features and a median average diameter of around 100 nm, according to NTA and iNTA. Moreover, a refractive index of 5-20% of non-water content suggested their effective biological cargo. After treatment of human intestinal organoids with Anisakis EVs, an overall parasitic strategy based on mitigation of the immune and inflammatory response was observed. Anisakis EVs impacted gene expression of main cytokines, cell cycle regulation and protein products. Seven key genes related to cell cycle regulation and apoptosis were differentially expressed in organoids exposed to EVs. In particular, the downregulation of EPHB2 and LEFTY1 and upregulation of NUPR1 genes known to be associated with colorectal cancer were observed, suggesting their involvement in tumorigenic microenvironment. A statistically significant reduction in specific mediators of inflammation and cell-cycle regulation from the polarized epithelium as IL-33R, CD40 and CEACAM1 from the apical chambers and IL-1B, GM-CSF, IL-15 and IL-23 from both chambers were observed. CONCLUSIONS: The results here obtained unravel intestinal epithelium response to Anisakis EVs, impacting host's anthelminthic strategies and revealing for the first time to our knowledge the host-parasite interactions in the niche environment of an emerging accidental zoonosis. Use of an innovative EV characterization approach may also be useful for study of other helminth EVs, since the knowledge in this field is very limited.

Assuntos

Anisakis , Vesículas Extracelulares , Organoides , Humanos , Organoides/parasitologia , Organoides/imunologia , Anisakis/imunologia , Anisakis/genética , Animais , Vesículas Extracelulares/imunologia , Anisaquíase/parasitologia , Anisaquíase/imunologia , Citocinas/metabolismo , Citocinas/genética , Intestinos/parasitologia , Intestinos/imunologia , Carcinogênese , Imunomodulação

RESUMO

Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) with Methicillin-Resistant S. aureus (MRSA) strains being a major contributor in both community and hospital settings. S. aureus relies on metabolic diversity and a large repertoire of virulence factors to cause disease. This includes α-hemolysin (Hla), an integral player in tissue damage found in various models, including SSTIs. Previously, we identified a role for the Spx adapter protein, YjbH, in the regulation of several virulence factors and as an inhibitor of pathogenesis in a sepsis model. In this study, we found that YjbH is critical for tissue damage during SSTI, and its absence leads to decreased proinflammatory chemokines and cytokines in the skin. We identified no contribution of YjbI, encoded on the same transcript as YjbH. Using a combination of reporters and quantitative hemolysis assays, we demonstrated that YjbH impacts Hla expression and activity both in vitro and in vivo. Additionally, expression of Hla from a non-native promoter reversed the tissue damage phenotype of the ΔyjbIH mutant. Lastly, we identified reduced Agr activity as the likely cause for reduced Hla production in the ΔyjbH mutant. This work continues to define the importance of YjbH in the pathogenesis of S. aureus infection as well as identify a new pathway important for Hla production.

Assuntos

Proteínas de Bactérias , Toxinas Bacterianas , Regulação Bacteriana da Expressão Gênica , Proteínas Hemolisinas , Staphylococcus aureus , Transativadores , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/genética , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Staphylococcus aureus/patogenicidade , Staphylococcus aureus/imunologia , Staphylococcus aureus/genética , Camundongos , Animais , Transativadores/genética , Transativadores/metabolismo , Infecções Cutâneas Estafilocócicas/microbiologia , Infecções Cutâneas Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/patologia , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/imunologia , Pele/microbiologia , Pele/patologia , Pele/imunologia , Fatores de Virulência/genética , Humanos , Infecções dos Tecidos Moles/microbiologia , Infecções dos Tecidos Moles/imunologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Citocinas/metabolismo , Citocinas/imunologia , Citocinas/genética

RESUMO

BACKGROUND: Lysosomal dysfunction (LD) impacts cytokine regulation, inflammation, and immune responses, influencing the development and progression of cancer. Inflammation is implicated in the pathogenesis of myeloproliferative neoplasm (MPN). With a hypothesis that LD significantly contributes to MPN carcinogenesis by inducing abnormal inflammation, our objective was to elucidate the pathophysiological mechanisms of MPN arising from an LD background. METHODS: Genotyping of the LD background was performed in a cohort of MPN patients (n = 190) and healthy controls (n = 461). Logistic regression modeling, utilizing genotype data, was employed to estimate the correlation between LD and MPN. Whole transcriptome sequencing (WTS) (LD carriers = 8, non-carriers = 6) and single-cell RNA sequencing data (LD carriers = 2, non-carriers = 2, healthy controls = 2) were generated and analyzed. RESULTS: A higher variant frequency of LD was observed in MPN compared to healthy controls (healthy, 4.9%; MPN, 7.8%), with the highest frequency seen in polycythemia vera (PV) (odds ratio = 2.33, p = 0.03). WTS revealed that LD carriers exhibited upregulated inflammatory cytokine ligand-receptor genes, pathways, and network modules in MPNs compared to non-carriers. At the single-cell level, there was monocyte expansion and elevation of cytokine ligand-receptor interactions, inflammatory transcription factors, and network modules centered on monocytes. Notably, Oncostatin-M (OSM) consistently emerged as a candidate molecule involved in the pathogenesis of LD-related PV. CONCLUSIONS: In summary, an LD background is prevalent in MPN patients and leads to increased cytokine dysregulation and inflammation. OSM, as one of the potential molecules, plays a crucial role in PV pathogenesis by impairing lysosomal function.

Assuntos

Lisossomos , Transtornos Mieloproliferativos , Humanos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Lisossomos/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Idoso , Inflamação/genética , Citocinas/metabolismo , Citocinas/genética , Policitemia Vera/genética , Policitemia Vera/metabolismo , Policitemia Vera/patologia , Adulto , Perfilação da Expressão Gênica , Análise de Célula Única

RESUMO

BACKGROUND AND AIMS: Various inflammatory and immune cytokines play key roles in the progression of hepatitis B virus (HBV)-related liver cirrhosis (LC). This study explored the relationship between single nucleotide polymorphisms (SNPs) in cytokines with the combined effect of polymorphisms and gender-polymorphisms interaction and LC risk. METHODS: In this study, a case-control design was used, samples were selected from 45 patients with hepatitis B-related cirrhosis and 45 age-gender-matched chronic HBV-infected patients without cirrhosis attending the tumor hospital of Wuwei Academy of Medical Sciences. Fifteen SNPs were examined using a real-time polymerase chain reaction allelic discrimination system. Logistic regression was utilized to assess cytokine-associated SNPs and the association between SNPs and LC progression in HBV-infected patients. RESULTS: The multivariate-adjusted logistic model revealed that the GG/AG dominant model (OR, 16.38; 95% CI, 1.13-236.70) and G allele (OR, 5.93; 95% CI, 0.98-36.01) of rs1800896 were associated with an increased risk of cirrhosis in CHB patients. Instead, rs2227306 CT presented a reduced cirrhosis risk (OR, 0.22; 95% CI, 0.04-1.38). Rs2055979 AA/AC was negatively associated with the risk of cirrhosis, potentially reversed in males (p = 0.021). Rs1799964 CC/CT was positively related to the risk of cirrhosis but reduced the risk of cirrhosis in males (OR, 0.13; 95% CI, 0.022-0.808; p = 0.028). Both rs1799964 TT and rs1799724 CT/TT genotype showed a synergistic effect in reducing the risk of cirrhosis with rs1800896 AA (OR, 0.08; 95% CI, 0.01-1.43 and OR, 0.12; 95% CI, 0.01-2.21). CONCLUSION: Polymorphisms rs1800896 and rs2227306 are potentially associated with the risk of cirrhosis. For the first time, the study highlights that the rs2055979 AA/AC and rs1799964 CC/CT polymorphism interact with gender and its potential reversal of cirrhosis risk in males. Furthermore, rs1800896 AA showed a synergistic effect with rs1799964 TT and rs1799724 CT/TT to prevent the progression of HBV infection to cirrhosis.

Assuntos

Citocinas , Predisposição Genética para Doença , Vírus da Hepatite B , Hepatite B Crônica , Cirrose Hepática , Polimorfismo de Nucleotídeo Único , Humanos , Masculino , Cirrose Hepática/genética , Cirrose Hepática/virologia , Feminino , Estudos de Casos e Controles , Pessoa de Meia-Idade , Citocinas/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/genética , Adulto , Alelos , Genótipo , Estudos de Associação Genética , Frequência do Gene

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal lung disease characterized by tissue scarring and declining lung function. The MUC5B promoter polymorphism rs35705950, a significant genetic predisposition for IPF, paradoxically associates with better survival and slower disease progression than other IPF genotypes. This study investigates the potential paradoxical protective effects of this MUC5B variant in lung fibrosis. For this purpose, we developed a transgenic mouse model overexpressing the human MUC5B rs35705950 variant in the proximal large airways. Lung fibrosis was induced through subcutaneous injection of bleomycin. Results demonstrated significantly reduced lung fibrosis severity in transgenic mice compared to wild-type mice, assessed by trichrome staining, Ashcroft scoring, and hydroxyproline levels. Additionally, transgenic mice showed significantly lower levels of inflammatory cells and cytokines (TNFα, IL-6, IFNγ) and growth factors (PDGF, CTGF, IL-13) in the bronchoalveolar lavage fluid and lung tissues. There was also a significant decrease in mRNA expressions of fibrosis-related markers (periostin, fibronectin, Col1a1). In summary, this study reveals that mucin overexpression related to the MUC5B rs35705950 variant in the large airways significantly attenuates lung fibrosis and inflammatory responses in transgenic mice. These findings suggest that the rs35705950 variant modulates inflammatory and fibrotic responses in the proximal airways, which may contribute to the slower disease progression observed in IPF patients carrying this variant. Our study offers a possible explanation for the paradoxical beneficial effects of the MUC5B variant despite its role as a significant predisposing factor for IPF.

Assuntos

Bleomicina , Camundongos Transgênicos , Mucina-5B , Animais , Mucina-5B/genética , Mucina-5B/metabolismo , Humanos , Camundongos , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Fibrose Pulmonar/induzido quimicamente , Citocinas/metabolismo , Citocinas/genética , Pulmão/patologia , Pulmão/metabolismo , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Modelos Animais de Doenças , Líquido da Lavagem Broncoalveolar

RESUMO

Ornithonyssus sylviarum (O. sylviarum) is an obligatory, blood-sucking ectoparasite widely distributed among poultry and other mammals, causing significant economic losses. This study represented the first report of molecular genotypic identification of O. sylviarum from pigeons, Columba livia domestica, in Egypt. PCR and sequencing of the 28S rRNA gene were conducted. The resulting mite sequences were subjected to BLAST analysis, revealing 90-100% similarity to O. sylviarum in all tested samples. The sequences were deposited in GenBank under the accession numbers PP049086 and PP033720. A phylogenetic tree was constructed to compare the obtained species with related species worldwide. Additionally, infected pigeons showed increased expression of IL-1, IL-10, IFN-γ, and TGF-ß3 genes and elevated serum levels of stress biomarkers. The increased level of these cytokines indicates there was a disturbance in the immune status of the infected host with parasite compared with control healthy ones. This increases the susceptibility to infection with other pathogens.

Assuntos

Biomarcadores , Columbidae , Ácaros , Filogenia , Animais , Columbidae/parasitologia , Columbidae/genética , Egito , Ácaros/genética , Biomarcadores/sangue , Infestações por Ácaros/veterinária , Infestações por Ácaros/genética , Infestações por Ácaros/parasitologia , Doenças das Aves/parasitologia , Doenças das Aves/genética , Citocinas/genética , RNA Ribossômico 28S/genética , Imunogenética

RESUMO

INTRODUCTION: In sarcoidosis granulomas, monocyte-derived macrophages are activated by pro-inflammatory cytokines including TNF and IL-6. Current drug treatment for sarcoidosis aims to suppress inflammation but disabling side effects can ensue. The macrolide azithromycin may be anti-inflammatory. We aimed to determine whether treatment with azithromycin affects blood inflammatory gene expression and monocyte functions in sarcoidosis. METHODS: Blood samples were collected from patients with chronic pulmonary sarcoidosis enrolled in a single arm, open label clinical trial who received oral azithromycin 250 mg once daily for 3 months. Whole blood inflammatory gene expression with or without LPS stimulation was measured using a 770-mRNA panel. Phenotypic analysis and cytokine production were conducted by flow cytometry and ELISA after 24h stimulation with growth factors and TLR ligands. mTOR activity was assessed by measuring phosphorylated S6RP. RESULTS: Differential gene expression analysis indicated a state of heightened myeloid cell activation in sarcoidosis. Compared with controls, sarcoidosis patients showed increased LPS responses for several cytokines and chemokines. Treatment with azithromycin had minimal effect on blood gene expression overall, but supervised clustering analysis identified several chemokine genes that were upregulated. At the protein level, azithromycin treatment increased LPS-stimulated TNF and unstimulated IL-8 production. No other cytokines showed significant changes following azithromycin. Blood neutrophil counts fell during azithromycin treatment whereas mononuclear cells remained stable. Azithromycin had no detectable effects on mTOR activity or activation markers. CONCLUSION: Blood myeloid cells are activated in sarcoidosis, but azithromycin therapy did not suppress inflammatory gene expression or cytokine production in blood. TRIAL REGISTRATION: EudraCT 2019-000580-24 (17 May 2019).

Assuntos

Azitromicina , Citocinas , Sarcoidose Pulmonar , Humanos , Azitromicina/uso terapêutico , Azitromicina/farmacologia , Pessoa de Meia-Idade , Feminino , Masculino , Sarcoidose Pulmonar/tratamento farmacológico , Sarcoidose Pulmonar/sangue , Citocinas/sangue , Citocinas/genética , Adulto , Interleucina-8/sangue , Interleucina-8/genética , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/sangue , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Expressão Gênica/efeitos dos fármacos , Idoso , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo

RESUMO

The present study aimed to investigate the effects of (R)-(-)-1-isothiocyanato-6-(methylsulfinyl)-hexane [(R)-6-HITC], the major isothiocyanate present in wasabi, in an ex vivo model of inflammation using lipopolysaccharide-stimulated murine peritoneal macrophages. (R)-6-HITC improved the immune response and mitigated oxidative stress, which involved suppression of reactive oxygen species, nitric oxide, and pro-inflammatory cytokines (IL-1ß, IL-6, IL-17, IL-18, and TNF-α) production and downregulation of pro-inflammatory enzymes such as inducible nitric oxide synthase, COX-2, and mPGES-1. In addition, (R)-6-HITC was able to activate the Nrf2/HO-1 axis while simultaneously inhibiting key signaling pathways, including JAK2/STAT3, mitogen-activated protein kinases, and canonical and noncanonical inflammasome pathways, orchestrating its potent immunomodulatory effects. Collectively, these findings demonstrate the potential of (R)-6-HITC as a promising nutraceutical for the management of immuno-inflammatory diseases and justify the need for further in vivo validation studies.

Assuntos

Isotiocianatos , Lipopolissacarídeos , Extratos Vegetais , Wasabia , Animais , Camundongos , Isotiocianatos/farmacologia , Lipopolissacarídeos/efeitos adversos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/administração & dosagem , Wasabia/química , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Modelos Animais de Doenças , Humanos , Citocinas/imunologia , Citocinas/genética , Citocinas/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/imunologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Óxido Nítrico/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Ciclo-Oxigenase 2/metabolismo , Agentes de Imunomodulação/farmacologia , Agentes de Imunomodulação/química , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/química