RESUMEN
BACKGROUND: One of the promising methods of influencing the wound process is photobiomodulation (PBM) therapy. The optimal parameters of PBM therapy have not yet been found because the molecular mechanisms of light interaction with tissue are not fully understood. OBJECTIVE: Studying the influence of PBM of various parameters on the regulation of reparative process- es of chronic wounds using the example of indicators of aggregation activity of platelets, platelet-derived growth factor (PDGF), interleukin-8 (IL-8), and amino-terminal propeptide of type III procollagen (PIIINP) at the remodeling stage. And also the study of the structural and functional features of chronic wound heal- ing in an experiment under various parameters of PBM therapy. METHODS: Experiments were carried out on Wistar rats. Chronic wounds were simulated. Experimental animals were exposed to PBM at a wavelength of 660 nm and an energy density of 1 J/cm2. In serum, PDGF, IL-8, and PIIINP levels were measured by enzyme-linked immunosorbent assay. The functional activity of platelets was measured using the turbidimetric method. Histological analysis was performed. RESULTS: The work noted the dose-dependent effect of PBM using the example of platelet aggregation at the remodeling stage during the healing of chronic wounds. The use of PBM therapy resulted in increased serum PDGF levels. Histological examination data indicate a positive effect of PBM therapy on the wound healing process. CONCLUSIONS: The effectiveness of the use of PBM therapy for the healing of chronic wounds to regulate reparative processes has been proven.
Asunto(s)
Terapia por Luz de Baja Intensidad , Factor de Crecimiento Derivado de Plaquetas , Ratas Wistar , Cicatrización de Heridas , Cicatrización de Heridas/efectos de la radiación , Cicatrización de Heridas/fisiología , Animales , Ratas , Terapia por Luz de Baja Intensidad/métodos , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Enfermedad Crónica , Interleucina-8/metabolismo , Interleucina-8/sangre , Modelos Animales de EnfermedadRESUMEN
We previously reported that leukotriene B4 (LTB4) contained in Trichomonas vaginalis-derived secretory products (TvSP) play an essential role in interleukin-8 (IL-8) production in human mast cell line (HMC-1 cells) via LTB4 receptor (BLT)-mediated Nuclear Factor-kappa B (NF-кB) activation. Dynamin, a GTPase, has been known to be involved in endocytosis of receptors for signaling of production of cytokine or chemokines. In the present study, we investigated the role of dynamin-mediated BLT1 endocytosis in TvSP-induced IL-8 production. When HMC-1 cells were transfected with BLT1 or BLT2 siRNA, TvSP-induced IL-8 production was significantly inhibited compared with that in cells transfected with control siRNA. In addition, pretreatment of HMC-1 cells with a dynamin inhibitor (Dynasore) reduced IL-8 production induced by TvSP or LTB4. TvSP- or LTB4- induced phosphorylation of NF-кB was also attenuated by pretreatment with Dynasore. After exposing HMC-1 cells to TvSP or LTB4, BLT1 was translocated from the intracellular compartments to the plasma membrane within 30 min. At 60 min after stimulation with TvSP or LTB4, BLT1 remigrated from the cell surface to intracellular areas. Pretreatment of HMC-1 cells with dynamin-2 siRNA blocked internalization of BLT1 induced by TvSP or LTB4. Co-immunoprecipitation experiments revealed that dynamin-2 strongly interacted with BLT1 60 min after stimulation with TvSP or LTB4. These results suggest that T. vaginalis-secreted LTB4 induces IL-8 production in HMC-1 cells via dynamin 2-mediated endocytosis of BLT1 and phosphorylation of NF-кB.
Asunto(s)
Dinamina II , Endocitosis , Interleucina-8 , Receptores de Leucotrieno B4 , Trichomonas vaginalis , Humanos , Interleucina-8/metabolismo , Interleucina-8/genética , Receptores de Leucotrieno B4/metabolismo , Receptores de Leucotrieno B4/genética , Endocitosis/efectos de los fármacos , Dinamina II/metabolismo , Dinamina II/genética , Línea Celular , Trichomonas vaginalis/metabolismo , Leucotrieno B4/metabolismo , Mastocitos/metabolismo , Mastocitos/inmunología , FN-kappa B/metabolismo , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genéticaRESUMEN
Trichomoniasis is caused by a sexually transmitted flagellate protozoan parasite Trichomonas vaginalis. T. vaginalis-derived secretory products (TvSP) contain lipid mediators such as leukotriene B4 (LTB4) and various cysteinyl leukotrienes (CysLTs) which included LTC4, LTD4, and LTE4. However, the signaling mechanisms by which T. vaginalis-induced CysLTs stimulate interleukin (IL)-8 production in human mast cells remain unclear. In this study, we investigated these mechanisms in human mast cells (HMC-1). Stimulation with TvSP resulted in increased intracellular reactive oxygen species (ROS) generation and NADPH oxidase 2 (NOX2) activation compared to unstimulated cells. Pre-treatment with NOX2 inhibitors such as diphenyleneiodonium chloride (DPI) or apocynin significantly reduced ROS production in TvSP-stimulated HMC-1 cells. Additionally, TvSP stimulation increased NOX2 protein expression and the translocation of p47phox from the cytosol to the membrane. Pretreatment of HMC-1 cells with PI3K or PKC inhibitors reduced TvSP-induced p47phox translocation and ROS generation. Furthermore, NOX2 inhibitors or NOX2 siRNA prevented CREB phosphorylation and IL-8 gene expression or protein secretion induced by TvSP. Pretreatment with a CysLTR antagonist significantly inhibited TvSP-induced ROS production, CREB phosphorylation, and IL-8 production. These results indicate that CysLT-mediated activation of NOX2 plays a crucial role in ROS-dependent IL-8 production in human mast cells stimulated by T. vaginalis-secreted CysLTs. These findings enhance our understanding of the inflammatory response in trichomoniasis and may inform the development of targeted therapies to mitigate this response.
Asunto(s)
Interleucina-8 , Mastocitos , NADPH Oxidasa 2 , Especies Reactivas de Oxígeno , Receptores de Leucotrienos , Trichomonas vaginalis , Humanos , Trichomonas vaginalis/efectos de los fármacos , Trichomonas vaginalis/metabolismo , Interleucina-8/metabolismo , Interleucina-8/genética , Especies Reactivas de Oxígeno/metabolismo , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 2/genética , Mastocitos/metabolismo , Mastocitos/efectos de los fármacos , Mastocitos/parasitología , Mastocitos/inmunología , Línea Celular , Receptores de Leucotrienos/metabolismo , Receptores de Leucotrienos/genética , NADPH Oxidasas/metabolismo , Transducción de Señal/efectos de los fármacos , Leucotrienos/metabolismoRESUMEN
To evaluate the efficacy of yellow light-emitting diode (LED) irradiation at 590 nm, alone or in combination with anti-inflammatory active substances against ultraviolet (UV)-induced inflammation in keratinocytes. HaCaT keratinocytes were pretreated with LED yellow light (590 nm) alone or in combination with an antiinflammatory active substance such as glycerophosphoinositol choline (GC), extract of grains of paradise (Aframomum melegueta Schum, AM), or a bisabolol and ginger root extract mixture (Bb-GE) before UVB irradiation. Following each treatment, we measured the levels of inflammatory mediators secreted by keratinocytes. HaCaT keratinocytes treated with UVB (300 mJ cm-²) and then cultured for 24 h exhibited significantly upregulated expression of proinflammatory factors, including interleukin (IL)-1α, prostaglandin E2 (PGE2), and IL-8. After pretreatment with 590 nm LED, UVB-induced inflammatory responses were significantly inhibited. Co-pretreatment with 590 nm LED irradiation and GC further inhibited the expression of IL-1α and IL-8. IL-8 expression was inhibited by co-pretreatment with 590 nm LED irradiation and AM, whereas PGE2 expression was inhibited by co-pretreatment with 590 nm LED irradiation and Bb-GE. Co-treatment with 590 nm LED irradiation and various active substances modulated UVB-induced inflammation in keratinocytes, suggesting the potential application of this approach to prevent damage caused by voluntary sun exposure in daily life.
Asunto(s)
Inflamación , Interleucina-8 , Queratinocitos , Rayos Ultravioleta , Humanos , Queratinocitos/efectos de la radiación , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Rayos Ultravioleta/efectos adversos , Interleucina-8/metabolismo , Dinoprostona/metabolismo , Interleucina-1alfa/metabolismo , Extractos Vegetales/farmacología , Sesquiterpenos/farmacología , Láseres de Semiconductores/uso terapéutico , Antiinflamatorios/farmacología , Sesquiterpenos Monocíclicos/farmacología , Células HaCaTRESUMEN
OBJECTIVE: The chronic pain syndromes (CPS) include syndromes such as chronic widespread pain (CWP), dry eye disease (DED) and irritable bowel syndrome (IBS). Highly prevalent and lacking pathognomonic biomarkers, the CPS are known to cluster in individuals in part due to their genetic overlap, but patient diagnosis can be difficult. The success of quantitative sensory testing (QST) and inflammatory biomarkers as phenotyping tools in conditions such as painful neuropathies warrant their investigation in CPS. We aimed to examine whether individual QST modalities and candidate inflammatory markers were associated with CWP, DED or IBS in a large, highly phenotyped population sample. DESIGN: Cross-sectional study. SETTING: Community-dwelling cohort. PARTICIPANTS: Twins from the TwinsUK cohort PRIMARY AND SECONDARY OUTCOME MEASURES: We compared 10 QST modalities, measured in participants with and without a CWP diagnosis between 2007 and 2012. We investigated whether inflammatory markers measured by Olink were associated with CWP, including interleukin-6 (IL-6), IL-8, IL-10, monocyte chemoattractant protein-1 and tumour necrosis factor. All analyses were repeated in DED and IBS with correction for multiple testing. RESULTS: In N=3022 twins (95.8% women), no association was identified between individual QST modalities and CPS diagnoses (CWP, DED and IBS). Analyses of candidate inflammatory marker levels and CPS diagnoses in n=1368 twins also failed to meet statistical significance. CONCLUSION: Our findings in a large population cohort suggest a lack of true association between singular QST modalities or candidate inflammatory markers and CPS.
Asunto(s)
Dolor Crónico , Síndromes de Ojo Seco , Síndrome del Colon Irritable , Humanos , Estudios Transversales , Masculino , Femenino , Dolor Crónico/diagnóstico , Persona de Mediana Edad , Síndrome del Colon Irritable/diagnóstico , Adulto , Síndromes de Ojo Seco/diagnóstico , Anciano , Biomarcadores/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Factor de Necrosis Tumoral alfa/sangre , Quimiocina CCL2/sangre , Reino Unido/epidemiología , Interleucina-10/sangre , Dimensión del Dolor/métodosRESUMEN
M2-polarized, tumor-associated macrophages (TAMs) produce pro-tumorigenic and angiogenic mediators, such as interleukin-8 (IL-8) and IL-10. Leucine-rich repeat-containing protein 8 members (LRRC8s) form volume-regulated anion channels and play an important role in macrophage functions by regulating cytokine and chemokine production. We herein examined the role of LRRC8A in IL-8 and IL-10 expression in THP-1-differentiated M2-like macrophages (M2-MACs), which are a useful tool for investigating TAMs. In M2-MACs, the pharmacological inhibition of LRRC8A led to hyperpolarizing responses after a transient depolarization phase, followed by a slight elevation in the intracellular concentration of Ca2+. Both the small interfering RNA-mediated and pharmacological inhibition of LRRC8A repressed the transcriptional expression of IL-8 and IL-10, resulting in a significant reduction in their secretion. The inhibition of LRRC8A decreased the nuclear translocation of phosphorylated nuclear factor-erythroid 2-related factor 2 (Nrf2), while the activation of Nrf2 reversed the LRRC8A inhibition-induced transcriptional repression of IL-8 and IL-10 in M2-MACs. We identified the CCAAT/enhancer-binding protein isoform B, CEBPB, as a downstream target of Nrf2 signaling in M2-MACs. Moreover, among several upstream candidates, the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) suppressed the Nrf2-CEBPB transcriptional axis in M2-MACs. Collectively, the present results indicate that the inhibition of LRRC8A repressed IL-8 and IL-10 transcription in M2-MACs through the NOX2-Nrf2-CEBPB axis and suggest that LRRC8A inhibitors suppress the IL-10-mediated evasion of tumor immune surveillance and IL-8-mediated metastasis and neovascularization in TAMs.
Asunto(s)
Proteína beta Potenciadora de Unión a CCAAT , Interleucina-10 , Interleucina-8 , Macrófagos , Proteínas de la Membrana , NADPH Oxidasa 2 , Factor 2 Relacionado con NF-E2 , Humanos , Interleucina-10/metabolismo , Interleucina-10/genética , Interleucina-8/metabolismo , Interleucina-8/genética , Factor 2 Relacionado con NF-E2/metabolismo , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 2/genética , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Transducción de Señal , Regulación hacia Abajo , Células THP-1RESUMEN
The coronavirus disease 2019 (COVID-19) survivors are frequently observed to present persistent symptoms constituting what has been called "post-acute COVID-19 syndrome" (PACS) or "long COVID-19". Some clinical risk factors have been identified to be associated with PACS development; however, specific mechanisms responsible for PACS pathology remain unknown. This study investigates clinical, immunological, and metabolomic risk factors associated with post-acute COVID-19 syndrome (PACS) in 51 patients, assessed 7-19 months after acute infection. Among the participants, 62.7% were male and 37.2% were female, with an average age of 47.8 years. At the follow-up, 37.2% met the criteria for PACS, revealing significant differences in immunological and metabolomic profiles at the time of acute infection. Patients with PACS were characterized by elevated levels of mature low-density granulocytes (LDGs), interleukin-8 (IL-8), pyruvate, pseudouridine, and cystine. Baseline multivariate analysis showed increased pyruvate and decreased alpha tocopherol levels. At follow-up, there was a decrease in absolute B lymphocytes and an increase in non-classical monocytes and 3-hydroxyisovaleric acid levels. These findings suggest that specific immunological and metabolomic markers during acute infection can help identify patients at higher risk of developing persistent PACS.
Asunto(s)
COVID-19 , Síndrome Post Agudo de COVID-19 , SARS-CoV-2 , Humanos , Femenino , COVID-19/inmunología , COVID-19/metabolismo , COVID-19/complicaciones , Masculino , Persona de Mediana Edad , Adulto , Factores de Riesgo , Biomarcadores , Metabolómica/métodos , Anciano , Metaboloma , Interleucina-8/metabolismoRESUMEN
Interleukin-8 (IL-8), a CXC chemokine, exerts pivotal effect on cell migration, inflammatory response, and immune regulation. In this study, we examined the immunological characteristics of an IL-8 like homologue (PoIL8-L) in Japanese flounder (Paralichthys olivaceus). PoIL8-L contains a conserved chemokine CXC domain and 105 amino acid residues. PoIL8-L expression in tissues was constitutive, and significantly regulated by V. havieri or E. tarda infection. In vitro, rPoIL8-L could bind to eight tested bacteria, exhibited bacteriostatic and bactericidal effects against certain bacteria, and could bind to the targeted bacterial â £ pilin protein rPilA of E. tarda. Furthermore, rPoIL8-L could attach to peripheral blood leukocytes, and enhance their immune genes expression, respiratory burst, chemotaxis, proliferation, acid phosphatase activity, and phagocytic activity. Additionally, rPoIL8-L induce neutrophils to extrude neutrophil extracellular traps. In vivo, rPoIL8-L could promote host resistance to E. tarda infection. In summary, these findings provide fresh perspectives on the immunological antibacterial properties of IL-8 in teleost.
Asunto(s)
Edwardsiella tarda , Infecciones por Enterobacteriaceae , Enfermedades de los Peces , Proteínas de Peces , Peces Planos , Inmunidad Innata , Interleucina-8 , Leucocitos , Animales , Enfermedades de los Peces/inmunología , Proteínas de Peces/inmunología , Proteínas de Peces/genética , Edwardsiella tarda/fisiología , Leucocitos/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Peces Planos/inmunología , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/veterinaria , Regulación de la Expresión Génica/inmunología , Vibrio/fisiología , Secuencia de Aminoácidos , Filogenia , Iridoviridae/fisiología , Alineación de Secuencia/veterinaria , Perfilación de la Expresión Génica/veterinariaRESUMEN
BACKGROUND: Antidiabetic therapies are effective, but could indirectly modify the inflammatory response in the ocular microenvironment; therefore, a study was developed to evaluate the inflammatory cytokine profile in the vitreous humor of diabetic patients with retinopathy under treatment with antidiabetic drugs. METHODS: Observational, comparative, retrospective, cross-sectional study. Interleukins 1ß, 6, 8, 10, and tumor necrosis factor-alpha (TNFα) were evaluated in the vitreous humor obtained from patients with type 2 diabetes mellitus, proliferative diabetic retinopathy, and concomitant retinal detachment or vitreous hemorrhage, and who were already on antidiabetic treatment with insulin or metformin + glibenclamide. The quantification analysis of each cytokine was performed by the cytometric bead array (CBA) technique; medians and interquartile ranges were obtained, and the results were compared between groups using the Mann-Whitney U test, where a p-value < 0.05 was considered significant. RESULTS: Thirty-eight samples; quantification of TNFα concentrations was higher in the group of patients administered insulin, while interleukin-8 was lower; in the metformin + glibenclamide combination therapy group, it occurred inversely. In the stratified analysis, the highest concentrations of interleukin-8 and TNFα occurred in patients with vitreous hemorrhage; however, the only statistical difference existed in patients with retinal detachment, whose TNFα concentration in the combined therapy group was the lowest value found (53.50 (33.03-86.66), p = 0.03). Interleukins 1ß, 6, and 10 were not detected. CONCLUSION: Interleukin-8 and TNFα concentrations are opposite between treatment groups; this change is more accentuated in patients with proliferative diabetic retinopathy and vitreous hemorrhage, where the highest concentrations of both cytokines are found, although only TNFα have statistical difference.
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Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Hipoglucemiantes , Interleucina-8 , Factor de Necrosis Tumoral alfa , Cuerpo Vítreo , Humanos , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Masculino , Cuerpo Vítreo/metabolismo , Femenino , Persona de Mediana Edad , Estudios Transversales , Factor de Necrosis Tumoral alfa/metabolismo , Estudios Retrospectivos , Hipoglucemiantes/uso terapéutico , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Interleucina-8/metabolismo , Insulina/uso terapéutico , Metformina/uso terapéutico , Gliburida/uso terapéutico , Quimioterapia CombinadaRESUMEN
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.
Asunto(s)
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
OBJECTIVE: Bidirectional influences between senescence and inflammation are newly discovered. This study aimed to clarify the roles and mechanism of Porphyromonas gingivalis (P. gingivalis) in exacerbating senescence in human gingival fibroblasts (HGFs). DESIGN: Subgingival plaque and gingivae were collected from twenty-four periodontitis patients and eighteen periodontally healthy subjects. Quantities of P. gingivalis in subgingival plaque were explored using real-time PCR and the expressions of p53, p21 and SIRT6 in gingivae were detected by IHC. Moreover, senescence in HGFs was induced by P. gingivalis lipopolysaccharide (LPS) and the expressions of senescence-related ß-galactosidase (SA-ß-gal), p53, p21 and senescence-associated secretory phenotype (IL-6 and IL-8) with or without treatment by SIRT6 activator UBCS039 were explored by IHC, western blot and ELISA, respectively. In addition, the levels of SIRT6, Nrf2, HO-1 and reactive oxygen species (ROS) were examined by western blot and flow cytometry. RESULTS: Quantities of P. gingivalis in subgingival plaque and semi-quantitative scores of p53 and p21 in gingivae of periodontitis patients were increased compared with healthy controls (p < 0.05), while SIRT6 score in periodontitis patients was decreased (p < 0.001). Quantities of P. gingivalis were positively correlated with p53 and p21 scores (0.6 < r < 0.9, p < 0.01), and negatively correlated with SIRT6 score (-0.9 < r<-0.6, p < 0.01). Moreover, P. gingivalis LPS increased the levels of SA-ß-gal, p53, p21, IL-6, IL-8 and ROS and decreased the levels of SIRT6, Nrf2 and HO-1 in HGFs, which was rescued by UBCS039 (p < 0.05). CONCLUSIONS: P. gingivalis LPS could induce senescence of HGFs, which could be reversed by SIRT6 via Nrf2-HO-1 signaling pathway.
Asunto(s)
Senescencia Celular , Fibroblastos , Encía , Factor 2 Relacionado con NF-E2 , Porphyromonas gingivalis , Especies Reactivas de Oxígeno , Sirtuinas , Humanos , Porphyromonas gingivalis/patogenicidad , Encía/microbiología , Encía/metabolismo , Fibroblastos/metabolismo , Sirtuinas/metabolismo , Sirtuinas/genética , Masculino , Femenino , Adulto , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Especies Reactivas de Oxígeno/metabolismo , Lipopolisacáridos/farmacología , Periodontitis/microbiología , Periodontitis/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Persona de Mediana Edad , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genéticaRESUMEN
Proliferative diabetic retinopathy (PDR) is a vision-threatening complication of diabetes mellitus (DM). Anterior chamber (AC) flare and intraocular cytokines are potent biomarkers reflecting the intraocular immune status in PDR. This study aimed to elucidate the complex interrelationship between AC flare and intraocular cytokines in PDR eyes. A retrospective observational study was conducted on 19 PDR eyes of 19 patients with type 2 DM, and on 19 eyes of 19 patients with idiopathic macular hole or epiretinal membrane as controls. AC flare was measured before pars plana vitrectomy (PPV). Aqueous humor (AH) and vitreous fluid (VF) samples were collected at the time of PPV, and the quantities of 27 cytokines in both intraocular fluids were analyzed. In the PDR and control groups, Spearman's rank correlation analysis revealed a positive correlation between AC flare and IL-8 level in both AH and VF. Additionally, IL-8 levels in AH correlated positively with IL-8 levels in VF. In the PDR group, receiver operating characteristic curve analysis identified IL-8 level in AH as a significant predictor for both diabetic macular edema (DME) and vitreous hemorrhage (VH) complications. The cut-off values of IL-8 were established at ≥26.6 pg/mL for DME and ≥7.96 pg/mL for VH. Given the positive correlation between AC flare and AH IL-8 level, the present findings suggest that AC flare value may potentially be a non-invasive biomarker for predicting DME.
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Cámara Anterior , Humor Acuoso , Retinopatía Diabética , Cuerpo Vítreo , Humanos , Retinopatía Diabética/inmunología , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Retinopatía Diabética/etiología , Masculino , Femenino , Cámara Anterior/patología , Cámara Anterior/metabolismo , Cámara Anterior/inmunología , Persona de Mediana Edad , Anciano , Humor Acuoso/metabolismo , Humor Acuoso/inmunología , Estudios Retrospectivos , Cuerpo Vítreo/metabolismo , Cuerpo Vítreo/patología , Edema Macular/etiología , Edema Macular/metabolismo , Edema Macular/inmunología , Edema Macular/patología , Vitrectomía , Biomarcadores , Citocinas/metabolismo , Interleucina-8/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/inmunología , Curva ROCRESUMEN
BACKGROUND: Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an apoptosis inducer that exhibits an ideal therapeutic safety profile with less adverse effects than conventional chemotherapy. However, the occurrence of TRAIL resistance has been reported in various cancers including colorectal cancer (CRC). Substantial efforts have been channelled towards managing TRAIL resistance including identifying molecular targets. Interleukins (ILs) have been recently shown to play critical roles in modulating TRAIL sensitivity in cancer cells. METHODS AND RESULTS: This study investigated the roles of two ILs, IL-8 and ILâº, in TRAIL resistance in CRC. TRAIL-resistant HT-29 and TRAIL-sensitive HCT 116 cells, were treated with human recombinant IL-8 and IL-1âº. The results indicated that treatment with IL-8 (2.5 ng/mL) significantly protected TRAIL-sensitive HCT 116 cells from TRAIL-induced cell death (p < 0.05). However, IL-1⺠did not play a role in modulating CRC cells' responses to TRAIL. Data from RT-qPCR and Western blotting revealed the molecular regulations of IL-8 on TRAIL decoy receptor genes (OPG) and autophagy-related genes (BECN1 and LC3B) expression. The activation of the phosphoinositide 3-kinase (PI3K) pathway was shown to counteract TRAIL-induced cell death. By inhibiting its activation with wortmannin, the protective role of IL-8 against TRAIL treatment was reversed, suggesting the involvement of the PI3K pathway. CONCLUSION: Collectively, findings from this study identified the role of IL-8 and PI3K in modulating CRC cells' sensitivity to TRAIL. Further validation of these two potential molecular targets is warranted to overcome TRAIL resistance in CRC.
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Apoptosis , Neoplasias Colorrectales , Interleucina-8 , Fosfatidilinositol 3-Quinasas , Transducción de Señal , Ligando Inductor de Apoptosis Relacionado con TNF , Humanos , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Interleucina-8/metabolismo , Interleucina-8/genética , Células HCT116 , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Células HT29 , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Muerte Celular/efectos de los fármacosRESUMEN
Introduction: Influenza virus infection can cause a range of clinical symptoms, including respiratory failure (RF) and even death. The mechanisms responsible for the most severe forms of the disease are not yet well understood. The objective is to assess the initial immune response upon admission and its potential impact on infection progression. Methods: We conducted a prospective observational study of patients with influenza virus infection who required admission to a tertiary hospital in the 2017/18 and 2018/19 flu seasons. Immune markers, surrogate markers of neutrophil activation, and blood levels of DNase I and Apolipoprotein-H (ApoH) were determined in the first serum sample available during hospital care. Patients were followed until hospital discharge or death. Initially, 792 patients were included. From this group, 107 patients with poor evolution were selected, and a random control group was matched by day of admission. Results: Patients with poor outcomes had significantly reduced ApoH levels, a soluble protein that regulate both complement and coagulation pathways. In multivariate analysis, low plasma levels of ApoH (OR:5.43; 2.21-13.4), high levels of C- reactive protein (OR:2.73: 1.28-5.4), hyperferritinemia (OR:2.83; 1.28-5.4) and smoking (OR:3.41; 1.04-11.16), were significantly associated with a worse prognosis. RF was independently associated with low levels of ApoH (OR: 5.12; 2.02-1.94), while high levels of IL15 behaved as a protective factor (OR:0.30; 0.12-0.71). Discussion: Therefore, in hospitalized influenza patients, a dysregulated early immune response is associated with a worse outcome. Adequate plasma levels of ApoH are protective against severe influenza and RF and High levels of IL15 protect against RF.
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Biomarcadores , Gripe Humana , Interleucina-15 , Interleucina-8 , Humanos , Gripe Humana/inmunología , Gripe Humana/sangre , Masculino , Femenino , Biomarcadores/sangre , Pronóstico , Persona de Mediana Edad , Interleucina-15/sangre , Anciano , Estudios Prospectivos , Interleucina-8/sangre , AdultoRESUMEN
BACKGROUND: Chronic hepatitis C (CHC) infection is a major public health problem in many low- and middle-income countries. The study aimed to find out how interleukin IL-6 and IL-8 levels in the blood affect the virological response to directacting antivirals (DAAs) and to find useful clinical or immunological markers for the response to HCV treatment. METHODS: CHC patients from a real Egyptian population (n = 4,300), who were treated during the Egyptian national initiative to eliminate HCV at the Sherbin Central Hospital, Dakahlia Governorate, Ministry of Health, Egypt, were enrolled in our study. They were all patients who did not obtain a sustained virological response (SVR) (n = 75; non-responder; the response rate was 98.26%), and a total of 100 patients were randomly selected from patients who obtained SVR (responder) and were age- and gender-matched (p > 0.05) with non-responder patients. Serum levels of IL-6 and IL-8 were measured by commercial ELISA kits. RESULTS: Non-responder patients were associated with significantly high levels of ALT, AST, ALP, and total bilirubin. Non-responders had significantly (p < 0.05) higher baseline IL-6 (16.7 ± 4.92 pg/mL) and IL-8 (37.81 ± 10.55 pg/mL) levels compared to responders (12.68 ± 2.06, 29.06 ± 5.94 pg/mL, respectively). There was a substantial (p < 0.05) association between the combination of two cytokines and a high likelihood of treatment failure, as indicated by all parameters examined, with the highest correlation values seen. CONCLUSIONS: The present study showed that increased IL-6 and IL-8 were associated with HCV treatment failure. Also, IL8 was associated with hepatic fibrosis.
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Antivirales , Hepatitis C Crónica , Interleucina-6 , Interleucina-8 , Humanos , Interleucina-6/sangre , Masculino , Femenino , Antivirales/uso terapéutico , Interleucina-8/sangre , Adulto , Persona de Mediana Edad , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/sangre , Hepatitis C Crónica/virología , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/inmunología , Egipto , Hepacivirus/inmunología , Hepacivirus/efectos de los fármacos , Biomarcadores/sangre , Valor Predictivo de las Pruebas , Resultado del Tratamiento , Respuesta Virológica SostenidaRESUMEN
Epstein-Barr virus (EBV) infection and various chemokines, including CCL20, CXCL8 and CXCL10 are considered to participate in the pathogenesis of multiple sclerosis (MS), and several studies point to a direct regulatory effect of EBV on the expression of these chemokines. In our study we hypothesized that serum concentrations of CCL20, CXCL8 and CXCL0 are induced in patients with relapsing-remitting MS (RRMS) in comparison to healthy individuals, and that they are associated with EBV infection. Serum concentrations of CXCL8 and CXCL10 were lower in RRMS patients in relapse in comparison to healthy controls. Although potential effects of corticosteroid therapy introduced in a subgroup of RRMS patients prior to sampling were excluded by subgroup comparison, this possibility has to be considered while interpreting the results. We found an inverse association between serum concentrations of CXCL8 and anti-Epstein-Barr Virus Nuclear Antigen (EBNA) IgG and decreased expression of CXCL8 in peripheral blood mononuclear cells (PBMC) in relapse compared to remission. Lower serum concentrations of CXCL8 and CXCL10 in RRMS patients and decreased peripheral production of CXCL8 in relapse may indicate compensatory anti-inflammatory counter-regulation in MS.
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Quimiocina CCL20 , Quimiocina CXCL10 , Herpesvirus Humano 4 , Interleucina-8 , Esclerosis Múltiple Recurrente-Remitente , Humanos , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/virología , Femenino , Quimiocina CXCL10/sangre , Adulto , Masculino , Herpesvirus Humano 4/inmunología , Quimiocina CCL20/sangre , Interleucina-8/sangre , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Persona de Mediana Edad , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Estudios de Casos y ControlesRESUMEN
Para-hydroxycinnamic acid (pHCA) is one of the most abundant naturally occurring hydroxycinnamic acids, a class of chemistries known for their antioxidant properties. In this study, we evaluated the impact of pHCA on different parameters of skin aging in in vitro skin models after H2O2 and UV exposure. These parameters include keratinocyte senescence and differentiation, inflammation, and energy metabolism, as well as the underlying molecular mechanisms. Here we demonstrate that pHCA prevents oxidative stress-induced premature senescence of human primary keratinocytes in both 2D and 3D skin models, while improving clonogenicity in 2D. As aging is linked to inflammation, referred to as inflammaging, we analyzed the release of IL-6, IL-8, and PGE2, known to be associated with senescence. All of them were downregulated by pHCA in both normal and oxidative stress conditions. Mechanistically, DNA damage induced by oxidative stress is prevented by pHCA, while pHCA also exerts a positive effect on the mitochondrial and glycolytic functions under stress. Altogether, these results highlight the protective effects of pHCA against inflammaging, and importantly, help to elucidate its potential mechanisms of action.
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Senescencia Celular , Ácidos Cumáricos , Queratinocitos , Estrés Oxidativo , Envejecimiento de la Piel , Piel , Humanos , Ácidos Cumáricos/farmacología , Senescencia Celular/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Piel/metabolismo , Piel/efectos de los fármacos , Envejecimiento de la Piel/efectos de los fármacos , Inflamación/metabolismo , Daño del ADN/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Rayos Ultravioleta/efectos adversos , Antioxidantes/farmacología , Células Cultivadas , Interleucina-8/metabolismo , Interleucina-6/metabolismoRESUMEN
The respiratory microbiome may influence the development and progression of COPD by modulating local immune and inflammatory events. We aimed to investigate whether relative changes in respiratory bacterial abundance are also associated with systemic inflammation, and explore their relationship with the main clinical COPD phenotypes. Multiplex analysis of inflammatory markers and transcript eosinophil-related markers were analyzed on peripheral blood in a cohort of stable COPD patients (n = 72). Respiratory microbiome composition was analyzed by 16S rRNA microbial sequencing on spontaneous sputum. Spearman correlations were applied to test the relationship between the microbiome composition and systemic inflammation. The concentration of the plasma IL-8 showed an inverted correlation with the relative abundance of 17 bacterial genera in the whole COPD cohort. COPD patients categorized as eosinophilic showed positive relationships with blood eosinophil markers and inversely correlated with the degree of airway obstruction and the number of exacerbations during the previous year. COPD patients categorized as frequent exacerbators were enriched with the bacterial genera Pseudomonas which, in turn, was positively associated with the severity of airflow limitation and the prior year's exacerbation history. The associative relationships of the sputum microbiome with the severity of the disease emphasize the relevance of the interaction between the respiratory microbiota and systemic inflammation.
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Biomarcadores , Microbiota , Enfermedad Pulmonar Obstructiva Crónica , Esputo , Humanos , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Enfermedad Pulmonar Obstructiva Crónica/sangre , Masculino , Femenino , Anciano , Proyectos Piloto , Esputo/microbiología , Biomarcadores/sangre , Persona de Mediana Edad , Inflamación , ARN Ribosómico 16S/genética , Interleucina-8/sangre , Interleucina-8/metabolismo , Eosinófilos/metabolismoRESUMEN
The level of cytokine expression was measured in human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells exposed to 500 ng/ml alkylating mutagen mitomycin C (MMC) and 5 µM atorvastatin. It was found that treatment of MMC-exposed HCAEC with atorvastatin decreased secretion of macrophage migration inhibitory factor (MIF), IL-8, and IL8 gene expression, but increased the expression of SERPINE1 gene encoding the PAI-1 protein. In atorvastatin-treated HITAEC, the concentration of MIF protein and the expression of the IL8 and SERPINE1 genes were reduced. We can conclude that atorvastatin prevents proinflammatory activation of endothelial cells cultured under conditions of genotoxic load. However, the molecular mechanisms of this effect require further research.
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Atorvastatina , Vasos Coronarios , Células Endoteliales , Interleucina-8 , Mitomicina , Inhibidor 1 de Activador Plasminogénico , Humanos , Atorvastatina/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Inhibidor 1 de Activador Plasminogénico/genética , Mitomicina/farmacología , Interleucina-8/metabolismo , Interleucina-8/genética , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/citología , Antiinflamatorios/farmacología , Células Cultivadas , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/metabolismoRESUMEN
Acne is a chronic inflammatory skin condition that involves Cutibacterium acnes (C. acnes), which is classified into six main phylotypes (IA1, IA2, IB, IC, II and III). Acne development is associated with loss of C. acnes phylotype diversity, characterised by overgrowth of phylotype IA1 relative to other phylotypes. It was also shown that purified extracellular vesicles (EVs) secreted by C. acnes can induce an acne-like inflammatory response in skin models. We aimed to determine if the inflammatory profile of EVs secreted by C. acnes phylotype IA1 from an inflammatory acne lesion was different from C. acnes phylotype IA1 from normal skin, thus playing a direct role in the severity of inflammation. EVs were produced in vitro after culture of two clinical strains of C. acnes phylotype IA1, T5 from normal human skin and A47 from an inflammatory acne lesion, and then incubated with either human immortalised keratinocytes, HaCaT cells, or skin explants obtained from abdominoplasty. Subsequently, quantitative PCR (qPCR) was performed for human ß-defensin 2 (hBD2), cathelicidin (LL-37), interleukin (IL)-1ß, IL-6, IL-8, IL-17α and IL-36γ, and ELISA for IL-6, IL-8 and IL-17α. We found that EVs produced in vitro by C. acnes derived from inflammatory acne lesions significantly increased the pro-inflammatory cytokines and anti-microbial peptides at both transcriptional and protein levels compared with EVs derived from normal human skin. We show for the first time that C. acnes EVs from inflammatory acne play a crucial role in acne-associated inflammation in vitro and that C. acnes phylotype IA1 collected from inflammatory acne lesion and normal skin produce different EVs and inflammatory profiles in vitro.