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1.
Front Cell Infect Microbiol ; 14: 1389527, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38756230

RESUMEN

Neisseria meningitidis (Nm, the meningococcus) is considered an asymptomatic colonizer of the upper respiratory tract and a transient member of its microbiome. It is assumed that the spread of N. meningitidis into the bloodstream occurs via transcytosis of the nasopharyngeal epithelial barrier without destroying the barrier layer. Here, we used Calu-3 respiratory epithelial cells that were grown under air-liquid-interface conditions to induce formation of pseudostratified layers and mucus production. The number of bacterial localizations in the outer mucus, as well as cellular adhesion, invasion and transmigration of different carrier and disease N. meningitidis isolates belonging to MenB:cc32 and MenW:cc22 lineages was assessed. In addition, the effect on barrier integrity and cytokine release was determined. Our findings showed that all strains tested resided primarily in the outer mucus layer after 24 h of infection (>80%). Nonetheless, both MenB:cc32 and MenW:cc22 carrier and disease isolates reached the surface of the epithelial cells and overcame the barrier. Interestingly, we observed a significant difference in the number of bacteria transmigrating the epithelial cell barrier, with the representative disease isolates being more efficient to transmigrate compared to carrier isolates. This could be attributed to the capacity of the disease isolates to invade, however could not be assigned to expression of the outer membrane protein Opc. Moreover, we found that the representative meningococcal isolates tested in this study did not damage the epithelial barrier, as shown by TEER measurement, FITC-dextran permeability assays, and expression of cell-junction components.


Asunto(s)
Adhesión Bacteriana , Portador Sano , Células Epiteliales , Infecciones Meningocócicas , Nasofaringe , Neisseria meningitidis , Células Epiteliales/microbiología , Humanos , Nasofaringe/microbiología , Neisseria meningitidis/metabolismo , Infecciones Meningocócicas/microbiología , Portador Sano/microbiología , Línea Celular , Citocinas/metabolismo
2.
Front Immunol ; 15: 1367053, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38756775

RESUMEN

Background: With the worsening of the greenhouse effect, the correlation between the damp-heat environment (DH) and the incidence of various diseases has gained increasing attention. Previous studies have demonstrated that DH can lead to intestinal disorders, enteritis, and an up-regulation of NOD-like receptor protein 3 (NLRP3). However, the mechanism of NLRP3 in this process remains unclear. Methods: We established a DH animal model to observe the impact of a high temperature and humidity environment on the mice. We sequenced the 16S rRNA of mouse feces, and the RNA transcriptome of intestinal tissue, as well as the levels of cytokines including interferon (IFN)-γ and interleukin (IL)-4 in serum. Results: Our results indicate that the intestinal macrophage infiltration and the expression of inflammatory genes were increased in mice challenged with DH for 14 days, while the M2 macrophages were decreased in Nlrp3 -/- mice. The alpha diversity of intestinal bacteria in Nlrp3 -/- mice was significantly higher than that in control mice, including an up-regulation of the Firmicutes/Bacteroidetes ratio. Transcriptomic analysis revealed 307 differentially expressed genes were decreased in Nlrp3 -/- mice compared with control mice, which was related to humoral immune response, complement activation, phagocytic recognition, malaria and inflammatory bowel disease. The ratio of IFN-γ/IL-4 was decreased in control mice but increased in Nlrp3 -/- mice. Conclusions: Our study found that the inflammation induced by DH promotes Th2-mediated immunity via NLRP3, which is closely related to the disruption of intestinal flora.


Asunto(s)
Microbioma Gastrointestinal , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Células Th2 , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Ratones , Microbioma Gastrointestinal/inmunología , Células Th2/inmunología , Calor , Alarminas/inmunología , Alarminas/metabolismo , Ratones Endogámicos C57BL , Macrófagos/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad
3.
Front Immunol ; 15: 1380846, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38756779

RESUMEN

Background: Although oxidative stress is involved in the pathophysiological process of chronic rhinosinusitis with nasal polyps (CRSwNP), the specific underlying mechanism is still unclear. Whether antioxidant therapy can treat CRSwNP needs further investigation. Methods: Immunohistochemistry, immunofluorescence, western blotting and quantitative polymerase chain reaction (qPCR) analyses were performed to detect the distribution and expression of oxidants and antioxidants in nasal polyp tissues. qPCR revealed correlations between oxidase, antioxidant enzymes and inflammatory cytokine levels in CRSwNP patients. Human nasal epithelial cells (HNEpCs) and primary macrophages were cultured to track the cellular origin of oxidative stress in nasal polyps(NPs) and to determine whether crocin can reduce cellular inflammation by increasing the cellular antioxidant capacity. Results: The expression of NOS2, NOX1, HO-1 and SOD2 was increased in nasal epithelial cells and macrophages derived from nasal polyp tissue. Oxidase levels were positively correlated with those of inflammatory cytokines (IL-5 and IL-6). Conversely, the levels of antioxidant enzymes were negatively correlated with those of IL-13 and IFN-γ. Crocin inhibited M1 and M2 macrophage polarization as well as the expression of NOS2 and NOX1 and improved the antioxidant capacity of M2 macrophages. Moreover, crocin enhanced the ability of antioxidants to reduce inflammation via the KEAP1/NRF2/HO-1 pathway in HNEpCs treated with SEB or LPS. Additionally, we observed the antioxidant and anti-inflammatory effects of crocin in nasal explants. Conclusion: Oxidative stress plays an important role in the development of CRSwNP by promoting various types of inflammation. The oxidative stress of nasal polyps comes from epithelial cells and macrophages. Antioxidant therapy may be a promising strategy for treating CRSwNP.


Asunto(s)
Antioxidantes , Pólipos Nasales , Estrés Oxidativo , Rinitis , Sinusitis , Humanos , Pólipos Nasales/metabolismo , Pólipos Nasales/inmunología , Sinusitis/metabolismo , Sinusitis/inmunología , Rinitis/metabolismo , Rinitis/inmunología , Enfermedad Crónica , Antioxidantes/metabolismo , Femenino , Masculino , Adulto , Persona de Mediana Edad , Oxidantes/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Citocinas/metabolismo , Mucosa Nasal/metabolismo , Mucosa Nasal/inmunología , Células Cultivadas , Rinosinusitis
4.
J Transl Med ; 22(1): 488, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773576

RESUMEN

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory condition of the colon, characterized by repeated attacks, a lack of effective treatment options, and significant physical and mental health complications for patients. The endoplasmic reticulum (ER) is a vital intracellular organelle in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is induced when the body is exposed to adverse external stimuli. Numerous studies have shown that ERS-induced apoptosis plays a vital role in the pathogenesis of UC. Mogroside V (MV), an active ingredient of Monk fruit, has demonstrated excellent anti-inflammatory and antioxidant effects. In this study, we investigated the therapeutic effects of MV on dextran sulfate sodium (DSS)-induced UC and its potential mechanisms based on ERS. The results showed that MV exerted a protective effect against DSS-induced UC in mice as reflected by reduced DAI scores, increased colon length, reduced histological scores of the colon, and levels of pro-inflammatory cytokines, as well as decreased intestinal permeability. In addition, the expression of ERS pathway including BIP, PERK, eIF2α, ATF4, CHOP, as well as the apoptosis-related protein including Caspase-12, Bcl-2 and Bax, was found to be elevated in UC. However, MV treatment significantly inhibited the UC and reversed the expression of inflammation signaling pathway including ERS and ERS-induced apoptosis. Additionally, the addition of tunicamycin (Tm), an ERS activator, significantly weakened the therapeutic effect of MV on UC in mice. These findings suggest that MV may be a therapeutic agent for the treatment of DSS-induced UC by inhibiting the activation of the ERS-apoptosis pathway, and may provide a novel avenue for the treatment of UC.


Asunto(s)
Apoptosis , Colitis Ulcerosa , Sulfato de Dextran , Estrés del Retículo Endoplásmico , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Apoptosis/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Colon/patología , Colon/efectos de los fármacos , Triterpenos/farmacología , Triterpenos/uso terapéutico , Ratones , Citocinas/metabolismo , Permeabilidad/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
5.
Theranostics ; 14(7): 2794-2815, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38773984

RESUMEN

Rationale: Idiopathic pulmonary fibrosis (IPF) is an irreversible, fatal interstitial lung disease lacking specific therapeutics. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage biosynthesis pathway and a cytokine, has been previously reported as a biomarker for lung diseases; however, the role of NAMPT in pulmonary fibrosis has not been elucidated. Methods: We identified the NAMPT level changes in pulmonary fibrosis by analyzing public RNA-Seq databases, verified in collected clinical samples and mice pulmonary fibrosis model by Western blotting, qRT-PCR, ELISA and Immunohistochemical staining. We investigated the role and mechanism of NAMPT in lung fibrosis by using pharmacological inhibition on NAMPT and Nampt transgenic mice. In vivo macrophage depletion by clodronate liposomes and reinfusion of IL-4-induced M2 bone marrow-derived macrophages (BMDMs) from wild-type mice, combined with in vitro cell experiments, were performed to further validate the mechanism underlying NAMPT involving lung fibrosis. Results: We found that NAMPT increased in the lungs of patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis. NAMPT inhibitor FK866 alleviated BLM-induced pulmonary fibrosis in mice and significantly reduced NAMPT levels in bronchoalveolar lavage fluid (BALF). The lung single-cell RNA sequencing showed that NAMPT expression in monocytes/macrophages of IPF patients was much higher than in other lung cells. Knocking out NAMPT in mouse monocytes/macrophages (Namptfl/fl;Cx3cr1CreER) significantly alleviated BLM-induced pulmonary fibrosis in mice, decreased NAMPT levels in BALF, reduced the infiltration of M2 macrophages in the lungs and improved mice survival. Depleting monocytes/macrophages in Namptfl/fl;Cx3cr1CreER mice by clodronate liposomes and subsequent pulmonary reinfusion of IL-4-induced M2 BMDMs from wild-type mice, reversed the protective effect of monocyte/macrophage NAMPT-deletion on lung fibrosis. In vitro experiments confirmed that the mechanism of NAMPT engaged in pulmonary fibrosis is related to the released NAMPT by macrophages promoting M2 polarization in a non-enzyme-dependent manner by activating the STAT6 signal pathway. Conclusions: NAMPT prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice. Targeting the NAMPT of monocytes/macrophages is a promising strategy for treating pulmonary fibrosis.


Asunto(s)
Bleomicina , Citocinas , Fibrosis Pulmonar Idiopática , Macrófagos , Ratones Endogámicos C57BL , Nicotinamida Fosforribosiltransferasa , Animales , Nicotinamida Fosforribosiltransferasa/metabolismo , Ratones , Macrófagos/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/inducido químicamente , Citocinas/metabolismo , Humanos , Modelos Animales de Enfermedad , Pulmón/patología , Pulmón/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Ratones Transgénicos , Masculino , Piperidinas/farmacología , Femenino , Acrilamidas
6.
Front Immunol ; 15: 1380628, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38774866

RESUMEN

Introduction: TAM receptor-mediated efferocytosis plays an important function in immune regulation and may contribute to antigen tolerance in the lungs, a site with continuous cellular turnover and generation of apoptotic cells. Some studies have identified failures in efferocytosis as a common driver of inflammation and tissue destruction in lung diseases. Our study is the first to characterize the in vivo function of the TAM receptors, Axl and MerTk, in the innate immune cell compartment, cytokine and chemokine production, as well as the alveolar macrophage (AM) phenotype in different settings in the airways and lung parenchyma. Methods: We employed MerTk and Axl defective mice to induce acute silicosis by a single exposure to crystalline silica particles (20 mg/50 µL). Although both mRNA levels of Axl and MerTk receptors were constitutively expressed by lung cells and isolated AMs, we found that MerTk was critical for maintaining lung homeostasis, whereas Axl played a role in the regulation of silica-induced inflammation. Our findings imply that MerTk and Axl differently modulated inflammatory tone via AM and neutrophil recruitment, phenotype and function by flow cytometry, and TGF-ß and CXCL1 protein levels, respectively. Finally, Axl expression was upregulated in both MerTk-/- and WT AMs, confirming its importance during inflammation. Conclusion: This study provides strong evidence that MerTk and Axl are specialized to orchestrate apoptotic cell clearance across different circumstances and may have important implications for the understanding of pulmonary inflammatory disorders as well as for the development of new approaches to therapy.


Asunto(s)
Tirosina Quinasa del Receptor Axl , Homeostasis , Pulmón , Macrófagos Alveolares , Ratones Noqueados , Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas Receptoras , Silicosis , Tirosina Quinasa c-Mer , Animales , Tirosina Quinasa c-Mer/metabolismo , Tirosina Quinasa c-Mer/genética , Silicosis/metabolismo , Silicosis/inmunología , Silicosis/patología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Ratones , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Ratones Endogámicos C57BL , Citocinas/metabolismo , Modelos Animales de Enfermedad
7.
Front Immunol ; 15: 1385863, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38774871

RESUMEN

Background: In response to the replace mammal research models with insects in preliminary immunological studies, interest has grown in invertebrate defense systems. The immunological response is regulated by cytokines; however, while their role in mammals is well understood, little is known of their function in insects. A suitable target for studies into insect immunology is Galleria mellonella (Lepidoptera), the wax moth: a common host for human fungal and bacterial pathogens. G. mellonella is also a perfect subject for studies into the presence of cytokine-like proteins. Specific objectives: The main goal of present research was detection in insect immunocompetent cells the 18 mammalian cytokines (IL-1α, IL-1ß, IL-2, IL-3, IL-6, IL-7, IL-8, IL-12, IL-13, IL-15, IL-17, IL-19, IFN-γ, TNF-α, TNF-ß, GM-CSF, M-CSF, G-CSF), which play important role in immunological response and indication how their level change after fungal infection. Methodology: The changes of cytokine-like proteins level were detected in hemocytes taken from G. mellonella larvae infected with entomopathogenic fungus, C. coronatus. The presence of cytokine-proteins was confirmed with using fluorescence microscopy (in cultured hemocytes) and flow cytometry (in freshly collected hemolymph). The ELISA test was used to detect changes in concentration of examined cytokine-like proteins. Results: Our findings indicated the presence of eighteen cytokine-like molecules in G. mellonella hemocytes during infection with C. coronatus. The hemocytes taken from infected larvae demonstrated higher fluorescence intensity for six cytokine-like proteins (GM-CSF, M-CSF, IL-3, IL-15, IL-1ß and IL-19) compared to untreated controls. ELISA test indicated significantly higher IL-3 and IL-15. M-CSF, IL-1α and IL-19 concentration in the hemolymph after fungal infection, and significantly lower TNF-ß and G-CSF. Conclusions: Our findings confirm that the selected cytokine-like molecules are present in insect hemocytes and that their concentrations change after fungal infection, which might suggest that they play a role in the anti-fungal immunological response.


Asunto(s)
Conidiobolus , Citocinas , Larva , Mariposas Nocturnas , Animales , Conidiobolus/inmunología , Larva/inmunología , Larva/microbiología , Citocinas/metabolismo , Citocinas/inmunología , Mariposas Nocturnas/inmunología , Mariposas Nocturnas/microbiología , Hemocitos/inmunología , Hemocitos/metabolismo , Hemocitos/microbiología , Proteínas de Insectos/inmunología , Proteínas de Insectos/metabolismo , Cigomicosis/inmunología , Cigomicosis/metabolismo
8.
Curr Protoc ; 4(5): e1061, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38775006

RESUMEN

Cytokines constitute a class of secreted proteins that activate transmembrane receptors to coordinate a vast array of physiological processes, particularly those related to immune activity. Due to their vital role in immune regulation, cytokines have garnered great interest as potential therapeutic agents. Unfortunately, the clinical success of cytokine drugs has been limited by their multifunctional activities, which hinder therapeutic performance and lead to harmful toxicities. In addition, the strikingly short circulation half-life of cytokines further hampers their efficacy as drugs. To overcome the translational challenges associated with natural cytokines, significant efforts have focused on engineering cytokines to target their activities and improve their pharmacological properties. One such strategy is the design of fusion proteins that tether a cytokine to an anti-cytokine antibody that selectively biases its functions and extends its serum half-life. These cytokine/antibody fusion proteins (termed immunocytokines) assemble intramolecularly to bias cytokine signaling behavior through multi-layered structural and molecular effects. Here, we present a detailed workflow for the design, production, and functional validation of intramolecularly assembled immunocytokines. In-depth procedures are presented for gene manipulation, mammalian cell-based expression and purification, binding analysis via bio-layer interferometry, and interrogation of cytokine signaling activity on human primary cells. In contrast with immunocytokines in which the tethered cytokine and antibody do not bind one another, intramolecularly assembled immunocytokines require special considerations with respect to their production to avoid oligomerization and/or aggregation. The protocol herein was developed based on experience with immunocytokines that incorporate interleukin-2 (IL-2); however, this modular approach can be extended to any cytokine of interest for a broad range of biomedical applications. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Design and generation of immunocytokine genes Basic Protocol 2: Immunocytokine expression and purification Basic Protocol 3: Validation of immunocytokine assembly and binding by bio-layer interferometry Basic Protocol 4: Analysis of immunocytokine signaling on human primary cells.


Asunto(s)
Citocinas , Proteínas Recombinantes de Fusión , Humanos , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/química , Citocinas/metabolismo , Ingeniería de Proteínas/métodos , Anticuerpos/inmunología , Anticuerpos/química , Interferometría , Animales , Células HEK293
9.
Sci Rep ; 14(1): 11566, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773199

RESUMEN

There is a worrying scarcity of drug options for patients with severe COVID-19. Glycine possesses anti-inflammatory, cytoprotective, endothelium-protective, and platelet-antiaggregant properties, so its use in these patients seems promising. In this open label, controlled clinical trial, inpatients with severe COVID-19 requiring mechanical ventilation randomly received usual care (control group) or usual care plus 0.5 g/kg/day glycine by the enteral route (experimental group). Major outcomes included mortality, time to weaning from mechanical ventilation, total time on mechanical ventilation, and time from study recruitment to death. Secondary outcomes included laboratory tests and serum cytokines. Patients from experimental (n = 33) and control groups (n = 23) did not differ in basal characteristics. There were no differences in mortality (glycine group, 63.6% vs control group, 52.2%, p = 0.60) nor in any other major outcome. Glycine intake was associated with lower fibrinogen levels, either evaluated per week of follow-up (p < 0.05 at weeks 1, 2, and 4) or as weighted mean during the whole hospitalization (608.7 ± 17.7 mg/dl vs control 712.2 ± 25.0 mg/dl, p = 0.001), but did not modify any other laboratory test or cytokine concentration. In summary, in severe COVID-19 glycine was unable to modify major clinical outcomes, serum cytokines or most laboratory tests, but was associated with lower serum fibrinogen concentration.Registration: ClinicalTrials.gov NCT04443673, 23/06/2020.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Glicina , Respiración Artificial , Humanos , Masculino , Glicina/administración & dosificación , Glicina/uso terapéutico , Femenino , Persona de Mediana Edad , Proyectos Piloto , Anciano , COVID-19/mortalidad , COVID-19/sangre , COVID-19/terapia , Resultado del Tratamiento , SARS-CoV-2 , Fibrinógeno/análisis , Fibrinógeno/metabolismo , Citocinas/sangre
10.
J Tradit Chin Med ; 44(3): 417-426, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38767625

RESUMEN

OBJECTIVE: To investigate the efficacy of substances containing 3 types of active ingredients-saponins, flavones, and alkaloids on experimental animals with autoimmune diseases (AIDs). METHODS: The protocol for this systematic review and Meta-analysis was prospectively registered with PROSPERO (CRD42023395741). Searches were conducted in the China National Knowledge Infrastructure, Wanfang, Chinese Science and Technology Journals, China Biomedical, PubMed, Cochrane Library, and Embase databases to screen for animal studies investigating the therapeutic effects of saponins, flavones, or alkaloids on autoimmune diseases; consequently, corresponding data extraction tables were prepared. Systematic Review Centre for Laboratory Animal Experimentation was used to assess the risk of methodological bias in the included literature. RevMan 5.4 was used for the Meta-analysis on the 8 serum cytokines. RESULTS: A total of 31 studies were included, all of which were randomized controlled studies. Meta-analysis indicated that substances rich in saponins, flavones, and alkaloids reduced serum levels of interleukin (IL)-1ß [standardized mean difference (SMD) = -1.94, 95% confidence interval (CI) (-2.99, -0.90), P = 0.0003], IL-6 [SMD = -1.65, 95% CI (-2.33, -0.97,) P < 0.000 01], IL-17 [SMD = -2.41, 95% CI (-3.61, -1.20), P < 0.0001], tumor necrosis factor (TNF)-α [SMD = -1.84, 95% CI (-2.61, -1.06), P < 0.0001], and interferon (IFN)-γ [SMD = -1.54, 95% CI (-2.43, -0.65), P = 0.0007], but increased serum levels of IL-4 [SMD = 1.30, 95% CI (0.15, 2.44), P = 0.03) and IL-10 [SMD = 2.05, 95% CI (1.39, 2.70), P < 0.000 01) in animal models. However, no significant regulatory effect of these three active components was observed on serum levels of IL-2 [SMD = -0.63, 95% CI (-1.82, 0.57), P = 0.30]. CONCLUTIONS: Substances containing saponins, flavones, and alkaloids regulated the changes of immune-related cytokines, it may be a novel dietary substance to relieve and control autoimmune diseases in the future.


Asunto(s)
Alcaloides , Enfermedades Autoinmunes , Citocinas , Medicamentos Herbarios Chinos , Flavonas , Saponinas , Animales , Flavonas/administración & dosificación , Citocinas/sangre , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Saponinas/farmacología , Humanos , Medicamentos Herbarios Chinos/administración & dosificación
11.
Support Care Cancer ; 32(6): 370, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38776028

RESUMEN

OBJECTIVE: Immune checkpoint inhibitors (ICIs), specifically targeting the programmed cell death protein-1 or its ligand (PD-1/PD-L1), have been extensively used in the treatment of a spectrum of malignancies, although the predictive biomarkers remain to be elucidated. This study aims to investigate the association between baseline circulating levels of cytokines and the creatinine/cystatin C ratio (CCR) with the treatment outcomes of ICIs in patients with advanced cancer. METHODS: The pre-treatment circulating levels of 10 cytokines (PD-L1, CTLA4, CXCL10, LAG3, HGF, CCL2, MIG, GRANB, IL-18, and IL-6) were measured via automated capillary-based immunoassay platform in the serum of 65 advanced cancer patients treated with anti-PD-1/PD-L1-based systemic therapy and 10 healthy volunteers. The levels of cytokines and CCR were quantified and categorized into high and low groups based on the median value. The associations of serum cytokines and CCR with response to treatment, survival, and immune-related adverse events were assessed. RESULTS: Elevated circulating levels of 6 cytokines (PD-L1, CXCL10, HGF, CCL2, MIG, and IL-6) were observed in cancer patients compared with that in healthy volunteers. The correlation coefficients between cytokines, CCR and nutritional risk index were also calculated. In the cancer cohort (N = 65), low circulating HGF (P = 0.023, P = 0.029), low IL-6 (P = 0.002, P < 0.001), and high CCR (P = 0.031, P = 0.008) were associated with significantly improved progression-free survival (PFS) and overall survival (OS). Multi-variable COX analyses adjusted for clinicopathological factors revealed that low HGF, low IL-6, and high CCR were independent favorable prognostic factors for PFS (P = 0.028, P = 0.010, and P = 0.015, respectively) and OS (P = 0.043, P = 0.003, and P = 0.026, respectively). Grade 2 irAEs occurred more frequently in patients with low levels of circulating CCL2 and LAG3. CONCLUSIONS: Pre-treatment circulating levels of serum IL-6, HGF, and CCR may serve as independent predictive and prognostic biomarkers in advanced cancer patients treated with ICIs-based systemic therapy. These findings might help to identify potential patients who would benefit from these therapies.


Asunto(s)
Biomarcadores de Tumor , Creatinina , Citocinas , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Masculino , Femenino , Neoplasias/tratamiento farmacológico , Neoplasias/sangre , Persona de Mediana Edad , Anciano , Citocinas/sangre , Pronóstico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Creatinina/sangre , Biomarcadores de Tumor/sangre , Adulto , Anciano de 80 o más Años , Antígeno B7-H1/sangre , Estudios de Casos y Controles
12.
Immunity ; 57(5): 1005-1018.e7, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38697116

RESUMEN

Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.


Asunto(s)
Factor de Unión a CCCTC , Diferenciación Celular , Interferón gamma , Interleucina-22 , Interleucinas , Células TH1 , Animales , Factor de Unión a CCCTC/metabolismo , Factor de Unión a CCCTC/genética , Células TH1/inmunología , Ratones , Diferenciación Celular/inmunología , Interferón gamma/metabolismo , Sitios de Unión , Interleucinas/metabolismo , Interleucinas/genética , Elementos de Facilitación Genéticos/genética , Ratones Endogámicos C57BL , Cromatina/metabolismo , Toxoplasmosis/inmunología , Toxoplasmosis/parasitología , Toxoplasmosis/genética , Regulación de la Expresión Génica , Toxoplasma/inmunología , Citocinas/metabolismo , Linaje de la Célula , Células Th17/inmunología
13.
Breast Dis ; 43(1): 93-98, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38701136

RESUMEN

BACKGROUND: Breast cancer (BC) cases in Makassar, Indonesia, are on the rise, with 2723 cases recorded in 2018. Tumor cells in the blood indicate metastasis, emphasizing the need for early diagnosis and monitoring. Pleiotrophin (PTN) is associated with various human malignancies, and recent studies suggest a correlation between PTN expression and advanced BC stages; therefore, PTN could serve as an independent predictor of metastasis. This study aimed to determine the correlation between serum PTN level, histopathological grading, and metastasis occurrence in BC patients in Makassar, Indonesia. METHODS: This study used an observational cross-sectional design. Pleiotrophin serum levels were examined using enzyme-linked immunosorbent assays. This study used a t-test and ROC curve analysis for the statistical tests. RESULTS: Of the 64 samples used in this study, metastasis was present in 26 cases and absent in 38 samples. The mean PTN serum levels in metastatic and non-metastatic breast cancer patients were 4.311 and 1.253, respectively. The PTN receiver operating characteristic curve showed an area under the curve of 2.47 ng/dL, which was statistically significant (p < 0.001). A significant relationship was found between PTN level and metastasis (p < 0.001). The correlation coefficient was 0.791, indicating a positive correlation. CONCLUSION: This study revealed that the serum PTN level among breast cancer patients had a cut-off value of 2.47 ng/dL. The research established a clear correlation between PTN level and metastasis occurrence in breast cancer patients, indicating a higher likelihood of distant metastasis with elevated PTN concentration.


Asunto(s)
Neoplasias de la Mama , Proteínas Portadoras , Citocinas , Humanos , Femenino , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Citocinas/sangre , Proteínas Portadoras/sangre , Persona de Mediana Edad , Estudios Transversales , Adulto , Biomarcadores de Tumor/sangre , Anciano , Curva ROC , Indonesia/epidemiología , Metástasis de la Neoplasia
14.
Medicine (Baltimore) ; 103(18): e37931, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38701286

RESUMEN

BACKGROUND: This study evaluates the efficacy of dexmedetomidine (DEX) in reducing postoperative delirium (POD) and modulating pro-inflammatory cytokines in elderly patients undergoing thoracolumbar compression fracture surgery. METHODS: In this randomized, double-blind, placebo-controlled trial conducted from October 2022 to January 2023 at Anting Hospital in Shanghai, 218 elderly patients were randomized into DEX (n = 110) and normal saline (NS, n = 108) groups. The DEX group received 0.5 µg/kg/h DEX, and delirium incidence was assessed using the Confusion Assessment Method (CAM) on days 1 to 3 post-surgery. Levels of interleukins IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were measured pre-operation (T0) and on postoperative days 1 (T1) and 3 (T3). Preoperative (T0) and postoperative day 1 (T1) cerebrospinal fluid (CSF) samples were treated with varying concentrations of olanzapine or DEX to observe their regulatory effects on the expression of Phospho-ERK1/2 and Phospho-JNK. RESULTS: Dexmedetomidine significantly lowered the incidence of POD to 18.2%, compared to 30.6% in the NS group (P = .033). While all patients showed an initial increase in cytokine levels after surgery, by T3, IL-6 and TNF-α levels notably decreased in the DEX group, with no significant change in IL-1ß levels across groups. The adverse events rate was similar between groups, demonstrating the safety of DEX in this population. In postoperative CSF samples, treatment with 0.5 mM DEX significantly downregulated Phospho-JNK and upregulated Phospho-ERK1/2 expression, demonstrating a dose-dependent modulation of inflammatory responses. CONCLUSION: Dexmedetomidine is effective in reducing early POD in elderly patients post-thoracolumbar compression fracture surgery. It also decreases IL-6 and TNF-α levels, indicating its potential in managing postoperative inflammatory responses. Treatment with 0.5 mM DEX significantly modulated Phospho-ERK1/2 and Phospho-JNK expressions in postoperative CSF samples, indicating a dose-dependent effect on reducing inflammation. This study contributes to understanding DEX's role in improving postoperative outcomes in elderly patients.


Asunto(s)
Citocinas , Dexmedetomidina , Fracturas por Compresión , Complicaciones Posoperatorias , Vértebras Torácicas , Humanos , Dexmedetomidina/uso terapéutico , Dexmedetomidina/administración & dosificación , Femenino , Masculino , Método Doble Ciego , Anciano , Citocinas/líquido cefalorraquídeo , Citocinas/metabolismo , Fracturas por Compresión/cirugía , Estudios Prospectivos , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/líquido cefalorraquídeo , Vértebras Lumbares/cirugía , Fracturas de la Columna Vertebral/cirugía , Delirio/prevención & control , Delirio/líquido cefalorraquídeo , Delirio/etiología , Delirio/tratamiento farmacológico , Cuidados Intraoperatorios/métodos , Persona de Mediana Edad
15.
Cytokine ; 179: 156632, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38701734

RESUMEN

The study was planned to evaluate the differences in certain proinflammatory cytokines(IL-6, TNF-α) with CRP and biochemical parameters (E2, D3, LDH, GGT, TSB, Ca, Ph, uric acid), between women with pre- and postmenopausal breast cancer and seemingly healthy women in Iraqi women as controls; at medical city in teaching Oncology hospital,70 breast cancer patients women their ages ranged (47.51 ± 1.18) and 20 healthy women with age (44.45 ± 2.66) begun from September (2020) to February (2021). The aims of this study to investigate the evaluation of chemotherapy effects especially doxorubicin and cyclophosphamide only use in this study in pre and postmenopausal breast cancer women on proinflammatory cytokines(IL-6, TNF-α) with CRP and on biochemical parameters(E2, D3, LDH, GGT, TSB, Ca, Ph, uric acid) in pre and postmenapausal breast cancer women. The patients were divided into five groups and each group contains 14 patients women with breast cancer during pre and postmenopausal periods. The control groups were divided into 10 pre and 10 postmenopausal women(Fig. 1). The results of proinflammatory cytokines of and biochemical parameters in premenopausal groups were as the levels of IL-6 (pg/ml),TNF-α(pg/ml) and CRP (ng/ml) showed significant increase differences (P < 0.01)among breast cancer treated (BCT) groups in comparison with control groups,While the Liver enzymes GGT,LDH and TSB showed highly significant increase (P < 0.01) in BCT groups, Estrogen levels (pg/ml) and D3(ng/ml) increased significantly (P < 0.01)among BCT groups. Blood serum calcium and phosphorus with uric acid levels (mg/dl) showed significant difference (P < 0.01); While the result in postmenopausal of IL-6(pg/ml), TNF-α (pg/ml) and CRP (ng/ml) showed highly significant differences (P < 0.01)among BCT groups.While GGT(IU/L), LDH(IU/L) and TSB (mg/dl) enzymes were increased significantly (p < 0.01), Estrogen (pg/ml) and D3(ng/ml) levels showed significant increase (P < 0.01) among BCT groups.Blood calcium and phosphorus showed significant increase (P < 0.01) while uric acid was non-significant increase (P > 0.05).


Asunto(s)
Neoplasias de la Mama , Citocinas , Posmenopausia , Humanos , Femenino , Neoplasias de la Mama/sangre , Posmenopausia/sangre , Persona de Mediana Edad , Citocinas/sangre , Adulto , Premenopausia/sangre , Factor de Necrosis Tumoral alfa/sangre , Interleucina-6/sangre , Proteína C-Reactiva/metabolismo , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico
16.
J Immunol Methods ; 529: 113681, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38701879

RESUMEN

Cerebrospinal fluid (CSF) is a critical body fluid to examine in attempts to discover potential biomarkers for neuroinflammatory and other disorders of the central nervous system (CNS). Serum and/or plasma cytokine levels have been associated with a variety of inflammatory conditions, and some have been shown to be actionable therapeutic targets. Less is known, however, about cytokine levels in CSF. Serum and plasma cytokine testing is widely available in clinical and research laboratories, but cytokine testing in CSF is extremely limited and if performed, accompanied by a disclaimer that it is an unvalidated specimen type. In this study, we validate CSF as a suitable specimen type and determine normal reference intervals for multiple cytokines as well as a soluble cytokine receptor. CSF was validated as a specimen type for testing using a laboratory developed multiplexed cytokine assay previously validated to measure 13 cytokines/markers in serum and plasma. Performance parameters including specimen dilution, specimen interference, linearity and precision were examined. Reference intervals were established using 197 normal and control CSF specimens by non-parametric quantile-based methods. CSF cytokine analysis demonstrated within and between run precision of <10% and < 20% CV, respectively and linearity of ±15% for all analytes throughout the analytical measurement range of the assay. Reference intervals for the 13 cytokines/markers were established from 197 normal and control CSF specimens (78 Male; mean 44.8 y ± 21.7 SD, 119 Female; mean 42.8 y ± 20.3 SD). Cytokine concentrations in CSF from normal donors and controls were less than the lower limit of quantitation of our assay for 6 of the 13 measured cytokines/markers. The chemokine IL8 demonstrated the highest concentration of all analytes measured. CSF demonstrated acceptable performance as a specimen type in our multiplexed cytokine assay. By validating CSF as a specimen type and establishing normal reference intervals for cytokine concentrations in CSF, their potential as biomarkers for infectious, autoimmune and other inflammatory CNS disorders can be more appropriately investigated.


Asunto(s)
Biomarcadores , Citocinas , Humanos , Citocinas/líquido cefalorraquídeo , Citocinas/sangre , Valores de Referencia , Femenino , Masculino , Adulto , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Persona de Mediana Edad , Anciano , Adulto Joven , Reproducibilidad de los Resultados , Adolescente
17.
Aging (Albany NY) ; 16(9): 8070-8085, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38728249

RESUMEN

BACKGROUND: Inflammation is one of the significant consequences of ox-LDL-induced endothelial cell (EC) dysfunction. The senescence-associated secretory phenotype (SASP) is a critical source of inflammation factors. However, the molecular mechanism by which the SASP is regulated in ECs under ox-LDL conditions remains unknown. RESULTS: The level of SASP was increased in ox-LDL-treated ECs, which could be augmented by KLF4 knockdown whereas restored by KLF4 knock-in. Furthermore, we found that KLF4 directly promoted PDGFRA transcription and confirmed the central role of the NAPMT/mitochondrial ROS pathway in KLF4/PDGFRA-mediated inhibition of SASP. Animal experiments showed a higher SASP HFD-fed mice, compared with normal feed (ND)-fed mice, and the endothelium of EC-specific KLF4-/- mice exhibited a higher proportion of SA-ß-gal-positive cells and lower PDGFRA/NAMPT expression. CONCLUSIONS: Our results revealed that KLF4 inhibits the SASP of endothelial cells under ox-LDL conditions through the PDGFRA/NAMPT/mitochondrial ROS. METHODS: Ox-LDL-treated ECs and HFD-fed mice were used as endothelial senescence models in vitro and in vivo. SA-ß-gal stain, detection of SAHF and the expression of inflammatory factors determined SASP and senescence of ECs. The direct interaction of KLF4 and PDGFRA promotor was analyzed by EMSA and fluorescent dual luciferase reporting analysis.


Asunto(s)
Senescencia Celular , Células Endoteliales , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel , Lipoproteínas LDL , Mitocondrias , Especies Reactivas de Oxígeno , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas , Factor 4 Similar a Kruppel/metabolismo , Animales , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Especies Reactivas de Oxígeno/metabolismo , Senescencia Celular/efectos de los fármacos , Mitocondrias/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacología , Ratones , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Humanos , Células Endoteliales/metabolismo , Citocinas/metabolismo , Fenotipo , Ratones Noqueados , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Masculino , Transducción de Señal
18.
J Neuroinflammation ; 21(1): 118, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38715090

RESUMEN

Maternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.


Asunto(s)
Encéfalo , Citocinas , Ratones Endogámicos C57BL , Trastornos del Neurodesarrollo , Placenta , Efectos Tardíos de la Exposición Prenatal , Caracteres Sexuales , Femenino , Animales , Embarazo , Masculino , Citocinas/metabolismo , Citocinas/genética , Ratones , Encéfalo/metabolismo , Encéfalo/inmunología , Encéfalo/embriología , Placenta/metabolismo , Placenta/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/inmunología , Trastornos del Neurodesarrollo/metabolismo , Poli I-C/toxicidad , Transcriptoma , Modelos Animales de Enfermedad , Feto/metabolismo
19.
Ital J Pediatr ; 50(1): 92, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38715105

RESUMEN

BACKGROUND: To explore the alterations of inflammatory markers and immune-related cytokines in children infected with Mycoplasma pneumoniae (MP) combined with Adenovirus (ADV). METHODS: The study population consisted of 201 children with MPP, and they were grouped according to whether they were coinfected with ADV infection and critically ill. Additionally, comparative analyses were performed. The diagnostic value of different indicators and combined indicators for SMPP combined with ADV was assessed using ROC curves. RESULTS: There was no difference between group A1 and group A2, group B1 and group B2 in terms of age, gender, duration of hospitalisation and fever. The levels of calcitoninogen(PCT), lactate dehydrogenase concentration(LDH), interleukin(IL)-6, IL-8, IL-10, IL-4, IL-12P70, and IFN-γ in group A were higher than group B. The severe group (A1, B1) was significantly higher than the mild group (A2, B2) in terms of D-dimer, CRP, PCT, LDH, IL-6, IL-8, IL-10, IL-17a and number of patients with pleural effusion, solid lung changes. Among the individual indexes of D-dimer, CRP, N%,LDH, and PCT, the AUC of the combined test was 0.977, which was higher than that of the individual indicators. Among IL-6, IL-8, IL-10, and IL-17a, the AUC of the combined assay was 0.802, which was higher than that of the individual indicators. CONCLUSION: MP combined with ADV infection was associated with increased expression levels of IL-6, IL-8, IL-10, IL-4, IL-12P70, IFN-γ, and LDH. IL-6, IL-8, IL-10, IL-17a, LDH, PCT, CRP, and D-dimer could be used as predictors of SMPP and the combined test can improve the diagnostic value.


Asunto(s)
Citocinas , Neumonía por Mycoplasma , Humanos , Masculino , Femenino , Neumonía por Mycoplasma/diagnóstico , Neumonía por Mycoplasma/complicaciones , Citocinas/sangre , Niño , Preescolar , Biomarcadores/sangre , Infecciones por Adenoviridae/diagnóstico , Índice de Severidad de la Enfermedad , Coinfección/diagnóstico , Curva ROC , Estudios Retrospectivos
20.
Trials ; 25(1): 309, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38715140

RESUMEN

BACKGROUND: Inflamm-aging is associated with the rate of aging and is significantly related to diseases such as Alzheimer's disease, Parkinson's disease, atherosclerosis, heart disease, and age-related degenerative diseases such as type II diabetes and osteoporosis. This study aims to evaluate the safety and efficiency of autologous adipose tissue-derived mesenchymal stem cell (AD-MSC) transplantation in aging-related low-grade inflammation patients. METHODS: This study is a single-group, open-label, phase I clinical trial in which patients treated with 2 infusions (100 million cells i.v) of autologous AD-MSCs were initially evaluated in 12 inflamm-aging patients who concurrently had highly proinflammatory cytokines and 2 of the following 3 diseases: diabetes, dyslipidemia, and obesity. The treatment effects were evaluated based on plasma cytokines. RESULTS: During the study's follow-up period, no adverse effects were observed in AD-MSC injection patients. Compared to baseline (D-44), the inflammatory cytokines IL-1α, IL-1ß, IL-8, IL-6, and TNF-α were significantly reduced after 180 days (D180) of MSC infusion. IL-4/IL-10 at 90 days (D90) and IL-2/IL-10 at D180 increased, reversing the imbalance between proinflammatory and inflammatory ratios in the patients. CONCLUSION: AD-MSCs represent a potential intervention to prevent age-related inflammation in patients. TRIAL REGISTRATION: ClinicalTrials.gov number is NCT05827757, first registered on 13th Oct 2020.


Asunto(s)
Tejido Adiposo , Citocinas , Inflamación , Trasplante de Células Madre Mesenquimatosas , Trasplante Autólogo , Humanos , Femenino , Masculino , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Trasplante de Células Madre Mesenquimatosas/métodos , Persona de Mediana Edad , Citocinas/sangre , Inflamación/sangre , Resultado del Tratamiento , Anciano , Envejecimiento , Mediadores de Inflamación/sangre , Factores de Tiempo , Factores de Edad , Adulto
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