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1.
Lung Cancer ; 145: 213-215, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32389426
2.
Zhongguo Zhong Yao Za Zhi ; 45(2): 361-366, 2020 Jan.
Artículo en Chino | MEDLINE | ID: mdl-32237319

RESUMEN

To investigate the effects of butyl alcohol extract of Baitouweng Decoction(BAEB) on neutrophil chemotaxis in vaginal mucosa of mice with vulvovaginal candidiasis(VVC). Seventy-two SPF female Kunming mice were randomly divided into normal control group, model group, fluconazole group, BAEB low-dose group, middle-dose group and high-dose group. Subcutaneous injection of estradiol benzoate was conducted to induce pseudo-estrus, and then 2×10~6 CFU·mL~(-1)of Candida albicans was inoculated into vaginal lumen, followed by drug treatment for 7 days. Gram staining was used to observe the morphological changes of C. albicans in vagina; vaginal fungal load was detected on agar plate. Histological changes of vaginal tissues in mice were observed by HE staining. Lactate dehydrogenase(LDH), interleukin-6(IL-6) and tumor necrosis factor(TNF-α) levels in mouse lavage fluid were detected by enzyme-linked immunosorbent assay(ELISA). Neutrophils in vaginal lavage fluid was observed and counted by using Pap smear. The levels of IL-8 and MIP-2 in vaginal mucosa were detected by ELISA. IL-8 and MIP-2 mRNA levels in vaginal mucosa of mice were detected by qRT-PCR. The results showed that as compared with the normal group, VVC model group had a large number of hyphae and a high level of fungal loadinvagina. The vaginal mucosa was completely destroyed, the number of neutrophils increased, and the protein and mRNA levels of IL-8 and MIP-2 were up-regulated. After BAEB treatment, the hyphae of the treatment group was decreased, the fungal load was decreased, the impaired mucosa showed different degrees of improvement, the inflammatory factors were decreased to varying degrees, and the protein and mRNA levels of chemokine IL-8 and MIP-2 were down-regulated. In conclusion, BAEB may be used to treat VVC by inhibiting vulvovaginal candidiasis via blocking neutrophils recruitment into vagina.


Asunto(s)
Candidiasis Vulvovaginal/tratamiento farmacológico , Quimiotaxis/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Neutrófilos/efectos de los fármacos , 1-Butanol , Animales , Candida albicans , Femenino , Ratones , Membrana Mucosa/citología , Membrana Mucosa/efectos de los fármacos , Neutrófilos/citología , Vagina/citología , Vagina/diagnóstico por imagen
3.
Physiol Genomics ; 52(5): 217-221, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32275178
4.
Ecotoxicol Environ Saf ; 194: 110412, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32155482

RESUMEN

Hydrogen sulfide (H2S) is a toxic air pollutant that causes immune damage. Recent studies have found that neutrophil extracellular trap (NET) formation is one way in which neutrophils exert immune functions. In addition, the formation of NETs is also related to thrombosis and autoimmune diseases. Recent studies have shown that miRNAs are involved in the regulation of a variety of pathophysiological processes. Here, we investigated the role of H2S in regulating the formation of NETs by affecting miR-16-5p. Our study established an in vitro H2S exposure model for neutrophils using phorbol-myristate-acetate (PMA) to induce NET formation. We observed the morphological changes of cells with scanning electron microscopy and fluorescence microscopy. Then, the content of extracellular DNA and the expression of MPO and NE in each group were detected. The results showed that H2S inhibited the formation of NETs. The expression of miR-16-5p and its target genes PiK3R1 and RAF1 was then measured by qRT-PCR. H2S upregulated miR-16-5p and inhibited expression of the target genes PiK3R1 and RAF1, and it subsequently inhibited the Pi3K/AKT and ERK pathways and decreased respiratory burst levels. Furthermore, H2S attenuated inositol 1,4,5-trisphosphate receptor (IP3R)-mediated endoplasmic reticulum calcium outflow as well as autophagy caused by PMA. This study enriches H2S immunotoxicity research and provides a possible solution for the treatment of NET-related diseases.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Trampas Extracelulares/efectos de los fármacos , Sulfuro de Hidrógeno/toxicidad , MicroARNs/genética , Neutrófilos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-raf/genética , Animales , Autofagia/efectos de los fármacos , Pollos , Trampas Extracelulares/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Modelos Animales , Neutrófilos/metabolismo , Neutrófilos/ultraestructura , Acetato de Tetradecanoilforbol/farmacología , Activación Transcripcional/efectos de los fármacos , Regulación hacia Arriba
6.
Ann Rheum Dis ; 79(4): 536-544, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32114511

RESUMEN

OBJECTIVE: Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout. METHODS: Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout. RESULTS: We identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher's exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10-5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry. CONCLUSION: Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.


Asunto(s)
Gota/genética , Interleucina-1/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Estudios de Casos y Controles , Grupo de Ascendencia Continental Europea/genética , Femenino , Predisposición Genética a la Enfermedad , Gota/inmunología , Humanos , Técnicas In Vitro , Interleucina-1/inmunología , Interleucina-1/farmacología , Interleucina-1beta/efectos de los fármacos , Interleucina-1beta/inmunología , Interleucina-6/inmunología , Interleucina-8/efectos de los fármacos , Interleucina-8/inmunología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Masculino , Ratones , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Grupo de Ascendencia Oceánica/genética , Polimorfismo Genético , Proteínas Recombinantes/farmacología , Ácido Úrico/inmunología , Ácido Úrico/farmacología
7.
Mol Immunol ; 120: 83-92, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32106023

RESUMEN

Pulmonary fibrosis is a progressive chronic inflammatory lung disease whose pathogenesis is complicated. Platelets and neutrophils play important roles in the progression of pulmonary inflammation. We have reported that cangrelor, a non-sepesific GPR17 antagonist, alleviates pulmonary fibrosis partly by inhibiting macrophage inflammation in mice. Cangrelor is also a well-known anti-platelet agent. To test whether cangrelor mitigated pulmonary fibrosis partly through the inhibition of platelets, bleomycin (BLM) was used to induce pulmonary fibrosis in C57BL/6 J mice. We found that cangrelor (10 mg/kg) not only significantly decreased BLM-induced release of inflammatory cytokines (PF4, CD40 L and MPO), but also decreased the increment of platelets, neutrophils and platelet-neutrophil aggregates in the fibrotic lung and in the peripheral blood of BLM-treated mice. In addition, cangrelor decreased the number of CD40 and MPO double positive neutrophils and the expression level of CD40 in BLM-treated mouse lungs. Based on these results we conclude that cangrelor alleviates BLM-induced lung inflammation and pulmonary fibrosis in mice, partly through inhibition of platelet activation, therefore reducing the infiltration of neutrophils due to the adhesion of platelets and neutrophils mediated by CD40 - CD40 L interaction. Cangrelor could be a potential therapeutic medicine for pulmonary fibrosis.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Activación Plaquetaria/efectos de los fármacos , Fibrosis Pulmonar/tratamiento farmacológico , Adenosina Monofosfato/uso terapéutico , Animales , Bleomicina/toxicidad , Antígenos CD40/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila/efectos de los fármacos , Infiltración Neutrófila/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Activación Plaquetaria/inmunología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/inmunología
8.
Chem Biol Interact ; 319: 108984, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-32061742

RESUMEN

OBJECTIVES: As one of the main active ingredients of Chinese herbal medicine Andrographis paniculate, andrographolide is used in domestic clinical treatment for respiratory infections and inflammation. This study was designed to investigate the effects of andrographolide as an antioxidant on the level of oxidative stress, neutrophil accumulation and infiltration in joints and synovial tissue of arthritis rats induced by complete freund's adjuvant. METHODS: A rat model of rheumatoid arthritis was induced by subcutaneous injection of complete Freund's adjuvant in the footpad. The model was established 14 days after induction. The treatment was performed from 14th day to 35th day with different doses of andrographolide (25, 50, 100 mg/kg) and positive control methotrexate (3 mg/kg). The effects of andrographolide on oxidative stress, neutrophil accumulation and infiltration were measured by the paw swelling, arthritis score, the hot plate test, biochemical analysis, and histology. RESULTS: The medium and high-dose andrographolide (50, 100 mg/kg) group declined the levels of tumor necrosis factor-α, interleukin-6 and CXC chemokine ligand2, articular elastase and myeloperoxidase, and increased the levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione. The activity of malondialdehyde and nitrite/nitrate in andrographolide (50, 100 mg/kg) group was weakened than the model group. The degree of swelling and arthritis score of andrographolide group was lower than the model group. The results of hot plate test showed that high dose of andrographolide significantly improved the anti-injury ability of rats; Radiological and histological results showed that the joint osteoporosis, inflammatory cell infiltration, synovial hyperplasia and other phenomena in the andrographolide group were significantly improved. CONCLUSIONS: Andrographolide acts as a protective agent for the treatment of complete freund's adjuvant induced rheumatoid arthritis by inhibiting lipid peroxidation and nitrite/nitrate levels in a dose-dependent manner, enhancing antioxidant enzyme activity, reducing levels of chemokines and inflammatory factors, preventing neutrophil accumulation and infiltration.


Asunto(s)
Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Diterpenos/farmacología , Adyuvante de Freund/farmacología , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Artritis Experimental/metabolismo , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Catalasa/metabolismo , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/tratamiento farmacológico , Edema/metabolismo , Glutatión/metabolismo , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Articulaciones/efectos de los fármacos , Articulaciones/metabolismo , Masculino , Metotrexato/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
9.
Mol Pharmacol ; 97(3): 226-236, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31900312

RESUMEN

Phosphatidylinositol (3,4,5) trisphosphate (PIP3)-dependent Rac exchanger 1 (P-Rex1) is a Rho guanine-nucleotide exchange factor that was originally discovered in neutrophils and is regulated by G protein ßγ subunits and the lipid PIP3 in response to chemoattractants. P-Rex1 has also become increasingly recognized for its role in promoting metastasis of breast cancer, prostate cancer, and melanoma. Recent structural, biochemical, and biologic work has shown that binding of PIP3 to the pleckstrin homology (PH) domain of P-Rex1 is required for its activation in cells. Here, differential scanning fluorimetry was used in a medium-throughput screen to identify six small molecules that interact with the P-Rex1 PH domain and block binding of and activation by PIP3 Three of these compounds inhibit N-formylmethionyl-leucyl-phenylalanine induced spreading of human neutrophils as well as activation of the GTPase Rac2, both of which are downstream effects of P-Rex1 activity. Furthermore, one of these compounds reduces neutrophil velocity and inhibits neutrophil recruitment in response to inflammation in a zebrafish model. These results suggest that the PH domain of P-Rex1 is a tractable drug target and that these compounds might be useful for inhibiting P-Rex1 in other experimental contexts. SIGNIFICANCE STATEMENT: A set of small molecules identified in a thermal shift screen directed against the phosphatidylinositol (3,4,5) trisphosphate-dependent Rac exchanger 1 (P-Rex1) pleckstrin homology domain has effects consistent with P-Rex1 inhibition in neutrophils.


Asunto(s)
Descubrimiento de Drogas/métodos , Factores de Intercambio de Guanina Nucleótido/antagonistas & inhibidores , Factores de Intercambio de Guanina Nucleótido/metabolismo , Neutrófilos/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Animales , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Células Cultivadas , Cristalografía por Rayos X/métodos , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos/métodos , Factores de Intercambio de Guanina Nucleótido/química , Humanos , Neutrófilos/efectos de los fármacos , Fosfatos de Fosfatidilinositol/química , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Pez Cebra
10.
Chemosphere ; 246: 125794, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31918102

RESUMEN

Environmental contamination by heavy metals, such as lead (Pb), can lead to severe immune dysfunction. MicroRNAs (miRNAs) are involved in regulating immunity. Whether Pb can regulate neutrophil apoptosis through miRNA, and whether selenium (Se) can antagonize this response are still unknown. We treated neutrophils with 12.5 µM (CH3OO)2Pb and 1 µM Na2SeO3 for 3 h, after which apoptosis was evaluated using acrideine orange/ethidium bromide (AO/EB) dual fluorescent staining and flow cytometry. The results showed that neutrophil apoptosis was significantly increased following Pb exposure, and that this response was prevented upon Se addition. Pb up-regulates miR-16-5p and leads to the subsequent down-regulation of the target genes phosphoinositide-3-kinase regulatory subunit 1 (PiK3R1), insulin-like growth factor 1 receptor (IGF1R), and phosphatidylinositol 3 kinase (Pi3K)-protein kinase B (AKT), followed by activation of the tumor protein P53 (P53)-B-cell lymphoma-2 (Bcl-2)/Bcl-2-Associated X protein (Bax)-cytochrome c (Cytc)-Caspase 9 (mitochondrial apoptotic pathway) and the tumor necrosis factor receptor superfamily member 6 (Fas)-Fas-associated death domain protein (Fadd)-Caspase 8 (death receptor pathway). Pb also triggered oxidative stress and indirectly activated the mitochondrial apoptotic pathway. We conclude that miR-16-5p plays a key role in the apoptosis of neutrophils exposed to Pb by down-regulating the expression of PiK3R1 and IGFR1, thereby activating the mitochondrial apoptotic pathway and death receptor pathway. Se can prevent Pb-induced apoptosis.


Asunto(s)
Contaminantes Ambientales/toxicidad , Plomo/toxicidad , MicroARNs/metabolismo , Neutrófilos/efectos de los fármacos , Fosfatidilinositol 3-Quinasa/metabolismo , Sustancias Protectoras/metabolismo , Receptor IGF Tipo 1/metabolismo , Selenio/metabolismo , Animales , Apoptosis/efectos de los fármacos , Pollos/metabolismo , Pollos/fisiología , Plomo/metabolismo , MicroARNs/genética , Mitocondrias/metabolismo , Neutrófilos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Selenio/química , Proteína p53 Supresora de Tumor
11.
Am J Physiol Lung Cell Mol Physiol ; 318(1): L180-L191, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31693392

RESUMEN

Exposure to agricultural bioaerosols can lead to chronic inflammatory lung diseases. Amphiregulin (AREG) can promote the lung repair process but can also lead to fibrotic remodeling. The objective of this study was to determine the role of AREG in altering recovery from environmental dust exposure in a murine in vivo model and in vitro using cultured human and murine lung fibroblasts. C57BL/6 mice were intranasally exposed to swine confinement facility dust extract (DE) or saline daily for 1 wk or allowed to recover for 3-7 days while being treated with an AREG-neutralizing antibody or recombinant AREG. Treatment with the anti-AREG antibody prevented resolution of DE exposure-induced airway influx of total cells, neutrophils, and macrophages and increased levels of TNF-α, IL-6, and CXCL1. Neutrophils and activated macrophages (CD11c+CD11bhi) persisted after recovery in lung tissues of anti-AREG-treated mice. In murine and human lung fibroblasts, DE induced the release of AREG and inflammatory cytokines. Fibroblast recellularization of primary human lung mesenchymal matrix scaffolds and wound closure was inhibited by DE and enhanced with recombinant AREG alone. AREG treatment rescued the DE-induced inhibitory fibroblast effects. AREG intranasal treatment for 3 days during recovery phase reduced repetitive DE-induced airway inflammatory cell influx and cytokine release. Collectively, these studies demonstrate that inhibition of AREG reduced, whereas AREG supplementation promoted, the airway inflammatory recovery response following environmental bioaerosol exposure, and AREG enhanced fibroblast function, suggesting that AREG could be targeted in agricultural workers repetitively exposed to organic dust environments to potentially prevent and/or reduce disease.


Asunto(s)
Anfirregulina/farmacología , Polvo/prevención & control , Exposición a Riesgos Ambientales/efectos adversos , Fibroblastos/efectos de los fármacos , Exposición por Inhalación/efectos adversos , Pulmón/efectos de los fármacos , Agricultura/métodos , Animales , Células Cultivadas , Quimiocina CXCL1/metabolismo , Citocinas/metabolismo , Femenino , Fibroblastos/metabolismo , Humanos , Interleucina-6/metabolismo , Pulmón/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
12.
Food Chem Toxicol ; 135: 110929, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31678262

RESUMEN

One of the most spread group of phenolics are flavonoids. Many studies focusing on the digestion and bioavailability of flavonoids have been carried out. Several possible directions of flavonoid metabolism are suspected and described in the literature. The aim of the present study was to evaluate the bioactivity of 8 flavonoid 3-O- and 7-O- glucuronides and 7 free aglycones on inflammatory response of PMNs and HUVECs in the context of their fate in humans after oral intake. The present study for the first time compared the activity of several most popular in plant flavonol and flavone aglycones and their beta-glucuronides. The results showed that in all in vitro experiments only aglycones have anti-inflammatory activity in PMNs and HUVECs models in the concentration range 1-50 µM. The most significant influence on the inflammatory response was observed in the case of HUVECs. Compounds were able to down-regulate levels of adhesion molecules (ICAM, VCAM and E-selectin). The possible deconjugation phenomenon at the inflammation site was evaluated using enzymes produces by stimulated PMNs. This is the first report suggesting the role of ß-glucuronidase in the inflammatory process taking place on the inflammation site. Additionally, the anti-inflammatory effect was significantly better for flavones.


Asunto(s)
Antiinflamatorios/farmacología , Flavonoides/farmacología , Glucurónidos/farmacología , Neutrófilos/efectos de los fármacos , Antiinflamatorios/toxicidad , Moléculas de Adhesión Celular/metabolismo , Endotelio/metabolismo , Flavonoides/toxicidad , Glucurónidos/toxicidad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inflamación/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Neutrófilos/metabolismo
13.
Surgery ; 167(2): 340-351, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31761396

RESUMEN

BACKGROUND: Early intravenous administration of tranexamic acid has been shown to protect the intestinal barrier after a model of trauma-hemorrhagic shock in the rat, but the potential mechanism remains unclear. Our previous studies have demonstrated that neutrophil extracellular traps contribute to the intestinal barrier dysfunction during sepsis and other critical conditions. Meanwhile, there are high levels of neutrophil infiltration in the intestine during trauma-hemorrhagic shock. Here, we hypothesized that neutrophil extracellular trap formation played a vital role during trauma-hemorrhagic shock-induced intestinal injury and that tranexamic acid, a serine protease inhibitor, may inhibit neutrophil extracellular trap formation and protect intestinal barrier function in trauma-hemorrhagic shock. METHODS: A model of trauma-hemorrhagic shock in male rats was established. The rats were divided into 6 groups: (1) sham group; (2) trauma-hemorrhagic shock group; (3) trauma-hemorrhagic shock + DNase I group; (4) trauma-hemorrhagic shock + tranexamic acid group; (5) trauma-hemorrhagic shock + tranexamic acid (different time) group; and (6) trauma-hemorrhagic shock + tranexamic acid (different doses) group. The DNase I solution was injected intravenously to disrupt neutrophil extracellular traps immediately after the trauma-hemorrhagic shock model was completed. After 24 hours, the small intestine and blood were collected for analysis. Human neutrophils were harvested and incubated with phorbol-12-myristate-13-acetate or tranexamic acid, generation of reactive oxygen species, and key proteins expression were detected. RESULTS: Trauma-hemorrhagic shock induced the formation of intestinal neutrophil extracellular traps and disrupted the intestinal tight junction proteins. Clearing of neutrophil extracellular traps by DNase I resulted in increased expression of tight junction proteins and alleviated the intestinal injury. Early intravenous tranexamic acid administration (1 hour after trauma-hemorrhagic shock) decreased neutrophil extracellular trap formation and prevented tight junction protein disruption compared to the non-tranexamic acid group; however, after delayed administration of tranexamic acid (6 hours), there were no changes in neutrophil extracellular trap formation and intestinal injuries compared to the non-tranexamic acid group. Furthermore, tranexamic acid inhibited neutrophil extracellular trap formation and protected the intestinal barrier in a dose-dependent manner and high-dose (20 mg/kg) treatment of tranexamic acid showed a better effect compared with the therapeutic dose (10 mg/kg). The results of thromboelastography demonstrated that the R and K values in the high-dose group decreased (R, 1.85 ± 0.14 vs 3.87 ± 0.16 minutes, P < .001; K, 0.95 ± 0.04 vs 1.48 ± 0.07 minutes, P < .001), accompanied by a decrease in LY30, indicating that treatment with a high dose of tranexamic acid may cause hypercoagulability and shutdown of fibrinolysis. In addition, less neutrophil extracellular trap formation was detected in neutrophils incubated with neutrophils via an reactive oxygen species-dependent pathway. CONCLUSION: We first demonstrated a novel role of neutrophil extracellular traps in the pathophysiology of intestinal barrier dysfunction during trauma-hemorrhagic shock. Notably, early but not delayed intravenous administration of tranexamic acid effectively inhibits neutrophil extracellular trap formation and protects intestinal barrier function. Therefore, these results suggested a potential theoretic intervention for the protection of the intestinal barrier during trauma-hemorrhagic shock. In such a process, tranexamic acid appears to regulate neutrophil extracellular trap formation via the classic reactive oxygen species/mitogen-activated protein kinase pathway.


Asunto(s)
Antifibrinolíticos/administración & dosificación , Trampas Extracelulares/efectos de los fármacos , Enfermedades Intestinales/prevención & control , Mucosa Intestinal/efectos de los fármacos , Choque Hemorrágico/complicaciones , Ácido Tranexámico/administración & dosificación , Animales , Células Cultivadas , Evaluación Preclínica de Medicamentos , Humanos , Enfermedades Intestinales/etiología , Mucosa Intestinal/lesiones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Neutrófilos/efectos de los fármacos , Distribución Aleatoria , Ratas Sprague-Dawley
14.
Fish Shellfish Immunol ; 96: 26-31, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31794841

RESUMEN

Di-(2-ethylhexyl) phthalate (DEHP), a common pollutant in the water environment, has been reported to be associated with immune functions, especially aquatic organisms. However, whether DEHP exposure causes neutrophils toxicity in common carp is still unclear. To investigate the toxic effect of DEHP on immune functions, common carp neutrophils were exposed to DEHP (40 µmol/L and 200 µmol/L) for 2 h. The common carp neutrophils exposed to DEHP showed a decrease in neutrophil phagocytosis rate compared with control group. DEHP exposure induced a significant decrease in mRNA expression levels of inflammatory cytokines-related genes (Interleukin-6, Interleukin-8, transforming growth factor, tumor necrosis factor (TNF)-α, TNF-R1, TNF-T1, Interferon (IFN)-2a, IFN-g2b, IFN-g1) in common carp neutrophils, while the expression levels of IL-1ß and IL-10 were increased compared with control group (P < 0.05). Furthermore, the detection of cytochrome P450 enzyme related genes showed that the mRNA expression levels of CYP (cytochrome P450 proteins)-1A, CYP-1B1, CYP-C1, CYP-2K were significantly decreased, and the mRNA expression level of CYP-3A was significantly reduced (P < 0.05). The results indicated that DEHP could affect the phagocytic ability of neutrophils by regulating the expression of inflammatory cytokines and disrupting cytochrome P450 homeostasis, which caused the immunosuppression in common carp.


Asunto(s)
Carpas/inmunología , Sistema Enzimático del Citocromo P-450/inmunología , Dietilhexil Ftalato/efectos adversos , Proteínas de Peces/metabolismo , Tolerancia Inmunológica/efectos de los fármacos , Neutrófilos/inmunología , Contaminantes Químicos del Agua/efectos adversos , Animales , Carpas/metabolismo , Homeostasis/inmunología , Neutrófilos/efectos de los fármacos , Plastificantes/efectos adversos
15.
Environ Pollut ; 257: 113583, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31780361

RESUMEN

In recent years, numerous studies paid more attention to the molecular mechanisms associated with fluoride toxicity. However, the detailed mechanisms of fluoride immunotoxicity in bovine neutrophils remain unclear. Neutrophil extracellular traps (NETs) is a novel immune mechanism of neutrophils. We hypothesized that sodium fluoride (NaF) can trigger NETs activation and release, and investigate the related molecular mechanisms during the process. We exposed peripheral blood neutrophils to 1 mM NaF for 120 min in bovine neutrophils. The results showed that NaF exposure triggered NET-like structures decorated with histones and granule proteins. Quantitative measurement of NETs content correlated positively with the concentration of NaF. Mechanistically, NaF exposure increased reactive oxygen species (ROS) levels and phosphorylation levels of ERK, p38, whereas inhibiting the activities of superoxide dismutase (SOD) and catalase (CAT) compared with control neutrophils. NETs formation is induced by NaF and this effect was inhibited by the inhibitors diphenyleneiodonium chloride (DPI), U0126 and SB202190. Our findings described the potential importance of NaF-triggered NETs related molecules, which might help to extend the current understanding of NaF immunotoxicity.


Asunto(s)
Trampas Extracelulares , Sustancias Peligrosas/toxicidad , Neutrófilos/efectos de los fármacos , Fluoruro de Sodio/toxicidad , Animales , Bovinos , NADPH Oxidasas , Especies Reactivas de Oxígeno
16.
Cancer ; 126(1): 76-85, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31584709

RESUMEN

BACKGROUND: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poor survival in patients with cancer, including those who receive immunotherapies. The authors sought to investigate NLR as a biomarker of treatment outcomes in patients with melanoma who were treated with PD-1 inhibition. METHODS: Patients undergoing initial treatment with PD-1 inhibitor monotherapy for stage IV melanoma at a single center from 2012 to 2015 were included. Clinical characteristics and the NLR at baseline and before subsequent treatment cycles were collected. The time to treatment failure (TTF) and overall survival (OS) were evaluated using Kaplan-Meier and landmark analyses. RESULTS: Among 224 study patients, 63 (28%) had a baseline NLR ≥5. The baseline NLR was significantly associated with Eastern Cooperative Oncology Group performance status and the number of involved metastatic sites. With a median follow-up of 39 months in survivors, a baseline NLR ≥5 was independently associated with shorter OS (hazard ratio, 2.0; 95% CI, 1.3-2.9) and TTF (hazard ratio, 1.7; 95% CI, 1.2-2.4). An NLR increase ≥30% during the first 2 cycles of treatment was associated with worse OS (median, 47 vs 13.5 months; P < .001) and a trend toward shorter TTF (12.8 vs 5.9 months; P = .05). A combined baseline NLR ≥5 and an NLR increase ≥30% identified a small cohort with markedly shortened OS (median, 5.8 months) and TTF (median, 1.8 months). CONCLUSIONS: Elevated baseline NLR and an increased NLR early during treatment are prognostic for TTF and OS in patients who have melanoma treated with PD-1 inhibitor monotherapy. Combined, these biomarkers can widely risk-stratify patients for treatment failure and survival.


Asunto(s)
Antineoplásicos Inmunológicos/administración & dosificación , Melanoma/tratamiento farmacológico , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Recuento de Linfocitos , Linfocitos/efectos de los fármacos , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Neutrófilos/efectos de los fármacos , Receptor de Muerte Celular Programada 1/inmunología
17.
Nanotoxicology ; 14(2): 250-262, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31855090

RESUMEN

Lung deposition and retention measurements are now required by the newly revised OECD inhalation toxicity testing guidelines 412 and 413 when evaluating the clearance and biopersistence of poorly soluble nanomaterials, such as multi-walled carbon nanotubes (MWCNTs). However, evaluating the lung deposition concentration is challenging with certain nanomaterials, such as carbon-based and iron-based nanomaterials, as it is difficult to differentiate them from endogenous elements. Therefore, the current 28-day inhalation toxicity study investigated the lung retention kinetics of tangled MWCNTs. Male Sprague Dawley rats were exposed to MWCNTs at 0, 0.257, 1.439, and 4.253 mg/m3 for 28 days (6 h/day, 5 days/week, 4 weeks). Thereafter, the rats were sacrificed at day 1, 7, and 28 post-exposure and the pulmonary inflammatory response evaluated by analyzing the bronchoalveolar lavage fluid. Plus, the blood biochemistry, hematology, and histopathology of the lungs were also examined. The lung deposition and retention of MWCNTs were determined based on the elemental carbon content in the lungs after tissue digestion. The number of polymorphonuclear cells and LDH concentration were both found to be significantly higher with the medium and high concentrations (1.439 and 4.253 mg/m3) and dose dependent. The estimated retention half-life for the high concentration (4.253 mg/m3) was about 35 days. The results of this study indicate that tangled MWCNTs seem to have a relatively shorter retention half-life when compared to previous reports on rigid MWCNTs, and the no-observed adverse effect level (NOAEL) for the tested tangled MWCNTs was 0.257 mg/m3 in a previous rat 28-day subacute inhalation toxicity study.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Exposición por Inhalación/efectos adversos , Pulmón/efectos de los fármacos , Nanotubos de Carbono/toxicidad , Aerosoles , Animales , Líquido del Lavado Bronquioalveolar/química , Relación Dosis-Respuesta a Droga , Semivida , Exposición por Inhalación/análisis , Pulmón/metabolismo , Pulmón/patología , Masculino , Neutrófilos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Pruebas de Toxicidad Subaguda
18.
J Dairy Sci ; 103(1): 723-736, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31668440

RESUMEN

Synthetic zeolites are used to control the availability of dietary minerals (e.g., Ca, Mg, and P) in dairy cows. Due to calcium demand increasing with lactation onset, most cows become hypocalcemic immediately postpartum, which likely contributes to poorer immune function because calcium is important for immune cell signaling. To overcome postpartum hypocalcemia, we fed transition cows synthetic zeolite A (sodium aluminosilicate) precalving and hypothesized that it would alter calcium and thus neutrophil function during the transition period. Multiparous Holstein-Friesian cows in late gestation were randomly allocated to an untreated control group (n = 10) or a treatment group in which each cow received 500 g of zeolite A daily (n = 10) for 14 d prior to the expected calving date (actual duration = 17 ± 3 d prepartum). The cows grazed pasture, and each was supplemented with 2 kg/d of maize silage (dry matter basis), with or without zeolite, until calving. Blood samples for neutrophil isolation and analysis of plasma indicators of mineral status, energy status, liver function, and inflammation were collected pretreatment (covariate; d -19); on d -14 and -7 precalving; on the day of calving (d 0); and on d 1, 4, 7, and 28 postcalving. Neutrophils were isolated and gene expression was analyzed using microfluidic gene expression arrays. Neutrophil respiratory burst was assessed using stimulation with phorbol 12-myristate 13-acetate and flow cytometry. Plasma calcium and phosphorus revealed a treatment by time interaction; cows offered zeolite had greater plasma calcium concentrations at d 0, 1, and 4 postcalving and plasma phosphorus concentrations were lower in zeolite-treated cows during the precalving period until d 1 postcalving compared with control animals. Zeolite treatment downregulated neutrophil gene expression of CXCR4 and S100A8 and tended to lower gene expression for other immune mediators (CXCR1, IFNG, S100A12, and S100A9) compared with the control. Zeolite treatment did not affect neutrophil respiratory burst or expression of the other genes investigated. Plasma concentrations of cytokine IL-6 were reduced with zeolite treatment, which was most evident immediately postcalving (d 0, 1, and 7). Overall, feeding zeolite precalving had few effects on neutrophil gene expression and function; however, the lower gene expression of neutrophil inflammatory mediators may be due to altered availability of dietary minerals prepartum and indicates that zeolite A may control inflammation during the transition period.


Asunto(s)
Suplementos Dietéticos , Regulación de la Expresión Génica/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Zeolitas/administración & dosificación , Alimentación Animal/análisis , Animales , Bovinos , Dieta/veterinaria , Femenino , Lactancia/fisiología , Leche/metabolismo , Neutrófilos/metabolismo , Periodo Posparto , Embarazo , Ensilaje , Zeolitas/síntesis química , Zeolitas/farmacología
19.
J Dairy Sci ; 103(1): 864-870, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31733852

RESUMEN

Neutrophils are innate immunity cells that represent the first line of cellular defense against invading pathogens. Dairy calves, however, experience neutrophil dysfunction during the first weeks of age, contributing to increased disease susceptibility during this period. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that improves neutrophil function in neonates of other species and mature cows. However, its capability to improve neonatal calf neutrophil function is unknown. Therefore, our objective was to evaluate the effect of GM-CSF on the functional capabilities of neutrophils of neonatal calves in vitro. We hypothesized that supplementation of neonatal neutrophils with GM-CSF would increase microbicidal functions to levels comparable with those of mature immunocompetent cattle. For this, we isolated blood neutrophils from 12 healthy 2- to 3-d-old Holstein calves, and neutrophils from 6 mid-lactation Holstein cows were used as a reference of robust neutrophil function. Subsequently, neutrophils from both calves and cattle were incubated for 9 h with 4 concentrations (0, 0.005, 0.05, or 0.5 µg/mL) of GM-CSF, and microbicidal function of neutrophils was assessed in terms of phagocytosis, respiratory burst, myeloperoxidase (MPO) activity, and extracellular trap formation. Mixed models with Tukey pairwise comparisons were used to identify differences among treatment and age groups. Supplementation of GM-CSF in vitro increased phagocytosis and MPO activity of calf and cow neutrophils, although not in a concentration-dependent manner. Respiratory burst and extracellular trap formation were not affected by GM-CSF supplementation. All the microbicidal capacity functions assessed were lower in neutrophils from calves, but supplementation with GM-CSF increased phagocytosis and MPO activity of calf neutrophils to levels comparable with unsupplemented cow neutrophils. Collectively, our results demonstrated that in vitro supplementation of calf neutrophils with GM-CSF enhanced some functional microbicidal capabilities to levels comparable with immunocompetent cattle. Hence, it may be possible to augment the functional capacity of calf neutrophils in vivo through the therapeutic application of GM-CSF and consequently enhance calves' resistance to infections. This should be tested in future in vivo studies.


Asunto(s)
Bovinos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Neutrófilos/efectos de los fármacos , Animales , Animales Recién Nacidos , Femenino , Técnicas In Vitro , Lactancia , Neutrófilos/inmunología , Fagocitosis/efectos de los fármacos , Estallido Respiratorio/efectos de los fármacos
20.
Environ Sci Pollut Res Int ; 27(6): 6540-6548, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31873886

RESUMEN

This study was conducted to verify a hypothesis that immune cells are a target for the action of endocrine disrupting chemicals (EDCs) by investigating whether methylparaben (MeP) modulates human neutrophil functions. Neutrophils isolated from 15 donor samples were studied. Cells were incubated in the presence of increasing MeP concentrations (0.06, 0.8, 10, and 20 µM). The cytotoxic effect of MeP on neutrophils was evaluated by the MTT test. The ability of the neutrophils for chemotaxis, phagocytosis, NADPH oxidase activity, and superoxide anion generation was assessed in Boyden's chamber, Park's method with latex, the NBT test, and the cytochrome C reduction test, respectively. The total nitric oxide (NO) concentration was measured by the Griess reaction. There was no observable cytotoxic effect of MeP on human neutrophils. MeP (10 and 20 µM) exposure decreased neutrophilic ability for the tested functions, except for NO production. In neutrophils incubated with MeP (0.8 µM as well as 0.06 and 0.8 µM, respectively), we observed a decreased activity of NADPH oxidase as well as decreased generation of superoxide anion. Our results suggest a suppressive effect of MeP on the tested functions of human neutrophils, which confirms that immune cells are vulnerable to EDC action. Therefore, the disturbance of neutrophils' oxygen-dependent phagocytic function as a result of exposure to environmental doses of MeP action could lead to impairment of innate immune responses in humans exposed to xenoestrogens.


Asunto(s)
Disruptores Endocrinos/toxicidad , Neutrófilos/efectos de los fármacos , Parabenos/toxicidad , Humanos , Superóxidos , Pruebas de Toxicidad
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