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1.
Environ Toxicol ; 39(5): 2634-2641, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38205902

RESUMEN

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a widespread inflammatory disease with a high mortality rate. Long noncoding RNAs play important roles in pulmonary diseases and are potential targets for inflammation intervention. METHODS: The expression of small nucleolar RNA host gene 6 (SNHG6) in mouse lung epithelial cell line MLE12 with or without cigarette smoke extract (CSE) treatment was first detected using quantitative reverse-transcription PCR. ELISA was used to evaluate the release of inflammatory cytokines (TNF-α, IL-1ß, and IL-6). The binding site of miR-182-5p with SNHG6 was predicted by using miRanda, which was verified by double luciferase reporter assay. RESULTS: Here, we revealed that SNHG6 was upregulated in CS-exposed MLE12 alveolar epithelial cells and lungs from COPD-model mice. SNHG6 silencing weakened CS-induced inflammation in MLE12 cells and mouse lungs. Mechanistic investigations revealed that SNHG6 could upregulate IκBα kinase through sponging the microRNA miR-182-5p, followed by activated NF-κB signaling. The suppressive effects of SNHG6 silencing on CS-induced inflammation were blocked by an miR-182-5p inhibitor. CONCLUSION: Overall, our findings suggested that SNHG6 regulates CS-induced inflammation in COPD by activating NF-κB signaling, thereby offering a novel potential target for COPD treatment.


Asunto(s)
Fumar Cigarrillos , MicroARNs , Neumonía , Enfermedad Pulmonar Obstructiva Crónica , ARN Largo no Codificante , Ratones , Animales , FN-kappa B/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Fumar Cigarrillos/efectos adversos , Neumonía/inducido químicamente , Neumonía/genética , MicroARNs/genética , MicroARNs/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Inflamación/genética , Inflamación/metabolismo
2.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 35(8): 856-859, 2023 Aug.
Artículo en Chino | MEDLINE | ID: mdl-37593866

RESUMEN

OBJECTIVE: To compare the effects of citrate and heparin anticoagulation on coagulation function and efficacy in children with septic shock undergoing continuous blood purification (CBP), and to provide guidance for CBP anticoagulation in children with septic shock. METHODS: A case control study was conducted. Thirty-seven children with septic shock admitted to the pediatric intensive care unit (PICU) of the First Affiliated Hospital of Gannan Medical University from July 2019 to September 2022 were enrolled as the research subjects. The patients were divided into citrate local anticoagulation group and heparin systemic anticoagulation group according to different anticoagulation methods. The baseline data, the level of coagulation indicators [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fib), D-dimer] before treatment and 1 day after weaning from CBP, serum inflammatory mediators [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), hypersensitivity C-reactive protein (hs-CRP), procalcitonin (PCT)], bleeding complications during CBP and 7-day mortality were collected. RESULTS: A total of 37 cases were enrolled finally, including 17 cases with citric acid local anticoagulation and 20 cases with heparin systemic anticoagulation. There was no statistically significant difference in general data such as gender, age, and body weight of children between the two groups. There were no statistically significant differences in baseline levels of coagulation indicators and inflammatory mediators before treatment of children between the two groups. One day after weaning from CBP, both groups showed varying degrees of improvement in coagulation indicators compared with those before treatment. Compared with before treatment, the PT of the heparin systemic anticoagulation group was significantly shortened after 1 day of weaning (s: 11.82±2.05 vs. 13.64±2.54), APTT and TT were significantly prolonged [APTT (s): 51.54±12.69 vs. 35.53±10.79, TT (s): 21.95±4.74 vs. 19.30±3.33], D-dimer level was significantly reduced (mg/L: 1.92±1.58 vs. 4.94±3.94), with statistically significant differences (all P < 0.05). While in the citrate local anticoagulation group, only APTT was significantly prolonged after treatment compared with that before treatment (s: 49.28±10.32 vs. 34.34±10.32, P < 0.05). There were no statistically significant differences in other coagulation indicators compared with before treatment. Compared with the citric acid local anticoagulation group, the PT of the heparin systemic anticoagulation group was significantly shortened after treatment (s: 11.82±2.05 vs. 13.61±3.05, P < 0.05), and the D-dimer level was significantly reduced (mg/L: 1.92±1.58 vs. 3.77±2.38, P < 0.01). The levels of inflammatory mediators in both groups were significantly reduced 1 day after CBP weaning compared with those before treatment [citric acid local anticoagulation group: hs-CRP (mg/L) was 12.53±5.44 vs. 22.65±7.27, PCT (µg/L) was 1.86±1.20 vs. 3.30±2.34, IL-6 (ng/L) was 148.48±34.83 vs. 202.32±48.62, TNF-α (ng/L) was 21.38±7.71 vs. 55.14±15.07; heparin systemic anticoagulation group: hs-CRP (mg/L) was 11.82±4.93 vs. 21.62±8.35, PCT (µg/L) was 1.90±1.08 vs. 3.18±1.97, IL-6 (ng/L) was 143.81±33.41 vs. 194.02±46.89, TNF-α (ng/L) was 22.44±8.17 vs. 56.17±16.92, all P < 0.05]. However, there was no statistically significant difference between the two groups (all P > 0.05). There was no statistically significant difference in bleeding complication during CBP and 7-day mortality in children between the citrate local anticoagulation group and the heparin systemic anticoagulation group (5.9% vs. 30.0%, 17.6% vs. 20.0%, both P > 0.05). CONCLUSIONS: Heparin for systemic anticoagulation and regional citrate anticoagulation can significantly reduce the levels of IL-6, TNF-α, hs-CRP and PCT in children with septic shock, and relieve inflammatory storm. Compared with citric acid local anticoagulation, heparin systemic anticoagulation can shorten the PT and reduce the level of D-dimer in children with septic shock, which may benefit in the prevention and treatment of disseminated intravascular coagulation (DIC).


Asunto(s)
Ácido Cítrico , Choque Séptico , Humanos , Niño , Heparina/farmacología , Choque Séptico/tratamiento farmacológico , Proteína C-Reactiva , Estudios de Casos y Controles , Interleucina-6 , Factor de Necrosis Tumoral alfa , Citratos , Fibrinolíticos , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico
3.
Contrast Media Mol Imaging ; 2022: 5687245, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36262980

RESUMEN

Lung cancer in its occurrence and development of different stages exist different biological behavior changes. This paper studies the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 in benign and malignant lung lesions and its early diagnosis value of nonsmall-cell lung cancer (NSCLC), aiming to provide reference for the early diagnosis and therapy of NSCLC. Some lung surgery specimens are selected from January 2021 to March 2022. All cases received no radiotherapy and chemotherapy before surgery, including 90 sufferers with benign lung lesions as the contrast set. hnRNP A2/B1 expressions are measured for comparison. The experimental results show that for lung cancer sufferers, the positive expression of hnRNP A2/B1 in their malignant lesion tissue is notoriously higher than that in their benign lesion tissue, and hnRNP A2/B1 is differently expressed in different differentiation and in different stages.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B , Neoplasias Pulmonares , Humanos , Detección Precoz del Cáncer , Carcinoma de Pulmón de Células no Pequeñas/patología , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Neoplasias Pulmonares/patología , Pulmón/patología
4.
Front Pediatr ; 10: 929665, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35935355

RESUMEN

Objective: The purpose of this systematic review was to explore the value of the expression level of the triggering receptor expressed on myeloid cell-1 (TREM-1) in the diagnosis and prognosis of neonatal sepsis. Methods: A comprehensive search was performed to identify the diagnostic and prognostic predictive values of the TREM-1 expression level in neonatal sepsis. Based on the retrieval strategy, Cochrane Library, Embase, Ovid, ProQuest, PubMed, Scopus, and Web of Science databases were searched from inception to February 2022. Studies were included if they assessed the accuracy of TREM-1 expression in the diagnosis of neonatal sepsis and distinguished survival and death in neonatal sepsis. Two authors independently evaluated the study and extracted the data, including the first author of the literature, country, total study population, basic population characteristics of the study group and the control group, study design (observational studies), type of sample, sepsis onset, type of biomarker, assay method, cut-off, sensitivity, specificity, true positives (TP), false positives (FP), false negatives (FN), and true negatives (TN). A third party will be consulted if disputed. The accuracy of TREM-1 expression in the diagnosis and prognostic prediction of neonatal sepsis was evaluated by a bivariate mixed-effects model. The source of heterogeneity was explored through meta-regression analysis. Results: Thirteen articles that met the research criteria were included in qualitative analysis, and 11 of them were included in quantitative analysis. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operator characteristic (SROC) curve of soluble TREM-1 (sTREM-1) were 0.94 (95% CI: 0.82, 0.98), 0.87 (95% CI: 0.70, 0.95), 7.36 (95% CI: 2.75, 19.74), 0.07 (95% CI: 0.02, 0.24), 111.71 (95% CI: 13.24, 942.92), and 0.96 (95% CI: 0.94, 0.98), respectively. Meta-regression and subgroup analysis were used to investigate the heterogeneity, owing to non-threshold effects caused by types of test sample and research design. sTREM-1 as a biomarker for distinguishing survival and death in neonates with sepsis had pooled sensitivity, specificity, area under the SROC curve, PLR, NLR, and DOR of 0.95 (95% CI: 0.83, 0.99), 0.98 (95% CI: 0.68, 1.00), 0.99 (95% CI: 0.97, 0.99), 39.28 (95% CI: 2.13, 723.99), 0.05 (95% CI: 0.01, 0.19), and 789.61 (95% CI: 17.53, 35,560.72), respectively. Conclusion: The study showed that TREM-1 was a potential biomarker for the diagnosis and prognosis of neonatal sepsis. The biggest advantage of this study is that it is the first to comprehensively explore the role of TREM-1 expression in the diagnosis and prognosis of neonatal sepsis. However, there are some limitations in this study, such as the reduced number of clinical studies on TREM-1 expression as a biomarker of neonatal sepsis, regional bias, and differences in detection methods. Hence, more large-scale and high-quality studies are needed to improve diagnostic accuracy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022338041.

5.
Toxicol Lett ; 357: 11-19, 2022 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-34953943

RESUMEN

Chronic obstructive pulmonary disease (COPD) is a global public health issue and is defined as persistent airflow limitation. COPD is a major cause of morbidity and mortality worldwide. Long noncoding RNAs are involved in the course of pulmonary diseases. Here, we revealed that a long noncoding RNA called myocardial-infarction-associated transcript (MIAT) is upregulated in lung tissues of cigarette smoke (CS)-exposed mice. Knockdown of MIAT attenuated CS or CS-extract-induced inflammatory processes, epithelial-mesenchymal transition (EMT), and collagen deposition. Moreover, according to bioinformatic analyses and luciferase reporter assays, MIAT binds to microRNA-29c-3p (miR-29c-3p) and upregulates hypoxia-inducible factor 3 alpha (HIF3A), a target gene of miR-29c-3p. When the MIAT-specific short hairpin RNA and an miR-29c-3p inhibitor were cotransfected into cells, the inhibitor reversed the effects of MIAT knockdown on cell proliferation, apoptosis, inflammation, EMT, and collagen deposition. Overall, these results indicate that MIAT participates in CS-induced EMT and airway remodeling in COPD by upregulating miR-29c-3p-HIF3A axis output, thereby offering a novel promising biomarker for the assessment of COPD exacerbation induced by CS exposure.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Proteínas Reguladoras de la Apoptosis/metabolismo , MicroARNs/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteínas Represoras/metabolismo , Animales , Apoptosis , Biomarcadores , Línea Celular , Fumar Cigarrillos/efectos adversos , Colágeno/metabolismo , Regulación hacia Abajo , Transición Epitelial-Mesenquimal , Técnicas de Silenciamiento del Gen/métodos , Inflamación , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad Pulmonar Obstructiva Crónica/patología , Transducción de Señal
6.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(9): 1040-1046, 2021 Sep.
Artículo en Chino | MEDLINE | ID: mdl-34839858

RESUMEN

OBJECTIVE: To systematically evaluate the effect of hydrocortisone combined with vitamin C and vitamin B1 on the efficacy of patients with sepsis or septic shock. METHODS: Databases including CNKI, Sino Med, VIP, Wanfang, PubMed, the Cochrane Library, and Embase were searched from inception to January 2021 for the randomized controlled trial (RCT) about hydrocortisone combined with vitamin C and vitamin B1 to treat sepsis or septic shock. The experimental group was given intravenous injection of hydrocortisone, vitamin B1 and vitamin C based on conventional treatment; the control group was given conventional treatment or placebo/hydrocortisone/hydrocortisone+vitamin B1 based on conventional treatment. Outcome indicators included sequential organ failure assessment (SOFA), mortality, the duration of vasoactive drugs, new acute kidney injury (AKI) patients, length of stay in intensive care unit (ICU) and in hospital. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. RevMan 5.3 software was then used to perform Meta-analysis. Funnel plot was used to test publication bias. RESULTS: A total of 6 articles involving 816 patients were included, with 411 patients in the experimental group and 405 patients in the control group. The Meta-analysis results showed that the duration of vasoactive drugs in the experimental group was significantly shorter than that in the control group [mean difference (MD) = -24.02, 95% confidence interval (95%CI) was -32.36 to -15.68, P < 0.000 01]. However, there were no significant differences in SOFA, mortality, new AKI patients, the length of ICU stay and hospital stay between the two groups [SOFA: MD = -0.14, 95%CI was -1.15 to 0.87, P = 0.79; mortality: relative risk (RR) = 0.99, 95%CI was 0.81 to 1.21, P = 0.92; new AKI patients: RR = 1.10, 95%CI was 0.42 to 2.87, P = 0.84; length of ICU stay: MD = 1.33, 95%CI was -2.22 to 4.89, P = 0.46; length of hospital stay: MD = 1.02, 95%CI was -0.66 to 2.69, P = 0.23]. The funnel plot showed that most of the points were symmetrical and showed an inverted funnel shape, suggesting that the publication bias among the studies was small. There was no significant publication bias on this Meta-analysis. CONCLUSIONS: Hydrocortisone combined with vitamin C and vitamin B1 can shorten the duration of vasoactive drugs in patients with sepsis or septic shock, but it cannot effectively reduce the SOFA score, mortality, new AKI patients, length of stay in ICU and in hospital. Limited by the number and quality of the included studies, further large-scale, multi-center, blinded, RCT are still needed for verification.


Asunto(s)
Hidrocortisona , Sepsis , Ácido Ascórbico/uso terapéutico , Humanos , Hidrocortisona/uso terapéutico , Unidades de Cuidados Intensivos , Sepsis/tratamiento farmacológico , Tiamina
7.
Chemistry ; 27(35): 9071-9076, 2021 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-33788317

RESUMEN

Scintillators are widely used for nondestructive testing, nuclear medicine imaging, space exploration and security inspection. Recently, lead halide perovskite scintillation crystals have been brought into focus due to their effective atomic number, fast scintillation decay time, strong luminous efficiency, and tunable band gap. However, their application is limited by lead toxicity. Here we report that Ce-doping can increase sensitivity in lead-free double perovskite crystals (Cs2 NaTbCl6 ) for X-ray detection and imaging. The introduction of Ce ions as sensitizer can be used to improve the radioluminescence of the crystals. The light output of Ce : Cs2 NaTbCl6 crystals is about 52153 ph/MeV, which is 25 % higher than that of un-doped crystal. The X-ray sensitivity is significantly enhanced. Based on our scintillation film X-ray detector the detection limit is 30 nGy ⋅ s-1 , which is about 1/183 of the typical medical imaging dose. Our scintillating film has excellent imaging ability with spatial resolution of up to 10 lp/mm. This research shows that Ce : Cs2 NaTbCl6 perovskite crystal scintillators are promising materials for X-ray imaging application.


Asunto(s)
Cerio , Doping en los Deportes , Compuestos de Calcio , Óxidos , Radiografía , Conteo por Cintilación , Titanio , Rayos X
8.
Adv Exp Med Biol ; 1278: 33-46, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33523441

RESUMEN

The FOXP3 transcription factor acts as a master regulator in the development and function of regulatory T cells (Tregs). Insufficient expression or mutation of FOXP3 gene impairs Treg abundancy and function and causes fatal autoimmune lymphoproliferative diseases in mice and humans. The available crystal structures of FOXP3 protein fragments provide insights into understanding details of the FOXP3 work mechanism in Tregs. This chapter consists of four sections. First, we introduce some features of Treg cells indispensable for the establishment of immune tolerance; second, we describe the critical roles of FOXP3 in Treg development and function; third, we summarize the current available crystal structures of FOXP3 functional domains and related pathogenic mutations in autoimmune diseases; finally, we discuss the potential functional and pathological relevance of FOXP3 protein structure modulation, partner interaction, and posttranslation modification based on the clinical significance in IPEX disease. The information presented in this chapter will help to consider therapeutic strategies to enhance FOXP3 activity and Treg function in the settings of autoimmune disease. Targeting Treg suppression based on FOXP3 structure and interactions hold great promises for the therapy of autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes , Enfermedades Genéticas Ligadas al Cromosoma X , Animales , Enfermedades Autoinmunes/genética , Factores de Transcripción Forkhead/genética , Tolerancia Inmunológica , Ratones , Linfocitos T Reguladores
9.
Front Immunol ; 10: 2486, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31681337

RESUMEN

Regulatory T cells (Tregs) are engaged in maintaining immune homeostasis and preventing autoimmunity. Treg cells include thymic Treg cells and peripheral Treg cells, both of which can suppress the immune response via multiple distinct mechanisms. The differentiation, proliferation, suppressive function and survival of Treg cells are affected by distinct energy metabolic programs. Tissue-resident Treg cells hold unique features in comparison with the lymphoid organ Treg cells. Foxp3 transcription factor is a lineage master regulator for Treg cell development and suppressive activity. Accumulating evidence indicates that the activity of Foxp3 protein is modulated by various post-translational modifications (PTMs), including phosphorylation, O-GlcNAcylation, acetylation, ubiquitylation and methylation. These modifications affect multiple aspects of Foxp3 function. In this review, we define features of Treg cells and roles of Foxp3 in Treg biology, and summarize current research in PTMs of Foxp3 protein involved in modulating Treg function. This review also attempts to define Foxp3 dimer modifications relevant to mediating Foxp3 activity and Treg suppression. Understanding Foxp3 protein features and modulation mechanisms may help in the design of rational therapies for immune diseases and cancer.


Asunto(s)
Factores de Transcripción Forkhead/inmunología , Regulación de la Expresión Génica/inmunología , Procesamiento Proteico-Postraduccional/inmunología , Linfocitos T Reguladores/inmunología , Acetilación , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Proliferación Celular/genética , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/genética , Homeostasis/genética , Homeostasis/inmunología , Humanos , Procesamiento Proteico-Postraduccional/genética , Linfocitos T Reguladores/metabolismo
10.
Am J Clin Exp Immunol ; 7(5): 81-87, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30498624

RESUMEN

Tumor cells evolve multiple sophisticated mechanisms to escape immune surveillance, one of which is to establish tolerogenic microenvironment by recruiting certain immune suppressive cells such as regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs). Tregs are subpopulation of CD4+ T cells, which specialize in suppressing immune responses and preventing autoimmune damage to collateral tissue. Emerging evidence suggests that Treg cell number increases in various types of cancer, which correlates with tumor grade and poor patient prognosis. This review will focus on discussion of the origins and features of tumor-infiltrating Treg cells. Ultimately, these features may provide insight into potential therapeutic intervention by targeting Treg cells to invigorate immune response against tumor.

11.
Nat Commun ; 8: 15677, 2017 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-28580955

RESUMEN

Foxp3+ T regulatory (Treg) cells suppress immune cell activation and establish normal immune homeostasis. How Treg cells maintain their identity is not completely understood. Here we show that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, is required for Treg cell stability and function. Ndfip1 deletion in Treg cells results in autoinflammatory disease. Ndfip1-deficient Treg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing TH2 effector cells. Proteomic analyses indicate altered metabolic signature of Ndfip1-deficient Treg cells and metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Ndfip1 restricts Treg cell metabolism and IL-4 production via distinct mechanisms, as IL-4 deficiency does not prevent hyperproliferation or elevated mTORC1 signalling in Ndfip1-deficient Treg cells. Thus, Ndfip1 preserves Treg lineage stability and immune homeostasis by preventing the expansion of highly proliferative and metabolically active Treg cells and by preventing pathological secretion of IL-4 from Treg cells.


Asunto(s)
Proteínas Portadoras/metabolismo , Inflamación/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas de la Membrana/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Animales , Presentación de Antígeno , Membrana Celular/metabolismo , Proliferación Celular , Femenino , Factores de Transcripción Forkhead/metabolismo , Glucólisis , Receptores de Hialuranos/metabolismo , Inflamación/inmunología , Péptidos y Proteínas de Señalización Intercelular , Interleucina-4/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteómica , Células Th2/inmunología , Ubiquitinación
12.
Nat Commun ; 7: 11226, 2016 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-27088444

RESUMEN

Nedd4 family E3 ubiquitin ligases have been shown to restrict T-cell function and impact T-cell differentiation. We show here that Ndfip1 and Ndfip2, activators of Nedd4 family ligases, together limit accumulation and function of effector CD4+ T cells. Using a three-part proteomics approach in primary T cells, we identify stabilization of Jak1 in Ndfip1/2-deficient T cells stimulated through the TCR. Jak1 degradation is aborted in activated T cells that lack Ndfips. In wild-type cells, Jak1 degradation lessens CD4+ cell sensitivity to cytokines during TCR stimulation, while in Ndfip-deficient cells cytokine responsiveness persists, promoting increased expansion and survival of pathogenic effector T cells. Thus, Ndfip1/Ndfip2 regulate the cross talk between the T-cell receptor and cytokine signalling pathways to limit inappropriate T-cell responses.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Proteínas Portadoras/metabolismo , Citocinas/metabolismo , Janus Quinasa 1/metabolismo , Proteínas de la Membrana/metabolismo , Transducción de Señal , Animales , Linfocitos T CD4-Positivos/citología , Proteínas Portadoras/genética , Proliferación Celular , Células Cultivadas , Colitis/genética , Colitis/metabolismo , Femenino , Immunoblotting , Péptidos y Proteínas de Señalización Intercelular , Recuento de Linfocitos , Masculino , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteolisis , Proteómica/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
13.
J Biol Chem ; 290(33): 20211-20, 2015 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-25987564

RESUMEN

Regulation of the extent of immune responses is a requirement to maintain self-tolerance and limit inflammatory processes. CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells play a role in regulation. The Foxp3 transcription factor is considered a dominant regulator for Treg cell development and function. Foxp3 function itself is directly regulated by multiple posttranslational modifications that occur in response to various external stimuli. The Foxp3 protein is a component of several dynamic macromolecular regulatory complexes. The complexes change constituents over time and through different signals to regulate the development and function of regulatory T cells. Here we identified a mechanism regulating Foxp3 level and activity that operates through discrete phosphorylation. The Pim-2 kinase can phosphorylate Foxp3, leading to decreased suppressive functions of Treg cells. The amino-terminal domain of Foxp3 is modified at several sites by Pim-2 kinase. This modification leads to altered expression of proteins related to Treg cell functions and increased Treg cell lineage stability. Treg cell suppressive function can be up-regulated by either pharmacologically inhibiting Pim-2 kinase activity or by genetically knocking out Pim-2 in rodent Treg cells. Deficiency of Pim-2 activity increases murine host resistance to dextran sodium sulfate-induced colitis in vivo, and a Pim-2 small molecule kinase inhibitor also modified Treg cell functions. Our studies define a pathway for limiting the regulation of Foxp3 function because the Pim-2 kinase represents a potential therapeutic target for modulating the Treg cell suppressive activities in controlling immune responses.


Asunto(s)
Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Linfocitos T Reguladores/inmunología , Secuencia de Aminoácidos , Animales , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Fosforilación , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/genética
14.
J Biol Chem ; 289(39): 26872-26881, 2014 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-25096571

RESUMEN

Previous reports have suggested that human CD4(+) CD25(hi)FOXP3(+) T regulatory cells (Tregs) have functional plasticity and may differentiate into effector T cells under inflammation. The molecular mechanisms underlying these findings remain unclear. Here we identified the residue serine 422 of human FOXP3 as a phosphorylation site that regulates its function, which is not present in murine Foxp3. PIM1 kinase, which is highly expressed in human Tregs, was found to be able to interact with and to phosphorylate human FOXP3 at serine 422. T cell receptor (TCR) signaling inhibits PIM1 induction, whereas IL-6 promotes PIM1 expression in in vitro expanded human Tregs. PIM1 negatively regulates FOXP3 chromatin binding activity by specifically phosphorylating FOXP3 at Ser(422). Our data also suggest that phosphorylation of FOXP3 at the Ser(418) site could prevent FOXP3 phosphorylation at Ser(422) mediated by PIM1. Knockdown of PIM1 in in vitro expanded human Tregs promoted FOXP3-induced target gene expression, including CD25, CTLA4, and glucocorticoid-induced tumor necrosis factor receptor (GITR), or weakened FOXP3-suppressed IL-2 gene expression and enhanced the immunosuppressive activity of Tregs. Furthermore, PIM1-specific inhibitor boosted FOXP3 DNA binding activity in in vitro expanded primary Tregs and also enhanced their suppressive activity toward the proliferation of T effector cells. Taken together, our findings suggest that PIM1 could be a new potential therapeutic target in the prevention and treatment of human-specific autoimmune diseases because of its ability to modulate the immunosuppressive activity of human Tregs.


Asunto(s)
Factores de Transcripción Forkhead/inmunología , Proteínas Proto-Oncogénicas c-pim-1/inmunología , Linfocitos T Reguladores/inmunología , Antígeno CTLA-4/biosíntesis , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Proliferación Celular/fisiología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/fisiología , Técnicas de Silenciamiento del Gen , Proteína Relacionada con TNFR Inducida por Glucocorticoide/biosíntesis , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Células HEK293 , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-2/biosíntesis , Interleucina-2/genética , Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-2/biosíntesis , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-6/metabolismo , Células Jurkat , Fosforilación/fisiología , Proteínas Proto-Oncogénicas c-pim-1/genética , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Serina/genética , Serina/inmunología , Serina/metabolismo , Transducción de Señal/fisiología , Linfocitos T Reguladores/metabolismo
15.
Environ Sci Pollut Res Int ; 21(18): 10594-600, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24875307

RESUMEN

With the analysis of eight heavy metals (As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) and sixteen polycyclic aromatic hydrocarbons (PAHs) in sediments from the Shenzhen River, South China, the ecological risks associated were evaluated using Hakanson's method (for the metals) and the Effect Range Low/Effect Range Median (ERL/ERM) method (for the PAHs). The result shows concentrations of heavy metal in the order Zn > Cu > Cr > Ni > Pb > As > Cd > Hg, and among which the Zn, Cu, Ni, and Pb are exceeding the maximum contaminant level for sediments while those of PAHs are far below. The potential ecological risk index value for the heavy metals in the sediment samples was 261.90, which is in the moderate risk category. Total PAH concentrations in the sediments ranged from 1,028 to 1,120 ng/g, which are all far lower than the sediment guideline concentration of 4,022 ng/g, indicating that the risks of biological impacts caused by PAHs in Shenzhen River sediments are, therefore, relatively low. Besides, the fluorene concentration was above the ERL, and would potentially cause negative biological effects in the Shenzhen River. Heavy metals risks are suggested among the most important concerns that the environmental recover measures pay attention to.


Asunto(s)
Sedimentos Geológicos/análisis , Metales Pesados/análisis , Hidrocarburos Policíclicos Aromáticos/análisis , Ríos/química , Contaminantes Químicos del Agua/análisis , China , Monitoreo del Ambiente , Medición de Riesgo
16.
Cell Rep ; 7(5): 1471-1480, 2014 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-24835996

RESUMEN

The human FOXP3 molecule is an oligomeric transcriptional factor able to mediate activities that characterize T regulatory cells, a class of lymphocytes central to the regulation of immune responses. The activity of FOXP3 is regulated at the posttranslational level, in part by two histone acetyltransferases (HATs): TIP60 and p300. TIP60 and p300 work cooperatively to regulate FOXP3 activity. Initially, p300 and TIP60 interactions lead to the activation of TIP60 and facilitate acetylation of K327 of TIP60, which functions as a molecular switch to allow TIP60 to change binding partners. Subsequently, p300 is released from this complex, and TIP60 interacts with and acetylates FOXP3. Maximal induction of FOXP3 activities is observed when both p300 and TIP60 are able to undergo cooperative interactions. Conditional knockout of TIP60 in Treg cells significantly decreases the Treg population in the peripheral immune organs, leading to a scurfy-like fatal autoimmune disease.


Asunto(s)
Proteína p300 Asociada a E1A/metabolismo , Factores de Transcripción Forkhead/metabolismo , Histona Acetiltransferasas/metabolismo , Transactivadores/metabolismo , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes/metabolismo , Proteína p300 Asociada a E1A/genética , Factores de Transcripción Forkhead/genética , Células HEK293 , Histona Acetiltransferasas/química , Histona Acetiltransferasas/genética , Humanos , Lisina/metabolismo , Lisina Acetiltransferasa 5 , Ratones , Datos de Secuencia Molecular , Mutación , Unión Proteica , Linfocitos T Reguladores/metabolismo , Transactivadores/química , Transactivadores/genética
17.
Exp Mol Pathol ; 93(3): 334-8, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23041265

RESUMEN

Regulatory T (Treg) cells are essential in preventing the host from developing certain autoimmune diseases and limiting excessive immune responses against pathogens. The normal function of most Treg cells requires sustained expression of functional FOXP3, a member of the FOXP family transcription factors. FOXP3 is distinct from other subfamily members because of its unique proline rich amino (N)-terminal domain. Mutations in this region are occasionally identified in certain patients with X-linked autoimmunity-allergic dysregulation syndrome (XLAAD) and similar mutations also increase susceptibility of autoimmune diseases in rodent models. Previous analyses of the FOXP3 N-terminal domain revealed a role in nuclear import, interaction with other transcription factors, and as sites of specific post-translational modifications of FOXP3 that contribute to FOXP3 stability.


Asunto(s)
Factores de Transcripción Forkhead/fisiología , Inmunidad Innata/fisiología , Linfocitos T Reguladores/inmunología , Animales , Modelos Animales de Enfermedad , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Predisposición Genética a la Enfermedad , Interacciones Huésped-Patógeno , Humanos , Ratones , Mutación , Procesamiento Proteico-Postraduccional
18.
FEBS Lett ; 586(16): 2342-5, 2012 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-22659186

RESUMEN

Hemidiscoidal phycobilisomes (PBS), the major light harvesting complexes of photosynthesis in most cyanobacteria, are composed of rods and cores, which are linked by the linker CpcG1 (L(RC)). Another type of PBS, CpcG2-PBS exits and their function in energy transfer has not been fully understood. We measured growth rates, absorption cross-sections and quantum efficiency of photosystem I in mutant strains of Synechococcus PCC sp. 7002 lacking the linker CpcG2. Our results showed that energy transfer from CpcG2-PBS to PSI in the absence of state transitions could be significant under PBS-absorbing light and energy transfer from two types of PBS is independent to each other. Evidence also suggested that CpcG2 anchors the CpcG2-PBS to thylakoid membranes.


Asunto(s)
Proteínas de Arabidopsis/genética , Cianobacterias/metabolismo , Regulación de la Expresión Génica , Complejo de Proteína del Fotosistema I/química , Ficobilisomas/metabolismo , Proteínas de Plantas/genética , Synechococcus/metabolismo , Absorción , Proteínas de Arabidopsis/fisiología , Clorofila/química , Ferredoxinas/química , Proteínas Fluorescentes Verdes/metabolismo , Mutación , Fotones , Fotosíntesis , Proteínas de Plantas/fisiología , Espectrometría de Fluorescencia/métodos , Tilacoides/metabolismo , Factores de Tiempo
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