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1.
Artigo em Inglês | MEDLINE | ID: mdl-34698812

RESUMO

OBJECTIVES: Dermatomyositis (DM) is characterized by skeletal muscle weakness and cutaneous manifestations. Plasma exosomes (EXOs) contain proteins, RNAs, DNA, and lipid cargoes and are transferred among cells. Deeply investigated plasma EXO RNAs potentially improve our understanding of DM pathogenesis. We aimed to identify new potential biomarkers and therapeutic targets of DM. METHODS: The RNAs (mRNA, miRNA and lncRNA) profiles of plasma EXOs were evaluated by sequencing on the Illumina HiSeq 3000 platform. Differentially expressed (DE) RNAs and bioinformatic analyses were performed. Human skeletal muscle myoblasts (HSkMCs) were stimulated with plasma EXOs, rapamycin or IFN-ß. Real-time PCR and western blot were used to detect related genes and proteins. RESULTS: A total of 689 DE mRNAs, 53 DE miRNAs and 452 DE lncRNAs were identified in DM plasma EXOs. Bioinformatic analysis inferred that plasma EXOs were secreted mainly by CD8+ T cells, regulatory T cells and natural killer cells. The DE miRNAs participated in the autophagy, TGF-ß and Wnt signalling pathways. Three DE miRNAs (hsa-miR-125a-3p, hsa-miR-1246 and hsa-miR-3614-5p) were correlated with serological indices, organs involvement and myositis-specific autoantibodies. The DE lncRNAs participated in autophagy, interferon-ß production and mTOR signalling. DM plasma EXOs can induce autophagy in HSkMCs by regulating 3 miRNAs (hsa-miR-125a-3p, hsa-miR-1246 and hsa-miR-3614-5p) and 3 lncRNAs (ENST00000584157.1, ENST00000523380.1, and ENST00000560054.1), which formed an autophagy network, playing the muscle damage roles. CONCLUSIONS: Our study provides an overview of distinct RNAs profiles in DM plasma EXOs, and verified some miRNAs as potential biomarkers and therapeutic targets. The findings provide important clues for more in-depth explorations of plasma EXOs in DM.

2.
Diagnostics (Basel) ; 11(10)2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34679604

RESUMO

BACKGROUND: Sepsis is the leading cause of mortality in intensive care units (ICUs). However, early diagnosis and prognosis of sepsis and septic shock are still a great challenge. Pentraxin-3 (PTX3) was shown to be associated with the severity and outcome of sepsis and septic shock. This study was carried out to investigate the diagnostic and prognostic value of PTX3 in patients with sepsis and septic shock based on Sepsis 3.0 definitions. METHODS: In this single-center prospective observational study, all patients' serum was collected for biomarker measurements within 24 h after admission. Logistic and Cox regression analyses were used to identify the potential biomarkers of diagnosis, severity stratification, and prediction. RESULTS: Serum levels of PTX3 were significantly increased on the first day of ICU admission, while septic shock patients had highest PTX3 levels than other groups. A combination between PTX3 and procalcitonin (PCT) could better discriminate sepsis and septic shock, and PTX3 was an independent predictor of mortality in sepsis and septic shock patients. CONCLUSION: PTX3 may be a robust biomarker to classify the disease severity and predict the 90-day mortality of sepsis and septic shock based on the latest Sepsis 3.0 definitions.

3.
Front Plant Sci ; 12: 727596, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646287

RESUMO

With increasing areas of direct sowing, low-temperature (LT) stress drastically affects global rice production. Exogenous applications of melatonin (MT) serve as one of the effective ways to improve seed germination under various stress conditions. In this study, we found that MT treatment greatly improved the LT stress-induced loss of germination percentage and the weak performance of seedlings under LT of constant 20°C (LT20). This was largely dependent on the activated antioxidant system and enhanced activities of storage substance utilization-associated enzymes. Moreover, we also detected that exogenous feeding of MT significantly increased the biosynthesis of gibberellin (GA) and endogenous MT but simultaneously inhibited the accumulation of abscisic acid (ABA) and hydrogen peroxide (H2O2) under LT20 stress. These results suggested that MT had antagonistic effects on ABA and H2O2. In addition, MT treatment also significantly enhanced the expression of CATALYSE 2 (OsCAT2), which was directly regulated by ABA-INSENSITIVE 5 (OsABI5), a core module of ABA-stressed signals, and thus promoting the H2O2 scavenging to reach reactive oxygen species (ROS) homeostasis, which consequently increased GA biosynthesis. However, in abi5 mutants, OsCAT2 failed in response to LT20 stress irrespective of MT treatment, indicating that OsABI5 is essential for MT-mediated seed germination under LT20 stress. Collectively, we now demonstrated that MT showed a synergistic interaction with an ABI5-mediated signal to mediate seed germination, partially through the direct regulation of OsCAT2.

4.
Int Immunopharmacol ; 100: 108118, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34492532

RESUMO

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by a large number of inflammatory cell aggregation and alveolar cell damage in pathophysiology, have extremely high morbidity and mortality in critically ill patients. In recent years, more and more studies have found that there are abundant extracellular vesicles (EVs) in animal models and patients with ALI/ARDS, and they play a critical role in the pathogenesis of lung injury. Clarifying the mechanisms of EVs in lung injury is of great significance in the diagnosis and treatment of ALI/ARDS. In this review, we will summarize the recent findings on the roles of EVs derived from different cells in ALI/ARDS, along with the formation, function, and related effects of EVs, and explore their potential clinical application for the diagnosis and treatment of ALI/ARDS.

5.
Hum Exp Toxicol ; : 9603271211038743, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34396798

RESUMO

OBJECTIVE: TGF-ß1-induced excessive deposition of extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) process of tubular epithelial cells play critical roles in the progression of renal fibrosis. We are aimed to explore the effects of lysine-specific demethylase 1 (LSD1) in TGF-ß1-treated HK-2 cells and in rats with unilateral ureteral obstruction (UUO), and to investigate the underlying molecular mechanism. METHODS: TGF-ß1-treated HK-2 cells and UUO-treated rats were used to establish the model of renal fibrosis in vitro and in vivo, respectively. Protein expression of LSD1, E-cadherin, a-smooth muscle actin (a-SMA), Vimentin, Jagged-1, Notch-1 and Notch-2 were detected by Western blot. The concentrations of type I collagen (Col-I) and Fibronectin (FN) were measured by ELISA. Transwell assay were used to assess cell invasion. RESULTS: LSD1 was dramatically increased in TGF-ß1-stimulated HK-2 cells. Knockdown of LSD1 decreased the TGF-ß1-induced secretion of Col-I and FN, and suppressed TGF-ß1-induced expression of E-cadherin,α-SMA and Vimentin, while suppressed cell invasion. Consistent with the in vitro data, the severe histopathological damage, collagen deposition and reduced E-cadherin, increased α-SMA induced by UUO was abated by the knockdown of LSD1 in vivo. Moreover, knockdown of LSD1 suppressed TGF-ß1-induced expression of Jagged-1, Notch-1 and Notch-2. Furthermore, we found that inhibition of Notch signaling by a γ-secretase inhibitor RO4929097 almost recapitulated the effects of LSD1 knockdown in TGF-ß1-induced HK-2 cells, and at least in part reversed the effects of LSD1 overexpression on EMT and ECM deposition in HK-2 cells. CONCLUSIONS: Taken together, LSD1 significantly impact on the progression of TGF-ß1-mediated EMT and ECM deposition in HK-2 cells, and it may represent novel target for the prevention strategies of renal fibrosis.

7.
PeerJ ; 9: e11699, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249516

RESUMO

Background: Early and accurate diagnosis of microorganism(s) is important to optimize antimicrobial therapy. Shotgun metagenomic sequencing technology, an unbiased and comprehensive method for pathogen identification, seems to potentially assist or even replace conventional microbiological methodology in the diagnosis of infectious diseases. However, evidence in clinical application of this platform is relatively limited. Methods: To evaluate the capability of shotgun metagenomic sequencing technology in clinical practice, both shotgun metagenomic sequencing and conventional culture were performed in the PCR-positive body fluid specimens of 20 patients with suspected infection. The sequenced data were then analyzed for taxonomic identification of microbes and antibiotic resistance gene prediction using bioinformatics pipeline. Results: Shotgun metagenomic sequencing results showed a concordance of 17/20 compared with culture results in bacterial detection, and a concordance of 20/20 compared with culture results in fungal detection. Besides, drug-resistant types annotated from antibiotic resistance genes showed much similarity with antibiotic classes identified by susceptibility tests, and more than half of the specimens had consistent drug types between shotgun metagenomic sequencing and culture results. Conclusions: Pathogen identification and antibiotic resistance gene prediction by shotgun metagenomic sequencing identification had the potential to diagnose microorganisms in infectious diseases, and it was especially helpful for multiple microbial co-infections and for the cases where standard culture approached failed to identify microorganisms.

8.
Ther Adv Respir Dis ; 15: 17534666211028072, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34266334

RESUMO

AIMS: Chronic obstructive pulmonary disease (COPD) is a systemic disease. Several long non-coding RNAs (lncRNAs) have been identified to be aberrantly expressed in COPD patients. This study investigated the role of lncRNA cancer susceptibility candidate 2 (CASC2) in COPD, as well as its potential mechanism. METHODS: Fifty smokers with COPD and another 50 smokers without COPD were recruited. Receiver operating characteristic curve was constructed to assess the diagnostic value of CASC2 in COPD patients. 16HBE cells were treated with cigarette smoke extract (CSE) to establish a cell model. qRT-PCR was used for the measurement of mRNA levels. The cell viability and apoptosis were detected by using Cell Counting Kit-8 and flow cytometry assay. Enzyme-linked immunosorbent assay was performed to detect the levels of proinflammatory cytokines. Luciferase reporter assay was performed for the target gene analysis. RESULTS: Serum CASC2 was dramatically decreased in COPD patients compared with smokers without COPD, and was positively associated with FEV1 (forced expiratory volume in one second). Serum CASC2 was overexpressed in severe COPD patients, and had the diagnostic accuracy to distinguish COPD patients from smokers. CASC2 overexpression alleviated CSE-induced apoptosis and inflammation in 16HBE cells. CASC2 functions as a ceRNA of miR-18a-5p. Upregulation of miR-18a-5p reversed the influence of CASC2 on cell apoptosis and inflammation in 16HBE cells. IGF1 was the target gene of miR-18a-5p. CONCLUSION: CASC2 was downregulated in COPD patients and it might be a promising biomarker for the disease diagnosis. Overexpression of CASC2 might inhibit the bronchial epithelial cell apoptosis and inflammation via targeting miR-18a-5p/IGF1 axis.The reviews of this paper are available via the supplemental material section.

9.
Exp Ther Med ; 22(2): 819, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34131442

RESUMO

To investigate the efficacy of simvastatin on carotid atherosclerotic plaque (CAP) and its effects on serum inflammatory factors and cardiocerebrovascular events in elderly patients, 130 elderly patients with CAP were randomly divided into observation (n=65) and control groups (n=65). The control group was treated with 75 mg/day aspirin enteric-coated tablets, and the observation group was administered additional 20 mg/day simvastatin. Serum total cholesterol, triglyceride, and high- and low-density lipoprotein cholesterol levels (evaluated via the endpoint method) were determined in both groups. Furthermore, the length, thickness and number of CAPs was measured using color Doppler ultrasonography. In addition, levels of inflammatory biomarkers including high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide, D-dimer and fibrinogen, as well as change in microemboli count, were also compared After treatment, the observation group exhibited a significant reduction in size, thickness, and number of CAP and intima-media thickness compared with before treatment. However, no significant difference was found in the indicators of CAPs in the control group before and after treatment. The levels of total cholesterol, triglyceride, and low-density lipid cholesterol decreased, while high-density lipid cholesterol increased in the observation group after treatment, with notable changes in the observation group compared with in the control group. Overall response rate was higher in the observation group compared with the control group. TNF-α, IL-6, and hs-CRP levels in the observation group decreased after treatment compared with those before treatment and those in the control group. Furthermore, the rate of microemboli positivity was lower in the observation group than in the control group. Moreover, the overall incidence of acute cardiocerebrovascular events was lower in the observation group than in the control group. Therefore, it was demonstrated that simvastatin can reduce blood lipid levels, decrease the quantity and size of plaques, alleviate inflammatory response, reduce microemboli formation and reduce the risk of cardiocerebrovascular events in elderly patients with CAP.

10.
J Food Sci ; 86(5): 1878-1892, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33884623

RESUMO

Phenolic acids and phytosterols, the main functional compounds in cereals, could promote wellbeing and reduce the risks of diet-related diseases. This study aimed to demonstrate phenolic acid and phytosterol profiles in rice grains and wheat flours, and estimate their intakes in five geographical regions and among different age groups. Phenolic acids and phytosterols mainly existed in bound form, and the whole rice grain had high amount of 161.39 to 368.74 µg/g and 37.50 to 93.31 mg/ 100 g, respectively. In total, nine phenolic acids and six phytosterols were detected with ferulic and p-coumaric acid, and ß-sitosterol the most abundant. The dietary intakes of phenolic acids and phytosterols were calculated combined with the dietary foods intake data of Chinese people. The intakes of total phenolic acids and phytosterols from rice grains and wheat flours varied across different regions with Beijing the highest among the five regions. At the age of 2 to 70 years, the average intakes of phenolic acids and phytosterols from rice and wheat flours were 7.74 to 17.52 and 58.02 to 135.61 mg/sp/day, respectively. If 3-ounce of polished rice was replaced by black rice grain, the predicted intakes of total phenolic acids and phytosterols from rice grains and wheat flours would increase by at least 196% and 68%, respectively, especially for free phenolic acids and phytosterols. PRACTICAL APPLICATION: This study would help the consumers know how much phenolic acids and phytosterols they would get from 3 ounces of black rice in a reasonable intake of staple food but shift away other kinds of foods. It could also provide inspirations for food industries to explore the functional cereal foods that are rich in phenolic acids and phytosterols for different regions and different age groups.


Assuntos
Dieta , Hidroxibenzoatos/análise , Oryza/química , Fitosteróis/análise , Triticum/química , Grãos Integrais/química , Adolescente , Adulto , Idoso , Pequim , Criança , Pré-Escolar , China , Ácidos Cumáricos/análise , Grão Comestível , Farinha/análise , Humanos , Pessoa de Meia-Idade , Sitosteroides/análise
11.
Molecules ; 26(8)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920363

RESUMO

As one of the common abiotic stresses, chilling stress has negative effects on rice growth and development. Minimization of these adverse effects through various ways is vital for the productivity of rice. Nanoparticles (NPs) serve as one of the effective alleviation methods against abiotic stresses. In our research, zinc oxide (ZnO) NPs were utilized as foliar sprays on rice leaves to explore the mechanism underlying the effect of NPs against the negative impact of chilling stress on rice seedlings. We revealed that foliar application of ZnO NPs significantly alleviated chilling stress in hydroponically grown rice seedlings, including improved plant height, root length, and dry biomass. Besides, ZnO NPs also restored chlorophyll accumulation and significantly ameliorated chilling-induced oxidative stress with reduced levels of H2O2, MDA, proline, and increased activities of major antioxidative enzymes, superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). We further found that foliar application of ZnO NPs induced the chilling-induced gene expression of the antioxidative system (OsCu/ZnSOD1, OsCu/ZnSOD2, OsCu/ZnSOD3, OsPRX11, OsPRX65, OsPRX89, OsCATA, and OsCATB) and chilling response transcription factors (OsbZIP52, OsMYB4, OsMYB30, OsNAC5, OsWRKY76, and OsWRKY94) in leaves of chilling-treated seedlings. Taken together, our results suggest that foliar application of ZnO NPs could alleviate chilling stress in rice via the mediation of the antioxidative system and chilling response transcription factors.


Assuntos
Antioxidantes/farmacologia , Clorofila/biossíntese , Nanopartículas/química , Oryza/efeitos dos fármacos , Fatores de Transcrição/genética , Óxido de Zinco/farmacologia , Catalase/genética , Catalase/metabolismo , Clorofila/agonistas , Temperatura Baixa , Regulação da Expressão Gênica de Plantas , Hidroponia/métodos , Malondialdeído/metabolismo , Nanopartículas/ultraestrutura , Oryza/genética , Oryza/crescimento & desenvolvimento , Oryza/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/genética , Peroxidase/metabolismo , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Prolina/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Plântula/efeitos dos fármacos , Plântula/genética , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de Transcrição/agonistas , Fatores de Transcrição/metabolismo
12.
Inflammation ; 44(5): 1856-1864, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33855682

RESUMO

Asthma-induced pulmonary fibrosis (PF) is an important public health concern that has few treatment options given its poorly understood etiology; however, the epithelial to mesenchymal transition (EMT) of pulmonary epithelial cells has been implicated to play an important role in inducing PF. Although previous studies have found atractylon (Atr) to have anti-inflammatory effects, whether Atr has anti-PF abilities remains unknown. The purpose of the current study was to validate the protective efficiency of Atr in both an animal model of ovalbumin (OVA)-induced asthma and an EMT model induced by transforming growth factor-ß1 (TGF-ß1) using TC-1 cells. The results of this study revealed that Atr treatment suppressed OVA-induced PF via fibrosis-related protein expression. Atr treatment suppressed OVA-induced circRNA-0000981 and TGFBR2 expression but promoted miR-211-5p expression. In vivo studies revealed that Atr suppressed TGF-ß1-induced EMT and fibrosis-related protein expression via suppressing circRNA-0000981 and TGFBR2 expression. The results also suggested that the downregulation of circRNA-0000981 expression suppressed TGFBR2 by sponging miR-211-5p, which was validated by a luciferase reporter assay. Collectively, the findings of the present study suggest that Atr treatment attenuates PF by regulating the mmu_circ_0000981/miR-211-5p/TGFBR2 axis in an OVA-induced asthma mouse model.

13.
Biochem Biophys Res Commun ; 551: 155-160, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33740622

RESUMO

OBJECTIVES: Clinically amyopathic dermatomyositis (CADM) is a subtype of dermatomyositis (DM) characterized by low-grade or absent muscle inflammation but frequent and rapidly progressive interstitial lung disease (RP-ILD) and skin ulcers with anti-melanoma differentiation-associated gene 5 (anti-MDA5) autoantibodies. Basic leucine zipper transcription factor ATF-like 2 (BATF2) is thought to function as an inhibitor of tumours and inflammation. Here, we aimed to investigate the roles of BATF2 in Th cell differentiation of CADM with an anti-MDA5 autoantibody (anti-MDA5+ CADM). METHODS: Naive CD4+ T cells from human peripheral blood mononuclear cells (PBMCs) of healthy controls (HCs) were isolated and then cultured with IL-12, TGF-ß or TGF-ß plus IL-6 following anti-CD3 and anti-CD28 stimulations. The expression of BATF2 was measured by real-time PCR. The percentages of Th1, Th17 and Treg CD4+ T cells were detected by flow cytometry. BATF2 knockdown of CD4+ T cells was performed using small interfering RNAs (siRNAs). RESULTS: The expression of BATF2 in PBMCs was higher in anti-MDA5+ CADM patients than in healthy controls. The BATF2 mRNA expression was increased under Th1 and Treg polarization but decreased under Th17 polarization. Th17 cell activation-associated genes were possibly increased while Th1 and Treg cell differentiation-associated genes were inhibited by posttranscriptional gene silencing of BATF2 in CD4+ T cells. CONCLUSIONS: BATF2 promoted Th1 and Treg cell differentiation but suppressed Th17 cell activation in anti-MDA5+ CADM.


Assuntos
Autoanticorpos/imunologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD4-Positivos/imunologia , Dermatomiosite/imunologia , Dermatomiosite/metabolismo , Imunidade Celular , Helicase IFIH1 Induzida por Interferon/imunologia , Proteínas Supressoras de Tumor/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Feminino , Humanos , Masculino , RNA Mensageiro/análise , RNA Mensageiro/genética , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Células Th1/citologia , Células Th1/imunologia , Células Th17/citologia , Células Th17/imunologia , Proteínas Supressoras de Tumor/genética , Regulação para Cima
14.
Life Sci ; 276: 119434, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785343

RESUMO

AIMS: Immunosuppressive myeloid-derived suppressor cells (MDSCs) continuously expand and lead to poor outcome during sepsis. The activation of liver X receptor (LXR) can mitigate sepsis-induced liver and myocardial damage. This study aims to determine whether LXR plays a protective role in sepsis by regulating MDSCs. MAIN METHODS: Cecal ligation and puncture(CLP)was used to induce sepsis in mice. The mice were then treated with LXR agonist GW3965 (3 mg/kg) or vehicle 1 h, 6 h, 12 h, 24 h, 48 h, 72 h postoperatively. The effect of LXR on the survival rate and multi-organ injury induced by sepsis was evaluated by survival analysis, histological staining, biochemical analysis and ELISAs. The percentages of MDSCs and T cells were detected using flow cytometry. The mRNA expressions of LXR and ATP-binding cassette transporter A1 (ABCA1) were measured using real-time quantitative PCR (RT-qPCR). ABCA1 protein level was determined using immunofluorescence staining. KEY FINDINGS: LXR agonist GW3965 treatment improved the survival of septic mice, accompanied by reduced multi-organ injury and a decreased level of inflammatory cytokines. Furthermore, GW3965 treatment decreased MDSCs abundance in spleen by boosting the apoptosis of spleen MDSCs, therefore ameliorating their immunosuppressive activity. Meanwhile, bacteria clearance in tissues was enhanced after the GW3965 administration in septic mice. Mechanistically, GW3965 activated LXRß and its downstream target ABCA1 to initiate the apoptosis of spleen MDSCs. SIGNIFICANCE: These findings provide new insights into the relationship between LXR and MDSCs in sepsis, thus revealing a potentially effective approach to target the immunosuppression of sepsis.


Assuntos
Apoptose , Benzoatos/farmacologia , Benzilaminas/farmacologia , Receptores X do Fígado/agonistas , Células Supressoras Mieloides/patologia , Substâncias Protetoras/farmacologia , Sepse/tratamento farmacológico , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Citocinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Sepse/metabolismo , Sepse/patologia
15.
Immunol Cell Biol ; 99(7): 697-710, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33655578

RESUMO

Defects causing concomitant loss of CD25 expression in regulatory T cells (Tregs) have been identified in systemic lupus erythematosus (SLE). However, the cause of this deficiency is not fully understood. Carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), an immune co-receptor, contributes to general T-cell function and activation. Our previous study revealed that CEACAM1 expression was upregulated in peripheral blood mononuclear cells (PBMCs) from patients with SLE. However, its role remains unclear. Herein, we confirmed CEACAM1, especially CEACAM1-S, was upregulated in PBMCs from patients with SLE. CEACAM1-S over-expression inhibits CD4+ CD25+ Treg differentiation, whereas knockdown of CEACAM1 had the opposite effect in vitro. CEACAM1-S is the target of miR-31. MiR-31 mimic inhibits CEACAM1 expression and enhances CD4+ CD25+ Treg differentiation, which was reversed by CEACAM1-S over-expression. Moreover, the circulating TGF-ß level was upregulated in SLE patients and TGF-ß reduced miR-31 expression via enhancing NF-κB activity. Importantly, CEACAM1 and TGF-ß mRNA levels were downregulated, while the miR-31 level and the abundance of CD4+ CD25+ Tregs were increased in inactive patients compared with that in patients with active SLE. In addition, CEACAM1-S expression was positively correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, while CD4+ CD25+ Treg abundance and miR-31 level were negatively correlated with the SLEDAI score. In conclusion, reduced activity of miR-31 by TGF-ß, via the inhibition of NF-ᴋB, acted to inhibit the differentiation of CD4+ CD25+ Tregs by directly targeting CEACAM1-S and to promote autoimmunity.


Assuntos
Lúpus Eritematoso Sistêmico , MicroRNAs , Antígenos CD , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular , Diferenciação Celular , Citometria de Fluxo , Humanos , Leucócitos Mononucleares , MicroRNAs/genética , Linfócitos T Reguladores , Fator de Crescimento Transformador beta
16.
Thromb Haemost ; 121(8): 1066-1078, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33506482

RESUMO

Sepsis is a life-threatening complication of infection closely associated with coagulation abnormalities. Heat shock factor 1 (HSF1) is an important transcription factor involved in many biological processes, but its regulatory role in blood coagulation remained unclear. We generated a sepsis model in HSF1-knockout mice to evaluate the role of HSF1 in microthrombosis and multiple organ dysfunction. Compared with septic wild-type mice, septic HSF1-knockout mice exhibited a greater degree of lung, liver, and kidney tissue damage, increased fibrin/: fibrinogen deposition in the lungs and kidneys, and increased coagulation activity. RNA-seq analysis revealed that tissue-type plasminogen activator (t-PA) was upregulated in the lung tissues of septic mice, and the level of t-PA was significantly lower in HSF1-knockout mice than in wild-type mice in sepsis. The effects of HSF1 on t-PA expression were further validated in HSF1-knockout mice with sepsis and in vitro in mouse brain microvascular endothelial cells using HSF1 RNA interference or overexpression under lipopolysaccharide stimulation. Bioinformatics analysis, combined with electromobility shift and luciferase reporter assays, indicated that HSF1 directly upregulated t-PA at the transcriptional level. Our results reveal, for the first time, that HSF1 suppresses coagulation activity and microthrombosis by directly upregulating t-PA, thereby exerting protective effects against multiple organ dysfunction in sepsis.

17.
Int J Mol Med ; 47(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33448325

RESUMO

Metabolism reprogramming influences the severity of organ dysfunction, progression to fibrosis, and development of disease in acute kidney injury (AKI). Previously we showed that inhibition of aerobic glycolysis improved survival rates and protected septic mice from kidney injury. However, the underlying mechanisms remain unclear. In the present study, it was revealed that sepsis or lipopolysaccharide (LPS) enhanced aerobic glycolysis as evidenced by increased lactate production and upregulated mRNA expression of glycolysis­related genes in kidney tissues and human renal tubular epithelial (HK­2) cells. The aerobic glycolysis inhibitor 2­deoxy­D­glucose (2­DG) downregulated glycolysis, and improved kidney injury induced by sepsis. 2­DG treatments increased the expression of sirtuin 3 (SIRT3) and phosphorylation­AMP­activated protein kinase (p­AMPK), following promoted autophagy and attenuated apoptosis of tubular epithelial cells in septic mice and in LPS­treated HK­2 cells. However, the glycolysis metabolite lactate downregulated SIRT3 and p­AMPK expression, inhibited autophagy and enhanced apoptosis in LPS­treated HK­2 cells. Furthermore, pharmacological blockade of autophagy with 3­methyladenine (3­MA) partially abolished the protective effect of 2­DG in sepsis­induced AKI. These findings indicated that inhibition of aerobic glycolysis protected against sepsis­induced AKI by promoting autophagy via the lactate/SIRT3/AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Injúria Renal Aguda/metabolismo , Autofagia/efeitos dos fármacos , Desoxiglucose/farmacologia , Glicólise/efeitos dos fármacos , Ácido Láctico/metabolismo , Sepse/metabolismo , Sirtuína 3/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Sepse/complicações , Sepse/patologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-33498026

RESUMO

We report growth, electronic structure and superconductivity of ultrathin epitaxial CoSi2 films on Si(111). At low coverages, preferred islands with 2, 5 and 6 monolayers height develop, which agrees well with the surface energy calculation. We observe clear quantum well states as a result of electronic confinement and their dispersion agrees well with density functional theory calculations, indicating weak correlation effect despite strong contributions from Co 3d electrons. Ex-situ transport measurements show that superconductivity persists down to at least 10 monolayers, with reduced Tc but largely enhanced upper critical field. Our study opens up the opportunity to study the interplay between quantum confinement, interfacial symmetry breaking and superconductivity in an epitaxial silicide film, which is technologically relevant in microelectronics.

19.
J Mol Cell Cardiol ; 150: 65-76, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33098823

RESUMO

Palmitic acid (PA)-induced myocardial injury is considered a critical contributor to the development of obesity and type 2 diabetes mellitus (T2DM)-related cardiomyopathy. However, the underlying mechanism has not been fully understood. Here, we demonstrated that PA induced the cell death of H9c2 cardiomyoblasts in a dose- and time-dependent manner, while different ferroptosis inhibitors significantly abrogated the cell death of H9c2 cardiomyoblasts and primary neonatal rat cardiomyocytes exposed to PA. Mechanistically, PA decreased the protein expression levels of both heat shock factor 1 (HSF1) and glutathione peroxidase 4 (GPX4) in a dose- and time-dependent manner, which were restored by different ferroptosis inhibitors. Overexpression of HSF1 not only alleviated PA-induced cell death and lipid peroxidation but also improved disturbed iron homeostasis by regulating the transcription of iron metabolism-related genes (e.g., Fth1, Tfrc, Slc40a1). Additionally, PA-blocked GPX4 protein expression was evidently restored by HSF1 overexpression. Inhibition of endoplasmic reticulum (ER) stress rather than autophagy contributed to HSF1-mediated GPX4 expression. Moreover, GPX4 overexpression protected against PA-induced ferroptosis, whereas knockdown of GPX4 reversed the anti-ferroptotic effect of HSF1. Consistent with the in vitro findings, PA-challenged Hsf1-/- mice exhibited more serious ferroptosis, increased Slc40a1 and Fth1 mRNA expression, decreased GPX4 and TFRC expression and enhanced ER stress in the heart compared with Hsf1+/+ mice. Altogether, HSF1 may function as a key defender against PA-induced ferroptosis in cardiomyocytes by maintaining cellular iron homeostasis and GPX4 expression.


Assuntos
Ferroptose , Fatores de Transcrição de Choque Térmico/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Ácido Palmítico/farmacologia , Animais , Linhagem Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição de Choque Térmico/genética , Ferro/metabolismo , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/ultraestrutura , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Ratos Sprague-Dawley , Transcrição Genética/efeitos dos fármacos
20.
Am J Med Sci ; 361(1): 63-68, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32988597

RESUMO

BACKGROUND: Specific factors correlated with hypothyroidism in systemic lupus erythematosus (SLE) patients remain unclear. Therefore, we aim to evaluate the prevalence of thyroid dysfunction in Chinese patients with SLE and the relationship between clinical hypothyroidism and SLE. METHODS: We conducted a cross sectional study of the prevalence of thyroid dysfunction in 672 patients with SLE and 605 age- and sex-matched healthy controls. Demographic, clinical, and biochemical data were compared between 58 patients with SLE with hypothyroidism and 197 patients with SLE with euthyroidism. Multivariate analysis was performed using binomial logistic regression analysis. Spearman's rank correlation was used to identify an association between thyroid function and disease activity. RESULTS: The prevalence of thyroid dysfunction was significantly higher in patients with SLE than in controls (70.7% vs 19.7%). SLE was associated with higher rates of hypothyroidism (9.6%, P ≤ 0.001) and euthyroid sick syndrome (49.6%, P ≤ 0.001) compared with control subjects. Further analyses showed that hypothyroidism in patients with SLE was associated with high blood pressure, renal disorder, high serum creatinine, high uric acid, hyperlipidaemia, low C3 and C4, positive anti-dsDNA antibodies, and high SLE disease activity index (SLEDAI) score. In multiple logistic regression models, albumin, platelet count, serum creatinine, and anti-dsDNA antibodies were associated with hypothyroidism. Finally, free tri-iodothyronine was significantly negatively correlated with SLEDAI score. CONCLUSIONS: Hypothyroidism was more prevalent in patients with SLE. There was a relationship between hypothyroidism with renal disorder and lupus activity. Albumin, platelet count, serum creatinine, and anti-dsDNA antibodies were correlated with hypothyroidism.


Assuntos
Hipotireoidismo/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Adulto , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Hipotireoidismo/complicações , Lúpus Eritematoso Sistêmico/complicações , Masculino , Prevalência
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