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1.
Mol Genet Genomic Med ; : e1048, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31962008

RESUMO

BACKGROUND: Acute pancreatitis in pregnancy (APIP) is a life-threatening disease for both mother and fetus. To date, only three patients with recurrent hypertriglyceridemia-induced APIP (HTG-APIP) have been reported to carry rare variants in the lipoprotein lipase (LPL) gene, which encodes the key enzyme responsible for triglyceride (TG) metabolism. Coincidently, all three patients harbored LPL variants on both alleles and presented with complete or severe LPL deficiency. METHODS: The entire coding regions and splice junctions of LPL and four other TG metabolism genes (APOC2, APOA5, GPIHBP1, and LMF1) were analyzed by Sanger sequencing in a Han Chinese patient who had experienced two episodes of HTG-APIP. The impact of a novel LPL missense variant on LPL protein expression and activity was analyzed by transient expression in HEK293T cells. RESULTS: A novel heterozygous LPL missense variant, p.His210Leu (c.629A > T), was identified in our patient. This variant did not affect protein synthesis but significantly impaired LPL secretion and completely abolished the enzymatic activity of the mutant protein. CONCLUSION: This report describes the first identification and functional characterization of a heterozygous variant in the LPL that predisposed to recurrent HTG-APIP. Our findings confirm a major genetic contribution to the etiology of individual predisposition to HTG-APIP.

2.
Plant Cell Environ ; 43(2): 463-478, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31713247

RESUMO

Transcriptional regulation is important for plants to respond to toxic effects of aluminium (Al). However, our current knowledge to these events is confined to a few transcription factors. Here, we functionally characterized a rice bean (Vigna umbellata) NAC-type transcription factor, VuNAR1, in terms of Al stress response. We demonstrated that rice bean VuNAR1 is a nuclear-localized transcriptional activator, whose expression was specifically upregulated by Al in roots but not in shoot. VuNAR1 overexpressing Arabidopsis plants exhibit improved Al resistance via Al exclusion. However, VuNAR1-mediated Al exclusion is independent of the function of known Al-resistant genes. Comparative transcriptomic analysis revealed that VuNAR1 specifically regulates the expression of genes associated with protein phosphorylation and cell wall modification in Arabidopsis. Transient expression assay demonstrated the direct transcriptional activation of cell wall-associated receptor kinase 1 (WAK1) by VuNAR1. Moreover, yeast one-hybrid assays and MEME motif searches identified a new VuNAR1-specific binding motif in the promoter of WAK1. Compared with wild-type Arabidopsis plants, VuNAR1 overexpressing plants have higher WAK1 expression and less pectin content. Taken together, our results suggest that VuNAR1 regulates Al resistance by regulating cell wall pectin metabolism via directly binding to the promoter of WAK1 and induce its expression.

3.
New Phytol ; 225(4): 1732-1745, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31608986

RESUMO

The mechanisms involved in the regulation of gene expression in response to phosphate (Pi) deficiency have been extensively studied, but their chromatin-level regulation remains poorly understood. We examined the role of histone acetylation in response to Pi deficiency by using the histone deacetylase complex1 (hdc1) mutant. Genes involved in root system architecture (RSA) remodeling were analyzed by quantitative real-time polymerase chain reaction (qPCR) and chromatin immunoprecipitation qPCR. We demonstrate that histone H3 acetylation increased under Pi deficiency, and the hdc1 mutant was hypersensitive to Pi deficiency, with primary root growth inhibition and increases in root hair number. Concomitantly, Pi deficiency repressed HDC1 protein abundances. Under Pi deficiency, hdc1 accumulated higher concentrations of Fe3+ in the root tips and had higher expression of genes involved in RSA remodeling, such as ALUMINUM-ACTIVATED MALATE TRANSPORTER1 (ALMT1), LOW PHOSPHATE ROOT1 (LPR1), and LPR2 compared with wild-type plants. Furthermore, Pi deficiency enriched the histone H3 acetylation of ALMT1 and LPR1. Finally, genetic evidence showed that LPR1/2 was epistatic to HDC1 in regulating RSA remodeling. Our results suggest a chromatin-level control of Pi starvation responses in which HDC1-mediated histone H3 deacetylation represses the transcriptional activation of genes involved in RSA remodeling in Arabidopsis.

4.
Huan Jing Ke Xue ; 40(11): 4810-4823, 2019 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854546

RESUMO

Northeastern China experiences severe atmospheric pollution, with an increasing occurrence of heavy haze episodes. Based on ground monitoring data, satellite products and meteorological products of atmospheric pollutants in northeast China from 2013 to 2017, the characteristics of spatial and temporal distribution of air quality and the causes of heavy haze events in northeast China were discussed. It was found that the "Shenyang-Changchun-Harbin" city belt was the most polluted area in the region on an annual scale. The spatial distribution of air quality index (AQI) values had a clear seasonality, with the worst pollution occurring in winter, an approximately oval-shaped polluted area around western Jilin Province in spring, and the best air quality occurring in summer and most of autumn. The three periods that typically experienced intense haze events were Period I from late-October to early-November (i. e., late autumn and early winter), Period Ⅱ from late-December to January (i. e., the coldest time in winter), and Period Ⅲ from April to mid-May (i. e., spring). During Period I, strong PM2.5 emissions from seasonal crop residue burning and coal burning for winter heating were the dominant reasons for the occurrence of extreme haze events (AQI>300). Period Ⅱ had frequent heavy haze events (200 < AQI < 300) in the coldest months of January and February(200 < AQI < 300), which were due to high PM2.5 emissions from coal burning and vehicle fuel consumption, a lower atmospheric boundary layer, and stagnant atmospheric conditions. Haze events in Period Ⅲ, with high PM10 concentrations, were primarily caused by the regional transportation of windblown dust from degraded grassland in central Inner Mongolia and bare soil in western Jilin Province. Local agricultural tilling could also release PM10 and enhance the levels of windblown dust from tilled soil.

5.
Sheng Li Xue Bao ; 71(6): 863-873, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31879742

RESUMO

The aim of this study was to investigate the inhibitory effect and the underlying mechanism of ethacrynic acid (EA) on the contraction in mice. BL-420S force measuring system was used to measure the tension of mouse tracheal rings. The whole cell patch clamp technique was utilized to record the channel currents of airway smooth muscle (ASM) cells. The calcium imaging system was used to determine the intracellular Ca2+ concentration ([Ca2+]i) in ASM cells. The results showed that EA significantly inhibited the high K+ (80 mmol/L) and acetylcholine (ACh, 100 µmol/L)-induced contraction of mouse tracheal rings in a dose-dependent manner. The maximal relaxation percentages were (97.02 ± 1.56)% and (85.21 ± 0.03)%, and the median effective concentrations were (40.28 ± 2.20) µmol/L and (56.22 ± 7.62) µmol/L, respectively. EA decreased the K+ and ACh-induced elevation of [Ca2+]i from 0.40 ± 0.04 to 0.16 ± 0.01 and from 0.50 ± 0.01 to 0.39 ± 0.01, respectively. In addition, EA inhibited L-type voltage-dependent calcium channel (LVDCC) and store-operated calcium channel (SOCC) currents in ASM cells, and Ca2+ influx. Moreover, EA decreased the resistance of the respiratory system (Rrs) in vivo in mice. These results indicated that EA inhibits LVDCC and SOCC, which results in termination of Ca2+ influx and decreases of [Ca2+]i, leading to relaxation of ASM. Taken together, EA might be a potential bronchodilator.


Assuntos
Ácido Etacrínico , Contração Muscular , Músculo Liso , Sistema Respiratório , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L , Inibidores Enzimáticos/farmacologia , Ácido Etacrínico/farmacologia , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Sistema Respiratório/citologia , Sistema Respiratório/efeitos dos fármacos
6.
Drug Des Devel Ther ; 13: 3391-3404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576113

RESUMO

Purpose: It has been reported that approximately 40% of ALI (acute lung injury) incidence resulted from sepsis. Paclitaxel, as a classic anti-cancer drug, plays an important role in the regulation of inflammation. However, we do not know whether it has a protective effect against CLP (cecal ligation and puncture)-induced septic ALI. Our study aims to illuminate the mitigative effects of paclitaxel on sepsis-induced ALI and its relevant mechanisms. Materials and methods: The survival rates and organ injuries were used to evaluate the effects of paclitaxel on CLP mice. The levels of inflammatory cytokines were tested by ELISA. MUC1 siRNA pre-treatment was used to knockdown MUC1 expression in vitro. GO203 was used to inhibit the homodimerization of MUC1-C in vivo. The expression levels of MUC1, TLR 4 and p-NF-κB/p65 were detected by Western blot. Results: Our results showed that paclitaxel improved the survival rates and ameliorated organ injuries especially lung injury in CLP-induced septic mice. These were accompanied by reduced inflammatory cytokines in sera and BALF (bronchoalveolar lavage fluid). We also found paclitaxel could attenuate TLR 4-NF-κB/p65 activation both in lung tissues of septic mice and LPS-stimulated lung type II epithelial cell line A549. At the upstream level, paclitaxel-upregulated expression levels of MUC1 in both in vivo and in vitro experiments. The inhibitory effects of paclitaxel on TLR 4-NF-κB/p65 activation were reversed in lung tissues of septic mice pre-treated with MUC1 inhibitor and in MUC1-knockdown A549 cells. Protection of paclitaxel on sepsis-induced ALI and decrease of inflammatory cytokines were also abolished by inhibition of MUC1. Conclusion: Collectively, these results indicated paclitaxel could significantly alleviate acute lung injury in CLP-induced septic mice and LPS-stimulated lung type II epithelial cell line A549 by activating MUC1 and suppressing TLR-4/NF-κB pathway.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31519041

RESUMO

BACKGROUND AND AIM: Hepatitis B-associated liver cirrhosis (HBC) leads to profound alterations of immune systems, especially disruptions of B cell immune responses. CXCR5+ CD4+ T cells (including T follicular helper [Tfh] cells and T follicular regulatory [Tfr] cells) are responsible for the regulation of B cell functions. The aim of this study was to dissect the roles of CXCR5+ CD4+ T cell subset in B cell disruption caused by HBC. METHODS: Forty-one patients with HBC and 15 healthy controls were enrolled in this study. ELISA, flow cytometric analysis, and cell coculture were performed to analyze the properties of Tfh and Tfr. RESULTS: We observed significantly decreased memory B cells and increased plasma B cells in HBC patients, as well as significant upregulation of lipopolysaccharide binding protein and soluble CD14 in plasma of decompensated HBCs patients. The downregulation of Tfh17 was observed in HBC patients with spontaneous bacterial peritonitis compared with those without. The decrease of Tfh17 was paralleled with Child-Pugh grade and negatively correlated with plasma B cells and soluble CD14 in HBC patients. Interleukin (IL)-21+ Tfh of HBC patients was also downregulated compared with healthy controls, and it was positively correlated with memory B cells and the upregulation of IL-10+ Tfr. It was then revealed that Tfr could inhibit the secretion of IL-21 by Tfh, and the blocking of IL-10 could diminish this effect. CONCLUSIONS: The changes of the frequency and function of Tfh and Tfr may play an important role in disease progression and immune dysfunction of HBC.

9.
Genet Test Mol Biomarkers ; 23(7): 442-447, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31219360

RESUMO

Background: Single nucleotide polymorphisms (SNPs) within precursor microRNAs (miRNAs) can affect the expression of the miRNAs and may be involved in the pathogenesis of pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB). Aims: We investigated the potential associations among four precursor miRNA SNPs (miR-149 A>G, C>T; miR-196a2 C>T; miR-499 C>T) and both PTB and EPTB. Methods: The study included 380 PTB patients, 242 EPTB patients, and 606 healthy control (HC) subjects from a Chinese Han population. We determined the miRNA relative expression levels from 10 HCs and 10 tuberculosis (TB) patients by quantitative PCR. Results: We found that the PTB group had a significantly lower miR-149 level (p < 0.05) versus the HCs. The allele and genotype frequencies of the miR-149 SNPs were significantly different between the TB patients and the HC group. The C allele at the rs2292832 and the A allele at the rs71428439 locus were associated with susceptibility to EPTB. The C allele of rs2292832 was associated with an increased risk of EPTB compared with that of HCs (p < 0.01), and the A allele of rs71428439 was protective against EPTB (p < 0.01) and PTB (p < 0.01). Conclusions: We identified genetic polymorphisms in miR-149 that appear to be associated with susceptibility to both PTB and EPTB within a Chinese population.


Assuntos
MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Tuberculose Pulmonar/genética , Tuberculose/genética , Adulto , Alelos , China , Feminino , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Precursores de RNA
10.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(4): 381-386, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31014433

RESUMO

OBJECTIVE: To study the etiology and genetic diagnosis of children with short stature. METHODS: A retrospective analysis was performed to study the etiological distribution and clinical features of 86 children with short stature. RESULTS: A total of 6 causes were observed in these children, among which idiopathic short stature (ISS, 41%) and growth hormone deficiency (GHD, 29%) were the most common causes, followed by genetic diseases (14%). There were no significant differences in age at the time of diagnosis, body height, body length and weight at birth, body height of parents and insulin-like growth factor-1 levels between the genetic disease group and the ISS/GHD groups (P>0.05). Compared with the ISS group, the genetic disease group had significantly lower deviation from the 3rd percentile for the height of children of the same age and sex (ΔP3) and height standard deviation score (P<0.05), while there were no significant differences between the genetic disease and GHD groups (P>0.05). The analysis of the clinical manifestations for the genetic disease group showed heterogeneity and phenotypic overlap in children with different genetic diseases. CONCLUSIONS: ISS, GHD and genetic diseases are major causes of short stature in children. For children with severe short stature, genetic testing should be performed to make a definitive diagnosis after GHD has been excluded.


Assuntos
Testes Genéticos , Estatura , Criança , Nanismo Hipofisário , Transtornos do Crescimento , Hormônio do Crescimento Humano , Humanos , Estudos Retrospectivos
11.
Lipids Health Dis ; 18(1): 68, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885219

RESUMO

BACKGROUND: Hypertriglyceridemia (HTG) is one of the most common etiologies of acute pancreatitis (AP). Variants in five genes involved in the regulation of plasma lipid metabolism, namely LPL, APOA5, APOC2, GPIHBP1 and LMF1, have been frequently reported to cause or predispose to HTG. METHODS: A Han Chinese patient with HTG-induced AP was assessed for genetic variants by Sanger sequencing of the entire coding and flanking sequences of the above five genes. RESULTS: The patient was a 32-year-old man with severe obesity (Body Mass Index = 35) and heavy smoking (ten cigarettes per day for more than ten years). At the onset of AP, his serum triglyceride concentration was elevated to 1450.52 mg/dL. We sequenced the entire coding and flanking sequences of the LPL, APOC2, APOA5, GBIHBP1 and LMF1 genes in the patient. We found no putative deleterious variants, with the exception of a novel and heterozygous nonsense variant, c.1024C > T (p.Arg342*; rs776584760), in exon 7 of the LMF1 gene. CONCLUSIONS: This is the first time that a heterozygous LMF1 nonsense variant was found in a HTG-AP patient with severe obesity and heavy smoking, highlighting an important interplay between genetic and lifestyle factors in the etiology of HTG.


Assuntos
Códon sem Sentido , Hipertrigliceridemia/complicações , Proteínas de Membrana/genética , Obesidade Mórbida/genética , Pancreatite/genética , Fumar/genética , Adulto , Predisposição Genética para Doença , Heterozigoto , Humanos , Hipertrigliceridemia/genética , Estilo de Vida , Masculino , Pancreatite/etiologia
12.
Front Microbiol ; 10: 130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30787914

RESUMO

Human adenovirus type 55 (HAdV-55) is considered a highly virulent pathogen causing severe and even deadly pneumonia in immunocompetent people. The mechanisms of HAdV-55-induced initiation and progression of severe pneumonia remain ambiguous. In the current study, we endeavored to identify novel immune response genes which are substantially involved in the pathogenesis of severe inflammation in HAdV-55-infected patients. HAdV-55-infected patients with upper respiratory tract symptoms (minor patients) and pneumonia (severe patients) were enrolled. Through transcriptome sequencing and quantitative real-time PCR, the peripheral blood mononuclear cells of the patients were analyzed. We found that the expression of eight genes, including Il18, Il36b, Il17rc, Tnfsf10, Tnfsf11, Tnfsf14, Tnfsf15, and Il1a, were closely correlated with the severity of HAdV-55 infection. Most of these genes belong to interleukin-1 family or tumor necrosis factor (TNF) superfamily, respectively. The changes in gene expression were confirmed by Western blot assay. Our data will be crucial for deepening the understanding of the pathogenic mechanisms of severe pneumonia in HAdV-55 infection.

13.
Sci Rep ; 9(1): 1190, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718786

RESUMO

Major depressive disorders are emerging health problems that affect millions of people worldwide. However, treatment options and targets for drug development are limited. Impaired adult hippocampal neurogenesis is emerging as a key contributor to the pathology of major depressive disorders. We previously demonstrated that increasing the expression of the multifunctional scaffold protein Axis inhibition protein (Axin) by administration of the small molecule XAV939 enhances embryonic neurogenesis and affects social interaction behaviors. This prompted us to examine whether increasing Axin protein level can enhance adult hippocampal neurogenesis and thus contribute to mood regulation. Here, we report that stabilizing Axin increases adult hippocampal neurogenesis and exerts an antidepressant effect. Specifically, treating adult mice with XAV939 increased the amplification of adult neural progenitor cells and neuron production in the hippocampus under both normal and chronic stress conditions. Furthermore, XAV939 injection in mice ameliorated depression-like behaviors induced by chronic restraint stress. Thus, our study demonstrates that Axin/XAV939 plays an important role in adult hippocampal neurogenesis and provides a potential therapeutic approach for mood-related disorders.

14.
BMC Med Genet ; 20(1): 7, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30634928

RESUMO

BACKGROUND: Host genetic factors affect the immune response to Mycobacterium tuberculosis (Mtb) infection as well as the progression of the disease. Epiregulin (EREG) belongs to the epidermal growth factor (EGF) family, which binds to the epidermal growth factor receptor (EGFR) to regulate the immune response of the host during infections. Our study aimed to compare EREG levels in tuberculosis (TB) patients and healthy controls and assess whether polymorphisms in EREG increase the risk of TB. METHODS: We used ELISA to determine the plasma EREG level from 30 healthy controls and 50 tuberculosis patients. By evaluating the EREG gene from 624 TB patients and 600 healthy controls, we determined the allelic and genotypic frequencies for association with susceptibility to TB infections in this group. RESULTS: This paper shows that the pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) groups showed a significantly higher plasma EREG level (1014 ± 733.9 pg/ml, 700.2 ± 676.6 pg/ml, respectively) than the healthy controls (277 ± 105.4 pg/ml). The rs2367707 polymorphism was associated with a higher risk of PTB and EPTB (P = 0.00051, P = 0.0012). Analyses of haplotype frequencies found that people with the haplotype CACAT had a higher risk of PTB and EPTB (P = 0.00031, OR = 1.43; P = 0.000053, OR = 1.65). Moreover, the rs6446993 polymorphism of the EREG gene was found to be associated with EPTB (P = 0.00087, OR = 1.54; 95% CI = 1.23-1.94). CONCLUSIONS: Compared to that of healthy controls, the level of EREG in the plasma of TB patients increased significantly. Based on these data, we demonstrated that EREG polymorphisms are genetic factors for susceptibility to TB and various forms of TB.


Assuntos
Epirregulina/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Tuberculose/genética , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Criança , China , Progressão da Doença , Epirregulina/sangue , Epirregulina/imunologia , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/genética , Adulto Jovem
15.
J Clin Med ; 8(1)2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30646625

RESUMO

The bacterial species, Helicobacter pylori, is associated with several gastrointestinal diseases, and poses serious health threats owing to its resistance to antibiotics. Lactobacillus spp., on the other hand, possess probiotic activities that have beneficial effects in humans. However, the mechanisms by which Lactobacillus spp. harbor favorable functions and act against H. pylori infection remain to be explored. The aim of this study was to investigate the ability of bacterial strains, Lactobacillus rhamnosus and Lactobacillus acidophilus, termed GMNL-74 and GMNL-185, respectively, to inhibit H. pylori growth and inflammation. Our results showed that GMNL-74 and GMNL-185 possess potent antimicrobial activity against multidrug resistant (MDR)-H. pylori. In addition, an in vitro cell-based model revealed that the inhibition of H. pylori adhesion and invasion of gastric epithelial cells and interleukin-8 production were significantly decreased by treatment with both the Lactobacillus strains. In vivo studies demonstrated that colonization of H. pylori and induced inflammation in the mouse stomach were also alleviated by these Lactobacillus strains. Furthermore, the abundance of beneficial gut bacteria, including Bifidobacterium spp. and Akkermansia muciniphilia, were significantly increased in H. pylori-infected mice treated with GMNL-74 and GMNL-185. These results demonstrate that Lactobacillus spp. ameliorate H. pylori-induced inflammation and supports beneficial gut specific bacteria that act against H. pylori infection.

16.
J Integr Plant Biol ; 61(2): 140-154, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29975451

RESUMO

Under conditions of aluminum (Al) toxicity, which severely inhibits root growth in acidic soils, plants rapidly alter their gene expression to optimize physiological fitness for survival. Abscisic acid (ABA) has been suggested as a mediator between Al stress and gene expression, but the underlying mechanisms remain largely unknown. Here, we investigated ABA-mediated Al-stress responses, using integrated physiological and molecular biology approaches. We demonstrate that Al stress caused ABA accumulation in the root apex of rice bean (Vigna umbellata [Thunb.] Ohwi & Ohashi), which positively regulated Al tolerance. However, this was not associated with known Al-tolerance mechanisms. Transcriptomic analysis revealed that nearly one-third of the responsive genes were shared between the Al-stress and ABA treatments. We further identified a transcription factor, ABI5, as being positively involved in Al tolerance. Arabidopsis abi5 mutants displayed increased sensitivity to Al, which was not related to the regulation of AtALMT1 and AtMATE expression. Functional categorization of ABI5-mediated genes revealed the importance of cell wall modification and osmoregulation in Al tolerance, a finding supported by osmotic stress treatment on Al tolerance. Our results suggest that ABA signal transduction pathways provide an additional layer of regulatory control over Al tolerance in plants.


Assuntos
Ácido Abscísico/metabolismo , Arabidopsis/metabolismo , Vigna/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Transdução de Sinais
17.
J Neurosurg Sci ; 63(4): 493-494, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-29115097
18.
Sci Transl Med ; 10(459)2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232226

RESUMO

Severe fever with thrombocytopenia syndrome (SFTS) caused by a recently identified bunyavirus, SFTSV, is an emerging infectious disease with extensive geographical distribution and high mortality. Progressive viral replication and severe thrombocytopenia are key features of SFTSV infection and fatal outcome, whereas the underlying mechanisms are unknown. We revealed arginine deficiency in SFTS cases by performing metabolomics analysis on two independent patient cohorts, suggesting that arginine metabolism by nitric oxide synthase and arginase is a key pathway in SFTSV infection and consequential death. Arginine deficiency was associated with decreased intraplatelet nitric oxide (Plt-NO) concentration, platelet activation, and thrombocytopenia. An expansion of arginase-expressing granulocytic myeloid-derived suppressor cells was observed, which was related to T cell CD3-ζ chain down-regulation and virus clearance disturbance, implicating a role of arginase activity and arginine depletion in the impaired anti-SFTSV T cell function. Moreover, a comprehensive measurement of arginine bioavailability, global arginine bioavailability ratio, was shown to be a good prognostic marker for fatal prediction in early infection. A randomized controlled trial demonstrated that arginine administration was correlated with enhanced Plt-NO concentration, suppressed platelet activation, and elevated CD3-ζ chain expression and eventually associated with an accelerated virus clearance and thrombocytopenia recovery. Together, our findings revealed the arginine catabolism pathway-associated regulation of platelet homeostasis and T cell dysregulation after SFTSV infection, which not only provided a functional mechanism underlying SFTS pathogenesis but also offered an alternative therapy choice for SFTS.


Assuntos
Arginina/deficiência , Infecções por Bunyaviridae/complicações , Infecções por Bunyaviridae/imunologia , Imunossupressão , Phlebovirus/fisiologia , Trombocitopenia/complicações , Trombocitopenia/virologia , Arginina/uso terapêutico , Plaquetas/metabolismo , Infecções por Bunyaviridae/sangue , Infecções por Bunyaviridae/tratamento farmacológico , Complexo CD3/metabolismo , Suplementos Nutricionais , Humanos , Imunidade , Metaboloma , Metabolômica , Células Supressoras Mieloides/metabolismo , Óxido Nítrico/metabolismo , Linfócitos T/imunologia , Trombocitopenia/sangue , Trombocitopenia/tratamento farmacológico
19.
Lipids Health Dis ; 17(1): 201, 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30153842

RESUMO

BACKGROUND: The macrophage plays an important role in innate immunity to induce immune responses. Lipid replacement therapy has been shown to change the lipid compositions of mitochondria and potentially becomes an alternative to reduce the inflammatory response. METHODS: We examined the effects of omega-6 arachidonic acid (AA), omega-3 eicosapentaenoic acid (EPA), and omega-3 docosahexaenoic acid (DHA) supplementation on the activated the macrophage cell line RAW264.7 via KdO2-lipid A (KLA). The mitochondrial cardiolipin (CL) and monolysocardiolipin (MLCL) were analyzed by LC-MS. RESULTS: After macrophage activation by KLA, CL shifted to saturated species, but did not affect the quantity of CL. Inhibition of delta 6 desaturase also resulted in the same trend of CL species shift. We further examined the changes in CL and MLCL species induced by polyunsaturated fatty acid supplementation during inflammation. After supplementation of AA, EPA and DHA, the MLCL/CL ratio increased significantly in all treatments. The percentages of the long-chain species highly elevated and those of short-chain species reduced in both CL and MLCL. CONCLUSIONS: Comparisons of AA, EPA and DHA supplementation revealed that the 20-carbon EPA (20:5) and AA (20:4) triggered higher incorporation and CL remodeling efficiency than 22-carbon DHA (22:6). EPA supplementation not only efficiently extended the chain length of CL but also increased the unsaturation of CL.


Assuntos
Cardiolipinas/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Animais , Ácido Araquidônico/farmacologia , Bicamadas Lipídicas/metabolismo , Lipopolissacarídeos/farmacologia , Lisofosfolipídeos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Células RAW 264.7
20.
Emerg Microbes Infect ; 7(1): 114, 2018 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973586

RESUMO

Different Mycobacterium spp. infections may indicate varied treatment regimens in the clinic. Thus, the species-level identification of Mycobacterium spp. is one of the most important tasks for a clinical microbiology laboratory. Although matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a rapid and accurate method for the identification of mycobacteria, this method lacks a comprehensive evaluation of the identification accuracy for clinically collected mycobacteria using VITEK MS Knowledge Base Version 3.0 (Ver 3.0). The objectives of the present study were to evaluate the identification performance of Mycobacterium spp. using Ver 3.0 and a sample processing kit for strain inactivation and protein extraction. Among the 507 Mycobacterium isolates, 46 isolates were M. tuberculosis, and 461 isolates were nontuberculous mycobacteria (NTM) (including 27 species: 17 species were slowly growing mycobacteria (SGM), and 10 species were rapidly growing mycobacteria (RGM)). The VITEK MS V3.0 library was used to correctly identify 476/507 (93.9%) isolates (425 isolates were correctly identified initially, and 51 more isolates were correctly identified on repeat), 23/507 (4.5%) isolates were unidentified, and 8/507 (1.6%) isolates were misidentified. In summary, we showed that Mycobacterium spp. can be adequately identified by Ver 3.0 in combination with the use of a standard sample processing kit.


Assuntos
Bases de Conhecimento , Infecções por Mycobacterium/microbiologia , Mycobacterium/classificação , Mycobacterium/isolamento & purificação , Técnicas Bacteriológicas , Humanos , Infecções por Mycobacterium/diagnóstico , Reprodutibilidade dos Testes , Manejo de Espécimes/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
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