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1.
Nat Commun ; 11(1): 340, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953413

RESUMO

Mikania micrantha is one of the top 100 worst invasive species that can cause serious damage to natural ecosystems and substantial economic losses. Here, we present its 1.79 Gb chromosome-scale reference genome. Half of the genome is composed of long terminal repeat retrotransposons, 80% of which have been derived from a significant expansion in the past one million years. We identify a whole genome duplication event and recent segmental duplications, which may be responsible for its rapid environmental adaptation. Additionally, we show that M. micrantha achieves higher photosynthetic capacity by CO2 absorption at night to supplement the carbon fixation during the day, as well as enhanced stem photosynthesis efficiency. Furthermore, the metabolites of M. micrantha can increase the availability of nitrogen by enriching the microbes that participate in nitrogen cycling pathways. These findings collectively provide insights into the rapid growth and invasive adaptation.

2.
Haematologica ; 105(2): 325-337, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31123027

RESUMO

Aproper choice of neutrophil-macrophage progenitor cell fate is essential for the generation of adequate myeloid subpopulations during embryonic development and in adulthood. The network governing neutrophil-macrophage progenitor cell fate has several key determinants, such as myeloid master regulators CCAAT enhancer binding protein alpha (C/EBPα) and spleen focus forming virus proviral integration oncogene (PU.1). Nevertheless, more regulators remain to be identified and characterized. To ensure balanced commitment of neutrophil-macrophage progenitors toward each lineage, the interplay among these determinants is not only synergistic, but also antagonistic. Depletion of interferon regulatory factor 2 binding protein 2b (Irf2bp2b), a well-known negative transcription regulator, results in a bias in neutrophil-macrophage progenitor cell fate in favor of macrophages at the expense of neutrophils during the stage of definitive myelopoiesis in zebrafish embryos. Mechanistic studies indicate that Irf2bp2b acts as a downstream target of C/EBPα, repressing PU.1 expression, and that SUMOylation confers the repressive function of Irf2bp2b. Thus, Irf2bp2b is a novel determinant in the choice of fate of neutrophil-macrophage progenitor cells.

3.
Oncologist ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784489

RESUMO

BACKGROUND: The objective of this study was to develop and validate a nomogram to predict 1-year overall survival (OS) and 2-year OS in patients with high-grade digestive neuroendocrine neoplasms (NENs) as well as to guide selection of subgroups that could benefit from systemic chemotherapy. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective analysis of 223 patients with NENs of the gut and hepato-biliary-pancreatic system from four centers included in the development cohort. The nomogram was externally validated in a cohort of 90 patients from another one. RESULTS: The final model included lactate dehydrogenase, performance status, stage, Ki67, and site of primary tumor, all of which had a significant effect on OS. The uncorrected C-index was 0.761 for OS, and the bias-corrected C-index was 0.744. Predictions correlated well with observed 1-year and 2-year outcomes (judged by eye). The area under the time-dependent receiver operating characteristic curve at 12 months and 24 months was 0.876 and 0.838, respectively. The nomogram performed well in terms of both discrimination and calibration when applied to the validation cohort, and OS was significantly different between the two groups classified by nomogram score (log-rank p < .001). CONCLUSION: The validated nomogram provided useful prediction of OS, which can be offered for clinicians to improve their abilities to assess patient prognosis, to create clinical risk groups for informing treatment or for patient stratification by disease severity in clinical trials. IMPLICATIONS FOR PRACTICE: The high-grade neuroendocrine neoplasms of the digestive system are rare malignancies with great heterogeneity. An overall survival nomogram was developed and externally validated in this study. Two subgroups were classified by the nomogram score, and platinum-based chemotherapy may not bring clinical benefit for the low-risk patients.

4.
Exp Ther Med ; 18(5): 3688, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31608129

RESUMO

[This corrects the article DOI: 10.3892/etm.2019.7253.].

5.
Sci Rep ; 9(1): 13625, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541161

RESUMO

Behavioral thermoregulation is a defensive strategy employed by some insects to counter infections by parasites and pathogens. Most reported examples of this type of thermoregulatory response involve behavioral fevering. However depending upon the life history of a host-insect and that of the parasite or pathogen, the host may respond by cold-seeking behavior. Thermoregulation is not only ecologically important; it may affect the success of parasites and pathogens as biological control agents. We examined if Frankliniella occidentalis (Pergande) thermoregulates in response to infection by Beauveria bassiana, a fungal pathogen commonly used for biological control. Fungal-infected thrips preferentially moved to cooler areas (~12 °C) while healthy thrips sought out warmer temperatures (~24 °C). This cold-seeking behavior suppressed the growth of B. bassiana in infected thrips, and significantly improved survivorship of infected thrips. At 24 °C, males only survived up to 10 d after infection and females up to 20 d after infection, which was substantially poorer survivorship than that of corresponding healthy individuals. However, individuals of both sexes survived up to 48 d after infection at 12 °C, which was a much less severe reduction in survivorship compared with the effect of B. bassiana infection at 24 °C. The proportion of females among progeny from infected thrips at 12 °C was higher than at 24 °C. Therefore, cold-seeking behavior is beneficial to F. occidentalis when infected by B. bassiana, and its effects should be considered in the use of B. bassiana in biological control programs.

6.
Mol Plant Pathol ; 20(12): 1696-1709, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31560825

RESUMO

Xanthomonas campestris pv. campestris (Xcc), the causal agent of black rot in crucifers, produces a membrane-bound yellow pigment called xanthomonadin to protect against photobiological and peroxidative damage, and uses a quorum-sensing mechanism mediated by the diffusible signal factor (DSF) family signals to regulate virulence factors production. The Xcc gene XCC4003, annotated as Xcc fabG3, is located in the pig cluster, which may be responsible for xanthomonadin synthesis. We report that fabG3 expression restored the growth of the Escherichia coli fabG temperature-sensitive mutant CL104 under non-permissive conditions. In vitro assays demonstrated that FabG3 catalyses the reduction of 3-oxoacyl-acyl carrier protein (ACP) intermediates in fatty acid synthetic reactions, although FabG3 had a lower activity than FabG1. Moreover, the fabG3 deletion did not affect growth or fatty acid composition. These results indicate that Xcc fabG3 encodes a 3-oxoacyl-ACP reductase, but is not essential for growth or fatty acid synthesis. However, the Xcc fabG3 knock-out mutant abolished xanthomonadin production, which could be only restored by wild-type fabG3, but not by other 3-oxoacyl-ACP reductase-encoding genes, indicating that Xcc FabG3 is specifically involved in xanthomonadin biosynthesis. Additionally, our study also shows that the Xcc fabG3-disrupted mutant affects Xcc virulence in host plants.

7.
J Bacteriol ; 201(20)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31358615

RESUMO

Cyclopropane fatty acids (CFAs) are synthetized by the addition of a methylene group from S-adenosyl-l-methionine across the carbon-carbon double bonds of unsaturated fatty acid chains of membrane phospholipids. This fatty acid cyclopropanation, catalyzed by the CFA synthase (CfaS) enzyme, occurs in many bacteria, including the human pathogen Helicobacter pylori Although the cyclopropane modification was reported to play a key role in the adaptation in response to environmental stress, its role in H. pylori remains unknown. In this study, we showed that H. pylori HP0416 encodes a functional CfaS. The enzyme was demonstrated to be required for acid resistance, antibiotic resistance, intracellular survival and mouse gastric colonization, and cell membrane integrity. Moreover, the tool compound dioctylamine, which acts as a substrate mimic, directly inhibits the CfaS function of H. pylori, resulting into sensitivity to acid stress, increased antibiotic susceptibility, and attenuated abilities to avoid macrophage killing and to colonize mouse stomachs. These results validate CfaS as a promising antibiotic target and provide new potentials for this recognized target in future anti-H. pylori drug discovery efforts.IMPORTANCE The increasing prevalence of multidrug-resistant Helicobacter pylori strains has created an urgent need for alternative therapeutic regimens that complement the current antibiotic treatment strategies for H. pylori eradication; however, this is greatly hampered due to a lack of "druggable" targets. Although the CFAs are present in H. pylori cytoplasmic membranes at high levels, their physiological role has not been established. In this report, deletion of the CFA synthase CfaS was shown to attenuate acid and drug resistance, immune escape, and gastric colonization of H. pylori These findings were validated by inhibition of the CfaS activity with the tool compound dioctylamine. These studies identify this enzyme as an attractive target for further drug discovery efforts against H. pylori.

8.
Front Microbiol ; 10: 1028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231314

RESUMO

Bacterial 3-oxoacyl-ACP reductase (OAR) catalyzes the 3-oxoacyl-ACP reduction step in the fatty acid synthesis pathway. At least 12 genes in the Pseudomonas aeruginosa genome are annotated as OAR-encoding genes. In this study, we characterized the functions of these genes with biochemical and genetic techniques. With the exception of PA2967, which encodes FabG, an essential protein in fatty acid synthesis, only the PA4389 and PA4786 gene products had OAR activity, and the single deletion of these two genes reduced the ability of P. aeruginosa to produce several specific quorum-sensing (QS) signals. However, PA4389 and PA4786 do not have key roles in fatty acid synthesis. Moreover, although most OAR homologs had no OAR activity, some may function in carbon utilization. The PA3128 product may play a role in the TCA cycle, and PA0182 and PA1470 seem to be required for the utilization of several amino acids. The rest of the OAR homologs have no roles in carbon utilization, but the deletion of one of these genes might affect the production of virulence factors by P. aeruginosa. We conclude that most OAR homolog genes do not encode OAR enzymes, and that these proteins do not function in fatty acid synthesis. Importance: We report that although all P. aeruginosa OAR homologs have similar structures and the conserved catalytic triad of the bacterial OAR enzymes, only a few OAR homologs have OAR activity.

10.
Cancer Biol Ther ; 20(7): 1017-1028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30983515

RESUMO

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited intestinal polyposis syndrome accounting for about 1% of colorectal cancers (CRC). Despite increasing researches on the molecular pathogenesis of CRC, we are still unclear about metabolic pathways and alterations probably involved in the development of CRC. To obtain new insights into the mechanisms underlying APC mutation and to elucidate the mechanisms of CRC development, we performed to identify the potential metabolites in FAP based on metabolomic strategy. Serum metabolites from FAP patients (n = 30) and healthy individuals (n = 34) were detected and qualified using Ultra Performance Liquid Chromatography and Tandem Mass Spectrometry (UPLC- MS/MS). 118 metabolites were identified with statistical tests of orthogonal partial least-squares-discriminant analysis (OPLS-DA), with the conditions of variable importance in projection (VIP) >1, p < 0.05 using the Mann-Whitney U test, and fold change (FC) ≥2 or ≤0.5. OPLS-DA model was useful for distinguishing FAP patients from healthy controls. Unique metabolic signatures were pooled in FAP patients covering tricarboxylic acid (TCA) cycle, amino acids metabolism, vitamin D, fatty acids metabolism, and bile acids (BAs) metabolism. Our results demonstrated that metabolites alterations in FAP can be helpful for further analysis of metabonomics induced by APC mutation, and these alterations might be involved in the progress of intestinal carcinogenesis.

11.
Exp Ther Med ; 17(4): 2451-2456, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30906432

RESUMO

Ulcerative colitis (UC) is an important risk factor for the occurrence of colon cancer, and changes in expression of p53 and inflammatory factors are closely related to the pathogenesis of colon cancer. Therefore, changes in expression of p53 and inflammatory factors in UC were investigated to explore its intrinsic pathogenetic laws. The levels of inflammatory factors, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), IL-10 and IL-4, in peripheral blood of UC patients and healthy adults were detected via enzyme-linked immunosorbent assay, and the changes in p53 expression were analyzed via immunohistochemistry and western blotting, and the correlation of p53 expression with changes in cytokines was also analyzed. Moreover, changes in 45S preribosomal ribonucleic acid (preRNA) transcriptional activity in four kinds of cell lines exposed to IL-6 were analyzed and determined by using reverse transcription-quantitative polymerase chain reaction. Finally, the C-myc protein expression after IL-6 stimulation was analyzed and evaluated via western blot analysis. The levels of IL-6 and TNF-α in peripheral blood in the UC patient group were significantly increased compared with those in the healthy adult group (P<0.01), while the levels of IL-10 and IL-4 in peripheral blood were significantly decreased compared with those in the healthy adult group (P<0.01). The p53 expression had a significant negative correlation with IL-6. The results showed that IL-6 activated C-myc messenger RNA (mRNA) translation, thereby upregulating the ribosomal RNA (rRNA) transcription. Additionally, IL-6 stimulated the mouse double minute 2 homolog (MDM2)-mediated proteasomal degradation of p53 by reducing the availability of ribosomal protein used for MDM2 binding, thus resulting in the downregulation of p53 protein expression. The findings of the study show that, expression level of IL-6 was increased in UC patients, which regulates the downregulation of p53 expression level and plays a role in tumorigenesis through enhancing cell proliferation and inhibiting apoptosis.

12.
Shock ; 51(6): 787-794, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29846361

RESUMO

BACKGROUND: Bacterial pneumonia is one of the most common diagnoses and a leading cause of death in the intensive care unit. NR4A1 is an early response gene that has been identified as a vital regulator of immune and inflammatory responses. This study aims to explore the role of NR4A1 in Escherichia coli (E. coli) pneumonia. METHODS: Alveolar macrophages (AMs) were isolated from wild-type (WT) and NR4A1 knock out (Nr4a1) mice, and the NR4A1 expression and phagocytic capacity against E. coli were measured in vitro. WT and Nr4a1 mice were subjected to E. coli or sham pneumonia. Bacterial load, lung injury severity, inflammatory cell infiltration, and cytokines were assessed at 0, 4, and 18 h after surgery. Survival rates within 48 h were evaluated in WT and Nr4a1 mice. In addition, NR4A1 antagonist (DIM-C-pPhCO2Me) was also used to confirm the role of NR4A1 in vivo and ex vivo. RESULTS: NR4A1 was rapidly induced in AMs at 15 min after E. coli stimulation. Compared with untreated WT AMs, NR4A1 deficiency and DIM-C-pPhCO2Me treatment showed an enhanced phagocytic function (47.72 ±â€Š0.74% vs. 62.3 ±â€Š0.9%, P < 0.001; 11.79 ±â€Š1.21% vs. 30.08 ±â€Š0.79%, P < 0.001, respectively) at 30 min after the E. coli challenge in vitro. NR4A1 deficiency significantly improved the survival rate (33.3% in WT vs. 82.4% in Nr4a1, P < 0.01), which is comparable with DIM-C-pPhCO2Me pretreatment. The survival advantage of Nr4a1 mice was associated with decreased bacterial burden and inflammation and alleviated lung damage. CONCLUSIONS: These data demonstrate that NR4A1 impairs the phagocytic capacity of AMs and disrupts the host defense against invading bacteria, worsening the outcome of E. coli pneumonia in mice.

13.
Biochem Biophys Res Commun ; 508(3): 959-964, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30545636

RESUMO

Gut-derived 5-hydroxytryptamine (5-HT) is well known for its role in mediating colonic motility function. However, it is not very clear whether brain-derived 5-HT is involved in the regulation of colonic motility. In this study, we used central 5-HT knockout (KO) mice to investigate whether brain-derived 5-HT mediates colonic motility, and if so, whether it involves oxytocin (OT) production in the hypothalamus and OT receptor in the colon. Colon transit time was prolonged in KO mice. The OT levels in the hypothalamus and serum were decreased significantly in the KO mice compared to wild-type (WT) controls. OT increased colonic smooth muscle contraction in both KO and WT mice, and the effects were blocked by OT receptor antagonist and tetrodotoxin but not by hexamethonium or atropine. Importantly, the OT-induced colonic smooth muscle contraction was decreased significantly in the KO mice relative to WT. The OT receptor expression of colon was detected in colonic myenteric plexus of mice. Central 5-HT is involved in the modulation of colonic motility which may modulate through its regulation of OT synthesis in the hypothalamus. Our results reveal a central 5-HT - hypothalamus OT - colonic OT receptor axis, providing a new target for the treatment of brain-gut dysfunction.


Assuntos
Colo/fisiologia , Motilidade Gastrointestinal , Hipotálamo/metabolismo , Ocitocina/metabolismo , Receptores de Ocitocina/metabolismo , Serotonina/fisiologia , Animais , Colo/metabolismo , Feminino , Masculino , Camundongos , Camundongos Knockout , Contração Muscular , Ocitocina/sangue , Hipófise/metabolismo , Triptofano Hidroxilase/genética
14.
Medicine (Baltimore) ; 97(40): e12673, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30290654

RESUMO

BACKGROUND: The World Health Organization (WHO) has endorsed school bystander cardiopulmonary resuscitation (CPR) training programs. But related researches in China are limited. Therefore, we conducted this study to assess bystander CPR training in school children in China and the impact of neighborhood socio-economic status (SES) on. METHODS: A total of 1,093 students from seven schools in Zhejiang province participated in this study. Theoretical and practical bystander CPR training were conducted in instructor-led classes. Students completed a 10-statement questionnaire before and after training, and then underwent a skills assessment during a simulated basic life support (BLS) scenario. Subgroup analyses were stratified according to neighborhood SES. RESULTS: Before training, most students (72.83%) had a strong desire to learn bystander CPR and share with others. After training, bystander CPR theory was significantly improved (P < .01), and 92.64% students reached an 85-100% performance rate in a simulated BLS scenario. Students from low-SES neighborhoods had less pre-training knowledge of bystander CPR (P < .01). However, their performance was similar with students from higher-SES neighborhoods on the post-training questionnaire and the skills assessment, and better among students aged 13-14 years. CONCLUSION: School children in China have a poor pre-training knowledge of bystander CPR. However, with training, there was a significant improvement in the basic theory and skills of CPR. Bystander CPR training efforts should be targeted to Chinese primary and secondary school children, especially in low-SES neighborhoods.


Assuntos
Reanimação Cardiopulmonar/educação , Conhecimentos, Atitudes e Prática em Saúde , Parada Cardíaca Extra-Hospitalar/terapia , Características de Residência , Serviços de Saúde Escolar/organização & administração , Adolescente , Criança , China , Competência Clínica , Feminino , Humanos , Masculino , Estudos Prospectivos , Classe Social
15.
J Orthop Surg Res ; 13(1): 229, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30189881

RESUMO

BACKGROUND: This meta-analysis aimed to evaluate the postoperative clinical outcomes and safety of the direct anterior approach (DAA) versus posterior approach (PA) in total hip arthroplasty (THA). METHODS: We searched PubMed, Embase, Web of Science, the Cochrane Library, and Google databases from inception to June 2018 to select studies that compared the DAA and PA for THA. Only randomized controlled trials (RCTs) were included. Outcomes included Harris hip score at 2 weeks, 6 weeks, 12 weeks, and 1 year; VAS at 24 h, 48 h, and 72 h; incision length, operation time, postoperative blood loss, length of hospital stay, and complications (intraoperative fracture, postoperative dislocation, heterotopic ossification (HO), and groin pain). RESULTS: Nine RCTs totaling 754 THAs (DAA group = 377, PA group = 377) met the criteria to be included in this meta-analysis. The present meta-analysis indicated that, compared with PA group, DAA group was associated with an increase of the Harris hip score at the 2-week and 4-week time points. No significant difference was found between DAA and PA groups of the Harris hip scores at 12 weeks, 1 year length of hospital stay (p > 0.05). DAA group was associated with a reduction of the VAS at 24 h, 48 h, and 72 h with statistical significance (p < 0.05). What is more, DAA was associated with a reduction of the incision length and postoperative blood loss (p < 0.05). There was no significant difference between the operation time and complications (intraoperative fracture, postoperative dislocation, HO, and groin pain). CONCLUSION: In THA patients, compared with PA, DAA was associated with an early functional recovery and less pain scores. What is more, DAA was associated with shorter incision length and blood loss.


Assuntos
Artroplastia de Quadril , Idoso , Artroplastia de Quadril/métodos , Feminino , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias , Período Pós-Operatório , Resultado do Tratamento
16.
Exp Ther Med ; 16(4): 2999-3003, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30214517

RESUMO

This study investigated the effect of glucocorticoids combined with probiotics on inflammatory factors and intestinal microflora in the treatment of Crohn's disease. Eighty-three patients with Crohn's disease were selected from March 2015 to December 2017 in PLA Army General Hospital (Beijing, China). A total of 83 patients were randomly divided into the control group and treatment group. Patients in the control group were treated with routine treatment of oral sulfasalazine. Besides oral sulfasalazine, patients in the treatment group were treated with probiotics combined with glucocorticoids. At the same time, a total of 40 healthy individuals were selected to serve as the healthy group (received no treatment). Clinical efficacy, changes of inflammatory factors, incidence of infection and changes of intestinal flora were compared between the different groups. After treatment, the levels of inflammatory factors in both groups significantly decreased, and the reduction in the treatment group significantly increased than that in the control group (P<0.05). The levels of inflammatory cytokines in the treatment group reached the levels of that in the healthy individuals after treatment. After treatment, the levels of yeast, enterococci and peptococcus of the two groups of patients were significantly decreased, while the level of lactobacillus was significantly increased, and the changes were more significant in the treatment group than those in the control group. After treatment, the number of intestinal flora in the treatment group reached that of the healthy individuals. Treatment efficiency of the treatment group was significantly higher than that of the control group, and the infection rate of the control group was significantly higher than that of the treatment group (P<0.05). The use of probiotics combined with glucocorticoid in the treatment of Crohn's disease can improve clinical curative effect, reduce the secretion of inflammatory factors and improve the level of intestinal flora, so as to achieve better outcomes compared with conventional method.

17.
Neuropsychiatr Dis Treat ; 14: 1795-1801, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30022828

RESUMO

Background: Gender differences may contribute to variances in the potential protective effects of tea against cognitive impairment in the elderly. Objective: To examine the association between different types of tea consumption and the risk of amnestic mild cognitive impairment (aMCI) along gender lines. Methods: A cross-sectional study was conducted with reference to 20 communities in China. The sample population included elderly participants aged 60 years or older. A standardized questionnaire was used to collect each participant's general demographic information. Trained psychologists administrated the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) to assess participants' cognitive function. An attending psychiatrist evaluated each participant's cognitive function. Finally, data from 2,131 participants were analyzed to assess the association. Results: With regard to male participants, the percentage of green tea consumption was higher in the normal control group than in the aMCI group (X2=4.64, P=0.031). Logistic regression analysis showed that green tea consumption reduced the risk of aMCI in male participants (OR=0.657, P=0.019), and this finding was highly significant in males aged under 70 years (OR=0.376, P=0.002). Regarding female participants across every age group, the results indicated that tea consumption failed to significantly decrease the risk of aMCI (P>0.05). Unlike green tea, black tea and oolong tea were not correlated with a reduced risk of aMCI in terms of gender or age group. Multiple linear regression analysis also revealed that age, years of education, and green tea consumption (B=0.996, P=0.000) were associated with MoCA and MMSE scores, though only in male participants. Conclusion: Green tea consumption showed a protective effect against aMCI in males but not in females, particularly in males aged <70 years. However, black tea and oolong tea failed to show any protective effect in either males or females.

18.
mBio ; 9(3)2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29739899

RESUMO

The precursors of the diffusible signal factor (DSF) family signals of Xanthomonas campestris pv. campestris are 3-hydroxyacyl-acyl carrier protein (3-hydroxyacyl-ACP) thioesters having acyl chains of 12 to 13 carbon atoms produced by the fatty acid biosynthetic pathway. We report a novel 3-oxoacyl-ACP reductase encoded by the X. campestris pv. campestris XCC0416 gene (fabG2), which is unable to participate in the initial steps of fatty acyl synthesis. This was shown by the failure of FabG2 expression to allow growth at the nonpermissive temperature of an Escherichia colifabG temperature-sensitive strain. However, when transformed into the E. coli strain together with a plasmid bearing the Vibrio harveyi acyl-ACP synthetase gene (aasS), growth proceeded, but only when the medium contained octanoic acid. In vitro assays showed that FabG2 catalyzes the reduction of long-chain (≥C8) 3-oxoacyl-ACPs to 3-hydroxyacyl-ACPs but is only weakly active with shorter-chain (C4, C6) substrates. FabG1, the housekeeping 3-oxoacyl-ACP reductase encoded within the fatty acid synthesis gene cluster, could be deleted in a strain that overexpressed fabG2 but only in octanoic acid-supplemented media. Growth of the X. campestris pv. campestris ΔfabG1 strain overexpressing fabG2 required fabH for growth with octanoic acid, indicating that octanoyl coenzyme A is elongated by X. campestris pv. campestrisfabH Deletion of fabG2 reduced DSF family signal production, whereas overproduction of either FabG1 or FabG2 in the ΔfabG2 strain restored DSF family signal levels.IMPORTANCE Quorum sensing mediated by DSF signaling molecules regulates pathogenesis in several different phytopathogenic bacteria, including Xanthomonas campestris pv. campestris DSF signaling also plays a key role in infection by the human pathogen Burkholderia cepacia The acyl chains of the DSF molecules are diverted and remodeled from a key intermediate of the fatty acid synthesis pathway. We report a Xanthomonas campestris pv. campestris fatty acid synthesis enzyme, FabG2, of novel specificity that seems tailored to provide DSF signaling molecule precursors.


Assuntos
Proteína de Transporte de Acila/metabolismo , Proteínas de Bactérias/metabolismo , Oxirredutases/metabolismo , Xanthomonas campestris/enzimologia , Proteína de Transporte de Acila/química , Proteína de Transporte de Acila/genética , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Regulação Bacteriana da Expressão Gênica , Dados de Sequência Molecular , Oxirredutases/química , Oxirredutases/genética , Alinhamento de Sequência , Transdução de Sinais , Xanthomonas campestris/genética , Xanthomonas campestris/crescimento & desenvolvimento
19.
Anesthesiology ; 129(2): 311-320, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29620575

RESUMO

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Pyroptosis, a type of proinflammatory programmed cell death, drives cytokine storm. Caspase-11-dependent macrophage pyroptosis contributes to mortality during sepsis. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling can amplify interleukin-1ß secretion in endotoxin-induced inflammation. Here, we hypothesized that S1PR2 signaling increases caspase-11-dependent macrophage pyroptosis and worsens Gram-negative sepsis outcome. METHODS: A Gram-negative sepsis model was induced through intraperitoneal injection of Escherichia coli. Primary peritoneal macrophages isolated from wild-type, S1pr2-deficient (S1pr2), or nucleotide-binding oligomerization domain-like receptor protein-3-deficient mice were treated with E. coli. Caspase-11 activation, macrophage pyroptosis, and Ras homolog gene family, member A-guanosine triphosphate levels were assessed in those cells. Additionally, monocyte caspase-4 (an analog of caspase-11) expression and its correlation with S1PR2 expression were determined in patients with Gram-negative sepsis (n = 11). RESULTS: Genetic deficiency of S1PR2 significantly improved survival rate (2/10 [20%] in wild-type vs. 7/10 [70%] in S1pr2, P = 0.004) and decreased peritoneal macrophage pyroptosis (pyroptosis rate: 35 ± 3% in wild-type vs. 10 ± 3% in S1pr2, P < 0.001). Decreased caspase-11 activation in S1PR2 deficiency cells contributed to the reduced macrophage pyroptosis. In addition, RhoA inhibitor abrogated the amplified caspase-11 activation in wild-type or S1PR2-overexpressing cells. In patients with Gram-negative sepsis, caspase-4 increased significantly in monocytes compared to nonseptic controls and was positively correlated with S1PR2 (r = 0.636, P = 0.035). CONCLUSIONS: S1PR2 deficiency decreased macrophage pyroptosis and improved survival in E. coli sepsis. These beneficial effects were attributed to the decreased caspase-11 activation of S1PR2-deficient macrophages. S1PR2 and caspase-11 may be promising new targets for treatment of sepsis.


Assuntos
Bacteriemia/metabolismo , Caspases/metabolismo , Escherichia coli , Macrófagos/metabolismo , Piroptose/fisiologia , Receptores de Lisoesfingolipídeo/deficiência , Animais , Bacteriemia/patologia , Células Cultivadas , Humanos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sepse/metabolismo , Sepse/patologia , Transdução de Sinais/fisiologia
20.
FASEB J ; 32(9): 4930-4940, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29634367

RESUMO

RING finger protein 4 (RNF4) is a multifunctional small ubiquitin-related modifier (SUMO)-targeted ubiquitin E3 ligase (STUbL) ubiquitously expressed in all tissues, and which mainly participates in DNA repair and in chromatin and transcriptional regulation. Although RNF4 has been implicated in hematopoietic disorders, its ontogenic role during hematopoietic development remains undiscovered. We generated a zebrafish rnf4 knockout line by using transcription activator-like effector nucleases technology to address the impact of rnf4 during hematopoiesis. Rnf4-deficient zebrafish embryos exhibited sharply decreased neutrophils numbers during both primitive and definitive hematopoiesis. Mechanistic studies revealed that repression of the key granulocytic activator, CCAAT/enhancer-binding protein α ( c/ebpα), via promoter hypermethylation by SUMOylated DNA methyltransferase 1 (DNMT1) was the main cause of impaired granulopoiesis in rnf4-deficient zebrafish. In addition, for the first time, we identified DNMT1 as a potential new STUbL substrate of RNF4, with knockdown of dnmt1 largely restoring primitive and definitive granulopoiesis in rnf4-deficient zebrafish. Collectively, RNF4 is indispensable for zebrafish granulopoiesis through regulation of the DNMT1-C/EBPα functional axis.-Wang, L., Liu, X., Wang, H., Yuan, H., Chen, S., Chen, Z., de The, H., Zhou, J., Zhu, J. RNF4 regulates zebrafish granulopoiesis through the DNMT1-C/EBPα axis.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Regulação da Expressão Gênica/genética , Mutação/genética , Proteínas Nucleares/genética , Proteína SUMO-1/metabolismo , Fatores de Transcrição/genética , Proteínas de Peixe-Zebra/metabolismo , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética , Reparo do DNA/genética , Hematopoese/genética , Humanos , Proteína SUMO-1/genética , Sumoilação/genética , Sumoilação/fisiologia , Fatores de Transcrição/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
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