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1.
Food Chem ; 305: 125461, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505412

RESUMO

The quality of fermented soybeans can be determined by diverse metabolites produced by microorganisms. Mass spectrometry-based metabolomic approach was applied to investigate the differences in volatile and non-volatile metabolite profiles of fermented soybeans by different microorganisms [e.g., molds, yeasts, lactic acid bacteria (LAB), and other bacteria]. The partial least squares-discriminant analysis (PLS-DA) for volatile metabolites profiles indicated that the fungi group (mold/yeast) was clearly discriminated from the bacteria group (bacteria/LAB). The metabolic pathways related to the formation of volatile metabolites also differed according to microorganisms. In particular, the formation of branched-chain aliphatic alcohols and esters increased in the fungi group, while that of volatiles derived from fatty acids was superior in the bacteria group. In addition, we could determine the microorganism-specific metabolites using a correlation network analysis. This study can provide the fundamental knowledge on the metabolic differences according to the type of microorganisms in fermented soybeans.

2.
Semin Immunopathol ; 41(5): 565-572, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31552471

RESUMO

Osteoclasts are bone-resorbing cells that play an essential role in the remodeling of the bone. Defects in osteoclasts thus result in unbalanced bone remodeling, leading to numerous pathological conditions such as osteoporosis, bone metastasis, and inflammatory bone erosion. Metabolism is any process a cell utilizes to meet its energetic demand for biological functions. Along with signaling pathways and osteoclast-specific gene expression programs, osteoclast differentiation activates metabolic programs. The energy generated from metabolic reprogramming in osteoclasts not only supports the phenotypic changes from mononuclear precursor cells to multinuclear osteoclasts, but also facilitates bone resorption, a major function of terminally differentiated, mature osteoclasts. While oxidative phosphorylation is studied as a major metabolic pathway that fulfills the energy demands of osteoclasts, all metabolic pathways are closely interconnected. Therefore, it remains important to understand the various aspects of osteoclast metabolism, including the roles and effects of glycolysis, glutaminolysis, fatty acid synthesis, and fatty acid oxidation. Targeting the pathways associated with metabolic reprogramming has shown beneficial effects on pathological conditions. As a result, it is clear that a deeper understanding of metabolic regulation in osteoclasts will offer broader translational potential for the treatment of human bone disorders.

3.
JAMA Dermatol ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31365038

RESUMO

Importance: Retinoids are bioactive forms of vitamin A that are essential in the maintenance of epithelial maturation and differentiation. Synthetic retinoids are used in chemoprevention of skin cancer among high-risk populations with potential adverse effects. Epidemiologic data on vitamin A intake and risk of cutaneous squamous cell carcinoma (SCC) are limited. Objective: To examine whether vitamin A intake is associated with a reduction in SCC risk. Design, Settings, and Participants: This cohort study prospectively examined intake of vitamin A and carotenoids and SCC risk in the Nurses' Health Study (1984-2012) and the Health Professionals Follow-up Study (1986-2012). Diet was assessed repeatedly. Incident SCC was confirmed by pathologic reports. Data analysis was performed from June 21, 2017, to December 4, 2018. Exposures: Intakes of vitamin A, retinol, and carotenoids. Main Outcomes and Measures: Incident SCC. Cox proportional hazards regression models were used to compute cohort-specific hazard ratios (HRs) and 95% CIs. Pooled HRs of the cohort-specific results were calculated. Results: A total of 3978 SCC cases in 75 170 women in the Nurses' Health Study (mean [SD] age, 50.4 [7.2] years) and 48 400 men in the Health Professionals Follow-up Study (mean [SD] age, 54.3 [9.9] years) were documented. Higher total vitamin A was associated with a reduction in SCC risk; with quintile 1 as the reference, the pooled multivariate HRs for the increasing quintiles of vitamin A intake were 0.97 (95% CI, 0.87-1.07) for quintile 2, 0.97 (95% CI, 0.80-1.17) for quintile 3, 0.93 (95% CI, 0.84-1.03) for quintile 4, and 0.83 (95% CI, 0.75-0.93) for quintile 5 (P < .001 for trend). Higher intakes of retinol and some carotenoids were also associated with a reduction in SCC risk; the pooled HRs for the highest quintiles of intake compared with the lowest quintiles were 0.88 (95% CI, 0.79-0.97; P = .001 for trend) for total retinol, 0.86 (95% CI, 0.76-0.96; P = .001 for trend) for beta cryptoxanthin, 0.87 (95% CI, 0.78-0.96; P < .001 for trend) for lycopene, and 0.89 (95% CI, 0.81-0.99; P = .02 for trend) for lutein and zeaxanthin. The results were generally consistent by sex and other SCC risk factors. Conclusions and Relevance: This study suggests that increased intake of dietary vitamin A is associated with decreased risk of incident SCC. Future studies are needed to determine whether vitamin A supplementation has a role in chemoprevention of SCC.

4.
Int J Food Microbiol ; 307: 108270, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31408740

RESUMO

Aspergillus oryzae is an important microbial starter for making diverse fermented foods due to its high hydrolytic enzyme activities. In this study, two strains of A. oryzae (AOB/AOK) with different activities of hydrolytic enzymes, such as α-amylase, protease and lipase, were cultured under various conditions of temperature, fermentation time, and initial pH. Comparative mass spectrometry (MS) based metabolomic analysis was performed to obtain primary metabolites and secondary volatile metabolite data sets. In the results of partial least square-discriminant analysis (PLS-DA), fatty acids and volatile metabolites derived from fatty acids and amino acids mainly contributed to AOK with higher protease and lipase activities, whereas carbohydrate-derived volatiles, sugars and sugar alcohols were related to main metabolites of AOB with higher α-amylase activity. The temperature and initial pH were critical factors for the generation of primary metabolites and secondary volatile metabolites, such as organic acids, fatty acids-derived volatiles, and some amino acids, in both A. oryzae strains. This study demonstrated that the specific culture conditions were closely linked to the formation of primary metabolites and secondary volatile metabolites of A. oryzae.


Assuntos
Aspergillus oryzae/metabolismo , Alimentos Fermentados/microbiologia , Metabolômica , Aspergillus oryzae/enzimologia , Fermentação , Concentração de Íons de Hidrogênio , Lipase/metabolismo , Compostos Orgânicos/análise , Compostos Orgânicos/metabolismo , Peptídeo Hidrolases/metabolismo , Temperatura Ambiente , alfa-Amilases/metabolismo
5.
Nat Commun ; 10(1): 3320, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346169

RESUMO

Activation of macrophage proinflammatory and antimicrobial phenotypes is regulated by IFN-γ and LPS via synergistic induction of canonical, inflammatory NF-κB target genes. However, whether IFN-γ negatively regulates components of the LPS response, and how this may affect macrophage activation, is still unclear. Here we use combined transcriptomic and epigenomic approaches to find that IFN-γ selectively abrogates LPS-induced feedback and alters macrophage metabolic pathways by suppressing TLR4-mediated gene activation. In contrast to superinduction of inflammatory genes via enhancers that bind IRF1 and STAT1, IFN-γ represses target enhancers that bind STAT3. TLR4-activated but IFN-γ-suppressed enhancers comprise two subsets discernable by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin. Our findings thus show that IFN-γ suppresses feedback inhibitory and metabolic components of TLR responses to enhance macrophage activation; they also provide insights for IFN-γ-mediated selective inhibition of TLR4-induced transcription. Such inhibition can contribute to severe and sustained inflammatory responses.

6.
Immunity ; 51(2): 241-257.e9, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31303399

RESUMO

Cytokine tumor necrosis factor (TNF)-mediated macrophage polarization is important for inflammatory disease pathogenesis, but the mechanisms regulating polarization are not clear. We performed transcriptomic and epigenomic analysis of the TNF response in primary human macrophages and revealed late-phase activation of SREBP2, the master regulator of cholesterol biosynthesis genes. TNF stimulation extended the genomic profile of SREBP2 occupancy to include binding to and activation of inflammatory and interferon response genes independently of its functions in sterol metabolism. Genetic ablation of SREBP function shifted the balance of macrophage polarization from an inflammatory to a reparative phenotype in peritonitis and skin wound healing models. Genetic ablation of SREBP activity in myeloid cells or topical pharmacological inhibition of SREBP improved skin wound healing under homeostatic and chronic inflammatory conditions. Our results identify a function and mechanism of action for SREBPs in augmenting TNF-induced macrophage activation and inflammation and open therapeutic avenues for promoting wound repair.

7.
Molecules ; 24(11)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195658

RESUMO

Rice has been fermented to enhance its application in some foods. Although various microbes are involved in rice fermentation, their roles in the formation of volatile compounds, which are important to the characteristics of fermented rice, are not clear. In this study, diverse approaches, such as partial least squares-discriminant analysis (PLS-DA), metabolic pathway-based volatile compound formations, and correlation analysis between volatile compounds and microbes were applied to compare metabolic characteristics according to each microbe and determine microbe-specific metabolites in fermented rice inoculated by molds, yeasts, and lactic acid bacteria. Metabolic changes were relatively more activated in fermented rice inoculated by molds compared to other microbes. Volatile compound profiles were significantly changed depending on each microbe as well as the group of microbes. Regarding some metabolic pathways, such as carbohydrates, amino acids, and fatty acids, it could be observed that certain formation pathways of volatile compounds were closely linked with the type of microbes. Also, some volatile compounds were strongly correlated to specific microbes; for example, branched-chain volatiles were closely link to Aspergillus oryzae, while Lactobacillus plantarum had strong relationship with acetic acid in fermented rice. This study can provide an insight into the effects of fermentative microbes on the formation of volatile compounds in rice fermentation.


Assuntos
Fermentação , Lactobacillales/metabolismo , Oryza/química , Compostos Orgânicos Voláteis/metabolismo , Leveduras/metabolismo , Análise Discriminante , Análise dos Mínimos Quadrados , Redes e Vias Metabólicas , Metaboloma
8.
Nat Rev Rheumatol ; 15(6): 327-339, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31000790

RESUMO

Rheumatic diseases have complex aetiologies that are not fully understood, which makes the study of pathogenic mechanisms in these diseases a challenge for researchers. Next-generation sequencing (NGS) and related omics technologies, such as transcriptomics, epigenomics and genomics, provide an unprecedented genome-wide view of gene expression, environmentally responsive epigenetic changes and genetic variation. The integrated application of NGS technologies to samples from carefully phenotyped clinical cohorts of patients has the potential to solve remaining mysteries in the pathogenesis of several rheumatic diseases, to identify new therapeutic targets and to underpin a precision medicine approach to the diagnosis and treatment of rheumatic diseases. This Review provides an overview of the NGS technologies available, showcases important advances in rheumatic disease research already powered by these technologies and highlights NGS approaches that hold particular promise for generating new insights and advancing the field.

9.
J Microbiol Biotechnol ; 28(8): 1260-1269, 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30301311

RESUMO

Production of good Koji primarily depends upon the selection of substrate materials and fermentative microflora, which together influence the characteristic flavor and aroma. Herein, we performed comparative metabolomic analyses of volatile organic compounds (VOCs) and primary metabolites for Koji samples fermented individually with Bacillus amyloliquefaciens and Aspergillus oryzae. The VOCs and primary metabolites were analyzed using headspace solid phase microextraction (HS-SPME) followed by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). In particular, alcohols, ketones, and furans were mainly detected in Bacillus-fermented Koji (Bacillus Koji, BK), potentially due to the increased levels of lipid oxidation. A cheesy and rancid flavor was characteristic of Bacillus Koji, which is attributable to high content of typical 'off-flavor' compounds. Furthermore, the umami taste engendered by 2-methoxyphenol, (E,E)-2,4-decadienal, and glutamic acid was primarily detected in Bacillus Koji. Alternatively, malty flavor compounds (2-methylpropanal, 2-methylbutanal, 3-methylbutanal) and sweet flavor compounds (monosaccharides and maltol) were relatively abundant in Aspergillus-fermented Koji (Aspergillus Koji, AK). Hence, we argue that the VOC profile of Koji is largely determined by the rational choice of inocula, which modifies the primary metabolomes in Koji substrates, potentially shaping its volatolome as well as the aroma characteristics.


Assuntos
Aspergillus oryzae/metabolismo , Bacillus amyloliquefaciens/metabolismo , Fermentação , Aromatizantes/análise , Compostos Orgânicos Voláteis/análise , Antioxidantes/metabolismo , Aromatizantes/química , Cromatografia Gasosa-Espectrometria de Massas , Redes e Vias Metabólicas , Metabolômica/métodos , Microextração em Fase Sólida , Soja/metabolismo , Fatores de Tempo , Triticum/metabolismo , Compostos Orgânicos Voláteis/química
10.
Cancer Epidemiol Biomarkers Prev ; 27(7): 776-782, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29636341

RESUMO

Background: Fat intake has been associated with certain cancers, including colorectal, breast, and prostate cancers. However, literature on dietary fat and skin cancer has been limited.Methods: We examined the association between fat intake and risk of skin cancer including cutaneous malignant melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) within two prospective studies: the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Dietary information on total, saturated, monounsaturated, polyunsaturated, omega-6, and omega-3 fat and cholesterol was repeatedly assessed generally every 4 years. Incident cases were identified by self-report. Diagnosis on melanoma and SCC was confirmed by pathologic records.Results: A total of 794 melanoma, 2,223 SCC, and 17,556 BCC in the NHS (1984-2012) and 736 melanoma, 1,756 SCC, and 13,092 BCC in the HPFS (1986-2012) were documented. Higher polyunsaturated fat intake was associated with risk of SCC [pooled HR for highest vs. lowest quintiles, 1.16; 95% confidence interval (CI), 1.05-1.28; Ptrend=0.001] and BCC (pooled HR, 1.06; 95% CI, 1.01-1.11; Ptrend=0.01). Higher omega-6 fat intake was associated with risks of SCC, BCC, and melanoma. Omega-3 fat intake was associated with risk of BCC, but not with SCC or melanoma. No other fats were associated with melanoma risk. The associations were similar in women and men and by other skin cancer risk factors.Conclusions: Polyunsaturated fat intake was modestly associated with skin cancer risk.Impact: Further studies are needed to confirm our findings and to identify relevant biological mechanisms. Cancer Epidemiol Biomarkers Prev; 27(7); 776-82. ©2018 AACR.

11.
Cell Mol Life Sci ; 75(14): 2519-2528, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29670999

RESUMO

Osteoclasts are bone-resorbing cells that play an essential role in bone remodeling. Defects in osteoclasts result in unbalanced bone remodeling and are linked to many bone diseases including osteoporosis, rheumatoid arthritis, primary bone cancer, and skeletal metastases. Receptor activator of NF-kappaB ligand (RANKL) is a classical inducer of osteoclast formation. In the presence of macrophage-colony-stimulating factor, RANKL and co-stimulatory signals synergistically regulate osteoclastogenesis. However, recent discoveries of alternative pathways for RANKL-independent osteoclastogenesis have led to a reassessment of the traditional mechanisms that regulate osteoclast formation. In this review, we provide an overview of signaling pathways and other regulatory elements governing osteoclastogenesis. We also identify how osteoclastogenesis is altered in pathological conditions and discuss therapeutic targets in osteoclasts for the treatment of skeletal diseases.


Assuntos
Remodelação Óssea , Reabsorção Óssea/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese , Animais , Doenças Ósseas/metabolismo , Humanos , Modelos Biológicos , Transdução de Sinais
12.
Psychiatry Investig ; 15(2): 186-192, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29475220

RESUMO

OBJECTIVE: In the current study, we investigated whether there are relations among depressive symptoms, cognitive performance and serum BDNF levels in the patients with chronic kidney disease (CKD). METHODS: Sixty patients with CKD and 65 healthy controls participated. Depressive symptoms were evaluated with Beck depression inventory (BDI) and Hamilton Depression Rating Scale (HDRS). Mini-Mental State Examination included in the Korean version of the Consortium to Establish a Registry for Alzheimer's disease (MMSE-KC) assessment packet was used for the evaluation of overall cognitive function. To assess memory function, the Korean version of the Hopkins Verbal Learning Test (K-HVLT) was used. BDNF levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: The CKD patients showed more depressive symptoms when compared with controls. The depressive symptoms and cognitive function were not associated with serum BDNF levels in the CKD patients. CONCLUSION: In the current study, CKD patients had more depressive symptoms when compared controls. However, the serum BDNF levels of CKD patients were not associated with depressive symptoms and cognitive functions. These findings suggested that the serum BDNF levels may not be reflect the cognitive function and depressive mood state in the CKD patients.

13.
J Investig Dermatol Symp Proc ; 19(1): S47-S50, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29273106

RESUMO

Few studies have examined the clinical epidemiology of alopecia areata (AA) in regard to patient race, and therefore, any disparities in incidence or prevalence of disease are largely unexplored. We sought to investigate potential racial disparities amongst two large cohorts of women. We conducted a cross-sectional analysis from the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII), wherein participants self-reported a diagnosis of AA. We determined odds ratios for AA by race in a multivariate analysis. Among 63,960 women from NHS and 88,368 women from NHSII with information on race and diagnosis of AA, we identified 418 and 738 cases of AA, respectively. In NHS, the multivariate-adjusted odds ratio for AA was 2.72 (95% confidence interval 1.61-4.61) amongst black women as compared with white women. In NHSII, the multivariate-adjusted odds ratio was 5.48 (95% confidence interval 4.10-7.32) amongst black as compared with white women. In a secondary analysis designating participants by Hispanic ethnicity, in NHSII the multivariate odds ratio was 1.94 (95% CI 1.24-3.02) in Hispanic compared with non-Hispanic white women. In this study, we found increased odds of AA based on self-reported race in black and Hispanic women as compared with white women. Further studies are needed to explore the mechanism of this racial disparity related to AA.

14.
Eur J Nutr ; 57(3): 1045-1057, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28275868

RESUMO

PURPOSE: To examine meal patterns in terms of frequency and circadian timing of eating in five European countries participating in the EFCOVAL project. METHODS: In this cross-sectional study, 559 men and women, aged 44-65 years, were recruited in Belgium, the Czech Republic, France (Southern part), The Netherlands, and Norway. Dietary data were collected by trained interviewers using standardized computerised 24-h recalls (GloboDiet). Means ± SE of (1) eating frequency, (2) overnight fasting, and (3) time between eating occasions were estimated by country using means from 2 days of 24-h recalls. We also estimated the frequency of eating occasions per hour by country as well as the proportional energy intake of meals/snacks by country compared to the mean energy intake of all countries. RESULTS: Mean eating frequency ranged from 4.3 times/day in France to 7.1 times/day in The Netherlands (p < 0.05). Mean overnight fasting was shortest in the Netherlands (9.2 h) and longest in Czech Republic (10.9 h) (p < 0.05). Mean time between single eating occasions was shortest in The Netherlands (2.4 h) and longest in France (4.3 h) (p < 0.05). Different patterns of energy intake by meals and snacks throughout the day were observed across the five countries. CONCLUSIONS: We observed distinct differences in meal patterns across the five European countries included in the current study in terms of frequency and circadian timing of eating, and the proportion of energy intake from eating occasions.


Assuntos
Ingestão de Energia , Comportamento Alimentar , Dieta Saudável , Estilo de Vida Saudável , Refeições , Cooperação do Paciente , Lanches , Adulto , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/etnologia , Ritmo Circadiano , Estudos Transversais , Escolaridade , Ingestão de Energia/etnologia , Europa (Continente) , Comportamento Alimentar/etnologia , Dieta Saudável/etnologia , Humanos , Refeições/etnologia , Pessoa de Meia-Idade , Inquéritos Nutricionais , Cooperação do Paciente/etnologia , Autorrelato , Fumar/efeitos adversos , Fumar/etnologia , Lanches/etnologia , Terminologia como Assunto
15.
JCI Insight ; 2(22)2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-29202453

RESUMO

While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for CaV1.2 L-type voltage-gated Ca2+ channels in osteogenesis and exploit a transgenic gain-of-function mutant CaV1.2 to stem bone loss in ovariectomized female mice. We show that endogenous CaV1.2 is expressed in developing bone within proliferating chondrocytes and osteoblasts. Using primary BM stromal cell (BMSC) cultures, we found that Ca2+ influx through CaV1.2 activates osteogenic transcriptional programs and promotes mineralization. We used Prx1-, Col2a1-, or Col1a1-Cre drivers to express an inactivation-deficient CaV1.2 mutant in chondrogenic and/or osteogenic precursors in vivo and found that the resulting increased Ca2+ influx markedly thickened bone not only by promoting osteogenesis, but also by inhibiting osteoclast activity through increased osteoprotegerin secretion from osteoblasts. Activating the CaV1.2 mutant in osteoblasts at the time of ovariectomy stemmed bone loss. Together, these data highlight roles for CaV1.2 in bone and demonstrate the potential dual anabolic and anticatabolic therapeutic actions of tissue-specific CaV1.2 activation in osteoblasts.

16.
Sci Rep ; 7(1): 17360, 2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29234060

RESUMO

Lactic acid bacteria (LAB) are the common probiotics. Here, we investigated the antiviral protective effects of heat-killed LAB strain Lactobacillus casei DK128 (DK128) on influenza viruses. Intranasal treatment of mice with DK128 conferred protection against different subtypes of influenza viruses by lessening weight loss and lowering viral loads. Protection via heat-killed DK128 was correlated with an increase in alveolar macrophage cells in the lungs and airways, early induction of virus specific antibodies, reduced levels of pro-inflammatory cytokines and innate immune cells. Importantly, the mice that were protected against primary viral infection as a result of heat-killed DK128 pretreatment developed subsequent heterosubtypic immunity against secondary virus infection. For protection against influenza virus via heat-killed DK128 pretreatment, B cells and partially CD4 T cells but not CD8 T cells were required as inferred from studies using knockout mouse models. Our study provides insight into how hosts can be equipped with innate and adaptive immunity via heat-killed DK128 treatment to protect against influenza virus, supporting that heat-killed LAB may be developed as anti-virus probiotics.

17.
Nat Immunol ; 18(10): 1104-1116, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28825701

RESUMO

Cross-regulation of Toll-like receptor (TLR) responses by cytokines is essential for effective host defense, avoidance of toxicity and homeostasis, but the underlying mechanisms are not well understood. Our comprehensive epigenomics approach to the analysis of human macrophages showed that the proinflammatory cytokines TNF and type I interferons induced transcriptional cascades that altered chromatin states to broadly reprogram responses induced by TLR4. TNF tolerized genes encoding inflammatory molecules to prevent toxicity while preserving the induction of genes encoding antiviral and metabolic molecules. Type I interferons potentiated the inflammatory function of TNF by priming chromatin to prevent the silencing of target genes of the transcription factor NF-κB that encode inflammatory molecules. The priming of chromatin enabled robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings reveal that signaling crosstalk between interferons and TNF is integrated at the level of chromatin to reprogram inflammatory responses, and identify previously unknown functions and mechanisms of action of these cytokines.


Assuntos
Epigênese Genética , Inflamação/etiologia , Inflamação/metabolismo , Interferon Tipo I/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Sítios de Ligação , Montagem e Desmontagem da Cromatina , Imunoprecipitação da Cromatina , Análise por Conglomerados , Biologia Computacional/métodos , Citocinas/genética , Citocinas/metabolismo , Epigenômica/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lipopolissacarídeos/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Motivos de Nucleotídeos , Regiões Promotoras Genéticas , Ligação Proteica , Transporte Proteico , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fatores de Transcrição/metabolismo
18.
Immunity ; 47(2): 235-250.e4, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28813657

RESUMO

Mechanisms by which interferon (IFN)-γ activates genes to promote macrophage activation are well studied, but little is known about mechanisms and functions of IFN-γ-mediated gene repression. We used an integrated transcriptomic and epigenomic approach to analyze chromatin accessibility, histone modifications, transcription-factor binding, and gene expression in IFN-γ-primed human macrophages. IFN-γ suppressed basal expression of genes corresponding to an "M2"-like homeostatic and reparative phenotype. IFN-γ repressed genes by suppressing the function of enhancers enriched for binding by transcription factor MAF. Mechanistically, IFN-γ disassembled a subset of enhancers by inducing coordinate suppression of binding by MAF, lineage-determining transcription factors, and chromatin accessibility. Genes associated with MAF-binding enhancers were suppressed in macrophages isolated from rheumatoid-arthritis patients, revealing a disease-associated signature of IFN-γ-mediated repression. These results identify enhancer inactivation and disassembly as a mechanism of IFN-γ-mediated gene repression and reveal that MAF regulates the macrophage enhancer landscape and is suppressed by IFN-γ to augment macrophage activation.


Assuntos
Artrite Reumatoide/imunologia , Montagem e Desmontagem da Cromatina , Interferon gama/metabolismo , Macrófagos/imunologia , Proteínas Proto-Oncogênicas c-maf/metabolismo , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Citocinas/metabolismo , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica , Histonas/metabolismo , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-maf/genética , Transcriptoma
19.
Immunity ; 47(1): 66-79.e5, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28723554

RESUMO

Hypoxia augments inflammatory responses and osteoclastogenesis by incompletely understood mechanisms. We identified COMMD1 as a cell-intrinsic negative regulator of osteoclastogenesis that is suppressed by hypoxia. In human macrophages, COMMD1 restrained induction of NF-κB signaling and a transcription factor E2F1-dependent metabolic pathway by the cytokine RANKL. Downregulation of COMMD1 protein expression by hypoxia augmented RANKL-induced expression of inflammatory and E2F1 target genes and downstream osteoclastogenesis. E2F1 targets included glycolysis and metabolic genes including CKB that enabled cells to meet metabolic demands in challenging environments, as well as inflammatory cytokine-driven target genes. Expression quantitative trait locus analysis linked increased COMMD1 expression with decreased bone erosion in rheumatoid arthritis. Myeloid deletion of Commd1 resulted in increased osteoclastogenesis in arthritis and inflammatory osteolysis models. These results identify COMMD1 and an E2F-metabolic pathway as key regulators of osteoclastogenic responses under pathological inflammatory conditions and provide a mechanism by which hypoxia augments inflammation and bone destruction.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Artrite Reumatoide/imunologia , Macrófagos/imunologia , Osteogênese/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Fator de Transcrição E2F1/metabolismo , Feminino , Humanos , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , NF-kappa B/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais
20.
Korean J Anesthesiol ; 70(3): 345-349, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28580087

RESUMO

Malignant hyperthermia (MH) may lead to metabolic crisis of skeletal muscle in susceptible individuals following exposure to triggering agents such as volatile anesthetics or depolarizing muscle relaxants. MH is a rare and a potentially lethal disease, which can lead to cardiac arrest. We report a case of severe MH, in which the rapidly evolving signs of hypermetabolism eventually resulted in cardiac arrest. Despite conventional treatments following cardiopulmonary resuscitation, the patient's vital signs did not improve. Therefore, we applied extracorporeal membrane oxygenation for providing hemodynamic support.

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