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1.
Gene ; 772: 145382, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33373661

RESUMO

Copy number variation (CNV) is a structural variation at the submicroscopic level of the genome, which can affect gene-related phenotypes by changing genes dosage and transcript structure. Hematopoietic prostaglandin D synthase (HPGDS) is a member whose functions are closely related to weight gain and inflammatory diseases of the glutathione S-transferase (GSTs) family. In this study, the growth characteristics (body weight, withers height, body length, and chest girth) of 336 Ashidan yaks were monitored at four stages (6 months, 12 months, 18 months, and 30 months). In addition, CNV of the HPGDS gene was detected, discovered relationships of CNV with growth traits, and explored the level of gene expression. Based on the statistical analysis by IBM SPSS software, significant correlations were observed between HPGDS-CNV and body weight in 12-month-old yak (P < 0.01), 18-month-old yak (P < 0.001) and 30-month-old yak (P < 0.001) and body length in 18-month-old yak (P < 0.05) and 30-month-old yak (P < 0.05), respectively. Additionally, the individuals with gain copy number type performed better in body weight and body length than those with normal or loss copy number type. To our best of knowledge, this is the first time to make efforts to probe into the role of HPGDS-CNV and its interaction with livestock growth traits. Our results suggested that the CNV of the HPGDS gene may be an active candidate gene for the marker-assisted selection (MAS) of yaks.


Assuntos
Bovinos/crescimento & desenvolvimento , Variações do Número de Cópias de DNA , Oxirredutases Intramoleculares/genética , Locos de Características Quantitativas , Animais , Peso Corporal , Cruzamento , Bovinos/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética/veterinária , Fenótipo
2.
BMC Med Genet ; 21(1): 201, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046033

RESUMO

BACKGROUND: CDKN2A hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between CDKN2A methylation status and MIF polymorphisms (rs755622 and rs5844572). METHODS: One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14ARF and p16INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP. RESULTS: We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated p14ARF or p16INK4a. Carrying the rs755622 C allele indicated a significantly higher risk for p14ARF methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08-4.32; p = 0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16INK4a methylation (OR, 2.57; 95% CI, 1.26-5.24; p = 0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both p14ARF and p16INK4a when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22-6.01; p = 0.015 and OR, 2.87; 95% CI, 1.25-6.62; p = 0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55-262.6; p = 0.0059 and OR, 4.38; 95% CI, 1.12-17.2; p = 0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46-144.3; p = 0.022). CONCLUSIONS: Taken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hypermethylation in patients diagnosed with UC.


Assuntos
Colite Ulcerativa/genética , Ilhas de CpG/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Colite Ulcerativa/diagnóstico , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
3.
PLoS One ; 15(8): e0237577, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790741

RESUMO

Abnormal skin melanin homeostasis results in refractory pigmentary diseases. Melanogenesis is influenced by gene regulation, ultraviolet radiation, and host epigenetic responses. Steroid receptor RNA activator (SRA), a long noncoding RNA, is known to regulate steroidogenesis and tumorigenesis. However, how SRA contributes to melanogenesis remains unknown. Using RNA interference against SRA in B16 and A375 melanoma cells, we observed increased pigmentation and increased expression of TRP1 and TRP2 at transcriptional and translational levels only in B16 cells. The constitutive phosphorylation of p38 in B16-shCtrl cells was inhibited in cells with knocked down SRAi. Moreover, the melanin content of control B16 cells was increased by SB202190, a p38 inhibitor. Furthermore, reduced p38 phosphorylation, enhanced TRP1 expression, and hypermelanosis were observed in A375 cells with RNA interference. These results indicate that SRA-p38-TRP1 axis has a regulatory role in melanin homeostasis and that SRA might be a potential therapeutic target for treating pigmentary diseases.


Assuntos
Oxirredutases Intramoleculares/metabolismo , Melaninas/metabolismo , Melanoma Experimental/patologia , Glicoproteínas de Membrana/metabolismo , Oxirredutases/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Regulação Neoplásica da Expressão Gênica , Oxirredutases Intramoleculares/genética , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Oxirredutases/genética , Fosforilação , RNA Longo não Codificante/genética , RNA Interferente Pequeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
4.
PLoS One ; 15(6): e0234565, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32525926

RESUMO

PURPOSE: The establishment of candidate genes associated with susceptibility to TB is a challenge especially due to divergent frequencies among different populations. The objective of this study was to evaluate the association between macrophage migration inhibitory factor (MIF) -173 G>C single nucleotide polymorphism (SNP) and susceptibility to pulmonary TB in a population of southern Brazil. METHODS: Case-control study. Patients > 18 years old, diagnosed with pulmonary TB were included. The control group consisted of blood donors and household contacts, not relatives, healthy and > 18 years old. MIF -173 G>C SNPs were genotyped using real-time PCR using a TaqMan SNP Genotyping assay. RESULTS: 174 patients and 166 controls were included. There were no statistically significant differences between cases and controls regarding genotype prevalence (p>0.05). Comparing patients with normal genotype (GG) with those with at least one C allele, there was also no statistically significant difference (p = 0.135). Also, there was no statistically significant difference comparing the homozygous for the mutation (CC) with the other patients (GG and CG) (p = 0.864). CONCLUSIONS: We did not find association between MIF -173 G>C polymorphism and susceptibility to pulmonary TB.


Assuntos
Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único , Tuberculose Pulmonar/genética , Adolescente , Adulto , Idoso , Brasil , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose Pulmonar/patologia
5.
Zhonghua Zhong Liu Za Zhi ; 42(4): 312-318, 2020 Apr 23.
Artigo em Chinês | MEDLINE | ID: mdl-32375447

RESUMO

Objective: To investigate the effect and mechanism of miR-451 on the proliferation and migration of human colorectal cancer cell SW480 by targeting macrophage migration inhibitory factor (MIF). Methods: Microarray analysis was used to screen differentially expressed microRNAs and messenger RNA in SW480 cells. Real-time quantitative PCR (RT-qPCR) was used to detect the expressions of miR-451 and MIF in SW480 cells before and after transfection. Cell clone formation assay and Transwell assay were used to detect the proliferation and invasion of SW480 cells, respectively. Cell scratch assay was used to detect the migration ability of SW480 cells. The TargetScan database was used to analyze the correlation between miR-451 and MIF. Dual luciferase reporter gene was used to detect the interaction of miR-451 and MIF. MTT assay was used to detect the viability of SW480 cells. Results: Compared with human normal colorectal mucosal cell FHC (1.00), the expression of miR-451 was down-regulated in SW480 cells ( 0.36±0.18, P<0.001). Knockdown of miR-451 promoted proliferation, and migration of SW480 cells. Compared with that in FHC cells, MIF expression was up-regulated in SW480 cells (2.28±0.45, P<0.001). MIF down-regulation inhibited SW480 cell proliferation, invasion and migration. MiR-451 specifically bind to the MIF 3'UTR and regulated the expression of MIF. Overexpression of miR-451 reduced while overexpression of MIF increased the viability of SW480 cells. Overexpression of MIF promoted the proliferation and migration of SW480 cells (P<0.01), reversed the effect of miR-451 suppressed proliferation and migration of SW480 cells. Conclusion: MiR-451 may regulate proliferation and migration of human colorectal cancer cells by targeting MIF.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , MicroRNAs/genética , Invasividade Neoplásica
6.
Sci Rep ; 10(1): 6741, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317702

RESUMO

This study sought to investigate the biological effects of specific MIF inhibitor, ISO-1, on the proliferation, migration and invasion of PANC-1 human pancreatic cells in vitro, and on tumour growth in a xenograft tumour model in vivo. The effect of ISO-1 on PANC-1 cell proliferation was examined using CCK-8 cell proliferation assay. The effect of ISO-1 on collective cell migration and recolonization of PANC-1 cells was evaluated using the cell-wound closure migration assay. The effect of ISO-1 on the migration and invasion of individual PANC-1 cells in a 3-dimensional environment in response to a chemo-attractant was investigated through the use of Transwell migration/invasion assays. Quantitative real time PCR and western blot analyses were employed to investigate the effects of ISO-1 on MIF, NF-κB p65 and TNF-α mRNA and protein expression respectively. Finally, a xenograft tumor model in BALB/c nude mice were used to assess the in vivo effects of ISO-1 on PANC-1-induced tumor growth. We found high expression of MIF in pancreatic cancer tissues. We demonstrated that ISO-1 exerts anti-cancer effects on PANC-1 cell proliferation, migration and invasion in vitro, and inhibited PANC-1 cell-induced tumour growth in xenograft mice in vivo. Our data suggests that ISO-1 and its derivative may have potential therapeutic applications in pancreatic cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica , Oxirredutases Intramoleculares/genética , Isoxazóis/farmacologia , Fatores Inibidores da Migração de Macrófagos/genética , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Bioensaio , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cultura em Câmaras de Difusão , Feminino , Humanos , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Carga Tumoral/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Clin Neurosci ; 78: 264-268, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32279906

RESUMO

The aim of this study to investigate the genetic polymorphisms in macrophage inhibitory factor (MIF) and mannose-binding lectin 2 (MBL2) gene in schizophrenia (SCZ) or bipolar disorder (BD) patients with attempted suicide by comparing with a non-attempted SCZ or BD patients and healthy controls. A sample of 108 patients with SCZ, 100 patients with BD and 100 healthy volunteers were included in the study. SCID-I was used to confirm the diagnosis according to DSM-IV-TR criteria. The patients were evaluated by data forms that included sociodemographic, suicidal behavior and symptom severity information. PCR-RFLP was used to determine MIF and MBL2 gene polymorphisms from DNA material. Our results demonstrated that the distributions of MBL2 genotype (AA, AB, BB), combined genotype (AA, AB/BB) and the allele frequencies (A, B) of attempted suicide patients in SCZ were significantly different from the non-attempted SCZ patients. The distributions of the MBL2 genotype of attempted suicide patients in SCZ were significantly different from the control group. The distributions of MIF genotype (GG, GC, CC), combined genotype (GG, GC/CC) and the allele frequencies (G, C) of attempted suicide patients in BD were significantly different from the non-attempted BD patients or control group. In summary MBL2 gene polymorphism may be associated with attempted suicide in SCZ and MIF gene polymorphism might be associated with attempted suicide in BD. However, further studies with other gene variants in different ethnic populations are needed to address the exact role of these polymorphisms in SCZ or BD.


Assuntos
Transtorno Bipolar/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Lectina de Ligação a Manose/genética , Polimorfismo Genético/genética , Esquizofrenia/genética , Tentativa de Suicídio , Adulto , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Tentativa de Suicídio/psicologia
8.
Appl Immunohistochem Mol Morphol ; 28(2): 111-122, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32044879

RESUMO

Genome-wide screening of transcriptional changes among normal, cancer, and nodal metastases provides insights into the molecular basis of breast cancer (BC) progression and metastasis. To identify transcriptional changes and differentially expressed genes (DEGs) in the metastatic progression of BC and to determine the prognostic role of these DEGs in clinical outcome, we compared transcriptome profiling in matched normal, cancer, and lymph node metastatic tissues of 7 patients with estrogen receptor-positive, HER2-negative BC by using massive parallel RNA sequencing. The global profiles of gene expression in cancer and nodal metastases were highly correlated (r=0.962, P<0.001). In 6 (85.8%) patients, cancer and corresponding nodal metastases from the same patient clustered together. We identified 1522 and 664 DEGs between normal and cancer and between cancer and nodal metastases, respectively. The DEGs in normal versus cancer and cancer versus nodal metastases were significantly clustered in 1 and 8 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, respectively. The chemokine signaling pathway was the most significant pathway in the cancer-to-nodal metastasis transition (false discovery rate=2.15E-13). The expression of 2 dysregulated RAC2 and PTGDS genes was confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry. Interestingly, the lower RAC2 and PTGDS expression were associated with significantly worse disease-free survival in patients with BC. Our results show a high concordance of gene expression in BC and their nodal metastases, and identify DEGs associated with the metastatic progression of BC. The DEGs identified in this study represent novel biomarkers for predicting the prognosis of patients with BC.


Assuntos
Neoplasias da Mama , Regulação Neoplásica da Expressão Gênica , Oxirredutases Intramoleculares/biossíntese , Proteínas de Neoplasias/biossíntese , Proteínas rac de Ligação ao GTP/biossíntese , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Oxirredutases Intramoleculares/genética , Metástase Linfática , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Valor Preditivo dos Testes , Taxa de Sobrevida , Proteínas rac de Ligação ao GTP/genética
9.
Biochem Biophys Res Commun ; 523(3): 719-725, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31948762

RESUMO

Parthanatos is a form of regulated cell death (RCD) that is closely linked to DNA damage, which is a common consequence of oxidative stress due to central nervous trauma, such as spinal cord injury (SCI). The mechanism by which apoptosis-inducing factor (AIF) mediates DNA strand breaks in parthanatos was not clear until the discovery of the nuclease function of MIF. A previous study suggested that observed results may not be reliable if the oxidative stress induced in cells observed under experimental pathological conditions does not accurately replicate the specific pathologies being studied. According to an earlier direct measurement of extracellular oxidative stress in a rat SCI model, post-SCI oxidative stress was approximately the same as exposure to 150 µM H2O2. However, this concentration has been reported as sublethal oxidative stress in other cell types related to senescence, apoptosis, and parthanatos. Using sublethal H2O2 concentrations to induce oxidative stress is equivocal. Also, different cell types have diverse tolerances and responses to oxidative stress, and, therefore, exposure to H2O2. To avoid these limitations, the present study explored the mechanism of neuronal death under this simulated post-SCI oxidative stress and determined the effects of MIF knockdown in parthanatos associated with SCI. Immunofluorescence and flow cytometry were used to reveal typical characteristics of parthanatos that were blocked by PARP-1 inhibitors but not caspase inhibitors. In addition to classic features like PARP-1 and caspase-3 cleavage that were absent, we determined that parthanatos instead of apoptosis played a major role in the cell death caused by oxidative stress following SCI. Flow cytometry analysis of cells transfected by adenovirus with MIF-shRNA then exposed to H2O2 showed a significant decrease in cell death for MIF knockdown cells, even after AIF nuclear translocation. The comet assay also displayed significantly fewer DNA strand breaks after MIF knockdown. This is the first study has verified that MIF knockdown enables to protect neurons from parthanatos under a simulated in vivo oxidative stress following SCI. It suggests that MIF knockdown is a promising therapy to rescue neurons suffering from oxidative stress-induced SCI pathology.


Assuntos
Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Neurônios/metabolismo , Estresse Oxidativo , Parthanatos , Traumatismos da Medula Espinal/genética , Animais , Linhagem Celular , Movimento Celular , Técnicas de Silenciamento de Genes , Terapia Genética , Camundongos , Neurônios/citologia , Neurônios/patologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia
10.
Sci Rep ; 10(1): 140, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924846

RESUMO

Macrophage migration inhibitory factor (MIF) has been recognized as a major player in the pathogenesis of atherosclerosis. This study determined the association between polymorphisms of MIF gene and acute coronary syndrome (ACS). The polymorphism of MIF gene (rs755622, rs1007888 and rs2096525) was analyzed in 1153 healthy controls and 699 ACS cases in Chinese Han population. Plasma MIF level was also measured in part of ACS patients (139/19.9%) and healthy controls (129/11.2%) randomly. Most participants including healthy controls and ACS patients carried rs755622 GG (63.1% vs. 56.7%) and CG genotypes (33.1% vs. 38.9%) and G allele of rs755622 (79.6% vs. 76.1%, respectively), while CC genotype (3.8% vs. 4.4%) and C allele (20.4% vs. 23.9%) carriers were the lowest. Multivariate logistic regression analysis showed that carriers with rs755622 C allele had a higher risk of ACS compared to other genotypes (AOR = 1.278, 95% CI: 1.042-1.567). In addition, CC genotype carriers had the highest plasma levels of MIF than other genotype carriers. The MIF level in ACS patients with CC genotype was significantly higher than ACS patients carrying GG genotype and healthy controls carrying 3 different genotypes of MIF gene rs755622. Our findings indicate that MIF gene rs755622 variant C allele is associated with increased risk of ACS. Identification of this MIF gene polymorphism may help for predicting the risk of ACS.


Assuntos
Síndrome Coronariana Aguda/genética , Grupos Étnicos/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único , Síndrome Coronariana Aguda/sangue , Estudos de Casos e Controles , China/etnologia , Feminino , Genótipo , Humanos , Oxirredutases Intramoleculares/sangue , Fatores Inibidores da Migração de Macrófagos/sangue , Masculino , Pessoa de Meia-Idade
11.
Molecules ; 25(2)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936865

RESUMO

Recent preclinical and clinical observations have offered relevant insights on the etiopathogenesis of late onset Alzheimer's disease (AD) and upregulated immunoinflammatory events have been described as underlying mechanisms involved in the development of AD. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by several cells of the innate and adaptive immune system, as well as non-immune cells. In the present review, we highlight experimental, genetic, and clinical studies on MIF in rodent models of AD and AD patients, and we discuss emerging therapeutic opportunities for tailored modulation of the activity of MIF, that may potentially be applied to AD patients. Dismantling the exact role of MIF and its receptors in AD may offer novel diagnostic and therapeutic opportunities in AD.


Assuntos
Doença de Alzheimer , Oxirredutases Intramoleculares , Fatores Inibidores da Migração de Macrófagos , Receptores Imunológicos , Regulação para Cima/imunologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/imunologia , Macrófagos , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Roedores
12.
Mol Cell Neurosci ; 102: 103450, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31794879

RESUMO

Macrophage migration inhibitory factor (MIF) is an important regulator of innate immunity with key roles in neural regeneration and responses to pathogens, amongst a multitude of other functions. The expression of MIF and its binding partners has been characterised throughout the nervous system, with one key exception: the primary olfactory nervous system. Here, we showed in young mice (postnatal day 10) that MIF is expressed in the olfactory nerve by olfactory ensheathing glial cells (OECs) and by olfactory nerve fibroblasts. We also examined the expression of potential binding partners for MIF, and found that the serine protease HTRA1, known to be inhibited by MIF, was also expressed at high levels by OECs and olfactory fibroblasts in vivo and in vitro. We also demonstrated that MIF mediated segregation between OECs and J774a.1 cells (a monocyte/macrophage cell line) in co-culture, which suggests that MIF contributes to the fact that macrophages are largely absent from olfactory nerve fascicles. Phagocytosis assays of axonal debris demonstrated that MIF strongly stimulates phagocytosis by OECs, which indicates that MIF may play a role in the response of OECs to the continual turnover of olfactory axons that occurs throughout life.


Assuntos
Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Neuroglia/metabolismo , Nervo Olfatório/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Fibroblastos/metabolismo , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Regeneração Nervosa , Nervo Olfatório/citologia , Nervo Olfatório/fisiologia , Fagocitose , Ligação Proteica
13.
J Neuroimmunol ; 339: 577120, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790982

RESUMO

Our knowledge about genetic factors that drive the worsening of neuromyelitis optica (NMO) is limited. Herein, we analyzed the macrophage migration inhibitory factor (MIF) -173G/C functional polymorphism in NMO patients and controls. Our data reveal that the frequency of the high-expression MIF genotypes (CC/GC) did not differ between the two groups. However, frequency of this genotypes was elevated in patients diagnosed with both optic neuritis and myelitis compared with patients that were diagnosed with only one symptom. Furthermore, patients carrying the CC/CG genotypes had significantly higher disability score. We conclude that MIF is associated with NMO severity rather than susceptibility.


Assuntos
Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/genética , Polimorfismo de Nucleotídeo Único/genética , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Zool Res ; 41(1): 39-50, 2020 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-31709785

RESUMO

D-dopachrome tautomerase (DDT), a member of the macrophage migration inhibitory factor (MIF) protein superfamily, is a newly described cytokine with chemokine-like characteristics. However, research on fish DDT remains limited. In this study, we identified a DDT homolog (LjDDT) from the Japanese sea bass, Lateolabrax japonicus. Sequence analysis showed that LjDDT had typical sequence features of known DDT and MIF homologs and was most closely related to DDT of rock bream ( Oplegnathus fasciatus). LjDDT transcripts were detected in all tested tissues of healthy Japanese sea bass, with the highest expression found in the liver. Upon infection with Vibrio harveyi, LjDDT transcripts were significantly down-regulated in the three tested tissues, including the liver, spleen, and head kidney. Recombinant LjDDT (rLjDDT) and the corresponding antibody (anti-rLjDDT) were subsequently prepared. The administration of 100 µg/g anti-rLjDDT had a statistically significant protective effect on the survival of V. harveyi-infected fish. Moreover, rLjDDT was able to induce the migration of monocytes/macrophages (MO/MФ) and lymphocytes both in vitro and in vivo, but without significant influence on the migration of neutrophils. rLjDDT exhibited chemotactic activity for lipopolysaccharide (LPS) -stimulated M1-type MO/ MΦ in vitro, but not for cAMP-stimulated M2-type MO/MΦ. Furthermore, the knockdown of LjCD74, but not LjCXCR4, significantly down-regulated the rLjDDT-enhanced migration of MO/MΦ and relieved the rLjMIF-inhibited migration of MO/MΦ. These results indicate that LjCD74 may be the major chemotactic receptor of LjDDT and LjMIF in Japanese sea bass MO/MΦ. Combined rLjDDT+ rLjMIF treatment had no significant effect on the migration of MsiRNA, LjCD74si-, or LjCXCR4sitreated MO/MΦ compared to the control group, suggesting that the roles of LjDDT and LjMIF may be antagonistic. In conclusion, our study demonstrates for the first time that DDT may play a role in the immune responses of fish against bacterial infection through chemotactic recruitment of MO/MΦ via mediation of CD74 as an antagonist of MIF.


Assuntos
Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Sequência de Aminoácidos , Animais , Movimento Celular , Relação Dose-Resposta a Droga , Peixes , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/fisiologia , Fatores Inibidores da Migração de Macrófagos/química , Fatores Inibidores da Migração de Macrófagos/farmacologia , RNA Mensageiro , Vibrio , Vibrioses/enzimologia , Vibrioses/microbiologia , Vibrioses/veterinária
15.
Am J Physiol Cell Physiol ; 318(1): C94-C102, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31618079

RESUMO

Matrix metalloproteinases (MMP) are important for cardiac remodeling. Recently, microRNA (miR)-451a has been found to inhibit the expression of both MMP-2 and MMP-9 in human malignancies, but its role in cardiomyocytes has not been explored. We hypothesized that miR-451a modulates MMP-2 and MMP-9 levels in human cardiomyocytes. The role of miR-451a on regulation of MMP-2 and MMP-9 was evaluated in two separate pathological models using Cor.4U human inducible pluripotent stem cell-derived cardiomyocytes (hiPS-CMs): 1) endothelin-1 (ET-1), and 2) 48-h hypoxia (1% O2). Both models were transfected with synthetic miR-451a mimics or scramble control. Expression of both mRNA and miR was determined by quantitative real-time polymerase chain reaction and protein activity by (MMP-2/9) activity assay. Bioinformatic analyses were performed using Targetscan 7.1 and STRING 10.5. hiPS-CMs stimulated by hypoxia increased both MMP-2 and MMP-9 expression levels compared with normoxia (P < 0.05), whereas ET-1 stimulation only increased the MMP-9 level compared with vehicle controls (P < 0.05). miR-451a mimics prevented the increase of MMP-2 and MMP-9 expression in both models. Protein activity of MMP-2 and MMP-9 was confirmed to be lower following treatment with miR-451a mimic compared with scramble-controls. Six of 28 predicted gene transcripts of miR-451a were linked to MMP-2 and MMP-9; Macrophage migration inhibitory factor (MIF) was the only predicted target of miR-451a that was increased by ET-1 and hypoxia and reduced following miR-451a mimic transfection. miR-451a prevent the increase of MMP-2 and MMP-9 in human cardiomyocytes during pathological stress. The modulation by miR-451a on MMP-2 and MMP-9 is caused by MIF.


Assuntos
Cardiomegalia/enzimologia , Células-Tronco Pluripotentes Induzidas/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/enzimologia , Cardiomegalia/genética , Cardiomegalia/patologia , Diferenciação Celular , Hipóxia Celular , Linhagem Celular , Endotelina-1/toxicidade , Ativação Enzimática , Regulação Enzimológica da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/patologia , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Transdução de Sinais
16.
Clin Rev Allergy Immunol ; 58(1): 15-24, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30680604

RESUMO

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that participates in innate and adaptive immune responses. MIF contributes to the resistance against infection agents, but also to the cellular and tissue damage in infectious, autoimmune, and allergic diseases. In the past years, several studies demonstrated a critical role for MIF in the pathogenesis of type-2-mediated inflammation, including allergy and helminth infection. Atopic patients have increased MIF amounts in affected tissues, mainly produced by immune cells such as macrophages, Th2 cells, and eosinophils. Increased MIF mRNA and protein are found in activated Th2 cells, while eosinophils stock pre-formed MIF protein and secrete high amounts of MIF upon stimulation. In mouse models of allergic asthma, the lack of MIF causes an almost complete abrogation of the cardinal signs of the disease including mucus secretion, eosinophilic inflammation, and airway hyper-responsiveness. Additionally, blocking the expression of MIF in animal models leads to significant reduction of pathological signs of eosinophilic inflammation such as rhinitis, atopic dermatitis, eosinophilic esophagitis and helminth infection. A number of studies indicate that MIF is important in the effector phase of type-2 immune responses, while its contribution to Th2 differentiation and IgE production is not consensual. MIF has been found to intervene in different aspects of eosinophil physiology including differentiation, survival, activation, and migration. CD4+ T cells and eosinophils express CD74 and CXCR4, receptors able to signal upon MIF binding. Blockage of these receptors with neutralizing antibodies or small molecule antagonists also succeeds in reducing the signals of inflammation in experimental allergic models. Together, these studies demonstrate an important contribution of MIF on eosinophil biology and in the pathogenesis of allergic diseases and helminth infection.


Assuntos
Suscetibilidade a Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Animais , Biomarcadores , Medula Óssea/metabolismo , Medula Óssea/patologia , Eosinófilos/patologia , Interações Hospedeiro-Parasita , Interações Hospedeiro-Patógeno , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Inflamação/patologia , Transdução de Sinais
17.
Cell Immunol ; 347: 103965, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708110

RESUMO

Recent studies have indicated that Macrophage migration inhibitory factor (MIF) plays an important role in the prevention and treatment of asthma. However the role of MIF in airway inflammation and airway epithelial barrier disruption in house dust mite (HDM)-induced asthma has not been addressed. We hypothesized that MIF contributed to HDM-induced the production of Th2-associated cytokines and E-cadherin dysfunction in asthmatic mice and 16HBE cells. In vivo, a HDM-induced asthma mouse model was set up and mice treated with MIF antagonist ISO-1 after HDM. The mice treated with the ISO-1 ameliorated airway hyper-reactivity, airway inflammation, increased serum IgE levels, the aberrant arrangement of E-cadherin as well as the release of Th2 cytokines induced by HDM. In vitro, the exposure of 16HBE cells to HDM and rhMIF resulted in airway epithelial barrier disruption, inflammatory cytokine production and enhanced glycolytic flux. While these changes were attenuated by MIF siRNA treatment. Sequentially, treatment of 16HBE cells with PFKFB3 antagonist PFK15 significantly lowered rhMIF-induced these changes in 16HBE cells. Therefore, these results indicate that MIF may be an important contributor in airway inflammation and airway epithelial barrier disruption of HDM-induced asthma. Moreover, HDM specifically induces airway inflammation and airway epithelial barrier disruption of 16HBE cells through MIF-mediated enhancement of aerobic glycolysis.


Assuntos
Antígenos de Dermatophagoides/imunologia , Asma/patologia , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Pyroglyphidae/imunologia , Junções Íntimas/patologia , Animais , Asma/tratamento farmacológico , Líquido da Lavagem Broncoalveolar , Caderinas/imunologia , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Glicólise/fisiologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfofrutoquinase-2/antagonistas & inibidores , Piridinas/farmacologia , Quinolinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Células Th2/imunologia
18.
J Biol Chem ; 295(3): 850-867, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31811089

RESUMO

Human macrophage migration-inhibitory factor (MIF) is an evolutionarily-conserved protein that has both extracellular immune-modulating and intracellular cell-regulatory functions. MIF plays a role in various diseases, including inflammatory diseases, atherosclerosis, autoimmunity, and cancer. It serves as an inflammatory cytokine and chemokine, but also exhibits enzymatic activity. Secreted MIF binds to cell-surface immune receptors such as CD74 and CXCR4. Plants possess MIF orthologs but lack the associated receptors, suggesting functional diversification across kingdoms. Here, we characterized three MIF orthologs (termed MIF/d-dopachrome tautomerase-like proteins or MDLs) of the model plant Arabidopsis thaliana Recombinant Arabidopsis MDLs (AtMDLs) share similar secondary structure characteristics with human MIF, yet only have minimal residual tautomerase activity using either p-hydroxyphenylpyruvate or dopachrome methyl ester as substrate. Site-specific mutagenesis suggests that this is due to a distinct amino acid difference at the catalytic cavity-defining residue Asn-98. Surprisingly, AtMDLs bind to the human MIF receptors CD74 and CXCR4. Moreover, they activate CXCR4-dependent signaling in a receptor-specific yeast reporter system and in CXCR4-expressing human HEK293 transfectants. Notably, plant MDLs exert dose-dependent chemotactic activity toward human monocytes and T cells. A small molecule MIF inhibitor and an allosteric CXCR4 inhibitor counteract this function, revealing its specificity. Our results indicate cross-kingdom conservation of the receptor signaling and leukocyte recruitment capacities of human MIF by its plant orthologs. This may point toward a previously unrecognized interplay between plant proteins and the human innate immune system.


Assuntos
Antígenos de Diferenciação de Linfócitos B/genética , Antígenos de Histocompatibilidade Classe II/genética , Imunidade Inata/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Receptores CXCR4/genética , Antígenos de Diferenciação de Linfócitos B/química , Arabidopsis/genética , Arabidopsis/imunologia , Quimiotaxia/genética , Quimiotaxia/imunologia , Sequência Conservada/genética , Sequência Conservada/imunologia , Citocinas/genética , Citocinas/imunologia , Células HEK293 , Antígenos de Histocompatibilidade Classe II/química , Humanos , Oxirredutases Intramoleculares/química , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/química , Fatores Inibidores da Migração de Macrófagos/imunologia , Monócitos/química , Monócitos/metabolismo , Ligação Proteica/genética , Receptores CXCR4/química , Homologia de Sequência , Linfócitos T/química , Linfócitos T/metabolismo
19.
Phytochemistry ; 169: 112152, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31606607

RESUMO

The CYP74 family of cytochromes P450 includes four fatty acid hydroperoxide metabolizing enzymes: allene oxide synthase (AOS), hydroperoxide lyase (HPL), divinyl ether synthase, and epoxyalcohol synthase (EAS). All P450s have six substrate recognition sites (SRSs) in their structures. Some CYP74 mutations in SRSs leading to their interconversions including substitutions in "F/L toggle" (SRS-1 region) were reported before. For further elucidation of the role of this site in CYP74 catalysis, the effect of Phe/Leu mutation on the specificity of selected AOSs was studied in the present work. Mutant forms of ZmAOS1 (CYP74A19, Zea mays), LeAOS3 (CYP74C3, Lycopersicon esculentum), and PpAOS2 (CYP74A8, Physcomitrella patens) acquired partial EAS activity. Mutant forms of ZmAOS1 and PpAOS2 possessed additional HPL activities. The results validate the significance of the "F/L toggle" as a catalytic determinant of CYP74s, as well as the importance of the conserved Phe at this site for the AOS catalysis.


Assuntos
Oxirredutases Intramoleculares/metabolismo , Leucina/genética , Fenilalanina/genética , Biocatálise , Oxirredutases Intramoleculares/genética , Mutação , Especificidade por Substrato
20.
Glia ; 68(1): 95-110, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31479164

RESUMO

We have previously reported that prostaglandin D2 Synthase (L-PGDS) participates in peripheral nervous system (PNS) myelination during development. We now describe the role of L-PGDS in the resolution of PNS injury, similarly to other members of the prostaglandin synthase family, which are important for Wallerian degeneration (WD) and axonal regeneration. Our analyses show that L-PGDS expression is modulated after injury in both sciatic nerves and dorsal root ganglia neurons, indicating that it might play a role in the WD process. Accordingly, our data reveals that L-PGDS regulates macrophages phagocytic activity through a non-cell autonomous mechanism, allowing myelin debris clearance and favoring axonal regeneration and remyelination. In addition, L-PGDS also appear to control macrophages accumulation in injured nerves, possibly by regulating the blood-nerve barrier permeability and SOX2 expression levels in Schwann cells. Collectively, our results suggest that L-PGDS has multiple functions during nerve regeneration and remyelination. Based on the results of this study, we posit that L-PGDS acts as an anti-inflammatory agent in the late phases of WD, and cooperates in the resolution of the inflammatory response. Thus, pharmacological activation of the L-PGDS pathway might prove beneficial in resolving peripheral nerve injury.


Assuntos
Oxirredutases Intramoleculares/biossíntese , Lipocalinas/biossíntese , Ativação de Macrófagos/fisiologia , Regeneração Nervosa/fisiologia , Neuropatia Ciática/enzimologia , Animais , Feminino , Oxirredutases Intramoleculares/genética , Lipocalinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Neuropatia Ciática/genética , Neuropatia Ciática/patologia
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