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1.
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
2.
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
3.
J Sci Food Agric ; 100(2): 672-681, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31583701

RESUMO

BACKGROUND: Hibiscus sabdariffa is commonly used in daily life and its extract is applied widely in food and cosmetics. However, it has not been evaluated for its anti-aging effects. RESULTS: Hibiscus sabdariffa calyx aqueous extract (HSCAE) has shown potential collagenase activity suppression effects, together with tyrosinase activity inhibition, and anti-oxidation as a free radical scavenger. The current investigation demonstrated that HSCAE was not cytotoxic in skin fibroblasts, and it significantly decreased ultraviolet B (UVB)-induced reactive oxygen species (ROS) on a flow cytometry assay. Moreover, HSCAE reduced matrix metalloproteinase (MMP) expression, increased tissue inhibition of metalloproteinase (TIMP)-1 level, and enhanced collagen content by inhibiting collagenase activity. It also blocked mRNA and protein expressions of melanin production pathway key factors, including the microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and dopachrome tautomerase-2 (TRP-2). CONCLUSION: These results demonstrated, for the first time, the potential of HSCAE as a natural antioxidant with the ability to maintain collagen production and to decrease melanin syntheses under UVB radiation, for anti-aging effects. © 2019 Society of Chemical Industry.


Assuntos
Depuradores de Radicais Livres/farmacologia , Hibiscus/química , Extratos Vegetais/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Animais , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Camundongos , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos
4.
Mol Med Rep ; 20(5): 4367-4375, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545425

RESUMO

Infection is a frequent complication of liver transplantation or partial hepatectomy (PH) and sometimes results in cholestasis. We examined factors involved in infection­induced cholestasis after PH, employing a rat PH model and lipopolysaccharide (LPS) as a bacterial toxin. Male Sprague­Dawley rats were subjected to 70% PH and/or LPS injection, and tissues were harvested at 0, 24, 72 and 168 h. Gene expression was analyzed by microarray analysis and reverse transcription­quantitative polymerase chain reaction, and protein levels and localization were analyzed by western blotting and immunohistochemistry, respectively. Plasma bile acid levels were significantly higher in the LPS + PH group than in the PH group. Ribonucleotide reductase regulatory subunit M2 and proliferating cell nuclear antigen peaked at 24 and 72 h in the PH group and LPS + PH group, respectively, indicating a delay in cell proliferation in the latter group. The sodium­dependent taurocholate cotransporting polypeptide and organic­anion­transporting polypeptide 1a1 and 1a2 were reduced in the PH group at 24 h, and were not further decreased in the LPS + PH group. Chemokine ligand 9 (Cxcl9), a chemokine involved in M2 macrophage polarization, increased after 24 h in the LPS and the LPS + PH groups. The number and shape of Cxcl9­positive cells were similar to CD163­positive cells, suggesting that such cells produced the chemokine. Hematopoietic prostaglandin D2 synthase (Ptgds2) was only detected in hepatocytes of the LPS + PH group exhibiting a delay in cell proliferation. Thus, Kupffer cells activated with LPS were suggested to be responsible for a delay in hepatocyte proliferation after PH.


Assuntos
Colestase/etiologia , Colestase/metabolismo , Endotoxinas/efeitos adversos , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Oxirredutases Intramoleculares/genética , Lipocalinas/genética , Animais , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/metabolismo , Bilirrubina/sangue , Biomarcadores , Proliferação de Células , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Modelos Animais de Doenças , Hepatectomia , Imuno-Histoquímica , Oxirredutases Intramoleculares/metabolismo , Macrófagos do Fígado/metabolismo , Lipocalinas/metabolismo , Masculino , RNA Mensageiro/genética , Ratos
5.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370326

RESUMO

Two polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF) - rs755622 and rs5844572 - exhibit prognostic relevance in inflammatory diseases. The aim of this study was to investigate a correlation between these MIF promoter polymorphisms and the severity of hepatitis C virus (HCV)-induced liver fibrosis. Our analysis included two independent patient cohorts with HCV-induced liver fibrosis (504 and 443 patients, respectively). The genotype of the single nucleotide polymorphism (SNP) -173 G/C and the repeat number of the microsatellite polymorphism -794 CATT5-8 were determined in DNA samples and correlated with fibrosis severity. In the first cohort, homozygous carriers of the C allele in the rs755622 had lower fibrosis stages compared to heterozygous carriers or wild types (1.25 vs. 2.0 vs. 2.0; p = 0.03). Additionally, ≥7 microsatellite repeats were associated with lower fibrosis stages (

Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Hepatite C Crônica/genética , Oxirredutases Intramoleculares/genética , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Fatores Inibidores da Migração de Macrófagos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/virologia , Estudos de Coortes , Técnicas de Imagem por Elasticidade , Feminino , Expressão Gênica , Frequência do Gene , Hepacivirus/patogenicidade , Hepacivirus/fisiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico por imagem , Hepatite C Crônica/virologia , Heterozigoto , Homozigoto , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/etiologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas , Índice de Gravidade de Doença
6.
Iran J Kidney Dis ; 13(4): 232-236, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31422388

RESUMO

INTRODUCTION: Nephrotic syndrome (NS), a common chronic pediatrickidney disease, is associated with immune system dysfunction.The exact role of MIF -137 G>C gene polymorphism on risk of NSis not clear. The current study aimed to evaluate the relationshipbetween MIF -173 G>C (rs755622) variant and susceptibility to NS. METHODS: This case-control study conducted on 134 children withNS and 141 healthy children. Extraction of genomic DNA fromwhole blood was done using salting out method. Genotyping ofthe MIF -173 G>C polymorphism was performed using polymerasechain reaction restriction fragment length polymorphism (PCRRFLP)method. RESULTS: The findings showed that MIF -173 G>C variant significantlyincreases the risk of NS in codominant (OR = 1.82, 95%CI = 1.08-3.08, P = 0.026, GC vs GG), dominant (OR = 1.90, 95%CI = 1.14-3.16,P = 0.015, GC+CC vs GG), overdominant (OR = 1.75, 95%CI = 1.04-2.94, P = 0.037, GC vs GG+CC) and allele (OR = 1.76, 95%CI = 1.13-2.74, P = 0.014, C vs G) inheritance models. Stratified analysisperformed by sex and response to treatment. The findings revealedthat this variant was associated with increased risk of NS in male.No correlation between the variant and response to treatment wasfound. CONCLUSION: In summary, the results indicated that MIF -137 G>Cis significantly associated with increased risk of NS. More studieswith larger sample size among different ethnicities are needed toverify our findings.


Assuntos
Predisposição Genética para Doença , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Síndrome Nefrótica/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Humanos , Modelos Logísticos , Masculino , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Fatores Sexuais
7.
Genes (Basel) ; 10(7)2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261784

RESUMO

Melanin plays a pivotal role in the cellular processes of several metazoans. The final step of the enzymically-regulated melanin biogenesis is the conversion of dopachrome into dihydroxyindoles, a reaction catalyzed by a class of enzymes called dopachrome tautomerases. We traced dopachrome tautomerase (DCT) and dopachrome converting enzyme (DCE) genes throughout metazoans and we could show that only one class is present in most of the phyla. While DCTs are typically found in deuterostomes, DCEs are present in several protostome phyla, including arthropods and mollusks. The respective DCEs belong to the yellow gene family, previously reported to be taxonomically restricted to insects, bacteria and fungi. Mining genomic and transcriptomic data of metazoans, we updated the distribution of DCE/yellow genes, demonstrating their presence and active expression in most of the lophotrochozoan phyla as well as in copepods (Crustacea). We have traced one intronless DCE/yellow gene through most of the analyzed lophotrochozoan genomes and we could show that it was subjected to genomic diversification in some species, while it is conserved in other species. DCE/yellow was expressed in most phyla, although it showed tissue specific expression patterns. In the parasitic copepod Mytilicola intestinalis DCE/yellow even belonged to the 100 most expressed genes. Both tissue specificity and high expression suggests that diverse functions of this gene family also evolved in other phyla apart from insects.


Assuntos
Oxirredutases Intramoleculares/genética , Animais , Evolução Molecular , Expressão Gênica , Oxirredutases Intramoleculares/química , Filogenia , Conformação Proteica
8.
Inflamm Res ; 68(10): 877-887, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342095

RESUMO

OBJECTIVE: Vascular endothelial (VE)-cadherin-mediated adherens junction is critical to maintain endothelial integrity. Besides its role of homophilic intercellular adhesion, VE-cadherin also has a role of outside-in signaling with functional consequences for vascular physiology. However, the nature of these signals remains not completely understood. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were used in cell culture experiments. Confluent HUVECs were treated with VE-cadherin function-blocking antibodies BV9 (50 µg/ml) or IgG control. Antibody array was used to screen for cytokine/chemokine in supernatant. For VE-cadherin knockdown, siRNA transfection was used. ELISA, Western blot, and qRT-PCR were used to confirm the expression of screened cytokine/chemokine. To explore the possible mechanisms, Scr phosphorylation was detected and Scr inhibitor PP2 (1 µM) was used. To investigate in vivo relevance of the findings, BV9 and the indicated neutralizing antibodies were injected into mice and then lung vascular leak and inflammation were examined by Evans blue assay and lung tissue H&E, respectively. RESULTS: Using a non-biased, high-throughout human cytokine/chemokine antibody array, we first found that disruption of VE-cadherin-mediated adhesion by function-blocking antibody BV9 triggered the release of migration inhibitory factor (MIF). This VE-cadherin-mediated release of MIF further confirmed by ELISA with both VE-cadherin blocking antibody and siRNA technique was due to enhanced expression of MIF mRNA, which was mediated by Src kinase activation. In addition, in vivo lung vascular leak induced by VE-cadherin function-blocking antibody was partly alleviated by neutralizing MIF. CONCLUSIONS: VE-cadherin regulates MIF synthesis and release via Src kinase. Our data provide additional evidence to the concept that VE-cadherin transfers intracellular signals to coordinate the state of cell-cell adhesion with gene expression.


Assuntos
Antígenos CD/genética , Caderinas/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Caderinas/imunologia , Caderinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética
9.
Int J Mol Sci ; 20(12)2019 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-31234561

RESUMO

The channeling of metabolites is an essential step of metabolic regulation in all living organisms. Multifunctional enzymes with defined domains for metabolite compartmentalization are rare, but in many cases, larger assemblies forming multimeric protein complexes operate in defined metabolic shunts. In Arabidopsis thaliana, a multimeric complex was discovered that contains a 13-lipoxygenase and allene oxide synthase (AOS) as well as allene oxide cyclase. All three plant enzymes are localized in chloroplasts, contributing to the biosynthesis of jasmonic acid (JA). JA and its derivatives act as ubiquitous plant defense regulators in responses to both biotic and abiotic stresses. AOS belongs to the superfamily of cytochrome P450 enzymes and is named CYP74A. Another CYP450 in chloroplasts, hydroperoxide lyase (HPL, CYP74B), competes with AOS for the common substrate. The products of the HPL reaction are green leaf volatiles that are involved in the deterrence of insect pests. Both enzymes represent non-canonical CYP450 family members, as they do not depend on O2 and NADPH-dependent CYP450 reductase activities. AOS and HPL activities are crucial for plants to respond to different biotic foes. In this mini-review, we aim to summarize how plants make use of the LOX2-AOS-AOC2 complex in chloroplasts to boost JA biosynthesis over volatile production and how this situation may change in plant communities during mass ingestion by insect pests.


Assuntos
Aldeído Liases/metabolismo , Arabidopsis/fisiologia , Sistema Enzimático do Citocromo P-450/metabolismo , Resistência à Doença , Oxirredutases Intramoleculares/metabolismo , Aldeído Liases/química , Aldeído Liases/genética , Sequência de Aminoácidos , Cloroplastos/metabolismo , Ciclopentanos/metabolismo , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/genética , Resistência à Doença/genética , Oxirredutases Intramoleculares/química , Oxirredutases Intramoleculares/genética , Redes e Vias Metabólicas , Modelos Moleculares , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Oxilipinas/metabolismo , Desenvolvimento Vegetal/genética , Ligação Proteica , Relação Estrutura-Atividade
10.
Nat Rev Rheumatol ; 15(7): 427-437, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31197253

RESUMO

The role of macrophage migration inhibitory factor (MIF) in autoimmunity is underscored by data showing that common functional polymorphisms in MIF are associated with disease susceptibility or clinical severity. MIF can regulate glucocorticoid-mediated immunosuppression and has a prominent function in cell survival signalling. Further specific functions of MIF are now being defined in different autoimmune diseases and MIF-targeted biologic therapeutics are in early-stage clinical trials. The unique structure of MIF is also directing the development of small-molecule MIF antagonists. Together, these efforts could provide a means of selectively intervening in pathogenesis and overcoming MIF-related genetic susceptibility to many rheumatic diseases.


Assuntos
Doenças Autoimunes/genética , Autoimunidade , Gerenciamento Clínico , Predisposição Genética para Doença , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo Genético , Medicina de Precisão/métodos , Doenças Autoimunes/terapia , Humanos , Oxirredutases Intramoleculares/biossíntese , Fatores Inibidores da Migração de Macrófagos/biossíntese
11.
Mol Med Rep ; 20(2): 1167-1177, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173234

RESUMO

Angiogenesis is a critical process of recovery from cerebrovascular disease. A growing body of evidence has confirmed that microRNAs (miRNAs/miRs) have an important role in the modulation of angiogenesis under physiological and pathological conditions including cerebral ischemia injury (CII). Therefore, the aim of the present study was to explore the function and mechanism of microRNAs in regulating angiogenesis using a cell model of CII. Firstly, a miRNA microarray was performed to analyze miRNA expression in serum samples from patients with cerebral ischemia and the results revealed that miR­451 was one of the miRNAs that was the most significantly downregulated. Subsequently, human umbilical vein endothelial cells (HUVECs) were used as an in vitro model to further explore the mechanisms governing angiogenesis during hypoxia. The results demonstrated that overexpression of miR­451 had a significantly anti­angiogenic effect by suppressing tube formation, migration and wound healing in vitro. By contrast, reducing the expression of miR­451 promoted HUVEC migration and tubulogenesis under normoxic conditions. The present study further identified that macrophage migration inhibitory factor (MIF), an important angiogenic regulator, was a novel target of miR­451 that could reverse the effects of miR­451 on the regulation of angiogenesis in HUVECs under hypoxic or normoxic conditions. These results revealed that downregulation of miR­451 promotes angiogenesis by targeting MIF in hypoxic HUVECs and indicated that miR­451 is a potential candidate for CII therapeutics.


Assuntos
Movimento Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hipóxia/metabolismo , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , MicroRNAs/metabolismo , Neovascularização Fisiológica/genética , Idoso , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Feminino , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Hipóxia/genética , Masculino , MicroRNAs/fisiologia , Pessoa de Meia-Idade , Neovascularização Patológica/genética
12.
Arch Dermatol Res ; 311(8): 589-594, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31154458

RESUMO

Alopecia areata (AA) is an organ-specific autoimmune disease that targets the bulb of the hair follicles and results in non-scarring hair loss that can range from patchy lesions to involvement of the entire scalp. AA develops when the hair follicles lose their physiologic state of immune privilege. One of the key factors that help in maintaining this immune privilege by suppressing natural killer cells is macrophage migration inhibitory factor (MIF). Surprisingly, MIF is also known to provoke autoimmunity by upregulating cytokines. To address this dilemma and understand the exact nature of the involvement of MIF in disease pathogenesis we investigated the association of MIF gene polymorphisms (- 173 G > C, rs755622) with AA by conducting a case-control study of 274 subjects. We observed that the frequency of the C allele in the patients was significantly lower than the control group (0.15, 0.23, respectively, p = 0.01) and the combined frequencies of the CC and GC genotypes (dominant Mendelian pattern) had the most prevalent difference between the two groups (odds ratio 0.60, 95% confidence interval 0.36-0.99; p = 0.048).Since the C allele is associated with higher MIF transcription levels, this could infer that MIF is more likely to attribute to the preservation of the immune privilege rather than acting as a proinflammatory factor.


Assuntos
Alopecia em Áreas/genética , Predisposição Genética para Doença , Folículo Piloso/imunologia , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Adolescente , Adulto , Idoso , Alelos , Alopecia em Áreas/imunologia , Alopecia em Áreas/prevenção & controle , Autoimunidade/genética , Estudos de Casos e Controles , Feminino , Genótipo , Folículo Piloso/patologia , Voluntários Saudáveis , Humanos , Privilégio Imunológico/genética , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
13.
Mol Carcinog ; 58(10): 1809-1821, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31219646

RESUMO

Macrophage migration inhibitory factor (MIF) has been shown to closely associate with the malignant progression of a variety of human carcinomas. However, the role and its underlying molecular mechanisms of MIF in the invasion and metastasis of oral squamous cell carcinoma (OSCC) still remains unclear. Here, we found that MIF silencing reduced the cell proliferation, migration, and invasion, as well as matrix metalloprotein-2 (MMP-2) and MMP-9 in OSCC cells. Overexpression of MMP-2 or MMP-9 restored the migration and invasion of MIF-knockdown cells, indicating that MMP-2 and MMP-9 are downstream targets of MIF. In the xenograft model, MIF silencing inhibited tumor growth and in lymph metastasis model, MIF silencing reduced tumor metastasis. More importantly, immunohistochemistry staining in a tissue microarray (TMA) demonstrated that MIF expression was positively correlated with clinic stage, recurrence, metastasis, and poor prognosis of patients with OSCC as well as with the levels of MMP-2 or MMP-9 in TMA. Therefore, our findings suggest that MIF may promote the invasion and metastasis of OSCC through the activation of MMP-2 and MMP-9 and prompt further investigation into the therapeutic value of MIF for OSCC treatment.


Assuntos
Carcinoma de Células Escamosas/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Neoplasias Bucais/genética , Idoso , Animais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico
15.
J Exp Clin Cancer Res ; 38(1): 180, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036057

RESUMO

BACKGROUND: Lung cancer often ranks one of the most prevalent malignancies in the world. One of the most challenging aspects of treating late-stage lung cancer patients is the development of drug resistance, from both conventional chemo- and targeted therapeutic agents. Tumor-associated microphages (TAMs) have been shown to promote the survival and distant metastasis of lung cancer cells. METHODS: This study investigated the TAMs - modulating potential of cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines, A549R and H460R by using bioinformatics approach, immunoblotting, immunofluorescence staining, migration, invasion, colony, lung sphere formation and xenograft tumorigenecity assays. RESULTS: In this study, we first demonstrated the elevated expression of oncogenic and stemenss markers such as Src, Notch1, macrophage inhibitory factor (MIF) and CD155 in trained cisplatin (CDDP)-resistant A549 and H460 cells (A549R and H460R cells). When co-cultured with TAMs, A549R and H460R cells promoted the M2-polarization in TAMs. In addition, A549R and H460R cells showed an increased self-renewal ability as they formed tumor spheres at higher frequency comparing to their parental counterparts. The increased MIF secretion by the A549R and H460R cells could be suppressed by a multiple kinase inhibitor, dasatinib, which resulted in the decreased of oncogenic network of Src, CD155 and MIF expression. Similarly, dasatinib treatment reduced the M2 polarization in TAMs and suppressed self-renewal ability of the A549R and H460R cells. CONCLUSION: In summary, cisplatin resistant lung cancer cells not only showed an increased self-renewal ability but also promoted M2 polarization of TAMs via the secretion of MIF. These findings were linked to the increased Src-associated signaling as dasatinib treatment significantly reversed these phenomena. Thus, kinase inhibitors such as dasatinib may be of potential for treating cisplatin-resistant lung cancer by targeting both tumor and the tumor microenvironment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Oxirredutases Intramoleculares/genética , Neoplasias Pulmonares/tratamento farmacológico , Fatores Inibidores da Migração de Macrófagos/genética , Receptores Virais/genética , Células A549 , Animais , Carcinogênese/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Dasatinibe/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/genética
16.
Poult Sci ; 98(9): 4182-4189, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31065698

RESUMO

Sperm motility is used to predict the semen quality and fertilization ability of breeder roosters. Indigenous chicken breeder roosters show variation in sperm motility, but less has been known about its relationship with other reproductive attributes. In this study, 40- to 44-wk-old Beijing-You breeder roosters with the high and low sperm motility phenotypes (n = 15 in each group) were identified and compared, with regard to their semen characteristics, reproductive hormone concentrations, testicular histomorphology, fertility capacity, and genes expression of hematopoietic prostaglandin D synthase (H-PGDS) and wingless-type MMTV integration site family, member 2 (WNT2). The low sperm motility roosters showed lower semen volume (P = 0.003) and sperm viability (P = 0.008). Like semen donors in the artificial insemination test, the low sperm motility roosters showed lower fertility than the high sperm motility roosters (P < 0.001). No difference in the serum concentration of follicle stimulating hormone (FSH, P = 0.347), luteinizing hormone (LH, P = 0.376), or testosterone (T, P = 0.068) was found between the high and low sperm motility roosters. Furthermore, among roosters with similar BW, the low sperm motility roosters had smaller testis mass (P = 0.037), seminiferous tubules diameter (P = 0.031), spermatogenic epithelium height (P = 0.001), and Johnsen score (P = 0.005) than the high sperm motility ones. Finally, the expression of both H-PGDS and WNT2, which are involved in the prostaglandin D2 and WNT signaling pathways, respectively, was low in the testis of the low sperm motility phenotype roosters (P < 0.05). Thus, the findings of the present study indicated that the testis of low sperm motility showed impaired testicular histomorphology as compared to normal; the BW, testis weight, and serum FSH, LH, and T levels are associated with sperm production, but not with sperm motility, and that low expression of H-PGDS and WNT2 may be related with the abnormal testicular morphology of low sperm motility birds which deserves further functional validation studies.


Assuntos
Proteínas Aviárias/genética , Galinhas/fisiologia , Fertilidade , Expressão Gênica , Motilidade Espermática/genética , Testículo/fisiologia , Animais , Proteínas Aviárias/metabolismo , Galinhas/genética , Hormônio Foliculoestimulante/metabolismo , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Hormônio Luteinizante/metabolismo , Masculino , Análise do Sêmen/veterinária , Testículo/anatomia & histologia , Testosterona/metabolismo , Proteína Wnt2/genética , Proteína Wnt2/metabolismo
17.
Neurobiol Dis ; 127: 482-491, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30954702

RESUMO

Dysfunctional regulation of inflammation may contribute to the progression of neurodegenerative diseases. The results of this study revealed that DJ-1, a Parkinson's disease (PD) gene, regulated expression of prostaglandin D2 synthase (PTGDS) and production of prostaglandin D2 (PGD2), by which DJ-1 enhanced anti-inflammatory function of astrocytes. In injured DJ-1 knockout (KO) brain, expression of tumor necrosis factor-alpha (TNF-α) was more increased, but that of anti-inflammatory heme oxygenase-1 (HO-1) was less increased compared with that in injured wild-type (WT) brain. Similarly, astrocyte-conditioned media (ACM) prepared from DJ-1-KO astrocytes less induced HO-1 expression and less inhibited expression of inflammatory mediators in microglia. With respect to the underlying mechanism, we found that PTGDS that induced expression of HO-1 was lower in DJ-1 KO astrocytes and brains compared with their WT counterparts. In addition, PTGDS levels increased in the injured brain of WT mice, but barely in that of KO mice. We also found that DJ-1 regulated PTGDS expression through Sox9. Thus, Sox9 siRNAs reduced PTGDS expression in WT astrocytes, and Sox9 overexpression rescued PTGDS expression in DJ-1 KO astrocytes. In agreement with these results, ACM from Sox9 siRNA-treated astrocytes and that from Sox9-overexpression astrocytes exerted opposite effects on HO-1 expression and anti-inflammation. These findings suggest that DJ-1 positively regulates anti-inflammatory functions of astrocytes, and that DJ-1 dysfunction contributes to the excessive inflammatory response in PD development.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Regulação da Expressão Gênica , Inflamação/genética , Oxirredutases Intramoleculares/genética , Lipocalinas/genética , Proteína Desglicase DJ-1/genética , Animais , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Inflamação/metabolismo , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Proteína Desglicase DJ-1/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
Biomed Res Int ; 2019: 7850392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30868074

RESUMO

Chronic periodontitis (CP) is an infection that affects the teeth supporting structure. Macrophage migration inhibitory factor (MIF) is an important effector cytokine of the innate immune system. Due to its functional characteristics, MIF may be involved in the immunopathology of CP. The aim of the present study was to evaluate MIF levels in gingival crevicular fluid (GCF), saliva, and serum of CP patients. A cross-sectional study was conducted on 60 subjects divided into two groups: subjects with CP (n= 30) and periodontally healthy subjects without CP (n=30). MIF was quantified in GCF, saliva, and serum of all participants by enzyme-linked immunosorbent assay. MIF concentrations were higher in GCF, saliva, and serum in the group with CP compared with the group without CP and a higher MIF concentration was observed in GCF (p=0.001) and saliva (p=0.009) in the group with CP. MIF intragroup comparisons between fluids demonstrated significant high levels of MIF in saliva compared with GCF and serum in both study groups (p<0.05). A positive correlation was found between clinical signs and MIF concentration in GCF (p<0.05). There is an association between the MIF and the clinical signs of the disease. Therefore, MIF could have an important role in the pathology and progression of CP.


Assuntos
Periodontite Crônica/genética , Periodontite Crônica/metabolismo , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Adulto , Periodontite Crônica/sangue , Periodontite Crônica/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Líquido do Sulco Gengival/imunologia , Líquido do Sulco Gengival/metabolismo , Humanos , Oxirredutases Intramoleculares/química , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/química , Fatores Inibidores da Migração de Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Saliva/imunologia , Saliva/metabolismo
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