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1.
Nat Commun ; 11(1): 1600, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32231244

RESUMO

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.


Assuntos
Estudo de Associação Genômica Ampla , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/genética , Alelos , Sequência de Aminoácidos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Glomerulonefrite Membranosa/imunologia , Humanos , Fatores Reguladores de Interferon/genética , Modelos Moleculares , Subunidade p50 de NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Receptores da Fosfolipase A2/genética
2.
Biochim Biophys Acta Proteins Proteom ; 1868(6): 140412, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32179183

RESUMO

Matrix metalloproteinases (MMPs) are zinc-dependent extracellular matrix remodeling endopeptidases. MMPs cleave various matrix proteins such as collagen, elastin, gelatin and casein. MMPs are often implicated in pathological processes, such as cancer progression including metastasis. Meanwhile, microorganisms produce various secondary metabolites having unique structures. We designed and synthesized dehydroxymethylepoxyquinomicin (DHMEQ) based on the structure of epoxyquinomicin C derived from Amycolatopsis as an inhibitor of NF-κB. This compound inhibited cancer cell migration and invasion. Since DHMEQ is comparatively unstable in the body, we designed and synthesized a stable DHMEQ analog, SEMBL. SEMBL also inhibited cancer cell migration and invasion. We also looked for inhibitors of cancer cell migration and invasion from microbial culture filtrates. As a result, we isolated a known compound, ketomycin, from Actinomycetes. DHMEQ, SEMBL, and ketomycin are all NF-κB inhibitors, and inhibited the expression of MMPs in the inhibition of cellular migration and invasion. These are all compounds with comparatively low toxicity, and may be useful for the development of anti-metastasis agents.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/antagonistas & inibidores , Cicloexanonas/antagonistas & inibidores , Metaloproteinases da Matriz/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Actinobacteria/metabolismo , Animais , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cicloexanonas/síntese química , Glioxilatos/antagonistas & inibidores , Glioxilatos/metabolismo , Humanos , Metaloproteinase 11 da Matriz/efeitos dos fármacos , Metaloproteinase 11 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Modelos Moleculares , Subunidade p50 de NF-kappa B/metabolismo , Invasividade Neoplásica , Neoplasias , Quinonas/química
3.
Ann Hematol ; 99(3): 609-618, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32002656

RESUMO

Graft-versus-host disease (GVHD) represents a significant cause of mortality after allogeneic hematopoietic stem cell transplantation (HSCT). NF-kB system is a master regulator of innate immunity responses. It controls the expression of various cytokines and chemokines many of which are involved in GVHD pathogenesis. Chemo(radio) therapy administered during conditioning induces DNA damage and activates DNA damage response (DDR) signaling resulting in irreversible cell cycle arrest - cellular senescence which has been described to be associated with robust pro-inflammatory secretion mostly controlled by NF-kB. The NFKB1 gene encodes the DNA-binding subunit of the NF-kB complex. Using the candidate gene approach, we analyzed possible association of two single-nucleotide polymorphisms (SNPs) rs3774937 C/T and rs3774959 A/G of the NFKB1 gene with GVHD and transplant-related mortality (TRM) occurrence in 109 recipients allografted from HLA-identical donor. Both SNPs in recipients were found to be strongly associated with acute GVHD. Nevertheless, no significant association with chronic GVHD and TRM was found. Presented pilot results contribute to pre-clinical observations and suggest that NF-kB may be an important regulator of HSCT-related inflammatory reactions such as acute GVHD. Novel pathogenic mechanisms of GVHD may arise from perspectives of DDR and cellular senescence where NF-kB plays an essential role.


Assuntos
Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas , Subunidade p50 de NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Adulto , Aloenxertos , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Taxa de Sobrevida
4.
Eur J Histochem ; 64(1)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31988533

RESUMO

Emerging evidence suggests that red blood cells (RBCs) are involved in many functions essential for life. Nuclear factor-kB (NF-kB), nitric oxide synthases (inducible nitric oxide synthase -iNOS-, endothelial nitric oxide synthase -eNOS-) and interleukin-1ß (-IL-1ß-) are all proteins that have been identified in RBCs. In nucleated cells, such as white blood cells (WBCs), these proteins have well investigated roles, linked to stress and inflammation. It is not the same in erythrocytes, for this reason, we considered obese patients for studying the morphology of RBCs. We studied a possible correlation between their morphological changes and several protein expressions. Moreover, we compared the results about the aforementioned proteins and antioxidant markers with those obtained in WBCs from healthy and obese patients before and after omega-3 polyunsaturated fatty acid supplementation. This latter scientific point is important in order to determine whether there are differences in the expression of nucleated and anucleated cells. The morphology of RBCs changed in obese patients, but it is significantly restored after six weeks of supplementation. The expression of antioxidant enzymes changed in RBCs and WBCs in obesity but all proteins restore their positivity after supplementation. We found that: the presence of NF-kB, antioxidant enzymes and eNOS in healthy RBCs could indicate a role of these proteins as regulators of cellular metabolism; obese WBCs showed a higher NF-kB, iNOS and IL-1ß positivity, whereas eNOS presence did not significantly change in these cells. We tried to explain the different positivity of NF-kB, proposing a dual role for this protein, as prolifespan and as proinflammatory processes, depending on examined cells. In conclusion, we have considered the literature that focuses on the omega-6/omega-3 ratio. The ratio changed from the past, especially in people whose diet is strongly westernized worsening the state of health of the patient and leading to an higher incidence of obesity. Our study hypothesizes that the supplementation could help to restore the correct ratio.


Assuntos
Eritrócitos/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Obesidade/fisiopatologia , Adulto , Catalase/metabolismo , Eritrócitos/patologia , Ácidos Graxos Ômega-3/farmacologia , Feminino , Humanos , Inflamação/fisiopatologia , Interleucina-1beta/metabolismo , Pessoa de Meia-Idade , Obesidade/patologia , Superóxido Dismutase-1/metabolismo
5.
Biomed Res Int ; 2019: 1030256, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815120

RESUMO

Background and Aims: The NF-κB pathway has been implicated in the genetic aetiology of psoriatic disease. However, since most patients with arthritis have psoriasis, discerning the genetic contributions to both aspects of psoriatic disease is not easy. Our aim was to study the association of common polymorphisms in genes of the NF-κB pathway in patients with psoriatic disease in order to dissect the contribution of this pathway in the appearance of each component (skin and joint) of the disease. Patients and Methods: We investigated the association between three common variants in NFKB1 (rs230526), NFKBIA (rs7152376), and NFKBIZ (rs3217713 indel) and the risk of developing psoriatic disease. We genotyped a total of 690 psoriatic disease patients and 550 controls. Patients with cutaneous psoriasis of at least 10 years of evolution without associated arthritis were defined to have pure cutaneous psoriasis (PCP). Results: The rare NFKBIA rs7152376 C was significantly more frequent in the PsA group vs. controls (OR = 2.03 (1.3-3.1), p < 0.01). The difference was even higher between PsA and PCP patients (OR = 3.2 (2.1-5.1), p < 0.001). Neither NFKB1 rs230526 nor NFKBIZ rs3217713 indel was associated with the risk of developing psoriatic disease as a whole compared to controls. Conclusions: Our study supports a significant effect of the NFKBIA gene on the risk of developing PsA, thus contributing to better discerning of the polymorphisms of this pathway that explain this risk within the spectrum of psoriatic disease. Additional studies with larger cohorts and from different populations are necessary to validate these results.


Assuntos
Artrite Psoriásica/genética , Artrite Psoriásica/metabolismo , Predisposição Genética para Doença/genética , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Subunidade p50 de NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Psoríase/genética , Fatores de Risco , Espanha
6.
Chem Commun (Camb) ; 55(86): 12980-12983, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31603440

RESUMO

Nuclear factor kappa B p50 (NF-κB p50) induces various biological processes. In this study, a highly selective and sensitive electrochemiluminescence (ECL) biosensor for the detection of NF-κB p50 has been developed, which combines the high selectivity of the proximity hybridization assay (PHA) with the high efficiency of the hybridization chain reaction (HCR).


Assuntos
Técnicas Biossensoriais/métodos , Subunidade p50 de NF-kappa B/análise , DNA/química , Técnicas Eletroquímicas , Eletrodos , Humanos , Medições Luminescentes , Técnicas de Amplificação de Ácido Nucleico , Hibridização de Ácido Nucleico
7.
Dis Markers ; 2019: 6523837, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31612070

RESUMO

Background: The role of the NFKB1 gene rs28362491 polymorphism and NFKBIA gene rs2233406 polymorphism in the development of head and neck cancer (HNC) remains controversial. This meta-analysis was performed to assess the relationship between the gene polymorphisms and HNC quantitatively. Methods: PubMed, Embase, Web of Science, WanFang Data, and China National Knowledge databases were used to search for eligible articles. The relationship was evaluated by STATA 11.0. Results: Eight eligible articles were included in our study. Nine case-control studies from the eight included articles were correlated with rs28362491 polymorphism. Four articles were related to rs2233406 polymorphism. Overall, a significant correlation was observed between the rs28362491 polymorphism and a decreased risk of HNCs (OR = 0.76, 95%CI = 0.60-0.97 for DD vs. II; OR = 0.80, 95%CI = 0.68-0.95 for DD vs. DI+II). In subgroup analyses, the rs28362491 polymorphism was associated with the risk of nasopharyngeal carcinoma (NC), but not with oral cancer (OC). In addition, no statistical correlation was found between the polymorphism of rs2233406 and HNCs. Conclusion: rs28362491 polymorphism was significantly associated with the risk of HNCs, especially with NC. Additionally, our results showed that no association was discovered between rs2233406 polymorphism and HNCs.


Assuntos
Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/genética , Inibidor de NF-kappaB alfa/genética , Subunidade p50 de NF-kappa B/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Expressão Gênica , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/etnologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Polimorfismo Genético , Fatores de Risco
8.
Biomed Pharmacother ; 118: 109382, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545257

RESUMO

Renal cell carcinoma (RCC) is one of the most lethal urological malignancies, yet its pathogenesis remains unclear. Here, we reported a long non-coding RNA (lncRNA), NONHSAT 113026 (NOAT113026), which may play an important role in the pathogenesis of RCC. The expression level of NOAT113026 was estimated by qPCR from 76 pairs of RCC and non-tumor (NT) samples. The correlation between NOAT113026 and clinical data of RCC patients was analyzed. NOAT113026 was overexpressed in 786-O and ACHN cell lines by lentivirus-mediated technology and the oncological behavioral changes of RCC cells were observed along with tumorigenicity in experimental nude mice. Compared to the adjacent tissues, NOAT113026 was noticeably downregulated in RCC. Survival analysis showed that the lower the expression level of NOAT113026 was, the shorter the disease-free survival and overall survival in RCC would be. Overexpression of NOAT113026 can decrease the ability of cell migration, invasion, proliferation, and colony formation by regulating NF-κB/p50 and SLUG through a mechanism that involves lncRNA-mRNA interactions. In conclusion, our data suggest that NOAT113026 could be a carcinostatic RNA in RCC, which may serve as a potential prognostic factor and a promising therapeutic target for malignant RCC.


Assuntos
Carcinogênese/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Subunidade p50 de NF-kappa B/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Biomarcadores Tumorais/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Inflamação/patologia , Masculino , Camundongos Nus , Invasividade Neoplásica , Prognóstico , RNA Longo não Codificante/genética , Regulação para Cima/genética
9.
Int J Mol Sci ; 20(18)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546763

RESUMO

Systemic lupus erythematosus (SLE) is a chronic, multifactorial autoimmune disease that predominantly affects young females. Dysregulation of different immune cell populations leads to self-tolerance breakdown and subsequent multiple organ damage as the disease develops. Plasmacytoid dendritic cells (pDCs) are potent producers of type I interferon (IFN), while myeloid dendritic cells (mDCs) are more specialized in antigen presentations. We have previously reported that bone-marrow (BM)-derived pDCs from the murine lupus model New Zealand black/white F1 (BWF1) possess abnormalities. Therefore, this study continues to investigate what aberrant properties peripheral pDCs and mDCs possess in BWF1 and how they mediate SLE progression, by comparing their properties in pre-symptomatic and symptomatic mice. Results showed that CD11chiCD11b+ myeloid DCs expanded during the disease state with down-regulation of co-stimulatory molecules and major histocompatibility complex class II molecules (MHC II), but their capacity to stimulate T cells was not hampered. During the disease state, this subset of mDCs displayed heightened toll-like receptors 7 and 9 (TLR 7/9) responses with increased interleukin 10 (IL-10) and C-X-C motif chemokine ligand 13 (CXCL13) expressions. Moreover, the expressions of myeloid differentiation primary response 88 (Myd88) and nuclear factor kappa B subunit 1 (Nfkb1) were higher in CD11chiCD11b+ DCs at the disease stage, leading to higher nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 phosphorylation activity. In summary, we reported aberrant phenotypic properties with enhanced TLR7/9 responses of CD11chiCD11b+ DCs in SLE mediated by aberrant NF-κB signaling pathway. Our findings add additional and novel information to our current understanding of the role of DCs in lupus immunopathogenesis. Lastly, molecular candidates in the NF-κB pathway should be exploited for developing therapeutic targets for SLE.


Assuntos
Antígenos CD11/imunologia , Antígeno CD11b/imunologia , Quimiocina CXCL13/imunologia , Células Dendríticas/imunologia , Interleucina-10/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Glicoproteínas de Membrana/imunologia , Subunidade p50 de NF-kappa B/imunologia , Receptor 7 Toll-Like/imunologia , Receptor Toll-Like 9/imunologia , Animais , Antígenos CD11/genética , Antígeno CD11b/genética , Quimiocina CXCL13/genética , Células Dendríticas/patologia , Modelos Animais de Doenças , Feminino , Interleucina-10/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Células Mieloides/imunologia , Células Mieloides/patologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Subunidade p50 de NF-kappa B/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptor 7 Toll-Like/genética , Receptor Toll-Like 9/genética
10.
Exp Mol Pathol ; 111: 104313, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31533021

RESUMO

PURPOSE: To analyze the activation of NFκB1/p50 in the inflammatory and non-inflammatory environment of uveal melanoma and its association with clinicopathological factors and patient outcome. METHODS: Activation of NFκB1/p50 was evaluated in 75 cases of uveal melanoma by immunohistochemistry. mRNA expression in 58 fresh UM specimen was measured by quantitative reverse-transcriptase PCR (qRT-PCR). Western blotting was performed to validate the immunohistochemistry results in representative cases. RESULTS: Forty-five cases showed both cytoplasmic and nuclear immunoreactivity of NFκB1/p50. Increased level of NFκB1/p50 activation was more frequent in the inflammatory environment group as compared to non-inflammatory environment group at both transcriptional and translational level. In multivariate analysis, infiltrating macrophages and nuclear immunoreactivity of NFκB1/p50 (p < .05) in tumor cells were found to be an independent prognostic factor for poor survival. CONCLUSION: Our results suggest that nuclear immunoreactivity NFκB1/p50 may serve as a useful marker in assessing the prognosis of uveal melanoma patients.


Assuntos
Núcleo Celular/metabolismo , Inflamação/patologia , Melanoma/patologia , Subunidade p50 de NF-kappa B/metabolismo , Neoplasias Uveais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/genética , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Melanoma/imunologia , Melanoma/metabolismo , Pessoa de Meia-Idade , Subunidade p50 de NF-kappa B/genética , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Neoplasias Uveais/imunologia , Neoplasias Uveais/metabolismo , Adulto Jovem
11.
Neurochem Res ; 44(11): 2619-2630, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31562575

RESUMO

Andrographolide from leaves of Andrographis paniculata has been known to possess various bioactivities. In the present study, we aimed to explore the neuroprotection of andrographolide against inflammation-mediated injury and oxidative damage. In initial studies, our findings showed that pretreatment with andrographolide could effectively reduce neuronal cell death caused by LPS-induced conditioned supernatants. The further results indicated that this neuroprotective effect may be mainly due to the inhibition on the production of NO, TNF-α, IL-6, ROS, iNOS and enhancement of expression of anti-inflammatory marker CD206. Moreover, mechanism study revealed that the anti-inflammatory activity of andrographolide may be related to the suppression of nuclear translocation of NF-κB as well as the activation of Nrf2 and HO-1. Our study also showed that andrographolide could scavenge ROS and protect PC12 cells against H2O2- and 6-OHDA-mediated oxidative damage. In addition, several derivatives of andrographolide were prepared for evaluating the role of 3, 14, 19-hydroxy group on anti-inflammatory effect and cytoprotection of andrographolide. In conclusion, andrographolide protected neurons against inflammation-mediated injury via NF-κB inhibition and Nrf2/HO-1 activation and resisted oxidative damage via inhibiting ROS production. Our results will contribute to further exploration of the therapeutic potential of andrographolide in relation to neuroinflammation and neurodegenerative diseases.


Assuntos
Diterpenos/farmacologia , Inflamação/tratamento farmacológico , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Heme Oxigenase-1/metabolismo , Peróxido de Hidrogênio/metabolismo , Lipopolissacarídeos , Proteínas de Membrana/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células PC12 , Ratos
12.
PLoS One ; 14(9): e0222033, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31490979

RESUMO

BACKGROUND: Pregnane X receptor (PXR) regulates the expression of drug-metabolizing enzymes and transport enzymes. NF-κB not only plays a role in liver homeostasis and injury-healing processes by regulating inflammatory responses but may also regulate the transcription of PXR. Currently, genetic polymorphisms in PXR are associated with adverse drug effects. Because little is known about the association between NF-κB1 genetic polymorphisms and adverse drug reactions, we explored the association between PXR and NF-κB1 single nucleotide polymorphisms (SNPs) and susceptibility to anti-tuberculosis drug-induced liver injury (ATDILI). MATERIALS AND METHODS: A total of 746 tuberculosis patients (118 with ATDILI and 628 without ATDILI) were prospectively enrolled at West China Hospital between December 2014 and April 2018. Nine selected SNPs (rs3814055, rs13059232, rs7643645 and rs3732360 in PXR and rs78872571, rs4647992, rs60371688, rs1598861 and rs3774959 in NF-κB1) were genotyped with a custom-designed 2x48-plex SNP Scan TM Kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between patients with or without ATDILI, while joint effect analysis of the SNP-SNP interactions was performed using multiplicative and additive models. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. RESULTS: The T allele of rs3814055 in PXR was associated with a decreased risk for ATDILI (OR 0.61; 95% CI: 0.42-0.89, p = 0.0098). The T alleles of rs78872571 and rs4647992 in NF-κB1 were significantly associated with an increased risk for ATDILI (OR 1.91; 95% CI: 1.06-3.43, p = 0.028 and OR 1.81; 1.06-3.10, p = 0.029, respectively). The allele, genotype and genetic model frequencies were similar in the two groups for the other six SNPs (all P>0.05). There were no multiplicative or additive interactions between the SNPs. CONCLUSION: Our study is the first to reveal that rs3814055 variants in PXR and rs78872571 and rs4647992 variants in NF-κB1 are associated with susceptibility to ATDILI caused by first-line anti-tuberculosis combination treatment in the Han Chinese population.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Subunidade p50 de NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Receptor de Pregnano X/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Masculino , Estudos Prospectivos
13.
Artigo em Inglês | MEDLINE | ID: mdl-31421522

RESUMO

We studied the influence of dietary n6/n3 ratio and docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids supplementation on fatty acid profile, lipid peroxidation and NFκ/p50 expression in diabetes type 2. Treatments consisted of three dietary n6/n3 ratios: 6 (Control), 50 (high n6) and 1 (DHA and EPA supplemented). Half of the rats in each of the dietary treatments were made diabetic using the fructose/low-streptozotocin model. The Control and high n6 diets decreased EPA/ARA (arachidonic acid) ratios in the plasma and in the hepatic tissue suggesting proinflammatory fatty acid profile. The high n6 diet additionally increased the 4-HNE and NFκ/p50 expression in the hepatic tissue. These changes were the consequence of a decrease in the plasma content of DHA and EPA and an increase in the content of arachidonic acid in the liver neutral lipids. The supplementation with the DHA and EPA attenuated the change in EPA/ARA ratios, which imply the importance of the n6/n3 ratio in diabetes type 2.


Assuntos
Ácido Araquidônico/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Suplementos Nutricionais , Ácido Eicosapentaenoico/sangue , Frutose/farmacologia , Subunidade p50 de NF-kappa B/metabolismo , Estreptozocina/farmacologia , Animais , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Graxos Ômega-6/metabolismo , Frutose/administração & dosagem , Peroxidação de Lipídeos , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem
14.
J Biol Chem ; 294(38): 14009-14019, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31362988

RESUMO

Lipid phosphate phosphatase 3 (LPP3), encoded by the PLPP3 gene, is an integral membrane enzyme that dephosphorylates phosphate esters of glycero- and sphingophospholipids. Cell surface LPP3 can terminate the signaling actions of bioactive lysophosphatidic acid (LPA) and sphingosine 1 phosphate, which likely explains its role in developmental angiogenesis, vascular injury responses, and cell migration. Heritable variants in the final intron PLPP3 associate with interindividual variability in coronary artery disease risk that may result from disruption of enhancer sequences that normally act in cis to increase expression of the gene. However, the mechanisms regulating PLPP3 expression are not well understood. We show that the human PLPP3 promoter contains three functional NF-κB response elements. All of these are required for maximal induction of PLPP3 promoter activity in reporter assays. The identified sequences recruit RelA and RelB components of the NF-κB transcription complex to chromatin, and these transcription factors bind to the identified target sequences in two different cell types. LPA promotes binding of Rel family transcription factors to the PLPP3 promoter and increases PLPP3 gene expression through mechanisms that are attenuated by an NF-κB inhibitor, LPA receptor antagonists, and inhibitors of phosphoinositide 3 kinase. These findings indicate that up-regulation of PLPP3 during inflammation and atherosclerosis results from canonical activation of the NF-κB signaling cascade to increase PLPP3 expression through nuclear import and binding of RelA and RelB transcription factors to the PLPP3 promoter and suggest a mechanism by which the LPP3 substrate, LPA, can regulate PLPP3 expression.


Assuntos
NF-kappa B/genética , NF-kappa B/metabolismo , Fosfatidato Fosfatase/biossíntese , Fosfatidato Fosfatase/genética , Regulação da Expressão Gênica , Humanos , Proteínas I-kappa B/metabolismo , Lisofosfolipídeos/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Fosfatidato Fosfatase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Regiões Promotoras Genéticas , Transdução de Sinais , Esfingolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Células THP-1 , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelB/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética
15.
Inflammation ; 42(6): 1925-1938, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31463646

RESUMO

Recently, microRNAs (miRNAs) have been demonstrated to play important roles in the cardiovascular system, including heart, blood vessels, plasma, and vascular diseases. Deep vein thrombosis (DVT) refers to the formation of blood clot in the deep veins of the human body and is a common peripheral vascular disease. Herein, we explored the mechanism of miR-9-5p in DVT through nuclear factor-κB (NF-κB). The expression of miR-9-5p in DVT rats was measured through the establishment of DVT rat models, followed by the alteration of miR-9-5p and NF-κB p50 in rats through the injection of constructed lentiviral vectors so as to explore the role of miR-9-5p and NF-κB p50 expression in rats. Next, the expression of NF-κB p50 and levels of inflammation-related factors plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin-8 (IL-8) were measured after the injection with lentiviral vectors, followed by the assessment of platelet aggregation and TXB2 content. MiR-9-5p was found to be downregulated in DVT rats. Through dual luciferase reporter gene assay, NF-κB p50 was verified as the target gene of miR-9-5p and miR-9-5p could negatively regulate NF-κB p50. MiR-9-5p over-expression decreased the levels of PAI-1, TNF-α, IL-6, and IL-8 and platelet aggregation as well as TXB2 content, thus inhibiting thrombosis. Meanwhile, over-expressed NF-κB p50 could reverse the anti-inflammatory or anti-thrombotic effect of miR-9-5p. In summary, miR-9-5p over-expression can suppress the NF-κB signaling pathway through p50 downregulation, thus alleviating inflammation and thrombosis in DVT rats. MiR-9-5p could serve as a potential therapeutic target for DVT.


Assuntos
Inflamação/prevenção & controle , MicroRNAs/fisiologia , Subunidade p50 de NF-kappa B/antagonistas & inibidores , Trombose Venosa/patologia , Animais , Regulação da Expressão Gênica , Inflamação/etiologia , Interleucina-6/sangue , Interleucina-8/sangue , MicroRNAs/genética , MicroRNAs/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Agregação Plaquetária , Substâncias Protetoras/farmacologia , Ratos , Tromboxano B2/sangue , Fator de Necrose Tumoral alfa/sangue
16.
Asian Pac J Cancer Prev ; 20(8): 2493-2502, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450925

RESUMO

Background: Biomarkers play an important role in oncology, including risk assessment, treatment prediction, and monitoring the progression of disease. In breast cancer, many genes are used as biomarkers. Since, several SNP variations of hallmark ­ related genes have been reported to be of value in risk prediction in various cancers and populations, some genetic polymorphism loci were combined and reported as biomarkers for use in the risk assessment of breast cancer in Thai people. Methods: Twelve cancer gene hallmarks (15 polymorphic loci) were selected and genotyped in 184 breast cancer patients and 176 healthy individuals in Phitsanulok, Thailand. Results: AA genotype of CD44 rs187116 (c.67+4883G>A), the C allele of CD133 rs2240688 (c.*667A>C), the *2 allele (4 bp deletion) of NF-κB1 rs28362491 and the homozygous null allele genotype of GSTM1 were significantly associated with an increased risk of breast cancer (p<0.05). A combination of these 4 significant loci showed that AA-AA-*1*1-homozygous null allele genotype has the greatest correlation with increased risk of breast cancer (OR = 21.00; 95% CI: 1.77 to 248.11; p = 0.015), followed by GA-AA-*2*2- homozygous null allele genotype (p = 0.037) and GG-AC-*1*2- homozygous null allele genotype (p = 0.028). Conclusion: These findings suggest that the polymorphisms of CD44 rs187116 (c.67+4883G>A), CD133 rs2240688 (c.*667A>C), NF-κB1 rs28362491 and GSTM1 homozygous null allele genotype might be associated with an increased risk of breast cancer, and this gene combination could possibly be used as biomarkers for risk prediction, which would be of benefit in planning health surveillance and cancer prevention.


Assuntos
Antígeno AC133/genética , Neoplasias da Mama/diagnóstico , Deleção de Genes , Glutationa Transferase/genética , Receptores de Hialuronatos/genética , Subunidade p50 de NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Biomarcadores Tumorais/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Incidência , Prognóstico , Fatores de Risco , Tailândia/epidemiologia
17.
Life Sci ; 233: 116731, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31394128

RESUMO

AIMS: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by widespread inflammation. LncRNA taurine-up-regulated gene 1 (TUG1) has been reported to be involved in multiple biological processes and human diseases. The aim of this study was to investigate the role of lncRNA TUG1 in MS and the underlying mechanism. MAIN METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Lentiviral vectors encoding sh-TUG1 was constructed to silence TUG1 in MOG-EAE mice by intracerebroventricular (ICV) injection. The effect of TUG1 on inflammation in MS was evaluated by real-time PCR, Western blot, ELISA and Hematoxylin-eosin staining. To further study the mechanism of TUG1 in MS, TUG1 knockdown and miR-9-5p overexpression were performed in LPS-induced BV2 cells. KEY FINDINGS: Down-regulation of TUG1 improved mice behavior, reduced granulocyte-macrophage colony stimulating factor (GM-CSF) level, decreased the levels of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-6 and IL-17, and increased IL-10 in EAE mice. Notably, TUG1 expression was negatively correlated with miR-9-5p expression, while positively correlated with NF-κB1/p50. Knockdown of TUG1 or enforced expression of miR-9-5p inhibited LPS-induced inflammation in BV2 cells, while these effects were abolished by inhibition of miR-9-5p. We further verified that TUG1 negatively regulated miR-9-5p expression and NF-κB1/p50 is a direct target of miR-9-5p. SIGNIFICANCE: Down-regulation of TUG1 attenuates MS through inhibition of inflammation by sponging miR-9-5p via targeting NF-κB1/p50, suggesting that TUG1 is a potential therapeutic target for MS treatment.


Assuntos
Encefalomielite Autoimune Experimental/prevenção & controle , Regulação da Expressão Gênica , Inflamação/prevenção & controle , MicroRNAs/genética , Esclerose Múltipla/prevenção & controle , Subunidade p50 de NF-kappa B/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , Animais , Apoptose , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/genética , RNA Longo não Codificante/genética , Ativação Transcricional
18.
Biosens Bioelectron ; 142: 111574, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408824

RESUMO

The monitoring of transcription factors (TFs) is critical for understanding the regulation of gene transcriptions. Here, by programming nucleic acid sequence-based and cascaded recycling amplifications, we developed a sensitive and non-label electrochemical biosensor for detecting TFs from tumor cell extracts. The binding of the target nuclear factor-kappa B p50 (NF-κB p50) with the dsDNA probes protects them from being digested by exonuclease III for subsequent initiation of three cascaded recycling cycles, which causes the generation of tremendous free G-quadruplex special sequences on the sensing electrode. Such G-quadruplexes can specifically bind and confine hemin within the vicinity of the sensor, generating substantially enhanced reduction current to achieve determination of NF-κB p50 within the range from 0.5 pM to 5 nM with the detection limit down to 0.13 pM. The proposed sensing system also has high selectivity and it can be used to interrogate the presence of NF-κB p50 in tumor cell extracts, demonstrating its potential for disease diagnosis and gene transcription-related studies.


Assuntos
Técnicas Biossensoriais/métodos , Subunidade p50 de NF-kappa B/análise , Sondas de DNA/química , DNA Catalítico/química , Técnicas Eletroquímicas/métodos , Exodesoxirribonucleases/química , Quadruplex G , Células HeLa , Hemina/química , Humanos , Neoplasias/patologia , Técnicas de Amplificação de Ácido Nucleico/métodos
19.
Acta Pharmacol Sin ; 40(12): 1503-1512, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31388087

RESUMO

Parkinson's disease (PD) is a multifactorial disorder characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LBs) consisting of misfolded α-synuclein protein. The etiology of PD is still not clear but systemic inflammation is proved to trigger and exacerbate DA neurons degeneration. Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) and plays a major role in promoting the host immune. TLR4-mediated signal pathways induce the release of many inflammatory cytokines. It is reasonable to hypothesize that TLR4 is the mediator in microglia contributing to the damage of DA neurons in the SNpc. In this study, we evaluated the role of TLR4 in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid mouse model. Both TLR4-deficient and wild-type (WT) mice were injected with probenecid (250 mg/kg, i.p.) followed by injection of MPTP (25 mg/kg, s.c.) every 4 days for 10 times. From D43 to D47, the behavioral performance in pole test and wire hang test was assessed. Then the mice were euthanized, and SN and striatum were dissected out for biochemical tests. We showed that compared with MPTP-treated WT mice, TLR4 deficiency significantly attenuated MPTP-induced motor deficits and TH-protein expression reduction in SNpc and striatum, suppressed MPTP-induced α-synuclein abnormality and neuroinflammation mediated through oxidative stress, glial activation, NF-κB and the NLRP3 inflammasome signaling pathways. These findings highlight the neuroprotective effect of TLR4-pathways in the chronic MPTP-induced PD mouse model.


Assuntos
Doença de Parkinson Secundária/fisiopatologia , Receptor 4 Toll-Like/fisiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Inflamassomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , Subunidade p50 de NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Probenecid , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/genética , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
20.
Exp Oncol ; 41(2): 90-94, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31262162

RESUMO

Asafoetida resin has been reported for various biological activities but its use has been widely restricted owing to its pungent smell and pool water solubility. AIM: In vitro study of the anticancer potential of microwave-extracted essential oil (EO) of Ferula asafoetida. MATERIALS AND METHODS: The phytochemical investigation and in vitro cytotoxicity assessment was carried out in two human liver cancer cell lines. The expression of NFKB1, TGFB1, TNF, CASP3 was analyzed by reverse transcription polymerase chain reaction. RESULTS: Ferula asafoetida EO contains high concentrations of dithiolane, which possess antiproliferative activity in human liver carcinoma cell lines (HepG2 and SK-Hep1) in a dose-dependent manner. The bioactive compounds in F. asafoetida are capable of induction of apoptosis and altered NF-kB and TGF-ß signalling with increase in caspase-3 and TNF-α expression. CONCLUSION: Further elucidation of bioactive molecules and underlying mechanisms could lead to potential intervention in liver cancer in animal models. The safety and efficacy as well as the mode of EO action in animal models would be highly crucial.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Óleos Voláteis/farmacologia , Óleos Vegetais/farmacologia , Caspase 3/biossíntese , Linhagem Celular Tumoral , Ferula/química , Células Hep G2 , Humanos , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/biossíntese , Proteínas/metabolismo , Resinas Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/biossíntese , Fator de Crescimento Transformador beta1/metabolismo
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