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1.
J Chem Phys ; 151(17): 175101, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703512

RESUMO

Recently, a "mode-hopping" phenomenon has been observed in a NF-κB gene regulatory network with oscillatory tumor necrosis factor (TNF) inputs. It was suggested that noise facilitates the switch between different oscillation modes. However, the underlying mechanism of this noise-induced "cellular mode-hopping" behavior remains elusive. We employed a landscape and flux approach to study the stochastic dynamics and global stability of the NF-κB regulatory system. We used a truncated moment equation approach to calculate the probability distribution and potential landscape for gene regulatory systems. The potential landscape of the NF-κB system exhibits a "double ring valley" shape. Barrier heights from landscape topography provide quantitative measures of the global stability and transition feasibility of the double oscillation system. We found that the landscape and flux jointly govern the dynamical "mode-hopping" behavior of the NF-κB regulatory system. The landscape attracts the system into a "double ring valley," and the flux drives the system to move cyclically. As the external noise increases, relevant barrier heights decrease, and the flux increases. As the amplitude of the TNF input increases, the flux contribution, from the total driving force, increases and the system behavior changes from one to two cycles and ultimately to chaotic dynamics. Therefore, the probabilistic flux may provide an origin of chaotic behavior. We found that the height of the peak of the power spectrum of autocorrelation functions and phase coherence is correlated with barrier heights of the landscape and provides quantitative measures of global stability of the system under intrinsic fluctuations.


Assuntos
NF-kappa B/metabolismo , Fatores de Necrose Tumoral/genética , Difusão , Redes Reguladoras de Genes , Fatores de Necrose Tumoral/metabolismo
2.
Artif Cells Nanomed Biotechnol ; 47(1): 3758-3764, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31556307

RESUMO

Diabetic retinopathy (DR) is one of the most common diabetic complications and remains the leading cause of vision loss among adults. C1q/TNF-related protein 3 (CTRP3) is a member of CTRP family that has been found to be involved in the progression of diabetes mellitus and diabetic complications. However, the role of CTRP3 in DR has not been fully understood. In the present study, the results showed that CTRP3 expression was significantly decreased in DR patients compared with controls. In vitro investigations proved that overexpression of CTRP3 improved cell viability of ARPE-19 cells in response to high glucose (HG) stimulation. CTRP3 also attenuated HG-induced oxidative stress in ARPE-19 cells with decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and increased superoxide dismutase (SOD) activity. Apoptotic rate was significantly decreased in CTRP3 overexpressing ARPE-19 cells. Besides, bcl-2 expression was increased, while bax expression was decreased by CTRP3 overexpression. Moreover, overexpression of CTRP3 enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) pathway in HG-stimulated ARPE-19 cells, and Nrf2 knockdown reversed CTRP3-mediated oxidative stress and apoptosis. These findings suggested that CTRP3 attenuated HG-stimulated oxidative stress and apoptosis in ARPE-19 cells, which were mediated by activation of Nrf2/HO-1 pathway.


Assuntos
Apoptose/efeitos dos fármacos , Glucose/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/citologia , Fatores de Necrose Tumoral/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo
3.
Diabetes Metab Syndr ; 13(3): 1923-1927, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31235116

RESUMO

Adipokines are cytokines produced by adipocytes that may mediate inflammatory processes, whilst adipocyte-derived proteins may have the converse effect. C1q/TNF-related protein-3 or CTRP3 is a novel adipokine that is expressed and released by most types of human tissues including adipose tissue. This adipokine, considered as an adiponectin, can normalize blood glucose by several mechanisms. In addition, it can modulate the expression/secretion of other cytokine and adipokines leading to lower insulin resistance in peripheral tissues. Beneficial effects of CTRP3 against hyperglycemia-induced complications in the kidney and eye have been reported. In this review, we have presented the latest findings on the in vitro and in vivo hypoglycemic effects of CTRP3, followed by the findings on the preventive/therapeutic effects of CTRP3 adipokines against diabetes related complications.


Assuntos
Complicações do Diabetes/prevenção & controle , Homeostase , Hiperglicemia/prevenção & controle , Fatores de Necrose Tumoral/metabolismo , Glicemia/análise , Complicações do Diabetes/etiologia , Complicações do Diabetes/metabolismo , Humanos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Resistência à Insulina
4.
Int J Biol Macromol ; 134: 73-79, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075328

RESUMO

In vertebrates, tumor necrosis factors (TNFs) are well-known cytokines involved in a diversity of physiological and pathological events. In the present work we identified a novel TNF-like gene (MnTNF) from Macrobrachium nipponense, which codes for a protein sharing detectable sequence identify (26-27%) to the mammalian TNFSF members, TWEAK and EDA. Tissue distribution analysis indicated that MnTNF was predominantly expressed in nervous tissue, and at relatively high level in haemocytes, gill, intestine and muscle, whereas was almost undetectable in hepatopancreas. In gill, MnTNF was significantly up-regulated at both mRNA as well protein levels upon Aeromonas veronii challenge. RNA interference (RNAi) mediated MnTNF silencing led to a significant overexpression of the antimicrobial peptide (AMP) gene crustin, but a non-significant overexpression of another AMP gene anti-lipopolysaccharide factor (ALF), and inhibited the activation of phenoloxidase (PO) significantly following bacterial challenge. Meanwhile, the expression of NF-κB-like factor gene relish was increased while that of dorsal and STAT was uninfluenced in MnTNF-depleted prawn. We suppose that MnTNF be involved in regulating the expression of AMP genes and the capacity of PO by coordinating with the Imd pathway.


Assuntos
Sistema Imunitário/fisiologia , Palaemonidae/fisiologia , Fatores de Necrose Tumoral/metabolismo , Animais , Clonagem Molecular , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Homeostase , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Filogenia , Análise de Sequência de DNA
5.
Asian Pac J Cancer Prev ; 20(5): 1457-1462, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31127908

RESUMO

Objectives: Hepatocellular carcinoma is one of the most frequent cancers worldwide, for the treatment of which various therapy protocols and drugs have been introduced; however, none of them has suppressed cancer tissues completely. New research programs have been developed on cancer and the accompanied effects of novel synthesized compounds on cancer cell lines. Our latest reports on the molecular basis of cancer revealed a pattern of changes in gene expression triggered in the cancer pathway. Methods: HepG2 cell lines were cultured under similar conditions in both test and control groups. The IC50 concentration of the (2R, 4S)-N-(2, 5-difluorophenyl)-4-hydroxy-1-(2, 2, 2-trifluoroacetyl) pyrrolidine-2-carboxamide compound was used in the treatment group. After 48 hours from the culture, the expressional profiles of apoptosis pathway genes (84 genes) were studied using the PCR array method. Results: The findings demonstrated that the expression of some apoptosis-related genes pertaining to TNF, BCL2, IAP, and caspase families was regulated by (2R, 4S)-N-(2, 5-difluorophenyl)-4-Hydroxy-1-(2, 2, 2-Trifluoroacetyl) Pyrrolidine-2-Carboxamide. In the same vein, an alteration was observed in the expression of both pro-apoptotic and anti-apoptotic genes associated with the extrinsic and intrinsic apoptosis signaling pathways. Conclusions: According to the data obtained, the pyrrolidine-2-carboxamide compound was demonstrated to be able to regulate the apoptotic activities of HepG2 cells by affecting both pro-apoptotic and anti-apoptotic relevant genes.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pirrolidinas/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Necrose Tumoral/metabolismo
6.
J Immunol ; 202(6): 1693-1703, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30760623

RESUMO

Although the expansion of myeloid-derived suppressor cells (MDSCs) has been reported in autoimmune disorders, it is largely unclear how MDSCs contribute to the development of primary Sjögren syndrome (pSS). In this study, we found significantly increased MDSCs with gradually diminished suppressive capacity during disease development in mice with experimental Sjögren syndrome (ESS). The ligand for glucocorticoid-induced TNFR family-related protein (GITRL) was increased along ESS progression, whereas the increased GITRL was found to attenuate the immunosuppressive function of MDSCs. Moreover, blocking GITR signal in MDSCs significantly restored their immunosuppressive function and alleviated ESS progression in mice. In pSS patients, expanded MDSCs were found to express low levels of arginase. Significantly increased serum GITRL levels were closely correlated with patients with higher Sjögren syndrome disease activity index. Furthermore, treatment with recombinant GITRL markedly reduced the immunosuppressive function of human MDSCs. Together, our studies have demonstrated a critical role of GITRL in modulating the suppressive function of MDSCs, which may facilitate the validation of GITRL as a therapeutic target for the treatment of pSS.


Assuntos
Células Supressoras Mieloides/imunologia , Síndrome de Sjogren/imunologia , Fatores de Necrose Tumoral/imunologia , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Síndrome de Sjogren/metabolismo , Fatores de Necrose Tumoral/metabolismo
7.
Nat Commun ; 10(1): 190, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30643147

RESUMO

A number of different B cell subsets have been shown to exhibit regulatory activity using a variety of mechanisms to attenuate inflammatory diseases. Here we show, using anti-CD20-mediated partial B cell depletion in mice, that a population of mature B cells distinguishable by IgDlow/- expression maintains tolerance by, at least in part, promoting CD4+Foxp3+ regulatory T cell homeostatic expansion via glucocorticoid-induced tumor necrosis factor receptor ligand, or GITRL. Cell surface phenotyping, transcriptome analysis and developmental study data show that B cells expressing IgD at a low level (BDL) are a novel population of mature B cells that emerge in the spleen from the transitional-2 stage paralleling the differentiation of follicular B cells. The cell surface phenotype and regulatory function of BDL are highly suggestive that they are a new B cell subset. Human splenic and peripheral blood IgDlow/- B cells also exhibit BDL regulatory activity, rendering them of therapeutic interest.


Assuntos
Subpopulações de Linfócitos B/imunologia , Dermatite de Contato/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Tolerância Imunológica , Linfócitos T Reguladores/imunologia , Animais , Subpopulações de Linfócitos B/metabolismo , Separação Celular/métodos , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Citometria de Fluxo/métodos , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Imunoglobulina D/metabolismo , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos C57BL , Oxazolona/imunologia , Baço/citologia , Baço/crescimento & desenvolvimento , Baço/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Necrose Tumoral/imunologia , Fatores de Necrose Tumoral/metabolismo
8.
Proc Natl Acad Sci U S A ; 116(7): 2634-2639, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30683721

RESUMO

Random amino acid copolymers used in the treatment of multiple sclerosis in man or experimental autoimmune encephalomyelitis (EAE) in mice [poly(Y,E,A,K)n, known as Copaxone, and poly(Y,F,A,K)n] function at least in part by generation of IL-10-secreting regulatory T cells that mediate bystander immunosuppression. The mechanism through which these copolymers induce Tregs is unknown. To investigate this question, four previously described Vα3.2 Vß14 T cell receptor (TCR) cDNAs, the dominant clonotype generated in splenocytes after immunization of SJL mice, that differed only in their CDR3 sequences were utilized to generate retrogenic mice. The high-level production of IL-10 as well as IL-5 and small amounts of the related cytokines IL-4 and IL-13 by CD4+ T cells isolated from the splenocytes of these mice strongly suggests that the TCR itself encodes information for specific cytokine secretion. The proliferation and production of IL-10 by these Tregs was costimulated by activation of glucocorticoid-induced TNF receptor (GITR) (expressed at high levels by these cells) through its ligand GITRL. A mechanism for generation of cells with this specificity is proposed. Moreover, retrogenic mice expressing these Tregs were protected from induction of EAE by the appropriate autoantigen.


Assuntos
Células-Tronco Hematopoéticas/citologia , Interleucina-10/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Animais , DNA Complementar , Encefalomielite Autoimune Experimental/imunologia , Feminino , Vetores Genéticos , Tolerância Imunológica , Interleucinas/metabolismo , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Fatores de Necrose Tumoral/metabolismo
9.
J Cell Sci ; 132(3)2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30659112

RESUMO

The interaction between tumor cells and macrophages is crucial in promoting tumor invasion and metastasis. In this study, we examined a novel mechanism of intercellular communication, namely membranous actin-based tunneling nanotubes (TNTs), that occurs between macrophages and tumor cells in the promotion of macrophage-dependent tumor cell invasion. The presence of heterotypic TNTs between macrophages and tumor cells induced invasive tumor cell morphology, which was dependent on EGF-EGFR signaling. Furthermore, reduction of a protein involved in TNT formation, M-Sec (TNFAIP2), in macrophages inhibited tumor cell elongation, blocked the ability of tumor cells to invade in 3D and reduced macrophage-dependent long-distance tumor cell streaming in vitro Using an in vivo zebrafish model that recreates macrophage-mediated tumor cell invasion, we observed TNT-mediated macrophage-dependent tumor cell invasion, distant metastatic foci and areas of metastatic spread. Overall, our studies support a role for TNTs as a novel means of interaction between tumor cells and macrophages that leads to tumor progression and metastasis.


Assuntos
Neoplasias da Mama/genética , Comunicação Celular/genética , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Macrófagos/metabolismo , Neoplasias Mamárias Animais/genética , Animais , Transporte Biológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Embrião não Mamífero , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Células Epiteliais/patologia , Células Epiteliais/ultraestrutura , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Xenoenxertos , Humanos , Macrófagos/ultraestrutura , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Cultura Primária de Células , Células RAW 264.7 , Ratos , Transdução de Sinais , Fatores de Necrose Tumoral/genética , Fatores de Necrose Tumoral/metabolismo , Peixe-Zebra
10.
Biochim Biophys Acta Mol Cell Res ; 1866(4): 598-611, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30615901

RESUMO

The Inhibitor of Nuclear Factor Kappa B Kinase Subunit Epsilon (IKKε) is an oncogenic protein that is up-regulated in various types of human cancers, including breast tumors. This kinase regulates diverse processes associated with malignant progression including proliferation, invasion, and metastasis. To delve into the molecular mechanisms regulated by this kinase we performed RNA-seq and network analysis of breast cancer cells overexpressing IKKε. We found that the TNF/NF-κB cascade was clearly enriched, and in accordance, NF-κB pathway inhibition in these cells resulted in a decreased expression of IKKε target genes. Interestingly, we also found an enrichment of a mammary stemness functional pathway. Upregulation of IKKε led to an increase of a stem CD44+/CD24-/low population accompanied by a high expression of stem markers such as ALDH1A3, NANOG, and KLF4 and with an increased clonogenic ability and mammosphere formation capacity. These results were corroborated with in vivo dilution assays in zebrafish embryos which showed a significant increase in the number of Cancer Stem Cells (CSCs). Finally, we found that Triple-Negative breast tumors, which are enriched in CSCs, display higher levels of IKKε than other breast tumors, supporting the association of this kinase with the stem phenotype. In conclusion, our results highlight the role of IKKε kinase in the regulation of the stem cell phenotype in breast cancer cells, as assessed by expression, functional and in vivo assays. These results add to the potential use of this kinase as a therapeutic target in this neoplasia.


Assuntos
Neoplasias da Mama/enzimologia , Quinase I-kappa B/metabolismo , Células-Tronco Neoplásicas/enzimologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Interferons/metabolismo , Células MCF-7 , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Fatores de Necrose Tumoral/metabolismo , Peixe-Zebra
11.
Behav Pharmacol ; 30(1): 36-44, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29847337

RESUMO

Parkinson's disease (PD) causes major changes in dopaminergic neurons of the brain, resulting in motor symptoms in older adults. A previous study showed that Danshensu alleviates the cognitive decline by attenuating neuroinflammation. In the present study, we investigated the neuroprotective effect of Danshensu in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. C57BL/6 mice were randomly divided into the following four groups: control, MPTP, Danshensu at 15 mg/kg, and Danshensu at 60 mg/kg. The mice were administered Danshensu intragastrically for 14 days. In the behavioral tests, Danshensu treatment alleviated motor dysfunction induced by MPTP. The number of tyrosine hydroxylase-positive neurons in the substantia nigra was significantly reduced in the MPTP group, relative to the control group; Danshensu partially blocked this reduction in tyrosine hydroxylase-positive neurons. In addition, Danshensu attenuated the reductions in striatal dopamine and 5-HT levels induced by MPTP. Danshensu also diminished the increase in Iba1-positive cells in the substantia nigra and reduced the levels of interleukin-1ß and tumor necrosis factor-α in the striatum. These findings suggest that Danshensu exerts neuroprotective effects and improves motor function in PD mice, at least in part, by reducing neuroinflammation.


Assuntos
Lactatos/uso terapêutico , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Teste de Desempenho do Rota-Rod , Serotonina/metabolismo , Fatores de Necrose Tumoral/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
12.
Mucosal Immunol ; 12(2): 363-377, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30487647

RESUMO

T-cell responses in the lung are critical for protection against respiratory pathogens. TNFR superfamily members play important roles in providing survival signals to T cells during respiratory infections. However, whether these signals take place mainly during priming in the secondary lymphoid organs and/or in the peripheral tissues remains unknown. Here we show that under conditions of competition, GITR provides a T-cell intrinsic advantage to both CD4 and CD8 effector T cells in the lung tissue, as well as for the formation of CD4 and CD8 tissue-resident memory T cells during respiratory influenza infection in mice. In contrast, under non-competitive conditions, GITR has a preferential effect on CD8 over CD4 T cells. The nucleoprotein-specific CD8 T-cell response partially compensated for GITR deficiency by expansion of higher affinity T cells; whereas, the polymerase-specific response was less flexible and more GITR dependent. Following influenza infection, GITR is expressed on lung T cells and GITRL is preferentially expressed on lung monocyte-derived inflammatory antigen presenting cells. Accordingly, we show that GITR+/+ T cells in the lung parenchyma express more phosphorylated-ribosomal protein S6 than their GITR-/- counterparts. Thus, GITR signaling within the lung tissue critically regulates effector and tissue-resident memory T-cell accumulation.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Vírus da Influenza A/imunologia , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Linfócitos T/imunologia , Fatores de Necrose Tumoral/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Células Cultivadas , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Memória Imunológica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Quinases S6 Ribossômicas/metabolismo , Fatores de Necrose Tumoral/genética
13.
Physiol Rev ; 99(1): 115-160, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30354964

RESUMO

The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies (TNFSF/TNFRSF) include 19 ligands and 29 receptors that play important roles in the modulation of cellular functions. The communication pathways mediated by TNFSF/TNFRSF are essential for numerous developmental, homeostatic, and stimulus-responsive processes in vivo. TNFSF/TNFRSF members regulate cellular differentiation, survival, and programmed death, but their most critical functions pertain to the immune system. Both innate and adaptive immune cells are controlled by TNFSF/TNFRSF members in a manner that is crucial for the coordination of various mechanisms driving either co-stimulation or co-inhibition of the immune response. Dysregulation of these same signaling pathways has been implicated in inflammatory and autoimmune diseases, highlighting the importance of their tight regulation. Investigation of the control of TNFSF/TNFRSF activities has led to the development of therapeutics with the potential to reduce chronic inflammation or promote anti-tumor immunity. The study of TNFSF/TNFRSF proteins has exploded over the last 30 yr, but there remains a need to better understand the fundamental mechanisms underlying the molecular pathways they mediate to design more effective anti-inflammatory and anti-cancer therapies.


Assuntos
Sistema Imunitário/metabolismo , Inflamação/imunologia , Ligantes , Receptores do Fator de Necrose Tumoral/metabolismo , Fatores de Necrose Tumoral/metabolismo , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Humanos , Inflamação/metabolismo
14.
Mol Med Rep ; 19(1): 41-50, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30387825

RESUMO

Wear particles generated between the interface of joints and artificial joint replacements are one of the primary causes of aseptic loosening. The aim of the present study was to investigate the influence of titanium (Ti) particles on the apoptosis and autophagy of osteoblasts, and probe into the potential use of hyperoside (Hy) as a protector for osteoblasts in Ti particle­induced injury. MC3T3­E1 cells were divided into control, Ti, Hy­1+Ti and Hy­2+Ti groups. Cell viability was detected using a Cell Counting Kit­8 assay. Apoptosis and autophagy rates were determined using flow cytometry. Expression levels of apoptosis­associated genes, including caspase­3, apoptosis regulator BAX, apoptosis regulator Bcl­2 and cellular tumor antigen p53, in addition to autophagy­associated genes, including Beclin1 and microtubule­associated protein light chain 3 conversion LC3­II/I, were measured using reverse transcription­quantitative polymerase chain reaction and western blotting. Activation of the tumor necrosis factor ligand superfamily member 12 (TWEAK)­mitogen activated protein kinase 11 (p38) mitogen activated protein kinase (MAPK) pathway was observed by western blotting. The present study demonstrated that pretreatment with Hy was able to increase cell viability and proliferation, and decrease apoptosis and autophagy to protect MC3T3­E1 cells against Ti particle­induced damage. Activation of the TWEAK­p38 pathway contributed to the repair processes of treatment with Hy. The present results suggested that Hy protected osteoblasts against Ti particle­induced damage by regulating the TWEAK­p38 pathway, which suggested the potential of Hy as a protective agent for bones.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Quercetina/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Fatores de Necrose Tumoral/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células 3T3 , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocina TWEAK/metabolismo , Camundongos , Osteoblastos/metabolismo , Quercetina/farmacologia , Titânio/efeitos adversos
15.
J Immunol ; 202(1): 183-193, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30510070

RESUMO

Both common and rare genetic variants of laccase domain-containing 1 (LACC1, previously C13orf31) are associated with inflammatory bowel disease, leprosy, Behcet disease, and systemic juvenile idiopathic arthritis. However, the functional relevance of these variants is unclear. In this study, we use LACC1-deficient mice to gain insight into the role of LACC1 in regulating inflammation. Following oral administration of Citrobacter rodentium, LACC1 knockout (KO) mice had more severe colon lesions compared with wildtype (WT) controls. Immunization with collagen II, a collagen-induced arthritis (CIA) model, resulted in an accelerated onset of arthritis and significantly worse arthritis and inflammation in LACC1 KO mice. Similar results were obtained in a mannan-induced arthritis model. Serum and local TNF in CIA paws and C. rodentium colons were significantly increased in LACC1 KO mice compared with WT controls. The percentage of IL-17A-producing CD4+ T cells was elevated in LACC1 KO mice undergoing CIA as well as aged mice compared with WT controls. Neutralization of IL-17, but not TNF, prevented enhanced mannan-induced arthritis in LACC1 KO mice. These data provide new mechanistic insight into the function of LACC1 in regulating TNF and IL-17 during inflammatory responses. We hypothesize that these effects contribute to immune-driven pathologies observed in individuals carrying LACC1 variants.


Assuntos
Artrite Experimental/imunologia , Artrite Juvenil/imunologia , Citrobacter rodentium/fisiologia , Infecções por Enterobacteriaceae/imunologia , Doenças Inflamatórias Intestinais/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Oxirredutases/metabolismo , Células Th17/imunologia , Alelos , Animais , Artrite Experimental/microbiologia , Artrite Juvenil/genética , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Doenças Inflamatórias Intestinais/genética , Interleucina-17/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredutases/genética , Polimorfismo Genético , Fatores de Necrose Tumoral/metabolismo
16.
Front Immunol ; 9: 2648, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538698

RESUMO

Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase+ T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1-60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for 1 h in vitro attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.


Assuntos
Adenilil Ciclases/metabolismo , Inflamação/metabolismo , Reflexo/fisiologia , Fatores de Necrose Tumoral/metabolismo , Animais , Proteína de Ligação a CREB/metabolismo , Linhagem Celular , Endotoxinas/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Baço/metabolismo , Nervo Vago/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
17.
Nat Commun ; 9(1): 5298, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30546010

RESUMO

To balance immunity and tolerance, the endogenous pool of Foxp3+ regulatory T (Treg) cells is tightly controlled, but the underlying mechanisms of this control remain poorly understood. Here we show that the number of Treg cells is negatively regulated by the kinase Lkb1 in dendritic cells (DCs). Conditional knockout of the Lkb1 gene in DCs leads to excessive Treg cell expansion in multiple organs and dampens antigen-specific T cell immunity. Lkb1-deficient DCs are capable of enhancing, compared with wild-type DCs, Treg cell proliferation via cell-cell contact involving the IKK/IKBα-independent activation of the NF-κB/OX40L pathway. Intriguingly, treating wild-type mice with lipopolysaccharide selectively depletes Lkb1 protein in DCs, resulting in Treg cell expansion and suppressed inflammatory injury upon subsequent challenge. Loss of Lkb1 does not obviously upregulate proinflammatory molecules expression on DCs. We thus identify Lkb1 as a regulatory switch in DCs for controlling Treg cell homeostasis, immune response and tolerance.


Assuntos
Proliferação de Células/genética , Células Dendríticas/imunologia , Proteínas Serina-Treonina Quinases/genética , Linfócitos T Reguladores/imunologia , Animais , Apoptose/imunologia , Técnicas de Inativação de Genes , Homeostase/fisiologia , Quinase I-kappa B/metabolismo , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores OX40/metabolismo , Fatores de Necrose Tumoral/metabolismo
18.
Cell Physiol Biochem ; 51(3): 1103-1118, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30476917

RESUMO

BACKGROUND/AIMS: Cellular senescence, or permanent growth arrest, is known as an effective tumor suppressor mechanism that can be induced by different stressors, such as oncogenes, chemotherapeutics or cytokine cocktails. Previous studies demonstrated that the growth-repressing state of oncogene-induced senescent cells depends on argonaute protein 2 (Ago2)-mediated transcriptional gene silencing and Ago2/Rb corepression of E2F-dependent cell cycle genes. Cytokine-induced senescence (CIS) likewise depends on activation of the p16Ink4a/Rb pathway, and consecutive inactivation of the E2F family of transcription factors. In the present study, we therefore analyzed the role of Ago2 in CIS. METHODS: Human cancer cell lines were treated with interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) to induce senescence. Senescence was determined by growth assays and measurement of senescence-associated ß-galactosidase (SA-ß-gal) activity, Ago2 translocation by Ago2/ Ki67 immunofluorescence staining and western blot analysis, and gene transcription by quantitative polymerase chain reaction (qPCR). RESULTS: IFN-γ and TNF permanently stopped cell proliferation and time-dependently increased SA-ß-gal activity. After 24 - 48 h of cytokine treatment, Ago2 translocated from the cytoplasm into the nucleus of Ki67-negative cells, an effect which was shown to be reversible. Importantly, the proinflammatory cytokine cocktail suppressed Ago2-regulated cell cycle control genes, and siRNA-mediated depletion of Ago2 interfered with cytokine-induced growth inhibition. CONCLUSION: IFN-γ and TNF induce a stable cell cycle arrest of cancer cells that is accompanied by a fast nuclear Ago2 translocation and repression of Ago2-regulated cell cycle control genes. As Ago2 downregulation impairs cytokine-induced growth regulation, Ago2 may contribute to tissue homeostasis in human cancers.


Assuntos
Proteínas Argonauta/metabolismo , Senescência Celular , Citocinas/metabolismo , Neoplasias/metabolismo , Transporte Ativo do Núcleo Celular , Proliferação de Células , Sobrevivência Celular , Humanos , Interferon gama/metabolismo , Células MCF-7 , Fatores de Necrose Tumoral/metabolismo
19.
Cell Physiol Biochem ; 51(1): 46-62, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30439713

RESUMO

BACKGROUND/AIMS: This study was developed to investigate a potential therapeutic method for myocardial ischemia/reperfusion injury involving the promotion of miR-24-3p expression. METHODS: Microarray analysis was used to screen differentially expressed genes in a myocardial ischemia/reperfusion (I/R) injury mouse model. Gene set enrichment analysis was utilized to determine vital signaling pathways. Targeting verification was conducted with a luciferase reporter assay. Myocardial I/R injury was developed in mice, and the expression levels of RIPK1 and miR-24-3p were investigated by qRT-PCR and Western blot. Hemodynamic parameters and the activity of serum myocardial enzymes were measured to evaluate cardiac function. Infarct area was observed through HE and TTC staining. Myocardial cell apoptosis was examined by TUNEL staining and caspase-3 activity analysis. RESULTS: RIPK1 was an upregulated mRNA found by microarray analysis and a verified target of the downregulated miRNA miR-24-3p. The upregulation of RIPK1 (1.8-fold) and the downregulation of miR-24-3p (0.3-fold) were confirmed in I/R mice. RIPK1 led to impaired cardiac function indexes, increased infarct area and cell apoptosis, while miR-24-3p could reverse the injury by regulating RIPK1. The TNF signaling pathway was proven to be involved in myocardial I/R injury through the detection of the dysregulation of related proteins. CONCLUSION: In conclusion, RIPK1 was upregulated and miR-24-3p was downregulated in a myocardial I/R injury mouse model. RIPK1 could aggravate myocardial I/R injury via the TNF signaling pathway, while miR-24-3p could suppress RIPK1 and therefore exert cardioprotective effects in myocardial I/R injury.


Assuntos
MicroRNAs/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Análise por Conglomerados , Creatina Quinase Forma MB/sangue , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Serina-Treonina Quinases de Interação com Receptores/química , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais , Fatores de Necrose Tumoral/metabolismo , Função Ventricular Esquerda/fisiologia
20.
J Microbiol Biotechnol ; 28(11): 1800-1805, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30270609

RESUMO

Inflammatory bowel disease, including Crohn's disease and ulcerative colitis (UC), is a chronically relapsing inflammatory disorder of the gastrointestinal tract. Intestinal epithelial cells (IECs) constitute barrier surfaces and play a critical role in maintaining gut health. Dysregulated immune responses and destruction of IECs disrupt intestinal balance. Dextran sodium sulfate (DSS) is the most widely used chemical for inducing colitis in animals, and its treatment induces colonic inflammation, acute diarrhea, and shortening of the intestine, with clinical and histological similarity to human UC. Current treatments for this inflammatory disorder have poor tolerability and insufficient therapeutic efficacy, and thus, alternative therapeutic approaches are required. Recently, dietary supplements with probiotics have emerged as promising interventions by alleviating disturbances in the indigenous microflora in UC. Thus, we hypothesized that the probiotic Bifidobacterium animalis subsp. lactis strain BB12 could protect against the development of colitis in a DSS-induced mouse model of UC. In the present study, oral administration of BB12 markedly ameliorated DSS-induced colitis, accompanied by reduced tumor necrosis factor-α-mediated IEC apoptosis. These findings indicate that the probiotic strain BB12 can alleviate DSS-induced colitis and suggest a novel mechanism of communication between probiotic microorganisms and intestinal epithelia, which increases intestinal cell survival by modulating pro-apoptotic cytokine expression.


Assuntos
Bifidobacterium animalis/fisiologia , Colite/terapia , Sulfato de Dextrana/toxicidade , Probióticos/administração & dosagem , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Colite/induzido quimicamente , Colite/patologia , Colo/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Probióticos/farmacologia , Fatores de Necrose Tumoral/metabolismo
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