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1.
Front Immunol ; 14: 1242659, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37869013

RESUMO

Nucleotide-binding oligomerization domain-containing proteins, NOD1 and NOD2, are cytosolic receptors that recognize dipeptides and tripeptides derived from the bacterial cell wall component peptidoglycan (PGN). During the past two decades, studies have revealed several roles for NODs beyond detecting PGN fragments, including activation of an innate immune anti-viral response, NOD-mediated autophagy, and ER stress induced inflammation. Recent studies have also clarified the dynamic regulation of NODs at cellular membranes to generate specific and balanced immune responses. This review will describe how NOD1 and NOD2 detect microbes and cellular stress and detail the molecular mechanisms that regulate activation and signaling while highlighting new evidence and the impact on inflammatory disease pathogenesis.


Assuntos
Proteínas Adaptadoras de Sinalização NOD , Proteína Adaptadora de Sinalização NOD1 , Humanos , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Inflamação , Nucleotídeos/metabolismo
2.
Int J Mol Sci ; 21(13)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32629865

RESUMO

Persistent activation of toll-like receptors (TLR) and nucleotide-binding oligomerization domain-containing proteins (NOD) in the innate immune system is one necessary driver of autoimmune disease (AD), but its mechanism remains obscure. This study compares and contrasts TLR and NOD activation profiles for four AD (autoimmune myocarditis, myasthenia gravis, multiple sclerosis and rheumatoid arthritis) and their animal models. The failure of current AD theories to explain the disparate TLR/NOD profiles in AD is reviewed and a novel model is presented that explains innate immune support of persistent chronic inflammation in terms of unique combinations of complementary AD-specific antigens stimulating synergistic TLRs and/or NODs. The potential explanatory power of the model is explored through testable, novel predictions concerning TLR- and NOD-related AD animal models and therapies.


Assuntos
Doenças Autoimunes/imunologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Receptores Toll-Like/metabolismo , Animais , Antígenos , Doenças Autoimunes/fisiopatologia , Modelos Animais de Doenças , Humanos , Imunidade Inata/imunologia , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Proteína Adaptadora de Sinalização NOD2/imunologia , Transdução de Sinais , Receptores Toll-Like/imunologia
3.
J Mol Neurosci ; 70(11): 1713-1727, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32474900

RESUMO

Cerebral ischemia represents a major cause of disability, yet its precise mechanism remains unknown. In addition, ischemia-reperfusion injury which occurs during the blood recovery process increases the risk of mortality, and is not adequately addressed with current treatment. To improve therapeutic options, it is important to explore the vital substances that play a pivotal role in ischemia-reperfusion injury. This study is the first to investigate the role of IL-32, a vital pro-inflammatory factor, in models of cerebral ischemia-reperfusion injury. The results showed that IL-32 was highly expressed in both in vivo and in vitro models. The proteins of the NOD/MAPK/NF-κB pathway were also up-regulated, indicating a potential signaling pathway mechanism. Inhibition of IL-32 and blocking of the NOD/MAPK/NF-κB pathway increased cell survival, decreased the level of inflammatory factors and inflammasomes, and attenuated nitrosative stress. Taken together, the results show that inhibition of IL-32 expression ameliorates cerebral ischemia-reperfusion injury via the NOD/MAPK/NF-κB signaling pathway. The findings in this study reveal that IL-32 is a vital target of ischemia-reperfusion injury, providing a new avenue for treatment development.


Assuntos
Infarto da Artéria Cerebral Média/metabolismo , Interleucinas/metabolismo , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Apoptose , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Inflamassomos/metabolismo , Interleucinas/genética , Masculino , NF-kappa B/genética , Fármacos Neuroprotetores/uso terapêutico , Proteínas Adaptadoras de Sinalização NOD/genética , Células PC12 , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ratos , Ratos Sprague-Dawley
4.
PLoS One ; 15(4): e0228764, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353008

RESUMO

The nucleotide-binding oligomerization domain-containing proteins (NOD) 1 and 2 are mammalian cytosolic pattern recognition receptors sensing bacterial peptidoglycan fragments in order to initiate cytokine expression and pathogen host defense. Since endothelial cells are relevant cells for pathogen recognition at the blood/tissue interface, we here analyzed the role of NOD1- and NOD2-dependently expressed microRNAs (miRNAs, miR) for cytokine regulation in murine pulmonary endothelial cells. The induction of inflammatory cytokines in response to NOD1 and NOD2 was confirmed by increased expression of tumour necrosis factor (Tnf)-α and interleukin (Il)-6. MiRNA expression profiling revealed NOD1- and NOD2-dependently regulated miRNA candidates, of which miR-147-3p, miR-200a-3p, and miR-298-5p were subsequently validated in pulmonary endothelial cells isolated from Nod1/2-deficient mice. Analysis of the two down-regulated candidates miR-147-3p and miR-298-5p revealed predicted binding sites in the 3' untranslated region (UTR) of the murine Tnf-α and Il-6 mRNA. Consequently, transfection of endothelial cells with miRNA mimics decreased Tnf-α and Il-6 mRNA levels. Finally, a novel direct interaction of miR-298-5p with the 3' UTR of the Il-6 mRNA was uncovered by luciferase reporter assays. We here identified a mechanism of miRNA-down-regulation by NOD stimulation thereby enabling the induction of inflammatory gene expression in endothelial cells.


Assuntos
Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação da Expressão Gênica , Inflamação/genética , Pulmão/patologia , MicroRNAs/metabolismo , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Animais , Células HEK293 , Humanos , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Reprodutibilidade dos Testes , Fator de Necrose Tumoral alfa/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-31843992

RESUMO

X-chromosome-linked inhibitor of apoptosis protein (XIAP) controls cell survival in several regulated cell death pathways and coordinates a range of inflammatory signaling events. Initially identified as a caspase-binding protein, it was considered to be primarily involved in blocking apoptosis from both intrinsic as well as extrinsic triggers. However, XIAP also prevents TNF-mediated, receptor-interacting protein 3 (RIPK3)-dependent cell death, by controlling RIPK1 ubiquitylation and preventing inflammatory cell death. The identification of patients with germline mutations in XIAP (termed XLP-2 syndrome) pointed toward its role in inflammatory signaling. Indeed, XIAP also mediates nucleotide-binding oligomerization domain-containing 2 (NOD2) proinflammatory signaling by promoting RIPK2 ubiquitination within the NOD2 signaling complex leading to NF-κB and MAPK activation and production of inflammatory cytokines and chemokines. Overall, XIAP is a critical regulator of multiple cell death and inflammatory pathways making it an attractive drug target in tumors and inflammatory diseases.


Assuntos
Proteínas Inibidoras de Apoptose/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Apoptose , Morte Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Sistema Imunitário , Inflamação , Sistema de Sinalização das MAP Quinases , Mutação , Subunidade p50 de NF-kappa B/metabolismo , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Transdução de Sinais , Síndrome
6.
Genes (Basel) ; 10(10)2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31601004

RESUMO

Chronic obstructive pulmonary disease (COPD) is a chronic disease characterized by a progressive decline in lung function due to airflow limitation, mainly related to IL-1ß-induced inflammation. We have hypothesized that single nucleotide polymorphisms (SNPs) in NLRP genes, coding for key regulators of IL-1ß, are associated with pathogenesis and clinical phenotypes of COPD. We recruited 704 COPD individuals and 1238 healthy controls for this study. Twenty non-synonymous SNPs in 10 different NLRP genes were genotyped. Genetic associations were estimated using logistic regression, adjusting for age, gender, and smoking history. The impact of genotypes on patients' overall survival was analyzed with the Kaplan-Meier method with the log-rank test. Serum IL-1ß concentration was determined by high sensitivity assay and expression analysis was done by RT-PCR. Decreased lung function, measured by a forced expiratory volume in 1 s (FEV1% predicted), was significantly associated with the minor allele genotypes (AT + TT) of NLRP1 rs12150220 (p = 0.0002). The same rs12150220 genotypes exhibited a higher level of serum IL-1ß compared to the AA genotype (p = 0.027) in COPD patients. NLRP8 rs306481 minor allele genotypes (AG + AA) were more common in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition of group A (p = 0.0083). Polymorphisms in NLRP1 (rs12150220; OR = 0.55, p = 0.03) and NLRP4 (rs12462372; OR = 0.36, p = 0.03) were only nominally associated with COPD risk. In conclusion, coding polymorphisms in NLRP1 rs12150220 show an association with COPD disease severity, indicating that the fine-tuning of the NLRP1 inflammasome could be important in maintaining lung tissue integrity and treating the chronic inflammation of airways.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Adaptadoras de Sinalização NOD/genética , Doença Pulmonar Obstrutiva Crônica/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Idoso , Alelos , Proteínas Reguladoras de Apoptose/metabolismo , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado/genética , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos/genética , Humanos , Interleucina-1beta/análise , Interleucina-1beta/sangue , Estimativa de Kaplan-Meier , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Proteínas NLR , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória/métodos
7.
Fish Shellfish Immunol ; 95: 336-348, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31586680

RESUMO

Streptococcus aglactiae(GBS) infection in tilapia is a serious global disease that causes significant production loss. Here, we studied the role of GBS in the spleen and the spleen's response against the pathogen through dual RNA-seq and proteome technology. Animals were divided into three groups: control, virulent treated (HN016), and attenuated treated (YM001). Spleen samples were collected and analysis when a disease outbreak. Dual RNA-seq result showed the virulence factor genes of GBS, included CAMP factor, PGK, OCT, enolase, scpB, Sip, bca, were upregulation. downregulation of GapA, cylE, OCT, scpB, C5AP, rlmB, hly, FBP, in HN016 and YM001. But for proteomic, OCT and bca were downregulation, the others were upregulation. For host transcriptome KEGG analysis showed, the NOD-like receptor signaling pathway (NLRs) and TOLL-like receptor signaling pathway (TLRs) were upreguoation in HN016 infected fish than the control fish; But for proteome KEGG, only the NLRS was up, the TLRS was not change. Compared with YM001 infected fishes, for transcriptome, NLRs and TLRs in infected HN016 fishes were significance rise (p < 0.01); for proteome, the NLRs was up (p < 0.05), but TLRs was no change.Analysis of pathogen-host interaction showed that the peptidoglycan (PNG), CD2, LCK, and host's Zap70 were involved in the regulation of NLRs; PNG, LCK, and ZAP70 were involved in the regulation of TRLs. Conclusion: the virulent strain HN016 and attenuated strainYM001 differed in the quantity of virulence factors. In tilapia's innate immune system, NLRs was the main defense factors, but bacteria avoided the host defense through TLRs.


Assuntos
Ciclídeos , Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteínas Adaptadoras de Sinalização NOD/genética , Baço/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus agalactiae/fisiologia , Animais , Doenças dos Peixes/genética , Doenças dos Peixes/microbiologia , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica/veterinária , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Proteoma , Proteômica , RNA-Seq/veterinária , Infecções Estreptocócicas/genética , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Transcriptoma
8.
Dev Comp Immunol ; 98: 148-156, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31103388

RESUMO

To evaluate effects of glutamine (GLN) on fish immune responses, leukocytes were isolated from head kidney of rainbow trout and cultured in GLN-free DMEM media supplemented with different combinations of lipopolysaccharide (LPS) and GLN. LPS significantly increased expression of pro-inflammatory cytokines, while GLN supplementation alleviated LPS-induced inflammation. Leukocytes in +GLN + LPS group showed more active GLN anabolism and catabolism, which signals could be sensed by O-GlcNAcylation, and then affected LPS binding to cell surface (LBP) and adjusted NODs signaling. The mRNA expression of immunoglobulins (Igs) and their receptor (pIgR) was also significantly increased after GLN supplementation. Further analysis showed that GLN increased the percentage of IgM+ B cells and IgT+ B cells, accompanied with the increased IgM and IgT secretion in culture media, which further increased complement C3 expression to perform effector functions. All these results illustrated the regulating mechanism of GLN against LPS-induced inflammation both via adjusted NODs signaling and increased Igs+ B cells to secrete Igs.


Assuntos
Glutamina/farmacologia , Imunoglobulinas/genética , Inflamação/genética , Leucócitos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Proteínas Adaptadoras de Sinalização NOD/genética , Oncorhynchus mykiss/genética , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células Cultivadas , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Rim Cefálico/citologia , Imunoglobulinas/metabolismo , Inflamação/metabolismo , Inflamação/prevenção & controle , Leucócitos/imunologia , Leucócitos/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Oncorhynchus mykiss/metabolismo , Substâncias Protetoras/farmacologia
9.
J Leukoc Biol ; 105(4): 669-680, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30517768

RESUMO

Interactions between pattern recognition receptors (PRRs) shape innate immune responses to particular classes of pathogens. Here, we review interactions between TLRs and nucleotide-binding oligomerization domain 1 and 2 (NOD1 and NOD2) receptors, two major groups of PRRs involved in innate recognition of bacteria. Most of experimental data both in vitro and in vivo suggest that NODs and TLRs synergize with each other at inducing the production of cytokines and antimicrobial peptides. Molecular mechanisms of this synergy remain poorly understood, although several scenarios can be proposed: (i) direct interactions of signaling pathways downstream of NODs and TLRs; (ii) mutual transcriptional regulation of unique components of NOD-dependent and TLR-dependent signaling pathways; and (iii) interactions at the post-transcriptional level. Potential practical implications of NOD-TLR synergy are dual. In sepsis, where synergistic effects probably contribute to excessive proinflammatory cytokine production, blockade of NOD1, and/or NOD2 in addition to TLR4 blockade may be required to achieve therapeutic benefit. On the other hand, synergistic combinations of relatively small doses of NOD and TLR agonists administered before infection could be used to boost innate resistance against bacterial pathogens.


Assuntos
Proteínas Adaptadoras de Sinalização NOD/metabolismo , Receptores Toll-Like/metabolismo , Animais , Humanos , Tolerância Imunológica , Ligação Proteica , Transdução de Sinais , Transcrição Gênica
10.
Vet Res Commun ; 42(4): 265-273, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30097755

RESUMO

Pigs are an important livestock and serve as a large animal model due to physiological and anatomical similarities with humans. Thus, components of the porcine immune system such as inflammasomes need to be characterized for disease control, vaccination, and translational research purposes. Previously, we and others elucidated porcine nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family Pyrin domain containing 3 (NLRP3) inflammasome activation. However, until now, porcine NLR family caspase recruitment domain (CARD)-containing 4 (NLRC4) and absent in melanoma 2 (AIM2) inflammasomes have been not well studied. In this study, we treated well defined NLRC4 and AIM2 inflammasome triggers to porcine peripheral blood mononuclear cells (PBMCs) and murine bone-marrow derived macrophages (BMDMs) and observed interleukin (IL)-1ß maturation as a readout of inflammasome activation. NLRC4 (flagellin) and AIM2 (dsDNA) triggers led to IL-1ß secretion in both porcine PBMCs and mice macrophages. In addition, porcine and mouse NLRC4 and AIM2 inflammasomes responded differently to NLRP3 inhibitors. Bacterial inflammasome triggers, Salmonella enterica serovar Typhimurium, Listeria monocytogenes, and Escherichia coli, also induced IL-1ß secretion in porcine PBMCs. Taken together, we suggest that known triggers of NLRC4 and AIM2 inflammasomes in mice induce IL-1ß secretion in porcine PBMCs.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Inflamassomos/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Salmonelose Animal/imunologia , Salmonelose Animal/metabolismo , Suínos , Doenças dos Suínos/imunologia , Doenças dos Suínos/metabolismo , Doenças dos Suínos/microbiologia
11.
CNS Neurol Disord Drug Targets ; 16(10): 1080-1089, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29173188

RESUMO

BACKGROUND & OBJECTIVE: The innate immune response is a common occurrence in many neuroinflammatory diseases. Central Nervous System (CNS) resident immune cells are able to detect and react to infections and sterile trauma. Peripheral immune cell migration into CNS is regulated by the blood-brain barrier, although peripheral immune cells can invade CNS through meninges, choroid plexus, perivascular spaces, and cerebrospinal fluid. Consequently, in the brain, immune reactions can be mediated by both resident and peripheral immune cells. Both in the periphery and within the CNS, innate immune response is regulated by a wide array of pattern recognition receptors, including Tolllike, scavenger, Retinoic Acid-inducible Gene-1 like, and nucleotide-binding oligomerization domainslike responsible for inflammasome formation. Inflammasome pathway activation induces pyroptosis, a highly inflammatory cell death pattern that occurs to remove intracellular pathogens. Legionella pneumophila is an intracellular microorganism responsible for Legionnaires' disease, a lung infection always associated to neurological dysfunctions. Recent studies have been shown that Toll-like receptors, nucleotide-binding oligomerization domains-like receptors, and RIG-1 like, are activated by L. pneumophila. This flagellated bacterium is able to replicate in phagocytic cells, including macrophages and microglia, responding by activating inflammasome pathways that may be the cause of CNS dysfunction detected in several infected patients. CONCLUSION: The aim of this review is to bring together the latest findings concerning L. pneumophila infection and innate immune host cell responses. A deeper knowledge of these processes could allow the use of immunomodulatory compounds able to counteract CNS involvement following L. pneumophila infection.


Assuntos
Imunidade Inata/fisiologia , Inflamassomos/metabolismo , Legionella pneumophila/fisiologia , Receptores Toll-Like/metabolismo , Animais , Proteína DEAD-box 58/metabolismo , Humanos , Macrófagos/metabolismo , Microglia/metabolismo , Proteínas Adaptadoras de Sinalização NOD/metabolismo
12.
Molecules ; 22(8)2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28786950

RESUMO

Purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, exhibits beneficial effects on metabolic syndrome. Sustained inflammation plays a crucial role in the pathogenesis of metabolic syndrome. Here we explored the effects of PSPC on high-fat diet (HFD)-induced hepatic inflammation and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + PSPC group, and PSPC group. PSPC was administered by daily oral gavage at doses of 700 mg/kg/day for 20 weeks. Nicotinamide riboside (NR) was used to increase NAD⁺ levels. Our results showed that PSPC effectively ameliorated obesity and liver injuries in HFD-fed mice. Moreover, PSPC notably blocked hepatic oxidative stress in HFD-treated mice. Furthermore, PSPC dramatically restored NAD⁺ level to abate endoplasmic reticulum stress (ER stress) in HFD-treated mouse livers, which was confirmed by NR treatment. Consequently, PSPC remarkably suppressed the nuclear factor-κB (NF-κB) p65 nuclear translocation and nucleotide oligomerization domain protein1/2 (NOD1/2) signaling in HFD-treated mouse livers. Thereby, PSPC markedly diminished the NLR family, pyrin domain containing 3 (NLRP3) inflammasome activation, ultimately lowering the expressions of inflammation-related genes in HFD-treated mouse livers. In summary, PSPC protected against HFD-induced hepatic inflammation by boosting NAD⁺ level to inhibit NLRP3 inflammasome activation.


Assuntos
Anti-Inflamatórios/farmacologia , Hepatite Animal/tratamento farmacológico , Hepatite Animal/metabolismo , Inflamassomos/metabolismo , Ipomoea batatas/química , NAD/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pigmentos Biológicos/farmacologia , Extratos Vegetais/farmacologia , Animais , Antocianinas/química , Antocianinas/farmacologia , Anti-Inflamatórios/química , Dieta Hiperlipídica , Estresse do Retículo Endoplasmático , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatite Animal/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , NF-kappa B/metabolismo , Proteínas Adaptadoras de Sinalização NOD/genética , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , Estresse Oxidativo/efeitos dos fármacos , Pigmentos Biológicos/química , Extratos Vegetais/química , Transporte Proteico
13.
PLoS One ; 12(8): e0182246, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28783736

RESUMO

The experiment was conducted to study the effect of the glutamate (Glu) on muscle protein loss through toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domain proteins (NODs), Akt/Forkhead Box O (Akt/FOXO) and mammalian target of rapamycin (mTOR) signaling pathways in LPS-challenged piglets. Twenty-four weaned piglets were assigned into four treatments: (1) Control; (2) LPS+0% Glu; (3) LPS + 1.0% Glu; (4) LPS + 2.0% Glu. The experiment was lasted for 28 days. On d 28, the piglets in the LPS challenged groups were injected with LPS on 100 µg/kg body weight (BW), and the piglets in the control group were injected with the same volume of 0.9% NaCl solution. After 4 h LPS or saline injection, the piglets were slaughtered and the muscle samples were collected. Glu supplementation increased the protein/DNA ratio in gastrocnemius muscle, and the protein content in longissimus dorsi (LD) muscle after LPS challenge (P<0.05). In addition, Glu supplementation decreased TLR4, IL-1 receptor-associated kinase (IRAK) 1, receptor-interacting serine/threonine-protein kinase (RIPK) 2, and nuclear factor-κB (NF-κB) mRNA expression in gastrocnemius muscle (P<0.05), MyD88 mRNA expression in LD muscle, and FOXO1 mRNA expression in LD muscle (P<0.05). Moreover, Glu supplementation increased p-Akt/t-Akt ratio (P<0.05) in gastrocnemius muscle, and p-4EBP1/t-4EBP1 ratio in both gastrocnemius and LD muscles (P<0.05). Glu supplementation in the piglets' diets might be an effective strategy to alleviate LPS-induced muscle protein loss, which might be due to suppressing the mRNA expression of TLR4 and NODs signaling-related genes, and modulating Akt/FOXO and mTOR signaling pathways.


Assuntos
Ácido Glutâmico/farmacologia , Lipopolissacarídeos/farmacologia , Proteínas Musculares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , DNA/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Musculares/genética , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteínas Adaptadoras de Sinalização NOD/genética , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Suínos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
14.
PLoS One ; 12(7): e0181932, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28742861

RESUMO

Antimicrobial resistance is a continuously increasing threat that severely compromises our antibiotic arsenal and causes thousands of deaths due to hospital-acquired infections by pathogens such as Pseudomonas aeruginosa, situation further aggravated by the limited development of new antibiotics. Thus, alternative strategies such as those targeting bacterial resistance mechanisms, virulence or potentiating the activity of our immune system resources are urgently needed. We have recently shown that mutations simultaneously causing the peptidoglycan recycling blockage and the ß-lactamase AmpC overexpression impair the virulence of P.aeruginosa. These findings suggested that peptidoglycan metabolism might be a good target not only for fighting antibiotic resistance, but also for the attenuation of virulence and/or potentiation of our innate immune weapons. Here we analyzed the activity of the innate immune elements peptidoglycan recognition proteins (PGRPs) and lysozyme against P. aeruginosa. We show that while lysozyme and PGRPs have a very modest basal effect over P. aeruginosa, their bactericidal activity is dramatically increased in the presence of subinhibitory concentrations of the permeabilizing agent colistin. We also show that the P. aeruginosa lysozyme inhibitors seem to play a very residual protective role even in permeabilizing conditions. In contrast, we demonstrate that, once the permeability barrier is overpassed, the activity of lysozyme and PGRPs is dramatically enhanced when inhibiting key peptidoglycan recycling components (such as the 3 AmpDs, AmpG or NagZ), indicating a decisive protective role for cell-wall recycling and that direct peptidoglycan-binding supports, at least partially, the activity of these enzymes. Finally, we show that recycling blockade when occurring simultaneously with AmpC overexpression determines a further decrease in the resistance against PGRP2 and lysozyme, linked to quantitative changes in the cell-wall. Thus, our results help to delineate new strategies against P. aeruginosa infections, simultaneously targeting ß-lactam resistance, cell-wall metabolism and virulence, ultimately enhancing the activity of our innate immune weapons.


Assuntos
Proteínas de Transporte/imunologia , Permeabilidade da Membrana Celular , Imunidade Inata/imunologia , Peptidoglicano/metabolismo , Pseudomonas aeruginosa/imunologia , Antibacterianos/farmacologia , Proteínas de Transporte/metabolismo , Colistina/farmacologia , Técnicas de Silenciamento de Genes , Testes de Sensibilidade Microbiana , Muramidase/imunologia , Muramidase/metabolismo , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidade
15.
Sci Rep ; 7: 46454, 2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28422189

RESUMO

Pediatric inflammatory bowel disease (pIBD) is a chronic heterogeneous disorder. This study looks at the burden of common and rare coding mutations within 41 genes comprising the NOD signaling pathway in pIBD patients. 136 pIBD and 106 control samples underwent whole-exome sequencing. We compared the burden of common, rare and private mutation between these two groups using the SKAT-O test. An independent replication cohort of 33 cases and 111 controls was used to validate significant findings. We observed variation in 40 of 41 genes comprising the NOD signaling pathway. Four genes were significantly associated with disease in the discovery cohort (BIRC2 p = 0.004, NFKB1 p = 0.005, NOD2 p = 0.029 and SUGT1 p = 0.047). Statistical significance was replicated for BIRC2 (p = 0.041) and NOD2 (p = 0.045) in an independent validation cohort. A gene based test on the combined discovery and replication cohort confirmed association for BIRC2 (p = 0.030). We successfully applied burden of mutation testing that jointly assesses common and rare variants, identifying two previously implicated genes (NFKB1 and NOD2) and confirmed a possible role in disease risk in a previously unreported gene (BIRC2). The identification of this novel gene provides a wider role for the inhibitor of apoptosis gene family in IBD pathogenesis.


Assuntos
Doenças Inflamatórias Intestinais/genética , Proteínas Adaptadoras de Sinalização NOD/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Exoma/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Lactente , Doenças Inflamatórias Intestinais/metabolismo , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Modelos Biológicos , Mutação , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Transdução de Sinais/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Sequenciamento do Exoma
16.
Eur J Nutr ; 56(4): 1433-1443, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26907088

RESUMO

PURPOSE: This study was conducted to investigate whether aspartate (Asp) could alleviate Escherichia coli lipopolysaccharide (LPS)-induced intestinal injury by modulating intestine inflammatory response. METHODS: Twenty-four weaned piglets were divided into four treatments: (1) non-challenged control; (2) LPS-challenged control; (3) LPS + 0.5 % Asp; and (4) LPS + 1.0 % Asp. After feeding with control, 0.5 or 1.0 % Asp-supplemented diets for 21 days, pigs were injected intraperitoneally with saline or LPS. At 4 h postinjection, blood and intestine samples were obtained. RESULTS: Asp supplementation to LPS-challenged pigs improved intestinal morphology, indicated by higher jejunal and ileal villus height/crypt depth ratio and lower ileal crypt depth linearly or quadratically. Asp also improved intestinal barrier function, indicated by increased jejunal and ileal diamine oxidase activities as well as enhanced protein expression of jejunal claudin-1 linearly or quadratically. In addition, Asp decreased plasma, jejunal and ileal tumor necrosis factor-α concentration and ileal caspase-3 protein expression linearly and quadratically. Moreover, Asp down-regulated the mRNA expression of toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain protein (NOD) signaling-related genes, nuclear factor-κB (NF-κB) p65 and p38, decreased phosphorylation of jejunal p38, and increased phosphorylation of ileal extracellular signal-related kinase 1/2 linearly or quadratically. Finally, Asp increased mRNA expressions of TLR4 and NOD signaling negative regulators including radioprotective 105, suppressor of cytokine signaling 1, toll-interacting protein, Erbb2 interacting protein and centaurin ß1 linearly or quadratically. CONCLUSIONS: These results indicate that Asp supplementation is associated with inhibition of TLR4 and NODs/NF-κB and p38 signaling pathways and concomitant improvement of intestinal integrity under an inflammatory condition.


Assuntos
Ácido Aspártico/farmacologia , Intestinos/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Caspase 3/sangue , Regulação para Baixo , Intestinos/patologia , Lipopolissacarídeos , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Proteínas Adaptadoras de Sinalização NOD/antagonistas & inibidores , Proteínas Adaptadoras de Sinalização NOD/genética , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Suínos , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/sangue , Desmame , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética
17.
Int J Mol Sci ; 18(1)2016 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-28029143

RESUMO

Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + Troxerutin group, and Troxerutin group. Troxerutin was treated by daily oral administration at doses of 150 mg/kg/day for 20 weeks. Tauroursodeoxycholic acid (TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that troxerutin effectively improved obesity and related metabolic parameters, and liver injuries in HFD-treated mouse. Furthermore, troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover, troxerutin notably suppressed nuclear factor-κB (NF-κB) p65 transcriptional activation and release of inflammatory cytokines in HFD-treated mouse livers. Mechanismly, troxerutin dramatically decreased Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by TUDCA treatment. These improvement effects of troxerutin on hepatic glucose disorders might be mediated by its anti-obesity effect. In conclusion, troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent inflammation, which might be mediated by its anti-obesity effect.


Assuntos
Anti-Inflamatórios/farmacologia , Gluconeogênese , Hidroxietilrutosídeo/análogos & derivados , Hiperglicemia/metabolismo , Fígado/metabolismo , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Estresse do Retículo Endoplasmático , Hidroxietilrutosídeo/administração & dosagem , Hidroxietilrutosídeo/farmacologia , Hidroxietilrutosídeo/uso terapêutico , Hiperglicemia/tratamento farmacológico , Hiperglicemia/etiologia , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
18.
J Cell Sci ; 129(11): 2261-72, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27122187

RESUMO

Paired box protein 5 (PAX5) plays a lineage determination role in B-cell development. However, high expression of PAX5 has been also found in various malignant diseases, including B-lymphoproliferative disorders (B-LPDs), but its functions and mechanisms in these diseases are still unclear. Here, we show that PAX5 induces drug resistance through association and activation of receptor-interacting serine/threonine-protein kinase 2 (RIP2; also known as RIPK2), and subsequent activation of NF-κB signaling and anti-apoptosis gene expression in B-lymphoproliferative cells. Furthermore, PAX5 is able to interact with RIP1 and RIP3, modulating both RIP1-mediated TNFR and RIP2-mediated NOD1 and NOD2 pathways. Our findings describe a new function of PAX5 in regulating RIP1 and RIP2 activation, which is at least involved in chemotherapeutic drug resistance in B-LPDs.


Assuntos
Linfócitos B/metabolismo , Resistencia a Medicamentos Antineoplásicos , Transtornos Linfoproliferativos/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição PAX5/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Transtornos Linfoproliferativos/patologia , Modelos Biológicos , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia
19.
Dev Comp Immunol ; 61: 116-25, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26979266

RESUMO

NOD-like receptors (NLRs) are essential intracellular pattern-recognition receptors that respond to pathogens and regulate innate immunity. NLRs include three distinct subfamilies: NLR-A, NLR-B and NLR-C, thereinto, NLR-C as a large subfamily is unique to bony fish and little research about it has been done. In the current study, we identified the members of NLR-B and NLR-C subfamilies containing 2 and 48 genes respectively in miiuy croaker. Compared with other teleosts except for zebrafish, NLR-C subfamily genes occurred expansion in miiuy croaker. The gene expansions of NLR-C subfamily may illustrate adaptive genome evolution in response to specific aquatic environments. Structural analysis showed that the N-terminus of NLR-C subfamily receptors has different characteristics of the domains including RING domain, FISNA domain or PYRIN domain. Interestingly, the C-terminus of 18 NLR-C subfamily members contains an extra B30.2 domain (named NLR-B30.2 genes) which plays an important role in antiviral immune recognition. Simultaneously, molecular evolutionary analysis indicated that the positively sites in miiuy croaker are mainly located in NACHT domain which was the vital region for signal transduction in immune response. Significantly, pathogens challenge in spleen and macrophages demonstrated that NLR-B30.2 genes exhibited more sensitive response to virus than bacteria, suggesting these genes play enhanced roles in innate antiviral immunity, which may represent a new family used for antiviral infection.


Assuntos
Infecções Bacterianas/imunologia , Genoma , Macrófagos/imunologia , Proteínas NLR/metabolismo , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Perciformes/imunologia , Viroses/imunologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Infecções Bacterianas/genética , Células Cultivadas , Evolução Molecular , Imunidade Inata/genética , Família Multigênica/genética , Proteínas NLR/genética , Proteínas Adaptadoras de Sinalização NOD/genética , Filogenia , Transdução de Sinais , Viroses/genética
20.
Implant Dent ; 25(3): 348-52, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26836127

RESUMO

BACKGROUND: Gingival epithelial cells have a pivotal role in the recognition of microorganisms and damage-associated molecular pattern molecules and in the regulation of the immune response. The investigation of the behavior of Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD) like receptors (NLRs) around a healthy implant may help to address the first step of periimplantitis pathogenesis. PURPOSE: To investigate by quantitative real-time polymerase chain reaction, the mRNA expressions of TLR2, TLR3, TLR4, TLR5, TLR6, TLR9, NOD1, NOD2, and NLRP3 from gingival epithelial cells of the sulcus around healthy implants and around healthy teeth. MATERIALS AND METHODS: Two types of implant-abutment systems with tube-in-tube interface were tested. After 6 months of implant restoration, gingival epithelial cells were obtained from the gingival sulcus around the implants and around the adjacent teeth of 10 patients. RESULTS: Our results did not reach statistical significance among the mRNA expressions of TLR2, TLR3, TLR4, TLR5, TLR6, TLR9, NOD1, NOD2, and NLRP3 in epithelial cells around the implant versus around natural teeth. CONCLUSION: This study shows that the implant-abutment systems tested did not induce an immune response by the surrounding epithelial cells at 6 months since their positioning, as well as in the adjacent clincally healthy teeth.


Assuntos
Implantes Dentários , Epitélio/metabolismo , Gengiva/citologia , Proteínas Adaptadoras de Sinalização NOD/metabolismo , Receptores Toll-Like/metabolismo , Implantes Dentários/efeitos adversos , Gengiva/metabolismo , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor 2 Toll-Like/metabolismo , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor 5 Toll-Like/metabolismo , Receptor 6 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Transcriptoma
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