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1.
Medicine (Baltimore) ; 99(22): e20494, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481463

RESUMO

Aims to explore the interaction between serum selenium level and CYP4F2 and CTRP9 gene polymorphisms in the development of coronary artery disease (CAD).A total of 200 cases of CAD were selected from the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei, China, and 200 healthy subjects cases were served as controls. The polymorphism of CYP4F2 and CTRP9 gene was detected by Sanger sequencing, and the serum selenium level was measured by hydride generation atomic fluorescence spectrometry.The serum selenium level in the CAD group was significantly lower than that in the control group. The risk of CAD was decreased in the patients carrying the AA genotype in CYP4F2 rs3093135, while the frequency of the CC genotype of CTRP9 rs9553238 in CAD patients was higher than that in control subjects. Low serum selenium level and CTRP9 rs9553238 CC genotype play a positive role in the occurrence of CAD.The serum selenium level is negatively correlated with CAD. The polymorphism of the CYP4F2 rs3093135 and CTRP9 rs9553238 was significantly related to the susceptibility of CAD, and there is a synergistic effect between the serum selenium level and the CTRP9 rs9553238 CC genotype, which significantly increases the risk of CAD.


Assuntos
Adiponectina/genética , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Família 4 do Citocromo P450/genética , Selênio/sangue , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
2.
Clin Immunol ; 215: 108448, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32353634

RESUMO

The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/genética , Azitromicina/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Gerenciamento Clínico , Regulação da Expressão Gênica , Humanos , Hidroxicloroquina/uso terapêutico , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/imunologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/imunologia
3.
PLoS One ; 15(1): e0226526, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945100

RESUMO

BACKGROUND: Cardiovascular disease (CVD) due to atherosclerosis is a major cause of death in renal allograft recipients. Recently, C1q/TNF-α related protein-9 (CTRP9), which is a paralog of adiponectin (ADPN), has been suggested to be related to the prevention of atherosclerosis and the occurrence of CVD, but this relationship has not been confirmed in renal allograft recipients. SUBJECTS AND METHODS: The relationships among the serum CTRP9 concentration, serum ADPN concentration, and vascular calcification were investigated in 50 kidney transplantation recipients at our hospital. Calcification of the abdominal aorta was evaluated according to the aortic calcification area index (ACAI) calculated from CT images. Changes in the serum CTRP9 and ADPN fractions and ACAI were examined for 8 years. In addition, the expression of CTRP9 and ADPN and their respective receptors AdipoR1 and R2 in muscular arteries of the kidney was examined by immunofluorescence. RESULTS: In renal allograft recipients, the serum CTRP9 concentration at the start of the observation was not significant correlated with eGFR or serum high-molecular-weight (HMW)-ADPN concentration (rS = -0.009, p = 0.950; rS = -0.226, p = 0.114, respectively). However, the change in the serum CTRP9 concentration was positively correlated with the change in the serum HMW-ADPN concentration (rS = 0.315, p = 0.026) and negatively correlated with the change in ACAI (rS = -0.367, p = 0.009). Multiple regression analysis revealed that the serum HMW-ADPN concentration was a significant positive factor for the change in the serum CTRP9 concentration. Moreover, for ACAI, an increase in the serum CTRP9 concentration was an improving factor, but aging was an exacerbating factor. Furthermore, colocalization of CTRP9 and AdipoR1 was noted in the luminal side of intra-renal arterial intima. CONCLUSION: In renal allograft recipients, both CTRP9 and HMW-ADPN were suggested to prevent the progression of aortic calcification through AdipoR1.


Assuntos
Adiponectina/sangue , Aorta/patologia , Transplante de Rim/métodos , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/sangue , Calcificação Vascular/prevenção & controle , Adulto , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Transplante Homólogo , Calcificação Vascular/sangue , Adulto Jovem
4.
Fish Shellfish Immunol ; 96: 13-25, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31760167

RESUMO

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) play crucial roles as signaling mediators for the TNF receptor (TNFR) superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. TRAFs collectively play important roles in multiple biological processes and organismal immunity. However, systematic identification of the TRAF gene family in teleost fish has not yet been reported, and there is little available information about its roles in innate immunity in Chinese tongue sole (Cynoglossus semilaevis), an aquaculture fish of high economic value. In the present study, we identified and characterized seven TRAF genes, namely, CsTRAF2a, CsTRAF2b, CsTRAF3, CsTRAF4, CsTRAF5, CsTRAF6 and CsTRAF7, in Chinese tongue sole, and the complete ORFs of the CsTRAFs were cloned. Sequence analysis revealed various genomic structures of the CsTRAFs and showed that they contain typical conserved domains compared with mammalian TRAFs. Phylogenetic analysis indicated the evolutionary relationships of TRAF family members in teleost fish and revealed an absence of TRAF1 in most species and TRAF5 in some species of teleosts. Analysis of the gene structures and motifs showed the diversity and distribution of exon-intron structures and conserved motifs in Chinese tongue sole and several other teleost species. Real-time quantitative PCR was used to investigate the expression patterns of CsTRAF genes in tissues of healthy fish and in the gills, livers and spleens of fish after bacterial infection with Vibrio harveyi. The results indicate that only CsTRAF2a is relatively highly expressed in the brain and that the other CsTRAFs are highly expressed in immune-related tissues and may participate in the immune response after infection with pathogenic bacteria. Functional analysis of CsTRAF3, CsTRAF4 and CsTRAF6 revealed that only CsTRAF6 could strongly activate the NF-кB pathway after overexpression of CsTRAF3, CsTRAF4 and CsTRAF6 in HEK-293T cells. This systematic analysis provided valuable information about the diverse roles of TRAFs in the innate immune response to pathogenic bacterial infection in teleost fish and will contribute to the functional characterization of CsTRAF genes in further research.


Assuntos
Doenças dos Peixes/imunologia , Linguados/genética , Linguados/imunologia , Regulação da Expressão Gênica/imunologia , Expressão Gênica/imunologia , Imunidade Inata/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica/veterinária , Genoma , Família Multigênica/imunologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Vibrio/fisiologia , Vibrioses/imunologia , Vibrioses/veterinária
5.
Cancer Lett ; 469: 380-389, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31730901

RESUMO

The tumor necrosis factor receptor-associated factor 7 (TRAF7) is a component of the tumor necrosis factor alpha (TNF-α)/nuclear factor kappa B (NF-κB) pathway and is a putative E3-ubiquitin ligase. Based on importance of chronic inflammation in hepatocellular carcinoma (HCC), we investigated the biological effects and the molecular mechanisms of deregulated TRAF7 signaling in HCC. Our results showed that high TRAF7 expression in HCC samples was inversely associated with Krüppel-like factor 4 (KLF4) expression and the prognosis of HCC patients. TRAF7 could degrade KLF4 protein through ubiquitin by interacting with its N-terminus. The up-regulation of TRAF7 promoted HCC cell migration and invasion in vivo and in vitro, and TRAF7 knockdown had the opposite effects. Restoration of KLF4 abrogated the motility promotion induced by TRAF7. TRAF7 promotes HCC cell motility through inducing KLF4 protein turnover.


Assuntos
Carcinoma Hepatocelular/genética , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Hepáticas/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Adulto , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , NF-kappa B/genética , Metástase Neoplásica , Prognóstico , Fator de Necrose Tumoral alfa/genética
6.
Int Immunopharmacol ; 77: 105934, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31727560

RESUMO

BACKGROUNDS: C1q tumor necrosis factor-related protein 9 (CTRP9) has been suggested to exert an atheroprotective effect by modulating the inflammation, foam cell formation, endothelia and smooth muscle cell function via Adenosine Monophosphate Activated Protein Kinase (AMPK) pathway. On the other hand, the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome plays an critical role in the atherosclerosis development, which is regulated by the AMPK. However, whether the CTRP9 affects the activity of NLRP3 inflammasome during the atherosclerosis development remains unclear, which would be elucidated in the current study. METHODS: The macrophage cells were stimulated with the oxidized low-density lipoprotein (ox-LDL) and also treated with the recombinant CTRP9 in the meantime. The activation of NLRP3 inflammasome was determined by measuring the releasing of IL-1ß and caspase-1 p10 via ELISA and western blot, respectively. Then the AMPK was inhibited in macrophages by Dorsomorphin. Finally, the CTRP9-AMPK-NLRP3 inflammasome pathway was validated in the mouse model of atherosclerosis. RESULTS: The CTRP9 could down-regulate the expression of NLRP3 protein and also the activity of NLRP3 inflammasome in the ox-LDL activated macrophages. Inhibiting the AMPK significantly restored the activities of NLRP3 inflammasome. In the apolipoprotein E-deficient mice, lentiviral expression of CTRP9 could suppress the atherosclerosis development, which could be abolished by AMPK inhibition. CONCLUSION: Our data here indicated that the CTRP9 showed atheroprotective function via CTRP9-AMPK- NLRP3 inflammasome pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/metabolismo , Aterosclerose/metabolismo , Glicoproteínas/metabolismo , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Animais , Aterosclerose/genética , Humanos , Interleucina-1beta/metabolismo , Lipoproteínas LDL/farmacologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células RAW 264.7 , Transdução de Sinais , Células THP-1
7.
J Pineal Res ; 67(4): e12611, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541591

RESUMO

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high-fat diet (HFD)-induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho-ASK1, phospho-MKK3/6, phospho-p38, phospho-MKK4/7, and phospho-JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor-associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein ß-arrestin-1 and enabled it to bind to ASK1, which antagonized the TRAFs-mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of ß-arrestin-1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.


Assuntos
MAP Quinase Quinase Quinase 5/metabolismo , Melatonina/farmacologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Ubiquitinação/efeitos dos fármacos , beta-Arrestina 1/metabolismo , Animais , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Estabilidade Enzimática/efeitos dos fármacos , Estabilidade Enzimática/genética , MAP Quinase Quinase Quinase 5/genética , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Ubiquitinação/genética , beta-Arrestina 1/genética
8.
Int J Biochem Cell Biol ; 115: 105589, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31442608

RESUMO

TNF receptor proteins were primarily recognized as adaptor proteins that ligate with the tumor necrosis factor receptor (TNFR)-associated factor (TNFR) family to execute various signaling pathways. However, recent studies showed that they act as a signal-transducing molecules and are reported to have a functional role as a Toll/interleukin-1 receptor family member. Seven members of this family have been identified to date. Among TNF receptor family, TRAF7 does not share a common TRAF domain homology. The tumor necrosis factor receptor associated factor (TRAF) domain comprises of about 230 amino acid motif at the C-terminal region that has the capability to bind TNFR and execute different downstream signaling pathways. Moreover, N-terminal RING and ZINC finger constituted by the tumor necrosis factor associated protein 2 and tumor necrosis factor associated protein 6 are critical and execute various downstream signaling events. TRAF proteins have emerged as critical regulators that provide the cellular response to stress and lead to cell death. Nuclear factor kappa beta (NF-KB) and c-Jun N-terminal kinases (JNK) pathways are activated through tumor necrosis factor associated protein 2, tumor necrosis factor associated protein 5 and tumor necrosis factor associated protein 6 members. TRAF proteins in pathogenesis were observed from their abnormal expression in diseased tissue and in normal tissue, suggesting its important role in physiological processes. Recently, unique specificity of TRAF4 for glycoprotein Ibß (GPIbß) and glycoprotein VI (GPVI) in human platelets has been reported. The multifunctional effects of TRAIP (TNF) interacting protein in many cellular signaling pathways emerged as very important signaling molecule. Furthermore, the new insights into the structure of TRAF members along with new studies involved in health and disease prompted to explore their role particularly the TNF receptor associated proteins with novel inhibitor protein TRAIP (TNF) interacting protein and human diseases associated with it. As such, this review emphasis on tumor necrosis factor receptor associated proteins, present their current understanding with novel inhibitor protein TRAIP (TNF) interacting protein.


Assuntos
Doença , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Humanos , Neoplasias/metabolismo
9.
mBio ; 10(4)2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311877

RESUMO

The protozoan parasite Toxoplasma gondii secretes proteins from specialized organelles, the rhoptries, and dense granules, which are involved in the modulation of host cell processes. Dense granule protein GRA15 activates the nuclear factor kappa B (NF-κB) pathway, which plays an important role in cell death, innate immunity, and inflammation. Exactly how GRA15 activates the NF-κB pathway is unknown. Here we show that GRA15 interacts with tumor necrosis factor receptor-associated factors (TRAFs), which are adaptor proteins functioning upstream of the NF-κB transcription factor. We identified several TRAF binding sites in the GRA15 amino acid sequence and showed that these are involved in NF-κB activation. Furthermore, a TRAF2 knockout cell line has impaired GRA15-mediated NF-κB activation. Thus, we determined the mechanism for GRA15-dependent NF-κB activation.IMPORTANCE The parasite Toxoplasma can cause birth defects and severe disease in immunosuppressed patients. Strain differences in pathogenicity exist, and these differences are due to polymorphic effector proteins that Toxoplasma secretes into the host cell to coopt host cell functions. The effector protein GRA15 of some Toxoplasma strains activates the nuclear factor kappa B (NF-κB) pathway, which plays an important role in cell death, innate immunity, and inflammation. We show that GRA15 interacts with TNF receptor-associated factors (TRAFs), which are adaptor proteins functioning upstream of the NF-κB transcription factor. Deletion of TRAF-binding sites in GRA15 greatly reduces its ability to activate the NF-κB pathway, and TRAF2 knockout cells have impaired GRA15-mediated NF-κB activation. Thus, we determined the mechanism for GRA15-dependent NF-κB activation.


Assuntos
NF-kappa B/metabolismo , Proteínas de Protozoários/metabolismo , Transdução de Sinais , Toxoplasma/fisiologia , Toxoplasmose/metabolismo , Toxoplasmose/parasitologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Sítios de Ligação , Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Ligação Proteica , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/química
10.
Genes (Basel) ; 10(7)2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31248009

RESUMO

Sponges, which are in close contact with numerous bacteria in prey/predator, symbiotic and pathogenic relationships, must provide an appropriate response in such situations. This starts with a discriminating recognition of the partner either by a physical contact or through secreted molecules or both. We investigated the expression of the Toll-like receptor, Caspase 3/7, Tumor Necrosis Factor receptor-associated factor 6, Bcl-2 homology protein-2 and macrophage expressed genes of axenic sponge cells in the presence of a symbiotic bacterium (Endozoicomonas sp. Hex311), a pathogen bacterium (Pseudoalteromonas sp. 1A1), their exoproducts and lipopolysaccharides. The vast majority of answers are in line with what could be observed with the symbiotic bacterium. The pathogenic bacterium seems to profit from the eukaryotic cell: suppression of the production of the antibacterial compound, inhibition of the apoptosis caspase-dependent pathway, deregulation of bacterial recognition. This work contributes new scientific knowledge in the field of immunology and apoptosis in early branching metazoan harboring within its tissue and cells a large number of symbiotic bacteria.


Assuntos
Gammaproteobacteria/fisiologia , Pseudoalteromonas/fisiologia , Suberites/imunologia , Suberites/microbiologia , Simbiose , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Gammaproteobacteria/efeitos dos fármacos , Gammaproteobacteria/metabolismo , Imunidade , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pseudoalteromonas/efeitos dos fármacos , Pseudoalteromonas/metabolismo , Pseudoalteromonas/patogenicidade , Suberites/genética , Receptores Toll-Like/metabolismo , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo
11.
Zhonghua Nei Ke Za Zhi ; 58(6): 449-452, 2019 Jun 01.
Artigo em Chinês | MEDLINE | ID: mdl-31159525

RESUMO

To explore the clinical significance of C1q tumor necrosis factor-related protein-9 (CTRP9) in patients with cerebral infarction. Our data showed that the serum CTRP9 was significantly lower than that of control group, especially in patients with large artery atherosclerotic cerebral infarction. CTRP9 was first decreased and even lower from day 4 to day 10, then gradually elevated. Logistic regression analysis suggested that high CTRP9 level was a protective factor for cerebral infarction. Thus, CTRP9 could be a factor for further classification of cerebral infarction and provides a potential option for disease prevention and treatment.


Assuntos
Adiponectina/biossíntese , Infarto Cerebral/metabolismo , Glicoproteínas/biossíntese , Adiponectina/sangue , Infarto Cerebral/patologia , Glicoproteínas/sangue , Humanos , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral
12.
BMC Cardiovasc Disord ; 19(1): 139, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182031

RESUMO

BACKGROUND: Biochemical marker has revolutionized the approach to the diagnosis of heart failure. However, it remains difficult to assess stability of the patient. As such, novel means of stratifying disease severity are needed. C1q/TNF-Related Protein 3 (CTRP3) and C1q/TNF-Related Protein 9 (CTRP9) are novel adipokines that contribute to energy homeostasis with additional anti-inflammatory and anti-ischemic properties. The aim of our study is to evaluate concentrations of CTRP3 and CTRP9 in patients with HFrEF (heart failure with reduced ejection fraction) and whether associated with mortality. METHODS: Clinical data and plasma were obtained from 176 healthy controls and 168 patients with HFrEF. CTRP3 and CTRP9 levels were evaluated by enzyme-linked immunosorbent assay. RESULTS: Both CTRP3 and CTRP9 concentrations were significantly decreased in the HFrEF group compared to the control group (p < 0.001). Moreover, patients with higher New York Heart Association class had significantly lower CTRP3 or CTRP9 concentrations. Correlation analysis revealed that CTRP3 and CTRP9 levels were positively related with LVEF% (CTRP3, r = 0.556, p < 0.001; CTRP9, r = 0.526, p < 0.001) and negatively related with NT-proBNP levels (CTRP3, r = - 0.454, p < 0.001; CTRP9, r = - 0.483, p < 0.001). After a follow up for 36 months, after adjusted for age, LVEF and NT-proBNP, we observed that CTRP3 or CTRP9 levels below the 25th percentile was a predictor of total mortality (CTRP3,HR:1.93,95%CI1.03~3.62,P = 0.042;CTRP9,HR:1.98,95%CI:1.02~3.85,P = 0.044) and hospitalizations (CTRP3,HR:2.34,95% CI:1.43~3.82,P = 0.001;CTRP9,HR:2.67,95%CI:1.58~4.50,P < 0.001). CONCLUSIONS: CTRP3 and CTRP9 are decreased in patients with HFrEF, proportionate to disease severity, and each is associated with increased morbidity and mortality. TRIAL REGISTRATION: NCT01372800 . Registered May 2011.


Assuntos
Adiponectina/sangue , Insuficiência Cardíaca/sangue , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/sangue , Fatores de Necrose Tumoral/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Progressão da Doença , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Volume Sistólico , Fatores de Tempo , Função Ventricular Esquerda
13.
J Neurooncol ; 144(1): 11-20, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177425

RESUMO

AIMS: Skull base meningiomas represent approximately 25% of all meningiomas, nearly 20% of which are atypical or anaplastic. To date, effective medical treatments for meningiomas are still lacking. Genetic aberrations (TRAF7, KLF4, AKT1, and SMO) and the effects of genetic aberrations on the expression of inhibitory immune checkpoint molecules (PD-L1, IDO, and TDO2) in skull base meningiomas are still unclear. METHODS: Genetic alterations in the four genes were identified in 92 skull base meningiomas by Sanger sequencing. The expression differences in immune checkpoints between mutant and wild-type (WT) tumors were determined by immunohistochemistry (IHC) and Western blot (WB). RESULTS: The four mutations were not concurrently detected in the patients with skull base meningiomas. Among the tumors from the KLF4-mutated group, almost half were petroclival meningiomas. KLF4- and TRAF7-mutated tumors were predominantly secretory meningiomas. SMO-mutated tumors exhibited higher calcification, and half of these tumors were observed in the brain midline. Receiver operating characteristic curve analysis indicated that tumor volume can predict KLF4 and TRAF7 mutation status with high sensitivity and specificity, respectively. The IHC and WB analyses indicated that PD-L1, IDO, and TDO2 levels in tumors with TRAF7 mutations were significantly higher than those in WT tumors. Meanwhile, there was a significant difference in TDO2 between tumors with AKT1 mutations and WT tumors. Specifically, TRAF7 mutations could play a key role in skull base meningiomas by regulating the expression of inhibitory immune checkpoints and thus suppressing immune responses. CONCLUSIONS: Checkpoint inhibitors may be potential strategies for targeted immunotherapies of these mutant meningiomas.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Meníngeas/patologia , Meningioma/patologia , Mutação , Neoplasias da Base do Crânio/patologia , Adolescente , Adulto , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Feminino , Seguimentos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/metabolismo , Meningioma/genética , Meningioma/imunologia , Meningioma/metabolismo , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Curva ROC , Neoplasias da Base do Crânio/genética , Neoplasias da Base do Crânio/imunologia , Neoplasias da Base do Crânio/metabolismo , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Triptofano Oxigenase/genética , Triptofano Oxigenase/metabolismo , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto Jovem
14.
J Invest Dermatol ; 139(7): 1426-1429, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31230639

RESUMO

A report in the June 2019 issue of the Journal of Investigative Dermatology reveals a role of neutrophil extracellular traps (NETs) in the induction of T helper type 17 cell responses and shows the relevance of this pathway in patients with psoriasis carrying a common risk variant in the TRAF3IP2 gene (Lambert et al., 2019). This work provides a new piece to the puzzle that links neutrophils to the T helper type 17-mediated pathogenesis of psoriasis.


Assuntos
Armadilhas Extracelulares , Psoríase , Proteínas Adaptadoras de Transdução de Sinal , Genótipo , Humanos , Neutrófilos , Células Th17 , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral
15.
J Neuroimmunol ; 333: 576968, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31129285

RESUMO

BACKGROUND: Recently, adipocytokines have been shown to play a pivotal role in autoimmune and inflammatory-related disease. The purpose of this study was to compare the levels of CTRP3, CTRP9, adiponectin and apelin- in Multiple Sclerosis (MS) patients with healthy subjects and their relationship with clinical parameters and the levels of pro-inflammatory mediators. METHODS: Plasma levels of CTRP3, CTRP9, apelin, TNF-α, hs-CRP, and adiponectin were evaluated in 24 healthy women and 26 women with relapsing-remitting MS using immunoassay methods. RESULTS: The plasma apelin level of the MS patients was significantly lower than that of healthy controls. The concentration of TNF-α and adiponectin were significantly higher in MS patients compared to the healthy controls. Plasma CTRP3, CTRP9 and hs-CRP levels were not significantly different between the two groups. There was no correlation between these adipokines and inflammatory mediators. A statistically significant negative correlation was observed between plasma concentrations of apelin with expanded disability status scale (EDSS) scores and number of relapse. CONCLUSIONS: Our findings suggest that adipokines, particularly apelin and adiponectin, may contribute to the pathogenesis of MS and can be considered as a biomarker or as a therapeutic target for the treatment of this disease.


Assuntos
Adiponectina/sangue , Apelina/sangue , Esclerose Múltipla Recidivante-Remitente/sangue , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/sangue , Fatores de Necrose Tumoral/sangue , Adulto , Proteína C-Reativa/análise , Feminino , Humanos , Inflamação , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/patologia , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
16.
Mol Cell ; 74(3): 436-451.e7, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30926242

RESUMO

The evolutionarily related deubiquitinating enzymes (DUBs) USP25 and USP28 comprise an identical overall domain architecture but are functionally non-redundant: USP28 stabilizes c-MYC and other nuclear proteins, and USP25 regulates inflammatory TRAF signaling. We here compare molecular features of USP25 and USP28. Active enzymes form distinctively shaped dimers, with a dimerizing insertion spatially separating independently active catalytic domains. In USP25, but not USP28, two dimers can form an autoinhibited tetramer, where a USP25-specific, conserved insertion sequence blocks ubiquitin binding. In full-length enzymes, a C-terminal domain with a previously unknown fold has no impact on oligomerization, but N-terminal regions affect the dimer-tetramer equilibrium in vitro. We confirm oligomeric states of USP25 and USP28 in cells and show that modulating oligomerization affects substrate stabilization in accordance with in vitro activity data. Our work highlights how regions outside of the catalytic domain enable a conceptually intriguing interplay of DUB oligomerization and activity.


Assuntos
Inflamação/genética , Conformação Proteica , Ubiquitina Tiolesterase/genética , Sequência de Aminoácidos/genética , Domínio Catalítico/genética , Enzimas Desubiquitinantes/química , Enzimas Desubiquitinantes/genética , Humanos , Inflamação/patologia , Mutação/genética , Ligação Proteica/genética , Domínios Proteicos/genética , Multimerização Proteica/genética , Proteínas Proto-Oncogênicas c-myb/química , Proteínas Proto-Oncogênicas c-myb/genética , Transdução de Sinais/genética , Especificidade por Substrato , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Ubiquitina/genética , Ubiquitina Tiolesterase/química
17.
J Immunol Res ; 2019: 7682827, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30882006

RESUMO

Sjögren's syndrome (SS) is a chronic autoimmune condition characterized by autoantibody production, sicca syndrome, and periepithelial lymphocytic lesions in target tissues. A predisposing genetic background is likely, and, to date, several polymorphisms in non-HLA genes have been explored with interesting results. We investigated the association between the STAT4, TRAF3IP2, HCP5, and IL10 polymorphisms and SS susceptibility and their possible role in the modulation of clinical and laboratory features. 195 consecutive patients with SS were enrolled and clinical and laboratory data were collected. 248 age- and sex-matched healthy subjects were used as controls. Genotyping was performed by allelic discrimination assays. A case-control association study and a phenotype-genotype correlation analysis were performed. A genetic risk profile was developed considering the risk alleles. Both the variant alleles of rs7574865 in the STAT4 gene and rs3099844 in the HCP5 gene were significantly more prevalent in patients than in controls (OR = 1.91 and OR = 2.44, respectively). The variant allele of rs3024505 of IL10 resulted to be a susceptibility allele (OR = 1.52), while the variant allele of rs1800872 seemed to confer a protective effect for the development of the disease (OR = 0.65). A risk genetic profile showed a higher probability to develop the disease in subjects with at least three risk alleles; subjects with 4 risk alleles were not observed in the controls. HCP5 rs3099844 was associated with anti-SSA (P = 0.006, OR = 3.07) and anti-SSB (P = 0.005, OR = 2.66) antibodies, severity of focus score (P = 0.03, OR = 12), and lymphoma development (P = 0.002, OR = 7.23). Patients carrying the STAT4 rs7574965 variant allele had a higher risk of monoclonal component and leukopenia (P = 0.002, OR = 7.6; P = 0.048, OR = 2.01, respectively). We confirmed the association of SS with the STAT4 and IL10 genes and we describe a novel association with HCP5. In particular, we describe an association of this specific SNP of HCP5 not only with disease development but also with autoantibody production and focus score suggesting a potential contribution of this variant to a more severe phenotype.


Assuntos
Predisposição Genética para Doença , Interleucina-10/genética , RNA Longo não Codificante/genética , Fator de Transcrição STAT4/genética , Síndrome de Sjogren/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
18.
Front Immunol ; 10: 104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30778351

RESUMO

TRAFs [tumor necrosis factor (TNF) receptor associated factors] are a family of signaling molecules that function downstream of multiple receptor signaling pathways and play a pivotal role in the biology of innate, and adaptive immune cells. Following receptor ligation, TRAFs generally function as adapter proteins to mediate the activation of intracellular signaling cascades. With the exception of TRAF1 that lacks a Ring domain, TRAFs have an E3 ubiquitin ligase activity which also contributes to their ability to activate downstream signaling pathways. TRAF-mediated signaling pathways culminate in the activation of several transcription factors, including nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs; e.g., ERK-1 and ERK-2, JNK, and p38), and interferon-regulatory factors (IRF; e.g., IRF3 and IRF7). The biological role of TRAFs is largely due to their ability to positively or negatively regulate canonical and non-canonical NF-κB signaling. While TRAF-mediated signaling regulates various immune cell functions, this review is focused on the recent advances in our knowledge regarding the molecular mechanisms through which TRAF proteins regulate, positively and negatively, inflammatory signaling pathways, including Toll-IL-1 receptors, RIG-I like receptors, and Nod-like receptors. The review also offers a perspective on the unanswered questions that need to be addressed to fully understand how TRAFs regulate inflammation.


Assuntos
Inflamação/metabolismo , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , RNA Helicases DEAD-box/metabolismo , Humanos , Imunidade Inata , Proteínas de Membrana/metabolismo , Proteínas NLR/metabolismo , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismo
19.
J Am Heart Assoc ; 8(4): e010475, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30764693

RESUMO

Background Autoantibodies against the second extracellular loop of the ß1-adrenoceptor (ß1- AA ) act similarly to agonist of ß1-adrenergic receptor, which plays an important role in the pathophysiological characteristics of ventricular remodeling. Recently, considerable lines of evidence have suggested that CTRP9 (C1q tumor necrosis factor-related protein 9) is a potent cardioprotective cardiokine and protects the heart from ventricular remodeling. The aim of this study was to determine the role of CTRP 9 in ventricular remodeling induced by ß1- AA . Methods and Results Blood samples were collected from 131 patients with coronary heart disease and 131 healthy subjects. The serum levels of ß1- AA and CTRP 9 were detected using ELISA . The results revealed that CTRP 9 levels in ß1- AA -positive patients were lower than those in ß1- AA -negative patients, and serum CTRP 9 concentrations were inversely correlated with ß1- AA . ß1- AA monoclonal antibodies (ß1- AA mAbs) were administered in mice with and without rAAV 9- cTnT -Full Ctrp9- FLAG virus for 8 weeks. Reverse transcription-polymerase chain reaction/Western analysis showed that cardiomyocyte CTRP 9 expression was significantly reduced in ß1- AA mAb-treated mice. Moreover, compared with the ß1- AA mAb alone group, cardiac-specific CTRP 9 overexpression improved cardiac function, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. Mechanistic studies demonstrated that CTRP 9 overexpression decreased the levels of G-protein-coupled receptor kinase 2 and promoted the activation of AMP-dependent kinase pathway. However, cardiac-specific overexpression of CTRP 9 had no effect on the levels of  cAMP and protein kinase A activity elevated by ß1-AAmAb. Conclusions This study provides the first evidence that the long-term existence of ß1- AA mAb suppresses cardiac CTRP 9 expression and exaggerates cardiac remodeling, suggesting that CTRP 9 may be a novel therapeutic target against pathologic remodeling in ß1- AA -positive patients with coronary heart disease.


Assuntos
Adiponectina/genética , Autoanticorpos/imunologia , Doença das Coronárias/metabolismo , Regulação da Expressão Gênica , Ventrículos do Coração/fisiopatologia , Receptores Adrenérgicos beta 1/imunologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Remodelação Ventricular , Adiponectina/biossíntese , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Doença das Coronárias/diagnóstico , Doença das Coronárias/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , RNA/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/biossíntese
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